Efficacy of conventional immunosuppressive drugs in IBD

Digestive and Liver Disease 36 (2004) 766–780

Clinical Review

Efficacy of conventional immunosuppressive drugs in IBD R. Caprilli∗ , E. Angelucci, A. Cocco, A. Viscido, M. Zippi GI Unit, Department of Clinical Science, University of Rome “La Sapienza”, Viale del Policlinico 155, 00161 Rome, Italy Received 22 April 2004; accepted 16 June 2004 Available online 21 September 2004

Abstract The introduction and rapid diffusion of biological agents in the treatment of inflammatory bowel disease had led us to believe that the old immunosuppressive drugs were destined to disappear. However, despite a decade of clinical experience in the use of biological agents, the old immunosuppressive drugs continue to play a pivotal role in the management of inflammatory bowel disease. Various factors may account for this change of view. Aim of the present review was to summarise key information currently available regarding the use of immunosuppressive drugs in the treatment of inflammatory bowel disease. © 2004 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. Keywords: Immunosuppressants; Inflammatory bowel disease

1. Introduction The introduction and rapid diffusion of biological agents in the treatment of inflammatory bowel disease (IBD) had led us to believe that the old immunosuppressive drugs were destined to disappear. However, despite a decade of clinical experience in the use of biological agents, the old immunosuppressive drugs continue to play a pivotal role in the management of IBD. Various factors may account for this change of view. As far as azathioprine (AZA) and 6-mercaptopurine (6MP) are concerned, the clinical application of these drugs was delayed and limited due to early controversial results of a National Cooperative Crohn’s Disease Study (NCCDS) [1] and despite the efficacy first reported, albeit, only by the New York Mount Sinai Hospital Group [2]. Only in the 1990s, following reports from several groups did the use of AZA/6MP become popular. Another finding that favoured the use of AZA/6-MP was the observation that these drugs are able to induce healing of intestinal lesions thus leading to stable clinical remission and altering the natural course of the ∗

Corresponding author. Tel.: +39 06 4460009; fax: +39 06 4463737. E-mail address: [email protected] (R. Caprilli).

disease [3]. Furthermore, it is worthwhile pointing out that AZA/6-MP is currently recommended, in combination with Infliximab, as the former enhance the efficacy and safety of the latter [4]. Also methotrexate (MTX), after a long series of uncontrolled studies, was recently found to be effective both in the induction and in the maintenance of remission in patients with Crohn’s disease (CD) [5,6] and today the drug is increasingly employed in this condition. Furthermore, cyclosporine A (CyA) is being used more and more in the treatment of severe ulcerative colitis (UC) refractory to steroids [7]. Last but by no means least, other immunosuppressants such as tacrolimus, mycophenolate mofetil (MMF) and thalidomide have recently been used in IBD with encouraging results, but their efficacy remains to be confirmed. This review aims to provide the gastroenterologist with an ordline of our current knowledge on the immunosuppressants that are currently used in the treatment of patients presenting CD and UC. The analysis, in accordance with the commonly used hierarchy of evidence, focuses primarily on meta-analyses including published randomised controlled trials (RCTs), and on single RCTs not included in any meta-analysis, performed

1590-8658/$30 © 2004 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.dld.2004.06.014

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on CD and UC, selected both from a computer search of the literature (Medline/Pubmed) and from congress proceedings (Digestive Disease Week, United European Gastroenterology Week) over the past decade. The main literature database was Medline (1966–2004). However, since Medline does not retrieve all studies, we also used other sources such as, for example, the Cochrane Library, as well as manual searches including references quoted in the most relevant articles and those of reviews, editorials and comments from experts in the field. Data, other than results of meta-analyses and RCTs, come from a personal overview of articles emerging from the same search strategy. The keywords used in the Medline search were: AZA, 6-MP, MTX, CyA, tacrolimus, MMF, thalidomide, immunosuppressants, CD, UC and IBDs.

2. AZA/6-MP AZA is a prodrug that is converted, after absorption, into 6-MP, also a prodrug, which, in turn, is converted into 6thioguanine nucleotides (6-TGN), which are thought to be the active metabolites. AZA, 6-MP, and 6-TGN were all used in the treatment of IBD, whereas the use of 6-TGN is still under investigation. The efficacy of AZA and 6-MP has long since been widely established in CD as second-line therapy, while in UC results are controversial. In active disease, AZA and 6-MP are often used in combination with other drugs primarily on account of their slow onset of action [8]. 2.1. CD One meta-analysis and two systematic reviews have shown that AZA/6-MP is effective both in inducing and maintenance of remission [9–11]. The meta-analysis included nine trials in steroid-dependent patients or patients refractory to steroid treatment [1,2,12–18]: four focused exclusively on treatment for active disease, two addressed maintenance of remission, and three had separate arms for patients with active and quiescent disease [9]. Of the two systematic reviews, one focused on inducing remission including eight RCTs (five dealt exclusively with active disease, three had multiple therapeutic arms) [10], and one focused on maintenance of remission including five RCTs (two comprised only patients in remission, three had multiple therapeutic arms both for induction and maintenance of remission) [11]. 2.1.1. Induction of remission 2.1.1.1. Meta-analysis and systematic reviews. In the metaanalysis, seven studies were considered [1,2,12–15,18]. A total of 367 patients under steroid treatment were enrolled; 177 received AZA or 6-MP and 190 received placebo (control group). The response rates for the treatment and control groups were 56% (95% CI, 49–64%) and 32% (95% CI, 25–38%), respectively. Compared with placebo, AZA or 6-

