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Urticaria and Angioedema
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Urticaria and Angioedema edited by
Malcolm W. Greaves Singapore General Hospital Singapore
Allen P. Kaplan Medical University of South Carolina Charleston, South Carolina, U.S.A.
hI ARC E L
MARCEL DEKKER, INC.
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NEW YORK· BASEL
Although great care has been taken to provide accurate and current information, neither the author(s) nor the publisher, nor anyone else associated with this publication, shall be liable for any loss, damage, or liability directly or indirectly caused or alleged to be caused by this book. The material contained herein is not intended to provide specific advice or recommendations for any specific situation. Trademark notice: Product or corporate names may be trademarks or registered trademarks and are used only for identification and explanation without intent to infringe. Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress. ISBN: 0-8247-5315-1
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Dedicated with gratitude to my wife Evelyn, son Kim, and daughter Suki for their constant encouragement during my professional career.
Malcolm W. Greaves
In 1965 I was a medical student delivering a paper as part of the senior class competition. My subject was penicillin-allergy-the consequences: hives of course. In the audience was Lee, my fiancee, who was almost as surprised as I was when I won. Now it is 38 years later and we have shared a lifetime of work, and lots of love, and watched two wonderful children, Rachel and Seth take off on their own. And I look around and there's Lee, smiling at me as usual, the balm of my soul, to whom I dedicate this book.
Allen P. Kaplan
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Preface
Urticaria and angioedema affect at least 20 per cent of the population, and frequently become chronic and persistent, causing significant personal, domestic, social, and occupational disability. That "urticaria" encompasses a group of very different disorders is incompletely understood by many clinicians who nevertheless confidently make this diagnosis. For this reason and because, until recently, little progress has been made in understanding of the pathomechanisms of the chronic forms, progress in diagnosis and treatment has been disappointingly slow. Our foremost objective in Urticaria and Angioedema is to provide clinicians with a clear guide to diagnosis and management of this often perplexing group of diseases, based upon contemporary understanding of pathogenetic mechanisms of the different subtypes. The uses and limitations of existing treatments including both "classical" and "new generation" antihistamines, as well as newer alternative therapeutic approaches, are discussed in the setting of recent insights into the molecular basis of urticaria and angioedema. We have included a discussion of the clinical significance of important and recently discovered autoimmune mechanisms in chronic "idiopathic" urticaria, and their impact upon patient management. We also believe the book will intrigue immunologists, cell biologists, and pharmacologists with an interest in clinical immunology and allergy. The unravelling of the ways in which dermal mast cells and basophil leucocytes become promiscuously activated, the interactions of the multiple inflammatory mediators thus released, and the ensuing cavalcade of cellular pruritic and vascular responses represent a paradigm for immunologically
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driven disease. Moreover. urticaria and angioedema are models potentially accessible for study in human skin. However, in many patients with chronic urticaria and especially in the physical urticarias, causation of dermal mast cell activation at a molecular level still remains elusive, and we have endeavoured, in the relevant chapters, to point the way forward to future developments in these fields. Overall we hope we have achieved a reasonable balance-satisfying both the clinician, who requires reassurance that recommended clinical practice is scientifically soundly based, and the investigator, who seeks a secure clinical context for research in this important and challenging area.
Malcolm W. Greaves Allen P. Kaplan
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Contents
Preface Contributors
1.
xi
What is Urticaria? Anatomical, Physiological, and Histological Considerations and Classification R. A. Sc'broe and Malcolm W. Greaves
1
2.
Mast Cells and Basophils Wei Zhao and L(lJl'rence B. Schll'art::.
19
3.
Mechanisms of Bradykinin Formation Allen P. Kaplan
51
4.
The Complement System: Mechanisms of Activation, Regulation, and Role in Innate and Adaptive Immunity Berhane Ghebreltill'el
5.
6.
73
The IgE-Mediated Cutaneous Late-Phase Reaction NanC1' Samolitis, Kristin M. Lei(erl1lan. and Gerald 1. Gleich
119
Acute Urticaria
141
T. Zuberbier
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Contents
viii
7.
Contact Urticaria Esther Kim and HOlvard Maibach
149
8.
Physical and Cholinergic Urticarias Anne Kob::a Black
171
9.
Urticaria and Angioedema in Infancy and Early Childhood Michael C. Zacharisen
215
10.
Papular Urticaria Larr]' lYlil/ikan
251
11 .
Diagnosis of Difficult Urticaria and Angioedema Allen P. Kaplan and Malcolm W. Greaves
259
12.
Hereditary Disorders with Urticaria or Angioedema Hal M. Hoffman and Alan A. Wanderer
271
13.
C1 Inhibitor Deficiency AI/en P. Kaplan
303
14.
Chronic Urticaria: Autoimmune Chronic Urticaria and Idiopathic Chronic Urticaria Malcolm W. Greaves and Allen P. Kaplan
15.
16.
321
Chronic Urticaria: General Principles and Management Clive Grattan
343
Urticaria: Principles of Antihistamine Treatment
369
F. Estelle R. Simons
17.
Treatment of Chronic Urticaria: Agents Other Than Antihistaminics Allen P. Kaplan
393
18.
Urticarial VasculitislVenulitis Nicholas A. SOler
401
19.
Angioedema: Some "New" Thoughts Regarding Idiopathic Angioedema Vincent S. Beltrani
421
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20.
Systemic Disorders with Urticaria and/or Angioedema Malcolm W. Greaves and Allen P. Kaplan
21.
Idiopathic Anaphylaxis, Systemic Mastocytosis, and the Hypereosinophilic Syndrome A lien P. Kaplan and M alcoll17 W. Grem'es
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453
467
lnde.\:
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Contri butors
Vincent S. Beltrani
Poughkeepsie, New York. U.S.A.
Anne Kobza Black St John's Institute of Dermatology, St Thomas' Hospital, London, United Kingdom Berhane Ghebrehiwet State University of New York, Health Sciences Center, Stony Brook, New York, U.S.A. Gerald J. Gleich The University of Utah Health Sciences Center, Salt Lake City, Utah, U.S.A. Ctive Grattan
West Norwich Hospital, Norwich, United Kingdom
Malcolm W. Greaves Hal M. Hoffman California, U.S.A.
Singapore General Hospital, Singapore University of California at San Diego, La Jolla,
Allen P. Kaplan Medical University of South Carolina, Charleston. South CarolIna, USA. Esther Kim University of California at San Francisco, San Francisco, California, U.S.A. Kristin M. Leiferman The University of Utah Health Sciences Center, Salt Lake City, Utah, U.S.A. Howard Maibach University Francisco, California, U.S.A.
of California
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at
San
Francisco,
San
xi
Contributors
xii Larry
Millikan
Tulane
University
Medical
Center,
New
Orleans,
Louisiana, U.S.A.
R. A. Sabroe
Barnsley District General Hospital, Barnsley, Sheffield, United Kingdom
Nancy Samolitis The University of Utah Health Sciences Center, Salt Lake City, Utah, U.S.A. Lawrence B. Schwartz
Virginia Commonwealth University, Richmond,
Virginia, U.S.A.
F. Estelle R. Simons
University of Manitoba, Winnipeg, Manitoba,
Canada
Nicholas A. Soter
New York University School of Medicine. New York,
New York, U.s.A.
Alan A. Wanderer
University of Colorado Health Sciences Center. Englewood, Colorado, U.S.A.
Michael C.
Zacharisen
Medical
College
of Wisconsin,
Milwaukee,
Wisconsin. U.S.A.
Wei Zhao
Virginia Commonwealth University, Richmond, Virginia,
U.S.A.
T. Zuberbier
University Hospital Charite, Berlin, Germany
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Urticaria and Angioedema
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1 What is Urticaria? Anatomical, Physiological, and Histological Considerations and Classification R. A. Sabroe Barnsley District General Hospital, Barnsley, Sheffield, United Kingdom
Malcolm W. Greaves Singapore General Hospital, Singapore
I.
INTRODUCTION
This chapter explains the structural, physiological, and molecular correlates of the symptoms and visible changes in the skin of the patient with urticaria and angioedema. The lesions of urticaria are, at first sight, straightforward. Localized vasodilatation causes redness; increased blood flow causes warmth; enhanced vascular permeability leads to swelling (edema). These are the features of Lewis's so-called 'triple response' (I), and itch is the dominant symptom. Similar processes underlie angioedema, but in this case increased vascular permeability predominates, leading to massive dermal and subcutaneous edema. Itching and visible redness are more variable. However, it is evident to anyone who deals with patients with these findings regularly that there is more to urticaria and angioedema than this. What determines the distribution of the lesions of urticaria and angioedema? Why do wheals of chronic so-called 'idiopathic' urticaria (other than delayed pressure urticaria and dermographism) often develop at sites of pressure such as around the waistband? Why does angioedema show a predilection for the eyelids and lips? Why do individual lesions in 'idiopathic' chronic urticaria last for ] 2 h or more, in contrast with wheals of most physical
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urticarias that last no more than an hour? Why is itching worse at night? Why do patients rub the itch of urticaria rather than scratch it? Why does chronic urticaria characteristically flare at times of stress? We cannot answer definitively these and other puzzling questions to the readers' (or our own) entire satisfaction, but we will address them.
II.
ANATOMICAL AND PATHOPHYSIOLOGICAL CONSIDERATIONS
Urticaria and angioedema are inflammatory and predominantly dermal processes. Patients rub the intense itch of urticaria and this may result in bruising, but the epidermis is unscathed, and even scratch marks are rare despite the severe pruritus. Thus inflammatory skin lesions that peel on resolution (desquamation) are not due to urticaria or angioedema. In such cases, other causes such as acute eczema or cellulitis should be sought. Besides the epidermis, the dermoepidermal junction is spared, the pathological involvement being mainly mid- or deep dermal. Therefore blistering or bulla formation is exceptionally rare, and if present should prompt consideration of alternative diagnoses including autoimmune bullous dermatoses, some of which (e.g, bullous pemphigoid) may manifest prodromal urticaria-like skin changes. Urticaria and angioedema are inflammatory processes and show the cardinal signs ofinllammation: redness, heat, and swelling. Itch is usually the dominant symptom of urticaria. Pain and tenderness are not usually features of straightforward urticaria, although patients with the less common urticarial vasculitis may complain of tenderness or even pain rather than itch.
III.
DERMAL MAST CELL
Inappropriate activation of the dermal mast cell is thought to be the prime pathophysiological event in most forms of urticaria. The detailed pathophysiology of the mast cell in urticaria is reviewed in Chapter 2. Dermal mast cells are derived from CD34+ pluripotent bone marrow stem cells, and express receptors for the growth factor c-kit 0,3). In some forms of cutaneous mastocytosis (urticaria pigmentosa) in adults a mutation in the c-kit gene leads to overactivation of c-kit. causing proliferation of dermal mast cells (4). There is controversy as to whether mast cell numbers alter in urticarial wheals (see Sec. VI£, 'Inflammatory Infiltrate'). In the skin, mast cclls are located throughout the dermis but with a predilection for the vicinity of appendages, including pilosebaceous follicles, nerve fibers, and blood vessels. The turnover 01' dermal mast cells is slow.
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They can be almost entirely ablated by repeated prolonged potent topical corticosteroid application (5) and it takes about 24 weeks for re-establishment of the dermal mast cell population (6). This finding has been used as a treatment option in patients with urticaria pigmentosa (7). Skin mast cells differ from pulmonary mast cells, being responsive to opioid peptides and neuron-derived substance P. The optimal temperature for skin mast cell activation is as low as 30°C whereas the same figure for lung mast cells is closer to 37°C (8). Unlike pulmonary mast cells, dermal mast cells possess complemen t C5a receptors. They can also be activated by other basic nonimmunological stimuli such as compound 48/80 (8). Immunological activation occurs via cross-linking of receptor-bound IgE by specific antigen. Cross-linking due to IgG anti-high-affinity IgE receptor (FcsR I) autoantibodies leading to activation also occurs in autoimmune urticaria (described in a later chapter). Although the pathways for activation differ, the end result (mast cell degranulation and release or secretion of mediators) is the same. However the types of mediators released may differ, depending upon the stimulus (9,10). Besides histamine, mediators released from human dermal mast cells include eicosanoids (prostaglandin O 2 [PG0 2 ] leukotriene C 4 [LTC 4 ]); cytokines, including tumor necrosis factor-a (TNF-a), interleukins (IL) 4, 6, and 8/CXCL8; fibroblast growth factors; and proteases including chymase and tryptase (II 16). Human dermal mast cells may be shown to release other mediators in due course, since human lung mast cells have been reported to be a source of IL 4, 5, 6, and 13, TNFa, granulocyte-macrophage colony-stimulating factor (GM-CSF) and monocyte chemoattractant protein-I (MCP-I/CCL2) (17-20). Human mast cell leukemia cell lines and murine mast cells secrete a number of additional factors, including IL 3, IL 16, regulated upon activation normal T-cell expressed and secreted (RANTES/CCL5), macrophage inflammatory protein-Ia (MIP-la/CCL3), and vascular permeability factor/vascular endothelial cell growth factor (VPF/VEGF) (21-24). It is reasonable to suppose that the different appearance and duration of wheals occurring in different types of urticaria are due to stimulusspecific combinations of the above mediators, or those released from incoming inflammatory cells. The susceptibility of an individual to get urticarial wheals, or to produce autoantibodies in autoimmune urticaria, may also be influenced by the mediators released.
IV.
CUTANEOUS VASCULATURE
The visible signs of urticaria and angioedema are due to local vasodilatation, increased blood flow, and increased vascular permeability. Lymphatic
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Figure 1
Cholinergic urticaria in a 12 year-old girl. The prominent blanching surrounding the wheals is due to a vascular steal effect (see text).
drainage contributes a modulating influence on the degree of local edema (whealing). The extent to which angioedema and urticaria develop depends on the severity of capillary leakage and efficiency of its clearance by lymphatics. The pale halo of blanching, which can frequently be observed to surround the red wheal, testifies to the role played by increased blood flow. It is due to a so-called 'steal' effect and is best seen in cholinergic urticaria (Fig. I). The redness of the wheal itself is caused by engorgement of the subpapillary venous plexus, although by analogy with the axon reflex flare of the histamine wheal (I) it is probable that neurovascular reflex mechanisms also playa part, at least in acute urticarial lesions. The main site of increased vascular permeability is the postcapillary venule (25). Increased blood flow raises the intraluminal pressure within postcapillary venules, altering the homeostatic balance between intraluminal hydrostatic pressure forcing fluid out and osmotic forces keeping it in (Starling's law). This process is augmented by increased leakiness of the venular endothelial cells. That histamine is the principal mediator, via HI and H2 receptors (26), of these vascular changes is probably true for most physical urticarias, in which the wheal is short-lived and manifests the features of a histamine wheal. Although increased tissue levels of histamine have been demonstrated in involved skin in chronic idiopathic urticaria (CIU) (27), the role of this mediator in the pathogenesis the wheal in CIU is less clear for the following reasons: (i) The visible vascular changes of CIU last for at least 12 h; histamine manifests rapid tachyphylaxis with respect to its vascular effects (28). (ii) Unlike the itch. the wheal of CIU is poorly responsive to H J antihistamines. (iii) The cellular infiltrate seen histologically in the affected skin of patients with CIU implies the involvement of other mediators. (iv) Lack of systemic manifestations of histamine release in patients with widespread CIU. Indeed, the wheal may be initiated by
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histamine, but it is likely that its perpetuation is attributable to additional mediators (see below). Kinetic data support this view (29). The role of other histamine receptors is unknown. Histamine 3 receptors are involved in autoregulation of histamine release from mast cells, but have not been found in human skin and so probably are not involved (30). Histamine 4 receptors may playa role in the regulation of immune function. They are expressed on eosinophils, and so have the potential for involvement in urticaria wheals (31). Histamine may also have the potential to alter the balance between ThJ and Th2 responses, which may be relevant in urticaria (see Sec. VII, 'Inflammatory Infiltrate'), depending on whether H I or H2 receptors are triggered (32).
V.
POTENTIAL ROLE OF OTHER MAST CELL MEDIATORS IN WHEAL FORMATION
The role of nonhistamine mast cell mediators in CIU has yet to be defined, but they may be important in the regulation of cell recruitment and the development of the urticarial wheal. PGD 2 and LTC 4 are vasodilators and increase vascular permeability (33), and similarly, VEGF increases the permeability of human endothelial cells in vitro (34). TNFa, IL 4, and LTC 4 (probably after conversion to LTD 4 ) upregulate adhesion molecule expression on endothelial cells, and promote leukocyte rolling and adhesion (12,35-37). MIP-la/CCL3 and RANTES/CCLS are variably effective chemoattractants for eosinophils in vitro (38), and can cause eosinophil and T-lymphocyte accumulation in human skin in vivo (39). PGD 2 , acting via the recently identified CRTH2 receptor, may also be important in regulating the recruitment and/or activation of eosinophils, basophils, and Th2-type T cells (40). Mast cell interactions with other cell types such as fibroblasts may regulate the generation of other chemokines such as eotaxin/CCLll, a potent stimulus of eosinophil, basophil, and perhaps Th2-type T cells (41). IL 8/CXCL8 can cause neutrophil accumulation in human skIn in vivo (42), and IL 16 is chemoattractant for human T lymphocytes in vitro (22). IL 3, 5, and GM-CSF are important in the proliferation, differentiation, maturation, viability, and priming of eosinophi Is, and GM-CSF is also important in neutrophil priming (43). In human 8 lymphocytes. IL 4 is an essential cofactor for IgE synthesis (44), and likewise IL J3 can induce IgE synthesis independently of IL 4 (45). IL 4 also directs the development of naive CD4-positive T lymphocytes into Th2 cells in mice and humans (46,47). The relative contribution of these mediators to both the susceptibility of patients to have urticaria and the development of individual wheals requires further investigation.
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VI.
ITCHING
The 19th century Scottish physician, William Heberden wrote of urticaria that ". by far the greatest number (of patients) experience no other evi,l besides the intolerable anguish arising from the itching... " (48). Itch in urticaria is classified as pruritoceptive (49). This means it is generated within the skin, and the contribution of central (neurogenic) components is minimal. Histamine appears to be the main, if not the only, cause of itching in most forms of urticaria, including CIU, since application of histamine to human skin reproduces the symptom convincingly, and Hlantihistamines are usually effective in suppressing this symptom (50). The pruritic response to histamine is due to activation of neuronal H 1- but not H2-receptors (50) associated with free nerve endings in skin. Pruritus is transmitted via unmyelinated C or A 8 neurons to the grey matter of the dorsal horn of the spinal cord. There, secondary neurons transmit the sensation via the contralateral spinothalamic tracts to higher centers. Recent application of microneurographic technology (51,52) has clearly demonstrated the existence of a subset of dedicated itch-transmitting C neurons, and lateral spinothalamic neurons, distinct from those transmitting pain. Studies of the diurnal distribution of pruritus in chronic urticaria revealed that itching is most prominent in the evening and at night (53), which is an important consideration when outlining a treatment strategy. The cause of nocturnal preponderance is unclear but may be due to warmth of the skin and to psychophysiological factors. Perception of itch is downregulated by sensory input from higher centers via inhibitory descending pathways from the periaqueductal grey matter. Such distracting stimuli may be reduced in the evening and at night. Patients rub rather than scratch the itch of urticaria. Rubbing activates myelinated fastconducting A neurons. This leads to activation of inhibitory neuronal circuits within the substantia gelatinosa of the spinal cord, modulating the traffic of itch. These proposed mechanisms ha ve recently been reviewed (54).
VII.
INFLAMMATORY INFILTRATE
The significance of the cellular infiltrate in different types of urticaria has been underinvestigated. There are qualitative data, but the functional and dynamic aspects are largely unknown. The classic histological features of the urticarial wheal are dermal edema, vasodilatation, including dilatation of lymphatics and an innammatory infiltrate consisting of mononuclear cells, mainly lymphocytes with a variable number of neutrophils and eosinophils (Fig. 2a). Unlike in urticarial vasculitis (Fig. 2b), there is no
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..
~~h: ~.....
~
a
b
c Figure 2
a. Histological appearance of a skin biopsy from a wheal of chronic idiopathic urticaria. There is no evidence of endothelial damage or leukocytoclasia. b. Histological appearances of a skin biopsy of a wheal of urticarial vasculitis. The endothelial cells are clearly damaged; there is prominent leukocytoclasia and red blood cell diapedesis. c. Histological appearances of a skin biopsy of a wheal of neutrophilic urticaria. There is no endothelial cell damage or leukocytoclasia, but the walls of the postcapillary venules show marked invasion by neutrophils (so-called 'polys in the wall'). (PhOlOmicrograph COlliNS!' of Dr RK Winkelman/l.)
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evidence of endothelial damage although these cells may be swollen. Erythrocyte extravasation and nuclear dust (karyorrhexis), other major features of urticarial vasculitis, are absent. Despite their central role in the pathogenesis of urticaria, light microscope examination of dermal mast cells usually shows no remarkable changes with no visible degranulation. However, there is some evidence to suggest mast cell degranulation on electron microscopic examination (55). There is also controversy as to whether or not mast cell numbers alter in urticarial wheals: some authors describe a reduced number and others a la-fold increase (55-59) Use of monoclonal antibodies and enzyme immunohistochemistry has allowed characterization of the mononuclear infiltrate. In chronic urticaria, Kaplan's group (56) reported that about 40% of the infiltrating cells were T lymphocytes, with a ratio of CD4 helper-inducer/CD8 cytotoxic-suppressor cells similar to that in normal healthy blood. In a recent joint publication, Kaplan's and Kay's groups, have demonstrated increases in intradermal CD3+, CD4+, CD8+, and CD25+ T lymphocytes. The cells had a ThO cytokine profile with significant increases in IL 4, IL 5 and interferon y mRNA (60). Our group (61) carried out timed biopsies from involved and uninvolved skin in 22 patients with CIU and from normal skin of 12 healthy control subjects. Biopsies from wheals aged <4 h or > 12 h showed increased numbers of EG2+activated eosinophils, neutral elastase+ neutrophils, and, to a lesser extent, CD3+ T cells compared with uninvolved skin. There was no difference between healthy skin of normal control subjects and uninvolved skin of patients with CIU. However, when biopsies of patients whose chronic urticaria was shown to have an autoimmune basis due to anti-Fcc:R I or anti-fgE autoantibodies were compared with those having no autoantibodies, there was little difference, except that the latter were found to have more activated eosinophils in wheals of greater than 12 h duration. The explanation for this finding is unclear, although it would suggest that eosinophil activation may occur later or persist for longer in these patients. That peripheral blood basophil leukocytes are depleted in patients wilh chronic urticaria has long been recognized (62,63). More recently we (64) have shown that this abnormality is associated with the presence in the peripheral blood of autoantibodies against the high-affinity IgE receptor or against IgE, which are the hallmarks of autoimmune urticaria. As recently suggested by Grattan (65), active recruitment of basophils into lesional skin of patients with autoimmune urticaria may not only explain this phenomenon but may also be a key factor in the palhogenesis of the disease. There is now evidence to support basophil accumulalion in lesional
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skin (60,66). However, circulating basophils could also be reduced by trapping in the reticuloendothelial system. Winkelmann (67) has delineated on histological grounds, that 15.8% of patients with chronic urticaria have either a diffuse dermal neutrophil infiltrate or neutrophils investing the postcapillary venules, in some cases invading the wall of the venules or any combination of these changes (68). There was no vasculitis (Fig. 2c). He was unable to attach any particular clinical significance to these findings, which were observed not only in patients with CIU but also in those with physical urticarias, and believed them to be representative of an 'intense stimulus response pattern' in urticaria. This conclusion was also reached by Her1Z's group (69) who believed neutrophilic urticaria to be an acute-phase urticarial reaction, not restricted to any specific type of urticaria. The present authors have observed the histological pattern of neutrophilic urticaria in several cases of Schnitzler's syndrome (70). Winkelmann (71) came to a similar conclusion. In timed biopsies from wheals in patients with CIU, we found that in wheals of <4 h duration neutrophils were predominantly in or close to vessels, whereas in wheals of > 12 h duration they were predominantly in the interstitium (61). This suggests that neutrophil accumulation may represent a phase of wheal evolution. It is the authors' view that much potentially fruitful research could be done on clinicopathological correlates using currently available monoclonal antibodies as cell markers and by focusing on the evolution of the cellular infiltrate in sequential biopsies from patients with different subtypes of acute and chronic urticaria, and urticarial vasculitis.
VIII.
LESIONAL DISTRIBUTION OF URTICARIA AND ANGIOEDEMA
In physical urticarias the distribution is determined by the physical provoking factors. Solar and cold urticaria occur predominantly in exposed areas and pressure urticaria or symptomatic dermographism mainly at sites of pressure or friction (waist band, soles, palms). Urticarial vasculitis also often occurs at pressure sites, probably due to the predilection of immune complex deposition for conditions of vascular stasis. Although sites of local pressure on the skin are often lIlvolved in the wheals of chronic idiopathic urticaria, this may be due to the high incidence of concurrent delayed pressure urticaria (72). Angioedema frequently affects the skin of the eyelids, lips, and genitalia, probably due to the relatively scanty connective tissue in these areas that offers low resistance to exudation and accumulation of tissue Iluid. Lymphatic clearance of rapidly accumulating
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tissue tluid may also be less effective in these areas. Whether differences in the cutaneous blood vascularization at different sites also plays a role is unclear. There is no consensus as to whether dermal mast cell population density is altered in patients with chronic urticaria and so this is probably not a determining factor in the distribution of lesions (56,57,59). Sites at which wheals of chronic idiopathic urticaria were present less than about 72 h previously are usually spared further wheal development. This may be due to refractoriness of dermal mast cells to renewed activation, or to tachyphylaxis manifested by the cutaneous vasculature to vasoactive mediators (28), or both
IX.
PSYCHOSOMATIC RESPONSES AND URTICARIA
Emotional factors can cause tlares of urticaria; serious emotional disturbance can also be a consequence of the disease. In many patients both may occur concurrently. Awareness of these factors is an essential component of a holistic approach to the patient with chronic urticaria and angioedema. Anyone who deals regularly with patients with chronic urticaria will be aware of the powerful intluence of what is termed 'stress' on the frequency and severity of relapses. The most straightforward example of this is found in patients with the very common physical urticaria, cholinergic urticaria. These patients regularly report that a stressful event such as speaking in public. a confrontation at work, or troublesome circumstances at home brings an immediate outbreak of intense itching and the typical monomorphic pinheadlike wheals. However patients with CIU typically report tlare-ups when traveling on business trips, during examinations, and coinciding with major personal life events. On the other hand, the impact of chronic urticaria and its associated pruritus on family harmony and on occupational performance. through irritability and depression from impaired sleep and loss of selfesteem as a result of continuous rubbing. should not be underestimated. Recent studies of the effect of chronic urticaria on quality of life (QOL), using recognized QOL instruments (73,74) have underscored the impact of chronic urticaria on personal, social, occupational, and domestic activities. Several patients under the care or one of us (MWG) have admitted recourse to alcohol abuse on the (no doubt genuine) grounds that it is the only measure that afrords them signiricant relief from the itch. In practice, it is often difficult to tease out cause rrom effect in an individual patient. In the patient with chronic urticaria, anxiety may express itself as disordered autonomic function. In a recent study (75) evaluation of
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autonomic function by measurement of R-R intervals on the electrocardiogram during controlled breathing showed that patients with chronic urticaria had altered autonomic function compared with healthy controls. This clinical observation is of especial interest since animal studies have demonstrated the increased secretion of salivary mast cell protease in rats in response to visual stimuli (76), suggesting functional links between the nervous system and mast cells. There is convincing evidence to show that psychological factors can participate in immunological responses in humans. For example, shifts in the dose-response curve for the PrausnitzKi.istner reaction could be brought about by direct suggestion under hypnosis (77). Stress management and behavioral therapy may be of benefit in the long-term management of patients with chronic urticaria in whom stress is clearly an exacerbating factor (78). For those patients in whom emotional disturbance is deemed to be the consequence rather than the cause of flares of disease, it is first important to determine if the reaction is one of anxiety, depression, or both (79). After attempting to rechannel or reduce stress, adjunctive treatment using anxiolytic and/or antidepressant drugs should be considered. However, drug therapy, although often useful, is no substitute for establishment of a close rapport with the patient, leading to patient education on the nature and causation of the conditon's symptoms, signs, and prognosis.
X.
CLASSIFICATION OF URTICARIA AND ANGIOEDEMA
The definitions of the different subtypes of urticaria will be elucidated further in the appropriate chapters. We provide here a classification of the main types of urticaria/angioedema for clinicians, incorporating advances in understanding of pathogenesis, and based upon a recent international consensus report (80). It is not comprehensive.
1. "Ordinary" urticarial angioedema A. Acute urticaria/angioedema
B. Chronic urticaria/angioedema
Wheals/angioedema occur randomly without local physical provocation. Isolated attacks of urticaria lasting <6 weeks, systemic causes including viral infections, allergic reactions. Attacks lasting >6 weeks; periodicity may be intermittent or persistent daily or almost daily wheals. Includes idiopathic chronic urticaria and autoimmune urticaria.
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II. Physical urticaria/angioedema
A. SVlI7ptomatic dermographism B. Delayed pressure urticaria
C. Cold contact urticaria
D. Heat contact Llnicaria
E. Solar urticaria
F. Vibr{{fO/T urticaria
G. Cholinergic urticaria
H. Aquagenic urticaria
XI.
Wheals/angioedema develop in response to external physical stimuli. Localized response to stroking the skin: no angioedema. Localized response to pressure applied against the skin: no angioedema. Localized response of skin to lowered temperature: may be associated with angioedema and anaphylaxis. Localized response of skin to raised temperature: rarely associated with angioedema. Localized response of skin to ultraviolet (UV) and/or visible light: rarely associated with angioedema. Localized response of skin to vibratory stimuli: frequently associated with angioedema. Widespread monomorphic urticarial eruption in response to exercise, rise in body temperature, or emotional provocation: may be accompanied by angioedema; exercise-induced anaphylaxis may occur rarely. Localized response of skin to wetting by water, morphologically resembling cholinergic urticaria: no angioedema.
SPECIAL TYPES OF URTICARIA/ANGIOEDEMA
Contact urticario is a localized response of skin to contact with an allergen, but the response can also be non-allergic (pseudoallergic). It may be associated with angioedema. Urticarial \'asclilitis, is a chronic urticaria with histological evidence of vasculitis in involved skin, which may be idiopathic
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or secondary to systemic disease. lL may be associated with angioedema. Urticaria pigmen/osa (cLI/Cineolls mClsLOc.J'!osis) is associated with hyperproliferation of dermal mast cells. and is only rarely associated with angioedema. Cl es/erase inhibitor deficienc), is a rare disorder leading to angioedema only. lL is usually hereditary, but can be acquired, for example. in association with lymphoproliferative disorders or other malignancy, or with systemic lupus erythematosus.
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Sabroe T, Hartnell A, Jopling LA, Bel S, Ponath PD, Pease JE, Collins PD, Williams TJ. Differential regulation of eosinophil chemokine signaling via CCR3 and non-CCR3 pathways. J Immunol 1999; 162: 2946-2955 Beck LA, Dalke S, Leiferman KM, Bickel CA, Hamilton R, Rosen H. Bochner BS, Schleimer RP. Cutaneous injection of RANTES causes eosinophil recruitment. Comparison of nonallergic and allergic human subjects. J Immunol 1997; 159:2962-2972. Hirai H, Tanaka K, Yoshie 0, Ogawa K, Kenmotsu K, Takamori Y, Ichimasa M, Sugamura K, Nakamura M, Takano S, Nagata K. Prostaglandin D2 selectively induces chemotaxis in T helper type 2 cells, eosinophils and basophils via seven-transmembrane receptor CRTH2. J Exp Med 2001: 193:255-261. Hogaboam C, Kunkel SL, Strieter RM, Taub DD, Lincoln P, Standiford TJ, Lukacs NW. Novel role of transmembrane SCF for mast cell activation and eotaxin production in mast cell-fibroblast interactions. J Immunol 1998; 1606166-6171 Leonard EJ, Yoshimura T, Tanaka S, Raffeld M. Neutrophil recruitment by intradermally injected neutrophil attractant/activation protein-I. J Invest Dermatol 1991; 96:690-694. Nicod LP. Cytokines: I. Overview. Thorax 1993; 48:660-667. Gascan H, Gauchat J-F, Roncarolo M-G, Yssel H, Spits H, de Vries JE. Human B cell clones can be induced to proliferate and to switch to IgE and IgG4 synthesis by interleukin 4 and a signal provided by activated CD4+ T cell clones. J Exp Med 1991: 173:747-750. Punnonen J, Aversa G, Cocks BG, McKenzie ANJ, Menon S. Zurawski G, de Waal Malefyt R, de Vries JE. Interleukin 13 induces interleukin 4-independent JgG4 and TgE synthesis and CD23 expression by human B cells. Proc Nall Acad Sci USA 1993; 90:3730-3734 Bonecchi R, Bianchi G, Bordignon PP, D'Ambrosio D, Lang R, Borsatti A, Sozzani S, Allavena P, Gray PA, Mantovani A, Sinigaglia F. Differential expression of chemokine receptors and chemotactic responsiveness of type I T helper cells (This) and Th2s. J Exp Med 1998: 187129-134. Swain SL Weinberg AD, English M, Huston G. IL-4 directs the development of Th2-like helper effectors. J Jmmunol 1990: 145:3796-3806. Heberden W. Commentaries on the history and cure of diseases. London: Payne, 1802. Twycross R, Greaves MW, Handwerker H, Jones EA, Libretto SE, Szepielowski, JC, Zylicz Z. Itch: snatching more than the surface. Q J Med 2003; 96:7-26. Robertson I, Greaves MW. Responses of human skin blood vessels to synthetic histamine analogues and to histamine. Br J Clin Pharmacol 1978: 5:319-322. Schmelz M, Schmidt R, Bickel A, Handwerker HO. TorcbJork HE, Specificreceptors for itch in human skin. J Neurosci 1997; 17:8003- 8008.
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Sabroe RA, Seed PT, Francis DM, Barr RM, Kobza Black A, Greaves MW. Chronic idiopathic urticaria: comparison of the clinical features of patients with and without anti-FcER I or anti-lgE autoantibodies. J Am Acad Dermatol 1999; 40:443-450 Yosipovitch G, Greaves, MW, Schmelz, M, Itch-new concepts. Lancet 2003; 361 :690-694. Toyoda M, Maruyama T, Morohashi M, Bhawan J. Free eosinophil granules in urticaria. A correlation with the duration of wheals. Am J Dermatopathol 1996; 18:49-57. Elias J, Boss E, Kaplan AP. Studies of the cellular infiltrate of chronic idiopathic urticaria: prominence of T-Iymphocytes, monocytes and mast cells. J Allergy Clin lmmunol 1986; 78:914-918. Natbony SF, Phillips ME, Elias JM, Godfrey HP, Kaplan AP. Histologic studies of chronic idiopathic urticaria. J Allergy C1in Immunol 1983; 71177-183 Barlow RJ, Ross EL, Macdonald DM, Kobza-Black A, Greaves MW. Mast cells and T lymphocytes in chronic urticaria. Clin Exp Allergy 1995; 25:317-322 Smith CH, Kepley C, Schwartz LB, Lee TH. Mast cell number and phenotype in chronic idiopathic urticaria. J Allergy Clin Immunol 1995; 96:360-364. Ying S, Kikuchi Y, Meng Q, Kay AB, Kaplan AP. THI/TH2 cytokines and inflammatory cells in skin biopsy specimens from patients with chronic idiopathic urticaria: comparison with the allergen-induced late-phase cutaneous reaction. J Allergy C1in Immunol 2002; 109694-700. Sabroe RA, Poon E, Orchard GE, Lane D, Francis DM, Barr RM, Black MM, Kobza Black A, Greaves MW. Cutaneous inflammatory cell infiltrate in chronic idiopathic urticaria: comparison of patients with and without anti-FcERl or anti-IgE autoantibodies. J Allergy Clin Immunol 1999; 103: 484-493 Rorsman H. Basopenia in urticaria. Acta Allergol 1961: 16:185-215. Greaves MW, Plummer YM, McLaughlan P, Stanworth DR. Serum and cellbound 19E in chronic urticaria. Clin Allergy 1974; 4:265-271. Sabroe RA, Francis DM, Barr RM, Kobza Black A, Greaves MW. AntiFCER 1 autoantibodies and basophil histamine releasability in chronic idiopathic urticaria J Allergy Clin Immunol 1998; 102:651-658. Grattan CEH. Basophils in chronic urticaria. J Invest Dermatol Symp Proc
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2 Mast Cells and Basophils Wei Zhao and Lawrence B. Schwartz Virginia Commonwealth University, Richmond, Virginia, US.A.
I.
INTRODUCTION
Mast cells and basophils are generally recognized as the principal cell types to initiate IgE-dependent immediate hypersensitivity reactions (type I), and more recently as cells that also contribute to innate and acquired immunity and to tissue remodeling (Fig. 1). Experimental challenge of an IgEsensitized host with allergen reveals two phases to the subsequent immediate hypersensitivity reaction. The early phase of the IgE-dependent reactions (5-30 min postchallenge), depending on the target tissue and distribution of allergen, involves local edema, smooth muscle contraction, vasodilation, and increased permeability of postcapillary venules. The late phase of an immediate hypersensitivity reaction (4-12h postchallenge) involves the recruitment and activation of basophils, eosinophils, and other cell types. These late reactions can persist for at least 2 days in the challenged lower airway, but eventually appear to resolve completely. In contrast, chronic allergic intlammation results from prolonged allergen exposure, and may provoke changes in the target tissue that resolve much more slowly, if at all. Mast cells occupy sentinel positions in tissues where noxious substances might attempt entry, and immediate-type hypersensitivity reactions typically begin. These cells are most concentrated at mucosal sites in the upper and lower airways, conjunctiva, and gastrointestinal mucosa, and also in dermal, cardiac, and perivascular sites. Elegant studies in mice have indicated important roles for mast cells in the innate immune response against bacteria and in immune complex-mediated hypersensitivity disorders, including classic Arthus reactions. Whether mast cells in humans
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Tissue Homeostasis
Acquired Immunity
Innate Immunity (rodent) bacterial infection viral infection
repairiremodeling angiogenesis Immediate Hypersensitivity Immune Complex Hypersensitivity (rodent)
(human & rodent)
anaphylaxis urticaria/angioedema atopic asthma, rhinitis conjunctivitis dermatitis
Intestinal Parasitosis (rodent)
Figure 1 Biology of mast cells and basophils. Mast cells and basophils are the primary effector cells in immediate hypersensitivity reactions, but also may participate in innate and acquired immune defense, immune complex hypersensitivity disorders, and various tissue homeostatic processes.
also extend their capabilities beyond immediate hypersensitivity reactions is uncertain. Basophils normally reside in the circulation, but enter tissues at sites of inflammation, particularly during the late phase of IgE-mediated immediate-hypersensitivity reactions and during the early phase of cell-mediated delayed-type hypersensitivity reactions. Mast cells and basophils are the only two cell types that constitutively express substantial quantities of the high-aCflnity, tetrameric receptor for IgE (FcsRI), and store histamine in their secretory granules. These two cell types are differentiated through pathways for growth, differentiation, and survival; patterns of cell-surface adhesion, cytokine, and chemokine receptors; responses to non-lgEdependent agonists; secretory granule proteoglycans and proteases; and morphologies For example, nuclei of basophils have deeply divided lobes, whereas those of typical mast cells do not. Mast cells in human tissues have been classified into two major types based on the protease content of their secretory granules. Those with
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tryptase together with chymase, carboxypeptidase, and cathepsin G are called MC Te cells; those with only tryptase are called MC T cells. Markers of basophil secretory granules identified with monoclonal antibodies (mAbs) also have been reported, but have not been precisely characterized. MC Te cells are the predominant mast cell type in normal and urticaria pigmentosa skin, small bowel submucosa, conjunctiva, perivascular sites, and cardiac tissue, whereas MeT cells are the predominant type found in the normal airway and in the small bowel mucosa. This chapter will focus on human mast cells and basophils, and their relevance to urticaria and angioedema.
II.
GROWTH AND DIFFERENTIATION OF MAST CELLS
Both mast cells and basophils originate from hematopoietic stem cells, as outlined in Fig. 2. Basophils, like most myeloid cells, complete their differentiation in the bone marrow, and then enter the circulation. In contrast, a cell destined to reside in peripheral tissues as a mast cell will leave the bone marrow as an immature progenitor, probably with multipotential capabilities, enter a peripheral tissue still without secretory granules and cell surface FCERI, and then complete its differentiation to a mast cell. Basophils develop largely under the influence of interleukin (lL)-3, a process that is augmented by transforming growth factor f3 (TGF-f3). Mast cells differentiate under the influence of stem cell factor (SCF) (1-4), the ligand
MC TC
MGT
-
- Iryptase
L
Basophils
Iryptase fhymase MC carboxypeptidase Cathepsin G
t
SCF+?
Mast Cen committed progenitor
Hematopoetic Progenitor Cells
Figure 2 Differentiation of human mast cells and basophils. Hematopoietic progenitor cells give rise to both mast cells and basophils. but basophils develop in the bone marrow under the innuence of IL-3 while mast cells develop in peripheral tissues under the innuence of SCF. What innuences mast cells to develop as MC Te or MC T cells is unclear. but is assumed to involve factors other than SCF.
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for Kit, a product of the c-kit proto-oncogene. SCF is a noncovalent homodimer (5). [L-3 has little if any influence on the differentiation of human mast cells other than to expand the pool of hematopoietic progenitor cells. Although IL-3R surface expression has not been observed on lung and skin mast cells, it has been found on intestinal mast cells, in which case IL-3 protects against apoptosis (6). In contrast, IL-3 is an important growth and differentiation factor for rodent mast cells in vitro and for mast cell hyperplasia to occur during parasitic infection (7). Mast cell progenitors identified in human peripheral blood have been differentiated from basophils, monocytes, and other leukocytes by patterns of cell surface molecules detected (8). Also, multipotential precursors isolated from cord blood or peripheral blood that are either positive for CD34 and CD38 (9) or for CD34, CDI3 and Kit (10) give rise to pure mast cell colonies along with other pure or mixed lineage colonies, principally monocytic, implying a distinct myeloid lineage for mast cells. Conditions that influence the selective development or recruitment of MC TC and MC T cells are not yet understood. Of interest is the experimental observation that intestinal mast cells attach to endothelial cells which preferentially support the survival and proliferation of MC TC cells (II). The expression of CCR3, CCR5, CXCRI, CXCR2, and CXCR4 on cord blood-derived mast cells (12-14) and the CXCR4-dependent migration of these mast cells in response to stromal cell-derived factor-I a (SDF-la) (15,16) suggest chemokine-dependent pathways for the recruitment of mast cells or their progenitors. Unlike other myelocytes that stop expressing Kit as they mature, maturing mast cells express increasing amounts of Kit. Thus, SCF exerts various effects on mast cells throughout their development, affecting their differentiation, survival, recruitment, activation, and priming. The effects on differentiation and survival are particularly evident in mice with inactivating mutations either in Kit or in SCF, both of which result in a profound mast cell deficiency. Removal of SCF from mast cells in mice, and humans (17) results in apoptosis. Gain of function mutations in the kinase region of Kit (18) are associated with systemic mastocytosis. On the other hand, gain of function mutations near the transmembrane regions that cause spontaneous homodimerization are associated with intestinal stromal cell tumors in 'vvhich interstitial cells of Cajal are transformed (19,20). MCTC and MC T cells develop along distinct pathways. In humans with inherited combined immunodeficiency disease and in those with acquired immunodeficiency syndrome. selective decreases in MC T cell concentrations occur in the boweL where MC TC cell numbers are unaff cted (21). This suggests that MC Te cell development proceeds independently from that of Mer cells. Also, immature MC T cells contain granules with
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scrolls and tryptase alone, while immature Mere cells have granules with electrondense cores and both tryptase and chymase (22). Thus, commitment to a particular mast cell type in vivo appears to occur by the time granules begin to form. Why mast cells fail to develop in the bone marrow where SCF clearly affects the development of other cell types is an enigma. Perhaps the microenvironment contains factors that do not permit mast cell development. For example, both granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL-4 appear to diminish SCF-dependent development of mast cells from progenitors in vitro, but have little effect on more mature mast cells (23,24). The ability of IL-4 to downregulate expression of Kit may help to explain the ability of this cytokine to attenuate mast cell development under some circumstances. However, I LA exhibits several effects on mast cells, including induction of surface FcsRI on in-vitro-derived mast cells (25,26), proliferation of intestinal mast cells (27), enhancement of cytokine and arachidonic acid product production by cord-blood-derived mast cells (28,29), and apoptosis of cord-blood-derived mast cells (30). Glucocorticosteroids inhibit mast cell development in vitro, whereas mature mast cells are relatively resistant to these agents. IL-6 also has pleiotropic effects on developing human mast cells that include blocking of fL-4-mediated apoptosis (30). Both IL-4 and IL-6 can enhance the maturation of mast cells expressing chymase (31,32).
III. ACTIVATION AND REGULATED SECRETION Immunological activation of mast cells and basophils typically begins when 1 9 IgE bound to the high-affinity Fcs receptor (FcsRI, Ka = 10 M- ) is crosslinked by multivalent allergen (Fig. 3). The complete FcsRI receptor is composed of four subunits, a(3Y2, which appear to float on the cell surface in lipid-based domains called rafts (33,34). The a chain contains the extracellular IgE-bindll1g domain. The (3 and two disulfide-linked Y chains are located primarily in the membrane and cytoplasmic regions. The Y chains also are present in CD16 (FcyRIII). Regulated secretion by mast cells.and basophils also may be induced by nonimmunological agonists. Multivalent lectins, such as bivalent concanavalin A, cross-link membrane FcsRI or IgE. Calcium ionophores activate by translocating calcium. Several basic biomolecules such as compound 48/80, C5a, morphine, codeine, mellitin, eosinophil-derived major basic protein, and various neuropeptides such as substance P. vasoactive intestinal peptide, somatostatin, calcitonin gene-related protein, p23 (35,36), and a-melanocyte stimulating hormone (37) activate human
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~ft~ w., Anti-lgE (FCE)
Aggregated IgE
COOO OJ
YY y
..v~- .---~~~ i. ~ .\-<>-Anti-Idiotype
r__
~~. • • ,.j:< ~~.~/ ~
Antl-FcERI
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y
y o
I~ IgG
UnivolJent AlHlgen
V
l'Vl u l.ttv3knt Anllgt'n
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Lectll1
Figure 3 Fct:RI-mediated activation of mast cells and basophils. IgE-mediated immediate hypersensivity typically begins when multivalent antigen binds to specific IgE on the surface of mast cells or basophils. Similar reactions also are initiated when anti-IgE or anti·Fc&RI antibodies cross-links this receptor, as seen in chronic idiopathic urticaria. Other stimuli acting on the same molecular pathway include aggregated IgE and certain lectins. In contrast, univalent antigens should not activate mast cells, because they cannot cross-link IgE.
mast cells derived from skin, but are inactive against mast cells derived from most other tissues. In contrast, basophils respond to C5a and C3a, but not to the neuropeptides, compound 48/80, morphine, and codeine. Mast cells from heart respond to C5a, but not to substance P (38) The desArg derivative of C5a is inactive on skin mast cells, while still being active against basophils. Basophils also can be activated as well as primed to respond better to antigen by IL-3. Differences in the secretory response between mast cells isolated frol11 different tissues may relate to microenvironmental intluences or to the type of mast cell. Basophils, like eosinophils but in contrast to mast cells, express surface FcaR. and can be activated by an IgA-dependent pathway (39,40). The peptide f-Met-Leu-Phe activates human basophils, but not mast cells. HIV-I gp 120 activates IgE-armed basophils to secrete IL-4 and IL-13 (41). which is of possible relevance to the immediate hypersensitivity reactions commonly observed in persons infected with human immunodeficiency virus (HIV). Immunological activation of mast cells can be enhanced by adenosine (42). possibly through the adenosine A2b receptor in humans (43). In contrast. mediator release from human basophils is inhibited by adenosine. ATP also can enhance mediator release from activated mast cells by binding to the P2Y surface purinoreceptor expressed on human lung-derived mast cells (44). lL-4-primed cord-blood-derived mast cells express CysLTI. a receptor for sulfidopeptide leukotrienes, and can be activated by leukotriene (LT)C 4 to secrete cytokines without releasing histamine or prostaglandin (PG)D 2 (45.46).
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Chemokines, initially discovered because of their abilities to attract predominantly monocytes or neutrophils, include potent basophil histamine-releasing and -attracting agents (47). Active chemokines include monocyte chemotactic protein (MCP)-I to -4; RANTES; monocyte inf1ammatory peptide (MIP)-Ia and -ltl; eotaxin and eotaxin-2; and ecalectin (galectin-9). Most of these chemokines affect eosinophils as well as basophils. The presence of the chemokine receptor, CCR3, on basophils and eosinophils dovetails with the cellular response profile of these CC class chemokines (48). However, a further level of complexity was revealed for MCP-I, which when intact preferentially activates basophils over eosinophils. After the N-terminal amino acid is removed, it preferentially activates eosinophils over basophils. In contrast to basophils, chemokines seem not to cause mediator release from mast cells (12,49-51). However, human mast cells can produce chemokines such as MCP-l and MIP-Ia (52,53), suggesting a mechanism in which basophils and eosinophils may be recruited to and activated at tissue sites of mast cell activation. Differences between basophils and mast cells with respect to their non-IgE-mediated pathways of activation, in theory, could lead to the activation of one cell type in the absence of the other. Pharmacological responsiveness of mast cells also varies depending on the tissue source and differs from that of basophils. Disodium cromoglycate and nedocromil, each used for the treatment of allergic asthma, rhinitis, and conjunctivitis, at high concentrations are weak inhibitors of lung-derived mast cells, and do not inhibit those from skin and intestine. tl-Adrenoceptor agonists, at concentrations theoretically although transiently achievable on the airway surface with inhaled medication, produce modest inhibition of IgE-dependent histamine release in vitro from dispersed human lung mast cells, and somewhat greater inhibition of LTC 4 and PGD 2 generation. Cyclosporin A, FK-506, and pimecrolimus (54) produce rapid and longlasting inhibition of IgE-dependent histamine release from human basophils and skin- and lung-derived mast cells. Rapamycin interferes with the inhibitory activity of FK-506 by competing for the same FK-binding protein, but by itself does not inhibit mast cell or basophil activation Dexamethasone in vitro inhibits degranulation of human basophils, but not mast cells. However, cytokine production by mast cells was inhibited (55). In vivo, local instillation of nasal glucocorticosteroids diminishes lumi nal mediator release during the early response to nasal allergen challenge, perhaps due to the capacity for local steroids to diminish mast cell concentrations or the recruitment that apparently occurs with allergen exposure. Mast cells undergo regulated exocytosis when FCERI (a, tl, Y2) are dimerized by multivalent antigen or antireceptor antibody. The earliest biochemical events involved in signal transduction after FCERJ aggregation
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involve phosphorylation of tyrosines on the {3 and y chains at immunoreceptor tyrosine activation motif (ITAM) sites. These ITAMs associate with Src-family protein tyrosine kinases (PTKs) such as Lyn and, when phosphorylated, with Syk, which initiate the activation of downstream effector pathways involving PLCy, MAP kinase, protein kinase C, and PI-3 kinase. Human basophils require Syk for IgEdependent signal transduction, because individuals with low expression of Syk in their basophils are non releasers to FcsRI cross-linking. This process can be reversed by IL-3, which induces Syk expression (56). These early events also are regulated by signal regulatory proteins (SIRPs) that contain immunotyrosine inhibition motifs (ITIMS), which act in part by recruiting SH2-bearing protein tyrosine phosphatases (SHP-I and -2) that dephosphorylate ITAMs on FcsRI-{3 and -y, thereby downregulating signal transduction and mediator release (57). In contrast, CD45, another protein tyrosine phosphatase, promotes mediator release (58). SLP-76, an adapter protein for Syk, also is critical for mediator release (59) Monomeric IgE promotes survival and may stimulate cytokine production without degranulation (60). The role of mast cells in host innate immunity has recently received great attention. The innate immune system using pattern recognition receptors has the capacity to detect microbes. Among them are mammalian toll-like receptors (TLRs). A total of 10 TLRs has been reported. Murine mast cells produce cytokines in response to bacterial peptidoglycan and lipopolysaccharide via TLR2 and TLR4, respectively (61,62). Human cordblood-derived mast cells express TLR I, TLR2, and TLR6 but not TLR4 (63). Peptidoglycan exposure leads to the production of GM-CSF, IL-I{3, and LTC 4 without causing mast cell degranulation, differentiating atopic from innate immune responses. Mast cell activation is also under the innuence of cytokines. IL-4 primes (5 days) human cord-blood-derived mast cells to release greater amounts of histamine as well as IL-13, TNF-O', IL-5, MIP-IO', and GM-CSF upon cross-linking FcsRI (28,29,64). IL-6 also upregulates IgE-dependent degranulation of mast cells (65). In contrast, IL-5 enhances release of certain cytokines without affecting degranulation. IL-5 also augmented ILA-priming of LTC 4 production. ILA increased LTC 4 synthase levels, while IL-5 enhanced translocation of 5-lipoxygenase (5-LO) to the nuclear membrane. Human mast cells normally do not express Fcy receptors (66). However, treatment with lFN-y induced the expression of FcyRI, which when aggregated caused mast cells to release histamine, cytokines, PGD,. and LTC 4 (67,68). These lindings suggest another mechanism by whicl1 human mast cells may be recruited into the innammatory processes associated with 19G-dependent immune responses.
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MEDIATORS
Mediators secreted by activated mast cells and basophils can be classified into those stored in secretory granules prior to cell activation and those that are newly generated after an activation signal. The former include histamine, proteoglycans and proteases; the latter include metabolites of arachidonic acid, cytokines and chemokines, as summarized in Fig. 4. A.
Biogenic Amine(s)
Histamine is the sole biogenic amine in human mast cells and basophils. Histamine (,B-imidazolylethylamine) is formed from histidine by histidine decarboxylase and then stored in secretory granules. Histamine is the only preformed mediator of human mast cells with direct potent vasoactive and smooth muscle spasmogenic effects. With degranulation, histamine is released and diffuses rapidly. Extracellular histamine is metabolized within minutes of release, suggesting that it is destined to act quickly and locally. Human mast cells and basophils contain 1-3 pg histamine/cell. Histamine concentrations of about 0.1 M are estimated to exist inside secretory granules; concentrations of 1-IOnM exist in plasma.
~
~~:::!~ 2z::~ •• • ~ .~
V J
minutes
Granule
Lipid
'histamine
'LTC 4
'chondroitin 504 'heparin, tryptase Jchymase, carboxypeptidase, cathepsin G
2PGDz
'2D7 antigen, basogranin
'Mer, MC TC & BAS
lIIillLlles fo
hours
Cytokine Chemokine
'I
'IL-4, 13
J
TNF-a. LL-S, 6, 8, 16 MCP-I I\1IP-Ia.
'IVIC T & MC TC
'
'MC 'BA~c
Figure 4
Mediators of activated mast cells and basophils. Mast cells and basophils release preformed granule mediators soon after the cells are actIvated. newly generated prostaglandins and leukotrienes somewhat later, and cytokines at variable times. Copyrighted Material
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Histamine exerts its biological and pathobiological effects through its in teraction with cell specific G protein-coupled receptors designated HI, H2, H3, and H4 (69). H I receptors (H I R) are blocked by chlorpheniramine, H2R by cimetidine, and H3R and H4R by thioperamide. Receptor specific agonists include 2-methylhistamine (HI R), dimaprit (H2R), a-methylhistamine (H3R), and clobenpropit (H4R). HI R mediate enhanced permeability of postcapillary venules, vasodilation, contraction of bronchial and gastrointestinal smooth muscle, and increased mucus secretion at mucosal sites. Increased vasopermeability will facilitate the tissue deposition of factors from plasma that may be important for tissue growth and repair and of foreign material or immune complexes that result in tissue inflammation. HI R-mediated enhancement of P-selectin surface expression by endothelial cells facilitates the recruitment of leukocytes. HI R -1- mice exhibit modest neurological alterations, but show no developmental abnormalities (70). H2R agonists stimulate gastric acid secretion by parietal cells, and inhibit mediator secretion by various leukocytes; enhance epithelial permeability across human airways; stimulate chemokinesis of neutrophils and eosinophils and expression of eosinophil C3b receptors; and activate endothelial cells to release a potent inhibitor of platelet aggregation, PGI 1 (prostacyclin). HI R are preferentially expressed on TH I cells, and stimulate this type of helper T cell; H2R are preferentially expressed on TH2 cells, and inhibit this cell type. HI R -1- mice show a reduced Th I response and enhanced TH2 response, while H2R - - mice show increased TH I and TH2 responses (71). Whether the use of antihistamines in humans affects immune responses in a similar fashion in vivo remains to be demonstrated. Stimulation of H3R affects neurotransmitter release and histamine formation in the central and peripheral nervous system. They are postulated to be involved in crosstalk between mast cells and peripheral nerves. In atopies with asthma bronchial hyperreactivity in response to irritant stimuli may in part be mediated by histamine-dependent neurogenic hyperexcitability. H4R are prominent in medullary and peripheral hematopoietic cells, but their function remains to be elucidated (72). Of potential interest is the finding of H4R-mediated chemotaxis of mast cells (73), raising the possibility of paracrine recruitment. The combined HI Rand H2R responses are required for the full expression of histamine vasoactivity. For example, the so-called triple response caused by an intraderm:1! injection of histamine,-a central erythema within seconds (histamine arteriolar vasodilation), followed by circumferential erythema (axon reflex vasodilation mediated by neuropeptides) and a central wheal (histamine vasopermeability, edema) peaking at about 15 min-is mostly blocked by HI R antagonists, but IS completely blocked only with a combination of HI Rand H2R antagonists (74).
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Analogous results have been observed for the tachycardia, widened pulse pressure, diastolic hypotension, flushing, and headaches resulting from intravenous infusion of histamine (75).
B.
Proteoglycans
The presence of highly sulfated proteoglycans in secretory granules of mast cells and basophils results in metachromasia when these cells are stained with basic dyes. Proteoglycans are composed of glycosaminoglycan side chains (repeating unbranched disaccharide units of a uronic acid and hexosamine moieties that are variably sulfated) covalently linked to a singlechain protein core via a specific trisaccharide-protein linkage region consisting of -gal-gal-xyl-ser. The intracellular proteoglycans of concern to mast cells are heparin (2.5 S04 residues/disaccharide) and chondroitin sulfate E (1.5 S04 resid ues/disaccharide). Chondroitin sulfate A (I S04 resid ue/ disaccharide) is the predominant type in human basophils and eosinophils. Heparin is selectively expressed by mast cells, and resides in the secretory granules of all mature mast cells (76). Glial progenitors are also capable of producing heparin (77). When mast cells are activated to degranulate, heparin proteoglycan is exocytosed along with other granule constituents in a complex with positively charged molecules. The biological functions of endogenous mast cell proteoglycans are somewhat speculative. They may facilitate processing of certain granule proteases as well as the uptake and packaging of mediators into the secretory granules. Heparin stabilizes the tetrameric form of tryptase at neutral pH. Heparin and chondroitin sulfate E (to a lesser extent) express anticoagulant, anticomplement, antikallikrein, and Hageman factor autoactivation activities. Heparin neutralizes the ability of eosinophil-derived major basic protein to kill schistosomula and enhances the binding of fibronectin to collagen. Heparin protects and facilitates basic fibroblast growth factor activity, which appears to reside in cutaneous mast cells (78), and modulates the cell adhesion properties of matrix proteins. Binding of heparin to L- and P-selectins inhibits inflammation (79), perhaps by blocking leukocyte rolling. Disrupting heparin expression in mice (80,81) yields mast cells with large vacuolated granules that are partially deficient in histamine and protease activities.
c.
Proteases
Proteases are enzymes that cleave peptide bonds, and certain ones are the dominant protein components of secretory granules in human and rodent mast cells. Some of these enzymes serve as selective markers that
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differentiate mast cells from other cell types, including basophils, and different mast cell subpopulations from one another. Basophils, compared to mast cells, are deficient in secretory granule protease activity.
1.
Tryptase
Trypsin-like activity was first associated with human mast cells in 1960 (82), and was biochemically characterized and named tryptase in 1981 (83,84). The granule-associated enzyme was stabilized with heparin (85). The crystal structure of lung-derived human f3-tryptase precisely defined this tetrameric structure and heparin-binding grooves (86,87). All active sites faced into the small, central pore of the planar tetramer, thereby restricting inhibitor (and substrate) access. The crystal structure of human recombinant a-tryptase was elucidated in 2002, showing a blocked substrate-binding region, which may explain why a-tryptase is proteolytically inactive (88).
a. Different Human Mast Cell Tn'ptases. Several cDNAs for human tryptase have been cloned (89). Tryptase genes are clustered on the short arm of human chromosome 16 (90,91). They have been classified into two types: a-tryptase f3-tryptase, and several subtypes. a- and 13tryptase each encode a 30 amino acid leader and 245 amino acid catalytic portions. a- Tryptases show ~ 90% sequence identity to f3-tryptases. Although some ambiguity still remains as to the number of tryptase genes per human haploid chromosome, at least one or two f3-tryptase subtypes, and zero or one a-tryptase subtype, reside on human chromosome 16. A third closely related gene, 8-tryptase, which terminates translation 40 amino acids earlier than a- and 13- tryptases. also may be expressed by human mast cells (92), although precise quantitation has not yet been performed. Other trypsin-like enzymes called tryptase are not closely related to the a- and 13- mast cell tryptases. b. Processing of rr.l'ptase Precursors. f3-Protryptase is processed in two proteolytic steps. pro to pro' by heparin-facilitated autocatalysis, and pro' to mature by a dipeptidyl peptidase. The mature peptide then spontaneously forms enzymatically active tetramers at acidic pH with heparin (93,94). Ineon trasl. beca use a-protryptase cannot undergo autocatalytic processing, it may not be processed to the pro' or mature peptide in vivo. a- and 13- protryptases that are not processed to a mature form are spontaneously-secreted by human mast cells in vitro, and presumably in vivo (164) (Table I). c. Tr.l'ptase Regulution. The quantity of catalytically active tryptase per mast cell (10-35 pg) (95) is extraordinarily high. What regulates tryptase activity after its release into the extracellular milieu is uncertain. because the
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Table 1 Characteristics of Immllnoassays for Different Forms of H U1l1all Tryptase Measured in Serum
Clinical condition Normal Systemic anaphylaxis (within 4 h or onset) Systemic mastocytosis (nonacule interval)
Mature tryptase (ng/ml)
Total tryptase
J-15ng/ml ::::2 rolel
::::20 ng/ml
Total/mature tryptase ratio
:'CIa
enzyme is resistant to classical biological inhibitors of serine proteases (96). Slow down regulation may occur at neutral pH when basic proteins such as antithrombin III displace f3-tryptase from heparin (96), resulting in the formation of inactive monomers. Active tetramers can reform at acidic pH in the presence of heparin (97). Another related observation is that f3-tryptase degrades fibrinogen ~50-fold faster at pH 6 than at 7.4 (98). Release of 13tryptase at sites of acidic pH (airway mucosal surface, foci of innammation and areas of poor vascularity, such as solid tumor margins and wound healing sites), might be optimal for the enzyme, while diffusion away from such sites would result in reduced proteolytic activity Such a mechanism would tend to limit the activity of f3-tryptase to its local tissue site of release. d. Biological Activities of T'TPtase. The biological activities of enzymatically active tryptase are not obvious from the involvement of mast cells in atopic diseases. Many potentially relevant substrate(s) have been identified in vitro. Predicted biological outcomes include anticoagulation, fibrosis vs. fibrolysis, kinin generation vs. destruction, cell surface PAR-2 activation, enhancement of vasopermeability, angiogenesis, inflammation, and airway smooth muscle hyperreactivity. Showing the importance of these potential activities In vivo remains a challenge. Studies on mice showed that the num bel's of neutrophils increased> J OO-fold when enzymatically active f3-tryptase was instilled into the lungs (99). The emerging availability of pharmacological inhibitors of tryptase and preliminary studies in animals may facilitate identification of the most important biological substrates (JOO,IOI).
2.
Chymase
Chymase, located on human chromosome 14. is one of two principal enzymes accounting for the chymotrypsinlike activity in human cutaneous mast cells (102,103). Chymase was selectively localized to a subpopulation
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of mast cells named MC TC cells (104,105). Dispersed skin-derived MC TC cells contain ~4.5 pg chymase/mast cell Human chymase is a monomer of 30,000 daltons whose crystal structure has been identified (106). Similar to tryptase, chymase is a serine esterase that is stored fully active in mast cell secretory granules, presumably bound to proteoglycan. Heparin facilitates processing of prochymase to active chymase by dipeptidyl peptidase I (107), and either attracts or repulses potential chymase substrates based on ionic forces (l08). Unlike tryptase, chymase stability is not substantially affected by heparin and its activity is inhibited by classical biological inhibitors of serine proteinases, such as O'j-antichymotrypsin, O't-proteinase inhibitor, and O'rmacroglobulin (109). Neither chymotrypsinlike enzymatic activity nor chymase mRNA was detected in lung-derived MC T cells (l10). Potential biological activities of chymase, like those of tryptase, are based on in vitro observations. Chymase is a potent activator of angiotensin I, inactivates bradykinin and PAR-I receptors, stimulates mucus production and leukocyte recruitment, processes procollagen to collagen fibrils, clea ves Kit from the cell surface, and attacks the lamina lucida of the basement membrane at the dermalepidermal junction of human skin.
3.
Cathepsin G
Human mast cell cathepsin G, like chymase, is a serine-class neutral protease with chymotryptic substrate specificity that is found in mast cells as well as in neutrophils and monocytes. The enzyme resides with chymase in MC TC cells (Ill) and exhibits a molecular weight of 30,000. Like chymase, it stimulates glandular secretions (112), which is of possible importance in allergic asthma and rhinitis.
4.
Mast Cell Carboxypeptidase
Human mast cell carboxypeptidase, a zinc-dependent exopeptidase, resides with chymase and cathepsin G in secretory granules of MC TC cells (l13). Stored fully active, when released it cleaves the carboxy terminal His 9-Leu 10 bond of angiotensin 1. Human mast cells dispersed from skin contain 5-16 pg carboxypeptidase/cell Human mast cell carboxypeptidase is a monomer with a molecular weight of 34,500 (114) and substrate specificity for carboxy terminal Phe and Leu residues.
5.
Other Proteases and Enzymes
Tissue-type plasminogen activator has been identified in tissue-derived mast cells (115), potentially complementing mast cell anti thrombotic and
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anticoagulant activities with the fibrinolytic properties of this protease. Matrix metalloproteinase-9, a gelatinase, has been identified in cord-bloodderived mast cells (] 16). Mast cells also concentrate various acid hydrolases in their secretory granules, perhaps reflecting the lysosomal origin of this organelle, including [J-galactosidase, aryl sulfatase, and [J-hexosaminidase, the latter enzyme serving as a marker to evaluate degranulation of dispersed preparations of mast cells (83).
D.
Lipids
Human mast cells dispersed and purified from lung incorporate exogenous arachidonic acid into neutral lipids and phospholipids, and store these lipids in membranes and cytoplasmic lipid bodies. Liberation of the arachidonic acid destined for oxidative metabolism, as shown in mice, is dependent upon cytosolic phospholipase A 2 (117). In general, oxidation of arachidonic acid occurs through the cyclo-oxygenase (COX) pathways to prostaglandins (PGs) and thromboxanes (TXs), or the 5-,12-, or 15-lipoxygenase (LO) pathways to monohydroxyl fatty acids, leukotrienes (LTs) that include both LTB 4 and the sulfidopeptides LTC 4 , LT0 4 , and LTE 4 [sLol1' reacting substances of anaphyLaxis (SRS-A)], and lipoxins. Platelet-activating factor is made by acetylating the Iysophospholipid remaining after arachidonic acid departs, but may not be a major secretory product of human mast cells and basophils. Dispersed and purified preparations of human mast cells obtained from lung, skin, and intestine, upon activation, produce PGD 2 (PGO synthase-dependent). LTC 4 (LTC synthase-dependent) is preferen tially produced by lung-derived rather than skin-derived mast cells. Smaller amounts of LTB 4 isomers are also produced by mast cells. In contrast, peripheral blood basophils, when activated, synthesize LTC4 , but not PG0 2 . However, cells other than mast cells and basophils produce PGD 2 (e.g., platelets and certain antigen-presenting cells) and LTC 4 (e.g., eosinophils). Thus, when these products are detected in a complex biological milieu, there may be ambiguity as to their cell source. Also, both leukotriene and prostaglandin production by activated mast cells can be blocked or augmented independently of granule mediators and cytokines. The biological importance of mast cell-derived products of arachidonic acid gained support with the advent of inhibitors of 5-lipoxygenase and the cysLTl receptor (118) for LT0 4 , both of which are helpful in atopic and in aspirin-induced asthma (J ]9); each condition also involves activation of mast cells and eosinophils. The importance of PG0 2 production in anaphylaxis was suggested when administration of aspirin inhibited generation of a urinary PGD 2 metabolite in patients with mastocytosis
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with recurrent hypotensive episodes and led to their clinical improvement (120).
E.
Cytokines and Chemokines
Human mast cells and basophils, when activated, produce a diverse array of cytokines and chemokines. These include TNF-O', IL-3, 4,5,6,8,10,13, and 16, Iymphotactin, MCP-1. TGF$I, MIP-10', and nerve growth factor (I21) by mast cells, and at least IL-4 and 13 by basophils. Although IL-25 is expressed in murine bone marrow-derived mast cells (122), its expression in human mast cell remains to be investigated. Cytokines are typically newly generated, being released hours after mast cells or basophils are activated. However, in some cases [e.g. TNF-O' and IL-8 (123)], cytokines also may be stored in secretory granules and released with other preformed mediators. Mast cells are a dominant IL-4+ cell in allergic nasal mucosa (124), and basophils in allergen-challenged peripheral blood cells (125). When mast cells reside in secondary lymphoid tissue, these cytokines might influence immunity, while in tissues they may serve to recruit and activate other cell types, thereby amplifying the host response during immediate hypersensitivity events.
V.
BIOLOGY AND PATHOBIOLOGY OF HUMAN MAST CELLS
A.
Clinical Markers of Mast Cells and Basophils
The involvement of mast cells and basophils in human diseases can be addressed in terms of both cell numbers and cell activation. Antibodies developed against cell-specific surface or granule components provide an immunohistological means for detecting these cells in tissues with greater sensitivity and specificity than classic dye-based histological stains. Moreover, immunoassays for mast cell-specific, releasable, and preformed granule mediators provide a precise measure of either local or systemic mast cell activation. The most selective surface marker phenotype [or all human mast cells is the coexpression of high levels of Kit and FcsRL This pattern can be readily demonstrated on dispersed mast cells by flow cytometry, but is technically more difficult to perform on tissue sections by immunohistochemistry. Tryptase is a granule marker selective for all human mast cells: the> J OO-fold smaller amounts present in basophils typically provide an adequate differcntial for differentiating these two cell types from each other. Monoclonal antibodies against chymase and mast cell carboxypeptidase serve to identify the MeTe type of mast cell, because no other cell type
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appears to express these products in sufficient quantity to be confused with mast cells. No specific marker for the MeT type of mast cell has been identified. Two immunoassays for human a/f3 tryptases are used clinically (Table I). One recognizes total tryptase levels (pro, pro!, and mature forms) using the B12 mAb for capture and the G4 mAb for detection. The other recognizes mature tryptase (predominantly if not exclusively f3-tryptase) using BI2 mAb for capture and G5 mAb for detection. Because immature forms of tryptase are spontaneously secreted by mast cells, while mature forms are stored in secretory granules until the cells are activated to degranulate, mature tryptase levels renect mast cell activation events, while total tryptase levels renect the burden of mast cells when mast cells are otherwise quiescent. Normal levels of total tryptase range [rom I to 15 ng/ml, while those for mature tryptase are less than 13ng/ml. Although an FCeRI+/KiC surface phenotype or FCeRI+jtryptasesurface/granule phenotype has been considered selectively to represent basophils, the abilities of activated monocytes, eosinophils, and antigenpresenting cells such as Langerhans cells to express FCeRI in its aY2 form make this phenotype problematic, particularly at sites o[ innammation (126). Two monoclonal anti bodies (127,128) that recognize componen ts of basophil secretory granules but do not label other cell types, including mast cells and eosinophils, identify basophils in tissues by immunohistochemistry. They are 207 antigen and basogranin, and may lead to the development of precise assays for assessing basophil activation that occurs in vivo. Immunocytochemistry has identified basophils in late cutaneous (129,130) and respiratory (130-132) allergic responses. In respiratory tissues, double-labeling techniques have shown basophils to be major IL-4producing cells. Following are discussions of mast cells and basophils in anaphylaxis, mastocytosis, and cutaneous allergic diseases.
B.
Systemic Anaphylaxis
Mature tryptase levels in serum or plasma are elevated in most subjects with systemic anaphylaxis of sufficient severity to result in hypotension (133). 13- Tryptase is released from mast cells in parallel with histamine (83). but diffuses more slowly than histamine, presumably due to its association with the macromolecular protease/proteoglycan complex. During insect sting-induced anaphylaxis, mature tryptase levels in the circulation are maximal 15-120 min after the sting, while histamine levels peak at about 5min and decline to baseline by 15-30min (134,135). Peak mature tryptase levels decline with a half-life of 1.5-2.5 h. The practical consequence of
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these different time courses is that plasma samples for histamine levels must be obtained within 15 min of the onset of such reactions, whereas those for mature tryptase levels can be obtained up to several hours after the reaction begins, depending on its severity. In insect-sting-induced systemic anaphylaxis, the ratios of total tryptase to mature tryptase were less than 6 in 16 of 17 subjects and 23 in the one outlier (J 36). Thus, when mature tryptase is detectable in serum, a total/mature tryptase ratio of .:510 favors systemic anaphylaxis. Elevated mature tryptase levels, implicating mast cell activation, also have been reported in anaphylactic reactions to cyclo-oxygenase inhibi tors (134,137), anesthetics (138), and COX inhibitors (139). Mature tryptase levels in postmortem serum also are elevated in many cases of fatal systemic anaphylaxis (140). In one study, elevated levels (> 10 ng/ml) appeared in 9 of 9 after Hymenoptera stings, 6 of 8 after food, and 2 of 2, in response to parenteral diagnostic/therapeutic agents. Levels were <5ng/ml in 57 sequential sera collected postmortem from six control subjects. In general, tryptase levels were dramatically higher after parenteral rather than oral introduction of the allergen, in spite of a fatal outcome in each case. ]n cases of clinically diagnosed anaphylaxis with a normal level of mature tryptase, as has been observed with foods, explanations to consider may include local reactions (e.g., laryngeal edema), distinct mast cell populations (e.g., intestinal mucosa), or non-mast-cell-dependent mechanisms such as basophil activation or complement anaphylatoxin generation. In all cases, a careful consideration of the clinical events should occur before making a final diagnosis.
C.
Systemic Mastocytosis
Systemic mastocytosis is associated with mast cell hyperplasia in skin lesions (urticaria pigmentosa), liver, spleen, lymph nodes, and bone marrow (14 I). The disorder is subdivided into indolent mastocytosis (local or systemic), systemic mastocytosis associated with a hematological disorder, and aggressive systemic mastocytosis (142). Activating mutations of Kit appear to be associated with systemic or persistent disease (18,143). The gold standard for the diagnosis of mastocytosis is a tissue biopsy showing a pathological increase in the number of mast cells (144). However, in skin there is no precise mast cell concentration that defines cutaneous mastocytosis. In bone marrow biopsies, paratrabecular collections of spindle-shaped mast cells intermixed with fibroblasts, mononuclear cells, and eosinophils are characteristic of systemic mastocytosis (141,1 45). Tryptase immunostaining may provide a more sensitive and specific marker of mastocytosis in bone marrow and perhaps skin biopsy specimens
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than classic histochemical or histoenzymatic stains (146). However, characteristic lesions in the bone marrow are not always evident. In studies of tryptase levels in subjects with biopsy-diagnosed mastocytosis, most of those with systemic disease have levels of total tryptase >20 ng/ml and ratios of total tryptase to mature tryptase >20 (147,148). Those with urticaria pigmentosa alone typically have n0n11al total tryptase levels. However, urticaria pigmentosa can be an early manifestation of what is to become systemic disease, presenting with a normal bone marrow biopsy and total tryptase level, but progressing to a positive biopsy result and an elevated total tryptase levels (149). In addition, bone marrow mastocytosis mast cells exhibit a CD25+/CD2+ surface phenotype not seen on normal mast cells (150). The appearance of such cells in bone marrow aspirates may occur even before characteristic mastocytosis granuloma appear in bone marrow biopsies or eleva ted total tryptase levels in blood. Anaphylactic or anaphylactoid reactions may be a presenting manifestation of systemic mastocytosis. For example, in subjects who experienced anaphylaxis to insect stings, but were later found to be without venom-specific IgE, elevated total tryptase levels were found that suggested underlying mastocytosis that predisposed them to these anaphylactoid reactions (15 I, I 52). A previous report of tryptase levels in experimental insect-sting-induced anaphylaxis found a total tryptase level > 10 ng/ml prior to the sting challenge in 5 of the 17 subjects who later developed severe anaphylactic reactions with higher acute levels of mature-tryptase (136). These elevated baseline levels varied from] I to 18 ng/ml. Whether tryptase levels in this range will prove to be an important risk factor for severe anaphylaxis needs further evaluation.
D.
Cutaneous Allergic Reactions
In studies of cutaneous allergic reactions using the skin chamber system, histamine levels are maximal by 30 min after allergen challenge and mature tryptase at about 60 min (153). Because degranulation releases mature tryptase and histamine simultaneously, this delayed appearance of mature tryptase most likely reflects its slower diffusion through the cutaneous tissue. If the allergen challenge is interrupted by replacement of the fluid with buffer alone after the first hour, mature tryptase and histamine levels decline back to unstimulated levels within 4 h in spite of an influx of leukocytes, including basophils, after the first hour. Of clinical interest is the observation that grass pollen immunotherapy administered to sensitive subjects results in declines both in skin test reactivity and cutaneous mast cell concentrations (154).
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A clinically apparent late response along with a greater recruitment of inflammatory cells occurs with a continuous allergen challenge over several hours in the skin chamber system. Nevertheless, mature tryptase levels return to baseline as before (ISS). In contrast, histamine levels decline to a modestly elevated level after the first hour of allergen and remain elevated for at least 6 h of continuous challenge. Glucocorticosteroid pretreatment has no effect on mature tryptase and histamine levels during the immediate response to allergen nor on codeine-induced release of mature tryptase and histamine, but completely blocks the persistent appearance of histamine (156). Direct evidence to support basophil involvement was provided by collecting biopsies 6 h after allergen challenge and staining them with a basophil-specific monoclonal antibody (129,130). Basophils were abundant in and around blood vessels of antigen-challenged sites but not at bufferchallenged sites, even though few if any metachromatic cells were associated with these areas. The findings indicate that basophils enter these sites through blood vessels, encounter allergen and a chemokinejinterleukin rich environment, and are strongly activated. In contrast to urticaria induced by cutaneous allergen injection, most patients with idiopathic urticaria exhibit no concomitant late-phase reaction and a variable cellular infiltrate, which can resemble a late phase lesion. Mast cell hyperplasia at lesional si tes has been found in some (160, I63), but not in other (157) studies. In vivo, autoantibodies against Fcc:Rla (158) and against IgE (159) in subjects with idiopathic urticaria have been detected, suggesting an autoimmune etiology in some patients with this disorder (160). However, these autoantibodies alone do not explain the tissue specificity of these diseases for mast cells in skin. This in turn might be explained by complement anaphylatoxin generated at these sites by ceIlbound IgG, because C5a activates mast cells from skin, but not those [rom lung (16 I). Recent studies ha ve detected eosinophils, basophils, and T cells of a THO phenotype in chronic urticaria lesions (162). Taken together, these findings suggest an autoimmune process involving antibody, complement, and cytokines leading to activation of mast cells in the skin of many patients with chronic urticaria.
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lrani AM, Goldstein SM, Wintroub BU, Bradrord T, Schwartz LB. Human mast cell carboxypeptidase. Selective localization to MC Te cells . .1 Immunol 199J; 147(1)247-253. Goldstein SM, Kaempfer CE, Kealey .lT, Wintroub BU. Human mast cell carboxypeptidase. Purification and characterization . .l Clin Invest 1989; 83(5) l630-1636. Sillaber C, Baghestanian M, Bevec D, Willheim M, Agis H, Kapiotis S, et al. The mast cell as site of tissue-type plasminogen activator expression and fibrinolysis . .1 Immunol 1999; 162(2):1032-1041 Kanbe N, Tanaka A, Kanbe M, Itakura A, Kurosawa M, Matsuda H. Human mast cells produce matrix metalloproteinase 9. Eur .1 Immunol 1999; 29(8): 2645-2649 Fujishima H, Sanchez Mejia RO, Bingham CO, HI, Lam BK, Sapirstein A, Bonventre .lV, et al. Cytosolic phospholipase A2 is essential for both the immediate and the delayed phases of eicosanoid generation in mouse bone marrow-derived mast cells. Proc Natl Acad Sci USA 1999; 96(9):4803--4807. Lynch KR, O'Neill GP, Liu Q, 1m DS, Sawyer N. Metters KM, et al. Characterization of the human cysteinyl leukotriene CysLT I receptor. Nature 1999; 399(6738):789-793. Mita H, Endoh S. Kudoh M, Kawagishi Y, Kobayashi M, Taniguchi M. et al. Possible involvement of mast-cell activation in aspirin provocation of aspirin-induced asthma. Allergy 2001; 56(11):1061-1067. Roberts LJ, Sweetman BJ, Lewis RA, Austen KF, Oates JA. Increased production of prostaglandin D2 in patients with systemic mastocytosis. N Engl .l Med 1980; 303(24): 1400-1404. Xiang Z, Nilsson G. IgE receptor-media ted release of nerve growth faclor by mast cells. Clin Exp Allergy 2000: 30(10):1379-1386. Ikeda K, Nakajima H, Suzuki K, Kagami SI, Hirose K, Suto A, et al. Mast cells produce interleukin-25 upon FCcRI-mediated activation. Blood 2003; 10 I(9):3594-3596. Gibbs BF, Wierecky .1, Welker P, Henz BM, WolA' HH, Grabbe .l. Human skin mast cells rapidly release preformed and newly generated TNF-O' and lL-8 following stimulation with anti-IgE and other secretagogues. Exp Dermatol 2001; 10(5):312-320. Wang M, Saxon A, Diaz-Sanchez D. Early IL-4 production driving Th2 differentiation in a human in vivo allergic model is mast cell derived. C1in lmmunol 1999; 90(1):47-54. Devouassoux G, Foster B, Scott LM, Metcalfe DD, Prussin C. Frequency and characterization of antigen-specific I LA- and 1L-13- producing basophils and T cells in peripheral blood of healthy and asthmatic subjects . .1 Allergy C1in Iml11unol 1999; 104(4 Pt 1):811-819. Rajakulasingam K, Durham SR, O'Brien F, Humbert M, Barata LT, Reece L, et al. Enhanced expression of high-affinity IgE receptor (FccRI) alpha chain in human allergen-induced rhinitis with co-localization to mast cells, macrophages, eosinophils, and dendritic cells . .1 Allergy Clin Immunol1997; 100(1):78-86.
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Zhao and Schwartz Kepley CL, Craig SS, Schwartz LB. Identification and partial characterization of a unique marker for human basophils. J Immunol 1995; 154( 12)6548-6555. McEuen AR, Buckley MG, Compton SJ, Walls AF. Development and characterization of a monoclonal antibody specific for human basophils and the identification of a unique secretory product of basophil activation. Lab Invest 1999; 79( I):27-38. Irani AM, Huang C, Xia HZ, Kepley C, Nafie A, Fouda ED, et a!. Immunohistochemical detection of human basophils 111 late-phase skin reactions. J Allergy Clin Immunol 1998; 101(3):354-362. Macfarlane AJ, Kon OM, Smith SJ, Zeibecoglou K, Khan LN. Barata LT, et a!. Basophils, eosinophils, and mast cells in atopic and nona topic asthma and in late-phase allergic reactions in the lung and skin. J Allergy Clin Immunol2000; 105(1 Pt 1):99-107. NOLll'i-Aria KT, Irani AM, Jacobson MR, O'Brien F, Varga EM, Till SJ, et a!. Basophil recruitment and IL-4 production during human allergen-induced late asthma J Allergy C1in Immunol 2001; 108(2):205-211. Wilson DR. Irani AM, Walker SM, Jacobson MR, Mackay IS. Schwartz LB, et a!. Grass pollen immunotherapy inhibits seasonal increases in basophils and eosinophils in the nasal epithelium. Clin Exp Allergy 200 I; 31(11):1705-1713. Schwartz LB, Metcalfe DO, Miller JS, Earl H, Sullivan T. Tryptase levels as an indicator of mast-cell activation in systemic anaphylaxis and mastocytosis. N Engl J Med 1987; 316(26)1622-1626. Schwartz LB, Yunginger JW, Miller J, Bokhari R, Dull D. Time course of appearance and disappearance of human mast cell tryptase in the circulation after anaphylaxis. J Clin Invest 1989; 83(5): 1551-1555. Van der Linden PW, Hack CE, Poortman J, Vivie-Kipp YC, Struyvenberg A. Van der Zwan JK. Insect-sting challenge in 138 patients: relation between clinical severity of anaphylaxis and mast cell activation. J Allergy Clin Immunol 1992; 90(1):110-118. Schwartz LB, Bradford TR. Rouse C, Irani AM, Rasp G, Van der Zwan JK. et a!. Development of a new. more sensitive immunoassay for human tryptase: use in systemic anaphylaxis. J Clin Immunol 1994; 14(3): 190-204. Silvers WS, Essember LJ. Williams PB, Selner Jc. Dolen WK. Anaphylaxis due lo diclofenac sodium (Voltaren): evidence of mast cell mediator release. Immunol Allergy Pract 1991; 13:193 196. Fisher M M, Baldo BA. Mast cell tryplase in anaesthetic anaphylactoid reactions. Br J Anaesth 1998; 80( I):26-29. Ordoqui E. Zubcldia JM, Aranzabal A, Rubio M, Herrero T, Tornero P, et al. Serum tryplasc levels in adverse drug reactions Allergy 1997; 52( II): 1102-1105. Yunginger JW, Nelson DR, Squillace DL. Jones RT. Holley KE. Hyma BA. et al. Laboratory investigation of deaths due to anaphylaxis. J Forensic Sci 1991.36(3)857-865
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Travis WD, Li CY, Bergstralh EJ, Yam LT, Swee RG. Systemic mast cell disease. Analysis of 58 cases and literature review. Medicine (Baltimore) 1988; 67(6)345-368. Metcalfe DD. Classification and diagnosis of mastocytosis: current status. J In vest Derma tol 1991; 96(3 ):2S-4S. Longley BJ, Tyrrell L, Lu SZ, Ma YS, Langley K, Ding TG, et al. Somatic c-KIT activating mutation in urticaria pigmentosa and aggressive mastocytosis: establishment of clonality in a human mast cell neoplasm. Nat Genet 1996; 12(3):312-314. Valent P, Horny HP, Escribano L, Longley BJ, Li CY, Schwartz LB, et al. Diagnostic criteria and classification of mastocytosis: a consensus proposal. Leuk Res 200 I; 25(7)603-625 Kettelhut BV, Parker RI, Travis WD. Metcalfe DD. Hematopathology of the bone marrow in pediatric cutaneous mastocytosis. A study of 17 patients. Am J Clin Pathol 1989; 91(5):558-562. Horny HP, Sillaber C, Menke D. Kaiserling E, Wehrmann M, Stehberger B, et al. Diagnostic value of immunostaining for tryptase in patients with mastocytosis. Am J Surg Pathol 1998; 22(9)1132-1140. Schwartz LB, Sakai K, Bradford TR, Ren S, Zweiman B, Worobec AS, et al. The alpha form of human tryptase is the predominant type present in blood at baseline in normal subjects and is elevated in those with systemic mastocytosis. J Clin Invest 1995; 96(6):2702-2710. Sperr WR, Jordan JH, Fiegl M, Escribano L, Bellas C. Dirnhofer S, et al. Serum tryptase levels in patients with mastocytosis: correlation with mast cell burden and implication [or defining the category of disease. Int Arch Allergy lmmunol 2002; 128(2):136-141. Noack F, Escribano L, Sotlar K, Nunez R, Schuetze K, Valent P, et al. Evolution of urticaria pigmemosa into indolent systemic mastocytosis: abnormal immunophenotype of mast cells without evidence of c-kit mutation ASP-816- VAL Leuk Lymphoma 2003; 44(2):313-319. Escribano L, Orfao A, Diaz-Agustin B. Villarrubia J. Cervero C. Lopez A, et al. Indolent systemic mast cell disease in adults: immunophenotypic characterization of bone marrow mast cells and its diagnostic implications. Blood 1998; 91 (8)2731-2736. Kors JW, van Doormaal JJ, de Monchy JG. Anaphylactoid shock following Hymenoptera sting as a presenting symptom of systemic mastocytosis. J Intern Med 1993; 233(3):255-258. Fricker M, Helbling A, Schwartz L, Muller U. Hymenoptera sting anaphylaxis and urticaria pigmentosa: clinical findings and results of venom immunotherapy in ten patients. J Allergy Clin Immunol 1997; 100( I): I I-IS. Schwartz LB. Atkins Pc. Bradford TR, Fleekop P. Shalit M, Zweill1an B. Release of tryptase together with histamine during the immediate cutaneous response to allergen. J Allergy Clin IIllll1Unol 1987; 80(6): 850-855
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Zhao and Schwartz Durham SR, Varney VA, Gaga M, Jacobson MR, Varga EM, Frew AJ, et al. Grass pollen immunotherapy decreases the number of mast cells in the skin. C1in Exp Allergy 1999: ~9(11):1490-1496. Shaht M, Schwartz LB, Golzar N, vonAliman C, Valenzano M, Fleekop P, et al. Release of histamine and tryptase in vivo after prolonged cutaneous challenge with allergen in humans. J [l11munol 1988: 141(3):821-826. Shalit M, Schwartz LB, von Allmen C, Atkins PC, Lavker RM, Zweiman B. Release of histamine and tryptase during continuous and interrupted cutaneous challenge with allergen in humans. J Allergy Clin [mmunol 1990: 86(1)117-125. Smith CH, Kepley C. Schwartz LB, Lee TH. Mast cell number and phenotype in chronic idiopathic urticaria. J Allergy C1in [ml11unol 1995: 96(3):360-364. Hide M, Francis DM, Grattan CE, Hakimi J, Kochan JP, Greaves MW. Autoantibodies against the high-affinity JgE receptor as a cause of histamine release in chronic urticaria. N Engl J Med 1993: 328(22):1599-1604. Gruber BL. Baeza ML, Marchese MJ, Agnello V, Kaplan AP. Prevalence and functional role of anti-lgE autoantibodies in urticarial syndromes. J Invest Dermatol 1988: 90(2):213-217 Sabroe RA. Fiebiger E, Francis DM, Maurer D. Seed PT, Grattan CEo et al. Classification of anti-FcepsiionRI and anti-lgE autoantibodies in chronic idiopathic urticaria and correlation with disease severity. J Allergy C1in [l1lmunol 2002: 110(3):492-499. Ferrer M, Nakazawa K, Kaplan AP. Complement dependence of histamine release in chronic urticaria. J Allergy Clin Immunol 1999: 104(1):169-172 Ying S, Kikuchi Y, Meng Q, Kay AB, Kaplan AP. THljTH2 cytokines and inflammatory cells in skin biopsy specimens from patients with chronic idiopathic urticaria: comparison with the allergen-induced late-phase cutaneous reaction. J Allergy Clin [ml1lunol 200~: 109(4):694-700. Natbony SF, Phillips ME, Elias JM, GodCrey HP, Kaplan AP. Histologic studies 01' chronic idiop~llhic urticaria. J Allergy Clin Immunol 1983;71: 177-183 Schwartz LB, Min HK, Ren S. Xia HZ, Hu.l. Zhao W. Moxley G. Fukuoka Y. Tryptasc precursors are preCerentially and spontaneously released, whereas mature tryptase is retained by H MC-I cells, Mono-Mac-6 cells. and human skin-derived mast cells .I [mmuno 2003: 170:5667-5673.
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3 Mechanisms of Bradykinin Formation Allen P. Kaplan Medical University of South Carolina, Charleston, South Carolina, U.S.A.
I.
INTRODUCTION
The plasma kinin-forming system consists of three essential proteins that interact in a complex fashion once bound to certain negatively charged inorganic surfaces, or to a macromolecular complex formed during an inflammatory response, or bound to proteins along cell surfaces. These are coagulation factor XII (Hageman factor, HF), prekallikrein, and highmolecular-weight kininogen (HK). Once factor XII is activated to factor XUa it converts prekallikrein to kallikrein and kallikrein digests HK to liberate bradykinin. Factor Xiia has a second substrate in plasma; namely, coagulation factor XI and activation of surface bound factor XI by factor Xiia initiates the intrinsic coagulation pathway. Thus the interactions of all four of these proteins are known as contact activation and the formation of bradykinin is therefore a cleavage product of the initiating step of the cascade (Fig. I) (I). There is also a tissue pathway (2) by which bradykinin is generated in which there is intracellular conversion of prokallikrein to tissue kallikrein by enzymes that are not yet well characterized. Tissue kallikrein is secreted into the local milien where it digests low-molecular-weight kininogen (LK) to generate Iysyl-bradykinin (kallidin) and an aminopeptidase converts kallidin to bradykinin. The bradykinin that is produced by either pathway is then degraded by plasma enzymes as well as enzymes that are active along the surface of endothelial cells (particularly pulmonary vascular endothelial cells) to lower-molecular-weight peptides. The major
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51
Kaplan
52 [ Factor XI
I Factor XII I·
I.,."
~~ ~
..
'moo, " -Intrinsic Coagulation Pathway
idt!tl:jlN
~~JIH:Hn:Hj9 'IWIii%' .......- . . . . . . 'HMW
K"'i"og~
B"'yKim"
- -'
c~
-:0,
Vasodilation ... Hypotensive action .. Pain ...
Figure 1 The contact activation pathway leading to bradykinin formation. (From Silverberg M, Reddigari SR, Kaplan AP. The contact system and its disorders. In: Handin SI, Lux S, Stossel TP, eds. Blood, Principles and Practice. Chapter 38, Philadelphia Lippincott, 1995: 1127-1150.)
plasma enzyme is carboxypeptidase N (3). This removes the C-terminal arginine from bradykinin to yield an eight amino acid peptide (des-arg-9 bradykinin) (4). The second kininase in plasma is termed kininase II and is identical to angiotensin-converting enzyme (5). Thus is this enzyme that predominates along the pulmonary vascular endothelial cell surface. Bradykinin is thereby rapidly degraded within one or two circulation times. This enzyme removes the dipeptide phe-arg from the C-terminus of bradykinin to yield a heptapeptide and a second cleavage removes ser-pro to leave a penta peptide (6). Bradykinin acls on the B2 receptor on the surface of endothelial cells to cause vasodilatation and to increase vascular permeability. Other vasodilators such as nitric oxide are produced secondarily as a result of a B2 receptor stimulation (7). Des-arg-9 bradykinin, the product of carboxypeptidase N, is predominantly active upon BI receptors (8). These latter receptors, in contrast to B2 receptors, are not consititively produced but are induced as a result of inflammation due to the presence of cytokines such as interleukin I and tumor neurosis factor-a (TNF a) (8,9). The heptapeptide and pentapeptide products of kininase II (ACl) are inactive. A schematic diagram of the formation and degradation of bradykinin is shown in Fig. 2. Table I summarizes some of major physical chemical properties of the various proteins of the contact activation cascade.
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Bradykinin Formation
53 Surfacc
Tissuc Kallikrein
Faclor XII, Prekililikrein, HK
j LK - - . Lys-Bradykinill
Plasma Kallikrein
1aminopeptidase
/
Bradykinin. KininJse I
/
"~
./
Des arg 9-bradykinill
Kinin:JSc" (ACE)
Arg pro pro gly pile scr pro + pile arg
1
1
Kininasc 2 (ACE)
Arg pro pro gly pile
-I-
1-1 K
ACE
ser pro pile
Arg pro pro gly pile + ser pro
Figure 2 Pathways for formation and degradation of bradykinin.
Table 1
Physiochemical Properties of Proteins of the Contact Activation Cascade
Protein Molecular weight (daltons; calculated) Carbohydrate (w/w; %) lsoelectric point Extinction coefficient (E 1% 280/nrn) Plasma concen tra tion (mg/ml) nrnol/L (average)
II.
Factor XII
Prekallikrein
Factor XI
HK
80A27
79,545
140,000
116,643
16.8 6.3 14.2
15 87 11.7
5 86 13.4
40 4.7 70
30-45
35-50
4-6
70-90
400
534
36
686
FACTOR XII
Factor XII circulates as a single-chain zymagen that is devoid of enzymatic activity. It has a molecular weight of approximately 80,000 on sodium dodecyl sulfate (SDS) gel electrophoresis, is synthesized in the liver, and circulates in the plasma at a concentration of 30-35IlgjmJ. lts primary sequence has been deduced from cDNA analysis and from direct protein sequence data (10,11). It has distinct domains analogous to fibronectin, plasminogen, and plasminogen activators at its N terminal end whereas the C terminus has the catalytic domain. This latter domain is homologous to serine proteases such as pancreatic trypsin and even more so to the catalytic
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Kaplan
domain of plasminogen activators. Factor XII is capable of autoactivating once it is bound to initiating surfaces (12) as a result of a conformational change that renders bound factor XII to become a substrate for factor XIIa (13). The source of the initiating molecules of factor XJIa is uncertain; however, it is assumed that trace quantities of factor XIIa are present and that the amount is far less than the limit of detection. The alternative, that uncleaved native factor Xll possesses some minute amount of enzymatic activity, seems less likely. Activation of factor XII is due to a cleavage at a critical arg-val bond contained within a disulfide bridge such that the resultant factor XIIa is a two-chain disulfide-linked 80 Kd enzyme consisting of a heavy chain of SO Kd and light of 28 Kd (14) The light chain contains the active site and is located at the C-terminal end, whereas the heavy chain contains the binding site for the surface at the amino terminal end (IS). Further cleavage can occur at the C-terminal end of the heavy chain to produce a series of fragments of activated factor XlI, which retain enzymatic activity (16). The most prominent of these is a 30 Kd species termed factor XIIf (17). Careful examination of factor XIIf on SDS gels under nonreducing conditions reveals a doublet in which the higher band at 30 Kd is gradually converted to the lower band, which has a molecular weight of 28.5 Kd (18). Reduced gels demonstrate that these species consist of the light chain of factor XIla disulfide-linked to a small peptide derived from the C-terminus of the heavy chain. These fragments lack the ability to bind to the surface and therefore are unable to convert factor XI to XIa (which requires interaction at the surface) but continue to be potent \.. activators of prekallikrein. Thus formation of factor XIIf allows bradykinin production to continue in the fluid phase until the enzyme is inactivated and the reactions can therefore proceed at sites distant from the initiating surface. This may be important for bradykinin formation in diseases such as Clinhibitor deficiency. in which the inhibitor of factor XUa and factor XIIf is absent or dysfunctional. A diagrammatic representation of these various steps in factor XII activation is shown in Fig. 3. Once factor XUa interacts with prekaJIikrein to generate the enzyme kallikrein, there follows an important positive feedback in which kallikrein digests surface bound factor XII rapidly to form factor XlIa and then factor XUf (19,20,21) This reaction is far more rapid than the initiating autoactivation reaction, thus there is a reciprocal reaction involving these two constituents: the initial small amount of factor XIIa formed by autoactivation converts prekallikrein to kallikrein and kallikrein digests the residual factor XII to factor Xlla. The slower activation of this cascade dependent upon autoactivation can be demonstrated in plasma that is congenitally deficient in prekallikrein (Fletcher trait), which cannot generate any kallikrein or bradykinin (20).
