Medical Therapy of Inflammatory Bowel Disease - Gastroenterology Clinics of North America Vol 33 Issue 2

Gastroenterol Clin N Am 33 (2004) xv–xvi Preface Medical Therapy of Inﬂammatory Bowel Disease Gary R. Lichtenstein, ...

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Gastroenterol Clin N Am 33 (2004) xv–xvi

Preface

Medical Therapy of Inﬂammatory Bowel Disease

Gary R. Lichtenstein, MD Guest Editor

Inﬂammatory bowel disease (IBD) constitutes multisystem diseases of idiopathic origin. Since Drs. Crohn, Ginzburg, and Oppenheimer’s initial description of Crohn’s disease in 1932 and Drs. Wilks and Moxon’s original description of ulcerative colitis in 1875, much has been learned about these two disorders. Both are found worldwide and spare no socioeconomic group. Recent scientiﬁc and technological advances have not only led to greater understanding of the pathogenesis underlying these disorders, but have also enabled physicians and scientists to create better and more eﬃcacious medical therapies for Crohn’s disease (CD) and ulcerative colitis (UC). Medical therapies for IBD aim to induce and maintain disease remission; decrease disease-associated complications, including malnutrition, osteoporosis, and colon cancer; and ultimately, improve the patient’s quality of life. This issue of the Gastroenterology Clinics of North America discusses drug therapy and management strategies for the various site-speciﬁc presentations for CD and UC. In this issue a highly distinguished group of sophisticated physicianscientists have been assimilated to present an updated guide to the current status of selected foci in gastroenterology as related to the medical therapy of IBS. The discussions range from laboratory-based ﬁndings to clinical pearls taking us from the bench to the bedside. These articles highlight many of the advances to date and also demonstrate the enthusiasm generated by

0889-8553/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.gtc.2004.05.003

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current work in each area. This issue not only reviews the current state of the art but will also prepare you for the future. The subject matter is wide ranging and thus every area as they relate to medical therapy of inﬂammatory bowel disease will not be covered. Thus, it is anticipated that this issue will serve as a repository of the current basic and scientiﬁc knowledge for investigators in the ﬁeld. We hope we have supplied a review of the pertinent pathophysiology for the practicing physician/ health care deliverer and a clinical framework for assessment and treatment of patients with IBD. I am indebted to my fellow contributors for providing uniformly outstanding, detailed critical reviews amid their already busy schedules. My gratitude is also extended to Ms. Heather Cullen for her outstanding editorial assistance and her superb guidance in this issue. Lastly, I am most appreciative and extend thanks to all my colleagues, patients, and those who have supported research in the ﬁeld and have helped me uncover and extend the boundaries of my knowledge of inﬂammatory bowel disease. Gary R. Lichtenstein, MD Gastroenterology Division, Department of Medicine Hospital of the University of Pennsylvania University of Pennsylvania School of Medicine University of Pennsylvania Health System 3rd Floor Ravdin Building 3400 Spruce Street Philadelphia, PA 19104-4283, USA

Gastroenterol Clin N Am 33 (2004) 141–169

Cyclosporine, tacrolimus, and mycophenolate mofetil in the treatment of inﬂammatory bowel disease Conor G. Loftus, MDa,b, Laurence J. Egan, MDa,b, William J. Sandborn, MDa,b,* a

Inﬂammatory Bowel Disease Clinic, Division of Gastroenterology and Hepatology, Mayo Clinic and Foundation, 200 First Street SW, Rochester, MN 55905, USA b Department of Medicine, Mayo Medical School, 200 First Street SW, Rochester, MN 55905, USA

In the past decade, immunosuppressive drugs have come to play an integral role in the treatment of patients with inﬂammatory bowel disease (IBD) [1]. Patients who fail to respond to corticosteroids, and those who are steroiddependent, are frequently treated with immunosuppressive drugs, such as azathioprine, 6-mercaptopurine, and methotrexate, and biotechnology technology agents, such as inﬂiximab [1]. The delayed onset of action (approximately 3 months) seen with azathioprine, 6-mercaptopurine, and methotrexate has limited their use for the acute treatment of patients with moderate to severely active IBD, but this problem has been at least partially circumvented by the introduction of a rapidly acting agent, inﬂiximab. In patients who fail to respond to the ﬁrst-line immunosuppressive agents listed previously, consideration may be given to use of the calcineurin inhibitors (cyclosporine and tacrolimus) and mycophenolate mofetil as alternative or adjunctive immunosuppressive therapies for refractory IBD. This article reviews the use of cyclosporine, tacrolimus, and mycophenolate mofetil in patients with IBD, with emphasis on pharmacology, results in controlled clinical trials, and safety, and issues related to dosing and toxicity monitoring. Calcineurin inhibitors Calcineurin inhibitors with proved or possible eﬃcacy in IBD include cyclosporine (Sandimmune), cyclosporine microemulsion formulation * Corresponding author. E-mail address: [email protected] (W.J. Sandborn). 0889-8553/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.gtc.2004.02.001

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(Neoral, Gengraf), and tacrolimus (FK506, Prograf). Sirolimus (rapamycin, Rapamune) is another calcineurin inhibitor that has been approved for use in the transplantation setting but has not been studied in patients with IBD.

Cyclosporine Clinical pharmacology Cyclosporine is a lipophilic peptide with inhibitory eﬀects on both the cellular and humoral immune systems. Cyclosporine acts to down-regulate the cellular immune response by blocking the production of interleukin-2 by T-helper lymphocytes [2]. At the molecular level, cyclosporine binds with the cyclosporine-binding protein, cyclophilin, forming a cyclosporinecyclophilin complex. This complex then binds to and inhibits calcineurin, a cytoplasmic phosphatase enzyme involved in the activation of T cells [3]. In addition to its direct inhibitory eﬀects on T-cell function, cyclosporine also indirectly inhibits B-cell function, by blocking the production of B-cell activating factors, and interferon-c, by T-helper cells [4]. It is not known which of these cyclosporine-induced eﬀects on cellular and humoral immunity account for any therapeutic action in Crohn’s disease or ulcerative colitis. In the United States, the original commercially available formulations of cyclosporine included a liquid oral preparation (Sandimmune, 100 mg/mL); oral gelatin capsules (Sandimmune, 25, 50, and 100 mg); and an intravenous concentrate (Sandimmune, 50 mg/mL). After an oral dose of the liquid cyclosporine preparation, maximal absorption occurs at approximately 4 hours with bioavailability ranging between 12% and 35% [5,6]. The oral gelatin cyclosporine capsules have an equivalent bioavailability to the oral liquid cyclosporine solution [7]. The absorption of cyclosporine in the small intestine is a function of contact time, which varies in accordance with small bowel length, motility, and mucosal integrity [5,6,8,9]. Crohn’s disease [9] and short-bowel syndrome [10] may impair the absorption of orally administered cyclosporine. Bile is also required for cyclosporine absorption, and biliary diversion may lead to drug malabsorption [11]. As a means of improving the bioavailability of orally administered cyclosporine, and eliminating the need for the presence of bile to allow for maximal absorption, new microemulsion cyclosporine formulations (Neoral, Gengraf) have been approved for use in the United States (see later). In addition, reports have suggested that the coadministration of vitamin E [12], or ursodeoxycholic acid [13], may improve the bioavailability of the standard oral cyclosporine formulation. Oral cyclosporine for autoimmune diseases can be divided into two groups based on the cyclosporine dose: low-dose oral cyclosporine (5 mg/

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kg/d, based on the Sandimmune formulation) and high-dose oral cyclosporine (>5 mg/kg/d). This classiﬁcation is based on the ﬁnding that oral cyclosporine at doses less than or equal to 5 mg/kg/d has a considerably lower risk of causing biopsy-proved cyclosporine nephropathy [14]. It has been recommended that patients with autoimmune diseases not be treated with oral cyclosporine at doses greater than 5 mg/kg/d to avoid nephrotoxicity and other dose-dependent toxicities [14]. Intravenous cyclosporine at doses of 2 to 4 mg/kg/d are best classiﬁed as high dose, being equivalent to oral cyclosporine doses of 8 to 16 mg/kg/d (assuming oral bioavailability of approximately 25%). It is of importance to consider the results of clinical trials of cyclosporine in terms of these drug-dosing categories.

Clinical response in Crohn’s disease Three large, controlled trials of low-dose oral cyclosporine (5 mg/kg/d) for treatment of chronically active Crohn’s disease and maintenance of medically induced remission failed to show a beneﬁcial treatment eﬀect (Table 1) [15–17]. The Cyclosporin Study Group of Great Britain and Ireland [15] reported on 146 patients with active Crohn’s disease who were randomized to oral cyclosporine (5 mg/kg/d) or placebo. There was no signiﬁcant diﬀerence in the number of patients who achieved remission in the cyclosporine group (26 [36%] of 72) as compared with the placebo group (32 [43%] of 74) at 3 months. In the Canadian Crohn’s Relapse Prevention Trial [16], 305 patients with either active Crohn’s disease or Crohn’s disease in remission (patients stratiﬁed according to disease activity) were randomized to oral cyclosporine (mean ﬁnal dose of 4.8 mg/kg/d) or placebo. After 18 months of treatment, there was no signiﬁcant diﬀerence in the number of patients who achieved or maintained remission in the cyclosporine group (60 [40%] of 151) as compared with the placebo group (74 [48%] of 154). The European Trial of Sandimmune in Crohn’s disease [17] randomized 182 patients with active Crohn’s disease to receive either oral cyclosporine (5 mg/kg/d) or placebo. After 4 months, there was no diﬀerence in remission rates between the treatment (35%) and placebo (27%) groups, whereas at 12 months only 20% of patients in both groups remained in clinical remission. One controlled trial of patients with active Crohn’s disease using highdose oral cyclosporine (7.6 mg/kg/d) did report a positive treatment eﬀect [18]. In this study by Brynskov et al [18], 71 patients with active Crohn’s ileitis, ileocolitis, or colitis were randomized to oral cyclosporine (mean ﬁnal dose 7.6 mg/kg/d) or placebo for 3 months. At follow-up, 59% of patients in the treatment group achieved remission as compared with 32% in the placebo group (P = .03). In patients who entered remission, the treatment eﬀect was seen within 2 weeks. Whereas the therapeutic advantage of cyclosporine was maintained during a 3-month cyclosporine taper, only 11% of patients maintained substantial improvement after cyclosporine was

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Response (%) Author (ref)

No. of Patients

Low dose Jewell 146 et al [15] Feagan 305 et al [16] Stange 182 et al [17] High dose Brynskov 71 et al [18]

Initial daily dose (mg/kg)

Site of disease

5

SB, IC, C

5

SB, IC, C

5

N.st

5–7.5

SB, IC, C, PA

Corticosteroids (%)

Treatment duration (mo)

Cyclosporine

Placebo

P

77

12

36

43

NS

61

18

40

48

NS

100

3

35

27

NS

34

3

59

32

0.03

Abbreviations: C, colon; IC, ileocolonic; NS, not signiﬁcant; N.st, not stated; PA, perianal; SB, small bowel.

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Table 1 Controlled trials of oral cyclosporine for active Crohn’s disease

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discontinued [19]. Patients receiving cyclosporine in combination with corticosteroids seemed to have a greater response rate than those receiving cyclosporine alone. Numerous uncontrolled trials of both oral and intravenous cyclosporine for active inﬂammatory Crohn’s disease have reported promising short-term but not long-term response rates [20–45]. Of 227 patients reported in 26 uncontrolled trials, clinical response was observed in 0% to 100%, with an overall mean response of 64% (145 of 227). In those patients who did respond, the eﬀect of cyclosporine was rapid, with improvement usually occurring within 2 to 3 weeks. The overall mean initial oral cyclosporine dose was 10 mg/kg/day (range 5–15 mg/kg/d). Initiation of cyclosporine by continuous intravenous infusion at a dose of 1 to 4 mg/kg/d may induce more rapid clinical improvement, and this strategy has been advocated by some groups [30,32–39,41,43]. A controlled trial comparing oral with intravenous cyclosporine in patients with Crohn’s disease has not been undertaken. The frequency of long-term clinical improvement after discontinuation of highdose cyclosporine was much lower than the frequency of initial short-term response, with an overall mean long-term improvement of 29% (58 of 200). In many of these studies, maintenance therapy with azathioprine, 6mercaptopurine, or methotrexate was not systematically used. The rates of sustained improvement seem to be substantially greater if cyclosporine is used as a rescue induction therapy that bridges the patient to maintenance therapy with one of the other slower-acting immunosuppressive agents [33,35,38–40]. Although there have been no controlled trials of cyclosporine for ﬁstulizing Crohn’s disease, a number of the uncontrolled trials that included patients with ﬁstulas suggested a positive treatment eﬀect with high-dose cyclosporine [21,23,25,29,30,33,34,36,39,43–45]. Of 53 patients with ﬁstulizing disease (pooled from all of the uncontrolled studies), the initial short-term ﬁstula closure rate ranged from 0% to 100% with an overall mean short-term closure rate of 77% (41 of 53). Long-term ﬁstula closure after discontinuation of cyclosporine treatment was reported in 42% (22 of 53) of patients. Oral cyclosporine doses ranging from 8 to 10 mg/kg/d were reported eﬀective for healing ﬁstulas, with time to ﬁstula closure ranging from 0.5 to 4 weeks. Some centers advocate initial therapy with intravenous cyclosporine, 4 mg/kg/d by continuous infusion for 10 days, followed by oral cyclosporine, 8 mg/kg/ d [30,33,34,36]. The clinical advantage of this approach has not been demonstrated in controlled trials. Controlled trials in Crohn’s disease have shown that low-dose oral cyclosporine (5 mg/kg/d) was not eﬀective either for treatment of chronically active inﬂammatory disease or for maintenance of remission. In contrast, one controlled trial of high-dose oral cyclosporine (mean dose 7.6 mg/kg/d), and multiple uncontrolled trials of oral cyclosporine at doses greater than 5 mg/kg/d or 4 mg/kg/d intravenously, suggest that high-dose cyclosporine may be eﬀective for both inﬂammatory and ﬁstulizing Crohn’s disease.

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Clinical response in ulcerative colitis There have been no controlled trials of either low- or high-dose oral cyclosporine in patients with ulcerative colitis. Four controlled trials of intravenous cyclosporine in patients with severe ulcerative colitis have reported a positive treatment eﬀect (Table 2) [46–49]. Lichtiger et al [46] randomized 20 patients with severe, steroid-refractory ulcerative colitis to treatment with placebo (N = 9) or intravenous cyclosporine, 4 mg/kg/d as a continuous infusion for 14 days (N = 11). Nine of 11 cyclosporine-treated patients (82%) responded compared with none of the placebo-treated patients. Those who responded were continued on oral cyclosporine, 8 mg/ kg/d. At 6 months, 5 (45%) of 11 cyclosporine-treated patients maintained a clinical response. In the second study, 30 patients with severe ulcerative colitis were randomized to monotherapy with a continuous infusion of cyclosporine, 4 mg/kg/d, or methylprednisolone, 40 mg/d [47]. After 8 days, 9 (64%) of 14 patients who received cyclosporine responded compared with 8 (53%) of 15 receiving methylprednisolone. Patients who responded received Table 2 Controlled trials of intravenous cyclosporine for severe ulcerative colitis Author (ref)

Agent Total administered patients (No. patients)

Initial IV daily dose Corticosteroids (mg/kg) (No. patients)

20

Cyclosporine (11)

4

11

Placebo (9)

—

9

Cyclosporine (14a)

4

0

9 (64)

7 (50)

Methylprednisolone (15)

40 (mg/d) 15

8 (53)

3 (20)

Response (No. patients) (%) 14 d

Lichtiger et al [46]

D’Haens et al [47]

Svanoni et al [48]

30

30

Cyclosporine (15)

4

0

Cyclosporine 4 4 + Prednisolone (15) +1 15 (mg/kg/d) Van Assche 70 et al [49]

9 (82) 0 8d

6 mo 5 (45) 0 12 mo

14 d

NA

10 (67)

—

14 (93)

—

8d

3 mo

Cyclosporine (34b)

4

16

28 (82)

23 (68)

Cyclosporine (35)

2

21

29 (83)

26 (74)

Abbreviations: NA, not available; NS, not signiﬁcant. a One patient was found to have C diﬃcile and was withdrawn on day 2. b One patient was withdrawn after the start of the ﬁrst infusion because of anaphylactic reaction.

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the same medication orally in combination with azathioprine. At 12 months, seven (78%) of nine patients initially controlled with cyclosporine maintained remission compared with three (37%) of eight treated with methylprednisolone. In the third study, 30 patients with severe steroid-refractory ulcerative colitis were randomized to monotherapy with intravenous cyclosporine, 4 mg/ kg/d (steroids were discontinued), or intravenous cyclosporine in combination with continued prednisolone, 1 mg/kg/d [48]. After 14 days, 10 (67%) of 15 patients in the cyclosporine-monotherapy group compared with 14 (93%) of 15 in the combination-therapy group had complete remission. Most recently, a Belgian study randomized 70 patients with severe ulcerative colitis to receive 2 or 4 mg/kg/d of intravenous cyclosporine [49]. After 8 days, 29 (83%) of 35 patients in the 2 mg/kg group and 28 (82%) of 34 in the 4 mg/kg group had responded to treatment. There have been numerous uncontrolled trials of both oral and intravenous cyclosporine in patients with severe ulcerative colitis, the results of which are similar to those from the controlled trials [25,26,30,35,40,41,43,50–84]. These patients had severe ulcerative colitis, had failed standard therapy, and were candidates for colectomy. Of 604 patients studied in 42 trials, the overall mean response (avoidance of colectomy) was 70% (422 of 604). The overall mean initial oral cyclosporine dose was 10 mg/kg/day (range 4–15 mg/kg/d). Cyclosporine by continuous intravenous infusion, at a mean dose of 4 mg/kg/d (range 1–7 mg/kg/d), was the preferred initial route of administration at 27 centers [30,41,43,54,55, 59–62,64–71,73–82,85]. Treatment eﬀect with cyclosporine was rapid, with improvement usually occurring within 1 to 2 weeks. The overall mean longterm response after discontinuation of cyclosporine was 39% (237 of 604). In many of these studies, maintenance therapy with azathioprine or 6mercaptopurine was not systematically used. The rates of long-term improvement seem to be substantially greater if cyclosporine is used as a rescue induction therapy, which bridges the patient to maintenance therapy with one of the other slower-acting immunosuppressive agents [47,65–67,70,71,75,77,80,84]. There has been one controlled trial reporting the use of cyclosporine enemas in patients with refractory left-sided ulcerative colitis [86]. In that study, 40 patients were randomized to receive cyclosporine enemas, 350 mg/d, or placebo for 4 weeks. At completion of the study, there was no diﬀerence in the number of patients who responded in the cyclosporine enema group (8 [40%] of 20) as compared with the placebo group (9 [45%] of 20). This negative controlled trial refutes the results from four small uncontrolled trials in 36 patients treated with cyclosporine enemas that suggested that topical cyclosporine therapy might be of beneﬁt [87–90]. In summary, controlled trials suggest that high-dose cyclosporine (2–4 mg/kg/d intravenously) is eﬀective for severe ulcerative colitis. Intravenous cyclosporine at a dose of 2 mg/kg/d seems to be as eﬀective as 4 mg/kg/d, and this intermediate dose may be preferable because of the potential for

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greater toxicity associated with the higher dose (see later). Low-dose cyclosporine has not been evaluated in ulcerative colitis, either for treatment of active disease or for maintenance of remission. Cyclosporine enemas are not eﬀective in patients with refractory left-sided ulcerative colitis. Blood concentrations: monitoring and correlation with clinical response Trough concentrations of cyclosporine can be measured in whole blood, serum, or plasma by a variety of methods including high-pressure liquid chromatography (HPLC), radioimmunoassay (RIA), and ﬂuorescence polarization immunoassay [5,6,91]. In contrast to polyclonal RIA and ﬂuorescence polarization immunoassay, monoclonal RIA, ﬂuorescence polarization immunoassay, and HPLC are speciﬁc for parent cyclosporine. The therapeutic window for these assays used in solid organ transplantation is approximately 150 to 300 ng/mL. In patients with autoimmune diseases, the trough whole blood concentrations of cyclosporine (HPLC or monoclonal RIA) that occur with low-dose therapy range from 100 to 250 ng/mL, whereas trough cyclosporine concentrations for high-dose cyclosporine therapy range 251 to 400 ng/mL. It is not entirely clear what whole blood concentrations of cyclosporine are necessary to produce clinical improvement in patients with IBD. In the negative controlled trial of oral cyclosporine for Crohn’s disease (mean ﬁnal dose 4.8 mg/kg/d) reported by Feagan et al [16], the mean whole blood concentration was 182 ng/mL (monoclonal RIA, target concentration 200 ng/ mL). Similarly, in the negative controlled trial of oral cyclosporine for Crohn’s disease (5 mg/kg/d) reported by Jewell and Lennard-Jones [15], the ﬁnal median whole blood concentration was 129 ng/mL (monoclonal RIA, therapeutic range 90–270 ng/mL). In contrast, the positive controlled trial of oral cyclosporine for Crohn’s disease (mean ﬁnal dose 7.6 mg/kg/d) reported by Brynskov et al [18] reported a trend toward higher whole blood concentrations in patients who responded, 471 ng/mL in responders versus 309 ng/mL in nonresponders (polyclonal RIA, therapeutic range 400–800 ng/ mL). In the two fully published controlled trials of intravenous cyclosporine for severe ulcerative colitis, whole blood cyclosporine concentrations did not correlate with clinical response [46,47]. In the study by Lichtiger et al [46], the mean whole blood cyclosporine concentration was 482 ng/mL in responders versus 484 ng/mL in nonresponders (monoclonal RIA, therapeutic range 100– 400 ng/mL). Similarly, in the study by D’Haens et al [47], the mean whole blood cyclosporine concentration was 361 ng/mL in responders versus 385 ng/ mL in nonresponders (monoclonal ﬂuorescence polarization immunoassay). From these ﬁve controlled studies [15,16,18,46,47], there does not seem to be a clear correlation between whole blood cyclosporine concentrations and clinical response in patients with IBD. What is clear, however, is that in studies showing a positive treatment eﬀect [18,46,47], high-dose cyclosporine was used (>5 mg/kg/d orally or 4 mg/kg/d intravenously) with high whole

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blood cyclosporine concentrations (>400 ng/mL), whereas in the studies showing a negative treatment eﬀect [15,16], low-dose cyclosporine was used (5 mg/kg/d), with lower mean whole blood concentrations (\ 200 ng/mL). It seems that there is a relatively strong correlation between clinical response and whole blood cyclosporine concentrations (HPLC or monoclonal RIA) when indirectly comparing low- versus high-dose cyclosporine therapy. Safety of cyclosporine in inﬂammatory bowel disease The incidence of adverse events was relatively low in three large, controlled trials of low-dose oral cyclosporine for Crohn’s disease [15–17]. Sandborn [92] summarized the adverse events reported in 27 studies, which included a total of 343 IBD patients, treated with high-dose cyclosporine therapy as follows: paresthesias (26%); hypertrichosis (13%); hypertension (11%); tremor (7%); nausea or vomiting (6%); renal insuﬃciency (6%); headache (5%); infection (3%); hepatotoxicity (3%); gingival hyperplasia (2%); seizure (1%); and anaphylaxis with intravenous cyclosporine (0.3%). In that summary, the frequency of adverse events was high (0.94 events per patient), but events were generally dose-related and reversed when either cyclosporine was discontinued or the dose was reduced. One of the most signiﬁcant concerns associated with the long-term (and perhaps short-term) use of high-dose cyclosporine is the potential for permanent nephrotoxicity. Almost all patients undergoing chronic cyclosporine therapy for autoimmune diseases have a 20% reduction in glomerular ﬁltration rate [93,94], without necessarily manifesting a rise in serum creatinine [95]. The decrease in renal function is usually caused by vasoconstriction of the aﬀerent arteriole, reverses within 2 weeks of cyclosporine discontinuation, and was not thought to cause signiﬁcant histopathologic changes. A recent study of renal biopsy data from 192 patients with autoimmune diseases (without associated renal insuﬃciency) treated with oral cyclosporine, however, has suggested that histologic evidence of nephropathy may occur in 21% of these patients [14]. Multivariate analysis showed that risk factors for the development of nephropathy included a greater mean oral cyclosporine dose (9.3 mg/kg/ d versus 8 mg/kg/d); greater maximum increase in serum creatinine; and greater patient age. The authors recommended that patients receiving oral cyclosporine for autoimmune diseases should not receive doses of greater than 5 mg/kg/d, and that the cyclosporine dose be adjusted downward if the serum creatinine increased to levels greater than 30% above baseline [14]. Based on this evidence it is possible that as many as 21% of IBD patients treated with high-dose oral and intravenous cyclosporine may have irreversible renal damage despite having normal serum creatinine levels. Infectious complications were not reported in controlled trials of low-dose oral cyclosporine for Crohn’s disease [15,16]. Severe and fatal opportunistic infections have been reported, however, in patients with IBD who had

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received treatment with high-dose cyclosporine therapy (either > 5 mg/kg/ d orally or 4 mg/kg/d intravenously) [33,61,68,69,74,78,92,96–101]. Opportunistic infections occurred more frequently in patients who received concomitant corticosteroids or azathioprine–6-mercaptopurine. Infections that have been reported in this setting include Pneumocystis carinii pneumonia (three cases, one fatality) [68,69,96]; Staphylococcus aureus sepsis (three cases, one fatality) [74,78,81]; invasive aspergillosis (two cases, one fatality) [97,100]; cytomegalovirus infection [98,99]; herpes esophagitis [61]; a carotid artery mycotic aneurysm requiring surgical resection [33]; and a case of Nocardia asteroides lung abscess [101]. The fact that such infections were not seen in patients receiving low-dose cyclosporine in combination with corticosteroids suggests that the combination of high-dose cyclosporine with corticosteroids ( azathioprine–6-mercaptopurine) increases the risk of opportunistic complications. Hepatotoxicity has been relatively uncommon in the setting of cyclosporine treatment in IBD. Up to 20% of renal transplant patients on cyclosporine have developed hepatotoxicity, with a predominantly cholestatic picture [102]. Cyclosporine may act to inhibit the excretion of bile acids into bile [103]. The potential for hepatotoxicity seems to be higher in cyclosporine-treated IBD patients who are also receiving total parenteral nutrition [104–106]. This observation has led to at least one group recommending that total parenteral nutrition not be used to support patients requiring cyclosporine for control of autoimmune disease [104]. Although paresthesia was a relatively common adverse event in the Sandborn [92] review (26% of patients), serious neurologic sequelae in IBD patients receiving cyclosporine are much less common. The most frequently reported serious adverse neurologic event is grand mal seizure [46,107,108]. The risk of seizures seems to be higher in patients with a total serum cholesterol level of less than 120 mg/dL [109], and it is recommended that these patients not be treated with cyclosporine [110]. There have also been case reports of reversible cortical blindness [107], and optic neuropathy in association with external ophthalmoplegia [111], in patients receiving cyclosporine for IBD. Although malignant lymphoma may be slightly more common in patients with autoimmune diseases treated with cyclosporine (approximately 0.3%) [112,113], lymphoma has not been reported in IBD patients treated with cyclosporine. In addition, although patients with ulcerative colitis are at increased risk of colonic cancer, there have been no reports to suggest that cyclosporine therapy adds to this risk. Dosing and toxicity monitoring Controlled trials have shown that low-dose oral cyclosporine (5 mg/kg/ d) is ineﬀective in Crohn’s disease [15–17], and low-dose cyclosporine is not recommended in patients with IBD. High-dose cyclosporine may be

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initiated either orally, at a dose of 8 to 10 mg/kg/d, or intravenously at a dose of 2 to 4 mg/kg/d. Although it remains unclear as to whether initial highdose oral or intravenous cyclosporine is more eﬀective, intravenous therapy has been favored historically in the severely ill, hospitalized patient, and in Crohn’s disease patients with extensive small bowel disease. Patients receiving cyclosporine by continuous intravenous infusion should have whole blood cyclosporine levels and electrolytes checked every 1 to 2 days, aiming for target drug concentrations in the 251 to 350 ng/mL range (HPLC or monoclonal RIA) [110]. When these patients are converted to the oral cyclosporine formulation on discharge from hospital, it is recommended that trough levels and electrolytes be checked weekly for the ﬁrst month, biweekly for the second month, and monthly thereafter [114]. Total serum cholesterol should be measured at baseline, and cyclosporine should not be initiated if the cholesterol is less than 120 mg/dL. The cyclosporine dose should be adjusted to maintain a serum creatinine level that is no more than 30% above the baseline value. Total duration of cyclosporine therapy should not exceed 4 to 6 months (because of the risk of irreversible nephrotoxicity), remission being maintained thereafter with an alternate immunosuppressive drug.

Cyclosporine microemulsion formulation Clinical pharmacology To improve the bioavailability of orally administered cyclosporine (bioavailability 12% to 35%), microemulsion formulations of cyclosporine (Neoral, Gengraf) were developed [115]. The microemulsion formulations contain polyethylene glycol, caster oil, medium-chain triglycerides, and lowmolecular-weight glycols. The bioavailability of the microemulsion formulations, relative to the standard oral formulation, is increased signiﬁcantly (145% to 239% increase) [115,116]. In patients receiving the microemulsion formulation, there is less interindividual and intraindividual variation in cyclosporine pharmacokinetics [117], improved absorption in the setting of small bowel disease [118], and decreased dependence on bile for absorption [119]. As with standard oral cyclosporine, bioavailability of oral liquid microemulsion cyclosporine is equal to a gelatin capsule of microemulsion cyclosporine [120]. In addition, the microemulsion formulation has been shown to be therapeutically equivalent to the standard oral cyclosporine formulation in transplant patients [121]. Clinical response in inﬂammatory bowel disease Three uncontrolled studies have evaluated one oral microemulsion cyclosporine formulation (Neoral) in patients with IBD [83,122,123]. In the

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ﬁrst study, Actis et al [83] compared oral microemulsion cyclosporine with a historical cohort treated with a combination of intravenous followed by standard oral cyclosporine in patients with severe steroid-refractory ulcerative colitis. Forty patients received intravenous cyclosporine (2 mg/kg/d), with an initial response rate of 65% (26 of 40). The responders subsequently received standard oral cyclosporine (6–8 mg/kg/d) for a 6-month maintenance period, during which the sustained response rate fell to 37.5% (15 of 40). Fourteen patients were treated with oral microemulsion cyclosporine (4.6 mg/kg/d) for a period of 3 months, with an initial response rate of 100%. At 6 months, the sustained response rate in the microemulsion group had dropped to 50% (six patients failing during the 3-month treatment period, and one patient failing after discontinuation of treatment). Azathioprine was used (in combination with cyclosporine) in 38% (10 of 26) of responders to intravenous therapy, and in 42% (6 of 14) of responders to microemulsion therapy. The mean whole blood cyclosporine concentrations (monoclonal RIA or monoclonal PFIA) were 216 ng/mL and 211 ng/mL in the standard cyclosporine and microemulsion cyclosporine groups, respectively. Seven (17.5%) of 40 patients who received intravenous cyclosporine experienced severe adverse events, with discontinuation of therapy in three (two patients who developed severe cholestasis [104], and one fatality caused by pulmonary embolism). No major toxicity or need for discontinuation of therapy occurred in the patients receiving microemulsion cyclosporine. The second study evaluated whether or not oral microemulsion cyclosporine allows for rapid corticosteroid tapering in patients with steroid-dependent chronic active ulcerative colitis [122]. Microemulsion cyclosporine was administered to nine patients (5 mg/kg/d), with an initial short-term response rate of 89% (eight of nine) and a long-term response rate at 3 months of 56% (ﬁve of nine). At the beginning of cyclosporine treatment, the median 1-month cumulative corticosteroid dose was 750 mg (range 375–1050 mg), compared with a median 1-month cumulative dose of 225 mg during the third month of cyclosporine therapy (range 0–570 mg). Seven patients reached whole blood cyclosporine levels in the range of 200 ng/mL (monoclonal assay, otherwise unspeciﬁed). No major toxicity related to microemulsion cyclosporine was observed. The authors concluded that the microemulsion formulation may be useful in weaning patients with chronic active ulcerative colitis from corticosteroids. In the third study, Navazo et al [123] reported on 11 patients treated with oral microemulsion cyclosporine (10 patients with steroid-refractory ulcerative colitis and 1 patient with steroid-refractory indeterminate colitis). The dose was 7 to 7.5 mg/kg/d of microemulsion cyclosporine, with an initial short-term response rate of 82% (9 of 11) and a long-term response of 55% (6 of 11). The six patients manifesting a long-term response were all treated with azathioprine–6-mercaptopurine. Target whole blood cyclosporine levels in this study were 250 to 350 ng/mL (monoclonal RIA). No major toxicity related to microemulsion cyclosporine was observed.

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153

Although randomized controlled trials are needed to assess deﬁnitively the eﬃcacy and safety of microemulsion cyclosporine compared with standard intravenous and oral cyclosporine, these results suggest that microemulsion cyclosporine may be as eﬀective as standard intravenous or oral cyclosporine in severe ulcerative colitis with potentially less toxicity. Tacrolimus Clinical pharmacology Tacrolimus is a macrolide antibiotic with immunomodulatory properties similar to cyclosporine [124]. Tacrolimus has relatively low oral bioavailability ranging from 21% to 27%, but there is less interpatient variability than there is with standard oral cyclosporine (Sandimmune) [125–127]. The low bioavailability of tacrolimus is likely caused in part by its poor aqueous solubility, and the fact that as a macrolide antibiotic it likely has a promotility eﬀect. Tacrolimus, however, is not dependent on bile or mucosal integrity for absorption [128–130]. These pharmacologic diﬀerences suggest a possible advantage of treatment with oral tacrolimus over standard oral cyclosporine, particularly in patients with small bowel Crohn’s disease. In the United States, commercially available formulations of tacrolimus include an oral capsule (0.5, 1, or 5 mg) and an intravenous concentrate (5 mg/mL). Tacrolimus is usually dosed 0.1 to 0.2 mg/kg/d orally and 0.01 to 0.02 mg/kg/d intravenously. Clinical response The only randomized, controlled trial of tacrolimus in IBD patients has recently been reported by Sandborn et al [131] (Table 3). Forty-eight patients with Crohn’s disease and draining perianal or enterocutaneous ﬁstulas were randomized to treatment with oral tacrolimus, 0.2 mg/kg/d, or placebo for 10 weeks. The primary outcome measure was ﬁstula improvement, as deﬁned by closure of greater than or equal to 50% of draining ﬁstulas and maintenance of closure for at least 4 weeks. A secondary outcome measure was ﬁstula remission, as deﬁned by closure of all ﬁstulas and maintenance of closure for at least 4 weeks. The rate of ﬁstula improvement was signiﬁcantly greater in patients treated with tacrolimus (9 [43%] of 21) compared with placebo (2 [8%] of 25) (P = .01). The rates of ﬁstula remission were similar in patients treated with tacrolimus (2 [10%] of 21) compared with placebo (2 [8%] of 25) (P = 1). Clinical improvement was not seen in the small subgroup of patients with abdominal ﬁstulas. Sixty-three percent of patients had previously been treated with inﬂiximab, and 56% to 62% were receiving concomitant therapy with azathioprine or 6-mercaptopurine. The most signiﬁcant adverse event in patients treated with tacrolimus was nephrotoxicity, with 38% (8 of 21) of treated patients having an increase of serum creatinine from baseline of greater than 30%. No patients developed serious infections, sepsis, or opportunistic infections. The initial tacrolimus dose of 0.2 mg/kg/d resulted

154

Fistula location (No. of patients)

Concomitant medications (No. of patients)

Agent Administered

No. of patients

Abdo

PA

Both

Cort

A/6-MP

Abx

Initial daily dose (mg/kg/d)

Tacrolimus Placebo P value

21 25

0 3

20 22

1 0

5 4

13 14

13 19

0.2 —

Response (No. of patients) (%) Fistula improvementa

Fistula remissionb

9 (43%) 2 (8%) 0.01

2 (10%) 2 (8%) 1

Abbreviations: A/6-MP, azathioprine/6-mercaptopurine; Abdo, abdominal; Abx, antibiotics; Cort, corticosteroids; PA, perianal. a Closure of 50% of particular ﬁstulas that were draining at baseline, and maintenance of closure for at least 4 wk. b Closure of all ﬁstulas, and maintenance of that closure for at least 4 wk. Sandborn WJ, Present DH, Isaacs KL, et al. Tacrolimus for the treatment of ﬁstulas in patients with Crohn’s disease: a randomized, placebo-controlled trial. Gastroenterology, in press.

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Table 3 Patient response in a controlled trial of tacrolimus for ﬁstulizing Crohn’s disease

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in a mean whole blood tacrolimus concentration at 1 week of 22.5 ng/mL (target 10–20 ng/mL), and 90% (19 of 21) of patients required dose reduction because of either high tacrolimus levels or adverse events. The authors concluded that oral tacrolimus at an initial dose of 0.2 mg/kg/d was eﬃcacious for the treatment of perianal ﬁstulas in patients with Crohn’s disease and that adverse events, which were seen frequently in tacrolimustreated patients, could be managed in most instances with dose reduction. There have been a number of uncontrolled studies reporting positive treatment eﬀects in patients with Crohn’s disease [132–136] and ulcerative colitis [134,136,137]. In the series by Ierardi et al [135], 13 patients with refractory Crohn’s ileitis, ileocolitis, or colitis were treated with tacrolimus, 0.1 to 0.2 mg/kg/d, aiming for target tacrolimus trough levels of 5 to 10 ng/ mL (competitive binding microparticle enzyme immunoassay). Patients in this series did not receive concomitant treatment with either azathioprine or 6-mercaptopurine. The median treatment period was 27.3 months (range, 2– 93 months). Signiﬁcant clinical improvement was reported in 85% (11 of 13) at 6 months and 69% (9 of 13) at 12 months. Of six patients with ﬁstulizing disease, three had complete ﬁstula closure with one further patient having signiﬁcant ﬁstula healing without complete closure. Although minor adverse eﬀects (headache, tremor) were reported in 46% (6 of 13) of patients, treatment was discontinued in only one patient because of toxicity (severe tremor). Nephrotoxicity was not reported in this series. Fellermann et al [136] reported on 30 patients (21 ulcerative colitis, 6 Crohn’s disease, 2 indeterminate colitis, and 1 pouchitis) who participated in an open-label trial with tacrolimus. All patients had been refractory to standard therapy. Of 21 patients with severe steroid-refractory ulcerative colitis, 71% (10 of 14) receiving intravenous tacrolimus (0.01–0.02 mg/kg/d) and 71% (ﬁve of seven) receiving oral tacrolimus (0.1–0.2 mg/kg/d) achieved rapid remission. Six (75%) of eight patients with either Crohn’s or indeterminate colitis showed initial improvement, but when tacrolimus was discontinued, four of six patients relapsed. The single patient with pouchitis had clinical but not endoscopic improvement. The mean duration of treatment was 8 months. In the pediatric series reported by Bousvaros et al [134], 14 patients (10 ulcerative colitis, 2 Crohn’s colitis, and 2 indeterminate colitis) were treated with oral tacrolimus, 0.1 mg/kg twice daily, to achieve whole blood trough tacrolimus levels of 10 to 15 ng/mL. Nine (69%) of 13 patients responded to treatment within 14 days (one patient withdrew from the study after 48 hours, not speciﬁed). The long-term response rate at 1 year was 22% (two of nine) in the ulcerative colitis group and 75% (three of four) in those with Crohn’s or indeterminate colitis. Nephrotoxicity or opportunistic infections were not observed in this series. Both Sandborn [132] and Lowry et al [133] reported positive treatment eﬀects in ﬁstulizing Crohn’s disease treated with oral tacrolimus. Sandborn [132] successfully used oral tacrolimus, 0.15 to 0.29 mg/kg/d, adjusted to

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achieve target trough levels of 10 to 20 ng/mL, in three patients with complicated Crohn’s disease with proximal small bowel involvement or ﬁstulas. Tacrolimus was used as a bridge to maintenance therapy with either methotrexate or azathioprine–6-mercaptopurine. Lowry et al [133] reported on the outcome of 11 patients with perianal Crohn’s disease (one to four perianal ﬁstulas) who were refractory to standard therapy, and were treated with oral tacrolimus, 0.15 to 0.31 mg/kg/d for 5 to 47 weeks. Azathioprine or 6-mercaptopurine was administered concomitantly. Nine (82%) of 11 underwent perianal surgical procedures during tacrolimus therapy. Seven (63%) of 11 patients had complete ﬁstula closure, and a further four patients (36%) had partial ﬁstula healing. Long-term remission was maintained, after discontinuation of tacrolimus, in six of seven patients who achieved complete ﬁstula closure. Four patients developed nephrotoxicity, peak creatinine ranging from 1.6 to 2 mg/dL (see later). Based on the controlled data of Sandborn et al [131] demonstrating that tacrolimus is eﬀective for Crohn’s disease ﬁstulas, and the absence of controlled data regarding the eﬃcacy of cyclosporine for this indication, tacrolimus may be considered, in preference to cyclosporine, for the treatment of Crohn’s disease ﬁstulas in patients who have failed antibiotics, azathioprine or 6-mercaptopurine, and inﬂiximab. Preliminary data suggest that tacrolimus may also be beneﬁcial in the treatment of refractory Crohn’s ileocolitis and ulcerative colitis, but controlled trials are needed to conﬁrm these ﬁndings. Safety of tacrolimus in inﬂammatory bowel disease In the controlled study by Sandborn et al [131], the most commonly reported adverse events among 21 patients receiving tacrolimus were as follows: paresthesia (11 [57%] of 21); headache (10 [48%] of 21); creatinine increase greater than 30% from baseline (8 [38%] of 21); insomnia (6 [29%] of 21); tremor (6 [29%] of 21); nausea or vomiting (6 [29%] of 21); leg cramps (5 [24%] of 21); diarrhea (4 [19%] of 21); and pruritus (4 [19%] of 21). Nephrotoxicity was the most serious adverse event noted, and there were no episodes of sepsis, serious infection, or opportunistic infection. Although adverse events were frequently reported in tacrolimus-treated patients, most of these events were dose-related and were managed successfully with dose reduction (see later). Dosing and toxicity monitoring Tacrolimus in patients with IBD is usually administered at a dose of 0.1 to 0.2 mg/kg/d orally or 0.01 to 0.02 mg/kg/d intravenously. Whole blood tacrolimus concentrations and electrolytes should be measured weekly for the ﬁrst month, biweekly for the second month, and monthly thereafter. The target range for tacrolimus concentrations is 10 to 20 ng/mL. The tacrolimus dose should be adjusted to maintain a serum creatinine level that is no more than 30% above the baseline value. In the study by Sandborn, a tacrolimus

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157

dose of 0.2 mg/kg/d led to a mean whole blood tacrolimus concentration of 22.5 ng/mL at week 1. The mean ﬁnal tacrolimus dose at week 10 was 0.16 mg/ kg/d and the mean ﬁnal tacrolimus blood concentration was 8.3 ng/mL. These results suggest that an initial tacrolimus dose of 0.2 mg/kg/d, adjusted to a target blood concentration range (10–20 ng/mL) and for toxicity, is the maximal tolerated dose for the treatment of Crohn’s disease. An uncontrolled pilot study of low-dose tacrolimus (2–4 mg/d) reported a beneﬁcial eﬀect despite low blood concentrations (\10 ng/mL) in patients with rheumatoid arthritis [138]. Because many of the adverse events among IBD patients treated with tacrolimus seem to be dose-related, the eﬃcacy of low-dose tacrolimus (0.05–0.15 mg/kg/d) adjusted to lower target blood levels (3–10 ng/ mL) should be determined in patients with Crohn’s disease.

Mycophenolate mofetil (Cellcept) Clinical pharmacology Mycophenolate mofetil is an ester prodrug of mycophenolic acid, the active moiety that gives the drug its immunosuppressive properties [139]. Mycophenolic acid decreases de novo synthesis of guanosine nucleotides by reversible inhibition of inosine monophosphate dehydrogenase. This drug has a directed action against T and B lymphocytes, because they depend on the de novo synthesis of purines for proliferation, whereas other cell types, such as neutrophils and macrophages, can use salvage pathways [139]. Mycophenolic acid can also inhibit growth of intestinal smooth muscle and synthesis of ﬁbronectin [140], and theoretically may be useful in preventing smooth-muscle hyperplasia and stricture formation in patients with Crohn’s disease. Most experience with mycophenolate mofetil has been in the context of cardiac and renal transplantation. It has been compared with either placebo or azathioprine in combination with cyclosporine and steroids in randomized controlled trials in renal-transplant recipients [141–143]. Patients receiving mycophenolate mofetil had signiﬁcantly fewer biopsy-proved rejection episodes, but there was no diﬀerence in graft loss or mortality at 12 months [141–143] or 3 years [142]. Patients receiving 2 g daily had a better safety proﬁle than those receiving 3 g daily [141–143], and the cumulative incidence of combined graft loss and death was reduced with the lower dose. In the United States, commercially available formulations of mycophenolate mofetil include an oral capsule (250 mg) and tablet (500 mg), and powder for solution (200 mg/mL) and suspension (200 mg/mL). Clinical response There have been two randomized trials [144,145] and a number of small, uncontrolled series [146–152] suggesting a possible therapeutic role for

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mycophenolate mofetil in patients with Crohn’s disease and ulcerative colitis (Table 4). In the ﬁrst randomized trial [144], 70 patients with steroiddependent chronic active Crohn’s disease received either mycophenolate mofetil, 15 mg/kg (approximately 1.5 g/d), or azathioprine, 1.5 mg/kg/d, in combination with prednisone, 50 mg daily, which was tapered to a maintenance dose of 5 mg daily. In patients with moderately active Crohn’s disease (Crohn’s disease activity index 150–300), decline in disease activity with mycophenolate mofetil was similar to that with azathioprine. In patients with highly active disease (Crohn’s disease activity index > 300), however, those treated with mycophenolate mofetil had a signiﬁcantly greater decrease in Crohn’s disease activity index score after the ﬁrst month of treatment, compared with those receiving azathioprine (mean Crohn’s disease activity index decline of 265 versus 117 points). The positive results in the subgroup of patients with high disease activity should be interpreted with caution because this was a secondary end point. Only two patients treated with mycophenolate mofetil experienced adverse events (drug rash, vomiting), compared with seven in the azathioprine group [144]. In the second randomized trial [145], 24 patients with active ulcerative colitis were randomly assigned to mycophenolate mofetil, 20 mg/kg (approximately 1.5 g/d), or azathioprine, 2 mg/kg/d, in combination with prednisone, 50 mg daily, which was tapered according to a standard protocol. Remission rates were higher in the azathioprine group, compared with the mycophenolate mofetil group, at 4 weeks (92% versus 67%); 3 months (92% versus 67%); 6 months (83% versus 78%); and 1 year (100% versus 88%). Patients receiving azathioprine experienced no severe adverse events, compared with two severe adverse events among those receiving mycophenolate mofetil (recurrent upper airways infection, bacterial meningitis) [145]. The data from these two small controlled trials suggest that mycophenolate mofetil, in combination with corticosteroids, may be a therapeutic alternative to combination therapy with azathioprine and corticosteroids in patients with active Crohn’s disease or ulcerative colitis [144,145]. In uncontrolled series or reports [146–152] a total of 75 patients (56 Crohn’s disease, 19 ulcerative colitis) with refractory IBD were treated with mycophenolate mofetil with positive [146,147,150,151] and negative [148,149,152] treatment eﬀects reported. Of the 56 Crohn’s disease patients treated with mycophenolate mofetil, the overall response rate was 52% (29 of 56). Four of the series reported treatment of perianal Crohn’s disease [146,147,151,152], with overall improvement in 69% (11 of 16) and complete ﬁstula closure in 44% (7 of 16) [146,151]. Of 19 ulcerative colitis patients treated with mycophenolate mofetil, the overall response rate was 47% (9 of 19). The overall mean dose of mycophenolate mofetil was 2 g daily (range, 1–3 g daily). Adverse events were reported in 20% (15 of 75) of the patients treated in these uncontrolled series (see later) [147–149,151,152].

Table 4 Randomized trials of mycophenolate mofetil in patients with steroid- dependent inﬂammatory bowel disease No. of Patients

Diagnosis

Treatment (no. of patients)

Initial dose (mg/kg/d)

Corticosteroids (no. of patients)

Response Delta CDAIa CDAI \ 300b CDAI > 300b 0–1 mo 3–6 mo 0–1 mo 3–6 mo

Neurath et al [144]

70

CD

MM (35)

AZA (35) P value

15

2.5

35

35

120

97 0.42

45

12c 0.1

265

117 0.01

3

42c 0.23

Remission (No. patients)d

Orth et al [145]

24

UC

4 wk

3 mo

6 mo

12 mo

MM (12)

20

12

8

8

8

7

AZA (12)

2

12

11

11

11

12

Abbreviations: AZA,azathroprine; CD, Crohn’s disease; MM, mycophenolate mofetil; UC, ulcerative colitis. a Change in Crohn’s disease activity index (CDAI) with treatment at speciﬁed time intervals. b Baseline CDAI. c Negative changes indicate decreases in CDAI scores. d Remission as deﬁned by clinical colitis activity index 4 at speciﬁed time points.

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Author (ref)

159

160

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Safety of mycophenolate mofetil in inﬂammatory bowel disease Of the total 169 patients treated with mycophenolate mofetil for IBD [144–152], 9% (16 of 169) discontinued therapy because of adverse events attributed to the medication. These adverse events were nausea and vomiting (4 [25%] of 16); atypical (possibly medication-related) colitis (2 [12.5%] of 16); and one case each of recurrent upper airway infections, bacterial meningitis, migraine, depression, multidermatomal herpes zoster, diﬀuse maculopapular rash, increased diarrhea, bone marrow suppression, headache, and conjunctivitis or parotitis (1 [6%] of 16). In the two patients who developed atypical colitis (both had ulcerative colitis and one developed life-threatening gastrointestinal bleeding) [152], the histologic features were highly suggestive of a drug etiology. The dose of mycophenolate mofetil in both cases was 1 g daily. The development of colitis in patients treated with mycophenolate mofetil has also been described in a series of four renal-transplant recipients [153]. The patients in that series, however, were receiving high-dose immunosuppression that included mycophenolate mofetil, 3 g daily. The development of colitis in these patients may be caused by enterohepatic cycling of mycophenolic acid resulting in high colonic concentrations of the metabolite [154]. Although this adverse event may occur with lower doses of mycophenolate mofetil [152], it seems more likely to be a dose-dependent phenomenon [153,154]. These data contrast with the paucity of adverse events reported by Neurath et al [144] in 70 patients receiving 1.5 g daily (two patients had adverse events: drug rash and vomiting). When compared with azathioprine, mycophenolate mofetil, 2 to 3 g daily, has also been reported to be associated with a higher incidence of lymphoproliferative disorders after 3 years of follow-up (3% versus 0.6%) [142]. In addition, mycophenolate is teratogenic and should be avoided in pregnancy, whereas azathioprine may be used cautiously in this group.

Dosing and toxicity monitoring In hepatic transplantation, the recommended dose of mycophenolate mofetil is 1 g intravenously twice daily or 1.5 g orally twice daily. Cardiac transplant patients receive 1.5 g either orally or intravenously twice daily. Patients receiving mycophenolate mofetil should have blood counts checked weekly for the ﬁrst month, and monthly thereafter, monitoring for myelosuppression. In the setting of IBD, the most commonly used dose is 2 g daily orally [144–152]. Although this dosing schedule seems reasonable given the limited published experience, large double-blind placebo-controlled trials are needed to address the outstanding questions regarding eﬃcacy, dosing, and safety of mycophenolate mofetil in patients with IBD. Outside of such studies, this medication should be reserved for patients who are refractory to, or intolerant of, azathioprine–6-mercaptopurine, methotrexate, and inﬂiximab.

Crohn’s disease

Cyclosporine Tacrolimus Mycophenolate mofetil

Ulcerative colitis

Inﬂammatory induction

Fistulizing induction

Steroid sparing

Maintenance therapy

Steroid refractory

Steroid dependent

Maintenance therapy

+ +/

+ +

+/

++

+ +/ +/

+, One controlled trial. ++, More than one controlled trial. þ/, uncontrolled data. , no clear indication.

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Table 5 Indications for cyclosporine, tacrolimus and mycophenolate mofetil in patients with inﬂammatory bowel disease

161

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Summary Controlled trials have shown eﬃcacy for intravenous cyclosporine in patients with severe ulcerative colitis, oral tacrolimus in patients with Crohn’s disease complicated by draining perianal ﬁstulas, and mycophenolate mofetil in patients with active Crohn’s disease. Based on these controlled data, patients with IBD refractory to treatment with corticosteroids, azathioprine or 6-mercaptopurine, methotrexate (Crohn’s disease), and inﬂiximab (Crohn’s disease) may be treated with the second-line immunosuppressive agents cyclosporine, tacrolimus, and mycophenolate mofetil in selected circumstances (Table 5).

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Treatment of inﬂammatory bowel disease with corticosteroids Jeﬀry A. Katz, MD Division of Gastroenterology, Department of Medicine, Case Western Reserve University School of Medicine, University Hospitals of Cleveland, 11100 Euclid Avenue, Cleveland, OH 44106–5066, USA

Corticosteroids are the ‘‘Dr. Jekyll and Mr. Hyde’’ of inﬂammatory bowel disease (IBD) therapy. No other medication produces such consistent and rapid clinical beneﬁt in both ulcerative colitis (UC) and Crohn’s disease (CD); however, no other commonly used therapy causes so many diﬃcult and damaging treatment-related side eﬀects. Despite the well-recognized potential dangers associated with their use, especially with prolonged use, corticosteroids remain one of the most eﬀective therapies in the medical treatment of IBD [1–4]. When used judiciously and wisely, corticosteroids can produce rapid improvement and drug toxicity can be minimized. This article discusses the rational use of corticosteroids in the management of IBD.

Corticosteroid preparations Available corticosteroid preparations diﬀer in their potency and, to a lesser degree, in their side eﬀects. Initial controlled trials in the 1950s were performed using the natural corticosteroid compound cortisone [5], which is rapidly metabolized by the liver to hydrocortisone. Prednisone is a synthetic glucocorticoid, which undergoes similar hepatic hydrolysis to prednisolone. The modiﬁcation of hydrocortisone to prednisolone increases its glucocorticoid activity fourfold, and decreases its mineralocorticoid activity. Further modiﬁcation to methylprednisolone increases glucocorticoid activity another 20%. Newer synthetic glucocorticoids, such as dexamethasone, are even more potent (Table 1). In addition to being more potent, prednisolone has greater bioavailability after oral administration than hydrocortisone (80% versus 60%). Corticosteroids may be administered topically as suppositories E-mail address: [email protected] 0889-8553/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.gtc.2004.02.002

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Table 1 Commonly available glucocorticoid preparations Drug

Route of administration

Strength

Hydrocortisone Prednisone Methylprednisolone Dexamethasone Budesonide

IV, po, suppository, enema IV, po IV, po IV, po Po, enema

1 4 5 10 16

Abbreviations: IV, intravenously; po, orally.

or enemas, orally, or intravenously. In the United States, most physicians use hydrocortisone or methylprednisolone for intravenous administration and prednisone for oral administration. Budesonide is a novel synthetic corticosteroid structurally related to 16ahydroxyprednisolone. Budesonide has a very strong aﬃnity for the glucocorticoid receptor, giving it potent local anti-inﬂammatory activity. The systemic eﬀects of budesonide are signiﬁcantly less than conventional corticosteroids because of rapid, near complete ﬁrst-pass hepatic conversion to metabolites with limited activity [6]. Budesonide capsules are designed to delay the release of budesonide until reaching the ileum and ascending colon. The capsules start releasing their content at a pH of over 5.5. Systemic availability is approximately 10%. Adrenocorticotrophic hormone (ACTH) has also been used to treat UC by stimulating endogenous corticosteroid production, and has the advantage of avoiding adrenal suppression. Despite controlled evidence favoring intravenous ACTH over hydrocortisone, particularly in patients not previously treated with corticosteroids, ACTH is now rarely used [7,8]. The necessity for parenteral administration, excessive mineralocorticoid side eﬀects, reports of anaphylaxis, and rare episodes of adrenal hemorrhage have combined to contribute to its disuse [9]. Mechanism of action The actions of glucocorticoids, both natural and synthetic, are mediated by speciﬁc intracytoplasmic glucocorticoid receptors [10]. These receptors are present in most mammalian cells. Receptor density is suppressed by glucocorticoid administration in vitro and in vivo [11]. Besides glucocorticoids, other factors, such as the cell cycle, may also inﬂuence receptor density. Glucocorticoids diﬀuse from the plasma or interstitium through the cell membrane into the cytoplasm of the target cell and bind with the cytosolic receptor. The hormone-bound receptor is rapidly transported to the cell nucleus where it binds to glucocorticoid-responsive elements on speciﬁc glucocorticoid-inducible genes [12]. Hormone-receptor binding to DNA leads to activation and expression of a number of diﬀerent genes and eventual anti-inﬂammatory eﬀect.

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Because most cells express glucocorticoid receptors, glucocorticoids aﬀect the function of a large number of diﬀerent cell types. The beneﬁcial and deleterious eﬀects of glucocorticoid administration result from this widespread, multifactorial eﬀect and cannot be explained by any one particular action. Glucocorticoids impair speciﬁc and nonspeciﬁc immune reactions, aﬀecting both early and late inﬂammatory events [13]. They inhibit early events, such as vasodilation, leukocyte inﬁltration, increased vascular permeability, and the release of inﬂammatory cytokines, and also act to suppress later processes including ﬁbroblast activations and vascular proliferation (Fig. 1). These actions are mediated in large part through direct eﬀects on lymphocytes, monocytes and macrophages, and neutrophils. Glucocorticoid administration results in a transient lymphopenia caused by redistribution of lymphocytes from the blood to other lymphoid organs. This eﬀect is maximal at 4 to 6 hours, involves all lymphocyte subpopulations, and returns to normal levels after 24 hours. Glucocorticoids strongly inhibit lymphocyte activation and proliferation [14] through inhibition of interleukin-2 and interleukin-2 receptor production [15]. Glucocorticoids suppress the production of a wide array of lymphokines, including interferon-c, tumor necrosis factor-a, interleukin-3, interleukin-4, interleukin-5, and granulocyte-macrophage colony–stimulating factor, impairing helper and cytotoxic lymphocyte function and reducing activation of other immune cells [13].

GLUCOCORTICOIDS INHIBIT CYTOKINES PROSTAGLANDINS LEUKOTRIENES HISTAMINE

CYTOKINES GROWTH FACTORS

RELEASE OF INFLAMMATORY MEDIATORS

PROLIFERATION AND DIFFERENTIATION IMMUNE CELL

RECRUITMENT FACTORS CYTOKINES ADEHESION MOLECULES

MIGRATION

GLUCOCORTICOIDS INHIBIT Fig. 1. Summary of glucocorticoid eﬀects on immune cell function.

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Glucocorticoid administration markedly reduces circulating monocytes by redistribution. The release of arachidonic acid metabolites and the synthesis elastase, collagenase, cytokines, such as interleukin-1, interleukin-6, and tumor necrosis factor-a are also diminished [16]. This impairs much of the function of monocytes and macrophages. The acute eﬀect of glucocorticoids on circulating neutrophil is in the opposite direction of the eﬀect on lymphocytes and monocytes, and there is a transient neutrophilic leukocytosis caused by increased neutrophil release from the bone marrow and reduced migration out of the blood [17]. The reduced migration of neutrophils to the site of inﬂammation is an important factor in reducing inﬂammation in IBD. Glucocorticoids also have eﬀects on eosinophils, basophils, and mast cells [11]. In addition to cells of the immune system, glucocorticoids also aﬀect nonimmune cells, such as endothelial cells and mesenchymal cells inﬂuencing microvascular permeability and adhesion [18]. The combination of glucocorticoid eﬀects on the recruitment and proliferation of lymphocytes, monocytes, and macrophages at sites of inﬂammation, along with eﬀects on the production of soluble inﬂammatory mediators, such as cytokines, leukotrienes, and prostaglandins, explains the potent anti-inﬂammatory eﬀects of these compounds.

Corticosteroid therapy of ulcerative colitis Systemic corticosteroids The ﬁrst uncontrolled reports documenting the beneﬁcial eﬀect of corticosteroids and ACTH in the treatment of UC appeared more than 50 years ago [19,20]. Shortly thereafter, the landmark placebo-controlled trial of Truelove and Witts [5,21] reported a response rate of approximately 80% for hospitalized UC patients treated with oral cortisone at an initial dose of 100 mg/d compared with a placebo response rate of between 30% to 40%. Subsequent studies documented similar beneﬁts with oral prednisone for moderate UC [22] and intravenous prednisolone for severe UC [23]. These studies solidiﬁed the role of systemic corticosteroids as the mainstay of medical therapy for acute attacks of moderate to severe UC. In mild to moderate UC there is a documented dose response between 20 and 60 mg of prednisone per day, with no obvious beneﬁt from higher oral doses [24]. A comparison of once a day dosing at 40 mg versus 10 mg four times a day showed no diﬀerence in response [25] and most clinicians use the more convenient once a day dosing. Split-dosing two to four times a day may be helpful in patients who remain symptomatic after a trial of oncedaily dosing, particularly if they are bothered by nocturnal bowel movements. It may also be useful for hospitalized patients transitioning from parenteral steroids to oral therapy [26]. Once the decision has been made to initiate oral steroid therapy for the treatment of UC, no rationale exists for

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starting at lower doses to prevent steroid side eﬀects [26]. This approach leads to inadequate clinical response and typically results in a longer duration of steroid therapy. Likewise, premature tapering of steroids before a complete response is obtained is likely to lead to rapid symptom relapse [26]. Corticosteroids should be continued at full dose until clinical remission has been obtained, typically within 2 weeks, but occasionally longer, followed by gradual dose tapering. Parenteral corticosteroids are the treatment of choice for hospitalized patients with severe UC [27]. Although a recent small study comparing intravenous cyclosporine with intravenous methylprednisone for severe UC showed similar eﬃcacy and safety [28], the body of clinical evidence and experience over time continues to support the initial use of corticosteroids in this patient population [23,29–32]. The optimal dose response for parenteral steroids in the treatment of severe UC has not been clariﬁed. Most treatment regimens use methylprednisolone, 60 mg/d, or its equivalent [23], and there is little evidence to support the use of higher doses [33]. Compared with equivalent doses of intravenous hydrocortisone, methylprednisolone results in less renal potassium loss. Likewise, it is unclear whether parenteral steroids are most eﬀective when administered as a bolus or by continuous intravenous infusion [26,34]. Although a continuous infusion of ACTH was superior to intermittent infusions of hydrocortisone for patients never before treated with corticosteroids [7], similar data do not exist for conventional steroids. Some debate remains as to how long to continue intensive intravenous steroid therapy in patients with severe UC before deciding it has failed to bring about remission. Most patients respond within 5 days [23]. Recently, it has been reported that after only 3 days of intensive treatment most (85%) patients with persistent frequent stools (>8 per day) or a raised C-reactive protein (>45 mg/L) need colectomy [35]. Other studies suggest that continued responses may be seen up to 10 to 14 days of therapy [7,31], or even longer [36]. Most practitioners treat severe colitis with 7 to 10 days of intravenous corticosteroid before moving to other medical treatments or surgery. Oral corticosteroids are neither eﬀective nor indicated in preventing relapse of UC. Doses of prednisone, up to 15 mg/d, have failed to maintain remission, and continuation of corticosteroids beyond several months risks short- and long-term complications [37,38]. Patients unable to taper oﬀ of corticosteroids need to be evaluated for alternative medical therapy or surgical intervention. Topical corticosteroids The rectal administration of corticosteroids is an important component of UC treatment, with topical steroids having a primary role in the treatment of distal UC [39–41] and an adjunctive role in the management of severe colitis [23,31]. Controlled trials suggest a therapeutic gain of topical corticosteroids of approximately 30% over placebo [39]. Although studies of

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rectally administered steroids have reported fewer systemic side eﬀects than with oral steroids, plasma concentrations of prednisolone are similar with identical oral and rectal doses [42] and suppression of the pituitary-adrenalhypothalamic axis does occur [43]. A variety of topical steroid formulations, including hydrocortisone, prednisolone, and betamethasone, are available as suppositories, foams, and enemas. In general, suppositories are useful for the treatment of proctitis, whereas enemas and foams are useful for more extensive left-sided disease, with documented spread to the splenic ﬂexure [44]. Many patients prefer foam preparations to enemas because of ease of administration and retention. Despite their use in the treatment of UC, topical glucocorticoids are less eﬀective than topical aminosalicylates [39]. Nonsystemic corticosteroids The clinical beneﬁt of steroid therapy is counterbalanced by the many well-recognized acute and chronic complications. This dilemma has led to the development for both oral and rectal administration of a variety of novel corticosteroid derivatives with enhanced topical mucosal activity and decreased systemic activity [45]. Prednisolone-metasulfobenzoate, beclomethasone diproprionate, tixocortol pivalate, ﬂuticasone, and budesonide are some of the novel compounds under investigation [46]. Of these, budesonide has been the most extensively studied in UC. Budesonide commercially available in the United States as a delayed-release oral preparation. Topical budesonide is eﬀective treatment for left-sided UC, with beneﬁts similar to prednisolone with less plasma cortisol suppression [39,47–52]. The lowest eﬀective budesonide enema dose for the treatment of active distal UCs is 2 mg/d, with no advantage of twice a day dosing [47,48]. Expected remission rates are between 20% and 50%. The role of budesonide enema in the maintenance of remission in distal UC has not been extensively evaluated, but a 2-g enema twice a week was not eﬀective at maintaining remission over 6 months [47]. Limited information exists on the eﬃcacy of oral budesonide in the treatment of UC. A pilot study compared budesonide, 10 mg/d, with prednisolone, 40 mg/d, with both drugs gradually tapered over 9 weeks [53]. Although endoscopic scores improved signiﬁcantly and similarly in both groups, the budesonide-treated group had less overall clinical beneﬁt. Budesonide-treated patients with more extensive disease tended to do better than those with left-sided colitis. It is believed that insuﬃcient drug levels in the distal colon explain this result, possibly because the dose was too low or release too slow [53]. Importantly, no patient in the budesonide-treated group had suppression of plasma cortisol, although this had not been the case in CD studies of oral budesonide [54]. Budesonide has also been used in corticosteroid-dependent UC patients as a means discontinuing conventional steroids [55]. Another novel steroid, beclomethasone diproprionate, has recently shown eﬃcacy as oral therapy in the treatment of active UC,

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with results comparable with treatment with 5-aminosalicylates [56,57]. The results of these studies are encouraging; however, obtaining suﬃcient spread through the colon and preventing bacterial metabolism and inactivation of nonsystemic steroids continue to be practical obstacles in the widespread use of these medications as oral therapy for UC.

Natural history of steroid-treated ulcerative colitis Although corticosteroids are eﬀective for the acute therapy of UC, not all patients respond to corticosteroid treatment (steroid resistant), and some patients who respond are either unable to taper oﬀ medication or relapse shortly after discontinuing corticosteroids (steroid dependent). The 30-day and 1-year outcome after the ﬁrst course of corticosteroids had been reported for a group of 185 UC patients treated at the Mayo Clinic between 1970 and 1993 [58]. Less than 50% of patients ever required steroid therapy for their IBD. Among 63 UC patients treated with steroids, short-term response was remission in 54%, partial response in 30%, and no response in 16%. At 1 year, prolonged response was seen in 49%, corticosteroid dependence in 22%, and colectomy in 29% [58]. Why some patients do not respond to steroid therapy remains unclear. It is often assumed that responsiveness to corticosteroid treatment in UC is simply a function of disease severity. Some patients with mild disease fail to respond to steroids, however, and studies have shown little diﬀerence in disease severity scores between responders and nonresponders [35]. A small study has suggested that in vitro measurement of the steroid sensitivity of proliferating peripheral blood lymphocytes correlates directly with clinical response to systemic corticosteroid therapy [59]. This preliminary work requires conﬁrmation and more investigation into the mechanisms controlling steroid responsiveness in IBD is needed.

Corticosteroid therapy of Crohn’s disease Systemic corticosteroids In 1979 the National Cooperative Crohn’s Disease Study (NCCDS) conclusively showed the beneﬁt of prednisone (0.25–0.75 mg/kg/d) treatment in patients with CD [60]. In this randomized, double-blind, placebo-controlled trial of 569 patients, remission at 17 weeks occurred in 60% of prednisone-treated patients compared with just 30% of placebotreated patients. Using a slightly higher dose of methylprednisolone (48 mg initially, tapered by 8 mg per week), the European Cooperative Crohn’s Disease Study (ECCDS) reported even better results with 80% of all steroidtreated patients achieving remission at 18 weeks, compared with less than 40% of placebo-treated patients [61]. More recently, controlled trials have

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shown methylprednisolone or prednisone at doses of 48 mg and 40 mg, respectively, achieve remission rates of 60% to 73% at 8 to 10 weeks treatment [62,63]. Both the NCCDS and the ECCDS failed to show any signiﬁcant beneﬁt of steroid therapy in the prevention of relapse for patients with quiescent disease [60,61]. Although the ECCDS did suggest a beneﬁcial eﬀect of lowdose prednisone in the initial 6 months for patients who had responded initially to steroid treatment of active disease, the NCCDS and earlier studies have shown no eﬀect of corticosteroids in the maintenance of medical or surgical remissions in CD [60,64,65]. Although some authors have suggested alternate-day steroid therapy for the maintenance of remission in CD [66], controlled data are lacking. Patients with CD unable to discontinue corticosteroids after several months should be considered for alternative therapies, such as azathioprine, 6-mercaptopurine, methotrexate, or inﬂiximab. Nonsystemic corticosteroids The targeted delivery of budesonide to the distal ileum and ascending colon makes it an ideal therapy for CD. Seven controlled trials using budesonide controlled ileal release for active CD have been published and are summarized in Table 2. Budesonide, 9 mg/d or 4.5 mg twice a day for 8 weeks, in patients with active CD achieved remission in 48% to 53% of patients and was statistically superior to placebo [67,68]. Compared with mesalazine, 2 g twice a day, budesonide, 9 mg/d, was statistically better over 16 weeks at inducing remission [69]. Four trials have shown that budesonide is almost as eﬃcacious as prednisolone for the treatment of active CD [62,63,70,71]. Combining the data from these four trials together, budesonide is 13% less eﬀective than prednisone for the induction of remission in active CD [72]. Although slightly less eﬀective than conventional steroids at induction of remission, budesonide-treated patients are 35% less likely to have steroidrelated side eﬀects [72]. Budesonide does cause a dose-related reduction in basal- and corticotropin-stimulated cortisol concentrations [67,68]. Compared with prednisolone, however, budesonide causes less moon facies, weight gain, acne, and mood change [62,63,70,71]. The combination of clinical eﬃcacy with fewer side eﬀects makes it clear that budesonide in a controlled-release, targeted formulation at 9 mg/d for 8 to 10 weeks oﬀers an eﬀective and attractive alternative to traditional systemic corticosteroids for the treatment of active CD involving the ileum, ileocolic region, and ascending colon. Similar to conventional corticosteroids, budesonide does not prevent relapse in patients with quiescent CD. Three controlled trials have evaluated budesonide, 3 or 6 mg daily, compared with placebo in the maintenance therapy of over 200 CD patients with prednisolone- or budesonide-induced

Table 2 Controlled trials of budesonide in active Crohn’s disease

Author

Year

No. patients

Greenberg et al Rutgeerts et al

1994 1994

258 176

Gross et al

1996

67

Campieri et al

1997

178

Thomsen et al

1998

182

Bar-Meir et al

1998

201

Tremaine et al

2002

200

Drug and dosage Budesonide, 3, 6, or 9 mg vs placebo Budesonide, 9 mg 6 wk, then 6 mg 2 wk, vs prednisolone, 40 mg 2 wk then taper Budesonide, 9 mg, vs methylprednisolone, 48 mg tapered weekly Budesonide, 9 mg QD or 4.5 mg BID, vs prednisolone, 40 mg tapered after 2 wk Budesonide, 9 mg, vs mesalazine, 2 g BID Budesonide, 9 mg, vs prednisone, 40 mg tapered after 2 wk Budesonide, 9 mg QD or 4.5 mg BID, vs placebo

Duration (wk)

Budesonide

Control

P value

Ref

8 10

51 (9-mg dose) 53

20 66

\.001 NS

[68] [63]

56

73

NS

[62]

12

60 (9 mg QD) 42 (4.5 mg BID)

60

NS

[71]

16

62

36

\.01

[69]

8

51

52.5

NS

[70]

8

48 (9 mg QD) 53 (4.5 mg QD)

33

\.05 (combined budesonide group)

[67]

8

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Remission rates (%)

Abbreviations: BID, twice a day; QD, every day.