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MP therapy had an odds ratio (OR) of response of 3.09 (95% CI, 2.54–3.91) in patients with active CD. Only one trial was performed using 6-MP. When this trial was excluded from the analysis, the OR of response was 1.45 (95% CI, 1.12–1.87). Increased cumulative dose and continuation of therapy for at least 17 weeks improved response. Analysis of the data for the effect of both drug dose (range, AZA 2.0–3.0 mg/kg per day) and duration of therapy (range, 2–12 months) showed that both are statistically significant by itself (P < 0.0001 for each). However, only duration of therapy was found to be significant when the two variables were considered simultaneously (P < 0.0003). The estimated common OR for response increased by 1.25 (95% CI, 1.20–1.30) with each additional month of therapy. Continuation of therapy for at least 17 weeks improved response (P < 0.03) as the OR reached statistical significance at 17 weeks and increased thereafter. A steroid-sparing effect was seen in active CD (OR, 3.69; 95% CI, 2.12–6.42). Fistula response was reported in five studies and was reported to be significant [2,12,13,15,16]. Of 41 patients receiving thiopurines, 22 responded (54%; 95% CI, 37–69%) compared with 6 out of 29 patients receiving placebo (21%; 95% CI, 8–40%). This resulted in a pooled OR of 4.44 (95% CI, 1.50–13.20) favouring fistulae healing. Adverse events requiring withdrawal from a trial (allergy, leukopenia, pancreatitis, and nausea) were increased with therapy (OR, 5.26; 95% CI, 2.20–12.60). In the systematic review including eight RCTs [10], the OR of a response to AZA or 6-MP therapy for inducing remission of CD compared with placebo was 2.36 (95% CI, 1.57–3.53). When the two trials using 6-MP were excluded from the analysis, the OR of response was 2.04 (95% CI, 1.24–3.35). Treatment for at least 17 weeks increased the OR of a response to 2.51 (95% CI, 1.63–3.88). A steroid-sparing effect was seen with an OR of 3.86 (95% CI, 2.14–6.96). Adverse events requiring withdrawal from a trial (allergy, leukopenia, pancreatitis and nausea) were increased on therapy with an OR of 3.01 (95% CI, 1.30–6.96). 2.1.1.2. RCTs. An RCT evaluated the combination of 6-MP and prednisone as first-line therapy for children with newly diagnosed moderate-to-severe CD. In the 6-MP group, the duration of steroid use was shorter (P < 0.001), and the cumulative steroid dose lower (P < 0.01). Although remission was induced in 89% of both groups, only 9% of the remitters in the 6-MP group relapsed compared with 47% of controls (P < 0.007) [19]. 2.1.2. Maintenance of remission 2.1.2.1. Meta-analysis and systematic reviews. In the metaanalysis, six studies were considered [1,13,16–18]. A total of 319 patients were enrolled; 136 received AZA and 183 received placebo (control group). 6-MP was not used in any trial. The response rates for the treatment and control groups were 67% (95% CI, 59–75%) and 53% (95% CI, 45–60%), respectively. Compared with placebo, AZA had an OR of

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response of 2.27 (95% CI: from 1.76 to 2.93) in patients with quiescent CD. A higher dose significantly improves response. Analysis of the data for the effect of both AZA dose (range, 1.0–2.5 mg/kg per day) and duration of therapy (range, 5.5–12 months) showed that each is statistically significant by itself (P < 0.0001 and P < 0.002, respectively). However, only the dose resulted significant when the two variables were considered together (P < 0.008). The estimated common OR for response increased by 1.75 (95% CI, 1.51–2.03) with each additional mg/kg per day. A steroidsparing effect was also seen in quiescent disease (OR: 4.64; 95% CI: from 1.00 to 21.54). Adverse events requiring withdrawal from a trial, primarily allergy, leukopenia, pancreatitis and nausea, were increased with therapy (OR: 5.26; 95% CI: from 2.20 to 12.60) [9]. The systematic review, performed by the same authors, confirmed that AZA had a positive effect on maintaining remission in CD. The OR for maintenance of remission was 2.16 (CI: from 1.35 to 3.47) with an NNT of 7. Higher dosages improved response, and the steroid-sparing effect was confirmed [11]. 6-MP was also used as maintenance therapy in patients with surgically induced remission and resulted superior to both placebo and 5-ASA in the prevention of endoscopic and clinical post-operative recurrence at a 2-year follow-up; however, the study was published only as an abstract in 1998 [20].

achieve remission in patients with UC than with CD: remission was achieved in 64% of patients with CD and 87% with UC (P < 0.0001) [27]. 2.2.2. Maintenance of remission 2.2.2.1. RCTs. The only RCT evaluating AZA for the maintenance of remission in UC showed that patients in whom remission was induced by AZA benefited from maintenance treatment [25]. In this trial, it was observed that maintenance treatment with AZA is effectively beneficial as withdrawal of therapy resulted in doubling of the relapse rate in patients who had previously achieved complete remission. Another RCT showed that AZA is effective in avoiding colectomy in patients with steroid-dependent or steroidresistant UC [28]. 2.2.2.2. Uncontrolled studies. The above-mentioned retrospective survey on AZA use in IBD showed that, although most effective in active UC with respect to active CD, AZA was equally effective for maintenance of remission both in UC and the CD [27]. The proportion of patients still in remission at 1, 2, 3, 4 and 5 years was 0.95, 0.90, 0.69, 0.63 and 0.62, respectively. If patients with a short and mild relapse that promptly remitted are excluded, the proportion of patients still in remission at 1, 2, 3, 4 and 5 years was 0.99, 0.92, 0.85, 0.81 and 0.81, respectively. No differences were observed between UC and CD patients (P = 0.5) [27].