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55
Factor Xlla
Factor XII zymogen
Factor XIII (1)
Factor XIII (2)
HOOC
Hoac
Figure 3
Diagrammatic representation of the sequential cleavages occurring in factor Xiia leading initially to factor XIla, followed by cleavages external to the disulfide bridge to form factor XlIf (I) and factor Xllf (2). Note the C-terminal portion of the heavy chain disulfide-linked to the light chain. (From Silverberg M, Reddigari SR, Kaplan AP. The contacl system and its disorders. In: Handin SJ, Lux S, Stossel TP, eds. Blood. Principles and Practice. Chapter 38, Philadelphia: Lippincott 1995:1127-1150.)
Coagulation (i.e., conversion of factor Xl 10 factor Xla by factor Xlla) does proceed, albeit at a much slower rate, and the partial thromboplastin time (PTT) can be shown to shorten progressively as the time of incubation of the plasma with the surface is increased prior to recalcification. This appears due to progressive factor Xlla autoactivation as the incubation time with the surface is increased. As more and more factor XUa forms, the rate of factor XI activation increases and the PTT approaches normal. The difference in PTT with short incubation times between normal plasma and prekallikrein-deficient plasma is due to the absence of the feedback activation of factor XII by kallikrein.
III.
PREKALLIKREIN
Prekallikrein is also a circulating proenzyme, which requires proteolytic cleavage to generate an active protease. On SDS gels it has two bands at
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56
88 and 85 Kd and the heterogeneity observed is not reflected in its amino acid sequence (22). Thus it appears likely to be due to two variant glycosylated forms present in everyone. It is secreted with a signal peptide of 19 residues, which is removed prior to secretion. The mature plasma prekallikrein has 619 amino acids with a calculated molecular weight of 69,710 including J 5% carbohydrate (23). Activation of prekallikrein by factor XlIa or factor XIIf is the result of cleavage of a single arg-Ile bond within a disulfide bridge such that a heavy chain 56 Kd is disulfide-linked to light chains of either 33 Kd or 36 Kd, reflecting the heterogeneity within the two forms of the zymogen. Thus the heterogeneity is reflected in the light chain and the light chain also contains the active site of the enzyme (22). The amino acid sequence of the kallikrein heavy chain is unusual and homologous only to the corresponding portion of factor XI. It has four tandem repeats, each of which contains 90~91 amino acids (23). The presence of six cysteines per repeat suggests that each repeat contains three disulfide loops. The gene coding for this ancestral structure may have duplicated and then the en ti re segmen ted d uplica ted once again to create the four tandem repeats. The light chain containing the active site is homologous to the catalytic domains of many other enzymes of the coagulation cascade. Prekallikrein circulates in plasma bound to HK in a l: I bimolecular complex (24) through a site contained in the heavy chain. The binding is firm with a disassociation constant of 12-15 nM, which is unchanged upon conversion of prekallikrein to kallikrein (24,25). It has been shown that 80-90% of prekallikrein is normally complexed in this way and it is the prekallikreinjHK complex that binds to surfaces during contact activation. That binding occurs primarily through HK. The disassociation of 10-20% of the kallikrein that forms along the surface may serve to propagate the formation of bradykinin in the fluid phase at sites distant from the initiating reaction (26,27).
IV.
FACTOR XI
Coagulation factor XI is an altcrnative substrate of factor Xlla: however. it has no role in bradykinin formation. Factor XI is unique among coagulation factors because the circulating zymogen consists of tlVO identical chains linked by disulfide bonds (28,29). This dimer has an apparent molecular weight of 160 Kd on SDS gel electrophoresis and is h::t1f that size when reduced. Faclor XI activation, like that of prekallikrein, requires a cleavage of a single arg-Ile bondlVithin a disull~de bridge lo yield 3n amino terminal heavy chain of 50 Kd and a disulfide-linkcd light chain of 33 Kd. Since both subunits can be activated, the active enzyme has two active sites each of Copyrighted Material
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Bradykinin Formation
which is located on a light chain. Factor XIla is therefore a four-chain protein with two active sites. Its concentration in plasma is only 4-8 ~lg/ml, which is among the lowest of the contact activation proteins, and its heavy chain, like that of prekallikrein, binds to the light chain of a high-molecularweight kininogen. Thus factor XI and HK also circulate as a complex (30). The disassociation constant of 70 nM is high enough to ensure that virtually all of factor Xl contained in plasma is complexed to HK. The molar ratio of the complex can consist of one or two molecules of HK per factor Xl because of the dimeric nature of factor Xl. The binding site for HK on factor Xl has been localized to the first of the four tandem repeats contained within the factor Xl heavy chain. The factor XI/HK complex binds to surfaces by the HK moiety and conversion to factor Xla occurs as a resul t of cleavage by factor XIIa or by thrombin (3 I ,32). Factor XIlf has only 2-4% of the activity of factor Xlia (16), thus factor XIU remains a potent activator of prekallikrein but has little impact on the coagulation pathway. The primary function of factor Xla is to activate factor IX to factor IXa, which is the first calcium-dependent reaction in the intrinsic coagulation cascade. The amino acid seq uence of factor X I is closely homologous to that of prekallikrein (33). It also has a 19 amino acid leader peptide, which is cleaved to yield a protein of 607 amino acids contained in each of the two chains of the mature protein. The heavy chain of factor Xla has four tandem repeats of approximately 90 amino acids each with 6 cysteines, implying 3 double bonds per repeat as is seen in prekallikrein. However, unpaired cysteines in the first and fourth repeats are postulated to form the interchain disulfide bridges between monomers to produce the homodimer.
V.
HIGH-MOLECULAR-WEIGHT KININOGEN
HK circulates in plasma as 115 Kd nonenzymatic glycoprotein with a concentration of 70-90 pg/ml (24,34). Its apparent molecular weight by gel filtration is approximately 200,000, indicating a large partial specific volume resulting from its conformation in solution. It forms noncovalent complexes with both prekallikrein and factor Xl as indicated above. There is sufficient HK in plasma theoretically to bind both factor XIJa substrates leaving 10-20% of circulating HK uncomplexed. The attachment of prekallikrein or factor XI to HK occurs within the e-terminal region of HK, corresponding to the light chain that results after cleavage to release bradykinin (24,25,35,36). The isolated light chain (after reduction and alkylation) derived from cleaved HK possesses the same binding characteristics as the whole molecule. HK therefore functions as a coagulation co-factor and this activity resides in the light chain (35-37). Within that light chain there is a
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basic histidine-rich N-terminal domain that binds to initiating surfaces and a carboxy-terminal domain that binds prekallikrein or factor Xl. The single cysteine within the light chain forms the disulfide bridge that links it to the heavy chain. The kallikrein binding site maps to residues 194-224 and the factor XI binding site maps to residues 185-252 (36,38). Since these sites overlap, one molecule of H K can interact with one molecule of prekallikrein or one molecule of factor Xl, but not both. During contact activation kallikrein cleaves HK at two positions within a disulfide bridge. The first is at a C-terminal arg-ser bond followed by cleavage at the N-terminal Iys-arg bond to release the nonapeptide bradykinin (arg-pro-pro-gly-phe-ser-prophe-arg). The two-chain disulfide-linked kinin-free HK results, consisting of a heavy chain of 65 Kd disulfide linked to a light chain of molecular weight 46-49Kd (37,35-41). It is important to note that tissue kallikrein is immunologically and structurally unrelated to plasma kallikrein. It is secreted by various organs or cells such as salivary glands, kidney, pancreas, prostate, pituitary gland, and neutrophils, and is found in high concentrations in saliva, urine, and prostatic nuid. Its primary substrate is LK, but it can release kallidin (lysl BK) from either HK or LK (42,43). Kallidin is functionally very similar to bradykinin although slightly less potent. A plasma aminopeptidase removes the N terminal Iys to convert kallidin to bradykinin. The very unusual domain structure of HK is shown in Fig. 4. Domain 5 of the histidine-rich region at the N terminal end of the light chain binds to initiating surfaces while the binding of prekallikrein or factor XI to the C-terminal domain 6 of the light chain accounts for the cofactor function of HK in intrinsic coagulation and kinin generation. HK has 626 amino acids with a calculated molecular weight of 69,896: an unusually high content of carbohydrate accounts for 40% of its residual molecular weight totaling 115 Kd. The heavy chain of 362 residues is derived from the N terminus. This is followed by the bradykinin sequence (domain 4) and then the light chain of 265 residues. The N-terminal end is blocked with a pyroglutamic acid. The carbohydrate is distributed via three N-Iinked glycosidic linkages on the HK heavy chain and nine O-Iinked glycosidic linkages on the light chain. The heavy chain has three contiguous and homologous domains consisting of amino acids 1-116, 117-238, and 239360. There are 17 cysteines, one of which is disulfide-linked to the light chain and the others form eight disulfide loops within these domains. The three domains of the heavy chain are homologous to the cyst;) tin family of protease inhibitors. Domains 2 and 3 (but not I) retain this inhibitory function so that native HK is capable of binding and inactivating two molecules of papain (44-46). Limi ted proteolysis of the hea vy chai n can occur at susceptible bonds that separate these domains so that individual domains can be isolated.
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Bradykinin Formation
59
HK Domains
cysteine protease inhibitor
I I I I
bradykinin
surtace binding I
I
I
I
I
I
I
I
I
Binding
Binding
to
10
Cyfuke ....afin I
gCI'lH
Endothelial Cell
Figure 4 Domain structure of high-molecular-weight kininogen depicts attachment to an endothelial cell by domains 3 and 5 interacting with cytokeratin I and gClqR respectively.
Plasma also contains another kininogen known as LK. Its digestion by tissue kallikrein yields Iysyl-bradykinin and a kinin-free two chain molecule consisting of a 6S Kd heavy-chain disulfide link to a light chain of only 4 Kd. LK is not cleaved by plasma kallikrein. However the heavy chain of the two forms of the kininogen are identical in amino acid sequence, starting at the amino terminus through the bradykinin sequence plus the next 12 residues. After that the two sequences diverge. Thus their light chains have no homology to each other. LK does not bind to surfaces nor to prekallikrein or factor Xl. The two forms of kininogen are formed from a single gene thought to have originated by two successive duplications of a primordial cystatin-Iike gene (47). As represented in Fig. 5 there are II exons. The first nine code for the heavy chain thus each of the three domains in this portion of the protein is encoded by three exol1S. The 10th exon codes for bradykinin and the light chain of HK whereas the light chain of LK is encoded by exon II. The mRNAs for HK and LK are produced by alternative splicing at a point 12 amino acids beyond the bradykinin sequence. thus enabling the two proteins to have different light chains (47,48).
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Kaplan
60 3'
5'
Transcription 5' - - - - - 1
- - - 3'
. . ._. . ._. . .
5'
_
_
3'
Unprocessed mRNAs
~RNAsPlicin~ 5' ---1
I I I I I I I I. Mature preHMWK mRNA
f- 3'
5' -j
poly A
I I I I I I I I • Mature preLMWK mRNA
f--- 3' poly A
Translation
I Heavy chain
•
BK
I Light chain
pre HMWK
Heavy chain
•
BK
Light chain
pre LMWK
Figure 5 The gene for high-molecular-weight kininogen. The mature mRNAs are assembled by alternative splicing events in which the light chain sequences are attached to the 3' end of the 12 amino acid common sequence C-terminal to bradykinin. (From Silverberg M, Reddigari SR, Kaplan AP. The contact system and its disorders. In: Handin SI, Lux S, Stossel TP, eds. Blood, Principles and Practice. Chapter 38, Philadelphia: Lippincott, 19951127-1150.)
VI.
MECHANISMS OF BRADYKININ FORMATION (CONTACT ACTIVATION)
Contact activation was initially defined by virtue of the interaction of blood with glass surfaces to initiate coagulation as well as the formation of bradykinin. Subsequently various substances bearing negative charges along the surface were shown to be effective activators of the factor-XIldependent pathways, including elagic acid and dextran sulfate. Dextran sulfate is among the few truly soluble activators and is often used to initiate contact activation. High-molecular-weight preparations of 500 Kd are typically used, but much smaller aggregates have been shown to be effective. Of particular interest is that the rate of factor XII activation increases markedly with dextran sulfate polymers of 10 Kd or more as the theoretical number of factor XII molecules capable of binding per particle increases from one to two. This presumably provides a critical intermolecular interaction required for optimal autoactivation. Naturally occurring polysaccharides are effective activators if they are highly sulfated Copyrighted Material
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/
ENDOTHELIA L CELL
i
Zn+-I.
20++
FACTORXIf
~ \---..... :lC--+'
HK + BRADYKININ
FACTORXfla _ _
KALLIKREIN
EIJ>
uPAR - Cytokcratin
mB
qCI gR - Cytokcrattn I
J
Bmdyklnin 8-2 Receptor
Figure 6 Diagrammatic representation of the binding of factor XII and the primarily HK-PK complex to endothelial cells indicates that factor XII binds to the U-PAR-cytokeratin I complex, HK binds to the gClqR-cytokeratin I complex, and that activation to produce bradykinin can occur along the cell surface.
and these include heparin and condroitin sulfate E (49,50). To a lesser degree factor XII autoactivation can be catalyzed by derma tan sulfate, keratin poJysulfate, or chondroitin sulfate C. One pathophysiological substance likely to initiate contact activation in vivo is endotoxin and there is good reason to believe that the contact activation cascade is activated in septic shock and that observed symptoms are due in part to the generation of bradykinin (I). The pooling of fluid outside the vascular tree and the attendant hypotension are examples of abnormalities associated with septic shock that may be dependent upon the generation of bradykinin. The various interactions of the constituents required for the formation of bradykinin are shown in Fig. 6. The initiating step is a slow autoactivation of factor XII (12). However, once this has occurred and prekallikrein is converted to kallikrein there is a positive feedback in which the kallikrein generated rapidly activates factor XII to factor XlIa. This reaction is much more rapid than is autoactivation, thus the majority of the factor X[[a generated is due to kallikrein. The presence of a surface plus this reciprocal interaction leads to a tremendously rapid activation of the cascade. [t has been calculated that if one molecule each of factor XlIa and kallikrein is present per milliliter in a mixture of factor XII and prekallikrein at plasma concentration, the addition of an initiating surface
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will lead to a 50% conversion of factor XII to factor Xlla in 13 s (13). The source of the active enzyme in vivo is unknown but may be formed by other plasma proteases or by endogenous activation along cell surfaces. In fact, a very slow turnover of the cascade may always be occurring but is controlled by plasma inhibitors (51). The addition of the cofactor HK (which was not included in the aforementioned kinetic analysis) accelerates these reactions even further. The surface appears to provide a local milieu in the contiguous fluid phase where the local concentration of reactants is greatly increased (52). In addition, surface-bound factor XII undergoes a conformational changes that render it more susceptible to cleavage. The alternative idea-that binding of factor XII induces a conformational change that exposes an active site-has been disproven and formation of the active enzyme (factor XJfa) requires cleavage of the zymogen (factor XII). Inhibitors such as CI inhibitor are not bound to the surface; thus the balance between activation and inactivation is lost. The effect of dilution of plasma diminishes the effect of inhibitors far more than slowing of enzymatic reaction rates; thus the net effect is a facilitation of activation. Using dextran sulfate as the initiator, the effect of the surface on factor XIIa conversion of prekallikrein to kallikrein was 70-fold whereas the effect on digestion of factor XII by kallikrein was as much as 3000-12,000-fold (13). This latter reaction is about 2000 times more rapid than the rate of factor XII autoactivation. Because of the predominance of kallikrein as a factor XII activator, the PTT of prekallikrein-deficient plasma is prolonged but autocorrects if the incubation time with the surface is increased prior to the addition of calcium ion. This allows factor XII activation to occur by the slower autoactivation mechanism. On the other hand, factor-Xli-deficient plasma has a markedly abnormal PTT that does not autocorrect by increasing the time of incubation with the surface, clearly demonstrating that factor XII is absolutely requisite for initiation to occur whereas prekallikrein is not. In plasma the involvement of HK as a coagulation factor was due to the discovery of persons whose plasma had a very prolonged PTT and who generated no bradykinin upon incubation with initiating surfaces yet were not deficient in factor XU or prekallikrein. Subsequently HK was identified to be a nonenzymatic cofactor (53,54). rt appeClred to accelerate activation of both factor Xll and prekallik rein as well as factor Xl (Fig. 6) The discovery that prekallikrein and factor XI circulate bound to highmolecular-weight kininogen provided the mechanistic key to the explanation. One function of HK is to present the substrCltes of factor Xlla in a conformation that facilitates their activation (26,53). Thus prekallikrein or factor XI that is bound directly to the surface in the absence of a HK is not readily cleaved and cannot disassociate from the surface. Consistent with
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this idea is the demonstration that a synthetic peptide containing the HKbinding site for prekallikrein can interfere with contact activation by competitively interrupting the binding of prekallikrein to the HK light chain. A monoclonal antibody to this binding site likewise inhibits contact activation as well as bradykinin formation in plasma. Factor XI activation is almost totally dependent on the formation of a surface-binding complex with HK. More difficult to explain is the effect of HK on the rate of factor XII activation in plasma, since HK does not interact with factor XII, nor does it augment the activity of kallikrein. This effect seems to be largely indirect. First, HK is required for efficient formation of kallikrein in surface-activated plasma (53,55). Second, since kallikrein can dissociate from surface bound HK it can interact with surface-bound factor XLI on an adjacent particle thereby disseminating the reaction (26,27). As a result, the effective kallikrein/factor Xll ratio is increased in the presence of HK (26). Finally in plasma HK can displace other adhesive glycoproteins such as fibrinogen from binding to the surface (56). In this sense HK, like factor Xli and prekallikrein, is also a coagulation cofactor because it is required for the generation of kallikrein (a factor XII activator) as well as the activation of factor Xl. HK-deficient plasma has a profoundly prolonged activated PTT that is almost as abnormal as that of factor XII deficiency, although persons with congenital HK deficiency have no bleeding diathesis. This is also true of factor XU deficiency as well as prekallikrein deficiency (57,58-60). Patients with factor Xl deficiency, however, do have a form of hemophilia, although the magnitude of the abnormality varies greatly among different patients. For homeostasis the tissue-factor-dependent pathway clearly predominates and the role of factor Xl in augmenting coagulation appears to be dependent upon its activation by thrombin when incorporated into a clot (I). Thus the biology of factor XII, prekallikrein, and high-molecularweight kininogen in physiological as well as pathological processes may relate to inf1ammation, control of the microvasculature, and possibly fibrinolysis rather than homeostasis or pathological bleeding.
VII.
CELL SURFACE ASSEMBLY OF THE PLASMA KININ-FORMING CASCADE
All the components of the bradykinin-forming cascade have been demonstrated to bind to endothelial cells. Schmaier et al. and Van lwaarden et al. first described binding of HK to human umbilical vein endothelial cells (HUVEC) in a zinc-dependent fashion (61,62). This binding was subsequently demonstrated in situ by immunochemical staining of umbilical cord segments following incubation with HK (63). HK binding to these cells was
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reversible, dependent upon 25-50 ~lM zinc, and there were approximately I million binding sites/cell with a high affinity (Kd 40-50 nM). Binding is seen with both the heavy and light chain of HK (64), thus a complex interaction with cell membrane constituents is likely. Since prekallikrein binds to HK within the circulation, the complex is brought to the surface of the endothelial cell by virtue of HK binding. There appear to be no separate receptor sites for prekallikrein or factor XI. When factor XII interaction with HUVEC was studied, the former was found to bind with characteristics strikingly similar to those seen with HK including a similar requirement for zinc (65). We subsequently demonstrated that HK and factor XII can compete for binding at a comparable molar ratio, suggesting that they compete for binding to the same receptor sites. Three endothelial cell-binding sites for HK and for factor XII have been described thus far. These include gClqR, (the receptor for the globular heads for the C Iq subcomponent of the first component of complement) (66,67), cytokeratin I (68,69), and the urokinase of plasminogen activator receptor (u-PAR) (70). The binding of factor XH and HK to each of these proteins is zinc-dependent. gClqR binds specifically to the light chain of HK and not to the heavy chain, and the binding locus is on the C-terminal domain of gClqR (69). This is in contradistinction to Clq, which binds to the N-terminal domain of gClqR. Thus Clq does not compete with either HK or factor XII for binding and the interaction of Clq with gClqR is not zinc-dependent. Domain 5 of HK located within the N-terminus of the light chain is rich in histidine and arginine residues and contains the site for interaction with gClqR. A 20 amino acid peptide termed HKH20 has been shown to be the site of interaction within domain 5 and this peptide can be used to inhibit the interaction of HK with intact endothelial cells (71). The other site for attachment of HK to endothelial is found within domain 3 and a peptide containing that binding site has been designated LDC27 (72). The binding affinity of the heavy chain to the cell is approximately 100-fold less than the light chain. The second endothelial cell-binding site for HK is cytokeratin I. Like gClqR, this protein was isolated from cell membrane preparations employing affinity chromatography with HK or LDC27 as ligand. Cytokeratin I therefore represents a major site of interaction for the HK heavy chain; however, it is capable of binding light chain as well. Thus it does not possess the specificity that gClqR does. However, light-chain binding to gClqR appears to predominate because of the affinity of the interaction as well as the much larger number of gClqR-binding sites. u-PAR represents a third cell membrane constituent capable of binding to HK. We were unable to isolate this molecule by HK affinity chromatography; however, it was identified to participate in binding because antisera
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directed to u-PAR can inhibit the cell interaction with HK, and HK can be shown to bind to purified u-PAR in a zinc-dependent fashion. However, affinity chromatography using factor XII as ligand leads to purification of u-PAR rather selectively, with only trace quantities of cytokeratin I or gClqR present (73). Thus u-PAR may represent an important ligand for interaction with factor XII, while gC IqR and cytokeratin I predominate in terms of HK binding. It had been proposed that gClqR, cytokeratin I, and u-PAR may form a trimolecular complex within the cell membrane. However, when we examined this in detail we were able to show that they actually interact as two bimolecular complexes, with cytokeratin I being the common constituent (74). Thus antisera to gC IqR can be used to purify both gClqR and cytokeratin I but not u-PAR, whereas antibody to u-PAR can be used to isolate u-PAR and cytokeratin I but not gClqR. It is of interest that none of these three proteins possesses a transmembrane domain, thus its mechanism of attachment within the cell membrane is not clear with the exception of u-PAR. This is known to have a phosphatidylinositol linkage within the cell membrane, whereas gClqR and cytokeratin I do not. Nevertheless each of them has been isolated from purified cell membranes and have been demonstrated to exist within the cell membrane by immunoelectronmicroscopy (75). In agreement with calculations of numbers of binding sites, gClqR appears to predominate within the cell membrane. A summary depicting these interactions is shown in Fig. 6.
VII.
KININ FORMATION AT THE SURFACE OF ENDOTHELIAL CELLS
We have also demonstrated that factor XII can slowly autoactivate when bound to endothelial cells (76), and that addition of kallikrein can digest bound HK to liberate bradykinin at a rate proportional to the kallikrein concentration. The final bradykinin level was dependent upon the amount of bound HK. Thus activation of the cascade may occur along the endothelial surface in a fashion analogous to that seen with contact activation of plasma. Bradykinin that is generated can then interact with the endothelial cell B-2 receptor to increase vascular permeability (7,77). Bradykinin can also stimulate cultured endothelial cells to secrete tissue plasminogen activator, prostaglandin [2 (prostacyclin), and thromboxane A2 and thereby modulate platelet function and stimulate local fibrinolysis (78). An alternative pathway for activating the cascade has recently been demonstrated in which factor XII is absent from the reaction mixture (79-82). Two different groups have isolated two different proteins, each of which seems to be able to catalyze activation of the HK prekallikrein
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Kaplan
complex. One is heat shock protein 90 (83) and the other is a prolylcarboxypeptidase (84). The active site actually responsible for the conversion of prekallikrein to kallikrein is not clear in either case. They have strikingly similar inhibition profiles even though the two proteins are completely different. Heat shock protein 90 has ATPase activity but no clear peptidase capability, and the prolylcarboxypeptidase is an exopeptidase whereas prekallikrein activation requires an endopeptidase. Nevertheless, each of these appears to make a contribution to factor-XIlindependent prekallikrein activation and antisera to each protein have been shown to inhibit the process. When whole endothelial cells are incubated with normal plasma or factor-XII-deficient plasma, the rate of activation of the deficient plasma is very much slower than that of the normal plasma, the latter being factor-XIl-dependent (82). There are a number of interesting interactions between the proteins of the plasma kinin-forming cascade and the fibrinolytic pathway (85) as well as the renin~angiotensin pathway (86). For example, kallikrein converts plasma prourokinase to urokinase, and prourokinase that is bound to uPAR is more readily activated (85). Thus kallikrein that has been produced along the cell surface can generate urokinase, which converts plasminogen to the fibrinolytic enzyme plasmin. Kallikrein has also been shown to mediate the acid phase of conversion of prorenin to renin in whole plasma. Renin converts angiotensinogen to angiotensin I. Angiotensin-converting enzyme cleaves his-leu from angiotensin I to yield angiotensin 2 and it is also a major inactivator of bradykinin. The aforementioned prolylcarboxypeptidase does the reverse: it degrades angiotensin 2 but leads to bradykinin formation (81). Bradykinin formation relates to a variety of other innammatory and noninnammatory disorders including allergic rhinitis, asthma, anaphylaxis (87), pancreatitis, endotoxic shock, hypertension (1,2), coronary artery blood flow, ischemic cardiomyopathy, and Alzheimer's disease (88,89).
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81 82.
71
to the globular "heads" of Clq (gClqR). Proc Nat! Acad Sci USA 1996; 93:8552-8557. Herwald H, Dedio J, Kellner R, Loos M, Muller-Esterl W. Isolation and characterization of the kininogen binding protein p33 from endothelial cells. J BioI Chem 1996; 271:13040-13047. Hasan AAK, Zisman T, Schmaier AH. Identiflcation of cytokeratin 1 as a binding protein and presentation receptor for kininogens on endothelial cells. Proc Natl Acad Sci USA 1998; 95:3615-3620. Joseph K, Ghebrehiwet B, Kaplan AP. Cytokeratin I and gClqR mediate high molecular weight kininogen binding to endothelial cells. Clin Immunol 1999; 92:246-255. Colman RW, Pixley RA, Najamunnisa S, Yan W, Wang J, Mazar A, et a!. Binding of high molecular weight kininogen to human endothelial cells is mediated via a site within domains 2 and 3 of the urokinase receptor. J Clin Invest 1997; 100:1481-1487. Hasan AAK, Cines DB, Herwald H, Schmaier AH, Muller-Esterl W. Mapping the cell binding site on high molecular weight kininogen domain 5. J Bioi Chem 1995; 270:19256-19261 Herwald H. Hasan AA K, Godovac-Zimmermann J, Schmaier AD, Muller-Esterl W. Identiflcation of an endothelial cell binding site on kininogen domain D3 .I BioI Chem 1995; 270:14634-14642. ./oseph K, Kaplan AP. Unpublished observations. ./oseph K, Tholanikunnel BG, Ghebrehiwet B, Kaplan AP. Interaction of high molecular weight kininogen binding proteins with each other. .I Thromb Haemost (in press). Mahdi F, Shariel-Madur S, Todd RF IJI, Figueroa CD, Schmaier AH. Expression and colocalization of cytokeratin 1 and urokinase plasminogen activator receptor on endothelial cells. Blood 200 I; 97:2342-2350. Joseph K, Shibayama Y, Ghebrehiwet B, Kaplan AP. Factor XII-dependent contact activation on endothelial cells and binding proteins gClaR and cytokeratin 1. Thromb Haemost 2001; 85:119-124. Vavrek RJ, Stewart .1M. Competitive antagonists of bradykinin. Peptides 1985; 6161-164 Rojkjaer R, Schmaier AH. Activation of the plasma kallikrein/kinin system on endothelial cells. Proc Asoc Am Physicians 1999; III :220-227. Motta G, Rojkjaer R, Hasan AAK, Cines DB, Schmaier AH. High molecular weight kininogen regulates prekallikrein assembly and activation on endothelial cells; a novel mechanism for contact activation. Blood 1998: 91 :516-528. Rojkjaer R, Hasan AAK, Motta M, Schousboe I, Schmaier AH. Factor XII does not initiate prekallikrein activation on endothelial cells. Thromb Haemost 1998; 8074--81 Schamier AH. Contact activation: a revision. Thromb Haemost 1997; 78: 101-107. Joseph K, Ghebrehiwet B, Kaplan AP. Activation of the kinin-forming cascade on the surface of endothelial cells. Bioi Chern 2001; 38271-75.
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Kaplan
83.
Joseph K, Tholanikunnel BG, Kaplan AP. Heat shock protein 90 catalyzes activation of the prekallikrein-kininogen complex in the absence of factor XII. Proc Natl Acad Sci USA 200 I; 99:896-900. Shariat-Madar Z, Mahdi F, Schmaier AH. Identification and characterization of prolylcarboxypeptidase as an endothelial cell prekallikrein activator. J Bioi Chem 2002; 277: 17962-17969. Lin YL, Harris RB, Van W, McCrae KR, Zhang H, Colman RW. High molecular weight kininogen peptides inhibit the formation of kallikrein on endothelial cell surfaces and subsequent urokinase-dependent plasmin formation. Blood 1977; 90:690-697. Schmaier AH. The plasma kallikrein-kinin system counterbalances the reninangiotensin system. J Clin Invest 2002; 109:1007-1009. Kaplan AP, Joseph K, Sliverberg M. Pathways for bradykinin formation of inflammatory disease. J Allergy Clin Immunol 2002; 109: 195-209.
84
85.
86. 87.
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4 The Complement System: Mechanisms of Activation, Regulation, and Role in Innate and Adaptive Immunity Berhane Ghebrehiwet State University of New York, Health Sciences Center, Stony Brook, New York, US.A.
The complement system is a well-orchestrated, highly complex, and tightly controlled biological system, which constitutes a major part of both the innate and adaptive immune systems 0-3). Its primary function is to recognize and destroy pathogenic micro-organisms, and in this capacity, therefore, it has evolved a sophisticated mechanism of discrimination between self and nonself. There are situations however, in which complement can turn against the self, thereby causing tissue damage and destruction. Comprised of three independent activation pathways, the complement system consists of more than 30 serum and cell surface proteins, which, together with an intricate array of modulators and regula tors, form one of the proteolytic cascade systems of blood plasma (4). In the classic sense, complement is activated primarily when antigenantibody complexes are formed in either plasma or tissues and, as a consequence, secondary activation peptides are generated that play an important role in many types of immunological reactions and inflammatory
Terminology used to describe the complement proteins is that agreed on by the World Health Organization in 1968. Thus components are named by uppercase letters followed by a number (e.g .. C I). Fragments derived from a component are denoted by a lowercase letter after the component from which it was derived (e.g .. C3a). Some alternative pathway components are designated by upper case letters only: factors S, D, J. H, or P (properdin).
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74
Ghebrehiwet
processes. Activation of complement requires an initial contact with and recognition of an activator. This initial contact is thought to provide the subtle molecular signal necessary to trigger a series of protein-protein interactions involving, sequentially, the conversion of proteolytic zymogens to active proteinases and the assembly of functionally defined protein complexes on the surface of the activator particle. If the activating agent is a virus, a bacterium, or a tumor cell, activation of complement will lead to its destruction by causing irreversible structural and functional impairment of its membrane. There are three independent pathways of complement activation, each of which culminates in generating the so-called 'killer' macromolecule: a self-assembling, nonenzymatic cascade referred to as the membrane attack complex (MAC) or membrane attack pathway. The MAC is responsible for the well-known complement-mediated 100 A lesions seen on biological membranes by electron microscopy (5). The classic pathway (CP) is initiated by immune complexes of the IgG and IgM types and results in the sequential interactions of nine distinct complement components, designated numerically and in their order of participation in the sequence, as C I, C4, C2, C3, C5, C6, C7, C8, and C9 (Table I). Three of these components-C J r, CIs, and C2-constitute the classic pathway serine proteases. The alternative pathway (AP), on the other hand, is activated by IgA antibodies or certain complex polysaccharides of bacterial and microbial cell walls such as bacterial endotoxins, inulin (a polyfructose from plant cell walls), zymosan (an insoluble residue of yeast cell walls), or cobra venom factor (a glycoprotein from cobra venom), which is the cobra equivalent of C3b. Six proteins can be considered components proper of the alternative pathway: C3, factor B, factor D, factor H, factor I, and properdin (P). Of these, factors Band D belong to the class of serine proteases and represent the alternative pathway enzymes, whereas factor I is an unusual serine enzyme, which is resistant to the classic serine protease inhibitor, such as diisopropylphosphonuoridate, although sequence evidence suggests that it too is a serine protease (6,7). Factor B and perhaps C2 of the classic pathway are examples of a new type of serine protease with catalytic peptide chains of about 60 kD (8), and factor D is believed to be the only complement enzyme that circulates in plasma in its active form. The third pathway of complement activation, designated lectin pathway or mannan-binding lectin (MBL), pathway was discovered only recently (9,10). M BL belongs to the group III of a family of Ca2+-dependent carbohydrate-binding lectins that include the plasma proteins, conglutinin, collectin-43, and two lung surfactant proteins, SP-A and SP-D (11,12). These proteins, collectively known as collcctins (collagen containing lectins), have structural similarity
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Table 1 Plasma Proteins of the Complement Pathways
MW Components
(kDa)
Electrophoretic mobility
Polypeptide chains
Chromosome location
Y2
(3
18 2
0'
I
(32
I 2 3
Ip34.1 12pl3 12pl3 6p21.3
Mean serum level (~g/ml)
Classic path,,'cl.l'
Clq Clr Cis C2 C3" C4
462 83 83 102
185 205
fh f3,
80 50 50 25
19
1600
6p213
550
10 3q27-q28 Ip363-2 3q27-q28 6p21.3
1-5
MEL or lecrin par!J\I·o)'
MBL MASP I MASP-2 MASP-3 C2 C3 C4
540 90 74 94 102
J8
f32 -
185
fh
205
(31
I I I I
25
2 3
19
1600
6p213
550
2 I
19
1600
6p21.3
200
Alrematil'l' pmllll'Cll'
C3 Factor B Factor D Factor H Factor I Properdin /I;fel77hrone
C5 C6 C7 C8 3 C9
185
(32
93 25 150 88 225
f32
OIlOC/{
f3
I I
fJ y
2 4
fJ-y
I
Iq 4q24 Xpll.23
500 35 25
9q32-34 5q 5q (I p34, 1p34,9q) 5pl3
75 60 55 80 60
complex (por!llror)
190 120 110 150 71
(31 (32 f32 YI
Y
2 I I
3 (O',(3,y) I
"C3 is the key protein where each pathway converges. bChrol11osol11e location ror each or the CS chains is given in the order shown.
with CI q and consist of 12-18 polypeptide chains with N-terminal collagenlike regions and C-terminal globular heads (13). Whereas the globular heads of C I q recognize 19G or IgM, the globular heads of the collectins contain a unique carbohydrate recognition domain (CRD). The CRD of MBL can therefore recognize and bind to microbial surface structures containing mannose and N-acetylglucosamine, thereby triggering a carbohydrate-mediated, antibody-independent activation of
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complement in a manner that involves so-called Cl riC Is-like serine enzymes designated MBL-associated serine proteases (MASPs). Both genetic evidence and functional similarity suggest that the MASPs and C I I' and Cis enzymes may have evolved from a common ancestral gene by duplication or exon reshuffling. Therefore, the regulatory mechanisms that control the C Iq-C I r2·C IS2 and the MBL-MASP pathways are likely to be similar. For a meaningful activation to occur, all three pathways more or less must obey the same sequential steps of molecular organization: I. 2. 3. 4.
S.
An initial contact with, and recognition of, an activator Initiation of the cascade by conversion of zymogens to active proteinases Assembly and amplification through newly formed enzyme complexes Generation of C3/CS converting enzymes Nonenzymatic assembly of protein-protein complexes that lead to the formation of MAC
Although the significance of complement in health and disease has been recognized almost since its discovery in the latter part of the 19th century (14), a number of critical discoveries made over the past few years, including the recent discovery of the MBL pathway, have collectively underscored the importance of complement in both innate and adaptive immunity. This chapter will first review the present status of the field by discussing the activation and regulation of the three independent pathways of activation and then provide few examples of the many roles complement plays in host defense and innammation.
I. THE CLASSIC PATHWAY: ACTIVATION AND REGULATION Activation of the classic pathway is primarily dependent on the ability of the first component, C I, to recognize and bind polymeric structures of activating substances such as circulating immune complexes, bacteria, viruses, and other activating substances of diverse origin (IS) (Fig. I, Table 1). Although in vivo it is generally agreed that immune complexes of the IgG (IgG} > IgG I > IgG 2 ) and IgM isotypes are particularly effective initiators of the classic pathway, activation can, however. proceed without mediation by immunoglobulins. For example, direct activation of CI can occur by certain biological particles such as RNA tumor viruses (16), vesicular stomatitis virus (17), complexes of C-reactive protein and pneumococcal polysaccharide (18), the lipid A region of certain
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77
pathway
MBLLectin pathway
CJqrs
MBL-MASP-l,2
C4
C4
C2
C2
Alternative pathway
C5 C6
C7 C8 C9
Lytic pathway
Figure 1 The three pathways of complement activation and the central role of C3. Activation is initiated by immune complexes (classic) or man nose-rich structures on pathogenic micro-organisms (MBL) or complex carbohydrate structures (alternative). Each pathway has its own recognition unit, which is responsible for discriminating between self and nonself proteins. All three pathways must first activate C3 and then C5 before the final lytic pathway is activated.
Iipopolysaccharides (19), Toxoplasma (20), and plasma enzymes such as kallikrein (21), Hageman factor fragment (HFf, factor XII f) (22,23), and plasmin (24).
A.
Recognition and Initiation
The first component of complement, Cl (MW 790 kDa), is a l5S-16S glycoprotein and actually includes the recognition unit, C Iq (460 kDa), and two modular serine proteases, Cl I' and CIs (MW 75 and 74 kD, respectively), associated as a Ca 2 +-dependent tetra mer, Cls-Clr-Clr-Cls, to give a molecular formula ofClqClr2Cls2 (25-30), However, because CI in serum is readily dissociable into Clq and the Ca2+-dependent tetrameric structure C Ir2C I S2, it may be regarded as a macromolecular assembly of these two weakly interacting proteins (26). During activation of the classic
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pathway, the Clq molecule, which has no known enzymatic activity, plays a critical role by first recognizing and directly binding to either immune complexes or pathogenic micro-organisms, and then converting the subtle conformational signals generated as the result of binding into highly specific proteolytic events (29,31). C Iq is a collagenlike molecule (32) with six flowerlike globular heads that constitute the binding sites (33) for the C H 2 domain of IgG (34) and C H 3 or C H 4 domains of IgM (35,36), respectively. Each globular head contains the carboxyl-terminal ends of three highly similar but distinct polypeptide chains A, B, C with molecular weights (MW) of 28, 25, and 24 kD, respectively, that occur six times in the molecule forming six structural and functional subunits (37-42). The three chains of Clq are the product of three distinct genes, which are aligned 5'_3' in the same orientation in the order A-C-B on a 24 kb stretch of DNA on human chromosome I p (41). Each chain has a short N-terminal region involved in the formation of A-B and C-C interchain disulfide bonds and is followed by a collagenlike sequence that gives rise to the formation of six heterotrimeric CA, B, C) collagenlike triple helices. These first associate as a stalk and then, due to interruptions in the Gly-Xaa-Yaa collagenlike motif, diverge to form six arms, ultimately merging into a Cterminal globular head region formed by association of the C-termini known as the C Iq modules (29). The C Iq binding site for C I r2C 1S2 resides in the collagenlike triple helical segment (37,38). With each globular head capable of binding one IgG molecule, C Iq can bind a maximum of six molecules of IgG (33). However, although monomeric IgG can bind Clq, this binding is very weak (1-5 x W· M- 1) and therefore cannot trigger complement activation. On the other hand, the affinity ofClq for clustered IgG, such as those on immune complexes, increases more than 100 fold I . on the number of globular heads engaged (4).This ( 5 x I 04 M - ) dependll1g type of interaction is thought to induce a series of intramolecular changes within the CI macromolecule that eventually lead to the autocatalytic conversion of the single-chain proenzyme Clr to its two-chain proteolytic form. The conversion of Clr to an active protease is the first step in the initiation of the classic pathway (Fig. 2). The mechanism by which this occurs is unclear; however, it has been proposed that complex formation induces a conformational change in the Clq within the CI macromolecule (43) and that this change exposes a proteolytic site in CI I' prior to peptide bond cleavage, converting it to an intermediate form designated active zymogen or Clr* (40). This form ofClr in turn can cat~llyze the conversion of CI I' ~ CI 1'* ~ fully active CI 1'* (40). Activation occurs through cleavage of a single Arg-Ile bond in the single chain CI 1', thereby converting it to a two-chain structure in which a heavy chain of 60kDa is disulfide-linked to
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Complement System Clr
Clr
H2 N -
HL-
H2N -
HL-
79
9:..::°~,O:.::.OO=___
.:.6(:..:1,O::.:O:..:O
_,_-----__._-------lf-COOH
Ls--s=:J -,:J@CD-C:30,(l00
L
CIs
Cis
H,N -
@.jL
1-I,N
[email protected]
f_COOH
s ---- "s -_I
-=9.::.0,1.:::.00::.:0~ _ ___r-----___,--~f-COOH
Ls--s=:J
.::.6::!.O,::.::OC:.::.IO
---,--.J! ~ ~
30,000
f_COOI-I
Ls-s=:J
Figure 2 Proteolytic cleavage and activation of C I rand Cis. The activation patterns ofClr and Cis are almost identical. Cleavage ofClr occurs at a single site between arginine (R) and isoleucine (I) to give lwo chains of MW 60 kDA and MW 30 kDA, which remain disulfide-bonded. The smaller fragment contains the catalytic site of the molecule, which converts Cis to Cis by a single peptide bond cleavage between Arg-Ile or Lys-Ile. Again the active site of the molecule resides in the smaller chain at the carboxy-terminal end.
a 30 kDa, carboxy-terminal end light chain, which bears the chymotrypsinlike serine protease or catalytic domain (Fig. 2). This site was found to contain three active residues (His, Asp, Ser), which are common to all serine proteases (44). Activated Clr in turn converts Cis to enzymatically active CIs by cleavage of an Arg-fle bond within a disulfide bridge in a fashion similar to that described for Clr (45) (Fig. 2). Both Clr and Cis are modular serine proteases, exhibiting homologous structural organizations comprising sequentially and starting from the N-terminus of CUB module, an epidermal growth factor (EGF)-like module, a second CUB module, two complement control protein (CCP) modules, and a C-terminal chymotrypsinlike serine protease domain (29). In spi te of their structural and functional similarities, C Irand Cis are two distinct and specific enzymes with entirely different proteins as their substrates. The only natural substrate known for Clr is Cls, whereas both C4 and C2 represent the natural substrates for Cis. Thus, CIs cleaves the
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fourth (C4) and second (C2) components of complement, each of which is sequentially cleaved into two fragments. For continuity of the cascade, however, cleavage of C4 must precede cleavage of C2. Furthermore, whereas CIs in free solution can cleave free or C4b-bound C2, the cellbound enzyme does not cleave C2 unless it is bound to C4b (46). C4 consists of three disulfide-Ii nked chains (each of which is a distinct gene product) of differing MWs (n: = 97 kDA, (3 = 75 kDA, and y = 33 kDA) in which a single cleavage of the largest chain (termed a) by CIs results in the generation of two fragments: C4a, a 9 kDA fragment, and a larger fragment of 198 kDA, termed C4b. This cleavage not only exposes a labile binding site for cells on the a l chain of C4b but also allows firm binding to C2b via the y chain (6). The active site in the a l chain of C4b is a reactive acyl group,which has the capacity to bind covalently to hydroxyl or amino groups on any biological membranes. C4a is one of the three complement-derived anaphylatoxins (47,48), which are important mediators of innammation because they have the capacity to react with basophils and mast cells, causing them to degranulate (49,50 ). In this fashion, histamine and other mediators typical of allergic reactions can be released into tissues, resulting in vascular permeability and contraction of smooth muscle. The larger fragment, C4b, that results from this digestion (whether cell-bound or in solution) can bind C2 in the presence of Mg 2 + If the binding of C2 to C4b occurs in the vicinity of activated C I, then C4b acts as a cofactor for the next enzymatic step of the cascade in which C2 becomes cleaved by Cis to yield two fragments: the C-terminal catalytic fragment C2a (70 kDA) and the noncatalytic, 30 kDA N-terminal piece, C2b (51). The larger fragments, C4b and C2a, form a bimolecular complex (C4b2a) to form the next enzyme 111 the cascade: the C3 convertase (52). The active site resides on the C2a portion of the molecule (53), and C4b functions as a modulator to facilitate C2 cleavage by Cis (54-57) and stabilize the C2a enzymatic site (55). C4b also possesses a metastable binding site by which the C4b2a enzyme can attach to target cells. C2 has not been shown to possess any biological activity of its own. It has been proposed, however. that a kininlike peptide is released as a consequence of C2 cleavage (58.59). This would, therefore. represent another way in which a potent vasodilator is released as a consequence of complement activation and, together with bradykinin generated by the kinin-forming cascade, may contribute significantly to the pathogenesis or hereditary angioedema (60-62).
B.
C3 Plays a Central Role in the Cascade
or
the 20+ distinct plasma proteins recognized to date as constituents of the complement system, the third component of complement, C3, is the
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Complement System
81
most abundant (~l.6mg/ml in plasma) and versatile, and fulfills a pivotal role in the function of the system (Fig. 3, Table 2). All three pathways of complement activation merge at the C3 step and continue on to generate MAC. Therefore, complete deficiency of C3 would have a devastating, but
B,N - ~
00:..:O -,----_-----=ca."-"1:..:2-'-'0,c.:...
r-
I
I
S
S
SI
S!
I
-Jf.@-COOH
I
C3
C3 CONVERTASE
t
C3a 19,0001 ,[--------=-1:-::14-0:,07. 00, - - - - - - -
I
I
sI
S
S!
S
C3b
I j
75,000 (l + H)
k
=====~=:..:6-:c:8~,0=0::-0=-_-_-_-_-_-----,--;1 0
3,000
1=-4-;:3-;:,0.".,00-----,
I
iC3b
I SI
sI SI
SI 75,000
TRYPTIC ENZYME
~
t
L....:2::;.7.L.:,0.:..:00',-J1 [
o. 2D (C3dgl 41,000
I
43,000
I
sI
s I
C3c
S
S
I
I
75,000
Figure 3 Structure and activation pattern of human C3. The C3 convertase of either pathway removes a 9 kDA fragment. C3a. by single peptide bond cleavage (Arg-Ser) of the Q' chain. The a chain of C3b is further cleaved by the regulatory enzyme, factor 1, which in the presence of factor H makes two cleavages and removes a 3 kDA fragment, leaving 68 kDA and 43 kDA fragments disulfide-bonded to the f3 chain to give an inactive C3b (iC3b). iC3b is. at this stage, susceptible to proteolytic cleavage by trypticlike enzymes to generate C3c and a2D or C3dg. S, serine; A, alanine.
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Table 2 Cleavage Products of C3 and their Known Biological Activities Cleavage product
Polypeptide chains
MW (kDa)
Biological activities
C3a
9
C3b
186
Anaphylatoxin Release of histamine from mast cells Release of enzymes from PMNs Smooth muscle contraction Suppression of immune responses (T cells) Secretion of I L-I from macrophages Stimulation of prostaglandin and thromboxane production (macrophages) Opsonization of biological particles Recognition unit of the alternative pathway Subunit of C3/C5 convertase of the AP Subunit of the C5 convertase of the CP Receptor for P and Factor H Ligand for CR I (PMNs. erythrocytes. monocytes) Potentiation of antibody-dependent cellular cytotoxicity (ADCC) Ligand for PMN, monocyte, and B lymphocyte receptors (CR3) Potentiation of ADCC Enhancement of phagocytosis Precursor of C3e Ligand for cellular receptors (CR2) Potentiation of ADCC None Suppression of T cell functions Leukocytosis Induction of leukocytosis Enhanced vascular permeability Release of lysosomal enzymes Ligand for PM Ns and monocytes
iC3b
3
177
C3c C3d
3
140 25-35
Clg C3d-k C3e
8 40 10-12
not necessarily fatal, consequence on the individual since the complementdependent lytic machinery would be impaired and opsonic fragments, which play such a significant role in phagocytosis and immune clearance, would not be generated (63). C3 also functions as a subunit of the initial C3 convertase of the alternative pathway. It is no surprise therefore that the structure, molecular biology, and functions of C3 have been the subject of much study during the last two decades (63). The chain structure ::\l1d
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Complement System
83
cleavage pattern during complement activation have been substantially worked out (Fig. 3). C3 is a 9.5S $-globulin consisting of two nonidentical polypeptide chains, 0' and $, with MWs of 120 and 75 kDA, respectively, which are held together by disulfide bonds and noncovalent forces (64,65). Serine has been found to be the N-terminal amino acid residue of both chains, as well as the C-terminal residue of the 0' chain, whereas alanine constitutes the C-terminal residue of the $ chain (65). C3 is synthesized in the liver (66-68) and by monocytes and macrophages (69,70) as a single polypeptide chain. After translation, it is processed in the cytoplasm to the two-chain molecule that occurs in serum (69,70). Several individuals have been described with a homozygous C3 deficiency, and they have been reported to have had numerous episodes of infection caused by pathogenic bacteria, including septicemia and meningococcal meningitis (71,72). In addition, deficiency in C3 results in suppression of complement-mediated functions: hemolytic and bactericidal activity, opsonization of bacteria, and mobilization of leukocytes in response to chemotactic stimuli. Native C3 is cleaved by the classic, MBL or alternative pathway C3 convertases into two fragments, C3a and C3b, by hydrolysis of peptide bond 77 (Arg-Ser) of the 0' chain (50,65). The activation peptide C3a is a 9 kDA basic peptide, which constitutes one of the three complement-derived anaphylatoxins (C4a and C5a are the others and are derived by a single cleavage of an Arg-X bond in the 0' chain) and as such, is an important mediator of acute innammatory responses (Fig. 3, Tables 2, 3). Doses as low as I x 10- 12 mol are active, and when compared on a molar basis, C3a is less potent than C5a but more potent than C4a (C5a > C3a > C4a). [t causes release of histamine from mast cells, induces smooth muscle contraction of guinea pigs, causes release of lysosomal enzymes from neutrophils, and upon intracutaneous injection into humans or guinea pigs enhances vascular permeability (49,50,73). It has been found that C3a suppresses both specific and polyclonal antibody responses by induction of a suppressor T-cell population, indicating that C3a may be involved in a nonspecific immunoregulatory network capable of suppressing ongoing immune responses (74). /11 vivo, the functions of C3a are controlled by serum carboxypeptidase N (anaphylatoxin inactivator [AI]), which removes the essential C-terminal arginyl residue (75). Its structure has been found to be homologous to that of C4a (48) and C5a (76) with a 45% a-helical conformation (77). The large fragment, C3b, like C4b, has a metastable binding site (78-80), and the reactive group appears to be an intramolecular thiolester bond, which in native C3 is inaccessible. However, cleavage and removal of the N-tenninal C3a induce a conformational change in the C3b molecule.
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84 Properties of Human Anaphylatoxins
Table 3
C4a
C3a
Properties
C5a
Electrophoretic mobility
+2.1
+21
-1.7
Molecular weight (kDa) Total Protein Carbohydrate Aminoacid residues NH-terminus COOH-terminus a-Helical structure
9,000 9,000 0 77 Serine Arginine 50%
8,650 8,650 0 77 Asparagine Arginine 54%
11,200 8,200 3,000 74 Threonine Arginine 45%
Biological activity Ira! contraction Chemotaxis Histamine release Letha! shock (guinea pig) Edema and erythema Immuno potentiation Iml11uno suppression
I x 10-8M None I x JO- 6 M I x 10-8 mo l I x 10-11 mo l None 100-500 ng/ml
I x 10-~ M None
5xlO- l oM 3 x 10- 9 M I x 10-6M 1 x 10-9 mo l J x 1O- 15 1110! 10-JOOng/ml None
I x 10- 9 11101
exposing an internal thiolester bond capable of covalently binding with any
o II (--e-S-)
o II (--e-oH HS-)
nucleophile including H 2 0 and the hydroxyl or amino groups of any biological surfaces. Such interaction converts the thiolester to C3b and performs several biologically important functions in vivo. First, there are receptors for C3b on numerous cells including neutrophils, eosinophils, macrophages, monocytes, and B lymphocytes (81,82). Because neutrophils and macrophages (and, to a lesser degree, eosinophils) are phagocytic cells, interaction of these cells with immune complexes to which C3b is attached appears to be sufficient to trigger phagocytosis. In this fashion, immune complexes are ingested, and as a consequence of this reaction secretion of enzymes, which can destroy tissue, is initiated. Second, C3b is capable of differentiating between an activator and a nonactivator of the alternative pathway. This is reflected by the differential accessibility of bound C3b to the
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regulator (factor H) (83) and the C3b inactivator (factor I), which cleaves the c/ chain at two arginyl-serine peptide bonds. This removes a 3 kDA fragment designated C3f (84) and two c/ chain fragments, 68- and 43 kDA, that remain disulfide-bonded to the f3 chain (83) (Fig. 3). Such inactivated C3b i termed iC3b and at this stage is extremely susceptible to further enzyn'latic degradation by tryptic-like enzymes. These cleave the c/ chain in the N-terminal region, removing a 41 kDA piece designated C3dg, which contains the C3d and C3g fragments (85) (Fig. 3, Table 2). C3d contains a particle-binding site and remains bound while C3c is released to the nuid phase. Although the physiological fragments of C3b (ie. iC3b, C3dg, and C3d) do not participate further in the activation process, they nevertheless fulfill a diversity of immunoregu!atory functions including clearance and solubilization of immune complexes and stimulation of immune responses, by interacting with specific cell surface receptors such as CR2 (for C3dg and C3d) and CR3 (for iC3b). The larger fragment, C3c (140KDa), is the precursor of a 10 kDA fragment, C3e, which appears to be derived late in the degradation process from the (Y chain by a yet unidentified plasma, leukocyte, or bacterialy derived enzyme (86,87). Although its exact chemical structure has not been elucidated, C3e is of particular interest, as it has been shown to induce leukocytosis in rabbits upon intravenous injection and when injected intradermally causes increased vascular permeability (86) (Table 4) with cellular infiltration. It has also been postulated that polymorphonuclear neutrophils (PM s) possess specil~c receptors for C3. Upon interaction with the peptide they are induced to release lysosomal enzymes (86), one of which is an enzyme
Table 4
Properties of H ulllan C3e
Molecular weight (kDa) Gel clectrophoresis Amino acid analysis Electrophoretic mobility. pH 8.6 Isoelectric point No. of amino acid residues Biological acti vi ty Induction of leukocytosis (rabbits) Increased vascular permeability with leukocyte infiltration Release of lysosomal enzymes (PM s) Ligand for PMNs Ligand for monocytes
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12 10 -7.5 x 10- 5 cIll 2/volts/sec 4.3 101 10/lg/kg. intravenously 5 pg intradermally 4-25 ~lg/ml 62.000 sites/cell 43,400 sites/cell
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capable of generating a chemotactic activity when incubated with highly purified C5. Another fragment expressing similar biological properties to C3e has also been generated from iC3b by limited proteolytic digestion with kallikrein (88). This fragment, designated C3dK, also induces leukocytosis and is postulated that both C3e and C3dK may share overlapping sequence homology. A summary of the physiological split products and functions of C3 will be shown in Table 2. Another important physiological function of C3b is that it forms a subunit of the C5-converting enzymes of all three pathways (I). Formation of C3b in the vicinity of a C4b2a complex confers upon this enzyme the ability to activate and cleave C5, thereby changing its specificity (2). This C4b2a3b enzyme is the classic pathway C5 convertase and releases a 12 kDA peptide from C5, called C5a, and generates C5b, the first protein of the membrane attack complex (Fig. I). C5a possesses two important activities: It hares with C3a and C4a the property of being an anaphylatoxin, and it is a potent chemotactic factor that can attract neutrophils, eosinophils, and monocytes into the vicinity of an inflammatory reaction. Because the predominant cell in the circulation is the neutrophil, it is the most prominent cell seen in C5a-dependent inflammatory reactions. Furthermore, other findings indicate that. in contrast to C3a, which suppresses immune responses, addition of C5a to cultures results in the enhancement of specific and nonspecific humoral responses (74). C5a has been shown to augment antigen- and alloantigen-induced T cell proliferative responses but not mitogen-induced proliferative responses (88,90). In addition, the adjuvant effects exerted by C5a were found to occur within the first 24 h of culture, with T cells being involved in the C5a-mediated enhancement of humoral immune responses (74).
C.
Regulation
Regulation of the classic pathway (Table SA,B) occurs through a number of mechani ms. The first is the intrinsic lability of the activated or assembled proteins (e.g. activated C I is unstable and the C4b2a enzyme decays in serum with a half-life of only S min). The second is regulation by serum inhibitors such as CI-INH (or O'::,-neuraminoglycoprotein), which provides the main control mechanism for activated Cl by binding irreversibly to activated Clr and Cis and dissociating them from the CI macromolecule (27,91). Furthermore, CI-INH plays a crucial role in the homeostatic regulation of CI by preventing its dissociation, which
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Complement System Table 5A
Proteins CI-INH C4-bp Factor H Factor I Al S-protein" Sp40,40
87
Control Proteins of Complement Activation M W Electrophoretic Polypeptide Chromosome Mean serum (kDa) mobility chains location concentration (flg/ml) 110 500 150 88 310 83 80
I
a2 (31 (3 (3 a
? I 2 multiple al 1
II P 11.2 Iq32 Iq 4q24 17q II 8p21
200 250 500 35 50 600 50
"Also known as vitronectin.
Table 58 Membrane protein DAF MCP (CD46) CD59 HRF
Membrane Regulators of Complement Activation MW (kDa)
Target protein
Chromosome location
70
C4b2a
Iq32
45-70
C3b,C4b
Iq32
~19
C5b-8
1 I P 13
65
C5b-8
ND
Function Decay acceleration of C3/C5 convertases Causes breakdown of C3b.C4b Protection of homologous cells from MAC attack Similar to CD59
otherwise results in the autocatalytic activation of C I r (92,93). Genetic deficiency in CJ-INH, which is inherited as an autosomal dominant trait, results in a fatal disease called hereditary angioneurotic edema. It is postulated that a kinin-like activity derived from C2 as well as bradykinin derived from the intrinsic coagulation cascade may playa crucial role in perpetuating the symptoms of this disease. Regulation also occurs by proteolytic digestion of certain components such as cleavage of C4b by C4-binding protein (C4-bp) and factor I and digestion of C3 by factor I in the presence of factor H. The C4-bp like molecule, decay-accelerating factor (OAF), has the property of accelerating the dissociation of C4b2a complex and is an essential cofactor for the cleavage of C4b by factor I (94,95). In this respect its action is analogous to that of factor H in the alternative pathway. In addition, membrane proteins such as CR I (receptor for C3b and MCP) can serve as cofactors for factor I in the cleavage of C3b and C4b (96).
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II.
THE MANNAN-BINDING LECTIN PATHWAY
A.
General Considerations and Background
MBL pathway of complement activation (9-13.97) is the last of the pathways (Fig I, Table I) to be discovered and therefore, its structurefunction relationship at the molecular level has been worked out only recently (98.99). Mannan-binding lectin (also known as mannan-binding protein or mannose-binding lectin) belongs to a family of C-type lectins known as collectins (13,100-102). These molecules are structurally similar to C Iq: they are formed from three homologous chains each containing collagen-like sequences contiguous with non-collagen-like stretches that form the so-called 'globular heads' (10 I). Therefore the electron microscopic profi Ie of MBL resem bles the bouq uetlike structure of C Iq, although unlike C Iq, MBL can exist in various oligomeric forms including dimers, trimers, tetramers, pentamers, or heaxamers (l03,104). Other members of this family of proteins include lung surfactant protein A (SP-A), lung surfactant protein D (SP-D), collectin-43 (CL-43), and bovine conglutinin (105, 106). Their genes characteristically reveal the presence of a small exon encoding a 36amino acid-long neck region, which links the collagen domain with the globular head containing the CRD. The neck region forms a homotrimeric a-helical coiled-coil, which is essential for orienta~ion of the three 50 A-apart CRDs so as to have the ability to recognize high-mannose- and fucosecontaining glycoconjugates. These are generally found decorating the surface of micro-organisms but not on self proteins (107). This unique ability of MBL to recognize patterns of carbohydrate structures on microorganisms and thereby differentiate between self-proteins and nonself components. allows it to playa critical role in innate immunity (98).
B.
Initiation, Activation, and Regulation
[n plasma, MBL circulates in association with three structurally related serine protease zymogens designated MASP-I, MASP-2, MASP-3, and a nonenzymatic, truncated version of MASP-2 called MAp-19 (reviewed in 98,99) Whereas MASP-I and Map-19 form an association with lowermolecular-weight forms of MBL, MASP-2, and MASP-3 appear to associate preferentially with the higher-molecubr-vveight form of MBL (103.107-109). When compared at the molecular level, the domain structure of MASPs is identical to those of Clr and Cis (99). Whereas MASP-l is strikingly similar to Clr, MASP-2 is similar to Cis, suggesting that MASPs and ell' and Cis genes may have evolved from the same ancestral gene (98,99). MASP-I and MASP-3 are alternative splice products ;f a single gcnc and have identical A chains but have individual B-chains
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encompassing the serine protease domain. MASP-2 and Map 19, on the other hand are alternative splice products of the MASP-2 gene, with Map 19 consisting of the first two domains of MASP-2 and additional four amino acid residues (99). It is not surprising therefore, that activation or the MBL pathway is remarkably similar to that of the classic pathway, except that initiation does not require the presence of IgG or 19M on the surface of pathogenic micro-organisms. Instead, MBL binds directly to microbial carbohydrates and this in turn induces a conformational change within the MBL-MASP macromolecule, resulting in the activation of MASP-2. What role, if any, MASP-I, MASP-3, and MApl9 play in the MBL-complex is still unclear. Indeed, although the MASP-I concentration in plasma is approximately 20-fold more than MASP-2, the latter is fully responsible for the subsequent cleavage of C4 and C2 in a manner reminiscent of CIs (98). In this manner the C4b2a enzyme (C3 convertase) is generated and subsequent cleavage of C3 and C5 can proceed to form the lytic molecule, MAC. Another group of Iectins capable of activating complement by forming complexes with MASPs is the ficolins (110, III). Unlike M BL, these lectins do not have a typical C-type lectin recognition domains, but instead contain fibrinogen-like domains recognizing specific carbohydrate structures on activating microbial surfaces. Prominent among these lectis are L-ficolin and H-ficolin, both of which are able to associate with MASPs (Ill). In fact it is assumed that in ]'iva, most of the surplus MASP that is not bound to MBL is associated with these proteins.
III.
ALTERNATIVE PATHWAY OF COMPLEMENT ACTIVATION
A.
Initiation and Activation
Like the MBL pathway, the alternative pathway plays a significant role in innate immunity. It is one of the first lines of host defense capable of neutralizing a variety of potential pathogens in the total absence of antibody (78,112). Six proteins are necessary for activation of the alternative pathway: C3, factors B, D, 1, and H, and properdin (P) (3) (Fig. 1, Table I). The most critical and essential component of the alternative pathway, however, is surface-bound C3b, since, by virtue of its discriminatory interaction with biological surface structures, it serves as a recognition unit and dictates whether the pathway is triggered or aborted (3). Initiation and activation of this pathway therefore require the initial deposition of C3b molecules on a biological surface and recognition of this surface by the C3b molecules as an activator or nonactivator. However,
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generation of C3b molecules cannot occur unless C3 is acted on by a C3converting enzyme. According to the currently accepted theory, a C3b-like C3 [C3(H 1 0) or C3i] arises by nonenzymatic, spontaneous thiolester bond hydrolysis of C3 so that a low, steady-state concentration of the initial C3 convertase (C3iBb) of the alternative pathway (80-113,114) is generated (Fig. I). This C3b-like C3 or C3i, which has undergone thiolester hydrolysis without the loss of its C3a fragment, does not have hemolytic activity. However, it behaves functionally like C3b with respect to its ability to bind factors Band H, its susceptibility to cleavage by factor I, and, most importantly, its ability to form a fluid-phase C3 convertase in the presence of factors Band D and Mg1 + Thus, in the presence of Mg 1 +, C3i and factor B form a loose complex, C3iB, such that the factor B can now be cleaved by factor D to generate the initial fluid-phase C3 convertase: C3iBb (132). The first molecule of C3b produced by this enzyme thus sets in motion the C3b-dependent positive-feedback mechanism if it binds to an activating surface capable of protecting it from cleavage by factors H and I .(115). The surface-bound C3b is able to form a surface-bound C3bB complex, in which C3b serves as a cofactor (I 16), for the cleavage of factor B by factor D (I 17). Factor B is cleaved into two fragments: Ba (MW 30 kDA) is released into the medium and has been shown to have some chemotactic activity (I 18), whereas Bb remains bound to C3b to form the first surface bound C3bBb, which is the C3 convertase of the alternative pathway. The larger fragment Bb (MW 93 kDA) bears the active site for C3 cleavage. In addition, Bb has been reported to cause monocytes or macrophages to spread on surfaces (119). Because factor D is not incorporated into the C3bBb complex, it can thus generate multiple C3 convertases in a short time. However, C3bBb is labile and in the presence of factor H dissociates to form an inactive Bb (iBb) plus C3bH. This enzyme can be stabilized upon addition of the cofactor properdin (P), which binds reversibly to C3b and forms a more stable PC3bBb enzyme (120,12 I). This stabilized enzyme then digests C3 to yield C3a and C3b. By analogy with the classic pathway, addition of a second C3b molecule to this complex forms P(C3b)lBb, which then acts as a CS convertase (120). The CS convertases (like the C3 convertases) of both pathways share the same specil~city (120,12 I). There is therefore considerable structural and functional similarity between the enzymes of the alternative and classic and MBL pathways. Factor B is the equivalent of C2. and C3b acts like C4b . However, C2 is cleaved by Cis even in the absence of C4b, but factor B is cleaved by factor D only when it is in complex with its modulator, C3b. The remainder of the cascade (i.e., formation and assembly of the MAC) proceeds exactly in the same manner for all pathways and is described below.
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Complement System B.
91
Regulation
Like the MBL pathway, the alternative pathway is a major player in innate immunity. Initiation of the alternative pathway also differs from that of the classic pathway in that the initiating enzyme, factor D, which has an unusual substrate specificity, appears to circulate as an active enzyme and has no precursor or proenzyme form (122-124). However. unless the substrate of D is assembled properly on a sllrface, activation does not proceed. Although the alternative pathway can be activated immunologically, it is by and large triggered by a variety of nonimmunological agents such as endotoxin (lipopolysaccharide) (125), inulin (polyfructose), zymosan (126), rabbit erythrocytes (126), or certain Iymphoblastoid cells (112). In addition, activation can be triggered by immune complexes involving IgA antibody or by TgG antiviral antibody complexed to cells infected with virus. This last reaction has been demonstrated using measles, mumps, influenza, and herpes simplex viruses (127). Of particular interest is the special function played by two plasma regulators in controlling initiation and amplification of the alternative pathway (Table SA-B). One protein, factor H, is alSO KDa , single-chain molecule that binds to C3b (128) and can therefore dissociate Bb from C3bBb. Once dissociated, Bb is inactive (iBb) and cannot bind (i.e., C3bBb + factor H -7 C3bH + iBb), thus dissassembling the C3 convertase. Another regulator is factor l, which in the presence of factor H can cleave C3b to form iC3b, which can no longer interact with Bb to form a viable enzyme (128). However. cleavage of fluid-phase C3b by factor I is dependent on the presence of factor H and inactivation of surface-bound C3b is greatly enhanced by factor H (129). It has been shown that surfaces that initiate the alternative pathway have the property of excluding or preventing the reactions involving factors I and H so that initiation by D proceeds, whereas nonactivating surfaces allow these inhibitors to function and activation is prevented (78,130,131). In one model system it has been shown that rabbit erythrocytes can initiate the human alternative pathway and sheep erythrocytes cannot Treatment of sheep erythrocytes with neuraminidase to remove sialic acid converts the sheep erythrocytes into an initiator (114,131,132). As predicted, rabbit cells were relatively deficient in sialic acid. It therefore appears that the presence of sialic acid, as well as polyanions such as heparan, favors binding of factor H to the surface so that initiation of the alternative complement pathway is inhibited. Thus although a large number of cells are capable of binding C3b, only those that are capable of providing the C3b molecule with a microenvironment protected from the actions of factors H
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and I can succeed in promoting a self-destructive event (i.e., activation of complement on their surface). One of the mechanisms by which bystander cells or self-cells are protected against accidental lysis by complement is due to the presence of two types of regulatory proteins with factor H-Iike activities that have been isolated from human erythrocytes. The first of these proteins is a 105 kOA glycoprotein, which is the C3b receptor or CR I (133-135) and is present on B cells, PMNs, monocytes, and a certain subpopulation of T cells. It is characterized by its ability to dissociate the C3bBb and C4b2b enzymes, bind C3b, block binding of factor B to C3b, and modulate C3b and C3bi cleavage by factor T to form C3c plus C3dg. The second is a 70 kOA glycoprotein, designated OAF (136) because it can efficiently cause the decay dissociation of both the classic and alternative pathway C3-converting enzymes (133,137). More recently, another cell surface protein with complement regula tory properties has been identified (138). This molecule, called membrane cofactor protein (MCP), can also serve as a cofactor for factor T in the cleavage of C3b and C4b and, like OAF, has a wide tissue distribution. The biological significance of these regulators was recognized when it was shown that 44% of the red blood cells from a patient with paroxysmal nocturnal hemoglobinuria (PNH), which were susceptible to lysis by acidified complement, were found to be devoid of OAF even though CR I antigen was present (139) The molecular defect underlying the clinical manifestations of PNH may thus be in part due to the absence of membrane-associ a ted OA F (139). OAF is therefore the critical factor for dissociation of cell-bound C4b2a or C3bBb, although CRI or fluidphase C4b-bp and factor H are capable of doing the same thing. CR I is also critical as a factor I cofactor, a property it shares with C4b-bp and factor H but not with OAF. Patents with systemic lupus erythematosus (SLE) have been shown to have an inherited partial deficiency in erythrocyte C3b receptors. Tn addition, some SLE patients with proliferative glomerulonephritis had an absence of glomerular C3b receptors. These deficiencies were postulated to contribute to systemic and organ-specific abnormalities in the clearance of immune complexes and thereby to the pathogenesis of this disease (135).
IV.
MEMBRANE ATTACK COMPLEX
A.
Inititaion of MAC Pathway
Complement-induced mcmbrane damage and cytolysis are the final steps of complement ~Ictivation regardless of which pathway was initially
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Complement System
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activated (Fig. I, Table I). Membrane damage is caused by the so-called killer molecule or MAC. This in turn is entirely dependent on the initial cleavage of CS into CSa and CSb and CSb-mediated assembly of four structurally and functionalJy related proteins: C6, C7, C8, and C9. These proteins have the capacity to undergo a hydrophilic-amphiphilic transition. The C8 molecule is a heterotrimer composed of a, (3, and y chains, which are the products of three distinct genes. They are organized in the molecule such that the a and y subunits are disulfide-linked with each other while the (3 subunit is noncovalently associated with the a, y dimer. A striking feature of all the members of the MAC with the exception of C8y, is that they contain several structural and functional modules including a thrombospondin (TSR) module, an LOLl' module, an EGF module, a MAC-specific domain. and a lytic domain approximately 200 residues in length. While the C8a and C8(3 have an extra TSR module at the C-terminal end, the C8y, which is not required for hemolytic function. is structurally different from the other members of MAC and therefore does not contain these modules (140-145). The only enzymatic cleavage in the initiation and assembly of MAC is a single peptide bond clea vage in CS by CS convertases. This resul ts in the generation of two fragments: CSa and CSb. CSa is one of the most potent complementderived anaphylatoxins, whereas CSb is responsible for the initiation and assembly of the proteins into the supramolecular organization known as MAC (146). Assembly proceeds from formation of the stable bimolecular complex CSb-6 to the reaction of CSb-6 with C7. This results in formation of the intermediate complex CSb-7, which possesses a strong binding site for biological membranes (147). After the three-chain C8 molecule is bound to the CSb-7 via its CSb recognition site on the (3-chain, the CSb-8 complex reacts with multiple C9 molecules via its a-chain, leading to the formation of MAC (148). No enzymatic function has been attributed to C8; however, C6 has been reported to contain a catalytic site, which can hydrolyze acetyl glycyl-Iysine-methyl ester and is inactived by DFP (149); it is assumed that C7 might have similar properties (150). In the fluid phase C8 has a single binding site for C9, and the interaction is reversible (Ka ~ 10 7 M -I (151). However, several C9 molecules are bound to a target cell-bound CSb-8, and this association is virtuaIJy irreversible (Ka~ lO" M- ) (151). Binding of a molecule of C9 to CSb-8 further ' facilitates C9-C9 interaction. The energy derived from this interaction affects the unfolding of monomeric C9 (long axis changes from 80 to 160 A) (151) as it polymerizes to form poly-C9. Poly-C9 is amphophilic and capable of inserting itself into hydrophobic environments such as lipid bilayers (151). Individually spaced CSb-8 molecules can bind 12-16 molecules of
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C9, and clusters of C5b-8 molecules can bind 6-8 molecules. It appears that a larger poly-C9 is generated by an individually spaced C5b-8, and clusters of two C5b-8 form a poly-C9 (152) with fewer molecules. Assembly of the MAC results in the expression of hydrophobicity by the otherwise hydrophilic proteins. This property seems to be responsible for the insertion of C5b-7 into target membranes (153) and for membrane damage caused by the binding of C8 and C9 to C5b-7 complexes (154,155). Membrane damage and cytolysis caused by MAC have been attributed to lipid bilayer perturbation (156,157) and transmembrane channel (152,158) formation (148,152), followed by osmotic lysis due to ion exchange with the external environment with uptake of water accompanying sodium influx. Each lesion on the target cell membrane actually consists of (C5b-8) poly-C9 and is visualized by electron microscopy as a circular hollow structure ~ 12 nm above the membrane surface with inner and outer diameters of 10-llnlTI and 21nlTI. respectively (159). Although it is not an essential component of immune hemolysis. C9 markedly increases the rate of lysis of cells bearing C5b-8 [erythrocytes. Escherichia coli (160), Raji cells (l 12). and other nucleated cells]. C9 is also a critical component of the MAC-induced ultrastructural membrane lesions (161,162). Without C9, the C5b-8 complex possesses a certain degree of membranolytic activity since it can destroy organisms such as Neisseria gOl/orrhoeae (163). and individuals with homozygous C9 deficiency do not experience infections (164-167). Apparently the phospholipid-binding capacity and the ability of the complex to organize and thereby weaken membrane structures are sufficient to impair the normal function of some structures (153,157). It has also been shown that isolated C9 could undergo spontaneous polymerization at 37°C to form circular polymers resembling the ultrastructure of MAC (168). Such poly-C9 can become an integral membrane protein with membranolytic activity and the ultrastructural appearance characteristic of complement-ind uced membrane lesions (169). Circular poly-C9 forms spontaneously upon prolonged incubation of C9 at 37°C but require greater activation energy than that mediated by C5b-8 . On ultrastructural examination poly-C9 is described as a 160 A long tubule with an internal diameter of 100-110 A. rimmed on one end bv ~a torus with a 210 Aouter diameter terminated on the opposite end by a m~mbrane binding hydrophobic domain (169). Polymerization is accompanied by a change in secondal} structure with doubling of its axis from 80 A (C9 monomer) to 160 A and is accompanied by a hydrophilic-amphophilic transition enabling C9 Lo insert itself into phospholipid bilayers (169). One unique characteristic of poly-C9 is that it becomes extremely resistant to
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SDS as well as protease digestion. lL is suggested that this resistance may be a prerequisite for its function as the cytotoxic unit of the MAC complex (151).
B.
Regulation and Control
The MAC is under control of several plasma (S-protein, SP40,40) or membrane-associated [homologous restriction factor (HRF), CD 59] proteins that closely regulate the undesired assembly of MAC on homologous surfaces (Table I). The S-protein (vitronectin, 65-80 kDA) binds to C5b-7 complex and prevents C8 from binding and polymerization of C9. The apolipoprotein SP40,40. likewise also binds to C5b-7 activity and inhibits membrane insertion. SP40,40 is highly homologous to clusterin [also known as Sertoli's cell glycoprotein-2 (SCP-2)] is found at high concentrations in seminal fluid where it is thought to play an important role in protecting spermatozoa from complement attack. On the surface of cell membranes, however, the major regulatory proteins are integral membrane proteins such as CD 59 (19 kDA) and HRF (MW 65 kDA). Both of these proteins, which are anchored to the membrane by a glycosyl phosphatidylinositol (GPO anchor, bind to C8 and interfere with the formation of MAC assembly by preventing C9 polymerization. Complement-mediated and cytotoxic cell-mediated membrane lesions have striking similarities, which were further confirmed when two types (Tl and T2, 16 and 5 nm diameter, respectively) of complement-like membrane lesions were observed using cloned mouse natural killer (NK) cells as effectors and rabbit erythrocytes as target cells (170). The lesions apparently arise by membrane insertion of tubular complexes called perforins, which are assembled from subunits during the cytolytic action. Perforin. like MAC, has a lytic domain of approximately 200 amino acid residues and is about 25% identical to that of MAC. Unlike MAC however, perforin does not appear to require other proteins for its assembly and lytic function, but does require Ca"+ for its function.
V.
COMPLEMENT-DERIVED BIOACTIVE FRAGMENTS
One of the many striking features of the complement system is that its activation results not only in the destruction of a marked target cell but also in the concomitant generation of several biologically active cleavage products. That such fragments play an important role in various types of immune reactions (e.g., phagocytosis, chemotaxis. anaphylaxis, acute shock, and acute allergic reactions) as well as several other inflammatory responses
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is well documented (171). It was shown that certain active peptides such as C5a and C3a can interact with the immune system and modulate the immune response (74). A.
Anaphylatoxins and Inflammation
Activation of the classic pathway leads to the generation of most of the presently well-characterized fragments (Tables 2-4). Enzymatic digestion of C4 by CIs produces two fragments: C4a and C4b. Isolated C4a was found to be spasmogenic (guinea pig ileum at I ~lM), to cause muscle desensitization with respect to C3a but not C5a (i.e., tachyphylaxis at 0.33 /-lM), and to enhance vascular permeability (human skin, I nmol) with immediate erythema and edema formation (48,50). Because the spasmogenic, tachyphylactic, and vascular activities of C4a were abrogated by removal of the C-terminal arginine, a property that is characteristic of C3a and C5a, it was concluded that C4a represents the third complement-derived anaphylatoxin. All three anaphylatoxins (i.e., C3a, C4a, and C5a) are generated by proteolytic cleavage in the course of complement activation and as such share several structural and functional properties. First, all three are regulated by serum carboxypeptidase N or AI, which removes the C-terminal arginine residue to generate what is termed the des Arg forms of the proteins (Table 5A) Although the spasmogenic and permeabilityenhancing functions of the des Arg forms of C3a and C4a are abrogated, C5a still maintains some of its functions, notably its vascular permeability and chemotactic activity. Second, partial sequence analysis suggests that there is structural homology between these polypeptides with a helical conformation of 50, 54, and 45% for C3a, C4a, and C5a, respectively (48,50,172) (Table 3). In addition, C3a, C4a, and C5a are capable of inducing histamine release from mast cells and release of hydrolytic enzymes from neutrophils, causing contraction of smooth muscle, and enhancing vascular permeability (171). These activities are mediated by specific anaphylatoxin receptors expressed on these cells. The C5a receptor acts via a guanosine triphosphate (GTP)-binding protein complex and has approximately 35% sequence identity with the f-Met-Leu-Phe receptor. Both mediate similar but not identical responses on monocytes and neutrophils. Contrary to previously held theory that there are two types of anaphylatoxin receptors, one for C5a and the other common to both C3a and C4a, recent studies have suggested that there are in fact two distinct receptors for C3a and C4a, at least on monocytes and macrophages. Furthermore, although ncither the structure ofC3a-R nor that ofC4a-R has been yet elucidated, the structure ofC3a-R at least is most likely going to be similar to that of C5a-R since C3a activates the respiratory burst (173-176)
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Complement System Table 6
97
Major Cell Surface Receptors/Sites of Complement
SurCace protein
MW (kDa)
CO designation
250 220 190 160 145 ex = 165
Cm5
C3b/C4b
Iq32
C3clgjC3d iC3b
Iq32 lq32
f3=95 a= 150 f3=95
CD21 COllb COIS COlic COIS
iC3b
Iq32
C3a-R C5a-R cClq-R/CRc
45 60
None None
gClq-Rjp33
33
None
ClqRp
126
CD93
CRI-type CRI-type CRI-type CRI-type CR2 CR3(exj (3)
D" B A C
CR4 (ajf3)h
Ligand specificity
C3a/C4a C5ajC5a des Arg C Iq collagen domain, collectins (MBL, SP-A) C Iq-globular heads. HK, FXIl MBL, (Clq?)
Chromosome location
19 17p 13.3 not known
"Four structural allotypes. bHeterodimer of ct and fJ chains. "Identity with calreticulin.
and stimulates Ca1+ innux in neutrophils (173,174) via a pertussis toxinsensitive G protein (176). The C5a receptor (Table 6) is a member of the rhodopsin superfamily of molecules characterized by a seven transmembrane segment. It induces transmembrane signals via a GTP- and guanosine diphosphate (GDP)-binding intracellular mechanisms (175). Although the mechanism of C3a and C5a-mediated signaling is similar in many ways, C3a does not activate phosphatidylinositol 3-kinase, whereas C5a does. This suggests that overlapping but similar pathways are activated (177). Another unique property of C5a is that it contains in its structure a single oligosaccharide through which it associates with a 60 kDA plasma protein, thereby expressing enhanced chemotactic activity. This plasma protein is a vitamin-D-binding protein (Gc globulin) designated chochemotaxin (178,179). Furthermore. removal of the oligosaccharide moiety has been shown to restore anaphylatoxin activity to C5a (des-Arg), demonstrating the functional importance of this site (180). It has also become apparent that these activation peptides can playa role in immune regulation. For example. when cultures of human peripheral blood lymphocytes were
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incubated with human C3a, the ability of these cells to produce polyclonal antibody was suppressed Addition of C3a des Arg failed to cause any significant suppression, suggesting that the COOH-terminal arginine was required for this activity (89,90). In contrast to C3a, however, highly purified preparations of CSa or CSa des Arg were found to enhance the primary in vi/ro anti-SRBC responses of both human and mouse lymphocytes (89,90). Concentrations of CSa as low as 10 ng/ml significantly increased the response of mouse spleen cells (89).
B.
Leukocytosis-Mobilizing Activity
Another complement-derived fragment capable of exhibiting certain types of immunoregulatory functions is C3d-K, which is a cleavage product derived from iC3b by kallikrein (Table 2) and as such represents a novel peptide with biological functions (89,90). C3d-K was found to inhibit mitogen-antigen- and alloantigen-induced T-Iymphocyte proliferation (88). Furthermore, this fragment induced leukocytosis when injected intraveneously into mice or rabbits. Because leukocytosis-mobilizing activity was reported to be a property of C3e (86,87), a ] 0 kDA fragmen t derived late in the degradation process from C3c, it is postulated that C3d-K possesses some of the functional domains of C3e (88) The C3e fragment, in addition to its ability to induce leukocytosis, causes vascular permeability (Table 4), with cellular infiltration when injected intradermally (86), and causes the release of lysosomal enzymes from PMNs (87). These enzymes can generate chemotactic activity when incubated with highly purified human CS (87). PMNs and monocytes are also known to bindC3e (87). Because the fragment can be generated from serum by certain types of gram-negative bacteria (e.g., Pseudol71onCis aeruginosa) (86), the hypothesis is that it represents a late degradation polypeptide released during bacterial infections and septicemia.
C.
Phagocytosis and Clearance of Immune Complexes
The larger physiological or activation products also participate in several immunological reactions. The well-known complement-dependent immune adherence reactions, for instance, are mediated largely by the covalently bound complement cle,lvage products (C3b and C4b), which react with receptors of various types of cell (Table 6). These receptors include CRI (CD3S), which binds both C3b and C4b (181); and CR3 (CD] Ib/CDI8 or Mac-I antigen" aM{32); and CR4 (CDllc/CDJ8 or pISO,9S), which are specific for iC3b. CR3 and CR4 are members of the integrin f'amily of helerodimeric proteins and play important roles in leukocyte cell
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adhesion. Another member of the C3 receptor family is CR2, which binds iC3b or C3d and is primarily expressed on B cells. CR2 on B cells is part of a multimolecular complex that includes CDI9 and target for antiproliferative antibody I (TAPA-I) (182,183). It is not involved in phagocytosis but plays an important role in the immunoregulatory functions of B cells as evidenced by experiments in which the immune response of animals is impaired upon administration of anti-CR2. It is also now well established that Epstein Barr virus (EBV) gains access into B cells via CR2 and induces enhanced proliferative response, leading to cellular immortalization (183). The C3b in serum or on the surface of activating particles is rapidly cleaved to iC3b by factor I and its serum or cell surface cofactors (137,184). The subsequent conversion of iC3b to the two physiological fragments, C3c and C3dg, is however relatively slow. Therefore, the most important receptor in terms of opsonization and phagocytosis is CR3. Receptor-bound C3b (and C4b) is able to opsonize target cells and facilitate phatocytosis. In addition, these molecules are able to induce the release of lysosomal enzymes from a variety of cells (including PMNs, macrophages, and platelets), and potentiate cell-mediated cellular cytotoxicity (182). From studies of the mechanism of phagocytosis (185), it became clear that macrophages possess membrane receptors for Fc and C3b. Ingestion of sensitized erythrocytes depends on the interaction between these receptors and the red blood cell-associated ligands C3b and IgG (186). Furthermore, these receptors have synergistic roles in phagocytosis: C3b receptors mainly promote adherence of the sensitized particles to phagocytes, and the Fc receptors promote ingestion of the particles (186). It appears that C4b reacts with the same receptor and has similar biological effects, although the amount of C4b bound to the complement fixation site is smaller than that of C3b and thus of less significance in vivo. In addition, C3b and C4b have a role in the solubilization of immune complexes. This solubilization apparently results from the intercalation of these proteins into the immune complex lattice (186). Deposition of immune complexes is known to be a major mechanism of tissue injury and inflammation. Thus the interaction of complement-derived peptides with cellular receptors and its contribution to the clearance of immune complexes are of great potential significance (186). The significance of complement receptors in immune complex clearance is well documented, especially in immune complexmediated diseases in which complement deficiency is known to perpetuate the inflammatory process. The most abundant cell type in the blood of primates expressing CR I, the receptor for C3b and C4b, is the red cell (platelets in nonprimates), which, upon encountering complement-bearing immune complexes, shuttles them to the liver and spleen. Here, they are
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dislodged from the erythrocytes and digested by macrophage enzymes while the erythrocyte recirculates into the bloodstream. Other complement receptors (Table 6) that playa role in phagocytosis and immune clearance are those that bind Clq. Binding of Clq to cells is known to elicit a plethora of immunological responses (187-189). These functions include promotion of cell adhesion of fibroblasts, induction of 2 antiproliferative response on Band T cells, stimulation of Ca +-activated K+ channels and initiation of chemotaxis on mouse fibroblasts and mast cells, and enhancement of phagocytosis by neutrophils (187) and clearance of immune complexes and 3poptotic cells (190). Several cell-associated molecules referred to as C Iq-binding proteins or receptors have been described. These include gClq-R (191), cClq-R (187,188). ClqRp (189), and, most recently, CR I (192). Whereas the role of CR I in C3-mediated responses, is well established, its role in Clq-mediated responses, and indeed whether it binds Clq at all, is still being debated. Furthermore, crosslinking experiments using Clq as a ligand indicate that whereas both cClq-R and gClq-R are coimmunoprecipitated from B-cells or monocytes with anti-Clq, CRland Clq-Rp are not. Although ClqRp, a transmembrane protein, has been shown to enhance the phagocytosis of IgG- or C3b-opsonized particles by monocytes (189), it likewise does not directly bind Clq (193). Therefore, it is postulated that Clq-Rp constitutes a common component activated during a phagocytosis-inducing signal (26) regardless of the nature of the extracellular ligand that triggered the process (194). C Iq-Rp is an ~ 120 kDA O-sialoglycoprotein selectively expres ed on cells of the myeloid lineage 3nd has been shown recently to be identical to CD93 (194). Two molecules that have been shown to bind Clq with moderate to high affinity and induce direct, Clq-mediated responses are cClq-R and gClq-R respectively. The cClq-R molecule. which was the first to be i olated from Raji cell membranes, is a 60 kDA. highly acidic protein (187) and is identical to calreticulin (CR) (188). an unconventional. high-affinity. high-capacity. calcium-binding protein originally isolated from the skeletal muscle sarcoplasmic reticulum (195). It exists in t\\'o forms: a 52kDA endocalreticulin and a 60 kDA ectoc3lreticulin, and may serve 3S a putative receptor for multiple ligands transmitting information in both directions across the membrane (18~). CR has been cloned and sequenced and is encoded by a 1.9 kb mRNA. The gcne, which consists of 9 exons and 8 introns, has been localized to chromosome 19 (187). cClq-R/CR sharcs 64.4% identity with RALI (rabbit anti-larval), an antigen encoded by the filarial nematode Onc!l(}ccrcu l'o/m/us, the causative agent of onchocerciasis (river blindness). The striking similarity of the parasite antigen and the human autoantigen has led to the
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hypothesis that RALJ may induce a cross-reactive immune response to cClq-R/CR, which in turn raises the possibility that infectious organisms such as O. \lolpulus might trigger an autoimmune response (195). [n addition to Clq, cClq-R/CR has been shown Lo serve as a receptor for some members of the collectin family of proteins including M BL and SP-A (188). Another characteristic f'eature of cClq-R/CR is its ability to inhibit the hemolytic activity of C Iq by preventing immune complexes from binding to it . Thus, at sites of innammation or infection, the presence of nuid-phase cC lq-R may prevent immune complexes from binding C Iq and triggering complement activation. Whereas the likely binding site on C Iq for cC Iq- R/CR has been identified to be a region of high charge density near the bend region in the collagenous domain of Clq, MBL, or SP-A, the binding site on cClq-R/CR for Clq has been localized to residues 160-283 spanning the intersection between the N- and P-domains (188). The binding of Clq to cClq-R does noL require calciulll ions but is pH- and ionic strength-dependent. Furthermore, Clq within the pentameric complex does not bind to cClq-R/CR, suggesting that the receptorbinding site on Clq either overlaps with or is similar to the site for Clr2s2 binding (188). Like cClq-R/CR, the gClq-R/p33 molecule is also associated with many compartments of the cell (reviewed in 187) and possesses many characteristic features that make it a unique and an unconventional protein. It is a single-chain, ubiquitously distributed, and highly negatively charged (p[,4.15) cellular protein, which bi nds to the globular heads of C 1q under physiological conditions. The human as well as the mouse gClq-R genes have been recently cloned and are essentially similar in their exon/intron organization, composed of 6 exons and 5 introns each within a total length of approximately 6 kb DNA. The molecule is encoded by a single gene located on human chromosome 17 at a position corresponding to 17pl3.3. The mouse gC lq-R gene has been mapped to chromosome II, closely linked to DIlMit4 (187). The three-dimensional structure ofgClq-R/p33 has also been recently solved (196). Its structure is unique in that three monomers form a doughnut-shaped quaternary structure with a partially covered channel of about 20 A and an unusually asymmetrical surface charge distribution. One face contains significantly higher negatively charged residues (solution or s-phase) than the opposite surface (membrane or m-phase), indicating that the two faces fulfill different functions (196). An intriguing feature of the membrane-associated form of gClq-R, although it is expressed on the surface of cells. is that. like cClq-R/CR. its translated amino acid sequence does not predict the presence of either a sequence motif compatible with a transmembrane segment or a consensuS site for a GPI and does not bind
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directly to the phospholipid bilayer of the membrane in a nonintegral fashion (187). On endothelial cells in particular, gClq-R associates with the urokinase plasminogen activator receptor (u-PAR), and cytokeratin I, to form the zinc-dependent HK receptor complex (187). Recent evidence from our laboratory has established that gClq-R, which does not have a direct conduit to intracellular signaling elements, can nevertheless circumvent this deficiency by forming a signaling/docking complex with transmembrane proteins, one of which has been identified as a member of the ,BI-integrins (197). The evidence accumulated to date therefore suggests that the two ubiquitously expressed molecules, cClq-R and gClq-R, may playa fundamental role in Clq-mediated cellular responses as well as in infection and intlammation. More specifically, either or both molecules in association with other membrane proteins may participate in apoptotic cell uptake by macrophages and dendritic cells. This hypothesis is further strengthened by recent findings showing that engagement of cell surface cClq-R/CR and CD91 by Clq and MBL initiates macropinocytosis and uptake of apoptotic cells. This uptake was Il1hibited by antibody to cClq-R/CR but not by anti-CRl or antiClqRp (190).
VI.
INTERACTION BETWEEN THE COMPLEMENT SYSTEM AND THE PLASMA KININ-FORMING SYSTEM
A remarkable similarity exists between the mechanisms involved in the activation of the complement system and those of the Hageman factor (factor Xll)-dependent pathways that lead to blood coagulation, fibrinolysis, and kinin formation. Both systems require initial contact with an activator, which in turn initiates a cascade of reactions involving the sequential activation and conversion of zymogens to their proteolytic form. The inhibitor of Cl (CI-INH), which inactivates CI by binding to the activated Clr and CIs subcomponents of the molecule, is also a major plasma inhibitor of activated Hageman factor (HFa or XIIa), Hageman factor fragment (HFf, XIlf), factor Xla , and kallikrein by the formation of stoichiometric complexes. It is also a minor inhibitor of plasmin (198-203). This inhibitor is known to be functionally absent in patients with hereditary angioedema (58), a disease inherited as an autosomal dominant mendelian characteristic, which manifests by swelling and recurrent attacks of mucosal edema of the gastrointestinal and upper respiratory tracts. Uninhibited activation of factor XII may trigger the kinin system by conversion of prekallikrein to kallikrein, which in turn cleaves bradykinin from HK.
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The recent discovery that the endothelial cell surface receptor for both factor XlI and HK is the complement receptor gCl q-R (in association with cytokeratin-l and uPAR) has made the interrelationship between the classic pathway of the complement system and the contact activation even more intriguing. On the endothelial cell surface, therefore, binding of factor Xll and or HK can recruit and assemble the contact pathway proteins, leading thus to the generation of bradykinin (204,205). In the absence of Cl-INH any tissue injury that might trigger activation of the kinin-generating cascade would generate large amounts of bradykinin, a potent mediator that causes increased vascular permeability (198). Because the autoactivation of factor XlI, the conversion of prekallikrein to kallikrein, and the effects of kallikrein on factor XII and HK would be augmented in the absence of Cl-INH, it is of particular interest to know that factor XIIf (205,206), plasmin (20]), and, to a very small degree, factor XIIa can also activate complement via the classic pathway. Kallikrein (198), on the other hand, activates both the classic and alternative pathways. Ln terms of potency, the major complement activator appears to be factor XlIf, which directly cleaves and enzymatically activates C Ir (205). Activation of complement leads to the production and release of vasoactive peptides such as C4a, and a C2dependent peptide with kinin-like activity (58). The inactivation of bradykinin in plasma is dependent on carboxypeptidase N (kininase I), which cleaves the C-terminal arginine from bradykinin. Kininase r inactivates bradykinin (208) in a manner similar to the inactivation of the anaphylatoxins, C3a, C4a, and C5a. Because the anaphylatoxins lead to histamine release from basophils and mast cells, this plasma carboxypeptidase acts to control t\,VO types of vasodilators, which have similar phlogistic properties. In contrast, kininase II, which inactivates bradykinin, is also capable of generating the vasoconstrictor angiotensin II from angiotensin I (198). Interaction of these pathways is also seen in acute gout. In this case monosodium urate crystals are believed to initiate the inflammatory reaction (209,210). In addition to activation of the classic (211) and alternative pathways of complement, urate crystals have been shown to activate factor XII in human plasma and synovial fluid (212). That complement participates in the pathogenesis of gout has been reported previously (213). In view of these findings, it is possible to postulate that activated factor XII plays a role in the pathogenesis of this disease, either through the generation of bradykinin or activation of complement to produce vasoactive peptides. In general, the absence of an inhibitor such as CI-INH may upset homeostatic mechanisms that involve more than one pathway and are more likely to lead to severe disease than is the absence of
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a proenzyme, particularly if the function of the latter can be bypassed by some other pathway.
VII.