179

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remissions [54,73,74]. Although budesonide prolonged time to relapse, relapse rates were similar in all groups at 1 year. Likewise, budesonide has been ineﬀective in the maintenance of postoperative remission in CD [75]. Natural history of steroid-treated Crohn’s disease Crohn’s disease patients treated with conventional corticosteroids for the ﬁrst time can expect a complete remission between 48% and 58%, a partial response between 26% and 32%, and no response between 16% and 20% of the time [58,76]. Thirty days after discontinuation of steroids, 55% to 65% of CD patients continue to do well, whereas 35% to 45% of patients relapse and require continued steroids. At 1 year 32% to 44% of steroid-treated patients are doing well, 28% to 36% are steroid dependent, and 20% to 22% are steroid resistant or require surgery [58,76]. Similar natural history data do not yet exist for budesonide. Recognizing that slightly less than half of all CD patients treated with steroids are well and oﬀ steroids at 1 year, the need for steroid therapy must be considered a marker of poor prognosis in CD. With this in mind, the initiation of steroid therapy in CD justiﬁes the consideration of alternative treatments, such as immunomodulators or inﬂiximab, for long-term management. Corticosteroids in children with inﬂammatory bowel disease Although the strategy of corticosteroid therapy in children with IBD is similar to that in adults, steroid-related side eﬀects are particularly damaging. Although weight gain, acne, and mood swings are common and diﬃcult for children and families to manage, the most important side eﬀect of corticosteroid therapy in childhood is growth retardation [77,78]. Alternate-day corticosteroids have been shown to reduce this complication, and linear growth velocity can be maintained with an alternate-day steroid regimen if disease activity is controlled and nutrient intake is adequate [79,80]. The undesirable cosmetic side eﬀects of steroid therapy often gradually resolve after 1 to 2 months of alternate-day treatment [77]. Budesonide pharmacokinetics is similar in children and adults [81], and preliminary studies suggest budesonide is eﬀective therapy for children with Crohn’s disease [82]. It remains preferable, however, to discontinue corticosteroid therapy in children with IBD whenever possible, and both immunomodulators and inﬂiximab may be used safely in children and adolescents [83,84]. Corticosteroids in pregnancy Corticosteroids cross the placenta and are transferred into breast milk, but the ratio of maternal to fetal serum concentration depends on the choice of corticosteroid used. Prednisolone is more eﬃciently metabolized

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compared with dexamethasone, and fetal levels are only approximately 10% of maternal levels [85]. Although there is a concern regarding possible adrenal suppression among the neonates of mothers taking corticosteroids, in practice this has rarely occurred [86]. If steroids must be used during pregnancy it makes sense to use one more extensively metabolized by the placenta, such as prednisone or prednisolone. Among patients with IBD, corticosteroid therapy has not been found to be harmful to the fetus [87,88]. In a study of 531 pregnant women [87], 168 received corticosteroids for an extended period of time, mostly during the second and third trimester. No increased incidence of prematurity, spontaneous abortion, stillbirth, or developmental defects was noted. When necessary, corticosteroids can be used safely to control active disease during pregnancy. Small amounts of glucocorticoids may be present in the breast milk of women taking these medications at 5% to 25% of maternal serum concentrations [89]. The concentrations are not thought to represent a clinically signiﬁcant risk to the fetus, and no adverse eﬀects have been reported. Corticosteroids are safe for the breast-feeding infant and women on steroid therapy should be encouraged to continue breast-feeding if they so desire.

Complications of corticosteroid therapy The adverse eﬀects of corticosteroids relate directly to the dose and duration of therapy, and can be expected to impact on every organ system and metabolic process of the body. Corticosteroid side eﬀects are the major factors limiting long-term use of glucocorticoids in IBD. The toxicities of corticosteroid therapy are listed in Box 1. The metabolic eﬀects of steroid therapy include hyperglycemia and an unmasking of a genetic predisposition to diabetes mellitus, hyperlipidemia, alteration of fat distribution with development of a cushingoid appearance, and hepatic steatosis. Glaucoma and cataracts have been described in both adults and children and correlate with the intensity and duration of treatment [90]. Wound healing is impaired after steroid therapy, and corticosteroids are associated with increased postoperative infectious complications [91,92]. Steroid-induced subcutaneous tissue atrophy causes striae, and predisposes to purpura and ecchymoses. Corticosteroid-induced neuropsychiatric complications occur in approximately 25% of patients and are severe in up to 6% of patients, with symptoms including psychosis, depression, mania, and delirium [93]. Milder more common side eﬀects include irritability, anger, insomnia, and excessive talkativeness [94]. At high corticosteroid doses cognitive impairment and hallucinations have been reported [95]. A case report suggests that budesonide can be eﬀective and well tolerated in patients with neuropsychiatric symptoms after treatment with conventional systemic steroids [96].

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Box 1. Side effects of corticosteroid therapy Metabolic Hyperglycemia, diabetes mellitus Hypertension Hypercholesterolemia Hypokalemia Adrenal suppression Musculoskeletal Osteoporosis Aseptic necrosis of bone Proximal myopathy Growth retardation Dermatologic Acne Plethora Striae Ocular Cataracts Glaucoma Neuropsychiatric Neuropathy Insomnia Psychosis Immunologic Increased risk of infection Miscellaneous Moon face ‘‘Bualo hump’’ Weight gain Ulcer disease Osteopenia and osteoporosis are common complications of IBD. Using dual-energy X-ray absorptiometry scanning, osteopenia is deﬁned as a T score between ÿ1.5 and ÿ2.5 and osteoporosis deﬁned as a T-score less than or equal to ÿ2.5. Population estimates range from 5% to 15% for osteoporosis and 15% to 45% for osteopenia [97,98]. Most studies have implicated corticosteroids as a major risk factor for reduced bone mineral density in IBD, although bone loss may be related to inﬂammation and occur independent of steroid therapy [99]. Corticosteroids accelerate the rate of bone loss irrespective of other risk factors for osteoporosis, aﬀecting men and women equally. Corticosteroids aﬀect both bone resorption and formation, ultimately resulting in decreased bone mass and fractures [100]. In IBD, the higher the total lifetime steroid dose, the lower the bone

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density [101]. Although budesonide has lower systemic bioavailability than conventional corticosteroids, it can aﬀect the pituitary adrenal axis and contribute to loss of bone density [54,102]. Despite the high prevalence of bone loss in steroid-treated IBD patients, it remains uncertain whether these patients suﬀer an increased rate of osteoporotic fractures, with two population studies coming to opposite conclusions [103,104]. All IBD patients treated with corticosteroids for greater than 3 months should have dual-energy X-ray absorptiometry scanning. Osteopenia should be treated with calcium and vitamin D supplementation. Patients with osteoporosis should receive calcium and vitamin D supplementation and a bisphosphonate compound, such as alendronate or risedronate [100]. Aggressive attempts should be made to discontinue steroid treatment and follow-up dual-energy X-ray absorptiometry scanning should be yearly until stability or improvement of bone density is conﬁrmed [105]. Steroid-related osteonecrosis, particularly of the femoral head, is a less common musculoskeletal complication of IBD [106]. The precise pathogenesis of this condition is uncertain and it can be diﬃcult to anticipate and diagnose. This dreaded complication can lead to premature arthritis and joint collapse, leading to early prosthetic joint replacement. Patients treated with high doses of steroids for prolonged periods of time are at an increased risk of infectious complications [107]. Patients receiving greater than 40 mg/d of prednisone have a greater risk of infectious complications, whereas there is no increased risk in patients on less than 10 mg/d. In the ECCDS, infectious and septic complications were particularly increased in steroid-treated patients who presented with an abdominal mass [61]. The rate of perianal complications, abdominal abscesses, or peritonitis, however, is not increased in patients treated with corticosteroids [60]. Long-term steroid treatment suppresses the hypothalamic-pituitaryadrenal axis and can cause adrenal insuﬃciency and addisonian crises after discontinuation of steroid therapy. It is diﬃcult precisely to predict the risk of developing adrenal insuﬃciency [108]. Short courses of steroids lasting less than 2 weeks duration are generally considered safe and unlikely to suppress adrenal function. After longer courses of steroid therapy, adrenal function may be suppressed for up to 1 year after cessation of treatment. Patients on chronic corticosteroids and those who have discontinued longterm steroid therapy in the past year should receive supplemental ‘‘stress’’ dose steroids for elective surgical procedures. Summary For over 50 years corticosteroids have occupied center stage in the treatment of IBD, showing clear beneﬁt in the management of moderate to severe UC and CD. No other class of medication acts as rapidly and with such consistent results to control disease activity; improve patient symptoms; and, in UC, promote endoscopic and histologic improvement.

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Unfortunately, no other class of medication produces such diverse and diﬃcult to manage side eﬀects. As the dangers of long-term chronic steroid therapy have become recognized, a better understanding of the mechanism of steroid action has led to the development of potent new steroids with fewer side eﬀects, such as budesonide. The promise of these less toxic steroids has yet to be realized fully, and the search continues for the optimal glucocorticoid with the best balance of eﬃcacy and side eﬀects. In the meantime, clinicians can continue to relieve their patients’ suﬀerings through the appropriate and judicious use of both conventional corticosteroids and budesonide. Attention to appropriate patient selection, dose, and duration of treatment can maximize beneﬁt and minimize steroid-related toxicity.

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General principles of medical therapy of inﬂammatory bowel disease Sonia Friedman, MD Gastroenterology Division ASBII, Department of Medicine, Harvard Medical School, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115, USA

Ulcerative colitis (UC) and Crohn’s disease (CD) are chronic gastrointestinal diseases that aﬀect patients in the prime of their lives. Most patients need to take daily medications from diagnosis until death. Because inﬂammatory bowel disease (IBD) patients generally have a normal lifespan, chronic medical therapy for IBD must be tolerable, simple to adhere to, and have as few side eﬀects as possible. Diﬀerent patients require diﬀerent types of medical therapy and treatment goals of physicians should reﬂect those of their patients. This article discusses the impact of IBD on quality of life and stresses the importance of appropriate and individualized medical therapy. To help clinicians determine the eﬃcacy of particular IBD medications, this article oﬀers a brief, practical interpretation of clinical, endoscopic, and quality-of-life end points used in clinical trials. Finally, it provides a summary of the current accepted medical therapies for UC and CD and recommendations for using these medications in clinical practice.

Impact of inﬂammatory bowel disease on quality of life Given its young age of onset, morbidity, and the side eﬀects of medical therapy, IBD can have a profound aﬀect on quality of life. CD and UC can aﬀect patients not only physically but can also limit social, professional, educational, and emotional activities. The McMaster inﬂammatory bowel disease questionnaire is a validated, disease-speciﬁc instrument that has been used to measure quality of life in many clinical trials. It is a 32-item questionnaire that measures systemic and bowel symptoms, social impairment, and emotional health. When compared with the general population, IBD patients have an impaired quality of life in all four categories. The most frequent concerns of UC patients are having an ostomy bag, developing E-mail address: [email protected] 0889-8553/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.gtc.2004.02.003

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cancer, side eﬀects of medication, the uncertain nature of the disease, and the need for surgery. The most frequent concerns of CD patients are the uncertain nature of the disease, impaired energy level, side eﬀects of medication, the need for surgery, and having an ostomy bag [1]. The best form for use in the oﬃce is the short-form IBD questionnaire [2]. This is a validated 10-question version of the McMaster IBD questionnaire and can be used to quickly assess a patient’s status. In a more recent comprehensive analysis of 22 studies of quality of life in CD [3], health-related quality of life was better in healthy controls and UC patients (except precolectomy) than in CD patients. Health-related quality of life in CD was similar to or worse than that in many other chronic medical conditions. Health-related quality of life was directly correlated with CD activity and was worse in active disease than in remission. Healthrelated quality of life improved for a short time after surgical resection [4]. In addition, active IBD had a negative impact on labor force participation [5] and relationship and sexual health [6]. In view of these quality-of-life data, physicians should remember that the most important goal of medical therapy is not to avoid surgery, but to make the patient well [7,8]. Simple quality-of-life scales can and should be used in the oﬃce to measure the eﬃcacy of medical therapy.

Measures of disease activity in ulcerative colitis Measures of disease activity in UC are mostly used in clinical trials but can also be useful in clinical practice. The ﬁrst activity index used in clinical trials of medical therapy for UC was developed by Truelove and Witts [9]. These authors classiﬁed disease activity as mild, moderate, or severe based on a variety of clinical, physical, and laboratory parameters. Powell-Tuck et al [10] incorporated additional variables, but their index has not been used extensively. One of the most useful validated indices is the Mayo scoring system (Box 1) [11]. It is quick and easy to use in the oﬃce to track a patient’s symptoms. The Mayo score takes into account stool frequency, rectal bleeding, endoscopic ﬁndings, and the physician’s global assessment. The physician’s global assessment acknowledges the three other criteria, the patient’s recall of abdominal discomfort and general sense of well-being, and the patient’s performance status. Patients in remission score less than or equal to 2 points and generally have solid bowel movements, no blood, and normal mucosa on endoscopy. Those with severe activity score 11 or 12 points and generally have multiple bloody bowel movements a day and spontaneous bleeding and frank ulceration on endoscopy. A partial Mayo score without endoscopy is also useful to assess quickly disease activity. In UC, mucosal healing (absence of ulceration, granularity, and friability) correlates with histologic quiescence (residual crypt architectural distortion without crypt abscesses or epithelial neutrophil accumulation). In

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Box 1. The Mayo scoring system for assessment of ulcerative colitis activity Stool frequency 0 = Normal number of stools for this patient 1 = 1 to 2 more stools than normal 2 = 3 to 4 more stools than normal 3 = 5 or more stools than normal Rectal bleeding 0 = No blood seen 1 = Streaks of blood with stool less than half the time 2 = Obvious blood with stool most of the time 3 = Blood alone passed Findings of endoscopy 0 = Normal or inactive disease 1 = Mild disease (erythema, decreased vascular pattern, mild friability) 2 = Moderate disease (marked erythema, absent vascular pattern, friability, erosions) 3 = Severe disease (spontaneous bleeding, ulceration) Physician’s global assessment 0 = Normal 1 = Mild disease 2 = Moderate disease 3 = Severe disease

general, histologic and endoscopic healing correlate with clinical remission [12]. General principles of medical therapy of ulcerative colitis 5-Aminosalicylic acid agents The aminosalicylates are the mainstay of treatment for mild to moderate UC and prevention of relapse of remitted UC. Sulfasalazine and the newer 5-aminosalicylic acid (5-ASA) derivatives (mesalamine in North America, mesalazine in Europe) have been in use for over 50 years. There are three delivery systems for oral aminosalicylates and several topical (rectal) formulations. The oral formulations include azo-bond conjugates (sulfasalazine, olsalazine, balsalazide); pH-dependent mesalamine with varied Eudragit (USP) coatings (Asacol, Salofalk, Claversal; the last two are not available in the United States); and time-pH release formulations of

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mesalamine encapsulated into ethocellulose beads (Pentasa). All have been compared with sulfasalazine in controlled trials and are just as eﬀective if equal amounts of mesalamine are delivered to the colon [13–15]. The dose response for mesalamine continues up to 4.8 g/d and most likely beyond [16]. One of the most common mistakes physicians make in treating IBD patients is undertreating with aminosalicylates [8]. Many experts advocate that the doses of aminosalicylates used to induce remission should be used to maintain remission [8,13]. Side eﬀect proﬁles of mesalamine agents and balsalazide are similar. Sulfasalazine is associated with well-recognized sulfapyridine-induced toxicities, and olsalazine is associated with dose-dependent diarrhea [17]. All agents can cause an idiosyncratic interstitial nephritis that is not doserelated. The rare risks of nephropathy, hepatotoxicity, pancreatitis, pulmonitis, and pericarditis require semiannual or annual therapeutic monitoring. Recent trials suggest that patients treated with more potent therapy for UC, such as corticosteroids or cyclosporine, have a poor prognosis for maintenance therapy with mesalamine [18–20]. These patients should be maintained on immunomodulators. There is also thought to be a therapeutic beneﬁt of using mesalamine concurrently with 6-mercaptopurine (6-MP) or azathioprine (AZA). Mesalamine inhibits thiopurine methyltransferase, shunting more drug to 6-thioguanine while reducing 6methylmercaptopurine production. 6-Thioguanine has been shown to be the most important factor associated with 6-MP–AZA treatment eﬃcacy. Theoretically, this drug combination can be used in patients failing therapy with 6-MP or AZA because of overproduction of 6-methylmercaptopurine [21]. Topical aminosalicylates are a useful and often forgotten additional mode of therapy. In cases of distal colitis, topical therapy is more eﬀective than oral therapy in inducing and maintaining remission. Combined topical and oral therapy is the most eﬀective [22,23]. Patients who require topical therapy to enter remission require some interval of topical therapy, be it every other night or twice a week, to maintain remission. This type of individualized therapy is equally eﬀective in maintaining remission and less intrusive than daily topical therapy. Rectally administered aminosalicylates are more eﬀective than topical hydrocortisone or topical budesonide therapy in the treatment of distal colitis [24–26]. Oral aminosalicylates have not been shown to prevent proximal disease progression [13]. For patients with pancolitis and symptoms of urgency and tenesmus, topical 5-ASA agents are a useful adjunct to oral therapy. One of the drawbacks of 5-ASA agents is decreased adherence caused by the large numbers of pills. In one study, only about 40% of UC patients were adherent with mesalamine maintenance therapy [27]. Patients who were nonadherent had a higher risk of relapse than those who consumed more than 80% of their prescribed regimen [28]. Once-daily dosing of mesalamine was shown in a pilot study to improve adherence and studies are

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ongoing as to whether once-a-day dosing also improves disease outcome [29]. Corticosteroids Corticosteroids were the ﬁrst agents used to treat UC and have an important role in inducing remission in patients with moderate to severe disease who have failed mesalamine. A dose-response phenomenon exists but there is no therapeutic beneﬁt at doses over 40 mg of prednisone a day [30,31]. A dose of 40 mg a day should be maintained until symptoms normalize. There is no optimal tapering regimen and little data on such, but in general it works best to decrease the dosage by 10 mg a week until 30 mg is reached and then by 5 mg a week. There is no role of steroids in maintaining remission in UC. Patients who fail oral prednisone should be hospitalized and given intravenous corticosteroids in the form of methylprednisolone (48–60 mg/d) or hydrocortisone (300–400 mg/d) in either continuous or bolus infusion. There are no data on the superiority of bolus versus continuous confusion. Every patient considering steroid therapy should be cautioned about the signiﬁcant risks of steroids, including infection, hypertension, weight gain, acne, cataracts, emotional lability, myopathy, and ﬂuid retention. The most signiﬁcant long-term toxicity of steroid therapy is loss of bone density. Bone loss occurs in 31% to 59% of patients with IBD and steroid therapy compounds this risk, increasing the rate of trabecular bone loss independent of the usual risk factors. Although the risk of steroid-related bone loss seems to be related to the dose and duration of therapy, it is increased even with low doses and begins early in the course of treatment. Osteoporosis prophylaxis with calcium and vitamin D should be started when steroid therapy is initiated because bone loss is easier to prevent than reverse and steroidinduced bone loss is likely to be most signiﬁcant in the ﬁrst few weeks of therapy, when the highest doses are usually given [32]. Osteonecrosis develops in 4% of steroid-treated patients with IBD and is also a major concern [33]. Suppression of the hypothalamic-pituitary-adrenal axis is an overlooked complication of steroid therapy. In a recent paper, 65% of patients on a several month–long prednisone taper for IBD had an abnormal cosyntropin test [34]. Hypothalamic-pituitary-adrenal axis suppression was observed in 30% to 100% of patients treated for 2 to 8 weeks by corticosteroid enema with mucosal absorption (hydrocortisone, bethamethasone phosphate, or prednisolone) [35–38]. Only budesonide enemas did not produce hypothalamic-pituitary-adrenal axis impairment [36]. Physicians should be aware of this complication of even short-term steroid therapy and consider checking a cosyntropin test before discontinuing steroids. Given these severe complications of corticosteroids, it is reassuring to know that in population-based studies, only about a third of patients have required systemic steroid therapy. In a large population-based study, 63 of

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185 UC patients (34%) required steroio therapy. 34 of 63 (54%) of UC patients went into complete remission and 19 of 63 (30%) partial remission after treatment with oral prednisone. One-year outcomes for UC were prolonged response in 31 of 63 (49%), corticosteroid dependence in 14 of 63 (22%), and operation in 18 of 63 (29%) [20]. For patients receiving intravenous steroids for severe UC, long-term remission rates are only about 50% [39]. This suggests the need for maintenance therapy with immunomodulators in patients requiring steroid-induction therapy. Cyclosporine For patients with severe UC who fail intravenous corticosteroids, intravenous cyclosporine is a viable alternative [40]. The usual dose is 4 mg/kg/d in a continuous infusion. Levels as measured by monoclonal radioimmunoassay should be maintained between 300 and 500 mg/mL. Levels as measured by the high-performance liquid chromatography assay should be maintained between 200 and 400 mg/mL. Side eﬀects can be serious and include renal insuﬃciency, hypertension, infection, paresthesias, hypertrichosis, tremor, nausea, gingival hyperplasia, and seizures, especially with low magnesium levels and cholesterol levels less than 120 mg/dL [31]. Because of the risk for opportunistic infection with Pneumocystis carinii, one double-strength tablet three times a week of trimethoprim-sulfamethoxazole should be given. Lower doses of cyclosporine (2 mg/kg/d) [41,42] and oral microemulsion cyclosporine [43] can also be successful in treating severe UC. As a single therapy, intravenous cyclosporine alone can be more successful than intravenous corticosteroids. In a Belgium study, 8 (53%) of 15 patients on intravenous methylprednisolone versus 9 (64%) of 14 patients on intravenous cyclosporine responded after 8 days. At 12 months, three (37%) of eight patients who initially received methylprednisolone maintained their remission on azathioprine versus seven (78%) of nine patients who initially received cyclosporine [44]. This further supports the point that 5-ASA agents should not be used as monotherapy after induction with cyclosporine or corticosteroids. 6-MP and AZA should be used, often in addition to 5-ASA agents, in this setting. Given its toxicity, cyclosporine has limited indications in UC. If a patient fails to improve on intravenous corticosteroids after several days to at most a week, cyclosporine should be initiated quickly before the patient gets too sick for any kind of medical therapy. Cyclosporine should not be used when severe colitis is fulminating or exsanguinating or complicated by perforation, sepsis, or toxic dilatation. Here the only therapy indicated is immediate colectomy [8]. Factors on admission that are predictive of a colectomy (either immediate or by 9 months) are high white blood cell count; high percentage of band neutrophils; and a low albumin (\3 mg/dL) [45]. Colectomy is often a better option than cyclosporine. In a young person with a ﬁrst attack of severe colitis, it is reasonable to give cyclosporine a try

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but in a patient with decades of steroid dependency and an increasing risk of colon cancer, surgery is the better option. In addition, because of its toxicity, cyclosporine cannot be used as maintenance therapy. Patients must be maintained on 6-MP or AZA. In patients who cannot tolerate immunomodulators, cyclosporine many not be worth considering [8]. 6-Mercaptopurine and azathioprine Although clinical experience demonstrates their usefulness as steroidsparing therapy and to maintain remission after induction with cyclosporine, there are little data on immunomodulators in UC. Because they take several months to reach therapeutic eﬃcacy, they should not be used to induce remission but rather to maintain it. In a retrospective study from Mount Sinai Hospital of 105 chronic refractory UC patients, complete clinical remission was maintained with 6-MP in 68 patients (65%) and partial remission in 25 (24%). Twelve patients (11%) failed to achieve remission. Patients in complete remission tapered oﬀ steroids completely and those in partial remission tapered oﬀ 50% of their steroid dose. Of the complete responders who discontinued 6-MP, 87% relapsed. 6-MP should probably be continued long-term to maintain remission [46]. The use of AZA in corticosteroid-resistant and corticosteroid-dependent UC was demonstrated in a retrospective analysis of 56 patients, all of whom were taking corticosteroids when AZA was initiated. Remission with complete elimination of corticosteroids was achieved in more than 60% of patients with continued AZA treatment [47]. In addition to their steroid-sparing eﬀects, 6-MP–AZA is useful in distal, refractory UC in conjunction with 5ASA oral or topical therapy. One of the most common mistakes in using 6-MP–AZA is undertreatment with these agents. Often, patients are started too late in the course of disease after multiple courses of steroids or not started at all, even when unable to taper steroids after many months. In addition, many patients are underdosed and the drug falsely deemed a failure [8]. Although it is controversial whether to check thiopurine methyltransferase genotype or phenotype before initiating therapy, doing so enables initial dosing at 1 to 1.5 mg/kg for 6-MP and 2 to 2.5 mg/kg for AZA [21]. 6-Thioguanine and 6methylmercaptopurine levels can also be checked to assess compliance and adequate dosage. The optimal duration of 6-MP–AZA therapy is unclear and has not been studied in UC. Side eﬀects of 6-MP–AZA include pancreatitis, fever, leukopenia, hepatotoxicity, nausea, and vomiting. Complete blood count monitoring should be performed at 2, 4, and 8 weeks after initiating therapy, irrespective of thiopurine methyltransferase status. Liver and pancreatic enzymes are tested concurrently. The complete blood count should be repeated every 3 months thereafter, or 15 days after a dose adjustment. 6-MP metabolite levels can be determined after 2 to 3 weeks on therapy or after a dose

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change, when a steady state is reached [21]. Some patients can be switched successfully from 6-MP to AZA or vice versa if the side eﬀect is nausea or vomiting and not fever or pancreatitis [21]. Measures of disease activity in Crohn’s disease Unlike in UC where endoscopy and histology correlate with activity, in CD clinical remission does not necessarily correspond to mucosal healing. The most commonly used assessment of CD, the Crohn’s Disease Activity Index measures a series of clinical symptoms, complications, laboratory criteria, and a physician’s global assessment of a patient’s well-being [48]. There are no endoscopic or histologic criteria incorporated into the Crohn’s Disease Activity Index and subsequent trials have not been able to correlate clinical response according to the Crohn’s Disease Activity Index with endoscopic end points [12]. In addition, the only validated endoscopic index of disease severity, the CrohnÕs disease endoscopic index of severity provides a numerical score but no deﬁnition of remission [49]. As opposed to the continuous inﬂammation of UC, the focality of histologic changes in CD may preclude accurate measurement of mucosal healing [50]. The potential for sampling error is high and correlation between histologic improvement and other assessments of disease activity is poor. The use of capsule endoscopy in small bowel CD may help determine the importance of mucosal healing in achieving and maintaining remission. For quick use in the oﬃce, the Harvey Bradshaw Index is the most helpful (Table 1). It is a validated index with only ﬁve questions and correlates well Table 1 The Harvey Bradshaw Index Item

Scale

General well-being

0 = very well 1 = slightly below par 2 = poor 3 = very poor 4 = terrible

Abdominal pain

0 = none 1 = mild 2 = moderate 3 = severe

Number of liquid stools per day Abdominal mass

Complications: arthritis, uveitis, erythema nodosum, aphthous ulcers, pyoderma gangrenosum, anal ﬁssure, new ﬁstula, abscess

0 = none 1 = dubious 2 = deﬁnite 3 = deﬁnite and tender Score 1 per item

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with Crohn’s Disease Activity Index scores [51]. For ﬁstulizing disease, the Perianal Crohn’s Disease Activity Index [52] is cumbersome but the Fistula Drainage Assessment [53] is quick and easy to use. Improvement on the latter index is deﬁned as a decrease from baseline in the number of open draining ﬁstulas of greater than or equal to 50% for at least two consecutive visits. Remission is deﬁned as closure of all ﬁstulas over the same time period. General principles of medical therapy of Crohn’s disease There are no clinical trials that compare ‘‘step-up’’ versus ‘‘top-down’’ therapy in treating active CD [12]. For example, for a patient with moderate Crohn’s colitis, there is no consensus among experts whether to start with 5ASA agents or prednisone. In addition, few clinical trials test combinations of therapeutic agents used commonly in clinical practice. For example, there has never been a comparison between 5-ASA agents and antibiotics versus budesonide in treating ileitis. The current practice guidelines recommend using a sequential approach to treatment according to the severity of the clinical presentation and associated complications [54]. Categories of severity include the following [54]: Mild to moderate disease: Patients who are ambulatory, eating and drinking without dehydration, toxicity, abdominal tenderness, painful mass, obstruction, or more than 10% of weight loss. Moderate to severe disease: Patients who have failed to respond to therapies for mild to moderate disease or those with more prominent symptoms of fevers; signiﬁcant weight loss; abdominal pain or tenderness; intermittent nausea or vomiting (without obstructive ﬁndings); or signiﬁcant anemia. Severe to fulminant disease: Patients with persistent symptoms despite the introduction of corticosteroids as outpatients or those presenting with high fever, persistent vomiting, evidence of intestinal obstruction, rebound tenderness, cachexia, or evidence of an abscess. 5- Aminosalicylic acid agents Sulfasalazine and mesalamine are ﬁrst-line therapies for mild to moderate disease with disease location determining the formulation and delivery system. Sulfasalazine is more eﬀective than placebo in treating Crohn’s ileocolitis or colitis [54,55] but side eﬀects limit its usefulness. As in UC, higher doses bring better response, and 4 g/d of mesalamine (Pentasa) was better than placebo in active CD [56]. In comparison with a variety of agents including antibiotics [57,58], budesonide [59,60], and 6-methylprednisolone [61], mesalamine at doses of 3.2 to 4g/d induced clinical remissions in 40% to 60% of patients with mild to moderate CD [62]. Although the role of 5-ASA agents in inducing remission is fairly well established, their role in maintaining remission is not as well documented. In

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a meta-analysis of 15 randomized, controlled trials with 2097 patients, mesalamine signiﬁcantly reduced the risk of relapse when remission was surgically induced but not when it was medically induced [63]. In addition, if remission was induced with corticosteroids, mesalamine was not eﬀective at preventing relapse [64,65]. This subgroup of patients should be placed on immunomodulators. Studies are in progress to see if higher doses of mesalamine (6 g/d) maintain remission. Antibiotics For mild to moderate disease, the antibiotics metronidazole and ciproﬂoxacin are useful as ﬁrst-line agents for inducing remission. In a 105patient placebo-controlled trial, metronidazole, 10 mg/kg/d or 20 mg/kg/d, was associated with signiﬁcant improvements in disease activity [66]. Remission rates, however, were no diﬀerent than those with placebo. In the Swedish Cooperative Crohn’s Disease Study, metronidazole (400 mg twice a day) was slightly more eﬀective than sulfasalazine [58]. Dose-limiting side eﬀects of metronidazole include nausea, headache, anorexia, glossitis, abdominal cramps, and peripheral neuropathy. Evidence that supports the eﬃcacy of ciproﬂoxacin alone or in combination with metronidazole includes a retrospective chart study, an open-label trial, and one randomized controlled trial [67,68]. These agents are also ﬁrst-line therapies for perianal ﬁstulizing disease; however, 50% of ﬁstulas relapse when antibiotics are stopped [62]. Corticosteroids Corticosteroids are highly eﬀective for induction of remission in patients with moderate to severe disease who fail 5-ASA and antibiotic therapy. The National and European Cooperative Crohn’s Disease Studies [55,69] demonstrated a substantial beneﬁt of prednisone and prednisolone compared with placebo. Even at low doses, however, steroids may cause intolerable side eﬀects and dependency. Over 50% of Crohn’s patients treated acutely with steroids become steroid dependent or steroid resistant, particularly smokers and those with colonic disease [70]. In the Olmstead County population-based study, of 74 patients with CD treated with their ﬁrst course of corticosteroids, 43 (58%) had complete remission, 19 (26%) had partial remission, and 12 (16%) had no response at 30 days. One-year outcomes were prolonged response in 24 (32%); corticosteroid dependence in 21 (28%); and operation in 28 (38%) [20]. There are no short or long-term beneﬁts from the addition of an aminosalicylate to corticosteroids [54] and no role for the use of corticosteroids in remission maintenance. Whenever possible, corticosteroidsparing regimens should be used to establish remission. Budesonide is a glucocorticosteroid with a high aﬃnity for the glucocorticoid receptor and possesses a high topical anti-inﬂammatory eﬀect without appreciable systemic activity. It undergoes a rapid and extensive (85% to 90%) ﬁrst-pass metabolism in the liver that produces metabolites

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with minimal or no biologic activity. Budesonide controlled ileal release capsules (3 mg each) contain granules that allow slow release of budesonide, mainly in the ileum and ascending colon [71]. Budesonide is eﬀective in mild to moderate CD. In a meta-analysis of 16 studies, budesonide was signiﬁcantly more eﬀective than placebo or 5-ASA agents for inducing remission of active CD. Although it was 13% less eﬀective for induction of remission than conventional corticosteroids, it was less likely to cause corticosteroid-related adverse aﬀects [72]. In a dose-ranging, placebocontrolled trial, 9 mg/d was the most aﬀective dose. In a quality-of-life study, patients taking budesonide had a better quality of life than those taking mesalazine [72]. Although the short-term safety of budesonide is well established, its long-term eﬀect on bone and the hypothalamic-pituitaryadrenal axis remains to be determined. Lower daily doses of 3 or 6 mg/d do not seem to be of beneﬁt in the maintenance of long-term remission. 6-Mercaptopurine and azathioprine In patients who have achieved remission with corticosteroids, 6-MP– AZA is generally safe and eﬀective in maintaining remission. A metaanalysis of ﬁve placebo-controlled trials for a total of 319 patients with quiescent CD found remission rates of 67% among patients treated with AZA versus 53% among patients receiving placebo with an overall odds ratio of response of 2.27 (conﬁdence interval, 1.76–2.93). Two trials in this meta-analysis reported that AZA had a steroid-sparing eﬀect [73]. Another study demonstrated that AZA was signiﬁcantly more eﬀective than placebo in maintaining remission after the cessation of steroids (at 12 weeks) over a period of 15 months [74]. The optimal duration of 6-MP–AZA is unclear. One retrospective study found a statistically signiﬁcant increase in relapse rates at 1, 2, 3, and 5 years in patients who discontinued 6-MP while in remission. The authors recommend indeﬁnite use of 6-MP once remission has been achieved [75]. In another retrospective study, the relapse rates for patients in remission and taking 6-MP–AZA for at least 6 months were 11% at 1 year and 32% at 5 years versus 38% and 75% for patients who stopped their medication. This same study found that for patients taking 6-MP–AZA for more than 4 years, the 2-year relapse rate of those who discontinued the drug was not statistically diﬀerent from those who continued the drug [76]. Although there is good evidence in favor of 6-MP–AZA for remission maintenance, the eﬃcacy after 4 years of use has yet to be determined. In controlled and uncontrolled experience, 6-MP is more eﬃcacious than placebo in postoperative prophylaxis of CD [77,78]. Methotrexate The eﬃcacy of intramuscular methotrexate as inductive therapy in moderate to severe CD is well established [79,80]. In a 16-week randomized,

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double-blind, placebo-controlled trial, intramuscular methotrexate, 25 mg/ wk, induced remission in 37 of 94 (39.4%) patients compared with 9 of 47 (19.1%) of placebo-treated patients [81]. Methotrexate has also been eﬀective at maintaining remission for patients who respond in the acute setting. In a randomized, controlled trial using intramuscular methotrexate, 15 mg/wk [82], and in two open-label studies [83,84], two thirds of patients maintained remissions oﬀ steroids for 1 year. The toxicities of methotrexate include myelosuppression and hepatotoxicity and necessitate frequent monitoring of blood cell counts and liver enzymes. The most frequently occurring adverse events are nausea and vomiting, abdominal pain, joint pain, cold symptoms, and fatigue [32]. Because of these toxicities, methotrexate is a second-line agent for patients who fail or who cannot tolerate 6-MP–AZA. Patients receiving more than 1.5 g of methotrexate probably do not need liver biopsies unless they have risk factors for hepatic ﬁbrosis, such as alcohol use, diabetes mellitus, and obesity. Inﬂiximab Inﬂiximab, a chimeric monoclonal antibody directed against the proinﬂammatory cytokine tumor necrosis factor-a, is approved by the US Food and Drug Administration for use in moderate to severe CD. It is eﬀective in those patients refractory to 5-ASA, antibiotics, steroids, and immunomodulators. In clinical practice, it is sometimes used as an alternative induction therapy to prednisone or as a ﬁrst-line agent for severe perianal ﬁstulizing disease. For refractory inﬂammatory or ﬁstulizing disease, infusions of 5 mg/kg are given at 0, 2, and 6 weeks. In a study of 108 treatment-refractory patients, there was a statistically signiﬁcant response rate of 65% for active disease compared with 17% placebo [85]. There are equally good results in patients were perianal ﬁstulizing disease (response: 68% inﬂiximab, 26% placebo) [53]. Reinfusion, typically every 8 weeks, is necessary to continue therapeutic beneﬁts in many patients [86,87]. The development of antibodies to inﬂiximab is associated with an increased risk of infusion reactions and decreased response to treatment [88]. Patients who receive on-demand or episodic infusions are more likely to develop antibodies to inﬂiximab and lose response to inﬂiximab. Decreased antibodies to inﬂiximab are associated with immunomodulator use and with hydrocortisone pretreatment [89]. To maximize therapeutic eﬃcacy, it is best to use one of several strategies. One strategy is the use of three-dose induction therapy followed by regular maintenance therapy (usually every 8 weeks). Another is to place the patient on immunomodulators (6-MP, AZA, or methotrexate) 2 to 3 months before inﬂiximab infusion. The third is to pretreat with 200 mg intravenous hydrocortisone before using inﬂiximab [90]. No combination of these strategies has been formally tested. Most experts believe that patients should be started on 6-MP or AZA if they are

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sick enough to warrant treatment with inﬂiximab [8]. It is unclear if and when inﬂiximab can be discontinued. In addition to the common (10%) side eﬀects of nausea, headache, upper respiratory infections, fatigue, and fever, more serious side eﬀects of inﬂiximab include fungal and other invasive opportunistic infections. There have been 117 cases of disseminated inﬂiximab-associated tuberculosis reported to the Food and Drug Administration as of November 30, 2001 [91], and puriﬁed protein derivative placement is required before inﬂiximab therapy. Inﬂiximab has also been implicated in causing demyelinating central nervous system lesions and activating latent multiple sclerosis [92]. In addition, it can worsen congestive heart failure and should be avoided in these patients.

The placebo eﬀect In treating patients with IBD, physicians use ‘‘potent drugs knowing very little about the course of the untreated patient—the patient in his or her natural environment’’ [93]. In the absence of such knowledge, the placebo arm of available, randomized, controlled trials has been studied to understand the natural history of these disorders. In a study of the placebo response in 38 studies of UC, the clinical remission with placebo alone was 9.1% and the beneﬁt rate was 26.7% (endoscopically and histologically). The placebo response was greater in trials with more frequent study visits (greater than three) [94,95]. In a summary of the placebo response in CD trials, 8% to 42% of patients achieved remission with placebo and 36% to 75% of patients maintained remission at 1 year with placebo [96]. For active disease, patients with no prior therapy, milder disease activity, recurrent disease after surgery, small bowel involvement, and absence of perianal disease were more likely to have a favorable placebo response. For inactive disease, patients who had had recent steroid therapy, small bowel involvement, or radiographs showing only extramural mass, deep sinuses, or ulcers were more likely to have a favorable placebo response. Physicians who treat IBD should take into account that patients who are seen more frequently and have milder disease in general have a better placebo response. This could be a factor in deciding whether or not to ‘‘step-up’’ therapy.

Summary In considering the optimal medical therapy of IBD, it is most important to individualize treatment according to the particular needs of each patient. Maintaining a patient’s quality of life is the most important goal, whether it is with mesalamine, 6-MP, inﬂiximab, or surgery if indicated. For UC, it is important to remember that topical therapy can be useful in distal disease

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and that the higher the dose of 5-ASA, the better the response. For CD, activity should be treated according to severity. Budesonide is a promising treatment for mild to moderate ileitis and right-sided colitis and inﬂiximab is an eﬀective therapy for moderate to severe inﬂammatory and ﬁstulizing CD. For both UC and CD, corticosteroids are eﬀective in inducing remission, but not maintaining it. 6-MP–AZA is eﬀective in maintaining remission in both diseases. There are quick and simple ways to measure disease activity and quality of life and these scales can be used everyday in outpatient practice. Newer advances in medical therapy and diligence by physicians and patients alike should make IBD a more tolerable, albeit chronic disease. References [1] Irvine EJ. Quality of life issues in patients with inﬂammatory bowel disease. Am J Gastroenterol 1997;92:18S–24S. [2] Jowett SL, Seal CJ, Barton JR, Welfare MR. The short inﬂammatory bowel disease questionnaire is reliable and responsive to clinically important change in ulcerative colitis. Am J Gastroenterol 2001;96:2921–8. [3] Cohen RD. The quality of life in patients with Crohn’s disease. Aliment Pharmacol Ther 2002;16:1603–9. [4] Thirlby RC, Land JC, Fenster LF, Lonborg R. Eﬀect of surgery on health-related quality of life in patients with inﬂammatory bowel disease. Arch Surg 1998;133:826–32. [5] Boonen A, Dagnelie PC, Feleus A, Hesselink MA, Muris JW, Stockbru¨gger RW, et al. The impact of inﬂammatory bowel disease on labor force participation: results of a population sampled case-control study. Inﬂamm Bowel Dis 2002;8:382–9. [6] Trachter AB, Rogers AI, Leiblum SR. Inﬂammatory bowel disease in women: impact on relationship and sexual health. Inﬂamm Bowel Dis 2002;8:413–21. [7] Sachar DB. Indications for surgery in inﬂammatory bowel disease: a gastroenterologist’s opinion. In: Kirsner JB, editor. Inﬂammatory bowel disease. 5th edition. Philadelphia: WB Saunders; 2000. p. 611–5. [8] Sachar DB. Ten common errors in the management of inﬂammatory bowel disease. Inﬂamm Bowel Dis 2003;9:205–9. [9] Truelove SC, Witts LJ. Cortisone in ulcerative colitis: ﬁnal report on a therapeutic trial. BMJ 1955;4947:1041. [10] Powell-Tuck J, Bown RL, Lennard Jones JE. A comparison of oral prednisolone given as single or multiple daily doses for active proctocolitis. Scand J Gastroenterol 1978;13:833. [11] Schroeder KW, Tremaine WJ, Ilstrup DM. Coated oral 5-aminosalicylic acid therapy for mildly to moderately active ulcerative colitis. N Engl J Med 1987;317:1625–9. [12] Hanauer SB. Crohn’s disease: step up or top down therapy. Best Pract Res Clin Gastroenterol 2003;17:131–7. [13] Hanauer SB. Update on medical management of inﬂammatory bowel disease: ulcerative colitis. Rev Gastroenterol Disord 2001;1:169–76. [14] Sutherland L, Roth D, Beck P, May G, Makiyama K. Oral 5-aminosalicylic acid for maintaining remission in ulcerative colitis. Cochrane Database Syst Rev 2000;2: CD000544.5. [15] Sutherland L, Roth D, Beck P, May G, Makiyama K. Oral 5-aminosalicylic acid for inducing remission in ulcerative colitis. Cochrane Database Syst Rev 2000;2:CD000543. [16] Hanauer SB. Review articles: drug therapy; inﬂammatory bowel disease. N Engl J Med 1996;334:841–8.

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Treatment of inﬂammatory bowel disease with azathioprine and 6-mercaptopurine Chinyu Su, MD, Gary R. Lichtenstein, MD* Division of Gastroenterology, Department of Medicine, University of Pennsylvania School of Medicine, 3rd Floor Ravdin Building, 3400 Spruce Street, Philadelphia, PA 19104–4283, USA

Since the initial report of 6-mercaptopurine (6-MP) for the treatment of ulcerative colitis (UC) in 1962 [1,2] and for the treatment of Crohn’s disease (CD) in 1969 [2], this medication and its derivative azathioprine (AZA) have become an important therapeutic option for patients with inﬂammatory bowel disease (IBD). A British nation-wide survey in 1999 suggests that most gastroenterologists have prescribed these agents for patients with UC [3]. Although accumulating data in the literature have supported the use of these immunomodulators in the management of IBD, marked variation exists in the pattern of clinical practice regarding AZA or 6-MP therapy in patients with IBD [3]. This variability is likely in part caused by limited data on the administration of these drugs, including dosing and duration. This article provides a critical review of the data on the clinical eﬃcacy and toxicities of these agents in the management of IBD. Emerging literature on the potential application of pharmacogenetic testing and metabolite monitoring are also discussed. Pharmacology Both AZA and 6-MP are thiopurine analogues that modulate immune response, and are considered immunomodulatory agents. They are inactive prodrugs with subtle structural diﬀerences. AZA is the nitromidazole derivative of 6-MP. Once administered, AZA is rapidly cleaved by nonenzymatic reaction to 6-MP and glutathionyl imidazole within erythrocytes. Several enzymatic pathways then compete to transform 6MP to active and inactive end products (Fig. 1). The three key enzymes

* Corresponding author. E-mail address: [email protected] (G.R. Lichtenstein). 0889-8553/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.gtc.2004.02.004

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6-TU

Imidazole

XO

CH3 N

SCH3 NO2 N

N

N

AZA

SCH3

N

N

N

N

IMPDH

HPRT

6-TIMP N

GMPS

6-TXMP

6-TGN

N

6-MP TPMT

6-MMP

TPMT

6-MMPR

Fig. 1. Metabolism of AZA and 6-MP. GMPS, guanosine monophosphate synthetase; HPRT, hypoxanthine phosphoribosyltransferase; IMPDH, inosine monophosphate dehydrogenase; 6MMP, 6-methylmercaptopurine; 6-MMPR, 6-methylmercaptopurine ribonucleotides; 6-TGN, 6-thioguanine nucleotides; 6-TIMP, 6-thioinosine 59-monophosphate; TPMT, thiopurine methyltransferase; 6-TU, 6-thiouric acid; 6-TXMP, 6-thioxanthosine 59-monophosphate; XO, xanthine oxidase.

involved in the metabolism of 6-MP are (1) xanthine oxidase, (2) hypoxanthine phosphoribosyltransferase, and (3) thiopurine methyltransferase. Xanthine oxidase, which is present in high concentrations in both enterocytes and hepatocytes, converts 6-MP to the inactive metabolite 6thiouric acid. This extensive catabolism of 6-MP by xanthine oxidase on the ﬁrst pass signiﬁcantly reduces the oral bioavailability of the drug. The second key enzyme, hypoxanthine phosphoribosyltransferase, initiates the biotransformation of 6-MP to its active metabolite, 6-thioguanine nucleotide (6-TGN). Thiopurine methyltransferase (TPMT) converts 6-MP and the intermediate of the hypoxanthine phosphoribosyltransferase pathway, 6-thioinosinic acid, to the inactive metabolites 6-methylmercaptopurine and methylmercaptopurine ribonucleotide. Thiopurine methyltransferase enzyme plays an important role at two steps of the metabolism of AZA and 6-MP. In the absence of or decreased xanthine oxidase, as in the case with concurrent allopurinol therapy, TPMT becomes the major catabolic pathway and competes with hypoxanthine phosphoribosyltransferase enzyme to form the inactive metabolite 6-methylmercaptopurine. In the second step, it competes with the enzymatic pathways leading to the formation of active metabolites by methylating the intermediate 6thioinosinic acid to form 6-methylmercaptopurine ribonucleotide metabolite. The TPMT gene is inherited as an autosomal-codominant trait, and an apparent genetic polymorphism has been observed in TPMT activity [4]. Approximately 0.3% of the population has homozygous mutations in TPMT genotype. These individuals have virtually absent enzyme activity. Eleven percent of the population has heterozygous mutations and intermediate enzyme activity [5]. Most of the population has homozygous

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wild-type TPMT, and normal to high enzyme activity. There are also ethnic variations in the mutant TPMT alleles [6–11]. There are at least nine allelic variants for the TPMT gene located on chromosome 6. The most common of these variants is the normal TPMT*1 or wild-type allele. TPMT*3A is the most common mutant allele and is seen predominantly in whites. By contrast, TPMT*3C is the most prevalent variant in black and Asian populations. These mutant variants are associated with diﬀerent degrees of reduction in TPMT activity. For example, TPMT*3A correlates with complete loss of TPMT activity. Although it is unknown how variations in the hypoxanthine phosphoribosyltransferase enzyme may inﬂuence thiopurine metabolism, there is substantial evidence supporting that inherited diﬀerences in TPMT are responsible for most of the variability in drug response observed among individuals. The exact molecular mechanisms for the immunomodulatory and antiinﬂammatory eﬀects of AZA and 6-MP are unknown but likely occur by a number of mechanisms. The active metabolites, 6-TGNs, act as purine antagonists, thereby interfering DNA and RNA synthesis, and chromosomal replications [12]. AZA and 6-MP also inhibit proliferation of T and B lymphocytes, interfere with cytotoxicity of natural killer cells, and decrease suppressor T-cell function and cell-mediated immunity [12,13]. Recent evidence also suggests that the immunosuppressive properties of these drugs are mediated in part by inducing T-cell apoptosis [14]. The oral bioavailability of AZA and 6-MP is only 47% and 16%, respectively, in healthy individuals [12,15]. The absorption of these drugs may be less in patients with IBD because of altered gut transit time during active disease state. Because the molecular weight of 6-MP is 55% of that of AZA, and 88% of AZA is converted to 6-MP [16], 1 mg of 6-MP is equivalent to 2.07 mg of AZA.

Eﬃcacy Crohn’s disease Since the initial report of successful treatment of patients with CD with AZA [2], many studies, both controlled and uncontrolled, have been reported in the literature using AZA or 6-MP in CD. There have been 11 randomized controlled trials evaluating these agents in the management of active or quiescent CD (Tables 1 and 2) [17–27]. Current indications for these agents in patients with CD include induction of remission for moderately to severely active disease, maintenance of remission, steroid sparing, and treatment of ﬁstulizing disease (Table 3). Although results from studies evaluating the use of these agents vary because of diﬀerences in study design, such as patient selection, drug dose, duration of therapy, and deﬁnition of outcomes, these data in aggregate suggest that AZA and 6-MP are eﬀective in inducing remission in patients

212

Study Rhodes et al [18] Willoughby et al [19] Klein et al [20] Summers et al [21] (part I, phase 1) Present et al [22] Ewe et al [23] Candy et al [24] (part I) Oren et ala [25]

No. of patients 16 12 26 136

72 42 63 58

Drug dose AZA 2 mg/kg/d AZA 2 mg/kg/d AZA 3 mg/kg/d AZA 2.5 mg/kg/d 6-MP 1.5 mg/kg/d AZA 2.5 mg/kg/d AZA 2.5 mg/kg/d 6-MP 50 mg/d

Duration of therapy

Response in treatment group

Response in placebo group

P value

2 mo

0 (0%) of 9

0 (0%) of 7

NS

6 mo

6 (100%) of 6

1 (17%) of 6

NR

4 mo

6 (46%) of 13

6 (46%) of 13

NS

17 wk

21 (36%) of 59

20 (26%) of 77

.25

12 mo

26 (72%) of 36

5 (14%) of 36

\.001

4 mo

16 (76%) of 21

8 (38%) of 21

.03

3 mo

25 (76%) of 33

20 (67%) of 30

.6

9 mo

13 (41%) of 32

12 (46%) of 26

NSb

Abbreviations: AZA, azathioprine; 6-MP, 6-mercaptopurine; NR, not reported; NS, not signiﬁcant. a 3-arm study comparing 6-MP with methotrexate with placebo. b NS compared with both placebo and methotrexate groups.

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Table 1 Summary of randomized-controlled trials of AZA or 6-MP for active Crohn’s disease

Study

Inclusion

Willoughby et al [19] Rosenberg et al [26] O’Donoghue et al [27] Summers et al [21] (part I, phase 2) Summers et al [21] (part II) Candy et al [24] (part II) Markowitz et ala [17]

All steroid-dependent All steroid-dependent AZA-induced remission AZA-induced remission

No. of patients 10 20 50 39 155

AZA-induced remission Steroid-induced remission

45 49

Drug dose

Duration of therapy

Response in treatment group

Response in placebo group

P value

AZA AZA AZA AZA

6 mo 6 mo 12 mo 35 wk

4 7 13 16

2 4 8 15

NR \.05 \.05 NS

AZA 1 mg/kg/d

12 mo

37 (69%) of 54

65 (64%) of 101

AZA 2.5 mg/kg/d 6-MP 1.5 mg/kg/d

12 mo 18 mo

14 (56%) of 25 91%

2 (10%) of 20 53%

2 mg/kg/d 2 mg/kg/d 2 mg/kg/d 2.5 mg/kg/d

Abbreviations: AZA, azathioprine; 6-MP, 6-mercaptopurine; NR, not reported; NS, not signiﬁcant. Pediatric patients with newly diagnosed CD.

a

(80%) (70%) (57%) (84%)

of of of of

5 10 23 19

(40%) (40%) (30%) (75%)

of of of of

5 10 27 20

.53 NR .007

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Table 2 Summary of randomized-controlled trials of AZA or 6-MP for quiescent Crohn’s disease

213

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Table 3 Indications for azathioprine and 6-MP therapy in IBD Indication

Crohn’s Disease

Ulcerative colitis

Mild to moderate inﬂammatory (steroid-refractory) disease Severe inﬂammatory (steroid-refractory) disease Steroid-dependent disease Maintenance of remission Fistulizing disease

Yes

?Yes

No Yes Yes Yes

No Yes Yes —

Abbreviations: AZA, azathioprine; IBD, inﬂammatory bowel disease; 6-MP, 6-mercaptopurine.

with active CD. A meta-analysis of eight randomized, placebo-controlled trials found these agents to be more eﬃcacious than placebo in the treatment of active CD [24,28]. The overall rate of response as deﬁned by achieving clinical improvement or remission based on individual studies is 54% for patients with active CD treated with AZA (2–3 mg/kg/d) or 6-MP (50 mg/ d or 1.5 mg/kg/d) compared with 33% in patients receiving placebo therapy [28]. The pooled odds ratio for response to AZA or 6-MP is 2.36 (95% CI, 1.57–3.53), corresponding to a number needed to treat of 5 to observe an eﬀect of therapy in one patient [28]. Although there was no dose eﬀect on the response, most of the studies used AZA at 2.5 mg/kg/d. The optimal dose for the treatment of active CD is generally considered 2.5 mg/kg/d for azathioprine and 1.5 mg/kg/d for 6-MP. An important property of AZA and 6-MP is their steroid-sparing beneﬁt. In patients with active CD, reduction of steroid dose to less than 10 mg/ d (prednisone equivalent) was achieved in 65% of patients receiving AZA or 6-MP compared with 36% of patients receiving placebo in ﬁve randomized, controlled trials [19,20,22–24,28]. In patients with quiescent but steroiddependent disease, addition of AZA allowed reduction of steroid consumption in 87% of patients compared with 53% of patients on placebo [19,26,29]. In both scenarios, the superiority of AZA over placebo therapy corresponds to a minimum of only three patients needed to be treated to obtain a steroid-sparing beneﬁt (to a dose of prednisone \10 mg/d) in one patient. In pediatric populations where corticosteroid therapy is associated with an added concern for growth impairment, the steroid-sparing property of these agents may be particularly attractive. In a randomized, placebocontrolled trial of 55 children with newly diagnosed CD requiring corticosteroids, addition of 6-MP at 1.5 mg/kg/d at the outset was associated with signiﬁcantly lower cumulative steroid dose requirement and allowed the subjects to remain steroid-free signiﬁcantly longer once it was weaned oﬀ than those not on 6-MP [17]. Only 9% of the 6-MP–treated patients who achieved remission relapsed at 18 months of follow-up compared with 47% of the placebo-treated patients (P = .007) [17]. Whether similar beneﬁt of AZA or 6-MP may be observed in adult

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populations with newly diagnosed CD has not been evaluated in controlled trial. Once remission is achieved, these agents also provide maintenance beneﬁt in patients with CD. Although no randomized-controlled study has evaluated 6-MP for maintaining remission in CD, the interchangeable properties of these two drugs have allowed extrapolation of beneﬁt of one agent to the other. In a meta-analysis of ﬁve randomized-controlled trials evaluating patients with quiescent CD, AZA therapy allows maintenance of remission in 67% of patients compared with 52% of patients receiving placebo therapy [19,21,24,26,27,29]. This superiority of AZA over placebo corresponds to an odds ratio of 2.16 (CI 1.35–3.47) [29]. More importantly, there is a dose-dependent beneﬁt. A statistically signiﬁcant response is seen at dose above 2 mg/kg/d, and further increases at dose of 2.5 mg/kg/d [29]. There are limited data on the potential beneﬁt of AZA or 6-MP in maintaining surgically induced remission in CD. In an uncontrolled study reporting outcomes of 6-MP therapy in patients with CD, 9 of 10 patients receiving prophylactic therapy remained disease free after a mean follow-up of 41 months after surgical resection [30]. In the only randomized controlled trial reported in an abstracted form, 131 patients undergoing surgical resections for CD were randomized to receive 6-MP at 50 mg/d; mesalamine (Pentasa) at 3 g/ d; or placebo [31]. Prophylactic 6-MP therapy was associated with a signiﬁcant decrease in clinical, endoscopic, and radiographic relapse rates at 24 months postsurgery compared with placebo therapy, and 6-MP was superior to mesalamine in preventing endoscopic recurrence. Whether additional preventive beneﬁt against postoperative recurrence can be achieved with a higher dose of 6-MP has not been evaluated. Another important beneﬁt of AZA and 6-MP is their ability to heal ﬁstulas. In the initial report on the use of AZA for CD, a dramatic improvement in the ﬁstulas was observed in all six patients [2]. In a randomized, controlled trial 6-MP at 1.5 mg/kg/d resulted in complete closure in 31% of the ﬁstulas compared with 6% of the ﬁstulas in those patients receiving placebo therapy (P \ .001) [22]. This was a secondary end point in this particular trial. In a subsequent series that included patients from this placebo-controlled trial, 13 (39%) of 34 patients with ﬁstulizing CD had complete closure of ﬁstulas on 6-MP therapy and additional 9 (26%) patients had signiﬁcant improvement [32]. Furthermore, ﬁstulas remained closed for 1 to 5 years on continued 6-MP therapy in seven patients, and most of them relapsed within 2 weeks to 9 months following discontinuation of 6-MP. All types of ﬁstulas responded to 6-MP, but the most impressive results occurred in patients with abdominal wall and enteroenteric ﬁstulas [32]. Combining the data from three randomized controlled trials for active CD that included 18 patients with ﬁstulas, AZA therapy was associated with a more favorable response rate than placebo therapy [28]. Complete healing or decreased drainage of ﬁstulas was reported in 56% of the patients on AZA compared with 29% of the placebotreated patients.

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Ulcerative colitis The data on the use of AZA or 6-MP in patients with UC are less robust than those in CD (Table 4). Current indications for these agents in patients with UC include induction of remission for moderately to severely active disease, maintenance of remission, and steroid sparing (see Table 3). All eight controlled studies evaluating the eﬃcacy of these agents in the management of patients with UC [33–40] used AZA. Two early controlled trials evaluating AZA as an induction therapy for the treatment of active UC reported conﬂicting results [33,38]. The ﬁrst study of 1-month duration failed to show beneﬁt of AZA therapy for inducing remission compared with placebo therapy [38]. In the second study of 3-month duration, AZA at 2.5 mg/kg/d was found to be as eﬀective as sulfasalazine for the treatment of an acute ﬂare [33]. In contrast, there is good evidence for AZA and 6-MP as steroid-sparing agents. Two controlled trials of patients with chronic active, steroid-dependent UC demonstrated a signiﬁcant reduction in steroid dosage at 6 months of AZA therapy at 1.5 mg/kg/d or 2 to 2.5 mg/kg/d, compared with placebo therapy [39,40]. This steroid-sparing beneﬁt has also been shown to be superior to mesalamine; 58% of patients with steroiddependent active UC achieved clinical and endoscopic remission and steroid withdrawal following 6 months of AZA at 2 mg/kg/d compared with 3.2 g/ d of mesalamine [34]. Uncontrolled studies further supported the beneﬁt of AZA and 6-MP as steroid-sparing agents [41,42]. Two placebo-controlled studies showed conﬂicting results on the beneﬁt of AZA for maintaining remission in patients with UC [37,38]. An early study failed to demonstrate a statistically signiﬁcant diﬀerence between AZA and placebo therapy in maintaining remission [38]. A subsequent study reported a 36% relapse rate at 1 year in patients who achieved remission on AZA and continued to receive AZA, compared with a 59% relapse rate in patients who were switched to placebo maintenance therapy (P = .04) [37]. The relapse rate following discontinuation of 6-MP has been reported as high as 87% in one retrospective review of 105 patients treated with 6-MP for chronic refractory UC, where complete clinical remission was achieved in 65% of the patients [43]. A recently published, randomized but open-label study of 25 patients with severely active UC, however, suggested that AZA monotherapy at 2.5 mg/kg/d was at best comparable with sulfasalazine at 6 g/d as maintenance therapy following steroid-induced remission [35]. In patients with steroid-dependent UC who are able to achieve remission and discontinue steroids with AZA and mesalamine therapy, remission can be maintained successfully with AZA alone without the addition of mesalamine [36], minimizing the number of pills for maintenance therapy. Another important indication for AZA or 6-MP as a maintenance therapy is in the setting of remission induced by intravenous cyclosporine [44–46]. The addition of AZA or 6-MP to oral cyclosporine eliminates the need for colectomy in up to 80% of patients at 6 months following response to

Study Induction of remission Jewell and Truelove [38] Caprilli et al [33] Maintenance of remission Jewell and Truelove [38] Hawthorne et al [37] Steroid-sparing Hawthorne et al [37] Rosenberg et al [40] Kirk and Lennard-Jones [39] Ardizzone et al [34] Mantzaris et al [36]

Treatment indication

No. of patients

Drug dose

Active disease Active disease

80 20

AZA 2.5 mg/kg/d AZA 2.5 mg/kg/d

Quiescent disease Quiescent disease

80 67

Steroid-dependent or chronic active disease Steroid-dependent, disease Steroid-dependent disease Steroid-dependent, active disease Steroid-dependent, active disease

Duration of therapy

Response in treatment group

Response in placebo group

P value

1 mo 3 mo

31 (78%) of 40 6 (60%) of 10

27 (68%) of 40 8 (80%)of 10a

.45 NS

AZA 1.5–2.5 mg/kg/d AZA 100 mg/d (mean)

11 mo 12 mo

16 (40%) of 40 21 (64%) of 33

9 (23%) of 40 14 (41%) of 34

.18 .04

12

AZA 100 mg/d (mean)

12 mo

2 (29%) of 7

3 (60%) of 5

30 44 52

AZA 1.5 mg/kg/d AZA 2–2.5 mg/kg/d AZA 2 mg/kg/d

6 mo 6 mo 6 mo

NR NR 15 (58%) of 27

NR NR 6 (26%)of 25c

73

AZA 2.2 mg/kg/d

2y

25 (74%) of 34

27 (70%) of 39d >.10

Abbreviations: AZA, azathioprine; 6-MP, 6-mercaptopurine; NR, not reported; NS, not signiﬁcant. a Control group treated with sulfasalazine. b Reduction of steroid dose active treatment arm versus placebo arm. c Control group received mesalamine, 3.2 g/d. d Control group received AZA, 2.2 mg/kg/d and olsalazine 3 g/d.

NS \.05b \.001b .04

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Table 4 Summary of randomized-controlled trials of AZA or 6-MP for ulcerative colitis

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intravenous therapy [44,45]. These statistics are based on retrospective cohort data. Currently, there is a prospective randomized trial ongoing attempting to discern if data are similar. Onset of action and duration of therapy One limitation of the clinical use of AZA and 6-MP in the management of active disease is their delayed onset of action. Present et al [22] reported that the mean time to response to 6-MP therapy in active CD was 3.1 months, with 19% of the responders requiring at least 4 months of therapy to observe beneﬁt. This ﬁnding was conﬁrmed in a meta-analysis of placebocontrolled trials of active CD, where a consistent clinical beneﬁt was observed with at least 17 weeks of AZA or 6-MP therapy [28]. The reason for the slow onset of action of these drugs is unclear, and likely relates to their pharmacokinetics. Although the half-life of AZA or 6MP in plasma is short, ranging from 1 to 2 hours, the half-life of the active metabolite 6-TGNs in erythrocytes is longer (3–13 days) [12,15,47,48]. Pharmacologic studies have shown a prolonged and variable duration of therapy required to reach steady state for these active metabolites, ranging from 4 days to 3 years [49–54]. Attempts to shorten the time required for a therapeutic response with intravenous loading of AZA at 40 mg/h for 36 hours did not occur in a placebo-controlled trial [55]. The results from this study, however, suggest that the onset of action for AZA may be more rapid than previously thought. The steady-state concentration of erythrocyte 6TGN was achieved by 2 weeks in patients treated with oral AZA alone, and most of the responders achieved remission by 8 weeks of therapy [55]. Although similar results were reported in a small, open-label pilot study evaluating intravenous AZA for severe UC [56], relying solely on AZA or 6-MP rapid symptom relief in patients who require rapid symptom relief is generally considered impractical. The duration for which maintenance therapy with AZA or 6-MP should be continued is unknown. In an uncontrolled study of patients with CD in clinical remission on AZA or 6-MP, duration of less than 4 years in remission was associated with a higher risk of relapse on discontinuing AZA or 6-MP maintenance therapy [57], suggesting that patients in remission on AZA for over 4 years were at low risk of relapse when AZA was stopped. A subsequent retrospective study reported that the beneﬁcial eﬀect of 6-MP in maintaining remission for CD was observed at up to 5 years following withdrawal of treatment [58]. A recently published large series of patients with IBD receiving AZA reported the rates of remaining in remission after stopping therapy were 63%, 44%, and 35% at 1, 3, and 5 years, respectively [59]. The duration of therapy did not inﬂuence the likelihood of relapse following discontinuation of therapy. In the only randomized-controlled trial evaluating AZA as a maintenance agent, CD patients in clinical remission for at least 42 months on AZA who remained on therapy had a signiﬁcantly lower relapse rate of

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7.9% at 18 months compared with 21% in patients who discontinued AZA [60]. Although the relapse rate in patients who discontinued AZA maintenance therapy in this study was relatively low and aforementioned studies did not have outcomes in patients on AZA or 6-MP maintenance therapy for over 5 years, the decision to continue AZA or 6-MP therapy beyond 5 years needs to be individualized. When the beneﬁt of therapy was weighed against side eﬀects in a statistical model, the beneﬁt of AZA or 6-MP for maintaining remission in CD patients seems to extend up to 10 years, particularly in younger patients [61]. There are no data available on the duration of maintenance therapy for patients with UC. Continued therapy with AZA or 6-MP so long as it maintains remission is probably desired given the data in CD and the limited options for maintenance therapy in UC.

Side eﬀects Common side eﬀects of AZA and 6-MP include allergic reactions, pancreatitis, bone marrow suppression, nausea not related to pancreatitis, and infections. Signiﬁcant adverse events requiring withdrawal from clinical trials occur in up to 10% of patients [28]. In a single center, retrospective study of over 600 patients with IBD treated with AZA, 28% of patients discontinued therapy because of side eﬀects [59]. Allergic reactions to AZA or 6-MP usually manifest as fever, rash, or arthralgia, and resolve following discontinuation of medications [62,63]. Recurrence of similar reactions occurs with medication challenge, although individuals who develop allergic reactions to 6-MP may be able to tolerate subsequent challenge with AZA [64]. As is allergic reaction, pancreatitis is also idiosyncratic and doseindependent [63,65,66]. It usually occurs during the ﬁrst month of therapy and is reversible on drug withdrawal. There has been no report of chronic pancreatitis caused by 6-MP or AZA therapy in the literature. Baseline pancreatic enzyme levels should probably be obtained, but routine laboratory testing for these values is not recommended without clinical suspicion for pancreatitis. Other gastrointestinal side eﬀects of AZA and 6-MP unrelated to pancreatitis include nausea, vomiting, and abdominal pain. These symptoms are usually mild, occur early during the course of therapy, and improve over time. Bone marrow suppression is an important toxicity of AZA and 6-MP therapy, occurring in 2% to 5% of patients [63,67]. All three cell lines may be aﬀected, but the most common presentation is leukopenia. This hematologic side eﬀect is dose-related, and may be inﬂuenced by such factors as drug interactions, which are discussed in a subsequent section; viral infections; and blood transfusions [68]. Bone marrow suppression is managed with dose reduction or medication withdrawal. Routine monitoring for hematologic toxicity is recommended for patients receiving AZA or 6-MP for their IBD. Baseline complete blood counts should be obtained

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before initiating therapy. One sample algorithm for subsequent monitoring consists of complete blood count studies weekly for 4 weeks, biweekly for 4 weeks, and then every 1 to 2 months for the duration of therapy (Box 1). Because myelosuppression may occur any time during therapy, as far out as 11 years after starting the drug [67], continued monitoring is necessary as long as the patient remains on the medication. The active metabolites are primarily responsible for the myelotoxicity of AZA and 6-MP therapy. Studies have shown signiﬁcantly higher erythrocyte 6-TGN levels in patients who develop leukopenia compared with those without leukopenia [69]. 6-TGN levels above 450 pmol/8 108 red blood cells (RBCs) are associated with an increased risk of myelosuppression (Fig. 2). Cytopenia, however, occurs at normal 6-TGN levels. Measurement of 6-TGN levels should not replace routine laboratory monitoring and is not recommended for reducing bone marrow toxicity. Alternatively, the determination of TPMT genotype or enzyme activity before initiating AZA or 6-MP therapy has been proposed to reduce the risk of bone marrow toxicity. Because approximately 11% of the general population has mutant TPMT genotypes and consequent low or absent TPMT enzyme activity, AZA or 6-MP therapy in these individuals is associated with increased myelotoxicities caused by preferential shunting of 6-MP metabolism toward the excessive production of 6-TGN [5]. This is supported by a study showing higher 6-TGN levels in patients with one mutant TPMT allele compared with individuals with homozygous wild-type TPMT genotype [69]. Furthermore, the delay between administration of AZA or 6-MP and development of myelotoxicity seems to be shorter in patients with TPMT mutation compared with those with wild-type TPMT genotype [68]. The a priori knowledge of TPMT activity may have a safety

Box 1. Recommended routine laboratory monitoring for potential toxicities Baseline studies Complete blood count Liver chemistry tests Complete blood count Weekly for 4 weeks, then Every 2 weeks for 4 weeks, then Every 1 to 3 months indefinitely Liver chemistry tests Every 3 to 4 months for 1 year, then Every 4 to 6 months thereafter Pancreatic chemistries (amylase and lipase) Only in the presence of abdominal pain

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AZA

6-MP

6-TIMP

221

6-TGN

TPMT 6-MMPR

Clinical Efficacy

Bone Marrow Toxicity

≥ 235-250*

≥ 450*

Hepatotoxicity ≥ 5700* Fig. 2. Relationship between metabolites and drug response in terms of eﬃcacy and toxicities. The likelihood of clinical response and bone marrow suppression increases with 6-TGN levels above 235 to 250 and 450 pmol/8108 RBCs, respectively. Similarly, hepatotoxicity is more likely to develop at 6-MMPR levels above 5700 pmol/8108 RBCs. *Units for 6-TGN and 6-MMPR = pmol/8108 RBCs. 6-MMPR, 6-methylmercaptopurine ribonucleotides; 6-TGN, 6-thioguanine nucleotides; TPMT, thiopurine methyltransferase; 6-TXMP, 6-thioxanthosine 59-monophosphate.

advantage. Because only 27% of patients with leukopenia have TPMT mutation [68], relying solely on TPMT genotype for monitoring bone marrow toxicities is inadequate. The concept that pretreatment analyses of TPMT genotype or phenotype may minimize potential toxicities by allowing appropriate dose usage, and whether such a practice is cost eﬀective, have not been evaluated in controlled studies. Azathioprine and 6-MP therapy is associated with an increased risk of infections. Serious infectious complications reported in the literature include cytomegalovirus infection (colitis, hepatitis, and disseminated infection); liver abscess; pneumonia; listeria cerebritis; herpes zoster; septic phlebitis with arthritis; viral hepatitis; Q fever; and genital warts [43,59,63,70,71]. Many of these cases occurred in the absence of leukopenia. One frequently encountered question regarding AZA and 6-MP therapy in patients with IBD is whether its use increases infectious complications in patients undergoing surgery. A recent retrospective study reported no signiﬁcant increase in the risk of postoperative infectious complications with AZA or 6-MP therapy, alone or as an addition to corticosteroids, in patients with IBD undergoing elective surgery [72]. Other uncommon but important side eﬀects of AZA or 6-MP therapy include hepatic toxicity and malignancy. Abnormal liver chemistry tests that develop on AZA or 6-MP therapy but resolve following drug withdrawal occur in approximately 2% of patients [57]. Because liver biopsy is not routinely performed, the pattern of hepatic injury in patients who develop abnormal liver chemistry tests on AZA or 6-MP is unknown. Deﬁnitive drug-induced hepatitis conﬁrmed by response to drug withdrawal and

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recurrence on rechallenge has been reported [63]. Liver biopsy in that case showed cholestasis with inﬂammation. Other rare hepatic toxicities reported with AZA or 6-MP therapy include nodular regenerative hyperplasia and peliosis [57]. As is the case for complete blood count, baseline liver chemistry tests should be obtained before starting therapy. Periodic liver chemistry tests should be obtained for the duration of therapy with these agents. A sample algorithm is every 3 to 4 months during the ﬁrst year, and subsequently every 4 to 6 months (see Box 1). Although 6-methylmercaptopurine levels greater than 5700 pmol/8108 RBCs seem to be associated with abnormal liver chemistry (see Fig. 2), there is currently no role for routine measurement of metabolite levels for assessment of hepatotoxicity. There may be patients who develop abnormal levels of 6-methylmercaptopurine who have normal liver chemistries. In these patients, continuation of medical therapy with antimetabolites is appropriate. One adverse event that may deter patients from receiving AZA or 6-MP is the concern for long-term potential for developing neoplasia. Malignancy has been reported to occur in 3% to 4% of patients treated with these agents for IBD [63,73]. This frequency does not seem to be greater than that of the control population not receiving these agents [73]. Case reports of lymphoma in patients with IBD treated with AZA or 6-MP, however, have raised particular concerns regarding safety of these agents [57,63,74–76]. These agents have been associated with an increased risk of non-Hodgkin’s lymphoma in patients with rheumatoid arthritis and patients undergoing solid organ transplantations [77–82]. Most studies, both hospital-based and population-based, have reported no increased risk of lymphoma in patients with IBD treated with AZA or 6-MP [73,83,84]. One study based on a single institution reported a signiﬁcantly higher risk of non-Hodgkin’s lymphoma with immunosuppressive therapy in IBD patients [85]. Of the four cases of IBD patients with non-Hodgkin’s lymphoma, two received AZA. The other two patients received methotrexate or cyclosporine, which may carry diﬀerent risks of lymphoma from AZA or 6-MP. The only population-based study to date of 1465 patients with IBD treated with AZA or 6-MP reported no signiﬁcant increase in the risk of lymphoma, with a relative risk of 1.27 (95% CI 0.03–8.20) compared with expected rates [84]. The general consensus in this regard is that if any association exists, it is likely to be of minimal clinical signiﬁcance, and unlikely to outweigh the beneﬁt of clinical eﬃcacy at least during the ﬁrst decade of therapy [61]. In patients with CD treated with AZA or 6-MP, the development of lymphoma seems to be associated with Epstein-Barr virus infection [86].