2.2. UC 2.3. Side-effects No meta-analysis or systematic review has been published. Earlier RCTs using AZA or 6-MP were negative. However, the negative effect was attributed to the fact that the drug takes a long time to achieve a therapeutic effect. 2.2.1. Induction of remission 2.2.1.1. RCTs. Compared to CD, there are fewer data on the efficacy of AZA/6-MP for the treatment of UC. An early RCT showed that AZA was similar to salazopyrin in inducing remission in UC patients [21]. Other RCTs showed that 6-MP is an effective treatment in patients with UC who have relapsed, and those who are treated with steroids or are steroid dependent [22–26]. Two controlled trials have shown a steroid-sparing effect for chronic active UC but found no significant improvement in disease activity [23,24]. 2.2.1.2. Uncontrolled studies. In contrast, other trials and a number of open studies with AZA and 6-MP have shown that these two drugs were both efficacious and safe in treating patients who were either steroid dependent or steroid resistant and allowed complete remission, or a significant clinical improvement, together with discontinuation of steroids in 60–70% of cases [22,25,36]. In a recent large and long-term retrospective clinical survey on the use of AZA in IBD, AZA was more likely to

Two types of side-effects have been reported. Some, presumably dose related, such as leucopenia and some forms of hepatitis, others, “allergic” non-dose related such as pancreatitis, hepatitis, fever, rash, malaise, nausea, and diarrhoea. The bone marrow-suppressive effect leading to leucopenia is the major limit for therapy. In a large cohort series of 739 patients with IBD followed prospectively for 29 years, a record was kept of the monthly full blood count [29] which showed that 4% of patients experienced leucopenia defined as white blood cell count (WBC) <3.000 dL. Three patients who did not comply with the blood count monitoring experienced major sepsis related to bone marrow suppression (two died), while no severe complications were recorded in the monitored group [28]. The probability of side-effects, sometimes severe, determines that patients treated with AZA and 6-MP should be submitted to frequent clinical and laboratory controls. The British National Formularium recommends that patients starting thiopurine require a blood count every week for the first 8 weeks of treatment and at least every 3 months thereafter. A number of observations have suggested that measurement of S-methyltransferase (TPMT) activity or genotype could be used to “tailor” therapy. However, routine therapeutic drug monitoring of 6-TGN or TMPT genotype in patients receiving AZA appeared not to be necessary [30,31].

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Another potential concern with long-term AZA use, especially long-term use, is the increased risk of malignancies, in particular, Hodgkin’s and non-Hodgkin’s lymphoma. Data on risk of malignancies on long-term thiopurine treatment are conflicting but somewhat reassuring [32]. CD is characterised by chronic inflammation with continuous immune activation. The state of immune activity could, therefore, enhance the risk for malignant transformation in the lymphatic tissue, as described in other chronic conditions such as rheumatoid arthritis [35]. However, drug-induced immunosuppression could also contribute to malignant transformation of lymphatic tissue [36]. A study, including a case cohort larger than all of the other combined populationbased studies (17,000 IBD patients and more than 60,000 matched controls using the resources of the General Practice Research Database from the United Kingdom), showed that, although a modest increased risk of lymphoma with AZA or 6-MP therapy cannot be completely ruled out, an increased risk was not observed in the study cohort (the relative risk (RR) of lymphoma among the 1465 IBD patients treated with thiopurines was 1.27; 95% CI 0.03–8.20) [37,38]. 2.4. Latency of effect The meta-analysis and the systematic review showed that in active disease, continuation of AZA or 6-MP therapy for at least 17 weeks improved response [9–11]. This point has been clearly elucidated by an RCT, which included 63 patients with active CD who were treated with a 12-week decreasing dose of prednisolone and, at the same time, entered into a 15-month RCT trial with either AZA (2.5 mg/kg) or placebo. There was no significant difference in the proportion of patients in remission by week 12, but at 15 months there was a highly significant difference (proportion of patients in remission: 42% on AZA versus 7% receiving placebo; P = 0.001) [18]. These results demonstrate the need of at least 12 weeks for the drug to work. Intravenous AZA load does not accelerate the appearance of response. 2.5. Duration of therapy As to how long this therapy needs to be continued, there are no clear answers. A long-term open study compared relapse rates in 157 CD patients in remission who continued AZA or 6-MP for more than 6 months after steroid withdrawal, with 42 patients who stopped therapy for reasons other than relapse. Relapse rates at 1 and 5 years were 11 and 32% in the immunosuppressive group versus 38 and 75% in the group who had discontinued immunosuppressives. The same study showed that the benefit of continuing AZA or 6-MP therapy tended to disappear after 4 years. In fact, CD patients who have maintained remission on AZA therapy for over 4 years are at low risk of relapse when AZA is stopped. This finding led to the hypothesis that there is no advantage in continuing AZA or 6-MP for over 4 years [33].