ACKNOWLEDGMENTS
The author expresses his gratitude to Miss Claudia CebadaMora for help with the figures. This chapter is dedicated to Larry and Sheila Dalzell, whose generosity over the past few years has been extraordinary.
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5 The IgE-Mediated Cutaneous Late-Phase Reaction Nancy Samolitis, Kristin M. Leiferman, and Gerald J. Gleich The University of Utah Health Sciences Center, Salt Lake City, Utah, U. S.A.
I.
INTRODUCTION
Antigen exposure with production of an immediate wheal and Oare in allergic individuals may lead to a prolonged inOammatory response known as the late-phase reaction (LPR) and also referred to as the dual-phase response. In 1873, Blackley (I), who was allergic to grass pollen, underwent a bout of sneezing and coryza lasting 6-8 h after pollen inhalation. On a different occasion, he accidentally inhaled a considerable quantity of pollen and developed nasal and systemic symptoms that lasted for many hours and prevented him from working for 2 days. Prausnitz and Klistner observed that the cutaneous inOammation associated with passive transfer of sensitivity lasted at least a day (2). In 1922, Cooke described a similar cutaneous reaction following exposure to horse dander (3). He developed a typical wheal and Oare followed by erythema and edema continuing into the following day. In 1924, Vaughn noted persistent inOammation at the site of skin tests (4). In 1952, Herxheimer stressed that the "late bronchial response" was "of great practical importance" and was associated with more severe asthma than the asthma in patients without late reactions (5). During the 1960s, Pepys and his colleagues called attention to dual skin reactions in patients with allergic aspergillosis and showed deposition of TgG, IgM, and C3 as well as marked tissue infiltration by neutrophils, suggesting an Arthus (Gell and Coombs type If I) reaction as the mechanism
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for prolonged inflammation. However, late reactions also occurred after skin testing with grass pollen extract (6), in which precipitating antibodies are uncommon, thus pointing away from a type III reaction. A key observation was that of Dolovich and his colleagues who showed that the LPR occurred after injection of specific antibody to IgE (7,8) suggesting that IgE played a central role in provocation of the LPR. Subsequently, Solley et al. (9) reported that the LPR could be passively tfansferred by purified IgE antibodies and that a reaction similar to the LPR could be stimulated by mast cell activators, such as compound 48/80. Their observations implicated IgE and the mast cell as critical elements for the provocation of cutaneous LPR. The objective of many recent studies has been to identify the mediators involved in the LPR and pharmacological agents able to block the reaction, in hopes that this information will yield insights into the pathogenesis of allergic diseases and means to thwart their expression. The skin is a useful model for studying the LPR because it is easily accessible for experimentation. Although the LPR has been investigated most intensely in the skin, it is intuitively obvious that it may be linked to the pathogenesis of chronic allergic disease in other epithelial organs, especially the respiratory tract, including nasal mucosa and bronchial tissues. The late-phase reaction has been reviewed previously and the reader is directed to this literature for discussions of its role in chronic allergic diseases (10-14).
II.
CHARACTERISTICS
The cutaneous LPR usually follows injection of a known allergen in a sensitized individual, although the reaction has also been triggered by intradermal injection ofanti-lgE or by passive sensitization with specific IgE antibody and subsequent allergen challenge (7-9,15). The LPR can theoretically be induced by any antigen that induces a wheal and tlare, and it is more likely to occur with higher concentrations of antigen. However, the LPR does not reproducibly [ollow upon an immediate reaction; for example, the wheal and flare reaction stimulated by cold exposure in patients with cold urticaria does not usually evolve into a LPR. Typically, the immediate IgE-mediated cutaneous reaction peaks at 15-30min following antigen exposure (Fig. I). Over the next 30min, the involved area becomes increasingly edematous and erythematous with loss of a distinct wheal. Symptoms remain minimal over the following 2-3 h. but then the onset of pruritus heralds an increase of inflammation peaking at 6-11 h after the initial antigen exposure. The peak LPR lesion is characterized by intense erythema. edema, tenderness. pruritus, and
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Figure 1 IgE-mediated late cutaneous reaction. A. Result at IS min. Note the small scar just to the left of the ring of erythema that serves as a landmark for the development of innammation. The antecubital fossae is on the left. B. Result at 90 min. Note that the edema has almost extended to the scar and the margins of the wheal are less distinct than at IS min. C. Result at 5 h. The edema has extended to and beyond the scar and down the forearm. D. Result at 8 h. Spreading edema has now enveloped the landmark small scar and has also extended down the forearm. A reticulated erythema covers the reaction area. (From Ref. 9.)
warmth. It is more diffuse and less defined than the immediate wheal and flare reaction and is proportionally larger. The LPR nearly always follows a wheal and flare stimulated by allergen if of sufficient magnitude. and it appears that an immediate wheal of about 8-9 mm is required to stimulate a clinicaJly observable LPR. Dolovich et al. found that a wheal of at least 8 mm is usuaJly required to stimulate the LPR (8) and Solley later noted that a wheal of 15 mm or greater will reproducibly induce the LPR (9). The duration of the LPR is usually 24-48 h and residual petechiae may remain for days. Shaikh et al. showed that the skin develops a relatively refractory state. with repeated antigen stimulation producing a less intense response (J 6)
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Figure 1
Continued.
On histological examination, the LPR is characterized by progressive edema and infiltration of inflammatory cells (9). There may also be significant vascular damage with hyalinization, fibrin deposition, hemorrhage, or necrosis. The composition of the inflammatory infiltrate varies with the progression of the reaction. Initially, there is perivascular infiltration primarily of eosinophils and mononuclear cells. At the peak of the LPR, a more diffuse infiltration of leukocytes is present consisting of mononuclear cells, neutrophils, and eosinophils. Studies using immunohistochemical staining demonstrate the significant presence of other inflammatory cells, such as mast cells and basophils, which may not be readily apparent on histological examination due to degranulation or loss of characteristic staining properties due to the effects of fixation (17).
III.
DEPENDENCE ON IgE
In
1968, Pepys et al. studied the LPR in patients with allergic bronchopulmonary aspergillosis (6). Using immunonuorescence studies of
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biopsy tissue, they found deposition of IgG, TgM, and C3 indicating that the LPR should be classified as a type III (Arthus) immune response relying on complement activation. However, as noted above, later studies have pointed to TgE as the major immunoglobulin involved. Some of the strongest evidence for this conclusion was provided by Dolovich et a!. who, in 1972, found that the LPR is stimulated by injection of sheep anti-lgE or its F(abh fragments and not by normal sheep serum or IgG F(abh fragments (7). In the LPRs of atopic persons sensitized with Bacillus sub!i!i.\', Dolovich and his colleagues found no evidence of IgA, IgM, or IgG (8). Additional significant support for the role of IgE came from the work of Solley et a!. using the passive transfer (or Prausnitz-Ktistner) model (9). Although passive transfer of aJlergic serum produces a less intense and shorter-lived LPR, it served as a useful model for study of the role of TgE due to the ability to manipulate TgE contained within the sensitizing serum. First, sera from allergic donors was heated at 56°C for 4 h in order to denature IgE (radioimmunoassay showed that IgE was 97-99% lost); the heated serum lost its ability to transfer passively the immediate reaction and the LPR. Second, removal of 99.7% IgE by an anti-lgE solid-phase immunoabsorbent abolished the ability of the serum to transfer both the immediate and late-phase response. Third, when the IgE was recovered by acid elution from anti-lgE solid-phase immunoabsorbent, the capacity for passive transfer of both immediate and late-phase responses was also recovered. Finally, as shown in Table I, a mixture of myeloma 19E in excess of the serum IgE resulted in an inhibition of the dual-phase response, suggesting competition between myeloma IgE and the sensitizing IgE required to initiate the response. The use of passive sensitization and injection of anti-lgE have both reliably reproduced the LPR in numerous later studies, although the former is no longer utilized because of concern for transmission of blood borne diseases.
IV.
DEPENDENCE ON INFLAMMATORY CELLS AND THEIR MEDIATORS
The histological observations demonstrating progressive infiltration of various innammatory cells during the LPR suggest that these cells contribute uniquely as well as interactively to the development of the LPR. However, enumeration of infiltrating cells by routine histological examination can be misleading because degranulating cells are often unrecognizable (17). To reveal the contribution of cells, immunohistochemical staining is necessary, especially to identify the presence of granulated cells such as basophils, mast cells, neutrophils, and eosinophils. Ying et a!. stained biopsies of cutaneous allergen-induced LPRs to delineate
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"'"
Table 1 Competitive Inhibition of Immediate and Late-Phase Responses by IgE Myeloma P.S. Composition of sensitizing material ()
.g ~
'§: CD
Solution number I
0..
2
~
3 4 5
CD
~
IgE myeloma P.S. 0.1 0.1 oI 0.1
(5I1lg(ml) (0.5mg(l1ll) (0.05I1lg(ml) (5I1lg(ml)
-
M.C serum b (ml)
0.9% NaCI
P.S . IgE(M.C IgE
01 0.1 0.1 0.1
1.0001 100:1 10:1 0.1 0.1
6c
Average diameter of edema (mm)"
o
)/, h
o
7 12
o o o o o
Ih
2'/, h
5h
8h
12 h
15.5
10 115
39
30
44
40
20
19
33.5
375
50
54
"After challenge of sensitized site with ragweed antigen. bAllergic serum from patient M.e., IgE protein 5,OOOng(ml. CSite not sensitized before allergenic challenge. Source: Adapted from Ref. 9. (/) Ql
3
Q.
a:
III
~
!!!.
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125
sequentially infiltration of various inflammatory cells (18). He and his colleagues analyzed the cutaneous LPR using a series of monoclonal antibodies specific for eosinophils, C03 lymphocytes, mast cells, neutrophils, macrophages, and basophils. The specificities of these monoclonal antibodies and the staining results of LPR biopsies from 6 h to 7 days are shown in Table 2. These results indicate a dynamic flux of infiltrating cells as the LPR proceeds, with a predominance of neutrophils at 6 h, a predominance of C03 lymphocytes at 24 h and a predominance of macrophages at 48 h, 72 h, and 7 days. Mast cell numbers decreased at 6h compared to the diluent control site, suggestive of mast cell degranulation early in the reaction. At 24 h, T-cell numbers peaked, and the numbers of neutrophils and eosinophils decreased. At this time point, mast cell counts increase likely due to regranulation and recovery. Other studies have shown similar results (19-22). To illustrate the extent of eosinophil and neutrophil degranulation, Leiferman et al. used immunofluorescence to localize neutrophil elastase, eosinophil-derived neurotoxin (EON), and eosinophil major basic protein (MBP) in biopsy specimens taken from allergen-induced and passively transferred LPRs (17). The deposition of these proteins peaked at 8 h, decreased by 24 h, and persisted at 56 h. The deposition of these granule proteins was out of proportion to the numbers of eosinophils and neutrophils seen on hematoxylin and eosin staining. Further support for the occurrence of degranulation was obtained by electron microscopy, which showed the presence of degenerating eosinophils as well as free eosinophil granules in the tissue. In agreement with the findings of Ying et al. (18), Leiferman et al. also found a significant decrease in the numbers of mast cells in the first 8 h of the reaction, with recovery at 56 h (17). Reactions that were passively transferred to nonatopic subjects showed a similar response but with lessened intensity in all aspects. In passively sensitized subjects, as in the atopic subjects primarily challenged, deposition of eosinophil and neutrophils granule proteins was dependent on the presence of IgE antibodies and was out of proportion to the number of infiltrating cells (17). Overall these results indicate that the flux of infiltrating cells shown in Table I must be viewed with the knowledge that, at least for eosinophils and neutrophils, extensive degranulation occurs so that simple enumeration of the numbers of cells underestimates their participation in the LPR. Thus, the findings in Table 2 may critically misrepresent neutrophil and eosinophil involvement because these cells are known to degranulate and lose their morphological integrity. A thorough analysis of the LPR should not only enumerate the numbers and kinds of infiltrating cells but also quantitatively describe the degree of cell degranulation.
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O'l
Table 2
()
Infiltration of InOammatory Cells in Allergen-Induced Skin LPR
Elastase+ neutrophils
0
"b
~
EGD2+ eosinophils
CD
BB- I+ basophils
s:
Tryptase+ mast cells
'§: 0.. Q)
CD
~
CD3+ T cells CD68+ macrophages
Diluent
6h
24 h
48 h
72h
7 days
42 (0.0-38.2) 0.0 (0.0-2.5) 04 (0.0-2.9) 833 (35.8-100.4) 74.2 (46.2-1079) 523 (11.8-151.9)
1014 (11.8-1534) 789 (44.8-1617) 177 (0.1--404) 37.7 (147-58.8) 92.6 (59.9-1308) 54.2 (14.7-214.5)
593 (14.7-122.9) 66.1 (19.6-160.2) 33.1 (12.1-619) 532 (4.9-85.3) 181.1 (86.4-290.1 ) 1179 (15.7-328.3)
48.5 (15-1166) 42.1 (10.5-94.2) 5.6 (0.8-36.9) 495 ( 19.6-84.3) In7 (47.0-214.6) 116.9 (18.6-3014)
416 (304-80.1) 403 (215-649) 35 (0.3-3.8) 53.9 (38.2-71.8) 694 (45.1-71.9) 1633 (I 58.3-208.7)
7. I (1.9-114) 78 (4.3--45.9) 17 (0.0-3.7) 58.8 (46.7-60.9) 67.1 (39.6-75.6) 1023 (95.6-130.9)
Results are expressed as median and range or positive cells per mm 2 or skin biopsies. Source: Modified rrom Ref 18. (J)
III
3
Q. C/l
!2. III
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The Mast Cell
Evidence points to a central role for the mast cell in the cutaneous LPR. This conclusion is based on knowledge that JgE is the major immunoglobulin mediator of the LPR: that the mast cell is the predominant tissuedwelling cell possessing a high-affinity receptor for JgE: that the mast cell contains mediators, such as histamine, capable of initiating innammation; and that the LPR is preceded by the immediate reaction. Thus, mast cells are activated early in the response to injected allergen and playa critical role in the LPR evolution. The Fc£RJ receptor (high-affinity IgE receptor) is present on the mast cell surface and is cross-linked when bound fgE interacts with multivalent allergen, leading to activation and degranulation (23,24). Additional evidence for the centrality of the mast cell comes from experiments using nonspecific mast cell activators. For example, injection of compound 48/80, a potent mast cell activating substance (25), provokes the LPR (9). Furthermore, injection of anaphylatoxin and complementfixing immune complexes induces the LPR (26). Finally, injection of mast ceJl granules or purified granule proteins also may produce the LPR (27,28). Mast cells degranulate early in the allergic reaction and their numbers are correspondingly decreased on histological specimens as described above. Leiferman et al. observed morphological changes in mast cells, with large granules in contact with the extracellular space on electron microscopy 3 h after allergen challenge (Leiferman KM, unpublished observations). The mechanisms by which the mast cells contribute to the intense innammation found in the LPR remain a subject of investigation. Although the immediate reaction is clearly dependent on release of mediators, such as histamine and leukotrienes, the mast cell mediators critical for the LPR are still not known. Studies on rat mast cells established that a LPR could be produced by injection of granules (27-35) and that the neutrophil is the predominant infiltrating ceiL Characterization of the granule factors responsible for neutrophil infiltration revealed the existence of biologically active high- and low-molecular-weight moieties (35); the high-molecularweight innammation-producing activity could be separated from chymase and heparin. Beca use of the central position of the mast cell in the LPR, the experimental approach taken in these investigations, namely characterization of the mast ceJl granule-derived proteins, appears valid, but it has not as yet been used for studies of factors from human mast cell granules. This approach also assumes that preformed proteins in the mast cell granule have the ability to transfer the LPR, and, as will be discussed below, the possibility exists that the mast cell de novo synthesizes molecules critical for the LPR.
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The mast cell contains many factors that may be active in the LPR and several are discussed below. This is by no means a complete list of mast cell mediators, but includes those thought to be pertinent to the LPR (36-38). Histamine is a preformed mediator released by mast cell granules and is an important contributor to the immediate hypersensitivity response (39). During the evolution of the LPR, histamine tissue levels typically increase in the first hour following antigen exposure, and then sharply decline and remain low through the duration of the LPR (38). A second, small histamine peak occurs around 8 h and is correlated with basophil infiltration and activation (37). Injection of histamine does not stimulate the LPR nor do classic H I blockers robustly inhibit it as they do the immediate reaction (40,41), although certain reports have shown a modest inhibitory effect of antihistamines on the cutaneous LPR (42). Tryptase and chymase are proteases released from mast cells. Tryptase makes up the majority of mast cell protein, and antibody to tryptase (labeled with a suitable tag) is an excellent mast cell stain. In the LPR, tryptase levels lag slightly behind those of histamine (43). Four classes of tryptase inhibitors have been devised and have been tested in the airways and skin of allergic sheep (44) and in the skin of mice (45), with results supporting a role for tryptase in the LPR. Aerosol administration of these inhibitors has abolished late-phase bronchoconstriction and airway hyperresponsiveness in a dose-dependent manner (45). A test of one of these, APC-366, a peptidic inhibitor, significantly reduced the late-phase response to allergen inhalation in atopic asthmatic patients without affecting bronchial hyperreactivity (46). It will be of interest to learn the effects of these inhibitors on the cutaneous LPR. Newly formed lipid mediators derived from the arachidonic acid pathway such as prostaglandin-D2 (PGD 2 ) and leukotreine-C4 (LTC 4 ) are able to stimulate a wheal-and-Oare response when injected intradermally (47,48). These mediators have actions similar to histamine and potentiate effects such as vasodilatation, increased vascular permeability, and smooth muscle contraction. Leukotrienes also have chemoattractant properties, particularly for neutrophils and eosinophils. PGD 2 levels rise early in the LPR and remain elevated throughout its peak (47). LTC.) levels are increased at 4-6 h following antigen exposure. near the peak of the LPR (49). Although H I antihistamines do not inhibit the LPR. the combination of a potent antihistamine. loratidine. and a leukotriene receptor antagonist, zafirlukast, markedly inhibited allergen-induced early- and late-phase airway obstruction (approximately 75%) (50). Another potentially active lipid mediator is platelet-activating factor (pAF) (51). PAF produces prolonged pulmonary inOammation following inhalation and, for a time. was believed to be a critical mediator of the LPR
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in asthma. However, trials with PAF inhibitors discourage belief that PAF is critical for the LPR, at least that in the lung (52). Mast cell derived cytokines include tumor necrosis factor-a (TNF-a), interleukin (lL)-4, IL-5, IL-G, and IL-8. Cytokines that likely playa role in the LPR will be discussed below, but it is pertinent to note that mast cell production of lL-4 and lL-5 implies a role for the mast cell in promoting a Th2 environment (53). lL-8 is a potent neutrophil chemoattractant. Chemokines released from mast cells include macrophage inflammatory protein-I a (MIP-la), monocyte chemotactic protein-l (MCP-I), regulated on activation, normal T-cell expressed and secreted (RANTES), and eotaxin (54).
B. The Basophil The basophil is similar to the mast cell in several ways including its highaffinity IgE receptor and its role in the LPR. However, it resides in the circulation and must be recruited to tissue to participate in the inflammatory response. The peak of basophil infiltration in the LPR is at 6-8 h after antigen exposure, and basophil numbers continue to increase through 24 h before tapering off (18). Chemoattractants of basophils include C5a as well as the chemokines, RANTES and MCP-I, which are known to be secreted by cells involved in the LPR (22,55) Basophils are often difficult to recognize on hematoxylin-and-eosin-stained specimens, so immunohistochemical staining with BB-I or 207 antibasophil monoclonal antibodies has been useful (20,21). Many of the mediators released by activated basophils are similar to those described for mast cells including histamine, tryptase (only I % of that seen in mast cell granules), arachidonic acid metabolites, and PAF. Basophils also have some features in common with eosinophils in that they contain molecules such as major basic protein (MBP) and the CharcotLeyden crystal protein. Basophils also release a kallikreinlike activity that may contribute to the development of angioedema and is able to simulate a LPR when injected intradermally (40). Cytokines and chemokines released by basophils include lL-4, lL-8, lL-13, and MJP-la.
C. The Eosinophil The eosinophil begins to infiltrate the perivascular region of tissues involved in the cutaneous LPR within the first hour following antigen exposure. Significant degranulation also begins this early and continues with a peak correlating roughly with the peak of the LPR (17). As noted above, this degranulation results in difficulty visualizing intact cells on histological
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examination; therefore, immunohistochemical staining with EG2 monoclonal antibody, reactive with eosinophil-derived neurotoxin (EDN) and eosinophil cationic protein (ECP) (56), or with antibodies to MBP, EDN, or ECP, have been useful to measure eosinophil involvement (17,18). Eosinophils are attracted into tissue by several mediators released from mast cells including LTB 4 and PAF as well as chemokines (see above). In in vitro studies, PAF potently attracts eosinophils as well as induces degranulation and production of free radicals and lipid mediators (57,58). Cytokines found in the LPR such as IL-5 and IL-9 promote eosinophil maturation and enhance survival (59). Although some reports have claimed that the eosinophil, like the mast cell and basophil, expresses a high-affinity IgE receptor, other reports have failed to confirm this claim (60,61). Eosinophils do, however, possess low-affinity IgE receptors (57,58). These receptors may be important in the eosinophil's role in parasite immunity, but their role in the allergic response remains unclear. The principal granule proteins in the eosinophil are MBP, EON, ECP, and eosinophil peroxidase (57,58). These are primarily cytotoxins and are bactericidal and helminthotoxic, but have other inllammatory properties as well. MBP, in particular, activates neutrophils and stimulates histamine release from mast cells and basophils. Both MBP and EON stimulate a wheal and flare response when injected intradermally (62,63). Activated eosinophils also release lipid mediators including PAF, destructive enzymes, and oxygen free radicals. Numerous cytokines and chemokines are liberated from eosinophils; those with activity in the LPR include IL-I, IL-4, IL-5, JL-6, IL-8, RANTES, and MJP-I Ci.
D. The Neutrophil Neutrophils infiltrate early and are one of the predominant cells (together with the lymphocyte) throughout the LPR. Neutrophils are recruited to tissue by numerous chemotactic factors that are known to be involved in the LPR such as JL-8 and LTB4. I L-8 is J member of the C-X-C chemokine family and appears to be the most potent neutrophil chemotactic factor. IL-8 is also involved in neutrophil degranulation, respiratory burst, and adherence to endothelial cells (64). lL-8 increases progressively in LPR blister Iluid during the first 6 h following antigen exposure and correlates with increasing infiltration of neutrophils (38). Although the exact role of the neutrophil in allergic inflammation is unclear. neutrophil degranulation is known to produce tissue damage correlating with pathological changes in the LPR (65). The azurophilic or primary neutrophilic granules contain elastase that is deposited diffusely throughout LPR biopsy specimens (17). Activation of neutrophils also
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results in liberation of numerous enzymes, oxygen free radicals, and lipid mediators, specifically LTB 4 , PAF, and thromboxane A 2 (TXA 2 ).
E. The Lymphocyte The primary lymphocyte infiltrating the LPR is the CD45RO+ memory T lymphocyte and it peaks in number at 24 h following antigen exposure (18). T cells may be transformed to the Th2 subtype by the environment of Th2 cytokines such as IL-4 and lL-5. In the LPR, these Th2 cytokines are released by mast cells, eosinophils, and the T cells themselves (53). Not only do lL-4 and IL-5 serve to perpetuate the Th2 environment, they also stimulate B-cell class switching to production of IgE and participate in eosinophil recruitment and survival. Other cytokines produced by Th2 lymphocytes in the LPR include IL-l, IL-6, IL-9, I L-I 0, and IL-13. The role of these and other cytokines is discussed further below.
V.
CYTOKINES AND CHEMOKINES IN THE LPR
A.
Cytokines
Cytokines are proteins or glycoproteins involved in virtually all types of inflammation. They are secreted by a large variety of cells and have numerous and overlapping functions. Several cytokines have been identified as important mediators in the LPR. IL-l and IL-6 are proinflammatory cytokines functioning as lymphocyte activators (64). They enhance fL-2 production and IL-2 receptor expression. B cells are also stimulated to proliferate and to increase immunoglobulin synthesis. These cytokines have been found in the LPR with both an early and a late peak (66,67). IL-4 and IL-5. as mentioned above, are important in supporting a Th2 environment. enhancing IgE production. and recruiting eosinophils (53.57). In situ hybridization analysis of mRNA for IL-4 and IL-5 in LPR biopsy specimens demonstrated colocalization and a significant increase in production of these cytokines in the first 6 h following antigen exposure. and they continued to increase through 24 h paralleling the clinical LPR (53); in this study, immunohistochemistry was employed to show colocalization of IL-4 and IL-5 mRNA with CD3+ T-cells, EG2+ eosinophils, and tryptase+ mast cells supporting the role of each of these cells in potentiating the Th2 environment. IL-9 is another T-cell-derived cytokine found in the LPR (68). IL-9 participates as a cofactor with IL-4 and IL-5, functioning to stimulate IgE production by B cells and eosinophil development (59). IL-9 also
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upregulates IL-5 receptor expression. Analysis of IL-9 mRNA using in situ hybridization demonstrated a progressive increase with a peak at 48 h after antigen exposure in the skin of atopic patients (68). The rise in IL-9 mRNA production correlated with the rise of Congo-red-positive eosinophils in these specimens as well. IL-13, another T -cel1-derived cytokine, likely contributes to the LPR along with IL-4 and IL-5. IL-13 is genetically linked to the gene cluster on chromosome 5, as wel1 as granulocyte-monocyte colony-stimulating factor (GM -CSF) (69-72). IL-13 is functionally similar to IL-4 in its ability to activate B-cell proliferation and IgE production. It also is a cofactor with IL-4 in the induction of vascular cell adhesion molecule-I (YCAM-I) expression. YCAM-I is an adhesion molecule that binds the integrin CJ.4f31 on the surface of inflammatory cel1s and is important in the recruitment of lymphocytes, monocytes, eosinophils, basophils, and mast cells in the LPR. Ying et al. identified the mRNA and protein products of IL-4 and IL13 in cutaneous LPR specimens and found that they correlated with the progression of the LPR with a peak at 24 h (73). Immunoreactivity of YCAM-l was found to parallel the LPR, the mRNA, and protein products of IL-4 and IL-13, as wel1 as the infiltration of neutrophils and eosinophils.
B.
Chemokines
Chemokines are chemotactic proteins that typical1y mediate cel1ular locomotion. They, like other cytokines, derive from various cel1 sources and have overlapping functions. Chemokines are organized into families based on the structure of the first cysteine residue. C-C indicates adjacent cysteines and C-X-C indicates a single amino acid separating the cysteines. Most of the chemokines that appear to be important in the LPR are C-C chemokines such as eotaxin, eotaxin-2, RANTES, MIP-IO', MCP-3, and MCP-4 (18,22). Eotaxin and eotaxin-2 bind to the receptor CCR3, which is expressed on eosinophil, basophil, and mast cel1 surfaces. The effect of eotaxin on eosinophil infiltration appears to be dependent on IL-5 (74). Ying et al. found peak expression of eotaxin mRNA and protein product at 6 h fol1owing introduction of antigen into skin of sensitized subjects, suggesting that eotaxin regulates eosinophil infiltration at this time point (22). These same investigators also showed a correlation between eosinophil infiltration at 24 h and expression of eotaxin-2 and MCP-4 mRNA (22). Expression of eotaxin mRNA was paralleled by the occurrence of the eotaxin receptor CCR3 on 8YYo of the eosinophils. No significant correlations were observed between BB I + basophil infiltrates, peaking at 24 h, and expression of eotaxin, eotaxin-2, RANTES, MCP-3, and MCP-4 (22). The results of
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Ying et al. suggest the eotaxin has a role in the early (6 h) recruitment of eosinophils whereas eotaxin-2 and MCP-4 are involved in the later (24 h) infiltration of eosinophils. Other chemokines such as RANTES. MCP-3, and MCP-4 bind to the CCR3 receptor leading to eosinophil and basophil chemotaxis, but they also bind the CCR I receptor located on neutrophils, eosinophils, monocytes, T cells, and basophils. Ying et al. described the peak expression of MCP-3 at 6 h in the LPR; MCP-4 and RANTES peaked later, at 24 h (22). In a different study, Ying and his colleagues described the activity of another chemokine that acts on the CCR I receptor, M IP-I a (18). In addition to stimulation of cellular motility, this chemokine also stimulates histamine release from mast cells and basophils. Ying and his colleagues found the peak expression of M IP-I a at 6 h after antigen challenge, with contin ued elevation through 24 h. At 6h, there was colocalization of MIP-Ia mRNA to neutrophils and basophils; at 24 h, colocalization was with macrophages. The expression of the CCRI receptor also correlates with presence of MIP-Ia.
VI.
PHARMACOLOGICAL INTERVENTION
The cutaneous LPR serves as a useful tool for the investigation of pharmacological agents that may be treatments for chronic allergic diseases in the skin, nose, and lung. Most drugs that inhibit the immediate hypersensitivity response do not inhibit the LPR and vice versa. Typical HI antagonists, for example, significantly attenuate the immediate wheal and nare, but they ha ve mll1imal effect on the LPR (41). Ceti rizine, however, has been found to have some effect on the size and symptoms of the LPR with a decrease in inflammatory cell infiltration but without a change in the mediator profile (75). This indicates an anti-inflammatory mechanism for cetirizine other than histamine blockade. Glucocorticoids remain the most effective agents for inhibition of the LPR. When given prior to antigen exposure or injection of IgE, a wheal and nare is produced without a subsequent LPR (76). Minimal or variable inhibition of the LPR has been observed with cyclooxygenase inhibitors, 5-lipoxygenase inhibitors, and beta-adrenergic agonists (77).
VII.
MECHANISMS RESPONSIBLE FOR THE CUTANEOUS LPR
As noted earlier, the mast cell is key to understanding the LPR, and IgE and its high-affinity receptor are the fuse that ignites the reaction (although, as
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noted above, other means to activate the mast cell, such as anaphylatoxin, appear to be sufficient). Although a few early studies showed the critical importance of IgE by stimulating the LPR through the use of anti-IgE and by passive transfer of IgE antibodies, essentially all of the recent analyses have stimulated the LPR by injection of allergens into allergic subjects. While this is eminently reasonable and clearly the safe way to proceed in view of the dangers of transmitting blood borne diseases, this approach may obfuscate investigations of the LPR because the allergens have the ability to stimulate both the LPR and the immune response. For example, the striking evidence for lymphocyte participation in the LPR (see Table 2) may be, at least in part, a response not as a component of the LPR but as part of the immune response to this antigen. Ideally one would prefer to dissect the LPR using tools to activate the mast cell and not stimulate an immune response in the recipient. Thus, a comparison of the LPR stimulated by allergen injection in a sensitive subject and the LPR stimulated by only mast cell activation might yield valuable information about the mechanisms critical for the instigation of the reaction and not a part of the immune response to the allergen.
VIII.
SUMMARY
The cutaneous LPR is clearly not a product of a single inflammatory cell or mediator. It does require the production of IgE in a Th2 environment. Although the LPR itself is a transient even!, its mechanism correlates with the pathogenesis of chronic allergic disease. The LPR is easily induced in skin with the use of intradermal allergen or anti-lgE, and this model is accessible for study using biopsy specimens or skin chamber fluid. As an alternative, the absence of a LPR in physically induced urticarias, such as cold urticaria or dermatographism, may point to a requirement for persisting antigen or at least a persisting stimulus for mast cell dearanulation. With increased knowledge of the m;chanism of the LPR, more directed therapy may be developed for treatment of chronic allergic disease with a focus on immunomodulatory effects.
ACKNOWLEDGMENT Supported in part by a grant from the National Institute of Allergy and Infectious Diseases, A r 09728.
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6 Acute Urticaria T. Zuberbier University Hospital Charite, Berlin, Germany
I.
DEFINITION
Acute urticaria is defined by a spontaneous appearance of wheals, possibly accompanied by angioedema, for a duration of no more than 6 weeks (1). Acute urticaria must be differentiated from acute attacks of physical urticaria, special defined types of urticaria, or other diseases related to urticaria (e.g., urticaria pigmentosa) in which whealing may also occur. There is no consensus in the international literature about the minimum duration of acute urticaria. This is of special importance since the term acute urticaria is used by most dermatologists to describe a disease entity clearly differentiated from the short occurrence of wheals (less than a few hours) as an accompanying symptom of other diseases or anaphylactic reactions. According to the consensus of the German Dermatological Society, a short appearance of wheals in a patient with anaphylaxis would be called an urticarial reaction, but not urticaria (2). This stands in clear contrast to the disease termed acute urticaria, in which whealing generally lasts for a few days at least. To many this distinction may appear semantic, but it has particular relevance for the interpretation of data regarding the epidemiology and causes of acute urticaria.
II.
EPIDEMIOLOGY
In the older literature lifetime prevalence of acute urticaria, based on questionnaires, ranges from 12 to 15% (3,4) or as high as 23.5% (5). In a Copyrighted Material
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prospective study [for a doctoral thesis (6), a summary of the data has been published in English (7)], in a rural area of Brandenburg a I-year incidence of 0.154% was found, which eq uals a lifetime prevalence of 11.56% based on a life expectancy of 75 years (7). These data can be considered reliable regarding the accuracy of the diagnosis of urticaria, since all patients were seen by the same dermatologist while still symptomatic. This was possible due to the fact that only one dermatologist was working in the area of investigation and all other doctors were instructed to refer all patients with urticaria to him. However, there is no way of estimating the number of patients with mild symptoms considering them to be of minor importance and who did not therefore contact any physician. This is conceivable in a rural area with a disease that is mostly self-remitting. Thus the true life prevalence for the area may be estimated to be approximately 15-20%. In our own retrospective, representative study of the population of Berlin, a I-year incidence rate of acute urticaria 0.6% was found, which is a four times higher life-time prevalence than was observed in the prospective study in the rural area (8). However, these data are based on a questionnaire asking persons if they had wheals within the last 12 months. The definition for wheal used was "the appearance of a fleeting elevation of the skin similar to that known after contact with nettles." Furthermore, the duration of the wheals was inquired. Although the investigators tried to contact all positive responders by telephone to verify the patients' history, the prevalence may be regarded as possibly too high due to the limiting factor that this was only a retrospective study. The prevalence of acute urticaria is higher in persons with atopic diseases, thus hay fever, allergic asthma, or atopic dermatitis was found in 50.2% of patients with acute urticaria in the above cited study of Ifflander (6). Simons (9) reports on a prospective study Il1 more than 800 12-24month-old children with atopic dermatitis, in which the study group not treated with antihistamines (11 = 396) had an incidence of acute urticaria of 16.2% over a period of 18 months. Further epidemiological data reveal a female preponderance (59%) (7) and 77% of the patients are younger than 40 years, while 37% are younger than 25 years. The average age is 31.4 years. There is an even distribution of this prevalence throughout the year (7).
III.
CLINICAL ASPECTS
Acute urticaria is char~lCterized by scattered wheals with a light red color (88%) and a diameter larger than I cm (80%).]n fewer than 5% of patients, wheals are accompanied by angioedema. In 18% of the patients disease
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severity is mild, with less than 10% of the body area affected. In 4~% the disease activity is moderate with 10-50% of body area affected, and in 40% of patients the disease activity is severe with more than 50% of body area affected and/or systemic symptoms. The coexisting systemic symptoms reported are mild shortness of breath (7.3 %), dizziness (2.7%), headache (1.8%), na usea (1.8 %), and diarrhea (0.9%). Full anaphylaxis can occur, but it is very rare. In more than 99% of patients the disease is self-limited and resolves within 3 weeks (7).
IV.
CAUSES
In the our prospective study of acute urticaria (7), 63% of the patients suspected food to be the cause. since they had consumed some food items within 2 h prior to the onset of urticaria. However, in only I of 109 patients was food shown to be the causative agent upon thorough investigation. Thus it appears that the patient's history. especially in acute urticaria, may be misleading. However, food is more frequently implied in children. since Legrain et al. (J 0) reported food. mainly cow's milk, to be relevant for acute urticaria in 10 of 12 children younger than 6 months of age. In older children with urticaria (6 l11onths-16 years), Kauppinen et al. (11) observed a prevalence of food intolerance of 15% as the eliciting factor for acute urticaria, whereas in an epidemiological study in 50 adult patients by Aoki et al. (12) not a single case of food allergy was found. Drugs can elicit acute urticaria both as allergens and as pseudoallergens. While penicillin is the most frequent example of an IgE-mediated drug-induced urticaria, acetylsalicylic acid is the most popular example of a pseudoallergen. The first example of urticaria and angioedema observed subsequent to acetylsalicylic acid intake was described by Hirschberg as early as 1902 (12). In our own study, drugs were responsible for 9.2% of the cases with acute urticaria; these were mostly nonsteroidal analgesics (acetylsalicylic acid in four cases, diclofenac in two, other nonsteroidal anti-innammatory drugs (NSAID] in three, sulfonizide in one) (7). NSAID, however, appear to play only a minor role in children, as in the study of Simons in which the only drugs incriminated were penicillin and amoxicillin, being responsible for 3.6% of the patients with acute urticaria (9). The most frequent cause of acute urticaria appears to be infectious and most of these are acute viral upper respiratory infections. The rate ranges between 28% and 62% of patients (Table 1). A possible explanation for the role of viral infections in acute urticaria is the triggering of mast cells via IgG receptors. However, it is also possible that in addition to the usual IgG response to the viral infection, specific IgE
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144 Table 1 Prevalence of Upper Respiratory Infections in Patients with Acute Urticaria Prevalence (%)
Study (Ref.)
28 39.5
Kauppinen et a!. (Il) Zuberbier et a!. (7) Legrain et a!. (10) Simons et a!. (9) Aoki et a!. (12)
SO 54.5
62
is being produced under certain conditions. Thus, Grunewald et al. (14) have shown in an experimental model that infection with an influenza A virus can lead to cutaneous anaphylaxis in mice due to the presence of low levels of virus-specific 19E antibodies. After rechallenge with the antigen the mice developed virus-specific mast cell degranulation in the skin for more than 48 h. Regarding the pathophysiology of whealing, like other forms of urticaria, histamine release by mast cells may not be the only mediation responsible for symptoms. Although the wheal itself is clearly histamine mediated, release of cytokines by mast cells, by other inflammatory cells, by the endothelium, or even by keratinocytes may modulate the clinical appearance. In acute urticaria these additional cytokine effects are probably of less importance, but they are still not negligible in patients with severe acute urticaria. Fujii et al. (15) have shown that in a group of patients with severe acute urticaria not responding to antihistamine treatment, elevated levels of circulating interleukin (IL-)6 could be found, while the other mast cell cytokines IL-8 and tumor necrosis factor-a (TNF-a) were not increased. The cytokine increase of TL-6, however, was not consistent in all patients, but limited to 9 of 16 individuals. This shows that like in other forms of urticaria, the pathophysiological reactions in acute urticaria are heterogeneous in different patients, which explains the different response to treatment and emphasizes the need for an individualized approach.
V.
NATURAL COURSE
No epidemiological studies available have monitored the natural course of acute urticaria in patients without treatment. In our own study the course of the disease was carefully monitored in a follow-up of patients organized into two treatment groups. The first group received loratadine 10 mgjday until remission of symptoms, the second group received prednisolone 50 mgjday for 3 days, followed by loratadine IOmgjday only in cases in which
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Follow-up o[ Patients with Acute Urticaria
Cessation o[ whealing within 3 clays 7 clays 14 clays 21 days >21 clays
Loratadine (10 mgjday)
Prednisolone (50 mgjday [or 3 clays)
65.9% 15.9% 15.9% 2.3% 0%
93.8% 3.1% 1.5% 1.5% 0%
Arter initial treatment with loratacline (17=44) or preclnisolone (11=65) ror 3 clays, all patients were then treatecl with loratacline (10 mg/c1) until remission.
Source: From Ref. 7.
symptoms persisted for longer than 3 days (Table 2) (7). None of the patients developed chronic urticaria and the disease can be regarded as mostly self-limited. However, 12% of the 109 patients reported preceding brief episodes of acute urticaria that occurred between the previous 6 months and 10 years earlier.
VI.
DIAGNOSIS
A thorough investigation of patient history is essential and may reveal eliciting factors. However, in the majority of cases this is not the ease, except for a possible infection within 7 days prior to onset of urticaria. According to an international consensus, further diagnostic procedures should be limited to cases in which a patient history raises suspicions. These tests may include prick tests (native prick-to-prick) with ingested food as well as provocation tests with drugs at a later time. In view of the mostly self-limited disease duration, skin tests or laboratory investigations in patients with suspected reactions to NSAIDs are not helpful due to the pseudoallergic nature of these drug reactions. They may be indicated for other drugs known to induce IgE-mediated reactions, such as penicillin. Blood tests for viral antibodies are not helpful even if viral infections appear to be the most com1110n cause. They are too nonspecific and expensive to warrant their use.
VII.
TREATMENT
According to an international consensu (1), the first-line treatment for acute urticaria is nonsedating HI-antihistamines, which may be increased up to
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four times the standard dosage with consideration of possible dose-related side effects like sleepiness (16). The second-line treatment is a short course of corticosteroids, typically 50 mg/day for 3 days is sufficient. According to our own study an initial short course of prednisolone may reduce the duration of the disease, but does not have any influence on the final outcome, since complete remission occurred in all patients (Table 2) (7). Regarding the choice of a nonsedating H I-antihistamine, the general considerations explained in Chapter 15 should be adhered to. Furthermore, in patients with acute urticaria it is important to choose an H l-antihistamine with a short onset of action at the patient's first visit to guarantee a fast relief of symptoms. Some of the new H I-antihistamines are effective as early as 20 min after oral intake. Thus emergency intraveneous treatment is of little benefit, especially since only sedating H I-antihistamines are available for parenteral use, which require a slow injection over a few minutes to avoid side effects, such as headache. Intra veneous, treatment should be reserved for patients with accompanying, possibly life-threatening, systemic reactions or angioedema of the throat or larynx, which is a rare finding. In a double-blind study by Watson et al. (17), intramuscular treatment with famotidine and diphenhydramine has been compared. Both treatments were found to be effective, which is very interesting, but the study was not placebo-controlled. For practical reasons intramuscular treatment has no advantage over oral treatment, but is more expensive and bears a higher risk of side effects. It can therefore not be regarded as first choice of treatment. In summary, the overall approach to patients with acute urticaria should start with reassurance of anxious patients that this type of urticaria is not dangerous, it is self-limited in more than 99%, of cases, and symptomatic relief can be achieved. Thorough diagnosis is only required in the unlikely case of persisting symptoms if no obvious cause is found in the patient history. ]n case of a viral infection in the past, a comforting explanation for the patient is that the wheals are a sign of an overactive and potent immune system.
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Zuberbier T, Greaves MW, Juhlin L Kobza-Black A, Maurer D, Stingl G, Henz BM. Definition, classification and routine diagnosis of urticaria-a consensus report. .I Invest Dermatol Symp Proc 200 I; 6: t23-I27. Zuberbier T, Aberer W, Grabbe .I, Hartmann· K, Merk H, Oller! M, RueA' F, Wedi B, Wenning J. Di~lgnostik und Ther~1pie der Urtikaria. [DDG-Leitlinie]. JDDG.
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Sheldon JM, Mathews KP, Lovell RG. The vexing urticaria problem. Present concepts of etiology and management. J Allergy 1954; 25:525-560. Champion RH, Roberts SOB, Carpenter RG, Roger JH. Urticaria and angioedema: a review of 554 patients. Br J Dermatol 1969: 81 :588-597. Swinny B. The atopic factor in urticaria. South Med J 1941; 34:855-858. lffliinder J. Akute Urtikaria-Ursachen, Verlauf und Therapie. Berlin, Humboldt University, M D dissertation, 1999. Zuberbier T, lfflander J, Semmler C, Czarnetzki BM. Acute urticaria-clinical aspects and therapeutical responsiveness. Acta Derm Venereol (Stockh) 1996: 76:295-297. Balke M. Epidemiologie del' Urtikaria. Eine prospektive, reprasentative Querschnittsuntersuchung zu Epidemiologie, atopischen Begleiterkrankungen und Lebensqualitatseinschrankung del' Urtikaria. Berlin, Humboldt University, MD dissertation, 2003. Simons FER. Prevention of acute urticaria in young children with atopic dermatitis. J Allergy Clin Immunol 2001; 107:703-706. Legrain V, Taieb A, Sage T, Maleville J. Urticaria in infants: a sludy in 40 patients. Pediatr Dermatol 1990: 7:101-107. Kauppinen K, Juntunen K, Lanki H. Urticaria in children. Retrospective evaluation and follow-up. Allergy 1984; 39:469-4 n. Aoki T, Kojima M, Horiko T. Acute urticaria: history and natural course of 50 patients. J Dermatol 1994: 21 :73-77. Hirschberg L. Miltheilung Libel' einen Fall von Nebenwirkung des Aspirin. Dtsch Med Wochenschr 1902; 23:416. Grunewald S, Hahn C, Wohlleben G, Teufel M, Major T, Moll H, Brocker EB, Erb KJ. Infection with influenza A virus leads to flu antigen-induced cutaneous anaphylaxis in mice. J Invest Dermatol 2002: 118:645-651. Fujii K, Konishi K, Kanno Y, Ohgou N. Acute urticaria with elevated circulating interleukin-6 is resistant to anti-histamine treatment. J Dermalol 2001; 28:248-250 Zuberbier T, Greaves MW, Juhlin L, Merk H, Stingl G, Henz BM. Management of urticaria-a consensus report. J Invest Dermatol Symp Proc 2001; 6:128-131 Watson NT, Weiss EL, Harter PM. Famotidine in the treatment of acute urticaria. Clin Exp Dermatol 2000; 25: 186-189.
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7 Contact Urticaria Esther Kim and Howard Maibach University of California at San Francisco, San Francisco, California, U.S.A.
I.
DEFINITION AND PATIENT HISTORY
Maibach and Johnson defined the contact urticaria syndrome as a biological entity in 1975 (l). Contact urticaria is an immediate contact reaction that appears on the skin within minutes to an hour after an eliciting substance has been in contact with the skin. The prototype reaction of contact urticaria is a local wheal and flare, although other reactions such as nonspecific symptoms (itching. tingling, burning). generalized urticaria, and anaphylaxis occur (Table I) (2). Many substances cause contact urticaria; therefore. a detailed history is essential to establish the cause. Contact urticaria symptoms usually appear within an hour after contact with the eliciting substance, and the patient may be able to associate these symptoms to a specific exposure. The extent of extracutaneous involvement should be obtained. The patient may be able to identify exactly what he or she was doing at the onset of the symptoms. allowing the physician to narrow down the possibilities. Details of a patient's employment should be ascertained, since many of the causes of contact urticaria are occupational. A personal or family history of atopy should always be ascertained as part of the history, as wel1 as a history of previous anaphylaxis when applicable. Signs on physical examination may be variable depending on when the patient presents. since contact urticaria lesions disappear by definition within 24 h of onset (62). The prevalence of contact urticaria in the general population is unknown because much of the epidemiological data are derived frol11
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Table 1 Staging of Contact Urticaria Syndrome Stage
Reaction
Cutaneous (skin) reactions only I
2 Extracutaneous reactions 3
4 SOI/rce:
Localized urticaria (redness and swelling) Dermatitis (after repeated exposures) Nonspecific symptoms (itching, tingling, burning) Generalized urticaria Bronchial asthma (wheezing) Rhinitis. conjunctivitis (runny nose. watery eyes) Orolaryngeal symptoms (lip swelling, hoarseness, difficulty swallowing) Anaphylactoid reactions (shock)
Adapted from Ref. 2.
occupational settings. Kanerva gathered statistical data on occupational contact urticaria in Finland; the most affected occupations were (in decreasing order) farmers, domestic animal attendants, bakers, nurses, chefs, and dental assistants (3). Elpern studied the relationship among race, gender, and age in Hawaii and found no difference in racial predisposition, a slight increase incidence in female patients, and constant incidence from the second to the eight decade (4). Contact urticaria syndrome can be categorized into two broad categories based on its mechanism of action: nonimmunological contact urticaria (NICU) and immunological contact urticaria (ICU).
II.
NONIMMUNOLOGIC CONTACT URTICARIA
A.
Natural History
NICU is the most common type of immediate contact reaction and occurs without prior sensitization. The NICU reactions usually appear within minutes to an hour and the edema disappears within I h, but redness may last for 6 h after contact with the eliciting substance (5). The symptoms vary depending on the substance, concentration, site of exposure, vehicle, and the mode of exposure. The symptoms usually appear and remain in the contact area (I). Generalized urticaria is rare after contact with an NICU substance and is usually seen in ICU. DilTerent JnHtomical sites show marked variation in susceptibility to NICU agents, with the most sensitive area being (in decreasing order) the face, antecubital fossa, upper back, upper arm, volar forearm, and lower back (18).
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The guinea pig ear swelling test has been used as an animal model to screen for putative agents and to clarify the mechanisms. Substances are applied to the earlobes and a positive reaction is comprised of erythema and edema. The increase in thickness is measured, with a maximal response being a 100% increase. The swelling response in the guinea pig depends on the concentration of the substance, which is similar to human skin. The guinea pig also demonstrates the tachyphylaxis phenomenon, which is a decrease in reactivity to NICU agents after repeated application of the eliciting substance. The refractory period for the following substances are 4 days for methyl nicotinate, 8 days for diethyl fumarate and cinnamic aldehyde, and 16 days for benzoic acid, cinnamic acid, and dimethyl sulfoxide (2).
B.
Mechanism
The mechanism of NICU is incompletely understood. ft was previously assumed that the reaction was a result of nonspecific histamine release from mast cells in response to exposure to an eliciting susbtance. However, antihistamines do not inhibit reactions to common NfeU agents such as dimethyl sulfoxide, benzoic acid, cinnamic acid, cinnamic aldehyde or methyl nicotinate (6). However, these common NICU agents can be inhibited by acetylsalicylic acid (ASA) and nonsteroidal anti-inflammatory drugs (NSAIDS) both orally and topically administered, suggesting the role of prostaglandins (7-9). The duration of inhibition by ASA taken orally may be up to 4 days (10). There is a release of prostaglandin D 2 without concomitant histamine release following topical application of sorbic acid, benzoic acid, and cinnamic aldehyde (lLJ2,15). Ultraviolet A (UVA) and UVB irradiation inhibits the NICU reaction for at least 2 weeks. This inhibition also includes areas of the skin sheltered from irradiation, suggesting a systemic effect (13). PsoralenjUV A (PUV A) treatment also has an inhibitory effect on NICU reaction (14). These results suggest that prostaglandin rather than histamine is the main mediator of NICU reactions, and that the source of prostaglandiins is in the epidermis, although the cells that produce prostaglandins in the skin remain to be identified. The systemic effect of UV irradiation suggests that some other susbstances are also involved in the reaction (5). The role of cutaneous nerves has been studied using capsaicin, which releases substance P and other acti ve pep tides from the axons of unmyelinated C-fibers of sensory nerves. Capsaicin pretreatment does not impair NICU in response to benzoic acid and methyl nicotinate but does inhibit the flare of histamine prick tests (16, I 7). Local anesthesia has shown a slight inhibitory effect on the NICU reaction (16).
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The molecular structure of an NfCU-causing substance is important, since a minor change in the structure can greatly alter its capacity to produce a reaction. Pyridine carboxaldehyde (PCA) has three isomers: 2-, 3-, and 4-PCA. Among the three isomers of PCA, 3-PCA was the strongest in both human skin and in the guinea pig ear-swelling test and 2-PCA was the weakest (19).
III.
IMMUNOLOGICAL CONTACT URTICARIA
A.
Natural History
fCU, a type I hypersensitivity immunological reaction, is mediated by allergen-specific IgE in a previously sensitized individual. Sensitization can be at the cutaneous level, but also can be through the mucous membranes or the respiratory or gastrointestinal tr3cts. The radioallergoabsorbent test (RAST) is an assay used to detect the specific JgE antibodies in the serum. ICU is mediated primarily by histamine, although other mediators such as prostaglandins, leukotrienes, and kinins are involved (2). The reaction usually appears within 5-15 min after contact with the eliciting susbstance, and a reaction of medium intensity usually disappears in 20-30 min. The severity of the reaction varies from mild symptoms such as a local itch and erythema to widespread generalized urticaria and anaphylactic shock (5). Anaphylactic reaction IS a clinical syndrome 111 which the predominant clinical feature is cardiovascular collapse, along with other manifestations such as bronchospasm, airway impairment and pulmonary edema. Anaphylactic reactions are immediate. allergic, and JgE-mediated. Complications of contact urticaria in the form of anaphylaxis are rare; however, it is a serious concern since it can be lethal. Contact urticaria and anaphylaxis are most commonly observed with latex allergy (53). However, contact urticaria with anaphylactic reactions is caused by numerous substances: oxybenzone (55), formaldehyde (56), rifamycin (57), Bacitracin and Polysporin ointment (58), raw potato (59), codfish (60), chestnu t (35), cornsta rch glove powder (41) and benzophenone (49). A common cause of ICU is natural rubber latex. The route of exposure to natural rubber latex includes direct contact with intact or inOamed skin as well as mucosal exposure, such as inhalation of powder from lalex gloves (38.39). The majorily of cases involve reaction to natural rubber gloves, although reactions from nonmedical natural rubber latex such as balloons, condoms, and toys occur (40). In the case of glove-related reactions to natural rubber latex, diagnosis
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can often be confounded by the presentation of JCU from cornstarch glove powder, which absorbs the protein (41,42) The number of reported cases has increased more than any other agent and as a result has become a major medical, occupational health, medicolegal, and financial problem for health care workers and glove-wearing occupations (21,22) Murine models have been used to investigate the role of route of exposure on the development of latex allergy to provide a mechanism for the evaluation of new technologies aimed at reducing the allergenicity of latex products (32,37). Numerous causes have been documented as causing JeU (Table with newly reported cases discussed later in the chapter.
n
B.
Mechanism
The mechanism of JeU is a type 1 hypersensitivity immunological reaction that requires that the person has previously been sensitized; he or she has already been exposed to the causative agent and therefore has produced specific IgE antibodies. In immediate allergy, sensitization most usually takes place in the airways. The specific TgE reacts with high-affinity 19E receptors on mast cells, basophils, eosinophils, Langerhans cells, and numerous other cells. An allergen molecule reacts with two adjacent IgE molecules bound to the cell membrane of mast cells, leading to the release of histamine, neutral proteases, exoglyosidases, and proteoglycans. The aliergen-JgE reaction also leads to a synthesis of leukotrienes, prostaglandins, and platelet-activating factor in the cell membranes of the activated mast cells. This results in a wheal-and-nare reaction in the skin and sometimes can lead to anaphylaxis if massive amounts of these active substances are released (2,5). Nitric oxide has been shown to be involved in immediate immunological reactions. The nitric oxide synthase inhibitor NG-nitro-L-arginine (L-NAME) was injected intracutaneously prior to provocation tests and was shown to augment immediate immunological reactions (prick test) (43). Cross allergy is often seen in many lCU reactions. The patient may be sensitized to one protein and react to other proteins that contain the same or a chemically rela ted allergenic molecule. One of the largest crosssensitization relationships is among birch pollen, fruits. and vegetables and was found in the 1970s (23) followed by observations of pollen and spice allergies (24). One of the main causes of cross-sensitization between pollens and fruits and vegetables was a pan botanical protein, profiling (25). The cross-reactivity of IgE antibodies with these allergens were demonstrated in vitro (26). Many patients with latex allergy
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expenence symptoms from banana, chestnut, and avocado (27-29). Hevein is one of the panallergens among latex and related foods. We would recommend that patients with latex allergy avoid fruits such as chestnuts due to a high risk of contact urticaria and even anaphylaxis as recent cases have been reported (35). Another recent case demonstrated cross-reactivity of shrimps and scallops, with the primary cross-reactive allergen being the muscle topomyosin seen in both phyla (36).
C.
Testing
The diagnosis of contact urticaria is based on both a detailed history and skin testing. Commonly used in vivo skin testing for both immunological and nonimmunological urticaria are the open test. the prick test. the scratch test. the scratch-chamber test. and the use test. In any of the above tests. it is important to perform positive (histamine. Img/ml) and negative (normal saline) controls. In addition to in vivo methods. the diagnosis of ICU can be done using in vitro RAST. This method detects antigen-specific IgE molecules from the patient's serum and is seldom needed for ICU diagnosis. although it may be beneficial in determining cross-allergenity. NSAIDs, antihistamines. and exposure to UV light can cause false-negative results, as can tachyphylaxis. In testing for ICU in patients with a history of extracutaneous involvement. particular care must be taken to use low concentrations of test substances, beginning with very dilute allergen concentrations and using serial dilutions if required to avoid reproducing
Table 2 Open Test
Materials
Method Reading time In terpretation Precautions
Controls
Allergen in vehicle (petrolatum, ethanoL water) Vehicle Cotton-tipped applicators or other devices to spread the preparations Allergen and vehicle are applied to skin. Up to I h U!'lica rial reaction is posi ti ve. General anaphylaxis not very likely because of the small amount of allergen introduced. but a physician should always be available in case of such occurrences. The patient should not leave the premises during the Arst 30 min after the test. Required to aid in differentiating lCU from NICU: in NICU the reaction will be noted in most controls.
Source: Adapted rrOI1l Ref. 33.
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Prick Test
Materials
Method:
Reading time In terpreta tion
Precautions Controls
A Ilergens in vehicles Vehicle (negative control) Histamine in 0.9% NaCI (positive control) Prick lancets One drop of each test allergen, vehicle. and histamine control is applied to the volar aspects of forearms. The test site is pierced with a lancet to introduce the allergen into the skin. 15-30 min An edematous reaction (wheal) at least 3 mm in diameter and at least half the size of the histamine control is considered positive in the absence of such reaction in the vehicle control. See Table 2. Required
Source: Adapted frol11 Ref. 33.
Table 4
Scratch Test
Materials
Method
Reading time lnterpretation
Precautions Controls
Allergens in vehicles Vehicle (negative control) Histamine in 0.9% NaCI (positive control) Needles A drop of each test allergen, vehicle, and histamine control is applied to the volar aspects of forearms or back. and needles are used to scratch the skin slightly at these areas. Up to 30 min Difficult because of unstandardizecl procedure. Edematous reaction at least as wide as the histamine control is considered positive in the absence of such reaction in the vehicle control. See Table 3. Required
Source: Adapted frol11 Ref. 33.
systemic reactions. Resuscitation equipment should be immediately available (2,33). It is generally recommended that suspected agents be tested 1I1 the following manner (20): 1. 2. 3.
Open test application to normal skin. If negative. open test application to previously affected, yet normal-appearing, skin. If testing on eczematous skin, test on an area showing only slight erythema so that urticarial responses can occur.
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Table 5
Scratch-Chamber Test
Materials Method Reading time Interpreta lion Precautions Controls SOllrc~:
Scratch lest materials (See Table 4) Chambers As with scratch test. but scratch site are covered with aluminum chambers for 15 min. 30 min See Table 4. See Table 3. Required
Adarted from Rer. 33.
4. 5.
If all the above results are negative, then occluded patch tests on normal or previously affected skin. If results are still negative, then perform prick testing. Scratch and scratch-chamber tests are more likely than other tests to produce false-positive responses.
In the open test, O.lml of the test substance in a vehicle (petrolatum, ethanol, water) is spread over a 3 x 3 cm area on the desired site. Alcohol vehicles are suggested, since the addition of propylene glycol to a vehicle enhances the sensitivity of the test compared with previously used petrolatum and water vehicles. The test should first be performed on nondiseased skin and, if results are negative, then on previously or currently affected skin. This is because there is a marked difference between skin ites in their capacity to elicit contact urticaria typically in IC but also seen in ICU (30,31). The test sites are usually read at ~O, -W. ~lI1d 60 min. in order to see the maximal response. ICU reactions typically appear within 15-~0 min, while NICU reactions can be delayed up to 45-60 min following application 0). The prick test is often the method of choice for testing if the open test gives negative results. The allergen in vehicle is applied 10 the volar aspect of forearms and the site pierced with a lancet to introduce the allergen into the skin. In theory, prick testing loses the lowest risk of anaphylaxis, as only minute amounts of allergen arc introduced into the skin. The test sites are usually read within 30 min. The scratch test is a less standardized method than the prick test, but it is useful for nonstandardized allergens. It is important to have at least 10 people as controls to avoid false interpretation of results. The allergen in vehicle is applied to the skin site and the area is scratched using needles. The test sites arc usually read within 30 min.
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Scale to Score Erythema
Score
Description Slight erythema, either spotty or diffuse Moderate uniform erythema Intense redness Fiery redness with edema
1+
2+ 3+ 4+ Source: Adapted I'rol11 ReI'. 61.
Table 7
Scale to Score Edema Descri ption
Score
Slight edema, barely visible or palpable Unmistakable wheal, easily palpable Solid, tense wheal Tense wheal, extending beyond the test area
I
2 3 4 Suurce: Adapted I'rol11 ReI'. 18.
The chamber test is an occlusive method of applying the substance to be tested. The substances to be tested are applied in small aluminum containers and attached to the skin via a porous tape for 15 min. The results are read at 20, 40, and 60 min. The advantages of this method are that occlusion enhances percutaneous penetration and, therefore, the sensitivity of tbe test is probably higher and a smaller area of the skin is required than in an open test. The use test is a method in which a subject known to be affected uses the causative substance in the same way as when the symptoms first appeared; for example, wearing surgical gloves 011 wet hands if that has provoked la tex leU. In all of the above test methods, contact urticaria can be graded visually by degree of erythema and edema on an ordinal scale (Tables 6 and Table 7) (61,18).
IV.
AGENTS CAUSING CONTACT URTICARIA
A.
NICU
Table 8 lists many substances identified as nonimmunolgical causes of contact urticaria, with the new addition of chrysanthemum (34).
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Kim and Maibach Possible Nonimmunological Causes of Conlact Urticaria
Foods Fish Cayenne pepper (capsicum) Thyme Fragrance and flavoring Balsam of Peru Benzaldehyde Cassia (cinnamon) oil Cinnamic acid Menthol Vanilla Med ica men ts Alcohols Benzocaine Camphor Cantharides Capsaicin Chloroform Dimethylsul fox ide Friar's balsam Methyl salicylate Mustard (black) Myrrh icotinic acid esters Tar extracts Tincture of benzoin Thyme oil Witch hazel Source: Adapled from Ref.
Animals Arthropods Caterpillars Jellyfish Moths Roe deer (Capreo{us capreo{us) Stinging insects Plants Coral ettles Sea anemone Chrysanthemum Preservatives and gerlllicidais Benzoic acid F orilla Idehyde Chlorocresol Sodium benzoate Sorbic acid Miscellaneous Acetic acid Ammonium persulfate Benzophenone Butyric acid Cobalt chloride Naphtha 21/99 Pine oil Sulfur Resorcinol Turpentine
~O.
A 34-year-old gardener and horticultural worker experienced local urticaria on the hands and forearms with no systemic symptoms after contact with chrysanthemum flowcrs. The patient was symptom-free on holidays and symptoms decreased on the weekends. Patch tests and results of RAST were negative to chrysanthemum. A positive rub test with chrysanthemum blossoms and a positive cellular antigen stimulation test (CAST) confirmed the skin reaction. The complement-activated (C5a) CAST stimulates isolated leukocytes of the patient with interleukin-2 and detects sulfidoleukotrienes when sensitization with the tested agent is present. The CAST was negative for control persons. These results favor a non-lgE mediated reaction classified as an NICU response (34).
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159
leu
Table 9 lists many of the substances that have been identified as immunological causes of contact urticaria. Recent additions to the list are reviewed below. A 55-year-old male professional hunter with no other past or present allergic diseases experienced contact urticaria and rhinitis after exposure to roe deer. Roe deer are among the most common game animals in Europe. Although occupational allergies to roe deer seem to be rare, the possibility should always be considered among people having contact with these animals. There is no specific deer dander allergen for specific fgE and skin tests, and therefore the relationship had to be confirmed using a rub test with the roe deer's fur. There was a clear positive urticaria reaction on the patient's skin as well as nasal itch, sneezing, and rhinorrhea following skin exposure to the fur. No reaction was noted in the control person (47). Potassium persulfate is a common ingredient in hair dyes. A 37-yearold homemaker experienced itch and erythema of the ears, neck, forehead, and hands after use of a hair dye kit. Prick tests were performed with isolated booster components found in the hair dye. All ingredients were negative except for potassium persulfate. Four controls were negative to this agent (52). There are two recent case reports of atopic patients who experienced contact urticaria from a hydrocortisone injection or infusion. Patient I showed positive skin prick tests in reaction to hydrocortisone, prednisolone, and methylprednisolone. Patient 2 had a positive intradermal test reaction to prednisolone. Eleven control persons were negative when tested with the same corticosteroids. Both patients had elevated 19E values (patient I: 286, kUjl; patient 2: 488 kUjI) and patient 2 had fgE antibodies to hydrocortisone and methylprednisolone conjugated with human serum albumin (54). An atopic 31-year-old woman worked as a florist for 5 years, and for the last 2 years she experienced severe rhinitis and urticarial lesions on her hands after contact with bishop's weed. Skin prick test was performed using the flower proper, which was positive in the patient but negative in the four atopic and six nona topic controls. The patient had elevation of bishop-weed-specific IgE level of 9.7 PRUjml in the serum documented by RAST (48). Occupational contact urticaria (CU) from plants is often reported, but it is less often attributed to decorative houseplants. A 22-year-old atopic gardener and caretaker of plants experienced contact urticaria when exposed to decorative houseplants. Contact with weeping fig. spathe flower, and yucca caused immediate skin symptoms and the patient
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Animal products Amniotic fluid Blood Brucella ahor! liS Cercariae Cheyletus malaccensis (house dust mite) Chironomidae, ChirOIlOl1l11S {hlll1//ni 'hll/lll11i
Cockroaches Dander Dermestes maculatus (beetle) Gelatin Gut Hair Listrophorus gibbus (mite) Liver Locust Mealworm Placenta Roe deer Saliva Seminal fluid Serum Silk (all kinds) Spider mite Wool Food Dairy Cheese Egg Milk Fruit Apple Apricot Apricot slone Banana Kiwi Litchi Lime Mango Orange Peach
Plum Strawberry Watermelon Grains Buckwheat Maize Malt Rice Wheat Wheat bran Honey Nuts Peanuts Peanut butter Sesa me seed Sunflower seed Meats Beef Chicken Lamb Liver Pork Sausage Turkey Salami casing mold Seafood Cod Crab Oysters Prawns Shrimp Vegetables Beans Cabbage Carrot Castor bean Celery Chives Cucumber Cucumber pickle Endive Garlic (CO/II illlled)
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Table 9 Continued
Lettuce Onion Parsley Parsnip Potato Rutabaga Tomato Soybean Winged bean (Goa bean) Fragrances and flavorings Balsam of Peru Benzoic acid Cinnamic aldehyde Menthol Vanillin Hair care products Basic Blue 99 Henna Hydrolyzed animal proteins Pa ra phen ylened iam ine Potassium persulfate Medicaments Acetylsalicylic acid Antibiotics Ampicillin Bacitracin Cephalosporins Chloramphenicol Gentamycin Iodoch lorhyd roxyq uin Mezlocillin Neomycin Penicillin Rifamycin Streptomycin Benzocaine Benzoyl peroxide C1obetasol 17-propionate Dini trochlorobenzene Diphenylcyclopropene Etophenama te Fumaric acid derivatives
Hydrocortisone Lindane Mech lorethami ne Mexiletine hydrochloride Phenothiazines Chlorpromazine Levomepromazi ne Promethazine Pyrazolones Aminophenazone Methamizole Propyl phenazone Tocopherol Metals Cobalt Copper Gold Iridium Mercury Nickel Palladium Platinum Rhodium Ruthenium Tin Zinc Plant products Abietic acid Algae Birch Bishop's weed: AII/Illi majus Bougainvillea Chamomile Chrysanthemum Cinchona Colo phony Corn starch Cotoneaster Elm tree Emetin Eruca sativa Eucalyptus (COl/IiI/lied)
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Fennel Ficus belljamilla Garlic Grevillea jUl1iperilla Hakea suaveolem Hawthorn: Craloegus mOllogYllo Henna Hops: Humulus lupulus Latex rubber Lichens Lily Limba LilllOlliul1I lalriell/II Mahogany Mulberry Mustard Obeche Papain Perfumes PllCIseolus 1I/L111iflorus Rose Rouge Semecarpus anacardium Spathe Flower: Spalhiph.1'llulII ll'ollisii Spices Teak Tobacco Tulip Yucca Preservatives and disinfectants Ammonia Benzoic acid Benzyl alcohol Butylated hydroxy toluene Chlorhexidine Chloramine Chlorocresol Chlorohexidine IJ-Diiodo-2-hydroxypropane Forma Idchyde Gentian violet Hexantriol
para-Hydroxybenzoic acid Parabens Phenylmercuric propionate Phenylmercuric acetate orlho-Phenylphena te Polysorbates Sodium hypochlorite Sorbitan monolaurate Sorbi tan sesq uiolea te Tropicamide Enzymes alpha-Amylase Cellulases Xylanases Miscellaneous Acetyl acetone Acrylic acid Acrylic monomer Alcohols (amyl, butyl, ethyl, isopropyl) Aliphatic polyamide p-A minod iphen ylam ine Ammonia Ammonium persulfate Ammonium chloride Baeililis-sublilis-derived detergent protease Benzophenone Benzophenone-3 Carbonless copy paper Chlorothalomil Chlorothanil Citraconic anhydride Cu( II )-acetyl acetona te Cyclopentolate hydrochloride Dentanium benzoate Dicyanidiamide Diethyltoluamide Ethylenediamine Epoxy resin Formaldehyde resin Hypoch lori te (C()I/Iil/lled)
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Table 9 Continued
Lanolin alcohols Methyl ethyl ketone Methylhexahydropthalic acid Methyltetrahydropthalic anhydrides Monoamylamine Morph oli nyImerca pto benzo thiaole Naphtha Naphlhylacetic acid Nylon Oleylamide Patent blue dye Perlon Phosphorus sesquisulfide Plastic Polypropylene
Polyethylene Polyethylene glycol Potassi um ferricya nide Sodium silicate Sodium sulfide Sulfur dioxide Terpinyl acetate Tinofix S I, I, I-Trichloroethane Textile finish Vinyl pyridine Xylene Zinc diethyldithicarbamate Zi nc pen tamethylenedi thiocarbamate Zinc dibutyldithiocarbamate
Source: Adapted from Refs. 2 and 20.
subsequently underwent allergologic investigation. Strong allergic prick test reactions were noted to yucca leaves, spathe flower (leaves and pollen), and weeping fig. Control testing of the three plants was done on 20 unexposed persons, and results were negative. Specific IgE antibodies were elevated to birch, spathe nower, and weeping fig based on results of RAST. Total IgE was 169 kU/I (46). HUl11ulus IUjJlIIlIs is a perennial vine that grows female nowers resembling cones that mature in the late summer. These ripe dried cones are called hops, and they are used in breweries and in herbal therapy. A 29-year-old man, who also had experienced urticaria-angioedema after ingesting peanut, chestnut, and banana, complained of urticaria on both hands while handling ripe dried hops. Prick testing was positive and total IgE was 64 IU/ml to ripe dried hops. A 27-year-old atopic man who worked at a chemical enzyme factory experienced contact urticaria after contact with liquid proteases and amylases. Prick tests were performed with Bacilus-slIbtilis-derived detergent protease (BSDDP), which provoked a strong test reaction. Twenty controls were negative when prick tested with BSDDP. RAST reactions to BSDDP were also elevated (50). Benzophenone-3 is a common sunscreen ingredient and is also known as oxybenzone. The occurrence of contact urticaria with benzophenone-3 is rare. However, a recent case reports a patient who experienced a contact urticarial reaction to the agent. The patient is a 40-year-old childcare assistant who showed urticaria and anaphylaxis after applying a sunscreen to
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her daughter's skin. She also experienced contact urticaria to certain lipsticks and shampoos that were later found to contain benzophene-3. Patch testing was positive for benzophenone-3, with five controls being negative (49). Among the most common mydriatic eye-drops is cyclopentolate hydrochloride, and a recent case reports contact urticaria to cyclopentolate hydrochloride eye-drops with tolerance to other eye-drops. A 72-year-old man experienced erythema, edema, itching, and burning in his right eye with a urticarial rash on his right cheek following the path of drug-containing tears after administration of several drugs in his right eye: Colircusi Tropicamida, 1% cyclopentolate hydrochloride, and 10% phenylephrine. Patch testing showed positive results with cyclopentolate hydrochloride but was negative with all other eye-drops. Eight healthy controls were negative for cyclopentolate hydrochloride. Tests are not available to test the presence of IgE against cyclopentolate to confirm an immunological mechanism, although this is the most probable mechanism since negative results in all controls challenge the concept of an NICU mechanism (51). A 46-year-old cook had had chronic urticaria and had been treated at many hospitals, which had prescribed him antihistamine and antiallergenic drugs, with no improvement. After a detailed interview, it was established that his condition worsened when he put on polyethylene gloves at work. Prick and scratch tests with a solution extracted from his gloves showed a wheal-and-flare reaction at 15 min. Control testing on three healthy persons was negative to the extracts (44).
V.
TREATMENT AND PROGNOSIS
Contact urticaria is treated by prevention. which re-emphasizes the importance of clinical testing to identify the causative substance. The pa tient should then be advised to avoid that substance or products containing that substance, in order to prevent recurrence. Patient education is critical to prevention and patients need to be well informed about the nature of their reaction. Patients with leU should be advised to carry a medic alert tag listing their allergen as well as potential cross-reacting substances and should also carry antihistamines and self-administered subcutaneous epinephrine. Other than avoiding the specific eliciting substance, there is no need to observe specific dietary guidelines nor is there any restriction on physical activity. Prognosis is entirely dependent on the ubiquity of the eliciting substance and the patient's ability to avoid contact with it. The prognosis is usually quite good in patients who take an active role to avoid the substance as well as controlling their environment.
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CONCLUSION
Contact urticaria is the whealing of skin when it comes into contact with certain substances. The urticarial lesions disappear by definition within 24 h of onset. Contact urticaria can be described in two broad categories: NTCU and lCU. Nonimmunological is more common than immunological urticaria. NICU does not require presensitization of the patient's immune system to an allergen. The mechanism ofNlCU is incompletely understood. However, there is evidence that NICU may be primarily mediated by prostaglandins rather than histamine, since the NICU reaction is inhibited by ASA and NSA10s administered both orally and topically. Immunological contact urticaria is a type I hypersensitivity reaction mediated by IgE antibodies and is less frequent in clinical practice than nonimmunological contact urticaria. Prior immune (lgE) sensitization is required to the eliciting substance. Sensitization may be via the skin, mucous membranes, and respiratory or gastrointestinal tracts. Atopic persons are predisposed towards ICU. Establishing a diagnosis of lCU is important because ICU reactions may spread beyond the site of contact and progress to generalized urticaria or may lead to anaphylactic shock, which can be life-threatening. Both types can be identified using skin testing methods. ICU agents are confirmed by positive RAST reactions to specific agents and by negative skin tests on control subjects. N1CU agents elicit a positive reaction in previously unexposed subjects; therefore control subjects test positive. Numerous substances commonly encountered in daily life may cause contact urticaria. The list of agents causing contact urticaria is large and dynamic. Numerous case reports of contact urticaria caused by a variety of compounds continue to be reported. It is important to identify the eliciting substance. since contact urticaria is treated primarily by prevention. Prognosis is usually good in patients who avoid the eliciting substance.
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Maibach HI. and Johnson HI. Contact urticaria syndrome: contact urticaria to diethyltoluamide (immediate type hypersensitivity). Arch Dermatol 1975; 111726-730. Amin S, Maibach HI. Nonimmunologic contact urticaria; Immunologic contact urticaria definition. In: Amin S. Lahti A. Maibach HI, eds Contact Urticaria Syndrome. eRC Press, Totonto. 1997.
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Kanerva L, Toikkanen J, Jolanki R. Statistical data on occupational contact urticaria. Contact Dermatitis 1996; 35(4):229-233. Elpern DJ. The syndrome of immediate reactivities (contact urticaria syndrome). An historical study from a dermatology practice. 1. Age, sex, race, and putative substances. Hawaii Med J 1985; 44:426-439. Hannuksela M. Mechanisms in contact urticaria. Clin Dermatol 1997; 15:619-622 Lahti, A. Terfenadine (H I-antagonist) does not inhibit nonimmunologic contact urticaria. Contact Dermatitis 16, 220, 1987. Lahti A, Oikarinen A, Viinkka L. Ylikorkala 0, Hannuksela M. Prostaglandins in contact urticaria induced by benzoic acid. Acta Dermatol Venereol (Stockh) 1983; 63:425-427. Lahti A, Vaananen A, Kokkonen E-L. Hannuksela M. Acetylsalycilic acid inhibits nonimmunologic contact urticaria. Contact Dermatitis 1987; 16:133-135. Johansson J, Lahti A. topical non-steroidal anti-inflammatory drugs inhibit nonimmunologic immediate contact reactions. Contact Dermatitis 1988: 19161-165. Kujala T. Lahti A. Duration of inhibition of non-immunologic contact reactions of acetylsalicylic acid. Contact Dermatitis 1989; 21 :60-61. Morrow JD, Minton TA, Awad JA, Roberts LJ. Release of markedly increased quantities of prostaglandin D2 from the skin in vivo in humans following the application of sorbic acid. Arch Dermatol 1994; 130: 1408-1412. Downard CD, Roberts LJ. Morrow JD. Topical benzoic acid induces the increased synthesis of prostaglandin D2 in human skin in vivo. Clin Pharmacol Ther 1995; 74:441-445. Larmi E. Systemic eflect of ultraviolet irradiation on nonimmunologic immediate contact reactions to benzoic acid and methyl micotinate. Acta Derm Venereol (Stockh) 1989; 69:296-301. Larmi E. PUVA treatment inhibits nonimmunologic immediate contact reactions to benzoic acid and methyl nicotinate. Int J Dermatol 1989; 28:609-611. VanderEnde D, Morrow J. Release of markedly increased quantities of prostaglandin D2 from the skin in vivo in humans after the application of cinnamic aldehyde. J Am Acad Dermatol 2001; 45: 61-67. Larmi E. Lahti A. Hannuksela M. Effects of capsaicin and topical anesthesia on nonimmunologic immediate contact reactions to benzoic acid and methyl nicotinate. In: Frosch PJ. Dooms-Goossens A. Lachapelle J-M. et al.. eds. Current Topics in Contact Dermatitis. Berlin/Heidelberg: Springer-Verlag, 1989:441-447. Bernstein JE, Swift RM. Keyoumars S. Lorinez AL. Inhibition of axon vasodilation by topicaly applied capsaicin. J Invest Dermatol 1981; 76:394. Gollhausen R. Kligman AM. Human assay for identifying substances which induce non-allergic contact urticaria: The NICU test. Contact Dermatitis 1985: 13:98-106
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Rasanen L, Tarvainen K, Makinen-Kiljunen S. Urticaria to hydrocortisone. Allergy 2001; 56:352-353 Emonet S, Pasche-Koo F, Perin-Minsini MJ, Hauser C. Anaphylaxis to oxybenzone, a freq uent consti tuent of sunscreens. J Allergy Cli n IITImunol 200 I; 107(3):556-557 Moder B, Kranke B. Anaphylactic reaction to formaldehyde. Allergy 200 I; 56:263-264 Mancuso G, Masara N. Contact urticaria and severe anaphylaxis from rifamycin SY. Contact Dermatitis J 992; 27(2): J 24-125. Knowles S, Shear N. Anaphylaxis from bacitracin and polymixin B (polysporin) ointment. Int J Dermatol 1995; 34(8):572-573. Beausoleil JL Spergel JM, Pawlowski NA. Anaphylaxis to raw potato. Ann Allergy Asthma [mmunol 200 I, 86( I ):68-70. Kalogeromitros 0, Armenaka M, Katsarou A. Contact urticaria and systemic anaphylaxis from codfish. Contact Dermatitis 1999; 41 (3): 170-171. Frosch PJ. Kligman AM. The soap chamber test. A new method for assessing the irritancy of soaps. J Am Acad Dermatol J 979; I(I ):35-41.
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8 Physical and Cholinergic Urticarias Anne Kobza Black St John's Institute of Dermatology, St Thomas' Hospital, London, United Kingdom
I.
APPEARANCE AND PREVALENCE
The physical urticarias are a distinct subgroup of urticarias in which a specific physical stimulus induces reproducible whealing (1-3). They are classified according to the eliciting stimulus (4,5) (Table I) Cholinergic urticaria occurs in response to stimulation of sweating such as caused by general overheating compared to local heat application. Although it is not strictly a physical urticaria, because it also may be triggered by stimulation of emotional and gustatory sweating, it is frequently included in the physical urticaria group for convenience. Aquagenic and adrenergic urticaria, which morphologically resemble cholinergic urtiaria, are also included. Wheals induced by physical stimuli usually occur in minutes at the site of contact with the skin and resolve within 2 h (immediate contact type). However, sometImes a physical stimulus needs to induce a generalized body challenge to induce a reflex type. For example, cooling the body core temperature can induce ret1ex cold urticaria and raising core body temperature can induce cholinergic urticaria. In these urticarias, multiple wheals occur on widespread areas of the body. In a few forms of physical urticaria (e.g., delayed pressure urticaria, delayed dermographism) a delay, often of several hours, occurs from the stimulus to the onset of whealing, which can persist for 24 h or longer. Combinations of a physical urticaria with other physical urticarias or with ordinary urticaria in the same person are not uncommon. The quality of life of patients with physical urticarias can be markedly reduced, in particular due to cholinergic and delayed pressure urticaria (6).
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Table 1 Classification of Physical and Cholinergic Urticarias Due to mechanical trauma Dermograhism Immediate dermographism Simple Symptomatic Localized Delayed: occurring after a delay of 30 min Variants Red dermographism Cholinergic dermographism Associated with mastocytosis Immediate pressure urticaria Delayed pressure urticaria Vibratory angioedema Inherited Acquired Temperature changes Heat Cholinergic urticaria Variants Cholinergic pruritus Cholinergic erythema Cholinergic dermographisn Exercise-induced anaphylaxis (some) Localized heat contact urticaria Cold Typical positive cold contact stimulation test Primary Secondary: cryoglobulins, cryofibrinogen, cold hemolysins, Atypical cold stimulation tests Familial Acquired contact: Delayed cold urticaria Localized cold urticaria Cold-induced dermographism Cold erythema Localized rellex Cold-induced vasculitis Systemic: Reflex cold urticaria Cold-induced cholinergic Exercise-induced anaphylaxis Pure Food-dependent, exereise-Illduccd anaphylaxis Specific NonspeciiC Cold-dependent exercise ind uced :1 na ph ylaxis Adrenergic urticaria Solar urticaria Aquagenic urticaria Combinations of dil1Crcnt types of physic,11 utricarias "re COlllmOIl.
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Figure 1 Proposed mechanisms of localized contact urticarias. (Courtesy of the Department of Photography, St Johns Institute of Dermatology, St Thomas Hospital.)
The frequency of physical urticarias in the general population is unknown. However, of all urticaria cases seen in a dermatology clinic 19% were physical urticarias (7), but 30% were in a more recent series (8). In patients with chronic urticaria the physicalurticarias accounted for 31 (9) and 33 % (10). In children, the reported freq uency of physical urticarias among patients with chronic urticaria varies between 6.2% (II) and 25.5% (12), with cold urticaria predominating in many series. The pathogenesis of physical urticarias is not well defined. A working hypothesis for immediate contact urticarias is that the physical stimulus induces a neoantigen. This stimulates production of an IgE antibody that binds to the mast cells. On further challenge a type 1 allergic response ensues with liberation of mast cell mediators, inducing a whealing response (Fig. I). It is important to establish the diagnosis of physical urticarias, by appropriate history and challenge tests, to prevent unnecessary investigation, such as for food allergies, and to institute correct therapy.
II.
URTICARIA DUE TO MECHANICAL FORCES
A.
Dermographism
Dermographism (3,14) literally means skin writing. The more common forms are simple dermographism and immediate symptomatic dermographism (factitious urticaria). Firm stroking of the skin of normal people can
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induce some erythema and wealing at the site, but in 5% of normal young people the whealing response is conspicuous enough to warrant the term simple dermographism (J 5). There is no associated itching, and this response can be regarded as an exaggerated physiological response. The people are aware of their condition and no treatment is necessary. In immedia te symptomatic dermographism (factitious urticaria), erythema and whealing occur in response to minor stroking of the skin, and are accompanied by itching. The response is maximal in 5-10 min and subsides within 30-60 min (15). The prevalence of symptomatic dermographism in the community is not well defined and varies, but in one study an incidence of 4.2% in the 2 population was found if a stroking pressure of 49.0 g/mm was used (16). In some dermatology departments 9% patients with urticaria had predominant dermographism (7-9) but 17% in an other series (J 0), and is the most common physical urticaria. There is a report ofa family with dermographism in an autosomal dominant inheritance (17) and in identical twins (18). In symptomatic dermographism there is no evidence for increased mast cells in the skin (19,20). However mast cell degranulation and an associated rise in plasma histamine levels (20) occurs in dermographic skin, and mast cells are necessary to induce dermographism (21). Mast cell activation may have an immunological basis. Dermographism has been successfully transferred with JgE (22) and occasionally JgM (23) when patients' sera has been injected into normal recipients' skin. It is also possible to transfer the whealing response from the serum of patients with severe dermographism to monkeys (24). It is postulated that an antigen induced by mechanical stimulation of the skin induces specific antibodies (usually IgE) directed against itself. When the antigen reacts with these antibodies bound to mast cells, activation and mediator release occurs. Substance P and vasoactive intestinal peptide (VIP) may potentiate histamine in the wheal formation (25). Symptomatic dermographism can occur at any age, but the greatest incidence is in young adults (13), with 29% occurring in persons below 9 years of age (16). Patients complain of itching, which is often disproportionately severe compared with visible signs. The itching is worse with heal, alcohol, and stress and often is most severe at night (13). rt can occur on the scalp, palms, and soles and may be a cause of genital pruritus and vulvodynia (26). Erythema and whealing occur at at sites of friction, for example, at collar and culT lines and at sites of scratching. The eliciting stimulus determines the shape of the weals, but these are often linear at scatch sites. The erythema and wheals usually subside within 30-60 min. It is unusual for mucosal surfaces to be affected. There is no association with systemic disease or food allergy or an increased incidence
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in chronic urticaria (13). Dermographism is usually idiopathic. Occasionally it occurs transiently after medication such as penicillin (27) and famotidine (28), after dinitrochlorobenzene (DNCB) sensitization (29) and after infestations such as scabies. Dermographism may last for months or years with an average course of 5 years in one study (13), although it can persist for 10 years or longer, or be present intermittently. Symptomatic dermographism is most precisely diagnosed using a calibrated instrument: the dermographometer (30). This penlike instrument has a spring-loaded stylus, the pressure application of which can be adjusted to a predetermined setting (Fig. 2). Stroking the skin at a pressure on the 2 skin of lower than 36 g/mm (13) induces a linear itching wheal within 10 min (Fig. 3). Weighted knitting needles have also been used for objective testing (31). If these are not available, moderate friction with a blunt instrument such as a spatula can be used with practice. Treatment of symptomatic immediate dermographism with 10wsedating H I-antihistamines is often effective, sometimes in low dosages. For the more severely affected, higher than the recommended dosages may be necessary, but there is no clinical benefit in combining HTantagonists
Figure 2 A dermographometer' a penlike instrument containing a spring. The markings can be calibrated, with the settings of this intrument being 0 = 20.4 g/mm", 10= 59.9 g/l11m", 10 = 99.4 g/mm" and 15 = 144 g/mn/. (Courtesy of the Department of Photography, St Johns Institute of Dermatology. St Thomas HospItal.)
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Figure 3 Itchy linear wheals with surrounding nare appeared 10 min after stroking by the dermographometer (Fig. 2) perpendicular to the back at the settings shown. There is a large wheal and nare even at the lowest setting. (Courtesy of the Department of Photography. St Johns Institute of Dermatology, St Thomas Hospital.)
with HI-antagonists (32). Some improvement of itching may be obtained with broad spectrum UYB (33) but psoralen and UYA (PUYA) provides only temporary relief of itching (34). Localized dermographism may occur rarely on areas with prior skin condition such as site of previous patch tests (30), fixed drug eruption (35), or tattoos. Red dermographism differs in that repeated rubbing (rather than a simple stroke to the skin) is necessary to induce erythematous areas studded with small wheals (36). Cholinergic dermographism is seen in some patients with cholinergic urticaria whose dermographic response consists of an erythematous line studded with punctate wheals characteristic of cholinergic wheals (37) (Fig 4). Pure delayed dermographism is rare. After a normal fading of the triple response or an immediate dermographic response, a wheal returnS in the same site but is usually tender and persists up to 48 h (38,39). The mechanism is unknown but is closely related to pressure urticaria (40), in cases of which a delayed dermatographic response may occur in 55% of patients (41) (Fig. 5). The presence of whealing following friction (Darier's sign) is characteristic of the lesions of urticaria pigmentosa in which mast cells are increased and may be a presenting sign of systemic mastocytosis (42). Not all forms of dermographism are urticarial. White dermographism (due to capillary vasoconstriction rollowing light stroking or the skin) occurs normally and is particularly pronounced in atopics. Black
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Figure 4 (a) Small punctate wheals along two vertical lines, after linear stroking of the back, being most marked on the right side. (b) Small punctate linear wheals in a patient with cholinergic urticaria and dermographism, appearing within minutes of scratching his back. Some of the wheals had coalesced. (Courtesy of the Department of Photography, St Johns Institute of Dermatology, St Thomas Hospital.)
dermographism describes discoloration of the skin after pressure from a metallic object.
B.
Immediate Pressure Urticaria
Immediate pressure urticaria occurs when whealing occurs within minutes of applying perpendicular pressure stimulus to the skin. Histological examination of the lesions shows dermal edema with a mild perivascular infiltrate (43). Patients experience itchy wheals within minutes after leaning against furniture, crossing legs, or handling a steering wheel (43). These may persist for 30 min to a few hours. There is no evidence of dermographism from stroking the skin. Immediate pressure urticaria may occur in association with the hypereosinophilic syndrome (44) or with delayed pressure urticaria (43). Antihistamine administration is helpful.
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Figure 5 Upper part of the figure shows, firm ,·vide linear wheals, 6 h after stroking the back of a patient with a dermographometer at the settings shown, in a patient with delayed pressure urticaria. Lower part shows firm papules appearing on the back of a patient with delayed pressure urticaria. The dermographometer set at 100 g/mm" was applied perpendicular to the back, and held there for 5-180 s. The required application time at the above pressure for the diagnosis of delayed pressure is 70 s. This patient also showed papules even after 5 s application. (Courtesy of the Department of PllOtography, St Johns Institute of Dermatology. St Thomas HospitaL)
C.
Delayed Pressure Urticaria
Delayed pressure urticaria (DPU) (41.45-47) is characterized by development of swellings at sites of sustained pressure on the skin after a delay of at least 30 min. These can persist for several days. Delayed pressure urticaria as the predominant or only problem is uncommon, accounting for 1-2% of urticarias (7-9). However, it occurs to some degree in up to 37% of patients with chronic ordinary urticaria, although they may not be aware of this unless directly questioned or tested (48)
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The underlying mechanism for delayed pressure urticaria is unclear. On histological examination of OPU wheals, there are decreased numbers of stainable mast cells (49) suggesting previous activation. Release of chemoattractant factors could account for the lesional dermal leukocyte infiltrate, (50) which has been likened to a late-phase cutaneous reaction (51), but no allergen can usually be identified. Neutrophils are present in the majority of early lesions (less than 9 h) and the minority of late lesions (over 24 h), and eosinophils are found in early and especially in late wheals (50). These cellular changes correlated with upregulation of vascular adhesion molecules E-selectin and vascular cell adhesion molecule (YCAM) (50). Increased levels of interleukin (lL) 6 (52) and tumor necrosis factor alpha (TNF-a) and IL3 expression derived from mast cells or the innammatory cell infiltrate (53) in lesions may amplify and perpetuate the process. A proposed scheme is shown in Figure 6. The swellings of OPU occur withn 30 min to 12 h after pressure application, are usually red, often itchy and painful, and persist for 12-72 h (41) and very occasionally can blister (54). Lesions appear at sites of tight clothes (Fig. 7): at the waistline, on hands after manual work, on buttocks after sitting on hard surfaces, and on soles after prolonged walking or standing, especially up ladders. Locally it may cause problems after sexual intercourse (55) and even urinary obstruction (56). OPU may be associated
Delayed pressure urtlcarla Pressure
..;J~
Kr}: . . . . .\..:. 5:'
'-tS; .
'.'
Mast cetl
? a(jtobodles against I!lE receptors
mediatr release
up-regulation of vascular endothelial adhesion molecules
l
cellular infiltrate-of neutrophlls, eoslnophils, I'll0nocytes
t
ampl1ficaflonby eoslnapl1i1 basIc ' I>rotein ~Jld rL~.",
Figure 6 Proposed mechanisms for delayed pressure urticaria. The possibility of involvement of autoantibodies directed against the fgE receptor IS included, since more than 30% of patients with ordinary urticaria have these autoantibodies, and 40% of these patients have delayed pressure uricaria. However, any involvement is conjectural. (Courtesy of the Department of Photography, St Johns Institute of Dermatology, St Thomas Hospital.)
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Figure 7 A firm, red, tender wheal, at the site of a brassiere strap. The wheal occurred several hours after wearing the garment, and lasted for many hours. The patient did not have immediate symptomatic dermographism. (Courtesy of the Department of Photography, St Johns Institute of Dermatology, St Thomas Hospital.)
with flulike symptoms, leukocytosis, myalgia, and arthralgia (41), sometimes of sufficient severity that patients present initially to a rheumatologist. oru may also be mistaken for urticarial vasculitis, in which some wheals also can appear at pressure sites (57). There is no good evidence for associated atopy or food allergy. Generally oru may severely affect the quality of life (6), and can cause lead patients to give up manual occupations. Patients with delayed pressure urticaria nearly always have associated chronic ordinary urticaria (40,46) and sometimes angioedema. Other physical urticarias such as delayed dermographism (55%), symptomatic immediate dermographism, and cold urticaria may also be associated (41). The diagnosis of OPU is confirmed by objective testing. After application of standardized weights to defined areas for specified times, red palpable wheals result al lhe application sites 2-8 h later. One method is to apply weighted rods, modified from Illig (58), with a convex end diameter of 1.5 cm to the lhighs and back. Weights of 2.5 or 4.5 kg applied for 20 min
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b
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Figure 8 (a) Two lucite platforms are supported firmly at the corners with fixed supporting rods. Rods with varying weights attached can be slotted into circular holes in the platforms to rest on the thighs for varying times (b) The lest areas on the thighs are examined 6 h later for development of rounded tender plaques. (Courtesy of the Department of Photography, St Johns Institute of Dermatology, St Thomas Hospital.)
and 15 min, respectively, in patients with delayed pressure urticaria result in an indurated wheal occurring 6 h later at the application site (Fig. 8). Using this response as a gold standard for the diagnosis of DPU, pressing a dermographometer set at 100 gjmm 2 at right angles on the back for various times, a wealing response at the 70 s site shown 6 h later gave the best combination of sensitivity and specificity (48,59) (Fig. 5) Less precise methods include hanging a weight (15 lb) on a wide strap for 15 min over the shoulder (45,46) or strapping a marble onto the forearm for 5 min (60) to induce wheals after several hours. Areas of delayed pressure urticaria may be refractory to further pressure-induced lesions for up to 48 h (61). Histological examination of a pressure-induced wheal would exclude urticarial vasculitis. In the latter, in addition to a dermal cellular infiltate, leukocytoclasia and less frequently fibrinoid necrosis would also be evident. Treatment of DPU is difficult and only a few controlled trials exist. Usually DPU responds poorly to antihistamine therapy (41,46), which, however, may help the ordinary associated urticaria. Cetirizine in high dosages (10 mg three times a day) has been advocated because it also
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inhibits eosinophils (62) but in clinical practice it has been generally disappointing. Although nonsteroidal anti-inflammatory drugs may be helpful for the pressure-induced wheals (46) they may exacerbate the ordinary urticaria. Anti-inflammatory drugs such as dapsone, 50 mg daily (63); sulfasalazine (64); and the leukotriene receptor antagonist montelukast, 10mg daily (65), have been reported to be beneficial in isolated case reports. A controlled trial of nimesulide 100 mg daily for 2 weeks, then combined with ketotifen j mg twice daily for 3 weeks, then ceasing nimesulide at 7 weeks showed improvement (66), but this requires confirmation. Systemic steroids can provide symptomatic relief but at dosages that are usually not justifiable for long-term therapy, usually over 30 mg prednisolone per day (41,46). However, they can be used in the short term for severe exacerbations such as difficulty walking due to gross foot swelling. Topical steroids applied under occlusion may be helpful in pretreating frequently affected localized areas (67). Oral cyclosporin at a dosage of 4 mg/kg/day is helpful in the treatment of chronic urticaria associated with delayed pressure urticaria and may help in cases where pressure urticaria is the predominant symptom. The prognosis is variable, with symptoms fluctuating in severity. In a series of 44 pat ients, the mean duration was 3-9 years (41), but it can persist longer.
D.
Vibratory Angioedema
Vibratory angioedema is a very rare physical urticaria, which was first described in its familial autosomal dominant form (68) and also in another family (69). Any vibratory stimulus such as jogging, vigorous towelling, or using a lawn mower induces a localized, red, itchy swelling within minutes and lasting less than a few hours. Increased levels of circulating histamine have been found in patients with the familial vibration-induced swellings, and may play an important role (70,71). If the stimulus is severe, generalized erythema and headache may occur. Occasionally, an acquired vibratory angioedema occurs (72,73). This is usually milder, and can be associated with other physical urticarias such as delayed pressure urticaria and immediate dermographism (74). A recolllmended screening test is application 01':1 laboratory vortex resting on the forearm or finger for 1-5 min to induce angioedema. However, a positive response is not uncommon in patients with cholinergic urticaria (71) and in controls (75) The diagnosis is best made by a calibrated vibrationinducing machine, in which frequency and amplitude can be adjusted (74) (Fig. 9). Avoiding thc precipitating stimuli enables patients to lead normal lives.
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b
Figure 9 (a) Vibration amplitude and frequency to the vertical rod held by the patient can be altered. (b) The patient experienced an itchy, red swelling of the lower forearm from transmitted vibration from the rod, which did not touch the forearm (under label), within minutes after vibration. The patient also had mild dermographism and the erythema of the palms could have been due to this or vibratory angioedema. (Courtesy of the Department of Photography. St Johns Institute of Dermatology. St Thomas Hospital.)