Dosing, metabolite monitoring, and pharmacogenetic testing The optimal dose of AZA or 6-MP for treating IBD is unknown. There is currently no formal dose-ranging study in the literature. A study of this

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nature will soon take place in the form of a multicenter trial. The eﬀective dosages based on reported clinical trials are approximately 2.5 mg/kg/d and 1.5 mg/kg/d for AZA and 6-MP, respectively. At these doses, however, there may still be nonresponders and higher doses may be necessary. In children receiving 6-MP for acute lymphoblastic leukemia, the erythrocyte (RBC) concentration of the active metabolites, 6-TGNs, correlates inversely with the risk of relapse and the absolute neutrophil counts [5,50,87–89]. In the past, induction of leukopenia has been advocated for dose optimization in patients with IBD. In a retrospective study of 98 refractory CD patients treated with 6-MP, signiﬁcantly more patients with leukopenia (deﬁned as white blood cell count less than 5000 mm3) achieved remission compared with patients who did not become leukopenic (92% versus 64%; P = .001) [90]. Among patients who achieved remission, the time to remission was also signiﬁcantly shorter in those who developed leukopenia. This observation has not been conﬁrmed in subsequent studies, however, including one randomized, placebo-controlled study [55,69,90,91]. In those studies, most of patients achieving clinical response did so in the absence of leukopenia. Leukopenia is clearly not required for induction of remission in patients with active disease. An alternative and biologically plausible parameter of clinical response is the level of 6-TGNs. This concept of therapeutic dosing based on metabolite levels in the management of IBD patients was ﬁrst reported in pediatric and adolescent IBD patients [69,92]. These retrospective data suggest that erythrocyte 6-TGN levels greater than 235 to 250 pmol/8108 erythrocytes (RBCs) correlate with a clinical response in patients with CD (see Fig. 2) [69,93]. The likelihood of a therapeutic response increases by ﬁvefold when the 6TGN level exceeds 235 pmol/8108 RBCs [69]. Subsequent studies have similarly reported a positive correlation between clinical response and 6-TGN level in both adult and pediatric patients with IBD treated with AZA or 6-MP [93–95]. Whether this observation applies to all disease subtypes or distribution is unknown. Two studies have in fact reported that the correlation between 6-TGN level and response is limited to patients with CD and not patients with UC [93,95]. The incorporation of 6-TGN metabolite measurement in AZA or 6-MP therapy is controversial and represents an evolving area of clinical practice. Few studies have examined the beneﬁt of measuring metabolite levels to tailor AZA or 6-MP therapy and achieve response. In one prospective, controlled study of 22 CD patients who had no or incomplete response to moderate dose of AZA, 18 patients entered remission on dose escalation [93]. Most of these responders (12 of 18) achieved a therapeutic 6-TGN level (> 250 pmol/8108 RBCs) compared with only two of the four nonresponders, suggesting that measuring 6-TGN metabolite levels can be used for dose optimization to achieve an improved clinical response in patients receiving AZA or 6-MP. A recent retrospective study examining the change in metabolite levels following dose escalation showed that there may

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be a subgroup of patients resistant to 6-MP therapy [96]. In this study of 51 IBD patients with active disease on 6-MP therapy, 14 patients achieved a clinical response following dose escalation. Importantly, the median change in 6-TGN levels was signiﬁcantly higher among the responders compared with the nonresponders (median 122 versus 26; P = .0003), whereas the reverse held true for 6-methylmercaptopurine ribonucleotide levels (median 1908 versus 7986 for responders versus nonresponders, respectively; P = .006). A subgroup of patients emerged from these data. These 6-MP–resistant patients are characterized phenotypically by preferential 6-methylmercaptopurine ribonucleotide production and suboptimal 6-TGN level even with dose escalation [96]. Clinical nonresponders to 6-MP therapy may be stratiﬁed into three groups based on their metabolite proﬁles [97]. The most common scenario for therapy failure is inadequate treatment and is characterized by subtherapeutic 6-TGN levels and low 6-methylmercaptopurine ribonucleotide levels. Reasons for inadequate treatment include underdosing, noncompliance, or sometimes malabsorption. Patients who are resistant to 6-MP therapy have subtherapeutic 6-TGN and high 6-methylmercaptopurine ribonucleotide levels. True 6-MP refractory patients have a metabolite proﬁle similar to that of responders: high 6-TGN and low 6-methylmercaptopurine ribonucleotide levels. Such phenotypic stratiﬁcation may be clinically useful because appropriate measures can be taken to achieve a clinical response in the ﬁrst group of patients, whereas patients in the latter two groups may beneﬁt from alternative therapy. This aforementioned hypothesis needs to be tested in a prospective, randomized, blinded fashion. An alternative or complimentary approach to measuring 6-TGN levels that may have potential clinical use is determination of TPMT phenotype. Because TPMT mutation should in theory enhance the likelihood of clinical response by shunting of metabolism toward excessive 6-TGN production, one study has accordingly showed a higher response rate of 100% in patients with heterozygous TPMT mutations than 46% in individuals with homozygous wild-type TPMT genotypes [69]. The gaussian distribution of the enzyme activity even among individuals with normal TPMT genotypes [4], however, suggests great variability in clinical response. The ﬁndings from a recently reported study supported this concept. In this study comparing AZA therapy in patients with normal versus high TPMT activity, patients with normal TPMT activity level had higher 6-TGN levels than those with high TPMT activity [98]. Importantly, 81% of patients with normal TPMT activity responded to therapy compared with 47% of those with high TPMT activity, whereas AZA doses were similar in the two groups. The potential clinical use of pretreatment TPMT phenotype for tailoring optimal treatment dose is under investigation. There is no prospective, controlled study showing improved clinical outcomes with routine TPMT determination or metabolite monitoring. A retrospective study showed that measuring metabolite levels was associated

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with more favorable long-term outcomes only in patients with active, nonﬁstulizing CD [99]. From a practical standpoint, measuring metabolite levels is probably most useful for identifying reasons for nonresponse to therapy and for suspected noncompliance. If used, metabolite levels should be determined at least 2 weeks following dose adjustment to allow suﬃcient time for the metabolites to reach steady state. Given the controversies regarding the optimal dosages for AZA and 6-MP therapy, initial and subsequent adjustment of dosages vary in clinical practice. One approach is to start the medication at 50 mg daily and increase by 25 mg every 1 to 2 weeks while monitoring for cytopenia. An alternative approach is to start the medication at weight-based optimal dose (1.5 mg/ kg/d for 6-MP and 2.5 mg/kg/d for AZA). If the latter approach is used, pretherapy determination of TPMT genotype or phenotype is recommended, because patients with decreased TPMT enzyme activity are more likely to experience bone marrow toxicity caused by preferential shunting of 6-MP metabolism toward the excessive production of 6-TGN. Patients with homozygous wild-type TPMT or normal (to high) TPMT enzyme activity level can receive these agents starting at 2.5 mg/kg/d for AZA or 1.5 mg/kg/ d for 6-MP. For patients with heterozygous TPMT mutation or intermediate enzyme activity level, medications should be started at 50% of the weight-based optimal dose. Alternative therapy should be considered in individuals with homozygous mutations for TPMT. In either approach, monitoring blood counts remains necessary as previously outlined.

Drug interactions A number of compounds, when coadministered with AZA or 6-MP, may inﬂuence drug metabolism and potential clinical eﬃcacy. The two major categories of drug-drug interactions with AZA or 6-MP therapy are sulfasalazine-mesalamine and allopurinol therapy. In vitro studies have shown sulfasalazine, balsalazide, olsalazine, and 5aminosalicylate to be potent inhibitors of TPMT activity [100–102]. There was one case report of a patient with CD receiving both 6-MP and olsalazine who developed two episodes of bone marrow suppression that ultimately required withdrawal of both medications [100]. Two studies reported no inﬂuence on TPMT activity, metabolite levels, or clinical response by concurrent mesalamine therapy [69,96]. These ﬁndings are in contrast to the study by Lowry et al [103], which showed increased erythrocyte 6-TGN levels in CD patients with concurrent mesalamine or sulfasalazine, but not balsalazide therapy. Whether in vitro inhibition of TPMT activity by these agents translates to signiﬁcant enhancement of clinical eﬃcacy has not been evaluated in a prospective fashion. It should be noted that inhibition of TPMT in vivo is not necessarily reﬂected by a lower enzyme activity measured in vitro in the absence of the inhibitor.

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Allopurinol, by inhibiting xanthine oxidase activity, may reduce the oxidative metabolism of AZA or 6-MP and thereby increase 6-TGNs and bone marrow suppression. This drug interaction poses particular problems in cancer treatment where allopurinol is often coadministered with AZA or 6-MP, and is a less important issue in the treatment of IBD. Other medications that have been implicated to potentially interfere with TPMT activity include aspirin and the loop diuretic furosemide [104,105]. The clinical signiﬁcance of these drug-drug interactions is yet to be clariﬁed. Pregnancy The safety of AZA and 6-MP during pregnancy in patients with IBD is controversial. Limited data are available on the pregnancy outcomes in patients receiving these agents for IBD. Animal data suggest potential teratogenicity of these agents, including skeletal anomalies, cleft palate, decreased thymic size, hydrops fetalis, and hematopoietic suppression in the absence of signiﬁcant maternal hematopoietic suppression [106,107]. Chromosomal aberrations in the spermatocytes of male mice exposed to 6-MP has also been reported [108–112]. In humans, AZA readily crosses the placenta, mostly in the form of inactive metabolites, thiouric acid [113]. Fetal bone marrow suppression and chromosomal aberrations in cultured cells of the oﬀspring of mothers receiving AZA during pregnancy have been reported [114–117]. In renal transplant patients and patients with systemic lupus erythematosus, the use of AZA or 6-MP during pregnancy is generally considered safe [118–122]. In patients with IBD, a retrospective analysis of the outcome of 16 pregnancies in 14 women exposed to AZA during pregnancy reported no congenital anomalies or subsequent health problems in the oﬀspring, except one case of hepatitis B infection [123]. The results were similar in a larger retrospective, case-controlled study of 325 pregnancies in 155 patients with IBD [124]. Treatment with 6-MP before conception, at conception, or during pregnancy was not associated with any signiﬁcant increase in prematurity, spontaneous abortion, congenital abnormalities, neonatal and childhood infections, or neoplasia. Another single-center, retrospective study, however, suggested a slightly increased rate of adverse outcomes with prior exposure to 6-MP [125]. Among 72 pregnancies in female patients with IBD who conceived at least 6 months after cessation of 6-MP therapy (median 6 years), there were 16 (22%) spontaneous abortions and 2 cases of abnormal amniocentesis resulting in therapeutic abortions, in contrast to 18 (13%) spontaneous abortions and no abnormality on amniocentesis among those without prior 6-MP exposure. The overall frequency of fetal loss seems to be higher in patients with prior 6-MP therapy than those without prior 6-MP, implicating the need to exercise some degree of caution when considering 6-MP therapy in childbearing patients. This needs to be weighed,

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however, against the risk for disease ﬂare in patients during pregnancy because this particular factor is most predictive of poor infant outcome. Long-term follow-up of these children showed no increased incidence of developmental defects with 6-MP exposure before pregnancy [125]. Although paternal use of AZA or 6-MP is generally considered safe in childbearing based on organ-transplant data [121,126–128], it may be associated with an increased risk of pregnancy complications in patients with IBD [65]. In a retrospective study of 50 pregnancies fathered by patients with ongoing or prior exposure to 6-MP for IBD, there were two spontaneous abortions and two congenital anomalies among 13 pregnancies fathered by male patients receiving 6-MP within 3 months before conception. This incidence was signiﬁcantly higher than two complications in pregnancies fathered by men without 6-MP exposure (P \ .002), and one complication in those with 6-MP exposure at least 3 months preceding conception (P \ .0013) [65]. Azathioprine and 6-MP are currently Food and Drug Administration pregnancy category D. Although exposure to these agents during pregnancy may be associated with a small risk of congenital or developmental abnormalities in the newborns, clinical data in aggregate support no appreciable risk of complications except for a possibly higher incidence of spontaneous abortion. Termination of pregnancy is not mandatory for women who conceive while taking these drugs. The use of AZA or 6-MP in patients planning to conceive or during pregnancy should be individualized based on informed discussions between patients and physicians, weighing the beneﬁt of therapy against the potential toxicities. Summary Azathioprine and 6-MP are arguably the most widely used immunosuppressive agents in patients with IBD. Despite variations in study design, data from controlled and uncontrolled trials support the eﬃcacy of these medications for the treatment of active and quiescent CD. The eﬀective dosages based on these studies are generally considered 2.5 mg/kg/d for AZA and 1.5 mg/kg/d for 6-MP. The clinical onset of action most often requires 3 to 6 months of treatment before eﬃcacy, although limited data suggest shorter onset of action. Similar eﬃcacy has also been demonstrated in the literature, with less substantive data, for both induction and maintenance of remission in patients with UC. Other unique and important indications for AZA or 6-MP therapy are treatment of ﬁstulizing CD and steroid-dependent CD and UC. The eﬃcacy of therapy persists for up to and probably longer than 5 years. Although therapy is associated with many potential side eﬀects, there is growing evidence for its safety. As with all therapies, beneﬁts must be weighed against potential toxicities. The duration of therapy needs to be individualized. Further individualization of AZA and 6-MP therapy in patients with IBD may involve use of metabolite

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measurement and enzymatic phenotyping. The clinical applications of these tests will likely be the focus of research in AZA and 6-MP therapy for the next several years.

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[97] Dubinsky M. Maximizing thiopurine therapy in inﬂammatory bowel disease: the role of TPMT analysis and metabolite monitoring as predictors of safety and eﬃcacy. Clinical Perspectives in Gastroenterology 2002;5:343–6. [98] Cuﬀari C, Dassopoulos T, Turnbaugh L, Thompson R, Bayless TM. Thiopurine methyltransferase (TPMT) activity inﬂuences clinical response to maintenance azathioprine therapy in patients with IBD. Gastroenterology 2002;122:A221. [99] Su C, Wang S, Deren J, Weinberg A, Lichtenstein GR. The long-term beneﬁt of therapeutic drug monitoring in IBD patients receiving AZA/6-MP. Gastroenterology 2002;122:A77. [100] Lewis LD, Benin A, Szumlanski CL, Otterness DM, Lennard L, Weinshilboum RM, et al. Olsalazine and 6-mercaptopurine-related bone marrow suppression: a possible drug-drug interaction. Clin Pharmacol Ther 1997;62:464–75. [101] Lowry PW, Szumlanski CL, Weinshilboum RM, Sandborn WJ. Balsalazide and azathioprine or 6-mercaptopurine: evidence for a potentially serious drug interaction. Gastroenterology 1999;116:1505–6. [102] Szumlanski CL, Weinshilboum RM. Sulphasalazine inhibition of thiopurine methyltransferase: possible mechanism for interaction with 6-mercaptopurine and azathioprine. Br J Clin Pharmacol 1995;39:456–9. [103] Lowry PW, Franklin CL, Weaver AL, Szumlanski CL, Mays DC, Loftus EV, et al. Leucopenia resulting from a drug interaction between azathioprine or 6-mercaptopurine and mesalamine, sulphasalazine, or balsalazide. Gut 2001;49:656–64. [104] Woodson LC, Ames MM, Selassie CD, Hansch C, Weinshilboum RM. Thiopurine methyltransferase: aromatic thiol substrates and inhibition by benzoic acid derivatives. Mol Pharmacol 1983;24:471–8. [105] Lysaa RA, Giverhaug T, Wold HL, Aarbakke J. Inhibition of human thiopurine methyltransferase by furosemide, bendroﬂumethiazide and trichlormethiazide. Eur J Clin Pharmacol 1996;49:393–6. [106] Rosenkrantz JG, Githens JH, Cox SM, Kellum DL. Azathioprine (Imuran) and pregnancy. Am J Obstet Gynecol 1967;97:387–94. [107] Polifka JE, Friedman JM. Teratogen update: azathioprine and 6-mercaptopurine. Teratology 2002;65:240–61. [108] Generoso WM, Preston RJ, Brewen JG. 6-mercaptopurine, an inducer of cytogenetic and dominant-lethal eﬀects in premeiotic and early meiotic germ cells of male mice. Mutat Res 1975;28:437–47. [109] Meistrich ML, Finch M, da Cunha MF, Hacker U, Au WW. Damaging eﬀects of fourteen chemotherapeutic drugs on mouse testis cells. Cancer Res 1982;42:122–31. [110] Mosesso P, Palitti F. The genetic toxicology of 6-mercaptopurine. Mutat Res 1993;296: 279–94. [111] Oakberg EF, Crosthwait CD, Raymer GD. Spermatogenic stage sensitivity to 6mercaptopurine in the mouse. Mutat Res 1982;94:165–78. [112] Russell LB, Hunsicker PR. Study of the base analog 6-mercaptopurine in the mouse speciﬁc-locus test. Mutat Res 1987;176:47–52. [113] Saarikoski S, Seppala M. Immunosuppression during pregnancy: transmission of azathioprine and its metabolites from the mother to the fetus. Am J Obstet Gynecol 1973;115:1100–6. [114] Davison JM, Dellagrammatikas H, Parkin JM. Maternal azathioprine therapy and depressed haemopoiesis in the babies of renal allograft patients. Br J Obstet Gynaecol 1985;92:233–9. [115] DeWitte DB, Buick MK, Cyran SE, Maisels MJ. Neonatal pancytopenia and severe combined immunodeﬁciency associated with antenatal administration of azathioprine and prednisone. J Pediatr 1984;105:625–8. [116] McGeown MG, Nevin NC. Cytogenetic analysis on children born of parents treated with immunosuppressive drugs. Proc Eur Dial Transplant Assoc 1978;15:384–90.

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[117] Price HV, Salaman JR, Laurence KM, Langmaid H. Immunosuppressive drugs and the foetus. Transplantation 1976;21:294–8. [118] Erkman J, Blythe JG. Azathioprine therapy complicated by pregnancy. Obstet Gynecol 1972;40:708–10. [119] Farber M, Kennison RD, Jackson HT, Sbarra AJ, Widmere B, Barnes BA. Successful pregnancy renal transplantation. Obstet Gynecol 1976;48(Suppl 1):2S–4S. [120] Hou S. Pregnancy in organ transplant recipients. Med Clin North Am 1989;73:667–83. [121] Huynh LA, Min DI. Outcomes of pregnancy and the management of immunosuppressive agents to minimize fetal risks in organ transplant patients. Ann Pharmacother 1994;28: 1355–7. [122] Meehan RT, Dorsey JK. Pregnancy among patients with systemic lupus erythematosus receiving immunosuppressive therapy. J Rheumatol 1987;14:252–8. [123] Alstead EM, Ritchie JK, Lennard-Jones JE, Farthing MJ, Clark ML. Safety of azathioprine in pregnancy in inﬂammatory bowel disease. Gastroenterology 1990;99: 443–6. [124] Francella A, Dyan A, Bodian C, Rubin P, Chapman M, Present DH. The safety of 6-mercaptopurine for childbearing patients with inﬂammatory bowel disease: a retrospective cohort study. Gastroenterology 2003;124:9–17. [125] Zlatanic J, Korelitz BI, Rajapakse R, Kim PS, Rubin SD, Baiocco PJ, et al. Complications of pregnancy and child development after cessation of treatment with 6-mercaptopurine for inﬂammatory bowel disease. J Clin Gastroenterol 2003;36:303–9. [126] Golby M. Fertility after renal transplantation. Transplantation 1970;10:201–7. [127] Penn I, Makowski E, Droegemueller W, Halgrimson CG, Starzl TE. Parenthood in renal homograft recipients. JAMA 1971;216:1755–61. [128] Lingardh G, Andersson L, Osterman B. Fertility in men after renal transplantation. Acta Chir Scand 1974;140:494–7.

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Medical management of severe ulcerative colitis Justin C. Chang, MD, Russell D. Cohen, MD* Section of Gastroenterology, Department of Medicine, The University of Chicago, 5841 South Maryland Avenue, MC 4076, Chicago, IL 60637, USA

Severe ulcerative colitis (UC) represents one of the true potential emergencies facing physicians treating patients with inﬂammatory bowel disease. Care must be taken to identify patients who have severe disease, and provide them with the comprehensive, multidisciplinary care that is essential to minimize morbidity and avoid the rare mortality that can be associated with this condition. The initial (presenting) attack of UC may be severe in 3% to 14% of the population [1], with higher frequencies occurring in the elderly. Despite aggressive treatment, mortality rates as high as 3% have been reported [2]. Disease severity has been categorized based on the composite of clinical and endoscopic criteria. The Truelove and Witts’ categorical scale [3] (Table 1) has been widely adopted to evaluate clinical disease activity, whereas the modiﬁed Sutherland Scale lists the ﬁnding of frank ulcerations and spontaneous hemorrhage as endoscopic evidence of severe disease [4].

Evaluation Patients with severe UC often need inpatient management, unless rapidly improved on high-dose oral steroids [5]. Infectious agents must be ruled out by multiple stool specimens, with care to specify opportunistic infections (eg, Clostridium diﬃcile and cytomegalovirus) and organisms, such as Escherichia coli 0157:H7, which require special medium. Throughout the hospitalization, repeated checks for C diﬃcile may be necessary, especially if the patients’ clinical course deteriorates. Initial assessments also should include complete blood count with differential and platelet count, coagulation proﬁle, comprehensive metabolic * Corresponding author. E-mail address: [email protected] (R.D. Cohen). 0889-8553/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.gtc.2004.02.005

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Table 1 Modiﬁed Truelove and Witts’ Criteria Sign or symptom

Mild

Moderate

Severe

Bowel movements Temperature ((F) Weight loss (%) Pulse (beats/min) Hematocrit (%) Sedimentation rate (mm/h) Albumin (g/dL)

\4/d Normal None \90 Normal \20 Normal

4–6/d 90–100 1–10 90–100 30–40 20–30 3–3.5

>6/d (mostly bloody) >100 >10 >100 \30 >30 \3

Modiﬁed from Truelove SC, Witts LJ. Cortisone in ulcerative colitis: ﬁnal report on a therapeutic trial. BMJ 1955;2:1041–8; with permission.

panel, serum cholesterol, and magnesium. Additional assessments of nutritional status may also be desirable. Excluding other possible confounding diagnoses, such as undiagnosed thyroid disease and celiac sprue, may be helpful. Abdomen radiographs (two to three views) should be performed on admission, and if abnormal or the patient deteriorates, every 24 to 48 hours. Endoscopic evaluations may be helpful in assessing for active disease and ruling out infectious etiologies, but should be limited to a gentle ﬂexible sigmoidoscopy to a distance only necessary (15–30 cm) to conﬁrm severe colitis and to allow for biopsy specimens. Care should be taken to minimize insuﬄation. Surgical consultation is suggested early, especially if signs of toxicity (dilation of the colon on abdominal radiographs, fever, abdominal pain, sepsis, hypotension, leukocytosis with elevated band counts) are noted. Patients who show signs of decompensation or failure to respond to medical therapy in a timely basis should be sent for colectomy.

Management The development of fulminant colitis and toxic megacolon could be lifethreatening, and inciting agents, such as narcotics, anticholinergics, and full colonoscopic evaluation, should be avoided [5]. There is little, if any, role for narcotics in the management of patients with UC. Ambulation is encouraged, and bed-bound patients with evidence of dilation of the colon should have their position changed every few hours from decubitus to supine to prone (ie, rolling technique), which sometimes has surprisingly successful results [6]. Patients who can eat without suﬀering worsening of the symptoms should be provided a diet low in residue, but hyperalimentation is often necessary to replace the profound protein, calorie, and fat stores lost. Prophylactic subcutaneous heparin is advised, because these hypercoagulable patients may develop venous thromboses, particularly if a central venous catheter is

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in place. Intravenous broad-spectrum antibiotics are advised if patients show signs of infection or toxicity.

Medical therapies As is the case in the management in most patients with inﬂammatory bowel disease, the medical management paradigm for patients with severe UC typically follows a stepwise progression (Fig. 1). For the purposes of this article, the medications have been grouped together by class (Box 1).

Severe ulcerative colitis despite oral corticosteroids

IV corticosteroids

Symptoms not improved or worsened after 7-10 days

Symptoms improved

Oral corticosteroids with taper; Consider 6-MP

IV cyclosporine

Remission

No response after 4-5 days or No remission after 14 days

Surgery

or other novel agent?

Steroid dependent

Oral cyclosporine Oral corticosteroids Start 6-MP

Relapse

Wean off corticosteroids and cyclosporine Maintenance on 6-MP or azathioprine Fig. 1. Flowchart depicting the recommended progression in management of patients with severe ulcerative colitis. IV, intravenous; 6-MP, 6-mercaptopurine.

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Box 1. Medical therapies for severe ulcerative colitis Corticosteroids Oral: prednisone or equivalent Intravenous: methylprednisolone, hydrocortisone, dexamethasone, and so forth Immunomodulators Azathioprine 6-mercaptopurine Cyclosporine Tacrolimus (FK506) Anti–tumor necrosis factor antibodies Infliximab CDP-571 Anti-CD3 antibodies Visilizumab Other therapeutic approaches Heparins: unfractionated, low molecular weight Leukocytopheresis

Corticosteroids Before the era of corticosteroids, patients with moderate or severe UC faced high mortality rates [7,8]. Glucocorticoids are ﬁrst-line induction therapy for moderate to severe disease, with approximately 75% of patients responding to therapy [3,9]. Nevertheless, glucocorticoids do not seem to have maintenance beneﬁt after induction to remission [10]. Results from a recent population-based survey in Olmsted County, Minnesota, showed complete or partial remission in 84% of UC patients treated with systemic corticosteroids, no response in 16%, and prolonged 1year response rates of only 49%, with 29% requiring colectomy [11]. These observations have been consistent with reported rates of long-term remission (38%–71%) induced by parenteral steroids in severe UC [12]. Although less toxic corticosteroids have been used for patients with mild to moderate UC, their role in severe UC has not yet been established. Cyclosporine Cyclosporin A (CSA) has emerged as the ‘‘next step’’ for medical therapy in patients with steroid-refractory severe UC, or in those with severe colitis who have contraindications to corticosteroid use. CSA selectively blocks the activation of T helper and cytotoxic lymphocytes and their production of lymphokines (interleukin-2 and interferon-c) aﬀecting both humoral and cell-mediated immunity [13].

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The landmark randomized, placebo-controlled trial of CSA for steroidrefractory UC conducted at the University of Chicago and Mt. Sinai Hospital in New York showed a response rate of 82% in hospitalized steroid-refractory patients treated with intravenous corticosteroids plus 4 mg/kg intravenous CSA, compared with 0% in the group receiving corticosteroids alone [14]. Initial response rates of 56% to 91% have been reported in subsequent studies [15–18]. The ability of CSA to maintain remission has been disappointing, resulting in the institution of 6-mercaptopurine (6-MP) or azathioprine as long-term maintenance therapies [19]. Five-year colectomy-free survival rates of 66% have been reported in those patients who received one of the purine analogues in conjunction with or following CSA, versus 40% who did not (P = .045) [15]. Intolerance to 6-MP or azathioprine, or patient inability or refusal to take such medications, precludes the use of CSA in most instances. Initial success in treating severe UC with CSA monotherapy [20] led to a comparative trial of intravenous monotherapy with either CSA or corticosteroids [21]. Although equivalent response rates were seen in the patients receiving CSA monotherapy, 4 mg/kg (64%), with those receiving 40 mg/d of methylprednisolone (53%), the failure to reach the 80% response rates in the dual-therapy trials suggests that monotherapy should be reserved for those patients with a contraindication to corticosteroid use [22]. Lower doses of intravenous CSA (2 mg/kg) have also been proved eﬀective in severe UC [23], as has oral microemulsion CSA [24], which may prove to be safer than the higher dose, intravenous formulations. Predicting response to CSA would be helpful in guiding this potentially toxic therapy to those patients most likely to beneﬁt. CSA responders require lower levels of CSA to inhibit lymphocyte proliferation than nonresponders [25], although the wide variation in CSA sensitivity in the population limits the use of this predictive test. Other clinical signs and biochemical tests shown to be associated with initial response to CSA include lower pulse rate, higher albumin level, and lower percentages of band forms neutrophils [26]. Prospective studies are needed to demonstrate the reliability of these predictors. Concerns have been raised over the long-term eﬃcacy and safety of CSA therapy. In the authors’ 5-year retrospective study, 5 (12%) of the 42 patients with steroid-refractory UC on CSA developed major complications (including one with Pneumocystis carinii pneumonia) requiring discontinuation CSA, whereas 18 patients (43%) experienced at least one minor complication, all of which were reversible with CSA dose reduction [15]. Other authors have reported other opportunistic infections, neurologic, renal, cardiovascular, and metabolic complications from therapy [26,27]. Perioperative complications do not seem to increase with CSA administration [28]. The safety concerns must be balanced with the success rate of this agent, and quality of life studies that suggest that patients who avoid colectomy score similar to or better than postsurgical patients on formalized quality-of-life analyses [29].

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Tacrolimus Given the similarities of tacrolimus (FK506) to CSA, it is not surprising that this agent is also eﬀective in the treatment of severe UC. Tacrolimus inhibits the serine-sensitive phosphatase calcineurin, an enzyme that is responsible for activating the nuclear factor of activated T cell to transcribe proinﬂammatory cytokines [30,31]. Tacrolimus has been used successfully on children with severe steroid-refractory UC [32] and in severe adult colitis [33]. As is the case with CSA, patients may be bridged eﬀectively to longterm maintenance treatment with 6-MP or azathioprine. A comparison of the eﬃcacy of oral versus intravenous tacrolimus in treating refractory UC revealed similar day 14 improvement rates (47%) and colectomy rates (34%) [34]. Because tacrolimus is more potent and has better absorption than CSA, the potential of treating these patients with oral therapy (and avoiding the cost and complications associated with hospitalizations) is intriguing. The substantially lower success rates than those seen with intravenous CSA, however, with similar adverse event frequencies, question the preferential use of tacrolimus in these patients. Purine analogues Azathioprine and 6-MP have been used for the treatment of inﬂammatory bowel disease for over 30 years, including steroid-dependent or steroidrefractory UC and for the maintenance of remission [35,36]. Their slow onset of action has relegated their role in severe UC to the maintenance of remission induced by corticosteroids, CSA, tacrolimus [15,19,37], or perhaps inﬂiximab or visilizumab. Although one retrospective analysis suggested that it may be possible to avoid the oral CSA bridge between cessation of intravenous CSA and onset of action of azathioprine [38], prospective trials are needed to establish the eﬃcacy of this therapeutic regimen. The possibility of hastening the onset of action of azathioprine with intravenous therapy was evaluated in nine severe UC patients who received an intravenous loading dose of 20 to 40 mg/kg azathioprine followed by a daily oral dose of 2 mg/kg for duration of 12 weeks [39]. Before intravenous therapy, the presence of the thiopurine methyltransferase enzyme was conﬁrmed. Thirty-three percent achieved clinical remission by week 12, and 56% avoided colectomy. Two patients had transient leukopenia and one had transient hepatotoxicity. Although these results suggest that azathioprine may exhibit its therapeutic eﬀect faster than initially thought, whether an intravenous load hastens that eﬀect remains to be proved; a controlled trial in Crohn’s disease failed to show such a beneﬁt [40]. Inﬂiximab The startling success of inﬂiximab (a chimeric monoclonal antibody directed against tumor necrosis factor-a) in the treatment of Crohn’s disease

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has sparked much interest in the role of tumor necrosis factor in the pathogenesis of inﬂammatory bowel disease [41–47]. The ﬁrst randomized, placebo-controlled pilot study of inﬂiximab in 11 severe steroid-refractory UC patients reported week 2 clinical response rates of zero of three (placebo) versus four of eight (single dose of inﬂiximab at 5, 10, or 20 mg/ kg) [48]. An abstract described a second randomized, placebo-controlled trial in steroid-resistant UC patients given two doses of inﬂiximab (5 mg/kg) at weeks 0 and 2, and reported week 6 remission rates of 8 (36%) of 22 versus 6 (30%) of 20 in those receiving placebo [49]. Similar results were also seen in changes of quality of life scores between the two groups. Open-label studies of inﬂiximab in UC patients have had mixed results. Kaser et al [50] reported initial clinical improvement (including colonoscopic and histologic improvement) in all six severe, steroid-refractory patients treated, with four long-term remissions (median follow-up 5.5 months) after a single dose of 5 mg/kg inﬂiximab. Chey et al’s [51,52] reports of initial clinical, endoscopic, or histologic responses in 14 of 16 severe refractory patients have been tempered by concerns over the patient population, which included patients with previous colonic resections, a sigmoid stricture, and possibly with Crohn’s disease [53]. Notable results were also reported in 13 steroid-refractory patients receiving a single infusion of 5 mg/kg inﬂiximab, whereby 77% responded and 90% were maintained oﬀ of steroids at a mean of 10 months [54]. Short-term reports in pediatric patients with moderate to severe colitis have shown improvement in seven of nine, with steroid discontinuation in six [55]. Most recently, a consortium of academic and private American gastroenterologists have published their open-label experience of inﬂiximab in 27 patients, 33% with steroid-refractory and 37% with steroid-dependant UC [56]. Many (89%) had received up to three infusions of inﬂiximab, 5 mg/kg. Median time to response was 4 days (range 1 day to 3 weeks), whereas median duration of response was 8 weeks (range 2 weeks to 15 months), with 5 of 10 still in remission at 6 months. Response rates were worse in the steroid-refractory group (one of three versus two of three). Relapses were seen in 50%, but most responded to repeat infusions. Serious adverse events included one death from postoperative line sepsis death, and one case of candidemia that responded to medical management. The results of another open-label study, however, were not so optimistic. Four of the eight patients with severe, steroid-refractory UC did not respond to a single dose of inﬂiximab and required colectomy, as did a ﬁfth patient following a second inﬂiximab infusion [57]. The failure of most open-label studies to show convincing results past 6 months also raises the question of placebo-eﬀect in some of these patients [58], although the endoscopic and histologic ﬁndings are intriguing. Large-scale placebo-controlled trials are currently underway, which it is hoped will determine whether inﬂiximab is truly eﬀective in UC patients, and if so, whether there are certain patient subsets more likely to respond to the medication.

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CDP-571 CDP-571 is a humanized monoclonal anti–tumor necrosis factor antibody that was studied open-label in 15 patients with mild to moderately active UC who received a single dose at 5 mg/kg [58]. Mean Powell-Tuck scores fell from 6.7 to 4.6 (P = .023) at week 1 and to 5.5 (P = .218) at week 2. There were no diﬀerences in the other assessments of disease activity, however, such as subjective symptom reporting, visual analogue disease activity score, and subjective scoring on ﬂexible sigmoidoscopy. The possibility of eﬃcacy in UC with repeated or higher doses of CDP-571 needs to be validated.

Visilizumab Visilizumab is a humanized IgG-2 antibody that binds to the CD3 antigen, which results in apoptosis of activated T lymphocytes. A recent abstract reported preliminary phase I data in ﬁve patients with severe UC despite 5 days of intravenous corticosteroids who subsequently received two consecutive daily infusions of visilizumab (15 lg/kg) [59]. All ﬁve patients achieved clinical and endoscopic remission at day 30, and all three patients with at least 90 days of follow-up have successfully tapered oﬀ of steroids. These initial promising results require further validation in a larger population.

Antibiotics The role of antibiotics in the treatment of UC has never been clearly deﬁned. Patients with severe colitis with evidence of toxicity (fevers, bandemia, and hypotension) or with concerning ﬁndings on radiographic evaluations (colonic bowel wall thickening with mesenteric streaking on CT scan, or ‘‘thumbprinting’’ on abdominal radiograph) are often empirically treated with broad-spectrum antibiotics for fear of infection [60]. Randomized, placebo-controlled trials of intravenous ciproﬂoxacin [61], intravenous metronidazole [62], or oral vancomycin [63], however, have all failed to show a beneﬁt. More promising results have been reported with some other agents. Eighty-four UC patients with acute relapses treated with tobramycin as an adjuvant to intravenous corticosteroids had higher remission rates (74% versus 43%, P = .008) and better histologic scores than those receiving adjuvant placebo [64]. Success with rifaximin (versus placebo) has been reported in a 14-patient communication [65], although a recent study has shown that the administration of high doses of rifaximin does not signiﬁcantly modify the colonic microﬂora [66]. At this point, the use of antibiotics as therapeutic agents in UC is not well supported by the literature.

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Heparin The potential role of heparin as a therapeutic agent in UC stemmed from a paradoxical decrease in disease activity in UC patients receiving the anticoagulant to treat thromboembolic events [67,68]. Evidence of microthrombi formation within the intestinal mucosa in inﬂammatory bowel disease suggests that a hypercoagulable state may play a role in the pathogenesis of inﬂammatory bowel disease [69,70]. Although uncontrolled trials of unfractionated heparin reported clinical responses and remissions [71,72], and decreases in serum levels of tumor necrosis factor [73] and C-reactive protein [71], these patients were all also treated with other agents with proved therapeutic eﬃcacy in inﬂammatory bowel disease, such as sulfasalazine, 5-aminosalicyclic acid, corticosteroids, or immunosuppressants. Although an initial randomized pilot study comparing unfractionated heparin with corticosteroids as a ﬁrst-line therapy in severe UC claimed similar response rates and no serious adverse events (all patients also received concomitant 5-aminosalicylic acid therapy) [74], a subsequent 25-patient multicenter randomized trial reported remission rates of 0% in the unfractionated heparin group versus 69% in the intravenous methylprednisolone (0.75–1 mg/kg) group [75]. There were also signiﬁcant bleeding complications associated with the unfractionated heparin treatment in this study. Investigations into the use of low-molecular-weight heparin have also suggested possible beneﬁt in patients with steroid-refractory UC [76,77]. Future controlled studies are needed, however, to evaluate its therapeutic eﬃcacy and safety in severe disease. Until heparin has been established in controlled clinical trials as a safe and eﬀective therapy, it should not be used therapeutically to treat severe UC.

Leukocytopheresis Studies into the pathogenesis for colonic injury in UC suggest that activation and inﬁltration of granulocytes and monocytes-macrophages into the colonic mucosa [78] leads to the release of degradative proteases [79], reactive oxygen derivatives [80], and proinﬂammatory cytokine [81]. Removing these oﬀending agents by centrifugal leukocyte apheresis was studied in 14 steroid-refractory UC patients, with a purported 4-week clinical remission rate of 93% 4 weeks after completing the apheresis cycle, and mean remission maintenance of 8 months [82]. A subsequent multicenter openlabel study in 50 steroid-resistant UC patients reported improvement in 74%, colonoscopic remission in 58%, and histologic improvement in 54% [83]. Preliminary studies using leukocyte absorptive apheresis have also demonstrated marked clinical improvement [84,85] or remission [86]. In a multicenter randomized controlled trial comparing the leukocytopheresis column with high-dose corticosteroids in 76 patients with moderate to

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severe UC, the leukocytopheresis column group showed a signiﬁcant higher eﬀectiveness (74% versus 38% P = .005) and a lower incidence of adverse eﬀects [87]. It is hoped that ongoing clinical trials will validate these ﬁndings.

Current treatment strategies Severe UC or UC refractory to oral corticosteroids requires intravenous corticosteroids as an induction therapy (see Fig. 1). At the authors’ institution [88], methylprednisolone is started at 40 mg/d and is given as a continuous infusion, although some other centers prefer higher doses, or dosing split during the day [2]. Topical corticosteroids may also be used as an adjunctive therapy in addition to intravenous corticosteroids [89,90]. Most patients respond to high-dose corticosteroids in 7 to 10 days [91]; in those who do not, CSA (or other advanced therapies discussed in this article) is started, or patients proceed to colectomy. Patients who achieve remission on intravenous corticosteroids may be switched to oral corticosteroids, with plans for an outpatient taper. Strong consideration should be given to start (or optimize dosing of) 6-MP or azathioprine. Topical corticosteroids or mesalamine is continued, and oral mesalamine started as the corticosteroids are tapered. Those individuals in whom CSA therapy is contemplated must have the physical and emotional ability to undergo the weeks to months of intensive therapy, timely blood draws, frequent oﬃce visits, and be willing and able to take maintenance therapy with 6-MP or azathioprine. Contraindications include patients with active or chronic infections, seizures, hypertension, renal insuﬃciency, electrolyte abnormalities, or other serious medical or psychologic problems. Because both low cholesterol and hypomagnesemia increase the risk of seizures with CSA treatment, and changes in other critical electrolytes may be seen, cholesterol and complete blood chemistry levels should be obtained before administrating CSA, and repeatedly during therapy. Prophylaxis against P carinii pneumonia is recommended, and patients with a history of recurrent herpes simplex may beneﬁt from prophylactic antiviral therapy. The initial CSA dose is typically 4 mg/kg/d, given as a continuous infusion. Patients with slightly low serum cholesterol levels require dose reduction (2 mg/kg); those with very low levels (\ 100 mg/dL) should not receive CSA. CSA levels should be acquired every 48 to 72 hours, with a target of 350 to 500 ng/mL for those on 4 mg/kg dosing. Initial responses should be seen by the third day, and progressive daily improvement afterward, with total course of intravenous CSA generally not exceeding 10 to 14 days. Complete responses (remission) should be expected, with normalization of stool frequency, consistency, and the absence of visible blood, abdominal pain, and urgency. Patients who fail to meet these criteria in a timely fashion should proceed to surgery.

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Patients who achieve remission are then switched to oral microemulsion CSA dosed twice a day, at a total daily dose double that of their ﬁnal intravenous dose. Intravenous corticosteroids are switched to oral prednisone, 40 mg (divided doses), and azathioprine or 6-MP is started. Target trough CSA levels on oral therapy are 200 to 350 ng/mL. Prophylactic antiinfective agents are continued, and many beneﬁt from the continuation of topical corticosteroid or mesalamine. Frequent monitoring of electrolytes, hematology, and CSA levels is required. The CSA and corticosteroids are tapered over the ensuing 2 to 3 months, while the dose of the purine analogues is optimized. Patients who relapse or still exhibit signs of steroiddependant disease require colectomy [19]. Consideration of using some of the newer agents or approaches discussed in this article, in lieu of CSA, should be given on an individual basis.

Summary Progress in the medical management of severe UC has been focused on the rapid induction and maintenance of remission. Treatment strategies have been ﬁne-tuned over the past years relying on the same therapeutic agents. The trend has been moving away from prolong steroid therapy, however, and toward immunomodulators. With a better understanding of immune regulations and inﬂammatory mechanisms, the challenges are to identify target sites for rapid induction to remission and long-term maintenance therapies with less complications and side eﬀects. The addition of new agents in the future may complicate present treatment regimens and may require constant reﬁnement and adaptation to new therapies. Because UC can be cured by colectomy, the main objectives of medical management are to maintain quality of life and prevent complications of this complex chronic disease.

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Novel biologics in inﬂammatory bowel disease Georgios I. Papachristou, MD, Scott Plevy, MD* Division of Gastroenterology, Hepatology and Nutrition, The University of Pittsburgh School of Medicine, Scaife Hall, Room 566, 3550 Terrace Street, Pittsburgh, PA 15261, USA

The major mission of the systemic immune system is to recognize foreign molecules (or antigens) and direct a concerted attack against them. The mucosal immune system, however, is in constant proximity to the harsh external environment of intestinal luminal contents. Within this complex external milieu of food particles and enteric microbes, the mucosal immune system must perform the daunting task of discriminating between those antigens that are potentially harmful from those that are not. In a healthy mucosal immune system, proinﬂammatory and anti-inﬂammatory events coexist in a delicate balance with the overall tone being one of suppression (ie, inhibition of inﬂammatory responses). The appropriate response of the mucosal immune system against an invading enteric pathogen is inﬂammation. The production of inﬂammatory cytokines and the recruitment of inﬂammatory cells are necessary to eradicate a pathogenic microorganism. After it has served its purpose, the mucosal inﬂammatory response is rapidly down-regulated in a process known as ‘‘controlled inﬂammation.’’ In patients with inﬂammatory bowel disease (IBD) the initiation of an inﬂammatory response (eg, against an enteric pathogen) may be appropriate, but this response is not down-regulated, and chronic, uncontrolled intestinal inﬂammation ensues. In individuals who are genetically susceptible to IBD, the mucosal immune response to environmental stimuli that are usually innocuous causes an excessive inﬂammatory (T helper-1 [Th1]) response or, conversely, a lack of an appropriate anti-inﬂammatory T regulatory response [1]. These inﬂammatory and anti-inﬂammatory pathways are explored as speciﬁc targets for biologic therapies in IBD that can favorably alter this tenuous balance in the intestinal immune system.

* Corresponding author. E-mail address: [email protected] (S. Plevy). 0889-8553/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.gtc.2004.02.007

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Biologic therapies are designed to block, rapidly and completely, mucosal inﬂammatory pathways that have been uncovered within the past decade. Studying mouse models of IBD and using murine analogues of human compounds to alter inﬂammatory pathways formed the theoretic framework for these advances. Many of the inﬂammatory changes observed in experimental models can also be observed in patients with Crohn’s disease (CD) and ulcerative colitis (UC). It remains uncertain to what extent eﬃcacy and toxicity reported in mice reﬂect the human condition, highlighting the importance and need for further human studies [2].

Categories of biologics The biologic therapies being investigated for the treatment of IBD are predominantly proteins. Therapeutic proteins under study include recombinant human proteins, such as cytokines and growth factors, and monoclonal antibodies. Monoclonal antibodies are classiﬁed based on their target molecule of inhibition (ie, anti–tumor necrosis factor [TNF] or anti– interleukin [IL]-12 antibodies) and the murine content that comprises the antibody structure. The premise of monoclonal antibody technology is to create a single clone of antibody-producing cells (plasma cell) in a mouse that can bind a human protein with high speciﬁcity and avidity. The original biologic products were fully murine antibodies used to prevent allograft rejection in organ transplant recipients (anti-CD3; OKT3). Although eﬀective, it was apparent and predicted that the human immune system would generate a strong immune response to this fully murine protein, creating signiﬁcant diﬃculties with immune-mediated infusion reactions, particularly with repeated use in an individual patient. To circumvent this diﬃculty, newer generations of monoclonal antibodies have used genetic engineering technology to reduce signiﬁcantly the mouse component of the antibody structure (Fig. 1). Chimeric antibodies contain murine components in the antigen binding variable region of the antibody. The constant region is fully human; thus, these antibodies are 75% human in structure. Inﬂiximab is a prototype chimeric antibody used in immune-mediated inﬂammatory disorders. As a Food and Drug Administration–approved therapy for CD, important issues relating to the use of inﬂiximab have been extensively reviewed elsewhere. Humanized monoclonal antibodies contain murine components within the speciﬁc sequences in the variable regions required for direct binding to its cognate antigen (complimentary determining regions). A humanized antibody is, in essence, 95% human protein. A prototype anti-TNF humanized monoclonal antibody, CDP571, has been studied in CD. Finally, fully human monoclonal antibodies against human proteins can now be generated in transgenic mice [3]. Recently, a fully human anti-TNF monoclonal antibody, adalimumab, was FDA approved for use in rheumatoid arthritis [4]. Studies are ongoing in CD.

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Chimerized: Infliximab

Humanized: CDP571

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Human: Adalimumab

Mouse Human Fig. 1. Comparison of chimerized, humanized, and human antibodies. Chimeric antibodies, such as inﬂiximab, are 75% human in structure. Humanized antibodies, such as CDP571, are 95% human protein. Adalimumab is a fully human antibody.

In addition to monoclonal antibody technology, another molecular approach to neutralize an inﬂammatory protein is through the creation of a receptor fusion protein. With this strategy, the actual cell surface receptor that binds to a protein, such as TNF, is fused to the constant region of an immunoglobulin molecule (eg, the TNF-receptor fusion protein, etanercept). Nucleic acids in the form of antisense oligonucleotides that inhibit protein translation in the cell have also been used. Novel cell-based therapies are also reviewed (Box 1). Because tissue damage in IBD is largely mediated by proinﬂammatory cytokines, it is not surprising that most biologics target these proteins. This article initially reviews the status of therapeutics targeting proinﬂammatory cytokines, such as TNF, IL-12, and interferon (IFN)-c. Subsequently discussed are biologics related to anti-inﬂammatory cytokines, adhesion molecules, T-cell membrane receptors, signal transduction pathways, transcription factors, and hematopoietic growth factors (see Box 1). Tumor necrosis factor inhibitors Considerable attention has been focused on TNF as a therapeutic target in IBD. TNF plays a central role in the innate immune system’s response against viral and bacterial infections. TNF is an early, pivotal mediator of inﬂammation. Speciﬁcally, TNF is a potent proinﬂammatory molecule leading to activation of the ‘‘master switch’’ inﬂammatory transcription factor, nuclear factor-jB, which leads to production of other proinﬂammatory cytokines; recruitment of inﬂammatory cells by up-regulation of adhesion molecules (cell traﬃcking); and apoptosis of target cells through ligation of the TNF receptor [5]. Furthermore, there is increased TNF expression in the mucosa of patients with CD [6]. Monoclonal antibodies to

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Box 1. Biologics investigated in IBD 1. Proinflammatory cytokine inhibitors TNF Anti-TNF monoclonal antibodies: infliximab, CDP571, CDP870, adalimumab Soluble TNF receptors: etanercept, onercept Anti–IL-12 monoclonal antibody Anti–interferon-c monoclonal antibody: HuZAF 2. Anti-inflammatory cytokine mediators IL-10 Recombinant IL-10: rHuIL-10 Ex vivo IL-10 gene transfer to vectors 3. Adhesion molecule inhibitors Anti-a4 integrin monoclonal antibody: natalizumab Anti-a4b7 integrin monoclonal antibody: LDP-02 Antisense oligonucleotide to intercellular adhesion molecule-1: Isis 2302 4. T-cell inhibitors Cyclosporine A Anti-CD3 monoclonal antibody: visilizumab Anti-CD25 monoclonal antibodies: daclizumab, basiliximab 5. Cell-based therapies Extracorporeal photoimmunotherapy Adsorption apheresis Autologous stem cell bone marrow transplantation 6. Signal transduction inhibitors P38 mitogen-activated protein kinase inhibitor: CNI-1493 7. Transcription factor inhibitors Antisense oligonucleotide to P65 nuclear factor-jB 8. Hematopoietic growth factors Granulocyte-macrophage colony–stimulating factor: sargamostim Granulocyte colony–stimulating factor: filgrastin

TNF (inﬂiximab, CDP571, CDP870, adalimumab) and recombinant TNFreceptor fusion proteins (etanercept, onercept) are being investigated. Inﬂiximab Inﬂiximab (Remicade) is a chimeric IgG1 monoclonal antibody. Inﬂiximab binds with high aﬃnity to soluble and transmembrane TNF. Because inﬂiximab is an IgG1 protein, binding to soluble TNF inhibits its

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interaction with cellular receptors, whereas binding to cell surface TNF induces lysis of TNF-producing cells by antibody-dependent cytotoxicity, complement ﬁxation, or apoptosis. Clinical trials with inﬂiximab demonstrated its powerful eﬀect on reversal of rheumatoid arthritis–induced disability and cessation of progression of erosive joint disease determined by radiographic criteria [7]. Results in CD trials have demonstrated comparable efﬁcacy [8], and have been reviewed in detail elsewhere. As expected from a murine-human chimeric antibody, inﬂiximab is immunogenic. A recent study evaluated the incidence and clinical signiﬁcance of antibodies to inﬂiximab in a cohort of 125 consecutive patients who were treated episodically with inﬂiximab infusions [9]. Antibodies to inﬂiximab were detected in a much higher percentage of patients (61%) than previous studies [7,8], but a different assay system was used. The presence of high concentrations of antibodies to inﬂiximab (8 lg/mL) before an infusion predicted a shorter duration of response (35 versus 71 days among patients with lower concentrations) and a higher risk of infusion reactions [9]. Studies in rheumatoid arthritis and in CD indicate two effective strategies to prevent antibody formation: concomitant immunosuppressive therapy with azathioprine, 6-mercaptopurine, or methotrexate; and use of inﬂiximab in maintenance rather than an episodic manner [7–10]. The clinical consequences of immunogenicity have in part prompted the search for biologics that are less immunogenic over the long term. Antibody formation has been reported against both humanized and fully human monoclonal antibodies [4]. Whether the incidence and clinical signiﬁcance of immunogenicity are similar with newer-generation antibodies compared with chimeric antibodies remain to be determined. Similarly, whether humanized or human antibodies require concomitant immunomodulator therapy and regular administration to optimize efﬁcacy are important unresolved issues. Other clinically important toxicities of biologic therapies that neutralize TNF are considered ‘‘class eﬀects,’’ that is they are not unique to one compound, but rather are a direct consequence of TNF inhibition. TNF blockade is immunosuppressive. Infections occur more frequently in patients treated with inﬂiximab compared with placebo [11]. Serious but rare infections reported include sepsis; reactivation of tuberculosis [12]; and opportunistic infections, such as histoplasmosis, listeriosis, and aspergillosis [13]. Other rare but reported class effects include autoimmunity (lupus-like reactions) [14]; exacerbation of congestive heart failure; exacerbation of demyelinating disorders; and a possible increase in the incidence of lymphomas [10,15].

Soluble tumor necrosis factor–receptor fusion proteins Another strategy for blocking TNF is based on the use of soluble TNF receptors. There are two distinct cell-membrane TNF receptors: p55 and p75.

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The ﬁrst soluble TNF receptor used was etanercept (Enbrel). Etanercept is a genetically engineered, fully human, dimeric fusion protein consisting of two chains of the extracellular, ligand-binding portion of the human p75 TNF receptor fused with the Fc portion of a human IgG1 molecule. Etanercept has a half-life of approximately 5 days, and is administered subcutaneously twice weekly. Experience with etanercept in CD has been disappointing, despite the fact that it is a highly eﬀective FDA-approved therapy in rheumatoid arthritis [16]. A small pilot study suggested efﬁcacy in CD [17]; however, a randomized, placebo-controlled trial in 43 patients showed at week 4 that 39% of etanercept-treated patients had clinical response as compared with 45% of placebo-treated patients [18]. There are many possible explanations for these negative results. Higher doses, shorter intervals of administration, or more sustained follow-up periods (the studies had only an 8-week follow-up) may be required to detect responses in patients with CD. There also may be diﬀerent mechanisms of action between inﬂiximab and etanercept. This concept is discussed in more detail. Onercept is a genetically engineered recombinant human TNF-receptor p55 monomer [19]. A small open label study suggests efﬁcacy in CD [20], and a large placebo-controlled study is underway to assess onercept deﬁnitively in induction of remission. CDP571 Another antibody against TNF, CDP571, has been studied in patients with CD. CDP571 is an IgG4 humanized monoclonal antibody. Four placebo-controlled studies with CDP571 have been reported in CD [21–24]. Although initial studies suggested clinical responses and steroid-sparing effects, signiﬁcant differences in remission and maintenance of remission compared with placebo were not seen. In the largest study, 396 patients with active CD were randomized to receive intravenous CDP571, 10 mg/kg, or placebo at weeks 0, 8, 16, and 24 [22]. The number of patients treated with CDP571 that achieved clinical response was higher than placebo at weeks 2 and 4, but not at week 28, which was the primary end point of the study. Subgroup analysis suggested efﬁcacy of CDP571 treatment in patients with elevated baseline C-reactive protein ([10 mg/dL). Anti-idiotype antibodies against the humanized antibody were detected in 5.3% of the patients receiving CDP571 [22,24], illustrating the concept that immunogenicity is not completely eliminated with newer-generation monoclonal antibodies. CDP870 CDP870 is a genetically engineered anti-TNF antibody FabÕ fragment conjugated to polyethylene glycol. Polyethylene glycolation of an anti-TNF antibody theoretically serves two purposes. First, it extends serum and tissue half-life compared with unpolyethylene glycolated antibodies. Second, the

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large polyethylene glycol molecule may function to reduce immunogenicity of this compound. CDP870 was eﬃcacious in a phase II double-blinded, randomized trial of 4 weeks in rheumatoid arthritis [25]. Two phase II trials for active CD have been completed, but the results have not yet been reported. Adalimumab (D2E7) A fully human, TNF-neutralizing IgG1 antibody, designated D2E7 or adalimumab (Humira), is currently being studied in CD. Adalimumab was recently approved by the FDA for the treatment of rheumatoid arthritis, and is currently administered subcutaneously every other week when given with methotrexate, or weekly when used alone. A 24-week trial of adalimumab at doses of 20 to 80 mg subcutaneously every other week was compared with placebo in patients with rheumatoid arthritis treated with methotrexate [4]. This study demonstrated that any dose used provided signiﬁcant rapid and sustained improvement in disease activity over 24 weeks compared with methotrexate plus placebo. Open-label experience with adalimumab at several IBD centers has suggested safety in CD patients who have had signiﬁcant infusion reactions with inﬂiximab (University of Pittsburgh and others, unpublished data). At present, a phase II trial has completed enrollment, and phase III studies are under way to determine the efﬁcacy of adalimumab for induction and maintenance of remission in active CD.

Why all tumor necrosis factor inhibitors may not be the same: an immunologic perspective Structural diﬀerences between inﬂiximab and other TNF inhibitors may be related to diﬀerences in eﬃcacy reported in studies to date. For example, CDP571 and etanercept do not ﬁx complement or cause antibody-dependent cytotoxicity of TNF-producing cells. This is in contrast to inﬂiximab, an IgG1 antibody that ﬁxes complement and can result in antibody-dependent cytotoxicity. Furthermore, inﬂiximab treatment causes apoptosis of lamina propria lymphocytes, most likely by binding of the antibody to the transmembrane TNF and activation of caspase-3–dependent apoptosis [2]. This property may not be translatable to etanercept and CDP571, which may neutralize only TNF molecules ﬂoating in the soluble phase, and would not induce cell death of activated lymphocytes. Diﬀerent immunologic mechanisms, however, may not be the only explanation of diﬀerent eﬃcacy results between TNF inhibitors. Interestingly, C-reactive protein, long dismissed by clinicians as a nonspeciﬁc marker of inﬂammation, has become an important biomarker for response to anti– TNF-based therapies, if not all biologic agents in CD. C-reactive protein, an acute-phase reactant, is made predominantly by the liver and is induced by the cytokines IL-6 and TNF. C-reactive protein has been demonstrated to drop precipitously following therapy with anti-TNF antibodies, and this

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drop has correlated with clinical improvement [26,27]. Although studies with CDP571 suggest that it may not be as efﬁcacious as inﬂiximab, particularly over the long term, it seemed to work very well in the patient population with elevated baseline C-reactive protein. In the negative study of etanercept in CD, responses have not been stratiﬁed by baseline C-reactive protein. Because placebo responses have been dramatically higher in studies performed after the initial inﬂiximab trials, the elevated C-reactive protein patient population may be the most relevant comparator. The placebo response is much lower in this patient population, and they seem to derive beneﬁt from most anti-TNF agents. Although there may be mechanistic differences between anti-TNF agents that explain differences in efﬁcacy, another possibility is that different patient populations were evaluated in each of these studies. As a general rule, TNF inhibition seems to be an effective therapy in patients with elevated baseline C-reactive protein. Whether differences in efﬁcacy between anti-TNF agents can be demonstrated in patients who do not have elevated baseline C-reactive protein is an interesting question for future study. Given the clear trend toward increasing placebo responses in clinical trials of patients with moderate to severe CD, stratiﬁcation based on C-reactive protein will become standard.

Tumor necrosis factor inhibition in ulcerative colitis Although much attention has been devoted to TNF inhibition in CD, there is a recent interest in investigating anti-TNF therapies in UC. Studies with inﬂiximab have been mixed. Although dramatic improvements have been described in open-label experience from several groups [28,29], placebo-controlled studies and further open-label experience suggest that inﬂiximab may not be effective in steroid-resistant UC [30–32]. Two large pivotal phase III studies (ACT 1 and ACT 2) are ongoing.

Other cytokine inhibitors Although TNF plays a central role in the inﬂammatory process, there are many other cytokines that are important regulators of chronic inﬂammation and are viable candidates for therapeutic intervention in IBD. Biologic agents that inhibit Th1 polarization or enhance T regulatory responses include monoclonal antibodies to IL-12 and IFN-c, and recombinant human IL-10. An oversimpliﬁed but clinically useful model of immunologic pathways in IBD is the description of inﬂammatory and regulatory T cells. An inﬂammatory T-cell population that has been best characterized in mouse models of IBD and human CD is the Th1 cell. Th1 cells make the cytokine IFN-c. IFN-c has numerous biologic eﬀects including the up-regulation of inﬂammatory molecules in macrophages, dendritic cells, and intestinal

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epithelial cells [33]. The cytokines IL-12 and IL-18, when released by macrophages and dendritic cells, are strong inducers of inﬂammatory Th1 cells. Recently a cytokine, IL-23, produced by macrophages and dendritic cells has been demonstrated to play a central role in chronic inﬂammatory diseases in mice [33]. IL-23 shares a p40 subunit with IL-12. Antibody therapy directed at the p40 subunit in mice and humans may neutralize both IL-12 and IL-23, and may be particularly therapeutically relevant in IBD. Conversely, recent research has characterized a T-cell population that inhibits inﬂammation, the T regulatory cell. T regulatory cells produce the anti-inﬂammatory proteins IL-10 and transforming growth factor-b. IL-10 in particular has attracted much attention as a potential therapeutic modality in IBD. Interleukin-12 and interleukin-18 Studies in animal models of IBD have shown that neutralization of IL-12 using a monoclonal antibody has therapeutic eﬀects on intestinal inﬂammation [34]. IL-18 shares biologic activities with IL-12 in driving the development of Th1 cells by inducing IFN-c. In animal model studies, antibodies to IL-18 were effective in reducing trinitrobenzene sulfonic acid– induced colitis [35]. A dose-ﬁnding trial using a human anti–IL-12 antibody in patients with active CD has been completed, although results are not yet reported. Interferon-c Production of IFN-c is a hallmark of Th1 cells and is increased in CD. Despite the increased production by lamina propria lymphocytes, the role and importance of IFN-c in the pathogenesis of CD has been questioned by studies showing that IFN-c or IFN-c-receptor–deﬁcient mice are not protected from Th1-mediated colitis [36]. Two small pilot studies using low-dose recombinant IFN-c in patients with CD did not result in disease exacerbation, as might be expected in theory [37,38]. A genetically engineered IgG1 humanized monoclonal antibody against IFN-c (HuZAF) is under investigation . A phase II European study of 45 individuals with moderate to severe CD did not show any difference in the response rate between the HuZAF and the placebo group. Unusually high responses were noticed in the placebo group, reaching 60% [39]. A larger phase II study is ongoing to determine the activity of HuZAF in CD. Anti-inﬂammatory cytokines: interleukin-10 Interleukin-10 is a T regulatory cytokine that inhibits antigen presentation and subsequent release of proinﬂammatory cytokines, such as IL-12 and IFN-c. The pivotal role played by IL-10 within the mucosal immune system is demonstrated by the chronic enterocolitis that develops in

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gene-targeted IL-10–deﬁcient mice, and by its therapeutic eﬃcacy in several animal models of colitis [40]. Trials of systemic IL-10 administration in CD patients have not resulted in a consistent therapeutic beneﬁt, however, and initial promising results [41] were not conﬁrmed in subsequent large phase III trials [42,43]. Furthermore, there was no evidence of prevention of endoscopic recurrence of CD in patients who received recombinant human IL-10 treatment for 12 consecutive weeks after intestinal resection [44]. Finally, a phase II trial of recombinant human IL-10 in 94 patients with UC failed to show any beneﬁcial effect [45]. These results could be explained by limited bioavailability, IL-10 resistance, and unexpected proinﬂammatory eﬀects. High doses of IL-10 may up-regulate inﬂammatory pathways, including the production of IFN-c [46]. Furthermore, lamina propria cells from CD patients have been shown to be resistant to the effects of IL-10 [47]. The analysis of functional genetic polymorphisms in the interleukin-10 gene may allow therapy to be targeted to patients who will respond [48]. Recent animal studies have shown that genetically engineered lactococcus bacteria secreting IL-10, transduced peripheral blood CD4+ lymphocytes with IL-10, and adenoviral vectors encoding IL-10 may ameliorate IBD. Local and cell-based IL-10 therapy may provide a novel approach to delivery of immunomodulatory signals to the intestine in patients with CD or UC [49–51].

Adhesion molecule inhibitors The recruitment of leukocytes from the blood into tissue is regulated by sequential engagement of adhesion molecules on leukocytes with signaling molecules on endothelial cells [52,53]. The integrins are a family of cell-surface glycoproteins that act as adhesion molecules. The a4 integrins are heterodimeric cell-surface proteins consisting of a a4 subunit and either a b1 or b7 subunit. a4b1 Integrin binds to vascular cell adhesion molecule-1, which is up-regulated on the vascular endothelium at sites of chronic inﬂammation, including the intestine. The a4b7 dimer interacts with mucosal addressin cell adhesion molecule-1 and mediates homing of lymphocytes speciﬁcally to the gut. Natalizumab Natalizumab is a recombinant, humanized IgG4 monoclonal antibody against a4 integrin. It binds with high afﬁnity to a4 chain irrespective of its associated b chain. Natalizumab’s proposed mechanism of action is by blocking the ability of a4b1 and a4b7 to bind to their respective endothelial counter-receptors, vascular cell adhesion molecule-1 and mucosal addressin cell adhesion molecule-1. Three placebo-controlled trials of natalizumab have been conducted in patients with CD [54,55]. Interestingly, although these studies failed to

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demonstrate statistically signiﬁcant differences between natalizumab and placebo at the primary end point (which differed between studies), efﬁcacy (based on secondary end points and trends) was suggested overall. Furthermore, a placebo-controlled trial showed that treatment with natalizumab led to fewer inﬂammatory brain lesions and fewer relapses over a 6-month period in patients with relapsing multiple sclerosis [56]. This observation supports the notion ﬁrst demonstrated with anti-TNF therapy that clinically diverse diseases designated ‘‘immune-mediated inﬂammatory disorders’’ share striking immunologic commonalities and many of them can be treated successfully with the same biologic compounds targeting speciﬁc immunologic pathways. Whether efﬁcacy of natalizumab can be demonstrated in the maintenance arm of a recently completed study in CD will provide critical information to guide future development. LDP-02 LDP-02 is a recombinant IgG1 humanized antibody speciﬁcally against a4b7 integrin. Large, placebo-controlled trials have recently been reported in both CD and UC patients [57–59]. Efﬁcacy in induction of remission of LDP-02 at two doses compared with placebo was demonstrated in a study of UC patients [58]. Although a study in CD did not demonstrate differences in response or remission rates compared with placebo, incomplete saturation of a4b7 binding suggests that LDP-02 may have been underdosed in this study [59]. Antisense oligonucleotide to intercellular adhesion molecule-1 (Isis 2302) Intercellular adhesion molecule-1 is a transmembrane glycoprotein that plays an important role in the traﬃcking and activation of lymphocytes. Intercellular adhesion molecule-1 is up-regulated in the inﬂamed mucosa of CD. Isis 2302 (alicaforsen) is a 20-base antisense phosphorothioate oligodeoxynucleotide that inhibits intercellular adhesion molecule-1 expression. Isis 2302 hybridizes to the 39 region of the intercellular adhesion molecule-1 mRNA. The oligonucleotide-RNA heterodimer formed serves as a substrate for the nuclease RNase-H with subsequent reduction in intercellular adhesion molecule-1 expression. A positive small placebo-controlled pilot study [60] led to two negative large placebo-controlled studies of subcutaneous [61] and intravenous [62] Isis 2302 in CD. In the largest trial of 299 patients, pharmacokinetic studies showed that a small subgroup of nine patients who achieved high serum concentrations of Isis 2302 had a statistically signiﬁcant increase rate of remission compared with the placebo group [62]. All patients in the study using subcutaneous Isis 2302 may have been signiﬁcantly underdosed. An additional randomized placebo-controlled study in active CD, in which high serum concentrations of Isis 2302 are ensured, is under way.