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Recently, an RCT was conducted by the same group to test this observation and 83 patients with CD who were in clinical remission, induced by AZA over the last 42 months, were randomised to receive either AZA (mean dose: 1.7 ± 0.5 mg/kg per day) or placebo (control group), for 18 months. Relapse rates at the end of follow-up were 7.9% in the AZA group compared to 21.3% in the placebo group. The authors concluded that albeit the difference is significant, the low number of relapses in the placebo group (21%) would suggest that withdrawal of the drug can be considered in selected groups of patients [34]. 2.6. Pregnancy Use of AZA in a female with CD who is pregnant or contemplating pregnancy is debated. The considerations to bear in mind in this scenario concern the control of CD activity before and during pregnancy, the effects of the drug on fertility, and the safety of the drug on the developing foetus (teratogenicity) and nursing the newborn. Theoretically, AZA and 6-MP should be discontinued during pregnancy because of the risk of teratogenicity [39], and chromosomal damage in adults and in infants born to mothers treated during pregnancy [40]. There is, however, no evidence of permanent genetic damage in humans and AZA has been reported to be safe during pregnancy in renal transplantation recipients, in patients with auto-immune disorders and in a small series of patients affected by IBD [41,42]. However, few data regarding toxicity associated with pregnancy are available, raising both patients’ and physicians’ concerns and, sometimes, resulting in elective abortion. A recent cohort study analysed the outcome of pregnancy in 155 patients receiving 6-MP, who had conceived at least one child after starting the drug; a group of IBD patients’ who had started their pregnancies before taking 6-MP were used as a control group. There were no statistical differences in conception failures (defined as spontaneous abortion), abortion secondary to a birth defect, major congenital malformations, neoplasia, or increased infections in male or female patients taking 6-MP compared with controls (RR 0.85; 95% CI 0.47–1.55; P = 0.59). The authors conclude that 6-MP use, before or at conception or during pregnancy, appears to be safe and that discontinuation of the drug before or during pregnancy is not indicated [43]. Furthermore, the influence of AZA on male fertility has been analysed and it was demonstrated that AZA does not reduce semen quality (sperm density, motility, morphology, ejaculate volume, or total sperm count) and thereby male fertility in IBD patients [44]. 3. Methotrexate Methotrexate (MTX) is an analogue of dihydrofolic acid and inhibitor of dihydrofolate reductase, which is involved in several reactions of purine and pyrimidine synthesis. It was initially used as a cytotoxic chemotherapeutic agent for leukaemia and other malignancies. Over the past four decades, low-dose MTX has been used for the treatment of

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various inflammatory diseases such as psoriasis, rheumatoid arthritis and inflammatory bowel diseases (IBD). 3.1. Crohn’s disease MTX is established as effective treatment for inducing remission [5] and preventing relapse [6] in CD. A systematic review [45], RCTs [46–49], an initial openlabel study [49] and several retrospective studies [51–54,64] showed a high remission rate (primary outcome in these studies) in steroid-dependent and in steroid-refractory CD patients treated with a dose of 12.5–25 mg/week of MTX (orally, i.m. or i.v.). Steroid tapering (secondary outcome in a lot of these studies) was possible in a large number of CD patients. 3.1.1. Induction and maintenance of remission 3.1.1.1. Meta-analysis and systematic reviews. No metaanalysis has been published. A recent systematic review [45] identified three randomised placebo-controlled trials. The outcome measure was the rate of induction of remission and a complete withdrawal from steroids in the treatment and control CD patients groups. Two studies, which employed low doses of MTX orally showed no statistically significant difference between MTX and placebo-treated patients and another, which employed a higher dose i.m. showed a substantial benefit. 3.1.1.2. RCTs. A first RCT assessed 141 patients with chronically active CD who were treated with 25 mg MTX i.m. weekly or placebo over a 16-week period. After 16 weeks, 39% of the MTX group were in remission compared to 19% in the placebo group (P = 0.025) [5]. In an Israeli RCT, 84 patients with active CD were randomised to receive MTX 12.5 mg/week orally or 6-MP 50 mg/day, or placebo for 9 months in addition to steroids and 5-aminosalicylic acid (5-ASA). Only 10 out of 26 patients (38%) in the MTX group were found to be n remission at the 9th month compared to 13 out of 32 (41%) in the 6-MP group and to 12 out of 26 (46%) in the placebo group. After remission, only 1 out of 10 patients (10%) in the MTX group relapsed, compared to 5 out of 13 (38%) in the 6-MP group and 4 out of 12 (33%) in the placebo group [55]. In another RCT, 33 patients with steroid-dependent CD, 33% of whom had previously failed therapy with 6-MP, were given placebo or oral MTX 15 mg/week, or adjusted to 22.5 mg/week, for up to 1 year or until treatment failure. Five patients were withdrawn from the study. Fewer MTXtreated patients (6/13 or 46%) had flares of CD compared to placebo-treated patients (12/15 or 80%), but this does not reach statistical significance (P < 0.1) [46]. A randomised dose–response study of MTX for refractory IBD compared subcutaneous MTX, 15 or 25 mg/week, in 32 patients for 16 weeks. For induction of remission, initial doses of 15 or 25 mg were equally effective. However, after the 16-week trial was completed, 4 of the 11 patients

improved significantly when the dose was increased from 15 to 25 mg weekly [47]. In an RCT, 65% MTX responders, who had achieved remission on 25 mg/week i.m., were randomised to receive i.m. MTX 15 mg or placebo every week. After 40 weeks, 65% of the patients given MTX were in remission compared with 39% in the placebo group [6]. In a Spanish RCT, steroid-dependent IBD patients were randomised to receive 1.5 mg/kg per day of 6-MP or 15 mg/week of MTX orally or 3 g/day of 5-ASA added to prednisone. 6-MP or MTX could be effective in steroid sparing, as well as in achieving (93.7 and 80%) and in maintaining (53.3 and 66.6%) remission in steroid-dependent CD patients [48]. In an Italian RCT, 54 patients with chronic active CD were randomised to receive i.v. MTX 25 mg/week, or oral AZA 2 mg/kg per day, for a 6-month follow-up period. No statistically significant difference was found between the two treatment regimens with respect to remission rate after 3 months (MTX 44%, AZA 33%, P = 0.28 [95% CI, 0.369–0.147]), and 6 months (MTX 56%, AZA 63%, P = 0.39 [95% CI, 0.187–0.335]), respectively. MTX is effective in inducing remission in CD patients, therapeutic efficacy being comparable, but not faster than that of AZA [49]. 3.1.1.3. Uncontrolled studies. On a clinical trial, in 37 patients with active refractory CD at MTX initiation the probability of remission was 72% at 3 months. The probability of remission and steroid withdrawal was 42% at 12 months. In patients in clinical remission, the probability of relapse on MTX was 58% at 12 months [65]. In a clinical trial, oral MTX was given at 15 mg/week to 10 refractory CD patients. In these 10 patients, daily prednisone dose dropped from a mean of 37 ± 9.6 mg to 8.3 ± 2.1 mg/day (P < 0.02); two patients had complete withdrawal and four a partial response (7.5 mg/day) [66]. An initial open-label study in 1989 showed that MTX induced remission in 11 out of 14 patients with CD. Five patients out of 11 achieved endoscopic remission and 4 out of 5 histologic remission at 12 weeks [50]. A Belgian retrospective study on 20 steroid refractory and AZA-resistant or -intolerant CD patients showed that only 33% remained in remission on MTX after 12 months [53]. In Paris, 41 out of 49 (84%) patients with refractory CD given MTX (25 mg/week i.m. for 3 months, beginning with a dose of 7.5 mg/week) achieved remission [54]. In the Chicago investigation, 76 steroid-refractory CD patients were treated for a mean duration of 55 weeks, at a mean dose of 20 mg (mostly given parenterally), and 64% showed an improvement. Data suggest better efficacy for parenteral treatment [52]. In another retrospective study, 70 patients (48 CD) were reviewed. The remission rate was 62% in those patients that completed more than 3 months’ treatment with a median dose of 20 mg of MTX (orally or i.m.) for 3 months and, for all patients, the remission rate was 45% [51].