A rare delayed form also occurs within 1-2 h of the vibra tory stimulus, peaking in 4-6 hours (76). In the patient reported trauma produced by vibration, but not by static pressure, resulted in angioedema
III. TEMPERATURE CHANGES A.
Heat Urticaria
1.
Cholinergic Urticaria
Cholinergic urticaria is a very distinctive type in which characteristic small wheals appear due to stimulation of sweating, whether induced by a rise
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in core temperature or emotional stress (77,78). Sometimes it occurs in response to gustatory stimuli such as peppery or sour foods or alcohol (79). Cholinergic urticaria is not uncommon, with a prevalence of 11 % in young ad ults (80). In one family there were several cases reported (81). The pathogenesis is still not clear. It is thought to be related to stimulation of the cholinergic postganglionic sympathetic nerve supply to the sweat glands (82). The urticarial wheal does not depend on sweating, since cholinergic urticaria occurs in patients with acquired anhidrosis (83) and hypohidrosis (84,85). The abnormality at the nerve-ending receptor level is unclear. There is a report of impaired cholinesterase with likely accumulation of acetylcholine (86). A temporary increase in acetylcholine receptors has been described in one patient (87). There is not a generalized disturbance of autonomic function (88). Increased histamine levels have been detected in the blood of patients with cholinergic urticaria (71). It was originally postulated that acetylcholine can release histamine, perhaps in an indirect way (82), but such a mechanism is conjectural. Passive transfer tests with serum of affected individuals are sometimes positive, probably due to an immunoglobulin (89). Such an antibody may prime the mast cell for activation. Recently, an allergy to sweat itself has been postulated (90). Decreased levels of the protease inhibitor antichymotrypsin have been detected in the serum of some patients (91). For proposed mechanisms, see Figure 10. The condition typically occurs in adolescents of either gender and may be worse in the winter months (92). The patient complains of itching wheals that appear within minutes of exertion, when hot, after sudden emotional
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postganglionic , sympathetic
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Figure 10 Proposed mechanisms for cholinergic urticaria. (Courtesy of the Depart, ment of Photography, St Johns Institute of Dermatology, St Thomas Hospital.)
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Figure 11 Itchy, small wheals (2-3 mm in diameter) with a surrounding nare occurring on the trunk within minutes of moderate exercise in a patient with cholinergic uticaria. (Courtesy of the Department of Photography, St Johns Institute of Dermatology, St Thomas Hospital.)
disturbances, or even eating spicy food. The wheals characteristically are small (1-3 mm diameter), with or without a well-marked flare (Fig. 11). Sometimes the erythematous component is more pronounced, especially in the blush areas, and is confluent and studded with wheals. Oblique lighting is helpful to observe the wheals, especially in dark skin Sometimes tbe wheals become large and coalesce to form large areas of wheals (Fig. 12). Angioedema of face and limbs may occur (78,93). The lesions persist for a few minutes to an hour or two. Ordinary so-called idiopathic urticaria as well as other physical urticarias may coexist in some patients with cholinergic urticaria. The dermographic response may consist of small wheals at sites of friction (cholinergic dermographism) (37). There is an increased incidence of atopy (78). In some patients cholinergic urticaria is mild (78,80), but in others systemic symptoms such as flushing. faintness, palpitations (94), headache, abdominal pain. salivation, or wheezing may occur (95,96). Exercise-induced anapbylaxis may occur as part of the cholinergic urticaria spectrum after severe exercise (97). However, exercise-induced anaphylaxis in others does not appear to be associated with cholinergic urticaria and often occurs in patients sporadically and unpredictably, and appears to be a distinct entity (98). It is possible that some cases are examples of unrecognized food- and exercise-induced anaphylaxis. Cholinergic urticaria tends to improve gradually, but in a series of 35 patients 60% had had it for more than 5 years, and 30% for more than 10 years (78).
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Figure 12 Severely affected patient with cholinergic urticaria. A typical small wheal is seen on his chest, but on his arms they had enlarged and coalesced. (Courtesy of the Department of Photography, St Johns Institute of Dermatology, St Thomas Hospital.)
The diagnosis of cholinergic urticaria is best confirmed by provoking typical wheals after warming, for example, in a hot bath (42°C) for 15 min to raise the core temperature by 0.7-l o C or by exercise in a hot environment (99). Intradermal injections of cholinergic drugs such as methacholine may produce satellite wheals round the injection site, but this test is unreliable (99). Some patients receive partial relief from antihistamines used either regularly or before they predict attacks will occur, but most have to modify their lifestyle by reducing exercise. Ketotifen, an antihistamine with mastcell stabilizing properties, may be more helpful in some patients than other antihistamines (100). A few patients find that they can bring on a severe attack by suitable exertion, and afterwards can achieve freedom for up to 24 h. One report suggested that the addition of montelukast, a leukotriene receptor antagonist, is useful for the treatment of exercise-induced cholinergic urticaria (10 I). There is a report that t3-adrenergic blockers may improve cholinergic urticaria, but should not be given if patients have asthma (102). For selected severely affected patients not responding to antihistamines, the attenuated androgen, danazol, improved whealing (91). Usefulness is limited by its side efrects, but in appropriate patients it could be used short term (e.g., in summer months for a few years). Cholinergic itching without wheals has been described (J03,104). Heat, excrcise, and emotion can induce itching that may be burning and intolerable. The condition may progress to cholinergic urticaria (104). Antihistamines have not been helpful (104,105) nor ultraviolet B therapy
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Figure 13 Typical small erythematous maCltles of cholinergic erythema, usually 2-4 mm in diameter distributed symmetrically on the forearms. If individual macules are marked as in diagram, they will be seen to disappear in 40-60 min, with others appearing elsewhere. (Courtesy of the Department of Photography, St Johns Institute of Dermatology. St Thomas Hospital.)
in the author's patients. One patient responded to treatment with stanozolol (104). In patients wi th persistent cholinergic erythema, multiple, small erythematous macules are distributed symmetrically on trunk and limbs (Fig. 13), increasing in number after exercise. Individual macules are short-lived (45 min to 1 h) but appear at different sites over a prolonged period, sometimes continuously, giving the overall impression of a persisting rash (106). In cold-induced 'cholinergic urticaria' only exercise in the cold induced whealing that resembled cholinergic urticaria (107).
2.
Localized Heat Urticaria
Warmth applied to the skin induces whealing restricted to the warmed area (108,109). This is one of the rarest forms of physical urticaria, with fewer than 50 cases described. It usually affects female adults (110) but it has been described in a child (110). The pathomechanism is variable, with reported histamine release in some (112-114) and complement activation in some cases (115,116) but not in others (J 13-117).
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Figure 14 Wheals appearing in a patient with localized heat contact urticaria, within I min of application of a beaker at 55"C, and within 5 min of application at 4SOC. (Courtesy of the Department of Photography, St Johns Institute of Dermatology, St Thomas Hospital.)
Patients experience whealing within minutes of contact with heat, for example, on hands after washing in warm \vater. in areas in contact with radiant heat such as a radiator, and on skin exposed to warm sunshine. It must be differentiated from cholinergic urticaria and solar urticaria (118). Systemic symptoms such as nushing, syncope (119) headache, nausea. wheezing, and abdominal pain have been described. Localized heat urticaria may be associated with cold urticaria (120). Diagnosis is made by applying heated objects such as a heated cylinder at 39-56°C for 2-5 min onto the skin. Whealing occurs within minutes at the test site lasting I h (Fig. 14). Treatment with H I-antihistamines. combination of H 1- and H2-antihistamine (113). or induction of tolerance by repeated heat exposure may be helpful ( I 14, I J9, 121.122). A family with a delayed heat urticaria has been described (123). B.
Cold Urticaria
Cold urticaria encompasses a variety of syndromes in which cold induces urticaria (124-127). Idiopathic cold-contact urticaria is the most common,
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making up 95% of a series of patients with cold urticaria (126), while others are rare. The incidence in the population is unknown, but cold urticaria was diagnosed in 2% of patients with urticaria in some studies (7-9). Histamine released from cutaneous mast cell activation has been recovered from venous blood (128) and tissue fluid draining from whealed areas induced by cold (129,130) and plays a partial role in cold urticaria. (131). Histological changes are mild, but electron microscopy shows some evidence of mast cell degranulation with evidence of edema in epidermis and dermis (132). The serum of some patients with idiopathic cold-contact urticaria can passively transfer the cold urticarial response to normal recipients (133), monkeys (134) and guinea pigs (135). This autoantibody is usually IgE-like (125) but IgM has been recorded (136). In vitro histamine release occurred from skin challenged with cold (133). The antigen may be either a protein produced normally by cold exposure or, less likely, an abnormal protein. The immunological change may in some cases be triggered by infection. Human immunodeficiency virus (HIV) infection may predispose to cold and aquagenic urticaria. The mechanism may be due to the HIV-I gp 120 acting as a superantigen and interacting with the VH3 region of IgE, to induce histamine release from cells bearing high affinity IgE receptors such as mast cells (137) Elevated antibodies to measles, cytomegalovirus, (Fct:RI) and Mycoplasma pneumonia in patients with cold urticaria were considered to be a sign of disordered immunity (138). The contribution of other mediators detected, such as neutrophil (139) and eosinophil chemotactic factors (140), prostaglandin 2 (PGD 2) (141), leukotriene E4 (142), platelet-activating factor (143), and TNF-o: (144), remains to be elucidated. Reduced serum 0:1 antitrypsin was found in some studies (145) but as this was it was unrelated to disease activity
1.
Cold Urticarias with a Typical Cold Stimulation Test
Idiopathic immediate cold urticaria (without an underlying cause) is by far the most common form, occurring in patients at any age but most frequently in young adults. It may be preceded or associated with nonspecific upper respiratory viral infections, steptococcal throat infections (126), infectious mononucleosis (146), den tal infections (147), and HIV (148,149) or after wasp (ISO) or jellyfish stings. Itching and whealing of the skin occur on cold exposure within minutes and last up to I h. Patients also may have problems washing up in cold water or taking food out of the freezer. Cold winds and cold rain are particularly effective stimuli. Cold urticaria, however, may occur in the tropics (151, j 52). Sometimes, the mouth and pharynx may swell after drinki ng cold liquids (126). Systemic symptoms include flushing, palpitations, headache, wheezing, and loss of consciousness. Thirty percent
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a
b
Figure 15 (a) Circumscribed connuent wheal appearing at the site of application of an ice cube in a plastic cover for 10 min on the forearm of a patient with contact cold urticaria. (b) Small wheals localized to cold application of a wet and covered ice cube in a patient with the not uncommon combination of contact cold and cholinergic urticaria. This morphology is unusual in a positive reaction to the ice cube test. (Courtesy of the Department of Photography, St Johns Institute of Dermatology. St Thomas HospitaL)
of patients have other associated urticarias, both physical and ordinary (126). The mean duration of cold urticaria was 6 years in one series (126), but it may persist longer (153). Diagnosis is made by application of an ice cube in a thin plastic bag for 20 min to the skin, and whealing occurs within 15min at the test site, on rewarming the skin (126) (Fig. 15). The vast majority of patients have a positive response to the ice cube test, and the severity can be partially judged by the time of application of the ice cube needed (varying from I s to 20 min) to induce wheals. Negative results from this test may occur very rarely even in cold contact urticaria (154). In a few patients temperatures of7-1 5°C may be necessary or be more effective than ice to induce whealing (154). If cold urticaria is mild and the ice cube test is negative, sometimes a more extensive local challenge, such as placing a hand and forearm into cold water at
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10°C for 5min, or iced water for 2min, may induce whealing. It is very rare to find a cryoprotein in typical cold contact urticaria, but cryoglobulins (clotted blood must be kept warm until tested in the laboratory) should be sought. ]n addition, in older patients ifindicated, evidence for a myeloma or leukemia, with a blood count and serum immunoglobulins and serum protein electrophoresis, should be sough t. Patients should avoid cold exposure as much as possible, but this limitation may have an impact on occupation (155). 11 is important to warn against cold-water bathing due to risk of anaphylaxis and drowning. This is particularly important for those who have associated oropharyngeal angioedema after ingesting cold foods/liquids who they may be more at risk of anaphylaxis (156). For the most severely affected in special situations where there is a risk of falling into cold water, epinephrine injections should be available for administration. Prior to an operation, medical attendants should be informed so that special precautions can be taken (157). Treatment with low-sedation antihistamine is variably effective (126,158,159) but at least as effective as the previously favored cyproheptadine, with fewer side effects (160). In one study a combination of terbutaline 2.5 mg and aminophylline 150 mg each given three times a day was helpful (147). One patient is reported to have improved after treatment with montelukast, a leukotriene receptor antagonist (161). Ind uction of tolerance by repeated graduated exposures to cold can be helpful for selected patients (128,159) but it is time-consuming (1-2 weeks), and preferably administered in hospital. The procedure is not always effective, and some patients cannot continue taking a cold shower or bath daily (162). The mechanism of induction of tolerance in unknown but is not due to mast cell mediator depletion or tachyphylaxis of cutaneous vasculature (163). In one series, high dosages of antibiotics (e.g., penicillin 1.2 megaunits equivalent to 750 mg penicillin V daily or tetracycline 2 g) (158) daily were given for 3 weeks. The reported improvement was not reproduced in the author's experience. Systemic steroids does not appear to be effective (13 J). Cyclosporin and intravenous immunoglobulin treatment in a few of our patients was not useful, but the role of immunomodulation needs further investiagation.
2.
Cold Urticaria Secondary to Serum Cryoproteins
This is rare and was found in only I % of one series (126). It is associated with other manifestations such as Raynaud's phenomenon, purpura, and skin necrosis. Cryogobulinemia may be idiopathic or occur in collagen vascular disease, chronic lymphatic leukaemia, myeloma, and in infectious diseases including infectious mononucleosis Cold urticaria is said to occur
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in only 3% of people with cryoglobulinemia (164). Treatment is directed against the underlying condition. Cryofibrinogen occurred in the blood of 3.4% of a large hospital population (165) and in 3% of patients with cold urticaria (166). Its significance in relationship to cold urticaria remains to be determined. Cold agglutinins are not usually associated with cold urticaria (167). Cold hemolysins usually associated with syphilis have not been detected in recent series.
3.
Cold Urticaria with Atypical Stimulation Tests
Delayed contact cold urticaria, in which whealing occurs after a delay of hours after cold contact, is very rare (168,169). The delay be up to 24 h (169) and persist for 48 h. A single patient whose immediate wheal persisted for 7 days has been described (170). A familial form has been reported (171). A peristent ice cube test may suggest the presence of cold urticaria with vasculitis (172). In localized cold-contact urticaria cold-induced whealing occurs on restricted areas of the body only. It is very rare (173-175). Onset has been reported at sites of ragweed immunotherapy, pollen immunotherapy (176), and after insect stings. An obvious cause may not be present (174,175). In a case of localized reflex cold urticaria, a patient developed small wheals in the vicinity of, but not in the area of contact with, an ice cube (177). Coldprecipitated dermographism occurred in a person with ordinary contact cold urticaria, who showed dermographism only in areas that had been exposed to cold (178). A patient with systemic cold urticaria and dermographism exaggerated by cold has been also described (179). Acquired cold-contact erythema occurred as painful erythema without whealing occurred in response to cold (180), but in other patients it may be a forme fruste of immediate cold-contact urticaria.
C.
Systemic
Familial cold urticaria, a rare form is inherited as an autosomal dominant trait. In these cases, the cold-induced wheals occur as a result of generalized cooling and are widespread. They are persistent and associated with fever. arthralgia, and leukocytosis, and sometimes with amyloidosis. The ice cube test is negative. The condition is caused by mutations of the same gene CIASI on Iq44. as for the Muckle-Wells syndrome (181,182) Familial cold urticaria has been renamed as familial cold autointlammatory syndrome and classified into the group of familial periodic fever syndromes (181). In one family with familial cold urticaria there was a good clinical response to the oral anabolic steroid stanozolol (183).
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I n generalized reflex cold urticaria, widespread wheals, often more marked on elbows, knees, and buttocks, occur in response to cooling of core body temperature (179,184,185). The ice cube test is negative. Placing the patient in a cold room at 4°C for 30 min in light clothes induces the lesions. As this test is not usually performed, the incidence may be underestimated. Tn cold-induced cholinergic urticaria, additional exercise is necessary in the cold room to induce wheals (107,186).
IV.
EXERCISE-INDUCED ANAPHYLAXIS
Exercise-induced anaphylaxis (ETA) is a syndrome in which anaphylactic symptoms occur in response to exercise (187-189). Symptoms of severe cholinergic urticaria, which is associated with typical small cholinergic wheals on exercise, occur in response to passive heating without exercise (97,190) This should not strictly be included in the syndrome of exerciseinduced anaphylactic syndromes (191,192). In true ETA, anaphylaxis occurs only after exercise. In some patients this is not related to prior food ingestion (188,192). However, in the majority (188), symptoms occur only if exercise is taken within 4 h after food ingestion. The meal may not contain a specific constituent (nonspecific food-dependent ETA). Sometimes it may occur only after ingestion of single or multiple specific foods followed by exercise (specific food-dependent ETA). The incidence is unknown. It is more common in young adult women, but can occur in children (193). It can be familial (194). EAT is associated with mast cell degranulation (192). In those with a specific food sensitivity, the mechanism is partly TgE-dependent: prick and/ or specific IgE tests to these foods are positive (195-198,188). A lower mast cell threshold for mediator release has been demonstrated after exercise (192,195,196). The most common precipitants of EIA are jogging, and active sport, for those participants it can be a major problem (199). Often the first symptom is itching, followed by urticaria and often angioedema, which tend to persist during an episode that lasts 30 min to 4 h. Systemic symptoms that may follow include nausea, vomiting, abdominal colic, stridor, and collapse. There may be reduced pulmonary function (200). Atopy is more common in individuals with EIA (187,195). In specific fooddependent EAT common foods or combination of foods involved (200) include shellfish (195,198), wheat (195,198,201), and vegetables such as celery (202). Involvement of fruits such as grapes (195), apples, tomatoes, and also nuts has been described. The induction and severity of fooddependent ETA also may depend on other factors such as the amount of food allergen ingested (197), prior ingestion of aspirin (198), and other
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nonsteroidal an ti-innama tory medication and alcohol ( 188). One patient developed EIA only if exercising in the cold (203). An ice cube test was positive, so it could be differentiated from cold-induced cholinergic urticaria (/85). Diagnosis is suspected from history. If food-associated ErA is suspected, prick tests for specific IgE su bstances commonly causing specific-food dependent EIA can be undertaken. Confirmation can be made by reproducing clinical induction of lesions, under close supervision. A hot bath should be undertaken to exclude cholinergic urticaria. Treatment is as for any other anaphylaxis. Prevention is to restrict exercise in EIA. Patients should have self-injectable epinephrine available as sometimes the occurrence and severity are unpredictable. In food-dependent EIA, exercise should be avoided within 4 h of ingestion of food, alcohol, and aspirin, and, if known, specific inciting food(s) should be eliminated. Although prick tests may be positive to a number of foods, and symptoms appear to occur only after ingestion of one of them, it is best to avoid all prick-test-positive substances before exercise (188). There is a report that oral disodium cromoglycate taken before exercise may be helpful (201).
V.
SOLAR URTICARIA
In solar urticaria (204), itching erythema and wheals develop within minutes at sites of sun exposure, with lesions usually fading within 2 h. By convention the name is applied to the urticarial response from the ultraviolet and visible parts of the electromagnetic spectrum from any source. Solar urticaria is rare. Passive and reverse passive transfer of solar urticaria, have been demonstrated since 1942. It was postulated that irradiation with ultraviolet or visible irradiation, of either a circulating or cutaneous photoreactive precursor molecule, induces a photoallergen with production of an autoantibody, possibly IgE. Recently, two patient groups of solar urticaria have been proposed, based on their skin reactions to in vitro irradiated serum (204). Type I patients developed a wheal only to their own irradiated serum, but type 2 patients produced wheals also on injection of irradiated serum from normal subjects. This suggested that in type I patients an abnormal photoreactive factor capable of inducing an allergic reaction was formed. These type I patients are more frequently reactive to visible wavelengths. In type :2 patients a normal contiluent precursor molecule [orms an allergen on irradiation (204) and no activating wavelengths predominate. For ethical reasons, an in vitro histamine release from blood basophils to replace skin tests has been suggested (205). An unusual aspect of solar urticaria is the phenomenon of inhibition spectra, found mainly
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in Japanese patients with solar urticaria (206), occurring in 69%. Inhibition spectra are usually of longer wavelengths than the action spectrum. In some patients these wavelengths may inactivate photoallergens produced by the action spectrum and stabilize the mast cells (207). In addition patients with solar urticaria due to visible light may demonstrate inhibition spectra if irradiated with longer wavelengths (208), but this occurred in only 4 of 14 patients (206). In solar urticarial lesions there is evidence of mast cell degranulation (209,210). At 2-4h the site shows infiltration with neutrophils and eosinophils without visible lesions (211). Increased histamine in venous efnuent fr0111 urticated areas (209,211,212) have been detected as well as neutrophil and eosinophil chemotactic factors (213), but the relative importance of all these factors is not known. Most cases of solar urticaria occur in patients in their 20s-30s (206214,215) but it can occur in children (216,217) Erythema, itching, burning, and wheals occur in some exposed areas within minutes (Fig. 16). Areas commonly affected are chest and shoulders, less so the face and back of hands possibly due to tolerance from repeated exposure (218). Patients may be affected through window glass (if wavelengths are greater than 320 nm), through light clothing, and from artificial radiation sources such as Ouorescent tubes. Widespread exposure can cause flushing, headache, or collapse. In rare instances, solar urticaria may occur in erythropoietic protoporphyria and porphria cutanea tarda (219), in systemic lupus erythematosus, and following use of drugs such as
Figure 16 Wheals localized to areas on the back exposed to the sun, and sparing covered areas in a patient with solar urticaria. (Courtesy of the Department of Photography, St Johns Institute of Dermatology, St Thomas Hospital.)
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Figure 17 Wheals appearing at test sites with a monochromator at 320, 340, and 360 nm wavelengths but not at 300 and 307 nm in a patient with solar urticaria. (Courtesy or the Department or Photography, 5t Johns Institute of Dermatology, 5t Thomas Hospital.)
chlorpromazine (206), tetracycline (220), and repirinast (221). Usually no cause can be identified Only a few studies suggest that there is an increased incidence of atopy (218). The condition may last for many years: 4-11 years in one series (218). Fifty percent were clear in 5 years in an Italian series (215), but none in 40 Japanese patients (296). Diagnosis can be confirmed by exposure to strong natural sunlight or to a solar simulator, and erythema and wheals occur in minutes. The activating wavelengths may be categorized broadly by additional use of filters (218). The most sophisticated method is using a narrow-band monochromator (222), to test the reactivity to individual wavelengths (Fig. 17). The activating wavelengths occur between 280 and 700 nm. Various classifications relating to activating wavelengths have been proposed, the simplest by Ramsay (223). He suggested four categories: group 1 reacting to ultraviolet B, group 2 to ultraviolet A, group 3 to visible, and group 4 to a wide spectrum, but not all patients fit into these groups. The most common differential diagnosis is polymorphic light eruption, in which urticated plaques can occur within 30 min from sun exposure. but these persist for days. Secondary causes such as medication, systemic lupus erythernatosus. or porphyria should be excluded. Treatment can be dilTicult, but low-sedation antihistamines with appropriate sunscreen may improve milder cases. However, many are refractory. Treatments that have been used include UVA therapy (224) and PUVA (225), but these must be administered carefully, sometimes under oral steroid cover. In some patients tolerance can be induced by graduated
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repeated exposures to the eliciting wavelengths (210,226,227). For the most severe unresponsive cases, plasmapheresis has been used with some success in a few patients (228-230) but not in others (231) by itself or in combination with PUVA (232). More recently the successful use of intravenous immunoglobulin, (233), cyclosporin (234), and photopheresis (235) has been reported in individual patients. Variations of classic solar urticaria include solar erythema, when itching erythema without whealing occurs (236). Solar urticaria localized to specific areas of the body (fixed solar urticaria) has been described (237,238). Solar urticaria may rarely have a delayed onset (239). Rarely olar urticaria has the histological appearance of a vasculitis (240).
VI.
AQUAGENIC URTICARIA
In aqagenic urticaria contact with water at any temperature induces an eruption of small usually pruritic wheals, surrounded by a flare, resembling cholinergic urticaria but sparser (241,242). Jt is rare, with fewer than 40 cases describe (243). It occurs in young adults (243), although it has been described in a young child (244). A few cases are familial (245) and in one family was associated with lactose intolerance (246). It has been proposed that water carries an epidermal antigen to the sensitized mast cell (247). There is mast cell degranulation and histamine release (248,249). Some authors have implicated acectyJcho1ine (248) but not others (243). Usually all forms of water-tap, swimming pool, distilled water (248), high humidity (250), tears (251), sweat (252), and saliva (249)-can induce lesions within a few minutes. The upper trunk and neck are particularly affected, sparing the face (Fig. 18). Very occasionally it occurs on localized areas only such as the back of hands (252) and face (253). Systemic symptoms such as wheezing are rare (243,249). In two cases, induction of wheals was dependent on the salinity of the water (253,254). Organic solvents such as ethanol and acetone usually enhance the water-induced whealing (248) but occasionally they may induce wheals (249). Prior application of barrier substances such as petrolatum reduces wheaJing (248). Combinations with other physical urticarias occur such as with dermographisma, cholinergic urticaria (255), and cold urticaria (256). Aquagenic urticaria has occurred in association with HIV in one patient (257). Diagnosis consists of excluding other urticarias that can also be induced by physical properties of water such as temperature of the water (cold urticaria, cholinergic urticaria) and force of water (dermographism). Wheals should be induced within minutes under a wet swab kept at body temperature (at sites usually affected by aqua genic urticaria) for 20-30 min Copyrighted Material
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Figure 18 Aquagenic urticaria with small sparse wheals, resembling cholinergic urticaria, appeared within minutes of bathing in water at skin temperature for 15 min. (Courtesy of the Department of Photography, St Johns Institute of Dermatology, St Thomas HospitaL)
or after immersion in a body-temperature bath for 15 min. It is different from aquagenic pruritus, in which there is water-induced itching but no whealing (258,259). Aquagenic pruritus occurs predominantly on the legs and lower trunk. Very rarely the condition can be associated with blood disorders such as polycythemia rubra vera. Treatment is difficult. In some patients low-sedation antihistamines may be helpful. Others respond to treatment with ultraviolet B (251) or photochemotherapy (PUVA) (252). lnd uction of tolerance by repeated bathing (261) was useful 111 one patient, although not 111 the author's experience. The patient with HIV responded to treatment with stanozolol (257).
VII.
ADRENERGIC URTICARIA
Adrenergic urticaria is characterized by multiple small wheals, induced by stress. It is said to be differentiated from cholinergic urticaria by the
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.. f$r.J.~... Figure 19 The appearance of adrenergic urticaria: small wheals 3-4 mm in diameter resembling cholinergic urticaria, surrounded by areas of blanching. (Courtesy of the Department of Photography, St Johns Institute of Dermatology, St Thomas Hospital.)
presence of blanching and vasoconstriction surrounding the wheals (Fig. 19). Heat and exercise do not induce whealing, but they can be reproduced by intradermal injections of epinephrine and norepinephrine but not by acetylcholine (262,263,264). Beta-adrenergic blockers such as propanalol reduced the severity of adrenergic urticaria (262-264); they also ameliorate cholinergic urticaria.
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9 Urticaria and Angioedema in Infancy and Early Childhood Michael C. Zacharisen Medical College of Wisconsin, Milwaukee, Wisconsin, US.A.
I.
INTRODUCTION
When urticaria and angioedema occur in young children, parents can become distressed and frustrated, resulting in multiple calls or visits searching for the cause, hoping to eliminate the culprit and thus curing the hives. Urticaria also can be frustrating to physicians who weigh the utility of obtaining costly laboratory tests or implementing an elimination diet, realizing that both can frequently lead to disappointing results. Although it is common to treat urticaria and angioedema symptomatically, parents are usually concerned to determine the underlying cause. In young children, there are diverse triggers and disease states that must be borne in mind when evaluating these patients. Most urticaria is acute, limited and benign in nature, but it can be chronic, a sign of a systemic disease, or part of a multisystem allergic reaction.
II.
HISTOLOGY AND PATHOPHYSIOLOGY
The histological pattern in patients with both acute and chronic urticaria is similar despite the various pathogenic mechanisms involved and is the same as urticaria occurring at other ages. Acute urticarial lesions exhibit: vasodilation, engorgement of capillaries, and small venules; superficial dermal lymphatic vasodilation; widening of the dermal papillae; flattening
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of the rete pegs secondary to nuid extravasation and swelling of collagen fibers; and minimal perivascular cell infiltrate with or without eosinophils. In contrast to urticarial vasculitis, there is no vascular damage, red cell extravasation, or nuclear debris (I). Urticaria results from mast cell degranulation releasing preformed mediators such as histamine, and newly generated mediators such as eicosanoids, leukotrienes, and prostaglandins. Other mediators include kinins, neuropeptides (substance P, vasoactive intestinal polypeptide, calcitonin gene-related peptide, neuropeptide Y), adenosine triphosphate, neutral proteases, cytokines, and platelet-activating factor. In patients with chronic urticaria, there are increased numbers of skin mast cells and a late-phase-Iike reaction can occur with the early innux of neutrophils followed within 24 h by predominant CD4+ lymphocytes. The role of lymphocytes in urticaria is not well defined. In 14 children ages 2-1 J years with milk-induced urticaria, memory T lymphocytes expressing cutaneous lymphocyte antigen (CLA), a unique skin-homing receptor, were selectively activated compared to children with milk-induced gastrointestinal (Gl) symptoms, and control subjects (2). The results are similar to children with milk-induced atopic dermatitis, suggesting a role for the CLA antigen in allergic skin conditions. Pathophysiological mechanisms to explain urticaria include immunemediated, complement-mediated, and nonimmune-mediated. Immunemediated refers to specific IgE bound on tissue mast cells and circulating basophi1s that release mediators after interaction with a protein. The protein cross-links the bound fgE, resulting in a cascade of events leading to the release of multiple mediators. Complement-mediated urticaria and angioedema occur when C3a, C4a, or C5a triggers mast cell degranulation in such disorders as collagen vascular diseases, serum sickness, and blood product reactions. Nonimmune mechanisms include direct degranulation of mast cells without prior sensitization, requiring IgE or complement. Urticaria and angioedema can occur after antigen exposure by many routes including direct local contact. ingestion, inhalation, injection, or through mechanisms occurring internally due to disease states.
III.
EPIDEMIOLOGY
It is estima ted tha t 15-20% of chi Id ren experience at least one episode of acute, transient hives by adolescence (3). A prospective study of 57 children 1-36 months old hospilalized with acute urticaria were evaluated and 40 of them followed for 1-2 years. In 92% of cases, a cause was identified or suspected. Infection either associated wilh drug intake or not was suspected
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in 81 % of cases. Viral infections predominated. Amoxicillin and cephalosporins were the antibiotics used most commonly and the timing of the urticaria suggested serum sickness. Hemorrhagic lesions were seen in nearly half of these children and, in addition to articular symptoms, were more frequent in those with infections. Urticaria caused by foods (II %) was accompanied by lip angioedema and frequently associated with atopic dermatitis. Angioedema occurred in 60% of cases. Half of the patients were atopic. This cohort likely represents the more severe spectrum of urticaria since they required hospitalization (4). Compared to adults, the causative factors are more readily identified in infants (65%). Acute urticaria appears to be the most common presentation, occurring in 85% of children (3). However, a study of 44 children Jess than 14 years old evaluated at a referral center reported that 80% had chronic urticaria (5). Of interest and contrary to the adult population, a cause was identified in 74% of these children (5) The trigger for urticaria is influenced by age. Cow's milk protein allergy is the most common trigger before 6 months of age, while drug allergy and infections appear to be a more frequent trigger between 6 months and 2 years (6). The natural history of urticaria in children is distinct from that in adults. A review of 94 children with chronic urticaria revealed that 58% became symptomfree for 6 months or more, whereas the remaining 42% continued to have episodes of urticaria (7). A cause in this study was determined in only 16% In another report of 226 children ages 1-14 years with chronic urticaria, only 21 % were determined to have a causal factor. These were 6.2% physical, 4.4% infection, 4% food allergy.. 2.6% food additive, 2.2% aeroallergens, and 1.8% drugs (8). The age distribution was not provided, but the mean age was 8 years. This contrasts with another retrospective study of chronic pediatric urticaria, where physical factors was the most common occurring in 25%, followed by infections (7.3%), food allergy (9%), food additive (1.8%), and drugs (1.7%) (9).
IV.
CLINICAL MANIFESTATIONS
Urticaria and angioedema are classified as acute or chronic based on the duration. Symptoms persisting] beyond 6 weeks are classified as chronic, while those less than 6 weeks are defined as acute. Urticaria can affect any area of the body, although it usually is absent on the mucus membranes, with the exception of cold urticaria on the tongue or palate. The skin findings can be impressive and occur rapidly with a fluctuating course. The lesions are characteristically pruritic and occur in
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Figure 1 Infant with acute recurrent urticaria. Note the round, raised lesions on the trunk and extremities, sparing the diaper area.
various patterns ranging from several-millimeter-sized wheals with a large, blanching, erythematous nare to round to oval, erythematous raised individual lesions (wheals) with a pale center and pseudopodia with surrounding erythema (see Fig. 1). They can appear as diffuse connuent plaques with erythema. The eruption may last for days to weeks or even months, but an individual lesion typically lasts less than 24 h. In urticarial vasculitis, individual lesions persist beyond 48 h. Symptoms seem to worsen at night; the explanation of this is unclear. There is no associated scaling of the skin. Infants may experience extreme fussiness or crying as the intense pruritus may be interpreted as painful stimuli. Angioedema is similar to urticaria, but affects the deep dermal and subcutaneous or submucosal tissues resulting in nonpitting, nondependent swelling with or without the characteristic erythema of urticaria and often without pruritus. Angioedema can occur on any area of the body, but tends to occur more frequently in the periorbital region, tongue. lips, and genitals. The frequency with which angioedema occurs in association with urticaria in children ranges from 6 to 60% (4, 5, 7, 10).
V.
CAUSES
The various causes of urticaria are outlined in Table I.
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NOMID. neonatal onset mullisystem inflammatory disorder: CINCA. chronic infantile neurological cutaneous and articular syndrome: FCAS. I-amilial cold ~lutoinl1ammalory disorder: SLE. systemic lupus erythem~ltosu>: J RA. juvenile rheumatoid arthritis: VZV. I'aricella zoster \·irus.
Cutaneous vasculitis: Henoch-Schonlein purpura Egg Blood products Stinging nettle Respira tory Primary acquired Mast cell infiltration Wheat Antisera Food Influenza Secondary Urticaria pigmentosa acquired Soy Vaccines Langerhans Cell Animal saliva Adenovirus FCAS Histiocytosis Peanut Radiocontrast Collagen Vascular Topical medications: Enterovirus Cholinergic/hea t Disorders media corticosteroids SLE, JRA RSV Tree nuts Insulin EBV Localized heat NOMID/CINCA Insects Seafood VZV Aquagenic Serum sickness Prostaglandin E I Moths Fruit/berries Acute annular Stings/bites Ca terpi Iia rs Rotavirus Vibratory Food additives Neonatal autoimmune Butterflies Bacterial Solar Urticarial vasculitis Tartrazine Mosquito Sea life: Portugese Group A strep man-o-war Azo dyes Flea E. coli Idiopathic Salicylates Bedbugs Protozoan Medications Hymenoptera Inhalants H. priori Angioedema only Hereditary angioedema: Antibiotics Vespids Food Giardia HAE types L II. III Aspirin/NSAID Bees Fish/Seafood Fire Ants Pollen Opiates Spiders Grass and tree
Food Milk
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Table 1 Triggers of Urticaria and Angioedema in Infants and Young Children
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A.
Allergic
1.
Inhalant-Induced Urticaria
Airborne allergens are usually associated with rhinitis or asthma, but the target tissue can be the skin. The diagnosis should be considered if a recurrent seasonal pattern emerges and specific IgE testing confirms sensitivity In children with chronic urticaria, the prevalence was 2.2% and the culprit antigens were grass and tree pollen (8). Because most seasonal allergies require 2 pollen seasons of exposure to sensitize, seasonal airborne allergen triggers would be unlikely in infants.
2.
Food-Induced Urticaria
Urticaria is second only to exacerbations of atopic dermatitis in the manifestation of food allergies. Food allergy accounts for nearly 20% of cases of acute urticaria (I J). It can occur via direct contact. leading to a local reaction termed contact urticaria (12) or after ingestion of food leading to perioral or generalized urticaria with or without angioedema. Onset of symptoms after ingestion or contact is minutes to several hours. It would be unlikely for a food to trigger urticaria more than 24 h after contact. Two hypotheses have been proposed to account for the local and systemic manifestations of food allergy: absorption-deposition hypothesis and immune-response hypothesis. The skin as the hyperreactive target organ develops overt hives after exposure within the GI tract (II). Urticaria induced by food antigens varies by age: 22% of children 0-3 years old who have food allergy present with urticaria, while over 40% of children with food allergy 3-15 years old present in this manner (II). Although almost any food can elicit an allergic reaction, a short list (egg, cow's milk, soybean, wheat, seafood, peanut, tree nuts) accounts for the vast majority of reactions (II). The most common food allergen to elicit acute urticaria in infants less than 6 months old is cow's milk (6). A 6-week-old infant was hospitalized for severe angioedema that was determined to be due to cow's milk-based infant formula. Percutaneous allergy skin tests. followed by a strict elimination diet, confirmed the diagnosis (KJ Kelly, personal communication, 2002). Occasionally an infant will present with urticaria/angioedema on the first known exposure to that food. Milk, egg, and peanut proteins may cross into human milk and apparently sensitize the infant during breastfecding. When the child ingests that food for the "first time," acute urticaria can occur. While ill IItero sensitization to food proteins has been postulated, other disorders with onset in the neonatal period need to be considered. Food allergy has been reported to occur in 2-9% of children
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with chronic urticaria with milk being the most frequently implicated food (7-9). Other implicated foods include grapes causing lip angioedema in a 5-year-old, (13) and urticaria and angioedema to cooked white potato in 2 infants less than 6 months old (14). Although tomato is commonly believed responsible for hives, true IgE-mediated tomato allergy is very uncommon or not reported. Fresh fruits and berries are also frequently implicated in urticaria, although published data are scarce. Direct histamine-releasing factors may be present in egg while, strawberries. and shellfish. The currently available commercial food extracts for skin testing may lack factors that are present in fresh foods, thus resulting in falsenegative skin reactions. Prick-on-prick percutaneous skin testing with fresh fruit has been advocated. Histamine may be a present in some foods or as the result of spoilage of various fish species whereby histadine is converted to histamine, resulting in urticaria upon ingestion.
3.
Food Additive-Induced Urticaria
Preservatives and azo and nonazo dyes have been reported to be responsible for chronic urticaria through a nonimmunological mechanism. The difficulty in diagnosis is due to the lack of a confirmatory skin or in vitro test, thus leading to a reliance on challenge tests. The wide variation in positive challenge tests may be attributed to predisposing factors, the difference in the quantity of the additive, and the inclusion of uncertain reactions (16). In pediatric studies, the incidence ranges from 2.6 to 18% (8,9). Tartrazine (yellow dye) and salicylates appear to be the most commonly implicated foods (8), yet carefully controlled studies are lacking. Data on natural salicylates in food are contradictory and scarce (17). Commonly reported foods include fruits and vegetables (apples, apricots, oranges. cucumbers), herbs/spices (cinnamon, curry, thyme) and honey. Other reported sources are birch bark. wintergreen. and willow bark. Mint-flavored candy, pills, foods, and beverages contains higher levels of salicylates. Aspartame used as a sweetener has not been reported to cause urticaria.
4.
Contact Urticaria
Direct antigen exposure and penetration of intact skin resulting in urticaria were first described in 1975. Examples of contact urticaria include transfer of the affected allergen by kissing, licking. or spilling upon oneself. This commonly occurs with foods (milk, peanut, egg) and animal saliva or hair (12). Contact with animal saliva or dander can produce acute urticaria either by inhala tion or direct absorption though the skin.
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5.
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Latex Allergy-Induced Urticaria
Latex allergy is uncommon in otherwise healthy children, but in high-risk groups such as patients with neural tube defects including spina bifida the incidence can reach over 60%. An atopic 2-month-old infant suckling a latex nipple developed repeated stridor suggesting angioedema of the larynx (18). B.
Physical Urticaria
Physical urticaria is a common cause of chronic urticaria occurring in 24% in one series (5).
In
children,
1. Dermographism
This common urticaria occurs after firm stroking of the skin (Darier's sign), and can be performed using a dermographometer or simply stroking the skin with a tongue blade or other rigid object. This commonly occurs after firm rubbing of the skin with a towel or along areas of skin prone to friction. 2.
Cholinergic/Heat-Induced Urticaria
Increases in core body temperature achieved through exercise or external ources such as hot baths or overbundling result in the classic 2--4 mm punctate wheals with surrounding erythema. The lesions are transient, resolving in minutes to within 2 h. Fever is not a trigger. This frequently coincides with symptomatic dermographism and is most common among teenagers (I). Studies in young children are lacki ng. 3.
Localized Heat Urticaria
Fewer than 50 cases of localized heat urticaria have been described and none were in infants, although a familial pattern was reported in which older children were affected. Most cases are acquired and occur in women over 17 years old. Treatment options are limited and have been variably effective (19). 4.
Cold Urticaria
Primary acquired cold urticaria can affect children. Wheals and pruritus occur within a few minutes of applying a solid or nuid cold stimulus to the skin. The wheal fades 3fter 30 min. Urticaria may occur in the mouth after drinking a cold beverage. Systemic symptoms may occur after immersion in cold water. This type of urticaria is more common in older children and may
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follow an infection that produces cold agglutinins. Histamine is released after cold challenge and can be measured in the plasma (20). Leukotriene E4 is released into the blood draining the site of cold-induced urticaria (21). Seconda ry acq ui red cold urtica ria is associ a ted wi th an underlyi ng disorder that results in the production of cryoglobulin, cryofibrinogens, or cold agglutinins. Familial cold urticaria, also called familial cold autoinllammatory syndrome is a rare autosomal dominant disorder with episodic macular papular erythematous pruritic patch or conlluent plaques on the extremities after exposure to cold. Petechiae may be present. The onset is within 6 months of age, but can appear within the first days of life in 60% of those affected and is lifelong. After 1 h generalized cold exposure, skin lesions appear and last less than 24 h. Fever and polyarthralgia occur in nearly all patients; conjunctivitis without periorbital edema, profuse sweating, drowsiness, headache, extreme thirst, and nausea occur with variable frequency. The ice cube test is negative, but the white blood cell count and markers of inllammation are elevated. This syndrome is linked to chromosome I q44 and the gene mutation (T I 058C) has been seq uenced and designated CIAS I. It is one of the hereditary periodic fever syndromes, but the only one associated with cold exposure (22,23). Treatment includes rest, warming, and analgesics for joint pain. Antihistamines and steroids have minimal effect.
5.
Vibratory Angioedema
A rare familial form with autosomal dominance has been described in infants (24). It is characterized by swelling without urticaria occurring within minutes of a vibratory stimulus. Symptoms are proportional to the duration and intensity, lasting up to 24 h.
6.
Solar Urticaria
Six categories of solar urticaria have been described based on the wavelength of light that induces the lesion. While photosensitivity reactions are not uncommon in children, pediatric idiopathic solar urticaria is exquisitely rare. Therefore, in children with recurrent photosensitivity reactions, evaluations for other conditions such as erythropoietic protoporphyria, drug reactions, systemic lupus erythematosus (SLE), xeroderma pigmentosum, polymorphous light eruption, hydroa vacciniforme, and Hartnup's disease needs to be undertaken (25). Drugs causing photosensitivity reactions are sulfonamides, chlorpromazine, grizeofulvin, tetracycline, and phenothiazines. Xeroderma pigmentosum is an autosomal recessive disorder in which ultraviolet (UV) light-induced thymidine dimers
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cannot be repaired, resulting In severe sunburns in early childhood and an increased risk of skin cancer with continued sun exposure.
7.
Aquagenic Urticaria
Aquagenic urticaria is extremely rare, with only 26 cases reported through 1998. Contact with water, regardless of temperature or salinity, induces urticaria through mast cell degranulation. This is distinct from aquagenic pruritus without urticaria. The youngest reported case was in a 3-year-old child without dermographism or other systemic disorder. A familial pattern was noted in some patients (26,27). Diagnosis is with a direct water challenge with room temperature tap water applied to intact skin as a compress. Small wheals with erythema develop within 30 min. Treatment includes rapid drying after bathing, water-occlusive agents, and antihistamines. Other modalities with limited success include psoralen and UYA (PUY A) or UYB with hydroxyzine.
8.
Delayed Pressure Urticaria
Delayed pressure urticaria frequently occurs concurrently with chronic idiopathic urticaria in adults. Delayed pressure urticaria in young children has not been descri bed.
C.
Medication-Induced Urticaria
While any medication can cause urticaria, the most commonly implicated agents in children are antibiotics in the classes of penicillin, cephalosporin, and sulfa. Drugs received orally or parenterally can cause acute urticaria. Drug-induced urticaria may occur through IgE-mediated, complementmediated, or serum-sickness type reactions.
1. Antibiotics Multiple courses of an antibiotic can sensitize and eventually trigger an allergic reaction in a predisposed individual. Penicillin is the most common antibiotic implicated in causing urticaria in infants. likely because this is still the most commonly prescribed class of antibiotic. Cephalosporin antibiotics are structurally related to penicillin and. by virtue of cross-reactivity, can trigger urticaria and angioedema. Serum sickness is a type III hypersensitivity reaction mediated by antigen-antibody complexes deposited in the small blood vessels leading to urticaria, fever. and arthralgia within 20 days (typically 7-11 days) of antibiotic exposure. There appears to be an excess risk of serum sickness reactions with Cefaclor. It may be more appropriate
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Figure 1.1 Cholinergic urticaria in a 12 year-old girl. The prominent blanching surrounding the wheals is due to a vascular steal effect.
Figure 8.3 Itchy linear wheals with surrounding flare appeared 10 min after stroking by the dermographometer (Fig. 8.2) perpendicular to the back at the settings shown. There is a large wheal and flare even at the lowest setting. (Courtesy of the Department of Photography, St Johns Institute of Dermatology, St Thomas Hospital.)
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Figure 8.4 (a) Small punctate wheals along two vertical lines, after linear stroking of the back, being most marked on the right side. (b) Small punctate linear wheals in a patient with cholinergic urticaria and dermographism, appearing within minutes of scratching his back. Some of the wheals had coalesced. (Courtesy of the Department of Photography, St Johns lnstitute of Dermatology, St Thomas Hospital.)
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Figure 8.5 Upper part of the figure shows, firm wide linear wheals, 6 h after stroking the back of a patient with a dem10graphometer at the settings shown, in a patient with delayed pressure urticaria. Lower part shows firm papules appearing on the back of a patient with delayed pressure urticaria. The dermographometer set at 100 gjmm 2 was applied perpendicular to the back, and held there for 5-180s. The required application time at the above pressure for the diagnosis of delayed pressure is 70 s. This patient also showed papules even after 5 s application. (Courtesy of the Department of Photography, St Johns Institute of Dermatology, St Thomas Hospital.)
Figure 8.7 A fim1, red, tender wheal, at the site of a brassiere strap. The wheal occurred several hours after wearing the garment, and lasted for many hours. The patient did not have immediate symptomatic dermographism. (Courtesy of the Department of Photography, St Johns Institute of Dermatology, St Thomas Hospital.)
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Figure 8.8b Two lucite platforms are supported firmly at the corners with fixed supporting rods. The test areas on the thighs are examined 6 h later for development of rounded tender plaques. (Courtesy of the Department of Photography, 5t Johns Institute of Dermatology, 5t Thomas Hospital.)
b
Figure 8.9b The patient experienced an itchy, red swelling of the lower fOreal111 from transmitted vibration from the rod, which did not touch the foreal111 (under label), within minutes after vibration. The patient also had mild dermographism and the erythemia of the palms could have been due to this or vibratory angioedema. (Courtesy of the Department of Photography, 5t Johns Institute of Dermatology, 5t Thomas Hospital.)
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Figure 8.11 Itchy, small wheals (2-3 mm in diameter) with a surrounding flare occurring on the trunk within minutes of moderate exercise in a patient with cholinergic uticaria. (Courtesy of the Department of Photography, St Johns Institute of Dermatology, St Thomas Hospital.)
Figure 8.12 Severely affected patient with cholinergic urticaria. A typical small wheal is seen on his chest, but on his arms they had enlarged and coalesced. (Courtesy of the Department of Photography, St Johns Institute of Dermatology, St Thomas Hospital.)
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Figure 8.13 Typical small erythematous macules of cholinergic erythema, usually 2--4 mm in diameter distributed symmetrically on the forearms. If individual macules are marked as in diagram, they will be seen to disappear in 40~60 min, with others appearing elsewhere. (Courtesy of the Department of Photography, St Johns Institute of Dermatology, St Thomas Hospital.)
Figure 8.14 Wheals appearing in a patient with localized heat contact urticaria. within I min of application of a beaker at 55°C, and within 5min of application at 45°C, (Courtesy of the Department of Photography, St Johns lnstitute of Dermatology, St Thomas Hospital.)
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a Figure 8.15 (a) Circumscribed confluent wheal appearing at the site of application of an ice cube in a plastic cover for lO min on the forearm of a patient with contact cold urticaria. (b) Small wheals localized to cold application of a wet and covered ice cube in a patient with the not uncommon combination of contact cold and cholinergic urticaria. This morphology is unusual in a positive reaction to the ice cube test. (Courtesy of the Department of Photography, St Johns Institute of Dermatology, St Thomas Hospital.)
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Figure 8.16 Wheals localized to areas on the back exposed to the sun, and sparing covered areas in a patient with solar urticaria. (Courtesy of the Department of Photography, St Johns Institute of Dermatology, St Thomas Hospital.)
Figure 8.17 Wheals appearing at test sites with a monochromator at 320.340, and 360 nm wavelengths but not at 300 and 307 nm in a patient with solar urticaria. (Courtesy of the Department of Photography, St Johns Institute of Dermatology, St Thomas Hospital.)
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Figure 8.18 Aq uagenic urticaria with small sparse wheals, resembling cholinergic urticaria, appeared within minutes of bathing in water at skin temperature for 15 min. (Courtesy of the Department of Photography, St Johns Institute of Dermatology, St Thomas Hospital.)
Figure 8.19 The appearance of adrenergic urticaria: small wheals 3-4 mm in diameter resembling cholinergic urticaria, surrounded by areas of blanching. (Courtesy of the Department of Photography, St Johns Institute of Dermatology, St Thomas Hospital.)
Figure 9.1 Infant with acute recurrent urticaria .. Note the round, raised lesions on the trunk and extremities, s~Afl¥r{gNfU/pM~.t&lJal
Figure 11.1
Acute dermatitIs of eyelids due to latex hypersensitivity.
Figure 11.2 Persistent swelling of the lips in a patient with Crohn's disease and gra n ulol11atous cheili tis.
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Figure 11.3
Urticarial-like lesions in a patient with recurrent erythema multiforme.
Figure 12.2 Photograph of the lower leg of a patient with FCAS. The leg was not directly exposed to cold prior to onset of disease.
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Figure 14.2 A uto]ogolls serum skin test.
Figure 19.1
Angioedema appeared within 15 min of a dose of ampicillin.
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Figure 19.2 Aspirin-induced AE.
Figure 19.3 Angioedema caused by enalapriL
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Figure 19.5
Idiopathic AE of upper lip with urticaria.
Figure 19.6
Idiopalhic orbital AE.
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Figure 19.7 A 62-year-old African-American man (in a nursing home) had a history of recurrent AE without urticaria of 2 years' duration. Episodes lasted from 96 to 108 h, unresponsive to epinephrine, hydroxyzine, and methylprednisone, occurring every 2-6 weeks. Upper Ie/I. Episode of AE first noted at 7 am and patient was given zileuton 600 mg and doxepin 25 mg. Middle leji. At 8 am, lower lip edema was noted to be progressing. BOI/OI11 Ie/I. At 9 am, lower lip and upper chin became more edematous. Upper righl. At 11 am, entire lower lip and chin were markedly swollen. Second dose of zileuton 600 mg advised. Middle righl. At 12 noon, before dose was administered AE had resolved. Patient was given zileuton 600 mg every 6 h for that day and every 12-24 h thereafter. Each time the zileuton was discontinued, the AE recurred within 5-7 days.
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Figure 21.1 A child with systemic mastocytosis shows lesions of urticaria pigmentosa, a facial f1ush, and Darier's sign (midabdomen).
Figure 21.2
Urticaria pigmentosa in an adult with systemic mastocytosis.
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to describe it as a serum-sickness-like reaction since direct evidence of immune complex formation has not been sought (28).
2.
Aspirin
Salicylates are rarely utilized in young children due to the potential risk of Reye's syndrome, yet nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used. Ibuprofen-induced urticaria in children is very rare and has only been reported in two children (7 and 14 years old) (29). The pathophysiological mechanism is likely through blockade of cyclooxygenase, resulting in increased levels of leukotrienes by means of the lipoxygenase pathway. Aspirin and NSAIDs can produce phototoxic reactions, pruritus, urticaria, and erythema multiforme. No available skin or in vitro test is currently available. Escalating dosages in a challenge test or oral desensitization protocols can be employed if acceptable substitutes are not available.
3.
Vaccines
Immunizations are routinely administered at birth and thereafter at 2 months of age. All vaccines have been associated with acute urticaria. Several vaccine components may be responsible, such as egg protein in tbe influenza vaccine and gelatin in the measles-mumps-rubella (MMR) and varicella vaccines. Initially allergic reactions to M M R were believed to be due to egg protein (two patients), but it is likely that gelatin is causative because the majority of the reactions occurred in children who could tolerate egg (30). Gelatin was the causative trigger in four children ages 1-4 years who developed urticaria with or without systemic symptoms after receiving the varicella vaccine (31).
4.
Opiates
Opiate analgesics are commonly associated with pruritus and urticaria. The mechanism of action is direct mast cell degranulation. Implicated drugs include meferidine hydrochloride, morphine, and weaker analgesics sucb as oxycodone, hydrocodone, and codeine. Fentanyl appears to have less of such activity and may be an alternative. Skin testing to codeine or morphine is not valuable, as it would be expected to induce a wheal and flare reaction.
5.
Steroid-Induced Urticaria
Corticosteroid allergy is suspected when dermatitis worsens witb topical steroid therapy. A 2-year-old with asthma and atopic dermatitis developed contact urticaria during treatment with c1obetasone. He had positive
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immediate skin tests to several topical steroids including clobetasone. Patch tests were immediately positive He tolerated oral, intranasal, and inhaled corticosteroids. A 5-year-old developed immediate urticaria and angioedema after oral ingestion of cortisone, prednisolone, and dexamethasone. Skin puncture but not patch tests were positive (32).
6.
Other Medication-Induced Urticaria
A 2-day-old infant with congenital heart disease developed recurrent acute urticaria related to infusions of prostaglandin El. The severity of urticaria varied directly with the dosage (33). Experimental evidence suggests that the mechanism is direct mast cell degranulation. Facial nushing, in contrast, is very common. An 8-week-old infant experienced hand puffiness and generalized urticaria 2 h after receiving the third dose of oral vitamin K (34).
D.
Urticaria Associated with Infections
It is very challenging to confirm infections as the causative agent and most often the diagnosis is presumptive, based on circumstantial evidence at best. 1.
Viral
Viruses suspected of triggering urticarial reactions include hepatitis B, Epstein-Barr, innuenza, adenovirus, enterovirus, respiratory syncytial virus. rota virus. and varicella zoster (4,3536). Chronic urticaria can occur in association with human immunovirus (HIV) (37) and hepatitis C infection in adults (38). No pediatric cases have been published.
2.
Bacterial
Bacterial infections are considered controversial causes of urticaria. In 1980. group A beta-hemolytic streptococcal infection was diagnosed in 16% of cases of acute urticaria. Thirteen of the 33 children who were assessed for this type of infection showed positive results by either serology or throat culture (39). The youngest child was 4 years old. Since 1947. anecdotal reports have associated urticaria in adults with apical dental abscess (9 patients), sinusitis (3 cases), cholecystitis (3 cases). prostatitis and rectal abscess/fistula (I patient), and urinary tract infection (2 cases). In many of these cases. the infection was asymptomatic. The association between these local bacterial infections and urticaria is probably coincidental rather than causal. Histamine-releasing factors other than IgE have been postulated to be the underlying mechanism for infection-induced urticaria (40), but this
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remains an area of considerable controversy. E. coli infection was a presumed cause of urticaria in a young child with gastroenteritis (4), but the occurrence could have been fortuitous.
3.
Protozoa
Urticaria in association with protozoal infections is rare, with only 10 cases (2 pediatric) reported. The initial case in 1949 was a 16-year-old and 20 years ago a 4-year-old girl was determined to have Giardia as a trigger of acute urticaria. She had normal-appearing stools but Giardia lamblia cysts were identified. Within I h of the second dose of oral metronidazole, she experienced generalized worsening of urticaria, postulated to be due to the release of large amounts of parasite antigen entering the bloodstream. After completion of the drug course, she experienced resolution of urticaria and negative stool samples (41). A review of 44 children from India with urticaria revealed that 25% had evidence of infestation with Giardia Lamblia or helminths; however, eradication of the infestation did not improve the urticaria (6). A direct role of Helicobacter pvlori infection in adult chronic idiopathic urticaria (CrU) is controversial due to the lack of randomized controlled trials with adequate masking and sample sizes (42,43). Pediatric data are scarce. 4.
Fungal
No cases of fungal infection could be discovered that were associated with urticaria or angioedema in children. However, Trichophyton-specific IgE was elevated in a group of adults with recurrent urticaria and angioedema (44). Whether the absorption of dermatophyte allergen contributed to clinical symptoms is still uncertain.
E.
Stings and Bites
1.
Hymenoptera
The venom from the stings of honey bees, yellow jackets, wasps, and hornets can induce urticaria with or without angioedema through an IgE-mediated mechanism. A local reaction with pain and swelling is normal Large local reactions can occur in a delayed fashion and be confused with cellulitis. In contrast to adults, generalized cutaneous reactions in children do not significantly increase the risk of anaphylactic reactions. For those children experiencing a systemic reaction, skin testing with venom can identify the culprit insect and venom immunotherapy can significantly reduce the risk of an anaphylactic reaction in the event of a subsequent sting.
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2.
Fire Ants
In the Gulf coast of the United States, imported fire ants live in tall mounds. Their venom can induce IgE-mediated allergic reactions ranging from generalized urticaria to anaphylaxis. At the site of the sting are characteristic sterile pustules in a ring formation caused by the stinger as the ant pivots. Skin testing with a whole body extract is available and desensitization recommended for those experiencing systemic reactions.
3.
Mosquitoes, Fleas, and Bedbugs
Some infants will experience large local reactions to insect bites. Papular urticaria refers to pruritic 3-10 mm firm urticated papules, often with a central punctum, that occur in crops or clusters in response to the bite of mosquitoes, fleas, bed bugs, or other insects (45). Also known as lichen urticatus. papular urticaria has been described in infants as young as 2 weeks old, although it primarily affects children 2-7 years of age. Lesions persist for 2-10 days resulting in temporary postinflammatory erythema. If exposure continues, attacks may persist for years. On histopathological examination papular urticaria is identical to insect bites, although the reaction may be IgE-mediated. Treatment consists of disinfecting all pets. fumigating the house, applying insect repellant indoors until the fumigation is complete, and symptomatic treatment with topical steroids and systemic antihistamines. Large local urticarial reactions to mosquito bites are frequently reported. Some reports identify specific IgE against mosquito. Mosquito skin testing extract is available but not generally warranted.
4.
Spiders
Acute generalized urticaria can be the result of spider bites. In a young child, history revealed that the urticarial lesions began on the back. Close examination of the area revealed the presence of 2 fang marks, presumably from a spider (personal observation). These reactions are likely to be nonIgE mediated, although specific studies are lacking.
F.
VaSCUlitis
Urticarial vasculitis can be differentiated from other forms of urticaria by the presence of persistent, tender, or burning erythematous wheals with central clearing. Typically there is petechia or purpura with individual lesions persisting for 48-72 h, resulting in skin hyperpigmentation.
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Associated symptoms include fever, arthralgia or arthritis, renal disease with proteinuria or hematuria, gastrointestinal symptoms (vomiting and abdominal pain), and pulmonary symptoms: cough, dyspnea, or rarely hemoptysis (46). Urticarial vasculitis has been associated with SLE, rheumatic fever, juvenile rheumatoid arthritis (Still's disease), and other collagen vascular diseases. Henoch-Schonlein purpura or anaphylactoid purpura is a common cause of small-vessel vasculitis in children between the ages of 2 and 12 years, affecting boys twice as often as girls. The cause is unknown. The clinical cutaneous feature is the sudden onset of a distinct palpable, purpuric rash distributed symmetrically and predominantly on the lower extremities and buttocks. The rash may initially appear urticarial or petechia!, but rapidly evolves within hours to the classic rash. The rash slowly darkens, fades, and becomes flat over 2-3 weeks leaving a transient darkish pigmentation. Occasionally there is soft tissue swelling over the head or extremities. Commonly there are gastrointestinal (abdominal pain, vomiting, guaiac-positive stools, or even melena) and joint (arthralgias and periarticular swelling) manifestations that typically follow, but may precede, the rash. Renal involvement including transient microscopic hematuria or proteinuria is present in nearly 30% of patients; renal failure is responsible for most of the 1-3% mortality. The pathological hallmark is tissue deposition of IgA-containing immune complexes. Skin and blood vessel biopsies reveal IgA deposits, C3, and, occasionally, IgG and IgM. HSP in children less than 2 years old has a distinctive clinical presentation (47). In a series of 12 young children, all had angioedema affecting primarily the feet, hands, scalp, lips, or scrotum. The purpuric rash was more likely to be distributed over the face, although all had lower extremity involvement. Involvement of the GJ tract, joints, and kidneys was significantly less common. All patients recovered completely. Other similar syndromes include acute hemorrhagic edema of infancy or acute benign cutaneous leukocytoclastic vasculitis of infancy. Direct immunofluorescent staining of the involved skin confirms the diagnosis. Although no specific treatment affects the rash or renal involvement, systemic steroids may improve joint and GI symptoms. Aspirin should be avoided as it may increase the risk of GI hemorrhage. Of the various types of juvenile rheumatoid arthritis, the systemic form can present in infants or young children and in 95% of cases is associated with rheumatoid rash. The rash is characterized by recurrent, evanescent, small, pale, pink-red maCLtles with central pallor on the trunk and proximal extremities, together with fever, emotional stress, heat, and skin trauma.
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G.
Underlying Systemic Disorders
Occasionally urticaria is a presenting sign of a systemic disorder. Neonatal onset multisystem innammatory disorder, also known as chronic infantile neurological cutaneous and articular syndrome, presents with urticarial rash that appears within the first days of life and is chronic, mayor may not be pruritic, nuctuates, and is unresponsive to treatment with antihistamines. Arthropathies ranging from transient arthritis to deforming polyarthritis may follow the rash by J 8 months. Developmental delay is nearly universaL Other central nervous system (CNS) findings can include cerebrospinal nuid (CSF) pleocytosis, papilledema, uveitis, deafness, seizures, and macrocephaly with brain atrophy. Hematological abnormalities are common and may include anemia, thrombocytosis and elevated peripheral white blood cells. Autoantibodies are negative. The cause is unknown (48). Hashimoto-Pritzker Langerhans cell histiocytosis (LCH) is a benign condition without systemic involvement, compared to the more aggressive systemic forms of LCH. In these conditions, there is an abnormal proliferation of bone marrow-derived cells that can manifest clinically as red-brown papules. A 2-month-old infant had urticaria and a positive Darier's sign due to the increased number of mast cells in the LCH (49).
H.
Angioedema
Angioedema can occur with or without urticaria. Angioedema without associated urticaria is a presenting symptom of C I esterase inhibitor deficiency. Hereditary angioedema (HAE) is an autosomal dominant disease that affects I: I,000-150,000 persons and has been described in all races and without gender predominance. It is caused by a 30% reduction of serum CI inhibitor in 85% of patients (HAE type T) or by a nonfunctional CI inhibitor in 15% of patients (HAE type IT). Type III HAE has been described that only affects females (50). The clinical presentation is the same regardless of the type. A deficiency of the activi ty or function of C I inhi bi tor leads to the activation of CI, uncontrolled CIs activity, and a cascade of events in the complement and kallikrein/bradykinin system resulting in recurrent, nonpitting edema. Acquired CI esterase inhibitor deficiency is a rare condition associated with autoimmune or B-cell Iymphoproliferative disorders occurring primarily in middle-aged adults and the elderly (51). This type of angioedema has not been described in children. The hereditary form can present within the first 2 years of life with rapid painless swelling withollt associated 'urticaria, itching, discoloration, or redness. Severe abdominal pain can be mistaken for what is termed
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an acute abdomen, leading to recurrent emergency room visits and even exploratory abdominal surgery. Other gastrointestinal symptoms include watery, nonbloody diarrhea. Laryngeal edema can progress to complete airway obstruction and is potentially fatal. Severe attacks typically do not occur until late childhood. Attacks last 2-3 days and resolve spontaneously. Triggers include minor trauma, menstruation, increased estrogen (oral contraceptive use), vigorous exercise, and emotional stress. Diagnostic studies include a marked reduction of serum C4 in 80-85% of cases and serum C2 levels during an attack. Between attacks serum C4 is characteristically low; C3 and C2 levels are normal. Measuremen ts of serum CI inhibitor and the functional activity of CI esterase inhibitor can be performed to confirm the type of hereditary angioedema. In the type III variant, all the above studies are normal both during and between attacks. Acute treatment of HAE in the United States is fresh frozen plasma (FFP), which contains adequate amounts of CI inhibitor. However, FFP administration is controversial because it also contains the complement components that could fuel symptoms. Other risks include the transmission of infections, alloimmunization, and anaphylaxis. In Europe, the intravenous (IV) administration of CI inhibitor concentrate, 500-1000 units, will begin to resolve the edema in 30-120 min with complete remission by 24 h. There is little jf any effect of epinephrine, antihistamines, or corticosteroids, although a trial is warranted. With laryngeal involvement, endotracheal intubation or tracheostomy may be necessary. For children requiring long-term therapy, prophylactic treatment includes the avoidance of known precipitating factors, attenuated androgens, or epsilon aminocaproic acid (EACA) (51). EACA, an anti fibrinolytic agent (a plasmin inhibitor), is given initially as a loading dose, followed by 7-10 g daily. Side effects may incl ude myalgias, muscle weakness, hypotension, and fatigue. Attenuated androgens such as danazol and stanozolol are generally more effective than antifibrinolytic agents and have relatively mild adverse effects. The major contraindications to therapy with attenuated androgens are pregnancy and lactation, prostate cancer, and young age. They should, however, be used with caution as they can affect growth rate and promote virilization in girls. Stanozolol seems to have fewer adverse affects than danazol therapy. The lowest effective dosage and alternate-day therapy have been shown to be effective and may decrease the incidence of adverse effects.
I. Other Acute annular urticaria (AA U), a type of giant urticaria occurring in infants from 4 months to 4 years old, presents suddenly with numerous small,
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round, erythematous wheals that rapidly spread across the body enlarging into polycyclic, blanching wheals with a bright violaceous center. The lesions fade within 1-2 h, but new lesions wax and wane over 10 days and then resolve completely. There may be transient periorbital, hand, or foot edema and fever to 39°C. Pruritus occurs in half the patients. While the cause is uncertain, nearly two-thirds of children have a history of diarrhea treated with furazolidone. Laboratory tests were normal. Treatment was symptomatic. Since furazolidone has been replaced with newer drugs, AAU is rarely seen (52). J.
Idiopathic
CIU is reserved to describe cases in which a cause has not been established. CIU and angioedema is less common in childhood, with estimates approaching 25% (5) compared to over 90% in adults. Recurrent intermittent hives are less well characterized. The findings of functional autoantibodies directed against the alpha chain of the high-affinity IgE receptor or, less commonly, IgG have not been studied in children as in adults.
VI.
DIFFERENTIAL DIAGNOSIS
A.
Urticaria
Recognizing urticaria does not usually pose a significant clinical dilemma, but several skin eruptions can masquerade as urticaria and in turn may be treatable. Tissue swelling that resembles angioedema can be due to unrelated disorders (50). The differential diagnosis is extensive and outlined in Table 2. Benign facial flushing associated with bottle- or breastfeeding is frequently reported by parents. This is not associated with other symptoms and resolves spontaneously. The underlying mechanism has yet to be established.
1.
Urticaria Pigmentosa
This disorder refers to collections or mast cells in the skin appearing as welldemarcated tan macules and papules beginning in the first 6 months of lire. The lesions can enlarge to become plaques several centimeters in diameter. These are termed mastocytomas and can be either solitary or multiple. They urticate with genLle trauma such as stroking the skin (Darier's sign).
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Table 2 Masqueraders of Urticaria/Angioedema in Infants and Young Children Urticaria Well-circumscribed rashes Urtica ria pigmen tosa Diffuse cutaneous mastocytosis Erythema ma rgi na tum Erythema multiforme ("target" lesions) Erythema annular centrifugum Familial annular erythema Food-associated erythematous rashes Gustatory flushing, auriculotemporal nerve syndrome (Frey's syndrome) Irritant dermatitis Benign facial flushing Food intolerance due to food additives or biochemical reactions In fections/in festations Parasitic disease (Strongyloides stercoralis) Scabies Lyme disease (erythema chronicum migrans) Angioedema Skin swelling Derma tom yosi tis Scleroderm a Periorbital swelling Sinusitis: unilateral or bilateral infraorbital swelling Blunt trauma/child abuse Parasitic disease (trichinosis) Melkersson-Rosenthal syndrome (cheilitis granulomatosa or Miescher's syndrome) Superior vena cava syndrome Scalp swelling Blunt trauma: accidental or child abuse Cellulitis, abscess Bleedi ng dia thesis Tumors or infiltra tion from malignancies (neuroblastoma, leukemia cutis) Periorbital, face, extremity swelling Nephrotic syndrome Lym phedema Myxedema-congenital hypothyroidism
The formation of bullae or vesicles is more common in children less than 2 years old. Mastocytomas and urticaria pigmentosa are the most common form of mast cell disease in children. When mast cells infiltrate the bone marrow, spleen, lymph nodes, or liver, the disorder is termed systemic
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mastocytosis. Triggers of mast cell degranulation include exercise, change in body temperature, infections, and certain drugs resulting in pruritus, tlushing, and even hypotension (53). Diffuse cutaneous mastocytosis often presents by age 3 years with either normal-appearing skin or reddish-tan, thickened, edematous skin with an orange-peel texture. On microscopic examination there is infiltration of the entire skin by mast cells. Bullae are common and these patients are more likely to develop systemic mastocytosis.
2.
Erythema Multiforme
This is rare in young children. The lesions are typically target-shaped macules, papules, or bullae and extend across the extremities, lips, and face. Unlike in typical urticaria, these lesions remain fixed and persist for several days. Associated symptoms include malaise, fever, and arthralgias. The rash is resistant to treatment with epinephrine.
3.
Infections
a. Scabies. Scabies is caused by the burrowing into the skin and release of toxic substances by the female mite Sarcoples scabiei. Symptoms are intense pruritus and a 1-2 mm erythematous papular rash that can become scaly, excoriated, and crusted. The classic lesion of threadlike burrows may not be seen in infants, although bullae and pustules are common. Wheals and papules can be mistaken for urticaria and papular urticaria, respectively. In infants, the palms, soles, face, and scalp are frequently infected. Diagnosis is by microscopic identification of the mite, ova, or scybala in skin scrapings from burrows, eczematous lesions, or fresh papules. b. Spirochetal Disease. Lyme borreliosis is associated with the appearance of a single annular erythematous rash termed erythema chronicum migrans occurring after an arthropod bite and infection. There may be multiple lesions that slowly enlarge over weeks or months, followed by the onset of arthritis. The skin lesion may not feel hot to the touch but the child may complain of itching or burning. In nearly half of the patients, multiple, smaller, annular secondary lesions will occur that are recurrent and evanescent. c. Parasitic Disease. Strongyloides stercora;;s is a nematode of worldwide distribution including southern Appalachia and Eastern Europe that can infect humans through direct skin invasion and eventually reside in the upper GI system. With repeated skin invasion, a papular rash may
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occur. Larva curens describes a large erythematous urticarial-like lesion with rapidly spreading edges usually localized within 30cm of the anus. Peripheral eosinophilia is common and associated symptoms include colicky abdominal pain, vomiting, mucus diarrhea, and failure to thrive (54). d. Other. Other annular eruptions in childhood can be confused with urticaria. Erythema annulare centrifugum is characterized by erythematous plaques with a scaly leading edge. The condition is chronic, tending to persist for months to years. Annular erythema of infancy presents as erythematous papules that develop into arcs and polycyclic lesions. While the individual lesions resolve in 2 days, eruptions can occur for months to years (55). Familial annular erythema was described in one family and is inherited in an autosomal dominant pattern. Infiltrated papules gradually enlarge to form erythematous rings with areas of central fading and transient residual hyperpigmentation (56) Frey's syndrome, also known as auriculotemporal nerve syndrome, can be mistaken for urticaria related to a food allergy. After unilateral injury to the nerve such as by birth trauma, aberrant reinnervation of the nerve to the skin as opposed to the salivary gland can result in a unilateral Oushing erythematous rash with or without sweating occulTing within minutes of eating especially tart foods. The absence of pruritus and angioedema and its unilateral distribution differentiates this from urticaria. Acute non lymphocytic leukemia presented as asymptomatic erythematous wheal-like papules, mantles and nodules in a 15-month-old boy who had been treated for urticaria for 6 months (57). Leukemic infiltration of the skin is termed leukemia cutis.
B.
Angioedema
1.
Child Abuse
Recurrent scalp angioedema was misdiagnosed as child abuse in an 18month-old child (58).
2.
Nephrotic Syndrome
Nephrotic syndrome is characterized by edema, proteinuria, hypoproteinemia, and hyperlipidemia. More than 90% of children with nephrotic syndrome have an idiopathic form, usually minimal change disease. It occurs in children ages 2-6 years old, affecting boys more than girls (2: I). Children presenting with morning bilateral periorbital edema that is unresponsive to antihistamines, but gradually resolves over the day, should be assessed for nephrotic syndrome. The finding of lower extremity
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pitting edema may eventually progress to generalized edema, weight gain, ascites, and pleural effusion with decreased urine production. Urinalysis reveals protein and occasionally microscopic hematuria.
3.
Superior Vena Cava Syndrome
Superior vena cava syndrome in children can present with head and neck edema in association with distended neck veins, plethora, cyanosis, and proptosis. Superior mediastinal masses that could precipitate this include lymphoma.
4.
Myxedema
Congenital hypothyroidism can present with nonpitting edema of the extremities and genitals and facial puffiness. In the first month of life, associated symptoms include enlarged head size. prolonged physiological icterus, and feeding difficulties. Thereafter. somnolence. sluggishness, poor appetite, constipation, subnormal temperature, pericardial effusion, heart murmur, bradycardia. and large abdomen with umbilical hernia can be seen. Despite normal results of a routine newborn screen, laboratory errors can occur. Thyroid function studies confirm the diagnosis.
5.
Dermatomyositis
This is a multisystem disease of unknown cause characterized by inflammation of striated muscle and accompanied by cutaneous lesions. Clinical presentation includes insidious onset and gradual progression of proximal muscle weakness, especially of the extremities and trunk. Nonpitting edema and thickening of the skin can occur. It rarely presents before age 2, with a verage age of onset at 8-9 years. Elevated levels of serum muscle enzymes and abnormal electromyographic results support the diagnosis. Early treatment is associated with a favorable prognosis.
6.
Scleroderma
Morphea and linear scleroderma are cutaneous manifestations of a chronic fi brotic disturbance of connective tissue. This rare disease of unknown cause can occur at any time in childhood. Early skin findings include slightly erythematous and edematous patchy 3reas of skin, often in a linear pattern and commonly occurring on one side of the body. The child may complain of a prickly sensation or pain. With disease progression, the involved skin becomes further indurated and enlarges peripherally exhibiting a violaceous center. It may progress to involve an entire extremity, resulting in an atrophic and shiny appearance to the skin with scarring, limb shortening,
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and flexion contractures. Laboratory findings are nonspecillc and no specific therapy is available, although many therapeutic interventions have been attempted (59).
7.
Parasitic Disease
Trichinosis is caused by Trichinella spira/is, which is transmitted by ingestion of undercooked pork, wild pig, walrus, bear, or horse meat. Periorbital and facial edema occur in up to 80% of cases and generally follows gastroenteritis and diarrhea by 1 week and lasts another 2-3 weeks. The edema phase is due to larval invasion and is associated with myalgia, fever, and peripheral eosinophilia. Affected muscles include the masseters, intercostals, and diaphragm. Diagnosis is based on results of serology and muscle biopsy
VII.
DIAGNOSTIC STRATEGIES
The evaluation of urticaria in childhood may require the combined skills of the pediatrician, allergist, and dermatologist. Table 3 outlines a suggested approach to evaluation.
A.
Acute Urticaria/Angioedema
The most important factor in determining the trigger in urticaria is a detailed history (Table 3). A thorough physical examination can identify other associated findings beside cutaneous features and help to confirm that the eruption is indeed urticaria or that the edema is angioedema. An extensive laboratory evaluation of acute urticaria or angioedema is not required. As part of the examination, assess for dermographism by briskly stroking the skin. Within 2-5 min, linear pruritic wheals with a flare develop at the site. Dermographism may follow a viral infection or drug reaction and its presence can invalidate percutaneous allergy testing that relies on the presence of a wheal and flare reaction. When urticaria occurs during the course of a febrile illness and antibiotics are administered concomitantly, it may be necessary to determine whether the causative trigger was the antibiotic or a cutaneous manifestation related to the infection itself. The only commercially available validated antibiotic skin test preparation for penicillin is the major determinant penicilloyl-polylysine (Pre-Pen) The major determinant penicilloyl appears to be responsible for most cases of urticaria. while the minor determinants are involved in anaphylactic reactions. Skin testing with drugs that are of
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Table 3 Evaluation of Young Children with Urticaria and/or Angioedema History (Acute and Chronic) Onset Duration: individual lesions <24 h, all lesions Distribution Pattern: Relation to meals or specific food, medication, infectious illness, exertion, recent sting or bite Pruritus: presence or absence of Physical: Cold, heat, vibratory, sunlight, water Associated symptoms: Rhinitis, fever, arthritis, cough, vomiting, diarrhea, weight loss Medical History (atopy): Eczema, allergic rhinitis, asthma Diet: formula, foods Medications: Specifically ASA, NSAIDs, antibiotics, narcotics, over-the-counter, herbal Immunizations: gelatin- or egg-based vaccines Environment: Pets (fleas), roaches, insect infestation (bedbugs) Day care Travel: tropical or subtropical, drinking water Family history: Angioedema, atopy Growth and development: Developmental delay Physical Examination Vital signs, temperature, weight, height, occipital frontal circumference Skin Chest Abdomen Laboratory (Acute) Specific serum IgE Percutaneous skin testing or in vitro: RAST or ELISA reactions to foods, inhalants, latex Penicillin skin testing (if indicated by history) Throat culture (for Strep.) if over 4 years old Laboratory (Chronic) Total serum IgE Specific serum IgE Percutaneous skin testing or in vitro assay (RAST or ELISA) Foods, latex, inhalants Basophil histamine release assay (research applications) Complete blood count with manual difrerential (evaluate for eosinophilia) Erythrocyte sedimentation rale (Continued)
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Table 3 Continued C-reactive protein Antinuclear antibodies Serum complement levels: C2, C4 C I esterase inhibitor level and functional assay (if angioedema only) Viral titers: Hepatitis Band C panel, HIV, EBV, HSV Cryoglobulins Urinalysis for white blood cells, bacteria, protein Free red blood cell protoporphyrin and fecal protoporphyrins (if solar-induced) Procedures Tests for physical urticaria Dermographism: stroking skin for Darier's sign Cold: Ice cube test Vibratory: laboratory vortex Cholinergic: partial submersion in 40°C water Tests for urticarial vasculitis Skin biopsy: lesional skin Tests for food allergy Elimination diet and reintroduction of a single food Open food challenge vs. double-blind placebo-controlled food challenge OFC, occipital frontal circulTIference: CBC, complete blood count: ESR, erythrocyte sedimentation rate: CRoP, C reactive protein: ANA, antineutrophil antibody: RAST, radioallergosorbenl test: ELJSA. enzyme linked imlTIunosorbenl assay: DBPCFC, doubleblind placebo-controlled food challenge.
low-molecular-weight is problematic and not predictive: these drugs combine with serum proteins to form haptens to which the antibody is then directed. A negative skin test to a low-molecular-weight medication is not satisfactory to confirm safe use of that drug. A positive skin test suggests avoiding that medication or may indicate an irritant reaction. Highmolecular-weight drugs that can act as complete antigens may be used for skin testing. Radioallergosorbent test (RAST) for penicillin is not sensitive enough to exclude penicillin as the culprit. Food allergy evaluation (Table 4) includes a detailed history documenting that symptoms improved after elimination of the sLlspect food. An extreme or prolonged elimination diet should be avoided to prevent nutritional deprivation. Identification of specific 19E using percutaneous skin testing or an in vitro method such as RAST or enzyme-linked immunosorbent assay (ELISA) can be used. Currently available CAP RAST are of sufficient sensitivity and specificity to provide 95% confidence intervals for peanut, milk, and egg. This allows the
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Table 4
Evaluation of Food-induced Urticaria
History Diet Dyes/coloring Well water, drinking from streams Examination Measures of specific IgE Skin Testing Fresh (prick on prick) Commercial preparations In vitro testing IgE RAST or ELISA IgG4 subclass controversial (specific IgG not useful) Food challenge Double-blind placebo-controlled Open Research: Basophil histamine release assay
practitioner to decide whether to pursue open challenge if the result is low or, conversely, to continue avoidance if the level is elevated (15). Skin tests are particularly helpful if negative, in the presence of a positive histamine control, in ruling out a food allergy because there is a good predictive value with true negatives. False-positive skin tests with foods occur at a rate approaching 50%, thus highlighting the importance of clinical correlation. Intradermal skin testing with food allergens frequently causes irritant local reactions and is not recommended. An elimination diet for 2 weeks, followed by reintroduction of the food, may reveal the culprit. Open, singleblind, and double-blind food challenges can be performed in the office setting where immediate treatment can be provided if a reaction occurs. Although the double-blind placebo-controlled food challenge is the gold standard and utilized in research protocols, it is time-consuming in both preparation and administration. In younger children, blinding may not be necessary because a psychological component is less likely.
B.
Chronic Urticaria and Angioedema
As with acute urticaria, the history and physical examination are of key importance. Special attention to nondermal organ systems may uncover an underlying systemic disease. Tests for physical urticaria should be
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performed. A battery of basic laboratory tests may indicate the presence of an underlying systemic disorder (Table 3). However, an extensive laboratory evaluation in the absence of other organ system involvement either identified by the history or the examination may not be warranted. An elimination diet, if undertaken, should not be broad or extended. A skin biopsy may prove helpful in atypical lesions, or in those cases in which urticarial vasculitis is suspected.
VIII.
MANAGEMENT
Treatment is primarily directed at identifying the underlying trigger and, if possible, avoiding it. Additional treatment is aimed at relieving the pruritus and decreasing the size and number of urticarial lesions (Table 5). A variety of pharmacotherapeutic options have been used in urticaria and angioedema in adults. Less published experience is available in the pediatric age groups. Likely the most important aspect of management is reassurance to the parents and child.
A.
Antihistamines
1.
Systemic H1-Antagonists
Although oral HI-antagonists have been shown to be effective in the treatment of pediatric aJlergic rhinitis, their use in children with urticaria contains large gaps. The first-generation antihistamines are presumed to be safe for young children and have undoubtedly been administered without apparent harm to millions in this age group as they have been available for over 50 years. It is suspected, however, that CNS impairment beyond the typical drowsiness is more common than realized. Use of first-generation antihistamines should probably be restricted to children with either urticaria or atopic dermatitis whose pruritus is so severe that the sedative effect is a benefit rather than a risk (60). The second-generation antihistamines are virtually free of CNS adverse effects and are becoming the preferred medication, particularly since pediatric formulations are available. Cetirizine (Zyrtec, Pfizer. Inc.) is the metabolite of hydroxyzine and is available as a I mg/ml syrup approved for children 6 months of age and older for the treatment of urticaria. Loratadine (Claritin, Schering Corp.) is also available in a I mg/ml syrup that became available without a prescription in early 2003. Fexofenadine, the acti ve meta bolite of terfenadine, is marketed as AJlegra (A ventis, Inc.) and available in a 30 mg tablet approved for twice daily administration
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Table 5 Treatment of Infants and Young Children with Urticaria and/or Angioedema
Avoidance Avoid aspirin If a drug is suspected, discontinue and monitor for symptom resolution If food or food additive is suspected, discontinue completely for 2 weeks and monitor for symptom resolution~ consider reintroduction Pharmacotherapy Antihistamines Second-third-generation H I-antagonist antihistamines Combine with H2-antagonist antihistamines Traditional or first generation H I-antagonist antihistamines If severe: Corticosteroids (prednisolone) Epinephrine intramuscularly if angioedema compromises airway Other Leukotriene modifiers: LTC4, LTD4, LTE4 receptor antagonists Oral beta 2-agonists Calcium channel antagonists Tricyclic antidepressants Mast cell stabilizer (not available in US) Generic name Antihistamines HI-antagonist Cetirizine
H2-a ntagonist Leu kotricnc modifier
Trade name
Zyrtec syrup
Formulation
Dosing
Age indication
:U-5 ml >6 months daily/twice daily Loratadine Claritin 25-5 ml I mg/ml >2 years syrup daily/twice daily Cimetidine Tagamet Twice daily NA Ranitidine Zanlac 50 mg/ml Twice daily NA Monlelukasl Singulair 4mg chewable Daily > I" year or oral granule ZafirlUKast Accolate 20 mg Twice daily >6" years I mg/ml
"Age indication for asthma.
for ages 6 and older. It was shown to be effective in the treatment of chronic idiopathic urticaria in children over 12 years of age (61,62). The pharmacokinetics of fexofenadine administered 30 mg twice daily to 60 mg daily in children ages 8-12 years is similar to that in adults with 80°';;, of a dose eliminated unchanged in the feces. Onset of action
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based on suppression of histamine-induced wheal and llare reactions was 1-2 h and duration was 24 h (63). Studies in younger children are not available.
2.
Topical H1-Antagonists
Use of these agents is not recommended. While preparations of diphenhydramine are available for topical use and parents frequently report using this method, the efficacy is unclear and not studied. The waxing and waning nature of urticaria limits this treatment's potential for efficacy and the risk of contact dermatitis is increased with topical administration.
3.
H2-Antagonists
Data are lacking in pediatric patients, but the addition of H2-antagonists to HI-antagonists has reduced wheal formation and pruritus in adult patients, although this remains an area of controversy. In most adult studies, cimetidine was used. Few studies using ranitidine have been reported. Monotherapy does not appear to be beneficial.
B.
Beta-Agonists
Epinephrine is beneficial in the treatment of acute severe urticaria or angioedema. The effect, however, is short-lived. Intermediate-acting epinephrine is no longer available. Orally administered drugs have mixed results and data are lacking in young children.
C.
Tricyclic Antidepressants
Many compounds in this category have H \-antihistaminic properties. Doxepin, a highly potent H I-antagonist with weak H2-antagonist properties, is effective in adults with chronic urticaria at dosages as low as 10 mg daily. Pediatric results are not available.
D.
Calcium Channel Blockers
Since calcium inllux is required for allergen-induced mast cell activation and secretion of histamine and leukotrienes, it is logical that calcium channel blockers could inhibit release of these mediators. Nifedipine demonstrated a beneficial effect in 10 adults with CIU in a double-blinded placebocontrolled trial (64). Two small studies involving adults with CIU exhibited mild improvement. Pediatric studies are lacking.
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E.
Mast Cell Stabilizers
Ketotifen po sesses H I-antagonistic activities as well as mast-cell-stabilizing properties. In adults, it has shown partial effectiveness in the treatment of cold urticaria, dermographism, and exercise-induced urticaria. This is not available in the United States and studies in young children are not available. Cromolyn and nedocromil, although effective at stabilizing mast cells in the nose, conjunctiva, and lungs, do not effectively stabilize skin mast cells.
F.
Anabolic Steroids
Attenuated androgens, including stanozolol and danazol, are useful as prophylactic therapy in hereditary angioedema as well as cholinergic urticaria and steroid-dependent urticaria. These androgens may act through their ability to augment protease inhibitor levels that could thereby inhibit proinnammatory mediators. Side effects limit their widespread use, particularly in young children who have yet to reach their growth potential. The adverse effects are, however, relatively mild and their efficacy greater than that of the fibrinolytic agents.
G.
Corticosteroids
1.
Systemic
Oral or injectable corticosteroids, while highly effective in treating urticaria and angioedema, in general should be reserved for patients with severe symptoms. This form of therapy is ineffective in patients with hereditary angioedema.
2.
Topical
Data are unavailable to determine the efficacy of topical corticosteroids. It is not uncommon to have patients present who have used steroid creams or lotions without relief of symptoms. Due to the nature of urticaria and potential for widespread involvement, it is unlikely that a topical approach would be beneficial.
H.
Leukotriene Modifiers
Leukotriene receptor antagonists, including zafirlukast (Accolate, AstraZeneca) and montelukast (Singulair, Merck, Inc.) have demonstrated improvement in CI U in small open-label and one single-blinded trial in
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adults when used alone or in combination with antihistamines (65-67). In addition to symptom reduction, the need for antihistamine rescue was reduced. Although pediatric studies in urticaria are not available, safety in this age group has been established down to I year of age and an oral granule formulation will be available soon. Zilueton (Zyflo, Abbott) a 5-lipoxygenase inhibitor has similarly showed improvement in urticaria in adults. Its use in pediatrics is limited by the lack of appropriate formulation, four times daily dosing, and need for liver function testing. In some cases, the use of leukotriene modifiers has allowed the discontinuation of steroids. Leukotrienes have been demonstrated to playa role in urticaria (I). When injected into the skin, they induce a dose-dependent wheal and flare response similar to that of histamine (68).
I.
Immunosuppressive Therapy
Cyclosporin inhibits the release of mediators from mast cells as well as inhibiting the effect of interleukins. Administered at a dosage of 2mgjkgj day eliminated the need for oral steroids in four of six adults whose urticaria was refractory to combination therapy with a leukotriene modifier, and H Jand H2-antagonists (69). Serious adverse side effects limit its widespread use. Pediatric experience in the treatment of urticaria with cyclosporin is preliminary. J.
Other Therapies
Due to the recurrent nature of chronic urticaria, and the unresponsiveness of severe urticaria to standard therapy, many unconventional treatments have been attempted to achieve relief. Sulfasalazine induced remission of steroid-dependent CIU in three adults (70). Methotrexate, antimalarial drugs, dapsone, gold, colchicine, and plasmapheresis have been utilized in either small, uncontrolled series or individual adult patients with limited benefit. Pediatric data are not available. Data are lacking to support the empiric use of antibiotics for treatment of a presumed underlying bacterial infection.
IX.
CONCLUSIONS
Urticaria and angioedema in infants and young children is clinically and causatively different from older children and adults. Angioedema is more common and pruritus is less consistent or more difficult to recognize.
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Generally the acute form is more common, uncomplicated, short-lived, and easily managed with H I-antagonists. Depending on the age of the child, food allergy and medication reactions are the most common triggers for acute urticaria in children, while physical causes are common for chronic urticaria. Parental reassurance is necessary in addition to measures to decrease symptoms. An extensive search utilizing laboratory studies is typically not necessary.
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Greaves M. Chronic urticaria. J Allergy Clin Immunol 2000; 105:664-672. Beyer K, Castro R, Feidel C, Sampson HA. Milk-induced urticaria is associated with the expansion of T cells expressing cutaneous lymphocyte antigen. J Allergy Clin Immunol 2002; 109:688-693 Legrain V, Taieb A, Sagi T. Maleville J. Urticaria in infants: a study of forty patients. Pediatr Dermatol 1990: 7:101-107. Mortureux P, Leaute-Labreze C, Legrain-Lifermann V, Lamireau T, Sarlangue J, Taieb A. Acute urticaria in infancy and early childhood. Arch Dermatol 1998; 134319-323. Ghosh S, Kanwar AJ, Kaur S. Urticaria in children. Pediatr Dermatol 1993; 10: 107-110 Legrain V, Taieb A, Maleville J. Epidemiology of urticaria in infants. Allerg lmmunol 1993; 25(8):324-326. Harris A, Twarog FJ, Geha RS. Chronic urticaria in childhood: natural course and etiology. Ann Allergy 1983; 51:161-165. Volonakis M, Katsarou-Katsari A, Stratigos J, Etiologic factors in childhood chronic urticaria. Ann Allergy 1992; 69:61-65. Kauppinen K, Juntunen K, Lanki H. Urticaria in children. Retrospective evaluation and follow-up. Allergy 1984: 39:469-472. Tuchinda M, Srimurta N, Habananda S, Vareenil J, Assatherawatts A. Urticaria in Thai children. Asian Pac J Allergy Immunol 1986; 4:41-45. Sicherer SH. Determinants of systemic manifestations or food allergy. J Allergy Clin lmmunol 2000; 106:S251-S257. Oranje AP, Van Gysel D, Mulder PGH. Dieges PH. Food-induced contact urticaria syndrome (CUS) in atopic dermatitis: reproducibility of repeated and duplicate testing with a skin provocation test, the skin application food test (SAFT). Contact Dermatitis 1994; 31:314-318. Rodriguez A, Trujillo MJ, Matheu V, Baeza ML. Zapatero L. Martinez M. Allergy to grape: a case report. Pediatr Allergy lmll1unol 200 I: 12:289-290. De Swert L, Cadot P, Ceuppens JL, Allergy to cooked white potatoes in infants and young children: a cause of severe, chronic allergic disease. J Allergy Clin Immunol 2002; 110:524-529.
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Sampson HA, Ho DG. Relationship betwecn food-specific IgE concentrations and the risk of positive food challenges in children and adolescents. J Allergy Cli n Imm unol 1997; I00:444-45 l. Simon RA. Adverse reactions to food additives. Current Allergy Asthma Rep 2003; 3:62-66 Perry CA. Dwyer J, Gelfand JA, Couris RR, McCloskey WW. Health effects of salicylates in foods and drugs. Nutr Rev 1996; 54:225-240 Freishtat RJ, Goepp JG. Episodic stridor with latex nipple use in a 2 month-old infant. Ann Emerg Med 2002; 39:441-443. Chang A, Zic JA. Localized heat urticaria. J Am Acad Dermatol 1999; 41: 354-356 Capulong MC, Tomikawa M, Tahara K, Akasawa A, Iikura Y. Cold stimulation test and histamine release in primary acquired cold urticaria. Intern Arch Allergy lmmunol 1997; 114:400-403. Maltby NH. Ind PW, Causon RC, Fuller RW, Taylor GW. Leukotriene E4 release in cold urticaria. Clin Exp Allergy 1989; 19:33-36. Hollman HM, Wanderer AA, Broide DH. Familial cold autoinflammatory syndrome: phenotype and genotype of an autosomal dominant periodic fever. J Allergy Clin Immunol 200 I; 108:615-620. Johnstone RF, Dolen WK, Hollman HM. A large kindred with familial cold autoinflammatory syndrome. Ann Allergy Asthma Immunol 2003; 90:233-237. Patterson R, Mellies CJ. Blankenship ML, Pruzansky JJ. Vibratory angioedema: a hereditary type of physical urticaria. J Allergy Clin lmmunol 1972; 50:174-182 Williams-Arya P. Hogan MB. Wilson NW. Solar urticaria in a 6-year-old child. Ann Allergy Asthma Jmmunol 1996; 75:141-143. Wasserman D, Preminger A, Zlotogorski A. Aquagenic urticaria in a child. Pediatr Dermatol 1994; 11:29-30 Luong K VQ, Nguyen LTH. Aquagenic urticaria: report of a case and review of the literature. Ann Allergy Asthma Immunol 1998; 80:483-485. Heckbert SR, Stryker WS, Coltin KL, Manson J E, Platt R. Serum sickness in children after antibiotic' exposure: estimates of occurrence and morbidity in a health maintenance organization population. Am J Epidemiol 1990; 132:336-342 Diaz JM, Perez Montero A, Gracia Bara MT, Cabrerizo S. Zapatero L, Martinez Molero MI. Allergic reactions due to ibuprofen in children. Pediatr Dermatol 200 I: 18:66-67 Kelso JM, Jones RT. Yunginger JW. Anaphylaxis to measles, mumps, and rubella vaccine mediated by IgE to gelatin. J Allergy Clin lmmunol 1993; 91:867-872. Sakaguchi M, Yamanaka T, Ikeda K. Sano Y, Fujita H, Miura T. Inouye S fgE-mediated systemic reactions to gelatin included in the varicella vaccine. J Allergy Clin Immunol 1997; 99:263-264. Peng YS, Shyur SO. Lin HY. Wang CY. Steroid allergy: report of two cases. J Microbio lmmunollnfect 2001; 34(2):150-154.
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10 Papular Urticaria Larry Millikan Tulane University Medical Center, New Orleans, Louisiana, U.S.A.
I.