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T-cell surface membrane protein inhibitors Antibodies that bind to certain T-cell surface molecules have demonstrated profound immunomodulatory eﬀects, such as the anti-CD3 antibody OKT3 that is widely used in organ transplant rejection. Monoclonal antibodies targeting the membrane receptors CD3 and CD25 are being investigated in IBD. Cyclosporine A has been used successfully in IBD, particularly in severe, steroid-resistant UC for over a decade [63]. Cyclosporine A mechanistically acts by inhibiting T-cell activation and inﬂammatory cytokine production through inhibition of the transcription factor NFAT (nuclear factor of activated T cells). Cyclosporine A use in IBD patients has been associated with numerous adverse events, however, including nephrotoxicity, opportunistic infection, and death. The rationale behind development of T-cell–based inhibitory therapies of IBD is to recapitulate the short-term efﬁcacy of cyclosporine A while minimizing toxicity. This can potentially be achieved if a therapy directly can inhibit inﬂammatory T cells, or activate regulatory T cells while minimizing the duration and magnitude of immunosuppression. Not all efforts will be successful. Studies using an antibody to the T-cell surface protein CD4 in CD resulted in profound T-cell depletion and immunosuppression [64–66]. Anti-CD3 antibodies A humanized anti-CD3 monoclonal antibody, visilizumab, binds to the T-cell receptor associated molecule CD3. CD3 is expressed on all T cells, but visilizumab is postulated to cause apoptosis of activated, but not resting T cells. Preliminary results from a phase I dose-escalation study of visilizumab by intravenous infusion on two consecutive days in patients with severe, steroid-resistant UC have suggested tolerability, clinical activity, and durable responses [67]. Peripheral T-cell depletion was observed, but resolved in weeks. Further dose-ﬁnding studies are ongoing. Anti–interleukin-2 receptor (CD25) antibodies Interleukin-2 is a proinﬂammatory cytokine secreted by Th1 lymphocytes. IL-2 is a requisite T-cell growth factor and is necessary for proliferation of activated T cells. Recently, a humanized monoclonal antibody that neutralizes the binding capacity of the IL-2 receptor (CD25) on antigen-exposed T lymphocytes (CD25+ cells), daclizumab, has been developed. An open-label pilot study in 10 patients with chronic active UC who received intravenous daclizumab showed clinical beneﬁt along with endoscopic improvement [68]. A recent open-label, pilot trial evaluated the efﬁcacy of a chimeric monoclonal anti–IL-2R antibody, basiliximab, as a steroid-sensitizing agent in steroid-resistant UC [69]. Fifteen patients received basiliximab intravenously in addition to their standard steroid treatment and 80% achieved clinical remission within 6 weeks. Interestingly,

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IL-2 exposure of T cells in culture has been shown to induce steroid resistance. In this study, basiliximab was shown to render steroid-resistant T cells from treated CD patients steroid-sensitive. Large placebo-controlled trials of daclizumab and basiliximab in UC are ongoing.

Cell-based therapies Extracorporeal photoimmunotherapy is an apheresis-based procedure comprising ex vivo exposure of autologous peripheral white blood cells to 8-methoxypsoralen and ultraviolet A light, inducing white blood cell apoptosis. These autologous apoptotic cells are then reinfused to the donor as part of the pheresis process. This treatment has been an FDA-approved therapy for cutaneous T-cell lymphoma for over a decade and is extremely well tolerated. Although immunologic mechanisms of how this procedure may modulate inﬂammation remain to be determined, the uptake of autologous apoptotic cells by macrophages and dendritic cells may inactivate inﬂammatory responses [70]. A prospective pilot study evaluated the safety and efﬁcacy of extracorporeal photoimmunotherapy in 10 steroid-dependent CD patients with promising results [71]. The mildly invasive procedure was well-tolerated, albeit time consuming. Further phase I testing is ongoing. Additionally, studies of selective adsorption apheresis of granulocytes and monocytes-macrophages from peripheral blood of patients with active UC resulted in suppression of proinﬂammatory cytokine production, suppression of neutrophil chemotaxis, and down-regulation of leukocyte adhesion molecules [72]. Clinical responses have been suggested. The most dramatic example of a cell-based therapy in CD is the recent reports of improvement in refractory disease following autologous stem cell bone marrow transplantation [73–75]. Future research will look to expand and modify autologous cells to augment anti-inﬂammatory responses (ie, the generation of autologous IL-10 producing T regulatory cells) for readministration to donor patients with IBD [76].

Signal transduction pathway inhibitors The mitogen-activated protein kinase family of signal transduction proteins is an important intracellular mediator of inﬂammation. When antigen-presenting cells (macrophages and dendritic cells) and intestinal epithelial cells encounter bacteria or bacterial products in the intestine, mitogen-activated protein kinase pathways are rapidly activated. Activation of mitogen-activated protein kinase results in the expression of multiple inﬂammatory genes, including TNF, IL-12, IL-6, and IL-8. Mitogenactivated protein kinase activation is also an important downstream event in inﬂammatory T-cell activation. The theoretic advantage of mitogenactivated protein kinase inhibition is the ability to inhibit multiple mediators

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of inﬂammation rather than a single cytokine target. Intense eﬀorts are under way to develop compounds that selectively target components of mitogen-activated protein kinase pathways. A recent pilot study evaluated CNI-1493, a guanyl-hydrazone that inhibits p38 mitogen-activated protein kinase activation. Intravenous administration of CNI-1493 demonstrated promising results in 12 patients with severe CD [77].

Transcription factor inhibitors Transcription factors are downstream targets of signal transduction pathways, such as the mitogen-activated protein kinases, that bind to genomic DNA in the promoters of inﬂammatory genes and regulate their activation. Similar to mitogen-activated protein kinases, speciﬁc transcription factors regulate expression of multiple inﬂammatory mediators. Perhaps the best characterized family of transcription factors in the inﬂammatory response is nuclear factor-jB, which is considered to be a master switch for inﬂammatory gene expression. Nuclear factor-jB has been implicated in the transcriptional control of promoters of proinﬂammatory cytokines, such as IL-2, TNF-a, and IL-12; co-stimulatory cellsurface receptors; and adhesion molecules, such as intercellular adhesion molecule-1 [78]. Selective nuclear factor-jB inhibition is an attractive therapeutic target in IBD and has been demonstrated to be an effective intervention in mouse models [79]. Recently, an antisense oligonucleotide to the p65 subunit of nuclear factor-jB was used in a clinical trial [80] in ﬁve patients with UC and six patients with CD who were randomized to receive a single rectal installation of the p65 nuclear factor-jB antisense oligonucleotide versus placebo. An overall improvement in clinical symptoms and endoscopic and histologic scores was seen in ﬁve of seven treated patients versus one of four in the placebo group at day 7. The transcription factor T-bet has a key regulatory role in the pathogenesis of Th1-mediated colitis [81]. Speciﬁc targeting of T-bet pathway may be a promising novel approach for the treatment of CD patients and other autoimmune diseases mediated by Th1 cells.

Hematopoietic growth factors Most IBD therapeutic strategies have tried to suppress an overactive immune response, and most therapeutic approaches have focused on the adaptive (T cell) immune system. The evolutionarily conserved innate immune system has developed to defend the host against microbial invaders. Cells of the innate immune system include neutrophils and macrophages. The observation that inherited disorders associated with defective innate immunity (ie, chronic granulomatous disease, cyclic neutropenia) are often associated with CD-like intestinal inﬂammation has led to a novel

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alternative therapeutic strategy to stimulate the innate immune system with hematopoietic growth factors, including granulocyte-macrophage colony– stimulating factor (sargamostim) and granulocyte colony–stimulating factor. The recent description of mutations in NOD2, a receptor of the innate immune system that recognizes bacterial products, as conferring susceptibility to CD strongly suggests that inﬂammation in CD is a result of an innate immunodeﬁciency. A pilot trial investigating the eﬀectiveness and safety of human granulocyte-macrophage colony–stimulating factor [82] and granulocyte colony–stimulating factor [83] in CD was promising. Recently, results from a multicenter phase II placebo-controlled trial demonstrated that granulocyte-macrophage colony–stimulating factor administered daily by the subcutaneous route is more effective than placebo in induction of remission in active CD.

Summary Based on the limited therapeutic beneﬁt of the conventional therapeutic agents and the success of inﬂiximab, the era of biologics as the cornerstone of IBD treatment has begun. Although mouse models of IBD have been useful to identify appropriate candidates, it is only through further trials in human disease that these targets can be validated. It is incumbent on clinicians to have a basic understanding of immunologic mechanisms and follow the clinical evidence on biologic therapies as it emerges.

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Left-sided ulcerative colitis Douglas B. Haghighi, MD*, Bret A. Lashner, MD Department of Gastroenterology and Hepatology, Cleveland Clinic Foundation, 9500 Euclid Avenue, A30, Cleveland, OH 44195, USA

Left-sided ulcerative colitis is not a distinct entity, but a less extensive form of pancolitis. The epidemiologic and genetic characteristics are thought to be analogous. The rate of colorectal cancer, however, seems to be proportional to the extent of disease. Primary treatment for left-sided disease is topical 5-aminosalicyclic acid (5ASA) agents. In patients who do not respond to topical therapy, oral 5ASA agents of diﬀering delivery methods to the distal bowel can be used. There is much debate pertaining to the clinical superiority of the oral 5ASA agents.

Incidence and prevalence The incidence and prevalence of left-sided disease in ulcerative colitis is diﬃcult to quantify because no epidemiologic studies have been conducted that consider that particular subset of the disease. The current data pertain only to the overall incidence and prevalence of the disease. The highest incidence of ulcerative colitis is seen in the northern hemisphere, notably the United States, Canada, Scandinavia, Israel, and Northern Europe. Depending on the demographic area studied the annual incidence of ulcerative colitis ranges from 0.5 to 6.3 per 100,000 [1,2]. The prevalence of ulcerative colitis ranges between 10 and 70 per 100,000 but was noted to be as high as 169 per 100,000 in an Israeli study [3]. Studies in the United Kingdom and the United States have demonstrated that the disease does not predilect to a particular gender with a male to female ratio approximating 1. Whites, however, are at an increase risk of developing ulcerative colitis versus nonwhites [4]. Interestingly, a study from the United Kingdom reported that ﬁrst-generation Asian migrants developed ulcerative colitis at the same rate as native Europeans within one generation, which points to an

* Corresponding author. E-mail address: [email protected] (D.B. Haghighi). 0889-8553/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.gtc.2004.02.008

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environmental exposure as a possible factor in developing the disease [5]. Additional evidence for an environmental cause for ulcerative colitis, especially from an exposure at a young age, is the extreme variability in mortality among birth cohorts [6].

Genetic susceptibility It is not known if patients with left-sided ulcerative colitis have any diﬀerent genetic predisposition from those with more extensive disease. Several studies, however, have evaluated the overall genetic susceptibility of ulcerative colitis in certain ethnic groups. In Israel, Ashkenazi Jews, who are of eastern European descent, have nearly a six time higher risk of developing the disease versus Sephardic Jews, who have Spanish, African, and Middle Eastern backgrounds, despite analogous environmental exposures. Moreover, as many any as 20% of ulcerative colitis patients have a ﬁrst- or second-degree relative aﬄicted with the disease. The relative risk for a ﬁrstdegree relative of an ulcerative colitis patient to develop the disease is 5.1 [7]. The patients who manifest the human leukocyte antigen-B27 antigen are more likely to develop ankylosing spondylitis and uveitis [1]. The perinuclear antineutrophil cytoplasmic antibodies have also been associated with ulcerative colitis. One study noted 75% manifest the perinuclear antineutrophil cytoplasmic antibodies [8]. Jewish patients with the disease have a high rate between being perinuclear antineutrophil cytoplasmic antibody–positive and developing primary sclerosing cholangitis. Also, a positive test for perinuclear antineutrophil cytoplasmic antibodies allows for the diﬀerentiation between ulcerative colitis and Crohn’s disease and aids in the diagnosis of indeterminate colitis. Perinuclear antineutrophil cytoplasmic antibodies were observed in 100% of patients with chronic pouchitis, 50% of patients with a pouch but no pouchitis, and 70% of patients with ulcerative colitis who underwent a colectomy with ileostomy [9]. Several studies have alluded to a speciﬁc mutation that represents linkages to ulcerative colitis. The chromosomes involved include 1, 3, 4, 6, 7, 10, 12, 16, and 22 [10,11].

Environmental factors Current smokers are not as likely to develop ulcerative colitis as community-based nonsmoking controls. Moreover, former smokers are more likely to develop the disease when compared with controls [12,13]. Former smokers, when compared with nonsmokers, are diagnosed at a younger age and have a greater degree of active disease at the time of diagnosis [14]. This information is complicated by the fact that passive smoking exposure in nonsmoking children increases risk of the development of ulcerative colitis when compared with community-based controls [15]. Nicotine, in the form

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of a transdermal patch or as chewing gum, has successfully treated ulcerative colitis, especially in former smokers, by a mechanism that has yet to be elucidated [16,17]. Nicotine addiction may occur if therapy lasts longer than 8 weeks and maintenance therapy with nicotine patches is not eﬀective [18]. There are several other potential studied risk factors for ulcerative colitis. Three cohort studies have demonstrated deleterious eﬀects of oral contraceptive use on the development of ulcerative colitis, but these ﬁndings could not be supported by case-control studies of incident cases and community-based controls [19]. A case-control study noted that a high intake of monounsaturated and polyunsaturated fat, and vitamin B6 has been shown to be associated with the development of ulcerative colitis [20]. Finally, a meta-analysis of 13 case control studies involving 2270 ulcerative colitis patients demonstrated that appendectomy reduced the risk of developing the disease by 69% [21]. The reason for this is unclear. There are no data that speciﬁcally evaluate if left-sided disease is modiﬁed with any of these risk factors. Clinical features The typical presentation of an ulcerative colitis patient includes rectal bleeding, diarrhea, tenesmus, and abdominal pain. Criteria developed by Truelove and Witt [22] in 1955 have been used to classify the severity of the disease as mild, moderate, or severe. Patients with mild disease have four or fewer bowel movements per day; small amounts of blood in their stool; a normal sedimentation rate; and no fever, tachycardia, or anemia. Those who are classiﬁed as severe have greater than six bowel movements per day; have anemia, tachycardia, and fever; and a sedimentation rate greater than 30. Patients who are considered toxic with fulminate colitis are febrile, tachycardic, commonly have greater than 10 bowel movements per day with bleeding, and have abdominal tenderness and distention. These patients also have radiologic evidence of bowel wall edema with possible dilation. Patients with left-sided disease have numerous trips to the washroom to pass small amounts of blood and mucous and have tenesmus. The subsets of patients who are considered as having a mixed clinical picture are considered to be in the moderate category. Because patients with moderate disease according to Truelove and Witt [22] have a wide variability, such a classiﬁcation is inadequate for clinical trials where objective and sensitive measures of disease activity are required. A combination of endoscopic, histologic, and symptom score usually is preferred in clinical trials. Numerous objective markers of inﬂammation including erythrocyte sedimentation rate, orosomucoid, C-reactive protein, leukocyte and platelet count, neopterin, interleukin-8, indium-labeled white blood cell scanning, and fecal a1-antitrypsin determinations have been investigated as markers of disease activity, but none is as sensitive as the history, physical examination, and colonoscopy [23].

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Establishing the diagnosis Visualization of the colonic mucosa is invaluable in establishing the diagnosis of ulcerative colitis. Colonoscopy with biopsy for histologic analysis can correctly diﬀerentiate ulcerative colitis from Crohn’s colitis and from other colonic diseases in 85% to 90% of the patients. The remaining 10% to 15% are classiﬁed as indeterminate colitis. Of note, greater than half of those patients with indeterminate colitis eventually are diagnosed with Crohn’s colitis [24]. Colonoscopy to establish the diagnosis should not be performed in patients with severe disease because of the increased risk for bowel perforation. The necessary information can be obtained by ﬂexible sigmoidoscopy in an unprepared colon and minimal air insuﬄation. Assessing the extent of disease: left-sided disease versus pancolitis Untreated ulcerative colitis usually involves the rectal mucosa and extends proximally in a continuous fashion. To determine the extent of disease adequately, it is important to perform a colonoscopy, which deﬁnes the extent of the disease. Radiology is rarely used for this reason because it underestimates the true extent of the disease, and does not allow for biopsy specimens to be obtained. Unlike Crohn’s disease, the extent of disease in ulcerative colitis is the principle variable in elucidating the prognosis. In a series of 1116 patients, 46% had endoscopic presentation of proctosigmoiditis; 17% had left-sided disease (to the splenic ﬂexure); and 37% had pancolitis at the time of presentation [25]. Patients presenting with pancolitis were more likely to develop refractory symptoms, toxic megacolon, malignancy, extraintestinal manifestations, and require surgery. On follow-up, more than half the patients with limited disease advanced to more extensive disease. Another series demonstrated that of 1736 patients with ulcerative colitis nearly 20% were diagnosed with ulcerative proctitis at presentation [26]. Also, in 27% of the patients extension of disease was noted: 16% to the sigmoid colon, 7% to the splenic ﬂexure, with extensive disease in just fewer than 5%. The estimated risk of disease extension to the sigmoid colon or to the splenic ﬂexure is 20% at 5 years and 54% at 10 years. The risk of extension beyond the splenic ﬂexure is 10% at 10 years. The risk is further increased by being a nonsmoker, having three or more relapses a year, and receiving immunosuppressants or systemic steroids. Based on this information repeated examinations may be necessary to conﬁrm that the disease has not advanced proximally, which alters prognosis. Complications Cholestatic liver disease is the most common hepatic abnormality of inﬂammatory bowel disease and is approximately three times more common

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in ulcerative colitis than in Crohn’s disease [27]. Approximately 5% of ulcerative colitis patients develop cholestasis, most commonly pericholangitis. Only 1% to 2% of ulcerative colitis patients develop primary sclerosing cholangitis, a cholestatic liver disease diagnosed by the appearance of extrahepatic and intrahepatic strictures on a cholangiogram. Primary sclerosing cholangitis usually is a consequence of pancolitis and is not seen often in leftsided disease. Pericholangitis usually does not progress to cirrhosis, but primary sclerosing cholangitis can progress and may require liver transplantation. Rarely, primary sclerosing cholangitis patients develop cholangiocarcinoma. Cholestatic liver disease in ulcerative colitis is a risk factor for colorectal cancer and dysplasia [28]. Treatment of bowel symptoms, even total proctocolectomy, does not inﬂuence the course of cholestatic liver disease. Fatty inﬁltration of the liver, chronic active hepatitis, amyloidosis, and drug liver disease (from steroids, azathioprine, 6-mercaptopurine, or sulfasalazine) are other reported hepatic manifestation of inﬂammatory bowel disease. Erythema nodosum, present in up to 3% of patients, is characterized by raised tender erythematous nodules, typically appearing on the extremities. Pyoderma gangrenosum, a rare ulcerating and necrotic lesion, is seen in both Crohn’s and ulcerative colitis and represents an extraintestinal manifestation of vasculitis. Healing is prolonged and usually requires immunosuppressive therapy with steroids, 6-mercaptopurine or azathioprine, oral antibiotics for superinfection, and steroid injections for indurated margins. Cyclosporine has been successful in cases refractory to steroids, azathioprine, or 6-mercaptopurine. Arthritis of inﬂammatory bowel disease is usually nonerosive, monoarticular or pauciarticular, and asymmetric. The large joints are most often aﬀected, and there is no synovial destruction. Arthritis more often aﬀects women, exhibits no subcutaneous nodules, and correlates with disease activity. Ocular symptoms and signs of inﬂammatory bowel disease include blurred vision, eye pain, photophobia, inﬂammatory cells in the anterior chamber, and kerititic precipitates. Patients with uveitis often have HLA-B27, whereas patients with episcleritis and iritis usually do not. Colorectal cancer Over the course of the disease, colorectal cancer is expected to occur in nearly 6% and be the cause of death in approximately 3% of ulcerative colitis patients with extensive disease. Colorectal cancer incidence and mortality rates seem to be decreasing and are approaching the rates of populations unaﬀected by inﬂammatory bowel disease [29]. The risk of colorectal cancer in ulcerative colitis patients is elevated, however, and has been estimated to be over four times what is expected among age- and sex-matched controls [30]. Most of the studies conducted to evaluate cancer in ulcerative colitis are done

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on patients with pancolitis. The risk in patients with left-sided disease seems to be lower. The colorectal cancer risk in ulcerative colitis increases with increasing extent and duration of disease, older age at symptom onset, and cholestatic liver disease [31]. High-risk patients, such as those with disease proximal to splenic ﬂexure of more than 7 years, should be enrolled in surveillance programs where colonoscopy with multiple biopsies is performed every 1 to 3 years, depending on the patient’s individual risk. The screening interval should decrease as the duration of disease increases [32]. Total proctocolectomy is often recommended if low-grade dysplasia, high-grade dysplasia, or cancer is detected [33]. Although these recommendations have not universally reduced cancer-related mortality, have not been recommended by all gastroenterologists, and are not predicted in the Markov model to improve cancer-related survival, cancer surveillance for ulcerative colitis patients has become the standard-of-care and must be oﬀered to eligible patients [31,34,35]. Surveillance should be performed in patients with leftsided disease, but because the risk is lower, it can be done less often [31]. Research is being done to understand better the biology of cancer and determine whether intermediate markers of malignancy provide a more objective, accurate, sensitive, speciﬁc, and clinically useful marker than dysplasia. Candidate markers include DNA aneuploidy detected by ﬂow cytometry and suppressor gene (particularly p53) mutations and loss of heterozygosity detected either immunohistochemically or with polymerase chain reaction techniques [36–38]. Distinguishing a dysplasia-associated lesion or mass from an adenoma or a pseudopolyp may be impossible, but is vital in determining appropriate therapy. Typically, dysplasia-associated lesions or masses are elevated and have nodular appearance of a sessile adenoma [39]. Dysplasia-associated lesions or masses are thought to carry a poor prognosis and should prompt consideration for a colectomy. Recently, this thought has been challenged, because two series of patients with dysplasia-associated lesion or mass did not have colectomy and did not develop cancer [40,41]. To be safe, polypoid lesions with dysplasia in an area never aﬀected with colitis (ie, a right-sided polyp in a patient with left-sided disease) in patients over the age of 50 years are the only lesions that should be considered adenomas and should be treated with polypectomy. Polypoid lesions with dysplasia in an area previously aﬀected with colitis or in a younger person should be considered dysplasiaassociated lesions or masses and treated with colectomy [42]. Patients with a stricture that cannot be traversed or adequately biopsied should have a colectomy as a result of the high risk of cancer or dysplasia in the stricture [43]. Management of colitis The general principles of medical therapy in ulcerative colitis, whether it be for distal disease or pancolitis, are to induce remission of the disease,

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maintain it, and prevent the number of extraintestinal manifestations of the disease, which were noted previously. Initially, a patient with ulcerative colitis should be counseled on dietary modiﬁcations and supplements to optimize nutrition status, outlined later. Medical therapy for distal disease or extensive disease should be instituted in a stepwise fashion. The spectrum of medical treatment in ulcerative colitis begins with 5ASA agents (topical or oral); then progresses to steroids (oral or intravenous); and ﬁnally to immunosuppressive therapy. The initial therapy for extensive disease is an oral 5ASA agent and if the patient does not respond topical 5ASA therapy is added. When juxtaposed to the treatment of extensive disease, initial therapy for left-sided disease is topical 5ASA and if the patient does not respond, an oral 5ASA agent is used to supplement therapy. Therapy for patients with mild or moderate disease ﬂare should include supportive therapy with ﬂuids, anticholinergics, and antidiarrheals. Antidiarrheals in patients with severely active disease, however, could precipitate toxic megacolon. Supportive therapy allows the naturally remitting feature of the ulcerative colitis to occur. Indeed, approximately one third of patients given placebo in randomized clinical trials achieve remission. Diet recommendations should include a multivitamin supplement. Complete bowel rest with total parental nutrition is not eﬀective primary therapy for ulcerative colitis patients. Dietary supplements may be helpful. Eicosapentaenoic acid (ﬁsh oil) competes arachidonic acid for metabolism by lipoxygenase to produce leukotriene B5, a much less potent proinﬂammatory cytokine than arachidonic acid metabolite leukotriene B4. High oral ﬁsh oil can treat ulcerative colitis and enable patients to reduce steroid intake [44,45]. Extremely high doses, however, cause odoriferous side eﬀects, which limits the use of such therapy. Short-chain fatty acids (acetate, butyrate, and propriate), which are products of colonic bacteria metabolism of dietary ﬁber, are fuel sources preferred by the colonic mucosa over glucose and ketones bodies. Shortchain fatty acid enemas may be useful in patients with moderately active proctosigmoiditis, especially those refractory to more conventional therapy [46,47]. Oral butyrate coated in pH-dependant soluble polymer targeted for colonic delivery when combined with oral 5ASA improves symptoms in ulcerative colitis better than 5ASA alone [48]. Administration of a nonpathogenic strain of Escherichia coli was as eﬀective as 5ASA in maintaining remission in patients with ulcerative colitis [49]. Such a ﬁnding suggests that favorably altering the colonic ﬂora with a probiotic may negate the proinﬂammatory eﬀects of as yet unidentiﬁed pathogenic bacteria. Aminosalicylates For the past 50 years, sulfasalazine, the combination of sulfapyridine and 5ASA, has been the most commonly used medication for ulcerative colitis.

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5ASA is the therapeutically active ingredient that is released when colonic bacteria cleave a diazo bond with sulfapyridine. 5ASA interferes with both the cyclooxygenase and lipoxygenase pathways of arachidonic acid metabolism, and free-radical scavenging. Sulfasalazine given in divided doses of 2 to 4 g/d usually is helpful for treating mildly to moderate active ulcerative colitis and for maintaining remission [50]. Sulfasalazine is a competitive inhibitor of folic acid absorption and an oral supplement is needed in patients so treated [51]. Up to half of patients are allergic to or intolerant of sulfasalazine especially at high doses, primarily to the sulfapyridine moiety of the medication. 5ASA can be delivered directly to the patient with similar eﬀectiveness by using newer, but more expensive, topical (Rowasa enemas, Solvay, Marrietta, GA) and oral preparations (olsalazine, [Dipentum and Celltech]); resin-coated mesalamine (Asacol, Procter & Gamble, Cincinnati, OH); and ethylcellulosecoated 5ASA beads (Pentasa, Shire, Florence, NY). Olsalazine consists of two 5ASA molecules linked by a diazo bond that requires cleavage from colonic bacteria. Although eﬀective, a secretory diarrhea in 10% of patients limits its usefulness [52]. The frequency of diarrhea from Dipentum can be diminished by taking the medication with food. All of these compounds can induce and maintain remission. Balsalazide (Colazide, Salix, Raleigh, NC) is 5ASA attached by a diazo bond to an inert carrier molecule. Theoretically, 5ASA products with a diazo bond delivery system should have an advantage over the resin-coated agents in regard to drug delivery to the distal colon and eﬃcacy in treating leftsided disease. Over the last several years there have been several studies comparing the eﬃcacy of balsalazide with mesalamine in inducing remission of left-sided ulcerative colitis. The results of these studies have yielded conﬂicting results. A randomized placebo-controlled study in 1998 from England compared balsalazide, 6.75 mg, with mesalamine, 2.4 mg, with the primary end point being the proportion of patients in complete remission, deﬁned as patient score of none to mild and endoscopy score of 0 to 1. At the end of 3 months 62% of patients taking balsalazide achieved remission compared with 37% who were administered mesalamine. Moreover, 48% of the patients taking balsalazide had adverse aﬀects compared with 71% for the group prescribed mesalamine [53]. These results should be tempered, however, by the fact that formulation of mesalamine in the United Kingdom releases less than 80% of a comparable dose manufactured in the United States. Another randomized clinical United Kingdom study from 2002 compared balsalazide, 6.75 g, with mesalamine, 2.5 g, with the primary end point as a patient functional assessment in regard to rectal bleeding with the secondary end point being time to remission, proportion in complete remission, and improvement in sigmoidoscopic score. No signiﬁcant difference was demonstrated in the primary end point, with remission occurring in 46% in the balsalazide group and 44% in those taking mesalamine.

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None of the secondary end points demonstrated a signiﬁcant diﬀerence [54]. A third randomized clinical study conducted in the United States in 2002 examined the dose response of balsalazide (2.25 and 6.75 mg) and mesalamine, 2.4 mg, in inducing remission in mild to moderate ulcerative colitis patients. The primary end point was the improvement in rectal bleeding plus at least one other variable, which included a physician assessment, abdominal pain, stool frequency, improvement with sigmoidoscopy, and patient functional assessment at 8 weeks. The secondary end points included the measurement of patients who achieved complete remission and had an improved biopsy score and quality of life with decrease in adverse outcomes. The primary end points were not met in this study. Balsalazide at a dosage of 6.75 mg, however, led to a statistically signiﬁcant diﬀerence versus lower balsalazide dosage [55]. Despite the theoretical advantage of balsalazide over mesalamine in treating left-sided ulcerative colitis, there is no clear clinical advantage. For inducing remission in left-sided ulcerative colitis topical 5ASA therapy should be the ﬁrst-line therapy followed by any oral 5ASA if the patient does not respond favorably. The ultimate goal of therapy is to maintain remission with the oral 5ASA agent that induced reversal of disease and to try to avoid corticosteroid use because of the many side eﬀects. Corticosteroids Oral, intravenous, or topical steroids are very eﬀective for treating active ulcerative colitis through inhibition of phospholipase A2 and the subsequent decrease in the levels of leukotrienes. There is no diﬀerence in outcome if steroids are given on a continuous basis or given as a pulse [56]. Prolonged prednisone administration, however, is limited by its side eﬀects. Budesonide, a steroid analogue, is 90% inactivated by the liver during the ﬁrst pass. The compound is modiﬁed by packaging with ethylcellulose beads and eudrigit-L, ensuring small bowel and colonic eﬀects before it is absorbed and inactivated. Budesonide has fewer adverse eﬀects than prednisone [57,58]. Because of adrenal suppression, long-term use for its maintenance is not recommended. Immunosuppressives 6-Mercaptopurine and its S-imidazole precursor, azathioprine, are purine ring analogues that interfere with DNA replication or rapidly dividing cells, such as lymphocytes and macrophages. These drugs are safe and eﬀective, have diﬀerent adverse eﬀects from corticosteroids, and can be considered steroid-sparing. Approximately 10% of patients require discontinuation for reversible marrow suppression; about 3% experience acute pancreatitis; and 1% develop allergy characterized by abdominal pain, fever, and rash. Both azathioprine and 6-mercaptopurine are eﬀective maintenance therapy in

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ulcerative colitis, enabling patients to avoid long-term use of corticosteroids [59,60]. The duration of therapy, before clinical response is observed, can be longer than 3 months. Because of this delay in response, adjusting the dose according to response may not be appropriate. Some have suggested that the dose of immunosuppressives be increased until mild leukopenia develops, because patients treated to leukopenia have a faster and more complete response [61]. Metabolite levels of 6-thioguanine, the active metabolite, and 6-methylmercaptopurine, the toxic metabolite, can be determined to identify the dose that ﬁnds the narrow window between toxicity and eﬀectiveness [62]. Cyclosporine is a cyclic polypeptide that is used extensively as an immunosuppressive agent in organ transplantation. It inhibits (interleukin2) gene transcription and reduces activation of lymphocytes, mostly T helper cells. Cyclosporine binds to lipoproteins and requires bile salts for absorption. It is metabolized and inactivated by hepatic cytochrome P-450 activity. Nephrotoxicity, hepatotoxicity, hypertrichosis, gingival hyperplasia, tremors, paresthesias, seizures, and lymphoproliferative disorders are the most common adverse eﬀects. High-dose intravenous cyclosporine can initiate a quick response and successfully delay colectomy in up to 80% of patients with severely active ulcerative colitis [63]. Long-term success of avoiding a colectomy is 50% or less. Responders have a superior quality-oflife than patients who require surgery [64]. Once remission is induced with intravenous cyclosporine, patients should be maintained on oral cyclosporine for at least 6 months as prednisone is tapered and azathioprine or 6mercaptopurine becomes eﬀective [65]. Biologic therapies, such as inﬂiximab and the anti-inﬂammatory cytokines interleukin-10 and -11 have not been approved for patients with ulcerative colitis.

Summary Despite the fact that there have been no epidemiologic or genetic studies speciﬁcally evaluating left-sided ulcerative colitis it is likely the results would be analogous to those of pancolitis. The risk of cancer, however, is proportional with extent of the disease. First-line therapy in left-sided colitis is topical 5ASA agents. In patients who are refractory to these agents, an oral form of 5ASA is administered. Studies evaluating the eﬃcacy of oral 5ASA agents that have diﬀering drug delivery mechanisms have demonstrated a minor clinical diﬀerences. If one of the 5ASA agents is successful in a particular clinical setting it is best to maintain that therapy. In patients who do not respond to the 5ASA class of medications, steroids and immunosuppressives are then used, respectively, in a stepwise fashion to treat left-sided disease.

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Crohn’s disease: future anti–tumor necrosis factor therapies beyond inﬂiximab Joshua R. Korzenik, MD Gastrointestinal Unit, Department of Internal Medicine, Massachusetts General Hospital, 55 Fruit Street Boston, MA 02114-2622, USA

The dramatic beneﬁt experienced by many Crohn’s patients treated with the anti– tumor necrosis factor-a (TNF-a) antibody inﬂiximab underscores the centrality of this cytokine in the pathogenesis of Crohn’s disease and the potential use of the therapeutic strategy of blocking TNF-a in this disease [1,2]. Before the development of inﬂiximab, strong scientiﬁc rationale supported this approach [3–5], but given a redundant set of inﬂammatory mediators, the inhibition of a single cytokine seemed a questionable strategy. After impressive clinical experience with inﬂiximab, some view TNF-a as the holy grail of Crohn’s disease. Twenty percent to 40% of patients, however, fail to respond to inﬂiximab [6]; others loose their response because of antibody formation to inﬂiximab [7] or develop adverse events precluding its further use. Consequently, in the hopes of emulating and improving on the success of inﬂiximab, numerous strategies are being devised and studied to inhibit the actions of TNF-a. Several of these medications are likely to join the ranks of widely used therapy for inﬂammatory bowel disease (IBD) in the not too distant future. In the wake of inﬂiximab, most medications being studied for Crohn’s disease attach their stake claiming a therapeutic beneﬁt to an assertion that one of their mechanisms of action is interference with TNF-a, whether directly or indirectly, however tenuous or peripheral that contention might be. In addition, many therapies currently used for IBD have been identiﬁed as having some eﬀect on TNF-a, such as sulfasalazine [8], although that mechanism is not established as the probable primary pathway. This article focuses only on those agents, other than inﬂiximab, which target TNF-a to treat IBD as their central mechanism of action. The appropriate use and indications of anti–TNF-a therapy in IBD continue to evolve as experience with these compounds increases. Many of E-mail address: [email protected] 0889-8553/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.gtc.2004.02.009

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these agents have been studied in Crohn’s disease; fewer have been evaluated in ulcerative colitis (UC). In this group, only inﬂiximab has been approved for use in Crohn’s disease and none have a Food and Drug Administration approved indication for the treatment of UC. In addition, anti–TNF-a agents have signiﬁcant potential adverse complications, some of which are class eﬀects, likely common to most or all compounds in this group, such as the activation of latent tuberculosis or other infectious complications. Knowledge of these diﬀerences and commonalities is crucial to guide selection of medications for an individual patient. As newer agents in this class are studied in IBD, the diﬀerences in eﬃcacy, complications, and cost will be of great importance. Mechanisms of action, while seemingly straightforward, are likely more complex and diverse than the immediate action of binding to or inhibiting TNF-a. Understanding these mechanisms will yield signiﬁcant insight into the pathologic process of IBD and help reﬁne the therapeutic approach further. A variety of agents has been used, with varying success, ranging from small molecules, such as pentoxifylline [9] and thalidomide [10,11], to antibodies, such as CDP-571 [12–14] (Celltech Group, London, UK), with newer, promising agents under study at present including the pegylated antibody fragment CDP-870 (Celltech Group, London, UK) and adalimumab, an IgG1 antibody, recently approved by the FDA for the treatment of rheumatoid arthritis (Abbott Laboratories, Abbott Park, IL). The therapeutic failures are as instructive as the successes. Furthermore, the role of TNF-a in Crohn’s disease merits re-evaluation in light of the positive and negative results and mechanisms of action of these therapies.

A brief review of tumor necrosis factor and strategies for interfering with tumor necrosis factor function An overview of TNF-a, its function, and associated proteins is essential to understand the potential strategies for interfering in its activity. More comprehensive reviews are available than is discussed here [15,16]. The central broad function of TNF-a is to protect against invading microbes, acting at an early step in the inﬂammatory process to augment host defense, although coagulation and apoptosis, associated with immune activation, also are strongly inﬂuenced. The body’s defense against Mycobacteria tuberculosis [17], Listeria monocytogenes [18], and other intracellular pathogens in particular relies heavily on TNF-a. Administration of TNFa itself intravenously replicates the characteristic clinical signs of a septic shock–like syndrome [19]. The wasting syndromes seen in numerous cancers and possibly HIV are caused in large part by TNF-a [20,21]. Its clinical use as an antineoplastic agent continues to be investigated, with a variety of strategies for local or regional administration to limit the low therapeutic index when delivered systemically [19]. TNF-a inhibition seemed a promising

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approach in sepsis, although a randomized, controlled trial of nearly 2000 patients found no beneﬁt to patients receiving an anti–TNF-a antibody over placebo [22] and a similarly large trial of lanercept (p55 TNF receptor fusion protein) in sepsis was also negative [23]. Early negative trials in sepsis nearly dampened the enthusiasm for other clinical applications of this concept. The use of an anti–TNF-a antibody in Crohn’s disease was subsequently studied, reviving this approach and leading the way for its use in a variety of illnesses, such as rheumatoid arthritis and psoriasis.

Regulation of tumor necrosis factor-a Bacterial antigens or products initially induce the generation of TNF-a in a number of cell types including monocytes, macrophages, and T-cells primarily and neutrophils [24]. TNF-a production is further controlled, depending on cell type, through activation of nuclear factor jB (NFjB) the common end point leading to transcription of TNF-a [25]. Several pathways critical in the inﬂammatory response control NFjB including primarily the mitogen-activated protein kinase p38 pathway [26]. This pathway is an attractive target to inhibit the inﬂammatory process at an earlier stage of its arborization, before release of TNF-a. An open-labeled trial of CNI-1493, an agent that inhibits this pathway, suggested a beneﬁt in 7 of 12 Crohn’s patients including three of six patients not responding to inﬂiximab (Cytokine PharmaSciences, King of Prussia, PA) [27]. A larger placebocontrolled trial is ongoing. After being transcribed in the cell, TNF-a circulates as a propeptide attached to the cell surface. A speciﬁc metalloproteinase cleaves the propeptide form, although TNF is not yet released until it is in direct contact with another cell. Two receptors have been identiﬁed that are found on most cells: a 55-kd protein (TNF-a RI) and a 75-kd protein (TNF-a RII) [24]. Tumor necrosis factor-a has been found to be elevated in the intestinal mucosa and stool of patients with active IBD [4,28]. The actions of TNF-a reasonably place it as a central mediator of the inﬂammatory process characteristic of Crohn’s and UC [24]. TNF-a functions to augment the inﬂammatory response [29] leading to tissue injury but is also involved in apoptosis [30], thrombosis [31] and granuloma formation (in M tuberculosis) [32]. Interference with the multiple actions of TNF-a is possible at a variety of steps in its transcription, processing, or release from the cell surface. Phosphodiesterase IV (inhibited by pentoxifylline) regulates the transcription of TNF-a [33]. Thalidomide is thought to cause mRNA destabilization, and more rapid degradation, leading to reduced transcription [34]. Antisense strategies are also being evaluated (although currently in clinical trials in rheumatoid arthritis and not IBD) (Isis Pharmaceuticals, Carlsbad, California). Blocking the metalloproteinase, or TNF-a converting enzyme,

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which cleaves the propeptide, is also being explored. Antibodies can bind to the cell surface TNF-a (eg, inﬂiximab) and numerous similar approaches have been and are being studied clinically in Crohn’s disease with modiﬁcations: a humanized antibody (5% murine) (CDP-571, Celltech, London, UK); a fully human antibody (100% human) (adalimumab, Humira, Abbott Laboratories, Abbott Park, Illinois); an antibody that binds TNF-a more avidly than inﬂiximab (Protein Design Labs, Freemont, California); and a pegylated humanized antibody fragment (CDP-870; Celltech, London, UK). Another strategy binds soluble TNF-a after it is released from the cell surface, using a TNF receptor as was tried with etanercept, a dimerized form of the 75-kd receptor (TNF-a RII) (Amgen, Thousand Oaks, California), or onercept, a dimerized form of the 55-kd receptor (TNF-a RI) fused by the Fc portion of IgG1 antibody. These and other strategies for antagonizing TNF-a have been studied or are being currently investigated. Numerous others are at various early stages of development. The beneﬁt in IBD has varied between the signiﬁcant eﬃcacy of inﬂiximab and the surprising failure of etanercept. The results of strategies designed to antagonize TNF-a, other than inﬂiximab and their implications for the treatment of IBD are discussed next.

Thalidomide Thalidomide was relatively recently resurrected for a variety of therapeutic uses from well-deserved abandonment by the medical community after it had been linked to horriﬁc birth defects in the 1950s. Widely prescribed in Europe, thalidomide was originally prescribed as a mild sedative and antiemetic. Thought safe and used commonly during pregnancy, thalidomide was eventually identiﬁed as causing phocomelia (limb foreshortening) and other serious birth defects, including craniofacial malformations and cardiac valvular abnormalities, aﬀecting more than 10,000 babies. During its initial use in Europe, thalidomide’s approval for use in the United States was delayed by FDA concerns over a link to peripheral neuropathy. During the period of review, the teratogenicity of thalidomide was realized and consequently the compound was not released for use in the United States. This tragedy eventually led to an expanded mandate for the FDA. Medical applications of thalidomide were almost completely terminated in 1961. A variety of groups, victim advocacy foundations in particular, called for its elimination worldwide. Nevertheless, thalidomide continued to be used, although in a limited way, for the treatment of erythema nodosum leprosum, (Hansen’s disease) [35]. Thalidomide was subsequently identiﬁed as having a primary eﬀect in vivo of reducing TNF-a levels by destabilizing its mRNA, opening its potential use for a variety of diseases and Crohn’s in particular. As a TNF-a suppressant, thalidomide has a relatively modest eﬀect [36]. Although the

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renewed interest in thalidomide developed out of its capacity to suppress TNF-a, thalidomide has been demonstrated to act on several potentially important pathways. Thalidomide alters the expression of other proinﬂammatory cytokines, in particular NFjB, a transcription factor that regulates the expression of a number of important proinﬂammatory cytokines, including interleukin-1a, -2, -6, and -12. Thalidomide had been demonstrated to suppress nuclear factor kappa B through inhibition of IjB kinase. In diminishing interleukin-12 and augmenting interleukin-4, thalidomide may also act by shifting a Th1-type response toward a Th2type response [37]. Thalidomide also has antiangiogenic properties, inhibiting VEGF and bFGF, the mechanism likely responsible for phocomelia [38,39], which may also be a mechanism contributing to its beneﬁt in Crohn’s disease. Initial case reports suggesting a beneﬁt in Crohn’s disease focused on improvement in patients with refractory oral aphthoid ulcerations because earlier case reports indicated a beneﬁt in oral aphthoid lesions independent of Crohn’s disease. Two early reports describe the successful use of thalidomide in children, an 8-year-old boy [40] and a 13-year-old girl [41], with refractory Crohn’s disease. The young boy had oral aphthoid ulcerations despite control of his intestinal disease with azathioprine and prednisolone. The young girl had severe colonic disease resulting in an ileostomy and her predominant disease manifestation was oral aphthoid ulcerations, despite treatment with 6-mercaptopurine, 50 mg, and prednisone, 20 mg daily. In both cases, thalidomide resolved the oral lesions rapidly, using low doses (50 mg and 25 mg, respectively), and the beneﬁts persisted with continued treatment over a long period. A number of open-labeled trials similarly report an impressive beneﬁt. A higher-dose trial by Ehrenpreis et al [10] selecting the dose of 200 or 300 mg/ d as used in leprosy was studied in 22 patients, with 14 patients completing the 14-week trial and 9 entering remission (three with luminal disease and six primarily ﬁstulous disease), having an overall improvement in 64%. A response was relatively rapid, seen within 4 weeks. The median Crohn’s disease activity index (CDAI) on entry of all patients was 371 (range 95–468) and reduced to 175 (range 30–308) for the 14 completing the trial. A similar but lower-dosed trial (50 or 100 mg/d) by Vasiliauskas et al [11] had comparable results with 70% response of 12 steroid-dependent patients and 20% achieved remission. Complete steroid withdrawal was possible in 44%. In a separate open-labeled trial, ﬁve steroid-dependent pediatric patients (mean age 17 years) were treated with thalidomide. One patient discontinued after 1 week, but the other four achieved remission, conﬁrmed endoscopically, were able to taper oﬀ steroids, and continued for 19 to 24 months on therapy with signiﬁcant adverse events. The dose used in this pediatric group was 1.5 to 2 mg/kg/d. The eﬃcacy of thalidomide in UC is minimally described in case reports, despite that the initial report recommending the use of thalidomide in IBD

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was in a UC patient in 1979 [42]. Otherwise, a recent open-labeled series of 11 patients included four patients with UC. Two UC patients withdrew early, but the other two demonstrated a marked improvement as did the remaining Crohn’s disease patients [43]. Ongoing open-labeled trials investigated the use of thalidomide in UC, which seemed promising from Digestive Disease Week abstracts but no published detailed reports are currently available. Another open-labeled trial investigated the use of thalidomide (100 mg/d) as a means of prolonging the beneﬁt of inﬂiximab in Crohn’s disease. Patients were initiated on thalidomide after they had demonstrated a response to inﬂiximab and followed for a mean follow-up of 238 days. Most patients continued to be in remission, with a further improvement in CDAI after initiation of thalidomide. Four patients discontinued the drug because of adverse events (sedation, rash, and neuropathy) [44]. A separate case series of four patients were treated with thalidomide as salvage therapy after having had complete responses to inﬂiximab but then developed delayed hypersensitivity responses to subsequent treatments [45]. Although one discontinued treatment after only 1 week because of sedation (at 50 mg/ d), three of the four had remission, with two of three having a longer-term beneﬁt. All four eventually discontinued the medication, however, because of adverse events (sedation, hypertension, and peripheral neuropathy). Although the chief concern with regard to its use is the avoidance of pregnancy in these patients, a variety of adverse events were noted. Not surprisingly, all patients in the higher-dosed trial noted sedation, its original indication, and many (7 of 12) in the lower dose (even three of six in the 50 mg/d subgroup) reported fatigue. Nearly half of those in the higher-dose trial required some dose reduction. Other adverse events included peripheral neuropathy, again even at the lower dose, which may be more signiﬁcant in limiting its use, dermatitis, and hypertension. Thalidomide is available, although with signiﬁcant oversight, including an educational requirement concerning its use for prescribing physicians and close monitoring being mandated. Although thalidomide’s niche in the armamentarium against IBD may be limited, a sponsoring company (Thalomid Celgene, Warren, New Jersey) is exploring structural analogues (ImiDs), which may be more potent in suppressing TNF-a without the teratogenicity of thalidomide, although whether the newer compounds retain the other possible mechanisms of action attributed to thalidomide has not been published. The use of these newer analogues in IBD has not yet been determined. Pentoxifylline Pentoxifylline, initially used for peripheral venous insuﬃciency, has been re-evaluated as a compound capable of suppressing TNF-a and having a potential role in Crohn’s disease. Pentoxifylline limits TNF-a transcription

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through inhibition of phosphodiesterase IV, increasing cyclic AMP concentrations [46]. Small, open-labeled studies oﬀer little hope that pentoxifylline can produce a signiﬁcant clinical response in Crohn’s disease [9]. The capacity of this molecule to reduce TNF-a production is relatively mild, with a decrease of 30% to 50% seen in in vitro studies of pentoxifylline in Crohn’s biopsy specimens. Monocytes from ﬁve healthy volunteers given pentoxifylline, 400 mg four times a day for 2 days, demonstrated a marked suppression of TNF when stimulated by lipopolysaccharide [33]. An open-labeled trial tested pentoxifylline in 16 stable, steroid-dependent patients with Crohn’s disease at a dose of 400 mg orally four times daily for 4 weeks [9]. In addition to steroids, only mesalamine was permitted. Steroiddependent patients were selected in particular because steroids have been suggested to potentiate the inhibitory eﬀects of pentoxifylline. CDAI scores were similar at the beginning and end of the study period (189 versus 185) and no patient was able to discontinue steroids with four ending participation in the trial prematurely because of increasing disease activity. Most patients did ﬁnd mild improvement in terms of night sweats and sleep, but no other clinical change was noted. No endoscopic or histologic amelioration was seen either. Inﬂammatory markers, erythrocyte sedimentation rate, and C-reactive protein did not change by pentoxifylline during the study. The duration and nature of the trial may have been inadequate to determine if a treatment eﬀect could be assessed. Other phosphodiesterase inhibitors are being investigated in clinical trials in IBD. Etanercept The most surprisingly ineﬀective therapy in the treatment of Crohn’s disease has been etanercept (Enbrel, Amgen, Thousand Oaks, California). Etanercept is a fully human fusion protein composed of two identical units of the human recombinant soluble receptor TNFR type II (p75) fused with the Fc domain of human IgG1. This receptor fusion molecule binds soluble TNF-a (and lymphotoxin [also known as tumor necrosis factor-b]) acting as a decoy for soluble TNF. Positive results were anticipated because of its considerable beneﬁt in rheumatoid arthritis. A small open-labeled trial in Crohn’s disease suggested a likely beneﬁt with 6 of 10 patients demonstrating a decrease of at least 70 points in the CDAI with a reduction in inﬂammation seen endoscopically in the four patients who achieved remission [47]. A modestly sized placebo-controlled trial (N = 80, 40 patients in each arm) showed no beneﬁt, and if anything a trend toward a worse response in etanercept-treated patients (placebo: CDAI response, decrease of 70 points in 45% placebo group versus 39% etanercept at week 4) [48]. Adverse events were minimal in the Crohn’s trial. In rheumatoid arthritis, however, although highly eﬀective, numerous side eﬀects overlapping inﬂiximab have been noted (see later). One report found a beneﬁt in ankylosing spondylitis associated with Crohn’s in two patients, with resolution of back pain,

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whereas no relief was seen with the intestinal symptoms [49]. Onercept, a similar fusion receptor protein for the other TNF-a receptor, p55 (unlike etanercept, which is the p75 receptor fusion protein), has also been studied in Crohn’s disease in a small dose-ﬁnding pilot trial. Twelve patients with active Crohn’s disease were treated three times a week for 12 weeks and followed for 6 months. Seven individuals demonstrated a decrease in the CDAI of over 100 points, with ﬁve achieving remission [50]. A larger trial is underway. No clear understanding has been presented why etanercept does not ameliorate Crohn’s disease, although it can be highly eﬀective in rheumatoid arthritis. Intestinal concentrations of TNF-a may require a higher dose to be antagonized. The dose of inﬂiximab used in rheumatoid arthritis (3 mg/kg) is lower than what is used in Crohn’s. Martinez-Borra et al [51] suggested that poor response to inﬂiximab correlated to higher levels of TNF than seen in responders. Inﬂiximab also binds irreversibly to TNF but etanercept has a high on-oﬀ rate (binding then releasing). In addition, inﬂiximab has been found to induce T-cell apoptosis for which binding to the membrane surface is essential [52]. Although etanercept is capable of binding to cell surface–associated TNF-a, etanercept binds to soluble TNF-a much more commonly. The mechanism of etanercept may be limited to reducing TNF-a levels rather than inducing other mechanisms attributed to inﬂiximab’s beneﬁt in Crohn’s disease, such as inducing apoptosis or complementmediated cell lysis. CDP-571 CDP-571 aimed to improve on the success of inﬂiximab by being less immunogenic and having fewer adverse events. The complementarydetermining region of an anti-TNF antibody, the part of the antibody that binds to the antigen, raised in mice was transferred to a human IgG4 antibody. The antibody sequence is 95% human and 5% murine as compared with inﬂiximab, which is 25% murine. This diﬀerence was anticipated to be less likely to induce antibody formation against the therapy and translate into a safer compound with fewer infusion reactions; less delayed hypersensitivity reactions; and perhaps decrease other autoantibody formations, such druginduced lupus. An initial, small randomized controlled trial (31 patients in 2:1 randomization) demonstrated a statistically signiﬁcant beneﬁt in response at 2 weeks, although the response was lost beyond that time point [13]. These promising results were followed-up with a larger placebo-controlled trial aiming to examine two higher doses (10 mg/kg and 20 mg/kg compared with 5 mg/kg dose tested in the initial study) assuming that the limited beneﬁt and duration seen in the initial pilot study could be improved on with a larger dose [12]. This larger trial, which randomized 193 patients to the diﬀerent doses and time intervals of administration, did ﬁnd a statistical beneﬁt at 2 weeks in a decrease in the CDAI by 70 (45% versus 27%

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placebo; P = .023) and at 100 points (30% versus 14% placebo; P = .026) in analyzing all CDP-571–treated patients together. Dose subgroup analysis produced inconsistent results, with a statistically signiﬁcant 70-point improvement seen at 2 weeks in the10 mg/kg group (54% versus 27% placebo; P = .003), but not in the 20 mg/kg group (37% versus 27% placebo; P = .248). At the 100-point decrease end point, however, the converse was observed, where the 20 mg/kg dose performed better (32% versus 14% placebo; P = .026) and the 10 mg/kg group failed to demonstrate a statistical beneﬁt, although a trend toward improvement was maintained (28% versus 14%; P = .087). Although a trend toward remission was seen in both dosing groups and at diﬀerent dosing intervals, this diﬀerence was not statistically signiﬁcant and was not seen at all time points. Similarly, maintenance of remission during the 24-week study was not demonstrated. Better results with regard to maintaining remission while withdrawing steroids were suggested in Feagan et al [53]. Although comparisons across studies can be misleading, the robust results of inﬂiximab were not reproduced with a diﬀerent TNF antibody. Serious adverse events were comparable between the CPD-571–treated patients and those receiving placebo, although any adverse events were experienced by more receiving CDP-571. Lymphoma and lupus-like reactions were not seen in any patient and antidouble stranded DNA, antinuclear antibodies, and anticardiolipin antibodies were seen in very few patients (2%, 4%, and 3%, all equivalent to what was seen in the placebo group). Infusion reactions were seen in 12% of patients, which responded to slowing the infusion or administration of diphenhydramine. CDP-571 has been studied in 15 patients with UC in an open-labeled trial [14]. Patients were administered one infusion of CDP-571 and followed for 8 weeks for clinical and endoscopic and histologic end points. Statistically signiﬁcant, although clinically modest, reductions in the Powel-Tuck score were seen at week 1 but not beyond that. Similarly, mild reductions were seen in the erythrocyte sedimentation rate and Creactive protein, which persisted for 2 weeks. Endoscopic and histologic improvement was not seen. Although CDP-571 may have diﬀerent binding kinetics than inﬂiximab, these neutralizing antibodies, at least at the higher doses, are more than suﬃcient to diminish levels of TNF dramatically. The diﬀerent clinical results may be explained by the diﬀerences in antibody subtype. CDP-571, an IgG4 antibody, does not activate complement and does not induce antibody-dependent cellular cytotoxicity. IgG1 possess these attributes and may explain the diﬀerences in results between these antibodies, with inﬂiximab being an IgG1 subtype. Consequently, inﬂiximab binding to cell surface TNF-a may be eﬀective in part by targeting immune cells participating in the inﬂammatory process and lysing them through complement and antibody-dependent cellular cytotoxicity. Inﬂiximab acts through inducing T-cell apoptosis as well, although whether CDP-571

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participates in this pathway is unknown. This observation suggests that neutralizing TNF-a alone may be inadequate to control this disease. Consequently, TNF-a, although critical in the disease process, may be somewhat less important than the results of inﬂiximab might imply at initial impression. Several other anti-TNF antibodies are being investigated for use in Crohn’s disease or are anticipated to be studied in the near future. Farthest along in this process is adalimumab (D2E7), an IgG1 fully humanized antibody, recently approved for the treatment of rheumatoid arthritis and marketed as Humira (Abbott Laboratories, Chicago, Illinois). The studies in rheumatoid arthritis, which are not necessarily a valid indicator of the probability of their success in Crohn’s disease, seem competitive with results seen in inﬂiximab and rheumatoid arthritis. Adalimumab hopes to distinguish itself by being less antigenic as a fully humanized antibody, with the complementarity determining regions being the only murine portion preserved from the initial antibody, with human portions preserved for the remainder of the newly generated antibody. Whether most antibodies to inﬂiximab are generated against the murine portion, while likely, is not yet known and whether these humanized or fully human antibodies will be less immunogenic in Crohn’s disease remains to be determined. The antigenicity of adalimumab in Crohn’s disease has not yet been studied. Two large trials are underway evaluating adalimumab in Crohn’s disease. Another approach has been a humanized antibody fragment, CDP-870 (Celltech, United Kingdom), with high-aﬃnity binding to TNF-a, which has bound polyethylene glycol to increase plasma half-life. The drug has been recently tested in a study of nearly 300 patients with active Crohn’s disease receiving CDP-870 every 4 weeks. Although not yet published, the results presented at Digestive Disease Week seem promising. Although the molecule failed to achieve the primary end point of a beneﬁt at week 12, most time points indicated a statistically signiﬁcant beneﬁt. In a post hoc subgroup analysis of patients with a C-reactive protein greater than 10 mg/dL, which included about 40% of the patients in the trial, the improvement of those receiving CDP-870 over the placebo group was much more clinically impressive. Another antibody to be tested, developed by Protein Design Labs (Fremont, California), has a higher aﬃnity for TNF than does inﬂiximab and it is hoped that this alteration in binding kinetics will translate into a clinical improvement above that seen with inﬂiximab. Antisense strategies are also being evaluated, although currently in clinical trials in rheumatoid arthritis and not IBD (Isis Pharmaceuticals, San Diego, California). Adverse events Many of the initial adverse events seen in inﬂiximab are now recognized not to be unique to inﬂiximab but are present as a class eﬀect in individuals

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treated with anti– TNF-a therapies. Although miraculous for some, these agents have also been associated with a signiﬁcant number of deaths related to infection, lymphoma, and congestive heart failure. The most common serious concern is infection, not surprisingly, given the role TNF-a plays in combating microbial invasion. Although it may seem surprising that infectious complications are not more common, studies of inﬂiximab have demonstrated that peripheral T-cell function remains intact after individuals are treated with inﬂiximab [54] and neutrophil function peripherally continues to be undiminished after treatment with etanercept in rheumatoid arthritis patients [55]. Still, with inﬂiximab, 2% to 4% over the course of a 54-week treatment had serious infections [2,6]. An increase in serious infectious complications also has been seen with etanercept. The risk of activation of tuberculosis has been recognized for all of these agents, ﬁrst reported with adalimumab. TNF-a has been recognized as critical to defense against tuberculosis and Listeria and other intracellular pathogens. Blocking the actions of this cytokine might be predicted to activate latent tuberculosis as has been the case [56]. Best described is the experience with inﬂiximab, but all three agents with a broader database convey this risk. Whether the FDA warning that all patients should undergo skin tests for tuberculosis will reduce the risk is uncertain. The other main concerns with anti–TNF-a therapy are demyelinating illness, the development of autoimmunity, and increased risk of lymphoma [57]. The development of autoimmunity markers, antinuclear antibodies, and anti-dsDNA antibodies, seems also to be a class eﬀect of TNF inhibitors, although the clinical signiﬁcance of these ﬁndings is uncertain because few patients develop a lupus-like syndrome. Why and how autoimmune markers develop in response to TNF-a inhibition is unclear. TNF-a itself might function to prevent this phenomena and blocking it might create a cytokine context in which autoimmunity can occur more than it already does in these disease, although no constitutive function of TNF-a has been established. Demyelinating disease has been reported with those agents in which there has been broader use, with a larger study population treated, namely inﬂiximab, etanercept, and adalimumab. Other adverse events seen in postmarketing experience with these agents include seizures, aplastic anemia, intestinal perforation, cutaneous lupus rash, and opportunistic infections. Individuals treated for rheumatoid arthritis comprise a signiﬁcant proportion of the database for these agents, and in the case of adalimumab, the data are exclusively from patients with rheumatoid arthritis because no individuals treated for Crohn’s disease have yet been reported. With other medications, such as pentoxifylline, CDP-571, and thalidomide, insuﬃcient numbers of patients treated preclude an accurate assessment of their risk when used in a broader population. More recently, the development of congestive heart failure, even in individuals without risk factors, adds another concern in the clinical use of

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these compounds. Congestive heart failure was initially considered a potential indication for these medications. TNF-a has been found to be elevated in congestive heart failure, although its role in the pathophysiology of congestive heart failure is unclear. A phase 2 trial of inﬂiximab in NYHA class III or IV congestive heart failure was discontinued prematurely because of safety issues. No improvement was noted in left-ventricular ejection fractions at week 28 and increase in serious adverse events was noted in those individuals receiving the higher dose (44% versus 29.2% in placebo arm) and an increased risk of death from any cause or hospitalization was higher in the 10 mg/kg treated group [58]. This potential indication is no longer being pursued and a number of reports suggest that the development of congestive heart failure may occur in individuals without signiﬁcant risk factors. A recent summary of reported cases identiﬁed 47 individuals who developed new-onset congestive heart failure (38 patients) and congestive heart failure exacerbation (nine patients) subsequent to treatment with an anti–TNF-a agent (inﬂiximab or etanercept), of whom three died. Of the group with congestive heart failure, half had identiﬁed risk factors for development of congestive heart failure. Ten patients were less than 50 years old. Of these 10 patients, three had risk factors for congestive heart failure. Median time to onset of congestive heart failure after therapy was 3.5 months. All discontinued the anti–TNF-a therapy after onset of congestive heart failure. Three had complete resolution, six improved with therapy, and one died [59]. Current recommendations warn against using inﬂiximab in patients with congestive heart failure and this likely should extend to other anti-TNF agents. The risk of lymphoma in this population, both rheumatoid arthritis and Crohn’s disease, has been the focus of considerable debate. In rheumatoid arthritis, particularly in more active disease, an increased risk of lymphoma has been assessed, although whether a risk of lymphoma exists in Crohn’s disease is questionable, with more recent data suggesting that Crohn’s at baseline does not confer an increased risk of lymphoma [60]. A recent evaluation of individuals studied in trials submitted to the FDA for drug approval assessed the risk of lymphoma in these patients. The Standardized Incidence Ratio (ratio of observed rate to age-, gender-, and race-adjusted expected frequency in the general population) for malignancies in adalimumab-treated patients (only with rheumatoid arthritis) was 1 (95% CI, 0.7–1.3) and for lymphomas was 5.4 (95% CI, 2.6–10). The observed Standardized Incidence Ratio for lymphoma in studies of inﬂiximab for Crohn’s disease studies was 8.7 (range 31.05–1.05) (representing two cases). The observed Standardized Incidence Ratio for lymphomas was 2.3 to 3.5 seen in etanercept rheumatoid arthritis clinical trials, which falls within the expected range. In postmarketing data, 70 additional cases had been reported, which suggests a rate of lymphoma of 0.03 cases per 100 patient years, which is expected. This almost certainly represents an underestimate of the true incidence, however, because the extent of underreporting is diﬃcult to estimate [61].

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Summary Strategies designed at blocking or reducing TNF-a can be highly eﬀective in treating Crohn’s disease and rheumatoid arthritis. TNF-a clearly plays an important role in Crohn’s disease and probably a similar, although less deﬁned role in ulcerative colitis. The results of clinical studies of anti–TNF-a in Crohn’s disease reinforce this importance but the contrasting results between inﬂiximab with the less impressive results of another TNF-a antibody, CDP-571, and the negative results of etanercept, suggest that either higher doses are required to produce a more signiﬁcant response or reduced levels of TNF-a alone may be insuﬃcient. Although TNF-a is certainly of central importance in Crohn’s disease, its primacy may be questioned. The additional eﬀects of inﬂiximab, other than binding to its targeted cytokine alone, may be of greater importance, distinguishing it from its less potent competitors. This is paramount both in understanding the role of TNF-a in Crohn’s disease and to design more eﬀective therapy. The choice depends on eﬃcacy, adverse events, and cost. Certain side eﬀects are common to the three main anti–TNF-a agents approved for rheumatoid arthritis and may be an unavoidable complication when these agents are used in a large population. Clinically, this approach has yielded medications, which have revolutionized the care of patients with Crohn’s disease. The beneﬁt comes at a signiﬁcant burden of complications and adverse eﬀects, however, including infection, autoimmunity, lymphoma, and death. Furthermore, the use of inﬂiximab is limited in some by the development of antibodies and waning eﬃcacy. It remains to be proved whether other anti–TNF-a therapies following in the footsteps of inﬂiximab will be as eﬀective and overcome the obstacles involved with inﬂiximab therapy. Whether the signiﬁcant side eﬀects of treatment associated with inﬂiximab are all class eﬀects or vary between agents is not yet established. At present, although only one anti–TNF therapy is FDA approved, several others are likely to be in use in the near future. A diversity of strategies to block TNF-a is being researched including administration of antibodies, small molecules, or even the development of autoantibody vaccines, referred to as pharmaccines. The calculus of adverse events and eﬃcacy will guide their use in the years ahead. References [1] Present DH, Rutgeerts P, Targan S, Hanauer SB, Mayer L, van Hogezand RA, et al. Inﬂiximab for the treatment of ﬁstulas in patients with Crohn’s disease. N Engl J Med 1999;340:1398–405. [2] Targan SR, Hanauer SB, van Deventer SJ, Mayer L, Present DH, Braakman T, et al. A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor alpha for Crohn’s disease. Crohn’s Disease cA2 Study Group. N Engl J Med 1997;337:1029–35. [3] Murch SH, Lamkin VA, Savage MO, Walker-Smith JA, MacDonald TT. Serum concentrations of tumour necrosis factor alpha in childhood chronic inﬂammatory bowel disease. Gut 1991;32:913–7.

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[4] Braegger CP, Nicholls S, Murch SH, Stephens S, MacDonald TT. Tumour necrosis factor alpha in stool as a marker of intestinal inﬂammation. Lancet 1992;339:89–91. [5] Reinecker HC, Steﬀen M, Witthoeft T, Pﬂueger I, Schreiber S, MacDermott RP, et al. Enhanced secretion of tumour necrosis factor-alpha, IL-6, and IL-1 beta by isolated lamina propria mononuclear cells from patients with ulcerative colitis and Crohn’s disease. Clin Exp Immunol 1993;94:174–81. [6] Hanauer SB, Feagan BG, Lichtenstein GR, Mayer LF, Schreiber S, Colombel JF, et al. Group AIS. Maintenance inﬂiximab for Crohn’s disease: the ACCENT I randomised trial. Lancet 2002;359:1541–9. [7] Baert F, Noman M, Vermeire S, Van Assche G, Carbonez A, Rutgeerts P. Inﬂuence of immunogenicity on the long-term eﬃcacy of inﬂiximab in Crohn’s disease. N Engl J Med 2003;348:601–8. [8] Rodenburg R, Ganga A, van Lent P, van de Putte L, van Venrooij W. The antiinﬂammatory drug sulfasalazine inhibits tumor necrosis factor alpha expression in macrophages by inducing apoptosis. Arthritis Rheum 2000;43:1941–50. [9] Bauditz J, Haemling J, Ortner M, Lochs H, Raedler A, Schreiber S. Treatment with tumour necrosis factor inhibitor oxpentifylline does not improve corticosteroid dependent chronic active Crohn’s disease. Gut 1997;40:470–4. [10] Ehrenpreis ED, Kane SV, Cohen LB, Cohen RD, Hanauer SB. Thalidomide therapy for patients with refractory Crohn’s disease: an open-label trial. Gastroenterology 1999;117: 1271–7. [11] Vasiliauskas EA, Kam LY, Abreu-Martin MT, Hassard PV, Papadakis KA, Yang H, et al. An open-label pilot study of low-dose thalidomide in chronically active, steroid-dependent Crohn’s disease. Gastroenterology 1999;117:1278–87. [12] Sandborn WJ, Feagan BG, Hanauer SB, Present DH, Sutherland LR, Kamm MA, et al. An engineered human antibody to TNF (CDP571) for active Crohn’s disease: a randomized double-blind placebo-controlled trial. Gastroenterology 2001;120:1330–8. [13] Stack WA, Mann SD, Roy AJ, Heath P, Sopwith M, Freeman J, et al. Randomised controlled trial of CDP571 antibody to tumour necrosis factor-alpha in Crohn’s disease. Lancet 1997;349:521–4. [14] Evans RC, Clarke L, Heath P, Stephens S, Morris AI, Rhodes JM. Treatment of ulcerative colitis with an engineered human anti-TNFalpha antibody CDP571. Aliment Pharmacol Ther 1997;11:1031–5. [15] Blam ME, Stein RB, Lichtenstein GR. Integrating anti-tumor necrosis factor therapy in inﬂammatory bowel disease: current and future perspectives. Am J Gastroenterol 2001;96: 1977–97. [16] Mueller C. Tumour necrosis factor in mouse models of chronic intestinal inﬂammation. Immunology 2002;105:1–8. [17] Keane J, Gershon S, Wise RP, Mirabile-Levens E, Kasznica J, Schwieterman WD, et al. Tuberculosis associated with inﬂiximab, a tumor necrosis factor alpha-neutralizing agent. N Engl J Med 2001;345:1098–104. [18] Zerlauth G, Eibl MM, Mannhalter JW. Induction of anti-mycobacterial and anti-listerial activity of human monocytes requires diﬀerent activation signals. Clin Exp Immunol 1991; 85:90–7. [19] Eggimann P, Chiolero R, Chassot P, Lienard D, Gerain J, Lejeune F. Systemic and hemodynamic eﬀects of recombinant tumor necrosis factor alpha in isolation perfusion of the limbs. Chest 1995;107:1074–82. [20] Bossola M, Muscaritoli M, Bellantone R, Pacelli F, Cascino A, Sgadari A, et al. Serum tumour necrosis factor-alpha levels in cancer patients are discontinuous and correlate with weight loss. Eur J Clin Invest 2000;30:1107–12. [21] Kelly P, Summerbell C, Ngwenya B, Mandanda B, Hosp M, Fuchs D, et al. Systemic immune activation as a potential determinant of wasting in Zambians with HIV-related diarrhoea. QJM 1996;89:831–7.

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[43] Bariol C, Meagher AP, Vickers CR, Byrnes DJ, Edwards PD, Hing M, et al. Early studies on the safety and eﬃcacy of thalidomide for symptomatic inﬂammatory bowel disease. J Gastroenterol Hepatol 2002;17:135–9. [44] Sabate JM, Villarejo J, Lemann M, Bonnet J, Allez M, Modigliani R. An open-label study of thalidomide for maintenance therapy in responders to inﬂiximab in chronically active and ﬁstulizing refractory Crohn’s disease. Aliment Pharmacol Ther 2002;16:1117–24. [45] Kane S, Stone LJ, Ehrenpreis E. Thalidomide as ‘‘salvage’’ therapy for patients with delayed hypersensitivity response to inﬂiximab: a case series. J Clin Gastroenterol 2002;35: 149–50. [46] MacDonald TT. Oxpentifylline, tumour necrosis factor-alpha and Crohn’s disease [comment]. Gut 1997;40:559. [47] D’Haens G, Swijsen C, Noman M, Lemmens L, Ceuppens J, Agbahiwe H, et al. Etanercept in the treatment of active refractory Crohn’s disease: a single-center pilot trial. Am J Gastroenterol 2001;96:2564–8. [48] Sandborn WJ, Hanauer SB, Katz S, Safdi M, Wolf DG, Baerg RD, et al. Etanercept for active Crohn’s disease: a randomized, double-blind, placebo-controlled trial. Gastroenterology 2001;121:1088–94. [49] Marzo-Ortega H, McGonagle D, O’Connor P, Emery P. Eﬃcacy of etanercept for treatment of Crohn’s related spondyloarthritis but not colitis. Ann Rheum Dis 2003;62: 74–6. [50] Rutgeerts P, Lemmens L, Van Assche G, Noman M, Borghini-Fuhrer I, Goedkoop R. Treatment of active Crohn’s disease with onercept (recombinant human soluble p55 tumour necrosis factor receptor): results of a randomized, open-label, pilot study. Aliment Pharmacol Ther 2003;17:185–92. [51] Martinez-Borra J, Lopez-Larrea C, Gonzalez S, Fuentes D, Dieguez A, Deschamps EM, et al. High serum tumor necrosis factor-alpha levels are associated with lack of response to inﬂiximab in ﬁstulizing Crohn’s disease. Am J Gastroenterol 2002;97:2350–6. [52] Van den Brande JM, Braat H, van den Brink GR, Versteeg HH, Bauer CA, Hoedemaeker I, et al. Inﬂiximab but not etanercept induces apoptosis in lamina propria T-lymphocytes from patients with Crohn’s disease. Gastroenterology 2003;124:1774–85. [53] Feagan B, Sandborn W, Baker J, et al. A randomized, double-blind, placebo-controlled trial of the engineered human antibody to TNF (CDP571) for steroid sparing and maintenance of remission in patients with steroid-dependent Crohn’s disease. Gastroenterology 2000;118:A655. [54] Cornillie F, Shealy D, D’Haens G, Geboes K, Van Assch G, Ceuppens J, et al. Inﬂiximab induces potent anti-inﬂammatory and local immunomodulatory activity but no systemic immune suppression in patients with Crohn’s disease. Aliment Pharmacol Ther 2001;15: 463–73. [55] Moreland L, Bucy R, Weinblatt M, Mohler K, Spencer-Green G, Chatham W. Immune function in patients with rheumatoid arthritis treated with etanercept. Clin Immunol 2002; 103:13–21. [56] Keane J, Gershon S, Wise R, Mirabile-Levens E, Kasznica J, Schwieterman W, et al. Tuberculosis associated with inﬂiximab, a tumor necrosis factor alpha-neutralizing agent. N Engl J Med 2001:1098–104. [57] Summaries for patients. Tumor necrosis factor antagonists and heart failure. Ann Intern Med 2003;138:I48. [58] Chung E, Packer M, Lo K, Fasanmade A, Willerson J. Randomized, double-blind, placebo-controlled, pilot trial of inﬂiximab, a chimeric monoclonal antibody to tumor necrosis factor-alpha, in patients with moderate-to-severe heart failure: results of the antiTNF Therapy Against Congestive Heart Failure (ATTACH) trial. Circulation 2003: 3133–40. [59] Kwon HJ, Cote TR, Cuﬀe MS, Kramer JM, Braun MM. Case reports of heart failure after therapy with a tumor necrosis factor antagonist. Ann Intern Med 2003;138:807–11.