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3.1.2. Fistulizing disease Although MTX has been demonstrated to be of benefit versus placebo for induction [5] and maintenance [6] remission in luminal CD, its effect on fistulizing CD remains to be elucidated. Only one RCT [49] has appeared in the literature, which demonstrated long-term fistula response to MTX i.v. 3.1.2.1. Meta-analysis and systematic reviews. No metaanalysis or systematic review has been published. 3.1.2.2. RCTs. In the Italian RCT [49], 54 patients with chronic active CD were randomised to receive MTX i.v. 25 mg/week, or oral AZA (2 mg/kg per day), for a 6-month follow-up period. Ten patients had perianal fistulas, four were treated with AZA, six with MTX. At 3 months, 50% of patients in the AZA group presented closure of the fistulas, compared to 67% of patients in the MTX group. At 6 months, only 25% of patients in the AZA group had closure of the fistulas in compared to 67% in the MTX group. 3.1.2.3. Uncontrolled studies. In a case series [60], 9 out of 16 patients (56%) with Crohn’s fistulas on MTX treatment at an initial dose of 25 mg/week i.m. for 3 months showed a complete (25%) or partial (31%) closure. All 16 patients had either failed or were intolerant to AZA. 3.2. UC A few studies have been carried out on the efficacy of MTX in the treatment of UC, frequently with conflicting results. An Israeli RCT, in 1996, showed no significant difference between MTX (12.5 mg/week orally) and placebo, in the induction and maintenance of remission in UC [61]. A dose of 15 mg (s.c. per week) was found to be effective in inducing remission in UC patients, in a RCT in 1999 [47]. Another RCT, in 2000, found oral MTX (15 mg/week) to be effective in inducing, but less in maintaining, remission in UC [48]. However, more comparative studies are needed before any definite conclusions could be drawn. 3.2.1. Induction and maintenance of remission 3.2.1.1. Meta-analysis and systematic reviews. No metaanalysis or systematic review has been published. 3.2.1.2. RCTs. In an early RCT, in 1996, 67 UC patients were randomised to receive oral MTX (12.5 mg week) or placebo for 9 months. Results showed no difference in the induction and maintenance of remission [61]. In a Spanish RCT, steroid-dependent IBD patients were randomised to receive 6-MP (1.5 mg/kg per day) or MTX (15 mg/week) orally or 5-ASA (3 g/day) added to prednisone. 6-MP or MTX could be effective in steroid-sparing, as well as in achieving remission in steroid-dependent IBD patients,

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but MTX is less effective in maintaining remission in UC patients [48]. A randomised dose–response study of MTX for refractory IBD in 1999, compared subcutaneous MTX (15 or 25 mg/ week) in 32 patients for 16 weeks. For induction of remission, initial doses of 15 or 25 mg were equally effective [47]. 3.2.1.3. Uncontrolled studies. In a clinical trial, oral MTX (15 mg/week) was given to eight refractory UC patients. The daily prednisone dose dropped from a mean of 26.3 ± 3.2 mg/day to 12.7 ± 2.0 mg/day (P < 0.001); three had a partial response [65]. An initial open-label study in 1989 showed that MTX induced remission in five out of seven patients with UC. None of these patients achieved endoscopic or histologic remission at 12 weeks [50]. An Italian open-label study was carried out comparing AZA (2 mg/kg per day) to MTX (12.5 mg/week i.m.) in the treatment of steroid-dependent and steroid-resistant UC. MTX administered for 6 months to patients intolerant or resistant to AZA-induced complete remission in 60% of patients and improvement in 40% [62]. A retrospective study showed that the remission rates (62%) and the maintenance of remission were similar in 22 UC patients and in 48 CD treated with a median dose of 20 mg of MTX (orally or i.m.) for 3 months [51]. 3.3. Side-effects In a systematic review [45], adverse effects were more common with high dose i.m. MTX therapy than with placebo. In the RCT by Feagan et al. [5] 16 out of 94 (17%) CD patients developed adverse events and 2 out of 16, severe adverse events (one optic neuritis and one pneumonia, probably due to mycoplasma). Patients in the MTX group had 2.6 such events per patient, as compared to 2.9 events per patient in the placebo group (P = 0.35). In the other RCTs [6,46–49] the rate of side-effects was between 11 and 44%. A charge number of patients developed nausea and vomiting. In three retrospective studies [51,52,54], treatment was discontinued in 10–18% of patients due to side-effects. A retrospective study [56] has also been carried out to evaluate the hepatic effects of long-term MTX treatment in patients with IBD and to determine whether the established guidelines for monitoring MTX-related hepatotoxicity with surveillance liver biopsy in patients with psoriasis [57,58] or rheumatoid arthritis [59] are applicable to these patients. Cumulative MTX ≥ 5410 mg given for up to 281 weeks in IBD patients are associated with little hepatotoxicity. Surveillance liver biopsies, based on cumulative doses, are not warranted in these patients. In a case series [60], 2 out of 33 CD patients (16 with fistulizing disease), treated with MTX developed severe adverse events (one hypersensitivity pneumonitis and one hepatic fibrosis, at liver biopsy).