DEFINITIONS AND HISTORY
The definition of papular urticaria varies with the clinician, since its original description by Bateman in 1813 (1). It is of interest that the most recent additions of Rook, Andrews, and Fitzpatrick do not list papular urticaria in the index. The numerous synonyms do appear in various formats (Table I). The many synonyms attest to the variety of so-called questionable etiologies that, in a more genteel time, were an important disguise of symptoms related to less "desirable" causes (i.e., arthropods). For many clinicians the diagnosis of papular urticaria translated into what appeared to be unclean habits (lice, scabies, insect bites) and this was often difficult for the patient to accept. Indeed while we use the clinical pattern in supporting such a diagnosis, the science behind it was and still is significantly lacking. A reaction to various proteins in insect venom and secretions was thought to be the primary mechanism. Papular urticaria has long been primarily related to arthropod bites and stings. Some of this work was originally done by Melanby (2) in 1946. Many other authors have subsequently documented their apparent association with various degrees of scientific confirmation (3-5). Of particular interest has been the association of mosquitoes and mites. In tropical climates the tropical rat mite has caused recurrent "epidemics" after municipal attempts at rodent control leave the mites with a human host as a target, albeit second best (6,7). Children are often the primary targets and Frieden reviewed this in 1996 (7,8). While usually only mildly symptomatic, papular urticaria would seem to be a minor problem and challenge; the
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Millikan
Synonyms for Papular Urticaria
Strophulus Strophulus pruriginosus Lichen urtica tus Prurigo acute Prurigo simplex
complications of viral illnesses including the various encephalitides (and the notable epidemic of West Nile virus in 2002) from insect bites periodically has prompted work on the basic pathophysiology. Starting in the 1950s the work by Schaffer and Beerman (9) on histopathological characteristics and skin test reactions was followed by the concern of the transmission by mosquitoes of human immunovirus (HIV) was investigated by Penneys (10). The immune response was investigated by Alexander (I I) and Reunala, who reported looking at IgE and fgG (12) antibodies to mosquitoes. All of these confirm the association of arthropod bites with the clinical syndrome of papular urticaria. Accepting environmental !lying insects as a cause of papular urticaria is generally not a problem for most patients. However, in the lIlstances in which it is presumed to be related to other arthropods, such as mites and lice, there is less acceptance by the patient or the patient's family. In these cases, the clinician needs to educate the patient carefully as to the possible causes during evaluation and treatment. The highly sensitive IgE type I reaction causes immediate wheal and !lares and is most easily diagnosed. Diagnosis becomes much more difficult when there is delayed association between exposure and the symptoms and where there is a less obvious association with arthropods. In delayed reactions one also must consider a foreign body reaction with retained remnants of the arthropod. We now know more about the association of the delayed hypersensitivity reaction with arthropod exposure, which leads to a more long lasting, sometimes lichenoid, reaction. One that usually is not easily missed is the reaction to Solel/opsis (fire ant). Standard reactions usually are easily diagnosed; the immediate, often painful symptoms from the acute sting and the usual evolution through the pustular phase. In some patients IgE anaphylactic sensitivity to the Solenopsis venom occurs. Because of the ubiquity of these organisms in southern parts of the United States, the results are potentially life-threatening. In these circumstances, the urticarial characteristics can be visible immediately. Patients must be treated as those with bee/hornet/wasp hypersensitivity: with the ready availability of parenteral agents including epinephrine, certain antihistamines, and aggressive use of steroids.
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DIFFERENTIAL DIAGNOSIS
The differential diagnosis is summarized in Table 2. While the pathophysiology, history, and clinical pattern in most instances point to arthropod sources, many other possible causes must be ruled out for the sake of completeness (13,14). The classic pattern of papular urticaria secondary to environmental causes presents on exposed areas of the body. When lesions occur under clothing and around elastic and other restrictive materials, arthropods such as lice, scabies, and other mites must be considered. Another common consideration in the differential diagnosis is follicular eczema. [n patients with dermographism, the pruritus associated with eczema results in recurrent scratching and patterns of perifollicular urticarial wheals, often small, resembling cholinergic urticaria Over time, more lichenification appears, which helps considerably in differentiating evanescent urticaria from eczema. Follicular eczema, like urticaria, is primarily pruritic (according to Marion Sulzberger, eczema is "the itch that rashes"). This process is more common in patients of color, but shows no documented racial predilection. Drug reactions can present as a papular urticaria or classic urticarial lesions. The significance in these instances is the anaphylactoid potential that re-exposure to the drug could cause. All the usual steps in the evaluation for any possible causative drug should be done. Treatment (see below) must be expeditious because of the potential for anaphylactoid sequelae. Instances of drug reactions are increasing as is the awareness that drug interactions can cause allergic and other types of reactions. This is particularly true in older patients who may be taking multiple medications. Therefore, careful review in the older patient presenting with papular urticaria is mandated to rule out drug-related causes. A drug interaction
Table 2 Differential Diagnosis of Papular Urticaria
"Follicular" (papular) eczema Papular drug eruption Allergic contact dermatitis Miliaria Papular PM LE Insect bites Gianotti Crosti syndrome Cholinergic urticaria
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can cause reactions that would not be expected when a single drug is involved. While new medications are usually most likely the cause, a patient can develop an allergy to a drug that he or she has taken for a long time. Contact dermatitis (usually from plants) can also present as isolated papules. It is assumed that the reaction is follicular due to the portal of entry of the antigen. Multiple follicular spongiotic lesions can be clinically and grossly indistinguishable from urticarial lesions. The subsequent course in the sensitized patient will be progression vesicles and bullae, which is rare in papular urticaria. Miliaria is another consideration, especially simple miliaria. Miliaria crystallina or miliaria pustulosa is different enough that it is usually not a confounding factor in the diagnosis. The history of heat stress is very significant in supporting the diagnosis, since papular urticaria is rare under these circumstances. Involvement of the sweat glands, and challenge with exposure to further heat, confirm the diagnosis. Cholinergic can be confused with papular urticaria and with miliaria, because it presents as a papular syndrome occurring after exercise and/or heat exposure. The classic papular 3-5 mm lesions around the sweat apparatus can be easily confused with papular urticaria. A history of sweating and exercise or emotional stress is crucial in the tentative diagnosis. Polymorphous light eruption (PMLE) is a rare consideration. Several varieties occur, including a papular forlll, but the key clinical and historical fact is sun exposure. Confusion with light and heat stress is seen with miliaria may require very careful review of the patient's history. A factor that is very helpful in the diagnosis is the so-called autohyposensitization that usually occurs in patients with PMLE. PMLE may recur annually and the presence of hyposensitization is helpful in sustaining the diagnosis. Depending on one's definition of papular urticaria. allergy to insect bites Illay be considered central to this syndrome. Certain types of insect bites including those from Solenopsis and some other arthropods evolve from a different mechanism, usually related to the toxicity of saliva or venom and to hypersensitivity. Suspect insect bites have other characteristics (sun-exposed vs. non-sun-exposed, linear vs. dermatomal) and all of these considerations may help in making the diagnosis. Jf the process is primarily acraL one needs also to consider the Gianotti Crosti syndrome, or infantile popular acrodermatitis, which usually is limited to younger patients (15). Its symmetrical and ultimately lichenoid lesions are usually less of a problem in the differential diagnosis as the syndromc develops. Possible underlying viral causes sueh as Epstein-Barr and sometimes hepatitis B also are important considerations.
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III. TREATMENT Simple cases of papular urticaria often resolve, with the patient "out growing" the hypersensitivity. This seems to be the rule rather than the exception. When these patients have significant acute symptoms it may be necessary to treat them aggressively to keep the acute papular urticarial lesions from becoming infected or chronic and lichenoid. The longer the duration of the clinical signs and symptoms, the more difficult it is to control symptoms pharmacologically. Treatment in these patients should be related directly to the severity of the symptoms. Some cases have also responded to desensitization (16). Mild (and most) cases of papular urticaria will often respond to topical therapies. Topical steroids have even been shown to minimize the skin reaction as well as the reactivity of the skin to Arthropod proteins. Symptomatic relief of itching should be the mainstay of treatment, especially in younger patients. This includes the use of various agents that contain forms of menthol, camphor, or pramoxine. These can be very soothing, and one should consider vehicle selection as important as the active ingredient. In general, the best vehicles are lotions or gels: these agents go on easily and the flash of evaporation provides a cooling sensation and physical relief of the pruritic stimulus in many instances. We also have had increasing success using pimecrolimus and tacrolimus topically. Chronic symptoms may result from repeated exposure, which initiates the "itch scratch" cycle that is maintained without further exposure to arthropods or venom proteins. Patients with moderate symptoms require systemic therapy in addition to adequate topical therapy Traditional first-line drugs are H I antihistamines: many effective agents containing hydroxyzine and cyproheptadine have been considered standards. The development of nonsedating agents, initially terfenadine and astemizole, has drastically altered treatment approaches. Problems with drug interactions resulted in both of these being withdrawn over much of the world. The derivative of hydroxyzine, cetirizine, currently is my first choice, terfenadine has been replaced by fexofenadine. Also used are loratadine and its metabolite desloratadine. At the present time precscription agents of choice are hydroxyzine, cyproheptadine, fexofenadine, cetirizine, and desloratadine. In cases with primarily nocturnal pruritic symptoms, the sedation of older HI blockers has definite utility. The choice of agent may relate to available preparations, such as syrups, chewable tablets or dissolving tablets. Patients usually respond to loratadine 10 mg daily or desloratadine 5 mg daily, Fexofenadine 180 mg daily, and cetirizine 10mg daily. I prefer to use loratadine, desloratadine. or fexofenadine during the day and to reserve cetirizine and possibly
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cyproheptadine or hydroxyzine at bedtime especially when pruritic symptoms tend to keep the patient awake. This regime usually is sufficient to control acute symptoms, but when they are long-standing the therapeutic challenge is greater. Among the H2 blockers, the most commonly used has been cimetidine. The newer derivatives are more expensive and questionably more effective. Cimetidine now is available over the counter and patients may have already tried it. Combination agents to block both HI and H2 also are attractive; the most frequently used is doxepin, available in topical and oral preparations. The oral dosage for this indication is usually lower than that used for psychiatric indications, and as a result has significantly fewer side effects. In extensive and/or severe cases it may be necessary to treat aggressively with steroids in a short burst to break the cycle, and then use soothing baths such as oilated oatmeal (A veeno) or tar baths (Balnetar). In some patients the response to ultra violet (either ultraviolet B or psoralen/ ultraviolet A [PUY AD can be dramatic. One can expect the same dramatic results with patients with papular urticaria as are seen in those in atopic patients in response to PUYA. In very severe cases treatments similar to that used in mastocytosis may be considered. We have had good success in these patients with the use of oral cromoglycate. The literature is variable: Greaves (17) found this agent less effective than previous reports by such experts as Soter (18) and Czarnetzki (19). We believe that this has intriguing possibilities because of the different mechanisms that cromoglycate provides in the overall treatment of hyperactive mast cells. The absorption and tissue levels of cromoglycate do not seem to be sufficient to explain all of the benefit, but we find often a clear relationship between therapeutic compliance and symptom relief. Steroids, which are used in the treatment of other types of urticaria, are rarely the drug of choice unless the patient is unstable and his or her condition is worsening rapidly. The results of treatment can be dramatic: a dosage of I mg/kg may be necessary to control the progression of the disease. Beyond steroids the ascomyins (primecrolimes and tacrolimus) are also a possible choice for the treatment of difficult cases. In severe cases, potent therapy (with potentially much higher incidence of side effect) can be administered such as cyclosporin, methotrexate, Imuran, IYIG, and plasmapheresis. It is rare for a case of papular urticaria to require such therapy; then usage is described elsewhere in this book. Following the tree of therapy described here, from minimal to severe cases, one can usually control the condition. Continued therapy is routine with a slow taper, and in most cases this is successful. Improvement in many of these patients may result from changes their activities, such as withdrawal from the unknown precipitating antigen or other immunological changes
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(e.g., anti-antibodies) that result in symptomatic relief. The clinicians' role is to provide symptomatic relief until the cause can be determined and eliminated, or to support the patient until the cause has diminished. The majority of patients respond rapidly and simply to minimal therapy. A skilled clinician is needed to control the more severe variants.
REFERENCES I. 2. 3.
4. 5. 6.
7. 8. 9.
10.
II. 12.
13. 14. 15.
Bateman T. A Practical Synopsis of Cutaneous Disease. 2nd ed. London, England: Longman, Hirst, Rees, Orme and Brown, 1813: 13. Mellanby K. Man's reaction to mosquito bites. Nature 1946; 158:554-556. Schorr WF, Tauscheck AL. Dickson KB, Melski JW. Eosinophilic cellulitis (Wells' syndrome): histologic and clinical features in arthropod bite reactions. JAm Acad Dermatol 1984; Il(6):1043-1049 Heng Me Kloss SG, Haberfelde Gc. Pathogenesis of papular urticaria. J Am Acad Dermatol 1984; 100(6): 1030-1034. Rustin MH, Munro DD. Papular urticaria caused by Damestes maculatus Degeer. Clin Exp Dennatol 1984; 9(3):317-321. Theis J, Lavopierre MM, LaPerriere R, Kroese H. Tropical rat mite dermatitis. Report of six cases and review of mite infestations. Arch Dermatol 1981; 117(6):341-343. Burns DA. Papular urticaria produced by the mite Listrophorus gibbus. Clin Exp Dermatol 1987; 12(3):200-20 I. Howard R, Frieden 11. Papular urticaria in children. Pediatr Dermatol 1996; 13(3):246-249. Schaffer B, Jacobsen C. Beerman H. Histopathologic correlation of lesions of papular urticaria and positive skin test reactions to insect antigens. Arch Dermatol Syphilol 1954; 70:437-442. Penneys NS, Nayar JK, Bernstein H, Knight JW. Circulating antibody detection in human serum to mosquito salivary gland proteins by the avidinbotin-peroxidase technique. J Am Acad Dermatol 1988: 18(1 ):87-92. Alexander JO. Papular urticaria and immune complexes. JAm Acad Dermatol 1985; (2 Pt l):374-375. Reunala T, Brummer-Korvenkontio H, Palosuo K, Miyanij M, RuizMaldonado R, Love A, Francois G, Palosuo T. Frequent occurrence of IgE and IgG4 antibodies against saliva of Aedes communis and Aedes aegl'pti mosquitoes in children. Int Arch Allergy Immunol 1994; 104(4):366-371. Jordan HF, Schneider JW. Papular urticaria: a histopathologic study of 30 patients. Am J Dermatopathol 1997; 19:119-126. Millikan LE. Papular urticaria. Semin Dermatol 1993; 12:53-56. Gianotti F. Papular acrodermatitis of childhood and other papulovesicular arolocated syndromes. Hr J Dermatol 1979; 100:49-59.
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18. 19.
Millikan Giraldi S, Ruiz-Maldonado R, Tamayo L, Sosa-de-Martinez C. Oral desensitization in papular urticaria in children. Trop Doct 2002; 32(3): 142-145. Mallet AL, Norris P, Wong E, Greaves MW. The effect of disodium cromoglycate and ketotifen or the excretion of histamine and N-methylimidozole acetic acid in urine of patients with mastocytosis. B J Clin Pharmacol 1989: 2788-91. Soter NA, Austen KF, Wasserman SI. Oral disodium cromoglycate in the treatment of systemic mastocytosis. N Engl J Med 1979; 301:465-469. Czarnetizki BM, Behrendt H. Urticaria pigmentosa: clinical picture and response to oral disoclium cromoglycate. Br J Dermatol 1981; 105:465-469.
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11 Diagnosis of Difficult Urticaria and Angioedema Allen P. Kaplan Medical University of South Carolina, Charleston, South Carolina, US.A.
Malcolm W. Greaves Singapore General Hospital, Singapore
I.
INTRODUCTION
Most types of urticaria can be readily diagnosed based on the history and tests (provocation or laboratory) that are relatively simple to administer. However, some patients present with a confusing array of symptoms and the hives mayor may not be present at their initial presentation. A wide variety of possibilities need to be considered until a definitive diagnosis is made, including the possibility that more than one type of urticaria may be present. Before considering specific possibilities one may encounter, some general guidelines may be helpful in an initial consideration of any patient.
II.
SKIN CONDITIONS THAT CLINICALLY MIMIC URTICARIA AND ANGIOEDEMA
Even experienced specialists in allergy or dermatology can be taken in by urticaria-like skin manifestations of nonurticarial disease. The following sections provide actual examples; a more detailed (but not fully comprehensive) list is included in Table I.
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Figure 1 Acute dermatitis of eyelids due to latex hypersensitivity.
A.
Contact Allergic Dermatitis
A 50 year-old Afro-Caribbean woman with a history of admissions for psoriasis vulgaris was admitted for in-patient treatment by the Ingram regimen (tar bath, ultraviolet phototherapy and dithranol [anthralin]). Soon after admission she experienced swelling, redness. and itching of the eyelids and scattered irritant red lesions on the trunk and limbs. [nitially diagnosed as urticaria and angioedema, the lesions proved to be persistent and eventually peeled, leading to a revised diagnosis of contact dermatitis to synthetic rubber, which was finally confirmed by results of patch testing. She had been in the habit of self-applying her dithranol using rubber gloves she had obtained at home (Fig. I).
B.
Crohn's Disease
A 35-year-old man presented with recurrent swelling of the lower lip for
3 months. The lips, especially the lower lip, would swell for 2-3 days and then partially subside. There was no itching and no other cutaneous signs or symptoms. Examination showed nontender swelling of the lower lip with some induration. An initial diagnosis of recurrent angioedema was made and the patient underwent a panel of allergy skin tests. A subsequent, more thorough. examination of the mouth revealed cobblestone thickening of the oral mucosa and the liver was found to be enlarged. A revised diagnosis of Crohn's disease with secondary lymphedema was made. Further questioning
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Figure 2 Persistent swelling of the lips in a patient with Crohn's disease and granulomatous cheilitis.
revealed a history of intermi tten t bowel disturbance, previously la beled as irritable bowel syndrome. Results of endoscopic bowel investigations, a liver biopsy, and oral mucosal biopsy confirmed Crohn's disease. It should be noted that Melkersson-Rosenthal syndrome (facial lymphedema, facial nerve palsy, and scrotal tongue) can produce a similar clinical and granulomatous histological picture (Fig. 2).
C.
Recurrent Erythema Multiforme
A 42-year-old man presented with a 2 year history of red, tender, and itchy lesions mainly on the hands, feet, and limbs, and with variable crusted cheilitis with labial edema. The eyes, genitalia, and interior of the mouth were una/lected. Individual skin lesions lasted 1-2 weeks and desquamated. Initially the patient was referred with a presumed diagnosis of intermittent urticaria and angioedema. However this was ruled out on the basis of prolonged duration of individual skin lesions and the presence of desquamation (urticaria and angioedema do not peel). Urticarial vasculitis was considered, but a skin biopsy showed upper dermal lymphocytic infiltration, exocytosis of CD8+ cells into the epidermis, and satellite cell necrosis, indicative of erythema multiforme. PCR examination of the skin biopsy material revealed herpes simplex DNA and the patient's attacks were greatly reduced following long-term acyclovir treatment. The final diagnosis was recurrent erythema multiforme secondary to chronic herpes simplex infection (Fig 3).
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Figure 3 Urticarial-like lesions in a patient with recurrent erythema multiforme.
Table 1 Some Skin Conditions Clinically Mimicking Urticaria and Angioedema Contact allergic dermatitis (especially of the face) Dermatomyositis (especially of the face) Acute photosensitivity (especially polymorphous light eruption) Recurrent cellulitis, erysipelas Fixed drug eruption Erythropoietic protoporphyria (early childhood) Hypoalbuminemia (especially the nephrotic syndrome) Crohn's disease (granulomatous cheilitis with lymphoedema) Melkersson-Rosenthal syndrome (lymphedema, fissured tongue, facial nerve palsy) Myxedema
D.
Recurrent Erysipelas of the Forearms
An obese 45-year-old woman presented with a :2 year history of six episodes of acute swelling of the right forearm and three similar episodes of swelling of the left forearm. Each attack was painless, accompanied by fever, lasted a month, and resolved with scaling. The patient was referred for investigation of angioedema but examination of the hands revealed bilateral cheiropompholyx (vesicular eczema of the palms) and careful observation showed that the episodes of swelling were accompanied by signs of forearm lymphangitis. The overall picture was that of recurrent erysipelas, the portal of entry for infection being the palmar eczema. The patient experienced a reduction in attacks after commencing long-term penicillin treatment and application of topical corticosteroids for the eczema.
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URTICARIA AND ANGIOEDEMA: ACUTE VS. CHRONIC
It is useful to differentiate acute from chronic disease because an acute, brief (less than 6 weeks) episode of urticaria/angioedema is likely due to some identifiable allergen (drug, food, infection) (I). Urticaria/angioedema that is persistent and exceeds 6 weeks is more likely to be endogenous and may, in fact, represent either autoimmune chronic urticaria/angioedema or idiopathic urticaria/angioedema (2). This distinction, however breaks down in a variety of circumstances. The various types of physical urticaria typically persist for many months or even years, and in that sense are chronic, yet these need to be differentiated from the aforementioned types of chronic urticaria/angioedema. Statistics regarding the incidence of finding a cause for chronic hives vary tremendously in the literature, not only because of the erroneous attribution of some ingested substance as a cause of chronic urticaria, but also by the inclusion of the physical urticarias within the groups where a definite diagnosis has been made and, in that sense, the cause already found. It is also possible that any patient presenting with urticaria/angioedema of only a few weeks duration may have disease that represents the beginning of a more chronic process. The diagnosis will not become evident until a much longer period has passed, with persistence of the process.
IV.
PHYSICAL URTICARIA VS. OTHER CAUSES
One of the important distinctions to be made between different causes of hives is the duration of individual lesions. Most types of hives that are physically induced have lesions that last less than 2 h. This is generally true of cold urticaria, cholinergic urticaria, dermatographism, and solar urticaria. The major exception is pressure-induced urticaria (often called delayed pressure urticaria), in which not only is there a delay of 4-8 h before urticaria appears after a pressure stimulus, but also the duration of the hives certainly exceeds 2 h and may remain 12-36 h (3). Other causes of hives (e.g., allergic reactions to foods or drugs or chronic urticaria, whether idiopathic or autoimmune) may result in individual lesions that last longer than 2 h and typically last between 4 and 24 h. Thus it is extremely helpful to inquire about the duration of individual lesions as well as asking about the stimulus, shape, and location of lesions, particularly when a physically induced hive is suspect. If angioedema occurs concurrently with the urticarial process (e.g., a pa tient with cold urticaria who places one hand in ice water rather than doing an ice cube test), the swelling will remain for most of the day because it
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takes much longer to resorb the interstitial fluid. The swelling will stop increasing in less than :2 h if it is part of the aforementioned physical processes. Next we will consider some of the more difficult presentations of patients with urticaria and angioedema.
V.
COLD URTICARIA, CHOLINERGIC URTICARIA, AND DERMATOGRAPHISM
Although most patients with one of these disorders are readily identified, (i.e., hives due to touching cold objects vs. exercising, sweating, and hot showers vs. hives caused by scratching), historical clues can sometimes be misleading. There are patients with cholinergic urticaria who will describe hives occurring while swimming (a typical complaint of patients with cold urticaria) who do not have cold urticaria but induce hives as a result of the exercise of swimming. Many patients with severe dermatographism have hives when they shower and the urticaria is caused by the fine spray hitting their skin regardless of the temperature. However, because it is more common to take a hot than a cold shower, one might think that cholinergic urticaria is present. An exercise challenge (running in place in a heated room for 10 min or exercising on a stationary bicycle in a warmed room for 10-15 min) should be negative but clothing rubbing against the skin while exercising can cause hives in patients with severe dermatographic disease. Once the diagnosis of severe dermatograph ism is made by scratching the person's skin. the diagnosis of concomitant cholinergic urticaria can only be made based on the distribution and appearance of the hives. For example, do hives appear on the face or will exercise without clothing still cause hives? Combinations of these physically induced hives can occur; for example, cold urticaria and cholinergic urticaria (4,5) may both be present; thus patients will have both a positive ice cube test and a positive exercise challenge, fulfilling criteria for each disorder. Dermatographism can also occur in combination with cold urticaria or cholinergic urticaria, although this is infrequent. With severe dermatographism, the diagnosis of concomitant cholinergic urticaria (as described above) or cold urticaria can be dimcult to affirm. We have seen an occasional patient with dermatographic disease whose ice cube test was positive only because the ice cube was moved somewhat when the test was done, whereas other types of cold challenge, for eX~lmple, placing one hand in the water or holding an ice-lilled glass, were negative. Disorders lhat can be missed are those in which combinations 01' physical stimuli are needed to produce urticaria but
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a single challenge is negative. Examples are cold-induced cholinergic urticaria and cold-dependent dermatographism (6,7). rn cold-i nd uced cholinergic urticaria, exercise produces symptoms only when it occurs in a cold environment. The ice-cube test is negative and exercise in a heated room is negative as well. The term cholinergic urticaria was used here because the lesions had the appearance of cholinergic hives and were exercise related, but there is no evidence that released acetylcholine into the skin causes the urticaria, as is true of classic cholinergic urticaria. Colddependent dermatographism is seen in patients in whom scratching the skin causes linear hives only when the skin has been cooled (e.g., scratching while outside during the winter).
VI.
SOLAR URTICARIA
Difficulties regarding the diagnosis of solar urticaria arise because of confusion with other light-sensitive rashes, most of which are not urticarial. The fact that patients may present without a rash and most offices lack the equipment to challenge patients with the appropriate wavelength contribute to this. Type I solar urticaria (8) is due to medium wavelength ultraviolet (UV) light that does not pass through ordinary window glass and does not typically occur indoors. It should be differentiated from rare causes of solar urticaria occurring within the visible spectrum, and that can be induced by standing near a closed window on a sunny day. Most patients who have solar urticaria will have lesions that last less than 2 h if they are removed from the stimulus; most other photosensitive rashes, whether urticarial or not, last for many hours and often days to weeks. Alternative considerations are photoallergic or phototoxic contact dermatitis, photosensitivity due to an ingested medication, or polymorphous light eruption, a particular delayed hypersensitivity-type rash, or cutaneous manifestations of one of the porphyrias.
VII.
CHRONIC INTERMITTENT URTICARIA/ANGIOEDEMA AND IDIOPATHIC ANAPHYLAXIS
When urticaria occurs intermittently, the diagnostic possibilities actually increase, although persistent urticaria can be far more troublesome for the patient. For example, a patient may have hives for 1-2 weeks, a respite of 2-3 weeks, and then recurrence that follows such a pattern for 6 months. The patient's condition does not fulfill criteria for chronic urticaria and the intermittent nature makes one consider that an allergen may be responsible.
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Skin testing for IgE-mediated hypersensitivity to foods, spices, or condiments should be done even if the history provides no clue regarding foods that might be ingested in such an intermittent fashion. A thorough consideration of any medication used intermittently must also be made including nonsteroidal anti-in(lammatory drugs, (NSAIDS), hormone preparations, vitamins, and others. Such patients may have chronic urticaria with a presentation that is intermittent, and perhaps less severe. The idiopathic version becomes a diagnosis of exclusion whereas a positive test for IgG antibody to the IgE receptor or IgE itself suggests autoimmune chronic urticaria. Thyroid function tests and measurements of thyroid antibodies (anti thyroglobulin and antimicrosomal) should be done since the incidence is 24% in patients with chronic urticaria (9) and provides a clue to this diagnosis. These antithyroid antibodies segregate with the autoimmune subtype of chronic urticaria rather than those that remain idiopathic (10), suggesting a more general immune abnormality. The incidence of these antibodies in the population at large is 7-8% which is about the same percentage of antithyroid antibodies in patients lacking antibody to the IgE receptor or to IgE (10%) (II). Angioedema occurs in approximately 40% of patients with chronic urticaria and can also be present intermittently in association with urticaria. If severe, the symptoms can be confused with idiopathic anaphylaxis, which is always intermittent and has an unpredictable frequency. One major difference, however, is that episodes of idiopathic anaphylaxis typically last 1-2 days, while episodes of intermittent-chronic urticaria/angioedema usually but not always last much longer. The identifying features depend on the presence or absence of other hallmarks of anaphylaxis or, in the absence of such symptoms, the severity of the angioedema. Idiopathic anaphylaxis presents with symptoms that can include facial (lushing, urticaria, angioedema, asthma, nausea, vomiting, cramps, diarrhea, and hypotension. Chronic mticaria and angioedema are not associated with hypotension and rarely, if ever, with gastrointestinal complaints or wheezing. On the other hand, a patient with flushing, urticaria, and angioedema in the absence of other symptoms most likely has chronic urticaria and angioedema, but there may be exceptions. Chronic urticaria can be associated with angioedema of the tongue or pharynx but not laryngeal edema, and the swelling of the tongue ;}nd throat should not be of such severity as to causeJ-espiratory embarrassment (e.g., inability to handle secretions, or pharyngeal or glottal swelling of such magnitude that intubation is a serious consideration). The latter patients have been considered to have idiopathic anaphybxis (12). The distinction in the absence of other anaphylactic manifestations is, in part, semantic since
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there is no laboratory test for idiopathic anaphylaxis (anti-FcsRI autoantibody test is negative) (13), but therapy will be influenced by the distinction. Although alternate-day steroids have been advocated as treatment for each disorder, when severe (12,14), the dosage for patients with idiopathic anaphylaxis often begins at 40-60 mg daily for months at a time. Chronic urticaria and angioedema can typically be treated with 20-2Smg every other day (I) with decrements in dosage every 2-3 weeks (15).
VIII.
ANAPHYLAXIS: WHAT MAKES IT IDIOPATHIC
In cases when anaphylaxis is recurrent and the diagnosis is not obviously due to latex hypersensitivity, fire ant stings, drugs, foods, or other identifiable stimuli, it is deemed idiopathic: a cause cannot be found. Extensive skin testing is typically done in an attempt to identify an exogenous allergen. Some unusual causes of anaphylaxis are listed in Table :2 that should be kept in mind. Patients in whom a diagnosis of idiopathic anaphylaxis has been made should be reassessed if alternative possibilities become evident that had not previously been considered.
Table 2
Unusual Ingestants Reported to Cause Anaphylaxis (with Urticaria)
Coriander in teriyaki sauce Carrageenan Thiamine Anisakis simplex (parasite of fish) Wheat flour contaminated with dust mite in dust-mite-allergic subject Cumin Oregano Thyme Caraway seeds Carmine (naturally derived red dye) Sesame seeds Saffron Condurango bark in herbal tea Prednisone Methylprednisolone succinate Diphenhydramine Omeprazole (Prilosae) Celecoxib (Celebrex) Source: From Rers. 20-26.
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It is not uncommon that patients initially presenting with symptoms consistent with idiopathic anaphylaxis are also considered to have systemic mastocytosis or carcinoid syndrome. Patients with systemic mastocytosis may have Oushing, cramps or diarrhea, and hypotension, in common with idiopathic anaphylaxis. They rarely have hives and swelling of the type seen 111 chronic urticaria and angioedema, which are signs characteristic of idiopathic anaphylaxis. The skin lesions vary from urticaria pigmentosa (i.e. pigmented lesions that iraticate with scratching), or frank derma tographism in which the cutaneous mast cell infiltration is more generalized. These can be differentiated biochemically by the increased QI-tryptase (and total tryptase) seen in patients with systemic mastocytosis. Patients with idiopathic anaphylaxis have a normal tryptase level between episodes and elevated tryptase (particularly ,B-tryptase) levels when anaphylaxis occurs. Skin biopsy or bone marrow examination may reveal evidence of mast cell proliferation in systemic mastocytosis, whereas mast cell numbers are normal in patients with idiopathic anaphylaxis. This is considered in greater detail in Chapter 21.
IX.
ANGIOEDEMA: OTHER CONSIDERATIONS
Angioedema occurring in the absence of any urticaria requires evaluation for C I INH deficiency (see Chap. 12), allergic reaction to foods or drugs, or use of angiotensin converting enzyme (ACE) inhibitors before it is assumed to be idiopathic. The swelling typically affects the face, lips, tongue, pharynx, genitalia (in men), hands and feet, and, to a lesser degree, swelling on the trunk or more proximal extremities. If true laryngeal edema occurs, the CI INH deficiency, use of an ACE inhibitor, or idiopathic anaphylaxis is much more likely than idiopathic angioedema, in which laryngeal edema virtually never occurs. Pharyngeal edema is, however, relatively common. Angioedema is episodic: after a period of many hours to a maximum of 2-3 days, it completely resolves and may later occur at the same site or other sites. Swelling that persists, particularly involving the face. is more likely Melkersson-Rosenthal syndrome. This is a persistent granulatomous inOammation, most commonly involving the lips and lower face, that may be associated with a fissured tongue, chronic facial lymphoedema. and Bell's palsy (16-18; Table I). More general persistent and symmetrical facial swelling (or swelling elsewhere) can be a manifestation of nephrotic syndrome, cardiac or liver failure, myxedema, trichinosis, or lymphatic obstruction. Granulomatous cheilitis, virtually indistinguishable from the lip swelling of Melkersson-Rosenthal syndrome. CeLn be seen with Crohn's disease (19)
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CONCLUDING COMMENTS
A specific diagnosis can be readily made in most patients presenting with urticaria and angioedema based on the history, appearance of lesions, and simple challenge tests or laboratory studies. However, occasionally patients present with confounding symptoms that do not correspond to any particular entity. In those circumstances, one should consider the possibility that multiple types of urticaria/angioedema are present simultaneously, or that the diagnosis is an unusual type of hives or swelling, or that the presumption of urticaria and angioedema is not correct, and that some other cutaneous disorder or manifestation is present. It is important to see the lesions rather than to reJy on a description of the rash; obtain photographs of lesions if the lesions cannot be visualized; and, where appropriate, try to induce hives or swelling. Some dermatitides can have an appearance that resembles urticaria and a skin biopsy demonstrating spongiosis or other nonurticarial skin pathologic findings can help to resolve the issue. Even more difficult can be the occasional simultaneous occurrence of hives and some other skin rash, such as a dermatitis or other rash in systemic lupus erythema tOSllS.
REFERENCES I.
2. 3. 4.
5.
6. 7. 8. 9.
Kaplan AP. Urticaria and angioedema. In: Middleton E Jr, Reed CE, Ellis EF, Adkinson NF Jr, Yunginnger JW, Busse WW, eds. Allergy-Principles of Practice. Vol. 2. 5th ed. St Louis, MO Mosby, 1998:1104-1122. Greaves MW. Chronic urticaria. N Engl J Med 1995; 332: 1767-1772. Estes SA, Yang CWo Delayed pressure urticaria: an investigation of some parameters of lesion induction. J Am Acad Dermatol 1981; 5:25-31. Ormerod AD, Lobza-Black A, Milford-Ward A, Greaves MW. Combined cold urticaria and cholinergic urticaria-clinical characteristics and laboratory findings. BrJ Dermatol1988; 118:621-627. Sigler RW, Levinson AI, Evans III R, Horakova Z, Kaplan AP. Evaluation of a patient with cold and cholinergic urticaria. I Allergy C1in Jmmunol 1979; 60:35-38. Kaplan AP. Unusual cold-induced disorders: cold dependent dermatographism and systemic cold urticaria. I Allergy Clin lmmllnol 1984; 73:453-456. Kaplan AP, Garolalo I. Identification ofa new physically induced urticaria: cold induced cholinergic urticaria. J Allergy Clin Immunol 1981; 63:438-441. Sams WM If. Epstein IH, Winkelmann RK. Solar urticaria: investigation of pathogenic mechanisms. Arch Dermatol 1969; 99:390-397. Kaplan AP, Finn A. Autoimmunity and the etiology of chronic urticaria. Can I Allergy Clin Immunol 1999; 4:286-292.
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13. 14. 15. 16. 17.
18.
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23. 24. 25. 26
Kaplan and Greaves Kikuchi Y, Fann T, Kaplan AP. Antithyroid antibodies in chronic urticaria and angioedema. J Allergy Clin lmmunol 2003; 112:218. Ajjan RA, Weetman AP. Autoimmune thyroid disease, Addison's disease, and autoimmune polyglandular syndromes. In: Austen KF, Frank MM, Atkinson JP, Cantor H. eds. Samter's Immunologic Diseases. Vol. 2. Philadelphia: Lippincott. Williams & Wilkins, 200 1:605-626. Patterson R, Stoloff RS, Greenberger PA, Grammer LC, Harris KE. Algorithms for the diagnosis and management of idiopathic anaphylaxis. Ann Allergy 1993; 7:40-44. Lieberman P, Kaplan AP. Unpublished observations. Patterson R, Wong S. Dykewicz MS, Harris KE. Malignant idiopathic anaphylaxis. J Allergy Clin Immunol 1990; 85:86-88. Kaplan AP. Chronic urticaria and angioedema. N Engl J Med 2002; 346:175-179 Greene RM, Rogers II IRS. Melkersson-Rosenthal syndrome: A review of 36 patients. J Am Acad Dermatol 1989; 21: 1263-1270. Sussman G L, Yang WH, Steinberg S. Melkersson-Rosenthal syndrome: clinical, pathologic, and therapeutic considerations. Ann Allergy 1992; 69187-1994 Zimmer WM, Rogers III RS, Reeve CM, Sheridan PJ. Orofacial manifestation of Melkersson-Rosenthal syndrome A study of 42 patients and review of 220 cases from the literature. Oral Surg Oral Med Oral Pathol 1992; 74610-619 Kano Y, Shiohara T, Yagita A, Nagashima M. Granulomatous cheilitis and Crohn's disease. Br J Dermatol 1990; 123:409-412. Proebstle TM, Gall H, Jugert FK, Mark HF, Sterry W. Specific IgE and IgG serum antibodies to thiamine associated with anaphylactic reaction. J Allergy Clin Immunol 1995; 95: 1059-1060. Audieana MT, de Corres LF, Munoz D, Fernandez E, Naverro JA. del Pozo MD. Recurrent anaphylaxis caused by AI/isakis simp/ex parasitizing fish. J Allergy Clin Immunol 1995; 96:558-560. Bianco C. Quiralte, J, Castillo R, Delgado J, Arteaga C. B:1rber D, Carrillo T. Anaphylaxis after ingestion of wheat Aour contaminated with mites. J Allergy Clin lmmunol 1997; 99:308-313 Boxer M, Roberts M, Grammer L. Cumin anaphylaxis: a case report. J Allergy Clin Immunol 1999; 99:722-723. Wuthrich B, Kagi M K, Stucker W. A naphylactic reactions to ingested carmine. Allergy 1997; 52: 1133-1137 Wuthrich B, Schmid-Grendelmeyer P, Lundberg M. Anaphylaxis to saA'ron. Allergy 1997; 52:474-475. Burgdorff T, Venemalm L, Vogt T, Landthaler M, Stolz W. IgE medicated anaphylactic reaction induced by succinate ester of methylprednisolone. Ann Allergy 2002; 89:425-428.
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12 Hereditary Disorders with Urticaria or Angioedema Hal M. Hoffman University of California at San Diego, La Jolla, California, U.S.A.
Alan A. Wanderer University of Colorado Health Sciences Center, Englewood, Colorado, U. S.A.
In a typical clinical practice it is not uncommon to see patients with urticaria/angioedema who report relati ves wi th urticaria/angioedema, suggesting that there is a genetic intluence on these disorders. However, the diagnosis of true hereditary urticaria/angioedema is rare, because most diseases do not follow a classic hereditary pattern. In the first section of this chapter we will discuss the initial diagnostic evaluation and counseling of patients with a family history of these disorders. We will also discuss models of heredity and the methods used by investigators to identify the genetic bases of diseases. In the second section, we describe a group of rare inherited systemic intlammatory diseases that present with atypical urticaria as a prominent feature. Finally, we discuss several disorders with urticaria and/or angioedema that appear to be inherited.
I.
A.
HEREDITARY DISEASE Evaluation and Counseling of Patients
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one must rely on history and physical examination. A detailed family history of urticaria or angioedema as well as immunological diseases, neonatal deaths and miscarriages, and unexplained deaths or illnesses is important. The creation of a complete and accurate pedigree, while difficult, can help to identify patterns of inheritance. Tdeally this is done by direct evaluation of family members; however, when necessary some information can be obtained from others It is also important to identify environmental exposures (e.g., toxic or infectious); the significance of genetics can be overestimated because close family members have had similar environmental exposures. An example might be a brother and sister who develops cold urticaria with a history of a father who developed cold urticaria as a child. At first glance, this might suggest a hereditary disease. However, further questioning reveals that the hives of both siblings developed weeks after confirmed mononucleosis, suggesting a nongenetic cause for the hives. However, it is possible that these two siblings and their father are genetically predisposed to the development of cold urticaria and this was triggered by viral infection. The difficulty of definitive diagnosis, such as in this case, illustrates the complexity of accurately counseling parents about the risk of transmission for most diseases. Physical examination of the patient as well as family members presumed to be affected while they are experiencing symptoms is crucial, because patients often assume that what they are experiencing is the same as their relative. Photographs of rashes may be used in place of a direct physical examination. Skin biopsies may also be helpful to confirm a diagnosis. Genetic testing may be performed in patients whose symptoms and family history are consistent with one of the illnesses for which a genetic basis has been identified. Tn all but the most extensively studied inherited conditions. it is difficult to be confident of inheritance patterns. Tn suspected cases of inherited disease, the physician may consider referral to a genetic counselor. Multiple complicating factors make risk determination an intricate task, even for experienced counselors. Fortunately, this may become easier as the underlying genetic defects in diseases are elucidated.
B.
Mendelian Disease Inheritance Patterns
Four basic mendelian inheritance patterns are seen in human disease: autosomal recessive, autosomal dominant, X-linked recessive, and X-linked dominant. Thcse pattcrns are based on the assumption that mutations in a singlc gene are responsible for a disease and that no other complicating factors are involved. Often one can only infer a disease's mode of
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inheritance, because of the limited size of families, but there are several identifying features that aid in this determination. Diseases with autosomal inheri tance (genes on chromosome 1-22) affect persons of each gender equally, and recessive diseases generally skip generations. X-linked diseases (genes on the X chromosome) are never passed from father to son (I). Figure Ia demonstrates a classic a utosomal recessive mode of inheritance in which affected individuals possess two copies of a mutated gene (one from each parent) and carriers possess only one mutated gene. Affected individuals or carriers can be either male or female and affected individuals are usually born to unaffected parents who are carriers. Diseases with this inheritance are often seen in physically or culturally isolated populations, and are particularly frequent in cases of parental consanguinity. If both parents are carriers, each child has a 25% chance of being affected. Adenosine deaminase deficiency, a type of severe combined immune deficiency, is an example of an autosomal recessive inherited disease. The pedigree in Figure Ib shows a classic autosomal dominant mode of inheritance in which possession of one mutated gene inherited from either parent results in disease. In this example affected individuals can be either male or female and have one affected parent. An affected parent has a 50% chance of having an affected child. Hereditary angioedema discussed elsewhere in this book is an example of an autosomal dominant disease. Figure Ic demonstrates an X-linked recessive inheritance pattern in which males are exclusively affected because the Y chromosome does not possess a normal copy of the mutated gene located on the X chromosome. Females can be asymptomatic carriers and often have affected male relatives. One-half of the male offspring of female carriers will be affected. Bruton's agammaglobulinemia, a humoral immunodeficiency, is an example of X-linked recessive disease. X-linked dominant disorders (shown in Fig. ld) are extremely rare. Pedigrees are similar to those in autosomal dominant transmission except that affected fathers never have affected sons. In generaL more females are affected than males, but females are often more mildly affected than males (sometimes lethal). The child of an affected female has a 50% chance of being affected. Hypophosphatemia, a form of vitamin-D-resistant rickets, is an example of a disease with this mode of inheritance.
C.
Complex Inheritance
A number of factors complicate mendelian inheritance of human diseases. Many individuals display no symptoms despite having an alteration in a
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a
c
d
Figure 1 Mendelian inheritance patterns. (a) Pedigree of autosomal recessive disorder. (b) Pedigree 01' autosomal dominant disorder (FCAS family). (c) Pedigree of X-linked recessive disorder. (d) Pedigree of X-linked dominant disorder. Filled squares (males) and circles (females) indicate affected individuals, open squares and circles indicate unaffected individuals, dotted squares and circles indicate carrier individuals.
dominantly inherited disease gene, but they still transmit the disease gene and disease to their offspring. This phenomenon is called nonpenetrance. While the hallmark of many inherited diseases is an early age of onset, some genetic diseases do not present until later in life, such as Huntington's disease. This is referred (0 as age-dependent penetrance. Another complicating factor is variable expression in which individuals with
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mutations in the same gene display different signs and symptoms or different levels of severity, to the point where relatives with mutations can be indistinguishable from members without mutations. Sporadic cases with no family history of affected parents or offspring may not appear to have a genetic basis, but many autosomal dominant diseases arise from spontaneous mutations in the absence of affected parents. Some inherited diseases affect lifespan or reproductive capacity so no affected offspring are generated. It is common for abnormalities in different genes to cause the same or similar clinical picture. This is referred to as genetic heterogeneity and is seen in common conditions such as anemia and cancer (I). Few diseases are inherited in a purely mendelian fashion. Most diseases or clinical syndromes are inherited in a complex fashion due to the contribution of one or multiple genes and/or environmental influences. The number of genes and the relative impact of genetic and environmental factors varies among conditions. In some diseases, such as X-linked Iymphoproliferative disease, patients possess a single susceptibility gene and develop symptoms only after they are exposed to Epstein-Barr virus. It is predicted that several diseases possess a few major susceptibility genes with contributions from many minor modifying genes. Asthma is an example of a complex disease that probably has multiple major and minor susceptibility genes as well as several factors in the environment that modify the disease presentation. Although significant advances have been made in our knowledge of the role of genetics in illness, the complex interactions between "nature and nurture" make it difficult to describe definitively the cause in most diseases.
D.
Identifying Genes and Diagnosing Genetic Diseases
The development of molecular genetic methods over the last decade has made it more feasible to identify the genetic basis of diseases. The physical mapping and sequencing performed by the Human Genome Project and the creation of databases of potential genes over the last 5-10 years has provided very powerful tools for human geneticists. Initially, disease genes were identified using clues based on the known pathophysiology of the disease, but with modern mapping techniques it is possible to identify these genes with little or no understanding of the underlying mechanisms involved. Genetic mapping utilizes numerous identifiable markers with known locations throughout the genome. When a marker is identified that consistently segregates with illnesses in affected families, it is said to be genetically linked to the disorder and points to the approximate chromosomal location of a disease gene. By systematically surveying
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the chromosomes with enough markers, one can identify the specific location of a disease gene. Candidate genes in the region can then be screened using a number of techniques that identify specific alterations in the DNA sequence. The application of these methods to a wide range of genetic illnesses has had spectacular success in the last few years, resulting in the identification of genes responsible for disorders such as cystic fibrosis and Duchenne's muscular dystrophy (I). The process of identifying the gene responsible for familial cold autoimmunity syndrome (FCAS) is discussed later in the chapter. The identification of genes often improves our understanding of the underlying pathophysiology. It has also become a diagnostic tool and will have a significant impact on clinical practice in the future. Increasingly, genetic information will be used with clinical findings to delineate specific groups that may have certain prognostic features or therapeutic responses. However, several limitations including genetic heterogeneity and environmental inlluences will ensure that careful clinical evaluations will always be necessary.
II.
DISORDERS WITH ATYPICAL URTICARIA OR ANGIOEDEMA WITH KNOWN GENETIC BASIS
There are now several diseases associated with urticaria or angioedema for which genes have been identified. Hereditary angioedema (discussed elsewhere in this book) has been associated with mutations in the CI inhibitor gene in several families. Sporadic cases of mastocytosis! urticaria pigmentosa have been associated with mutations in the c-kit gene (discussed elsewhere in this book). In this section, we will discuss three inherited inllammatory syndromes whose symptoms include an atypical urticarial rash. The category of autoinllammatory disorders is a relatively new classification used to describe a group of diseases characterized by recurrent episodes of inllammation without the high-titer autoantibodies or antigenspecific T cells commonly seen in traditional autoimmune disease (2). The inherited periodic fever disorders such as familial Mediterranean fever, hyper-lgD with periodic fever, and tumor necrosis factor-associated periodic syndrome (TRAPS) are the classic illnesses in this group. These rare disorders have rash as a prominent feature, but urticaria is unusual. Recently, three additional diseases with an atypical urticaria as a prominent feature have been added to the group of autoinflammatory syndromes. These disorders have several similarities and are caused by mutations in
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the same gene, but will be discussed separately because of their distinct clinical features.
A.
Familial Cold Autoinflammatory Syndrome
1.
Clinical Features and Heredity
In 1940, Kile and Rusk described a large North American family with members who experienced urticaria-like eruptions after cold exposure (3). These physicians clearly demonstrated that this syndrome was distinct from classic cold urticaria (discussed elsewhere in this book): patients did not develop localized urticaria immediately after direct contact with cold water, but instead developed rash hours after a generalized cold exposure. The family in that report described symptoms of fever, chills, and arthralgias associated with the rash. Since that time there have been approximately 20 families reported with this same clinical picture primarily in North America and Europe. This syndrome has been referred to as cold hypersensitivity, familial cold polymorphous eruption, cold pathergy, and cold-specific vasomotor neuropathy. It is most commonly known as familial cold urticaria, but recently was renamed familial cold autoinllammatory syndrome (FCAS) to reflect accurately the systemic nature of this disease and to prevent confusion with the more C0111mon acquired cold urticaria (4). In our cohort up to 60% of patients with FCAS developed rash at birth and 95% developed rash in the first 6 months of life. Other symptoms developed later in childhood and persisted throughout a patient's life. Longevity was usually normal in patients with FCAS. Most patients experienced some baseline daily symptoms in the absence of cold exposure; however, exposure to mild temperatures, such as air conditioned rooms, was sufficient to elicit attacks. Most attacks lasted less than I day and several patients described a diurnal pattern of attacks in the afternoon or evening that resolve by morning. The rash occasionally has urticarial features but IS more commonly characterized by erythematous and edematous papules and plaques (Fig. 2). The rash can be pruritic, but is often described as tender. Additional symptoms experienced by patients included conjunctivitis, sweating, headache, drowsiness, thirst, and nausea (4) FCAS is transmitted in a classic autosomal dominant fashion with complete or near complete penetrance (see Fig. lb). Sporadic cases have been documented, as is common for autosomal dominant diseases. There is variable expression in the clinical picture of FCAS: some family members
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Figure 2 Photograph of the lower leg of a patient with FCAS. The leg was not directly exposed to cold prior to onset of disease.
have more severe symptoms and a few families have members that have developed amyloidosis. Two groups used genetic mapping of large families to identify a single locus on chromosome lq44 for FCAS (5,6). Our group narrowed the chromosomal region of interest to approximately I million nucleotides (~0.4% of chromosome I), a region that allowed for a gene-bygene search. After screening approximately 80 potential genes (expressed sequence tags), we identified mutations in patients from families with FCAS in a single novel gene we termed CrASI (cold-induced autoinflammatory syndrome-I) (Fig. 3). Since that time, we and several other investigators have identified a total of nine mutations in exon 3 of C1ASl in patients with FCAS. There are patients with classic FCAS features that do not appear to possess mutations in CrASI, suggesting genetic heterogeneity.
2.
Proposed Mechanisms
Despite the association of FCAS with cold, no role for cryoglobulins has been demonstrated in FCAS. Passive transfer studies were negative, arguing against a serum factor or circulating antibody. There is no evidence for histamine release as is seen in true urticarial diseases. Laboratory evaIuations have iden ti fied a polymorphon uclea I' leukocytosis that increases during the acute episodes, and patients with FCAS have increased markers of inllammation such as elevated sedimentation rates and acute phase reactants such as C-reactive protein (7).
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Chromosome 1p
Chromosome 1q
1q
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DNA Bases
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GAGCCGCC GTCGGCTCCG T
Genetic Mapping
Sequencing
Mutation
Figure 3
Mapping of the CIASI gene. Chromosomal location is identified by genetic mapping and further limited by fine genetic mapping. Potential genes in the region of interest are screened by DNA sequencing to identify DNA base changes (mutations).
Figure 4 Skin biopsy from shoulder shows primarily neutrophils in the superficial and deep perivascular dermis (H&E; original magnification, X20).
Increased serum levels of interleukin-6 (IL-6) have been described some patients. We have demonstrated elevated IL-6 levels peaking approximately 4 h after an experimental cold challenge. Serum granuloctye colony-stimulating factor (GCSF) was elevated in one patient with FCAS (8). Skin biopsies taken from patients with FCAS have shown dermal edema and perivascular leukocytic infiltrate consisting primarily of neutrophils (Fig. 4). Increased vascularity has also been described, although 111
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Hoffman and Wanderer Nucleotide Binding Site
Leucine Rich Repeats
Figure 5 Cryopyrin protein domain structure.
vasculitis is not commonly reported. There is no increase in mast cells or histamine. These features are not seen in skin biopsies from patients with typical urticaria (7). Identification of the gene responsible for FCAS has provided several clues to the pathogenic mechanisms involved. CfASJ is expressed primarily in leukocytes (monocytes and granulocytes), which is consistent with the inflammatory nature of the disease as granulocytes clearly play a significant role in these diseases. CfASJ codes for a protein we have termed cryopyrin that has structural features (domains) similar to a number of proteins involved in inflammation and apoptosis (programmed cell death) (Fig. 5). Several of these proteins have been linked to specific inflammatory diseases. The pyrin domain, located at the beginning of cryopyrin, was first identified in pyrin, a protein with unclear function that, when mutated, causes familial Mediterranean fever. This domain is similar to death domains or caspase activation and recruitment domains (CARDs), which are part of several proteins that control apoptosis. Structural features at the end of cryopyrin include a nucleotide-binding site domain and multiple leucine-rich repeats. This combination is conserved 111 critical proteins in organisms as distantly related as plants (plant resistance proteins) and insects (toll genes) (9). Important human genes with this structure are toll-like receptors and nucleotide oligomerization domain (NOD) proteins, which are critical players in innate immunity. The NOD2 protein has been implicated in a significant percentage of patients with Crohn's disease. However, these are merely structural predictions based on the gene sequence; the actual function of cryopyrin remains to be elucidated. Some progress has been made in determining the pathways involved in cryopyrin function. Several group have shown that cryopyrin interacts with another pyrin-containing protein called ASC (apoptosis-associated specklike protein with a CARD) leading to acti ation of nuclear factor kappa B (NF-KB). NF-KB is one of the transcription factors involved in regulating many inflammatory cytokines including IL-6. It has also been shown that cryopyrin-ASC interactions lead to activation of caspase I, an enzyme involved in I L-I f-l production. I t has also been demonstrated that cryopyrin may playa role in apoptosis (programmed cell death) (10-12). These in vitro protein functions are consistent with inflammatory pathways seen in vivo. Clearly cryopyrin plays a regulatory role in innate immune responses.
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However, it is still unclear how alterations in cryopyrin cause the unregulated intlammation seen in the diseases with which it has been associated.
3.
Differential Diagnosis and Confirmatory Tests
rt is important to differentiate classic urticarial diseases such as cold urticaria and chronic urticaria as well as the other periodic fever disorders from FCAS. The rash may have an urticaria-like appearance and pruritus is sometimes reported, but the additional symptoms experienced during an attack, including fever and arthralgia, are rarely seen in the true urticarial diseases. FCAS is often confused with other coldinduced urticarial diseases (discussed elsewhere), but there are several features of FCAS that are very unlike these disorders including the early age of onset, the delay of 1-2 h after cold exposure, and leukocytosis. FCAS can be differentiated from classic acquired cold urticaria and delayed coldinduced urticaria (discussed later in this chapter) by the lack of local response to cold demonstrated by negative results of an ice cube test. Some patients with atypical acquired cold urticaria develop urticaria without direct contact to cold, but there is no delay of rash onset and the rash is a true urticaria. The main differentiating feature of FCAS from the other periodic fever disorders is the response to cold; however, other differences include a short length of episodes (often less than I day), the early age of onset (less than 6 months), and lack of abdominal symptoms during attacks. Diagnostic criteria for FCAS have been proposed and validated that include recurrent intermittent episodes of fever and rash following generalized cold exposure; autosomal dominant pattern of inheritance; age of onset < 6 months; duration of most attacks < 24 h; presence of conjunctivitis associated with attacks; absence of deafness, periorbital edema, lymphadenopathy, and serositis The presence of at least four of six criteria has been shown to be specific for FCAS (4,13). The finding of a mutation in CIASJ is confirmatory of FCAS; however, there are patients with classic clinical presentation who do not possess any identifiable mutations in CIASJ. Skin biopsy may be useful, because the presence of perivascular neutrophilic infiltrate is usually seen in FCAS and not in classic urticaria. 4.
Management
Management has consisted primarily of avoidance of cold, so patients dress warmly, avoid air conditioned rooms, and sometimes move to warmer climates. Corticosteroids have been effective if used in high
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enough dosages (greater than 30 mgjday prednisone), but their long term use is limited by side effects. Nonsteroidal anti-inflammatory drugs (NSAIDs) do provide some relief from arthralgias, but not other symptoms. Colchicine. anabolic steroids, and gold have been effective in a few cases (14). Recently, we have demonstrated the remarkable effectiveness of an IL-I receptor antagonist called Anakinra, which is currently approved for the treatment of rheumatoid arthritis. Anakinra completely blocked symptoms and innammatory responses when given prior to an experimental cold challenge in FCAS patients. Early reports show efficacy when given every other day. however, no formal clinical trials have been performed in FCAS patients.
B.
Muckle-Wells Syndrome
1.
Clinical Features and Heredity
In 1962. Muckle and Wells described a European family who reported transient attacks of an atypical urticaria rash accompanied by chills, malaise, and limb pains. There were no identifiable triggers for the episodes that occurred intermittently and lasted several hours to days. Most of the affected patients in the original description also developed late-onset sensorineural hearing loss. Some of the affected patients also developed lateonset renal failure due to systemic amyloidosis (15). Since that time there have been at least 30 reports of families and sporadic cases in Europe and North America (16). The classic triad of Muckle-Wells syndrome (MWS) includes rash, deafness, and amyloidosis. However, MWS displays significant variable expression in that deafness only occurs in ~ 60% of patients and amyloidosis is only seen in ~ 30% of affected patients. In MWS, rash is often not reported until later in childhood, hearing loss is progressive beginning in childhood, and renal disease often develops later in adulthood due to amyloid deposition. Primary morbidity and mortality are associated with the renal disease in MWS. MWS is transmitted in a classic autosomal dominant fashion with complete or near-complete penetrance. Sporadic cases have been documented, as is common for autosomal dominant diseases. Two groups used genetic mapping of large families to identify a locus on chromosome 1q44 for M WS, suggesting that the gene for M WS was the same as the gene for FCAS (5,17). This was confirmed when mutations in CfASl were also found in patients with MWS (9,18,19). At least six C1ASI mutations have been identified in patients or families with MWS but. as seen in FCAS. there are MWS patients for whom no C1ASI mutations have been found.
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Proposed Mechanisms
Polymorphonuclear leukocytosis is consistently observed in patients with MWS and increases during attacks. Gerbig et al. reported elevated lL-6 levels with a circadian pattern with the highest levels in the late evening (16). Skin biopsies also show dermal edema and perivascular neutrophilic infiltrate. Synovial fluid samples from MWS patients have demonstrated a primarily neutrophilic infiltrate (20). Renal tissue from patients with MWS shows classic AA (Amyloid Type A) amyloidosis, a feature seen in some other inflammatory diseases (21). It is unclear why some patients develop amyloidosis while others with equal or more evidence of inflammation do not develop amyloidosis. Inflammation is rarely a direct cause of hearing loss. Therefore, the hearing loss in MWS is more likely the result of cryopyrin involvement in apoptosis in sensory cells.
3.
Differential Diagnosis and Confirmatory Tests
The presence of the complete MWS triad of rash, deafness, and amyloidosis is unique; however less than one-third of patients with MWS have all three features. The rash is rarely pruritic and usually lasts for several hours to days, unlike most true urticarias. There are several forms of hereditary deafness, but rash is a rarely an associated feature. The combination of deafness and renal disease is seen in Alport's syndrome, but in this disorder there is no amyloidosis. There are hereditary forms of amyloidosis, but AA amyloidosis is usually secondary to chronic inflammation. MWS is most often confused with other periodic fevers such as familial Mediterranean fever, which also has a significant frequency of amyloidosis but does not include deafness. The finding ofa mutation in CIASJ confirms MWS; however, there are patients with classic clinical presentation who do not possess mutations in CIASI. ]n combination with episodic rash, demonstration of high-frequency hearing loss by audiometry or AA amylodosis on renal biopsy would be highly suggestive of MWS. Skin biopsy may be useful: perivascular neutrophilic infiltrate is usually seen and is not seen in classic urticaria.
4.
Management
High-dosage corticosteroids (greater than 30 mgjday) are sometimes effective but limited by side effects. NSAIDs are helpful for the treatment of arthralgias. While clinical experience is limited, there are recent reports indicating that Anakinra, an IL-I receptor antagonist, is effective at preventing symptoms and chronic inflammation in MWS patients (22). However, no formal clinical trials have been performed. Urine should be
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monitored for the development of proteinuria, which is an early sign of renal amyloidosis. Dialysis is often necessary when renal function deteriorates. There is one report of recurrence of renal amyloidosis in a transplanted kidney. Hearing should be monitored regularly and hearing aids should be used when appropriate.
C.
Chronic Infantile Neurological Cutaneous and Articular Syndrome
1.
Clinical Features and Heredity
In 1981, Prieur and Griscelli described three patients with a rare disease characterized by a neonatal onset urticaria-like rash, chronic meningitis and other neurosensory abnormalities, significant joint deformities, and recurrent fever (23). Since that time, more than 40 additional cases have been described in Europe and North America. This condition is known both as chronic infantile neurologic cutaneous and articular (CINCA) syndrome and neonatal onset multisystem inflammatory disease (NOMID), but will be referred to as CINCA in this chapter. Additional clinical features in these patients may include lymphadenopa thy, hepa tosplenomegaly, persistent open fontanelle, dysmorphic features, growth and developmental retardation, seizures, papilledema, and hoarseness (24). One unique feature is patellar and distal femur overgrowth resulting in significant deformity and disability ('25). Leukemia has also been reported in CINCA patients (23). Rash is consistently reported in the first few months of life in patients with CINCA. Pathological patellar and distal femur overgrowth and neurological manifestations begin in childhood and are often progressive. Mortality is primarily associated with infection and vasculitis and systemic amyloidosis in longer-lived patients. CINCA has been described in a few families with pedigrees consistent with autosomal dominant inheritance, but most cases are sporadic. Like MWS, there IS significant variable expression 111 CINCA: many patients do not display all clinical features. Several patients have been reported with no significant neurological findings (26). At least 13 CIASI mutations have been identified in patients with CINCA, but approximately 50% of patients with CINCA do not appear to possess CIASl mutations ('27). 2.
Proposed Mechanisms
Persistent polymorphonuclear leukocytosis in peripheral blood is commonly seen and moderate eosinophilia is observed in some cases of CINCA (27).
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Skin biopsies show perivascular neutrophiJs and eosinophils. Spinal fluid from several patients with CINCA has shown pleocytosis (24). Synovial fluid from CINCA patients has demonstrated a primarily neutrophilic infiltrate (28). Increased mast cells were noted on synovial biopsies (29). Serum IL-6 levels were elevated in one patient with CINCA (27). Tumor necrosis factor {31 levels were elevated in two patients with CINCA (27,30). Monocytes from one patient with CINCA demonstrated high levels of IL-I{3 protein by Western blot (27). This is consistent with predicted CtASl function based on in vitro studies demonstrating NF-KB and caspase I activation. Expression of leukocyte mRNA for IL-3 and IL-5 was elevated in one patient with CINCA, which is consistent with reported tissue and blood eosinophilia (27). Cryopyrin is expressed in cartilage, which is consistent with the finding of patellar and femur overgrowth in patients and suggests a role of cryopyrin in chondrocyte apoptosis (26).
3.
Differential Diagnosis and Confirmatory Tests
The primary differential diagnosis of CINCA is Still's disease (systemic juvenile rheumatoid arthritis) and other periodic fever disorders, but the rash in these diseases rarely occurs in the neonatal period. Neurological signs and patellar overgrowth are also unusual in patients with Still's disease and other periodic fever disorders. Inherited metabolic storage disorders may present with dysmorphic features and developmental delay, but a urticaria rash is rare. Classic urticarial diseases rarely present in the neonatal period. The finding of a mutation 111 CtASl IS confirmatory of CINCA; however, up to 50% of patients with CINCA classic clinical presentation do not appear to possess mutations in ClASI. Papilledema and optic atrophy in conjunction with other features are unique to this syndrome. Skin biopsy may be useful because perivascular neutrophilic infiltrate is usually seen, but not in classic urticaria.
4.
Management
A multidisciplinary approach is necessary for managing these severely affected patients, including pediatric rheumatologists, opthalmologists, neurologists, audiologists, and orthopedists. Partial therapeutic responses have been seen with high-dosage corticosteroids (> I mgjkgjday), intravenous immunoglobulin, chlorambucil, and NSAIDs. Although clinical experience is limited, there is considerable hope that Anakirna will be
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effective for CINCA. Patients should be monitored for the development of amyloidosis, malignancy, and infection.
D.
A Clinical Spectrum of One Disease
The three cryopyrin-associated diseases all share features of an atypical urticarial rash, recurrent fever, and joint manifestations. The rash is generalized, polymorphic in nature, and nonpruritic. Each disease has features that identify it: cold sensitivity in FCAS, a significant risk of systemic amyloidosis in MWS, and epiphyseal or patellar overgrowth in CINCA (see Table I). However, there can be overlaps in clinical features that blur the margins, making it difficult to differentiate between FCAS and MWS (some patients with MWS report worsening with cold exposure and some families with FCAS develop amyloidosis) or MWS and CINCA (some patients with CINCA have no obvious neurological manifestations and some patients with MWS have dysmorphic features consistent with CINCA). This has prompted investigators to suggest that these diseases are actually a spectrum of one disease, with FCAS being the mildest and CINCA the most severe (Fig. 6). The presence of neutrophils is a common feature in tissues and blood from patients with cryopyrin-associated disease, and suggests a key role for these innate immune cells in the pathogenesis of these diseases. The elevated IL-I and lL-6 cytokine levels seen in these patients also have an integral role in innate immune responses. It is likely that cryopyrin has a crucial role in normal innate immune function and inflammatory responses. We may eventually find other inflammatory diseases that fall into the spectrum of cryopyrin-associated disorders. Further elucidation of cryopyrin may shed light on the underlying mechanisms of other inflammatory diseases with urticaria.
III.
HEREDITARY DISORDERS WITH TYPICAL URTICARIA OR ANGIOEDEMA
Several case reports describe diseases with urticaria or angioedema with a significant family history consistent with inherited disease. It has been difficult to confirm inheritJnce patterns and identify chromosomal locations of genes responsible for these diseases due to the limited number of affected patients and family members available for study. We first discuss disorders for which there is sufficient evidence to suggest a heritable disease and then discuss a few additional disorders that may be hereditary, but for which there is less evidence to support this possibility.
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Table 1 Distinguishing Features of Cryopyrin-Associated Diseases
Familial cold autoinflammatory syndrome ()
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Inheri ta nce Autosomal dominant/sporadic Age of onset 95% < 6 months Usually < I day Length of attacks Musculoskeletal Arthralgia. myalgia Lymphadenopathy None Neurological Headache
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Sensory Amyloidosis Trea tmen t
Conjunctivitis ~2%
NSAIDs for arthralgia, fever +/- steroids
Muckle-Wells syndrome
Chronic infantile neurological cutaneous and articular syndrome
.... Vl
Autosomal dominant/sporadic Sporadic/autosomal dominant ~ 85% < 20 years < 6 months Constant inflammation 1-2 days Arthritis, patellar/distal fibular overgrowth Arthralgia. myalgia, arthritis Occasional Common Chronic aseptic meningitis, developmental Headache delay, seizures, persistent open fontanelle Papilledema, uveitis. deafness Conjunctivitis, deafness ~ 30% Occasional NSAIDs for arthralgia, fever steroids NSAIDs for arthralgia, fever +/- steroids +/colchicine
I\,')
(l)
-...J
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Severity
FCAS
MWS
CINCA
Figure 6 Spectrum of CIASI-associated diseases
A.
Hereditary Vibratory Urticaria
1.
Clinical Features and Heredity
Patterson et a!. described a familial syndrome characterized by development of urticaria and angioedema at the site of a vibratory stimulus. In general, the signs and symptoms are localized to the site of the vibratory stimulus. On rare occasions, systemic symptoms may evolve as generalized or facial erythema and headaches. No hypotensive symptoms have been described and there are no deaths ascribed to this syndrome. Signs and symptoms appear at birth and continue throughout life. Evaluation of a few families suggests that the syndrome is multigenerational and is transmitted as an autosomal dominant trait with high penetrance (31).
2.
Proposed Mechanisms
Metzger et a!. confirmed that histamine is released following provocation challenges with vibratory stimulation. Other mediators such as serotonin and bradykinin were not detected in the same studies. Serum passive transfer from affected to normal individuals did not transfer vibratoryinduced angioedema, suggesting that there was no operative serum factor such as an immunoglobulin, which has been observed with other physical urticarias (i.e., cold urticaria, solar urticaria). The authors concluded that this syndrome serves as a model of nonimmunological hypersensitivity reaction that is physically induced (32).
3.
Differential Diagnosis and Confirmatory Tests
Dermographism should be excluded using conventional blunt instruments to stroke the skin. Diagnosis is confirmed using a vibrating tool, such as a Vortex mixer, that is applied to the forearm for about 4 min. The speed, time, and pressure of Vortex mixer application needed to induce the skin reaction may vary with each individual. Epstein et a!. described a syndrome referred to as dermodistortive urticaria. It is transmitted as an autosomal dominant trait and appcars to have many of the same characteristics as hereditary vibralory angioedema. There is a good
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likelihood that dermodistortive urticaria and hereditary vibratory angioedema are the same disorder (33,34).
4.
Management
Avoidance of vibratory stimuli would be the mainstay of management. Occupations requiring use of vibratory tools such as a jackhammer should by necessity be curtailed. There is not adequate clinical data regarding the use of suppressive antihistamines, but prophylactic use of second- and third-generation antihistamines would certainly be reasonable.
B.
Delayed Cold-induced Urticaria
1.
Clinical Features and Heredity
Soter et al. described a familial syndrome characterized by late-onset also referred to as urticaria, that developed at the site of a cold stimulus. The skin lesions were also described as intermittently pruritic and generally are localized to the site of the cold stimulus. They resolve leaving transient hyperpigmentation. No systemic symptoms or signs are described in the report. It is considered a benign disorder with no reports of serious clinical sequelae. The age of onset was specified for only one affected family member who developed symptoms at age 4. Signs and symptoms typically continue throughout life (35). Analysis of one multigenerational family suggests that the syndrome is transmitted as an autosomal dominant trait. Acquired delayed cold-induced urticaria (OCU) has also been described in sporadic cases in which a wheal response develops 18-24 h following cold stimulation (36). Although the timing is slightly different, it is possible that these are new mutations in the same gene. There is apparently no discernible linkage of delayed cold urticaria to human leukocyte antigen (HLA) loci (35).
(9-18 h) "deep erythematous indurated swelling,"
2.
Proposed Mechanisms
Skin biopsies revealed edema of the dermis with lymphocyte and monocyte/ macrophage cells located around venules. No mast cell degranulation was noted and there was no evidence of vascular necrosis. lmmunofluoresence studies did not reveal deposits of immunoglobulins, complement 3, or fibrin. There was no evidence of histamine release following provocation challenges with cold stimulation. Serotonin and complement components were not detected in the same studies. Passive transfer studies of the patient's serum and skin tissue extract to monkey skin were negative. These studies suggest
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that there was no operative serum factor, such as an immunoglobulin, observed with other physical urticarias (i.e., cold urticaria and solar urticaria).
3.
Differential Diagnosis and Confirmatory Tests
Classic acquired cold urticaria is characterized by an immediate response to cold stimulation (37), compared to DCU which is associated with a delayed or biphasic response to cold. Cold urticaria with leukocytoclastic vasculitis is delayed in onset and leaves residual hyperpigmentatian, as does DCU. However, skin lesions in this disorder persist for more than 24---36 h following cold stimulation and skin biopsy reveals microscopic features of leukocytoclastic vasculitis (38) In some respects, the clinical description of acquired and familial DCU is similar to the delayed swelling of deep pressure urticaria, although they are induced by different physical stimuli. The diagnostic test for DCU is a cold stimulus (ice water) applied to the forearm for about 5 mll1, which in the case of DCU results in a deep erythematous skin reaction typically developing 9-18h following the cold stimulation The duration of cold stimulus application needed to induce the skin reaction may vary with each individual.
4.
Management
Avoiding cold stimulation is the mainstay of management. Hydroxyzine appeared to have some suppressive effect, but the skin lesions were not abolished. In theory antihistamines would not suppress symptoms because histamine is not released following cold exposure. The delayed inflammatory nature of this disorder may suggest a role for low-dosage, alternate-day corticosteroids if symptoms persist in persons who cannot curtail their cold exposure.
C.
Estrogen-Dependent Inherited Form of Angioedema
1.
Clinical Features and Heredity
A unique type of hereditary angioedema (HAE) that only affects women has been described in two reports. one by Binkley et al. (39) and the other by Bork et al. (40), sometimes referred to as hereditary angioedema with normal C-l inhibitor activity in women. Clinically this type of hereditary angioedema exhibits many of the same signs and symptoms that characterize HAE types I and II (discussed elsewhere in this book). Affected members exhibit angioedema without urticaria, laryngeal edema with airway compromise, and abdominal p~lin due to intestinal edema. However,
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this form of hereditary angioedema only affects women taking estrogen or contraceptives or during pregnancy. The Binkley report made the interesting observation that affected women can accurately predict pregnancy by the spontaneous appearance of angioedema. Female patients may experience symptoms at any age if they are taking estrogen supplements or estrogencontaining contraceptives. Patients experience symptoms throughout the course of pregnancy and/or while taking exogenous estrogens and remain asymptomatic during nonpregnant intervals and while not taking exogenous estrogens. To date there have been no reported fatalities in this variant of HAE, although affected patients require close surveillance; there is reportedly an incidence of 25% mortality from laryngeal edema in patients with types I and II HAE. The Binkley report suggests an autosomal dominant inheritance even though all affected members were women who became symptomatic during pregnancy or while taking exogenous estrogens. An obligate male carrier was identified in one family whose phenotype did not express the disorder. Affected women were identified in three generations. The Bork report suggests an X-linked dominant mode of inheritance.
2.
Proposed Mechanisms
Measurements of CI esterase inhibitor, both antigenic and functional, and C4 levels were normal in asymptomatic patients and in one symptomatic patient who was receiving exogenous estrogens_ In addition, assessment of coagulation assays for factor XII, prekallikrein, and high-molecular-weight kininogen showed normal results in three tested patients. These studies suggest that CI esterase inhibitor deficiency is not a likely cause of this disorder. Binkley performed DNA sequence analysis of the C I inhibitor coding sequences and the Y flanking region of the gene encoding factor XII and described both sequences as being normal in three affected female subjects. However, Binkley et a!. speculate that this disorder could be caused by a mutation that downregulates CI inhibitor synthesis. Patients would presumably become symptomatic while on estrogens or during pregnancy because estrogens will cause additional decrease in CI inhibitor levels, as observed in other women during pregnancy or with use of oral con tracepti ves.
3.
Differential Diagnosis and Confirmatory Tests
HAE, types I and II, can be differentiated from this third type of hereditary angioedema in that this form of angioedema is estrogen dependent and only affects females. Type I HAE can affect males and females and is associated with reduced levels of antigenic CI esterase inhibitor. The less common
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type II HAE exhibits normal antigenic Cl esterase inhibitor levels but has abnormal function. Measurements of CI esterase inhibitor, both antigenic and functional, and C4 are normal in women with the estrogen-dependent form of HAE. The diagnosis is confirmed by excluding types I and II HAE, observing that affected women only develop symptoms during pregnancy or while taking exogenous estrogens, and noting the presence of angioedema without urticaria.
4.
Management
Patients are advised to avoid use of estrogen supplements or estrogencontaining contraceptives and, if possible, to avoid pregnancy. Bork et aJ. noted that treatment with CI inhibitor concentrate, steroids. and antihistamines was ineffective. Two patients received danazol and one experienced remission on taking it; the other was unresponsive to treatment with this androgen. Treatment of affected pregnant women is problematic because the use of attenuated androgens during pregnancy is con trai ndica ted
D.
Exercise-induced Urticaria and Anaphylaxis
1.
Clinical Features and Heredity
Grant et aJ. (41) reported exercise-induced anaphylaxis involving seven male family members in three generations. Longley et aJ. (42) described familial exercise-induced anaphylaxis involving two male siblings and a paternal nephew. Following exercise, patients typically experience pruritus. urticaria. angioedema, and cardiorespiratory symptoms. occasionally culminating in hypotensive episodes. Signs and symptoms appear in early childhood and continue throughout life. All affected members of the family described by Grant et al. were male, which could be consistent with an autosomal dominant mode of inheritance. A linkage of HLA haplotype A-3. B-8. and DR-3 was noted in a sister and a brother in the Longley study.
2.
Proposed Mechanisms
Histamine levels during induced episodes were not elev
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Differential Diagnosis and Confirmatory Tests
Exercise-induced anaphylaxis should be differentiated from cholinergic urticaria. Although exercise is a common trigger for cholinergic urticaria, the rash in exercise-induced anaphylaxis consists of large wheals and in cholinergic urticaria it consists of small punctate lesions. Wheezing, angioedema, and cardiovascular collapse may occur in severe cases of exercise-induced anaphylaxis; systemic symptoms are rare in cholinergic urticaria. A methacholine intradermal skin challenge (discussed later in the chapter) gives negative results. Placing an extremity in hot water (J04°F), a passive warming test, will induce punctate urticaria in patients with cholinergic urticaria and not in those with exercise-induced anaphylaxis. Exercise challenge testing under controlled conditions may reproduce signs and symptoms of anaphylaxis. However, a negative exercise challenge test does not rule out exercise-induced anaphylaxis. The key feature for diagnosis is confirming that symptoms occur during exercise and not with passive warming.
4.
Management
A voidance of vigorous exercise is the mainstay of management. Carrying a self-administered epinephrine kit IS advisable. There are no good clinical data regarding use of suppressive antihistamines, but prophylactic use of second- and third-generation antihistamines would be reasonable.
E.
Familial Dermographism
1.
Clinical Features and Heredity
Jedele et al. described a four-generation occurrence of dermographism (43). Familial dermographism is similar to sporadic dermographism and is characterized by wheal-and-flare responses to scratching or minor skin trauma. Responses usually occur within several minutes after stimulation and may last several hours. Headaches are the only systemic symptom and may occur if skin trauma affects more than 5% of the body surface area. No serious systemic signs of anaphylaxis have been observed. There is no association with other physical urticarias such as sensitivity to cold, heat, or exercise. Anecdotal evidence reports that affected males experience dermographism on a daily basis: the response typically occurs after shaving with a razor blade. Signs and symptoms appear in early childhood and can affect newborns. The symptoms continue throughout life.
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The dermographism described in the family described by ledele et a!. appears to be transmitted in an autosomal dominant manner. A total of five males and females in a four-generation family were affected with dermographism. Four of the eight children born to the affected parent exhibited dermographism, which is compatible with an autosomal dominant pattern of inheritance.
2.
Proposed Mechanisms
Mast cell degranulation in reaction to mild trauma has been observed in the sporadic type of dermographism, but the mechanism of this phenomenon is not understood. Mediator levels were not measured in this family.
3.
Differential Diagnosis and Confirmatory Tests
Delayed pressure urticaria is differentiated from familial dermographism by the presence of deep swelling that occurs only after a delay of several hours. It requires sustained pressure to produce a reaction. The areas of swellings are diffuse and painful. Vibratory angioedema requires repetitive vibration to induce angioedema, in contrast to dermographism, which requires a single application of pressure. A single stroke of the skin with a blunt object will induce an immediate, linear, continuous wheal-and-nare response.
4.
Management
Avoidance of vigorous skin trauma is the mainstay of management. Prophylactic use of second- and third-generation antihistamines would be reasonable, although there are no data to support this.
F.
Familial Localized Heat Urticaria of Delayed Type
1.
Clinical Features and Heredity
Michaelsson et a!. described a three-generation family with localized heat urticaria of delayed type (FLHU) (44). FLHU is characterized by delayed (2-14 h) onset of wheal with erythema localized and limited to the contact site of a heat stimulus. Constitutional symptoms such as headaches have been described with FLHU but no systemic reactions have been reported. Affected members may experience symptoms following direct contact with a warm object, such as a hot water bottle, or exposure to an ambient heat source, such as an open fire. Swelling and itching of the scalp may occur after use of a hair dryer. Sunlight is well tolerated although
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pronounced heating of the skin [rom sunbathing can produce wheals on areas covered by dark clothing. Exercise does not induce urticaria in these patients. Signs and symptoms appear in early childhood and continue throughout life. The syndrome described in the Michaelsson report appears to be transmitted in an autosomal dominant manner. Nine of 14 family members (males and females) of a three-generation family were affected.
2.
Proposed Mechanisms
Mast cell and basophil degranulation to heat stimulation has been observed in patients with FLHU. Mediator levels were not measured by Michaellson et al. Passive transfer studies (Prausnitz-Kustner test) from an affected patient to a control gave negative results. These studies suggest that there was no causative serum factor, such as a transferable immunoglobulin.
3.
Differential Diagnosis and Confirmatory Tests
The sporadic type of localized heat urticaria has a similar description but the wheal and erythema occur immediately following heat stimulation and have been associated with hypotensive episodes. Exercise-induced anaphylaxis and cholinergic urticaria should be considered in the differential diagnosis. An exercise tolerance test in patients with FLHU should not induce punctate or normal-sized urticaria and/or anaphylaxis. Methacholine skin test and passive warming test would be negative in patients with FLHU compared to those with cholinergic urticaria. Solar urticaria should also be ruled out by exposure to UV light in the absence of heat. Diagnosis is confirmed using a heated test jar (ranging from 40°-45°C) applied to different skin areas for various times 0.5, 3, 5, 15, and 20 min. A wheal and erythematous response will occur 2-4h after application and may persist up to 14 h. Apparently each patient has a minimum threshold for temperature and time of heat stimulus application required to induce a positive skin response.
4.
Management
Avoidance of sustained heat exposure, such as a hot tub or hot water bottle, would be the mainstay of management. As with the other disorders for which there are limited clinical data, prophylactic use of secondand third-generation antihistamines would be reasonable. The delayed inflammatory nature of this disorder may suggest a role for low-dosage,
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alternate-day corticosteroids if symptoms persist in persons who cannot curtail prolonged heat exposure.
G.
Familial Cholinergic Urticaria
1.
Clinical Features and Heredity
Qnn et al. reported on four families with presumed cholinergic urticaria with symptoms similar to sporadic cholinergic urticaria: the appearance of small, pruritic, punctate wheals following increased core body heating from exercise. None of the patients exhibited systemic symptoms of cardiovascular collapse. which is oCGlsionally observed with sporadic cholinergic urticaria. Signs and symptoms appear in patients' midteens and can continue throughout life (45). A total of 9 males from 16 family members in 4 families (i.e., approximately 50% affected individuals) exhibited signs of this disorder. This is most con istent with autosomal dominant transmission. 2.
Proposed Mechanisms
All patients had positive results of a methacholine skin test, which is also observed in patients with the sporadic disorder. The exact mechanism of familial and sporadic cholinergic urticaria is not known but an underlying exaggerated cholinergic response is assumed to develop in relation to an increase in core body temperature. The theory suggests that released acetylcholine causes mast cell degranulation and histamine mediation of urticaria. 3.
Differential Diagnosis and Confirmatory Tests
The diagnosis of exercise-induced anaphylaxis would be a consideration if the exercise tolerance test induced large wheals and the patient exhibited a negative results of the methacholine skin test and passive warming test. The diagnosis of cholinergic urticaria is conlirmed if an intradermal methacholine skin test at a concentration ofO.lmg, ml induces a wheJlwhen compared to a negative response with a saline control. The induction of small pruritic wheals following exercise would also confirm the diJgnosis. 4.
Management
Avoidance of sustained exercise would be the mainstay of management. Prophylactic Lise of second- and third-generation antihistamines would be reasona ble.
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297
Other Possible Hereditary Disorders with Urticaria or Angioedema
Familial aquagenic urticaria has been described by two groups. with only two individuals described in each report (46,47). The symptoms began in patients' mid-lOs and are similar to sporadic aquagenic urticaria: the appearance of wheals following exposure to water. without systemic symptoms. Pruritic urticarial papules and plaques of pregnancy is a polymorphic skin eruption characterized by urticarial papular wheals and erythematous plaques that initially affect abdominal stria and then spread to other regions. It occurs during the third trimester, more commonly in a patient's first pregnancy. and disappears a few weeks after delivery. Weiss et aI., who described two small familial cohorts. postulate that this is a reaction to a circulating paternal antigenic factor for which tolerance develops in subsequent pregnancies (48). Chronic idiopathic urticaria (CI U) does not have a clear pattern of inheritance. but in one study there was an eightfold increased incidence in first-degree relatives of affected patients (49). The symptoms in families studied are similar to those of sporadic CIU, but there was a much higher frequency of autoantibodies to IgE and IgE high-affinity receptor in patients from these families. These observations. in combination with the previously recognized association of CIU with human leukocyte antigen DR4, suggest that genetic factors are involved in the pathogenesis of ClU (50,51).
IV.
SUMMARY
Relatively little work has been done in the area of hereditary urticaria or angioedema. The reports we have described, except the cryopyrin-associated disorders. are mostly individual cases. which limit the conclusions that can be drawn. However, as more data are produced we will undoubtedly piece together the complex puzzle of the immune responses and innammatory processes that lead to urticaria and angioedema. As the pathogenetic mechanisms are elucidated for more of these illnesses, we will be able to use such tools as genetic testing and modulators of innammatory mediators to diagnose and treat these hereditary disorders more accurately.
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Cuisset L, Drenth JP, Berthelot JM, Meyrier A, Vaudour G, Watts RA, Scott DG, Nicholls A, Pavek S, Vasseur C, Beckmann JS, Delpech M, Grateau G. Genetic linkage of the Muckle-Wells syndrome to chromosome Iq44. Am J Hum Genet 1999; 65: 1054-1059. Dode C. Le Du N, Cuisset L, Letourneur F, Berthelot JM, Vaudour G. Meyrier A, Watts RA, Scott DG, Nicholls A, Granel B, Frances C. Garcier F, Edery P, Boulinguez S, Domergues JP, Delpech M, Grateau G. New mutations of eIAS I that are responsible for M uckle- Wells syndrome and familial cold urticaria: a novel mutation underlies both syndromes. Am J Hum Genet 2002; 70:1498-1506 Aganna E. Martinon F, Hawkins PN, Ross JB, Swan DC, Booth DR, Lachmann HJ, Gaudet R, Woo P. Feighery C, Cotter FE, Thome M, Hitman GA, Tschopp J, McDermott MF. Association of mutations in the NALP3/ CIAS I/PYPAFI gene with a broad phenotype including recurrent fever, cold sensitivity, sensorineural deafness, and AA amyloidosis. Arthritis Rheum 2002; 46:2445-2452. Watts RA. Nicholls A, Scott DG. The arthropathy of the Muckle-Wells syndrome. Br J Rheumatol L994; 33:1184-1187. Linke RP, Heilmann KL. Nathrath WB, Eulitz M. Identification of amyloid A protein in a sporadic M uckle- Wells syndrome. N-terminal amino acid sequence after isolation from formalin-fixed tissue. Lab Invest 1983; 48:698-704. Hawkins PN, Lachmann HJ, McDermot MF. Interleukin-I receptor antagonist in the M uckle- Wells Syndrome. N Engl J Med 2003; 19:2583-2584. Prieur AM, Griscelli C. Arthropathy with rash, chronic meningitis, eye lesions, and mental retardation. J Pediatr 198J; 99:79-83. Prieur AM, Griscelli C. Lampert F, Truckenbrodt H, Guggenheim MA, Lovell DJ, Pelkonnen P. Chevrant-Breton J, Ansell BM. A chronic, infantile, neurologicaL cutaneous and articular (CINCA) syndrome. A specific entity analysed in 30 patients. Scand J Rheumatof Suppl 1987: 66:57-68. Kaufman RA, Lovell DJ. Infantile-onset multisystem inflammatory disease: radiologic findings. Radiology 1986; 160:741-746 Feldmann J, Prieur AM, Quartier P, Berquin P, Certain S. Cortis E, Teillac-Hamel D, Fischer A, Basile Gd Gde S. Chronic infantile neurological cutaneous and articular syndrome is caused by mutations in CIAS I, a gene highly expressed in polymorphonuclear cells and chondrocytes. Am J Hum Genet 2002; 71: 198-203, Aksentijevich I, Nowak M, Mallah M, Chae JJ, Watford WT, Hofmann SR, Stein L, Russo R, Goldsmith D, Dent P, Rosenberg HF. Austin F, Remmers EF, Balow JE, Jr, Rosenzweig S, Komarow H, Shoham NG, Wood G, Jones J, Mangra N, Carrero H, Adams BS, Moore TL, Schikler K, Hofl'man H, Lovell DJ. Lipnick R, Barron K. O'Shea JJ, Kastner DL. Goldbach-Mansky R. De novo CIAS I mutations. cytokine activation, and evidence for genetic heterogeneity in patients with neonatal-onset multisystem inflammatory disease (NOMID): a new member of the expanding family of pyrin-associated autoinftammatory diseases. Arthritis Rheum 2002; 46:3340-3348.
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Hassink SG, Goldsmith DP. Neonatal onset multisystem inflammatory disease. Arthritis Rheum 1983; 26:668-673. Yarom A, Rennebohm RM, Levinson JE. Infantile multisystem inflammatory disease: a specific syndrome? J Pediatr 1985; 106:390-396 Huttenlocher A, Frieden IJ, Emery H. Neonatal onset multisystem inflammatory disease. J Rheuma tol 1995; 221171-1173. Patterson R, Mellies CJ, Blankenship ML, Pruzansky JJ. Vibratory angioedema: a hereditary type of physical hypersensitivity. J Allergy Clin lmmunol 1972; 50:174-182 Metzger WJ, Kaplan AP, Beaven MA, Irons JS, Patterson R. Hereditary vibratory angioedema: confirmation of histamine release in a type of physical hypersensitivity. J Allergy Clm Immunol 1976; 57:605-608. Epstein PA, Kidd KK. Dermo-distortive urticaria: an autosomal dominant dermatologic disorder. Am J Med Genet 1981; 9:307-315. Epstein PA, Kidd KK Sparkes RS. Genetic linkage analysis of dermodistortive urticaria. Am J Med Genet 1981; 9:317-321. Soter NA, Joshi NP, Twarog FJ, Zeiger RS, Rothman PM, Colten HR. Delayed cold-induced urticaria a dominantly inherited disorder. J Allergy Clio lmmunol 1977; 59:294-297. Back 0, Larsen A. Delayed cold urticaria. Acta Derm Venereol 1978; 58369-371 Wanderer AA. The spectrum of cold urticaria. Immunol Allergy Clin North Am 1995; 15:701-723. Wanderer AA, Nuss DO, Tormey AD, Giclas Pc. Urticarial leukocytoclastic vasculitis with cold urticaria. Report of a case and review of the literature. Arch Dermatol 1983; 119:145-151. Binkley KE, Davis A, 3rd. Clinical, biochemical, and genetic characterization of a novel estrogen-dependent inherited form of angioedema. J Allergy Clin Immunol 2000; 106:546-550. Bork K, Barnstedt SE, Koch P, Traupe H. Hereditary angioedema with normal Cl-inhibitor activity in women. Lancet 2000; 356:213-217. Grant JA, Farnam J, Lord RA, Thueson DO, Lett-Brown MA, Wallfisch H, Fine DP, Schmalstieg FC Familial exercise-induced anaphylaxis. Ann Allergy 1985: 5435-38. Longley S, Panush RS. Familial exercise-induced anaphylaxis. Ann Allergy 1987; 58257-259. Jedele KB, Michels VV. Familial dermographism. Am J Med Genet 1991; 39:201-203 Michaelsson G, Ros AM. Familial localized heat urticaria of delayed type. Acta Derm Venereol 1971; 51:279-283. Onn A, Levo Y, Kivity S. Familial cholinergic urticaria. J Allergy Clin Immunol 1996; 98:847-849 Bonnetblanc JM, Andrieu-Pfahl F, Meraud JP, Roux J. Familial aquagenic urticaria. Dermatologica 1979; 158:468--470.
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Juhlin L, Malmros-Enander 1. Familial polymorphous light eruption with aquagenic urticaria: successful treatment with PUVA. Photodermatology 1986: 3346-349. 48. Weiss R, Hull P. Familial occurrence of pruritic urticarial papules and plaques of pregnancy. J Am Acad Dermatol 1992; 26:715-717. 49. Asero R. Chronic idiopathic urticaria: a family study. Ann Allergy Asthma Immunol 2002; 89:195-196. 50. Greaves M. Chronic urticaria. J Allergy Clin lmmunol 2000; 105:664-672. 51. O'Donnell BF, O'Neill CM, Francis DM, Niimi N, Barr RM, Barlow RJ, Kobza Black A, Welsh KI, Greaves MW. Human leucocyte
47.
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13 C1 Inhibitor Deficiency Allen P. Kaplan Medical University of South Carolina, Charleston, South Carolina, US.A.
I.
INTRODUCTION
CI inhibitor deficiency causes angioedema as a result of excessive bradykinin production (see Chap. 3). Thus the pathways and control mechanisms for bradykinin formation and degradation are variables that one must consider in any patient with angioedema. Activated factor XII as well as factor XIIf are inhibited by Cl INH (1,2). Thus absence ofCI INH facilitates factor XII autoactivation, which augments the ability of factor XlIa to convert both prekallikrein to kallikrein and factor XI to factor Xla. rt is estimated that over 90% of plasma inhibition of factor XfIa and factor XlIfis due to Cl INH (2). The remainder is due to antithrombin III and the protein C, inhibitor The next enzyme in the cascade is kallikrein and it is inhibited by CI INH and O'~ macroglobulin in approximately equal proportions (3). Minor inhibitors of kallikrein are antithrombin In and 0'1 antitrypsin. Thus if there is any stimulus for activation of the plasma bradykinin-forming cascade, in the absence of functional C I INH, there is a marked augmentation of bradykinin formation with angioedema as the result. Urticaria is not seen in patients with CI INH deficiency, but at the inception of an episode of swelling they may have a rash resembling erythema marginatum. When patients present with both chronic urticaria and angioedema, assays for C I INH are generally unnecessary and the utility of a C4 determination depends whether an underlying vasculitis is suspected.
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II.
CAUSES AND INHERITANCE
CI inhibitor deficiency is an important cause of angioedema, which may involve almost any portion of the body. Sometimes local trauma to an extremity can initiate an exaggerated local swelling or a more generalized episode of swelling. However, a triggering event may not be immediately evident, so that swelling appears to occur spontaneously. CI inhibitor deficiency can be familial (in which there is a mutant CI inhibitor gene) or it can be acquired. Both the hereditary and acquired forms of CI inhibitor deficiency have two subgroups. For the hereditary disorder, type I hereditary angioedema (HAE) is typically an autosomal dominant disorder in which a mutant gene leads to markedly depressed Cl inhibitor levels (4). Type 2 HAE is also inherited as an autosomal dominant disorder and has a mutation that leads to synthesis of a dysfunctional protein; the Cl inhibitor protein level may then be normal or even elevated (5). The acquired form of CI inhibitor deficiency also has two forms. In the first type, there is an association with either a B-cell lymphoma or connective tissue disease in which there is sufficient consumption of CI inhibitor to cause angioedema (6-8). The second form of acquired CI inhibitor deficiency is an autoimmune disorder in which there is a circulating IgG antibody directed to CI inhibitor itself (9-11). A positive family history, the presence of a lymphoma, or an underlying connective tissue disease would each suggest CI inhibitor deficiency when swelling is a manifestation. The presence of visceral involvement in any patient with angioedema (in the absence of hives) is suggestive. The most severe complication is laryngeal edema, which had been a major cause of mortality in this disorder. Patients can also have abdominal attacks lasting 1-3 days, consisting of vomiting, severe abdominal pain, and guarding in the absence of fever, leukocytosis. or abdominal rigidity. This may nevertheless be difficult to differentiate from an acute surgical abdomen. However, the attacks are self-limited and caused by edema of the bowel wall (12). The ultrastructural lesions seen in the tissues of patients with hereditary angioedema, in particular, consists of gaps in the postcapillary venule endothelial cells, edema, and almost no cellular infiltrate, consistent with the release of a vasoactive factor such as a kinin (13)
III.
MOLECULAR GENETICS
Hereditary angioedema is transmitted as an autosomal dominant disorder due, in most instances, to alterations of the CI INH gene. Its prevalence is 1:50,000 (14); however. there is a high incidence of de novo mutations
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accounting for close to 25% of cases. Thus there may not be a family history to guide evaluation of such patients and it is therefore reasonable to obtain a C4 and Cl TNH determination in any patient presenting with recurrent angioedema in the ab ence of urticaria. Figure I, taken from a review by Tosi (14), summarizes the mutations that may be seen in patients with hereditary angioedema. Gene instability due to unequal crossing over between repetitive Alu sequences causes deletions or duplications, accounting for about 20% of mutations. The remainder involve microdeletions or duplications, or single nucleotide substitutions. Figure I summarizes the mutational spectrum seen in type 1 HAE in which the protein level is quantitatively low « 50%); episodes of swelling typically occur when the plasma level drops to 25% of normal or less. Point mutations and deletions or insertions are scattered along the entire C I TNH gene. Missense mutations are found along the entire coding sequence, with the exception of the 100 amino acid long N-terminal segment Deletions of few amino acids
Large deletions 21%
38%
Frameshifts 14%
Stop condons 10%
Missense or splice site Splice sites 3% Promoter variants 7% 4%
Figure 1 Distribution of 69 mutations found in 66 patients with type I HAE. Forty-three kindreds are from Ref. 5 and twenty-three are from Ref. 9 Double mutations were found in three kindreds (5). Note that only half of the changes observed (large deletions, frameshifts, and stop-codon mutations) can be considered directly as pathogenic. without the need of functional assays. (From Ref. 14.)