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[60] Lewis JD, Bilker WB, Brensinger C, Deren JJ, Vaughn DJ, Strom BL. Inﬂammatory bowel disease is not associated with an increased risk of lymphoma. Gastroenterology 2001;121: 1080–7. [61] Document FB. Update on the TNF blocking agents. Available at: www.fda.gov/ohrms/ dockets/ac/03/brieﬁng/3930B1_01_B-TNF.Brieﬁng.doc 2003. Accessed March 4, 2003.

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Mesalamine derivatives in the treatment of Crohn’s disease Laura E. Harrell, MD, Stephen B. Hanauer, MD* Section of Gastroenterology and Nutrition, University of Chicago Medical Center, 5841 South Maryland Avenue, MC 4076, Chicago, IL 60637, USA

Aminosalicylates have become the ﬁrst-line therapy to induce and maintain remissions for mild to moderate inﬂammatory bowel disease (IBD). Sulfasalazine was the ﬁrst aminosalicylate used for the treatment of IBD, although it was initially developed for the treatment of rheumatoid arthritis in the 1940s. Sulfasalazine is comprised of sulfapyridine linked to 5aminosalicylic acid ([5-ASA] mesalamine) by an azobond and was intended to provide antibacterial (sulfapyridine) and anti-inﬂammatory (5-ASA) eﬀects to arthritic joints. Subsequently, it was noted that rheumatoid arthritis patients with concomitant ulcerative colitis (UC) had improvement of their colitis [1]. A landmark study by Khan et al [2] determined 5-ASA to be the active component of sulfasalazine in the treatment of IBD. 5-ASA, when administered orally, behaves as a zwitterion and is absorbed proximally in the stomach and small intestine. Sulfapyridine functions as a carrier of the 5-ASA moiety preventing proximal absorption and delivering the sulfasalazine to the colon where the azobond is cleaved by bacterial azoreductases liberating sulfapyridine and 5-ASA. Sulfapyridine is absorbed from the colon and is acetylated by the liver. Depending on the acetylator status of a patient, free sulfapyridine in the serum accounts for most of the allergic and intolerant eﬀects of sulfasalazine (see later). After 5-ASA is released into the colon, a signiﬁcant amount is absorbed by the epithelium where it is metabolized by N-acetyltransferase 1 to N-Ac– 5-ASA, an inactive metabolite [3,4]. N-Ac–5-ASA is then secreted by a Pglycoprotein membrane eﬄux pump back into the lumen and mostly excreted in the feces [5,6]. A proportion of 5-ASA that is not acetylated by the intestinal epithelial N-acetyltransferase 1 enzyme is systemically absorbed, undergoes acetylation by N-acetyltransferase 1 in the liver, and * Corresponding author. E-mail address: [email protected] (S.B. Hanauer). 0889-8553/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.gtc.2004.02.010

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is excreted in the bile or the urine in a 10:1 ration of N-Ac–5-ASA:free-5ASA. A recent systemic review of the pharmacologic parameters of 5-ASA formulations found no signiﬁcant diﬀerence in the systemic absorption of 5ASA and N-Ac–5-ASA after administration of diﬀerent 5-ASA formulations [7]. To prevent proximal absorption and allow delivery of 5-ASA to distal sites of inﬂammation in UC and Crohn’s disease delayed- and sustainedrelease compounds and alternative azobond delivery systems have been developed. In addition, topical (rectal) formulations of mesalamine, including suppositories, enemas, and foams, have been marketed to allow direct application of 5-ASA to the rectum or left colon. Delayed- and sustained-release formulations use pharmacologic coatings that dissolve in a pH or time-dependent manner. Mesalamine is composed of 5-ASA incorporated into microgranules of ethylcellulose, a semipermeable membrane that dissolves when hydrated, allowing the slow release of mesalamine in a time-dependent manner [8]. Although approximately 20% to 50% of 5-ASA is released into the small intestine from mesalamine formulations [5], because of the impact of local pH and concentration, similar amounts of 5-ASA are systemically absorbed similar to other aminosalicylate formulations [8]. Other formulations use Eudragit, an acrylic-based resin, as a coating that dissolves at various intraluminal pH values and allows the release of mesalamine to the ileum (Eudragit-L) or distal ileum and colon (Eudragit-S). Asacol is designed to release 5-ASA in the colon where the intraluminal pH is greater than 7, whereas formulations of mesalamine coated in Eudragit-L (Claversal, Mesasal, and Salofalk) are released more proximally in the distal ileum and colon. Mesalamine may also be linked by an azobond to an alternative carrier to avoid side eﬀects commonly found with sulfapyridine. The ﬁrst such compound to be developed and marketed was olsalazine (azodisalicylate, Dipentum). Subsequently, balsalazide (Colazal) has been formulated to use aminobenzoyl-b-alanine, an inert carrier, attached by an azobond to 5-ASA. Similar to sulfasalazine, both compounds are delivered into the colon where the azobond is cleaved by intracolonic bacteria, releasing the active 5-ASA. The use of sulfasalazine has been limited by side eﬀects and drug intolerance primarily, but not exclusively, related to the sulfapyridine molecule [9]. Intolerance to sulfasalazine manifest by nausea, vomiting, anorexia, headaches, myalgias, and arthralgias is most often experienced by patients who are phenotypically slow acetylators of sulfapyridine [10–12]. These symptoms may be overcome by initiating therapy with a lower starting dose and gradual titration to therapeutic doses. Alternatively, nausea can be overcome by administration with meals or by an entericcoated formulation of sulfasalazine. Sulfapyridine and rarely mesalamine may also cause hypersensitivity reactions. These reactions range from fever and rash to more generalized allergic reactions. There are also rare reports of pancreatitis [13]; hepatitis

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[14–16]; pneumonitis [17]; drug-induced connective tissue disorder [18]; hemolytic anemia; and bone marrow suppression (the latter primarily with sulfasalazine) [19]. Sulfasalazine can also cause reversible abnormalities of sperm number and morphology that can, occasionally, be related to impaired male fertility. In rare instances, mesalamine may also cause worsening of colitis [20,21]. This hypersensitivity reaction should be considered in patients with refractory colitis receiving a mesalamine product. Olsalazine and the other azobond compounds may also be responsible for inducing diarrhea by enhanced bicarbonate secretion in the small intestine that increases ﬂuid volumes delivered to the colon. Inﬂamed colons may be unable to resorb increased ﬂuid volumes resulting in poor tolerance of high doses of these compounds (greater than 2 g/d of 5-ASA) in active IBD [22,23], although most with quiescent colitis are able to tolerate the azo formulations. Prior concerns regarding the theoretical potential of salicylate-induced nephrotoxicity in humans have been allayed by extensive experience with these agents. Although there certainly have been case reports of mesalamine-related interstitial nephritis, and animal data suggest a potential for nephrotoxicity [24,25], recent studies have found no reduction in glomerular ﬁltration rate during maintenance therapy with mesalamine or olsalazine [26]. Other series monitoring adverse events with mesalamine therapy have not observed an increase in renal insuﬃciency [27,28], although cases of idiosyncratic, allergic interstitial nephritis have led to regulatory recommendations for periodic monitoring of renal function.

Extensive ulcerative colitis Active disease Oral aminosalicylates are eﬀective therapy for mild to moderate UC. Many studies have been performed to assess the eﬃcacy and safety of oral 5ASA; however, comparisons across trials are hampered by a lack of standard indices for clinical or endoscopic ﬁndings in UC. Despite these variations, meta-analyses and systemic reviews examining the eﬃcacy and safety of 5-ASA drugs have been published, providing valuable conclusions regarding the treatment of UC. In 1993, Sutherland et al [29] performed one of the ﬁrst meta-analyses of randomized controlled trials comparing 5-ASA preparations with placebo and sulfasalazine. These authors concluded that newer 5-ASA drugs in doses greater than 2 g/d were superior to placebo in the treatment of UC. This meta-analysis also revealed that none of the newer preparations were superior to sulfasalazine in achieving remission [29]. The same authors have recently published an updated meta-analysis, which included more recent studies and aimed to determine the eﬀectiveness, dose-responsiveness, and

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safety of 5-ASA preparations. The outcome measures of this meta-analysis included endoscopic, global, and clinical measures of improvement or complete remission. The conclusion remains that 5-ASA is superior to placebo in achieving clinical improvement or remission in the treatment of UC. The updated Cochrane analysis also found a trend favoring the newer 5-ASA formulations over sulfasalazine, although this diﬀerence was not statistically signiﬁcant, with a pooled odds ratio of 0.9 (95% CI, 0.6–1.2) for the failure to induce global or clinical improvement or remission. The authors believed the clinical relevance of this ﬁnding was debatable [30,31]. There are also insuﬃcient data to support that any 5-ASA formulation provides superior eﬃcacy over others. Recent controversies have arisen as to whether balsalazide is superior to pH-release formulations of mesalamine in left-sided colitis. Although one published trial by Green et al [32] suggested that balsalazide, 6.75 g/d, was superior to mesalamine, 2.4 g/d, in the induction of complete remission at 12 weeks (P = .0159; (95% CI, balsalazide, 48.5–75.5; mesalamine, 23.5–50.5), others have reported conﬂicting results [33,34]. Levine et al [33] and Pruitt et al [34] both reported no diﬀerence in eﬃcacy between mesalamine and balsalazide in inducing remission of acute UC at 8 weeks. Both studies did observe the median time to symptomatic remission was shorter in patients receiving balsalazide [33,34]. Nevertheless, no trial has prospectively demonstrated overall superior eﬃcacy of any non–sulfa-containing aminosalicylate over another [35]. The safety of aminosalicylates has also been evaluated in the most recent Cochrane analysis. Although the adverse eﬀects attributable to the aminosalicylates are well known, compared with placebo-treated patients the analysis could ﬁnd no diﬀerence in the incidence of adverse events and withdrawals among the diﬀerent non–sulfa-containing formulations [30,31]. There were, however, signiﬁcantly more withdrawals because of adverse events in patients receiving sulfasalazine when compared with patients receiving the newer 5-ASA preparations [30,31]. In addition, a pooled metaanalysis of ﬁve olsalazine studies found signiﬁcantly more olsalazine-treated patients withdrew from studies because of adverse events (8.8%) versus patients receiving placebo (3.3%) (pooled odds ratio 2.53; [95% CI, 1.23– 5.22]) [31,36]. Maintenance Another recent meta-analysis evaluated the eﬃcacy and dose-responsiveness of newer 5-ASA formulations in maintaining remission compared with placebo and sulfasalazine. Five studies reporting the failure to maintain endoscopic and clinical remission were pooled comparing 5ASA with placebo. The combined odds ratio was 0.47 (95% CI, 0.36–0.62) with a number needed to treat of 6, showing 5-ASA to be eﬀective in

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the maintenance of UC. Of note, a dose-dependent trend was not found [37]. When evaluating the failure to maintain endoscopic or clinical remission with 5-ASA versus sulfasalazine, the same meta-analysis found sulfasalazine was superior to the other 5-ASA formulations at 6 months, with a combined odds ratio of 1.29 (95% CI, 1.05–1.57) and a number needed to treat of ÿ19. This statistical signiﬁcance was lost when only trials of 12 months duration were analyzed [37].

Distal ulcerative colitis Active disease Rectal formulations of mesalamine are an alternative to oral aminosalicylates as a ﬁrst-line therapy for the treatment of mild to moderately active distal UC and are available as suppositories or enema in North America, and in foam formulations elsewhere. Suppositories deliver mesalamine up to 20 cm from the anal verge and are often used for the treatment of ulcerative proctitis. Enemas deliver mesalamine, depending on volume, up to or beyond the splenic ﬂexure. Although topical mesalamine is the most eﬀective therapy for distal UC, the requisite for nocturnal administration, problems with retention, leakage, and bloating may hinder compliance. Development of better-tolerated topical products, such as gel enemas, is on the horizon and initial studies have shown mesalamine gel enemas to be equally eﬃcacious and better tolerated than foam formulations [38]. Topical mesalamine therapy has been shown to be the most eﬀective mode of therapy in distal UC. A recent systemic review of treatment options for distal UC by Cohen et al [39] found clinical improvement and remission rates with topical mesalamine to be consistently higher than with oral mesalamine. In another meta-analysis, topical mesalamine therapy also led to signiﬁcantly superior endoscopic and histologic improvement rates compared with placebo with a pooled odds ratio of 10 (95% CI, 5.7–17.6) and 10 (95% CI, 5.8–18.2), respectively [40,41]. From a dose-response standpoint, although formulations are available between 500 mg and 4 g, Cohen et al [39] concluded that there is no clear dose eﬀect found with mesalamine enemas or suppositories in doses greater than 1 g/d. Two recent meta-analyses have also shown topical mesalamine to be superior to rectal corticosteroids in achieving remission or clinical improvement in distal UC [39,40]. Although there has only been one controlled trial evaluating rectal steroids as adjunctive therapy to topical 5ASA [42], clinical experience suggests that combining topical steroid therapy with topical mesalamine may be useful for inducing a response in patients who are refractory to one or the other formulation.

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Maintenance Trallori et al [43] evaluated the maintenance of remission of distal UC comparing mesalamine enemas with oral treatment with mesalamine, sulfasalazine, or olsalazine. This meta-analysis conﬁrmed that topical therapy, primarily mesalamine enemas, was equally eﬃcacious as the oral mesalamine preparations. Their economic analysis also found enema therapy to cost less, and they concluded that mesalamine enemas are the treatment of choice for maintaining remissions in distal UC. Cohen et al [39] also reviewed studies of rectally delivered aminosalicylates for the maintenance of remission. They found that, despite the small size of most trials, topical mesalamine (enemas or suppositories) does maintain remissions and that varying dosing intervals only minimally decrease the eﬃcacy of topical therapy. In practice, the authors gradually reduce the dosing frequency of topical administration to identify the lowest weekly dosing schedule that maintains remissions in patients with distal UC. They usually try to transition patients to an oral aminosalicylate but ﬁnd (unpublished data) that most patients who require topical mesalamine to achieve remissions continue to require some dosing interval of topical therapy to maintain remissions.

The optimal dose No one study has identiﬁed the optimal dose of 5-ASA for the treatment of UC [44]. The most recent meta-analysis by Sutherland et al [31] observed a dose-response eﬀect of 5-ASA when compared with placebo in achieving complete global or clinical improvement, although the trend was less signiﬁcant when evaluating the rate of achieving complete global or clinical improvement. Although induction trials with time-release mesalamine have demonstrated a dose response up to 4 g [45] or 4.8 g [46] daily, a recent trial with a new pellet preparation of mesalamine failed to demonstrate beneﬁts of doses greater than 3 g daily (comparable with 5-ASA from 7.5 g of sulfasalazine) [44]. The study found no signiﬁcant dose response between mesalamine, 1.5, 3, or 4.5 g daily, and even after a subgroup analysis of patients with higher clinical activity indices, long-standing and extensive disease, or extraintestinal manifestations there was no signiﬁcant dose response [47]. Similarly, in a meta-analysis of maintenance trials of aminosalicylates in UC, a dose-dependent trend was not observed [37]. It remains unclear, however, whether patients with a high risk for relapse or those who have required higher doses of 5-ASA to achieve remission beneﬁt from higherdose maintenance therapy. The combination of oral and topical therapy can also be used for maintenance of left-sided UC as has been conﬁrmed in a trial comparing combination therapy with oral mesalamine, 1.6 g daily, and 4 g mesalamine enemas twice weekly with treatment with oral mesalamine, 1.6 g

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daily [48]. A study enrolling patients with similar high risk for relapse receiving higher doses of oral mesalamine is greatly needed to add evidence to the clinical impression that higher doses may be required in high risk of relapse patients.

Crohn’s disease Active disease Aminosalicylates remain a foundational therapy for the treatment of mild to moderate Crohn’s disease dating back to the trials evaluating sulfasalazine in the 1970s. The National Cooperative Crohn’s Disease Study (NCCDS) demonstrated that sulfasalazine was signiﬁcantly better than placebo in the treatment of active Crohn’s disease involving the ileum or colon, but not in patients with isolated small bowel disease [49]. These results were not, however, conﬁrmed in the European Cooperative Crohn’s Disease Study where only methylprednisolone, either alone or with sulfasalazine, was eﬃcacious compared with placebo [50]. Compared with the NCCDS where dosing went up to 6 g, however, the dose of sulfasalazine in the European trial was limited to 3 g/d. More recently, the development of formulations with alternative 5-ASA delivery systems has led to studies evaluating mesalamine formulations with the potential to deliver active drug to the small bowel or colon. Along these lines, a landmark study by Singleton et al [51] compared the eﬃcacy of the Pentasa formulation of mesalamine at 1, 2, or 4 g/d compared with placebo. This study enrolled 310 patients and demonstrated that the 4 g/d was statistically superior to placebo. Whereas lower doses were of no beneﬁt the three-dose and four-dose trends across these doses were statistically signiﬁcant. The same investigators repeated the study with a second identical trial involving 232 patients that eliminated the 1 g dosing group and compared Pentasa, 2 or 4 g/d, with placebo. Although the response to active drug was similar to that seen in the ﬁrst trial, the placebo response was higher. A third trial with Pentasa, 4 g/d, versus placebo also demonstrated consistent beneﬁts with reduction in the Crohn’s disease activity index (CDAI); however, a higher than expected placebo response precluded demonstration of statistical beneﬁts. In a pooled analysis of these three trials, however, a statistically signiﬁcant reduction in the CDAI with the 4 g/d dose compared with placebo [52]. Additional clinical trials have compared various formulations of mesalamine with placebo in the treatment of acute Crohn’s disease. Most of these studies are small and diﬀer greatly in their methodology. Most studies suggest a trend toward therapeutic beneﬁt of mesalamine over placebo, and several demonstrated statistically signiﬁcant beneﬁts [51–54]. Because of heterogeneity in both the release and delivery formulations of the aminosalicylates, inconsistent dosing, and quite varied patient population

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(diﬀering disease locations, complications, and disease activity), and similar to sulfasalazine, results of these trials preclude strong evidence of a consistent dose response with any individual formulation. Nevertheless, in most trials between 45% and 55% of patients treated with mesalamine formulations respond to the level of clinical remission (CDAI \ 150). Mesalamine formulations have also been compared with steroids in the treatment of acute Crohn’s disease [55,56]. Similar to the NCCDS, the European Cooperative Crohn’s Disease Study published in 1984 extended the comparison between sulfasalazine and corticosteroids in Crohn’s disease by comparing the eﬀectiveness of sulfasalazine and 6-methylprednisolone alone and in combination. Similar to the NCCDS the European Cooperative Crohn’s Disease Study identiﬁed 6-methylprednisolone to be the most eﬀective treatment in active disease (P \ .001); small bowel disease (P \ .05); and small bowel and colon disease (P \ .05). The combination of 6-methylprednisolone and sulfasalazine was the most eﬀective treatment in disease localized to the colon (P \ .001) but sulfasalazine alone was the least eﬀective treatment arm in all end points [57]. When budesonide, a potent glucocorticoid with ﬁrst-pass hepatic metabolism and formulated into microgranules for ileocecal release, was compared with slow-release mesalamine (Pentasa) in patients with mild to moderately active Crohn’s disease involving the ileum or right colon, the rates of remission after 8 weeks of treatment were 69% versus 45% in the budesonide and mesalamine groups, respectively (P \ .001) [56]. Although the glucocorticoid was superior in eﬃcacy to mesalamine, the 8-week results were consistent with the general eﬃcacy of mesalamine formulations in mild to moderate Crohn’s disease. When mesalamine in newer, microgranulated formulations was compared with methylprednisolone in a small Italian trial, the results were comparable [55]. Overall, it seems clear that steroid formulations are superior to the aminosalicylates in mild to moderately active Crohn’s disease [58]. Nevertheless, there may be compelling reasons to begin therapy with an aminosalicylate in patients with mild to moderately active Crohn’s disease (see later). In addition to comparisons of aminosalicylates with corticosteroids, the Pentasa formulation of slow-release mesalamine, 4 g daily, has been compared with ciproﬂoxacin, 1g daily, in patients with active Crohn’s disease at varied locations. In this French study there was no diﬀerence in achieving 6-week remissions between these treatment groups (56% and 55%, respectively) [59]. Again, the overall beneﬁts of mesalamine were consistent with other trials. Maintenance Although mesalamine has been found to have modest clinical beneﬁts in the treatment of active Crohn’s disease, there has been much debate regarding the eﬀectiveness of mesalamine maintenance therapy. Early studies of sulfasalazine used for maintenance therapy failed to demonstrate

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eﬃcacy in heterogeneous groups of patients either entering into or with established remissions [49,57,60]. In contrast, the French study group GETAID demonstrated that mesalamine may need to be administered immediately after achieving remission to demonstrate eﬃcacy, and that a delay beyond 3 months in therapy oﬀers no advantage compared with placebo [61]. The GETAID also has demonstrated that mesalamine is not eﬃcacious as a maintenance therapy after patients have been induced into remission with corticosteroids [62]. Subsequent studies have investigated various mesalamine formulations for the prevention of Crohn’s disease relapses, but many of these studies suﬀer from small sample sizes and heterogeneity of patients (disease location, complications, and inductive therapies with aminosalicylates, steroids, or surgery) [63–65]. Three metaanalyses have been performed to clarify the usefulness of mesalamine derivatives for the maintenance of Crohn’s disease. The ﬁrst meta-analysis by Messori et al [66] was published in 1994. Although there was heterogeneity among the studies included in the metaanalysis, the authors concluded that 5-ASA is eﬀective in the maintenance of Crohn’s disease, noting that in the included studies, virtually all relapse-free rates were consistently better in the treatment groups than in the controls. These authors also performed a pharmacoeconomic assessment of maintenance therapy with mesalamine calculating the cost for preventing a relapse to be $4000 to $10,000, an amount estimated to be less expensive than the estimated cost to treat a relapse. The same year, Steinhart et al [67] also published a meta-analysis that assessed 10 trials involving 1022 patients. The authors concluded that sulfasalazine or mesalamine reduced the risk of relapse at 12 months (RR = 0.77; 95% CI, 0.64–0.92) and in subgroup analysis, whereas mesalamine provided a statistically signiﬁcant therapeutic beneﬁt over placebo, the same was not seen when the sulfasalazine trials were analyzed alone. Most recently, Camma et al [68] updated the meta-analyses in 1997 but also divided maintenance trials into those enrolling patients after medically or surgically induced remissions. They included 15 studies in their analysis that enrolled 2097 patients. They found that although 5-ASA was eﬀective for the maintenance of Crohn’s disease, with a number needed to treat to prevent one relapse of 16, the pooled risk diﬀerence was statistically signiﬁcant in the surgical trials but not in the medical trials. They also performed a multivariate analysis that predicted mesalamine to be most eﬀective in patients with ileal disease, surgically induced remission, and prolonged disease duration. In contrast, they found neither a signiﬁcant diﬀerence between formulations, nor a dose response for mesalamine and also concluded that the starting point of treatment did not inﬂuence the eﬀectiveness of the therapy [68]. Because the recurrence rate of Crohn’s disease after surgically induced remission is predictably high with endoscopic recurrence rates of nearly 80% within 1 year [69] and clinical recurrence rates of 55% at 5 years and

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76% at 15 years [70], this setting oﬀers an important model to evaluate maintenance therapies in a more homogeneous population of Crohn’s disease patients. Nevertheless, disease location, complications, duration, prior therapies, and smoking status contribute to residual heterogeneity among patients [70]. There have been three trials evaluating sulfasalazine alone and one trial evaluating sulfasalazine in combination with corticosteroids for the prevention of postoperative recurrence of Crohn’s disease [49,71–73]. With the exception of 1-year follow-up data by Ewe et al [72], sulfasalazine has not proved to be superior to placebo in the postoperative setting. These results are not surprising considering that the active moiety of sulfasalazine, 5-ASA, is released into the colon and, in general, bypasses the anastomosis after an ileocolonic resection and should provide no theoretical beneﬁt in patients with small bowel Crohn’s disease. The newer derivatives of mesalamine designed to deliver active drug more proximally in the small bowel oﬀer more promise in the prevention of postoperative Crohn’s disease recurrence after an ileocolonic resection. In the meta-analysis by Camma et al [68], four trials were included that evaluated mesalamine for postoperative prevention and the pooled risk diﬀerence was ÿ13.1% (95% CI, ÿ21.8- ÿ4.5%; P = .0028) [68]. Since the publication of this meta-analysis a larger postoperative prevention trial by Lochs et al [74] evaluated 4 g of mesalamine (Pentasa) compared with placebo in 318 patients. Drug therapy was initiated within 10 days after the surgical resection and the patients were followed for 18 months postoperatively. In this trial there was no signiﬁcant diﬀerence in clinical recurrences with mesalamine compared with placebo; however, in a post hoc, subgroup analysis the authors described a signiﬁcant advantage for mesalamine maintenance therapy in patients with disease limited to the small bowel. Aminosalicylates as ﬁrst-line therapy for Crohn’s disease Despite published guidelines proponing aminosalicylates as a ﬁrst-line therapy for mild to moderate Crohn’s disease [75] a recent publication by Sandborn and Feagan [56] calls into question the strength of the evidence base for aminosalicylates in Crohn’s disease. The authors favor sulfasalazine for mild to moderate Crohn’s disease involving the colon based on the results of the NCCDS trial, yet disdain the results of numerous trials with mesalamine demonstrating positive beneﬁts for mild to moderate Crohn’s disease compared with placebo [51,54], corticosteroids [55], and antibiotics [59]. They focus on two subsequent placebo-controlled trials with the Pentasa formulation that did not demonstrate statistical beneﬁts despite the same magnitude of response to mesalamine (and an increased placebo response). Combining the Pentasa trials in a meta-analysis supports an overall statistical beneﬁt, although the combined reduction in CDAI across all trials is only approximately 11 points [52]. Furthermore, when all of the

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trials with aminosalicylates are combined, there is a consistent therapeutic remission induced in approximately 45% to 55% of patients with mild to moderate Crohn’s disease. The main issue when comparing aminosalicylates with corticosteroids (systemic or nonsystemic) is what happens after the initial induction. Granted, corticosteroids have been uniformly superior to aminosalicylates (except for the trial by Prantera et al [55]), yet the problem remains what to do with patients treated with corticosteroids after induction therapy. Corticosteroids, including budesonide, have not had a maintenance beneﬁt for Crohn’s disease [76,77] and approximately 75% of patients started on steroids become either steroid-dependent or relapse within 1 year [78,79]. In contrast, after mesalamine therapy patients can be continued on the same dose without the risk of accumulating side eﬀects [45,80]. These authors continue to advocate aminosalicylates as a ﬁrst-line agent with the option to continue therapy on a long-term basis or, if therapy is ineﬀective or there is a loss of response, a more potent and potentially more toxic therapy can be initiated. Summary The role of the aminosalicylates for induction therapy of mild to moderate UC and as maintenance treatment has been substantiated by a large series of controlled clinical trials and conﬁrmatory meta-analyses. Both sulfasalazine and the newer 5-ASA formulations have been found to be eﬀective in the treatment of active mild to moderate UC, with a trend favoring the newer 5-ASA drugs that is related to the safety of the non– sulfa-containing formulations. Both sulfasalazine and newer derivatives are eﬀective in preventing relapses. The optimal dose has yet to be clariﬁed for each clinical scenario, although there is a wide safety range for mesalamine formulations up to at least 4.8 g daily. It remains to be determined whether certain high-risk groups of patients may beneﬁt from higher doses of mesalamine induction or maintenance therapy. Mesalamine derivatives are also of beneﬁt in the treatment of Crohn’s disease. Sulfasalazine is eﬀective in mild to moderate disease involving the colon, but not for isolated small bowel disease. Formulations delivering mesalamine to the small bowel and proximal colon seem eﬀective in the treatment of mild to moderate active disease, although the eﬃcacy is less than corticosteroids. Sulfasalazine is likely not eﬀective in the maintenance of Crohn’s disease, although other mesalamine formulations continue to show some prophylactic activity after mesalamine-induced remissions and for patients with disease of the ileum who have undergone surgical resection. References [1] Svartz N. Sulfasalazine: II. Some notes on the discovery and development of salazopyrin. Am J Gastroenterol 1988;83:497–503.

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[72] Ewe K, et al. Postoperative recurrence of Crohn’s disease in relation to radicality of operation and sulfasalazine prophylaxis: a multicenter trial. Digestion 1989;42:224–32. [73] Bergman L, Krause U. Postoperative treatment with corticosteroids and salazosulphapyridine (Salazopyrin) after radical resection for Crohn’s disease. Scand J Gastroenterol 1976; 11:651–6. [74] Lochs H, et al. Prophylaxis of postoperative relapse in Crohn’s disease with mesalamine: European Cooperative Crohn’s Disease Study VI. Gastroenterology 2000;118:264–73. [75] Hanauer SB, Sandborn W. Management of Crohn’s disease in adults. Am J Gastroenterol 2001;96:635–43. [76] Steinhart AH, et al. Corticosteroids for maintaining remission of Crohn’s disease. Cochrane Database Syst Rev 2001;CD000301. [77] Simms L, Steinhart AH. Budesonide for maintenance of remission in Crohn’s disease (Cochrane Review). Cochrane Database Syst Rev 2001;1. [78] Faubion WA Jr, et al. The natural history of corticosteroid therapy for inﬂammatory bowel disease: a population-based study. Gastroenterology 2001;121:255–60. [79] Munkholm P, et al. Frequency of glucocorticoid resistance and dependency in Crohn’s disease. Gut 1994;35:360–2. [80] Hanauer SB, et al. Long-term management of Crohn’s disease with mesalamine capsules (Pentasa). Pentasa Crohn’s Disease Compassionate Use Study Group [see comments]. Am J Gastroenterol 1993;88:1343–51.

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Management of refractory inﬂammatory bowel disease Craig A. Solem, MDa, Edward V. Loftus, Jr, MDa,b,* a

Division of Gastroenterology and Hepatology, Mayo Clinic and Foundation, 200 First Street, SW, Rochester, MN 55905, USA b Department of Medicine, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA

One of the most challenging aspects of the management of inﬂammatory bowel disease (IBD) is the high frequency of incomplete or absent response to medical therapy. Indeed, even in the modern era of medical management with new aminosalicylates, modiﬁed steroids, immunosuppressive agents, and monoclonal antibodies, most IBD patients are not in remission at the end of the average clinical trial [1,2]. Although many patients may be truly refractory to medical therapy, a lack of response may indicate several possibilities including incorrect diagnosis, progression of disease extent, intestinal complication, superinfection, underdosing of therapy, monotherapy instead of combination therapy, or medication intolerance. This article provides a practical general approach to refractory IBD patients encountered in clinical practice. The details of individual medical therapies are discussed elsewhere in this issue. Establishing accurate diagnosis, disease extent, and disease severity Initially, it is imperative to establish or verify the speciﬁc IBD diagnosis and determine the extent and severity of disease. Correctly identifying the IBD subtype facilitates appropriate management decisions, because Crohn’s disease (CD) and ulcerative colitis (UC) are frequently treated diﬀerently. There is no single investigation that is diagnostic of UC or CD. The diagnosis is made when the clinical history and radiographic, endoscopic, and histologic ﬁndings are compatible with a particular IBD subtype. Similarly, IBD patients previously in remission who experience an exacerbation or who Dr. Loftus has received research support from Schering-Plough, Procter & Gamble, AstraZeneca, and GlaxoSmithKline. Dr. Loftus has served as a consultant for AstraZeneca. * Corresponding author. E-mail address: [email protected] (E.V. Loftus, Jr). 0889-8553/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.gtc.2004.02.011

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become refractory to therapy usually require a thorough assessment documenting the extent and activity of present disease. This is especially true of patients thought to have left-sided UC (eg, a study from Copenhagen County, Denmark, showed that 41% of patients with proctosigmoiditis had progression of disease extent over a 10-year period) [3]. The diagnostic evaluation depends on the clinical situation and IBD type if already known. A colonoscopy with terminal ileoscopy and biopsies should be performed in all patients at or soon after diagnosis. Patients experiencing prolonged exacerbations should undergo a colonoscopy with biopsies, except in cases of fulminant colitis (where a limited ﬂexible sigmoidoscopy with biopsies may be more appropriate). Colonoscopy in those who relapse conﬁrms the degree of disease activity; determines extent; and excludes complicating factors, such as stricture or malignancy. Patients suspected to have UC should undergo small bowel imaging (ie, small bowel follow-through, enteroclysis, or CT enterography) to exclude more proximal inﬂammation. Once the diagnosis of UC has solidly been established, this typically does not need to be repeated with disease ﬂares, except perhaps when proctocolectomy with ileal pouch–anal anastomosis is contemplated. Similarly, small bowel imaging should be performed in established refractory or relapsing CD patients not only to determine disease extent, but also to identify complications, such as ﬁstulas or strictures. CT of the abdomen and pelvis should be obtained in all refractory CD patients (and UC patients if clinically indicated) to exclude alternative intra-abdominal pathology, such as abscesses. When the diagnosis remains uncertain despite standard initial testing, such as in indeterminate colitis, further diagnostic investigation with nonstandard tests like serologic studies and wireless capsule videoendoscopy may be considered. Serologic tests used in IBD subtyping include perinuclear antineutrophil cytoplasmic antibodies, anti–Saccharomyces cerevisiae antibodies, and antibodies to outer membrane porin C of Escherichia coli. Although the details are beyond the extent of this article, the presence of anti– S cerevisiae antibodies or outer membrane porin C of E coli antibodies may suggest CD, whereas the presence of perinuclear antineutrophil cytoplasmic antibodies is more commonly found in UC [4–6]. These tests have incomplete sensitivity and speciﬁcity, however, and serve only as supplemental diagnostic aids. For example, only about half of patients with indeterminate colitis have positive serologic tests [7]. Preliminary reports suggest that wireless capsule videoendoscopy may identify small bowel inﬂammation not appreciated with standard imaging modalities, but this needs further study before routine clinical use for patients with indeterminate colitis or suspected IBD [8,9]. Identifying and managing complications of inﬂammatory bowel disease Complications of IBD may contribute to poor clinical response in refractory patients and should be identiﬁed. A particularly common

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situation is ﬁbrostenotic CD that is mistakenly treated as inﬂammatory CD. Refractory CD patients should undergo a small bowel barium study or CT enterography to exclude the possibility of stricturing, but narrowing caused by inﬂammation may often produce a similar appearance. One must use other clinical features to diﬀerentiate ﬁbrostenotic from inﬂammatory strictures, such as lack of elevation in erythrocyte sedimentation rate or Creactive protein level, stricture associated with prestenotic dilatation, or lack of clinical response to corticosteroids. Fibrostenotic strictures are best treated by surgical resection or stricturoplasty. The identiﬁcation of ﬁstulizing disease in refractory or relapsing CD patients may have important implications on medical management. Although internal ﬁstulas may be found by several imaging techniques, small bowel imaging and CT of the abdomen and pelvis represent the optimal diagnostic methods. Management of ﬁstulas is discussed more speciﬁcally elsewhere in this issue, but includes antibiotics, the purine analogues azathioprine (AZA) or 6-mercaptopurine (6-MP), methotrexate, cyclosporine, tacrolimus, and most eﬀectively inﬂiximab. Patients with symptomatic, medically refractory ﬁstulas, or those having particularly complicated or numerous internal ﬁstulas, may be better served with surgery. Intra-abdominal abscesses should be excluded in all CD patients with refractory or constitutional symptoms. Classic features, such as abdominal pain and fever, are frequently present, but patients may present with atypical manifestations, such as malaise, back pain, or cough (caused by diaphragmatic irritation). Abscesses may be identiﬁed by CT of the abdomen and pelvis or MRI of the abdomen and pelvis (for patients with iodine contrast allergy or signiﬁcant renal insuﬃciency). Intra-abdominal abscesses are typically treated by surgery or percutaneous drainage. Toxic megacolon may occur in patients with colitis of various extents, and patients typically have a fulminant presentation. These patients warrant hospitalization in all cases for supportive care and treatment, discussed more speciﬁcally elsewhere in this issue [10]. Stool is tested for infection, and a limited proctoscopy with biopsies to exclude cytomegalovirus (CMV) or other infection may cautiously be performed. Aggravating antidiarrheals or narcotics are discontinued. Patients are treated with broad-spectrum antibiotics and intravenous steroids. All patients are followed by a surgeon, and a proctocolectomy is warranted if the patient does not improve within a couple days or if the patient deteriorates.

Excluding and treating enteric infections Because enteric infections may mimic the clinical or endoscopic presentation of IBD or contribute to ﬂares of established disease, it is crucial to exclude such infections in all refractory IBD patients. Patients

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with a new possible IBD diagnosis or an exacerbation of disease formerly in remission should be tested for Clostridium diﬃcile toxin and for routine bacterial enteric pathogens (eg, Shigella, Campylobacter, E coli O157:H7, and Salmonella). Careful exposure, social, and travel histories should be taken to determine the need for testing for parasitic infections. CMV colitis and C diﬃcile colitis deserve particular attention and are discussed in-depth next. Cytomegalovirus is a widely prevalent virus that infrequently causes clinically signiﬁcant gastrointestinal infections, and its presence should be excluded in refractory IBD patients with colitis. The frequency of symptomatic CMV infection is estimated to range between 0.53% and 3.4% in all IBD patients [11,12]. The extent of colitis in aﬀected patients may range from proctitis to pancolitis [13]. Although most cases of CMV colitis in IBD occur in patients on corticosteroids or other immunosuppressive agents, cases among steroid-naı¨ ve patients have been described [13,14]. CMV colitis in IBD patients may lead to medically refractory disease, severe acute colitis, toxic megacolon, and even death [11,12,15]. Two thought-provoking case series detected active CMV colitis in 19% to 36% of patients with steroid-resistant acute severe colitis, and in both studies most patients treated with ganciclovir avoided colectomy, entered clinical remission, and successfully tapered oﬀ corticosteroids [11,15]. Histologic diagnosis of CMV (ie, presence of characteristically enlarged cells with intranuclear inclusion bodies) remains the gold standard, and a ﬂexible sigmoidoscopy with biopsies is usually suﬃcient to make the diagnosis [11,13]. If suspicion for CMV colitis remains high despite the absence of inclusion bodies on routine histology, however, immunohistochemical staining may be helpful in securing the diagnosis. Treatment of CMV colitis involves tapering oﬀ steroids and other immunosuppression as rapidly as possible while treating the patient with an antiviral agent, such as ganciclovir, valganciclovir, or foscarnet. Most patients subsequently improve clinically and avoid surgery [12,13]. Another pathogen that has been associated with exacerbations of IBD is C diﬃcile [16–19]. The prevalence of infection with this organism among IBD patients with ﬂares may be as high as 28% [17,18]. Importantly, C diﬃcile infection may be detected in IBD patients even in the absence of recent antibiotic use [17,18]. The role of C diﬃcile infection in contributing to an exacerbation of IBD is somewhat controversial, because some reports have suggested that C diﬃcile infections may actually be fairly uncommon and of limited importance [20,21]. A recent preliminary report, however, pointed to the usefulness of obtaining stool studies to exclude infection in patients with IBD exacerbations [22]. The prevalence of C diﬃcile infection in this series of patients was 19%, and most patients improved with antibiotic therapy [22]. The diagnostic yield of other stool studies, such as bacterial culture or ova and parasites, in this group of patients was low [22]. The authors believe that patients with refractory IBD, especially those with

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colonic involvement, should be tested for infection. The best diagnostic test is the assay for C diﬃcile toxins in the stool [23,24]. It is important to test for both C diﬃcile toxins A and B, because single toxin assays fail to detect a substantial number of infections in IBD patients [23]. Endoscopy, if performed, may demonstrate ﬁndings ranging from normal to patchy or diﬀuse colitis with or without pseudomembranes [16]. Treatment consists of oral metronidazole or vancomycin, or intravenous metronidazole in those unable to take oral medication, among other less eﬀective potential treatment options [24].

Optimizing medication doses The dosage of medications used to treat IBD should be fully optimized before considering a patient truly refractory to medical therapy. One of the 5-aminosalicylates (5-ASA), mesalamine, demonstrates a dose-response eﬀect, and increasing the daily dose of mesalamine to 4 to 4.8 g daily may increase response in those not adequately controlled with lower doses [2,10,25]. One of the ﬁrst studies of oral mesalamine for active UC performed in North America documented the superiority of oral mesalamine, 4.8 g daily, compared with 1.6 g daily [2]. Although higher doses of sulfasalazine are more eﬃcacious than lower doses, side eﬀects, such as headache and dyspepsia, often limit sulfasalazine dosing beyond 4 to 6 g daily. Balsalazide is another nonsulfa 5-ASA that is eﬀective in the induction of remission in UC [26]. The Food and Drug Administration approved induction dose of balsalazide is 6.75 g daily; whether higher doses may be more eﬃcacious remains to be determined. The Food and Drug Administration approved dosage of another 5-ASA, olsalazine, for the maintenance of remission of UC is 1 g daily. There are conﬂicting data as to whether higher doses are more eﬃcacious, and a watery, secretory-type diarrhea may occur at higher doses [27]. Prednisone doses between 40 and 60 mg daily may be required in refractory patients. The 60-mg dose may be appropriate in steroid-resistant patients not responding to lower doses [10]. The initial prednisone dose is maintained until signiﬁcant clinical improvement has been achieved before initiating a taper. Those with mild to moderately active CD who are on budesonide, 6 g daily, may be tried on the maximum dose of 9 g daily, but if the response is incomplete or symptoms are severe, patients should then be switched to oral prednisone. Hospitalized patients with severe CD or UC should be treated with intravenous methylprednisolone, 32 to 60 mg daily, or hydrocortisone, 300 to 400 mg daily, either in divided doses or as a continuous infusion [10]. The risk of early bone marrow suppression after initiating purine analogue therapy may be minimized by dosing according to the thiopurine methyltransferase genotype or phenotype. Patients with thiopurine

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methyltransferase tests that suggest intermediate enzyme activity should be initiated on a dose that is roughly half the standard dose of 1 to 1.5 mg/kg daily for 6-MP and 2 to 2.5 mg/kg daily for AZA. Patients with low thiopurine methyltransferase activity should not receive purine analogues, for fear of inducing prolonged severe leukopenia. Although the risk of early leukopenia may be minimized with this practice, continued periodic monitoring of blood counts is necessary [28]. The standard dose of 6-MP or AZA may be cautiously increased in selected refractory patients to higher doses in the absence of leukopenia (the primary dose-limiting factor) or other side eﬀects [29,30]. Measurement of thioguanine nucleotide metabolites may be helpful when increasing the dosage beyond the standard dose [30–32], although following changes in the mean corpuscular volume of red blood cells may be equally helpful [33]. Lastly, a clinically important subset of CD patients not responding to 5 mg/kg infusions of inﬂiximab may improve with the higher dose of 10 mg/kg [1].

Combination and sequential treatment Combination and sequential treatment of CD and UC is discussed elsewhere in this issue, but a few general principles regarding refractory IBD patients should be addressed here. Patients with CD who are steroiddependent or steroid-resistant should be treated with appropriate doses of a purine analogue or methotrexate [29,34–36]. Indications for inﬂiximab therapy in CD patients include moderate to severe inﬂammatory disease that has not responded to conventional therapy (including immunosuppressive agents); steroid-dependency; and ﬁstulizing CD [37]. CD patients who still remain refractory to optimal medical therapy, have ﬁbrostenotic disease, or complications, such as intra-abdominal abscesses, should undergo surgery. Refractory patients with UC should be given a trial of combination topical and oral therapy depending on disease extent. Unlike oral 5-ASA, no dose-response relationship for rectal mesalamine has been demonstrated [38,39]. Combination oral and rectal mesalamine treatment is more eﬀective than either oral or rectal treatment alone [40]. Patients who are steroiddependent, steroid-resistant, or relapsing despite optimally dosed 5-ASA treatment should be started on a purine analogue [41]. Although open-label experience suggests that methotrexate might be beneﬁcial for certain steroid-dependent or steroid-resistant UC patients [42], this has not been demonstrated by randomized trials [43]. Hospitalized patients with acute, severe UC who have not improved after 3 to 5 days of intravenous steroids may be treated with intravenous cyclosporine (2–4 mg/kg daily) initially and later converted to oral dosing to avoid proctocolectomy, but there is a high frequency of side eﬀects and relapse after drug discontinuation [10,25,44].

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A role for inﬂiximab in refractory UC patients has been suggested by uncontrolled trials [45,46], but early randomized trials have not shown a beneﬁt [47,48], and further studies are underway. Patients with refractory or relapsing UC despite 5-ASA, corticosteroids, and immunomodulators should be considered for proctocolectomy with Brooke ileostomy or ileal pouch–anal anastomosis, but the necessity and timing of surgery are inﬂuenced by patient preferences and disease severity. The combination management of toxic megacolon is discussed elsewhere in this issue.

Understanding mechanisms of drug resistance and failure Clinicians are ﬁnally gaining insight into the mechanisms of drug resistance and loss of response at the pharmacologic and cellular levels [49]. In population-based IBD cohorts, corticosteroid-resistance occurs in 16% to 20% of patients [50,51]. Clinical predictors of steroid-resistance in CD include prior bowel resection, perianal disease, and a high Crohn’s disease activity index [52]. From a molecular viewpoint, corticosteroid resistance might be explained by two potential mechanisms. First, steroid-resistant UC patients tend to have a predominance of glucocorticoid receptor beta receptors, rather than the standard alpha receptors [53]. Secondly, steroidresistance may be related to greater expression of the multidrug resistance gene in IBD patients [54]. The multidrug resistance gene produces a glycoprotein that functions as a drug eﬄux pump, and cells with high multidrug resistance gene expression have signiﬁcantly lower intracellular levels of corticosteroids, methotrexate, and cyclosporine [54]. The expression of multidrug resistance gene in peripheral blood lymphocytes among IBD patients who underwent surgical resection because of refractory disease was signiﬁcantly higher than healthy controls [54]. A substantial minority of patients treated with purine analogues seem to be refractory to these agents, even after escalation of dosage. One pharmacokinetic study suggested that many of these purine-refractory patients may metabolize AZA and 6-MP preferentially through a diﬀerent pathway, such that increasing doses of drug result in higher levels of the nontherapeutic metabolites 6-methylmercaptopurine ribonucleotides rather than the therapeutic metabolites 6-thioguanine nucleotides [55]. Because concomitant administration of 5-ASA drugs results in a clinically signiﬁcant drug interaction [56] (perhaps by blocking thiopurine methyltransferase, the enzyme that produces 6-methylmercaptopurine ribonucleotide), it is intriguing to speculate that co-administration of a 5-ASA agent with a purine analogue might reduce the frequency of purine-resistance; however, this remains unproved. Patients who have become refractory to inﬂiximab after repeated doses may have developed antibodies to inﬂiximab (formerly known as ‘‘human antichimeric antibodies’’). Such antibodies are associated with shortened

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duration and loss of response, and an increased risk of infusion reactions [37,57–59]. Three strategies may be used either individually or in combination to minimize the immunogenicity of inﬂiximab and thereby decrease the incidence of drug resistance [37,57–59]. First, concomitant administration of an immunosuppressive agent (eg, AZA, 6-MP, or methotrexate) with inﬂiximab seems to reduce immunogenicity [1,37,57,58]. Ideally, the immunosuppressive agent should be started well in advance of the ﬁrst inﬂiximab infusion, although this is obviously not always possible. Second, three-dose induction of inﬂiximab at 0, 2, and 6 weeks, followed by maintenance infusions approximately every 8 weeks, is associated with a lower prevalence of antibody formation [1,37]. Finally, premedication with intravenous hydrocortisone, 200 mg, has recently been shown to be an alternative approach to reducing the immunogenicity of inﬂiximab [58].

Recognizing and minimizing nonadherence to therapy Nonadherence to the recommended medical regimen should be sought in all refractory patients. The prevalence of nonadherence to medical regimens for IBD ranges from 40% to 60% [60,61]. Lack of compliance has been associated with relapse among UC patients previously in remission [62]. Patient-related factors, such as male gender, single marital status, and psychiatric disorders, and treatment-related factors, including multiple medications, frequent dosing intervals, side eﬀects, and expense, may contribute to nonadherence [60,63]. Direct questioning of patients about compliance is needed, because this information is not volunteered, but even direct questioning may not be fruitful. In selected situations, where the suspicion for noncompliance remains high, urinary salicylate levels and erythrocyte 6-thioguanine nucleotide levels can serve as surrogate markers for 5-ASA agents and purine analogues, respectively [30,64,65]. Recognizing nonadherence and adopting individualized strategies to optimize adherence should be important components in the management of refractory IBD patients. For example, once-daily or twice-daily dosing regimens should be considered for as many medications as possible.

Identifying drug intolerances and side-eﬀects The symptoms of either medication intolerance or allergy may be indistinguishable from those associated with IBD ﬂares. Gastrointestinal intolerances are particularly important with sulfasalazine and other 5-ASA drugs, accounting for most adverse events reported, but these typically resolve after drug discontinuation. Patients intolerant to one particular 5ASA formulation may tolerate another 5-ASA medication [66]. Flares of diarrhea and other typical IBD symptoms have been noted as adverse events

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with both sulfasalazine and mesalamine [66–74]. Although the exact mechanism behind these adverse events remains unclear, in some cases there seemed to be true hypersensitivity colitis [69–72,74]. The temporal relationship between initiation of medications and onset of symptoms, and carefully selected rechallenges after drug discontinuation, help diﬀerentiate drug intolerances and hypersensitivities from IBD ﬂares. If disease symptoms worsen shortly after increasing the dose of 5-ASA, or patients do not responding as expected to maximum 5-ASA dosages, then paradoxical reactions to 5-ASA must be considered. Olsalazine uniquely causes a secretory diarrhea that occurs in 10% to 15% of patients [75,76]. Olsalazine should be discontinued temporarily in patients with refractory IBD to see if symptoms improve. Refractory IBD patients should in general have a 5-ASA ‘‘holiday’’ to see if clinical improvement occurs, and 5-ASA may be resumed later if no beneﬁt from holding the drug is found.

Discontinuing nonsteroidal anti-inﬂammatory drugs Patients may take nonsteroidal anti-inﬂammatory drugs to treat IBDrelated arthritis, ankylosing spondylitis, or other painful ailments. Because many nonsteroidal anti-inﬂammatory drugs are available over-the-counter, physicians tend to underestimate the use of these medications. Nonsteroidal anti-inﬂammatory drugs are a well-described cause of acute colitis, even in patients without IBD [77,78]. Nonsteroidal anti-inﬂammatory drugs have been associated with ﬂares of both UC and CD in several case series and case-control studies [79–84]. The mechanism by which nonsteroidal antiinﬂammatory drugs may cause exacerbations of IBD is unknown, but may be related to inhibition of gut-protective prostaglandins [83]. A case-control study of 200 patients hospitalized for acute colitis and almost 1200 community controls found that prescription nonsteroidal anti-inﬂammatory drug use was signiﬁcantly higher among cases, especially among those newly diagnosed with IBD [82]. Others have argued that the association between nonsteroidal anti-inﬂammatory drugs and IBD ﬂares is spurious and may actually reﬂect patients taking nonsteroidal anti-inﬂammatory drugs for inﬂammatory arthritis, which heralds a ﬂare of IBD [85]. In support of this notion, a retrospective cross-sectional study of 192 IBD patients found no relationship between disease activity and prevalence of nonsteroidal antiinﬂammatory drug use [85]. A recent small retrospective study of IBD patients taking cyclooxygenase2 inhibitors (celecoxib and rofecoxib) found only two patients (7.4%) with worsening bowel symptoms after a median duration of therapy of 9 months [86]. This preliminary study suggests that the use of cyclooxygenase-2 inhibitors may be safe in IBD. Although cyclooxygenase-2 inhibitors may cautiously be tried in those with quiescent disease, a trial of stopping

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nonsteroidal anti-inﬂammatory drugs should be considered in patients with refractory IBD.

Understanding the role of smoking The interesting and opposite relationships between cigarette smoking and the occurrence of CD or UC are beyond the scope of this article and are reviewed elsewhere [87,88]. Not only does smoking impact the occurrence of IBD, it can signiﬁcantly modify the clinical course of CD and UC, again in divergent ways. Patients with CD who smoke cigarettes are more likely to have ileal involvement [89], and postoperative patients who continue to smoke are more likely to develop recurrent CD [90]. Smoking also increases the need for immunosuppressive agents [91]. CD patients who quit smoking are less likely than continued smokers to require corticosteroids or immunosuppressive therapy [92]. All CD patients, particularly those with refractory disease, should be strongly encouraged to quit smoking. In contrast to CD, smoking cessation may actually worsen the course of UC, with increased severity of disease, more frequent hospitalizations, and increased need for steroids or immunosuppression [93,94]. Continuation or resumption of smoking may have a beneﬁcial eﬀect on the clinical course of UC patients, with a reduction in symptoms and fewer hospitalizations [93,95]. Nicotine may be responsible for the potentially beneﬁcial eﬀect of smoking on UC. Transdermal nicotine may be eﬃcacious for the induction of remission in mild to moderately active UC, but is ineﬀective for maintenance [96–101]. It may be reasonable to consider transdermal nicotine patches in carefully selected patients with mild to moderate refractory UC that have not responded to 5-ASA and steroids, especially in former smokers. Given the substantial negative impact on overall health, cigarette smoking should never be recommended.

Addressing other important potential factors Especially in those who have no or minimal evidence of active disease after appropriate testing despite refractory symptoms, a few other potential contributing factors need to be considered. In these patients, an empiric lactose-free diet trial may identify patients with unrecognized lactose intolerance. Excessive caﬀeine intake, which may contribute to loose stools, should be stopped. Small bowel biopsies, if not previously taken, or serologic tests, such as tissue transglutaminase, should be performed to exclude celiac sprue. Superimposed irritable bowel syndrome may occur in IBD patients, and these patients should be treated similar to others with functional symptoms [29].

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Summary Numerous factors may contribute to refractory IBD and need to be addressed systematically. All patients require an accurate diagnosis of speciﬁc IBD type, and documentation of both disease activity and extent is crucial for management. Complications, such as strictures or abscesses, need to be recognized and treated appropriately. Enteric infections mimicking or exacerbating IBD should be excluded. Optimizing medication doses and stepwise combination and sequential treatment strategies are keys to successful medical therapy. Drug intolerances with paradoxical side eﬀects should be considered. Patients with chronic diseases like IBD may not adhere to medical therapy, and this possibility needs to be addressed with all refractory patients. Both conventional and cyclooxygenase-2–type nonsteroidal anti-inﬂammatory drugs should be discontinued in patients with refractory IBD. The role of smoking and nicotine replacement in IBD needs to be understood. Lastly, surgery very well may be the appropriate course for patients if refractory disease persists despite optimal medical management.

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Treatment of inﬂammatory bowel disease with antibiotics Kim L. Isaacs, MD, PhD*, R. Balfour Sartor, MD Division of Gastroenterology and Hepatology, Department of Medicine, University of North Carolina at Chapel Hill, CB# 1143, Bioinformatics Building, Chapel Hill, NC 27599–7080, USA

Although antibiotics are clearly recognized as having a role in treating the infectious complications of inﬂammatory bowel diseases (IBD), such as systemic sepsis and pelvic abscesses (Box 1), their impact in the primary treatment of IBD has long been an area of speculation. One of the earliest drugs used for the treatment of ulcerative colitis was sulfasalazine, which was developed as a combination of an antibacterial agent with a salicylate to treat rheumatoid arthritis [1]. Over the past decade there is increasing evidence that luminal gut bacteria play a role in the pathogenesis of IBD, particularly Crohn’s disease [2–5]. Patients with both Crohn’s disease and ulcerative colitis have increased mucosal adherence of anaerobic bacteria and Enterobacteriaceae [6] and loss of immunologic tolerance to commensal bacterial species [7]. The ability of normal, nonpathogenic enteric bacteria to induce and perpetuate chronic T-lymphocyte–mediated intestinal inﬂammation in genetically susceptible rodents is best demonstrated by the lack of experimental enterocolitis in sterile (germ-free) knockout and transgenic rodents [5,8–10]. Colitis develops as early as 1 week after colonization of germ-free, genetically engineered rodents with speciﬁc pathogen-free enteric bacteria [9], coincidental with T-cell responses to cecal bacterial lysates [10] and responses to broad-spectrum antibiotics [11–13]. Importantly, these animal model studies show that subpopulations of enteric bacteria can induce experimental colitis [8,14], host speciﬁcity for speciﬁc bacteria [9], diﬀerent bacterial species can cause diﬀerent phenotypes of disease in the same host [15], narrow-spectrum antibiotics are better at preventing than treating colitis [11], and that antibiotics and probiotics can have additive beneﬁts [12]. This compelling evidence that normal commensal bacteria

* Corresponding author. E-mail address: [email protected] (K.L. Isaacs). 0889-8553/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.gtc.2004.02.006

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Box 1. Complications of IBD requiring antibiotic treatment 1. Intra-abdominal or perianal abscesses, inflammatory phlegmon 2. Perianal fistulae and fissures 3. Small intestinal bacterial overgrowth secondary to strictures, loss of ileocecal valve, enteroenteric and enterocolonic fistulae 4. Postoperative infections 5. Toxic megacolon 6. Secondary infections (eg, Clostridium dicile)

induce chronic intestinal inﬂammation in susceptible rodents provides an excellent rationale for treatment of human IBD with antibiotics. Antibiotics can act by several mechanisms (Box 2). This article summarizes published studies of antibiotics in IBD patients (Table 1) and reviews available data for the use of antibiotic therapy in Crohn’s disease and ulcerative colitis.

Crohn’s disease Active therapy Despite the strong animal model evidence of the importance of gut bacteria in disease there is only limited evidence that antibiotics have eﬃcacy in the primary therapy of active luminal Crohn’s disease. Of interest, most of the drugs that have been studied in active Crohn’s disease have immunomodulatory activity in addition to their antimicrobial spectrum [16,17]. Sutherland et al [18] evaluated the eﬃcacy of two doses of metronidazole versus placebo in the treatment of patients with active luminal Crohn’s disease. A total of 105 patients were enrolled in the trial with 51 patients completing 16 weeks of therapy. Patients withdrew primarily because of either lack of eﬃcacy or drug side eﬀects. Signiﬁcant improvements in the Crohn’s disease activity index (CDAI) were noted as compared with placebo, although there was no signiﬁcant increase in the number of metronidazole-

Box 2. Mechanisms of action for antibiotics in IBD 1. Decrease luminal bacterial concentrations 2. Selectively eliminate bacterial subsets (alter ratio of beneficial to aggressive commensal bacteria) 3. Decrease tissue invasion, treat microabscesses 4. Decrease bacterial translocation and systemic dissemination

Table 1 Representative antibiotic trials in IBD Author

Date

Colombel et al [21] Arnold et al [27] Prantera et al [22]

1999 2002 1996

Greenbloom et al [19]

1998

Lieper et al [52] Steinhart et al [23]

2000 2002

Length

Result

Metronidazole, 800 mg/d Metronidazole, 10 or 20 mg/kg

16 wk 16 wk

Cipro, 500 mg bid Cipro, 500 mg bid Cipro, 500 mg bid, + metronidazole, 250 mg qid Cipro, 500 mg bid, + metronidazole 250 mg tid Clarithromycin, 250 bid Cipro, 500 mg bid, + metronidazole, 250 mg tid

6 wk 24 wk 12 wk

Equal to sulfasalazine Superior to placebo (# CDAI) no diﬀerence in remission Equal to mesalamine Superior to placebo (# CDAI) Equal to prednisolone

10 wk

Uncontrolled, 68% remission

4 wk 8 wk

Uncontrolled, 64% response 48% remission No improvement over budesonide alone (33% versus 38% remission)

Crohn’s disease: prevention of postsurgical relapse Rutgeerts et al [39] 1995 Metronidazole, 20 mg/kg Rutgeerts et al [40] 2002 Ornidazol, 1 g/d

12 wk 52 wk

# relapse 1 y versus placebo # severe endoscopic relapse versus placebo

Ulcerative colitis: primary therapy Turunen et al [42] 1999 Mantzaris et al [53] 1997 Casellas et al [54] 1998

6 mo 14 d 5d

Superior to placebo No beneﬁt versus placebo Decrease in mucosal IL-8

Pouchitis Madden et al [47] Shen et al [48]

1994 2001

Gionchetti et al [49]

1999

Ciproﬂoxacin, 500 mg bid Ciproﬂoxacin, 500 bid Amoxicillin-clavulanic acid, lg+ 250 mg tid

1 wk 2 wk 15 d

Abbreviations: CDAI, Crohn’s disease activity index; IBD, inﬂammatory bowel disease; IL, interleukin.

Superior to placebo Both eﬀective, cipro > metronidazole 89% response, 33% remission uncontrolled

337

Metronidazole, 400 mg tid Metronidazole, 20 mg/kg, or Cipro, 500 bid Cipro, 500 mg bid, and rifaximin, 1 g bid

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Crohn’s disease: primary therapy Ursing et al [20] 1982 Sutherland et al [18] 1991

Antibiotic

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treated patients achieving induction of remission. Patients receiving 20 mg/ kg/d of metronidazole had a greater degree of improvement than did those on 10 mg/kg/d. Of considerable importance to the interpretation of this and other antibiotic trials, metronidazole therapy was most eﬀective in those patients with isolated Crohn’s colitis or a combination of large and small bowel disease [18]. Preferential response in patients with colonic involvement has been seen in every antibiotic trial in which site of disease has been assessed [19,20]. Colombel et al [21] performed a controlled clinical trial that compared treatment of patients with a mild to moderate ﬂare of Crohn’s disease with ciproﬂoxacin at 1 g/d and mesalamine (Pentasa) at 4 g/d. The treatment trial was 6 weeks with end points based on improvement in the CDAI. A total of 40 patients were studied with 10 patients in the ciproﬂoxacin group (56%) and 12 patients in the mesalamine group (55%) achieving clinical remission. Prantera et al [22] compared the combination of metronidazole and ciproﬂoxacin with methylprednisolone for 12 weeks in 41 patients with active Crohn’s disease and showed nonsigniﬁcant diﬀerences in responses between the two groups with a 45.5% remission rate in the antibiotic-treated group and a 63% remission rate in the methylprednisolone group. There was a failure rate of 22.7% and 26.3%, respectively. This positive response in active CrohnÕs disease was further conﬁrmed in an uncontrolled trial that showed best results in patients receiving both corticosteroids and antibiotics [19]. Steinhart et al [23] performed a placebo-controlled clinical trial looking at the addition of a combination of metronidazole and ciproﬂoxacin (both at 1 g/d) to 9 mg of budesonide per day in the treatment of active Crohn’s disease conﬁned to the ileum or ileum and right colon. A total of 134 patients were enrolled in this 8-week randomized treatment trial. There was no signiﬁcant diﬀerence between the antibiotic-treated group and the placebo-treated group in terms of remission rate, although 20% of the antibiotic-treated group dropped out because of medication side eﬀects versus 0% in the budesonide-placebo group. When results were analyzed by site of disease, however, there was a diﬀerence in patients with colonic involvement. In this group 9 (55%) out of 17 patients were in remission on the metronidazole-ciproﬂoxacin combination, whereas only 4 (25%) of 16 who received the placebo were in remission at the end of the 8 weeks. Multiple studies with various combinations of antimycobacterial agents have explored the hypothesis that Crohn’s disease is caused by a mycobacterial infection. Most of these studies have been negative [5]. A recent openlabel trial examined the eﬀect of rifabutin and clarithromycin in a subset of patients with active Crohn’s disease with sera positive for p35 and p36 antigens, which are recombinant proteins of Mycobacterium avium subsp. paratuberculosis [24]. A total of 36 patients were enrolled with a withdrawal rate of 19.4% because of poor tolerance of the medications. Of the remaining 29 patients, 21 improved (overall 58%) as measured by a 70-point drop in the

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CDAI. This study suggests that therapy with agents directed at mycobacteria may be useful in a subset of patients with Crohn’s disease screened by serologic responses to M paratuberculosis. These results agree with a separate uncontrolled study of clarithromycin, rifabutin, and clofazimine by Gui et al [25], which reported improvement in 83% of patients. These antibiotics, however, have broad eﬀects on commensal enteric bacteria in addition to mycobacteria. Placebo-controlled trials of these antibiotics are in progress in Australia and the United States armed forces. Combination clarithromycin-ethambutol has been studied in a small placebo-controlled trial in patients with active Crohn’s disease [26]. A total of 31 patients were randomized and treated for 3 months with clarithromycinethambutol or placebo and clinically followed for 12 months. There was no signiﬁcant diﬀerence between the two groups at any of the time points studied using the Harvey Bradshaw Index, clinical activity assessment, and small bowel permeability measures. In this case an approach directed at mycobacteria was not successful in a controlled fashion, although it must be noted that M paratuberculosis is notoriously resistant to many therapeutic agents. Arnold et al [27] looked at ciproﬂoxacin as adjunctive therapy in patients with resistant active Crohn’s disease. In this study patients were treated with 1 g of ciproﬂoxacin per day or placebo over a 6-month period. A total of 47 patients were randomized and the CDAI was followed at 1, 3, and 6 months. Patients treated with ciproﬂoxacin had a decrease in CDAI from 187 to 112 and in the placebo group the CDAI dropped from 230 to 205. This was statistically signiﬁcant; however, the total number of patients ﬁnishing the trial in the treatment group was small and there were twice as many patients in the ciproﬂoxacin group as compared with the placebo. Fistulous disease Antibiotics have been used for the treatment of complications of perineal ﬁstulous disease, despite the lack of controlled trials for this indication. Uncontrolled data, however, support the eﬃcacy of antibiotics for perineal disease. As early as 1975, Ursing and Kamme [28] reported that ﬁstulae closed in three patients using metronidazole. Bernstein et al [29] reported in an open-label trial that metronidazole at a dose of 20 mg/kg/d was eﬀective in the treatment of 21 patients with Crohn’s perineal disease with an 83% response rate of ﬁstula closure. Ciproﬂoxacin has been used as well in perineal disease in uncontrolled trials. Turunen et al [30] treated eight patients with medically refractory perineal disease with 1 to 1.5 g of ciproﬂoxacin daily for 3 to 6 months with reported improvement in disease activity. In another open-label experience ﬁve patients with active perineal disease were treated with ciproﬂoxacin with complete resolution of perineal discomfort in four out of ﬁve of the treated patients [31]. In all of these, openlabel disease activity tended to recur when the antibiotic was discontinued [32]. Combination therapy with both metronidazole and ciproﬂoxacin in

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perineal disease has yielded similar results with a 9 of 14 patient improvement and a 3 of 14 patient closure of the ﬁstulous lesions, with recurrent disease on cessation of therapy [33]. On the basis of these small case series and widespread clinical response, antibiotics have become part of the mainstay of therapy in perianal Crohn’s disease. In the authors’ experience, antibiotics (either metronidazole, ciproﬂoxacin, the combination of these agents, or tetracycline) should be used as ﬁrst-line treatment of uncomplicated perianal ﬁstulae, following drainage of associated abscesses, as concomitant therapy with 6-mercaptopurine–azathioprine or inﬂiximab for more complex or refractory disease. The patient must be warned to watch for peripheral neuropathy with long-term use of 20 mg/kg/d of metronidazol. Postoperative recurrence Most patients who have surgery for active Crohn’s disease have a postoperative recurrence of disease. Clinical recurrence may occur in up to 30% of patients within the ﬁrst year after ileocolonic resection and endoscopic studies have documented that up to 93% of patients have visible aphthous ulcerations in the neoterminal ileum at 1 year postresection [34,35]. There is a suggestion that bacterial and bacterial by-products may play a role in disease recurrence. Disease does not recur following ileal resection, primary anastomosis, and proximal ileal diversion, but disease is evident by endoscopic evaluation within 3 months of ileal takedown with restoration of bowel continuity [36]. D’Haens et al [37] demonstrated in three patients that infusion of intestinal contents into the excluded ileum after ileocolectomy with ileocolonic anastomosis and temporary proximal loop ileostomy led to microscopic evidence of recurrent disease in the excluded segment within 1 week. It has been proposed that alteration of the luminal contents may lead to lower postoperative recurrence rates [38]. This same group evaluated the use of antibiotics postoperatively in a double-blind, placebo-controlled trial of 20 mg/kg/d of metronidazole administered for 3 months after ileocolonic resection. Outcomes included endoscopic evidence of aphthous ulcerations and clinical manifestations of disease recurrence. At 1 year there was a clinical symptomatic recurrence rate of 4% in the metronidazole group and 25% in the placebo group (P \ .05). Endoscopic recurrence was 12 of 23 at 3 months in the metronidazole group and 21 of 28 in the placebo group. This did not reach statistical signiﬁcance but was trending toward a beneﬁt to the metronidazole [39]. Ornidazole has been examined in a 1-year-long double-blind, placebocontrolled trial in 80 patients who had undergone a ‘‘curative’’ ileal or ileocolonic resection [40]. Patients were studied at 3, 12, 24, and 36 months after resection. The endoscopic recurrence rate was 34% in the ornidazole group and 59% in the placebo group at 3 months (P = .046). The clinical recurrence rate at 12 months was 8% in the ornidazole group and 37% in

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the placebo group (P = .002). Both of these studies suggest that alteration of bowel ﬂora with antibiotics in the postoperative period has some beneﬁt in reducing endoscopic and clinical postoperative recurrence in Crohn’s disease, but toxicity of these agents is high (nausea, anorexia, and peripheral neuropathy) and it remains unclear how long prophylactic treatment should be maintained and what dose of antibiotics is optimal to balance eﬃcacy with toxicity.