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In the Israeli RCT, 2 out of 30 (6.7%) UC patients in MTX group were withdrawn from the study due to transient leukopenia and migraine [61]. In the Italian open-label study, only 2 out of 10 (20%) UC patients in MTX group developed mild adverse effects (nausea) [62]. A recent editorial has concluded that the limited efficacy of MTX together with its known toxicity relegates this drug to a third position for CD maintenance and remission [63]. Folate supplements are able to reduce the incidence of liver function test abnormalities and gastrointestinal side-effects without reducing therapeutic efficacy (data from treatment of rheumatoid arthritis). Folic acid, 5 mg/week, given 2 days after MTX or folic acid 1 mg daily for 5 days showed similar efficacy to folinic acid. It was concluded that folic acid supplements should be prescribed routinely to all patients receiving MTX [66–68].

4. CyA CyA is an immunosuppressive macrolide that inhibits the production of interleukin 2 (IL-2) by activated T lymphocytes and, therefore, the function of T helper cells through a calcineurin-dependent pathway. Thereafter, the recruitment of cytotoxic T-cell populations is inhibited as well as the release of other cytokines, such as IL-2 receptor, IL-3, IL4, interferon gamma (IFN␥), tumour necrosis factor-alpha (TNF␣), granulocyte–monocyte colony-stimulating factor (GM-CSF). 4.1. CD Results of studies on the effectiveness of CyA in patients with CD have been controversial. In two RCTs, the rate of remission in patients with chronic active CD was significantly better with CyA than with placebo [69,72], but in two other RCTs, no significative difference was found between CyA and placebo in inducing remission in CD patients [70,71]. 4.1.1. Induction and maintenance of remission 4.1.1.1. Meta-analysis and systematic reviews. No metaanalysis or systematic review has been published. 4.1.1.2. RCTs. A first RCT in patients with chronic active CD was performed in 1989. A group of 71 patients, resistant or intolerant to corticosteroids were treated with oral CyA (5–7.5 mg/kg per day) or placebo for 3 months. At the end of the treatment period, 22 of the 37 (59%) CyA-treated patients showed an improvement, compared with 11 of the 34 placebo-treated patients (32%) (P = 0.032) [69]. In a British multicentre RCT, 146 patients with chronic active CD, resistant to corticosteroids, were treated with oral CyA (5 mg/kg per day) or placebo in combination with pred-

nisolone (20 mg) for 3 months. No significant differences were observed between the two groups as far as clinical outcome, corticosteroid dosage, or changes in the activity indices were concerned [70]. In another RCT, 305 patients with chronic active CD were randomly assigned to receive low-dose oral CyA (151 patients, 2.5 mg twice a day, followed by 5 mg/kg per day after 1 week, increased as needed to a maximal dose of 15 mg/kg per day to reach a whole-blood concentration of 200 ng/ml) or placebo (154 patients) in addition to their usual therapy for a period of 18 months. More patients showed deterioration in their condition with CyA than with placebo (91 out of 151, or 60.3% versus 80 out of 154, or 51.9%; P = 0.10). Median time to worsening of disease was 338 days in the CyA group, as compared with 492 days in the placebo group [71]. In a multicentre RCT, 182 patients with chronic active CD were randomly treated with oral CyA (89 patients, 5 mg/kg per day) or placebo (93 patients), in addition to their usual therapy, for a period of 12 months. During CyA therapy, 35% of the patients achieved full remission (CDAI < 150) after 4 months, compared with 27% in the placebo group (P > 0.05). At 12 months, only 20% versus 20% of the patients had maintained continuous remission [72]. 4.1.1.3. Uncontrolled studies. In an open clinical trial, using an i.v. CyA dose of 4 mg/kg per day for 14 days and then switched to oral CyA 6–8 mg/day, a favourable response rate was observed in 88% of the 16 patients. Closure of fistulas occurred in 44% of these patients, and improvement was noted in another 44%. Two-thirds maintained improvement with oral CyA (6–8 mg/kg per day) [73]. In an open prospective trial, eight CD patients with acute steroid-refractory attacks were treated with CyA i.v. (5 mg/kg per day). Of these patients, six improved and were then switched to oral CyA. On oral CyA, five patients maintained remission, but after discontinuation of oral CyA they relapsed over a mean follow-up period of 18.6 months [74]. In an open clinical trial, 18 patients with refractory CD were initially treated with CyA i.v. (4 mg/kg per day). Four out of nine patients with severe inflammatory CD and seven out of nine with fistulizing CD showed a partial response to CyA i.v. The four patients showing a response in the inflammatory group and four of six in the fistulising group maintained or improved the response on oral CyA treatment [75]. In an open clinical trial, CyA i.v. (4 mg/kg per day) was effective in inducing remission or improvement in 12 out of 13 patients with steroid refractory IBD (six CD and seven UC). Of the 12 initial responders, nine relapsed during follow-up despite oral CyA (8 mg/kg per day) and underwent elective surgery [76]. In a Spanish open clinical trial, CyA i.v. (4 mg/kg per day) was administered in 23 patients with severe IBD refractory to steroids. Of the 15 UC patients, 10 achieved remission, and seven of these patients remained stable with mesalazine 4 months after CyA treatment. Of the eight CD patients, six