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that is highly glycosylated and has little homology with other plasma proteinase inhibitors. The consequences of severe missense mutations have been determined by transfection of in vitro mutagenized constructs into COS cells. Amino acid substitutions seen in type I HAE often affect intracellular transport of CI fNH (as do other mutations in type I disease) with impairment of protein secretion. Amino acid substitutions, rather than deletions, insertions, stop codons, or frameshift mutations, characterize type 1I disease in which there is secretion of a dysfunctional protein (i.e., plasma protein levels may appear normal but a large fraction of the secreted protein is dysfunctional). Here the mutations cluster about the reactive site of Cl INH at Arg 444 (the protein is cleaved by the enzyme to which it will bind, exposing a reactive site that in turn covalently binds the active site serine of the enzyme, thereby inactivating it). These are sites of spontaneous deamination of methylated cytosines of a CpG dinucleotide which account for most of the type II abnormalities with secretion of a dysfunctional protein. It is important to note that in types I and It HAE, there is one normal gene; thus CIINH synthesis should theoretically be at 50% of normal. Yet in type I HAE, the total Cl INH protein is often much less (angioedema typically occurs at levels of 25% or less), and in type II disease normal and dysfunctional proteins circulate side by side. Further depletion of the normal gene product may occur because of hypercatabolism, that is, turnover as a resul t of binding to plasma proteases (15) or suppression of normal C I INH protein (transinhibition) by the mRNA or abnormal protein of the dysfunctional allele (16,17). An intermediate phenotype encompassing features of type I and II abnormalities may be seen in which an amino acid substi tu tion not only leads to decreased secretion of the protein but is also dysfunctional. A very rare recessive form of the diseases may be seen with mutations in the promotor region of the gene or within the first intron in which homozygosity is required to lower the CI INH level sufficiently to cause clinical symptoms. An estrogen-dependent form of hereditary angioedema has been described in which there is no abnormality of Cl INH, and C4 levels are normal (15). Symptoms occur only during pregnancy or while the patient is taking exogenous estrogen (which also increases angioedema in CI INH deficiency). The inheritance appeared to be dominant and no male patients were identified.
IV.
DIAGNOSIS
Patients with hereditary angioedema have measurable levels of the activated first component of complement (C I), although this protein generally
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circulates as an unactivated enzyme. The serum level of C4 is diminished, even when the patient is free of symptoms, and is virtually undetectable during an attack (18). A C4 determination is therefore the simplest way to screen for the hereditary disorder. Rocket immunoelectrophoresis for C4 clea vage prod ucts such as C4b is a very sensi live assay, more so than C4 quantitation (19). Levels ofC2, the other substrate ofC!, are usually within normal limits when the patient is asymptomatic, but the concentration is also diminished during an attack of swelling (20). When a diminished C4 level is obtained, a direct assay of the protein, Cl inhibitor, should be performed. A diminished or absent level of CI inhibitor protein would confirm the diagnosis: 80-85% of patients with hereditary angioedema have this type form of the disorder (type T). However. 15-20% of patients will have a mutant form of Cl inhibitor protein that renders it functionless (21) (type II). In these cases, the quantitative secretion of total Cl inhibitor protein is typically normal, and is sometimes actually increased, although the abnormal gene product may have an abnormal electrophoretic mobility. Thus an assay for functional Cl inhibitor is necessary to confirm the diagnosis.
V.
PATHOGENESIS
The pathogenesis of the swelling appears to involve primarily the plasma kinin-forming pathway rather than complement; however, it is germane to review the history of the complement data and to point out how it was first thought to be source of a kinin, and then to present the more recent data that suggest otherwise. Intracutaneous injection of Cl into normal individuals was reported to cause the formation of a small wheal reaction, whereas ll1jection into patients with hereditary angioedema yields localized angioedema (i.e .. an augmented response because of low CI levels of inhibitor) (22). A kininlike peptide was isolated from such patients and its formation appeared to be inhibited in C2-deficient plasma; C2 was therefore considered to be the source of the pathogenic peptide (23). However, direct demonstration of such a kinin-like peptide upon interaction of activated Cl with C4 and C2 or with C2 alone is lacking. Although it was originally reported that cleavage of C2b by plasmin generates a kinin (24), attempts to confirm this experiment have failed (25,26). The only identifiable kinin seen in subsequent studies was bradykinin (26). On the other hand. the amino acid sequence of C2b is known, and Strang et a!. (27) have now synthesized peptides of various lengths and tested each for kininlike activity. One such peptide was shown to cause edema when injected intracutaneously, reminiscent of the C2 kinin originally described However.
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it has not been shown to be a cleavage product of C2b, nor has it been shown to be present during attacks of swelling in patients with hereditary angioedema. Thus, at this time it seems unlikely that a kinin-like molecule is derived from C2b as a result of enzymatic cleavage. On the other hand, the presence of bradykinin has been documented as described below, and it is the likely ca use of the swelling. In fact when one of the proponents of the C2 kinin re-examined kinin formation in the plasma of patients with hereditary angioedema, only bradykinin was found (28). The 24 h urine histamine excretion level may also be increased during attacks of angioedema, suggesting that C3a, C4a, or C5a is being generated. Although the plasma levels of C3 and C5 are normal in this disorder, C3 turnover is clearly enhanced (29). The lesions, however, are not pruritic, and administration of antihistamines has no effect on the clinical course of the disease. Thus, complement activation is undoubtedly occurring, perhaps even during quiescent periods to lead to a low level of C4, but the vasoactive consequences of augmented complement activation that occur during attacks of HAE do not appear to be the cause of the swelling. Figure 2 is a diagrammatic representation of the plasma kinin-forming cascade, indicating the various enzymatic steps including the sites of inhibition by C 1 inhibitor. The cascade is initiated by factor XII (Hageman factor) binding to a site of tissue injury, followed by autoactivation in which traces of activated factor XII cleave native, i.e., unactivated factor XII, bound to the surface (30). A critical level of factor XUa is generated so as to convert prekallikrein to kallikrein. This autoactivation step is inhibited by Cl inhibitor. Since native factor XII has no measurable enzymatic activity, it is assumed that traces of factor XIIa normally exist in human plasma (31). Concentrations as low as 10- 13 molar are sufficient to initiate activation for the kinin system in plasma: 50% activation of the cascade can occur within 30 s (32). This concentration of factor XIIa is over a million times lower than our ability to assay factor XIIa in plasma, so that there is little hope of ever measuring it. Nevertheless, there is now evidence that the kinin cascade can be activated along the surface of endothelial cells, and that process may be a source of infinitesimal amounts of factor XIIa under normal physiological conditions (33,34). Factor XIIa then converts prekallikrein to kallikrein and kallikrein (35) cleaves high-molecular-weight kininogen to generate bradykinin. There is also an important positive feedback in the system in which the kallikrein generated rapidly converts unactivated factor XU to activated factor XI] (36), and the rate of this reaction is hundreds of times faster than the rate of autoactivation (32,37). Therefore, much of the unactivated factor XU can be cleaved and activated by kallikrein. CI inhibitor inhibits all functions of factor XIJa and it is one of two major plasma kallikrein inhibitors. Thus all functions of kallikrein are also inhibited, including
Copyrighted Material
C1 Inhibitor Deficiency
309 Factor XI
FactorXIl
Surface ,...------+
Factor Xlla
t
~
··_-u·~
"V
Prekallikrein - - - - . .
" ', : : ~ '"
n - I ~ ...
Kallikrein -
rh T
~
Plasminogen
~_uroki_nase _ _~
1
Plasmin
1
High molecular - - - - - . . Bradykinin weight kininogen
~
Fibrinolysis Angioedema
Factor Xlla Kalhkrein
-.
1---
Plasmin CI
Factor x l l r - - D - -
o Inhibited by C I fNH
~
C4
C I ----{}---
~
C4a + C4b
Figure 2 A diagrammatic representation of the plasma kinin-forming cascade indicating the steps inhibitable by CI INH. All functions of factor Xlla and kallikrein are affected. The lower figure indicates that further digestion of factor Xlla by kallikrein and plasmin generates faclor XII fragment (XII f), which is an initiator of the complement cascade. Both factor XIII' and CI are inhibited by CIINH.
the feedback activation of factor XII, the cleavage of high-molecularweight kininogen, and the activation of plasma prourokinase (38) to lead to plasmin formation. CI inhibitor also inhibits the fibrinolytic enzyme plasmin, although it is a relatively minor inhibitor compared to D:2-antiplasmin or D:2-macroglobulin. Patients with hereditary angioedema appear to be hyperresponsive to cutaneous injections of kallikrein as they are to CI (39), and elevated levels of bradykinin and cleaved kininogen have been observed during attacks of swelling (40,41). There is also evidence that CI activation observed in patients with hereditary angioedema may also be dependent on factor XII (20). Thus, a factor XII-dependent enzyme may be initiating the classic complement cascade. Plasmin is capable of activating Cis and may represent one such enzyme (42). Ghebrehivvet et al. demonstrated that Hageman factor fragment (factor XIJf) can directly activate the classic complement cascade by activating CI (43,44). This may represent a critical link between the intrinsic coagulation-kinin cascade and
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complement activation. The presence of kallikreinlike activity ll1 induced blisters of patients with hereditary angioedema supports this notion (45), as does the progressive generation of bradykinin upon incubation of hereditary angioedema plasma in plastic (26) (non-con tact-activated tubes) as well as the low prekallikrein and high-molecular-weight kininogen levels seen during attacks (46). More recent data support these indirect observations, favoring bradykinin as the critical pathogenic peptide for hereditary angioedema and-likely-acquired C I INH deficiency as well. One unique family has been described in which there is a point mutation in CI INH (Ala 443 -7 Val) leading to inability to inhibit the complement cascade but normal inhibition of factor XUa and kallikrein (47,48) No family member of this type II mutation has had angioedema. In recent studies, plasma bradykinin levels have been shown to be elevated during attacks of swelling in patients with hereditary and acquired forms of CI INH deficiency (41,49) and local bradykinin generation has been documented at the site of the swelling (50). The role of fibrinolysis needs also to be considered a part of the pathogenesis of the disease, since antifibrinolytic agents such as s-aminophoric acid and tranexamic acid appear to be efficacious. As shown in Fig. 1, kallikrein converts plasminogen to plasmin. Although kallikrein (Fig. 1) factor XIa, and even factor Xlia (not shown) have some ability to activate plasminogen directly, the plasma pathway via the prourokinase intermediate appears to be the major factor XII-dependent fibrinolytic mechanism. Among the functions of plasmin are the activation of Cis, the ability to cleave and activate factor XII just as kallikrein can (5]), and digestion ofCI inhibitor (52). Each of these would serve to augment bradykinin formation and further deplete the levels of C I inhibitor. Thus, the formation of plasmin may, in this fashion, contribute to the pathogenesis of the disease. There are also considerable new data regarding the formation of bradykinin along the endothelial cell surface and it is possible that this is a locus of bradykinin formation in hereditary angioedema (see Fig. 6, Chap. 3). The entire cascade can be activated along the surface of the cell. with gClqR as an initiating protein capable of catalyzing factor Xli autoactivation (53). Critical for this discussion is that Cl inhibitor can inhibit all of these reactions at the cell surface.
VI.
ACQUIRED C1 INHIBITOR DEFICIENCY
An acquired form of this disease has been described in patients with lymphoma who have circulating low-molecular-weight IgM and depressed
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CI inhibitor levels. This entity has an unusual complement utilization profile because Clq levels are low and C4, C2, and C3 are depleted. The low Clq level differentiates this condition from the hereditary disorder (54-56). The depressed C I inhibitor level may be caused by depletion secondary to CI activation by circulating immune complexes or Cl interaction with a tumor cell surface antigen. For B-cell lymphoma, the most common associated malignancy, C I fixation and C I inhibitor depletion are caused by an anti-idiotypic antibody bound to immunoglobulin on the surface of the B-cell (57). Other B-cell disorders associated with C I TN H depletion are acute and chronic lymphocytic leukemia, multiple myeloma, Waldenstrom's macroglobulinemia and essential cryoglobulinemia. Other patients with connective tissue disorders such as systemic lupus erythematous or carcinoma (58,59) can present with acquired CI inhibitor deficiency and, like patients with the hereditary form, will respond to androgen therapy, which enhances Cl inhibitor synthesis. A second form of CI inhibitor deficiency results from the synthesis of an autoantibody directed to Cl inhibitor itself (60,61). These patients also have low levels of C4, Clq, and CI inhibitor protein and function, and no family history. This form of acquired CI inhibitor deficiency appears to be increasingly recognized. Under normal circumstances, CI inhibitor is a substrate for the enzymes it inactivates: the active enzyme cleaves C I inhibitor, which exposes the active site in the inhibitor. The cleaved Cl inhibitor then binds stoichiometrically to the enzyme and inactivates it. When antibody to C I inhibitor is present, the CI inhibitor is cleaved and it is unable to inactivate the enzyme (62-64). Thus cleaved, functionless CI inhibitor circulates and unopposed activation of the complement- and kinin-forming cascade takes place. Plasmin is one of the enzymes capable of cleaving and inactivating CI inhibitor, and local CI inhibitor degradation by plasmin may be a critical event in the loss of protease inhibition during inflammation. In a more general sense, this observation may also explain the efficacy of antiplasmin agents such as c-aminocaproic acid or tranexamic acid in the treatment of CI inhibitor deficiency states (65). One circumstance in which the two forms of acquired Cl inhibitor deficiency merge is in an occasional patient with monoclonal gammopathy, indicative of an underlying lymphoproliferative disorder, in which the monoclonal immunoglobulin is in fact an antibody to CI inhibitor (66,67). The immune-complex-mediated depletion of CI inhibitor and the autoantibody directed to CI inhibitor represent types I and II acquired Cl inhibitor deficiency, respectively. The type II variety can be most readily determined by immunoblot with antibody to CI inhibitor. The presence of a Cl inhibitor cleavage product at 95 Kd differentiates the two forms of the acquired disorder, and it is not present in the hereditary disorder.
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Kaplan
Table 1 Assays for Cl Inhibitor Deficiency
Cl INH protein
Cl function
C4
C1Q
95kD CI INH
4N or t
44-
+
N N
44-
t
4-
4-
t
44-
No No No Yes
Hereditary type I Hereditary type II Acquired type I Acquired type II
t
Table I is a summary of the laboratory tests that may be used to identify the different forms of CI inhibitor deficiency. If a family history is present, one needs to differentiate the two types of HAE. Since the C4 level will be diminished in both, the distinction is usually made by comparing CI inhibitor protein level and CI inhibitor function. Both protein and function will be low in parallel in type LHAE, whereas the protein level will be normal or elevated in the type II form of this disorder with functional CI inhibitor diminished. Since a low Clq level and a 95 Kd cleaved CI inhibitor protein characterize types I and II acquired CI inhibitor deficiency, respectively, the absence of either abnormality or of any family history of swelling, in patients with low C4 and abnormally low functional Cl inhibitor, would define a patient with a probable new mutation. As indicated above, the acquired form of CI inhibitor deficiency with lymphoma or connective tissue disease, or cryoglobulinemeia, or an occasional carcinoma is identified by low CI, and more specifically low Clq, in addition to low C4 and diminished Cl inhibitor levels in which protein and function are diminished in parallel Occasionally this pattern may be obtained in someone who does not have any of the aforementioned predisposing immune conditions. Such patients need to be evaluated carefully over time because there have been reports of angioedema of this sort preceding the diagnosis of the underlying disorder. The type II acquired disorder with cleaved CI inhibitor as assessed by immunoblot or by specific assay for antibody directed to Cl inhibitor is the most difficult to diagnose because the tests required are not commercially available.
VII.
TREATMENT
The drugs of choice for treatment of hereditary angioedema are agents with weak androgenic properties such as dannol or stanozolol (Winstrol). For stanozolol, the typical dosage ranges between :2 and 4 mg taken daily and for danazol somewhere between 50 and 400 mg daily (68-73). The major side
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effects of these are liver dysfunction, weight gain, and mild virilization (74,75). Nevertheless, these drugs have been used successfully in young women, including some passing through puberty, without adverse effect. The maintenance dosage should be minimized, and occasionally treatment every other day can be sufficient to treat the disorder. As the dosages employed have decreased, side effects, even with long-term use, are few. Periodic assessment of liver function is most important. The minimum dosage required, however, has to be determined and titrated for each individual patient. Alternative drugs used to treat hereditary angioedema include antifibrinolytic drugs such as e-aminocaproic acid or tranexamic acid (76-79). These are generally less well tolerated, and because of concern with regard to side effects, they are not recommended as first-line agents. For acute attacks of angioedema, subcutaneous epinephrine is administered, fresh frozen plasma can be infused to replace CI inhibitor, or, if available, CI inhibitor concentrate (80,81). Initially, there was a theoretical concern that administration of plasma would provide more substrate for the production of vasoactive factors and worsen angioedema, but that has not proven to be true. In fact replacement of CI inhibitor, regardless of the form in which it is given, significantly slows down the enzymatic reactions and controls the cascade. Abdominal attacks of severe cramps, guarding, and in some instances diarrhea can be rapidly controlled in this fashion, although they tend to subside spontaneously within 48-72 h of observation. For severe laryngeal edema, there may be no choice but to do a tracheostomy, dependent upon the status of the patient when initially seen, Treatment of acquired C1 inhibitor deficiency requires, first, treatment of the underlying disease, if one has been identified, plus treatment with the aforementioned drugs, which is essentially the same as that for treatment of the hereditary disorder. Treatment of type II acquired C1 inhibitor deficiency with an autoantibody directed to Cl inhibitor is indeed more difficult because the ability to replete CI inhibitor is significantly compromised. Plasmapheresis and use of a cytotoxic agent in addition to the use of prophylactic androgenic compounds or e-aminocaproic acid may be necessary for chronic treatment, and infusion of plasma or CI inhibitor concentrate employed for acute emergency treatment. The latter is clearly preferable to prevent volume overload and to be able to give enough CI inhibitor to bind the autoantibody so as to raise the Cl inhibitor level significantly. 1n a practical sense, this is often not feasible. Tranexamic acid has also been successfully employed in the treatement of type II acquired C I inhibitor deficiency in which activation of the bradykinin-forming cascade and fibrinolysis (the latter determined by elevated levels of plasmin-a:!
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314
anti plasmin complexes) was observed (82). It is of interest that for treatment of the hereditary disorder the dosage of androgen required is based on clinical course (i.e., the frequency and severity of episodes) and not the level of C I inhibitor or even the increase in C4 that will result. It has been shown that the C4 level can approach normal with treatment and C I inhibitor levels rise beyond the critical 25% of normal levels, yet many patients are responsive to dosages of androgen that are insufficient to achieve this. The reason for that is not clear, unless it is possible to achieve changes at a local level that might not be evident in the systemic circulation.
VIII.
OTHER HEREDITARY AND NONHEREDITARY ANGIOEDEMAS
Other hereditary forms of angioedema do not relate to Cl inhibitor deficiency, but all of them are rare. Binkley et a!. reported an estrogendependent but familial form of angioedema has been described associated with pregnancy or with ingestion of estrogenic compounds. The disorder appears to have dominant inheritance, but is present only in women because of the hormonal dependence (65). No abnormalities involving complement or kinins have been demonstrated and the underlying genetic abnormality and pathogenic mechanism is unknown. There is also a familial vibratory angioedema that is a histamine-dependent (83) physically induced swelling (84) manifest when vibrating stimuli (e.g., rubbing a towel across the back after showering) are applied. Angioedema is frequently due to food or drug reactions, and is often associated with urticaria (in contrast to all of the aforementioned entities), angiotensin converting enzyme (ACE) inhibitor ingestion, or is a manifestation of idiopathic angioedema. The latter disorder (see Chap. 19) is quite common but little is known regarding the pathogenesis of the swelling. Perhaps subtypes will eventually emerge. Cicardi et al. have classified patients with the disorder into those that are histaminergic, (i.e., respond to antihistamines) and those whose condition is refractory to treatment with antihistamines (85). A role for bradykinin release in the latter group has been reported, but the data have not yet been confirmed. Others propose a role for leukotrienes B, C, and 0 secretion in patients resistant to antihistamines (Beltrani, V. personal communication) and suggest that inhibitors of leukotriene synthesis such as Zeileutin (ZyDo) may be helpful. The extensive knowledge regarding the pathogenesis of hereditary and acquired CI inhibitor deficiency can be instructive regarding mechanisms of angioedema that are clearly distinct from allergic mechanisms, and may yet prove to be relevant for the treatment of other nonhereditary forms of swelling.
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One of the most prominent causes of nonhereditary angioedema is the use of ACE inhibitors. These agents are not only employed for treatment of hypertension but are also indicated for congestive heart failure, diabetic nephropathy neuropathy, and scleroderma renal disease. ACE is identical to kininase ]J and destroys bradykinin by removing the C-terminal phe-arg dipeptide, followed by removal of ser-pro, leaving the inactive pentapeptide Arg-pro-pro-gly-phe (86). With drug inhibition of ACE, the primary mechanism for bradykinin degradation is eliminated and the resultant elevation of bradykinin levels appears to be the cause of angioedema (49). Like C I in hi bi tor deficiency, swelling of the tongue, pharynx, and even larynx can be severe, requiring intubation for treatment of airway obstruction. In contrast to patients with CI INH deficiency, urticaria is sometimes seen accompanying the angioedema, although the angioedema predominates. The reason for this difference is unclear and may relate to a different site of bradykinin action within the skin, or even a concomitant IgE-mediated reaction to the drug.
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Donaldson YH, Hess EY, McAdams PJ. Lupus-erythematosus-like disease in three unrelated women with hereditary angioneurotic edema. Ann Intern Med 1977: 86312-313. Cohen SH, Koethe SM, Kozin F, Rodey G. Arkins JA, Fink .IN. Acquired angioedema associated with rectal carcinoma and its response to danazol therapy. J Allergy C1in Immunol 1978; 62:217-221. Jackson J, Sim RB, Whelan A, Feighery C. An IgG autoantibody which inactivates CI inhibitor Nature 1986; 323:722-724. Alsenz J, Bork K, Loos M. Autoantibody-mediated Clcquired delkiency of CI inhibitor. N Engl J Med 1987; 313:1360-1366. Malbran A, Hammer CH, Frank MM, Fries LF. Acquired angioedema: observations on the mechanism of action of autoantibodies directed against C I esterase inhibitor J Allergy Clin Immunol 1988; 81:1199-1204. Jackson J, Sim RB, Whaley K, Feighery C. Autoantibody facilitated cleavage of C I inhibitor in autoimmune angioedema. J Clin Invest 1989; 83:698-707 He S, Sim RB, Whaley K. Mechanism of action of anti CI inhibitor autoantibodies: prevention of the formation of stable C IS-C I IN H complexes. Mol Med 1998; 4119-128 Binkley KE, Davis III AE. Clinical, biochemical, and genetic characterization of a novel estrogen-dependent inherited form of angioedema. J Allergy Clin Immunol 2000; 106:546-550 Cicardi M, Beretta A, Colombo M, Gioffre D, Cugno M, Agostoni A. Relevance of lymphoproliCerative disorders and anti CI inhibitor autoantibodies in acquired angioedema. Clin Exp Immunol 1996: 106:475-480. Chevailler A, Orland G, Ponard D, Pernollet M, Carrere F, Renser G, Drouet M, Hurez D, Gardais J. CI inhibitor binding monoclonal immunoglobulins in three patients with acquired angioneurotic edema. J Allergy Clin [mmunol 1996; 97998-1008 Gelfand JA, Sherin RJ, Alling OW, Frank MM. Treatment of hereditary angioedema with danazol; reversal of clinical and biochemical abnormalities. N Engl J Med 1976; 295:1444-1448 Sheffer AL, Fearon DT. Austen KF. Clinical and biochemical eA'ects of stanazolol therapy for hereditary angioedema J Allergy Clin Immunol 1981; 68181-187 Warin AP, Greaves MW, Gatecliff M, Williamson OM, Warin RP. Treatment of hereditary angioedema by low-dose attenuated androgens: dissociation of clinical response from levels of C I esterase inhibitor and C4. Br ] Dermatol 1980; 103405-409 Sheffer AL, Fearon DT, Austen KF. Hereditary angioedema: a decade of management with stanozolol. J Allergy Clin Immunol 1987; 80:855-860. Gadek JE. Hosea SW, Gellfand JA, Frank MM. Response of variant hereditary angioedema phenotypes of danazol therapy. J Clin Invest 1979; 64:280-286. Hosea SW, Santaella ML, Brown EJ, Burger M, Katusha K, Frank MM. Long term therapy of hereditary angioedema with Danazol. Ann Intern Med 1990; 93809-812.
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Cicardi M. Bergamaschini L, Cugno M. Hack E, Agostoni G, Agostoni A. Long term treatment of hereditary angioedema with attenuated androgens: a survey of a 13-year experience. J Allergy C1in Immunol 1991; 87:768-773. Cicardi M. Castelli R, Zingale LC, Agostoni A. Side eflects of long-term prophylaxis with attenuated androgens in hereditary angioedema: comparison of treated and untreated patients. J Allergy Clin Immunol 1997; 99: 194--196. Frank MM, Sergent JS, Kane MA, Alling DW. e-aminocaproic and therapy of hereditary angioneurotic edema: a double blind study. N Engl J Med 1972; 286:808-812. Lundh B, Laurell A. Wetterqvist H, White T. Granerus G. A case of hereditary angioneurotic edema successfully treated with e-aminocaproic acid. Clin Exp Immunol 1968; 3:733-745. Shetler AL, Austen KF, Rosen FS. Tranexamic acid therapy in hereditary angioneurotic edema. N Engl J Med 1972; 287:452-454. Soter NA, Austen KF, Gigli I. Inhibition by e-aminocaproic acid of the activation of the nrst component of the complement system. J Immunol 1975; 114:928-932 Gadek JE, Hosea SW, Glefand JA, Santaella M, Wickerhauser M, Triantaphyllopoulos DC, Frank MM. Replacement therapy in hereditary angioedema: successful treatment of acute episodes with partly purified Cl inhibitor. N Engl J Med 1980; 302:542-546 Visentin DE, Yang WH, Karsh J. CI esterase inhibitor transfusion in patients with hereditary angioedema. Ann Allergy Asthma Immunol 1998; 80:457-461. Cugno M, Cicardi M, Agostoni A. Activation of the contact system and fibrinolysis in autoimmune acquired angioedema: a rationale for prophylactic use of tranexamic acid. J Allergy C1in Immunol 1994; 93:870-876. Metzger WJ, Kaplan AP, Irons J, Patterson R. Hereditary vibratory angioedema: Confirmation of histamine release in a type of physical hypersensitivity. J Allergy Clin Illlmunol 1976: 57:605-608. Patterson R, Mellies CJ, Blankenship ML, Pruzansky JJ. Vibratory angioedema: a hereditary type of physical hypersensitivity. J Allergy C1in Immunol 1972; 50: 174--182. Cicardi M. Bergamaschini L Zingale LC, GioA-re D. Agostoni A. Idiopathic nonhistaminergic angioedema. Am J Med 1999; 106:650-654. Sheikh L Kaplan AP. The mechanism of digestion of bradykinin and Iysyl bradykinin (kallidin) in human serum: The role of carboxypeptidase. angiotension converting enzyme, and determination of nnal degradation products. Biochem Pharmacol 1989: 38:993-1000.
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14 Chronic Urticaria: Autoimmune Chronic Urticaria and Idiopathic Chronic Urticaria Malcolm W. Greaves Singapore General Hospital, Singapore
Allen P. Kaplan Medical University of South Carolina, Charleston, South Carolina, US.A.
I.
INTRODUCTION
Chronic urticaria is conventionally and arbitrarily defined as the daily or almost daily occurrence of wheals for 6 weeks or more (I). This encompasses a variety of different disorders that share whealing as the most prominent clinical feature (Table I). These include the physical urticarias. in which whealing occurs in response to a physical stimulus, usually applied directly to the skin. Cholinergic urticaria is usually included under the heading of a physical urticaria. although here the triggering stimulus is a rise in body temperature due to heat excercise or emotion. It also includes autoimmune urticaria. a relatively recently described entity (2-5) that will be considered in more detail below. Chronic urticaria. which cannot be ascribed to any of the above and for which an identifiable cause is elusive, is still a common and troublesome problem. termed chronic idiopathic urticaria. Of course co-existence of physical urticarias with chronic idiopathic urticaria or autoimmune urticaria frequently occurs in the same individual. Angioedema also occurs concurrently with chronic urticaria in 90% of patients with chronic idiopathic urticaria, and is also frequent in
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Table 1 Chronic Urticaria: Classification
Physical urticarias Symptomatic dermographism Cold urticaria Cholinergic urticaria Delayed pressure urticaria Solar urticaria Heat urticaria Aquagenic urticaria Autoimmune urticaria Chronic idiopathic urticaria Urticarial vasculitis
autoimmune urticaria (6). Urticarial vasculitis is frequently included under the heading of chronic urticaria because it is often clinically indistinguishable from chronic idiopathic urticaria and is a very important differential diagnosis of the latter. However it is reviewed fully in Chapter 18 and will not be considered in detail here. How common is chronic urticaria? Accurate figures are hard to determine. In patients visiting their general practitioners 5.1 % had experienced urticaria for more than 4 weeks (7). An overall average lifelong prevalence of chronic urticaria of 1-2% is likely. Chronic urticaria is also highly disabling. Use of an internationally recognized quality of life instrument has recently shown that the degrees of personal occupational and social disability are comparable with those found in patients who have undergone triple coronary artery disease and are awaiting bypass surgery (8). Thus better information on the causes and pathogenesis of this condition is badly needed.
II.
AUTOIMMUNE URTICARIA
A.
Indirect Evidence
We know that the wheals of chronic urticaria are in part due to release of histamine and other mediators from dermal mast cells (9). The suggestion that chronic urticaria might be the result of the action of circulating histamine releasing factors is not new, and has been proposed by earlier authors. In the early 1960s Rorsman (10) observed a paucity of circulating peripheral blood basophils in \xltients with urticaria, and proposed that '"antigen antibody reactions ... bring about degranulation of basophil leucocytes." Indirect evidence that chronic so-called idiopathic urticaria
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might have an autoimmune basis has been with us for many years. In 1983 Lesnoff et al. reported an association between thyroid autoimmunity and chronic idiopathic urticaria, and in 1989 Leznoff proposed what was termed a syndrome of autoimmune thyroid disease, chronic urticaria, and angioedema (11,12). Published figures for the incidence of thyroid autoantibodies in chronic idiopathic urticaria, reviewed by Zauli et al. (l3), range from 5 to 90%. Unpublished data from one of us (MWG) gives a figure of 14 antithyroid antibody-positive patients out of a total of 182 patient with chronic idiopathic urticaria, with a preponderance of positive findings in patients with evidence of autoimmune urticaria (O'Donnell, BF et ai., unpublished data). Most patients with chronic idiopathic urticaria and thyroid autoantibodies are euthyroid. Recently published guidelines (14) recommend that thyroid autoantibody and thyroid function testing be performed routinely only if there is clinical or family history evidence pointing to thyroid dysfunction. That treatment of thyroid dysfunction in patients with idiopathic urticaria favorably innuences the urticaria is often claimed (13) but remains unproved. It is also worth noting that determinations of the human leukocyte antigen (HLA) class 2 alleles in patients with chronic idiopathic urticaria revealed a significantly increased frequency of HLA DRB I *04 (corrected p = 3.6 x 10-6) for patients with evidence of autoimmune chronic urticaria (15), a result consistent with the view that an autoimmune basis underlies this subset of patients with chronic urticaria.
B.
Evidence for Involvement of a Circulating Histamine-Releasing Factor
In 1974 one of us (MWG) reported that blood basophil suspensions from patients with chronic idiopathic urticaria showed lowering of basophil histamine releasability using anti-IgE (16). This finding suggested basophil desensitization but its significance was overlooked at the time. We now know that basophil desensitization, together with a parallel reduction in basophil numbers in chronic urticaria, is due to the action of circulating histamine-releasing autoantibodies (17). That autoantibodies directed against epitopes expressed by mast cells or basophils could be an important cause of histamine release in urticaria is not a novel concept. As long ago as 1988 Gruber et al. (18) reported that more than 50% of patients with cold urticaria had autoantibodies of the IgG class directed against IgE as determined by enzyme immunoassay. These antibodies were also found in 50% of patients with chronic idiopathic urticaria and urticarial vasculitis. The sera of these patients was, in some cases, capable of releasing histamine
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from normal human basophils and causing a wheal-and-flare reaction upon intradermal injection. The authors proposed a pathogenic role for IgG in these patients. A role for IgG anti-IgE as an activator of mast cells and basophils was also proposed in patients with atopic dermatitis (19). Other nonimmunoglobulin histamine-releasing factors were also proposed, notably an IgE-dependent histamine-releasing factor (20) and a cytokinelike factor (21).
C.
Evidence that Serum Histamine-Releasing Activity in Chronic Urticaria is Due to an Autoantibody
The ability of sera from some but not all patients with chronic idiopathic urticaria to cause a wheal-and-flare reaction upon autologous intradermal injection was reinvestigated by Grattan et a!. (22), who showed a positive response in 7 of 12 patients. They noted that in these patients a positive result could only be obtained if the urticaria was currently active. Initial investigation of this activity suggested that it was a histamine-releasing autoantibody with the characteristics of anti-IgE based upon absorption of this activity by monoclonal IgE and inhibition by lactic acid stripping of normal human basophils (23). It was supposed that, in patients with positive sera, the development of urticarial wheals was due to the ability of these antibodies to cross-link dermal mast-cell-bound IgE, causing mast cell activation and histamine release (see Fig. IB). Further analysis of histamine-releasing activity of sera from four patients with chronic urticaria revealed that it consisted of IgG. or less commonly IgM. with novel epitope specificities. Inhibition experiments. using the human recombinant extracellular fragment of the high-affinity IgE receptor (FcERI) alpha subunit (FeRIa). identified immunoglobulin (lgG) autoantibodies with a-chain specifity. It was proposed that these cross linked adjacent alpha subunits of FCER I on dermal mast cells and basophils (2) (Fig. IC). It was concluded that cross-linking autoantibodies against the alpha chain of FCERI. leading to mast cell activation, could represent an important pathogenetic mechanism in chronic idiopathic urticaria. We subsequently studied 165 patients with chronic idiopathic urticaria, 105 of whom had a positive autologous serum skin test. Of these sera 43 (26% of all urticaria patients studied) released histamine from highand 10w-lgE donor basophils. indicating the presence of functional antiFCERla autoantibodies. anti-IgE autoantibodies. or both (3). Eight patients' sera reacted only with basophils from a high-IgE donor. suggesting that these patients possessed autoantibodies reacting with IgE. Sera from 19 healthy donors were nonreactive against basophils of low- or high-IgE donors (3). In the same study. autologous serum skin-test-positive sera from
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!l. Anti-FCERl
..........
£
""
...
Figure 1 Activation of dermal mast cell via FceR I. (A) Antigen cross-links specific IgE. (8) IgG anti-lgE cross-links via Fe portion of IgE. (e) IgG anti-FceRI crosslinks adjacent FceRI directly.
12 patients with chronic idiopathic urticaria caused 19O-mediated histamine release from dermal mast cells of healthy donors, which could also be inhibited by human recombinant FceRla (3). These data, taken together with the histological finding of dermal mast cell degranulation following intradermal injection of autologous serum (24), represent persuasive evidence that anti-FceRla autoantibodies are relevant to the pathogenesis of chronic idiopathic urticaria (ClU). Recently Sabroe et al. (25) have classified sera from 75 patients with ClU into five subsets: immunoreactive histamine-releasing anti-FceRl autoantibodies (26%); immunoreactive non-histamine-releasing anti-FceR I autoantibodies (15%); anti-lgE autoantibodies (9%); sera containing a non immunoglobulin mastcell-specific histamine-releasing factor (3) (9%); and sera with no identifiable factor (41 %). Positive autologous serum skin tests were strongly associated with histamine-releasing anti-FceRI autoantibodies, and no autoantibodies were detected in healthy subjects or in patients with physical urticarias (25). Fiebiger et a1. (4) used human recombinant FceRIQ' and Western blotting to demonstrate that 37% of sera of 32 patients with chronic idiopathic urticaria contained immunoreactive anti-FceRla autoantibodies, and in most cases these antibodies showed functional histamine releasing activity. No immunoreactivity was found in sera of healthy subjects or patients with atopic eczema. In a subsequent publication (26), the same
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laboratory showed that anti-Fct:R la immunoreactivity could be detected in the serum of patients with other autoimmune diseases including pemphigus vulgaris, bullous pemphigoid, dermatomyositis, and systemic lupus erythematosus. However, unlike the anti Fct:Rl autoantibodies found in chronic urticaria, which are mainly of the fgGI or IgG3 subtypes, anti-Fct:RI autoantibodies in these other autoimmune disorders were nonfunctional (non-histamine-releasing) and predominantly of the IgG2 or IgG4 subtypes. It is worth reiterating that the only disease in whicll histamine-releasing antiFct:Rl autoantibodies have been found is chronic idiopathic urticaria. Similar results were reported by Kaplan's group in 1996 (5). In 50 patients with chronic idiopathic urticaria, these authors used a rat basophil leukemia cell line expressing Fc.s R Ia to demonstrate the presence of functional (f)-hexosaminidase-releasing) anti-Fc.sRI autoantibodies in sera 01'38 (76%). All but I 01'20 healthy control subjects showed negative results in this assay. However, when human basophils were used as indicator cells. sera from 20 of 50 patients (40%) with chronic urticaria, but only I of 19 healthy controls, released histamine. D.
Mode of Action of Anti-FcsR1 Autoantibodies
Kaplan has also addressed the issue of complement involvement in autoantibody-mediated histamine release in patients with autoimmune urticaria (27-29). Earlier work (2,3) suggested that release of histamine from mast cells and basophils by anti-Fc.sRI autoantibodies was due to direct cross-linking of adjacent a-chains of Fc.sRI on the surface of these cells, without complement involvement. That complement activation may be involved was suggested by the earlier identification of IgG I and IgG3 as the principal immunoglobulin subtypes in autoimmune urticaria (26). Further evidence supporting a role for complement activation derives from histamine release experiments using highly purified 19G anti-FuRl. and decomplemented sera deficient in either C2 or C5. It was found that whole sera from patients with chronic urticaria, but not complement deficient sera, released histamine from dermal mast cells. It was further found that C5a may playa key role since in vitro release of histamine from normal human basophils was dependent upon the concentration of C5a and was inhibited by an antibody to the C5a receptor. It was concluded that release of histamine from dermal mast cells or basophils by anti-FuRl autoantibodies was at least augmented, if not dependent on complement. mainly CSa, activation. In this model, 19G anti-Fc.sR I cross-links the high-affinity IgE receptor directly, rclease of histamine being augmented by C5a. The involvcmcnt of C5a could also cxplain the otherwise puzzling lack or clinical evidence or pulmonary involvement in patients with autoimmune Copyrighted Material
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urticaria, since lung mast cells but not dermal mast cells are deficient in C5a receptors (30).
E.
Chronic Urticaria as an Autoimmune Disease
At least 30-50% of patients with chronic idiopathic urticaria have detectable functional anti-FccR I or anti-lgE autoantibodies and these patients show, as already mentioned (15), an increased frequency of HLA DR alleles characteristically associated with autoimmune disease. In the subset who possess these autoantibodies, the evidence that they are pathogenic is persuasive and can be summarized as follows: functional (histaminereleasing) anti-FccRI autoantibodies are not found in healthy people or in patients with other types of chronic urticaria (2,3,5); the antibodies release histamine from mast cells and basophils (2,3); they cause whealing upon intradermal injection in a healthy volunteer (31); the plasma levels of the autoantibodies correlate well with disease activity (32); and removal of the autoantibody leads to remission (33). Standard criteria for definition of an autoimmune disease require that, in addition to the above, reproduction of the disease IJ1 experimental animals be performed (34) and this has not yet been done using anti-FccRI autoantibodies. Therefore the evidence should properly be regarded as convincing, but a little short of fully proven. That autoantibodies against receptors can cause disease is by no means a novel concept. Recognized examples include myasthenia gravis (acetyl choline receptor) and insulin-resistant diabetes mellitus (insulin receptor). In these and other similar examples receptor activation is blocked or downgraded. Receptor activation due to a receptor-specific autoantibody is less common and autoimmune urticaria now joins Graves' disease (autoantibody against the thyroid-stimulating hormone receptor) as an example of this less common receptor-mediated cell activation autoimmune phenomenon. These interesting issues have previously been discussed in greater detail (35,36).
F.
Diagnosis
Clinical examination of the patient with chronic idiopathic urticaria IS generally not helpful differentiating autoimmune from nonautoimmune disease (37). Although the disease is usually more severe and persistent in autoantibody-positive patients, systemic symptoms are nevertheless not especially prominent in autoimmune, compared with nonautoimmune, patients. Likewise, histological examination of skin biopsy material is unrewarding (38). It was observed that EG2-positive (activated) eosinophils were more profuse in older (> 12 h) wheals in autoantibody-negative
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patients, but no diagnostically useful histological or immunocytochemical features could be discerned. Recently Ying et a!. (39) reported immunopathological studies of skin biopsies from 13 patients with chronic idiopathic urticaria, 6 of whom were positive for anti-FcERI autoantibodies. The immunopathology of skin biopsies from autoantibody-positive and autoantibody-negative patients did not differ significantly. The population density of CD3, CD4, CD8 and CD25 T cells, interleukin-4 (lL-4), IL-5, interferon-y (fFNy) mRNA +cells, eosinophils, neutrophils, basophils, macrophages, and tryptase-positive mast cells was similar in the two groups.
1. The Autologous Serum Skin Test The autologous serum skin test (Fig. 2) has proved to be a useful sceening test for autoimmune urticaria (40). In this test SO pi of the patient's autologous serum is injected intradermally into the flexor surface of the forearm along with equal volumes of normal saline and histamine (10 Ilg/ml) as negative and positive controls, respectively. Wheal-and-nare responses are measured at 30 min and their areas are calculated from measurement of two perpendicular diameters (d I and d2) according to the formula: rc((d I + d2)/4). Wheal volume is calculated by multiplying the wheal area by
Figure 2
AlIlologolis serUJl1 skin lest.
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half the change in skin fold thickness using a skin-thickness calliper. Whealand-flare measurements for serum-induced responses are corrected by subtraction of the equivalent values for the saline-induced responses in each subject. Using these measurements, a positive test is defined as a red serum-induced wheal with a diameter of 1.5 mm or more than the salineinduced response at 30 min. Under these conditions the sensitivity and specificity of the test proved to be 65-81 % and 71-78% respectively. Using the basophil histamine release test as the gold standard for positivity, the test was negative in 39/40 healthy controls, 15/15 patients with symptomatic dermographism, 10/10 atopic patients, and 8/9 patients with cholinergic urticaria. Although the measurements are straightforward, variations in injection technique can result in lack of reproducibility. Regular performance of the test, preferably in duplicate (right and left arms), reduces intertest variation and ensures clinically useful results that are predictive of functional anti-FcERl autoantibodies. However, we advise that results be confirmed if possible by in vitro testing of the serum for anti-FcERI and anti-IgE autoantibodies.
2.
In Vitro Tests
The goal of development ofa simple quantitative in vitro test for anti-FcERl and anti-lgE autoantibodies remains elusive. Although the use of enzymelinked immunosorbent assay (ELISA) and immunoblotting have been reported (26,28), the correlation between functional tests (release of histamine or other mediator) and tests relying upon immunoreactivity has proved to be poor. For this reason Kikuchi and Kaplan (28) concluded, on the basis of studies in 260 patients with chronic urticaria, that immunobinding assays were not acceptable as a screening method and that functional assays are required. Assays currently in use include release of histamine from basophils of low- and high-IgE donors (2,3,28) and use of a rat basophil leukemia cell line expressing FCERIa (5). Some published frequencies of positive results using these so-called gold standard assays are listed in Table 2.
G.
Basophil
That basopenia is a feature of chronic urticaria has long been recognized (10). It has also been frequently reported that basophils of patients with chronic idiopathic urticaria are unresponsive to evocation of histamine release by an ti-JgE (16,45), especially when the urticaria is in relapse, a finding suggestive of desensitization (46). More recently Grattan (47) was able to demonstrate an association between basopenia and histaminereleasing activity of the patient's serum in patients with chronic idiopathic
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Table 2 Frequency of Anti-Fc£Rl Autoantobodies in CIU Detected by Functional In Vitro Assays. RBL: rat basophil leukemia cell line; BHR: basophil histamine release; MCHR: mast cell histamine release
Source Tong et al. (5) Ferrer et aL (27) Ferrer et al. (27) Tanus et al. (41) Zweiman et al. (42) Zweiman et al. (43) Asero et al. (44) Niimi et al. (3) Sabroe et al. (25)
No. of patients with CIU studied
Assay
Percentage positive
50 68 68 37 28 70 121 165 28
RBL cells a BHR MCHR BHR BHR b BHR BHR BHR c BHR c
76 48 46 27 61 30 16.5 26 28
urticaria. Subsequently Sabroe (17) demonstrated a close inverse correlation between levels of anti-Fc.sRl autoantibodies on the other hand, and, peripheral blood basophils and total blood histamine on the one hand, and in patients with chronic idiopathic urticaria. That counting basophils could form the basis of a useful screening test for autoimmune urticaria has been considered (48), but must await rapid and convenient methods for the enumeration of peripheral blood basophils.
H.
Prognosis and Treatment
The general principles of management of chronic urticaria from any cause apply equally to autoimmune urticaria, and are reviewed in Chapter 15. Although quantitative follow-up data are lacking, autoimmune chronic urticaria tends to run a more protracted course than its nonautoil11l11une counterpart, and is also often relatively resistant to treatment. It is important to explain the nature of the disease to the patient in order to allay unjustified fears he or she may have regarding life-threatening underlying causes and to save unnecessary investigations. Use of HI-antihistamines should always be the first line of drug treatment. In mildly or moderately affected patients, fexofenadine I20mg daily or desloratidine 5 mg daily plus a sedative HI-antihistamine such as hydroxyzine 25 mg at night may be adequate, but it is often useful to prescri be off-Ia bel dosages of fexofenadine or desloratidine to control symptoms. Compliance is usually good due to the absence of adverse effects
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with these newer nonlipophilic nonsedative antihistamines. Patients receiving hydroxyzine at night must be warned of the continuing effecL of the drug on cognitive function throughout the following morning. However, some patients with autoimmune urticaria are severely disabled by constant pruritus, wheals, and angioedema. In these patients recourse to immunotherapy may be necessary. Systemic corticosteroids are usually disappointing, and incur troublesome adverse effects. Cyclosporin 2.5-5 mg/kg/day is a satisfactory alternative and has been proved to be effective in a well-controlled study (49) of patients with chronic idiopathic urticaria, all of whom had a positive autologous serum skin test and serum histamine-releasing activity and therefore likely had an autoimmune basis for their disease. Contraindications to cyclosporin include a history of renal impairment, cancer, or a positive cervical smear. The drug should be used with extreme caution in patients with hypertension or hyperlipidemia. In patients in whom cyclosporin is contraindicated, poorly tolerated, or ineffective, recourse can be made to intravenous immunoglobulin or plasmapheresis. The reader is referred to detailed accounts in the literature of the use of these treatments for autoimmune urticaria (32,33). One of the authors (AK) has, however, failed to observe a response Lo intravenous immunoglobulin in six of six patients in whom it was tried.
I.
Is a Diagnosis Important?
From the above account, the answer is "yes", with the caveat that in patients with mild to moderate impairment of quality of life and reasonable control of symptoms by H I-antihistamines there may be little advantage to be gained by further investigation. However, even in these patients, elucidation of an autoimmune cause can set the patient's mind at rest and obviate fruitless quests for dietary and other causes and expenses from unnecessary tests. In severely affected patients with resultant disruption of occupational family and social activities, the presence of anti-FuRl or anti-igE autoantibodies should be sought, since additional therapeutic options, outlined above, are available and effective and should be considered in each case.
III.
CHRONIC IDIOPATHIC URTICARIA
Up to 50% of patients with chronic so-called idiopathic urticaria turn out to have autoimmune urticaria. This leaves a remainder of at least 50%, conventionally described as having idiopathic disease. A few of these may in fact have autoimmune urticaria, false-negative results being the consequence
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of timing or insufficient sensitivity of available tests, but most appear to have a nonautoimmune basis. By definition, the term "idiopathic" indicates absence of an evident cause. Nevertheless these patients are frequently widely investigated, nearly always with disappointing results. A.
Clinical Features
These are clinically indistinguishable from those occurring in patients with chronic autoimmune urticaria (37). The duration of the disease is by generally accepted definition at least 6 weeks, during which wheals occur daily or almost daily associated with mucocutaneous angioedema in about 90% (37). About 50% of patients also have concomitant delayed pressure urticaria (see Chapter 8). Angioedema, although alarming to the patient, is rarely life-threatening in idiopathic chronic urticaria. Individual wheals, which are associated with increased tissue levels of histamine (9), last less than 24 h, usually about 12 h, depending on the size. They may be annular, serpiginous, or confluent to form large plaques and they fade without leaving any stain in the skin apart from the bruising effects of vigorous rubbing. Patients rarely scratch urticaria. Smaller wheals may be surrounded by a white halo due to a steal effect consequent to the increased blood flow within the wheals. The distribution is universal, including the palms and soles, although associated delayed pressure urticaria may be the cause of whealing at these sites. Pruritus is invariably troublesome, especially at night (37) and is of a burning or pricking quality. Lesions of angioedema also last less than 24 h unless they are massive, and the occurrence of itching is inconsistent. Associated systemic symptoms occur in 25-30% of patients and include gastrointestinal symptoms, flushing, palpitations, headache, arthralgia, and fatigue. Gastrointestinal symptoms often turn out to be due to irritable bowel syndrome and palpitations due to anxiety. ]J these symptoms are unusually prominent, idiopathic anaphylaxis should be considered. Two-thirds of patients report exacerbating factors (37), and these are listed in Table 3. B.
Diagnosis
The challenges in diagnosing chronic urticaria have recently been reviewed (50). A number of nonurticarial skin conditions mimic chronic urticaria with or without angioedema (pseudourticaria), and the more important of these are listed in Table 4. Once true urticaria is confirmed, the next step in diagnosis is to exclude a rhysicalurticaria by appropriate skin challenge testing. A physical urticaria may occur as an isolated event or in association with chronic
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Factors Reported by Patients to Exacerbate Chronic Idiopathic Urticaria
Drugs: Nonsteroidal anti-inflammatory drugs NSAIDS (including aspirin), antibiotics, hormone replacement therapy, amphetamines, herbal remedies Infections: Intercurrent virus infections Foods: Especially seafoods, flavored and colored soft drinks, alcoholic drinks, eggs, and dairy products Stressful events Menses: Premenstrual or during menses
Table 4 Pseudourticaria: Skin Conditions Commonly Misdiagnosed as Urticarial Angioedema Acute contact allergic dermatitis: Especially of the face and eyelids Cellulitis: Especially occurring in the setting of facial lymphoedema (Melkersson-Rosenthal syndrome) Dermatomyositis: Especially of the eyelids Discoid lupus erythematosus: Of the tumid type and on the face Crohn's disease: Of the lips Hypoalbuminemia: From any cause, especially resulting in scrotal edema Myxedema
idiopathic urticaria. The methodology for physical urticaria challenge testing is reviewed in Chapter 8. It is important to identify patients with physical urticarias because if the latter, confirmed by challenge testing, turns out to be the patient's sole or principal problem, then further investigations are obviated. No laboratory investigations are indicated in physical urticarias, with the rare exceptions of identification of cold-precipitating proteins in cold urticaria and action spectrum phototesting in patients with solar urticaria. Once physical urticarias have been excluded, the next step is to consider the possibili ty of urticarial vasculitis, described in detail in Chapter 18 and recently reviewed (51). Although apparently relatively rare, it is probably often missed, as inspection of the skin in this condition may reveal nothing unusual. However, there are a number of useful clinical pointers (Table 5). fndividual wheals invariable persist longer than the 24 h limit of so-called ordinary chronic urticaria. However, this measurement may be difficult to ascertain as most patients are poor witnesses in this respect. Wheals of urticarial vasculitis may leave residual staining of the skin due to vascular damage. Itching is inconsistent in urticarial vasculitis; the lesions may be tender and painful rather than itchy. Systemic symptoms are more
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Table 5 Clinical Features Differentiating Urticarial Vasculitis from Chronic Idiopathic Urticaria Urticarial vasculitis
Clinical feature" Duration of individual wheals Residual skin staining
>24h Common
Pruritus Pain and tenderness Systemic symptoms Response to antihistamines
Inconsistent Common Frequent Poor
Chronic idiopathic urticaria <24h Rare, except for bruising due to rubbing Invariable Unusual Infrequent Usually fairly good
"In at least 50% of patients with urticarial vasculitis the clinical picture is essentially indistinguishable from chronic idiopathic urticaria.
common than in chronic idiopathic urticaria and consist of arthralgia, fatigue, and weight loss. However, the disease may be surprisingly asymptomatic. One of our patients was evaluated regularly as an outpatient for several years with an invariably highly visible histologically confirmed rash of urticarial vasculitis but seemed unfazed by failure to find a cause or an effective treatment. Urticarial vasculitis should be considered in any patient whose chronic urticaria is poorly responsive to routine antihistamine treatment. The diagnosis should not be made without histological confirmation. It is important to establish the diagnosis because, if confirmed, Important underlying causes will have to be excluded. These include autoimmune connective tissue diseases, especially lupus erythematosus. Sjogren's syndrome, hepatitis C infection, inf1ammatory bowel disease, and paraproteinemia.
C.
Do Foods Cause Chronic Idiopathic Urticaria?
This issue has been discussed recently in some detail (52). Food allergy is a recognized cause of acute urticaria, but the role of food components in chronic urticaria is controversial. In a recent textbook on urticaria (53), Henz describes food proteins, preservatives, and coloring agents as major causative factors in chronic urticaria. The concept of food additives as a cause of chronic urticaria was first popularized in the European literature of the 1970s and 1980s by luhlin and Michaelsson, and later by Doeglas and by Supramal1lan and Warner (54-56). These studies involved challenge testing but were not adequately placebo-controlled, and the reproducibility of
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apparently positive reactions was not investigated, although positively reacting patients were said to respond subseq uently to dietary restrictions. The experience of one of us (MWG) in the routine use of placebo-controlled single-blind challenge testing for food additive intolerance, over a period of 20 years, indicates that patients who can reproducibly be shown to react to a food additive are extremely rare. We agree with Mathews (57) who stated in 1983 that "as a cause for chronic urticaria or angioedema food allergy can only be rarely implicated."
D.
Thyroid Function
Hashimoto's thyroiditis, and less commonly Graves' disease, show a positive association with chronic idiopathic urticaria (12,58). Antithyroid autoantibodies are found in 27% of patients with chronic urticaria and 19% have abnormal thyroid function (59). However, there is no evidence that treating the underlying thyroid dysfunction alters the course of the accompanying urticaria. Thyroid disease and chronic urticaria are frequently associated but there is no evidence that the thyroid autoantibodies are pathogenic in the context of chronic urticaria. The significance of the association lies in the separate autoimmune mechanisms found in both disorders.
E.
Other Claimed Causative Factors: Helicobacter pylori
That numerous anecdotal reports of different purported causes of chronic urticaria continue to appear in the literature bears witness to the frustrations of clinicians dealing with the disorder. It is pointless to itemize these, but one micro-organism, Helicobacler pvlori, is worth a brief mention because of its possible significance, not as a direct cause of chronic urticaria but because of its possible relevance to autoimmunity. This topic has recently been reviewed (60). Evidence of H. pylori infection is found in up to 50% of the general population in most regions of the world and in at least 30% of patients with chronic idiopathic urticaria. However treating the H. pvlori has no significant effect on the course of the chronic urticaria (6]). Recent evidence has demonstrated that H. pylori infection induces autoantibody formation due to the immunogenicity of its cell envelope polysaccharide Lewis x and y blood group antigens. Autoantibodies are formed by molecular mimicry analogous with the role of Campylobacler jejulli in the Guillain-Barre syndrome. H. pI'lori also induces human leukocyte antigen (HLA)-DR expression on gasric epithelium, enabling these cells to behave as antigen-presenting cells. The interesting possibility therefore arises that H. pl'lori might have an indirect
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role in chronic idiopathic urticaria through the reduction of immune tolerance and induction of autoantibody formation, including anti-FcsRla autoantibodies.
F.
Testing
Patients with chronic idiopathic urticaria are almost invariably overinvestigated, and usually present with a dossier of expensive but uninformative test results, including allergen-specific IgE determinations. Several recent publications have attempted to provide guidance on the rational investigation of these patients (62,63). In 2000, the European Working Group on the Diagnosis of Chronic Urticaria reported its diagnostic recommendations (62). It recommended use of a check list to assist with history-taking and to ensure exclusion of physical urticarias, which, when confirmed by appropriate challenge testing, usually require no further investigation, and urticarial vasculitis, which requires full investigation. An erythrocyte sedimentation rate (ESR) was advised, a positive result suggesting underlying systemic disease and prompting a skin biopsy to exclude urticarial vasculitis, together with a differential white blood cell count to exclude parasite infestation. In patients whose history yielded strong evidence of involvement of a food factor, the group advised double-blind placebo-controlled challenge testing. In the event that the above yielded negative results, the group advised further investigation for autoimmune urticaria, at least in severely handicapped patients. In a retrospective study of 130 patients with chronic urticaria, Bos (63) concluded that careful history-taking with the aid of a questionnaire elicited the cause in almost half of the patients studied. However, in most of these the diagnosis proved to be a physical urticaria, although apart from dermographism this was not routinely confirmed by physical urticaria challenge testing. Other diagnoses consisted of adverse drug reactions (3.4%), adverse food reactions (5.4%), and systemic disease (2.3%). In 55% no cause could be found. Laboratory testing was unhelpful, but the authors nevertheless recommend routine determination of the erythrocyte sedimentation rate and differential white blood cell count, to help exclude underlying systemic disease and parasite infestation. We are in general agreement with the above guidelines, but believe that there is a sufficiently strong association with thyroid disease to warrant routine laboratory screening, although we acknowledge that treatment of an underlying thyroid disorder is unlikely to intluence the a socia ted urticaria. More recognized in Europe than in North America, Schnitzler's syndrome
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Table 6 Guidelines for Investigation of Chronic Urticaria
Exclude physical urticaria / angioedema by history + appropriate challenge testing: A positive result obviates the need for further investigation, except in patients with cold and solar urticaria (see text). Exclude urticarial vasculitis by history, examination of the skin, an ESR, and skin biopsy: Positive results should prompt full work-up for hepatitis C infection, autoimmune connective tissue diseases, paraproteinemia, and inflammatory bowel disease. In patients with a convincing history, exclude reactivity to food components by placebo-controlled challenge testing: A positive result must be tested for reproducibility. Exclusion of thyroid disease by thyroid autoantibody screen and, if positive, thyroid function tests: A positive result strengthens the likelihood of an underlying autoimmune process. Differential white blood cell count to reveal a blood eosinophilia, allowing for exclusion of parasite infestation: Probably only worthwhile in regions where parasite infestation is endemic; stool examination for ova and parasites should not be requested in the absence of eosinophilia. Plasma protein in electrophoretic analysis as a screening test for IgM monoclonal gammopathy of Schnitzler's syndrome. ]nvestigate for autoimmune urticaria: Patients who are severely disabled, unresponsive to treatment, and in whom no causative factors have emerged.
(chronic urticaria accompanied by monoclonal IgM gammopathy) (64) is probably underdiagnosed and justifies a request for plasma protein electrophoretic analysis in treatment-resistant patients with chronic idiopathic urticaria. Our recommendations are set out in Table 6.
G.
Management
The principles of management of chronic idiopathic urticaria and angioedema have recently been reviewed (59,64). They are also discussed in detail in Chapters J 5 and 16 and will not be considered here.
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Greaves MW. Current concepts: chronic urticaria. N Engl J Med 1995; 332: 1767- 1772 2. Hide M, Francis DM, Grattan CEH, et al. Autoantibodies against the high affinity JgE receptor as a cause for histamine release in chronic urticaria. N Engl J Med 1993; 3281599-1604.
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Tong LJ, Balakrishnan G, Kochan JP, et a!. Assessment of autoimmunity in patients with chronic urticaria. J Allergy Clin Immunol. 1997; 99:461-465. Greaves MW, Sabroe S. Allergy and the skin. Br Med J 1998; 316:1447-1450. Lamberts H, Brouwer HJ, Mohrs J. Reason for Encounter and Episode and Process-Oriented Standard Output from Transition Project; Parts I and 2. The Netherlands, Amsterdam: Amsterdam University Press, 1991. O'Donnell BF, Lawlor F, Simpson J, et a!. The impact of chronic urticaria on quality of life. Br J Dermatol 1997; 136553-556 Kaplan AP, Horakova Z, Katz SI. Assessment of tissue fluid histamine levels in patients with urticaria. J Allergy Clin Immunol 1978; 61:350-354. Rorsman H. Basophilic leucopenia in different forms of urticaria. Acta Allergol 1962; 17:168-184 Leznoff A, Josse RG, Denburg J, et a!. Association of chronic urticaria and angioedema with thyroid autoimmunity. Arch Dermatol 1983; 119:636-640. Leznoff A, Sussman GL. Syndrome of idiopathic urticaria and angioedema with thyroid autoimmunity: a study of 90 patients. J Allergy Clin Immunol 1989; 8466~71. Zauli D, Grassi A, Ballardini G, et a!. Thyroid autoimmunity in chronic idiopathic urticaria, Am J Clin Dermatol 2002; 3:525-528. Grattan C. Powell S, Humphreys F. Management and diagnostic guidelines for urticaria and angioedema. Br J Dermatol 200 I; 144:708-714. O'Donnell BF, O'Neill CM, Francis DM, et a!. Human leucocyte antigen class 2 associations in chronic idiopathic urticaria. Br J Dermatol 1999; 140:853-858 Greaves MW, Plummer YM, Mc Laughlan P, Stanworth DR. Serum and cell bound IgE in chronic urticaria. Clin Allergy 1974: 4:265-27 I. Sabroe RA, Francis DM, Barr RM, et a!. Anti-Fet'RI autoantibodies and basophil histamine releasability in chronic idiopathic urticaria. J Allergy Clin Immunol 1998; 102:651-658. Gruber BL, Baeza ML, Marchese MJ, et a!. Prevalence and functional role of anti-igE autoantibodies in urtiC:1rial syndromes. J Invest Dennatol 1988; 90213-217 Marone G, Casolaro Y, Pganelli R, Quinti l. IgG anti-lgE from atopic derma ti lis ind uces med ia tor release from basoph i1s and mast cells. J Invest Dermatol 1989: 3:246-252 MacDonald SM, Rafnar T, Llngdon J, Lichtenstein LM. Molecubr identification of an IgE dependent histamine releasing factor. Science 1995: 2696R8-690
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Sabroe RA, Poon E, Orchard G, et al. Cutaneous inflammatory cell infiltrate in chronic idiopathic urticaria: comparison of patients with and without anti-FceRl or anti-IgE autoantibodies. J Allergy Clin Immunol 1999; 103: 484-493 Ying S, Kikuchi Y, Meng K, et al. Th IjTh2 cytokines and inflammatory cells in skin biopsy specimens from patients with chronic idiopathic urticaria: comparison with the allergen-induced late phase reaction. J Allergy Clin Immunol 2002; 109. Sabroe RA. Grattan CEH, Francis DM, et al. The autologous serum skin test: a screening test for autoantibodies in chronic idiopathic urticaria. Br J Dermatol 1999; 140446-452 Tanus T, A tkins pc, Zweiman B. Comparison of serum histamine releasing activity and clinical manifestations of chronic urticaria. Clin Diagn Lab Immunol 1996; 3:135-137. Zweiman B, Valenzano M, Atkins Pc. Modulation of serum histamine releasing activity in chronic idiopathic urticaria. Immunopharmacology 1998; 39225-234. Zweiman B, Valenzano M, Atkins Pc. et al. Characteristics of histamine releasing activity in the sera of patients with chronic idiopathic urticaria. J Allergy Clin Immunol 1996; 98:89-98. Asero R, Tedeschi A, Lorini M, et al. Chronic urticaria novel clinical and serological aspects. Cli n Exp Allergy 200 I; 3 I:1105-11 10 Kern F, Lichtenstein L. Defective histamine release in chronic urticaria. J C1in Invest 1976; 57:1369-1377 Lichtenstein LM, Mac Glashan DW. The concept of basophil releasability. J Allergy Clin Immunol 1986; 77:291-294. Grattan CEH, Walpole D, Francis DM, et al. Flow cytometric analysis of basophil numbers in chronic urticaria: basopenia is related to serum histamine releasing activity. Clin Exp Allergy 1997; 27: 1417-1424. Grattan CEH, Sabroe RA. Greaves MW. Chronic urticaria J Am Acad Dermatol 2002; 46:645-657 Grattan CEH, O'Donnell BF, Francis DM et al. Randomised double blind study of cyclosporin in chronic idiopathic urticaria. Br J Dermatol 2000; 143365-372 Greaves MW. Chronic urticaria. J Allergy Clin Immunol 2000: 105: 664-672 O'Donnell BF, Black AK. Urticarial vasculitis. Int Angiol 1995: 14:166-174. Greaves MW. Food intolerance in urticaria and angioedema and urticarial vasculitis. In: BrostolT J, Challacombe S, eds. Food Allergy and Intolerance. 2nd ed. Philadelphia: WB Saunders 2002:623-629. Henz BM, Zuberbier T. Causes ol'urticaria. In: Henz B, Zuberbier T. Grabbe 1. Monroe E. eds. Urticaria Clinical Diagnostic and Therapeutic Aspects. Berlin Heidelberg: Springer Verlag, 1998: 19. Michaelsson G, .Juhlin L. Urticari~l induced by preservatives and dye additives in food and drugs. Br.J Dermatol 197:\; 88:525-532.
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Doeglas HMG. Reactions to aspirin and food additives in patients with chronic urticaria including the physical urticarias. Br J Derlllatol 1975; 93: 135-144. 56. Supramanian G. Warner JO. Artificial food additive intolerance in patients with angioedema and urticaria. Lancet 1986; 2:907-910. 57. Mathews KP. Urticaria and angioedema. J Allergy C1in Illlmunol 1983; 72: 1-14. 58. Kaplan AP. Finn A. Autoimmunity and the aetiology of chronic urticaria. Can J Allergy C1in Immunol 1999; 4:286-292. 59. Kaplan AP. Chronic urticaria and angioedema. N Engl J Med 2002; 346: 175-179. 60. Greaves MW. Chronic idiopathic urticaria and Helicobacter pylori: not directly causative but could there be a link? ACI Int2001; 13:23-26. 61. Burova GP. Mallet AI. Greaves MW. Is Helicobacter pylori a cause of chronic urticaria? Br J Dermatol 1998; I 39(Suppl 51 ):42. 62. Bindslev-Jensen C, Finzi A, Greaves MW, et al. Chronic urticaria: diagnostic recommendations J Eur Acad Dermatol Venereol 2000; 14: 175-180. 63. Kozel MMA, Moein MCA, Mekkes JR, et al. Evaluation of a clinical guideline for the diagnoses of physical and chronic urticaria and angioedema. Acta Derm Venereol 2002; 82:270-274. 64. Schnitzler L. Lesions urticariennes chroniques permanents (erythellle petaloide?). Case cliniques n.46B Journee Dermatologique d'Angers. 1972, Oct. ~8 (Abstr. 46) 65. Greaves MW. Pathophysiology of chronic urticaria. lnt Arch Allergy Appl Immunol 200~; 127:3-9.
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15 Chronic Urticaria: General Principles and Management Clive Grattan West Norwich Hospital, Norwich, United Kingdom
I.
DEFINITION AND CLINICAL SPECTRUM
Urticaria becomes chronic when wheals fluctuate daily or almost daily for 6 weeks or more. Angioedema may also occur. In practice, there is a wide spectrum of clinical presentations of chronic urticaria. It may occur continuously for long periods or daily for a few days and then not for a week or two. When continuous urticarial activity is punctuated by gaps of several weeks or months, it is better called episodic, (or recurrent). Recognizing this pattern may be helpful in identifying an external trigger. It is also not uncommon to hear of previous episodes of chronic urticaria in patients who have undergone remission, followed by relapse years later. It is usual for wheals to occur anywhere on the body and they may be very numerous. On occasions, however, they may be relatively localized, such as predominantly above or below the waist or on the head and neck. This might suggest an external precipitant, especially with the physical urticarias. Some patients describe a few large wheals several centimeters in diameter at anyone time; others describe multiple papular wheals, with or without coalescence. The morphology of wheals is not often diagnostic but may be helpful in the physical urticarias, such as the linear wheals of dermographism or the pale papules and surrounding erythema of cholinergic urticaria. Angioedema is described commonly by patients with chronic urticaria. The term refers to deep swellings of the skin and mucosa and is not specific for any pattern of urticaria. There is sometimes
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Table 1 Clinical Classilication of Chronic Urticaria
Ordinary urticaria Idiopathic Autoimmune Drug and diet-related Infection-related Physical urticarias Symptomatic dermographism Cold urticaria Cholinergic urticaria Delayed pressure urticaria Others Urticarial vasculitis
difficulty in differentiating wheals from angioedema; for instance. the deep dermal swellings of delayed pressure urticaria or wheals affecting the face. Angioedema without wheals, on the other hand, tends to be episodic rather than continuous and is worth differentiating from angioedema with wheals, because some of these patients will have hereditary angioedema. The term chronic urticaria makes no assumption about its cause. The cause(s) of individual cases can be difficult, if not impossible. to define in the clinic. It is therefore useful to have a structure for classifying patients' conditions on the basis of their history, simple investigations, and challenge tests as shown in Table I. The physical urticarias (Chap. 8) and urticarial vasculitis (Chap. 18) are reviewed in other chapters. The remainder of this article will review other presentations of chronic urticaria, grouped together under the collective term "chronic ordinary urticaria," which defines about 70% of the patients presenting with continuous urticaria for 6 weeks or more. "Ordinary" urticaria describes the condition found is a grouping of patients with similar clinical features and implies nothing about its cause.
II.
CAUSES AND ASSOCIATED CONDITIONS
In many patients a specific cause remains indellnable after full evaluation and the term "idiopathic" is often used to reflect this. Current understanding of the etiopathogenesis of chronic ordinary urticaria does. however. allow two statements to be made with reasonable confidence. First. allergy is probably never the c~lLIse or chronic urticaria (but may cause acute urticaria). Second. autoimmunity probably accounts ror Copyrighted Material
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Chronic Ordinary Urticaria: Causes, Associations, and Aggravating
Causes "Idiopathic" Autoimmunity (histamine-releasing ;lutoantibodies) ? Pseudoallergens (diet and drugs) .) Infections (e.g., chronic dental abscess, H. p.1'/ori gastritis, intestinal parasites) Associations: Thyroid autoimmunity Aggra va ti ng factors Drugs (especially NSAIDs) Physical (overheating, local pressure, and rubbing) Dietary pseudoallergens (especially additives, salicylates) Alcohol Viral infections (e.g., adeno, rhino-, and enteroviruses) ? Stress
up to 50% of cases of chronic ordinary urticaria (although there are still no simple tests available in the clinic to prove it). The natural history of spontaneous resolution of chronic urticaria adds to the uncertainty regarding the relationship among possible causes, such as drugs, diet, and infections. Very few so-called associations with urticaria proposed in the past have been validated by large, properly conducted epidemiological studies. Only thyroid autoimmunity (1-4) has emerged convincingly frol11 several studies. External influences, such as dietary pseudoallergens, drugs, viral infections, and, perhaps, stress, may trigger exacerbations even when they are not the primary cause. Efforts should be made to identify them by thorough history-taking and investigation to ameliorate disease activity when possible. A structure for thinking about the causes, associations, and influences that aggravate chronic ordinary urticaria is shown in Table 2.
A.
Autoimmunity
There is now considerable evidence that functional and nonfunctional autoantibodies are detectable in the blood of up to 50% of patients with chronic ordinary urticaria (5-8). Debate continues about the importance of nonfunctional autoantibodies to the high-affinity IgE receptor (FccRI) on mast cells and basophils (9), but there can be no doubt about the biological activity of autoantibodies that release histamine from them in vitro. A minority of the chronic urticaria sera studied have functional anti-IgE autoantibodies (10). There is evidence that some patients who do not show histamine release on the basophil assay may nevertheless have l1onantibody
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histamine-releasing factors (II), which may be important in the pathogenesis of urticaria, although the nature of these remains uncertain. The lack of a simple reproducible functional assay has hampered evaluation of autoimmunity in the clinic and the overall understanding of the contribution of autoimmunity as a cause of urticaria. The absence of clear, identifying clinical differences between antibody-positive and antibody-negative patients adds to the difficulty of differentiating autoimmune from nonautoimmune urticaria. Supporting evidence for an autoimmune background comes from a highly significant association of human leukocyte antigen (HLA)-DR4 and its associated allele DQ8 with those chronic urticaria patients showing histamine-releasing activity but not those without (12). The concept of autoimmune urticaria as a subgroup of ordinary urticaria is presented in more detail in Chapter 14.
B.
Dietary Pseudoallergens
Many published accounts attest to the clinical contributions of food additives and salicylates to the activity of chronic urticaria and, more recently, aromatic substances in tomatoes and herbs have been mentioned (J 3). There is, however, no convincing laboratory evidence that dietary pseudoallergens cause histamine release or have a direct causative role in the condition. There is, however, increasing evidence that dietary pseudoallergens may aggravate existing chronic urticaria, analogous perhaps to the adverse effect of nonsteroidal anti-inflammatory drugs (NSAIDs). Intolerance of dietary pseudoallergens appears to be important in patients with and without functional autoantibodies (14), suggesting that the expression of urticaria could be under the combined influence of several factors at once in a predisposed individual.
C.
Infections
The old literature on chronic sepsis as a cause of urticaria is likewise largely based on uncontrolled series of reports of patients with dental abscesses. Infection of the bowel by Calldida yeasts or Helicobacter gastritis has not been confirmed as a cause of chronic urticaria by placebo-controlled studies of eradication therapies. An association of viral hepatitis Band C has been shown for urticarial vasculitis but not ordinary urticaria. The short-lived urticarial rashes seen at the onset of some acute viral infections, including hepatitis B and infectious mononucleosis, do not progress to chronic continuous urticaria. Intestinal parasitosis as a cause of urticaria is rare in developed countries, but may be more prevalent in rural and underdeveloped co 111 m unities.
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Associations
An association between thyroid autoimmunity was first observed in 1983 (I) and subsequently confirmed in several larger studies (2-4). Whether thyroid autoimmunity is more likely to be seen in patients with chronic urticaria and autoimmune urticaria than those without demonstrable autoantibodies has not been properly addressed. However, the frequency of organ-specific autoimmune diseases (including thyroid disease, vitiligo, insulin-dependent diabetes mellitus, rheumatoid arthritis, and pernicious anemia) was found to be higher in patients with histamine-releasing autoantibodies than in those without (15). The relevance of thyroid autoimmunity to the pathogenesis of urticaria remains unclear, but there may be some indirect influence as evidenced by the occasional response of some clinically euthyroid patients to thyroxine supplementation. Although there have been individual reports of a wide range of malignancies in patients with urticaria, a large retrospective epidemiological survey from Sweden showed no evidence of an association with cancer (16).
E.
Aggravating Influences on Disease Activity
The cause of chronic ordinary may remain elusive to the clinician, but there are a number of potentially avoidable situations that tend to make it worse and can be identified by careful history-taking. These include diet, some drugs, alcoholic beverages, coincidental minor viral infections, overheating, local heat and friction, and, perhaps, severe emotional stress.
1.
Diet
Many patients with chronic ordinary urticaria attribute exacerbations of their urticaria to what they have eaten, but these reactions are very rarely immediate (within minutes) and commonly are not reproducible. Most patients are able to eat a full diet once their urticaria has gone into remission. There is persuasive evidence from challenge studies and dietary avoidance that pseudoallergens may be important for some patients (17), but probably for those with milder forms of disease. Pseudoallergic reactions to additives, natural salicylates, and aromatic compounds are almost certainly dose-related. Tables listing the estimated content of salicylate in fresh foods are available (18), but it is not known how much has to be ingested to precipitate an attack and it seems likely that this would be highly variable between and within individuals. Even when patients with chronic urticaria appeared to respond to a strict lowpseudoallergen diet, only 19% of them reacted adversely to challenge capsules containing food additives and salicylic acid (17). The trace amounts
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of additives present in most foods would be well below the threshold amounts in challenge capsules unless eaten to excess. Although some urticaria diets have emphasised avoidance of natural amines, the contribution of dietary histamine to ordinary urticaria activity is almost certainly negligible.
2.
Drugs
The most important drug group is the NSAIDs, including aspirin. It has been estimated that they aggravate the condition of 20-30% of patients with chronic ordinary urticaria during the active phase, but probably not in remission (19). The effect depends on the potency and dosage of the NSAID. It possibly relates to inhibition of prostaglandin E 2 (PGE 2 ), which inhibits imlllunological mast cell degranulation. or the production of cysteinylleukotrienes, which cause vasopermeability directly. Cross-reactivity between the NSAlOs is common although the selective COX-2 inhibitors may be safe to use instead (20). Aspirin and other NSAIOs are also an uncommon cause of acute urticaria and anaphylactoid reactions. The mechanism for this is unclear but does not seem to involve IgE. Aspirin may also be a cofactor with food and exercise in food- and exercise·induced anaphylaxis (21). Although caution is often advised with opiates in patients with chronic urticaria, the evidence for an adverse effect is largely indirect from in vitro studies of nonimlllunologically stimulated degranulation of mast cells and in vivo skin testing, with codeine (22). The relevance of these findings to chronic urticaria is less certain: clinical experience suggests that opiates can be taken safely by most patients. The high frequency of reports of penicillin reactions in some retrospective surveys (23,24) may relate to the frequency of use of this antibiotic and preferential recall by patients with urticaria, rather than a relative contraindication to its use. Properly controlled prospective studies are needed to resolve this but, again, clinical experience does not suggest that penicillin should be avoided generically in patients with urticaria unless they have a history of previous allergy.
3.
Physical Stimuli
Overlap between ordinary and physical urticarias is well-recognized, especially between chronic ordinary and delayed pressure urticaria: concurrence of these two clinical patterns may be as high as 40% (25). Notwithstanding this, many patients with active continuous urticaria feel that overheating and local pressure of belts or clothing elastic will aggravate their condition by encouraging the eruption of wheals.
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Alcohol
Alcoholic beverages appear to aggravate urticaria nonspecifically by encouraging vasodilatation and this effect is probably dosage-related. There have been reports of ethanol itself causing urticaria (26), presumably through direct release of histamine from mast cells and basophils, but this is probably rare. Allergic reactions to the basic fruit or grain and pseudoallergic intolerance of additives in the product could, in theory, contribute to exacerbations during chronic urticaria but would be unlikely. The concentration of histamine in wine does not relate to symptoms of wine intolerance. including urticaria (27). 5.
Viral Infections
It is common clinical experience to hear that urticaria is aggravated by minor upper respiratory or gastrointestinal viral infections, perhaps through upregulation of cytokines with the acute-phase response, leading to a temporary state of enhanced mast cell releasability. 6.
Stress
There is increasing interest in the interactions between the central and peripheral nervous systems as potential causes of disease (28). Pathways that promote urticaria through stress might be important, although any direct or indirect proof of this is lacking.
III.
DIAGNOSIS
Diagnosis is based primarily on the history of fluctuating itchy wheals and deeper angioedema swellings. Duration of individual wheals is usually less than 24 h. Outlining the wheals with ink or a ball point pen can be helpful to confirm this. The wheals of physical urticarias last less than I h. with the exception of delayed pressure urticaria. which may last for 24 h or longer. The wheals of urticarial vasculitis typically last for days because there is blood vessel damage as well as leakage. Discoloration of the wheals from blood loss into the skin and burning rather than itch may be other features Angioedema swellings often persist for more than a day. Systemic features are usually lacking in patients with ordinary urticaria of mild to moderate severity. although severe disease is often accompanied by nonspecific symptoms of malaise, lethargy. poor concentration, and, sometimes, indigestion. By contrast, systemic features can be expected in
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patients with urticarial vasculitis, including arthralgia, joint swelling, fever, headache, and abdominal pain. A skin biopsy is essential if urticarial vasculitis is suspected, since the diagnosis can only be confirmed histologically. Routine investigations are otherwise unnecessary to differentiate among the main categories of chronic urticaria, although simple challenge tests are helpful to confirm the physical urticarias. A comprehensive questionnaire with a complete blood count and erythrocyte sedimentation rate (ESR) produced a similar diagnostic yield to a full work-up including a full blood profile; x-ray studies of chest, sinuses, and teeth; skin biopsy; a 3 week elimination diet; and appropriate drug provocation tests in a recent study (29). Identification of the different subcategories of ordinary urticaria is more difficult and will depend on the facilities available. Unless research facilities can be accessed for basophil and mast cell histamine release studies, a diagnosis of autoimmune urticaria cannot be made with certainty. However, it has been shown that intradermal injection of the patient's own serum (the autologous serum skin test) offers a simple but time-consuming clinical test with a sensitivity of around 70% and a specificity of 80% for basophil histamine-releasing activity, when compared with a saline control injection at 30 min (30). Infection as a cause of urticaria should be sought with appropriate tests when indicated by the history. Dietary pseudoallergens as a cause or aggrava ting factor in chronic urticaria can only be confirmed clinically with an appropriate diet for 3 weeks to look for improvement. Blinded challenge capsules containing known pseudoallergens given during a period of relative disease quiescence can be used to look for exacerbations. Thyroid autoantibodies should not be sought routinely for the purpose of diagnosing urticaria but may be relevant if second-line treatment with thyroxine is considered after first line measures have failed. A scheme for investigations based on disease severity is summarized in Table 3.
IV.
MANAGEMENT
The initial management of chronic ordinary urticaria should be directed by results of a full clinical assessment. Management plans may be different for each patient. The key features of any plan should include treatment of any identifiable cause, avoidance of aggravating factors, advice and written information on the condition, nonpharmacological approaches for relieving symptoms, and a trial of antihistamines. Second-line approaches for patients who need more help include a range of interventions determined by results of investigations and clinical need. Third-line management
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Investigations for Chronic Urticaria
Antihistamine-responsive urticaria: none Chronic urticaria responding poorly to antihistamines Complete blood count and ESR in all patients Stool examination for ova, cysts, and parasites if peripheral blood eosinophilia is present with travel history Thyroid autoantibodies and thyroid function tests if second-line treatment with thyroxine considered Skin biopsy if urticarial vasculitis suspected clinically Severe disabling urticaria responding poorly to Arst and second-line therapies Autologous serum skin test, if possible Functional basophil and mast cell histamine-releasing assays, when available from specialist centers
Table 4
Management Plan for Chronic Ordinary Urticaria
Removal of any identiAed cause Avoidance of aggravating factors Advice and information Creams and lotions for symptomatic relief First-line drugs (antihistamines) Second-line interventions (as determined by the clinical situation) Third-line immunosuppressive therapies
for patients with the most severe and refractory disease may include immunosuppressive and immunomodulating therapies (Table 4).
A.
Avoidance of Aggravating Factors (18)
1.
Overheating
Higher skin temperatures may encourage wheals and itching. It is best to avoid very hot baths or showers. Wearing lighter clothes and avoiding strenuous exertion may be helpful.
2.
Pressure
Wearing comfortable, well-fitting clothes and footwear that does not rub may be an advantage. Walking long distances or carrying heavy bags should be avoided if this results in pressure-induced swellings over the next few hours.
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3.
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Stress
Mental stress may make urticaria harder to live with. Tbere is little medical evidence that worry or emotional problems cause urticaria in tbe first place, but it is common to hear tbat stressful events may aggravate it. One study suggested that the itch of urticaria. but not wheal severity, may respond to hypnosis with relaxation therapy (3\).
4.
Food
Dietary pselldoallergens include some food additives. natural salicylates (present especially in fruits, beer, and wine) and unidentified aromatic substances in tomatoes, herbs, and white wine (13). The best known artificial food additives are the azo dyes (EI02-l24) and benzoate preservatives (E210-219). Processed foods should be avoided if possible in favor of fresh foods without seasoning or spices. A strict low-pseudoallergen diet for 3 weekS initially may be helpful for some patients with mild chronic ordinary urticaria (17). It could be introduced as an alternative to antihistamines in well-motivated patients as well as, or in addition to, antihistamines if treatment with these agents fails.
5.
Alcohol
Patients with urticaria are commonly advised to avoid alcohol, but any adverse effect is difficult to predict. It probably depends on how much is drunk, how strong the ethanol content. and the content of pseudoallergens. Being overheated or excited at the same time as drinking alcohol may aggravate urticaria further.
6.
Drugs
Aspirin may be present in analgesics that are widely available in drug stores. The brand names of these products do not necessarily indicate their content, so it is important to check the package labelling carefully. It is ::llso important to avoid other NSAIDs, such as ibuprofen and diclofenac. unless they are essential and can be taken without causing symptoms. Opiates. including codeine and its derivatives. should also be avoided routinely. Acetominophen is usu:llly a suitable alternative.
B.
Advice and Information
A clear explanation that chronic ordinary urticaria is not allergic is often a useful starting point to address the inevitable conviction ma~y patients hold that the cause or their problem is dietary. Failure to address this
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point often leads to dissatisfaction that allergy tests are not offered immediately. Clearly written evidence-based information and advice sheets from professional organizations can offer patients helpful initial guidance on their condition. Cooling lotions can be soothing when wheals erupt and are at their most pruritic; these include 0.5-1°Ic, menthol in aqueous cream, calamine lotions, and 10% crotamiton lotion. Menthol- or alcohol-containing lotions may sting broken or eczematous skin. Antihistamine creams are widely used in the community but poor cutaneous absorption limits their pharmacological effectiveness. Topical steroids are of no value in routine clinical practice, although it has been shown that regular applications of a very potent steroid to localized areas of skin will reduce the wheal response to pressure, presumably through cutaneous mast cell depletion (32).
c.
First-line Antihistamine Therapy
Antihistamines are the first-line treatment for all patients with chronic urticaria. The subject is covered fully in Chapter 16. The three main groups of antihistamines that may be used singly or in combination are the classic sedating HI-antihistamines, of which chlorpheniramine, hydroxyzine, and diphenhydramine are typical examples; the nonsedating second-generation HI-antihistamines and their derivatives; and the H 2 -antihistamines (Table 5). Antihistamines with theoretical mast-cell-stabilizing properties, such as ketotifen, or antiserotoninergic effects, such as cyproheptadine, offer no routine advantage to classic antihistamines for the treatment of chronic urticaria and are now seldom used. Treatment should be started with a nonsedating antihistamine at the licensed dosage taken at the same time each day. It is clinical experience that some patients do better with one product than another and their
Table 5 Use of Antihistamines in Chronic Ordinary Urticaria Classic (sedating) HI-antihistamines: chlorpheniramine, hydroxyzine, diphenhydramine. trimeprazine, promethazine Nonsedating second-generation HI-antihistamines: loratadine, b cetirizine, terfenadin", mizolastine Second-generation H I-anti histamine deriva tives: desloratadi ne, levocetirizine, fexofenadine Hrantihistamines: cimetidine. ranitidine, nizatadine "Only available as a generic named-patient product. bOnl y licensed for use in Europe.
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response may vary over the course of their disease, but there is probably little to choose between at licensed dosages. It has become common practice to double or even triple the dosage of nonsedating antihistamines for patients who respond poorly on the grounds that there may be additional antiallergic effects at these higher dosages (33), but the incremental benefit from doing so is usually slight. My own preference is to add an H 2antihistamine at full dosage since H 2 receptors have been demonstrated in the skin (34). This combination treatment often helps the indigestion that commonly accompanies more severe urticaria and may reduce wheal severity but not itch. Adding a sedating HI-antihistamine at night is logical if sleep is disturbed by itch and may lead to better control of the urticaria. However, long-acting products, such as trimeprazine, may have a carryover effect of sedation the following morning. Classic sedating antihistamines may be effective for some patients when taken regularly if nonsedating antihistamines do not work. Tolerance to sedation may develop, although impairment of performance must still be considered when planning treatment. A recent meta-analysis of studies comparing diphenhydramine with second-generation antihistamines used for the treatment of atopic disorders was unable to demonstrate a consistent difference between them in sedation and performance impairment (35).
D.
Second-line Therapies
1.
Antihistamines
Sixty percent of patients with chronic urticaria responded well or reasonably well to antihistamines but 40% derived little or no benefit from them in a retrospective case-note analysis from a secondary referral center (24). The challenge of helping these patients with nonresponding disease requires a thorough knowledge of the literature on alternative therapies that might be appropriate in specific circumstances and of the drugs themselves, which are often used outside their product licences and may carry an appreciable side-effect profile. The most commonly used drug therapies are listed alphabetically in Table 6, although the list is not exhaustive.
2.
Doxepin
Doxepin has been used as a treatment for urticaria since the 1980s. It has very powerful properties of an antihistamine but is better known as a tricyclic antidepressant. The dosages of doxepin used for the treatment of depression are usually much higher than those for urticaria. There is unlikely to be any mood-lifting effect when taken in this way, although it may be helpful if depression is also a problem. Doxepin is worth trying
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Table 6 Second-Line Drug Treatments of Chronic Ordinary Urticaria () 0
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Drug name
Drug class
Dosage range
Indication
Doxepin Epinephrine M onlelukast
10-50 Illg daily 300-500 pg 1M 10 mg daily
Nifedipine Prednisolone
Tricyclic antidepressant Sym pa thoillimetic Leukotriene receptor anlagonist Calcium antagonist Corticosteroid
Sulfasalazine
Sulfonamide
2-~
Thyroxine
Thyroid replacement
50-150 ~lg daih
Depression Angioedema of the throat Aspirin-sensitive urticaria and some ordinary and pressure urticaria Hypertension Severe flares (davs onlv) and delayed pressure urticaria Delayed pressure urticaria and some ~teroid-dependenl urticaria Thyroid autoimlllunity
Q.
s: Q)
~
I 5-60 mg daily 10-lOlllg daily g daily
en
to)
t11 t11
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if nonsedating antihistamines fail to help and may be most valuable when taken at night if patients' sleep is disturbed by itching or urticaria. a. Efficac)'. Doxepin was more effective than diphenhydramine at a dosage of 10mg three times a day (36) and as effective as mequitazine at 5 mg twice daily (37). It has not been compared to nonsedating antihistamines.
b. Dosuge alld Duratioll of Treatment. It is best to start at a low dosage, such as 10 mg daily, and work upwards to 20 or 30 mg daily. This can be either be taken as a single dose at night or divided into two or three smaller doses over the day. The highest daily dosage recommended for depression is 300 mg with a maximum single dosage of 100 mg, but these very high levels are probably never appropriate for patients with urticaria. There is no time limit to taking doxepin if it helps. c. Drug Interac/ions. One of the disadvantages of doxepin is the high number of possible interactions with other medicines (and alcohol). These include other antidepressants. some analgesics (e.g., tramadol), antiarrhythmics (e.g., amiodarone), anticonvulsants, and antihypertensives (e.g., diltiazem). A few treatments that may be used for urticaria, such as epinephrine and cimetidine, should be avoided in combination with dexepin if possible. d. Side Effects. Doxepin should not be taken after a recent myocardial infarction or by patients with severe liver disease. It should be used with caution in pregnant women and in the elderly since it may precipitate confusion, agitation, glaucoma, and urinary retention. Sedation is the most common unwanted effect. A dry mouth and blurring of vision are more likely as the dosage increases. Other side effects may include constipation. prostatism, postural hypotension, increased appetite, rashes and, rarely, bone marrow depression.
3.
Epinephrine
a. Elficael'. There is no recent literature on epinephrine because it is of clinically proven valuc for severe angioedema. except in hereditary angioedema. Its use should be restricted to life-threatening situations such as swelling of the larynx, which is rare in patients with chronic urticaria.
b. Dosage ulld il1ethod (~f Adlllinisiratioll. The most common method used by adults for self-administration is the Epipen containing 300 ~lg epinephrine. There is also a Junior Epipen for children weighing
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15-30 kg, which delivers 150 ~lg. A second injection may be necessary if the swelling has not started to go down within 10 min. An epinephrine puffer spray (Primatene Mist) is available on a named-patient basis in the United States for treatment of asthma and may be used for treatment of angioedema of the throat as an unlicensed indication. The aerosol should be puffed 5-10 times direct I)' onto the swelling ifl the throat and not inhaled (as directed for asthma attacks). The same number of puffs can be repeated after 5-10 min. An epineepinephrine injection can still be given if the swelling worsens despite the use of inhaler. c. Drug JnleraClions. Epinephrine may cause increased blood pressure, anxiety, shaking, and pallor. These effects wear off within an hour and usually present no problems. However, they may precipitate angina or stroke by a rapid increase in blood pressure in patients at risk, especially those with hypertension, ischemic heart disease, and concurrent treatment with tricyclic antidepressants (e.g., amitryptilene, doxepin, trimipramine) and {i-blockers (e.g., propranolol, atenolol).
d. Side Effects. The main side effects are anxiety, tremor, tachycardia, headache, and cold extremities. These are unimportant when epinephrine is used for emergencies because the drug may be life-saving. It should only be used when essential in patients with heart disease, high blood pressure, and stroke. 4.
Montelukast
The development of leukotriene receptor antagonists for asthma has provided an opportunity to try these medicines for subgroups of patients with chronic ordinary urticaria whose condition respond~ poorly to antihistamines. In theory, these subgroups might include patients in whom leukotrienes are considered to be an important mediator of whealing or there is a delayed component to the urticarial response, in which eosinophil and basophil infiltrates are prominent.
a. Efficacy. Leukotriene receptor antagonists do not help all types of urticaria. The most encouraging results have been seen in patients with aspirin-sensitive urticaria (38). Montelukast may also help some patients with chronic ordinary urticaria when taken with an antihistamine (39). Zafirlukast does not appear to be effective for the treatment of chronic urticarias (including dermographism) (40).
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seen within I week but accrues over 6. There is no limit to the duration of treatment. C. Drug Interactions. drug interactions.
There are no currently recognized important
d. Side Effects Gastrointestinal disturbances, dry mouth, thirst, asthenia, sleep disorders, fever, arthralgia, and myalgia may occur but are unpredictable. Urticaria, angioedema, and anaphylaxis have been reported but montelukast has not been shown to aggravate existing urticaria. 5.
Nifedipine
Nifedipine is a calcium channel-blocking drug licensed for use in the control of hypertension, the prevention of angina, and treating Raynaud's phenomenon. Lt may have clinically useful mast-cell-stabilizing properties through inhibiting the intlux of calcium required for degranulation. Despite early promise based on clinical studies, nifedipine has not lived up to expectations and is now used infrequently. It can be considered for patients with urticaria who also need an antihypertensive or treatment for vasospasm when treatment with antihistamines has been disappointing. Other calcium antagonists (such as amlodipine, diltiazem, verapamil) have not been tested.
a. EjficacI'. The first encouraging report was a placebo-controlled study of nifedipine in patients with disease unresponsive to antihistamines (41). Most patients took 10 mg three times a day for 4 weeks. The number of wheals and itch intensity both were during nifedipine treatment but not placebo. The second study compared nifedipine 10 mg four times a day with chlorpheniramine. Both treatments were helpful. with little difference between them (42). Nifedipine has not been compared with a nonsedating antihistamine. b. Dosage Clnd Duralion of Treall77ent. Nifedipine should be started at a dosage of 5 mg three times a day, titrating up to 20 mg three times a day. Higher dosages than this often cause adverse effects. c.. Drug Interactions 1I'itll Olher Medicines. The antihypertensive effect of nifedipine may be enhanced by cimetidine. Grapefruit juice may affect its metabolism and should be avoided. d. Side Effects. Nifedipine should not be started within a month of a heart attack or after recent angina. The most likely side effects are headache, tlushing, dizziness, ankle swelling, and an exaggerated fall in blood pressure,
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Prednisolone
Prednisolone has predominantly glucocorticoid activity and is the corticosteroid most commonly used by mouth for long-term disease suppression.
a. Efficacy. There are few published studies of steroids for the treatment of urticaria because they were introduced many years ago and are indisputably effective. They should only be used continuously in exceptional circumstances, such as disabling delayed pressure urticaria that does not respond to other measures or urticarial vasculitis (see Chap. 18). Short-term use for the treatment of acute exacerbations of chronic ordinary urticaria may be necessary. b. Dosage and Length 01 Treatment. Taking steroids at a relatively high dosage (e.g., prednisolone 30-40 mg) for 1-3 days can be very helpful for the most severe attacks of urticaria or angioedema. Low-dosage alternate-day dosing may be safe and effective when applied with care to patients with chronic urticaria whose conditions does not respond to other steroid-sparing measures (43). c. Drug Interactions. The only interactions are with aspirin and other NSAIDs, leading to an increased risk of bleeding and ulceration of the gu t.
d. Side Eflecr.s. Steroids should be used with care in patients with diabetes and in those with stomach ulcers, high blood pressure, and osteoporosis. A temporary increase of steroid dosage should be given at the time of any significant intercurrent illness, trauma, or surgical procedure. Prolonged courses of corticosteroids increase susceptibility to and severity of infections. Patients who have not had chickenpox should be regarded as being at risk of severe lllfection. Immunization with varicella-zoster hyperimmune serum is recommended for exposed nonimmune individuals within 3 days of exposure and no later than 10 days, or those who have been taking chronic treatment within the previous 3 months. Numerous potential adverse effects include well-known gastrointestinal, musculoskeletal, endocrine, neuropsychiatric, and cutaneous hazards. 7.
Sulfasalazine
Sulfasalazine is based on a long-acting sulfonamide, sulfapyridine, and a derivative of salicylic acid, 5-aminosalicylate. The sulfonamide component is regarded as a carrier molecule when sulfasalazine is used for its licensed indications, ulcerative colitis, or Crohn's disease. It is also licensed for the treatment of rheumatoid arthritis.
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a. Efficacy. Sulfasalazine may be effective for the treatment of delayed pressure urticaria on its own (44) or to reduce the dosage of steroids needed to control it. It has also been reported anecdotally for the treatment of steroid-dependent chronic ordinary urticaria (45) but is rarely used for this purpose and may exacerbate it in some patients. b. Dosage and Length of Treatment. A usual starting dosage might be I g twice daily, increased by 500 mg daily at intervals of 2 weeks to a maximum regular dosage of 4 g (eight tablets) daily. A complete blood count, glucose-6-phosphate dehydrogenase, assay, as well as liver and renal profiles should be checked before starting therapy. A blood count and liver and renal function should be checked monthly for the first 3 months, and then every 3 months. c. Drug Interactions. methotrexate.
Sulfasalazine should
not be taken
with
d. Side Effects. Sulfasalazine should be avoided in patients with a previous history of hypersensitivity to sulfonamides or aspirin. It should only be used by patients who are pregnant or breastfeeding if there is no alternative. A wide range of adverse effects have been described including anemia, rashes including Stevens-Johnson syndrome and exfoliative dermatitis, alopecia, loss of appetite, fibrosing alveolitis, stomatitis, aseptic meningitis, peripheral neuropathy, depression, dizziness, and reduced sperm counts. The urine may be colored orange and some soft contact lenses may be stained. 8.