Ulcerative colitis Although some evidence of altered enteric bacteria and loss of immunologic tolerance to commensal bacteria exists in ulcerative colitis, the role for antibiotics in treatment of this disease is even less well documented than for Crohn’s disease. Active therapy Most of the controlled trials of antibiotics in ulcerative colitis have failed to show overwhelming beneﬁt in terms of disease improvement. Mantzaris et al [41] treated 55 patients who presented with severe acute colitis with intravenous ciproﬂoxacin at 400 mg twice a day or placebo as an adjunct to hydrocortisone therapy. In the ciproﬂoxacin group 79.3% improved and in the placebo group 77% improved with no signiﬁcant diﬀerences between the groups. Turunan et al [42] examined 6 months of adjunctive therapy with ciproﬂoxacin at 500 to 750 mg twice a day as compared with placebo in an outpatient ulcerative colitis population. In contrast to the intravenous study these authors found 21% treatment failure in the ciproﬂoxacin group and 44% failure in the placebo-treated group, suggesting that addition of a 6month course of ciproﬂoxacin does improve the clinical response of patients treated with prednisone and mesalamine. This study has not been conﬁrmed, however, and the bulk of the data do not support use of antibiotics as a primary treatment of ulcerative colitis, although these agents may have a role in the febrile hospitalized patient to treat translocating bacteria. Maintenance therapy Pouchitis Total abdominal colectomy with ileal pouch–anal anastomosis has become the surgical treatment of choice for most patients with uncontrolled ulcerative colitis [43]. This procedure removes all the diseased mucosa while preserving continence and transanal defecation. The most frequent long-term complication following ileal pouch–anal anastomosis for ulcerative colitis is nonspeciﬁc inﬂammation of the ileal reservoir, commonly known as ‘‘pouchitis’’ [44]. Pouchitis occurs with an overall frequency of at least 32%, and in some series reaches an incidence of 50%. In the population

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studied by Penna et al [45] the cumulative risk of developing pouchitis at 1, 5, and 10 years after ileal pouch–anal anastomosis is 16%, 36%, and 46%, respectively. The cause of pouchitis is not known but fecal stasis with bacterial overgrowth, recurrent ulcerative colitis, an abnormal balance of beneﬁcial and aggressive commensal bacterial species (dysbiosis), immune alterations, ischemia, and a deﬁciency of mucosal nutrients have all been proposed as playing a role [46]. The etiology may be multifactorial with increased bacterial concentrations in the pouch (relative to an ileostomy) serving as a trigger in the genetically or immunologically susceptible host, resulting in a unique form of IBD. Therapy with antibiotics has been the mainstay of treatment in patients with pouchitis, although there are few controlled trials of antibiotic therapy in pouchitis, based on widespread agreement regarding their clinical eﬃcacy. Madden et al [47] performed a double-blind, placebo-controlled, crossover trial in which 13 patients with chronic active pouchitis were treated with metronidazole, 400 mg orally three times a day for 7 days. Eleven patients completed therapy with metronidazole and 10 patients completed therapy with placebo. The response rate was 73% in the metronidazole-treated group and 10% in the placebo-treated group. There are no other placebo-controlled trials for antibiotic therapy in chronic pouchitis, although uncontrolled studies indicate that both metronidazole, 20 mg/kg/d, and ciproﬂoxacin, 500 mg twice a day for 2 weeks, are eﬀective, with best results and less toxicity seen with ciproﬂoxacin [48]. In addition, the combination of ciproﬂoxacin plus metronidazole was reported to be eﬀective in most (89%) patients with refractory pouchitis [49]. Furthermore, the combination of antibiotics to induce remission and probiotics to maintain remission of chronic, relapsing pouchitis has been documented [50]. The VSL3 combination of probiotics has recently been documented to be eﬀective postoperative prophylaxis for pouchitis [51].

Summary Multiple studies strongly implicate enteric commensal bacteria in the pathogenesis of Crohn’s disease and pouchitis, and suggest that both aerobic and anaerobic bacteria contribute to the inﬂammatory response. The use of antibiotics as primary therapy of Crohn’s disease is poorly documented, however, because of signiﬁcant defects in study design, high dropout rates, and inadequate numbers of study subjects, and use of antibiotics in ulcerative colitis is not currently justiﬁed. All studies to date indicate the antibiotics are more eﬀective in Crohn’s disease of the colon than in isolated ileal involvement. The authors use either metronidazole (10 mg/kg/d in divided doses) or ciproﬂoxacin (500 mg twice a day) in Crohn’s colitis or ileocolitis as adjunctive treatment with 5-aminosalicylates (ASA), steroids, or immuno-

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suppressive agents; as initial treatment of uncomplicated perianal ﬁstulae; and as adjuncts to 6-mercaptopurine and azathioprine or inﬂiximab for refractory or complex perianal ﬁstulae. Although proper trials of antibiotics in pouchitis have not been conducted, widespread clinical eﬃcacy of most antibiotics active against enteric bacteria validates their use. The authors use short-term courses (7–10 days) of metronidazole, 10 mg/kg/d, or ciproﬂoxacin, 500 mg twice a day, for intermittent pouchitis, and combine use of antibiotics to induce a remission and probiotics to sustain remission in refractory, chronic pouchitis. Rigorous multicenter studies for optimal antibiotic regimens in Crohn’s disease (primary therapy and prevention of relapse) need to be conducted and novel broad-spectrum nonabsorbable agents need to be examined in ulcerative colitis. References [1] Swartz N. Salazopyridin, a new sulfanilamide preparation. Acta Med Scand 1942;118: 540–9. [2] Carter M, Lobo A. Genes, bacteria and inﬂammatory bowel disease. Colorectal Disease 2001;3(Suppl 2):2–6. [3] Campieri M, Gionchetti P. Bacteria as the cause of ulcerative colitis. Gut 2001;48:132–5. [4] Guslandi M. Of germs in inﬂammatory bowel disease and of how to ﬁght them. J Gastroenterol Hepatol 2003;18:115–6. [5] Sartor R. Microbial inﬂuences in inﬂammatory bowel disease: Role in pathogenesis and clinical implications. In: Sartor R, Sandborn W, editors. Kirsner’s inﬂammatory bowel diseases. Philadelphia: Saunders 2004. p. 138–62. [6] Swidsinski A, Ladhoﬀ A, Pernthaler A, et al. Mucosal ﬂora in inﬂammatory bowel disease. Gastroenterology 2002;122:44–54. [7] Duchmann R, Kaiser I, Hermann E, Mayet W, Ewe K, Meyer zum Buschenfelde K. Tolerance exists towards resident intestinal ﬂora but is broken in active inﬂammatory bowel disease (IBD). Clin Exp Immunol 1995;102:448–55. [8] Rath H, Herfarth H, Ikeda J, et al. Normal luminal bacteria, especially Bacteroides species, mediate chronic colitis, gastritis, and arthritis in HLA-B27/human beta2 microglobulin transgenic rats. J Clin Invest 1996;98:945–53. [9] Sellon R, Tonkonogy S, Schultz M, et al. Resident enteric bacteria are necessary for development of spontaneous colitis and immune system activation in interleukin-10deﬁcient mice. Infect Immun 1998;66:5224–31. [10] Veltkamp C, Tonkonogy S, De Jong Y, et al. Continuous stimulation by normal luminal bacteria is essential for the development and perpetuation of colitis in Tg (epsilon26) mice. Gastroenterology 2001;120:900–13. [11] Rath H, Schultz M, Freitag R, et al. Diﬀerent subsets of enteric bacteria induce and perpetuate experimental colitis in rats and mice. Infect Immun 2001;69:2277–85. [12] Dieleman L, Goerres M, Arends A, et al. Lactobacillus GG prevents recurrence of colitis in HLA-B27 transgenic rats after antibiotic treatment. Gut 2003;52:370–6. [13] Madsen K, Doyle J, Tavernini M, Jewell L, Rennie R, Fedorak R. Antibiotic therapy attenuates colitis in interleukin 10 gene-deﬁcient mice. Gastroenterology 2000;118:1094–105. [14] Rath H, Wilson K, Sartor R. Diﬀerential induction of colitis and gastritis in HLA-B27 transgenic rats selectively colonized with Bacteroides vulgatus and Escherichia coli. Infect Immun 1999;67:2969–74. [15] Kim S, Tonkonogy S, Albright C, Sartor R. Regional and host speciﬁcity of colitis in mice monoassociated with diﬀerent nonpathogenic bacteria [abstract]. Gastroenterology 2003; 124:A485.

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[16] Xu G, Negayama K, Yunube K, Hojo S, Yamaji Y, Kawanishi K. Eﬀect of macrolide antibiotics on macrophage functions. Microbiol Immunol 1996;40:473–9. [17] Morikawa K, Watabe H, Araake M, Morikawa S. Modulatory eﬀect of antibiotics on cytokine production by human monocytes in vitro. Antimicrob Agents Chemother 1996; 40:1366–70. [18] Sutherland L, Singleton J, Sessions J, et al. Double blind, placebo controlled trial of metronidazole in Crohn’s disease. Gut 1991;32:1071–5. [19] Greenbloom S, Steinhart A, Greenberg G. Combination ciproﬂoxacin and metronidazole for active Crohn’s disease. Can J Gastroenterol 1998;12:53–6. [20] Ursing B, Alm T, Barany F, et al. A comparative study of metronidazole and sulfasalazine for active Crohn’s disease: the cooperative Crohn’s disease study in Sweden. II Result. Gastroenterology 1982;83:550–62. [21] Colombel JF, Lemann M, Cassagnou M, et al. A controlled trial comparing ciproﬂoxacin with mesalazine for the treatment of active Crohn’s disease. Groupe d’Etudes Therapeutiques des Aﬀections Inﬂammatoires Digestives (GETAID). Am J Gastroenterol 1999;94:674–8. [22] Prantera C, Zannoni F, Scribano M, et al. An antibiotic regimen for the treatment of active Crohn’s disease: a randomized, controlled clinical trial of metronidazole plus ciproﬂoxacin. Am J Gastroenterol 1996;91:328–32. [23] Steinhart AH, Feagan BG, Wong CJ, et al. Combined budesonide and antibiotic therapy for active Crohn’s disease: a randomized controlled trial. Gastroenterology 2002;123: 33–40. [24] Shafran I, Kugler L, El-Zaatari FA, Naser SA, Sandoval J. Open clinical trial of rifabutin and clarithromycin therapy in Crohn’s disease [comment]. Dig Liver Dis 2002;34:22–8. [25] Gui G, Thomas P, Tizard M, Lake J, Sanderson J, Hermon-Taylor J. Two -year-outcomes analysis of Crohn’s disease treated with rifabutin and macrolide antibiotics. J Antimicrob Chemother 1997;39:393–400. [26] Goodgame RW, Kimball K, Akram S, et al. Randomized controlled trial of clarithromycin and ethambutol in the treatment of Crohn’s disease. Aliment Pharmacol Ther 2001;15: 1861–6. [27] Arnold GL, Beaves MR, Pryjdun VO, Mook WJ. Preliminary study of ciproﬂoxacin in active Crohn’s disease. Inﬂamm Bowel Dis 2002;8:10–5. [28] Ursing B, Kamme C. Metronidazole in Crohn’s disease. Lancet 1975;1:775–7. [29] Bernstein L, Frank M, Brandt L, Boley S. Healing of perineal Crohn’s disease with metronidazole [letter]. Gastroenterology 1980;79:599. [30] Turunen U, Farkkila M, Seppala K. Long-term treatment of perianal or ﬁstulous Crohn’s disease with ciproﬂoxacin. Scand J Gastroenterol Suppl 1989;24(Suppl 148):144. [31] Wolf J. Ciproﬂoxacin may be useful in Crohn’s disease [abstract]. Gastroenterology 1990; 98:A212. [32] Schwartz D, Pemberton J, Sandborn W. Diagnosis and treatment of perianal ﬁstulas in Crohn’s Disease. Ann Intern Med 2001;135:906–18. [33] Solomon M, McLeod R, O’Conner B, Steinhart A, Greenberg G, Cohen Z. Combination ciproﬂoxacin and metronidazole in severe perianal Crohn’s disease. Can J Gastroenterol 1993;7:571–3. [34] Olaison G, Smedh K, Sjodahl R. Natural course of Crohn’s disease after ileocolonic resection: endoscopically visualized ileal ulcers preceding symptoms. Gut 1992;33:331–5. [35] Rutgeerts P, Geboes K, Vantrappan G, Beyls J, Kerremans R, Hiele M. Predictability of the postoperative course of Crohn’s disease. Gastroenterology 1990;99:956–63. [36] Rutgeerts P, Goboes K, Peeters M, et al. Eﬀect of faecal stream diversion on recurrence of Crohn’s disease in the neoterminal ileum. Lancet 1991;338:771–4. [37] D’Haens G, Geboes K, Peeters M, Baert F, Penninckx F, Rutgeerts P. Early lesions of recurrent Crohn’s disease caused by infusion of intestinal contents in excluded ileum. Gastroenterology 1998;114:262–7.

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[38] Rutgeerts P. Strategies in the prevention of post-operative recurrence in Crohn’s disease. Best Pract Res Clin Gastroenterol 2003;17:63–73. [39] Rutgeerts P, Hiele M, Geboes K, et al. Controlled trial of metronidazole treatment for prevention of Crohn’s recurrence after ileal resection [comment]. Gastroenterology 1995; 108:1617–21. [40] Rutgeerts P, Van Assche G, D’Haens G, et al. Ornidazol for prophylaxis of postoperative: ﬁnal results of a double blind placebo controlled trial. Gastroenterology 2002;122:A80. [41] Mantzaris GJ, Petraki K, Archavlis E, et al. A prospective randomized controlled trial of intravenous ciproﬂoxacin as an adjunct to corticosteroids in acute, severe ulcerative colitis. Scand J Gastroenterol 2001;36:971–4. [42] Turunen U, Farkkila M, Hakala K, et al. Long-term treatment of ulcerative colitis with ciproﬂoxacin: a prospective, double-blind, placebo-controlled study. Gastroenterology 1998;115:1072–8. [43] Meagher A, Farouk R, Dozois RR, Kelly KA, Pemberton JH. J ileal pouch-anal anastomosis for chronic ulcerative colitis: complications and long-term outcome in 1310 patients. Br J Surg 1998;85:800–3. [44] Sandborn WJ. Pouchitis following ileal pouch-anal anastomosis: deﬁnition; pathogenesis; and treatment. Gastroenterology 1994;119:305–9. [45] Penna C, Dozois R, Tremaine W, et al. Pouchitis after ileal pouch-anal anastomosis for ulcerative colitis occurs with increased frequency in patients with associated primary sclerosing cholangitis. Gut 1996;38:234–9. [46] Stocchi L, Pemberton JH. Pouch and pouchitis. Gastroenterol Clin North Am 2001;30: 223–41. [47] Madden M, McIntyre A, Nicholls R. Double-blind crossover trial of metronidazole versus placebo in chronic unremitting pouchitis. Dig Dis Sci 1994;39:1193–6. [48] Shen B, Achkar J, Lashner B, et al. A randomized clinical trial of ciproﬂoxacin and metronidazole to treat acute pouchitis. Inﬂamm Bowel Dis 2001;7:301–5. [49] Gionchetti P, Rizzello F, Venturi A, et al. Antibiotic combination therapy in patients with chronic, treatment-resistant pouchitis. Aliment Pharmacol Ther 1999;13:713–8. [50] Gionchetti P, Rizzello F, Venturi A, et al. Oral bacteriotherapy as maintenance treatment in patients with chronic pouchitis: a double-blind, placebo-controlled trial. Gastroenterology 2000;119:305–9. [51] Gionchetti P, Rizzello F, Helwig U, et al. Prophylaxis of pouchitis onset with probiotic therapy: a double-blind, placebo-controlled trial. Gastroenterology 2003;124:1202–9. [52] Leiper K, Morris AI, Rhodes JM. Open label trial of oral clarithromycin in active Crohn’s disease. Aliment Pharmacol Ther 2000;14:801–6. [53] Mantzaris G, Archavlis E, Christoforidis P, et al. A prospective randomized controlled trial of oral ciproﬂoxacin in acute ulcerative colitis. Am J Gastroenterol 1997;92:454–6. [54] Casellas F, Borruel N, Papo M, et al. Anti-inﬂammatory eﬀects of enterically coated amoxicillin-clavulanic acid in active ulcerative colitis. Inﬂamm Bowel Dis 1998;4:1–5.

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Medical management of postoperative recurrence in Crohn’s disease Gert Van Assche, MD, PhD*, Paul Rutgeerts, MD, PhD Division of Gastroenterology, Department of Internal Medicine, University Hospital Leuven, 49 Herestraat, B-3000 Leuven, Belgium

Patients with Crohn’s disease have a 50% to 70% chance of facing surgery anywhere in the course of their disease [1]. Most of these operations involve resections of the terminal ileum and cecum because of Crohn’s disease complications, particularly ﬁbrostenosis, enteric ﬁstulas, and abscesses. The ileum is reconnected to the colon with an end-to-side or an endto-end anastomosis. The entire macroscopically involved segment is resected with 5- to 10-cm margins in normal bowel segments. This curative resection is aimed at inducing full surgical remission. Even if surgical remission is generally achieved, early disease recurrence at the site of the anastomosis is frequent. Detection of these lesions can be achieved with ileocolonoscopy or with barium-contrast radiographs, although endoscopy seems to be more accurate for limited lesions [2]. The extent and the endoscopic appearance of the postoperative ileal disease strikingly resemble the disease behavior before surgery. On the long term, recurrent lesions lead to recurrence of clinical symptoms and repeat surgery for uncontrolled inﬂammatory lesions or ﬁbrostenosis, but clinical recurrence rates increase at a slower pace as compared with radiologic or endoscopic postoperative lesions. Because of the need for repeated ileal resections in many patients, surgeons no longer perform radical resections increasing the risk of short-bowel syndrome. Alternative surgical strategies to avoid extensive resection have been developed. Strictureplasty is now widely used and has proved to be as eﬃcacious as extensive resection even if it is performed in diﬀusely inﬂamed segments. Bypass operations to divert the fecal stream from inﬂamed or stenosed segments have been generally abandoned because they frequently

* Corresponding author. E-mail address: [email protected] (G.V. Assche). 0889-8553/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.gtc.2004.02.012

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created blind loops with subsequent bacterial overgrowth. Despite progress in surgical techniques, medical prophylaxis of postoperative Crohn’s disease has also been studied in numerous trials. This article reviews the diﬀerent aspects of prophylactic medical therapy focusing on the evidence of eﬃcacy for the diﬀerent agents, on the need to deﬁne clear outcomes, and on identifying patients at high risk for early recurrence. Postoperative recurrence of ileal Crohn’s disease The deﬁnition of postoperative disease recurrence can be based on clinical, endoscopic, radiologic, or surgical criteria. The endoscopic deﬁnition is probably the most stringent and controlled, whereas clinical recurrence is most relevant to the patient but criteria are ill deﬁned. Endoscopic recurrence occurs very early after ileocolonic anastomosis. Rutgeerts et al [3] and Olaison et al [4] reported endoscopic recurrence in 73% to 93% of patients after 1 year and in 85% to 100% of patients after 3 years. Already after 3 months, however, endoscopic recurrence was found in up to 30% of patients. Clinical recurrence is slower with an estimated 20% to 30% of patients after 1 year and a cumulative rate of 10% of patients per year postsurgery [4,5]. Fortunately, the need for repeated surgery or endoscopic dilation of the anastomosis is much lower with ﬁgures between 15% and 45% after 3 years and 26% and 65% after 10 years [6]. The disease behavior of Crohn’s disease is not inﬂuenced by surgical resection. Patients with limited mucosal inﬂammation and a tendency slowly to develop ﬁbrostenosis continue to show this disease phenotype. The extent of ileal disease in a patient with postoperative recurrence is most often comparable with what was observed before the ﬁrst resection [7]. An important factor in the pathogenesis of recurrent ileal Crohn’s disease is the fecal stream. Postoperative lesions can develop within 2 weeks after surgery with ileocolonic anastomosis. Fecal stream diversion with loop ileostomy proximal to the anastomosis, however, invariably prevents this disease recurrence. Restoration of the fecal stream after closing the ileostomy induces new lesions within weeks and the lesions are characterized by eosinophilic inﬁltrates [8,9]. These observations have raised the hypothesis that stasis of endogenous bacterial ﬂora is involved in disease recurrence. The time shift between endoscopic, clinical, and surgical remission indicates that there is a gradual progression from early superﬁcial lesions; to mucosal inﬂammation and transmural disease; to extensive inﬂammation in the neoterminal ileum with clinical symptom recurrence; and to development of complications, such as stenosis and ﬁstulas, necessitating repeated surgery. Assessment of postoperative recurrence Although endoscopic lesions precede clinical symptom recurrence after surgery a clear correlation between the endoscopic appearance of the

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neoterminal ileum and the further clinical disease course has been demonstrated [3]. This observation has introduced the use of an endoscopic end point as the gold standard in most of the trials aimed at preventing postoperative disease recurrence. Rutgeerts et al [3] proposed a scoring system to assess the severity of the postoperative lesions that has been implemented in most studies (Box 1). The incremental score varies from i0 to i4 (ÔiÕ for ileal) and assesses the severity of the lesions in the proximity of the anastomosis [3]. The need for an indirect assessment of clinical recurrence, such as endoscopy, stems from the time delay between surgery and symptoms and from the limited value of clinical activity scores in the postoperative setting. In the ﬁrst months after surgery diarrhea and abdominal cramps can be caused by the postoperative state and by bile acid malabsorption. After 6 months the bowel has adapted to these changes and an increase in symptoms becomes relevant. Viscido et al [10] have demonstrated that the positive and negative predictive values of the Crohn’s disease activity index using 150 points as a cutoﬀ were only 71% and 65%, respectively, versus endoscopy as the gold standard. Bearing these shortcomings in mind, however, preventing clinical disease recurrence and the need for repeated surgery remains the ultimate goal in medical prophylaxis.

Risk stratiﬁcation for early postoperative recurrence Location and disease phenotype The anatomic site involved in the bowel resection is an important factor in disease recurrence. Recurrence rates are highest for ileocolonic anastomoses in patients operated on for ileal or ileocolonic disease (Box 2). Colocolonic anastomoses have a lower recurrence rate. Surgical disease recurrence for ileocolonic anastomosis is between 25% and 60% at 5 years and between 49% and 91% at 15 years. On the contrary, reoperation rates for colocolonic anastomoses vary from 8.5% to 42% at 5 years and from 2% to 40% at 14 years. Interestingly, recurrence at the ileocolonic

Box 1. Endoscopic severity score for postoperative Crohn’s disease i0: absence of any lesions at the site of anastomosis and in the neoterminal ileum i1: \5 aphthous ulcers (\5 mm) i2: >5 aphthous ulcers with normal mucosa between the lesions or lesion confined to the ileocolonic anastomosis (\1 cm) i3: diffuse aphthous ileitis with diffusely inflamed mucosai i4: diffuse ileitis with large ulcers, nodularity, or narrowing

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Box 2. Risk factors for early postoperative disease recurrence Established risk factors Ileocolonic anastomosis Perforating disease Smoking (particularly in women) Possible risk factors Young age Short disease duration

anastomosis also occurs when the ileum is not involved before surgery. Recurrence rates in the small intestine proximal to ileorectal anastomoses seem to follow the pattern of colocolonic anastomoses, but spreading of the disease into the rectum with local complications often occurs. Disease behavior before surgery was also found to be an important determinant of disease recurrence by studies from both Leeds [11] and Mount Sinai [12], New York. In the paper from New York perforating and nonperforating disease behavior as indication for bowel resection was found to be a discriminating factor. Perforating disease was associated with higher postoperative disease recurrence rates. The deﬁnition of perforating disease included acute free peroration with overt peritonitis, concealed perforation with abscess formation, and chronic perforating disease with intestinal ﬁstulas. Nonperforating surgical indications involved a broad spectrum of intestinal obstruction, intractable inﬂammatory disease, hemorrhage, and toxic dilation. In the retrospective cohort study time to reoperation was 4.7 years in the perforating group and 8.8 years in the nonperforating group. Indications for ﬁrst repeat surgery were again perforating disease in 64% of patients with ileitis and with initial perforating disease and in 77% of patients with ileocolitis. In 81% of patients with perforating disease at the time of the second resection, a third resection for perforating disease was necessary. It should be mentioned, however, that not all studies have found the same strong association between perforating disease and the risk of recurrence [13,14]. Smoking habits As a general rule, active smoking is associated with poor outcome in Crohn’s disease. Postoperative disease recurrence seems to be no exception. Almost all studies report active smoking as a risk factor for early recurrence. Cottone et al [15] reported in 1994 that 6 years after surgery 60% of nonsmokers (95% CI, 43%–72%), 41% (CI, 11%–70%) of ex-smokers, and 27% (CI, 17%–37%) of active smokers were free of clinical recurrence.

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Sutherland et al [16] demonstrated a similar diﬀerence for postoperative recurrence. Repeat surgery was performed in 20% of nonsmokers and in 36% of smokers. At 10 years the ﬁgures rose to 41% and 70%, respectively. In this study female smokers with small bowel disease were at highest risk for recurrence, an observation that has been conﬁrmed in nonsurgical series of refractory Crohn’s disease. An interventional study by the French Getaid group demonstrated that smoking cessation resulted in a less aggressive disease course [17]. The same French study group also reported that longterm immunosuppression antagonizes the deleterious eﬀect of smoking [18]. A recent study from the University of Pennsylvania did not identify smoking as a risk factor for postoperative recurrence [19]. Other factors Determinants of early postoperative recurrence supported by less evidence include age at surgery and time to onset of the disease. de Dombal et al [11] reported in 1971 that patients operated on early after initial diagnosis had higher postoperative recurrence rates probably reﬂecting a more aggressive disease course. These data were conﬁrmed by the Mount Sinai group in 1983 [20], but not in other series [21,22]. More recently, data from Lautenbach et al [19] clearly contradicted the correlation between short disease duration and postoperative recurrence risk using multivariate analysis. In their retrospective analysis a long disease history predicted early surgical recurrence. The authors hypothesize that the time of initial diagnosis may not accurately reﬂect disease onset and that patients with longer disease history may be those who are reluctant to undergo surgery and have more severe disease at the time of resection.

Prevention of lesions at the site of the ileocolonic anastomosis The implementation of early endoscopic lesions at the site of the anastomosis as an important end point in postoperative recurrence trials is based in the concept that prolonged mucosal healing prevents Crohn’s disease complications in the long term. Although the inﬂammatory inﬁltrate in early recurrent lesions is diﬀerent from that of long-standing disease, there is probably a continuum of early mucosal lesions to transmural disease with ﬁbrosis and perforation. Early recurrent lesions are so important for predicting the postoperative disease course. The most eﬃcacious surgical procedure to prevent postoperative recurrence is fecal diversion with ileostomy proximal to the anastomosis. Histologic evidence of the disease is found as early as 1 week after reinfusion of luminal contents [9]. Clinical trials incorporating endoscopic lesions as an outcome parameter have demonstrated conﬂicting results. Standard agents for luminal Crohn’s disease, such as aminosalicylates and corticosteroids, have generally failed in this respect. Mesalamine has been shown to suppress early endoscopic

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lesions at early time points after surgery, but this eﬀect is lost later on in the course of the disease. An Italian placebo-controlled trial with Pentasa, 3 g daily, initiated 1 month after surgery demonstrated a reduced rate of endoscopic and radiologic recurrence at 1 year, but there was no diﬀerence in clinical recurrence [23]. The recurrence rate was 24% in the Pentasa group versus 56% in the placebo group (P \ .004), a diﬀerence of 32% (95% CI, 22–52). In another trial Florent et al [24] compared mesalamine (Claversal, Eudragit coated), 1.5 g twice a day for 12 weeks and started within 15 days after surgery, with placebo. Endoscopic relapse was found in 50% of mesalamine-treated patients and in 63% of patients on placebo. This diﬀerence was not statistically signiﬁcant. Fiasse et al [25] failed to demonstrate an advantage of mesalamine over placebo in endoscopic recurrence after 1 year of treatment. This study has only been published in abstract form and the main shortcoming is that mesalamine treatment was only started 3 months after surgery. At that time most patients probably already have early lesions. It has been proposed that adequate mucosal 5-aminosalicylic acid (5ASA) concentrations at the site of the anastomosis are needed in the prevention of recurrent lesions. An Italian study in 25 patients found that 3 years after surgery patients with higher tissue concentrations had a lower risk of recurrence [26]. This was indirectly contradicted, however, by a recent trial from the Italian collaborative GISC group. In this trial 2.4 g of mesalamine (Asacol) started 2 weeks after surgery did not oﬀer a signiﬁcant advantage over 4 g in the endoscopic and clinical recurrence rates at 12 months [27]. A limited number of data are available about the eﬀect of antibiotics initiated very early after surgery. Nitroimidazole antibiotics, metronidazole and ornidazole, are more eﬃcacious than placebo at preventing early lesions 3 months after surgery [28,29]. As discussed later the eﬀect of these drugs fades rapidly after cessation of therapy and they are not tolerated long term. 6-Mercaptopurine (6-MP) was superior to placebo for preventing endoscopic recurrence at 1 year correlating with a clinical advantage as discussed further [30].

Prevention of clinical recurrence Even if early endoscopic lesions are probably closely related with the ensuing postoperative clinical disease course, prophylactic treatment is eventually aimed at reducing clinical symptom recurrence and repeated surgical resections. It was illustrated that endoscopic lesions precede clinical and surgical recurrence by several years in most patients and this complicates the design of clinical trials on prophylactic therapy. Clinical end points need to be ﬁxed at late time points (3 years or more) to power trials for detecting relevant diﬀerences between treatment groups.

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Aminosalicylates: sulfasalazine and mesalamine Arguably the largest number of clinical trials has focused on the use of aminosalicylates in the prevention of postoperative recurrence. These agents are considered very safe and mesalamine is well tolerated long-term. Mesalamine is expensive if given long term at appropriate doses, however, and recently the beneﬁt of aminosalicylates in the maintenance therapy of Crohn’s disease has been challenged. Three studies have looked at the eﬀect of sulfasalazine initiated early after surgery [31–33]. The study of Bergman and Krause [31] and of Wenckert et al [32] showed no beneﬁt over placebo, and only the study by Ewe et al [33] found a reduction of recurrence rates in patients on active treatment. Surgical and radiologic recurrence was 16% in the sulfasalazine group at 1 year versus 28% in the placebo group (P \ .01). At 3 years recurrence rates were identical, however, at 38% in both groups [33]. Studies exploring the prophylactic eﬀect of mesalamine (5-ASA) have faced problems of heterogeneous trial design. Dosing regimens, the interval between surgery and start of treatment (from less than 10 days to 8 weeks), and the duration of follow-up have been highly variable. An open label comparison study by Caprilli et al [34] demonstrated an important beneﬁt for 5-ASA (Asacol, 2.4 g). Eighteen percent of patients receiving Asacol and 41% of patients on placebo had a clinical recurrence after 2 years [34]. This study also reported a beneﬁt of 5-ASA on endoscopic recurrence rates but obviously was noncontrolled and open to observation biases. More recently Caprilli et al [27] reported on the results of a randomized controlled trial prospectively comparing two doses of 5ASA. Two hundred and six patients were randomized and 186 were available for clinical assessment after 12 months. Clinical recurrence was present in 12% in the 4-g Asacol group and in 14% of the patients in the 4.8g group (NS). There was no diﬀerence in severe endoscopic recurrence. The placebo-controlled trials investigating the role of 5-ASA in the prophylaxis of postoperative Crohn’s disease are summarized in Table 1. Only the Canadian study by McLeod et al [35] from 1995 showed a signiﬁcant beneﬁt for 5-ASA. In four subsequent studies it was not superior to placebo. In the study by McLeod et al [35] the 3-year clinical recurrence rate was 31% (27 of 87) with 1.5 g 5-ASA twice a day (Salofalk) versus 41% (31 of 76) in the control group. In this trial 5-ASA was initiated as long as 8 weeks from surgery, a time point at which numerous patients already have endoscopic lesions. A recent large German-Austrian multicenter trial with a high dose of 4 g mesalamine (Pentasa) or placebo initiated within 10 days from surgery failed to show a signiﬁcant beneﬁt for 5-ASA at 12 months [36]. Subgroup analysis showed a beneﬁt for patients operated on for isolated ileal disease but numbers needed to treat were high (8–13). This means that at least eight patients have to be treated long term with 5-ASA at considerable cost to prevent one postoperative recurrence.

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Table 1 Eﬃcacy of aminosalicylates in the prevention of postoperative Crohn’s disease: results of placebo-controlled trials Clinical recurrence (%) Trial reference McLeod et al, 1995 [35] Brignola et al, 1995 [45] Sutherland et al, 1997 [46] Lochs et al, 2000 [36] Adler et al [30]

5-ASA formulation

Start 5-ASA after surgery

Number

Duration (mo)

Placebo

5-ASA

Salofalk (3 g) Rowasa Pentasa (3 g)

8 wk

163

75

41

31a

4 wk

77

12

26

18

66

12

23

10

Pentasa (3 g) Pentasa (3 g)

10 d

318

18

31

24

Pentasa (3 g) (þ vs, 6-MP)

14 d

84

24

69

59

Abbreviations: 5 - ASA, 5 - aminosalicylic acid; 6 - MP, 6 - mercaptopurine. a Statistically signiﬁcant.

A meta-analysis by Camma et al [37] showed a pooled risk reduction of 13% when summarizing all trials with mesalamine. This meta-analysis, however, did not incorporate the recent negative trial by Lochs et al [36].

Budesonide A collaborative double-blind placebo-controlled European trial included 129 patients to be randomized to budesonide, 6 mg/d, or placebo within 2 weeks from surgery [38]. Most patients were operated on for ﬁbrostenotic disease. Endoscopic and clinical recurrence rates were not diﬀerent between both groups at 3 and 12 months. A subanalysis showed a signiﬁcant reduction in endoscopic lesions with budesonide (12 months: 32% versus 65% for placebo, P \ .05), but only in patients operated on for inﬂammatory luminal disease, not in patients with ﬁbrostenosis as the indication for surgery. Based on this trial there is currently no evidence to support the use of budesonide in this indication.

Purine analogues Immunosuppression is a highly eﬃcacious maintenance strategy for luminal Crohn’s disease inducing mucosal healing [39] and it is logical to assume that the recurrent lesions developing in the postoperative setting are caused by uncontrolled immune activation and would respond to immunosuppressive agents. Adler and Korelitz [30] have provided preliminary data supporting a role for 6-MP in the prevention of postoperative recurrence.

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Based on these ﬁndings a larger multicenter trial was initiated comparing 6-MP, 50 mg, with 5-ASA (Pentasa), 3 g, and placebo (Hanauer et al, submitted for publication, 2003). End points were endoscopic and clinical recurrence. The trial enrolled 131 patients in ﬁve centers and they were randomized to any of the three groups in a double-blind, double-dummy design. Patients were assessed for clinical, radiologic, and endoscopic recurrence at regular intervals throughout 24 months. Drop out rates were considerable in the course of the trial but evenly distributed over the three groups. Absence of endoscopic recurrence was demonstrated in 32% of patients on 6-MP (P \ .05 versus placebo, 20% with Pentasa (NS) and 10% with placebo). 6-MP was also more eﬃcacious at preventing severe endoscopic relapse (score > i2). A reduction of the clinical recurrence rate was only achieved with 6-MP. The beneﬁt of 6-MP was lower than anticipated (22% risk reduction versus placebo for endoscopic recurrence). The dose of 6-MP used may have been suboptimal, however, and the time to onset of action may have interfered with the prevention of early recurrent lesions.

Nitroimidazole antibiotics The rationale to use antibiotics in the prevention of postsurgical relapse can be deducted from the putative role of bacterial stasis in the pathogenesis of early recurrent lesions and the experiments with reinfusion of ileal contents [8,9]. A ﬁrst double-blind placebo-controlled trial explored the eﬀect of metronidazole, 20 mg/kg body weight, during 3 months and started within 1 week from surgery in 51 patients [28]. Only patients with a new ileocolonic anastomosis after ileal and segmental colonic resection were eligible. The total endoscopic recurrence rates after 3 months were not signiﬁcantly decreased in the metronidazole group (52% versus 75%). Severe endoscopic lesions were lower, however, in the active treatment group (13% versus 43%, P \ .02). Clinical recurrence was only suppressed at the 1-year time point, not at year 2 or 3. A more recent trial using ornidazole, 500 mg twice a day, or placebo for a total of 1 year after surgery and initiated within 1 week, demonstrated signiﬁcant reduction of endoscopic relapse rates at 3 months and 1 year [29]. Severe lesions (i2) were detected in 74% of patients in the placebo group versus 41% in the ornidazole group (P \ .02). As in the metronidazole trial clinical recurrence was only signiﬁcantly suppressed at 1 year in the ornidazole-treated patients (8% versus 37%). The principal drawbacks of nitroimidazoles in this setting are the side eﬀects associated with long-term use of these agents. Gastrointestinal intolerance with nausea and metallic taste and peripheral neuropathy preclude long-term administration and the role of these antibiotics is probably as an induction agent to bridge the gap to the eﬀect of immunosuppressives.

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Biologic agents Although biologic agents, such as the anti–tumor necrosis factor antibody inﬂiximab, are now widely used in treatment of refractory Crohn’s disease, no data are available on their eﬃcacy to prevent postsurgical relapse. Arguments to justify a trial with inﬂiximab are that it is highly eﬃcacious in luminal Crohn’s disease and that it induces mucosal healing in the ileum and in the colon [40,41]. Given the considerable cost associated with biologic treatment, however, it can be predicted that these agents, if proved to be eﬃcacious, will only be used in patients with a high-risk proﬁle for early relapse. A small multicenter trial investigated the role of the anti-inﬂammatory cytokine interleukin-10 in the prevention of postsurgical relapse. As in other studies with interleukin-10 in Crohn’s disease, the trial did not show a beneﬁt of this cytokine over placebo for endoscopic relapse [42].

Probiotics Two recently reported Italian trials have studied the role of probiotics in preventing postoperative recurrence of Crohn’s disease. A preliminary report from the Bologna group using VSL#3 indicated that probiotics had therapeutic potential as compared with mesalamine [43]. More recently, however, Prantera et al [44] found no diﬀerence between placebo and Lactobacillus GG 6 109 colony forming units twice daily given for 12 months and started within 10 days from surgery. Forty-ﬁve patients entered the trial and 37 were available for assessment at 12 months. Patients with high recurrence risk were excluded from the trial. Nine (60%) out of 15 patients in the probiotics and 6 (35%, NS) of 17 in the placebo group had endoscopic recurrence. Clinical recurrence was present in 17% of probiotics treated and in 10.5% of placebo-treated patients. The discrepancy between the two trials can be explained on several grounds: a diﬀerent probiotic preparation was used, in the VSL#3 trial patients received antibiotics for 3 months and this may have contributed to the apparent eﬃcacy, diﬀerent patient populations may have been studied, and the sample size did not power the study to detect subtle diﬀerences between groups. Clearly, the role of probiotics in this setting needs to be better deﬁned.

Algorithm for management of clinical recurrence of Crohn’s disease after curative resection Given the observation that probably 30% to 50% of patients never develop early recurrent lesions after curative surgical intervention, and the rather modest beneﬁt shown in the trials with medical prophylaxis, systematic treatment immediately after surgery is not indicated. Risk

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357

stratiﬁcation based on the known disease behavior before surgery and the smoking status combined with the ﬁndings of an early ileocolonoscopy 6 to 12 months from the operation, are key determinants in the medical treatment of these patients. Fig. 1 proposes a treatment algorithm that the authors adhere to, based on the available evidence.

Strategies for the future: where to go from here? The early recurrent lesions in the neoterminal ileum developing within months after surgical remission oﬀer a good model to study the natural history of Crohn’s disease. The mechanisms driving the uncontrolled inﬂammation and the progression toward established transmural disease should be explored further in patients with postsurgical relapse. The role of agents, such as biologic therapy, that may alter the course of the disease and prevent complications should be studied in this setting. The total body of evidence about the medical prophylaxis of postsurgical relapse in Crohn’s disease indicates that clinical practice needs critical appraisal. 5-ASA treatment in all patients does not seem to be a rational strategy given the data currently available. Immunosuppressive therapy with short-term antibiotics seems promising but more data are needed to deﬁne surgical remission (resection of all macroscopic disease)

low and intermediate risk

high risk ileo-colonic anastomosis and any of: active smoker repeated resection perforating disease

fibrostenosing disease · non smoker · first resection ·

· · ·

no treatment ileocolonoscopy or barium small bowel X-ray 6 months afer surgery

no or mild lesions (i0-i2)

no treatment yearly follow-up

severe lesions limited extent

azathioprine 2.5 mg/kg severe lesions extended area

or 6-MP 1.5 mg /kg

5-ASA 3-4 g/d (?) yearly follow up

6-monthly follow up (2-monthly blood counts)

Fig. 1. Treatment algorithm for the prophylaxis and treatment of early Crohn’s disease after curative resection based on risk stratiﬁcation and endoscopic surveillance. 5-ASA, 5-aminosalicylic acid; 6-MP, 6-mercaptopurine.

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better if all patients would beneﬁt from this treatment regime. Taken as a whole, however, the trials show that clinicians do not succeed in preventing the occurrence of new lesions. Medical prophylaxis only postpones their occurrence and in many of the trials the beneﬁt of active treatment is lost after 2 or 3 years. Future studies should be aimed at better deﬁning for which patients the beneﬁt of early systematic prophylaxis will outweigh the toxicity and cost of treatment.

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[40] D’haens G, Van Deventer S, Van Hogezand R, Chalmers D, Kothe C, Baert F, et al. Endoscopic and histological healing with inﬂiximab anti-tumor necrosis factor antibodies in Crohn’s disease: a European multicenter trial. Gastroenterology 1999;116:1029–34. [41] Baert FJ, D’Haens GR, Peeters M, Hiele MI, Schaible TF, Shealy D, et al. Tumor necrosis factor alpha antibody (inﬂiximab) therapy profoundly down-regulates the inﬂammation in Crohn’s ileocolitis. Gastroenterology 1999;116:22–8. [42] Colombel JF, Rutgeerts P, Malchow H, et al. Interleukin 10 (Tenovil) in the prevention of postoperative recurrence of Crohn’s disease. Gut 2001;49:42–6. [43] Campieri M, Rizello F, Venturi A, et al. Combination of antibiotic and probiotic treatment is eﬃcacious in prophylaxis of postoperative recurrence of Crohn’s disease: a randomized controlled study vs mesalamine. Gastroenterology 2000;118:A781. [44] Prantera C, Scribano ML, Falasco G, Andreoli A, Luzi C. Ineﬀectiveness of probiotics in preventing recurrence after curative resection for Crohn’s disease: a randomised controlled trial with Lactobacillus GG. Gut 2002;51:405–9. [45] Brignola C, Cottone M, Pera A, et al. Mesalamine in the prevention of endoscopic recurrence after intestinal resection for Crohn’s disease. Gastroenterology 1995;108:345–9. [46] Sutherland LR, Martin F, Bailey RJ, et al. A randomized, placebo-controlled, doubleblind trial of mesalamine in the maintenance of remission of Crohn’s Disease. The Canadian Mesalamine for Remission of Crohn’s Disease Study Group. Gastroenterology 1997;112:1069–77.

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Medical management of the pregnant patient with inﬂammatory bowel disease Adam F. Steinlauf, MD*, Daniel H. Present, MD Mount Sinai School of Medicine, Mount Sinai Hospital, 12 East 86th Street, New York, NY 10028, USA

Ulcerative colitis (UC) and Crohn’s disease (CD), collectively known as inﬂammatory bowel disease (IBD), demonstrate a bimodal age distribution with the ﬁrst peak between the ages of 15 and 25 (childbearing years), and the second peak between ages 50 and 80, possibly related to stopping smoking. The former is the greater of the two peaks. Although the incidence of UC has remained relatively stable, that for CD has been increasing over the past few decades [1]. For these reasons, gastroenterologists are not infrequently faced with questions regarding pregnancy when advising or treating their patients with IBD. To advise patients eﬀectively, the following factors must be considered: (1) the inheritance patterns of IBD for accurate counseling and family planning; (2) the eﬀects of active IBD versus medications or surgery on fertility; (3) the eﬀects of pregnancy on the course of IBD; (4) the eﬀects and potential risks of active IBD versus those of diagnostic tests, medical, and surgical treatments on the developing fetus; (5) approach to delivery; and (6) the risks of breast-feeding while receiving treatment for IBD.

Inheritance The mode of inheritance of IBD is complex and cannot be explained with a simple mendelian model [2,3]. It can be said that genetics does increase the susceptibility of developing IBD when exposed to the as yet uncertain ‘‘right’’ environmental triggers, but there are clearly multiple factors necessary for the development of IBD. Twin studies well demonstrate this point [4,5]. For CD, there is a concordance rate of 44% to 50% in monozygotic twins, whereas the concordance rate is 0% to 3% among dizygotic twins. UC demonstrates

* Corresponding author. E-mail address: [email protected] (A.F. Steinlauf). 0889-8553/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.gtc.2004.02.013

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a similar but less dramatic pattern with a concordance rate of 6% to 14% among monozygotic twins and a corresponding rate of 0% to 5% among dizygotic twins. The risk for UC and CD among oﬀspring of patients with IBD is 2 to 13 times higher than that for the general population [6]. It can be expected that a child has a 5% chance of developing IBD if one of the parents has CD, and a 1.6% chance if the aﬀected parent has UC. In Jewish families, the corresponding values are higher for CD and UC, 7.8% and 4.5%, respectively [7]. Family history is greater among CD patients than UC patients, and relatives of CD patients have a higher risk for IBD than those of UC patients. These ﬁndings suggest that CD is more often familial than UC and indicate that genetics seem to play a greater role in the predisposition for CD [8]. If both parents have IBD, the chances increase to at least 35% and possibly higher, depending on when the parents’ symptoms presented in relation to time of conception [9]. Recent research has begun to uncover chromosomal regions that are likely to contribute to the pathogenesis of IBD. Some seem to be speciﬁc for CD or UC, whereas others are nonspeciﬁc. Knowing a patient’s genotype may help predict the disease phenotype (stricturing versus perforating or ﬁstulizing, location); the presence of extraintestinal manifestations; response to treatments; and susceptibility to drug toxicities [10]. For example, the CARD15 gene (previously NOD2) on chromosome16q12 encodes for a protein, which is involved in the immune system’s preliminary response to infection by way of stimulating NF-KB [11,12]. Studies have demonstrated that mutations in the CARD15 locus are associated with ileal location [13], earlier age of onset, and stricturing disease. It does not seem to be associated with perianal disease or extraintestinal manifestations [14]. Until there are more data, it is premature to recommend genetic screening at the present time; however, in the future clinicians may be able to predict phenotype and individualize treatment plans.

Fertility In general, infertility rates in patients with IBD are similar to that of the general population, approximately 8% to 10% [1,15]. It was initially believed that fertility rates were lower in patients with IBD [16]. Indeed, patients with IBD do have fewer children than is expected for the general population [17]. Subsequent studies have shown that this decrease may likely be secondary to voluntary reasons, such as fear of pregnancy; fear of disease transmission to oﬀspring [1]; relationship diﬃculties (fear of intimacy or dyspareunia resulting in decreased libido [18]); body image problems [19]; or inappropriate medical advice [20,21]. There are special situations where infertility is increased. Although women with UC (quiescent or active) have normal fertility [16,22–24], there is an increase in infertility after ileal pouch–anal anastomosis (IPAA) [25–31]. The reasons are not clear. Ravid et al [32] attempted to identify possible factors

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that may contribute to infertility (deﬁned as the inability to conceive within 1 year). These included age at diagnosis of UC, age at time of surgery, use of a two-stage procedure, postoperative complications, weight changes, smoking status, number of hospitalizations, transfusions, medications used, or comorbid medical problems. None of these factors seemed to be implicated in post-IPAA infertility. It is likely that postoperative tubal occlusion from adhesions is responsible for this decreased fertility [28,30]. Another study by Ording Olsen et al [28] speciﬁcally evaluated fecundity (waiting time to pregnancy) after IPAA for UC. Here it was shown that patients with UC have normal fecundity before IPAA, but signiﬁcantly decreased fecundity afterward. The authors in this study also concluded that this decrease is likely caused by adhesions resulting from extensive surgery extending right down to the pelvic ﬂoor [28]. Other studies support this conclusion [30,33,34]. Although fertility seems to be decreased, the rates can likely be improved with the use of fertility medications and in vitro fertilization techniques. Indeed, the aforementioned study by Ravid et al [32] demonstrated that women who initially reported infertility were eventually able to conceive at a rate similar to the ‘‘fertile’’ group, but more frequently required medications or surgery to achieve a successful pregnancy [32]. Dyspareunia seems to be increased after IPAA; the frequency is reported to be as high as 22% to 38% [1,25,35]. Interestingly, sexual satisfaction was found to be increased after IPAA and improved general health is believed to be the reason [25,36]. In men, the incidence of impotence after IPAA has been observed to be 2% to 4% and is not a signiﬁcant issue [36–38]. Ejaculatory problems, including retrograde ejaculation, may also result from IPAA; however, this complication is also quite rare [25,39]. CD does not seem to aﬀect fertility when the disease is inactive: however, active disease does aﬀect female fertility [20,40]. Inﬂammation or adhesions involving the fallopian tubes or ovaries is believed to be responsible. Fertility seems to improve when disease remission is achieved. Fertility in men with CD is not signiﬁcantly diminished [41], although disease activity and nutritional status may alter male fertility in a minor way [42]. Medications used to treat IBD for the most part have no eﬀect on fertility except for the well-described eﬀect of sulfasalazine on male fertility. Sulfasalazine causes a reversible, dose-related decrease in sperm count and motility. Of all men receiving the drug, up to 60% report impairment in fertility [41,43–45]. When sulfasalazine is substituted by another 5-aminosalicylic acid product, sperm function improves [46–49]. The negative eﬀects of sulfasalazine are reversed 2 months after the drug is discontinued.

The eﬀects of pregnancy on the course of inﬂammatory bowel disease The course of UC during pregnancy tends to be similar to that in the nonpregnant population if conception occurs at a time of disease inactivity.

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That is, approximately one third relapses during the pregnancy or puerperium [50]. If a relapse does occur, it likely does so during the ﬁrst trimester [51,52]. If the disease is active at the time of conception, however, disease activity persists or worsens in approximately two thirds of the patients [22,40,53,54]. Physicians should strongly advise a couple contemplating pregnancy to wait until the prospective mother’s disease is in clinical remission before conception. An unusual but particularly worrisome situation is one in which a patient experiences her ﬁrst attack of UC during pregnancy. Here, the course tends to be particularly aggressive. Indeed, early reports of women in this group, before the use of steroids, demonstrate a substantial maternal mortality rate [55–57]. CD exhibits a similar trend. When conception occurs during a period of disease quiescence, approximately one third relapse during the pregnancy, a rate that is expected in the nonpregnant population [50]. If conception occurs at a time of active disease, two thirds have persistent activity and of these, about one half deteriorate during the pregnancy [15,40,58]. In addition to disease activity status at the time of conception as a predictor of disease activity during pregnancy, there are emerging data to suggest that disparity at both HLA-DR and DQ alleles between mother and fetus may be another predictor. Indeed, Kane [59] has shown that disease activity tends to improve if a mother is disparate from her child at both the HLA-DR and DQ alleles, whereas if they are disparate at only one allele, disease activity is unaﬀected. Two studies suggest that prior pregnancy status may inﬂuence the overall course of IBD [1]. The ﬁrst study by Nwokolo et al [58] evaluated the eﬀect of pregnancy on the course of CD. In this study, it was shown that as parity increases, the need for surgical intervention decreases. Furthermore, patients with a history of pregnancy required fewer resections and the interval between surgeries tended to be longer when compared with women who had never had children. A second study by Castiglione et al [60] demonstrated lower relapse rates of both UC and CD after pregnancy when compared with that before pregnancy. The pregnancy’s eﬀects on the immune system may be responsible for these ﬁndings [61].

The eﬀects of inﬂammatory bowel disease on the course and outcome of pregnancy There seems to be a misconception among patients and most primary physicians that pregnant patients with IBD should avoid medications during pregnancy. When advising patients and referring physicians, it is important to convey the risks of active IBD in and of itself, versus the risks of treated, controlled disease on the developing fetus. Most studies show that UC, when inactive, has little eﬀect on the course of pregnancy with regard to congenital abnormalities, spontaneous abortions, and stillbirths when compared with non-IBD controls [62,63]. The incidence

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of premature delivery is not likely to be substantially aﬀected; however, some studies do show this adverse event to be increased [20,64]. It is prudent to advise close obstetric follow-up during the third trimester. The data on the eﬀects of active UC on pregnancy are somewhat vague. Active UC during pregnancy persists in one third of the cases or worsens in another third of the patients. This poor course inevitably leads to poor maternal health resulting in prematurity and low birth weight [65]. Indeed, there seems to be an increased risk of preterm birth when the birth occurs after the mother’s ﬁrst hospitalization, especially when the hospitalization took place during the pregnancy [66]. Another recent study suggests that active UC may be associated with increased reporting of congenital malformations [67]. As the disease becomes more active, there is a greater threat posed to both the mother and the fetus. Active, nonfulminant UC carries a combined abortionstillbirth rate of 18% to 40% [22,52], whereas severe or fulminant UC requiring surgery carries a corresponding rate of up to 60% [68]. The Turnbull-Blowhole colostomy, a skin-level cutaneous (blowhole) colostomy with the formation of a loop ileostomy, oﬀers a relatively safe surgical option to manage this high-risk population [69]. With the use of steroids or cyclosporine, the disease often can be controlled medically during pregnancy [70,71]. Like UC, quiescent CD has minimal eﬀects on the course and outcome of pregnancy [40,62,63]. As in UC, close follow-up is advised during the third trimester [20,64]. Active CD, either at the time of conception or during the pregnancy, has been shown to increase the incidence of fetal loss, stillbirths, preterm delivery, low birth weight, and developmental defects. The risks seem to be related to the disease activity rather than the medications used to treat the disease [50,62,72,73]. In the most severe cases, surgery may be required. In these cases, maternal and fetal mortality is very high [16]. In CD, as in UC, there is every incentive to strive for clinical remission before conception, and to treat ﬂares aggressively medically to prevent complications.

Diagnostic studies used to assess the pregnant patient with inﬂammatory bowel disease Radiologic studies To evaluate and treat IBD eﬀectively, the clinician may wish to make use of radiologic studies. Radiologic studies fall essentially into two categories: those that emit ionizing radiation, and those that do not. Plain ﬁlms, CT, and barium studies all require ionizing radiation, whereas ultrasound and MRI do not. It is always best to avoid ionizing radiation during pregnancy if at all possible; however, most radiologic procedures are associated with little, if any, risk of cell death, teratogenic eﬀects, carcinogenesis, or genetic eﬀects [74–76]. According to the American College of Radiology, no single

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diagnostic radiologic procedure results in suﬃcient radiation to threaten the well-being of the fetus [75]. Fetal risk of anomalies, growth restriction, or abortion does not increase when the radiation exposure is less than 5 rad. To put this into perspective, an abdominal radiograph results in a mean exposure of 0.1 rad [77], a barium enema or small bowel series results in 2 to 4 rad, and a CT of the abdomen results in 2.6 rad. A pelvic CT using a lowexposure technique results in only a 250-mrad exposure [78]. The risk of carcinogenesis, particularly leukemia, may increase slightly. Fetal exposure to 1 to 2 rad increases the risk, from a background rate of 3.6 in 10,000, by 1 in 10,000 [74,79]. The decision to use studies with ionizing radiation should also involve consideration of the gestational age of the fetus. The preimplantation period (days 0 to 9 postconception) is the time during which the fetus is most sensitive to radiation-induced prenatal death. The period of organogenesis (days 15 to 50 postconception) is the time during which the fetus is most sensitive to radiation-induced malformations. Finally, the entire ﬁrst trimester (days 15 to 90) is the period during which radiation can induce growth and mental retardation, and childhood cancer [80]. In contrast to studies with ionizing radiation, there are no reports of detrimental fetal eﬀects of ultrasound waves including duplex Doppler imaging. Likewise, there are no documented detrimental fetal eﬀects of MRI, in which magnets are used to alter the energy state of hydrogen protons. Nevertheless, the National Radiologic Protection Board recommends that MRI not be used during the ﬁrst trimester [81]. Furthermore, gadolinium chelates, which can cross the placenta, should be avoided, because their longterm eﬀects are unknown. Attempts should be made to avoid nonemergent radiologic procedures using ionizing radiation during pregnancy, particularly during the ﬁrst trimester. If a procedure is strongly indicated, however, it should be recommended and performed after appropriate discussion with the patient. If modalities that do not use ionizing radiation are appropriate and available, they should be considered better alternatives. Gastrointestinal endoscopy Flexible sigmoidoscopy is frequently needed in the evaluation of the patient with IBD, and studies show that it is safe. In one study of 26 sigmoidoscopies in 24 pregnant women, there were no complications during the procedures. The pregnancies resulted in 18 healthy infants, four voluntary abortions, one involuntary abortion 9 weeks after the procedure in a diabetic hypertensive woman, and an unknown outcome in one patient [82]. In another study of 48 ﬂexible sigmoidoscopies in 46 patients, the pregnancies resulted in 38 healthy infants (27 full term); four voluntary abortions; three cases of fetal demise; and one unknown outcome [83]. This same study also reported on eight colonoscopies. Of the eight patients, six delivered normal infants; one underwent a voluntary abortion; and one

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resulted in fetal demise 4 months after the procedure, probably secondary to an unrelated cause. Occasionally esophagogastroduodenoscopy is required during pregnancy, and this procedure also seems safe. In one study, 83 women underwent esophagogastroduodenoscopy during pregnancy [84]. The outcomes were 70 healthy infants, 6 voluntary abortions, 3 unknown, and 4 cases of fetal loss. In this study, the cases of fetal loss were believed to be unrelated to the procedures. Additionally, two of the patients underwent therapeutic endoscopy, and these pregnancies resulted in healthy infants. Although it is probably a good idea to refrain from endoscopic procedures during pregnancy, if they are clearly indicated or emergent, they should be performed. Again, the risks, beneﬁts, and alternatives must be discussed with the patient beforehand.

The eﬀects of medications used to treat inﬂammatory bowel disease on pregnancy and nursing Although it is well established that it is best to achieve and maintain disease remission before conceiving, there are patients who conceive during the throes of a ﬂare. Many of these patients prefer to struggle through their pregnancy without the institution of medications, despite being counseled with the current available data. Furthermore, some patients prefer to stop their maintenance medications before conception [85]. This decision is often based on patient’s personal beliefs that all medications should be avoided in pregnancy. Indeed, physicians’ reference books, such as the Physician’s Desk Reference, often emphasize risks and side eﬀects without weighing risk:beneﬁt ratios. The Food and Drug Administration (FDA) pregnancy categories reﬂect this cautious approach (Table 1). Although it is important to inform couples contemplating pregnancy regarding drug risks and warnings, it is equally important to educate and counsel them with regard to the experience and safety of most currently used medications during pregnancy (Table 2). Aminosalicylates The initial available agent in this group was sulfasalazine, with 5aminosalicylic acid being the active therapeutic agent linked by a diazo bond to sulfapyridine. Two other products—the ﬁrst of which consists of two diazo-linked 5-aminosalicylic acid molecules, and the other a 5-aminosalicylic acid molecule linked to an inert molecule—were subsequently developed. These agents allow delivery of the drug to the colon. Other mesalamine agents have protective coatings, which are either pH-dependant or water-activated. These preparations allow delivery of drug to the small and large intestine. Sulfasalazine is the oldest medication available for the treatment of IBD with the longest track record. Studies have shown no detrimental eﬀects

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Table 1 Food and Drug Administration pregnancy categories Category

Interpretation

A B

Controlled studies show no risk No evidence of risk in humans Animals ﬁndings show risk but human studies do not OR Animal studies are negative but there are no adequate human studies Risk cannot be ruled out: Animal studies positive or lacking, human studies lacking Positive evidence of risk: Can still use if beneﬁt outweighs risk Contraindicated during pregnancy

C D X

during pregnancy or nursing [54,86,87]. Kernicterus is considered a theoretical risk because it can bind to plasma proteins thereby displacing bilirubin. This has not been a problem clinically, probably because of poor absorption and low-aﬃnity binding to plasma proteins [88]. Sulfasalazine does interfere with folate absorption. Folate is important for proper neural tube development. During pregnancy, folic acid requirements are already increased; folic acid should be prescribed in doses of 1 mg twice daily before and during pregnancy to prevent complications. Mesalamine allows for the delivery of the 5-aminosalicylic acid compound to aﬀected bowel without the sulfapyridine moiety, that which is responsible for most side-eﬀects [89]. These agents have also proved, for the most part, to be safe for use during pregnancy and nursing [90–93]. A recent study by Norgard et al [94] showed an increased risk of stillbirth and preterm birth; however, they could not determine whether the increased risk was secondary to the disease itself or the medication. Very high doses of mesalamine have been shown to be toxic in rats and rabbits; very high doses should be used with some degree of caution. Antibiotics The use of antibiotics in IBD is becoming increasingly more frequent not only for the treatment of intercurrent infections, but also as ﬁrst-line therapy for CD [95]. There are limited data regarding the safety of antibiotics for the treatment of CD during pregnancy. Metronidazole and ciproﬂoxacin are typically the ﬁrst antibiotics considered when treating active patients with CD. Although metronidazole has been shown to be mutagenic in some bacteria and carcinogenic in mice after longterm use, these eﬀects have not been observed in humans [96–98]. Short courses of metronidazole in the treatment of Trichomonas vaginalis during the ﬁrst trimester of pregnancy have proved to be safe [99–101]. There are no formal data evaluating the safety of long-term exposure to metronidazole;

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Table 2 IBD medications: summary of recent safety data

Medication

FDA pregnancy category Recent safety data during pregnancy

5-ASA Azulﬁdine Mesalamine Balsalazide (new)

B B B

All shown to be safe. Folate supplements required with sulfasalazine. Kernicterus is a potential but rare concern with sulfasalazine. Very high doses of 5-ASA should be used with caution.

Antibiotics Metronidazole Quinolones Penicillins Cephalosporins Erythromycin

B C B B B

Short courses of metronidazole seems safe when used for trichomonas. Ciproﬂoxacin seems safe. Possible arthropathogenicity with ciproﬂoxacin, but not seen in two major studies.

Corticosteroids Prednisone No rating Generally well tolerated and safe in pregnancy. Topicals are Prednisolone safe until seems third trimester unless miscarriage Solucortef or preterm delivery a concern. Budesonide was teratogenic Solumedrol and embryocidal in rats and rabbits, but safe during Budesonide (new) C pregnancy when inhaled. Purine analogues Mercaptopurine Azathioprine

D D

Seems safe for use during pregnancy.

Anti-TNF Inﬂiximab Thalidomide

B X

Inﬂiximab seems safe in murine models and postmarketing safety database, which demonstrates outcomes consistent with those in healthy women. Thalidomide associated with fetal abnormalities and a high mortality rate.

Immuno suppressives Cyclosporine C Tacrolimus C

Antimetabolites Methotrexate

X

Cyclosporine seems safe for use during pregnancy. Associated with low birth weight and prematurity, but high survival. Abstract showed successful pregnancies in four of ﬁve mothers with IBD. Tacrolimus seems safe. It compares favorably with other immunosuppressives with regard to congenital malformations, birth weight, and neonatal problems. Teratogenic and embryotoxic in animals, resulting in chromosomal damage and miscarriage. Used as an abortifacient in tubal pregnancies. Should be avoided.

Abbreviations: 5-ASA, 5-aminosalicylic acid; FDA, Food and Drug Administration; IBD, inﬂammatory bowel disease.

however, most obstetricians believe it is safe, especially in the second or third trimester [65]. The quinolones, of which ciproﬂoxacin is one, are probably safe for use during pregnancy and are unlikely to pose a substantial teratogenic risk, although the data are insuﬃcient to deﬁnitively state that there are no risks.

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This is according to the Teratogenic Information System [102]. Indeed, two studies looking at a total of 749 pregnancies with ﬂuoroquinolone exposure, most of which were during the ﬁrst trimester, failed to reveal an increased risk of spontaneous abortions, congenital malformations, prematurity, or low birth weight [103,104]. Although arthropathogenicity has been observed in immature animals [105], this outcome was not observed in the two aforementioned studies. Other antibiotics used for the management of CD that are believed to be safe for use during pregnancy include penicillins, cephalosporins, and the erythromycins [1]. Tetracyclines should be avoided during pregnancy because they can cause retardation of fetal skeletal development and teeth deformities. Consequently, the FDA rates them as category D. Sulfonamides interfere with folic acid metabolism. Furthermore, they have been shown to be teratogenic in animals (increased incidence of cleft palates), and when given in very high doses, result in increased fetal loss. Although human studies have demonstrated safety of these medicines [106], they are rated as category C by the FDA and should be avoided during pregnancy. Corticosteroids Corticosteroids are indicated for the treatment of moderate to severely active IBD. During pregnancy, corticosteroids cross the placental barrier but they are rapidly converted to less active metabolites by placental 11hydroxygenase resulting in lower fetal blood levels. For this reason, fetal pituitary-adrenal axis suppression is rarely seen. Some preparations, such as prednisone, are more eﬃciently metabolized than others (ie, dexamethasone). Animal studies have shown that corticosteroids were associated with a higher rate of spontaneous abortion, small litter size, and cleft palate [107]. Complications such as these have not been observed in humans [54,108]. Mogadam et al [54] followed a total of 168 pregnant patients with IBD who were taking corticosteroids and found no increase in congenital malformations. Corticosteroids are generally well tolerated during pregnancy. As with all drugs, risks of their use should be weighed carefully against the risks of the disease on the developing fetus and used when clinically indicated. Rectal preparations may be used until the third trimester unless miscarriage or premature delivery is a concern [51]. Budesonide is a more recent synthetic glucocorticoid. It is released in the small bowel and is indicated for the treatment of CD involving the terminal ileum or ascending colon. It acts topically and has a very high ﬁrst-pass metabolism (80%–90%) resulting in lower plasma levels. In animal studies, budesonide demonstrated teratogenic and embryocidal eﬀects in rabbits and rats when given subcutaneously in doses up to 0.5 times the recommended human dose on a body surface area basis. It is listed as pregnancy category C. Human studies have been done evaluating the safety of inhaled budesonide during pregnancy, and it seems to be safe [109,110]. There are no studies

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evaluating oral budesonide during pregnancy. It should theoretically be safer than other corticosteroids given the aforementioned high ﬁrst-pass eﬀect. With regard to breast-feeding, the commonly used steroid preparations, prednisone and prednisolone, result in very low breast milk concentrations [111,112] and they are safe for use during nursing, especially when administered at lower doses. To minimize neonatal exposure, some advocate at least a 4-hour delay after oral dosing [113]. Azathioprine and 6-mercaptopurine Azathioprine and 6-mercaptopurine (6-MP) are purine analogues that interfere with nucleic acid biosynthesis and are active against human leukemias. Azathioprine is a prodrug of 6-MP and is rapidly converted to 6MP in vivo. According to the FDA, these medications are rated as pregnancy category D. This rating is based on early human reports, which reveal increased abortion rates [114,115]. Animal studies evaluating high doses in rats, mice, and rabbits report increased incidences of congenital malformations, prematurity, low birth weights, and chromosomal abnormalities. In animal studies evaluating doses similar to those recommended in humans (1.5 mg/kg for 6-MP and 2.5 mg/kg for azathioprine), the only adverse outcomes reported were decreased fertility rates and low birth weights [116–118]. Most of the human experience with these medications in pregnancy is found in the rheumatology and transplant literature [113,119–127]. Azathioprine has been proved to be safe in these populations with no consistent reports of abnormalities in fertility, prematurity, or congenital defects. The only consistent ﬁnding was an increase in low birth weight infants in the renal transplant recipients; however, this was believed to be more likely secondary to the underlying abnormal renal function than the use of these medications. The IBD literature covering azathioprine and 6-MP use in pregnancy is much less extensive. Alstead et al [128] reported on 16 pregnancies in 14 women who received medication during pregnancy. All the pregnancies resulted in normal deliveries except in four cases (two elective terminations and two premature births resulting in healthy infants). Although azathioprine has no measurable eﬀect on semen quality and male fertility [129], paternal use can result in poor pregnancy outcome. Rajapakse et al [130] evaluated 50 pregnancies fathered by men on 6-MP and found that 6-MP use within 3 months of conception resulted in a signiﬁcant increase in complications including spontaneous abortions and congenital abnormalities. Most recently, a study by Francella et al [131] reported on 325 pregnancies in 155 patients (female and male) and found that 6-MP use was not associated with increased rates of prematurity, spontaneous abortion, congenital abnormalities, or neonatal and childhood infections. Azathioprine and 6-MP seem safe for use in pregnancy. Patients should not stop their medication before conception. Indeed, a recent study suggests that the discontinuation of 6-MP before conception may actually increase

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the chance of fetal loss [132]. Once pregnant, the patient can choose to stop their medication if the disease has been under good control for a prolonged period of time, or elect to remain on the drug if their disease was chronic, active, and diﬃcult to control before starting medication [133]. There are insuﬃcient safety data on the use of 6-MP and azathioprine during nursing, and patients should not breast-feed while taking these medications. Cyclosporine Cyclosporine is indicated for moderate to severe UC as either a steroidsparing agent or as a means of avoiding surgery in severe steroid-refractory cases [134]. It is also eﬀective in treating ﬁstulizing CD [135–137]. The indications in the pregnant patient are no diﬀerent. Its usefulness in pregnant patients with steroid-refractory disease cannot be overstressed because surgery in this setting carries a high risk of fetal mortality [70]. Like other immunosuppressives, most of the safety data in pregnancy comes from the transplant and rheumatology literature [113,138–142]. In theses studies, cyclosporine does not demonstrate teratogenicity. There was a higher rate of prematurity and low birth weight; however, the survival rate was high. The IBD literature is much less extensive. One case report was published in 1995 reporting on a pregnant patient who developed steroid-resistant toxic megacolon at 29 weeks gestation and was eﬀectively treated with cyclosporine resulting in a healthy baby boy delivered at 36 weeks [70]. Marion et al [143] reported successful pregnancies in four of ﬁve cases without congenital malformations or developmental defects. Since this abstract was published, the authors’ practice has cared for numerous pregnant patients requiring cyclosporine therapy, and all have resulted in healthy babies. Cyclosporine is safe for use in pregnancy if clinically indicated. As is true for all medicines, the risks of use should be weighed against the risks of the underlying disease. There are insuﬃcient safety data on the use of cyclosporine during nursing, and patients should not breast-feed while taking this agent. Tacrolimus Tacrolimus is a macrolide antibiotic whose action has a similar mechanism as cyclosporine, but diﬀers structurally. It is 100 times as potent as cyclosporine and is absorbed independent of bile ﬂow. It has been shown to be eﬀective in the treatment of complicated or ﬁstulizing CD and colitis (UC and Crohn’s colitis) [144,145]. It is predominantly used in a steroid-sparing role or for steroid-refractory disease as a bridge to other medications, such as azathioprine and 6-MP or methotrexate [146,147]. Data on the safety of this drug during pregnancy are very limited. Although it is rated as pregnancy category C by the FDA, the transplant

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literature shows that it seems to be safe [148–151]. The largest series was published by Kainz et al [152], in which 100 pregnancies were reported in 84 mothers. In this study, most pregnancies resulted in favorable outcomes. The rate of prematurity was high; however, it compares favorably with other immunosuppressives with regard to congenital malformations, low birth weight, and neonatal complications. Tacrolimus does gain access into breast milk, and because data addressing the safety of its use during nursing are lacking, patients should be advised not to breast-feed while taking this medication. Methotrexate Methotrexate is a folic acid antagonist. Feagan et al [153] described the antimetabolite’s role as an inductive agent in the management of CD. It is used as an alternative to azathioprine and 6-MP in the management of steroid-dependant or steroid-resistant CD. Animal studies have shown methotrexate to be teratogenic and embryotoxic, resulting in chromosomal damage and miscarriage [113,121]. Its negative eﬀects on the viability of a fetus are actually used therapeutically as an abortifacient in tubal pregnancies in high doses [154]. Although normal pregnancies have been reported while on methotrexate [121,155], the risks are too great. Methotrexate is contraindicated for use during pregnancy and is rated as category X by the FDA. Couples taking methotrexate should be informed to use reliable contraception. If conception should accidentally occur, therapeutic abortion should be discussed [1]. If abortion is not a viable option for the couple, the high risks of spontaneous abortion and congenital abnormalities should be discussed and documented clearly. The prospective mother should be instructed to stop methotrexate immediately and begin high-dose folic acid replacement [156]. If a couple is planning a pregnancy, the prospective father should remain oﬀ methotrexate for at least 3 months (time required for spermatogenesis), and the prospective mother for 1 month [1]. Breast-feeding should be avoided during methotrexate use. Inﬂiximab Inﬂiximab (Remicade) is a chimeric monoclonal antibody directed against anti–tumor necrosis factor-a and is indicated for the treatment and maintenance of moderate to severe refractory or ﬁstulizing CD [157– 160]. Murine models failed to demonstrate teratogenicity or embryotoxicity; however, anti–tumor necrosis factor-a antibodies are species speciﬁc. The literature reporting on its safety in humans during pregnancy is limited. One case report describes a pregnancy in a 26 year old who became pregnant while receiving inﬂiximab [161]. She delivered prematurely, at 24 weeks, and the neonate died on day 3, suﬀering intracerebral and intrapulmonary bleeding. In this case, the adverse outcome may have been caused by active IBD or other

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concurrent medicines and not necessarily by inﬂiximab. Analysis obtained from the inﬂiximab postmarketing safety database showed that of 35 pregnancies (74.3%), 26 resulted in live births; 5 (14.3%) resulted in miscarriage; and 4 (11.4%) resulted in therapeutic termination. Of the 26 live births, 2 were delivered with complications in mothers with CD, 1 delivered at 23 weeks and died 3 weeks later, and 1 was born with tetralogy of Fallot [162]. These results were consistent with data obtained from a national cohort of healthy women with regard to live births, miscarriages, and therapeutic terminations. The FDA rates Remicade as pregnancy category B. It is not known if inﬂiximab passes into breast milk; nor is it known if inﬂiximab is absorbed into the systemic circulation after oral ingestion. For these reasons, it is best to avoid breast-feeding while receiving inﬂiximab. Thalidomide Thalidomide has been shown to be eﬀective in the treatment of inﬂammatory and ﬁstulizing CD [163,164]. The mechanisms of action of thalidomide are not fully understood; however, its tumor necrosis factor-a suppression is believed to play a major role in its eﬀectiveness in the management of CD. Use of this agent has been associated with major human fetal abnormalities involving not only the limbs but also the ears and eyes. In addition, neural tube abnormalities, duodenal ﬁstulae, and midline hemangiomas have all been reported [165]. Furthermore, mortality at or shortly after birth has been reported in approximately 40% [166,167]. For these reasons, the FDA has rated thalidomide category X. In women and men of childbearing age, it should only be used when all other viable options have failed and only after the patient has been properly counseled with regard to prevention and risks of use during pregnancy. Like other medications, it is not known whether thalidomide is excreted in breast milk, and breast-feeding during use should not be advocated. Nonspeciﬁc symptomatic agents In addition to treating the underlying IBD with the medications listed previously, the patient’s sense of well-being can be improved dramatically with the addition of nonspeciﬁc symptomatic agents. This is particularly true in those who concomitantly suﬀer from irritable bowel syndrome. The symptoms most commonly encountered include nausea; pain (abdominal, musculoskeletal); abdominal cramping; and diarrhea. Metoclopramide can be used for the treatment of nausea. It has enjoyed use in Europe for over 30 years. It has no teratogenic eﬀects in animals when given at doses of 12 to 250 times the recommended maximal human dose, and reports of use in humans have shown no fetal abnormalities [168–170]. Other antiemetics, such as antihistamines (eg, meclizine) and phenothiazine derivatives, may be used in severe cases [171]. Vitamin B6 has been shown to decrease nausea during pregnancy without teratogenic or adverse

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side-eﬀects [172]. More recent studies suggest the safety of ondansetron for use during pregnancy [173–175]. Medications aimed at neutralizing or reducing gastric acidity may also help alleviate nausea. Antacids are safe for use during pregnancy and nursing. H2-receptor antagonists are classiﬁed as category B and are generally safe [176]. The proton pump inhibitors are also now considered safe for use during pregnancy. Most are category B except for omeprazole, which is category C; however, omeprazole has not been found to be associated with major malformations in humans when used during pregnancy [177]. Sucralfate is a minimally absorbed topical agent, which acts as an acid barrier. Sucralfate may be eﬀective in suppressing nausea and is safe for use during pregnancy. Musculoskeletal and some forms of abdominal pain can be treated safely with acetaminophen. It has not been associated with fetal abnormalities and seems safe for use during breast-feeding [65]. Aspirin use during pregnancy has been shown to cause prolonged gestations, prematurity, longer labor, and greater blood loss during labor and delivery. The ingestion of aspirin within 10 days of delivery can result in both maternal and neonatal hemostatic abnormalities [178]. Studies pertaining to the use of salicylates during pregnancy have been reviewed, and it was concluded that they are not contraindicated during pregnancy [121]. Aspirin is relatively safe for use during pregnancy, but should be discontinued at least 7 days before delivery [179]. Nonsteroidal medications have not been studied adequately during pregnancy, and they are not recommended for use. Codeine in low doses is advocated by some and is quite eﬀective in reducing abdominal pain and cramps associated with IBD [65]. It has not been associated with fetal abnormalities and is safe for use during pregnancy. The safest medications available to control diarrhea are those that are not absorbed. These include kaolin with pectin and stool bulking agents. Cholestyramine is eﬀective in treating diarrhea, especially those with ileal disease or resection. It is relatively safe for use during pregnancy. Indeed, it is indicated for the treatment of cholestasis of pregnancy. It should not be administered with other medications because of its nonspeciﬁc anion-binding capacity. Furthermore, it can interfere with the absorption of fat-soluble vitamins including vitamin K. Coagulation studies must be followed closely [180]. The systemic antidiarrheals include loperamide and diphenoxylateatropine. Loperamide, although pregnancy category B, should be used cautiously, and only if the beneﬁts clearly outweigh the risks. It is safe in animal studies at doses up to 30 times that recommended for humans; however, the human data are limited and daunting. Of 21 reports of pregnant women ingesting loperamide, only 9 were available for follow-up. Of these, four were unaﬀected, two demonstrated congenital malformations, two resulted in spontaneous abortions, and one suﬀered bilateral Erb’s palsy [171]. Diphenoxylate with atropine produces teratogenic eﬀects in animals [181], and malformations have been documented in humans [182]. It is rated as pregnancy category C.