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achieved remission and remained stable with mesalazine for 4 months after CyA treatment [77]. In a retrospective chart analysis, 11 steroid-refractory pyoderma patients (five UC and six CD) received CyA i.v. at a dose of 4 mg/kg per day for 7–22 days, and were discharged on oral CyA (4–7 mg/kg per day). All 11 patients achieved closure of the pyoderma. All seven patients with bowel activity went into remission. None of these patients experienced significant toxicity [78]. In a case series, three patients with steroid-refractory UC and two patients with steroid-refractory CD who failed to respond to treatment with MTX, 25 mg/week for 16 weeks, were treated with the combination of MTX and low-dose oral CyA (3 mg/kg per day) for an additional 16 weeks. Both patients with CD withdrew from the study due to toxicity. The three patients with UC experienced clinical improvement [79]. 4.2. UC In the past decade, CyA i.v. at a dose of 4 mg/kg per day, in combination with steroids i.v., has become a standard therapy in severe steroid-resistant UC, sparing 60–90% of patients from urgent colectomy [7,74,84–86]. Some responders to CyA will ultimately relapse, but 30–50% will not require surgery during long-term follow-up [72,83,84,87,88], particularly if also established on AZA [84]. 4.2.1. Induction and maintenance of remission 4.2.1.1. Meta-analysis and systematic reviews. No metaanalysis or systematic review has been published. 4.2.1.2. RCTs. In the first, and only, randomised placebocontrolled trial, 20 patients with severe UC, unresponsive to glucocorticosteroids, were randomised to receive CyA, 4 mg/kg per day, in continuous infusion, or placebo in addition to the glucocorticosteroids for up to 14 days. Nine out of 11 patients (82%) receiving CyA improved after a mean period of 7 days compared with none of 9 patients on placebo (P < 0.001) [7]. In a RCT, 30 patients with severe UC were randomised to treatment with CyA i.v., 4 mg/kg per day, in continuous infusion or with methylprednisolone, 40 mg/day in 250 ml 0.9% NaCl. After 8 days, 8 out of 15 patients (53%) who received methylprednisolone showed a response to therapy versus 9 out of 14 (64%) receiving CyA and then switched to oral methylprednisolone, 32 mg/day, or to oral CyA, 8 mg/kg, respectively. Methylprednisolone was gradually tapered, and CyA was discontinued after 3–4 months, the time window for AZA (2–2.5 mg/kg per day orally) to start its delayed action. At 12 months, seven out of nine patients (78%) initially controlled with CyA maintained remission versus three out of eight (37%) initially treated with methylprednisolone [80]. In a recent RCT, 73 patients with severe UC were given 4 mg/kg versus 2 mg/kg i.v. CyA in continuous infusion. After 8 days, response rates were 84.2% (32 out of 38, 4 mg/kg)

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and 85.7% (32 out of 35, 2 mg/kg) after a median of 4 days in both groups. It was concluded that high-dose CyA i.v. did not offer any additional clinical benefit compared to the low dose in the treatment of severe UC [81]. In a RCT, 40 patients with mildly to moderately active leftsided UC were randomised to treatment with 350 mg CyA (n = 20) or placebo (n = 20) enemas. At 4 weeks, 8 out of 20 patients (40%) who received CyA showed a clinical improvement compared with nine out of 20 (45%) who received placebo. It was concluded that CyA enemas administered in a dosage of 350 mg/day for 4 weeks are not efficacious in mildly to moderately active left-sided UC [88]. 4.2.1.3. Uncontrolled studies. In an open clinical trial, eight patients with acute steroid-resistant UC, four of whom presented toxic megacolon, were treated with only 2 mg/kg CyA for 15 days. Of these eight patients, seven (87.5%), including three with megacolon, went into remission. Five (62.5%) remained in remission on 6 mg/kg oral CyA, for 6 months, and on leaving the chronic phase, CyA was slowly tapered and replaced by 1.5–2 mg/kg AZA [82]. In an open clinical trial, 16 patients refractory to methylprednisolone i.v. were treated with CyA i.v. (4 mg/kg per day) with an initial response rate of 69%. More than half (9/16) the patients will avoid colectomy long-term (mean duration of follow-up 21.6 months) when using triple immunosuppressive therapy including AZA (2 mg/kg), oral CyA and oral tapering steroids [83]. In an American open clinical trial, out of 42 patients with severe UC unresponsive to i.v. steroids and treated with CyA i.v. (4 mg/kg per day), 36 (86%) responded. Of the 36 initial responders, 25 (69%) also received 6-MP or AZA, and CyA and steroids were tapered. A total of 20% required colectomy, versus 45% of those not receiving 6-MP/AZA. Overall, 62% of all patients, 72% of initial CyA responders, and 80% of initial CyA responders receiving 6-MP/AZA have avoided colectomy [84]. In an open clinical trial, CyA i.v. (4 mg/kg per day) was effective in inducing remission or improvement in 12 out of 13 patients with steroid-refractory IBD (seven CD and six UC). Of the 12 initial responders, 9 relapsed during followup despite oral CyA (8 mg/kg per day) and underwent elective surgery [76]. In a Spanish open clinical trial, CyA i.v. (4 mg/kg per day) was administered to 23 patients with severe IBD refractory to steroids. Of the 15 UC patients, 10 achieved remission, and seven of these patients remained stable with mesalazine, 4 months after CyA treatment [77]. In a case series, three patients with steroid-refractory UC and two patients with steroid-refractory CD, who failed therapy with MTX, 25 mg/week for 16 weeks, were treated with a combination of MTX and low-dose oral CyA (3 mg/kg per day) for a further 16 weeks. The three patients with UC experienced clinical improvement [78]. In a retrospective chart analysis, 11 steroid-refractory pyoderma patients (five UC and six CD) received CyA i.v.