Thyroxine
a. Efficacy. In the first open study, seven biochemically euthyroid patients with thyroid autoimmunity responded to thyroxine treatment for 4 weeks initially. Five needed treatment for at least a year because the initial response disappeared when thyroxine treatment was stopped. The other two patients' conditions improved over 4 weeks and remained clear (46). In the second study, 17 of 18 IXltients responded to thyroxine (47). Clinical experience nevertheless suggests that a response to thyroxine is unpredictable and that other treatment, including antihistamines, is often necessary. b. Dosage and Dllralian af Trf:'almf:'nl. The dosage of thyroxine used in the studies varied from as little as 50 pg to as much as 250 pg daily. A starting dosage of 1.7 ~lg/kg body weight has been recommended (48) although lower dosages should bc considered in the elderly. Thyroid function tests should be done before starting and rechecked after 4-6 weeks
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to ensure that thyroid-stimulating hormone levels have not been suppressed below normal. Treatment should be stopped after 8 weeks if the urticaria has not improved. If urticaria does respond, the thyroxine should be stopped after 1-2 months. Further courses may be given. c. Drug InTeractions. There are few clinically important interactions. The effect of warfarin and phenindione may be enhanced. Carbamazepine, phenytoin, and rifampicin increase the metabolism of levothyroxine. An increased dosage of antidiabetic drugs (including insulin) may be necessary.
d. Side EflecTs. The main contraindication is thyrotoxicosis Side effects do not occur at normal dosages but excessive thyroid replacement may result in angina, palpitations, rapid heartbeat, tremors, excitability, sweating, nushing, and weight loss 9.
Others
Other interventions for which there is fair evidence of effectiveness include narrow-band phototherapy (49) and warfarin (50).
E. Third-Line Treatments The arguments for using immunotherapy for the most refractory and disabling cases of chronic urticaria were strengthened substantially by the recognition that some patients have circulating functional autoantibodies. Most of the early trials looked at patients with evidence of autoantibodies in vitro using the basophil histamine-release assay and the autologous serum skin test as an in vivo marker of histamine-releasing factors. The demonstration that urticaria activity could be abolished for up to a month by plasmapheresis (51) supported the concept of an autoimmune subset of urticaria. Further trials of cyclosporin A and intravenous immunoglobulin (IVIG) in patients with evidence of autoimmune urticaria have strengthened the view that immunosuppressive therapies may be of value for this subgroup. Clinical experience has, however, shown that some severely affected patients without formal evidence of autoimmune urticaria may also respond to immunotherapies. Interest is returning to methotrexate as a useful long-term therapy for some patients because of its establisbed use in dermatology for the treatment of psoriasis and its generally favorable safety profile. It should be remembered that none of the above immunotherapies are licensed for the treatment of urticaria.
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1. Cyclosporin It is a powerful inhibitor of both cell-mediated and humoral responses. Most of the immunosuppressive effects are a consequence of inhibition of interleukin-2 and other cytokines from activated TH, lymphocytes. It also inhibits the release of histamine from basophils and tumor necrosis factoralpha (TNF-a) production by mast cells.
a. Efficacy. There have been several studies of cyclosporin in severe chronic ordinary urticaria (52-55) showing that about two-thirds of patients experience clearing of disease treatment but the condition often relapses on stopping treatment. Only about one-quarter of the responders were still clear 6 months later after treatment at 4mgjkgjday for a month (54). Relapses occurred more frequently in patients treated for 8 than 16 weeks in a large multicenter study using a higher initial starting dosage of 5 mgjkgjday (55). b. Dosage and Length of Treatment. There is still some discussion about the best dosage of cyclosporin and how long it should be taken for. My preferred protocol is 4 mgjkgjday for 4 weeks, reducing to 3mgjkgjday for 6 weeks and then 2 mgjkgjday for a final 6 weeks, unless there is a reason to change the dosage during treatment. More than I course of cyclosporin may be given, although it is probably better to look at other therapies if this proves necessary. Long-term treatment with cyclosporin for over a year should only be undertaken when there is no reasonable alternative because of concerns about increased risks of infection and lymphoma. c. Drug Interactions. There is a wide range of possible interactions. These can be grouped into drugs that increase blood levels of cyclosporin, those that reduce blood levels, and drug levels that are affected by cyclosporin. Increased blood levels may be seen with anabolic steroids (danazol), allopurinol, some antibiotics (macrolides), antiarrhythmics (amiodarone), antifungals (ketoconazole, itraconazole), antimalarials (chloroquine), calcium channel blockers (diltiazem, verapamil), progestagens, and grapefruit juice. Decreased levels of cyclosporin may be seen with anticonvulsants (phenytoin, carbamazepine) and St John's wort. Cyclosporin may increase levels of diclofenac and prednisolone. There is an increased risk of nephrotoxicity with NSAfDs, aminoglycosides, cotrimoxazole, quinolones, and cytotoxics, and of myopathy with the slatins. d. Side Eftecrs. The main contra indications are impaired kidney function, uncontrolled blood pressure, active serious infections, and cancers.
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Symptomatic adverse effects include slight tremor, burning sensations of the hands and feet, swelling of the gums, nausea, muscle weakness, missed menstrual periods, and increased facial hair growth, which all normalize when treatment is stopped. The effectiveness and safety of some immunizations may be reduced and live vaccines should not be used for 3 months after stopping treatment.
2.
Intravenous Immunoglobulin
IVIG is a concentrated preparation of immunoglobulins from healthy donors. it is mainly used for patients with humoral immune deficiencies. It is also licensed for the treatment of idiopathic thrombocytopenic purpura, Kawasaki syndrome, and Guillan-Barre syndrome. It may reduce the formation of pathogenic autoantibodies but the exact explanation for its efficacy in the treatment of urticaria remains uncertain.
a. Elf/cac)'. The only published evidence of IVIG for the treatment of urticaria is a study of 10 patients with disabling autoimmune chronic urticaria (56). Nine of the 10 patients felt better after the infusion but only five cleared completely. The urticaria came back in three of them within 6-20 weeks but remained clear for at least 3 years in two. The study has not been repeated using different groups of patients with urticaria, different dosages of IVIG, or compared against placebo. b. Dosage and Length oj Treatment. IVfG is given daily by slow infusion over 5 days in hospital at 0.4 g/kg body weight per day, making a total cumulative dose of 2 g/kg. Further courses can be given but there is no published information on this. IgA deficiency must be excluded before starting treatment because there is a risk of incompatibility reactions between natural anti-IgA antibodies and IgA from the blood of the IVIG donors. c. Drug Interactions. There are no known interactions with other medicines, although it would be usual to reduce or stop other treatments affecting the immune system. Antihistamines can be taken safely at the same time as IVIG.
d. Side Effects. Blood pressure may fall rapidly during infusions. Less severe side effects include headache, nausea, sweating, chest pain, muscle and joint aches, and fever. These relate to the speed of infusion and usually improve soon after slowing or stopping it. Like all blood products, there is always a slight concern about transmission of infections from IVfG. Copyrighted Material
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3.
Grattan
Methotrexate
Methotrexate is a derivative of folic acid that interferes with dihydrofolate reductase and the production of DNA in actively dividing cells. It is also a potent inhibitor of polymorphonuclear leukocyte chemotaxis and inhibits the secretion of TNF-O', interleukin-6, and interleukin-8 by monocytes and macrophages (57).
a. Ellicac)'. There have only been a few reports of methotrexate being used successfully for the treatment of chronic urticaria (58,59). No controlled studies comparing it against placebo have been published yet. Clinical experience has shown that it may be valuable for selected patients with urticaria who do not respond to treatment with antihistamines and are otherwise steroid-dependent. b. Dosage and Length of Treatment. A low test dosage of methotrexate may be given before starting regular treatment. It is essential to take methotrexate weekly rather than daily, as for psoriasis. The benefit is not immediate. There is no limit to the length of time methotrexate can be taken, provided that there are no complications. c. Dl'lIg Interactions. Aspirin and other NSAIDs (e.g .. ibuprofen, diclofenac, meloxicam) may reduce renal elimination of methotrexate and increase its levels. Some antibiotics (trimethoprim, cotrimoxazole, sulfonamides, and penicillins), sulfasalazine, and probenecid may increase the risk of toxicity. The antifolate effect is increased by pyrimethamine and phenytoin. Cyclosporin and acitretin should normally be avoided concurrently with methotrexate.
d. Side Eflects. Methotrexate should not normally be used in patients with an underlying blood disorder, reduced kidney function, persistent liver inflammation, peptic ulceration, or ulcerative colitis. The most important adverse effects are bone marrow suppression and hepatitis. Sore throats, mouth ulcers, or unusu::l1 bruising should be regarded as an important warning of possible bone marrovv suppression. Methotrexate should usually be stopped until a blood count is known. Pneumonitis may occur occasionally with prolonged treatment. Methotrexate should be stopped if breathlessness or persistent dry cough develops. Alcohol should be avoided completely if possible during treatment. Nausea may be a problem for a day or two after taking methotrexate in some people. but can be reduced by dividing the dose over 36 h and taking folic acid. Patients laking methotrexate should avoid pregnancy and fathering children and for 6 months after stopping treatment.
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REFERENCES I. 2.
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Leznoff A, Josse RG, Denburg J, Dolovich J. Association of chronic urticaria and angioedema with thyroid autoimmunity 1983; 119:636-640. Leznoff A, Sussman GL. Syndrome of idiopathic chronic urticaria and angioedema with thyroid autoimmunity: a study of 90 patients. J Allergy Clin [mmunol 1989; 84:66-71. Lanigan SW, Short P, Moult P. The association of chronic urticaria with thyroid autoimmunity. Clin Exp Dermatol 1987; 12:335-338. Turktas I, Gokcora N, Demirsoy S, Cakir N, Onal E. The association of chronic urticaria with autoimmune thyroiditis. lnt J Dermatol 1997; 36:187-190. Hide M, Francis DM, Grattan CEH, Hakimi J, Kochan JP, Greaves MW. Autoantibodies against the high affinity IgE receptor as a cause of histamine release in chronic urticaria N Engl J Med 1993; 328: 1599-1604. Niimi N, Francis DM, Kermani F, O'Donnell BF, Hide M, Kobza Black A, Winkelmann RK, Greaves MW, Bar RM. Dermal mast cell activation by autoantibodies against the high affinity IgE receptor in chronic urticaria. J Invest Dermatol 1996; 106:1001-1006. Fiebiger E, Hammerschmid F, Stingl G, Maurer D. Anti-FcsRla autoantibodies in autoimmune-mediated diseases. J Clin Invest J998; 101 :243-251. Ferrer M, Nakazawa K, Kaplan AP. Complement dependence of histamine release in chronic urticaria. J Allergy Clin Immunol 1999; 104: 169-172. Horn MP, Pachlopnik JM, Vogel M, Dahinden M, Wurm F, Stadler BM, Miescher SM. Conditional autoimmunity mediated by human natural antiFcsRlo: autoantibodies? FASEB J 200 J; J 5:2268-2274. Grattan CEH, Francis DM, Hide M, Greaves MW. Detection of circulating histamine releasing autoantibodies with functional properties of anti-IgE in chronic urticaria. Clin Exp Allergy 1991; 21 :695-704. Sabroe RA, Fiebiger E, Francis DM, Maurer D, Seed PT, Grattan CEH, Kobza Black A, Stingl G, Greaves MW, Barr RM. Classification of anti-FcsRI and anti-JgE autoantibodies in chronic idiopathic urticaria and correlation with disease activity. J Allergy C1in Jmmunol 2002; 110:492-499 O'Donnell BF, O'Neill CM, Francis DM, Niimi N, Barr RM, Barlow RJ. Kobza Black, Welsh KI, Greaves MW. Human leucocyte antigen class n associations in chronic idiopathic urticaria. Br J Dermatol 1999; 140: 853-858. Zuberbier T, Pfrommer C, Specht K, Vieths S, Basti-Borrmann R, Worm M, Henz BM. Aromatic components of food as novel eliciting factors of pseudoallergic reactions in chronic urticaria. J Allergy Clin Iml11unol 2002; 109343-348 Zuberbier T, Benz BM, Fiebiger E, Maurer D, Stingl G. Anti-FcsRla serum autoantibodies in different subtypes of urticaria. Allergy 2000; 55:951-954. Sabroe RA, Seed PT, Francis DM, Barr RM, Kobza Black A, Greaves MW. Chronic idiopathic urticaria: comparison of the clinical features of patients
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with and without anti-FcERI or anti-IgE autoantibodies. 1 Am Acad Dermatol 1999; 40443--450 16. Lindelbf B, Sigurgeirsson B, Wahlgren CF, Eklund G. Chronic urticaria and cancer: an epidemiological study of 1155 patients. Br 1 Dermatol 1990; 123453--456. 17. Zuberbier T, Chantraine-Hess S, Hartmann K, Czarnetzki BM. Pseudoallergen-free diet in the treatment of chronic urticaria. Acta Derm Vernereol (Stockh) 1995; 75484--487. 18. Swain AR, Dutton SP, Truswell AS. Salicylates in foods. 1 Am Diet Assoc 1985; 85:950-960 19. Grattan C. Aspirin sensitivity and urticaria. C1in Exp Dermatol 2003: 28: 123-127 20 Quiralte 1, Saenz de San Pedro B, Fernando Florido 11. Safety of selective cyclooxygenase-2 inhibitor rofecoxib in patients with NSAID-induced cutaneous reactions. Ann Allergy Asthma Immunol 2002; 89:63-66. 21. Harads S, Horikawa T, Ashida M, Kamo T, Nishioka E, Ichihashi M. Aspirin enhances the induction of type I allergic symptoms when combined with food and exercise in patients with food-dependent exercise-induced anaphylaxis Br 1 Dermatol 2001; 145:336-339. 22. Cohen RW, Rosentreich DL. Discrimination between urticaria-prone and other allergic patients by intradermal testing with codeine. 1 Allergy Clin Immunol 1986; 77802-807 23. luhlin L. Recurrent urticaria: clinical investigation of 330 patients. Br 1 Dermatol 1981; 104:369-381. 24. Humphreys F, Hunter .IAA. The characteristics of urticaria in 390 patients. Br 1 Dermatol 1998; 138:635-638. 25. Barlow Rl, Warburton F, Watson K, Kobza Black A, Greaves MW. Diagnosis and incidence of delayed pressure urticaria in patients with chronic urticaria. 1 Am Acad Dermatol 1993; 29: 954-958. 26. Stitcherling M, Brasch .I, Bruning, Christophel'S E. Urticarial and anaphylactoid reactions following ethanol intake. Br 1 Dermatol 1995; 132464--467 27. Kanny G. Gerbaux V, Olszewski A, Femont S, Empereur F, Nabet F, Cabanis l-e. Moneret-Vautrin D-A. No correlation between wine intolerance and histamine content of wine . .I Allergy Clin Immunol 2001; 107:375-378. 28. Esch T. Stefano GB, Fricchione GL, Benson H. An overview of stress and its impact in immunological disease. Mod Aspects Immunobiol 2002: 2187-192. 29. Kozel MA, Mek kes .I R, Bossuyt PMM. Bos .I D. The effectiveness of a historybased diagnostic approach in chronic urticaria and angioedema. Arch Dermatol 1998: 1341575-1580 30. Sabroe RA, Grallan CEH, Francis DM, Barr RM, Kobza B!Jck A. Greaves MW. The autologous serum skin tcst: a screening test for autoantibodies in chronic idiopathic urticaria. Br.l Derlllatol 1999; 140446--452. 31. Shertzer CL, Lookinbill DP. Elfects of rclaxation therapy and hypnotisability in clHonic urlicari~l. Arch Dermalol 1987; 123:913-916.
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32.
Barlow R.I, Macdonald DM, Kobza Black A, Greaves MW. The effects of topical corticosteroids on delayed pressure urticaria. Arch Dermatol Res 1995; 287285-288.
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Marone G, Genovese A, Granata F, Forte Y, Detoraki A, de Paulis A, Triggiani M. Pharmacological modulation of human mast cells and basophils. Clin Exp Allergy 2002; 32:1682-1689. Robertson I, Greaves MW. Responses of human skin blood vessels to synthetic histamine analogues. Br J Clin Pharmacol 1978; 5:319-322. Bender BG, Berning S, Dudden R. Milgrom H, Yu Tran Z. Sedation and performance impairment of diphenhydramine and second generation antihistamines: a meta-analysis. J Allergy C1in Immunol 2003; III :770-776. Greene SL, Reed CEo Schroeter AL. Double-blind crossover study comparing doxepin with diphenhydramine for the trcatment of chronic urticaria. J Am Acad Dermatol 1985: 12:669-675. Harto A, Sendagorta E, Ledo A. Doxepin in the treatment of chronic urticaria. Dermatologica 1985; 170:90-93. Pacor ML. Di Lorenzo G, Con'ocher R. Efilcacy of leukotriene receptor antagonist in chronic urticaria. A double-blind, placebo-controlled comparison of treatment with montelukast and cetirizine in patients with chronic urticaria with intolerance to food additives and/or salicylic acid. C1in Exp Allergy 200 I: 311607-1614 Erbagci Z. The leukotriene receptor antagonist montelukast in the treatment of chronic idiopathic urticaria: a single-blind, placebo-controlled. crossover clinical study, J Allergy C1in Immunol 2002; 110:484--488. Reimers A, Pichler C. Helbling A, Pichler WJ, Yawalker N. Zafirlukast has no beneficial effects in the treatment of chronic urticaria. Clin Exp Allergy 2002; 32: 1763-1768 Bressler RB, Sowell K, Huston DP. Therapy of chronic idiopathic urticaria with nifedipine: demonstration of beneficial effect in a double-blind. placebocontrolled, crossover trial. J Allergy Clin Immunol 1989; 83:756-763. Liu H-N, Pan L-M, Hwang S-C, Chu T-L. Nifedipine for the treatment of chronic urticaria: a double-blind cross-over study. J Dermatol Treat 1990: 1:187-189 Kaplan AP. Urticaria and angioedema. In: Kaplan AP. ed. Allergy. 2nd ed. Philadelphia: WB Saunders. 1997:573-592. Engler RJM, Squire E. Benson P. Chronic sulphas:liazine therapy in the treatment of delayed pressure urticaria. Ann Allergy Asthma Immunol 1995: 74:155-159. Jaffer AM. Sulfasalazine in the treatment of corticosteroid-dependent chronic idiopathic urticaria. J Allergy Clin Immunol 1991; 88:964--965. Rumbyrt JS, Katz JL. Schocket AL Resolution of chronic inAammation in patients with thyroid autoimmunity. J Allergy Clin Immunol 1995; 96:901-905. Gaig P, Garcia-Ortega, Enrique E, Richart C. Successful treatment of chronic idiopathic urticaria associated with thyroid autoimmunity. Invest Allergol Clin lmmunol 2000: 10:342-345.
34. 35.
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37. 38.
39.
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41.
42.
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45. 46. 47.
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Clark C, Pai S, Russell SC, Ibbotson SH, Ferguson J. TL-OI phototherapy for chronic idiopathic urticaria: 14 years experience. Br J Oermatol 200 I; 145 (suppl 59): 136 Parslew R, Pryce 0, Ashworth J. Friedmann PS. Warfarin treatment of chronic idiopathic urticaria and angio-oedema. C1in Exp Allergy 2000; 30:1161-1165. Grattan CEH, Francis OM, Slater NGP, Barlow RJ, Greaves MW. Plasmapheresis for severe unremitting. chronic urticaria. Lancet 1992; 3391078-1080 Barlow RJ, Kobza Black A. Greaves MW. Treatment of severe chronic urticaria with cyclosporin. Eur J Dermatol 1993; 3:273-275. Toubi E, Blant A, Kessel A, Golan TO. Low-dose cyclosporin A in the treatment of severe chronic idiopathic urticari
Copyrighted Material
16 Urticaria: Principles of Antihistamine Treatment F. Estelle R. Simons University of Manitoba, Winnipeg, Manitoba, Canada
I.
INTRODUCTION
Histamine is an important cell-to-cell messenger in the body, with activity at four types of G protein-coupled receptors (H 1-, H r , H r , and H 4 -receptors). In this chapter, we focus on the role of histamine at Hr and H 2 -receptors in urticaria. Information about the HI-receptor and the Hrreceptor, including expression, signal transd uction, and function is summarized in Table I (I). The role of histamine at H 3 - and H 4 -receptors in urticaria has yet to be determined. Histamine is produced and stored in cytoplasmic granules in mast cells and circulating blood basophils, from which it is released in large quantities by noncytotoxic mechanisms. Acting at HI-receptors in the skin, it causes itching, a predominant symptom in urticaria (2), via stimulation of thin, nonmyelinated afferent C-fibers, which have low conduction velocity and large enervation territories (3) (Fig. I). Acting at H I-receptors on postcapillary venules, histamine induces the endothelium to release nitric oxide, which stimulates guanyl cyclase and increases cyclic guanosine monophosphate (cGMP). This causes vasodilation, increased vascular permeability, and edema (4), evidenced as wheals and flares (erythema) that blanch under pressure. The vasodilation is enhanced by an axon retlex resulting from the release of substance P by antidromic conduction on afferent C-fibers, which in turn augments histamine release. Through the
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369
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Table 1 HistamineJ- and HrReceptors HI-receptor Proteins Chromosome Expression
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G-protein coupling Signal transduction
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Hrreceptor 359 amino acids. 40 kDa
5 Gastric mucosa, uterus, heart, CNS, vasculature smooth muscle, lung, immune cells
Gs t Cyclic t t t t t
AMP, Ca++, constItutive Hrreceptor signaling, phospholipase C Gastric acid secretion Vascular permeability Hypotension, flushing, headache, tachycardia, immune response Mucus production, airway Chronotropy and t inotropy
Neuroendocrine 1991
The information is based on studies in humans and in animal models, including H ,- and Hrknockoul mice, H ,-/Hrknockout mice, and histidine decarboxylase knockout mice. Peripheral and central H,-receptors do not diiTer, although isoforms of H,-receptors may exist. Targeted disruption of the HI-receplor gene in histamine H ,-receptor knockout mice leads to problems with neurophysiological functions such as learning, memory, sleep/waking cycle, emolions and behavior, and immunological problems (I). GMP, guanosine monophosphate: AMP, adenosine monophosphate: Ca++. calcium. Source: Ref. I.
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Time (min) Figure 1 Histamine is an important mediator of itching. The cutaneous branch of the peroneal nerve of 21 healthy human volunteers was studied using microneurography. A. Units were identified with a marking technique as "responsive" or "unresponsive" to mechanical stimulation and heat stimulation, then tested for responsiveness to histamine iontophoresed for :20 s from a 6 mm diameter probe. B. Histamine-induced itch sensations lasted several minutes. C-fibers, representing a new class of afferent nerves with extremely thin axons and excessive terminal branching. were found to mediate itch sensations. These fibers were mechanically insensitive and had low conduction velocities. Innervation territories on the lower leg were large (up to 85 mm in diameter). (From Rer. 3.)
HI-receptor, histamine is also involved in release of mediators of inflammation from mast cells and basophils, inflammatory cell activation, adhesion protein expression, and migration of inflammatory cells (5,6). In addition, histamine contributes to vasodilation, edema, and erythema in the skin through its activity at Hrreceptors in postcapillary venules, although its affinity for H 2-receptors in the vasculature is considerably less than its affinity for HI-receptors (4,7). Moreover, through its activity at Hrreceptors. histamine is likely involved in the modulation
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372
of immune responses, with immunomodulatory effects on dendritic cell function, lymphocyte proliferative responses, antibody synthesis, basophil chemotaxis, and cytokine production (6). Skin tissue fluid histamine concentrations are increased in urticarial lesions and in adjacent uninvolved skin. In approximately 50% of patients with chronic urticaria, the presence of hives correlates with histamine release from mast cells and basophils due to circulating IgG autoantibodies directed against the alpha subunit of the high-affinity IgE receptor or, less commonly, autoantibodies against the alpha subunit of IgE itself. Although total circulating histamine concentrations are not increased in patients with chronic urticaria, clinical tolerance to histamine is reduced. If urticaria is provoked locally by challenge with a relevant stimulus, histamine concentrations in venous blood draining the urticated skin are transiently increased, peaking at 2-5 min after challenge, and declining to baseline within 30 min. Other chemical mediators of itching and inflammation also play a role in urticaria. Proteases, tachykinins, eicosanoids including leukotrienes and prostaglandins, neuropeptides such as substance P, and other vasoactive substances also mediate increased vascular permeability, vasodilation, and produce wheals and flares (7,8).
II.
H1-ANTIHISTAMINES
A.
Pharmacology
All HI-antihistamines synthesized to date have been found to act as inverse agonists that combine with and stabilize the inactive conformation of the HI-receptor, shifting the equilibrium toward the inactive state. Even in the absence of histamine, HI-antihistamines downregulate constitutive H Ireceptor activity. For most H I-antihistamines, anti-allergic and antiinflammatory effects have been documented in vitro and in vivo. These effects are classified as being either H I-receptor-independent (for example, inhibition of mast cell and basophil histamine release, and inhibition of inflammatory cell activation), or HI-receptor-dependent (for example, adhesion protein expression, migration of inflammatory cells, and antibradykinin effects). The clinical relevance of the receptor-independent effects is uncertain, since they may require high H I-antihistamine concentrations in vitro and high HI-antihistamine dosages in vivo. The receptor-dependent effects, which can be demonstrated in individuals taking ordinary dosages of HI-antihistamines, may be more clinically relevant (5). Although HI-antihistamines differ in their chemical structure (Fig. 2). clinical pharmacology, and safety profiles, they have similar efficacy in urticaria treatment. Those introduced into clinical use from the 1940s to the
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Antihistamine Treatment of Urticaria
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HISTAMINE
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early 1980s are designated as first-generation or sedating HI-antihistamines. Those introduced more recently. are designated as second-generation H ,-antihistamines and are relatively nonsedating compared to thei r predecessors (I).
B.
Clinical Pharmacology
Clinical pharmacology studies provide an objective basis for selection of an appropriate HI-antihistamine dosage and dose interval. They also provide the rationale for the modified dosage regimens that may be required in specific populations such as the very young, the elderly. tho e with hepatic or renal dysfunction. or those taking other medications concurrently (9,10). The comparative pharmacokinetics (drug concentration vs. time) and pharmacodynamics (drug effect vs. drug concentration) of HI-antihistamines in healthy young adults are shown in Table 2. These agents are generally well absorbed after oral administration. Many of them appear to be extensively distributed into body tissues; apparent volumes of distribution vary more than LOO-fold, from 0.33 L/kg for levocetirizine to more than 100 L/kg for loratadine. For some HI-antihistamines such as loratadine. cetirizine. and levocetirizine, plasma protein binding is greater than 90%.
Copyrighted Material
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Table 2 Pharmacokinetics of Representative HI-Antihistamines in Healthy Young Adults (h) after a
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1.4 3.1 22 ± 4 (54 ± 15) 65-10 27 (103 19.3) 14.4 7± 1.5 78 ±4.2 (24±9.8) 12.9
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8 24/yes
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The mean terminal elimination half-life (t'l2/3) values of first-generation H I-antihistamines range from 9.2 h for diphenhydramine through 20 h for hydroxyzine, to 28 h for chlorpheniramine. The mean t'l2/3 for secondgeneration HI-antihistamines ranges from 6.5 h for cetirizine through 14 h for fexofenadine, to 27 h for desJoratadine. All of the first-generation H 1antihistamines and many of the second-generation medications in this class, such as ebastine, desloratadine, loratadine, and mizolastine, are extensively metabolized in the hepatic cytochrome P450 (CYP450) system (9) Some second-generation medications are excreted largely unchanged in the urine and/or feces. For example, more than 50% of a dose of cetirizine is eliminated unchanged in the urine, more than 85% of levocetirizine is eliminated unchanged in the urine, and more than 85% of fexofenadine is eliminated unchanged in the feces after biliary excretion (9). Drug interactions may occur for a variety of reasons. They may be due to interference with absorption, through P-glycoprotein efflux pump activity in the gastrointestinal tract mucosa, or due to inhibition of metabolism in the CYP450 system (I, I I). Information about the onset, intensity, and offset of HI-antihistamine activity is readily obtained by measuring suppression of the histamine- or allergen-induced wheal and flare in the skin (9,12-16) (Fig. 3). H Iantihistamines decrease the size of the wheal directly by acting on endothelial cells to reduce postcapillary venule permeability and leakage of plasma protein, and they decrease the size of the flare indirectly by blocking the histamine-induced axon reflex. Using a standardized whealand-flare bioassay as an objective end point, dose-response curves can be identified for each HI-antihistamine. During the first 24h after administration of a single dose, significant differences in onset, amount, and duration of activity can be identified among these medications. In contrast, clinical trials of H I-antihistamine efficacy in urticaria, in which outcomes include subjective scoring of itch and the number, size, and duration of hives, it is seldom possible to demonstrate clinically relevant differences between different HI-antihistamines or between different dosages of the same antihistamine (17,18) (Figs. 4, 5). The pharmacodynamics of H I-antihistamines are medication- and dosage-dependent. Peak plasma concentrations (Cm"x) in target organs such as the skin are achieved within 3 h after oral administration (Fig. 3). Significant suppression of the histamine-induced wheals and flares occurs within 0.5 h (cetirizine, levocetirizine) to 3 h (loratadine, desloratadine) (Table 2), peaks later than the HI-antihistamine Cm"x, and persists for hours after plasma concentrations have declined to the lowest limits of analytical detection. Few HI-antihistamines have been studied directly and concomitantly in plasma and skin. Where such studies have been performed,
Copyrighted Material
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Figure 3 Correlation of skin and plasma HI-antihistamine concentrations during multiple dose administration. [n a randomized. double-blind. parallel-group study. fexofenadine 120 mg/day or diphenhydramine 50 mg/day was administered for I week. At predose baseline and I. 3. 6. 9, and 24 h after the initial HI-antihistamine dose, skin and plasma fexofenadine concentrations were monitored. and wheal-andnare areas were measured after epicutaneous tests with histamine phosphate 1 mg/ m!. Subsequently, on each of 6 consecutive days. participants took fexofenadine 120 mg at 2100 h. and all the tests were repeated at 168 h (i.e. at steady-state. which is depicted in the shaded area), exactly 12 h after the 7th and last dose. Predose, plasma concentrations of both the H I-antihistamines were zero. The values shown are mean ± standard error of the mean. Fexofenadine (A. B) achieved significantly higher concentrations in the skin. and significantly greater wheal-and-nare suppression than diphenhydramine (C DJ. (From Ref. 13.)
for example, using cetirizine or fexofenadine. this persistent effect is associated with high tissue/skin concentration ratios. These second-generation HI-antihistamines are as or more effective than first-generation comparators such as hydroxyzine. diphenhydramine. and chlorpheniramine in wheal-and-llare suppression (12-14) (Fig. 3). For other HI-antihistamines such as desloratadine and loratadine. the presence of active metabolites in skin is probably important, although the metabolites have not been directly measured in tissue (14).
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Figure 4 First- and second-generation H I-antihistamines have similar efficacy in chronic urticaria. In a 4 week randomized, double-blind, double-masked, placebocontrolled study, J 88 patients with chronic idiopathic urticaria were treated with cetirizine IOmg once daily, hydroxyzine 25mg three times daily, or placebo. Cetirizine had a significantly more rapid onset of action. Cetirizine and hydroxyzine both significantly reduced (A) the number of episodes of urticaria and (B) the size of lesions. The number of lesions and the severity of pruritus were also decreased (not shown). Hydroxyzine was significantly more sedating than cetirizine. (From Ref. 17.)
Practical considerations include H I-antihistamine duration of action, residual action, and absence of decreased activity and efficacy with regular daily use. The duration of action of a single dose of some first-generation and most second-generation H I-antihistamines in the skin is at least 24 h, facilitating once-daily dosing (9,12-16) (Table 2). After regular use for a
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week or more, most HI-antihistamines need to be discontinued for 5-6 days before allergen skin tests are performed. Loss of H I-receptor activity and efficacy during regular daily administration of second-generation H Iantihistamines has not been found in rigorously controlled, double-blind studies of up to 12 weeks' duration in which the suppression of skin wheals and flares has been monitored objectively (16) or in clinical trials of up to 6 weeks' duration during which suppression of wheals, flares, and itching has been monitored subjectively (17-30).
C.
Efficacy in Acute and Chronic Urticaria
H I-antihistamines are the most important class of medications used for relieving symptoms in patien ts wi th urticaria (1,7,8,19). They decrease itching and also reduce the number, size, and duration of individual hives. In acute urticaria, the evidence base for the use of HI-antihistamines
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Cetirizine in prevention of acute urticaria. In the prospective, doubleblind, parallel-group Early Treatment of the Atopic Child (ETAC) Study, 817 children with atopic dermatitis who were 12-24 months of age at study entry were randomized to receive either cetirizine 0.25 mgjkg or placebo twice daily for 18 months. After this, they were evaluated for an additional 6 months, during which the study medication code remained unbroken. [n both these double-blind phases of the study, over a total of 24 months, caregivers recorded ::tll symptoms and events, including hives, in a diary. During active treatment, acute urticaria occurred in only 5.8% of the 399 children receiving cetirizine, in contrast to 16.2% of the 396 children receiving placebo (p < 0.00 I). In this high-risk population, the protective effect of the cetirizine disappeared when treatment was stopped. (From Ref. 33.)
remains small in spite of their widespread use for this indication (31,32). In a recent prospective, randomized, placebo-controlled, double-blind, 24-month-long study in 8] 7 atopic young children, regular cetirizine treatment had a significant preventative effect on episodes of acute urticaria (33) (Fig. 6). In chronic urticaria, the evidence base for the use of first-generation HI-antihistamines also remains surprisingly small by current standards, and consists mostly of short-term studies in which relatively small numbers of patients are enrolled (1,8, ]9,20). There are few randomized, placebocontrolled, double-blind studies in which a first-generation H I-antihistamine has been compared with a second-generation HI-antihistamine in the treatment of chronic urticaria. In one such study conducted over 4 weeks, although cetirizine 10mg once daily had a faster onset of action than hydroxyzine 25 mg three times daily in controlling symptoms and signs, the medications had similar overall efficacy (17) (Fig. 4). The evidence base for the use of second-genel'Miol7 HI-antihistamines in patients with chronic urticaria has improved considerably during the past few years (1,8,17-30). For example, fexofenadine has been studied in three different, randomized,
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double-blind, placebo-controlled trials of 4 weeks' duration, involving almost 1000 patients and dosages ranging from 20 to 240 mg twice daily (18,21,22) (Fig. 5). Moreover, in randomized, placebo-controlled, doubleblind studies of up to 6 weeks duration in patients with chronic urticaria, azelastine 4mg, cetirizine 10 mg, desloratadine 5 mg, ebastine 10 mg, loratadine 10 mg, and mizolastine 10 mg have been demonstrated to be effective in controlling symptoms and signs (23-27). There are not many studies of HI-antihistamine efficacy in young children with this disorder (10,28) In patients with chronic urticaria, H I-antihistamines should optimally be given on a regular basis to prevent hives from appearing, rather than as needed. Relief of the wheal-and-Oare response may be incomplete because the underlying increased vascular permeability, vasodilation, and extravasation are also mediated through the action of histamine at Hrreceptors and by other vasoactive mediators. The evidence base for the use of H Iantihistamines in the treatment of dermographism, cholinergic, cold, and pressure urticaria remai ns small, although high-dosage cetirizine (20 mg daily), which lacks anticholinergic activity, has been reported to give some relief in patients with cholinergic urticaria and in those with delayed pressure urticaria (8,27). H I-antihistamines are ineffective in the treatment of urticarial vasculitis and hereditary angioedema (l,8). Comparative studies of the efficacy of a second-generation H 1antihistamine and a leukotriene modifier have recently been performed in patients with chronic urticaria (29,30). Fexofenadine and montelukast appear to have similar efficacy in this disorder. However, in patients with chronic urticaria associated with intolerance to acetylsalicylic acid or food additives, montelukast was more effective than cetirizine (30).
D.
Adverse Effects
First-generation HI-anti histami nes, in contrast to their second-genera tion counterparts, potentially cause a wide variety of adverse effects. These incl ude an tichol inergic effects such as dry mucous mem bra nes and urina ry retention. antiserotonin elTects such as appetite stimulation (cyproheptadine, ketotifen), central nervous system (CNS) dysfunction, cardiac toxicity, gastrointestinal upset, and, rarely, jaundice or pancytopenia (1,8, I 0.33-47). 1.
Central Nervous System
I n the CNS, H I-anti histamines such as ch lorpheni ramine, diphenhydramine, hydroxyzine, and promethazine bind to cholinergic, serotonin, and other receptors, as well as to histamine receptors. More import::mt is that these
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first-generation H I-antihistamines penetrate the nonfenestrated endothelial lining of the capillaries of the CNS, the so-called blood-brain barrier, due to their Iipophilicityjsolubility ratios, relatively low molecular weight, and lack of recognition by the P-glycoprotein efnux pump expressed on the luminal surfaces of endothelial cells in the cerebral vasculature. 1n manufacturers' recommended dosages, as demonstrated by positron em is ion tomography, considered the new gold standard, they occupy > 70% of the H [-receptors in the frontal cortex, temporal cortex, hippocampus, and pons. Although their propensity to cause CNS adverse effects varies, all of them are more likely to cause these effects than their newer counterparts (1,34-36). Their central effects humans appear to be mediated primarily by preventing endogenous histamine from functioning as a neurotransmitter, as evidenced by the discovery that the sedative enantiomers of HI-antihistamines such as chlorpheniramine and dimethindene are those with the highest H I-receptor affinity. 1n contrast, most of the second-genera tion HI-an ti h istam ines, incl udi ng ceti rizi ne, desloratad ine, fexofenadine, levocetirizine, and loratadine, are not only highly specific for HI-receptors but also penetrate the CNS poorly due to their Iipophobicity, relatively high molecular weight, and, for fexofenadine, recognition by the P-glycoprotein efnux pump expressed on endothelial cells in the cerebral vasculature. Although second-generation H I-antihistamines differ from each other with regard to occupation of CNS H [-receptors, at recommended dosages, they all occupy fewer than 30% of the CNS HI-receptors (1,34-36). 1n usual dosages, all the first-generation H I-antihistamines potentially cause CNS effects, including somnolence and impaired cognitive and psychomotor performance (1,34-44). Self-reporting of adverse CNS effects caused by any sedating medication or chemical, for example, ethanol, underesti ma tes the true incidence of impai rmen t, beca use la pses and errors can be documented in the absence of symptoms, regardless of the specific substance inge ted or the objective test used (34,35). Use of potentially sedating H I-antihistamines is a concern in any patient, but particularly in employees in safety-critical jobs who require a high level of alertness, and in elderly individuals, those with pre-existing CNS disorders, and those who have sleep deprivation due to awakening at night because of hives. Additional risk factors for adverse CNS effecb include small body mass and consequent relatively large dose on a mgjkg basis, hepatic or renal dysfunction leading to H I-antihistamine accumulation in the CNS, and concomitant use of other CNS-impairing drugs or chemicals such as alcohol (1,34). First-generation HI-antihistamines are implicated as a cause of aviation and traffic accidents, based on the finding of elevated postmortem liver and blood HI-antihistamine levels (37). Military and commercial aircraft
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pilots are prohibited from using these medications before or during flights. On-the-job injuries and loss of productivity have been documented following their use (38,39). Driving performance has been reported to be worse after diphenhydramine ingestion than after alcohol ingestion sufficient to produce blood alcohol levels of 0.1 % (40). In some jurisdictions, drivers faulted for causing traffic fatalities can be fined or imprisoned if they have been taking a first-generation HI-antihistamine. Moreover, in a large retrospective cohort study involving more than 37,000 patients who received an antihistamine prescription, the rate of significant injury in the 30 days following the prescription was significantly higher in those receiving the first-generation H I-antihistamine diphenhydramine (308/ 1000 person years) than in those receiving the second-generation H Iantihistamine loratadine (137/1000 person years) (41). The elderly may be particularly vulnerable to adverse effects from first-generation H I-antihistamines. Diphenhydramine, for example, is associated with an increased risk of cognitive decline, delirium, inattention, disorganized speech, and altered consciousness in this population Cognitive impairment can be identified in 25% of individuals age 65 years or older, most of whom have no overt signs of CNS dysfunction. In elderly people with documented neurodegenerative disease, histamine transmission in the CNS is disrupted even in the absence of HI-antihistamine treatment (1).
2.
Cardiac Toxicity
HI-antihistamines are among many classes of drugs (antimicrobials, calcium channel blockers, and serotonin modifiers) that potentially prolong the QT interval and lead to ventricular arrhythmias including torsade de pointes. Blockade of the rapid component of delayed rectifier potassium (I K ,) channels and prolongation of the monophasic action potential (QT interval) may induce the development of early after-depolarization and dispersion of repolarization, leading to torsade de pointes through re-entry mechanisms. Other electrophysiological changes such as the ITo, lKi' and I Ks channels may also lead to prolongation of the action potential (5,45). Patient variables contribute to the development of potential cardiac toxicity. Female patients, individuals with pre-existing organic heart disease (ischemia, cardiomyopathy), cardiac arrhythmias (congenital or acquired), or those with electrolyte abnormalities (hypokalemia, hypocalcemia, or hypomagnesemia) are at increased risk. Also at higher risk are those who ingest foods, medications, or herbal rormulations that inhibit drug elimination by the CYP450 system, or those concurrently taking another drug that by itselr pi"Olongs the QTc interval (45).
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First-generation HI-antihistamines such as cyproheptadine, diphenhydramine, or hydroxyzine, and the H I-/H 2 -antihistamine doxepin have a dose-related effect on the QT interval and in overdose, may cause arrhythmias (45-47), incl uding torsade de pointes. Second-generation H 1_ antihistamines such as cetirizine, fexofenadine, and loratadine have been extensively investigated for potential cardiac toxicity, which has not been detected at therapeutic dosages, as confirmed in postmarketing surveillance studies, or after overdose. Regulatory agencies now aim to identify the potential risk for cardiac toxicity of all H [-antihistamines, and indeed all drugs, during preclinical and early clinical development.
E.
Pregnancy and Lactation
HI-antihistamines such as chlorpheniramine, diphenhydramine, cetirizine, and loratadine are rated by the U.S. Food and Drug Administration as Pregnancy Category B drugs and are considered to be relatively low risk for use in pregnancy. Others such as hydroxyzine and fexofenadine are rated as Pregnancy Category C drugs and should be used during pregnancy only if the expected benefits to the mother exceed the unknown risks to the fetus (48).
F.
Clinical Usage in Urticaria
In prospective, controlled, double-blind studies in chronic urticaria, secondgeneration HI-antihistamines have similar efficacy to first-generation H Iantihistamines (17) (Fig. 4). However, because they cause less sedation and impairment of cognitive and psychomotor function, they have a better benefit-to-risk ratio than their older counterparts (8). The relatively flat dose-response curve for efficacy of both first- and second-generation H 1antihistamines contrasts with the steep dose-response curve for adverse effects from first-generation HI-antihistamines (1). First-generation H I-antihistamines are still used in the treatment of urticaria despite their poor benefit-to-risk ratio. Although they are often given three or four times daily (7), this regimen is based on anecdote and tradition and is unnecessary for medications such as hydroxyzine or chlorpheniramine, which have elimination half-life values of 20 and 28 h, respectively (Table 2). This is considerably longer than the half-life values of most second-generation HI-antihistamines which are administered once daily (I). It is important to note that the total daily dosage of the H Iantihistamines recommended for chronic urticaria [e.g., hydroxyzine 50 mg 3 or 4 times daily (7)], is relatively large compared to the dosage at
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which CNS adverse effects have been regularly and consistently documented [e.g., hydroxyzine 50 mg once daily (34,35)]. Some physicians recommend first-generation HI-antihistamines for use only at bedtime, in the hope that sedation will occur only during the night. Unfortunately, the morning after the bedtime dose, an antihistamine hangover (sedation with or without cognitive and psychomotor impairment) may be present (42). Other physicians advise regular daytime use, anticipating that tolerance will develop to the adverse CNS effects. However, on objective testing, tolerance mayor may not be confirmed (43,44). H Ireceptors in the CNS do not differ from HI-receptors in peripheral tissues such as the skin, where, as stated previously, tolerance cannot be objectively documented (16). Combinations of first-generation HI-antihistamines such as hydroxyzine and cyproheptadine (7), or of a first- and second-generation H Iantihistamine such as cetirizine in the morning and hydroxyzine at night, are recommended empirically by some highly respected physicians. These regimens have not been tested in prospective, randomized, placebocontrolled, double-blind trials. Moreover, the administration of a firstgeneration HI-antihistamine at night places patients at risk for an antihistamine hangover (sedation with or without cognitIve and psychomotor impairment) the next morning (42). In addition, sequential use of two different second-generation H I-antihistamines in the same day is recommended on an empirical basis, despite the absence of randomized, double-blind, placebo-controlled studies to support this approach.
III.
H2 -ANTIHISTAMINES
A.
Clinical Pharmacology
During the late 20th century, the HTantihistamines cimetidine, ranitidine, famotidine. and nizatidine revolutionized the treatment of acid-peptic disorders,111 which they are now used only as alternatives to the more potent proton pump inhibitors. H 2 -antihistamines administered concomitantly with HI-antihistamines have an adjunctive role in the prophylaxis and treatment of urticaria (I). In addition. He-antihistamines. especially cimetidine. are reported to have immunomodulatory effects not mediated through H 2-receptors (6). These effects have not been specifically studied in patients with chronic urticaria, although they have been confirmed in randomized, double-blind. placebo-controlled studies in patients with Immune suppression secondary Lo burns, cancer, and other disorders (49,50).
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HTantihistamines are rapidly absorbed after oral administration, with peak plasma concentrations occulTing within 1-3 h. Volumes of distribution range from 0.8 to J .18 Ljkg. Plasma protein binding is low, ranging from 15 to 35%. In healthy young adults, terminal elimination half-life values range from 1.3 to 4 h. Clearance is decreased in patients with impaired renal function, who require dose or dose interval adjustments, and since cimetidine, ranitidine, and famotidine are subject to first-pass hepatic metabolism, clearance may also be decreased in patients with impaired hepatic function and in the elderly. Cimetidine and ranitidine, but not famotidine or nizatidine, bind to the heme portion of the hepatic cytochrome P450 system. In a dose-related manner, they inhibit hydroxylation, dealkylation, and other mixed-function oxygenase system actions. With cimetidine dosages as low as 400-800 mg daily, elimination of many commonly prescribed medications, including H ,-antihistamines eliminated in the cytochrome P450 system, is reduced by approximately 25%. Ranitidine binds to the cytochrome P450 system with 5-10-fold less affinity than cimetidine (51). HTantihistamines such as cimetidine, ranitidine, or famotidine administered alone have a variable, weak, dose-related effect on suppression of the histamine-induced wheal-and-flare reaction in the skin. Concomitant administration of an HI-antihistamine mayor may not lead to a greater suppressive effect than administration of either an H]-antihistamine or an H ,-antihistamine alone (51) (Fig. 7). The magni tude of the increased suppression is only about 10% and, in some studies, the increase has not been statistically significant or clinically relevant. The enhanced suppression is due primarily to reduced histamine activity at H]-receptors on the postcapillary venules in the skin and prevention of vasodilation. After cimetidine administration, enhanced suppression may also be due in part to pharmacokinetic inhibition of the hepatic elimination of the coadministered HI-antihistamine as described above, resulting in higher HI-antihistamine plasma and tissue concentrations, and higher HI-receptor occupancy than when the HI-antihistamine is administered alone (51) (Fig. 7).
B.
Efficacy in Acute and Chronic Urticaria
In patients with acute urticaria, chronic urticaria, or dermographism, concurrent treatment with an H I- and an HTantihistamine may be more efficacious in reducing symptoms than treatment with an HI-antihistamine alone. The main contribution of Hrantihistamines is to downregulate vascular leakage and whealing rather than itching (8,3 1,32). There are occasional studies demonstrating the efficacy of an Hrantihistamine used alone (52) Copyrighted Material
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Figure 7 Coadministration of an H ,-antihistamine and an Hrantihistamine. In a randomized. double-blind, parallel-group study in 16 individuals with chronic urticaria, the suppressive effect of hydroxyzine 25mg or cetirizine 10 mg. before and after treatment with cimetidine 600 mg every 12 h for 10 days. was examined. A. When hydroxyzine was given with or without cimetidine. wheal-and-nare suppression was significantly improved compared to baseline. Suppression was incrcased when hydroxyzine was given with cimetidine compared to when it was given alone; however. the difference was not statistically significant (p> 0.05). Coadministration of hydroxyzine with cimetidine resulted in significantly increased plasma hydroxyzine concentrations and a signilicant increase in the hydroxyzine arca under the curve from 227 ± 77 ng/ml/h to 303 ± 92 ng ml h (p < 0.05) (not shown). This suggests some rationale for a trial of concomitant administration of
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In some patients with urticaria and symptomatic dermographism refractory to treatment with an H I-antihistamine alone, concurrent HI-I H 2 -antihistamine treatment may provide enhanced relief (1,7,8,53). The synergistic effect bas not been found in all studies, however, and in some patients it is too small to be worthwhile. It should therefore never be suggested routinely and if, after a 3-4 week trial of therapy, enhanced efficacy has not been demonstrated, the H 2 -antihistamine should be discontinued. The H 2-antihistamines generally used are cimetidine 600 mg twice daily or ranitidine 150 mg twice daily, in combination with an Hr antihistamine sucb as chlorpheniramine, cyproheptadine, or hydroxyzine. Combined H1-/Hrantihistamine treatment is not effective in patients with urticarial vasculitis or hereditary angioedema. The tricyclic antidepressant doxepin has clinically important H I- and Hrantihistamine properties. with greater activity than either hydroxyzine or diphenhydramine at H I-receptors and greater activity tban cimetidine at H r receptors. In patients with chronic urticaria, doxepin 25mg tbree times daily suppresses whealing and itching to a significantly greater extent than placebo does; and even in a low dosage of 10 mg three times daily, doxepin is significantly more effective than diphenhydramine. Since doxepin has a t'l2{3 of 13 h and is extremely sedating, a single daily dose at bedtime is often recommended. It is not approved for use in children (1,7,8,54,55).
c.
Adverse Effects and Use in Pregnancy and Lactation
H 2 -antihistamines have a good safety record, considering the wide distribution of Hrreceptors in many body tissues, the potential of cimetidine and other H 2 -antihistamines for drug interactions, and the high frequency of Hrantihistamine use, with over-the-counter availability in most countries. Adverse effects involving the eNS, gastrointestinal tract, hematopoietic system, heart, or kidneys occur in fewer than 2% of individuals taking Hrantihistamines, are not usually serious, and resolve with cessation of the medication (I). Hrantihistamine ingestion during the first trimester of pregnancy does not represent a major teratogenic risk. However, use of these medications for treatment of urticaria in pregnancy should be restricted to women in
cimetidine and hydroxyzine in patients with chronic urticaria unresponsive to treatment with an HI-antihistamine alone. B. In the same study. the suppressive effect of cetirizine 10 mg with or without cimetidine was significantly improved compared to baseline. No therapeutic rationale for coadministration of cimetidine with cetirizine could be documented. (From Ref. 51.)
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whom the modest potential benefits anticipated when they are added to H I-antihistamine treatment outweigh the potential risks to the fetus. Hrantihistamines are excreted in breast milk (I).
IV.
SUMMARY
HI-antihistamines play an important role in the treatment of patients with acute and chronic urticaria. The potential benefits of each HI-antihistamine should be weighed against the potential risks, particularly the common, often subclinical eNS adverse effects of sedation and impaired cognitive and psychomotor function produced by the first-generation HI-antihistamines. Hrantihistamines playa limited role in the prevention and treatment of acute and chronic urticaria; however, tbey may be a useful adjunct to HI-antihistamine treatment in some patients.
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17 Treatment of Chronic Urticaria: Agents Other Than Antihistaminics Allen P. Kaplan Medical University of South Carolina, Charleston, South Carolina, U.S.A.
I.
INTRODUCTION
The treatment of chronic urticaria, as with virtually all other types of urticaria, begins with antihistamines as described in the preceding chapter. The amount and type used depend on the severity of urticaria and can be as simple as employing one of the second-generation antihistamines such as fexofenidine (1,2) deslora tidine (3), cetirazine (4,7), or high dosages of sedating antihistamines such as hydroxazine (50 mg four times daily) or a comparable dosage of diphenhydramine or doxepin (8). The latter agents are particularly useful for treatment of patients with severe disease in whom the nonsedating antihistamines provide only minimal relief. Their efficacy may rela te to properties other than blockade of H I-receptors such as effects of mast cell and basophil degranulation (5,6) or influx of cells [CD4(+) lymphocytes, monocytes, eosinophils and neutrophils] characteristic of chronic urticaria and delayed pressure urticaria (6). Somewhat greater antihistamine effect may be observed upon addition of an Hrreceptor antagonist because approximately 15% of cutaneous venule histamine receptors are of this subtype (7-9). Blockade of the H I-receptors is, however, required to observe any effect. Hrreceptor antagonists also are useful if corticosteroid is required to control severe chronic urticaria and
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angioedema, since these agents provide protection against the consequences of steroid-induced hyperacidity. This chapter will deal primarily with agents other than antihistaminics and will report on studies demonstrating efficacy and comment on the utility (or Jack thereof) of modalities that require further investigation.
II.
LEUKOTRIENE ANTAGONISTS
Although these agents were originally marketed for the treatment of asthma, new studies suggest their efficacy in allergic rhinitis as well as chronic urticaria. Both zafirlukast and montelukast have been shown to be superior to placebo in the treatment of patients with chronic urticaria (10-12), thus leukotrienes may also contribute to hives and swelling as has been suggested by recent in vitro studies (13,14). These agents have not, however, been studied when added to antihistamines to determine whether additional benefit is obtained. They are certainly worth trying because toxicity is low and may alleviate the need for agents such as corticosteroids or allow administration of a lower dosage.
III.
SYMPATHOMIMETIC AGENTS
Oral sympathomimetic agents such as terbutaline, a beta-2-selective adrenergic agonist, have been tried in patients with chronic urticaria and angioedema to decrease erythema and swelling. However, the effect upon urticaria is quite low and not comparable to subcutaneous epinephrine (which, for emergency use, gives prompt relief of pruritus with regression of urticaria, as well as halting progression of angioedema) and the side effects are substantial. These include difficulty sleeping, feeling jittery. and tachycardia. Tn general, these agents are not recommended.
IV.
CORTICOSTEROIDS
There are many patients whose symptoms are not sufficiently controlled by any dosage of antihistamines, including the addition of HTreceptor antagonists and leukotriene antagonists. Under such circumstances, it is reasonable to consider the usc of corticosteroids. However, use in a chronic (for many months. at least) fashion must be tempered by the potential side effects. For that reason, illternate-day steroid therapy, in a starting dosage range of 20-25 mg every other day has been recommended
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(9,15) and daily use of steroids should be avoided. Although a tapering short course of daily corticosteroids can be employed for treatment of a severe acute exacerbation or for urticaria and angioedema (e.g., 40-50 mgjday for 3 days in succession and then tapered by 5 mg per day), if this is done repeatedly it is far more dangerous and less effective than use of alternate day steroids at a fixed dosage. Symptoms of the disease vary from day to day but the dosage of alternate-day steroids should be reassessed at 2-3 week intervals for optimal control of symptoms. Then the dosage can be decreased at a rate of 2.5-5.0 mg every 2-3 weeks depending on symptom control down to 10mg every other day (q.o.d.). Other medications should be retained at a maximal dosage until the patient has been completely tapered off steroids. To decrease further from 10 mg q.o.d., the decrement can usually continue at 2.5-5.0 mg; however some patients may become too symptomatic as very low dosages are employed. One choice is to use Img prednisone tablets, and to try to decrease the dosage by I mg every 2-3 weeks. Although the efficacy of corticosteroids as a treatment for chronic urticaria is generally accepted, there are no long-term studies that document the optimal dosage, duration, extent of side effects, or cost-effectiveness. Thus the manner in which they are employed, as recommended herein, is based on personal experience. Corticosteroids have little or no effect upon cutaneous mast cell degranulation, thus they are generally ineffective as treatment for physically induced hives such as cold urticaria, cholinergic urticaria, or dermatographism. They would likewise not be expected to affect mast cell degranulation caused by anti IgE receptor autoantibodies or by C5a (see Chapter 14). Instead, like the allergic late phase reaction, they would act to prevent the perivascular cellular infiltrate that characterizes chronic urticaria and delayed pressure urticaria (J 6-20). The persistence of symptoms over many hours or even 1-2 days with each outbreak of hives is dependent on this cellular infiltrate. Thus the state of the art in treating chronic urticaria is akin to the treatment of asthma before inhaled corticosteroids were available. Unfortunately urticaria cannot be treated topically, as is true of atopic dermatitis. The commonly encountered side effects of steroid use, as described above, are weight gain and gradual development of cushingoid features in those patients in whom tapering of the dosage is particularly slow. These can be minimized with care to diet and exercise. Symptoms abate as the dosage decreases and are reversible once steroids are eliminated. More severe side effects (e.g., hypertension, diabetes, asceptic necrosis, or thrombophlebitis) are rarely encountered if the aforementioned limits to steroid use are followed, and if none of these are present before steroid use is begun. The presence of any of these in a patient with chronic urticaria is a relative
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contraindication to their use and other modalities should be employed whenever possible.
V.
ADDITIONAUEXPERIMENTAL AGENTS
Other anti-inflammatory drugs have been tried in patients with chronic urticaria. Success has been reported employing colchicine (21), sulfasalazone (22), dapsone (20), intravenous gamma globulin (23), plasmapharesis (24), and cyclosporine (25,27). There have been no long-term studies of any of these agents in large numbers of patients, thus most reports are anecdotal observations regarding particular patients. Hydroxychloroquine has been ineffective, in general, in our experience, with the exception of treatment of the hypocomplementemic urticarial vasculitis syndrome (see Chapters II and 17) for which hydroxychloroquine may be the drug of choice (28). Dapsone has generally been most effective for the treatment of cutaneous disorders in which a neutrophilic infiltrate is prominent. Thus it does have efficacy in some patients with urticarial vasculitis but its utility in those with severe chronic urticaria is questionable. Perhaps there is logic in trying it for those patients with neutrophilpredominant chronic urticaria (29), who make up an uncommon subgroup of patients who are often refractory to treatment. Intravenous gamma globulin is extremely expensive, but has been successfully employed by one of us MG, (23) but not the other (AK), indicating that the response is variable from patient to patient. Plasmapharesis has been strikingly beneficial in the series of patients in which it was tried. and provides additional evidence in favor of the pathogenicity of IgG anti-IgE receptor antibody (24). Thus it is most likely to work if the presence of antireceptor antibody has been documented. Yet it too is an expensive, inconvenient modality that places restrictions on the patient much as hemodialysis might, but may be employed in selected patients who are willing to try it. Thus far, the most promising has been the use of cyclosporine (25-27) in patients whose disease is refractory to treatment with steroids, or who require very high dosages, or where there is a contraindication to its use. Gratten et al. report a double-blind placebo-controlled study with excellent results (30). We have each observed many striking successes using a 200-300 mgjday dosage range, and have rarely encountered renal toxicity. Periodic checks of blood urea nitrogen, creatinine, and urinalysis are made every 2 weeks for the first 3 months, monthly for the second 3 months, and every 2-3 months thereafter. A trial of 3 months is warranted to determine whether it is or is not efficacious in any particular patient. A stepwise general approach to the treatment of chronic urticaria is outlined in Table l.
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Table 1 Stepwise Approach to the Treatment of Chronic Urticaria I. Maximize HI and H 2 -receptor blockade with appropriate antihistaminics depending on severity. For patients with mildest disease: fexofenadine 180 mg, desloratidine 5 mg. or cetirizine 10 mg as a single agent. For patients with somewhat more severe disease: fexofenadine 180 Illg or desloratidine 51llg in the morning. plus cetirizine 10 mg at midday and bedtime. For patients with most severe disease: fexofenadine 180 mg or desloratidine 5 mg in the morning, plus hydroxyzine or diphenyldramine 50 mg four times daily, plus ranitidine 150 mg twice daily or cimetidine 400 mg twice daily. 2. Consider adding a leukotriene antagonist. 3. Alternate-day corticosteroids starting at 20 mg prednisone (or equivalent) every other day. Decrease by 2.5-5.0 mg every 3 weeks. 4. If the patient's condition is refractory to corticosteroids or the dosage require to achieve reasonable control is loo high, consider cyclosporine 100 mg twice daily, maximal dosage 100 mg three times daily.
VI.
CONTROVERSIAL MEASURES
Although there is a clear association of chronic urticaria with Hashimoto's thyroiditis, it is not clear whether thyroid hormone can be employed for treatment of the urticaria and angioedema. It is clear that anyone who is hypothyroid should be treated~ however, there are studies suggesting that raising thyroid levels in euthyroid patients possessing antithyroid antibodies will substantially improve their urticaria (31,32). while other studies are negative (33). This is an area in which a large study is required to answer the question. However one of us (AK) has added thyroid hormone to the regimen of 10 patients with severe disease and did not ob erve any difference in their course. Thus we do not use thyroid hormone in this manner. It is of interest that many patients who have Hashimoto's thyroiditis requiring thyroid replacement therapy present with chronic urticaria years later. Thus replacement at an appropriate level does not seem to prevent urticaria. Hashimoto's thyroiditis also has an increased incidence in patients with autoimmune polyglandular syndrome, type J diabetes mellitus, vitiligo, and pernicious anemia. There is no literature to suggest that thyroid hormone improves any of these other autoimmune manifestations. It seems likely that these are all associated autoimmune abnormalities reflecting an underlying immune dysregulation but that they do not cause each other; treatment of one is not likely to affect another.
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The role of Hc!iobaCler pvlori in the pathogenesis of chronic urticaria and angioedema is also controversial. There are studies suggesting that eradication of the organism lead to marked improvement of the urticaria (34-36) and studies in which its eradication had no significant effect upon urticaria (37-38). The rate of infection of the population at large with this organism is very high (37), thus a large proportion of patients with chronic urticaria may test positive even if gastrointestinal symptoms are not evident. One recent publication reviewed the literature and concluded that the bulk of evidence is against a causative role but one should not rule out an indirect contribution (40). Clearly the number of persons infected by H. 1)]'lori who do not have chronic urticaria is substantial and the number of patients with chronic urticaria who are infected with H. pylori is 40-50%. Whether this percentage exceeds that of the general population is not clear, thus the best studies of this issue are those that treat the organism in an attempt to affect the urticaria. However, in the past, the number of patients on studies has been insurficient and critical controls omitted. A large controlled, blinded study is needed using a placebo control or antibiotics that are ineffective for H. pdori, as well as antibiotic treatment of H. IJl'lori-negative patients. The use of patient questionnaires, plus objective assessment of the frequency and severity of symptoms, will help to address this issue definitively.
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Finn AF Jr, Kaplan AP, Fret,vell R, Qu R. Long J. A double-blind placebocontrolled trial or rexorenadine HCI in the treatment or chronic idiopathic urticaria. ,I Allergy Clin Jmmunol 1999: 103: I 071-1 078. 2. Nelson HS, Reynolds R, Mason J. Fexofenadine HCI is safe and elTective for treatment of chronic idiopathic urticaria. Ann Allergy Asthma Immunol 2000: 84:517-522. 3. Ring J. Hein R, Ganger A, Bronsky E, Miller B. One-daily desloratadine improves the signs and symptoms of chronic idiopathic urticaria: a randomized double-blind. placebo-controlled study. Int ,I Dermatol 2001: 40: 1-5. 4. La Rosa M. Leonardi S, Marchese G. Corrias A, Barberio G. Oggiano N, Grimaldi, I. Double-blind multicenter study on the efficacy and tolerability of ectirizine compared with oxatomide in chronic idiopathic urticaria in preschool childrcn. Ann Allcrgy Asthma Immunol 2001: 87:48 53. 5. Breneman DL. Cetirizine versus hydroxizine and placebo in chronic idiopathic urticaria. Ann Pharmacol 1996; 30: 1075-1079. 6. Tharp MD. Cetirizine: a new therapeutic alternative for chronic urticaria. Cutis 1996: 5~94-98 7. Robertson I. Grcaves MW. Responses or human skin hlood vessels to synthetic histamlnc ~lnalogucs. Br ,I C1in Pharmacol 1978: 5:319-322.
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18 Urticarial Vasculitis/Venulitis Nicholas A. Soter New York University School of Medicine, New York, New York, U.S.A.
Episodes of recurrent urticaria are an uncommon manifestation of cutaneous necrotizing vasculitis that involves venules. Some patients have a multisystem disorder with extracutaneous manifestations. Although the variety of skin lesions and extracutaneous manifestations have led to a plethora of diagnostic appellations (1-18), the terms urticarial vasculitis or venulitis currently are widely used. A subset of patients with urticarial venulitis and systemic manifestations, hypocomplementemia with low Clq levels, and an anti-Clq autoantibody has been designated as having the hypocomplementemic-urticarial-vasculitis syndrome (HUVS) (17). Urticarial venulitis may occur in association with a variety of medical disorders; however, it may be an idiopathic condition (Table I).
I.
A.
CLINICAL MANIFESTATIONS Cutaneous Features
Urticarial venulitis involves the skin and infrequently the mucous membranes. Between 60 and 80% (17,19,20) of afflicted individuals are women. A few cases have been reported in children (19-25). There is one report of urticarial venulitis that occurred in identical twins (26). The signature skin lesions appear as raised, superficial, erythematous, edematous, and circumscribed wheals (Fig. I). Distinctive dermatological features include wheals with foci of purpura, induration, and residual contusions and transient hyperpigmentation (Table 2). When the wheals are examined by skin surface microscopy with a dermascope, a purpunc
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Table 1 Classification of Urticarial Venulitis
Serum sickness Connective tissue disorders Hematological malignant conditions Infections Therapeutic agents Schnitzler's syndrome ldiopatbic urticarial venulitis and bypocomplementemicurticarial-vasc.ulitis syndrome Physical urticarias
Figure 1 Wheals with foci of purpura, in which the erythema does not blanch with pressure (diascopy). Note glass slide at the top.
globular pattern is noted (27). Other skin manifestations include angioedema, which is prominent in patients with HUVS (17,28), macular erythema, livedo reticularis, nodules over the olecranon process (29), bullae (3,14,15), and lesions that resemble erythema multiforme (7,14). Although the individual urticarial lesions may last fewer than 24 h, they frequently persist up to 3-5 days. The lesions are pruritic, burning, or
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Dermatological Features
Distinctive features Long-lasting wheals Wheals with foci of purpura Induration Residual contusions and/or hyperpigmentation Other features Angioedema Macular erythema Livedo reticularis Nodules over the olecranon process Bullae Erythema multiforme-like lesions
painful. Occasionally there of urticaria are recurrent or years, and vary in frequency. basis of history and clinical without vasculitis.
B.
are no lesional symptoms. The episodes episodic, range in duration from months to The lesions may be indistinguishable on the appearance from those of chronic urticaria
Extracutaneous Manifestations
General features include fever, malaise, and myalgia. Specific organ involvement may involve lymph nodes, liver, spleen, synovia, kidneys, gastrointestinal tract, respiratory tract, eyes, central nervous system, peripheral nerves, and heart (Table 3). At times, patients may experience cutaneous features without extracutaneous involvement. Arthralgias are a major manifestation; multiple joints, especially knees, ankles, toes, elbows, wrists, and fingers are affected. A destructive polyarthritis occasionally occurs (30). Examination of a synovial biopsy specimen in one patient showed features of necrotizing vasculitis that were similar to the vascular alterations observed in the skin (4). Jaccoud's arthropathy with or without valvular heart disease may occur (28,31-34). One patient with Jaccoud's arthropathy, valvular heart disease, and reversible tracheal stenosis has been reported (35). Renal involvement usually occurs as mild glomerulitis or glomerulonephritis (3,5,9,36,37). Nephrotic syndrome rarely may occur (38,39). In renal biopsy specimens, mesangioproliferative and membranoproliferative lesions are predominant (9,17,25,36-38,40), but interstitial nephritis and immune complex deposition in the interstitium have been reported. In one patient with HUVS, after renal transplantation there was a flare
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Extracutaneous Manifestations
General features Fever Malaise Myalgia Specific organ involvement Lymphadenopa thy Hepa tosplenomegaly Synovia: arthralgia, arthritis, Jaccoud's arthropathy Kidneys: glomerulitis, glomerulonephritis with mesangioproliferative and membranoproliferative changes, nephrotic syndrome, end-stage renal disease Gastrointestinal tract: nausea, vomiting, pain, diarrhea Respiratory tract: laryngeal edema, dyspnea, chronic obstructive and interstitial pulmonary disease, emphysema, pleural effusion, pulmonary hemorrhage Eyes: conjunctivitis, episcleritis, iridocyclitis, uveitis Central nervous system: headache, benign intracranial hypertension (pseudotumor cerebri) Peripheral nerves: neuropathy, cranial nerve paralysis Heart: arrhythmias, valvular heart disease, pericardial effusion, myocardial infarct
of urticarial venuJitis with the development of chronic renal failure (41), Progression to end-stage renal disease is rare (41-43). Gastrointestinal tract manifestations include nausea, vomiting, pain, and diarrhea. Gastrointestinal hemorrhage is not a feature. Involvement of the respiratory tract includes laryngeal edema, dyspnea, and chronic obstructive pulmonary manifestations (29), especially in patients with HUYS (44), which are more severe in individuals who smoke cigarettes. Interstitial lung disease (45), emphysema (46). pleural effusion (47), and pulmonary hemorrhage (23) are infrequent findings. Necrotizing vasculitis of the pulmonary venules (48) and emphysema have been observed in lung biopsy specimens (17). Major pulmonary causes of death are laryngeal edema, chronic obstructive pulmonary disease, and respiratory failure (17). One patient with HUYS received a lung transplant and 15 months later had had no recurrence of urticarial venulitis (17). Conjunctivitis, episcleritis, iridocyclitis (49), and uveitis occur in some individuals, especially in those with HUYS (44). Optic atrophy has been reported in one patient (16), and blindness was observed in two patients ( 16,50). Central nervous system involvement occurs as headaches and benign intracranial hypertcnsion (pscuclotumor cerebri) (9,16,36) Peripheral
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neuropathy may occur (20), and bilateral paralysis of cranial nerves VIII, IX, and X was noted in one patient (51). Cardiac manifestations include atrial fibrillation (34,52), aortic stenosis and regurgitation, mitral regurgitation, pericardial effusion (17.33), and myocardial infarcts (28.32,34,35,53). The valvular abnormalities involve native aortic and mitral valves and homographic aortic valves (28). These cardiac manifestations may occur in association with Jaccoud's arthropathy with and without hypocomplementemia and anti-Clq autoantibody (28,32-34). Raynaud's phenomenon has been reported (16).
II.
ASSOCIATED DISORDERS
Urticarial venulitis has occurred in individuals with serum sickness, systemic lupus erythematosus [including a 4-year old girl (54)], and Sjogren's syndrome (20,55-61). Associated hematological malignan t disorders (19), some of which are case reports, include agnogenic myelodysplasia, Hodgkin's lymphoma, B-cell non-Hodgkin's lymphoma (62), acute nonlymphocytic leukemia, acute myelogenous leukemia, IgG monoclonal paraproteinemia (19,63-66), and IgA myeloma (67). Other case reports of associations include colon carcinoma (68), malignant testicular teratoma (69), polycythemia vera (70), Muckle-Wells syndrome (71), and Cogan's yndrome (72). Urticarial venulitis has occurred in patients with hepatitis B (73,74) and C (45,75,76) virus infections, infectious mononucleosis (77), Lyme borreJiosis (78), and the shunt nephritis syndrome with bacteremia, mixed cryoglobulinemia, and glomerulonephritis (79). Urticarial venulitis has developed after the administration of pota sium iodide (80), nonsteroidal anti-inflammatory agents, and in one instance each of fluoxetine (81), procarbazine (82), procainamide (83), cimetidine (84), and the use of nasal cocaine (85). Schnitzler's syndrome (86-91) consists of episodes of urticarial venulitis that occur in association with a monoclonal 19M" M component. Systemic features include fever, lymphadenopathy, hepatosplenomegaly, bone pain, and a sensorimotor neuropathy. A single patient with an IgG" M component has been reported (92). Urticarial venulitis has been described in rare instances of dermographism (93), cold urticaria (63,93-95), delayed-pressure urticaria (96), solar urticaria (97), and exercise-induced urticaria (98). The prevalence of necrotizing venulitis in individuals with physical urticaria is unknown, and the importance of this histological finding for prognosis and therapy remains to be determined. Individuals with physical urticarias have provided
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experimental models for time-course studies of the evolution of necrotizing venulitis in human skin (93,98).
III.
NATURAL HISTORY
The prevalence and natural history of idiopathic urticarial venulitis and its variants are unknown, although patients have been described with historical episodes of cutaneous lesions for up to 25 years (10). In one series with a follow-up period of I year, 40% of patients experienced complete resolution of skin lesions (16). In a series of patients (10), some of whom have been evaluated for as long as 12 years, associated diseases have not emerged. Deaths in patients with urticarial venulitis have occurred from laryngeal edema, obstructive pulmonary disease, sepsis, end-stage renal disease, valvular heart disease, and myocardial infarcts (16,17,19,28). The evolution of urticarial venulitis to systemic lupus erythematosus (54,61,99) and Sjogren's syndrome (100) has been reported. I t has been suggested that some patients with idiopathic urticarial venulitis represent a subset of patients with systemic lupus erythematosus (20), but this hypothesis remains speculative. In patients with HUVS, evolution from urticarial venulitis with normocomplementemia or from patients with hypocomplementemia without low C1q levels has not been reported in retrospective and prospective observations over 20 years (44). In patients with Schnitzler's syndrome, spontaneous remissions have not been reported, and evolution into a Iymphoplasmacytic malignant condition has been reported in 15% of patients (101). Urticarial venulitis in patients with associated systemic disorders depends on the prognosis and treatment of the underlying condition.
IV.
PATHOGENESIS
Studies in humans implicate immune complexes as the major pathobiological mechanism in the production of urticarial venulitis. Various types of physical urticaria have served as models for studies on the pathogenesis of urticarial venulitis (93,98). The presence of immune complexes is inferred from the occurrence of serum hypocomplementemia with activation of the classic activating pathway. Tissue immune complexes have been detected by direct immunonuorescence techniques as deposited immunoglobulins and complement proteins. Antigen has been identified in the case of hepatitis B virus. In patients with H UVS, hypocomplementemia, a low serum C Iq level, and
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a low-molecular-weight 7s Clq-precipitin (1-3,7,8,21), which has been identified as an IgG (I l) autoantibody that is directed against the collagenlike region ofClq (17,102-104), have been identified. There is no evidence that the anti-Clq autoantibodies contribute to the pathogenesis of urticarial venulitis. IgG and IgM autoantibodies against fgE, which have not been fully characterized, have been detected in some patients with urticarial venulitis (105). A role for lymphocytes, mononuclear cells, and Langerhans cells in the production of urticarial venulitis (4,58,59) is suggested by a perivenular infiltrate in skin lesions that is rich in lymphocytes. Evidence for the role of the mast cell is provided by an analysis of the time course of sequential histopathological changes in the skin of an individual with circulating immune complexes and hypocomplementemia, in whom cold and trauma elicited urticaria (93). Initial mast cell degranulation was followed by the infiltration of neutrophils and then by an innux of eosinophils and basophils, the deposition of fibrin, and venular endothelial cell necrosis. A postulated sequence of events would be the activation of the mast cell by physical stimuli, the release of vasoactive mediators, the deposition of circulating immune complexes with activation of the complement system, the innux of neutrophils, and the development of urticarial venulitis Another analysis of the time course of changes in the skin is provided by a study of the cellular and molecular changes in an individual with exercise-induced urticaria (98). At three hours, the number of mast cells decreased and eosinophils appeared around the venules with the deposition of eosinophil peroxidase. Tumor necrosis factor (TNF)-a levels were elevated, and E-selectin and vascular cell adhesion molecule-l (YCAM-I) were expressed on endothelial cells. Subsequently, an innux of neutrophils occurred with the deposition of neutrophil elastase and the development of urticarial venulitis. The importance of adhesion molecules in patients with urticarial venuli tis (106) was demonstrated by the detection of E-selecti n on endothelial cells in skin biopsy specimens of lesions less than 48 h. This observation was associated with the recruitment of an infiltrate of neutrophils expressing CD II b. The endothelial cells expressed human leukocyte antigen (HLA)-DR and very-late-activating antigen (YLA)-I but not P-selectin, and the perivascular cells demonstrated YCAM-l and HLA-DR. In some patients with Schnitzler's syndrome (101,107,108), but not in others (109), elevated serum levels of interleukin (lL)-6 and IL-2 receptors were detected. In some patients, serum IgG autoantibodies against IL-IO' (89, I 10,1 II) and against the alpha chain of FceRI (112) ha ve been observed.
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Histamine-releasing, functional antibodies have been noted in the serum of patients with urticarial vasculitis (l09). In one patient with urticarial venulitis, aggregates of platelet membranes with azurophil granules were observed in the dermis by electron microscopy, which suggested a role for media tors derived from platelets (I 13).
v.
HISTOPATHOLOGICAL AND IMMUNOPATHOLOGICAL FEATURES
Skin biopsy specimens stained with hematoxylin-eosin show segmental areas of fibrinoid necrosis of venules and various numbers of infiltrating neutrophils, eosinophils, and mononuclear cells; nuclear debris (leukocytoclasis); and extravasated erythrocytes (4). In some reports, rigorous diagnostic criteria were not required, which makes the diagnosis of necrotizing venulitis questionable. Although the histopathological features and infiltrating cell types are time-dependent, 111m sections (114-116) (Fig. 2) have allowed the recognition of a neutrophil-predominant and a less frequent lymphocyte-predominant pattern of cellular infiltration (114). Endothelial cells exhibit necrotic damage, hypertrophy, or shrinkage (114). Fibrin is deposited both in perivenular and in interstitial locations.
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Figure 2 Venulc with damaged cndothclial cells and perivenular fibrin. The infillrate conlains neulrophils and mononuclear cells (I pm section. Giemsa stain, original magnificalion x 100).
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On direct immunofluorescence examination (16,19,117,118), immunoreactants are deposited at the dermal-epidermal junction, or about the blood vessels. IgG, IgM, and C3 have been detected more frequently at the dermal-epidermal junction, although tgA, Clq, C4, factor B, properdin, and fibrin occasionally have been reported. tgM, C3, and fibrin have been detected frequently about the blood vessels, although fgG, IgA, IgE, factor E, and properdin have been occasionally noted. The prevalence of necrotizing venulitis in biopsy specimens obtained from patients with chronic urticaria has been reported to range from 2 to 50% (118-121), although the data are dependent on the definition of necrotizing venulitis and on reports from tertiary referral centers. Patients in some reports are assumed to have urticarial venulitis based on the presence of hypocomplementemia without histopathological confirmation in skin biopsy specimens. The prevalence of urticarial venulitis in individuals with chronic urticaria in the experience of the author and others is less than 1%. Although urticarial venulitis has been reported in patients with Schnitzler's syndrome, neutrophilic infiltrates without necrotizing venulitis are a more frequent observation in skin biopsy specimens (10 I). This finding has led to the suggestion that Schnitzler's syndrome should not be classified as urticarial venulitis (101). On direct immunofluorescence study, IgM was detected around the superficial dermal blood vessels and along the dermalepidermal junction (91). IgM autoantibodies of the same isotype can be present in the serum and deposited at the dermal-epidermal junction (91).
VI.
LABORATORY FINDINGS
Evaluation of patients with urticarial venulitis requires a history, laboratory tests, and consultations with other specialists (Table 4). In patients with idiopathic urticarial venulitis and with Schnitzler's syndrome, an elevated erythrocyte sedimentation rate (ESR) is a frequent laboratory abnormality (10,17,20), and it may fluctuate with disease activity (122). Occasionally leukopenia (122) or leukocytosis (10) may occur during flares. The platelet count is normal. Although antinuclear antibodies may be present in low titer, antibodies to double-stranded DNA are absent. Other laboratory abnormalities may include a positive rheumatoid factor, elevated immunoglobulin levels, cryoglobulins, and a false-positive serological test for syphilis. Elevated serum creatinine levels and the presence of hematuria and proteinuria may indicate renal involvement. In patients with hepatitis C virus infection, cryoglobulinemia is a frequent feature. tn a single patient with hepatitis C virus infection without cryoglobulinemia, IgM anticardiolipin and anti Ro (SS-A) antibodies were detected (123).
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Table 4
Patient Evaluation
Laboratory evaluation Erythrocyte sedimentation rate White cell count with differential analysis Platelet count Urinalysis with creatinine clearance and 24 h urine protein Blood chemistry profile Serum protein electrophoresis Hepatitis B antigen Hepatitis C antibody Cryoglobulins CH 50, Clq Antinuclear antibody Skin biopsy Consultations with nephrologists, pulmonologists, cardiologists, ophthalmologists, and neurologists when appropriate
Patients have been reported with normocomplementemia, hypocomplementemia, and hypocomplementemia with low Clq levels and anti-Clq autoantibodies (4,10,16,17,19). When hypocomplementemia is present, the classic activating pathway is involved with low levels of Clq and C4 and occasionally of C3 and C5. The complement protein factor B is rarely low (124). Cl inhibitor levels are normal. One patient with a familial partial deficiency of C3 (125) and two patients with C3 nephritic factor activity have been reported (126,127). Two patients with Schnitzler's syndrome have been reported with C4a deficiency (111). Although individuals with hypocomplementemia have more severe disease (17,18), systemic manifestations may occur in patients without hypocomplementemia (16). In patients with Schnitzler's syndrome, laboratory evaluation should include an ESR, a white cell count with differential analysis, bone radiographs, and serum electrophoresis. The patients should be evaluated for the emergence of a Iymphoreticular disorder.
VII.
THERAPY
Placebo-controlled, double-blind trials of therapy have not been reported in patients with urticarial venulitis, in those with HUVS, or in those with Schnitzler's syndrome. Most data are reported in small case studies and anecdotal case reports. The cutaneous lesions may respond to treatment with oral H I-antihistamines, nonsteroidal anti-innammatory agents,
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colchicine, dapsone, hydroxychloroquine, and when systemic medications are administered for internal organ involvement (18,20, 100,115,128). Oral glucocorticoids (16,19,20), hydroxychloroquine (L 7,19,129,130), methotrexate (131), colchicine (132,133), dapsone (17,25,46,100,134,135), cyclophosphamide (16,19), mycophenolate mofetil (66,136), thalidomide (107), interferon a2b (137), and cyclosporine (39,92) have been reported to be effective in some individuals with systemic features. Although chronic obstructive pulmonary disease in patients with HUVS failed to respond to cyclophosphamide (17), reversal of airways obstruction has occurred with cyclosporine (44). The skin lesions in one patient became worse after the administra tion of methotrexa te (138) The com bina tion of cyclophosphamide-dexamethasone pulse therapy (139), of dapsone and pentoxifylline (140), and of glucocorticoids and azathioprine (42) have been reported to be effective in case reports. The combination of doxepin, interferon-a, and ribavirin (76) has been used successfully in a patient with urticarial vasculitis and hepatitis C virus infection. Plasmapheresis resulted in transient resolution in some patients (41,100,115). A single patient improved with in tram uscular gold injections (141), and a si ngle pa tien t responded to narrowband ultraviolet B phototherapy (109). In patients with Schnitzler's syndrome, no treatment is constantly effective; however, the use of psoralen plus ultraviolet A (PUVA) photochemotherapy has allowed the reduction of the prednisone dosage (10 1,142). In some patients with HUVS, pharmacological control of the cutaneous lesions was associated with increased serum complement levels and decreased levels of anti-C Iq autoantibody levels (17).
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Hofbauer GF, Harner, Treub RM. Urticarial vasculitis following cocaine use. Br J Dermatol 1999; 141:600-60 I. JanieI'M, Bonvalet D, Blanc M-F, Lemarchard F, Cavelier B, Ribrioux A, Aguenier B, Civatte J. Chronic urticaria and macroglobulinemia (Schnitzler's syndrome): report or two cases. J Am Acad Dermatol 1989; 20: 206-211. Borradori L, Rybojad M, Puissant A, Dallot A, Verola 0, Morel P. Urticarial vasculitis associated with a monoclonal IgM gammopathy: Schnitzler's syndrome. Br J Dermatol 1990; 123: I 13-1 18. Berdy SS, Bloch KJ. Schnitzler's syndrome: a broader clinical spectrum. J Allergy C1in Immunol 1991; 87:849-854. Lebbe C, Rybojad M, Klein F, Okenhendler E, Catala M, Danon F, Morel P. Schnitzler's syndrome associated with sensorimotor neuropathy. J Am Acad Dermatol 1994; 30:316-318. Baty V, Hoen B, H udziak H, Aghassian C, Jeandel C, Canton P. Schnitzler's syndrome: two case reports and review or the literature. Mayo C1in Proc 1995; 70:570-572 Lipsker D, Spechner D, Drillien R, Schmitt P, Cribier B, Heid E, Humbel R-L, Grosshans E. Schnitzler syndrome: heterogeneous immunopathological findings involving IgM-skin interactions. Br J Dermatol 2000; 142: 954-959 Pascual-Lopez M, Hernandez-Nunez A, Sanchez-Perez J, Fernandez-Herrera J, Garcia-Diez A. Schnitzler's syndrome with monoclonal IgG kappa gammopathy: good response to cyclosporine. J Eur Acad Dermatol Venereol 2002; 16:214--219. Soter NA, Mihm MC Jr, Dvorak HF, Austen KF. Cutaneous necrotizing venulitis: a sequential analysis or the morphological alterations occurring after mast cell degranulation in a patient with a unique syndrome. Clin Exp Immunol 1978; 32:46-58 Eady RA, Keahey TM, Sibbald RG, Kobza Black A. Cold urticaria with vasculitis: report or a case with light and electron microscopic, immunofluorescence and pharmacological studies. Clin Exp Dermatol 1981; 6: 355-366. Wanderer AA, Nuss DD, Tormey AD, Giclas Pc. Urticarial leukocyclastic vasculitis with cold urticaria: report or a case and review of the literature. Arch Dermatol 1983; 119:145-151. Rajka G, Mork NJ. Clinical observations on the mechanism or delayed pressure urticaria. In: Champion RH, Greaves MW, Kobza Black A. Pye RJ, eds. The Urticarias. Edinburgh: Churchill Livingstone, 1985: 191-193. Armstrong RB, Horan DB, Silvers DN. Leukocytoclastic vasculitis in urticaria induced by ultraviolet irradiation. Arch Dermatol 1985; 121:1145-1148. Kano Y, Orihara M, Shiohara T. Cellular and molecular dynamics in exerciseinduced urticarial vasculitis lesions. Arch Dermatol 1998; 134:62-67. Bisaccia E, Adamo V, Rozan SW. Urticarial vasculitis progressing to systemic lupus erythematosus. Arch Dermatol 1988; 124:1088-1090.
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19 Angioedema: Some "New" Thoughts Regarding Idiopathic Angioedema Vincent S. Beltrani Poughkeepsie, New York, U.S.A.
Angioedema is a clinical symptom readily recognized as a usually asymmetrical, nonerythematous, nonpruritic, nonpitting, localized, transient, episodic (never persistent) swelling of a soft body area. involving lax skin, oropharyngolaryngeal tissue, and/or gastrointestinal wall.
I.
HISTORICAL BACKGROUND
The first description of angioedema (AE) in the literature is dated 1586, when Donati published a description of AE occurring in a young count who was allergic to eggs. Since it occurred with urticaria, he did not consider it a separate entity. Robert Graves (1796-1843) mentioned "acute circumscribed oedema," Perroud (Paris) in J 869 reported five cases of "ephemeral congestive swellings of the skin," and Cuntz (1874) reported four cases of "recurring edema of the skin," all of which could be considered descriptions of angioedema. John Laws Milton gave a detailed description in 1876, calling it giant urticaria but specified that it was a distinct entity from urticaria. While Heinrich Quincke described a case in 1882, it was his fellow countryman Felix Mendel who in 1902 first used his name eponymollsly. The term "angioneurotic edema" was first advocated by Smlbing in 1885. In 1888 William Osler differentiated the familial
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form of AE ("hereditary angio-neurotic edema") as a distinct entity (I). Although AE was noted to occur occasionally with urticaria, it was initially considered a distinct entity. However, that occasional association with urticaria, and its assumed resolution with antiurticarial treatment, led it to become a corollary of urticaria in the recent published literature. Warin and Champion endorsed the association when, in their excellent treatise on urticaria (I), they describe the clinical features of acute and chronic urticaria with the statement "Subcutaneous extension may occur, or the lesions may be subcutaneous from the start. For these, the term angio-oedema is preferred." Dermatology cannot assign angioedema as one of the so-called "primary" dermatological lesions (i.e., macule, papule, wheal, etc.), and it perhaps should be better appreciated as part of a spectrum of vascular (angio) phenomena occuring in the skin and/or mucous membranes.
II.
EPIDEMIOLOGY
The literature consistently refers to "urticaria and angioedema" conjointly, and their prevalence is reported as being common, occurring in 5-25°1c) of the population at any time (2-4). In a study of 554 patients, Champion et al. reported that 50% of patients with urticaria/angioedema experienced both urticaria and angioedema, 10% had angioedema alone (5). Women were reported to be affected more often than men (1.5: I ratio) (6), and angioedema seems to be included in those numbers. In my review of 86 pa tients wi th angioedema (1996-2002), the gender occurrence was reversed, with a male/female ratio of 1.5: I. The average age for chronic urticaria is repeatedly reported as 20-40 (6). In my series, the average age for AE was 49 (range, 7-72). The association with atopic disease remains debatable regarding urticaria. The dermatological literature reports that the history of atopic disorders is no more common in patients with chronic urticaria but more common for acute urticaria. Among the patients I as an allergist/dermatologist reviewed, 75% (72/96) with chronic urticaria had an atopic family or personal history, while only 25% of patients (21/86) with angioedema had an atopic history. J found that 12% of my patients with chronic idiopathic urticaria (CIU) reported a prior history of urticaria in their lifetime, while only 0.4% of patients with idiopathic angioedema had a prior history of urticaria and/or angioedema. Careful review of patients with AE reveals a different epidemiology than reported in the older litera tu reo
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PATHOGENESIS AND HISTOLOGICAL FINDINGS
The pathogenesis and histology of angioedema include the extravasation of plasma into soft tissue, induced by several potentially vasodilatory agents [i.e., histamine, bradykinin, kallidin (7), anaphylatoxins C3a, C4a, and CSa (8)]. Those vasodilatory mediators can be released by specific secretagogues [e.g., immunoglobulin E (lgE) antigens, acetylcholinesterase (ACE) inhibitors, aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), etc.], from an assortment of inflammatory cells (e.g., mast cells, eosinophils, neutrophils, basophils, etc.). Two common identifiable causes [i.e., ACE inhibitors (9,10), CI esterase inhibitor deficiency (11,12)] of AE are almost never associated with urticaria, and have in common a mechanism largely dependent upon the balance between bradykinin formation and degradation (13,14) AE, because of its association with urticaria, infers a histaminergic cause. Although histamine introduced to the upper layers of skin always elicits what is termed a hive (the triple response of Lewis), I have not been able to replicate AE by injecting histamine into the deeper layers of my skin. This, plus the lack of a consistent, effective response to antihistamines, suggests the probable role of other effector mediators. The role of inflammatory mediators in the pathogenesis and pathophysiology of skin disease is widely accepted. It is most unlikely for a single mediator to be the cause of a clinical disease. Mast cell activation, by either immunological or nonimmunological stimuli, can release a constellation of proinflammatory mediators. Higashi et aJ. reported an overproduction of cysteinyl leukotrienes (found in the urine) in asthmatic patients experiencing urticaria and angioedema (I S). Reilly et aJ. noted that leukotriene B4 was increased approximately 6.6-fold in patients with eczema (16). Leukotrienes have been recognized as a collection of metabolites of arachidonic acid, which have powerful pharmacological effects, including vasodilation and edema formation (17). Leukotriene B4 is a potent neutrophil and macrophage chemoattractant (i8).
IV.
CAUSES
Causes of AE include IgE (allergen)-induced (i.e., 13-lactam antibiotics, shellfish, nuts, etc.); activation of the kinin-forming system (e.g., ACE inhibitors); inhibition of the cyclo-oxygenase pathway of arachidonic acid metabolism (i.e., aspirin, NSAIDs, preservatives, dyes); complement activation [i.e., CIINH deficiency (HAE or AAE)]: physical (i.e., cold, pressure, etc.); so-called idiopathic AE is reserved for those cases of AE with none of the aforementioned identifiable causes.
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V.
DIAGNOSIS
The diagnosis of AE is made almost exclusively by physical examination. The history should readily support it, and often suggests a cause. AE is classified as acute (having a sudden onset, sharp rise, and short course) and may be episodic, but it is never chronic or persistent: marked by long duration (more than 6 weeks) or frequent recurrences (not acute). A more practical classification with regard to management would be based on its clinical and historical presentation. AE can occur always with urticaria, with or without an identifiable cause; occasionally with urticaria, with or without an identifiable cause; or never with urticaria, with or without an identifiable cause.
VI.
INITIAL WORK-UP
All patients with AE usually present to the specialist after the episode has resolved; most often reliance on the history is the only clue to the diagnosis. A detailed personal and family history is essential. A search for the findings discussed below is the intent of the history.
A.
IgE-induced (Food, Drug, or Latex) AE
Almost always accompanied by urticaria, this will occur within an hour of ingestion of, or contact with, the antigen. IgE-induced immediate reactions occur almost exclusively in the atopic population, and should not occur following the first exposure, since they require prior sensitization. This IgEinduced mast cell activation causes the release of histamine, as well as other preformed mediators. These reactions can be confirmed by skin prick test (SPT) or radioallergosorbent (RAST) test with the putative agent. Food allergens, especially fish, shellfish. and nuts. are common causes of allergen-induced AE. fJ-Lactam antibiotics remain the most frequent cause of allergic reactions to drugs. These immediate-type reactions present as generalized urticaria with or without angioedema (or anaphylaxis). They occur within a few minutes to I h following adminstration of the drug (Fig. I). Latex reaction occurs almost exclusively with urticaria (in atopics) (19).
B.
Inhibition of the Cyclo-Oxygenase Pathway (Aspirin, NSAIDs, etc.)
The prevalence of atopy is increased in challenge-proven aspirin/NSAIDintolerant patients (20). These reactions tend to occur laler than I h after
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Figure 1 Angioedema appeared within 15min of a dose of ampicillin.
ingestion. Patients almost always present with angioedema, and what are described as hives may occasionally be present (Fig. 2). Since this is very rarely JgE-induced, SPT are rarely of value. These reactions can be dose-related. COX-2 drugs, especially rofecoxib (Vioxx), are unlikely to cause this adverse reaction (10,20).
C.
Activation of the Kinin-forming System
This has been associated with ACE inhibitor-induced angioedema and CI esterase-inhibi tor deficiencies.
1.
ACE Inhibitor-induced AE
AE has been reported to occur in 0.1-5.0% of patients who use ACE inhibitors and it is indistinguishable from any other form of AE (2 I). It is five times more common in Afro-Caribbean Americans (22). ACE inhibitors have been reported to be the most frequent cause of acute AE in referral centers today (17-38% of AE patients) (23,24). Most cases have occurred during the first week of therapy, but cases have been reported after several years of therapy (24). Odynophagia (retrosternal pain with swallowing of food) and tongue swelling at the time of presentation should make one suspect this diagnosis (Fig. 3). Visceral AE has been noted in an increasing number of patients (25). ACE inhibitors seem to facilitate angioedema in predisposed patients (patients with a prior history of AE). The mechanism of ACE inhibitor-induced AE may be related to the
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Figure 2 Aspirin-induced AE.
Figure 3 Angioedema caused by enalapril.
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Figure 4 Patient in Figure 3 intubated following the administraion of captopril I year later.
pharmacological action of this class of medication, and the production of bradykinin is suspected as the cause of the AE. Increased levels of bradykinin have been identified in the tissue of these patients with AE (26). This AE resolves within 24-48 h after discontinuation of ACE inhibitors. It recurs (Fig. 4) irregularly, and may facilitate AE in susceptible individuals. Since angiotensin IT receptor antagonists do not increase the concentration of bradykinin, they are presumed to be safe to use in patients with ACE inhibitor-induced AE. However, in one study up to 32% of patients with ACE-induced AE experience AE when given these drugs (27). Although the incidence of AE in patients taking angiotensin IT antagonists is much less, alternatives such as an allergic (fgE) mechanism should be considered. Until the exact cause of these reactions is determined, angiotensin JI receptor blockers should be used with extreme caution in patients with a prior history of AE.
2.
C1 Esterase-Inhibitor Deficiency
This can be hereditary (HAE), or acquired and results in an excessive release of bradykinins and kallidin (see Chap. 3), which brings about vascular permeability (angioedema, including laryngeal edema), vasodilation, and contraction of the bowel smooth muscle plus bowel wall edema (abdominal cramps and pain) (18). In typical cases the symptoms of HAE appear in the first two decades of life, and the genetic defect is transmitted by
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Table 1 Differential Diagnosis: HAE and AAE HAE
AAE
Pathogenesis
lnherited genetic abnormality Deficient C1-INH
Age at onset
Early: within the first two decades of life Present
Acquired abnormality of CI-INH, most often associated with Iymphoproliferative disorders Later: usually after the fourth decade Present
Normal Decreased Decreased or normal Decreased Good
Decreased Decreased Decreased Decreased Variable
Findings
Complement abnormalities Clq complement C4 complement C IINH (Q) assay CIINH (F) assay Response to therapy
Q, quantitative; F, functional.
an autosomal dominant pattern of inheritance. However, 20-25% of cases are the result of spontaneous mutations (28). This rare but serious disorder, which can occur with or without provocation, is characterized by episodes of edema of the hands, face, airways, or intestinal wall, but urticaria is almost never seen. Acquired angioedema is a rarer disorder that has been categorized into two forms, AAE-I and AAE-H. AAE-I is associated with other diseases, most commonly B-cell Iymphoproliferative disorders. AAE-II is defined by the presence of an autoantibody directed against the C I-inhibitor molecule. Differentiating AAE-I from AAE-II is vital because different therapeutic interventions are required for each (27) (Table I).
D.
Physically Induced AE
Physically induced AE describes the episodes in which the soft tissue swelling occurs in susceptible individuals in response to a specific physical stimulus. Physical agents such as cold, pressure, vibration, and ultraviolet (UY) radiation can produce AE, which is usually associated with urticaria. Some patients react to the physical stimulus upon direct contact, and others react at the site of contact and distal to the sites, as in cold, or heat, or vibratory angioedema (30). The diagnosis of a physical AE is made from
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the patient's history, results of clinical examination, and by provoking the lesion if possible. The ice-cube test may be helpful to identify cold-induced mechanisms. Cold-induced AE and urticaria have been associated with cryoglobulins, cold agglutinin disease, cryofibrogenemia, and paroxysmal cold hemoglobulinuria.