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The eﬀects of inﬂammatory bowel disease surgery on pregnancy The eﬀects of surgery for IBD on fertility have already been discussed. Performing surgery for IBD during the course of a pregnancy has been associated with a high rate, approximately 50%, of spontaneous abortions and stillbirths [68,183,184]. Although surgery has been performed successfully during pregnancy [185], it is prudent to treat ﬂares medically in an aggressive fashion to delay and hopefully avoid surgery during this high-risk period. Surgery should be reserved for signiﬁcant emergencies only, such as severe fulminant colitis, toxic megacolon, perforation, obstruction, or hemorrhage [37].

Approach to delivery Patients with UC can expect normal labor and vaginal delivery, unless obstetric issues dictate otherwise. Patients who have undergone IPAA can probably deliver safely, vaginally, without compromising anastomotic integrity [186]. Most agree that patients with CD and active perineal involvement should undergo elective cesarean section. If vaginal delivery cannot be avoided, attempts should be made to avoid an episiotomy. If an episiotomy cannot be avoided, a mediolateral episiotomy is preferable to avoid the rectum. The approach to the patient with CD without perineal involvement is not as straightforward. A survey by Brandt et al [187] demonstrated that the rate of developing perineal complications after vaginal delivery, usually with episiotomy, in patients with no previous history of perineal disease was 17.9%. When planning delivery in this group, the risks of vaginal delivery must be clearly delineated. In addition, the obstetrician should take into account speciﬁc patient characteristics, which may help guide the decision. These include history of previous labors, pelvic size, and estimate of fetal weight. Again, episiotomy should be avoided [188].

Summary The IBDs frequently aﬀect women and men of childbearing age. Genetics seem to play a role in the development of these diseases (CD more than UC). IBD does not in and of itself seem to aﬀect fertility; however, infertility rates do increase after surgery secondary to the eﬀects of adhesions on tubal function. Medications used to treat IBD for the most part do not aﬀect fertility except for the reversible eﬀects of sulfasalazine on male fertility. If pregnancy occurs during disease activity, there is a greater chance that the disease will persist or worsen; every eﬀort should be made to control the disease before conception. As the disease becomes more severe, the threat to the mother and fetus increases. Surgery in this population carries a high risk to the developing fetus. Furthermore, most medications used to treat active IBD have proved to

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be safe. It is recommended that active disease during pregnancy be treated aggressively. The risks of not treating are greater than the risks of treating.

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Treatment of luminal and ﬁstulizing Crohn’s disease with inﬂiximab Lawrence W. Comerford, MD, Stephen J. Bickston, MD* University of Virginia Digestive Health Center of Excellence, Box 800708, UVA Health System, Charlottesville, VA 22908, USA

Crohn’s disease (CD) is a chronic inﬂammatory disorder of the gastrointestinal tract of unknown etiology that results in signiﬁcant morbidity and health care costs. More than 400,000 people in the United States have CD. The prevalence continues to increase because of its rising incidence and improved survival [1]. The chronic nature of the illness causes frequent hospitalizations; most patients eventually require surgery secondary to complications, such as strictures, abscesses, ﬁstula, or refractory disease. The disease seems to occur when the intestinal immune cascade is triggered by an antigen in genetically susceptible individuals. Overactivation of the enteric immune and inﬂammatory pathways causes mucosal damage resulting in the clinical signs and symptoms. Various medications, including 5-aminosalicylates, antibiotics, corticosteroids, and immunomodulators, such as purine antimetabolites and methotrexate, have traditionally been used to control inﬂammation. Their use is intended to prevent surgery and improve the patient’s quality of life. None cure the disease and unfortunately, many patients require steroids to control their symptoms. A wide range of dose-related adverse eﬀects makes this an unappealing strategy. Immunomodulators are eﬀective maintenance drugs, but have a slow onset of action with clinical remission rates of approximately 40%. The limitations of conventional agents leave the clinician in need of a medication that is steroid-sparing, quick acting, and maintains remission [2]. Genetic engineering advances have produced endogenous proteins in suﬃcient quantities to be used therapeutically. This process, called recombinant technology, involves incorporating mammalian DNA that codes for a speciﬁc protein into bacteria or cells. Pure proteins can then be

Drs. Comerford and Bickston have received honoraria from Centocor for lectures. * Corresponding author. E-mail address: [email protected] (S.J. Bickston). 0889-8553/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.gtc.2004.02.014

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produced in large quantities; the monoclonal antibody is a useful class of protein that evolved from recombinant technology [3]. These antibodies bind to a particular antigen with high aﬃnity and speciﬁcity [4]. Monoclonal antibodies are currently used to treat immune-mediated inﬂammatory diseases, transplant rejection, and malignancies [5]. Parallel advances in the understanding of the molecular biology of intestinal inﬂammation in animal models allow speciﬁc application to CD in humans. This article discusses inﬂiximab (Remicade, Centocor, Malvern, PA), a chimeric monoclonal antibody (75% human, 25% mouse) that targets tumor necrosis factor (TNF), a potent proinﬂammatory cytokine pivotal in the initiation and promotion of intestinal inﬂammation. This novel biologic agent is now used extensively in the treatment of patients with moderate to severe luminal and ﬁstulizing CD. An estimated 400,000 patients had been treated with inﬂiximab worldwide by April 2003 [6]. To date, it has proved to be safe and eﬀective for patients aﬄicted with CD.

Background Tumor necrosis factor is an important proinﬂammatory cytokine with a key role in several disease states. Interest in TNF as a possible therapeutic target began 20 years ago when its role in endotoxin-induced sepsis was investigated [3]. Elevated TNF concentrations have been found in inﬂamed tissues of patients with CD, rheumatoid arthritis, and multiple sclerosis [7]. Stool and mucosal concentrations of TNF in CD patients have been shown to correlate with clinical activity of disease [8]. Tumor necrosis factor is a 157–amino acid protein produced by T cells, monocytes, and macrophages; after secretion as an inactive precursor, it is rapidly proteolyzed to a 17-kd monomer. Three monomers rapidly combine to form the biologically active 51-kd trimeric cytokine that binds to either the 55- or 75-kd transmembrane TNF receptor located on the surface of a number of diﬀerent cell types. These receptors are designated TNF-R p55 and TNF-R p75 [3,9]. Intracellular signaling events then occur by the NFkB and JNK pathways as a result of the binding of the ligand to the receptor. Transcription of genes involved in the inﬂammatory response is initiated. Induction of apoptosis by proteins called caspases occurs [3,7]. This interaction causes up-regulation of endothelial cell adhesion molecules; proliferation of ﬁbroblast; induction of metalloproteinases critical to tissue destruction; induction of other inﬂammatory mediators, such as interferonc, platelet activating factor, nitric oxide synthase, and cyclooxygenase; activation of the coagulation cascade; and formation of granulomas. Increased intestinal permeability is a consequence [9–14]. Given the role of TNF in the inﬂammatory cascade, considerable research has been focused on studying the eﬀects of blocking this cytokine with novel biologic agents. Animal models of colitis, arthritis, and myelin

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destruction show clinical and histologic improvement with inhibition of TNF [3]. Investigators postulated because TNF was involved in granuloma formation, there might be a role for an anti-TNF agent in the treatment of granulomatous bowel disease, such as CD [15]. Recombinant technology allowed the development of monoclonal antibodies that could serve as these anti-TNF agents. Preliminary open-label trials showed mucosal healing and clinical improvement in CD patients treated with these monoclonal antibodies; the drug, formerly called cA2, is now named inﬂiximab [15]. The name reﬂects standard nomenclature with ‘‘mab’’ denoting monoclonal antibody, ‘‘xi’’ conveying its chimeric nature, and ‘‘inﬂi’’ showing its target is the inﬂammatory cascade. Inﬂiximab is conﬁgured by linking the constant regions of the human immunoglobulin G1k (IgG1k) to the variable antigen-binding regions of a murine anti–human TNF antibody, resulting in a chimeric antibody that is 25% mouse and 75% human protein [11,16]. Inﬂiximab neutralizes the biologic activity of TNF by binding to both the soluble and transmembrane forms of this cytokine and inhibiting binding of TNF with its receptors [16,17]. Binding to transmembrane or cell-bound TNF causes antibodydependent cell-mediated cytotoxicity or complement ﬁxation and lysis of cells bearing TNF on their surface [17]. The IgG1 Fc portion of the antibody causes apoptosis of T lymphocytes [18]. Blocking TNF also results in decreased expression of interleukins-1 and -6, interferon-c, and other proinﬂammatory cytokines. Additionally, acute-phase proteins, adhesion molecules, and inducible nitric oxide synthetase are down-regulated [19,20].

Pharmacology Inﬂiximab is produced by a recombinant cell line, which contains the genomic construct for the cA2 monoclonal antibody. The medication is intravenously administered, usually 5 mg/kg over a period of at least 2 hours. Data collected from clinical trials using single infusions of inﬂiximab at doses of 5, 10, and 20 mg/kg revealed a linear and direct relationship between the dose administered and the maximum serum concentration and area under the concentration-time curve. Volume of distribution at steady state was determined to be independent of dose, indicating that inﬂiximab was primarily distributed within the vascular compartment [3,14]. Based on infusions of 3 and 5 mg/kg, the terminal half-life of inﬂiximab is 8 to 10 days. After a single infusion, detectable levels of inﬂiximab were present for 8 to 12 weeks. Patients given up to four infusions of inﬂiximab at 4- or 8week intervals with doses as high as 10 mg/kg did not show any systemic accumulation. Currently, it is not known how the drug is metabolized or excreted. Additionally, it is not known how gender and severe renal or hepatic dysfunction aﬀect the clearance or volume of distribution of inﬂiximab [3,21].

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Approved gastrointestinal indications The evidence to date supports the use of inﬂiximab as induction therapy for the following indications as approved by the US Food and Drug Administration: reduction in signs and symptoms and induction of clinical remission in patients with moderately to severely active inﬂammatory CD where there is an inadequate response to conventional therapy; and reduction in the number of draining enterocutaneous ﬁstulas in patients with ﬁstulizing CD [22]. Oﬀ-label but clinically accepted indications for induction therapy include avoidance of initiating steroid therapy, using inﬂiximab as a rapidly acting induction therapy, followed by maintenance treatment with azathioprine, 6-mercaptopurine, or methotrexate; and steroid-sparing in steroid-treated patients. Improvement of nutritional status in sick, malnourished patients with active disease may also be a reasonable indication [22]. Inﬂiximab is now approved by the FDA for maintenance of remission as well, in both refractory and ﬁstulizing CD. The rationale for using this novel medication was initially based on uncontrolled studies, but now there is evidence from well-designed clinical trials to support its use. Derkx et al [23] reported clinical improvement in a CD patient after treatment with inﬂiximab. Subsequently, in an open pilot study, van Dullemen et al [15] provided direct evidence that a single infusion of inﬂiximab caused remission in 8 of 10 patients; the infusions signiﬁcantly decreased Crohn’s disease activity index (CDAI), and improved colonoscopic and histopathologic ﬁndings within 4 weeks of infusion. Sedimentation rates and C-reactive protein levels fell within days of treatment. The positive results of these initial studies led to a multicenter, randomized, placebo-controlled, double-blind trial of 108 patients with active CD [24]. Patients received a single infusion of inﬂiximab (5 mg/kg, 10 mg/kg, 20 mg/kg, or placebo). At 4 weeks, 22 (81%) of 27 patients given the 5 mg/kg dose had a clinical response, which was the primary end point of the study and deﬁned as a reduction of 70 or more points in the CDAI score. A total of 14 (50%) of 28 patients given the 10 mg/kg dose achieved clinical response, whereas 18 (64%) of 28 patients infused with 20 mg/kg improved their CDAI at least 70 points. Overall response in the inﬂiximab group was 65%. Only 4 (17%) of 24 patients given placebo responded at 4 weeks (P \ .001). Thirty-three percent of the patients infused with inﬂiximab achieved complete remission, deﬁned as a CDAI score less than 150, compared with only 4% of patients given placebo (P = .005). Forty-eight percent of the patients who received 5 mg/kg inﬂiximab achieved complete remission. At 12 weeks, 34 (41%) of 83 patients in the inﬂiximab group maintained their clinical response compared with 3 (12%) of 25 in the placebo group (P = .008). The investigators concluded a single infusion of inﬂiximab was an eﬀective short-term treatment in patients with moderateto-severe CD. Although a landmark study in the clinical investigation of

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inﬂiximab, constructive criticisms of the study include an unusually low placebo response rate, a lower mean concentration of C-reactive protein at baseline in the placebo group, and signiﬁcantly more patients with ileal disease alone in the placebo group compared with the three treatment groups. Approximately one third of CD patients develop ﬁstula; the eﬃcacy of inﬂiximab in closing these ﬁstula has been studied [25]. In a multicenter, randomized, placebo-controlled, double-blind trial, a total of 94 adults with active draining perianal or abdominal ﬁstulae were given either placebo, 5 mg/kg of inﬂiximab, or 10 mg/kg of inﬂiximab intravenously at 0, 2, and 6 weeks [26]. Fifty-ﬁve percent of patients who received 5 mg/kg and 38% of patients who received 10 mg/kg had closure of all ﬁstulas, compared with only 13% of patients who received placebo (P = .001 and P = .04, respectively). In addition, 68 percent of the patients receiving 5 mg/kg and 56% of the patients receiving 10 mg/kg achieved closure of at least half of their ﬁstulae compared with 26% of the placebo group (P = .002 and P = .02, respectively). The median length of time the ﬁstulas remained closed was 3 months. The clinical eﬀect after a single infusion of inﬂiximab wanes with time and relapses are common [27]. Patients often require retreatment with inﬂiximab. There is evidence from clinical trials to support using inﬂiximab as maintenance therapy. The Food and Drug Administration–approved indication for inﬂiximab as maintenance therapy is maintenance of clinical improvement and clinical remission in patients who previously had moderately to severely active inﬂammatory CD with an inadequate response to conventional therapy who responded to initial induction therapy with inﬂiximab. Inﬂiximab is now also indicated for maintenance in ﬁstulizing CD. Clinically accepted indications for maintenance therapy include maintenance of ﬁstula improvement (reduction in the number of draining perianal or enterocutaneous ﬁstulas) and complete ﬁstula response (no draining ﬁstulas) in patients with ﬁstulizing CD who responded to initial induction therapy with inﬂiximab; and steroid sparing in patients with steroid-treated CD who have failed an attempt at steroid sparing with one or more of the immunosuppressive agents including azathioprine, 6mercaptopurine, or methotrexate [22]. Rutgeerts et al [28] conducted a follow-up study to determine if response could be maintained with repeated infusions in patients who responded to an initial infusion. Seventy-three patients were randomized to receive 10 mg/kg doses of inﬂiximab or placebo at 8-week intervals through week 36 with follow-up through week 48. Fifty-three percent of patients receiving inﬂiximab maintained remission through week 44 compared with 20% of placebotreated patients. Most inﬂiximab-treated patients eventually relapsed 8 to 12 weeks after the ﬁnal inﬂiximab dose administered at week 36, suggesting the duration of beneﬁt for inﬂiximab in patients is approximately 8 weeks [18]. Median values for CDAI, inﬂammatory bowel disease questionnaire

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(a quality of life measurement), and serum C-reactive protein concentrations were maintained at remission levels with inﬂiximab retreatment. The ACCENT I trial was conducted to determine whether maintenance inﬂiximab therapy provides better long-term eﬃcacy than no further treatment for CD patients who respond to a single dose of inﬂiximab [2]. This study included 573 patients with active CD in a multicenter, randomized, placebo-controlled, double-blind trial. All patients received an open-label dose of 5 mg/kg inﬂiximab at week 0. Responders at week 2 (335 [59%] of 573) were then randomized into one of three groups. Group 1 received infusions of placebo at weeks 2 and 6 and then every 8 weeks until week 46. Group II received infusions of 5 mg/kg of inﬂiximab at the same time points. Group III received infusions of 5 mg/kg at weeks 2 and 6 followed by 10 mg/ kg every 8 weeks until week 46. Study end points were the proportion of patients who responded at week 2 and were in remission (CDAI \ 150) at week 30 and the time to loss of response up to week 54. At week 30, 23 (21%) of 110 patients of the placebo group were in remission, compared with 44 (39%) of 113 group II patients (P = .003), and 50 (45%) of 112 group III patients (P = .0002). These results show that retreatment with inﬂiximab every 8 weeks in initial responders is more eﬀective than placebo in maintaining remission. Analysis of a nested study at week 10 showed that a three-dose induction regimen with inﬂiximab (dosing at 0, 2, and 6 weeks) was more eﬀective at inducing remission than a single induction dose. Forty percent achieved remission after a three-dose induction compared with 28% remission after a single-dose induction [18,29]. Other regimens have also been advocated as improving response or decreasing adverse events. One study suggests that a single second infusion within 8 weeks is beneﬁcial [30]. The eﬃcacy of inﬂiximab as maintenance therapy for ﬁstulizing disease was evaluated over 54 weeks in ACCENT II, a multicenter randomized placebo-controlled trial. Patients were infused with 5 mg/kg inﬂiximab at 0, 2, and 6 weeks. Of the 282 patients who completed the study through week 14, 195 patients (69%) were responders with closure of at least 50% of draining ﬁstulas sustained over 1 month. These patients were then randomized to receive either 5 mg/kg inﬂiximab (96 patients) or placebo (99 patients) every 8 weeks. Sands et al [31] reported signiﬁcantly greater rates for ﬁstula improvement (reduction in the number of draining ﬁstulas) and ﬁstula remission (no draining ﬁstulas) in the inﬂiximab-treated group. Speciﬁcally, almost half (48%) of the inﬂiximab-treated patients maintained ﬁstula remission at week 30 compared with 27% of the placebo group. At week 54, 36% of the inﬂiximab-treated group maintained ﬁstula remission compared with 19% of the placebo group. The median time to loss of response was more than 40 weeks in the inﬂiximab-treated group compared with 14 weeks in the placebo group. Mucosal healing from inﬂiximab treatment was evaluated in a multicenter randomized placebo-controlled trial. A total of 30 patients underwent colonoscopy with terminal ileum intubation before treatment with

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inﬂiximab at doses of 5 mg/kg, 10, mg/kg, 20 mg/kg, or placebo. Endoscopy was repeated 4 weeks after infusion of either placebo or inﬂiximab. Mucosal lesions were scored using a validated Crohn’s Disease Endoscopic Index of Severity (CDEIS). Biopsy specimens were taken from 9 of 30 patients pretreatment and posttreatment. CDEIS scores decreased signiﬁcantly in most inﬂiximab-treated patients, although no dose response was noted. In contrast, placebo patients did not exhibit any endoscopic improvement. The inﬂammatory inﬁltrate observed on initial biopsies resolved after treatment in the inﬂiximab group but not the placebo group [32]. Rutgeerts et al [33] showed mucosal healing documented on endoscopy correlated with improved outcomes; speciﬁcally, fewer hospitalizations and surgeries occurred in the group with mucosal healing compared with the group with no mucosal healing. The ﬁndings of this small study are provocative but require validation in larger trials. A sub study of 99 patients in the ACCENT I trial evaluated endoscopic mucosal healing in patients receiving episodic retreatment with inﬂiximab compared to maintenance therapy every 8 weeks. At week 54, only 7% of the episodic retreatment patients had achieved mucosal healing compared to 50% of the patients receiving maintenance therapy. Improvements in CDEIS and CDAI scores were positively correlated in the maintenance therapy group [34]. Inﬂiximab is an option for patients who are intolerant of, resistant to, or dependent on steroids [35]. Of the ﬁrst 100 patients treated with inﬂiximab at Mayo Clinic, a total of 29 (73%) of 40 patients were able completely to withdraw from steroids [27]. Cohen et al [36] reported corticosteroid tapering was achieved in more than 90% of patients with luminal disease, with complete withdrawal of steroids in 54% of patients after the second infusion of inﬂiximab. This study included 81 patients with luminal disease and 48 patients with ﬁstulizing disease who received at least one infusion of inﬂiximab. In the ACCENT I trial, more than half of patients were taking corticosteroids at study entry. One third of patients receiving maintenance inﬂiximab both discontinued steroids and achieved clinical remission [2]. Other reported uses Refractory ulcerative colitis (UC) has two main presentations: severe illness requiring hospitalization and the more common ‘‘working wounded’’ that have persistent mild-to-moderate disease. Although inﬂiximab is not approved for treatment of UC, there are studies that suggest a future role for this therapy in refractory UC. Unfortunately, the available data come from studies that are small, uncontrolled, or retrospective. In a retrospective case series, 16 patients with varying levels of active UC received a single 5 mg/kg infusion of inﬂiximab [37]. Clinical, endoscopic, and histologic improvements were observed in 88% (14 of 16) of patients after initial treatment. Clinical remission was maintained in these patients for at least 4 months. Surgery was avoided in 86% (six of seven) of patients who were

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surgical candidates. Most of the treated patients were completely withdrawn from corticosteroid therapy. In a placebo-controlled trial, 11 patients with active severe, steroidrefractory UC were randomized to receive a single infusion of inﬂiximab or placebo [38]. The study was appropriately designed and powered to clarify whether inﬂiximab might serve in this presentation in like manner to the more established use of cyclosporine, but was aborted for lack of enrollment. Four (50%) of the eight patients receiving inﬂiximab experienced a clinical response at 2 weeks. Improvement in sedimentation rates and C-reactive proteins correlated with clinical response. None of the three placebo patients improved. Infusion with inﬂiximab produced no signiﬁcant adverse events. A retrospective analysis of clinical experience in four medical centers was conducted to assess the eﬀectiveness of inﬂiximab in UC [39]. A total of 27 patients with UC received single or multiple infusions of inﬂiximab. Twelve patients (44%) achieved remission and six patients (22%) had a partial response, whereas nine patients (33%) had no response. Five patients who did not respond subsequently underwent total colectomy. The median time to achieve response and remission was 4 days; the median duration of response was 8 weeks. Steroid-responsive patients were more likely to respond to inﬂiximab than steroid-refractory patients (83% versus 33%; P = .03). Of the 18 patients who responded, 9 experienced 19 relapses; 18 of these relapses (95%) were successfully retreated with further infusions of inﬂiximab. One death occurred. One placebo-controlled trial evaluating inﬂiximab in 42 patients with steroid-refractory UC showed no clinical beneﬁt [40]. This comparative trial only had 42 patients, underpowering the study to detect a diﬀerence. These small studies show promise, but larger controlled trials are required. The use of inﬂiximab for UC remains investigational until eﬃcacy and safety for this indication are demonstrated in controlled trials, such as the two phase III placebo-controlled trials currently in progress. Inﬂiximab has been reported to treat other gastrointestinal-related conditions, including CD of the ileoanal pouch. Medical records of seven patients with CD who underwent an ileal pouch anal anastomosis for an original diagnosis of presumed UC were reviewed at Mayo Clinic. The patients received one to four doses of inﬂiximab at 5 mg/kg for active inﬂammatory or ﬁstulizing disease after they had no improvement in their symptoms with conventional therapies. All patients improved clinically, with six of seven obtaining a complete response and one patient achieving a partial response. Six of the seven patients received concurrent treatment with immunomodulators [41]. Patients with CD often experience extraintestinal manifestations of their disease, which are often debilitating and diﬃcult to manage. There is evidence inﬂiximab may have a role in treating these conditions, which include ankylosing spondylitis, peripheral arthritis, pyoderma gangrenosum, and erythema nodosum [42–45].

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Inﬂiximab may also improve bone mineral density in CD patients both directly, through inhibition of TNF and indirectly through steroid sparing. CD patients are at increased risk for low bone mineral density; prevalences of osteopenia and osteoporosis as high as 50% and 10%, respectively, have been reported. The etiology for low bone mineral density is multifactorial; low body mass index through poor nutrition, corticosteroid use, decrease intake of calcium and vitamin D, and malabsorption of nutrients secondary to inﬂamed or resected bowel may all play a role. The systemic inﬂammatory disorder of CD may also cause bone loss through the action of cytokines, including TNF. Osteoclast function, stimulated by these cytokines, aﬀects bone resorption, which has been demonstrated in numerous in vitro and in vivo studies. Abreu et al [46] conducted a prospective study evaluating the eﬀect of inﬂiximab on surrogate markers of bone turnover in 38 CD patients. The results showed bone synthesis markers were increased in the inﬂiximab-treated patients. Longer-term studies are needed to clarify the eﬀect of inﬂiximab on bone mineral density.

Toxicity Although an eﬀective medication for CD, serious side eﬀects have been reported including acute infusion reactions, delayed hypersensitivity reactions, infections including reactivation of tuberculosis (TB), autoantibody formation, and a lupus-like syndrome. Clinicians need to be aware of these potential outcomes to diagnose and manage correctly the complications. Candidates for therapy should be counseled about these toxicities before infusions. Acute infusion reactions are adverse events occurring during the infusion or within 2 hours after the infusion is complete. They are common, occurring in approximately 22% of treated patients compared with 9% of patients receiving placebo according to the manufacturer’s drug insert [21]. Mayo Clinic, however, reported a much lower incidence in their clinical experience; only 19 (3.8%) of 500 patients who received infusions experienced an acute infusion reaction [47]. These events are non-IgE mediated anaphylactoid events. These include but are not limited to headache, nausea, dyspnea, urticaria, and chest tightness. Generally, these reactions can be managed easily by ﬁrst slowing or temporarily stopping the infusion, then treating with oral acetaminophen and serial doses of intravenous diphenhydramine, 25 to 50 mg, if symptoms persist. At the authors’ institution, they have also found intravenous famotidine to be helpful for the H2 component of the allergic response. After symptoms resolve, recommencing the infusion at a slower rate and then titrating upward as tolerated is usually successful. Most patients are able to complete their infusion. Patients with a history of infusion reactions should be considered for premedication with these medications approximately 30

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minutes before the infusion. There is no evidence that routine premedication in patients without a history of infusion reaction is necessary [22]. At times, prednisone may be required as a premedication in patients who have symptoms with infusions not alleviated with diphenhydramine and acetaminophen or those who are at risk because of a long interval (greater than 4 months) since last infusion. Any patient who has had prior infusion reaction should be considered for premedication with prednisone. Delayed hypersensitivity or serum-sickness–like reactions several days after the infusion can also occur. Symptoms include severe pruritus; headaches; hand, facial, or lip swelling; myalgias; rash; sore throat; or dysphagia. One study of 40 CD patients showed a 25% incidence rate, with 6 patients requiring hospitalization [48]. These patients had initially received an investigational liquid formulation of the drug, which is no longer in use with a follow-up infusion 2 to 4 years later with the commercialized formulation (lyophilized powder). These events occur much less frequently in clinical practice with retreatment intervals up to 1 year; in ACCENT I, where patients received repeated infusions every 8 weeks, the frequency of delayed hypersensitivity reaction was 2% [2]. In Mayo Clinic’s experience with 500 patients, only 14 patients (2.8%) had serum sickness related to inﬂiximab [47]. Infections requiring treatment have been associated with inﬂiximab therapy during clinical trials; speciﬁcally, 36% of inﬂiximab-treated patients compared with 26% of patients receiving placebo [21]. In postmarketing experience, infections have been observed with pathogens including viral, bacterial, fungal, and protozoal organisms. Most infections involved the respiratory (pharyngitis, sinusitis, bronchitis) and urinary tract. Serious and even fatal infections have been reported including abscess, sepsis, pneumonia, cellulitis, TB, disseminated coccidioidomycoses, Pneumocystis carinii pneumonia, histoplasmosis, listeriosis, and aspergillosis. During trials, no statistically signiﬁcant increase in serious infections or sepsis was seen in inﬂiximab-treated patients compared with placebo-treated patients [22]. Mayo Clinic reported 41 (8.2%) of 500 patients developed an infection related to inﬂiximab [47]. Twenty patients had a serious infection: two lethal sepsis; eight pneumonias, of which two were lethal; six viral infections, including three varicella-zoster virus infections; two abdominal abscesses requiring surgery; one arm cellulites; and one histoplasmosis. No cases of TB were observed. Because there was no control group in the Mayo series, it is diﬃcult to know what proportion, if any, of these infections were caused by inﬂiximab. Over 85% of the patients in this cohort were taking additional concomitant immunosuppressive medications. The overall mortality rate was not diﬀerent from the background rate in CD [49–52]. Active or suspected infections should be treated before infusing inﬂiximab. Reactivation of latent TB after infusion with inﬂiximab has been observed, mandating screening of patients for TB before infusions. This likely reﬂects the impact of inﬂiximab on the TNF-driven apoptosis of cells within

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granulomas. Over 70 cases have been reported; 48 of the cases developed TB after three or fewer infusions [53]. Most cases occurred within the ﬁrst 2 months after initiation of therapy with inﬂiximab suggesting activation of latent disease rather than new infection. Most cases (64 of 70) were from countries with a low incidence of TB. Forty of 70 patients had extrapulmonary disease. Interestingly, most cases involved patients being treated with inﬂiximab for rheumatoid arthritis; only 22% of patients had CD [22]. A puriﬁed protein derivative should be placed on all patients being considered for inﬂiximab infusion with the results interpreted according to the risk strata adapted from the American Thoracic Society [21,54]. Patients with negative readings and no risk factors for previous exposure obtained on history and physical examination can receive inﬂiximab therapy. Patients with a positive puriﬁed protein derivative should undergo a chest radiograph. If the radiograph is normal, patients should begin treatment for latent TB according to American Thoracic Society guidelines before beginning inﬂiximab therapy [22,55]. A 9-month course of isoniazid is the preferred treatment. If the radiograph is abnormal, inﬂiximab should not be given until the active TB is adequately treated. Chronically ill patients taking corticosteroids and immune modulators may be anergic [56]. For this reason, the criteria used when screening inﬂammatory bowel disease patients should be that a positive puriﬁed protein derivative is greater than or equal to 5-mm induration. It cannot be overemphasized that a thorough history for risk factors should also be taken. A chest radiograph should be performed if warranted by the medical history, despite a negative puriﬁed protein derivative in these patients. The authors’ pharmacy conﬁrms clearance for TB before releasing vials of inﬂiximab, a practical fail-safe mechanism. Although the safety of inﬂiximab in reproduction and pregnancy is unclear, there are accumulating data to show patients are delivering healthy children after exposure to the drug. Currently a pregnancy category B drug, animal reproduction studies have not been conducted because inﬂiximab does not bind TNF in species other than humans and chimpanzees [21]. A toxicity study in mice was conducted using an analogous antibody that selectively inhibits the functional activity of mouse TNF. No evidence of maternal toxicity, embryotoxicity, or teratogenicity was observed. There are case reports of patients delivering healthy babies after being infused with inﬂiximab during their pregnancy. Katz et al [57] recently queried the inﬂiximab safety database maintained by the manufacturer (Centocor, Malvern, PA) for pregnancy outcomes in 133 female patients and 14 male partners exposed to inﬂiximab. Pregnancy outcome data were available for approximately 50% (65 of 133) of patients. Fifty-six percent (74 of 133) of female patients were exposed to the drug within 3 months before conception; 45% (33 of 74) of these patients received inﬂiximab before conception and during the ﬁrst trimester. Results showed live births in 65% (42 of 65); miscarriages in 17% (11 of 65); and therapeutic terminations in 22% (14 of 65). These were not diﬀerent from expected outcomes in the

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general pregnant United States population. Of the 14 male partners, there were 7 live births, 1 miscarriage, 3 ongoing pregnancies, and 3 unknown outcomes. The available data suggest inadvertent exposure does not cause harm to the fetus. It should probably only be administered knowingly to pregnant patients when a ﬂare uncontrolled by other medications poses a greater health risk to the mother and unborn child than the risk of inﬂiximab. Although immunoglobulins and many medications are secreted in breast milk, it is unknown if inﬂiximab is excreted in breast milk [21]. It is also unknown if inﬂiximab is absorbed systematically after oral administration. Because there is a theoretical risk for adverse reactions in nursing infants, patients should make a decision either to discontinue inﬂiximab therapy before breast-feeding, or discontinue breast-feeding if the medication is required. Inﬂiximab is contraindicated in patients with moderate to severe congestive heart failure (NYHA class III to IV). Higher incidences of mortality and hospitalization caused by worsening heart failure were observed in a phase II study comparing inﬂiximab with placebo in 150 congestive heart failure patients treated with three infusions over 6 weeks. In follow-up at 38 weeks, nine inﬂiximab-treated patients had died compared with one placebo patient [21]. Despite this evidence that inﬂiximab may worsen pre-existing congestive heart failure, there is no evidence that inﬂiximab causes congestive heart failure.

Special considerations Inﬂiximab contains exogenous proteins that can prompt treated individuals to form antibodies to these proteins, called antibodies-to-inﬂiximab (ATIs). The clinical implications of ATIs are currently a topic of research. From the ACCENT I trial, 442 patients were assessed up to week 54 for the presence of ATIs [2]. A total of 64 (14.5%) of 442 developed antibodies, whereas 173 (39%) of 442 did not form antibodies. Approximately half of the patients (46%) had inconclusive results concerning formation of ATIs because inﬂiximab was detected in their serum, which can compete for the detection of antibodies to inﬂiximab in the immunoassay. When followed longer, most of these inconclusive patients were found to be negative for ATIs. These results are similar to previous studies. Patients receiving a single dose of inﬂiximab followed by either placebo or episodic inﬂiximab retreatment had higher incidence of ATI formation than patients receiving scheduled maintenance regimens of 5 or 10 mg/kg (28% of patients compared with 9% and 6% of patients, respectively). Patients had similar rates of clinical response independent of their antibody status. Sixty-four percent of patients with ATIs responded clinically to inﬂiximab (decrease in CDAI of [70 points from baseline and [25 points reduction in total CDAI

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score) compared with 62% who did not form ATIs. The rate of infusion reactions was slightly higher in the ATI positive group. Thirty-eight percent of patients with ATIs had one or more infusion reactions compared with 24% of patients without ATIs. Only a small minority of infusions in the ATI group, however, experienced an infusion reaction: 16% of infusions in the ATI-positive group compared with 8% of infusions in the ATI-negative group. Most of the infusion reactions were mild to moderate. Severe reactions and serum sickness–like reactions were rare and not increased in the ATI-positive group. Baert et al [58] conducted a study of 125 CD patients who received ‘‘on demand’’ (episodic) inﬂiximab therapy; patients with luminal disease received a single 5 mg/kg infusion, whereas patients with ﬁstulizing disease received three infusions of 5 mg/kg inﬂiximab at 0, 2, and 6 weeks [58]. Responders were retreated ‘‘as needed’’ when symptoms recurred. Sixty-one percent of patients developed ATIs, much higher than the 14% detected in ACCENT I. Of these patients, only 37% had clinically signiﬁcant levels of inﬂiximab (>8 lg/mL). There was a higher risk of infusion reactions in the ATI-positive group (relative risk 2.4), but the association of high ATI levels with loss of response is clearly the more important ﬁnding. Patients with high ATI levels had a substantially shorter duration of response (35 days) compared with the patients who did not form antibodies (71 days). This impact on durability of response is reshaping treatment strategies. Three approaches have been examined to date: (1) premedication-concomitant steroids, (2) concomitant antimetabolite therapy, and (3) regular rather than episodic infusions. The development of ATIs has generally been lower in patients receiving concomitant immunosuppressants. Rheumatoid arthritis patients given methotrexate in addition to inﬂiximab had lower antibody formation. In ACCENT I, only 4 (6%) of 64 patients developed ATIs who were receiving corticosteroids plus immunomodulator therapy [2]. Seventeen percent of patients receiving steroids alone and 10% of patients receiving immunomodulators alone formed ATIs. In comparison, 18% of patients receiving no additional immunomodulators formed ATIs. The lowest incidence of infusion reactions in the ACCENT I trial occurred in patients receiving both steroids and immunomodulators (8%), as compared with patients receiving neither (32%). In the Baert et al [58] study, patients receiving concomitant immunomodulator therapy had less antibody formation, higher concentrations of inﬂiximab, reduced incidence of infusion reactions, and increased duration of response, prompting the authors to recommend their use. In their randomized trial of 53 consecutive patients receiving 199 ‘‘on demand’’ infusions, Farrell et al [30] also showed that loss of initial response and infusion reactions postinﬂiximab were strongly related to ATI formation and level. Administering a second infusion within 8 weeks of the ﬁrst and concurrent immunosuppressant therapy signiﬁcantly reduced ATI formation. They also found that premedication with intravenous hydrocortisone signiﬁcantly reduced ATI levels but did not eliminate ATI formation or

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infusion reactions. Based on the results of these studies, most authorities now recommend that inﬂiximab be administered on a regular maintenance schedule and that strong consideration be given to the administration of concomitant immunomodulators. There was initial concern over a possible link between inﬂiximab and lymphoma, but early analyses and subsequent regulatory data show that malignancies are no more common in treated patients than in matched controls [59]. Nineteen new or recurrent malignancies were observed in 18 of 1372 patients treated with inﬂiximab for up to 102 weeks in clinical trials over 1430 patient-years of follow-up [21]. These included non-Hodgkin’s Bcell lymphoma; breast cancer; rectal adenocarcinoma; and melanoma, squamous cell, and basal cell skin cancers. The observed rates and incidences were similar to those expected for the populations studied. Patients with CD are probably more likely to develop lymphomas irrespective of concomitant inﬂiximab therapy. Data are insuﬃcient to determine whether inﬂiximab contributed to the development of these malignancies. Mayo Clinic reported 3 of 500 patients treated with inﬂiximab developed a malignancy (two lung cancers and one non-Hodgkin lymphoma) in a time frame that cannot exclude a relationship to the inﬂiximab therapy [47]. Patients treated with inﬂiximab may develop autoantibodies; in clinical trials, antinuclear antibodies and anti-double–stranded DNA antibodies developed in 44% and 22% of patients, respectively [21]. Most of these patients remain asymptomatic and inﬂiximab retreatment is not contraindicated in these patients [22]. Three CD patients developed signs of druginduced lupus [21]. All of these patients recovered without sequelae on discontinuation of inﬂiximab.

Cost Inﬂiximab is an expensive medication costing over $2000 US per infusion, raising the question whether or not it is a cost-eﬀective therapy for CD patients, especially in the current health care climate. To answer this question, one needs ﬁrst to study the cost of CD in general on society. Hay and Hay [60] provided landmark economic analysis of this disease. They found the lifetime direct medical cost of the illness per case in 1990 dollars was signiﬁcant ($18,000–178,000). For comparison, heart disease was estimated costing $10,000 to 60,000. The estimated annual average medical cost per patient was approximately $9500 [60,61]. The estimated direct total annual cost of CD in 1996 dollars was $1.4 to 1.7 billion. As expected, surgery and hospitalizations accounted for most of the direct cost, approximating 80% of the total bill, compared with medications, outpatient resources, complications, and diagnostic testing, which accounted for the remaining 20%. Indirect costs were also signiﬁcant with 5% to 10% of

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patients out of work and receiving disability beneﬁts annually. The average number of workdays missed per month because of CD among full-time workers is 3.3 days [62]. In the United States, the proportion of patients not working because of their disease was estimated to be one in six. In their study of insurance claims for over 600 patients with CD over a 1year period, Feagan et al [63] found results similar to Hay and Hay [60]. Patients were stratiﬁed into three disease-severity groups: group 1 required hospitalization, group 2 required chronic steroids or immunomodulator therapy, group 3 included all remaining patients. Group 1 consumed the most health care dollars; speciﬁcally $37,135 per patient-year compared with $10,033 and $6277 for groups 2 and 3 patients, respectively. Hospitalization accounted for 57% of all direct care costs in CD. A minority of patients was responsible for most of the costs: approximately 25% of patients requiring 80% of the cost. New therapies could reduce overall costs if the need for hospitalization could be reduced. Cohen et al [64] reviewed the computer database for all hospitalizations at the University of Chicago during a 1-year period with a primary diagnosis of CD. The major charge during hospitalization was for surgery, accounting for nearly 40% of the hospital charges. The authors concluded more eﬀective medical therapies could result in an overall decrease in medical costs if they reduce the need for hospitalization and surgery. Finally, a study was conducted by Rubenstein et al [65] to determine if inﬂiximab decreased health care use of CD patients. The investigation included an electronic and paper chart review up to 3 years before infusion and 1 year following the initial infusion. Patients served as their own controls; use rates were compared pre and post ﬁrst inﬂiximab infusion. Some health care resource uses were decreased by a statistically signiﬁcant percentage following inﬂiximab infusion including gastrointestinal surgeries (18%); emergency room visits (66%); endoscopies (43%); radiology examinations (12%); and all outpatient visits (16%). Patients treated for ﬁstulas had decreases in hospitalizations (59%) and gastrointestinal surgeries (59%). Rutgeerts et al [61] reviewed the ACCENT I data comparing CD patients treated with inﬂiximab episodically versus scheduled treatment strategies and evaluated the rate of hospitalizations and surgeries. In the inﬂiximab 5 and 10 mg/kg scheduled treatment groups, signiﬁcantly fewer CD-related hospitalizations were required (23 and 24 per 100 patients, respectively) compared with patients in the inﬂiximab episodic treatment group (38 per 100 patients) (P ¼ .047, P ¼ .023 respectively for each comparison). Additionally, signiﬁcantly fewer patients in the scheduled treatment group required CD-related surgery compared to the episodic treatment group. Scheduled therapy patients required hospitalization or surgery at approximately half the rate required by episodic therapy patients. Although these studies indicate cost savings can be accrued by attempting to reduce hospitalizations and surgical procedures, possibly with inﬂiximab, further cost-eﬀectiveness studies that factor in medication costs of inﬂiximab

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with its direct and indirect cost savings, including improvement in quality of life aspects, are needed. Summary Hundreds of thousands of patients have been treated with inﬂiximab since its approval in 1998. Clinical trials and practice have shown it to be safe, eﬀective, and generally well tolerated. On its debut as the earliest eﬀective biologic agent for CD, inﬂiximab was considered the ﬁrst truly novel therapy for CD in half a century. Thus far, complement activation and destruction of eﬀector cells distinguish it from agents like CDP571, other humanized monoclonal antibodies, and other anti-TNF products. Are these the critical diﬀerences? Drug factors aside, what about patient characteristics? Parsi et al [66] showed nonsmoking and the concurrent use of immunomodulators are predictors of response to inﬂiximab. One study showed that neither NOD2-CARD15, ASCA, nor ANCA were predictive of outcome with inﬂiximab treatment for CD [67,68]. What other factors could identify patients more likely to accrue beneﬁt from this drug? Other topics for future investigation include the role of inﬂiximab after surgical resection of disease to prevent recurrence; assessment of a possible synergy in combining immunomodulators and inﬂiximab; and ﬁnally, inﬂiximab as a possible ﬁrst-line drug in the treatment of CD. Because it is a relatively new medication, expensive, and novel in its mechanism of action, clinicians need to continue to reﬁne the strategy for using this drug. In 1998 there were substantial concerns over the safety and cost of inﬂiximab, very similar to the gastroenterology community’s response to 6mercaptopurine decades ago. Most clinicians have grown comfortable with 6-mercaptopurine over the years and are gaining experience with biologic therapy. As clinicians become more comfortable with inﬂiximab, more than 70 new biologic agents are upstream in the development pipeline. The speed of process from concept-to-drug is far faster than in the days when antimetabolites were newcomers: it is prudent to continue to examine inﬂiximab closely for lessons in therapeutic success.

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Methotrexate in inﬂammatory bowel disease Brian G. Feagan, MD*, Ahmad Alfadhli, MD University of Western Ontario, 100 Perth Drive, London, ON N6A 5K8, Canada

Despite the introduction of several treatment advances over the past decade, signiﬁcant limitations still exist in the medical management of patients with inﬂammatory bowel disease. Although corticosteroids are highly eﬀective for induction of remission [1,2], a substantial proportion of patients who respond relapse when steroids are withdrawn and become steroid dependent. Furthermore, corticosteroids exhibit signiﬁcant adverse eﬀects [3]. Treatment alternatives are required for patients who are refractory to glucocorticoid therapy. Methotrexate is an eﬀective and safe treatment for corticosteroid-dependent or corticosteroid-resistant patients in other chronic inﬂammatory diseases, such as psoriasis and rheumatoid arthritis (RA) [4–8]. It is logical to consider methotrexate as a treatment for inﬂammatory bowel disease. Methotrexate has been used in clinical medicine for over 40 years. Developed initially as a treatment for leukemia, the drug was synthesized based on knowledge of the three-dimensional structure of the enzyme dihydrofolate reductase, as identiﬁed by x-ray crystallography. This enzyme, which is essential for the synthesis of nucleic acid precursors, requires folic acid as a cofactor. Methotrexate was synthesized as a competitive antagonist of folic acid. Methotrexate is one of the earliest examples of a ‘‘designer drug.’’ Inhibition of dihydrofolate reductase by high-dose methotrexate interferes with DNA synthesis, which ultimately results in the death of leukemic cells [9]. In the course of the initial successful experience with methotrexate in oncology, it was recognized that children with leukemia and concomitant psoriasis or RA showed improvement of the latter conditions. This observation subsequently led to the evaluation of low-dose (5–25 mg weekly) methotrexate as a treatment for a number of immune diseases. Over * Corresponding author. E-mail address: [email protected] (B.G. Feagan). 0889-8553/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.gtc.2004.03.001

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the past decade clinical trials have shown that methotrexate has an emerging role for the treatment of Crohn’s disease (CD).

Clinical pharmacology Methotrexate can be administered by the oral, subcutaneous, intramuscular, or intravenous routes [10]. The drug is highly bioavailable at doses of 15 mg or less; however, absorption may be erratic with high oral doses [11]. Following absorption, methotrexate is concentrated in the liver, kidneys, and synovium and has a steady-state volume of distribution of approximately 1 L/kg. The parent molecule is transported into cells through an energy-dependent process. The enzyme hepatic aldehyde converts methotrexate to a primary metabolite, 7-hydroxymethotrexate. The drug is subsequently eliminated from the body by glomerular ﬁltration; both tubular secretion and reabsorption also occur. As a consequence, organic acids, such as aminosalicylic acid (ASA), and some nonsteroidal antiinﬂammatory drugs may interfere with renal tubular secretion and increase serum methotrexate levels. Because clinically signiﬁcant drug interactions have been reported in patients with RA methotrexate should be used cautiously in patients with renal impairment. Therapeutic drug monitoring has not been shown to be useful in patients with RA [12]. Although the mechanism of the anti-inﬂammatory eﬀect of methotrexate is poorly understood, it is not likely through the inhibition of dihydrofolate reductase because folate supplementation does not reduce clinical eﬃcacy in patients with RA [13]. Several immunosuppressive properties have been demonstrated in vitro including suppression of proinﬂammatory molecules, a decrease in cytotoxic T-cell function, and reduction in neutrophil activity [14]. Inhibition of adenosine metabolism does not seem to be an important mechanism of action in patients with inﬂammatory bowel disease [15].

Adverse event proﬁle Low-dose methotrexate was ﬁrst identiﬁed as an eﬀective treatment for severe psoriasis in the early 1960s [5]. The dose used as treatment for psoriasis and other autoimmune diseases is approximately one fortieth of that used in oncology. Despite impressive eﬃcacy an unacceptably high incidence of hepatic toxicity was noted in psoriatic patients who had received chronic treatment with methotrexate. For example, in a series of 104 patients who were treated for a mean duration of 3.4 years with doses of 20 to 25 mg/wk, 23% showed signiﬁcant pathologic changes (cirrhosis or active hepatitis) on liver biopsy [16]. These ﬁndings might have led to the abandonment of methotrexate as treatment for autoimmune disease if not for subsequent pharmacokinetic investigations, which demonstrated that continuous (daily) drug administration results in high hepatic methotrexate

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concentrations [17]. This ﬁnding is explained by the observation that polyglutamic folic acid is concentrated intrahepatically. Because methotrexate is a folate analogue, the drug likewise accumulates in the liver and causes toxicity. High intrahepatic concentrations of methotrexate do not occur, however, if suﬃcient time is allowed between doses for the drug to be redistributed from the liver and excreted by the kidney [18]. This understanding of the pharmacokinetics of methotrexate led to the development of once weekly dosing schedules for the treatment of RA, which in turn reduced the incidence of hepatic toxicity. The frequency of methotrexate hepatic toxicity may also relate to the underlying disease, however, because the incidence of this complication is higher in psoriasis and low in RA. This may reﬂect diﬀerences among populations in the prevalence of risk factors (alcohol use, diabetes mellitus, and obesity) for methotrexate toxicity. Only limited data are available to assess the potential risk of methotrexateassociated hepatic ﬁbrosis in inﬂammatory bowel disease [19]. Other important adverse eﬀects of methotrexate include nausea [20], bone marrow suppression [21], and hypersensitivity pneumonitis [22]. Methotrexate must not be given to women of childbearing potential because of the risk of teratogenicity [23].

Methotrexate therapy for Crohn’s disease Induction of remission Munkholm et al [24] have documented the natural history of active CD in Copenhagen County. Most patients who are treated with a course of conventional glucocorticoid therapy become either steroid dependent (36%) or steroid resistant (20%). Only a minority (44%) of patients experience a durable treatment response to glucocorticoid therapy. Patients who require chronic steroid therapy experience important morbidity and are at risk for disease-related mortality. Although surgery is an important treatment option, CD frequently recurs following a bowel resection. For this reason, it is current practice to oﬀer patients who require chronic steroid treatment immunosuppressive drug therapy. The greatest experience has been with the purine antimetabolites 6-mercaptopurine (6-MP) and azathioprine. Although early studies demonstrated conﬂicting results as to the eﬃcacy of these drugs [1], data from two subsequent randomized placebocontrolled trials [25,26] and a meta-analysis [27] indicate that they are eﬀective for the induction of remission and for maintenance therapy in CD [27,28]. The onset of action of azathioprine is relatively slow (3–6 months), which may be a consequence of individual variability in the time required obtaining a steady-state concentration of immunosuppressive drug metabolites. Moreover, less than half of patients who receive maintenance therapy with the purine antimetabolites remain free of a relapse over 1 year [25,26]. Although the purine metabolites are relatively well tolerated, serious toxicity

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can occur [29], most notably pancreatitis, leukopenia, and infection. Alternative treatments are desirable. It is noteworthy that methotrexate has been preferred to azathioprine for the treatment of RA on account of a more rapid clinical eﬀect and superior long-term tolerability [30–33]. In 1989 Kozarek et al [34] ﬁrst reported the use of methotrexate for the treatment of inﬂammatory bowel disease in an uncontrolled study that evaluated 21 patients (14 with CD, 7 with ulcerative colitis) with chronically active disease. Methotrexate was administered intramuscularly at a dose of 25 mg once weekly with conversion to a maintenance dose of 15 mg orally in patients who responded to therapy. Approximately two thirds of patients had improvement in symptoms and a steroid-sparing eﬀect was also demonstrated. Notably one third of the patients with CD demonstrated endoscopic improvement, whereas no such beneﬁcial eﬀect was seen in the patients with ulcerative colitis. On the basis of these promising results three randomized placebo-controlled trials were subsequently conducted. The results of these studies have been evaluated in a systematic review published in the Cochrane library [35]. In the largest study, the North American Crohn’s Study Group Study Investigators, conducted a randomized, multicenter, double-blind, placebocontrolled trial of intramuscular methotrexate in chronic steroid-dependent CD (N = 141) at seven centers in Canada and the United States [20]. Eligible patients had chronically active CD with at least 3 months of symptoms despite a daily dose of at least 12.5 mg of prednisone with at least one attempt to discontinue treatment. A total of 141 patients were randomly assigned in a 2:1 ratio to receive either 25 mg/wk methotrexate (94 patients) or placebo (47 patients). Remission was deﬁned as complete discontinuation of prednisone therapy and CD activity index (CDAI) score of less than 150 points at the end of 16 weeks. After 16 weeks, 37 patients (39.4%) were in clinical remission in the methotrexate group compared with 9 patients (19.1%) in the placebo group (P = .025). The patients in the methotrexate group received less prednisone overall than those in the placebo group (P = .026). The eﬀect of treatment was greatest in those patients who had required greater than 20 mg of prednisone per day to control their symptoms (Fig. 1). The mean score on the CDAI after 16 weeks of treatment was signiﬁcantly lower in the methotrexate group (162 12) than in the placebo group (204 17, P = .002). In the methotrexate group, 16 patients (17%) withdrew from treatment because of adverse events as compared with 1 patient (2%) in the placebo group. In the second trial, Oren et al [36] conducted a randomized, double-blind, placebo-controlled trial in 12 centers in Israel. The aim of the study was to evaluate the eﬀectiveness of oral methotrexate in chronic steroid-dependent CD. The study included patients with active CD who had received steroids or immunosuppressives for at least 4 months during the preceding 12 months, who had a Harvey-Bradshaw Score of more than 7. Patients were randomized to placebo, oral methotrexate, 12.5 mg/wk, or oral 6-MP, 50 mg daily for 9

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Percentage in Remission (%)

50

P=0.025

411

Methotrexate P=0.003

39.4

P=0.92 40.0

39.0 35.3

25

19.1 10.0 0

All Patients

High-Stratum Prednisone

Low-Stratum Prednisone

Fig. 1. Percentages of patients in remission at week 16 according to study group and stratum of daily prednisone dose before entry into the study. (From Feagan BG, Rochon J, Fedorak RN, et al. Methotrexate for the treatment of Crohn’s disease. N Engl J Med 1995;332:292–7; with permission.)

months. Corticosteroids and 5-ASA compounds were administered as clinically indicated. The authors evaluated four outcomes; however, a primary outcome was not deﬁned. Eighty-four patients were included (methotrexate, 26 patients; 6-MP, 32 patients; placebo, 26 patients). There was no statistically signiﬁcant diﬀerence between the groups in the proportion of patients entering ﬁrst remission or the proportion of patients relapsing after ﬁrst remission. The Harvey-Bradshaw Score and the mean monthly steroid doses were not diﬀerent between the methotrexate and placebo groups. In the third trial, Arora et al [37] randomized 33 patients with corticosteroid-dependent CD for at least 6 months and either a CDAI score greater than 150 despite 10 mg/d of prednisone or a score of less than 150 despite treatment with at least 15 mg of prednisone daily to either placebo or methotrexate, 15 mg/wk orally, with dose escalation to a maximum of 22.5 mg/wk according to clinical response. The investigators evaluated eﬃcacy by the average reduction in prednisone dosage, CDAI scores, and laboratory parameters. Treatment failure was deﬁned as no improvement in the CDAI at 3 months with any reduction in steroid dose or the development of severe clinical illness. Four patients were dropped from the study for noncompliance and one because of an intercurrent illness leaving 28 evaluable patients. There was no statistically signiﬁcant diﬀerence (P = .142) in exacerbations of CD between methotrexate-treated patients (6 of 13) and placebo-treated patients (12 of 15). No statistically signiﬁcant diﬀerence was observed (P = .175) in the number of adverse eﬀects that occurred in methotrexate-treated patients (3 of 13) as compared with the placebo-treated patients (0 of 15). What conclusions can be drawn from results of these three studies? The ﬁrst point to consider is that the trials [20,36,37] diﬀered considerably with

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respect to patient populations, the intervention, and the outcome measures used. Two studies, which used low doses of oral methotrexate, showed no statistically signiﬁcant diﬀerence between methotrexate- and placebo-treated patients, and one, which used a higher dose given intramuscularly, showed a substantial beneﬁt (number needed to treat = 5). This study also demonstrated an important improvement in quality of life (Mean Inﬂammatory Bowel Disease Questionnaire scores: methotrexate 169 4, placebo 151 6, P \.002) and a clinically meaningful reduction in the use of prednisone. The two trials that used low-dose oral methotrexate included relatively small numbers of patients and may have lacked suﬃcient statistical power to show a beneﬁt of treatment. In these two studies it was also diﬃcult to determine from the published results the precise numbers of patients who were in clinical remission and the status of these patients with respect to continued steroid treatment. In clinical practice, intramuscular administration is associated with higher costs and reduced patient quality of life because of the need for increased clinic visits. In RA subcutaneous administration of drug has produced similar pharmacokinetics to intramuscular injection, is easier to administer, and leads to greater patient comfort and a reduced rate of reactions at the injection site [38–40]. Adverse events were observed with approximately equal frequency in the methotrexate-treated (45%) and control (42%) groups in the study reported by Feagan et al [20]. Although no severe adverse eﬀects were observed, 17% of methotrexate-treated patients were withdrawn from treatment because of adverse events, compared with 2% in the placebo group (P = .012). The most common reasons for withdrawal were nausea and vomiting (six patients) and asymptomatic elevation of liver enzymes (seven patients). Although the protocol for this trial mandated withdrawal of the study drug, in clinical practice in patients with rheumatoid disease, adverse eﬀects, such as nausea, are often dealt with or prevented by the concomitant administration of folic acid [41,42] and asymptomatic elevations of transaminases on a single serum sample are not considered to reﬂect or predict existing or future hepatic disease [43]. In the two trials that used lower doses of oral methotrexate no serious adverse eﬀects were observed. In one trial [37], however, alanine transaminase levels were increased in 53% of patients receiving methotrexate, compared with 22% of patients receiving placebo. No clinically signiﬁcant hepatotoxicity was observed. In addition to the data from controlled trials, several large centers have published observational data regarding the eﬃcacy and safety of methotrexate. Although these data are retrospective and not placebo controlled, they conﬁrm methotrexate induces remission in a high proportion of patients, many of whom had previously failed treatment with a purine antimetabolite. In a review of 70 cases (48 CD, 322 ulcerative colitis) the remission rate was 62% for those patients who completed more than 3 months treatment and 45% for all patients who were treated for 1 year. In a similar study 76 steroid-refractory patients with CD were treated for

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a mean duration of 55 weeks with a mean dose of 20 mg [44]. Sixty-four percent improved and 37% were able to discontinue steroids. How do these results compare with those obtained with the purine antimetabolites? The beneﬁts and adverse eﬀects observed with methotrexate should be compared with those reported for azathioprine and 6-MP [45]. A metaanalysis of the results of eight trials yielded a risk diﬀerence of 20% and number needed to treat of 5, an identical ﬁgure to that for methotrexate in the trial of Feagan et al [20]. Most of the studies included in this overview analysis trial did not use complete clinical remission and total withdrawal from steroids as the primary measure of treatment success, however, making comparisons of the relative eﬃcacy diﬃcult. Moreover, these trials were for the most part not conducted in steroid-dependent patients. The only study that has directly compared the two drugs was performed by Ardizonne et al [46] who randomized 54 patients with steroid-dependent disease to either 25 mg of methotrexate administered intravenously once weekly or oral azathioprine, 2 mg/kg/d. The primary outcome of the trial was complete withdrawal from corticosteroid therapy and a CDAI score of less than 150 in 3 months. At the end of 3 months 44% of methotrexate-treated patients had entered remission as compared with 33% of those who received azathioprine (P = .28). The respective ﬁgures at 6 months were 56% and 63% (P = .39). Drug-related adverse events requiring withdrawal of treatment occurred in three patients in each treatment group. Although the authors concluded that their results did not support a more rapid treatment eﬀect of methotrexate it should be noted that the number of patients studied in the trial was inadequate to address this question. In fact, the 11% absolute diﬀerence in favor of methotrexate is consistent with a clinically meaningful diﬀerence in the 3-month remission rates (95% conﬁdence interval for the 11% diﬀerence; ÿ36.9%, 15%). With respect to the issue of the relative toxicity of the purine antimetabolites, in the meta-analysis [27], adverse events requiring withdrawal from study medication were observed in 9.3% of patients receiving azathioprine or 6-MP. A large retrospective observational study [29] lists serious adverse events occurring with 6 MP with the following frequencies: infection, 7.4%; pancreatitis, 3.3%; neoplasm, 3.1%; marrow suppression, 2%; allergy, 2%; and hepatitis 0.3%. On the basis of a single large randomized trial and several retrospective studies, methotrexate seems to be safe and eﬀective medication for induction of remission in patients with refractory, steroid-dependent CD when administered parenterally in a dose of 25 mg weekly. There is no evidence that lower doses administered orally are eﬀective. The relative eﬃcacy of methotrexate and the purine antimetabolites for this indication is unclear.

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Maintenance of remission in Crohn’s disease Data from a number of sources indicate that the purine antimetabolites are eﬃcacious in the maintenance of remission in high-risk patients. Methotrexate’s eﬃcacy as a maintenance agent in CD was conﬁrmed by a multicenter study in 76 patients with chronically active CD. In this trial, patients who had entered remission following 16 to 24 weeks of treatment with 25 mg of methotrexate given intramuscularly once weekly [44] were randomly assigned to receive either methotrexate at a dose of 15 mg intramuscularly once weekly or placebo for 40 weeks. No other treatments for CD were permitted. Remission was deﬁned as a score of 150 or less on the CDAI. Forty patients received methotrexate, and 36 received placebo. At week 40, 26 patients (65%) were in remission in the methotrexate group, as compared with 14 (39%) in the placebo group (P = .04; absolute reduction in the risk of relapse, 26.1%; 95% conﬁdence interval, 4.4%–47.8%) (Fig. 2). Fewer patients in the methotrexate group than in the placebo group required prednisone for relapse (28% versus 58%, P = .01). None of the patients who received methotrexate had a severe adverse event; one patient in this group withdrew because of nausea. The long-term tolerability and eﬃcacy of methotrexate is also suggested by the study of Kozarek et al [34], who reported that 51% of methotrexatetreated patients continued to receive the drug after 69 weeks.

Use of methotrexate with inﬂiximab The chimeric monoclonal antibody to tumor necrosis factor-a, inﬂiximab, is a highly eﬀective treatment for CD and RA (Targan et al). In patients with RA, combination therapy with inﬂiximab and methotrexate yields superior clinical outcomes and results in a lower incidence of human antichimeric antibodies compared with inﬂiximab monotherapy [47]. It is for this reason that inﬂiximab and methotrexate are routinely coadministered. In patients with CD, the development of human antichimeric time antibodies may lead to loss of clinical response. Baert et al studied 125 consecutive patients with refractory luminal or ﬁstulizing CD who were treated with inﬂiximab [48]. Concomitant medications including immunosuppressive agents and corticosteroids were used as indicated to control symptoms. Treatment with immunosuppressive agents consisted of azathioprine (2 to 2.5 mg/kg/d), MP (1 to 1.25 mg/kg/d), or methotrexate (15 mg intramuscularly once weekly) for a median of 9.5 months (range, 2 to 84) before inﬂiximab therapy was initiated. At the baseline visit no patients had antibodies to inﬂiximab. After the ﬁfth infusion, 76 patients (61%) had detectable antibodies. Patients receiving immunosuppressive drug agents had a lower incidence of antibody formation: 43% (24 of 56) as compared with 75% (52 of 69) (P \ .01). Concomitant immunosuppressive therapy

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Fig. 2. Kaplan-Meier estimates of the time to relapse in the methotrexate group and the placebo group. (From Feagan BG, et al. A comparison of methotrexate with placebo for the maintenance of remission in Crohn’s disease. N Engl J Med 2000;342:1627–32; with permission.)

was predictive of low titers of antibodies against inﬂiximab (P \ .001) and higher serum concentrations of inﬂiximab 4 weeks after an infusion (P \ .001). These data provide strong evidence that concomitant treatment with immunosuppressives reduces the risk of forming antibodies to inﬂiximab. Independent of any synergistic treatment eﬀect this interaction should be beneﬁcial in reducing the risk of infusion reactions and prolonging the duration of response. It is currently unknown whether azathioprine and methotrexate are equally eﬀective in preventing the formation of antibodies. Likewise, the minimum dose of these agents that is required to obtain the protective eﬀect is unknown and should be the subject of future clinical trials.

Methotrexate for the treatment of ulcerative colitis Most patients with ulcerative colitis are managed successfully with 5-ASA and brief courses of glucocorticoids. Patients with refractory disease, as deﬁned by the need for chronic glucocorticoid therapy, often undergo colectomy because many clinicians are reluctant to consider the use of

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chronic immunosuppression in a disease that can be treated surgically and has a time-dependent, increased risk of colon cancer [44]. It is not surprising that far less data are available to assess the eﬃcacy of immunosuppressive drugs in this condition as compared with CD. Although no large randomized controlled trials have demonstrated eﬃcacy for the purine antimetabolites in patients with chronically active ulcerative colitis, Hawthorne et al [49] have performed a withdrawal study that evaluated the eﬃcacy of azathioprine in 79 patients who entered remission after receiving azathioprine therapy. Patients who were assigned to withdraw from azathioprine had a greater rate of relapse at 1 year compared with those who remained on drug therapy (59% versus 35%, P = .04). The initial uncontrolled study by Kozarek et al [34] in 1989 reported that methotrexate induced remission in ﬁve of seven patients with ulcerative colitis. Two randomized, double-blind, placebo-controlled trials of methotrexate in chronic active ulcerative colitis have been performed. Oren et al [50] compared oral methotrexate (12.5 mg weekly) with placebo for 9 months in 67 patients who had received steroids or immunosuppressive drugs for at least 4 of the 12 preceding months. No statistically signiﬁcant diﬀerences were demonstrated between the treatment groups in the proportion of patients achieving remission, the time required to achieve remission, or the proportion of patients experiencing a relapse after a remission had been obtained. Mate-Jimenez et al [51] randomized 34 patients with chronically active steroid-dependent ulcerative colitis to receive either 1.5 mg/kg/d of 6-MP, 15 mg/wk of methotrexate, or 3 g/d of 5-ASA. At the end of 76 weeks of treatment 63.6% of those who received 6-MP were in remission compared with 14.3% of those assigned to methotrexate and 0% of those who received 5-ASA. Although these studies are at a high-risk of a false-negative conclusion their collective results do not support the use of methotrexate as a therapy for ulcerative colitis. A research priority should be to evaluate the eﬃcacy of a higher dose of methotrexate than 15 mg per week. Methotrexate in clinical practice Clinicians who gain experience with methotrexate ﬁnd it relatively easy to use in practice. The most common minor adverse eﬀect is nausea, which tends to develop for a period of 24 to 48 hours after the weekly injection. This problem, which occurs in at most 15% of patients, can usually be managed by coadministration of oral folate (1 mg every day); use of antinauseants around the time of dosing (metoclopramide, ondansetron); or, uncommonly, dose reduction. At the authors’ institution the subcutaneous route of administration is now used, because data from studies of RA show it is pharmacokinetically equivalent to intramuscular injection [39]. As with the purine antimetabolites, leukopenia and associated opportunistic infections occur uncommonly. In the authors’ experience,

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the overall frequency of leukopenia is lower than that observed with azathioprine treatment and lower than that reported in the rheumatologic literature; however, a complete blood count should be obtained monthly. Hypersensitivity pneumonitis occurs in no more than 1% of patients. A high clinical index of suspicion, prompt discontinuation of treatment, and initiation of corticosteroid therapy are essentials of management. Hepatotoxicity was ﬁrst documented in psoriatic patients. Subsequent understanding of pharmacokinetics and the conversion to weekly, from daily, dosing has virtually eliminated this problem. Patients should be monitored according to the American Rheumatological Association guidelines [43], paraphrased as follows: avoid treating patients with risk factors for hepatotoxicity (obesity, diabetes, excessive alcohol use); and measure transaminases every 4 to 6 weeks. If, over the course of 1 year, more than half of the transaminases are abnormal, perform a liver biopsy before continuing treatment. At the authors’ institution, they have not encountered clinically important hepatotoxicity using this strategy and very few liver biopsies are necessary. Finally, no good data indicate that methotrexate is associated with malignancy. In summary, methotrexate is a safe and effective maintenance therapy in patients with Crohn’s disease. Summary Over the past decade methotrexate has emerged as a new treatment for chronically active CD. Notwithstanding the data described previously, the purine antimetabolites remain the most frequently prescribed drug for these patients. This practice is based on the results of three relatively small, randomized controlled trials that used an adequate dose of either 6-MP or azathioprine [25,26,29]. In RA methotrexate has superseded azathioprine as a therapy because of superior eﬃcacy and long-term tolerability. In the absence of good comparative data, clinicians must decide which of methotrexate or the purine antimetabolites is the preferred treatment for CD [52,53]. Extensive long-term experience exists with the purine antimetabolites, whereas the risk of liver disease from methotrexate remains an issue. The risk of signiﬁcant hepatic toxicity in RA is low, however, and surveillance liver biopsy is no longer recommended. In the absence of biopsy data from patients with CD, the American Rheumatology Association guidelines regarding surveillance for hepatic toxicity should be followed [43]. The emergence of inﬂiximab as a new therapy for patients with refractory Crohn’s [54,55] should also focus additional attention on the use of methotrexate as an alternative to the purine antimetabolites. In patients with RA concomitant treatment with methotrexate has been shown to enhance the response to inﬂiximab therapy. Furthermore, patients who are receiving methotrexate are less likely to develop human antichimeric antibodies [47]. These antibodies, which may block the beneﬁcial action of inﬂiximab or cause adverse eﬀects, are a signiﬁcant limitation to the long-term use of this form of treatment. A

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strong rationale exists to consider methotrexate-inﬂiximab combination therapy in CD. Although controlled trials to compare the relative eﬃcacy and safety of azathioprine and methotrexate in therapy-resistant patients are desirable, in the authors’ opinion these studies are diﬃcult, if not impossible to conduct because of the relatively small diﬀerences in potency and tolerability between these agents. A more productive area for future investigations is to explore the use of these drugs in combination with inﬂiximab and other biologic treatments. References [1] Summers RW, Switz DM, Sessions JT Jr, et al. National Cooperative Crohn’s Disease Study: results of drug treatment. Gastroenterology 1979;77:847–69. [2] Rutgeerts P, Lofberg R, Malchow H, et al. A comparison of budesonide with prednisolone for active Crohn’s disease. N Engl J Med 1994;331:842–5. [3] Yang Y-X, Lichtenstein GR. Corticosteroids in Crohn’s disease. Am J Gastroenterol 2002; 97:803–23. [4] Klippel JH, Decker JL. Methotrexate in rheumatoid arthritis. N Engl J Med 1985;312: 853–4. [5] Black RL, O’Brien WM, Van Scott EJ, et al. Methotrexate therapy in psoriatic arthritis: double-blind study on 21 patients. JAMA 1964;189:743–7. [6] Willkens RF, Sharp JT, Stablein D, et al. Comparison of azathioprine, methotrexate, and the combination of the two in the treatment of rheumatoid arthritis: a forty-eight-week controlled clinical trial with radiologic outcome assessment. Arthritis Rheum 1995;38: 1799–806. [7] Weinstein GD, Jeﬀes E, McCullough JL. Cytotoxic and immunologic eﬀects of methotrexate in psoriasis. J Invest Dermatol 1990;95:49S–52S. [8] Weinblatt ME, Coblyn JS, Fox DA. Eﬃcacy of low-dose methotrexate in rheumatoid arthritis. N Engl J Med 1985;312:818–22. [9] Goodman LS, Gilman A. The pharmacological basis of therapeutics. New York: McGraw Hill; 1996. [10] Jundt JW, Browne BA, Fiocco GP, et al. A comparison of low dose methotrexate bioavailability: oral solution, oral tablet, subcutaneous and intramuscular dosing. J Rheumatol 1993;20:1845–9. [11] Hillson JL, Furst DE. Pharmacology and pharmacokinetics of methotrexate in rheumatic disease: practical issues in treatment and design. Rheum Dis Clin North Am 1997;23:757–78. [12] Bannwarth B, Pehourcq F, Schaeverbeke T, et al. Clinical pharmacokinetics of low-dose pulse methotrexate in rheumatoid arthritis. Clin Pharmacokinet 1996;30:194–210. [13] Morgan SL, Baggott JE, Vaughn WH, et al. Supplementation with folic acid during methotrexate therapy for rheumatoid arthritis. Ann Intern Med 1994;121:833–41. [14] Cronstein BN, Naime D, Ostad E. The anti-inﬂammatory mechanism of methotrexate. J Clin Invest 1993;92:2675–82. [15] Egan LJ, Sandborn WJ, Mays DC, et al. Plasma and rectal adenosine in inﬂammatory bowel disease: eﬀect of methotrexate. Inﬂamm Bowel Dis 1999;5:167–73. [16] Malatjalian DA, Ross JB, Williams CN, et al. Methotrexate hepatotoxicity in psoriatics: report of 104 patients from Nova Scotia, with analysis of risks from obesity, diabetes and alcohol consumption during long term follow-up. Can J Gastroenterol 1996;10:369–75. [17] Hall PD, Jenner MA, Ahern MJ. Hepatotoxicity in a rat model caused by orally administered methotrexate. Hepatology 1991;14:906.