E.
Idiopathic AE
ldiopathic AE is the diagnosis given to patients in which the AE cannot be attributed to any of the above identifiable causes and is not associated with concomitant urticaria. These patients have been classified as being histaminergic (those who respond to antihistamines) or nonhistaminergic (those who do not respond to antihistamines). Unfortunately, there is practically no literature regarding the natural history of idiopathic AE. Two of 10 patients with AE reported by Kozel et al. are reported to have been symptom-free after I year (31). In my cohort of 86 patients with idiopathic AE, the episodes would occur two to four times a year, with a rare patient experiencing more frequent episodes. Without treatment, these patients reported that the AE eventually resolved spontaneously within 96 h. None experienced serious airway obstruction. Eighty percent of the patients (69/86) reported involvement of the lip (Figs 5, 6), eye, or tongue.
Figure 5
Idiopathic AE of upper lip with urticaria.
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Figure 6
VII.
Idiopathic orbital AE.
MANAGEMENT
The history should suggest the treatment of choice for patients with each type of AE. Eliminating the identifiable trigger, if possible. is the key to management of AE. The incidence of airway obstruction in patients with idiopathic AE could not be found in textbooks, nor on Medline, but maintaining an adequate airway, if necessary, would be the main symptomatic priority. Antagonizing the proinf1ammatory mediator (5) remains the basis of medical intervention. Recognized mediators include histamine, leukotrienes, kinins, and anaphylotoxins: C3a. C4a, and C5a. Histamine is the predominant, but by no means the sole, mediator of IgE-induced AE. Leukotrienes are considered the major mediators of aspirin/NSAID-induced AE. Anaphylatoxins are the essential mediators of the complement-dependent syndromes and may, for example, relate to the urticaria and/or angioedema seen with serum sickness or connective tissue disorders. All, or anyone of these mediators may playa role in idiopathic AE.
A.
Antihistamines
Antihistamines are the mainstay of treatment for histaminergic AE. Allhough histamine may be implicated in the early phases of all AE. it is most unlikely that it plays the same role in the episodes lasting more
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than I h. Histamine antagonists (HI and H 2 ) are selective and compete peripherally with histamine for their respective receptor sites (32). The most effective blockade of the H I response requi res higher dosages than the manufacturer's recommended dosage, especially for the refractory cases. The relative number of receptors occupied by endogenous histamine compared with the therapeutic H I antagonist depends upon the relative concentrations of these substances near the receptor site (32). HI-receptors are located in the blood vessels of the skin (mediating vasodilation and increased vascular permeability), and at the dendritic terminals of C-fibers at the dermal-epidermal junction (mediating histamine-induced pruritus). H 2 -receptors are located only on the blood vessels of the skin (mediating vasodilation). Since HI-antagonists block histamine-induced vasodilation incompletely, the addition of Hrantagonists for patients with dermatograph ism (33), flushing (34), and/or dermatographia can contribute synergistically. The second-generation antihistamines (i.e., cetirizine, fexofenadine, loratidine) have been shown to posses some anti-inflammatory properties other than antagonizing histamine (e.g., vs. prostaglandin 2, leukotriene C4, kinins, and tryptase) (35). In addition, they decrease migration, accumulation, and activation of eosinophils, neutrophils, and others, and should be preferred to the earlier sedative antihistamines as first-line treatment. Other agents (hydroxyzine, diphenhydramine, doxepin), however, may be employed when they are ineffective. Doxepin (and amitryptaline) have clinically important H I and H r antagonist properties. In vitro studies estimate that they are 779 x more effective than diphenhydramine as an H I antagonist and 7 x more effective than cimetidine as an H 2 antagonist (36). They have also been shown to be more effective in vivo (37). Doxepin, 10-50 mg orally at bedtime, is my antihistamine of choice for the management of AE. B.
IJ-Agonists
;3-Agonists can reduce the mediator release from mast cells, and remain the essential treatment for anaphylaxis. The clinical experience of oral ;3agonists plus antihistamines for the treatment of urticaria or angioedema has, however, been inconsistent. Epinephrine is not effective for AE caused by CI-inhibitor deficiency (38). It is believed that the systemic levels required to inhibit mast cell degranulation in the skin would probably be toxic (39). For patients with severe laryngeal edema, high dosages (six to eight sprays) of aerosolized aqueous epinephrine sprayed onto the larynx have offered some relief when combined with systemic epinephrine and antihistamines (HI and H 2 ) (40).
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C.
Antileukotrienes
Antileukotrienes are of two classes. 5-Lipo-oxygenase inhibitors (i.e., zileuton) inhibit the synthesis of all the leukotrienes in the arachidonic acid cascade, including leukotriene B4, a potent neutrophil chemoattractant (41). Leukotriene receptor antagonists (i.e., montelukast. zafirlukast) antagonize the effect of leukotrienes C4, D4. and E4. The latter leukotrienes mediate airway smooth muscle contraction, chemotaxis, and increased vascular permeability (42). Most of the literature regarding antileukotrienes pertains to their effect on the airway. Spector and Tan were the first to report the effectiveness of leukotriene antagonists in some patients with chronic urticaria (43). Others subsequently reported similar findings (44-49). I have been prescribing zileuton 600 mg every 6-12 h plus doxepin 10-25 mg at bedtime for all patients (n = 86) with angioedema (with or without urticaria) since 1997, with good to excellent results in 85% (76/86) of patients. Patients were instructed to start the zileuton with the onset of AE, the dose was repeated every 6 h for 24 h, and every 8-12 h for 96 h after the AE has resolved. Of this total, 25% (22/86) continued the zileuton once or twice a day because they experienced episodes of AE more than four times a month. None of the patients taking zileuton once or twice daily experienced hepatic enzyme abnormalities (Fig. 7).
D.
Corticosteroids
Corticosteroids remain the mainstay for treatment of chronic allergic inflammatory disease because of their inhibitory effects on the cells involved in inflammation, as well as their ability to block the generation of mediators such as proinflammatory cytokines, chemokines, adhesion molecules, and lipid mediators. Oral systemic corticosteroids. including prednisone (0.51.0mg/kg/day), and prednisolone, are very effective treatment for exacerbations of asthma. very severe allergic rhinoconjunctivitis, urticaria, atopic dermatitis. and allergic contact dermatitis. (32) There are no reports in the literature specifically evaluating the use of corticosteroids for AE, yet it is almost always prescribed for that condition. Since there is virtually no inflammation noted histologically in patients with AE. it is not surprising that these potent anti-innammatory agents are only of questionable value in the management of AE. Yet they are often prescribed for 7-10 days for acute exacerbations, and some patients may respond to 60 mg prednisone followed by 40 mg on day 2. and then discontinued without a tapering of dosage. Occasionally some patients with severe refractory disease require prolonged treatment. Long-term use of systemic corticosteroids is associated
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Figure 7 A 62-year-old African-American man (in a nursing home) had a history of recurrent AE without urticaria of 2 years' duration. Episodes lasted from 96 to 108 h, unresponsive to epinephrine. hydroxyzine, and methylprednisone, occurring every 2-6 weeks. Upper Ie/i. Episode of AE first noted at 7 am and patient \Vas given zileuton 600 mg and doxepin 25mg. Middle Ie/i. At 8 am, lower lip edema was noted to be progressing. BO/lom left. At 9 am, lower lip and upper chin became more edematous. Upper righl. At II am, entire lower lip and chin were markedly swollen. Second dose of zileuton 600 mg advised. Middle righl. At 12 noon, before dose was administered AE had resolved. Patient was given zileuton 600mg every 6 h for that day and every 12-24 h thereafter. Each time the zileuton was discontinued, the AE recurred within 5-7 days.
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wi th increased risk for ad verse effects such as hypertension, glucose intolerance, osteoporosis, cataracts, immunosuppression, and growth suppression in children (50). Corticosteroids have been disappointing for the management of idiopathic (refractory) AE. They may be effective for IgE-induced AE, but have virtually no effect on aspirin/NSAIO-induced, ACE inhibitor-induced, and the C l-INH deficiency syndromes. Androgens (e.g., danazol, stano20101) are the most successful and commonly used medications in the prevention and treatment of symptoms of AE in patients with the Cl INH deficiency syndromes (8). These have been unsuccessful in the management of idiopathic AE (Table 2).
VIII.
IDIOPATHIC ANGIOEDEMA
By definition, idiopathic AE has no identifiable cause; therefore, symptom relief is the only available treatment. Textbooks do not differentiate the management of AE from urticaria; whenever AE is separated, so-called idiopathic AE is not differentiated and all treatments are directed towards the nonidiopa thic AE (especially the C I-IN H deficiency types). Thus neither textbook nor Medline searches discuss the management of idiopathic AE per se. It is fortunate that it is a self-limited symptom. Except for two of the 86 patients with this symptom seen by me, none required hospitalization due to significant airway obstruction. Although tongue and pharyngeal edema are common, laryngeal edema is rarely, if ever, actually present. Routine critical-care treatment with epinephrine, antihistamines (mostly intramuscular diphenhydramine), or corticosteroids offered little relief nor did it affect the natural course of the episode (e.g., resolution within 96 h). Given the panic accompanying the episodes, especially when the airway is involved, a more effective management of this problem would be desirable. Since AE is noted to be the most recurrent clinical manifestation of aspirin/NSA TO sensitivity, and since there is an overprod uction of cysteinylleukotriene (a potent vasodilator) in patients with aspirin/NSAIO-induced asthma (9), leukotrienes could be suspected of playing a role in some patients with idiopathic AE. The 1110St recently recommended treatment for aspirin/NSATO-induced asthma is the addition of antileukotrienes. Zileuton (a 5 lipo-oxygenase inhibitor) is more effective than zafurlukast [a leukotriene (C4, 04, E4) antagonist]. A trial of zileuton and doxepin for patients with idiopathic AE has been mOSl gratifying in this author's ex perience (Fig. 7).
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Management of Drug- and Food-induced AE
IgE-drug-induced reactions (usually with urticaria) Must discontinue the drug or food Epincphrine I: I000, 0.2-0.41111, subcutaneously may be required Antihistamines: preferably doxepin 10-25 mg immediately Aerosolated epinephrine (Primatine Mist) 4-6 sprays for epiglottal, uveal, 01' tongue involvement, every 10-20 min Prednisone 0.5-1.0 mgjgjday (for "late-phase") Without urticaria: antileukotriene (zileuton 600 mg every 6-12 h preferred; or zafurlukast 20 mg immediately, and four times daily) AspirinjNSAID-induced Discontinue the drug Zileuton 600 mg immediately and every 6-12 h for 4 days Doxepin 10-25 mg immediately and cvery 12-24 h for 4 days (especially with urticaria) ACE-inhibitor induced Discontinue the drug Epinephrine and intravenous methylprednisolone have been proposed for the medical management of airway obstruction, but no controlled studies have demonstrated their efficacy A trial of fresh-frozen plasma (4 units) is warranted if no response noted to above Management of CI-INH deficiency Patients with HAE require life-long treatment and careful monitoring Androgens (danazoL stanozolol) are used for prevention and treatment of AE with either HAE or AAE Intravenous administration of fresh frozen plasma (which contains CI fNH) has been helpful for acute attacks of HAE or AAE.lts prophylactic use prior to surgical procedures or dental extractions may be helpful (2 U, 12-24 h before the procedure) CI-INH concentrate (not available in the United States) is the treatment of choice for severe or life-threatening attacks of HAE. (It is not consistently effective for AA E) Antihistamines, epinephrine, or glucocorticoids are widely used, but are of questionable value Antifibrinolytic agents (tranexamic acid, 6-aminocaproic acid have had inconsistent success Cytotoxic and immunosuppressive medications (cyclophosphamide, glucocorticoids with or without plasmapheresis) are beneficial in decreasing the autoantibody of variant 2 AAE ACE inhibitors, and estrogens should be avoided in patients with HAE or AAE
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Management of Idiopathic Angioedema
Angioedema, always or occasionally with urticaria Antihistamines (H 1- and H2-antagonists): doxepin 10-50 mg every 8-12 h, as lolerated Zafirlukast 10 mg daily If no response within 2 h add zileuton 600 mg every 6-12 h as needed Continue treatment for 96 h after AE has resolved Angioedema, never with urticaria Zileuton 600mg every 6-12 h Doxepin 10-50 mg every 8-12 h, as tolerated Continue treatment for 96 h after AE has resolved In either case, prednisone 60 mg followed by 40 mg the second day may shorten the course
Eighty-five percent (76/86) of patients with idiopathic AE treated with doxepin (10-50 mg) and zileuton (600 mg every 6-12 h) reported good to exceJlent response. Although there was no control arm in my observations, each patient was contacted to obtain these results. More important was that many patients preferred the zileuton to the doxepin (or other antihistamine) alone, because of tbe better (abbeit subjective) results. Because of the uncontrolled, anectdotal nature of this reporting, further blinded controlled studies are warranted. [n patients with idiopathic nonhistaminergic AE (i.e., no response to antihistamines) with clinical features similar to a CI-JNH deficiency, a trial of androgens and/or tranexamic acid (1 g three times daily) may be warranted. There is a single double-blind placebo-controJled study showing a response (in six of eight patients) of chronic (idiopathic) urticaria and AE to treatment with warfarin. The rationale for either of these approaches is, however, not apparent (Table 3).
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Heilborn H, Hjemdahl HH, Daleskog M, et al. Comparison of subcutaneous injection and high-dose inhalation of epinephrine-implications for selftreatmenl. J Allergy C1in lmmunol 1986; 78: 1174-1179. A vila PC, Kishiyama JL, Adelman DC. Pharmacologic approaches. In: Zweiman B, Schwartz LB, eds. Inflammatory Mechanisms in Allergic Diseases. New York: Marcel Dekker, 2002:481. Onnen J M, Israel E, 0' Byrne PM Tre~ltment of asthma with drugs modifying the leucotriene pathway. N Engl J Med 1999; 340: 197-206 Spector S, Tan RA. Antileueotrienes in chronic urticaria. J Allergy C1in [mmunol 1998; 102:572. Ellis M H, Successful treatment of chronic urticaria with leucotriene antagonists. J Allergy Clin IIll1llunoi 1998; 102:786-787 Chiu TJ, Warren MS. Zafirlukast in the treatment of chronic urticaria-a case series. J Allergy C1in Immunol 1998; 10 I(suppl):S 155. Norris JG, Sullivan TJ. Leucotrienes and cytokines in steroid dependent chronic urticaria. J Allergy Clin [mlllunol 1998; (suppl):S 128 Asero R. Leucotriene receptor antagonists may prevent NSAID-induced exacerbations in patients with chronic urticaria. Ann Allergy Asthma lmll1unol 2000; 85: 156-J 57. Perez C" Sanches-Borges M, Capriles E. Pretreatment with montelukast blocks NSAID-induced urticaria and angioedema. J Allergy Clin Immunol 2001; 1060-1061. Pacor ML, DiLorenzo G, Con'ocher R. Efficacy of leukotriene receptor antagonists in chronic urticaria. Clin Exp Allergy 2001; 31:1607-1614. Barnes PJ, Pedersen S, Busse WW Effects and safety of inhaled corticosteroids. New developments. Am J Respir Crit Care Med 1998; 157:S I-S53.
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20 Systemic Disorders with Urticaria and/or Angioedema Malcolm W. Greaves Singapore General Hospital, Singapore
Allen P. Kaplan Medical University of South Carolina, Charleston, South Carolina, U.S.A.
Urticaria and angioedema may be caused by systemic disease or, theoretically, they may themselves cause systemic disease. In practice, at least with chronic urticaria, secondary systemic manifestations are rather rare. As indicated in Chapter 13, even severe unremitting chronic urticaria with or without angioedema rarely causes systemic upset apart from psychological distress. Systemic disturbance is also rarely a problem in severe relapses of hereditary angioedema, except when secondary to bowel obstruction (see Chap. 12). Of the physical urticarias (Chap. 7), only delayed pressure urticaria is regularly associated with systemic symptoms and these are usually of a vague nature (fatigue, arthralgia). Exceptionally cold contact urticaria may cause headache, palpitations, bronchospasm, bowel disturbance, and even anaphylactic shock (symptoms suggestive of histamine toxicity) if cold exposure is extensive, as in cold water bathing. ACLlte urticaria and angioedema are more frequently associated with systemic upset, especially if the outbreak is due to an allergic cause such as IgE-mediated hypersensitivity to foods or drugs, especially penicillin. Systemic reactions in the cardiovascular system, lungs, and gastrointestinal tract may be the dominant clinical presentation and may require urgent measures (Chap. 5). This account will focus on systemic disease as a cause of, or strong association with, urticaria and angioedema.
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I.
ACUTE URTICARIA AND ANGIOEDEMA
Acute urticaria and angioedema occur commonly in both adults and children. The clinical picture is perhaps most familiar to the primary care physician who may be asked to see the patient as an emergency. Since the natural history of the outbreak is usually brief, the cause often evident, and management straightforward, referral for a specialist opinion may not be required. The patient often initially experiences a feeling of warmth and pruritus accompanied by facial flushing that may become more widespread. The mouth and lips may also tingle. These symptoms herald the development of widespread urticarial lesions with angioedema of the lips, periorbital areas, and elsewhere. In more severely affected patients, systemic symptoms of acute anxiety, faintness, wheezing, bowel disturbance, and palpitations may be experienced. The most feared complications-upper respiratory obstruction, and anaphylactic shock-are fortunately rare and when they do occur the culprit is often IgE-mediated penicillin, peanut, or latex allergy. Acute allergic urticaria is reviewed in Chapter 5 and will not be considered further here. Many infections and infestations are associated with erythematous eruptions that superficially resemble urticaria. Only those that are genuinely urticarial are considered here.
A.
Systemic Infections and Infestations
Acute attacks of urticaria and angioedema can occur in response to intercurrent infection. especially in children. Sometimes unfortunately termed "acute infectious urticaria" in the published reports, it is not always clear if the eruption is caused by the infection or its treatment, or merely exacerbated by it.
1.
Bacterial Infections
In children acute bacterial infections are often associated with urticaria. Bivings (I) describes 22 children with acute urticaria ascribed to bacterial infections, streptococcal infection being especially common (2). A Japanese study (3) of 50 patients with less than I week's history of urticaria and angioedema reported that 43 cases remitted within 2 weeks, 5 cleared up between 2 weeks and 3 months, and 2 were persistent for at least I year. In 31 the apparent cause was infection, usually a respiratory or gastrointestinal infection. Urticaria developed after the infection was established. although occasionally the urticaria was prodromal. More recently Sakurai et al. investigated 19 patients with acute urticaria, most of whom were children
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(4). They were characterized by widespread urticaria, pyrexia, neutrophil leukocytosis, raised C-reactive protein, and poor response to antihistamines and systemic steroids. Throat cultures were positive for bacterial pathogens in eight, negative in four, and not done in seven patients. These patients usually responded to treatment with antibiotics with or without additional oral corticosteroids. They generally responded poorly to treatment with antihistamines. [n a large European study of S7 infants and small children (upper age limit, 3 years) with acute urticaria with or without angioedema, infection was believed to be the cause in 46 (8 J %) (5). Thirty percent went on to experience chronic urticaria.
2.
Infectious Mononucleosis
Due to the Epstein-Barr virus, and characterized by fever, pharyngitis, lymphadenopathy, and splenomegaly, the exanthem is classically erythematous and maculopapular, but urticarial eruptions may also occur (6).
3.
Schistosomiasis
Urticaria frequently occurs 4-8 weeks after the cercariae penetrate the skin, accompanied by fever, arthralgia, and diarrhea. There is also always a prominent blood eosinophilia (7). This syndrome is sufficiently common to be termed "urticarial fever" in some parts of the Far East and is due to an immunologically mediated phase of the infestation. Skin biopsy findings of urticarial lesions are generally unremarkable. Swimmer's itch is due to cercarial forms of schistosomes and may also be urticarial. Ultimately urticarial wheals are replaced by a nonurticarial pruritic papular dermatitis.
4.
Swimmer's Eruption
This eruption, which is endemic in Florida, Cuba, Hawaii, and as far north in the United States as the coast of Maine and Long Island, is due to larvae of several Cnidaria including the sea anenome and the thimble jellyfish (8,9). Urticarial wheals occur at the sites of penetration of the skin by nematocysts, are often follicular, and accompanied by fever, abdominal pain, diarrhea, and arthritis.
5.
African Trypanosomiasis
The initial systemic phase begins about a week after a local reaction to inoculation of trypanosomes into the skin by the tsetse fly. [t consists of fever and urticarial lesions that are transient, annular, and polycyclic, with intense pruritus. No cutaneous signs or symptoms are present in the later stages.
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B.
Other Causes of Acute Urticaria and Angioedema with Fever in Children
Not all acute urticaria or angioedema in infancy or childhood is associated with an infectious illness. Frequently no cause can be established, but other rare but recognized systemic syndromes should also be considered.
1.
Acute Infantile Hemorrhagic Edema
First described by Snow in 1913 (l 0), this striking acute angioedema was characterized by several reports mainly in the French literature in the 1950s and 1960s (11-13). Nowadays generally recognized as a variant of leukocytoclastic vasculitis and Henoch-Schonlein purpura, it presents an alarming clinical appearance in an infant or small child, which belies a usually benign outcome. It is characteristically preceded by an upper respiratory infection, followed by cocarde-Iike (targetoid), ecchymotic, urticarial, and angioedematous lesions often with a rosetted border, mainly on the head and neck and limbs, with or without accompanying fever. On histological examination the lesions show leukocytoclastic vasculitis. Transitory evidence of renal involvement may occur followed by total remission in about 10 days. The important differential diagnoses include meningococcal septicemia and purpura fulminans. Treatment is symptomatic.
2.
Tumor Necrosis Factor-Receptor-Associated Periodic Syndrome
This recently described autosomal dominantly inherited entity (14,15) is one of several hereditary periodic fever syndromes. In this disorder, characterized by intlammatory lesions including urticaria, a mutation in the tumor necrosis factor 55 kDa receptor causes loss of function and disordered homeostasis in leukocytes. The main clinical features include abdominal pain, pleurisy, arthritis, urticaria, conjunctivitis, periorbital edema. relapses of fever being associated with, among other symptoms, urticaria-like eruptions. It has been described in a British family of Scottish ancestry (15).
3.
Still's Disease
Still's disease (juvenile rheumatoid arthritis) characteristically occurs in children but also affects adults. It is a febrile arthritis of unknown cause. The rash is transient and serpiginous (erythema marginatum) and may appear urticarial. It occurs in 16% of patients (16). The rheumatoid factor is negative but the antinuclear factor may be positive. This disease in adults may also present with urticaria (17).
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Familial Mediterranean Fever
This rare, recessively inherited disorder (18) is characterized by attacks of abdominal pain, fever, arthritis, and skin lesions that may be urticarial (19). Urticaria may accompany attacks or may occur between attacks, and may be accompanied by angioedema (20).
II.
CHRONIC URTICARIA AND SYSTEMIC DISEASE
A.
Neonatal Urticaria
Urticaria is rare in neonates and, when present, usually denotes food allergy, drug reaction. or infection. In rare cases, however, urticaria in the neonate can be persistent, chronic, and associated with a systemic inflammatory disorder. About 100 cases of chronic infantile neurologic. cutaneous and articular syndrome (CINCA) have been described (see Chap. 12 for detailed account). Clinical features include skin. articular, and neurological changes associated with a raised erythrocyte sedimentation rate and C-reactive protein. No causative factors have been demonstrated. A rash is often the first symptom and is usually urticarial. Histological examination of a skin biopsy shows no evidence of vasculitis (21). CINCA should be considered in any child with early-onset urticaria and signs of systemic inflammation, with central nervous system and articular symptoms (22).
B.
Muckle-Wells Syndrome
This syndrome presents in children and consists of an autosomal dominant disorder with urticaria, progressive nerve deafness, arthralgia, nephritis, and amyloidosis (23). The criteria for diagnosis of this syndrome have subsequently been widened to include patients with dominantly inherited urticaria, arthritis, and sensorineural deafness (24), amyloid being deemed no more than a transitory phase of the disease. It usually runs a chronic course and is associated with a normal life expectation.
C.
Chronic Urticaria and Angioedema as an Initial Presentation of Common Variable Immunodeficiency
Recently (25) six adult patients with combined variable immunodeficiency have been described in whom chronic urticaria with or without angioedema was the initial presentation and four had a history of recurrent infections. All had reduced IgG and IgA levels and four also had reduced IgM.
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Four received intravenous immunoglobulin treatment, and in all these the urticaria subsequently remitted. In the light of these cases it seems reasonable to screen patients with chronic urticaria who have a history of recurrent infections for combined variable immunodeficiency.
D.
Human Immunovirus Infection
Human immunovirus (HIV) is associated with numerous cutaneous manifestations (26.27). Acute urticaria is recognized to occur in primary acute HIV infection when seroconversion occurs (26). There is only one report of chronic urticaria in association with HIV infection (28). In this report two patients with chronic urticaria are described. each of whom was found on investigation to be seropositive for HIV. One of these also had candidosis and dental sepsis. A causal association between the urticaria and HIV infection was not established in these patients. the urticaria being secondary to infection, drug treatment, or coincidental.
E.
Viral Hepatitis
Urticarial eruptions may occur as a prodrome before jaundice appears in patients with hepatitis B. The relationship of viral hepatitis with cryoglobulinemia and urticarial vasculitis is discussed in a later section and in Chapter 17. However. an association between viral hepatitis and socalled ordinary (nonvasculitic) chronic urticaria and angioedema has also been claimed. Kanazawa reported the presence of hepatitis C virus antibodies in 19 (24%) of 79 patients with urticaria (29). However. the same group also reported a high prevalence of hepatitis C infection in patients with psoriasis (30). These results have not been confirmed in other studies (31). In a case-control study. evidence of hepatitis C infection [detected by antibody measurement using enzyme-linked immunosorbent assay (ELISA) and genomic amplification of hepatitis C RNA] was found in only 0.9% of JIO palients and in the same percentage of age and gendermatched controls: the same incidence as in the general population (32). The rOlltine screening of patients with chronic urticaria for hepatitis C seems to be unjustified on the present evidence.
F.
Schnitzler's Syndrome
The association of chronic urticaria. fever. bone pain. raised erythrocyte sedimentation rate. and macroglobulinemia was I'irst reported by Sch11ltzler in 1972 (33). It has subsequently becn reported repeatedly. mainly in the European literature. Pruritus is usually minimal and angioedema rare.
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Skin biopsy specimens show a heavy perivascular neutrophilic infiltrate but no vasculitis (neutrophilic urticaria, see Fig. 2c in Chap. I). Although the histological appearances resemble those seen in patients with autoimmune urticaria, autoantibodies against FCE"RI have not been detected (34). The great majority of patients with Schnitzler's syndrome have a monoclonal IgM gammopathy with a light chain of the K type, but without other features of Iymphoproliferative disease (35). However, an IgG paraproteinemia has been reported (36) and was found in two patients (unpublished report) of one of the present authors (MWG). Bone marrow examination usually yields normal or nonspecific results. The condition needs to be differentiated from Waldenstr6m's macroglobulinemia, in which urticaria is an uncommon feature and the bone marrow usually shows lymphoid proliferation. The prognosis of Schnitzler's syndrome is benign and although occasional patients have developed Iymphoproliferative malignancy, this has occurred late in life (37).
G.
Urticarial Vasculitis
This condition is reviewed in detail in Chapter 17. It has also been recently reviewed (38). Urticarial vasculitis is an important differential diagnosis of chronic idiopathic urticaria and is probably substantially underdiagnosed. However, the diagnosis should not be made in the absence of histological confirmation from a skin biopsy specimen. It is due to deposition of immunoreactant in the walls of the postcapillary venules leading to complement activation. Urticarial vasculitis should be looked upon as a continuous spectrum ranging from patients with no evidence of systemic disease to those with severe systemic involvement. Hypocompementemia is an unusual finding in skin biopsy-proven urticarial vasculitis and is usually termed hypocomplementemic urticarial vasculitis syndrome. When it occurs, often in association with systemic lupus erythematosus, there is usually a marked and selective reduction in Clq due to antibodies against C Iq (39). Angioedema is common, as is associated systemic disease including obstructive pulmonary disease, glomerulonephritis, and ocular inflammation (39). However, most patients with confirmed urticarial vasculitis have no detectable circulating immunoreactants or hypocomplementemia (38). Nevertheless, in these patients systemic symptoms and signs are common. In a comprehensive review of 72 cases (40), Mehregan published figures for frequency of 40% for arthralgia, 21 % for pulmonary disease, 5-10% for renal disease, 20% for gastrointestinal complications, and fever in 10%. Underlying causative disease should always sought in patients with urticarial vasculitis (41). Human serum sickness is widely recognized to be
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Table 1 Frequently Recognized Causative Systemic Diseases in Urticarial Vasculitis Autoimmune connective tissue diseases: systemic lupus erythematosus hypocomplementemia, Sjogren's syndrome Serum sickness Infections: hepatitis C with cryoglobulinemia, Lyme disease Inflammatory bowel disease
+/~
an immune complex disease presenting in the skin with urticarial lesions. Lawley describes 12 patients with serum sickness, eight of whom had urticarial eruptions (42). However, it was surprising that in five patients from whom a skin biopsy was obtained none showed evidence of vasculitis. More commonly, urticarial vasculitis with or without hypocomplementemia is associated with autoimmune connective tissue diseases including systemic lupus, and less commonly Sjogren's syndrome and may precede these disorders (43) Inflammatory bowel disease is another important underlying cause (40). Of infections, the best recognized precursor of urticarial vasculitis is hepatitis C (44). Patients with urticarial vasculitis due to hepatitis C infection usually have evidence of polyclonal cryoglobulinemia. Urticarial vasculitis bas also been reported as a manifestation of Lyme disease due to infection with Borrelia bllrgdOljeri (45). The systemic diseases recognized to be associated with urticarial vasculitis are listed in Table I.
III.
ANGIOEDEMA AND SYSTEMIC DISEASE
Urticaria secondary to the above-mentioned systemic diseases is frequently associated with angioedema. However, angioedema may occasionally be the dominant clinical presentation. Hereditary angioedema due to autosomal dominantly inherited deficiency of the inhibitor of the first component of complement is described in detail in Chapter 13. However, acquired angioedema due to B-cell lymphoma and related causes has been reported and will be briefly mentioned here. This subject was reviewed in 1997 (46)
A.
Acquired Angioedema Due to B-Cell Lymphoproliferative Disease
This is a rare disease in which acquired deficiency or the inhibitor or the first component of complement occurs due to increased consumption
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(catabolism). The disease is associated with low levels of Clq and is thought to be due to production by the B cells of anti-idiotype antibodies that react with the idiotype of monoclonal immunoglobulins and cause increased consumption of complement Cl inhibitor and Clq. The presenting symptoms appear later tban in hereditary angioedema, usually after the fourth decade and there is no family history. Apart from lymphomas the disease may occur in association with chronic lymphatic leukemia, multiple myeloma, Waldenstr6m's macroglobulinemia, and monoclonal gammopathies. Occasional patients have been described in whom the deficiency was associated with non-B-cell malignancies (rectal carcinoma) (47) and T-cell lymphoma (48).
B.
Acquired Angioedema Due to Autoantibodies Against the Complement C1 Inhibitor Molecule
In this rare syndrome B cells secrete autoantibodies that bind to the active site on the molecule. Not only is the complement CI inhibitor inactivated but consumption of the inactivated inhibitor is also increased (49). Reported underlying diseases in patients with these autoantibodies include liver angioma, chronic lymphocytic leukemia, and breast cancer (50).
C.
Acquired Episodic Angioedema and Eosinophilia
In 1984 Gleich (51) reported four patients with recurrent attacks of angioedema and fever, leukocyte counts reaching over 100,000/cu mm, with 88% eosinophils. Affected patients, although suffering gross angioedema and marked weight gain, were otherwise well and the disease ran an essentially benign course in each patient. The edema was apparently due to degranulated eosinophils and released major basic protein. No evidence of cardiac or other internal organ involvement was detected and the condition appears to be distinct from the hypereosinophilic syndrome. Subsequent studies (52) in three patients showed that the eosinophils in this condition were distinct in terms of cell density from those found in the hypereosinophilic syndrome. All three patients with episodic angioedema and hypereosinophilia had circulating antiendothelial antibodies of the IgG subtype but these were not found in the sera of patients with the hypereosinophilic syndrome or in healthy controls. It is possible that the episodes of angioedema are due to the combined effects of endothelial damage and deposition of eosinophil major basic protein.
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Bivings L. Acute infectious urticaria. J Paediatr 1946; 28:602-604. Schuller DE, Elvey SM. Acute urticaria associated with streptococcal infection. Paediatrics 1980; 65:592-596 Aoki T, Kojima M, Horiko T. Acute urticaria: history and natural course of 50 cases. J Dermatol 1994; 21:73-77. Sakurai M, Oba M, Matsumoto K, et al. Acute infectious urticaria: clinical and laboratory analysis in 19 patients. J Dermatol 2000; 27:87-93. Mortureux P, Leaute-Labrez C, Legrain-Lifermann Y, et al. Acute urticaria in infancy and early childhood. Arch Dermatol 1998; 134:319-323. Cooper KD. Urticaria and angioedema: diagnosis and evaluation. J Am Acad Dermatol 1991: 25:146-154 Gonzalez E. Schistosomiasis, cercarial dermatitis, marine dermatitis Dermatol Clin 1989; 7291-300 Freudenthal, AR. Seabather's eruption range extended northward and a causative organism identified. Rev Int Oceanogr Med 1991; 101.137-147. Wong D, Meinking TL, Rosen LB, et al. Sea bather's eruption. J Am Acad Dermatol 1994; 30:399-406. Snow 1M. Purpura urticaria and angioneurotic edema of the hands and feet in a nursing baby. JAM A 1913; 61:18-19. Gerbaux J, Hebert- Jouas J. Sur une observation d'oedeme aigu hemorrhagique de la peau. Arch Fr Pediatr 1958; 15:1266-1269. Nouaille J, Gautier M. Lucet P. Un cas de vascularite allergique a type d'oedeme aigu haemorrhagique de la peau avec rnanifestations renales. Arch Fr Pediatr 1960; 17:110-113. Laugier F, Hunziker N, Rieffers J, et al. L'oedeme aigu hemorrhagique du nourisson (purpura en coca rde avec oedeme). Derma tologica 1970; 141:113-118 Me Dermott MF, Aksentijevieh I, Galon J, et al. Germline mutations in the extracellular domains of the 55 kDa TNF receptor, TNFR I, define a family of dominantly inherited autoinAammatory syndromes. Cell 1999; 97:133-144 Galon J, Aksentijevieh L Me Dermott MF, et al. TNFRSIA mutations and autoinAammatory syndromes. Curr Opin Immunol 2000; 12:479-486. Isdale IC, Bywaters EGL. The rash of rheumatoid arthritis and Still's disease. Q J Med 1956; 99:377-383 Setterfield JF, Hughes GYR. Black AK. Urticaria as a presentation of adult onset Still's disease. Br J Dermatol 1998; 118:904-927. Ehrenlleld EN, Eliakim M, Raehmilwitz M. Recurrent polyserositis (fami lia I Medilerranea n fever; periodic disease). Am J Med 1961; 3J: 107-111. Siegel S. Familial paroxysmal polyserositis. Am J Med 1964; 36:893-900. Sohar E, Gafni J, Pras M. Heller H. Familial Mediterrane~ln fever. A survey of 470 cases and a review of the literature. Am J Med 1967; 43:227-234.
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Guillet G, Dupre D, Guillet MH, et al. Bi-symptomatic CINCA syndrome with inaugural urticaria and major articular lesions. Ann Derm Venereol 1999; 126331-334.
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Ferdman RM, Shaham B, Church JA. Neonatal urticaria as a symptom of a multisystem inflammatory disease. J Allergy Immunol 2000; 106: 986-987. Muckle TL, Wells M. Urticaria deafness and amyloidosis-a new hereditofamilial syndrome. Q J Med 1962; 31 :235-238. Throssell D, Feehally J, Trembath R, Walls J. Urticaria, arthralgia and nephropathy without amyloidosis: another variant of the Muckle-Wells syndrome? Clin Genet 1996; 49: 130-133. Altschul A, Cunningham-Rundles C. Chronic urticaria and angioedema as the first presentations of common variable immunodeficiency. J Allergy Clin Immunol2002; 110:667-668. Dover JS, Johnson RA. Cutaneous manifestations of human immunodeficiency virus infection (part I). Arch Dermatol 1991; 127: 1383-1391. Dover JS, Johnson RA. Cutaneous manifestations of human immunodeficiency virus infection (part 2). Arch Dermatol 1991; 127:1549-1558 Friedman D, Picard-Dahan C, Grossin M, Belaich S. Chronic urticaria revealing an HIV infection. Eur J Dermatol 1995; 5:40-41. Kanazawa K, Yaoita H, Tsuda F, Okamoto H. Hepatitis C virus infection in patients with urticaria. J Am Acad Dermatol 1996; 35:195-198. Kanazawa K, Aikawa T, Tsuda F, Okamoto H. Hepatitis C virus infection in patients with psoriasis. Arch Dermatol 1996; 132: 1391-1392. Smith R, Caul EO, Burton JL. Urticaria and hepatitis C. Br J Dermatol 1997; 136980. Cribier B1, Santinelli F, Schmitt C, et al. Chronic urticaria is not significantly associated with hepatitis C or hepatitis G infection. Arch Dermatol 1999; 135: 1335-1339. Schnitzler L. Lesion urticariennes chroniques permanents (erytheme petaloide?). Case cliniques n. 46 B (Abstr 46). Journee Dermatologique Angers 1972; 28th October. Gallo R, Sabroe RA, Black AK, Greaves MW. Schnitzler's syndrome: no evidence for an autoimmune basis in two patients. Clin Exp Dermatol 2000; 25:281-284. Almerigogna F, Giudizi MG, Cappelli F, Romagnani S. Schnitzler's syndrome: what's new? J Eur Acad Dermatol 2002; 16:214-219. Nashan D, Sunderkotter C, Bonsmann G, et al. Chronic urticaria, arthralgia raised erythrocyte sedimentation rate and IgG4 paraproteinaemia: a variant of Schnitzler's syndrome? Br J Dermatol 1995; 133:132-134. Lipsker D, Veran Y, Grunenberger F, et al. The Schnitzler syndrome. Four new cases and a review of the literature. Medicine 200 I; 80:37-44. Black AK. Urticarial vasculitis. Clin Dermatol 1999; 17:565-569. Wisnieski JJ, Baer AN, Christensen J, et al. Hypocomplementaemic urticarial vasculitis syndrome. Medicine 1995; 74:24-41.
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21 Idiopathic Anaphylaxis, Systemic Mastocytosis, and the Hypereosinophilic Syndrome Allen P. Kaplan Medical University of South Carolina, Charleston, South Carolina, U.S.A.
Malcolm W. Greaves Singapore General Hospital, Singapore
The presence of urticaria and/or angioedema requires considerations of allergic reactions to drugs and foods as part of the differential diagnosis. Among the pathogenic hallmarks of allergy are the degranulation of cutaneous mast cells due to bridging of IgE molecules by allergen that is, at minimum, bivalent, and also to infiltration of eosinophils as part of a latephase reaction. The same can occur as a result of mast cell activation by alternative mechanisms. such as occurs in the autoimmune subgroup of patients with chronic urticaria and angioedema, as well as the group whose condition remains idiopathic because an initiating stimulus has not yet been identified. When activation of mast cells is systemic, rather than being confined to the skin, the result can be idiopathic anaphylaxis. Other disorders are characterized by a proliferation of either mast cells or eosinophils, with symptoms resulting not only from tissue infiltration by such cells but also because there is abnormaL seemingly spontaneous, secretion of mediators by the cells with resulting constitutional symptoms or organ damage. Systemic mastocytosis and the hypereosinophilic syndrome can be characterized in this fashion.
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I.
IDIOPATHIC ANAPHYLAXIS
This is a diagnosis by exclusion, in which symptoms of recurrent anaphylaxis occur with no identifiable cause. Among the symptoms are nushing, urticaria, and angioedema that appear similar to what one might see in a patient with food or drug allergy or with chronic urticarial angioedema whose symptoms are intermittent. The angioedema is often facial, with swelling of the lips, cheeks, or periorbital area, but may also include swelling of the tongue or pharynx as well as laryngeal edema or swelling of the extremities or genitalia. The presence of additional, noncutaneous symptoms prompts a diagnosis of anaphylaxis. These may include overt wheezing (or cough or dyspnea caused by bronchospasm), gastrointestinal symptoms including any combination of nausea, vomiting, cramps, or diarrhea, with the latter two symptoms being most common, and hypotension (1-3). A classification of patients presenting with idiopathic anaphylaxis has been reported by Wong et a!. (2) and is shown in Table I. This classifies patients into groups depending on the frequency of symptoms and the particular manifestations. It should be noted, however, that group IA-A-I and IA-A-F refer to patients with angioedema in whom the swelling is severe and potentially life-threatening, including angioedema of the tongue and pharynx to such a degree that secretions cannot be handled. Thus there is a risk of aspiration as well as mechanical airway compromise, or edema of the glottis and/or vocal cords (laryngeal edema). Since no test can be used to confirm a designation of idiopathic anaphylaxis, one might also consider such patients to have extreme versions of idiopathic angioedema. In all patients, CI inhibitor deficiency, use of acetylcholinesterase (ACE) inhibitors, or identifiable allergic precipitants of such reactions must be excluded before a diagnosis of idiopathic anaphylaxis can be made. Skin prick testing andlor radioallergosorbent test (RAST) for food allergy is required. If positive results are obtained. there must be absence of symptoms with omission of the putative allergen(s) andlor historically consistent correlation of symptoms with ingestion of the substance in question (4). An extensive array of food stuffs, spices, and condiments must be tested. Exercise-induced anaphylaxis (with or without food hypersensitivity) (5-8) must be ruled out (i.e., no relationship of episodes to physical activity). To confirm the authenticity of the anaphylaxis there should be objective documentation of the anaphylactic event based on personal observation. emergency room records, pulmonary function testing, or elevated f3-tryptase levels during an episode. There is an entity designated undifferentiated somatoform idiopathic anaphylaxis (9) with symptoms that resemble an~lphylaxis but without objective evidence, which responds
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Table 1 Classification of Idiopathic Anaphylaxis Disease
Symptoms
Idiopathic anaphylaxis generalized infrequent (lA-G-I)
Idiopa thic-anaphylaxis generalized frequent (IA-G-F)
Idiopathic anaphylaxis angioedema infrequent (lA-A-I)
Idiopathic anaphylaxis angioedema frequent (lA-A-F)
Idiopathic anaphylaxisquestionable: (lA-Q)
Idiopathic anaphylaxis variant: (lA-V)
Urticaria or angioedema with bronchospasm, hypotension, syncope, or gastrointestinal symptoms with or without upper airway compromise with infrequent episodes (fewer than six episodes per year) Urticaria or angioedema with bronchospasm, hypotension, syncope, or gastrointestinal symptoms with or without upper airway compromise with frequent episodes (six or more episodes each year) Urticaria or angioedema with upper airway compromise such as laryngeal edema, severe pharyngeal edema, or massive tongue edema without other systemic manifestations with infrequent episodes (fewer than six episodes per year) Urticaria or angioedema with upper airway compromise such as laryngeal edema, severe pharyngeal edema, or massive tongue edema without other systemic manifestations with frequent episodes (six or more episodes per year) A patient referred for management with a presumptive diagnosis or LA for which repeated attempts at documentation of objective findings are unsuccessful, response to appropriate dosages of prednisone do not occur, and the diagnosis of IA becomes uncertain Symptoms and physical findings of IA vary from classic findings or lA, IA-V may subsequently be classified as IA-Q, or IA is excluded, or IA-A or IA-G
Source: Ref. 2.
poorly (if at all) to therapy and may represent a psychiatric disorder (9). A combination of flushing syndrome, paradoxical motion of the vocal cords, and irritable bowel syndrome could present in this way. Treatment of idiopathic anaphylaxis depends on the frequency and severity of the attacks. If the episodes are infrequent, one may try to treat
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episodes as they occur: with an Epipen, a combination of H 1- and H 2antagonists, an albuterol inhaler, and 60-100 mg prednisone. However, frequent symptoms require sustained treatment to prevent attacks. A useful antihistamine regimen would consist of dyphenylhydramine 50 mg four times daily, rantidine 150 mg twice daily, an oral sympathomimetic might be added, plus an Epipen and albuterol inhaler for use as needed. More severe episodes require the addition of corticosteroid. For the most severe cases (3), a week of prednisone at 60 mg/day is recommended, followed by q.o.d. prednisone at 40-60mg/day for many months, and gradual tapering as symptoms allow. Patients with so-called malignant idiopathic anaphylaxis may have to continue steroid therapy for many years, although eventually most succeed in finally eliminating it (10).
II.
SYSTEMIC MASTOCYTOSIS
Whereas idiopathic anaphylaxis results from activation of mast cells by some uncertain mechanism, the symptoms of systemic mastocytosis result from a proliferation of mast cells that is also associated with cell activation. The skin manifestations can be varied; however, the urticaria associated with it corresponds to a physical urticaria: dermatographism. Patients may have classic dermatographism, associated with diffuse infiltration of the skin with mast cells, or may urticate in association with rubbing lesions of urticaria pigmentosa (Darier's sign) (II). There is considerable overlap of symptoms and signs between idiopathic anaphylaxis and acute exacerbations of systemic mastocytosis, although the elicitation of Darier's sign and presence or absence of other cutaneous signs of hyperproliferation of dermal mast cells should help in making the correct diagnosis. Patients with both conditions may complain of flushing, hypotensive episodes, cramps and diarrhea, less commonly nausea and vomiting, and occasionally asthma. Angioedema is much less likely to be seen with systemic mastocytosis than idiopathic anaphylaxis. Urticaria pigmentosa in children most commonly presents with tan to brown lesions that urticate and itch and may blister without evidence of symptoms in any other system or. organ. They usually gradually resolve uneventfully. The lesions are typically on the abdomen and trunk and spare the face, palms, soles, and scalp. Systemic symptoms including flushing, wheezing, and signs of distress m;Jy occur if the skin is extensively rubbed, for example, due to vigorous towelling (Fig. 1). Adults who present with urticaria pigmentosa are more likely to have systemic mastocytosis even if spread beyond the skin is not evident at the time of diagnosis (Figs. 2, 3). Uncommon forms of cutaneous mastocytosis presenting in children include
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Figure 1 A child with systemic mastocytosis shows lesions of urticaria pigmentosa, a facial Dush, and Darier's sign (midabdomen).
Figure 2
Urticaria pigmentosa in an adult with systemic mastocytosis.
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Figure 3
Histological specimen from a patient with urticaria pigmentosa shows mast cells stained for chloracetate esterase. Magnification is 40 x.
solitary tumors (mastocytomas), usually seen prior to 6 months of age but occasionally seen in older children or rarely adults, and diffuse cutaneous infiltration with mast cells presenting with erythroderma or with bullous skin lesions that can be hemorrhagic, or with diffusely edematous skin: so-called peau d'orange (12) Solitary local mastocytomas in children may result in severe acute systemic symptoms if made to wheal or blister by rubbing vigorously. A classification of the specific categories of systemic mastocytosis is given in Table 2. The most common form of systemic mastocytosis seen in adults is termed indolent mastocytosis, in which there is evidence of systemic involvement but it progresses very slowly over many years or even decades, and has a relatively good prognosis. Lesions of diffuse urticaria pigmentosa are seen in more than 90% of patients (1 I). Less frequently there may be diffuse cutaneous infiltration with mast cells. About I % of cases have telangiectasia macularis eruptiva perstans characterized by tan or brown macules with patchy erythema and telangiectasia (11, 12). The tryptase level (13-15) (representing pro Cl'-tryptase) is elevated, usually beyond 20, with a Cl'/fJ ratio that also exceeds 20 (16). !3-tryptase, representing the cleaved, active form of the enzyme, is associated with bonafide anaphylactic episodes
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Table 2 Classification of Systemic Mastocytosis Category l: [ndolent mastocytosis Syncope Cutaneous disease Ulcerative disease Malabsorption Bone marrow mast cell aggregates Skeletal disease Hepatosplenomegaly Lymphadenopathy Category H: Mastocytosis with an associated hematological disorder Myeloproliferative disease Myelodysplastic disease Category III: Aggressive mastocytosis Lymphadenopathic mastocytosis with eosinophilia Category IV: Mastocytic leukemia Source: Modified from ReI'. II.
(17) and thus becomes elevated when an acute event occurs. Thus tl-tryptase levels are elevated in patients with idiopathic anaphylaxis when a major episode occurs. The presence of elevated a-tryptase in systemic mastocytosis indicates that these proliferating cells also have an enhanced baseline secretory capacity. Among the other manifestations that may be seen are lymphadenopathy, hepatomegaly, and splenomegaly due to organ infiltration with mast cells, and infiltration of the gastrointestinal (Gl) tract with mast cells may contribute to the abdominal pain and diarrhea that may be seen. The GI involvement is very common (about 80% incidence) and pain and diarrhea may also be due to altered intestinal secretion or hypermotility, or rarely, peptic ulcer disease. There is an increased incidence of gastroesophageal retlux disorder and duodenal ulcer, and there may be infiltration of bone with mast cells causing lytic bone lesions osteoporosis and/or osteosclerosis. Osteoporosis appears to correlate with serum interleukin 6 levels (18). The bone marrow has an increased number of mast cells. Bone marrow biopsy can be helpful in making the diagnosis (19,20). Involvement can be detected in 70% of patients. Less commonly, other organ involvement may be seen, such as the lungs or heart. The secretion of heparin can lead to bleeding, although that is uncommonly seen. Hypotensive episodes can lead to stroke or acute tubular necrosis and renal failure. Three less commonly seen presentations of systemic mastocytosis have a poorer prognosis. One group has bone marrow (and peripheral blood) evidence of a myeloproliferative disorder or myelodysplasia and the
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prognosis relates to the cause of the underlying hematological abnormality. Another subgroup presents with the features described above for indolent mastocytosis but has more rapidly progressing organ involvement and is called aggressive mastocytosis (Table 2). With time, there are fewer symptoms attributable to the consequences of mast cell secretion, and more difficulty with organ infiltration. Such patients do not have urticaria pigmentosa and are less likely to be dermatographic. Some may evolve into a malignant lymphoma, having begun with more typical systemic mastocytosis (21). The third, and most rare (about I %), with the worst prognosis is seen in patients with mast cell leukemia. Patients with mastocytosis, and especially those with systemic involvement, are prone to development of anaphylactic shock due to bee or wasp stings (22). This may occur due to a direct effect of venom on mast cells or to an IgE-mediated hypersensitivity reaction. Patients at risk, including agricultural workers, hikers, golfers, and gardeners, should carry an Epipen and wear an engraved emergency advice bracelet. Immunotherapy may be indicated (23). The cause of the mast cell proliferation is not known in most instances: however, two general abnormalities have been identified that may be relevant to the pathogenesis in some patients. Increased levels of stem cell factor (mast-cell-activating factor or c-kit ligand) has been demonstrated in some patients with indolent mastocytosis. The source of the increased stem cell factor secretion is not clear, but the effect would be to drive both the proliferation and secretion of mast cells throughout the body. The cell surface receptor for stem cell factor is c-kit, a tyrosine kinase found in hematopoietic cells, mast cells, melanocytes, and germ cells. Most work regarding the underlying pathogenesis of systemic mastocytosis relates to mutations in this cell surface tyrosine kinase. An inactivating mutation of c-kit is associated with piebaldism (4), while mutations relating to systemic mastocytosis cause constitutive cell activation (24-27). Nagata et aL (25) have shown that a substitution of valine for aspartic acid 816 can be demonstrated in the mononuclear cells of patients with systemic mastocytosis, particularly those associated with a hematological abnormality that leads to autophosphorylation of c-kit and activation of mast cells to proliferate and to secrete. The mutation has also been found in indolent as well as aggressive mastocytosis and in children with extensive disease. A similar c-kit mutation expressed by melanocytes accounts for the increased melanogenesis, which in turn leads to the hyperpigmentation of urticaria pigmentosa. Other mutations have been identified that may modulate function of the kinase but are not within the catalytic domain (28). These are more likely seen with gastrointestinal stromal cell tumors. The diagnostic studies that are helpful to substantiate a diagnosis of systemic mastocytosis inclLlde elevated O'-tryptase leveL increased 24 h
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histamine excretion, a skin biopsy demonstrating markedly increased mast cells, and a bone marrow biopsy demonstrating increased mast cells. Increased numbers of dermal mast cells are found in a number of other inflammatory skin disorders, but a highly evident increase in a suitably stained skin biopsy supports a diagnosis of mastocytosis. Other studies that may be helpful and are indicated when other organ involvement seems likely or is suspected include skeletal scintigraphy, bone density scan, and computed tomographic (CT) scan of the abdomen with contrast. Although not discllssed in detail here, it is important to note that confusion with carcinoid syndrome may occur (29). Patients with carcinoid syndrome have a characteristic flush once an abdominal carcinoid has metastasized to the liver, but do not have urticaria or angioedema or hypotension. Abdominal cramps and diarrhea are characteristic, and patients may have right-sided heart disease with heart murmurs or heart failure. Some patients with carcinoid syndrome may wheeze. The typical patient will have an elevated 24 h urine 5-hydroxy indole acetic acid with normal 24 h urine histamine and a normal tryptase level. One must be aware of the fact that atypical carcinoids, usually gastric in origin, secrete histamine and/or 5-hyd roxytryptophen a nd may have symptoms of flushing, itch (usually without hives), wheezing, and hyperacidity but no hypotension or lower abdominal symptoms. Treatment of systemic mastocytosis can relate to the consequences of mediator release or organ infiltration, or hematological abnormality. A combination of H 1 - and Hrantagonists in high dosages (e.g., diphenhydramine 50 mg four times daily and ranitidine 150 mg twice daily) will help to control cutaneous systems and hypotension. Oral cromolyn sodium in high quantities (which is not significantly absorbed) may aid in controlling gastrointestinal symptoms. There is no clear evidence whether modalities that help osteoporosis (phosponates or miacalcin) will provide similar help for the bone disease of systemic mastocytosis. Alpha-interferon has been used in selected patients with severe systemic mastocytosis, but this expensive treatment is of uncertain benefit and is regularly a cause of troublesome side effects (30). The symptoms and signs of cutaneous mastocytosis can be effectively ameliorated by psoralen/ultraviolet A (PUVA) photochemotherapy (31).
III.
HYPER EOSINOPHILIC SYNDROME
A proliferation of eosinophils with clinically significant invasion of tissues
is the hallmark of the hypereosinophilic syndrome. This is a diagnosis of exclusion: other causes associated with eosinophilia, particularly with tissue
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invasIon, must be ruled out. These include drug reactions, parasitic infections, Loeffler syndrome, Churg-Strauss-type vasculitis, and eosinophilic leukemia. More extensive reviews of the hypereosinophilic syndrome ha ve been published elsewhere (32). The only urticarial cutaneous manifestations described is a rare physical urticaria termed immediate pressure urticaria (33). Patients with this symptom have prompt wheal-and-flare formation at sites of pressure, yet do not respond to the stroking that triggers dermatographism. Eosinophil infiltration of the skin may cause other cutaneous manifestations such as formation of nodules or plaques. It would then be necessary to differentiate this from Wells' syndrome, which is caused by a heavy dermal and subcutaneous infiltration by activated and degranulated eosinophils without involvement o"f other organs (34). It· should also be differentiated from eosinophilic folliculitis that can be seen in patients with acquired immunodeficiency syndrome (AIDS) as well as Kimura's disease, which presents with eosinophilia, cutaneous eosinophilic folliculitis, and lymphadenopathy (35). One of the major manifestations of the disease is eosinophilic infiltration of the heart. This can present as an acute myocarditis, or as an end-stage endomyocardial fibrosis. Restrictive cardiomyopathy or a dilated cardiomyopathy with congestive heart failure may be seen Cardiac manifestations are seen in over 50% of patients and the complication of heart disease represents the most frequent cause of mortality (36-38). Associated with this are embolic manifestations due to thrombus formation within the dilated cardiac chambers (39). Pulmonary emboli, stroke, or peripheral embolization may be seen. Pulmonary manifestations include eosinophilic pneumonitis that overlaps with the manifestations of Loerner syndrome, pulmonary emboli as noted above, or, more rarely, eosinophilic pleural effusions. Forty percent of patients have pulmonary manifestations, although wheezing is uncommon (28). Transudative effusions may be seen with congestive heart failure. The blood count is typically elevated and can be anywhere from 20,000-100,000. A differential with 70-90% eosinophils is not unusual (40). Differentiation from an eosinophilic leukemia is made by bone marrow examination. A myeloproliferative disorder will have blast cells or other immature forms, while the hypercosinophilic syndrome will show normal maturation progression and a marked proliferation of mature eosinophils. Although less definitive, the blood smear may also show immature forms and blast cells iC there is a frank leukemic phase. The end-stage eosinophils have characteristics of an activated eosinophil with a hypodense phenotype, positive staining for EG2, and expression of CD4 (41).
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Neurological manifestations of the hypereosinophilia syndrome are also quite Common and include peripheral neuropathy (sensory or motor, or combined), radiculopathy, and less likely central nervous system symptoms such as an eosinophilic meningitis. There may also be embolic stokes. Differentiation from Churg-Strauss vasculitis is necessary in cases in which there may also be a peripheral neuropathy or mononeuritis multiplex. Patients with Churg-Strauss syndrome are more likely to have an axonal neuropathy due to vasculitis of the vaso nervosum, while hypereosinophilic syndrome is more likely to be associated with eosinophilic infiltration and demyelination. Any organ can be infiltrated with eosinophils: hepatosplenomegaly or lymphadenopathy may also be seen. The underlying pathogenesis of the disorder is not yet clear; however, there is evidence that one underlying abnormality may be a predominance (or clonal expansion) of CD4 (+) T lymphocytes of the TH2 subtype (42) with secretion of interleukin-S (ILS), a major eosinophil growth factor (43). IL4 may be overproduced as well, and this can account for the high levels oflgE antibody seen in some patients (44,45). These patients are more likely to be responsive to steroid treatment. Treatment may include use of corticosteroids, or hydroxy urea; the most recent data suggest that interferon a may be the drug of choice for progressive disease (46).
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96: 1609- J614 Hirota S, lsozaki K, Moriyama Y, Hashimoto K, Nishida T, Ishiguro S, Kawano K, Hanada M, Kurata A, Takeda M, Muhammad TG, Matsuzawa Y, Kanakura Y, Shinomura Y. Katamura Y. Gain of function mutations of c-kit in human gastrointestinal stromal tumors. Science 1998; 279577-580. Metcalfe DD. Differential diagnosis of the patient with unexplained Aushing/ anaphylaxis. Allergy Asthma Proc 2000; 21 :21-24. Butterfield JH. Response of severe mastocytosis to interferon a. Br J Dermatol 1998; 138:489-495 Granerus G, Roupe G, Swanbeck G. Decreased urinary histamine metabolite after successful PUVA treatment of urticaria pigmentosa . .I Invest Dermatol 1981; 76:1-3. Boyce .lA, Owen WF Jr. Idiopathic hypereosinophilic syndrome. In: Allergy, Second Edition. Philadelphia: W.B Saunders, 1997:86J-875 Parillo .IE, Lawley TS, Frank MM, Kaplan AP, Fauci AS. Immunologic reactivity in the hypereosinophilic syndrome . .I Allergy Clin Immunol 1979; 64: I 13-121. Aberer W, Konrad K, Wolff K. Well's syndrome is a distinctive disease and not a histologic diagnosis . .I Am Acad Dermatol 1988; 18: 105-114. Tsukadaira A, Kitano K, Okubo Y, Horie S, Ito M, Momose T, Takashi S, Itoli S, Kiyosawa K, Sekiguchi M. A case of pathophysiologic study in Kimura's disease: measurement of cytokines and surface analysis of eosinophils. Ann Allergy Asthma Immunol J998; 81 :423-427. Spry CJ. The hypereosinophilic syndrome: clinical features, laboratory findings, and treatment. Allergy 1982; 37:539-551.
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Cogan E. Schandene L, Crusiaux A, Cochaux P. Velu T, Goldman M. Brief report: clonal proliferation of helper T cells in a man with the idiopathic hypereosinophilic syndrome. N Engl J Med 1994; 330:535-538 Takamizawa M, Iwata T. Watanabe K. Hayakawa H. Takahashi T, Furue M, Fukuda T. Jaji T, Minami M. Elevated production of interleukin 4 and interleukin 5 by T cells in a child with idiopathic hypereosinophilic syndrome. J Allergy Clin Immunol 1994; 93:1076-1078. Canonica BW, Passalacgue G, Pronzoto C. Corbetta L. Bagnasco M. Effective long-term a-interferon treatment for hypereosinophilic syndrome. J Allergy Clin [mmunol 1995; 96:131-133.
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Index
AA E (acq uired angioedema), 428 AA U See Childhood urticaria, acute annular urticaria (AA U) ACE inhibitors, angioedema and, 315, 425-427 Acquired CI inhibitor deficiency, 304, 310-312 Acute infantile hemorrhagic edema, 444. See a/so Systemic disorders Acute urticaria causes, 143-144 characteristics, 141 course of, 144-145 cytokines and, 143 description, 142-143 diagnosis, 145, 237-240 frequency, 141-142 histamines and, 143 NSAIDs and,143 prednisolone and, 146 systemic disorders and, 442 acute infantile hemorrhagic edema, 444 familial Mediterranean fever, 445 infectious disease, 442-443 Still's disease, 444
[Acute urticaria] tumor necrosis fac t 0 r- recept 0 r-associ a ted periodic syndrome, 444 treatment. 145-146 vs. chronic urticaria, 263 AE. See Angioedema (AE) African trypanosomiasis, 443. See a/so Systemic disorders Aggressive mastocytosis, 460 Allergic reactions, 19 childhood urticaria and, 220-222, 230-231 cutaneous basophils, 38 grass pollen immunotherapy. 37 histamine levels, 37-38 tryptase levels, 37-38 immunological contact urticaria (ICU) and, 153 Anabolic steroids hereditary urticaria and angioedema, treating, 244 papular urticaria, 256 Anaphylaxis anaphylotoxins
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Index
468 [A na phylaxis] complement system and, 103 receptors, 96 cold urticaria and, 191 description, 152 exercise-induced anaphylaxis (EIA) characteristics, 193-194 cold urticaria and, 185 diagnosing, 194, 293 heredity of, 292 mechanism, 194 treating, 194,293 urticari::l1 vasculitis and, 405 vs. cholinergic urticaria, 293 idiopathic causes (table), 267 classifying, 454, 455 conditions associated with, 268 defined, 267 diagnosing, 454-455 mast cells and, 453 symptoms, 454 systemic disorders and, 453 treatment, 455-456 vs. angioedema, 266-267 vs. carcinoid syndrome, 268 vs. systemic mastocytosis, 268 immunological contact urticaria (ICU) and, 152 insect-sting, 35 toxins created by complement system. 96-98 tryptase and, 35-36 Angioedema (AE) ACE inhibitors and, 315, 425-427 acquired angioedema (AAE), 428 acute vs. chronic, 263 blistering und, 2 CI inhibitor, 102 ca uses, 268, .\ I 5, 423 children and, 218. See a/so Childhood urticari~l chronic urticaria and, 321-322, 34.\-344 description, 421
[Angioedema] diagnosing, 235-237. 240-241, 259-262, 424 ACE inhibitor-induced AE, 425-427 C I inhibitor deficiency, 427-428 cyclo-oxygenase pathway inhibition, 424-425 idiopathic AE, 429 IgE-induced AE, 424 patient history, importance of, 424 physically induced AE, 428-429. See a/so Physical urticaria vs. Crohn's disease, 268 vs. idiopathic anaphylaxis. 266 vs. Melkersson-Rosenthal syndrome. 268 vs. urticaria, 1-2 epidermis, effects on, 2 frequency, 9, 42.\ hereditary angioedema (HAE1. 230-231,276-277,286. See a/so Hereditary urticaria C I inhibitor deficiency and. 305-306, 427-428 estrogen-dependent inherited angioedema, 290-292, 314 forms unrelated to CI inhibitor deficiency. 314-315 possible hereditary angioedemas. 297 treating, 312-314 vs. AAE (table), 428 histamine and, 430 histological characteristics. 423 history, 42] -422 hypocom plemen tem ic- urtica ria 1vasculitis syndrome (HUVS) and. 402 idiopathic, 429 defined. 434 treatment. 434-436 progression, 42.\ symptoms of, 1-2 systemic disorders and, 441, 448
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469
[Angioedema] acute infantile hemorrhagic edema, 444 B-cell Iymphoproliferative disease,
448-449 complement CI inhibitor molecule antibodies, 449 eosinophilia, 449 episodic angioedema, 449 familial Mediterranean fever. 445 infectious disease, 442-443 Still's disease, 444 tumor necrosis factor-receptorassociated periodic syndrome,
444 urticarial vasculitis, 447-448 treating, 430 antihistamines, 430-431 antileukotrienes, 432 l3-agonists, 431 corticosteroids, 432-434 vibratory, 182-183 without urticaria, 268 Antibiotics chronic urticaria and, 348, 398 penicillin, See Penicillin testing for allergies to, 237-239 urticaria and, 224-225 Antihistami nes acute urticaria, 145-146 aquagenic urticaria, 198 autoimmune urticaria, 331 childhood urticaria, 241-243 cholinergic urticaria, 186 chronic urticaria, 353-354 cold urticaria, 191 contact urticaria, 164
HI acute urticaria, treating, 378-379 angioedema, treating, 430-431 cardiac toxicity of, 382-383 central nervous system, damage to, 380-382 chronic urticaria, treating,
379-380
[A ntih istami nes] clinical usage, 383-384 considerations when using,
377-378 pharmacodynamics, 375-377 pha rmacology, 372-373 pharmacokinetics, 373-375 pregnancy and, 383 second-genera tion, 379-380 testi ng, 375 types (table) 374
He adverse effects, 387-388 acute urticaria, treating, 385-387 angioedema, treating, 431 chronic urticaria, treating, 385-387 dermographism, treating, 385-387 pharmacology, 384-385 pregnancy and, 387-388 hereditary vibratory urticaria, 189 idiopathic anaphylaxis, 456 immune response and, 28 late-phase reaction (LPR) and, 128 localized heat urticaria. 188 papular urticaria, 255 solar urticaria, 196 urticarial vasculitis, 410-411 Arthropods, papular urticaria and, 25] Aspirin, See also Nonsteroidal antiinnammatory drugs (NSAJ D) angioedema and, 424-425 prednisolone and, 359 urticaria and. 225, 348 Autoantibodies chronic urticaria and, 323-326 mechanism, 326-327 Autoimmune urticaria, 345-346 as immune disease. 327 autoantibodies, 324-326 basophils and, 329-330 diagnosing, 327-328 autologous serum skin test,
328-329 importance of, 331-332 in vitro tests, 329
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470 [Autoimmune urticaria] histamine-releasing factor and,
323-324 thyroid disorders and, 322-323 treating, 330-331 Autoinnammatory disorders, 276 Autosomal dominant inheritance pattern, 273 Autosomal recessive inheritance pattern, 273 fJ-agonists, 243, 431 B-Cell lymphoma, 311 Basopenia, 329-330 Basophils. 8-9 activating immunological, 23 nonimmunological, 23-24 allergic reactions and, 19, 38 anaphylaxis, 35-36 basopenia, 329-330 chemokines, 25, 34 chronic urticaria and, 323-324,
329-330 cytokines, 34 disease, involvement in, 34 growth, 21-23 histamine activity in basophils. 27-29 storage of, 20 HIV and, 24 immunoassays, 35 late-phase reaction and, 129 lipids, 33-34 location of, 20 markers Kit and FCfRI coexpression,
34 monoclonal antibodies, 34-35 tryptase, 34 mast cells, differencc from, 20 mcdia tors ATP and, 24 drugs and, 25 26 pharmacological response, 25-26
[Basophils] proteases, 29-33 proteoglycans, 29 urticarial vasculitis and, 407 Beta-agonists. See fJ-agonists. Borre/ia burgdo/jeri, urticarial vasculitis and, 448 Bradykinin formation CI inhibitor and, 303, 310. See a/so CI inhibitor complement system and, 103 coagulation factor XI amino acid sequence, 57 binding, 57 characteristics, 56-57 factor Xlla and, 56 hemophilia and, 63 HK and, 57, 63 coagulation factor XII, 51 activation of, 54 behavior, 54 CI inhibitor and, 303 characteristics, 53-54 coagulation, 55, 63 complement system and, 102-104 contact activation and, 61-62 endothelial cells. 64 factor X II a, 54, 102 factor XIII', 54. 102,303 contact activation, 51-53. 60-63 disease. involvement in, 66 en-ecls or. 52 endothelial cells binding, 63-65 complement system and, 103 kinin formation. 65-66 high-molecular-weight kininogen (HK).51 binding, 58 cha ractcristics, 57 coagulation in plasma, 62-63 contact activation and, 62 domain structure, 58-59 endothelial cells, 63-64 Cactor X I and, 57
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471
[Bradykinin formation] gene (diagram), 60 prekallikrcin and, 57 vs. LK, 59 kallikrein complement system and, 102 formation, 54 low-molecular-weight kininogen (LK), 51, 59 mechanisms, 60-61 overview, 51-53 prekallikrein, 51 activation of, 56 amino acid sequence, 56 characteristics, 55-56 contact activation and, 61 conversion to kallikrein, 54 factor Xil and, 54 Fletcher trait, 54 HK and, 56 tissue kallikrein LK and, 59 role in bradykinin formation, 51 vs. plasma kallikrein, 58 CI inhibitor acquired CI inhibitor deficiency, 304,310-312 description, 310-31 I diagnosis, 312 mechanism, 311 treatment, 312-314 angioedema and, 303. 427-428 B-cell lymphoma and, 31 I bradykinin formation and, 303, 309-310 complement CI inhibitor molecule antibodies, angioedema and, 449 deficiency, causes of, 304 diagnosing, 306-307 genetics. 304-306 laryngeal edema and, 304 leukemia and, 31J pathogenesis
rCI inhibitor] bradykinin, 310 C2 and, 307-308 C3 and, 308 C4 and, 307-308 C5a and, 308 factor XII and, 308-309 fibrinolysis. 310 plasma kinin-forming cascade, 308-309 plasmin, 310 C3 plasma Cl inhibitor deficiency and, 308 C3b,84-86 C3e, 85-86 C5a, 86 deficiency, effects of, 83 functions. 83-85 phagocytosis and, 98-100 role in complement system. 80-82 structure, 83 Calcium channel blockers nifedipine, 358 treating urticaria and angioedema, 243 Candida yeasts, 346 Capillary leakage. role in urticaria, 4 Carcinoid syndrome vs. idiopathic anaphylaxis, 268 vs. systemic mastocytosis, 461 Cathepsin G See Proteases, cathepsin G Chemokines basophil activation and. 38 described, 25 late-phase reaction (LPR) and, 132-133 mast cell development and. 22 types of, 34 Childhood urticaria acute annular urticaria (AA U), 231-232 causes, 216-217 allergic, 220-222 angioedema. 230-231
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472 [Childhood urticaria] infection, 226-227, 442-443 list of, 219 medication, 224-226 physical, 222-224 stings and bites, 227-228 stress, 229, 231 systemic disorders, 230 vasculitis, 228-229 description, 217-218 diagnosing angioedema, 235-237 distinguishing from urticaria from angioedema, 232-233 erythema multi forme, 234 infections, 234-235 masqueraders for urticaria (table),
233 methods for, 237-241 urticaria pigmentosa, 232-234 frequency, 216-217 histology, 215-216 idiopathic, 232 pathophysiology, 215-21.6 treating anabolic steroids, 244 antihistamines, 241-243 beta-agonists, 243 calcium channel blockers, 243 corticosteroids, 244 immunosuppressive therapy, 245 leukotriene modifiers, 244-245 mast cell stabilizers, 244 tricyclic antidepressants, 243 wheals, 218 Cholinergic urticaria anaphylaxis and, 185 characteristics, 183-184, 185 classification of (table), 1T2 course of, 184-185 defined, 171 diagnosis, 186 vs. cold urticaria, 264 265 vs. dermographism, 264 265 familial, 296
[Cholinergic urticaria] frequency, 184 pathogenesis, 184 steal effect. 4 stress and, 10-11 treatment, 1.86-187 wheal, 184-185 Chronic idiopathic urticaria (ClU) angioedema and, 321-322, 332 autoantibodies and, 323-326 autoimmune urticaria and, 331-332 childhood urticaria and, 232 defined, 331-332 diagnosing distinguishing from other urticarias, 332-334 guidelines for, 336-337 food additives and, 334-335 Heliobacrer pylori infection and, 227,
335-336, 398 irritants (table). 333 itching in, 6 nonhistamine mediators, 5 response to histamine, 4-5 stress, 10 thyroid disorders and, 335 treatment calcium channel blockers, 243 leukotriene 1l10difiers, 244-245 sulfasalazine, 245 wheals, 9, 332 vs. urticarial vasculitus, 333-334 Chronic infantile neurological cutaneous and articular (CINCA) syndrome, 284-287 Chronic urticaria angioedema and, 321-322, 343-34'+ associated disorders, 347 autoimmune urticaria. S('(' Autoimll1une urticaria causes allergies, 344 autoimmune disorders, 344-346 See also Autoimmune urticaria food additives, 346
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473
[Chronic urticaria] infections, 346 thyroid disorders, 345, 347 de~ned, 321-322, 343-344 diagnosi ng, 240-241, 349-350 freq uency, 322 histamines, 372 idiopathic urticaria. See Chronic idiopathic urticaria (CIU) irritants alcohol. 349 diet, 347-348 drugs, 348 physical stimuli, 348-349 stress. 349 viral infections, 349 systemic disorders and combined variable immunode~ciency, 445-446 hepatitis (viral), 446 H l V infection, 226, 446 Muckle-Wells syndrome, 445. See also Hereditary urticaria, Muckle-Wells syndrome neonatal urticaria, 445 Schnitzler's syndrome, 446-447 urticarial vasculitis, 447-448 treating, 350-351, 394-396 antihistamines, 353-354. See also Antihistamines approach for, 397 avoiding irritants, 351-352 counseling patients, 352-353 cyclosporin, 362-363, 396 doxepin, 354-356 epinephrine, 356-357 intravenous immunoglobulin (lVIG), 363 lotions, 353 methotrexa te, 364 montelukast, 357-358 nifedipine, 358 prednisolone, 359 second-line drugs (table), 355 steroids, 353
[Chronic urticaria] sulfasalazine, 359-360 third-line treatments, 361 thyroxine, 360-361 types (table), 322 vs. acute urticaria, 263 wheals, 343 Chymase. See Proteases, chymase CIU. See Chronic idiopathic urticaria (CIU) Cold urticaria cryoproteins and, 191-192 delayed, 192 dermographism and, 192 diagnosing, 190-191,264-265 freq uency of, 188-189 histamine and, 189 HIVand, 189 idiopathic immediate, 189-190 localized, 192 mediators and, 189 stimuli for, 189 symptoms, 189-190 treatment, 191 urticarial vasculitis and, 405 types of, 188-189 Collectins, 74. See also Complement system, mannin-binding lectin (MBL) pathway Combined variable immunode~ciency, 445-446 Complement system alternative pathway (AP) activation, 76, 89-90 de~ned, 74 description, 89 factor H, 90 factor I. 90 immunity, role in, 91 regulation, 91-92 bioactive fragments, 95-96 C3a. 96 C3d-K,98 C4a, 96 C5a, 97-98
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474 [Complement system] clearing, 98-102 classic pathway (CP) activation, 76-77 anaphylotoxins created by, 96-98 CI, 77-79, 100-102,308. See a/so CI inhibitor C2. 80, 307-308 C3, 80-86, 308. See a/so C3 plasma C4, 80, 98-100, 307-308 defined, 74 recognition of disease agents, 77-80 regulation of, 86-87 description, 73-74 gout and, 103-104 importance to immunity, 76 mannin-binding lectin (MBL) pathway activation. 76, 88-89 carbohydrate recognition domain (CRD), 75-76 defined, 74--75 description. 88 MBL-associated serine proteases (MASPs),76 regulation, 88-89 membrane attack complex (MAC) activation, 92-95 defined. 74 formation. 93-94 mechanism, 94 regulation of, 95 phagocytosis, 98-102 Contact allergic dermatitis, 260 Contact urticaria causes immunological contact urticaria (ICU), 159-164 nonimmunological contact urticaria (NICU). 157-158 characteristics, 149 frequency, 149-150 history, importance of, 149
[Contact urticaria] immunological contact urticaria (lCU) description, 152-153 latex and, 152-153 mechanism, 153-154 testing methods, 154--157 nonimmunological contact urticaria (NICU) description, 150-151 mechanism. 151-152 treatment, 164 Corticosteroids. 244, 331 angioedema and. 432--434 efficacy, 395 prednisolone, 359 side effects, 395-396 Crohn's disease, 260, 268 Cryopyrin, 280-281 Cyclosporin childhood urticaria and. 245 chronic urticaria, treating, 331, 362-363, 396 delayed pressure urticaria and. 182 mast cells and, 25 methotrexate and, 364 papular urticaria, treating, 256 prednisolone and. 362 urticarial vasculitis and, 411 Cystic fibrosis, '276 Cytokines acute urticaria and, 144 late-phase reaction (LPR) and, 129, 131-132 mast cells and. 26, 34 Dapsone. 396 Darier's sign. See Urticaria, urticaria pigmentosa Dermal mast cells. See Mast cells Dermatographism. See Dermographism Dermographism black, 176-177 chclracteristics, 174-175
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475
[Derm ogra ph ism] cold urticaria and, 192 delayed, 176 diagnosis, 175 duration, 175 familial, 293-294 frequency, 174 localized, 176 mast cells in, 174--175 simple, 173-174 symptomatic, 174-175 treatment, 175-176 urticarial vasculitis and, 405 vs. cholinergic urticaria, 264 white, 176 Desquamation, I Doxepin, 354-356. 387 Dual-phase response. See Late-phase reaction (LPR) Duchenne's muscular dystrophy. 276 EIA. See Anaphylaxis, exercise induced anaphylaxis (ErA) Eosinophilia, 449 Eosinophils, 25, 125, 129-130 CTNCA syndrome and, 285 hypereosinophilic syndrome, 461-463 Epinephrine, 356-357 Episodic angioedema, 449 Epstein-Barr virus. 275, 443. See also Mononucleosis Estrogen-dependent inherited angioedema, 3 I4 description, 290-29 J diagnosis, 291-292 heredity, 290 mechanism. 291 trea tmen t, 292 Exercise-induced anaphylaxis (EJA), J93-194. See also Anaphylaxis, exercise-induced anaphylaxis (ErA)
Familial cold autoinnammatory syndrome (FCASj, 277-282. See also hereditary urticaria, ['amilial cold autoinnammatory syndrome (FCAS) Familial Mediterranean ("ever, 445 See also Mediterranean fever Fibrinolysis, 310 Food additives chronic idiopathic urticaria (CIU) and, 334-335 chronic urticaria and, 346 GouL 103-104
H I antihistamines. See Antihistamines, HI H 2 antihistamines. See Antihistamines, He HAE. See Angioedema, hereditary angioedema (HAE) Hageman Factor (HF). See Bradykinin ("ormation, coagulation ("actor XII
Hashimoto's thyroidosis, 397. See also Thyroid disorders HeliobaCier gastritis, 346 HeliobaCier jJl'lori, 227, 335-336, 398 Hemophilia, 63 Henoch-SchbnJein purpura, 444 Heparin, 29 bradykinin formation, 61 chymase and, 32 tryptase and, 30 Hepatitis, 346, 446 Hereditary disorders angioedema. See Angioedema, hereditary C I inhibitor deficiency, 304 confirming, 271-272 cystic fibrosis, 276 diagnosing, 275-276 Duchenne's muscular dystrophy, 276 Huntington's disease. 274
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476 [Hereditary disorders] inheritance patterns complex, 273-275 Mendelian, 272-273 nonpenetrance, 274 urticaria. See Hereditary urticaria X-linked Iymphoproliferative disease, 275 Hereditary urticaria. See also Hereditary disorders autoinflammatory disorders and, 276-277 chronic infantile neurological cutaneous and articular (CINCA) syndrome description, 284 diagnosis, 285 genes responsible for, 284 heredity, 284 mechanism, 284-285 similarities to other hereditary urticarias, 286-287 treating, 285-286 delayed cold-induced urticaria description, 289 diagnosis, 290 mechanism, 289-290 vs. cold urticaria, 290 treatment, 290 exercise-induced anaphylaxis. See Anaphylaxis, exercise-induced anaphylaxis (EIA) familial cholinergic urticaria, 296 familial cold autoinnammatory syndrome (FCAS) amyloidosis and, 278 cryopyrin, 280-281 description, 277 diagnosis, 281 genes involved with, 278 heredity, 277-278 mechanism, 278 281 similarities to other hereditary urticarias, 286 287 trea ti ng, 2R I 282
[Hereditary urticaria] vs, cold urticaria, 277, 281 vs. periodic fever disorders, 28i familial dermographism. See Dermographism, familial familial localized heat urticaria (FLHU) description, 294 diagnosis, 295 heredity, 295 mechanism, 295 treatment, 295-296 hereditary vibratory urticaria description, 288 diagnosis, 288-289 mechanism, 288 treatment, 289 M uckle- Wells syndrome amyloidosis and, 283 chronic urticaria and, 445 description, 282 diagnosis, 283 genes involved with, 282 heredity, 282 leukocytosis and. 283 mechanism, 283 similarities to other hereditary urticarias, 286-287 treating, 283-284 possible hereditary urticarias, 297 Histamine acute urticaria and, 144 agonists, 28 allergic reactions and, 37 anaphylaxis, 35-36 angioedema and. 430 antihistamines. See Antihistamines autoantibodies, 323-327 basopenia, 329-330 in basophils and mast cells, 20 bronchial hyperactivity and, 28 chemokines, 25 chronic urticaria and, 323-325, 372 cold urticaria and, 189 complement system and, 103
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477
[Histamine] defined, 369 effects of, 28 formation, 27 hereditary vibratory urticaria and, 288 immunological contact urticaria (ICU) and, 152 itching and, 6, 371 late-phase reaction (LPR) and, 128 location, 372 mechanism, 28, 369-372 receptors, 28, 370 role in urticaria, 3-5, 216 storage, 20 Human Genome Project, 275 Human immunodeficiency virus (HIV), 24, 446 aquagenic urticaria and, 197-198 chronic urticaria and, 226, 446 cold urticaria and, 189 mast cells and, 24 papular urticaria and, 252 Huntington's disease, 274 Hydroxychloroquine, 396 Hypereosinophilic syndrome, 461--463 Hypocomplementemic-urticarialvasculitis syndrome (HUVS), 401,404. See also Urticarial vasculitis
leu. See
Contact urticaria, immunological contact urticaria (ICU) Idiopathic anaphylaxis. See Anaphylaxis, idiopathic IgE, 120, 122-123, 134 angioedema and, 425 basophils and, 129 eosinophils and, 130 mast cells and, 127 passive transfer model, 123 urticaria and, 216 urticarial vasculitis and, 407
IgG chronic urticaria and, 323-325 urticarial vasculitis and, 407 lmmunoassays basophils, 35 mast cells, 35 Immunosuppressive therapy, 245 Innammatory infiltrate dermal mast cells and, ~ role in urticaria, 6-9 Intra venous gamma globulin, 396 Intravenous immunoglobulin (IVfG), 363 Itching classification of. 6 histamines and, 6, 37 I neurology of, 6 time and, 6 Jaccoud's arthropathy, 403 Kinins. See also Bradykinin formation CI inhibitor deficiency and, 308-309 complement system and, 102-104 urticaria and, 216 Langherans cells. urticarial vasculitis and,407 Laryngeal edema, 304 Late-phase reaction (LPR) basophils and, 129 causes, 120 chemokines and, 131-132 course of. 120-121 cytokines and, 129, 131-132 eosinophils, 125, 129-130 experimental methods for studying, 127 histological characteristics, 122 history, 119-120 IgE and, 120, 122-123, 134 See also IgE innammatory cells and histological examination of. 123
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478 [Late-phase reaction] immunohistochemical staining of,
123-125 occurrence in LPR cycle, 125 types, 125 lesion, 120-121 mast cells and, 120, 125 chymase and, 128 evidence for, 127 histamine and, 128 lipid mediators, 128 mechanism, 127 platelet-activating factor (PAF),
128-129 role in LPR, 127-129 tryptase and, 128 mechanisms of, 133-134 neutrophils and, 125, 130-131 symptoms, 119 treatment of, 133 Latex, immunological contact urticaria (lCU) and, 153 Leukemia, 3, 311, 460 Leukocytoclastic vasculitis, 444 Leukocytosis CINCA syndrome and, 284-285 Muckle-Wells syndrome and, 283 toxins created by complement system, 98 Leukotrienes angioedema and, 423 antileukotrienes, 432 modifiers, 244-245, 394 montelukast, 357-358 Lewis's triple response, I, 28-29 Lipids, oxidative metabolism and,
33-34 Lung mast cell. See Pulmonary mast cell Lyme disease, urticarial vasculitis and, 448 Lymphocytes, 125, 131, 407 Mast cells activating, 3
[Mast cells] immunological, 23, 26 nonimmunological, 23-24 allergic reactions and, 19 anaphylaxis, 35-36 basophils, difference from, 20 bone marrow, 23 chemokines, 34 cytokines, 34 differentiation, 21-22 Fcy receptors and, 26 histamine, See also Histamines activity in mast cells, 27-29 storage, 20 HIV and, 24 idiopathic anaphylaxis and, 453 immune system and, 19,26 immunoassays, 35 inllammatory infiltrate and, 8 late-phase reaction and, 120, 125 leukemia and, 3, 460 links to nervous system, II lipids, 33-34 location of. 2, 19 markers Kit and Fcc:Rl coexpression, 34 monoclonal antibodies, 34-35 tryptase, 34 mast cell stabilizers, 244 MC T cells, 21-23 MeTe cells, 21-23 medialors, 3 ATP and. 24 biogenic amines, 27-29. See also Histamines drugs and, 25-26 pharmacological response. 25-26 pia telet -act iva ting factor (PAF),
128-129 production of, 21-23. 26 proteases, 29-33 prOleoglycans, 29 chondroitin sulfate A, 29 chondroitin sulfate E, 29 heparin, 29
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Index [Mast cells] pulmonary, 3 reducing, 3 relation to urticaria, 2-3, 216 systemic mastocytosis and, 456. See also Mastocytosis, systemic urticarial vasculitis and, 407 Mast cell carboxypeptidase. See Proteases, mast cell carboxypeptidase Mast cell leukemia, 3, 460 Mast cell stabilizers, 244 Mastocytosis anaphylactic reactions and, 37 diagnosis, 36 Kit and, 36 loca tions, 36 systemic aggressive mastocytosis, 460 bone marrow and, 459-460 classifying, 459 dermographism and, 456 diagnosing, 460-461 gastrointestinal tract and, 459 indolent mastocytosis, 458-459 mast cell leukemia, 460 mast cells and, 456 mechanism, 460 symptoms, 456-458 treatment, 461 urticaria pigmentosa, 456 vs. carcinoid syndrome, 461 vs. idiopathic anaphylaxis, 268 tryptase, 36-37 types of. 36 Mediterranean fever, 280. See also Familial Mediterranean fever Membrane attack complex (MAC) activation, 92-95 defined, 74 formation, 93-94 mechanism, 94 regulation of, 95 Melkersson-Rosenthal syndrome, 260, 268
Methotrexate childhood urticaria, treating, 245 chronic urticaria, treating, 361, 364 description, 364 papular urticaria, treating, 256 sulfasalazine and, 360 urticarial vasculitis, 411 Monkeys, 289 Mononucleosis, 346, 443. See also Systemic disorders Montelukast, 357-358 M uckle- Wells syndrome, 192,282-284, 445. See also Hereditary urticaria, Muckle-Wells syndrome Neonatal onset multisystem inflammatory disease (NOM.JD), 284-286 Neonatal urticaria, 445. See also Systemic disorders Neutrophils, 125, 130-131 C[NCA syndrome and, 285 delayed pressure urticaria (DPU) and, 179 NICU. See Contact urticaria, nonimmunological contact urticaria (NICU) Nifedipine, 358 Nonpenetrance. 274 Nonsteroidal anti-inflammatory drugs (NSAlD), 266 acute urticaria and, [43 angioedema and, 424-425 asthma and, 434 childhood urticaria and, 225 chronic infantile neurological cutaneous and articular syndrome, treating, 285 chronic urticaria and, 346, 348 cyclosporin and, 362 familial cold autoinflammatory syndrome, treating, 282 methotrexate and, 364
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Index
[Nonsteroidal anti-inflammatory drugs] Muckle-Wells syndrome, treating, 283 nonimm unological contact urticaria, treating, 151 prednisolone and, 359 Nucleotide oligomerization domain (NOD) proteins, 280 Papular urticaria arthropods and, 251 description, 251-252 diagnosis, 253-254 HIV and, 252 polymorphous light eruption (PMLE),254 .treatment 255-257 West Nile virus, 252 Parasitosis, 346 Passive transfer model. IgE and, 123 Peeling skin, I Penicillin acute urticaria and, 143,237 childhood urticaria and, 224 chronic urticaria and, 348 methotrexate and, 364 Physical urticaria andrenergic urticaria, 198-199 aquagenic urticaria, 197-198 children and, 222-224 cholinergic urticaria characteristics, 183-184, 185 course of, 184-185 diagnosis, 186 exercise induced anaphylaxis and, 185 frequency, 184 pathogenesis, 184 stress and, 184, 254 treatment, 186-] 87 wheals, 184 185 classification of (table), 172 cold urticaria, 188-] 92. See also Cold urticaria
[Physical urticaria] com binations of, 171-173 defined, 171 delayed pressure urticaria (DPU) associated conditions, 180 characteristics, 178 course of, 179 diagnosing, 180-181 duration of, 182 frequency, 178 mechanism, 179 neutrophils and, 179 prednisolone and, 182 treating, 181-182 urticarial vasculitis and, 405 dermographism, 173-] 77. See also Dermographism exercise-induced anaphylaxis (EIA), 193-194 frequency of, 173 immediate pressure, ] 77 localized heat urticaria, 187-188 reflex type, 171 solar urticaria characteristics, 194, 195-196 diagnosis, 196, 265 inhibition spectra, 194-195 lesions, 195 polymorphous light eruption (PMLE) and, 265 testing, 194-195 treatment, 196-197 urticarial vasculitis and, 405 variants, 197 systemic urticaria, 192-193 vi bra tory angioedema, 182-183 vs. other urticarias, 263-264 wheals, 171 PlaslllJpharesis, 396 Platelet-activating factor (PAF) defined, 128-129 [ormation, 33 immunological contact urticaria and, 153 urticaria, potenticll cause of, 189,216
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481
PMLE (polymorphous light eruption), 254 Prausnitz-Klistner model. See Passive transfer model Prednisolone acute urticaria and, 146 chronic urticaria and, 159 cyclosporin and, 362 delayed-pressure urticaria and, 182 description, 159 Prostaglandin immunological contact urticaria (lCU) and, 152 nonimmunological contact urticaria (NICU) and, 151 production of, 33 role in urticaria, 128, 216 Proteases acid hydrolases, 33 cathepsin G, 32 chymase chromosome location, 31 described, 32 effects of, 32 heparin and, 32 late-phase reaction (LPR) and, 128 mast cells and, 23, 32 mast cell carboxypeptidase, 32 matrix metalloproteinase-9, 33 tissue-type plasminogen activator, 32-33 tryptase allergic reactions and, 37 anaphylaxis, 35-36 effects of, 31 formation, 30 gene characteristics, 30 heparin and, 30-31 late-phase reaction and, 128 mastocytosis, 36-37 regula tion, 31 Proteoglycans, 29 chondroitin sulfate A, 29
[Proteoglycans] chondroitin sulfate E, 29 chymase, bonding to. 32 heparin, 29 Pseudourticarias (table), 333 Recurren t erythema multi forme, 260-261 Recurrent erysipelas of the forearms, 261-262 Schnitzler's syndrome defined, 446-447 urticaria, relation to, 9, 446-447 urticarial vasculitis and, 405, 406, 407-409.410 Schistosomiasis, 443. See also Systemic disorders Sjogren's syndrome, urticarial vasculitis and. 405-406 Skin cell factor (SCF), 21-23 Skin mast cells. See Mast cells Starling's law, 4 Stroma I cell-deri ved factor 1-0' (SDF-la),22 Steal effect, 4 Still's disease, 444. See also Systemic disorders Stress adrenergic urticaria and, 198 childhood urticaria and, 229, 231 cholinergic urticaria and . 184. 254 chronic urticaria and, 349, 352 dermographism and, 174 urticaria and, 10-11 Sulfasalazine, 359-360 chronic idiopathic urticaria (el U), treating, 245 delayed-pressure urticaria, treating, 182 methotrexate and, 364 Swimmer's eruption, 443. See also Systemic disorders Sympathomimetic agents, 394
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482 Systemic disorders acute urticaria and angioedema, 442 acute infantile hemorrhagic edema, 444 familial Mediterranean fever, 445 infectious disease, 442-443 Still's disease, 444 tumor necrosis factor-receptorassociated periodic syndrome, 444 angioedema and, 441, 448 B-ceillymphoproliferative disease, 448-449 complement C I inhibitor molecule antibodies, 449 eosinophilia, 449 episodic angioedema, 449 chronic urticaria combined variable immunodeficiency, 445-446 hepa ti tis (vi ra I), 446 HIV infection, 446 Muckle-Wells syndrome, 445. See also Hereditary urticaria, Muckle- Wells syndrome neonatal urticaria, 445 Schnitzler's syndrome, 446-447 urticarial vasculitis, 447-448 freq uency, 441 idiopathic anaphylaxis and, 453 lupus erythematosis, 405-406 systemic mastocytosis and, 456. SI!I? also Mastocytosis. systemic urticaria and, 230, 441 Systemic mastocytosis. See Mastocytosis. system ic Thyroid disorders autoimmune urticaria and. 323 chronic idiopathic urticaricl and, 335 chronic urticaria and, 345, 397 Hashimoto's thyroidosis, 397 thyroxine, 360 361 Thyroxine, 360 361 Toll-like receptor (TLR), 26, 280
Tricyclic antidepressants, 243 Tryptase. See Proteases, tryptase Tumor necrosis faetor-receptorassociated syndrome, 444. See also Systemic disorders Urticaria acute, 141. See also Acute urticaria antibiotics and. 224-225 aspirin and, 225 basophils, 8-9. 19 blistering and, 2 children and. Sel? Childhood urticaria cholinergic, 17\, 183-187. See also Cholinergic urticaria chronic, 38, 216. See also Chronic urticaria chronic intermittent, 265-267 contact, 149-150 See also Contact urticaria cutaneous allergic reactions, 38 dermal mast cells. See Dermal mast cell diagnosing acute urticaria vs. chronic urticaria, 263 chronic intermittent urticaria, 265-267 cold urticaria vs. cholinergic urticaria, 264-265 dermographism vs. cholinergic urticaria. 264-265 diseases mimicking urticaria, 259-262 idiopathic anaphylaxis, 266-267 physical urticaria vs. other urticarias, 263-264 sola r urticaria. 265 disease and, 226-227 epidermis, effects on, 2 hereditary, 271, 276-277, 286. See also Hereditary urticaria histamine. See Histamines
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483
[Urticaria] idiopathic, 38. See a/so Chronic idiopathic urticaria (CIU) innammatory infiltrate and, 6-9 itching, 6 mediators and, 3 medication and, 224-226 neonatal urticaria, 445. See a/so Systemic disorders neutrophilic, 9 papular, 251-252. See also Papular urticaria physical, 171-173. See also Physical urticaria physical causes, 9-10, 12 pressure urticaria, 9 pseudourticarias (table), 333 psychosoma tic ca uses, 10-1 I skin biopsy, 7 solar. See Physical urticarias, solar urticaria stings and bites, 227-228 stress and, 10-1 I symptoms, 1-2 systemic disorders and, 441 See a/so Systemic disorders treatments, 350-351 antihistamines. See Antihistamines approach for treating, 397 corticosteroids, 3, 394-396. See a/so Corticosteroids experimental treatments, 396 leukotriene antagonists. 394 sympa thomi metic agen ts, 394 triple response, I tryptase levels, 36 types of, 11-13 urticaria pigmentosa (Darier's sign), 176 diagnosing, 232-234 systemic mastocytosis and, 456 treating, 3 urticaria vasculitis distribution, 9
[Urticaria] symptoms, 2 vasculitis, 228-229. See a/so Urticarial vasculitis wheals, I. See a/so Wheals cause of, 3-5 distribution of, 9-10 Urticarial vasculitis associated disorders, 405-406 chronic urticaria and, 447-448 classification of (table), 402 defi ned, 40 I diagnosing, 409-410 histological characteristics, 408-409 hypocom plemen tem ic- urtica ria 1vasculitis syndrome (HUVS), 401, 404, 406-407 mast cclls and, 407 mechanism, 406-408 occurrence, 40 I progression, 406 Schnitzler's syndrome and, 407-409, 410 Sjogren's syndrome and, 406 symptoms cutaneous, 401-403 other, 403-405 systemic disorders and, 447-448 systemic lupus erythematosis and. 406 treating, 410-41 1 vs. chronic idiopathic urticaria (Cl U). 333-334 wheals, 402-403 Urticarial venulitis. See Urticarial vasculitis Vasculitis, urticaria and, 228-229. See a/so Urticarial vasculitis Venous plexus, 4 Viral infections, urticaria and, 349 West Nile virus, papular urticaria and, 252
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Index
Wheals, I, 3-5 acute urticaria and. 141-143, 144 CI inhibitor dellciency and, 307-308 childhood urticaria, 218 chronic urticaria and, 343 distribution or, 9-10 histamine and, 4-5 inflammatory inliitrate and, 6-9 late-phase reaction (LPR) and, 119-120 nonhistamine mast cell mediators and, 5 physical stimuli, 171
[Wheals] redness of, 4 skin biopsy, 7 solar urticaria, 195 urticarial vasculitis. 402-403 vs. normal skin, 8 X-linked dominant inheritance pattern, 273 X-linked Iymphoproliferative disease, 275 X-linked recessive inheritance pattern, 273
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