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[18] Lewis JH, Schiﬀ E. Methotrexate-induced chronic liver injury: guidelines for detection and prevention. Am J Gastroenterol 1988;88:1337–45. [19] Te HS, Schiano TD, Kuan SF, et al. Hepatic eﬀects of long-term methotrexate use in the treatment of inﬂammatory bowel disease. Am J Gastroenterol 2000;95:3150–6. [20] Feagan BG, Rochon J, Fedorak RN, et al. Methotrexate for the treatment of Crohn’s disease. N Engl J Med 1995;332:292–7. [21] Al-Awadhi A, Dale P, McKendry RJR. Pancytopenia associated with low dose methotrexate therapy: a regional survey. J Rheumatol 1993;20:1121–5. [22] Searles G, McKendry RJ. Methotrexate pneumonitis in rheumatoid arthritis: potential risk factors: four case reports and a review of the literature. J Rheumatol 1987;14:1164–71. [23] Kozlowski RD, Steinbrunner JV, MacKenzie AH, et al. Outcome of ﬁrst-trimester exposure to low-dose methotrexate in eight patients with rheumatic disease. Am J Med 1990;88:589–92. [24] Munkholm P, Langholz E, Davidsen M, et al. Frequency of glucocorticoid resistance and dependency in Crohn’s disease. Gut 1994;35:360–2. [25] O’Donoghue DP, Dawson AM, Powell-Tuck J, et al. Double-blind withdrawal trial of azathioprine as maintenance treatment for Crohn’s disease. Lancet 1978;2:955–7. [26] Candy S, Wright J, Gerber M, et al. A Controlled double blind study of azathioprine in the management of Crohn’s disease. Gut 1995;37:674–8. [27] Pearson DC, May GR, Fick GH, et al. Azathioprine and 6-mercaptopurine in Crohn’s disease: a meta-analysis. Ann Intern Med 1995;122:132–42. [28] Present DH, Korelitz BI, Wisch N, et al. Treatment of Crohn’s disease with 6-mercaptopurine: a long-term, randomized, double-blind study. N Engl J Med 1980; 302:981–7. [29] Present DH, Meltzer SJ, Krumholz MP, et al. 6-Mercaptopurine in the management of inﬂammatory bowel disease: short- and long-term toxicity. Ann Intern Med 1989;111: 641–9. [30] Ward MM. Trends in the use of disease modifying antirheumatic medications in rheumatoid arthritis, 1980–1995: results from the National Ambulatory Medical Care Surveys. J Rheumatol 1999;26:546–50. [31] Maetzel A, Bombardier C, Strand V, et al. How Canadian and US rheumatologists treat moderate or aggressive rheumatoid arthritis: a survey. J Rheumatol 1998;25:2331–8. [32] Cron RQ, Sharma S, Sherry DD. Current treatment by United States and Canadian pediatric rheumatologists. J Rheumatol 1999;26:2036–8. [33] Willkens RF, Stablein D. Combination treatment of rheumatoid arthritis using azathioprine and methotrexate: a 48 week controlled clinical trial. J Rheumatol 1996;44: 64–8. [34] Kozarek RA, Patterson DJ, Geland MD, et al. Methotrexate induces clinical and histologic remission in patients with refractory inﬂammatory bowel disease. Ann Intern Med 1989;110:353–6. [35] Alfadhli AA, McDonald JW, Feagan BG. Methotrexate for induction of remission in refractory Crohn’s disease. Cochrane Database Syst Rev 2003;1:CD003459. [36] Oren R, Arber N, Odes S, et al. Methotrexate in chronic active Crohn’s disease: a double blind, randomized, Israeli multicentre trial. Am J Gastroenterol 1997;92:2203–9. [37] Arora S, Katkoc W, Cooley J, et al. Methotrexate in Crohn’s disease: results of a randomized double-blind, placebo-controlled trial. Hepatogastroenterology 1999;46: 1724–9. [38] Balis FM, Mirro J Jr, Reaman GH, et al. Pharmacokinetics of subcutaneous methotrexate. J Clin Oncol 1988;6:1882–6. [39] Brooks PJ, Spruill WJ, Parish RC, et al. Pharmacokinetics of methotrexate administered by intramuscular and subcutaneous injections in patients with rheumatoid arthritis. Arthritis Rheum 1990;33:91–4.

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[40] Egan LJ, Sandborn WJ, Mays DS, et al. Systemic and intestinal pharmacokinetics of methotrexate in patients with inﬂammatory bowel disease. Clin Pharmacol Ther 1999;65: 29–39. [41] Griﬃth SM, Fisher J, Clarke S, et al. Do patients with rheumatoid arthritis established on methotrexate and folic acid 5mg daily need to continue folic acid supplements long term? Rheumatology 2000;39:1102. [42] Lorenzi AR, Johnson AH, Gough A. Daily folate supplements is adequate prophylaxis against methotrexate-induced nausea and vomiting and avoids the need for expensive anti-emetic prescription. Rheumatol 2000;39:812–3. [43] Kremer JM, Alarcon GS, Lightfoot RW Jr, et al. Methotrexate for rheumatoid arthritis: suggested guidelines for monitoring liver toxicity. American College of Rheumatology. Arthritis Rheum 1994;37:1829–30. [44] Chong RY, Hanauer SB, Cohen RD. Eﬃcacy of parenteral methotrexate in refractory Crohn’s disease. Aliment Pharm 2001;15:35–44. [45] Sandborn WJ, Sutherland L, Pearson D, May G, Modigliani R, Prantera C. Azathioprine or 6-mercaptopurine for induction of remission in Crohn’s disease (Cochrane Review). The Cochrane Library (database on disk and CD-ROM) (3). Oxford: Update software; 2002. [46] Ardizzone S, Bollani S, Manzionna G, Imbesi V, Colombo E, Bianchi Porro G. Comparison between methotrexate and azathioprine in the treatment of chronic active chron’s disease: a randomised, investigator blind study. Dig Liver Dis 2003;35:619–27. [47] Maini RN, Breedveld FC, Kalden JR, et al. Therapeutic eﬃcacy of multiple intravenous infusion of anti-tumor necrosis factor alpha monoclonal antibody combined with low-dose weekly methotrexate in rheumatoid arthritis. Arthritis Rheum 1998;41:1552–63. [48] Baert F, Norman MR, Vermeire S, et al. Inﬂuence of immunogenicity on the long-term eﬃcacy of inﬂiximab in Crohn’s disease. N Engl J Med 2003;348:601–8. [49] Hawthorne AB, Logan RFA, Hawkey CJ, et al. Randomized controlled trial of azathioprine withdrawal in ulcerative colitis. BMJ 1992;305:20–2. [50] Oren R, Arber N, Odes S, et al. Methotrexate in chronic active ulcerative colitis: a double-blind, randomized, Israeli multicenter trial. Gastroenterology 1996;110:1416–21. [51] Mate-Jimenez J, Hermida C, Cantero-Perona J, et al. 6-Mercaptopurine or methotrexate added to prednisone induces and maintains remission in steroid-dependent inﬂammatory bowel disease. Eur J Gastroenterol Hepatol 2000;12:1227–33. [52] Korelitz BI, Present DH. Methotrexate for Crohn’s disease. N Engl J Med 1995;333:600–1. [53] Feagan BG, McDonald JWD. Methotrexate for Crohn’s disease. N Engl J Med 1995;332: 292–7. [54] Targan SR, Rutgeerts P, Hanauer SB, et al. A multicenter trial of anti-tumor necrosis factor (tnf) antibody (ca2) for treatment of patients with active Crohn’s disease. Gastroenterology 1995;110:A1026. [55] Present DH, Rutgeerts P, Targan S, et al. Inﬂiximab for the treatment of ﬁstulas in patients with Crohn’s disease. N Engl J Med 1999;340:1398–405.

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Treatment of ﬁstulizing Crohn’s disease Thomas A. Judge, MDa, Gary R. Lichtenstein, MDb,* a

Gastroenterology Division, Robert Wood Johnson Medical School, Cooper University Hospital, University of Medicine and Dentistry of New Jersey, 401 Hadden Avenue, Room 374, Camden, NJ 08103, USA b Division of Gastroenterology, Department of Medicine, Hospital of the University of Pennsylvania, University of Pennsylvania School of Medicine, 3400 Spruce Street, 3rd Floor Ravdin Building, Philadelphia, PA 19104-4283, USA

Crohn’s disease (CD) is a chronic inﬂammatory disorder that may aﬀect the length of the bowel from mouth to anus. Although a number of speciﬁc disease patterns have been identiﬁed, the development of ﬁstula is a complication common to many patients with CD. In their initial description, Crohn et al [1] noted that 6 of 14 patients had ﬁstulizing disease aﬀecting various colon segments. Rectovaginal and enterocutaneous ﬁstulae were also observed by these authors. A potential mechanism underlying the pathogenesis of these ﬁstulas was suggested in their report: ‘‘As the necrotizing process of mucosa of the ileum progresses through its several coats, the serosa become involved. Any hollow viscus, usually the colon, now becomes adherent to the point of threatened perforation. A slowly progressive perforation is thus walled oﬀ, but results in a ﬁstulous tract being formed between the 2 viscera’’ [1]. Although no perianal ﬁstulae were observed in the initial case series, the association of anal disease and Crohn’s enteritis was soon reported by Bissell [2]. The diagnosis and treatment of ﬁstula complicating CD has also been a component of care for these patients since the recognition of this disorder. The lifetime risk of ﬁstula development in patients with CD has typically been reported to range from 20% to 40% [3–5]. The reported incidence of ﬁstulizing CD from referral-based case series has ranged from 17% to as much as 85% [6]. Two population-based studies reporting the natural history of Crohn’s-associated ﬁstula have been published to date. Hellers et al [7] reported a 23% cumulative incidence for perianal ﬁstula in CD * Corresponding author. E-mail address: [email protected] (G.R. Lichtenstein). 0889-8553/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.gtc.2004.03.002

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patients identiﬁed in Stockholm County, Sweden, during the years 1955 to 1974. More recently, Schwartz et al [8] reported the natural history of ﬁstulizing CD in patients from Olmstead County, Minnesota, diagnosed between 1970 and 1993. Similar to the Swedish experience, the cumulative incidence of perianal ﬁstula in the Olmstead County cohort was 20%. Fistulas of all forms were identiﬁed in 35% of the cohort studied. Including all forms of ﬁstula, the cumulative risk for ﬁstula development was 33% at 10 years and 50% after 20 years. The development of ﬁstula may precede or coincide with the diagnosis of CD, a feature noted by Gray et al [9] and conﬁrmed in the population-based studies by Heller et al [7] and Schwartz et al [8]. Approximately 45% of patients developed ﬁstula at or before the diagnosis of CD in these cohorts. The clinical course of ﬁstulas varies with their location and complexity. Complex ﬁstulas rarely heal spontaneously. Nonetheless, complete ﬁstula closure rates of 6% (for unspeciﬁed time duration) and 13% (for at least 1-month duration) have been reported in placebo-treated patients in randomized trials of 6-mercaptopurine (6-MP) and inﬂiximab, respectively, emphasizing the need for controlled trials evaluating therapeutic maneuvers in the management of ﬁstulizing CD [10,11]. In addition, small surgical series reported by Buchmann et al [12] and Halme and Sainio [13] have documented spontaneous healing of simple ﬁstula in ano in 50% of patients with CD. Recurrence of perianal ﬁstula has been frequently reported after medical and surgical therapy. Makowiec et al [14] reported that 47% of patients treated for ﬁstula complicating CD developed recurrent ﬁstula with a risk of recurrent ﬁstula of 59% at 2 years. Similarly, rates of recurrent ﬁstulas in Crohn’s patients following discontinuation of medical therapy derived from uncontrolled series have ranged from 71% to 82% [15–18]. In contrast, however, Schwartz et al [8] identiﬁed recurrent ﬁstula in only 34% of the Olmstead County cohort. The transmural nature of the inﬂammatory process that characterizes CD predisposes to ﬁstula formation. The development of a ﬁstula indicates that the inﬂammatory process has extended into adjacent organs, skin, and tissues. The clinical consequences of the ﬁstulous tract depend on the nature of the adjacent tissues, the origin and terminus of the ﬁstula, and any infectious processes resulting from transit of enteric microorganisms through the ﬁstula. In the case of perianal ﬁstula, identiﬁcation of speciﬁc routes created by ﬁstula tracts informs prognostic and therapeutic decisions. The treatment of ﬁstulas is dependent on location, severity of symptoms, number and complexity of the ﬁstula tracts, and the presence or absence of rectal inﬂammation. Patients with painful perianal ﬁstula and associated abscess formation require surgical drainage, possible seton placement, and in severe cases, proctectomy. In contrast, patients with asymptomatic internal ﬁstula require no intervention. A variety of measures to induce ﬁstula healing have been advanced in the literature. Studies of speciﬁc medical and surgical interventions have been limited by the absence of wellvalidated clinical measures of ﬁstula disease activity. Most recently, the

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absence of drainage on gentle compression of the external ﬁstula oriﬁce has been deﬁned as complete healing [19]. An established time to healing has yet to be standardized, however, limiting comparison of treatments between studies. Most clinical trials have been uncontrolled. As a result, treatment decisions have been guided largely by clinical experience and the few controlled clinical trials published to date.

Medical therapy of ﬁstulous Crohn’s disease Anti-inﬂammatory medications Sulfasalazine and mesalamine derivative have been demonstrated to be eﬃcacious in the induction of remission in patients with mild-to-moderate CD. No clinical trial has speciﬁcally demonstrated eﬀective healing of ﬁstula, however, with the use of these agents. Similarly, although corticosteroids are potent anti-inﬂammatory medications and eﬀective for the induction of remission in active CD, they have not proved eﬃcacious in the treatment of ﬁstulizing CD. Use of corticosteroids in patients with ﬁstulizing CD has been associated with deleterious outcomes including an increase incidence of surgery in two large uncontrolled clinical trials [20,21]. Three deaths reported in a large (452 patients) controlled trial occurred in corticosteroid-treated patients with abdominal masses resultant from ﬁstula [22]. Antibiotics Metronidazole Metronidazole, the antibiotic most frequently used in the management of ﬁstulizing perianal CD, has been evaluated in several clinical trials. All of these studies have been uncontrolled with small numbers of patients. In a letter published in 1975, Ursing and Kamme [23] reported that metronidazole healed perianal ﬁstulas in three patients. Subsequently, Bernstein et al [24] treated 21 patients with long-standing perianal ﬁstula with metronidazole, 20 mg/kg/d in divided doses. A clinical response was noted in 20 of 21 patients with complete healing noted in 56% of patients at 8 weeks. The response was rapid, with clinical improvement appreciated by 90% of patients within 2 weeks of therapy. Enthusiasm for metronidazole therapy was tempered by a follow-up report that noted symptomatic recurrence in 78% of these patients within 4 months following cessation of therapy [25]. Other uncontrolled studies of metronidazole therapy have conﬁrmed healing of perianal Crohn’s ﬁstula with closure rates of 40% to 50% [26,27]. Maintenance therapy with metronidazole seems to be necessary because a high rate of recurrence has been observed on cessation of treatment. Metronidazole in combination with an immunomodulatory medication, such as azathioprine (AZA), may be the most cost-eﬀective initial therapy for ﬁstulizing Crohn’s disease based on

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a cost-utility analysis performed by Arseneau et al [28]. Adverse reactions to high-dose metronidazole include paresthesias, dyspepsia, a metallic-taste, and disulﬁram-like response to alcohol ingestion. Peripheral neurologic dysfunction has been demonstrated by physical examination and nerve conduction studies in 85% of treated patients, although many of these were asymptomatic [29]. Ciproﬂoxacin Ciproﬂoxacin, a ﬂuoroquinolone with broad-spectrum activity against gram-negative organisms, has been the subject of two small, uncontrolled trials in severe perineal CD. Turunen et al [30] ﬁrst reported the use of ciproﬂoxacin in eight patients with perineal CD refractory to metronidazole therapy. Patients were treated with 1 to 1.5 g/d ciproﬂoxacin in divided doses for 3 to 12 months. All patients were reported to show improvement; however, four of eight patients had persistent perineal drainage and several patients required surgical intervention. In a separate trial, Wolf [31] reported resolution of perineal pain in four of ﬁve patients with active perineal Crohn’s within 5 weeks of therapy. No large controlled trials of ciproﬂoxacin for ﬁstulizing CD have been reported. As with metronidazole, there is a high rate of recurrence on cessation of ciproﬂoxacin therapy [32]. The potential of combination therapy using ciproﬂoxacin (1000–1500 mg/d) and metronidazole (500–1500 mg/d) has been examined in an uncontrolled study of 14 patients by Solomon et al [33]. Clinical improvement was noted in nine patients at 12 weeks with closure of the ﬁstula observed in three patients. Similar to the results seen with antibiotic monotherapy, recurrent disease was observed following cessation of therapy. Adverse reactions to ciproﬂoxacin include headache, nausea, diarrhea, and rash [34]. There have also been reports of spontaneous tendon ruptures (including the Achilles tendon) in patients using long-term ciproﬂoxacin [35]. Immunomodulators 6-Mercaptopurine and azathioprine The purine metabolites, 6-MP and AZA, are among the most successful immunomodulatory medications used in the treatment of CD. In addition, these medications are among the few agents that have demonstrated eﬃcacy in ﬁstulizing CD in controlled clinical trials. Although these agents are frequently discussed interchangeably, there have been no controlled trials directly comparing these medications in the treatment of inﬂammatory bowel disease. The eﬀect of 6-MP on ﬁstulizing CD was evaluated by Present et al [36] in a randomized, placebo-controlled trial. Thirty-six patients with a total of 40 ﬁstulas were assessed for clinical response, ﬁstula healing, and corticosteroid dose reduction. The overall response rate was 55% for patients treated with 6-MP as compared with 24% for those individuals receiving placebo. Complete ﬁstula healing was observed in 6 (31%) of 19 patients in the 6-MP cohort as compared with 1 (6%) of 17 in

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the placebo arm. Although suggestive, the study was insuﬃciently powered to demonstrate a statistically signiﬁcant diﬀerence among treatment groups. An uncontrolled follow-up article by Korelitz and Present [37] extended the ﬁndings of 6-MP therapy (1.5 mg/kg/d) in a total of 34 patients. A wide variety of ﬁstulas were examined including perirectal ﬁstulas [18], abdominal wall ﬁstulas [8], enteroenteric ﬁstulas [7], rectovaginal ﬁstulas [6], and vulvar ﬁstulas [2]. The overall response rate was 65% with complete healing observed in 39% of patients. The median time to clinical response was 3.1 months but some patients responded to therapy as late as 8 months after therapy was initiated. This study also documented the need for maintenance therapy. Of the 13 patients with complete ﬁstula closure, six patients remained on therapy with continued ﬁstula closure, whereas ﬁve of seven patients who discontinued therapy had a recurrence. Reinstitution of 6-MP therapy healed the ﬁstulas again. An uncontrolled study by O’Brien et al [38] evaluated the response of Crohn’s ﬁstulas to AZA. Complete ﬁstula closure was observed in 8 (31%) of 26 patients and partial healing in an additional 14 patients (54%). In a meta-analysis of ﬁve controlled trials of AZA and 6-MP for CD, Pearson et al [39] assessed those studies in which ﬁstula closure was described in detail. A total of 70 patients were included in these trials. Patients treated with AZA or 6-MP were more likely to respond to treatment (22 of 41) as compared with patients treated with placebo (6 of 29); the pooled odds ratio favoring ﬁstula healing with AZA or 6-MP was 4.44. Dosing and administration of AZA and 6-MP has not been standardized. Controlled trials indicate that AZA at doses of 2 to 3 mg/kg/d and 6-MP at a dose of 1.5 mg/kg/d are eﬀective for the treatment of CD. Although titration of either drug to a speciﬁed blood 6-thioguanine nucleotide metabolite concentration (6-thioguanines > 235 pM/108 erythrocytes) has been suggested to improve therapeutic eﬃcacy, this has not been demonstrated convincingly in the treatment of Crohn’s ﬁstulas [40]. Adverse events are reported to occur in 9% to 15% of patients receiving AZA or 6-MP for inﬂammatory bowel disease. The most commonly encountered serious adverse events are infections (aﬀecting 7% of treated patients); pancreatitis (3%); profound leukopenia (2%); allergic reactions (2%); and drug-induced hepatitis (0.3%) [41]. Methotrexate Although methotrexate has been demonstrated to be eﬃcacious in the induction of remission in patient’s with CD, initial controlled studies did not assess the eﬀect of methotrexate therapy on ﬁstula healing. Two recent, uncontrolled studies have examined the eﬃcacy of parenteral methotrexate in ﬁstulizing CD. Muhadevan et al [42] reported on 16 patients treated with intramuscular methotrexate (25 mg/wk). With treatment, 4 of 16 had ﬁstula closure, whereas an additional ﬁve patients had partial responses yielding an overall response rate of 56%. As with other medications, ﬁstula recurrence

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was noted on reduction in methotrexate dose or with conversion to oral formulation. A second, retrospective study reported by Vandeputte et al [43] examined the eﬀect of parenteral methotrexate on 20 patients with refractory CD including eight patients with ﬁstula. Although the authors noted induction of remission in 70% of patients treated with methotrexate, the speciﬁc response of patients with ﬁstulizing disease was not reported separately. Adverse events associated with parenteral methotrexate have been reported in nearly 50% of patients treated for more than 6 months and include elevation of serum transaminases (aﬀecting 5%–20% of patients); nausea (4%–12%); and bone marrow suppression (10%–20%) [44–46]. Hepatic ﬁbrosis was observed in 0% to 5% of inﬂammatory bowel disease patients who have undergone liver biopsy after a cumulative methotrexate dose of more than 1500 mg [47]. Serious adverse events requiring discontinuation of methotrexate occur in approximately 10% of patients [44]. Less common but potentially life-threatening interstitial pneumonitis has been observed in 3% to 12% of patients treated with long-term, lowdose methotrexate [46]. Cyclosporine A There are no published, randomized, placebo-controlled trials speciﬁcally designed to evaluate the eﬃcacy of cyclosporine A on ﬁstula closure in CD. Although cyclosporine A has been demonstrated to be eﬃcacious for induction of remission in patients with CD in only one of four placebocontrolled trials, the rapidity with which this clinical response is observed (often within 1–2 weeks) makes cyclosporine A a promising treatment for ﬁstulizing disease [48]. Present and Lichtiger [49] examined 16 patients with ﬁstulizing Crohn’s treated with intravenous cyclosporine A (4 mg/kg/d) as a continuous infusion. Fourteen patients (88%) responded acutely with complete closure observed in half of the responding patients. Nine of 10 patients with ﬁstulas refractory to AZA and 6-MP responded to cyclosporine A. The mean time to respond in this series was 7.4 days, conﬁrming the rapidity of clinical response. These results have subsequently been supplemented by a review of the literature including 39 patients with ﬁstulizing CD who have been treated with cyclosporine A [50]. Within this group, 90% of patients responded to intravenous cyclosporine A. Unfortunately, relapse in the absence of oral cyclosporine A therapy was quite high (82%). A modest reduction in the rate of ﬁstula recurrence has been demonstrated with combined use of cyclosporine A, AZA, and a tapering schedule of prednisolone for a period of 3 months before cessation of cyclosporine A therapy [51]. These results suggest that ﬁstula healing with cyclosporine A may necessitate short-term concurrent use of oral cyclosporine A with other immunosuppressants (AZA and 6-MP, or methotrexate) to allow adequate time for these latter immunosuppressants to take eﬀect. Adverse events observed in patients treated with high-dose cyclosporine include paresthesias (25%); hypertrichosis (13%); hypertension (11%); tremor (7%); renal

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insuﬃciency (6%); headache (5%); opportunistic infections (3%); gingival hyperplasia (2%); and seizure (1%) [46]. Tacrolimus Tacrolimus is a potent immunosuppressant agent that inhibits transcription of interleukin-2 in T helper cells in a manner similar to cyclosporine A. Most frequently used in prevention of allograft rejection, case reports and uncontrolled retrospective series have suggested eﬃcacy for treatment of ﬁstulizing CD including healing of rectovaginal ﬁstula [52–54]. Sandborn et al [55] recently reported results of the only placebo-controlled trial assessing the eﬃcacy of tacrolimus. Forty-eight patients with actively draining Crohn’s ﬁstulas were randomized to treatment with placebo or oral tacrolimus at an initial dose of 0.20 mg/kg/d. A clinical response (deﬁned as closure of at least 50% of ﬁstulas present at baseline maintained for at least 4 weeks) occurred in 43% of tacrolimus-treated patients as compared with 8% of patients treated with placebo (P = .004). No signiﬁcant diﬀerence was observed with respect to complete closure of baseline ﬁstulas, however, which was observed in 10% of tacrolimus-treated patients as compared with 8% of placebo-treated patients (P = .86). Adverse events observed in patients treated with tacrolimus include renal insuﬃciency, tremor, headache, paresthesias, leg cramps, paresthesias, and tremor. Mycophenolate mofetil Mycophenolate mofetil, a potent immunosuppressant that inhibits lymphocyte proliferation through blockade of guanosine nucleotide synthesis, has been reported to induce clinical remission of steroid-resistant CD in at least one uncontrolled clinical trial [56]. Uncontrolled case series have suggested eﬃcacy in ﬁstulizing CD, yet other reports have cast doubt on the eﬃcacy of mycophenolate in the long-term maintenance of remission [57–59]. No welldesigned, placebo-controlled trials have been published. Anti–tumor necrosis factor-a therapies Inﬂiximab Cytokines including tumor necrosis factor-a are critical to the inﬂammatory processes that characterize CD. Mucosal biopsy specimens and mononuclear cells isolated from the lamina propria of patients with CD express high levels of tumor necrosis factor-a. Inﬂiximab is a chimeric monoclonal antibody that binds and neutralizes human tumor necrosis factor-a. Therapy directed against tumor necrosis factor-a through infusion of inﬂiximab is anticipated to result in signiﬁcant reduction in Crohn’s-associated inﬂammation, as has been conﬁrmed in a number of randomized, placebo-controlled clinical trials. Present et al [60] demonstrated the eﬃcacy of inﬂiximab in treatment of ﬁstulizing CD in a placebo-controlled, multicentered study in which 94 patients with active abdominal (10% of patients) or perianal (90% of

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patients) ﬁstulas were randomized to receive either inﬂiximab at 5 mg/kg, inﬂiximab at 10 mg/kg, or placebo. Treatments were administered at weeks 0, 2, and 6 and the patients were monitored for clinical response, which was deﬁned as a 50% reduction in the number of draining ﬁstulas present at baseline examination, which was maintained for at least 4 weeks. Sixty-eight percent of patients who received inﬂiximab at 5 mg/kg and 56% of patients who received inﬂiximab at 10 mg/kg achieved a clinical response as compared with 26% of the patients infused with placebo. Additionally, 55% of patients receiving 5 mg/kg inﬂiximab and 38% of patients receiving 10 mg/kg inﬂiximab had complete closure of all ﬁstulas (deﬁned as an absence of discharge despite gentle compressions for at least 4 weeks) as compared with 13% of patients treated with placebo. Inﬂiximab seems to be an eﬀective medical therapy for induction treatment of ﬁstulizing CD. The median duration of ﬁstula closure following the initial series of inﬂiximab infusions was approximately 3 months, however, suggesting the need for maintenance therapy in patients responding to inﬂiximab. Eleven percent of the patients treated with inﬂiximab developed a perianal abscess, possibly caused by closure of the cutaneous end of the ﬁstula tract before the rest of the ﬁstula tract closed. The overall rate of infections in those treated with inﬂiximab did not diﬀer from those patients on placebo. A second controlled trial reported by Sands et al [61] conﬁrmed eﬃcacy of inﬂiximab in both induction and maintenance treatment of ﬁstulizing CD. This long-term study included 306 patients with actively draining ﬁstulas who received three open doses of inﬂiximab, 5 mg/kg, at 0, 2, and 6 weeks. Patients who responded to therapy (closure of at least 50% of ﬁstulas present at baseline maintained for at least 4 weeks) were then randomized into two groups 8 weeks after the initial infusion series was completed: group I received maintenance doses of placebo every 8 weeks beginning at week 14; group II received maintenance doses of inﬂiximab, 5 mg/kg, every 8 weeks beginning at week 14. Patients were monitored for 54 weeks and the time to loss of clinical response was the primary end point of this study. One hundred ninety-ﬁve (69%) of 306 patients had a ﬁstula response at week 14. The median time to loss of response through week 54 was 14 weeks for placebo-treated patients and more than 40 weeks for patients treated with inﬂiximab, 5 mg/kg (P \ .001). Despite these ﬁndings, the long-term use of inﬂiximab in management of ﬁstulizing CD has recently been challenged. Poritz et al [62] retrospectively reviewed the results of inﬂiximab infusion in 26 patients with ﬁstulizing CD at a single institution. Despite clinical improvement observed in 69% of patients including complete ﬁstula closure in six patients, surgical intervention was ultimately required in 14 patients (10 bowel resections, 4 perianal procedures) and an additional six patients continued to have draining ﬁstulas. No patients with enterocutaneous or peristomal ﬁstulas were healed with inﬂiximab. The cost-eﬀectiveness of inﬂiximab therapy has also been challenged by a cost-utility analysis reported by Arseneau et al

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[28]. Although clinically more eﬀective then either metronidazole or AZA, the substantially increased cost of inﬂiximab therapy was prohibitive in this analysis. Other therapies directed against human tumor necrosis factor-a have also been evaluated in clinical studies of ﬁstulizing CD. In the course of two randomized placebo-controlled trials, the eﬃcacy of CDP-571 (an alternative humanized chimeric antibody directed against human tumor necrosis factor-a) in ﬁstula closure has been assessed [63,64]. Thirty-seven patients with actively draining ﬁstulas were included in these trials. Twelve (50%) of 24 CDP-571 recipients and 2 (15%) of 23 placebo recipients had closure of 50% or more of their ﬁstulas. Although other agents that inhibit tumor necrosis factor-a activity, such as pentoxifylline and enteracept, have failed to demonstrate eﬃcacy in CD, two open-label studies of thalidomide, a potent inhibitor of tumor necrosis factor-a, have shown some degree of eﬃcacy in ﬁstulizing CD [65,66]. Together, these studies support a strategy of tumor necrosis factor-a inhibition as a basis for healing ﬁstulizing CD. Adverse events observed in patients treated with inﬂiximab include infusion reactions; delayed hypersensitivity reactions; formation of human antichimeric antibodies; formation of anti–double-stranded DNA antibodies; and, in rare cases, drug-induced lupus [67,68]. Infusion reactions were observed in 6% of inﬂiximab infusions in the ACCENT I maintenance trial [69]. Approximately 3% of patients in the ACCENT I trial developed delayed hypersensitivity reactions manifest by serum-sickness–like symptoms. There was also an increased overall rate of infections, and rarely, serious infections occur including pneumonia, sepsis, tuberculosis, and infections from opportunistic organisms [67,68,70–72]. In addition to its well-known teratogenic eﬀects, therapy with thalidomide has been complicated by marked somnolence and peripheral neuropathy [73]. Novel therapies A number of novel therapies have been advanced for the treatment of ﬁstulizing CD. Temporary fecal diversion has been successful in the induction of clinical response in combination with medical therapy. Fistula recurrence, however, frequently accompanies reversal of the diverting ileostomy [74–76]. More advanced perianal disease has been controlled successfully with proctectomy [77]. In addition, use of ﬁbrin glue and plasma factor XIII concentrates have been advanced as adjunctive therapies in the management of perianal ﬁstulas [78–80]. Hyperbaric oxygen has also been suggested as an adjunctive measure in healing ﬁstulizing CD [81–83]. Although case reports have documented successful healing during therapy, no well-controlled, randomized studies have been performed to conﬁrm these ﬁndings. Further study is necessary to assess the role of these therapies in the management of ﬁstulizing CD.

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Surgical management of ﬁstulous Crohn’s disease Perianal ﬁstula Perianal CD has been the subject of a variety of classiﬁcation systems. One commonly used classiﬁcation scheme for ﬁstulizing disease was introduced by Parks et al [84]. The Parks classiﬁcation uses the external anal sphincter as the reference point for description of the ﬁstula tract (Box 1, Fig. 1). Many complex ﬁstulas associated with CD are not easily classiﬁed anatomically. As a result, many clinicians deﬁne ﬁstulas associated with CD as either simple or complex based on their location in relationship to the anal sphincter; the nature of the ﬁstula track; associated inﬂammatory lesions, such as abscesses; and most importantly, the presence or absence of active rectal inﬂammation. Simple ﬁstula and ﬁstula in ano Simple ﬁstula and ﬁstula in ano are classically low-lying lesions with a single external opening. Other ﬁstulas with similar classiﬁcation include subcutaneous, low-intersphincteric, and low-transsphincteric ﬁstulas. The feature common to all of these ﬁstulas is that the ﬁstula tract lies below most of the anal sphincter. These ﬁstulas, which comprise most of the

Box 1. Classification of fistula in ano Intersphincteric Simple low track High blind track High track with rectal outlet High fistula without perineal outlet High fistula with extrarectal or pelvic extension Transsphincteric Uncomplicated High blind track Suprasphincteric Uncomplicated High blind track Extrasphincteric Secondary to transsphincteric fistula Secondary to anorectal disease Combined Horseshoe Intersphincteric Transsphincteric

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Fig. 1. Anatomic relationships in the para-anal and para-rectal spaces.

ﬁstulas observed in patients with CD, typically develop in patients without rectal involvement. Surgical series demonstrate excellent response to ﬁstulotomy in patients without macroscopic rectal inﬂammation with a low rate of associated fecal incontinence or delayed wound healing [85– 94]. Healing rates of 70% to 100% have been reported with low rates of recurrence (\20%) and minor incontinence reported in less than 10% of individuals (Table 1). In contrast, simple low ﬁstulas in patients with active Crohn’s proctocolitis should be treated by placement of noncutting setons rather than ﬁstulotomy because of poor wound healing in the setting of active rectal inﬂammation. Nordgren et al [91] noted that healing occurred after ﬁstulotomy in only 4 (27%) of 15 patients with active Crohn’s proctocolitis compared with 10 (83%) of 12 patients with classic intestinal CD. Caution should also be exercised in performing a ﬁstulotomy in patients with diarrhea and in women who have an anterior ﬁstula and short anal canal. In these settings, the risk of postoperative fecal incontinence following division of the anal sphincter has been reported to be substantial. The performance of a partial internal sphincterotomy at the site of the internal ﬁstula oriﬁce has been advanced as an alternative to the classical ﬁstulotomy [92,95]. An intersphincteric abscess, which is typically present in association with the ﬁstula, is unroofed, but the ﬁstula tract is not opened. This technique removes the source of infection while minimizing the risk of persistent perineal wounds. Use of an endorectal advancement ﬂap has also been suggested as an alternative to ﬁstulotomy in patients with simple ﬁstula who do not have active rectal inﬂammation. Sustained ﬁstula closure was reported in 74%

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Table 1 Results of ﬁstulotomy for treatment of simple perianal ﬁstulas in patients with Crohn’s disease Investigator

Year

Wound healed (%)

Patients without active proctitis Nordgren 1992 6/6 (100) Hobliss 1982 18/20 (90) Sohn 1980 4/4 (100) Includes patients with active proctitis Michelassi 2000 27/33 (82) Platell 1996 40/44 (91) Sangwan 1996 35/35 (100) McKee 1996 21/34 (62) Scott 1996 22/27 (81) Williamson 1995 7/26 (27) Halme 1995 10/10 (100) Winter 1993 22/26 (85) Nordgren 1992 2/5 (40) Williams 1991 38/41 (93)b Kangas 1991 3/5 (60) Levien 1989 29/46 (63) Fuhrman 1989 18/19 (95) Morrison 1989 16/17 (94) Fry 1989 13/13 (100) Bernard 1986 9/15 (60) Keighley 1986 1/12 (8) Marks 1981 25/32 (78) a b

Incontinence (%)

Recurrence (%)

0/6 (0) NA 0/4 (0)

2/6 (33) 4/18 (22) 0/4 (0)

NAa 0/44 (0) 0/35 (0) NA 5/27 (19) NA 5/10 (50) 0/26 (0) 0/5 (0) 7/33 (21) NA NA NA NA NA NA 6/12 (50) NA

NA 2/40 (5) 31/35 (89) 4/21 (19) NA NA 4/10 (40) 3/22 (14) NA NA NA 19/29 (41) NA 2/26 (13) NA NA NA NA

Proctectomy-diversion (%) 0/6 (0) 3/20 (15) 0/4 (0) NA 0/44 (0) 0/35 (0) 10/34 (29); 3 diversion 5/27 (19); 2 diversion NA 1/10 (10) 0/26 (0) 3/5 (60) 3/33 (9) 2/5 (40) 4/46 (9) 2/19 (11) 1/17 (6) 0/13 (0) 1/15 (7) NA NA

Not addressed in publication. Study included 33 patients with total of 41 lesions.

of 26 patients with ﬁstulizing CD treated with an endorectal advancement ﬂap procedure [96]. An advancement ﬂap involves incising a ﬂap of tissue around the internal opening of a ﬁstula. The internal opening of the ﬁstula tract is excised, and the ﬂap is pulled down to cover the opening (Fig. 2). Complex ﬁstulas Despite the excellent response of simple ﬁstulas to surgical intervention, complex ﬁstulas and ﬁstulas occurring in the presence of active rectal CD present a signiﬁcant challenge. Complex ﬁstulas include ﬁstulas with multiple openings, those with ﬁstula tracts passing high above the bulk of the anal sphincter, those with internal oriﬁces above the dentate line, those with horseshoe tracks, and those with high blind extensions. Additionally, ﬁstulas that recur after ﬁstulotomy, suprasphincteric, and extrasphincteric ﬁstulas are classiﬁed as complex ﬁstulas. In general, these ﬁstulas do not heal with surgical intervention alone without signiﬁcant postoperative morbidity. A combined medical and surgical approach is critical to the management of these patients. Examination under anesthesia is

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Fig. 2. Parks’ classiﬁcation scheme for ﬁstula-in-ano. (A) Intersphnicteric ﬁstula (simple low track) uncomplicated or with high blind track; (B) Intersphnicteric ﬁstula (high track with rectal opening) with or without perineal opening; (C) Intersphnicteric ﬁstula with extrarectal extension or secondary to pelvic disease; (D) Trans-sphnicteric ﬁstula, uncomplicated or with high blind track; (E) Suprasphnicteric ﬁstula, uncomplicated or with high blind track; (F) Extrasphnicteric ﬁstula, secondary to trans-sphnicteric ﬁstula or trauma; (G) Extrasphnicteric ﬁstula, secondary to anorectal disease or pelvic inﬂammation.

preferred to deﬁne the extent of disease and identify abscesses or infectious complications. Schwartz et al [97] have demonstrated that addition of either pelvic MRI or endoscopic ultrasound examination increased the accuracy of the diagnostic evaluation of perianal ﬁstulas. Abscesses detected during examination may be appropriately drained. Moreover, simple ﬁstulas

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mistakenly diagnosed as complex ﬁstulas on initial evaluation may be appropriately diagnosed and treated deﬁnitively. Tissue removed from curettage of ﬁstula tracts should be sent for pathologic examination because carcinoma has been identiﬁed on rare occasions in patients with refractory perineal and enterocutaneous ﬁstulas [98–100]. Placement of drains and setons may facilitate drainage of inﬂammatory debris and prevent reaccumulation of infectious material. Addition of aggressive medical therapy is frequently helpful in this population once the infected material has been removed. Patients with high ﬁstulas or complex tracks have been reported to experience signiﬁcant morbidity after surgical sphincterotomy even in the absence of rectal inﬂammation. Long-term placement of a seton is often preferable in these settings. Recent reports have described transposition of the internal ﬁstula opening distally to enable deﬁnitive surgical therapy to be performed more easily [101–103]. These remain preliminary reports, however, which have included few patients. Surgical techniques Noncutting setons Long-term placement of noncutting setons is the procedure of choice for patient with complex ﬁstulas and those patients with ﬁstulas associated with local sepsis or rectal CD. The ﬁstula tract is deﬁned while the patient is under general anesthesia and a suture or more commonly a thin Silastic loop is passed into the cutaneous outlet of the ﬁstula, through the ﬁstula tract, and across the internal oriﬁce into the rectum and anal canal. The loop, tied loosely around the sphincter, allows continued drainage, resolution of sepsis, and decreased pain (Fig. 3). Clinical reports have documented improvement in most patients (Table 2) [104–114]. The rate of ﬁstula recurrence is high following removal of the seton in several studies [104,109,112]. The optimal approach to long-term management of these patients is also controversial. Some investigators advocate indeﬁnite retention of setons [115]. Others suggest combination therapy with medications or more deﬁnitive surgical interventions including ﬁstulotomy or an endorectal advancement ﬂap procedure once local infectious complications have been treated [116,104]. Patients treated with staged ﬁstulotomy or cutting seton remain at signiﬁcant risk for fecal incontinence. Mucosal advancement ﬂap The use of the mucosal advancement ﬂap technique avoids division of the anal sphincter and is eﬃcacious in those individual without concurrent rectal inﬂammation, cavitary ulceration, anal stenosis, or a local abscess. It has been used most commonly in patients with complicated anal disease, rectovaginal ﬁstula, or perineal ﬁstulas. A semicircular incision centered on the internal ﬁstula oriﬁce is performed at the level of the dentate line. A 3- to 4-cm ﬂap of mucosa, submucosa, and smooth

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Fig. 3. Rectal advancement ﬂap procedure. This procedure requires a rhomboid-shaped incision of the rectal mucosa extending beyond the internal opening of the ﬁstula and the dentate line (A). After elevating the mucosal ﬂap, the ﬁstula track is excised and the internal muscular defect is sutured as illustrated (B). The distal portion of the mucosal ﬂap containing the internal opening is excised; the remaining ﬂap is draw forward over the closed muscular defect and secured in a tension-free manner. (Illustration by Joseph Pangrace. Copyright The Cleveland Clinic Foundation; with permission.)

muscle is elevated; the internal ﬁstula oriﬁce excised; and the ﬁstula tract curetted and closed. The ﬂap is then advanced to the anoderm below the origin of the ﬁstula and sutured into place (Fig. 4). Care is taken to avoid tension on the ﬂap as it is advanced. The external opening is curetted and drained with placement of a small catheter (typically a mushroom-tip catheter). Several surgical series have reported success with this technique with documented healing rates between 60% and 80% [96,107,108,117–122]. Recurrent ﬁstulas may also be treated with a second procedure. In their series of 26 patients treated with endorectal advancement ﬂap, Joo et al [96] noted success in four of ﬁve patients who underwent a second procedure. Selected patients with anal canal ulcerations or stricturing may beneﬁt from rectal sleeve advancement in combination with a temporary diverting ileostomy (Fig. 5) [123]. In contrast to a mucosal advancement ﬂap, this

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Table 2 Response to surgical therapy of complex perianal ﬁstulas in patients with Crohn’s disease Investigator Year Therapy

Improved (%)

Incontinence Recurrence Proctectomy (%) (%) (%)

Faucheron Scott Sangwan McKee Williamson Sugita Koganei Pearl Williams White Van Donegen McKee Nordgren Morrison Matos

1996 1996 1996 1996 1995 1995 1995 1993 1991 1990 1986

Seton Seton Seton Seton Seton Seton Seton Seton Seton Seton Seton

36/41 23/27 22/24 4/7 7/9 17/21 10/13 21/21 20/23 10/10 2/2

(88)a (85) (92) (57) (78) (81)b (77)c (100) (87)d (100) (100)

1996 1992 1989 1993

2/5 4/10 3/4 10/10

(40) 2/5 (40) (40) NA (75)e NA (100) 5/10 (50)

Joo Robertson Marchesa McKee Makowiec Williamson Lewis Fry Jones

1998 1998 1998 1996 1995 1995 1990 1989 1987

Fistulotomy Fistulotomy Fistulotomy Excision and closure Advancement Advancement Advancement Advancement Advancement Advancement Advancement Advancement Advancement

5/41 (12) 4/27 (15) NA NA NA 1/21 (5) 0/13 (0) 0/21 (0) 6/23 (26) NA NA

ﬂap 19/26 (73) NA ﬂap 3/6 (50) NA ﬂapf 8/13 (62) NA ﬂap 1/2 (50) NA ﬂap 16/20 (80) 0/20 (0) ﬂap 1/4 (25) NA ﬂap 5/6 (83) NA ﬂap 3/3 (100) NA ﬂap 2/6 (33) NA

8/36 4/27 17/24 3/7 2/9 9/17 3/10 0/21 9/20 2/10 0/2

(22) (15) (63) (43) (22) (53) (30) (0) (45) (20) (0)

5/41 (12) 4/27 (15) 7/24 (33) 2/7 (29) NA NA 1/13 (8) 0/21 (0) 5/23 (22) 0/10 (0) 0/2 (0)

3/5 (60) 1/4 (25) NA 6/10 (60)

2/5 6/10 1/4 0/10

7/26 3/6 5/13 1/2 4/20 3/4 1/6 0/3 4/6

2/26 (9) 0/6 (0) 3/13 (23) 1/2 (50) 0/20 (0) NA 0/6 (0) 0/3 (0) 1/6 (17)

(27) (50) (38) (50) (20) (75) (17) (0) (67)

(40) (60) (25) (0)

Abbreviation: NA, Not addressed. Advancement ﬂap: transanal advancement ﬂap. a Closure of ﬁstula observed in 11 patients (27%). b Closure of ﬁstula observed in 8 patients (38%). c Closure of ﬁstula observed in 8 patients (62%). d Closure of ﬁstula observed in 3 patients (13%). e In addition to ﬁstulotomy, setons were placed in two patients. f Sleeve advancement ﬂap.

procedure involves circumferential mobilization of the full thickness of the rectum following surgical resection of the strictured or ulcerated region. A proctoanal anastomosis is then performed in conjunction with the proximal diverting ileostomy (Fig. 6). Alternative techniques described in published reports include ﬂap repair with perianal skin, laser ablation, and ﬁstulectomy with sphincter repair [116,124,125]. Enterocutaneous ﬁstula Spontaneous external abdominal wall ﬁstulas in the absence of previous surgery rarely occur. Reviewing a series of 1500 patients, Greenstein [126]

Fig. 4. Rectal sleeve advancement for repair of a highly complex ﬁstula. (A) An asymmetric incision is performed with an increased incisional depth on the involved versus uninvolved side. (B) Outline of incision for proposed sleeve advancement anorectoplasty. (C) Sleeve advancement dissection prior to amputation. The vaginal and external ﬁstula tracks have been detached. The line of amputation is proximal to the diseased tissues (arrows). (D) Retoration of anorectal continuity by full-thickness anastomosis at site of initial incision. The anal transition zone has been retained on the uninvolved side. The vaginal and external tracks are curreted and left open for drainage. (Illustration by Lois Barnes. From Corman ED. Colon and Rectal Surgery. 4th edition. 1998. p. 1–1432; with permission.)

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Fig. 5. Anocutaneous advancement ﬂap. (A) An inverted U-shaped ﬂap is incised including the internal ﬁstula opening at the level of the dentate line. (B) The ﬂap is elevated and the ﬁstula track is excised or curreted. The internal mucosal defect is excised. (C) The defect in the internal anal sphnicter is sutured closed. The ﬂap is then advanced into the anal canal and approximated to the anal mucosa and underlying internal sphnicter muscle proximal to the ﬁstula site. (D) Additional advancement is gained by excising skin from the adjacent base (Burow’s triangles).

identiﬁed only four patients with spontaneous abdominal wall ﬁstulas, three being colo-umbilical and one connecting the ileum to the linea alba. Most external enterocutaneous ﬁstulas occur in the postoperative setting. These classically arise from the ileum or colon and commonly drain through the site of a previous scar. Early enterocutaneous ﬁstulas develop as a result of anastomotic breakdown and frequently present within 1 week of surgery. Fistulas developing at later stages (>7 to 10 days postoperatively) typically result from recurrent CD, although some may arise from the site of a contained anastomotic leak. The standard surgical approach to postoperative ﬁstula has been early fecal diversion in addition to resection of the ﬁstula and anastomosis. Somatostatin analogue has been used in selected patients to initiate ﬁstula closure associated

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Fig. 6. Transanal repair of midrectovaginal ﬁstula. The rectal mucosa surrounding the ﬁstula opening is excised and the muscular defect in the rectovaginal septum is repaired. A mucosal advancement ﬂap is then advanced and sutured. If the high pressure zone in the rectum is successfully repaired, a vaginal closure is unnecessary. (Illustration by Lois Barnes. From Corman ED. Colon and Rectal Surgery. 4th edition. 1998. p. 1–1432; with permission.)

with anastomotic breakdown but this has not been subjected to controlled clinical trials [127]. Late ﬁstulas resulting from recurrent CD usually require surgical intervention in addition to aggressive medical therapy. In selected patients with high operative risk and low ﬁstula output, aggressive medical therapy may be the initial treatment of choice. Peristomal Individuals with proctocolectomy and ileostomy may be at risk for two diﬀerent forms of cutaneous ﬁstulas: peri-ileostomy ﬁstulas and enteroperitoneal ﬁstulas. Peri-ileostomy ﬁstulas may develop either early or late in the postoperative period. Early postoperative ﬁstulas frequently result from excess tension at the site of sutures placed between the abdominal fascia and the bowel serosa, which initiates seromuscular damage or injury to the ileostomy within the abdominal wall. These ﬁstulas typically present during hospitalization and require exteriorization of the ileostomy and a second stomal maturation. In contrast, late ileostomy ﬁstulas develop as a result of recurrent CD. Therapeutic options for management of these ﬁstulas include primary resection of the neoterminal ileum and recreation of a neo-end ileostomy or aggressive medical therapy. When abscess or infection complicates the peristomal ﬁstula, relocation of the stoma may be required. Enteroenteric ﬁstulas Ileocolic ﬁstulas are the most common type of enteroenteric ﬁstulas. Most of these are ileocecal or ileosigmoid in location. Rarely, ﬁstulas arising from the ileum may connect to the transverse colon, stomach, or duodenum. Enteroenteric ﬁstulas usually present with few symptoms in

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the absence of obstruction or associated septic complications. They are best demonstrated by radiographic and endoscopic techniques including enteroclysis, barium enema, CT scan, MRI, and colonoscopy. Enteroenteric ﬁstulas identiﬁed in the absence of symptoms or evidence of signiﬁcant bowel diversion do not require surgical intervention. When symptomatic, internal ﬁstulas are usually indications for surgery. The natural history of enteroenteric ﬁstula was reported by Broe et al [128] in 1982. Patients with internal ﬁstulas were followed to evaluate the eﬀect of medical therapy. Surgical intervention was necessary within 1 year in 10 of 24 patients; an additional eight patients ultimately required surgery within a period of 9 years, largely because of intractable disease. The remaining six patients, none of whom had radiographically demonstrable ﬁstula, did not require surgical intervention and four of these patients remained healthy for more than 5 years following diagnosis. Identiﬁcation of an enteroenteric ﬁstula alone does not warrant surgical intervention. Rectovaginal ﬁstula The clinical hallmark of an enterovaginal ﬁstula is the discharge of gas or fecal material from the vagina. In most cases this represents an abnormal connection between the anus or rectum and the vagina. Although the true incidence of this disorder is unknown, Radcliﬀe et al [129] concluded from their series that rectovaginal or anovaginal ﬁstula developed in 9% of women with anal CD. Anovaginal ﬁstulas arise from deep ulcerations in the anterior anal canal or less commonly from a cryptoglandular abscess. Rectovaginal ﬁstulas have an internal oriﬁce above the anorectal ring and most frequently develop secondary to a deep rectal ulceration in the anterior wall that erodes into the vagina, typically in the midportion of the rectovaginal septum. Rarely, in patients who have undergone hysterectomy, ileal or sigmoid CD may ﬁstulize to the vagina. Anovaginal ﬁstulas have also been reported as a late complication of restorative proctocolectomy in patients with CD [130,131,132]. In these patients, the ﬁstula has been found both at and below the anastomosis. Clinically, symptoms may vary quite broadly. Some women experience dyspareunia, perineal pain, and recurrent yeast infections, whereas others may experience drainage of purulent material and passage of stool or ﬂatus [132]. Diagnosis of these ﬁstulas may be diﬃcult. Initial examination should include an examination under anesthesia including proctoscopy and vaginoscopy. If the tract cannot be identiﬁed, meglumine diatrizoate or methylene blue may be infused into the rectum with a tampon in the vagina. Alternatively, rectal insuﬄation while the vagina is ﬁlled with saline may reveal the ﬁstula. More recently, endoluminal MRI or endosonographic imaging with hydrogen peroxide enhancement has been used successfully to identify and characterize vaginal ﬁstulas [133,134].

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General principles for the treatment of perianal ﬁstulas also apply to rectovaginal ﬁstulas. Patients with minimal or no symptoms need no intervention. In contrast, patients who have abscesses associated with their ﬁstulas need drainage. Patients with low anovaginal ﬁstula with a superﬁcial tract may be treated with ﬁstulotomy [129]. Patients with transsphincteric and extrasphincteric rectovaginal ﬁstulas have been treated with mucosal advancement ﬂaps with clinical improvement noted in 70% to 75%, although recurrence rates exceed those documented for anorectal ﬁstulas (Table 3) [98,123,124,134,135–148]. The long-term success of these interventions remains controversial. Makowiec et al [148] reported a 70% recurrence rate at 24-month follow-up. In contrast, Fry et al [121] reported an 80% healing rate, and Hull and Fazio [146] documented improvement in 60%, although several patients required repeat procedures [147]. Patients with signiﬁcant Table 3 Results of surgical therapy for rectovaginal ﬁstulas in patients with Crohn’s disease Investigator

Year

Therapy

Improved (%)

Francois Radcliﬀe Fauloconer Hudson O’Leary Wiskind Cohen Radcliﬀe Bandy Givel Tuxen Hudson Michelassi O’Leary Simmang Hull Makowiec Hesterberg Fry Jones Radcliﬀe O’Leary Sher

1993 1988 1975 1970 1998 1992 1989 1988 1983 1982 1979 1970 2000 1998 1998 1997 1995 1993 1989 1987 1988 1998 1991

Fistulotomy Fistulotomy Fistulotomy Fistulotomy Primary closure Primary closure Primary closure Primary closure Primary closure Primary closure Primary closure Primary closure Advancement ﬂap Advancement ﬂap Advancement ﬂapc Advancement ﬂapd Advancement ﬂap Advancement ﬂape Advancement ﬂap Advancement ﬂap Advancement ﬂapf Transvaginal ﬂap Transvaginal ﬂap

9/9 6/12 0/3 3/5 1/2 3/3 3/6 2/4 8/9 1/2 1/2 3/4 4/16 3/6 2/2 21/35 10/12 7/10 2/3 6/10 7/11 0/1 13/14

(100) (50) (0) (60) (50) (100) (50) (50) (89) (50) (50) (75) (25) (50) (100) (60) (83) (70) (67) (60) (64) (0) (93)

Proctectomy-diversion (%) 0/9 4/12 2/3 0/5 0/2 0/3 2/6 0/9 0/2 02 0/4 11/16 0/6 0/2 5/35 0/12 0/10 0/3 1/10 0/1 1/14

(0) (33) (67) (0) (0) (0) (33)a (20)b (0) (0) (0) (0) (69) (0) (0) (14) (0) (0) (0) (10) (20)b (0) (7)

Advancement ﬂap: transanal advancement ﬂap. One patient treated with diverting ileostomy. b A total of 15 patients were treated with surgical therapy (primary closure or advancement ﬂap); 3/15 required proctectomy. c Sleeve advancement ﬂap procedure. d Includes patients treated with curvilinear (24), linear (6), and sleeve (2) advancement ﬂap procedures. e Transanal anocutaneous ﬂap procedure. f Includes patients treated with anterior (3) and transanal (4) advancement ﬂap procedures. a

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proctitis who cannot be treated with a mucosal ﬂap may be treated with an anocutaneous ﬂap (Fig. 7). This approach, however, is complicated by a 33% recurrence rate at 18 months [135]. An alternative transvaginal approach has been reported to be successful in 93% of patients with no recurrence in one published series with a mean follow-up of 55 months [136]. Use of healthy vaginal tissue may underlie the improved results with this technique. In addition, all patients underwent proximal diverting ileostomy as part of their surgical intervention. When the ﬁstula results from disease in the ileum or colon, resection of the contiguous bowel should be considered. The appropriate surgical intervention is dependent on the extent of disease and the origin of the ﬁstula to select the appropriate surgical intervention. Ileal resection may be suﬃcient if disease is limited to the small bowel. Similarly, segmental resection of the colon (typically the sigmoid colon) may be considered if the rectum and remainder of the colon are unaﬀected by CD. More extensive resection of the colon with an ileorectal anastomosis is dependent on the integrity of the anal sphincter. An omental pedicle is commonly interposed between the anastomosis and the vagina if the bowel anastomosis is in the region of the vaginal stump. When closure of a rectovaginal ﬁstula results from proximal fecal diversion, additional medical and surgical therapy is imperative, because the ﬁstulas recur frequently following ileostomy reversal in the absence of adjunctive or deﬁnitive therapy [74]. Finally, should other options fail or are inappropriate, proctocolectomy may allow healing. A two-stage procedure has been advocated in the presence of sepsis or severe rectal inﬂammation to minimize the risk of a persistent perineal wound [149]. Various surgical techniques including muscle ﬂap perineal reconstruction procedures have been applied as therapeutic options for Crohn’s patients with persistent perineal sinus tracts refractory to medical therapy [150–157]. Use of

Fig. 7. Management of complex perianal ﬁstulas. Sagittal view of perianal region demonstrates seton drain in place on the left, with catheter drainage of the ischiorectal fossa on the right. (Illustration by Lois Barnes. From Corman ED. Colon and Rectal Surgery. 4th edition. 1998. p. 1–1432; with permission.)

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adjunctive therapies, such as ﬁbrin glue, has not been shown to be eﬃcacious when applied to rectovaginal and anovaginal ﬁstulas presumably because of the short length of the ﬁstula tract. Medical therapy may also be useful for treatment of selected patients with vaginal ﬁstulas. The choice of speciﬁc medication should be dictated by the degree to which patients are symptomatic and the likely time of onset of action. Medications that have been applied as therapy for these ﬁstulas include AZA and 6-MP, intravenous cyclosporine A, and more recently inﬂiximab. The eﬃcacy of 6-MP in the treatment of rectovaginal ﬁstula was assessed by Korelitz and Present [37] in Crohn’s patients with rectovaginal or vulvar ﬁstulas. Clinical improvement was observed in three of six patients with rectovaginal ﬁstulas including two patients with ﬁstula closure. One of two patients with vulvar ﬁstulas was noted to be improved, although ﬁstula closure was not achieved. Hanauer and Smith [158] evaluated the eﬃcacy of intravenous cyclosporine A in refractory CD including ﬁve patients with a total of 12 ﬁstulas (ﬁve enterovaginal, three perianal, three enterocutaneous, and one enterovesical). Complete resolution of drainage was observed in 10 of 12 ﬁstulas after a mean of 7.9 days. Subsequently, recurrent drainage was documented in two perianal ﬁstulas and in two enterovaginal ﬁstulas. In their study of intravenous cyclosporine A for ﬁstulizing CD, Present and Lichtinger [159] evaluated two patients with rectovaginal ﬁstulas. Clinical improvement was initially observed in both with ﬁstula closure in one patient after 2 weeks of therapy. Both patients had recurrence, however, despite continued therapy and one required surgery. There have been no reported controlled trials of inﬂiximab focusing on the treatment of rectovaginal and anovaginal ﬁstulas. A recent uncontrolled study reported by van Bodegraven et al [160] failed to demonstrate healing of rectovaginal ﬁstulas in four patients treated with three inﬂiximab infusions (5 mg/kg) at baseline, week 2, and week 6. Enterovesical ﬁstula Enterovesical ﬁstulas, the most common Crohn’s-related urinary ﬁstula, aﬀect 2% to 8% of patients [161–164]. Ileovesical ﬁstulas comprised most enterovesical ﬁstulas (58%) in a large series of patients with inﬂammatory bowel disease reported by Greenstein et al [162]. Enteroureteral, rectourethral, urethrocutaneous, and enterourachal ﬁstulas also occur, although less frequently. These ﬁstula result as extension of inﬂammation from the small bowel and colon penetrates into adjacent bladder, ureter, urethra, perineum, or urachial remnant. Although ﬁstulas most commonly result from penetrating CD, they may complicate surgical resection in the setting of anastomotic breakdown. Complex ﬁstulas developing from pelvic abscesses may involve ileum, colon, vagina, and bladder [163]. Clinically, enterovesical ﬁstulas present with dysuria, recurrent cystitis, and passage of gas and fecal material with urine. Dysuria almost always precedes

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the development of pneumaturia or frank fecaluria. Nonspeciﬁc complaints including diarrhea, abdominal pain, and nausea are present in most patients. Physical examination ﬁndings are commonly nonspeciﬁc but abdominal tenderness may be appreciated in 29% of patients [165]. Although an accurate history and positive urinary culture provide a presumptive diagnosis of enterovesical ﬁstula in 95% of cases, diagnosis is frequently delayed with symptoms present for weeks to months in most patients [164,166]. Intravenous pyelograms and retrograde cystograms commonly fail to detect the ﬁstula track, although a ﬁlling defect may be observed in the bladder. Cystoscopy conﬁrms the diagnosis of ﬁstula in 30% to 67% of patients with urinary symptoms [164,165,167]. An area of bullous edema or mucosal inﬂammation with purulent (or rarely feculent) exudates characterizes the cystoscopic appearance of a ﬁstula. Multiple small ﬁstulous tracts extending from a perivesical abscess may not be appreciated by cystoscopy but may be diagnosed if intravesical contrast injection results in opaciﬁcation of an adjacent bowel lumen [168]. Other radiographic studies including barium enema, CT, and MRI may be useful to detect these ﬁstulas. Because the ileum is the most commonly involved bowel segment, colonoscopy and barium enema are most useful to identify or exclude associated colonic abnormalities (diverticulitis or colorectal malignancy), which may also ﬁstulize to the bladder. Detection of radiopaque barium in a centrifuged urine sample collected immediately after barium enema (Bourne test) conﬁrms the presence of a colovesical ﬁstula even when the ﬁstula tract cannot be deﬁned radiographically [169]. Oral charcoal may be similarly administered and microscopic examination of the urine sediment for charcoal suggests the presence of an intestinal-urinary ﬁstula [167]. CT scanning and MRI are the most sensitive techniques to detect enterovesical ﬁstulas. They may demonstrate small amounts of air in the bladder, which in the absence of instrumentation or infection are diagnostic of a ﬁstula. In addition, abnormalities in adjacent organs responsible for ﬁstula formation may be detected (Fig. 8). Although MRI has not been compared systemically with CT scanning for eﬃcacy in diagnosing enterovesical ﬁstulas, MRI has the greatest potential for detecting ﬁstulas because small amounts of ﬂuid in a ﬁstula may be identiﬁed as a high signal intensity tract on T2-weighted images [170,171]. Adjacent perivesical abnormalities may also be delineated with the use of specialized endoluminal surface coils and pelvic multiarray body coils. Management of enterovesical ﬁstulas parallels management of other internal ﬁstulas. The primary goals of therapy are reduction of bowel inﬂammation and treatment of any urinary infections. Medical therapy may be used initially in those patients without signiﬁcant risk for pyelonephritis or sepsis because some ﬁstulas close spontaneously. The use of medical therapy in treatment of enterovesical ﬁstulas has not been evaluated in a controlled fashion. In those patients in whom ﬁstulas persist, surgical intervention is nearly always necessary (Table 4) [161–164,172–177]. The most common procedure is resection of the diseased bowel segment, together with curettage

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Fig. 8. Enterovesical ﬁstula secondary to Crohn’s disease. T2-weighted MR image through the pelvis of a 65 year old man with pneumaturia. Urine in the bladder displays high-signal intensity. On sagittal view, air in the bladder (arrowheads) has risen to the most nondependent portion of the bladder (patient imaged in the recumbent position).

and primary closure of the bladder defect. Partial bladder resection is usually not indicated and if the bladder defect is small, it may require no particular repair. A single-stage approach may be used even in patients with multiple ﬁstulas but when the ﬁstula is associated with an intra-abdominal abscess (present in 34%–47% of cases), a two-stage operative intervention is often necessary [166]. Recurrence of ﬁstulas is uncommon when treated in this fashion. Postsurgical complications occur in 10% to 30% of patients and

Table 4 Response of enterovesical ﬁstulas to surgical therapy in patients with Crohn’s disease Investigator

Year

No. patients

No. treateda

Coexistent ﬁstulas

Resolved (%)

Recurrence (%)

Kyle Talamani Van Dongen Schraut Greenstein Glass Margolin Fazio Heyen McNamara

1969 1982 1984 1984 1984 1985 1986 1987 1988 1989

10 14 14 29 38 16 16 3 19 63

10 16 14 29 36 12 9 3 15 61

NA NA 9 19 12 NA NA 0 4 31

10/10 14/16 7/14 29/29 36/36 12/12 9/9 3/3 13/15 60/61

0/10 1/16 7/14 0/29 0/29 0/12 0/9 0/3 2/15 1/61

(100) (88) (50) (100)c (100) (100)c (100) (100)d (87)c (98)e

(0) (6)b (50) (0) (0) (0) (0) (0) (13) (2)

Abbreviation: NA, Not addressed in publication. a Patients treated with variety of surgical procedures. b One patient underwent proctectomy for intractable perianal disease during follow-up. c Urine leak complicated postoperative course in one patient. d Three patients with rectourethral ﬁstulas treated with rectal advancement ﬂap. e Urine leak complicated postoperative course in two patients.

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include abscess formation, sepsis, recurrent enterovesical or new enterocutaneous ﬁstula, urine and anastomotic leaks, and bowel obstruction. Although urine leaks may seal with prolonged bladder drainage, recurrent or new enteric ﬁstulas necessitate additional surgery. Urinary retention and impotence may develop if extensive pelvic surgery results in damage to preganglionic parasympathetic ﬁbers of the pelvic plexus. Rectourethral and urethrocutaneous ﬁstulas have also been associated with CD. They present with symptoms similar to enterovesical ﬁstulas. These ﬁstulas frequently develop in the setting of multiple perianal and scrotal abscesses that erode into the bulbous urethra [178]. Retrograde urethrogram and barium enema may demonstrate the ﬁstula. CT scan and MRI may also reveal associated perirectal or periurethral ﬁstulas, if present. In selected patients without active proctitis, a transanal rectal advancement ﬂap procedure may be used to close the ﬁstula [172]. Summary The primary goals of the clinician in the treatment of ﬁstulizing CD include (1) deﬁning the anatomy of the ﬁstula, (2) draining any associated infectious material, (3) attempting to eradicate the ﬁstulous tract through medical or surgical therapies, and (4) preventing recurrence of ﬁstulas. Evaluation and therapeutic decisions require close collaboration between the gastroenterologist and surgeon. This is particularly true when dealing with perianal disease. Appropriate evaluation should include identiﬁcation of septic complications; delineation of the ﬁstulous tract including the origin and terminus of the ﬁstula; and determination of the extent of bowel involvement with active CD, in particular the presence or absence of proctitis. Drainage of abscesses and control of septic complications through the placement of drains or setons is essential. Conservative therapy with avoidance of sphincter muscle-cutting procedures is the standard approach typically followed. Preservation of continence and sphincter integrity should be an essential goal of management. When simple ﬁstulas are present, surgery is appropriate because it avoids the potential risk of long-term immunosuppression without signiﬁcant risk of fecal incontinence. When complex ﬁstulas are present, surgical intervention should be minimized and medical therapy may be more appropriate. When internal ﬁstulas are present, it is important to ascertain the severity of the illness. In acutely ill patients in whom local abscess or sepsis is a concern, a surgical approach is often the best option with subsequent medical maintenance therapy of residual CD. In patients with internal ﬁstula who have minimal symptoms, medical therapy initiated with an antibiotic may be appropriate. The appropriate approach to asymptomatic patients is uncertain because there are little data to indicate if treatment alters the natural course of disease.

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