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(4–7 mg/kg perday). All 11 patients achieved closure of pyoderma. All seven patients with bowel activity went into remission. None of these patients experienced significant toxicity [79]. Several uncontrolled studies [85,86] confirmed the efficacy of CyA i.v. in patients with severe UC, refractory to glucocorticosteroid treatment. In a retrospective analysis, the records of patients with severe UC, unresponsive to steroids i.v. and treated with CyA i.v. were reviewed. A total of 27 responders following treatment with AZA, but without oral CyA as maintenance therapy, were included. Eighteen (75%) patients presented mild or moderate relapses, which were easily managed with 5ASA or steroids. Eleven (40.7%) patients underwent elective colectomy [87]. In a retrospective study, 31 patients with severe active UC received low-dose CyA i.v. (2 mg/kg per day) for a median period of 8 days. Only 11 patients received concomitant treatment with corticosteroids i.v. Twenty-four patients (77%) avoided urgent colectomy, and were discharged on oral CyA and AZA. After a median period of 18 months, 14 patients (45%) avoided colectomy [89]. In a retrospective analysis, nine steroid-dependent patients (prednisone 12–35 mg/day) with chronic active UC received oral microemulsion CyA (Neoral) at a dose of 5 mg/kg per day for 3 months and steroids were tapered according to the patient’s clinical condition. Of the nine patients, eight (89%) showed an initial response, and remission at the end of the third month was observed in five cases treated with steroids ≤15 mg/day [90]. In an open retrospective trial on 55 patients with acute steroid-resistant UC, 40 received Cya i.v. at a dose of 2 mg/kg per day for 14 days, with the responders being maintained on soft-gelatin-capsules of CyA at a dose of 6–8 mg/kg per day for 6 months; the remaining 15 received oral microemulsion CyA (Neoral), 5 mg/kg per day for 3 months. Results showed 100% of the patients receiving oral microemulsion CyA, and 65% of those receiving the i.v regimen achieved short-term remission (P = 0.011). Of the patients with CyA i.v., 17 developed major toxicity, including one fatality, whereas no major toxicity was observed in the microemulsion CyA group [91]. In an open trial, 10 patients presenting a steroid-refractory attack of UC and one patient with indeterminate colitis received oral microemulsion CyA (Neoral) (7–7.5 mg/kg per day). Nine patients (82%) presented a favourable response in a mean time of 3.6 days. It was concluded that oral microemulsion CyA (Neoral) is an effective drug in the initial management of patients presenting from a steroid-refractory attack of UC and indeterminate colitis [92]. In an open trial, 12 out of 13 patients with severe UC refractory to prednisone i.v. (1 mg/kg per day) went into remission after adding CyA i.v. (4 mg/kg per day) and then immediately started AZA plus mesalazine. The relapse rate on mainteinance therapy with AZA was 10% [93].

4.3. Side-effects Use of CyA is associated with considerable morbidity. Severe complications such as Pneumocystis carinii pneumonia (prophylaxis with sulfamethoxazole-trimethoprim should be included as part of the treatment protocol) and seizures may occur in as many as 12% of patients and even death has been reported [74,84]. In the British and the Canadian RCTs, 10 out of 72 (13.9%) and 22 out of 151 (14.6%) CD patients, respectively, withdrew from trials because of severe side-effects (hypertension, increase in serum creatinine levels, paresthesia, headache, hypertrichosis) [70,71]. Minor side-effects, including hypertension, liver and renal impairment, tremor, paraesthesiae and headache, occur in ≤50% of patients [7,69,85]. In the European trial [72], 84 of the 89 (95%) CD patients developed adverse effects (31% paresthesia, 24% hypertrichosis, 11% back pain). Three patients withdrew from the trial on account of severe adverse effects (one renal dysfunction with increases in serum creatinine levels, one depression, one septicaemia) and seven patients due to minor adverse events (hypertrichosis, paresthesia, nausea, headache and bronchopneumonia).

5. Tacrolimus Tacrolimus (FK 506) is a calcineurin inhibitor with immunosuppressive properties similar to those of cyclosporine. However, tacrolimus is better absorbed, even by diseased small bowel [94]. Tacrolimus is widely used in organ transplant patients. Uncontrolled studies have reported that tacrolimus is efficacious, in combination with AZA or 6-MP treatment, in some patients with refractory UC and CD [95]. Tacrolimus combined with perianal surgery has been shown to be an effective therapy for refractory perianal CD and may have a role as “bridging” therapy to long-term maintenance treatment with AZA or 6-MP [96]. No studies have been carried out so far on maintenance treatment with tacrolimus. To date, several clinical trials including also one RCT have provided encouraging results in the case of IBD. 5.1. Meta-analysis and systematic reviews No meta-analysis or systematic review has been published. 5.2. RCTs In one randomised, double-blind, placebo-controlled, multicentre clinical trial, 48 patients with CD and draining perianal or enterocutaneous fistulas were randomised to treatment with oral tacrolimus (0.2 mg/kg per day) or placebo for 10 weeks. The primary outcome measure was fistula improvement, as defined by closure of ≥50% of fistulas that

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were draining at baseline and in which closure was maintained for at least 4 weeks. A secondary outcome measure was fistula remission as defined by closure of all fistulas and maintenance of that closure for at least 4 weeks. Results showed that 43% of tacrolimus-treated patients presented fistula improvement compared with 8% of placebo-treated patients (P = 0.004). Of the tacrolimus-treated patients showing improvement, 10% had fistula remission compared with 8% of the placebo-treated patients (P = 0.86) [97]. 5.3. Uncontrolled studies In a prospective, open-label, uncontrolled study, 13 steroid-resistent CD patients were treated long-term with oral tacrolimus, aimed both at resolving the acute attacks and maintaining remission. Tacrolimus was administered at the dose of 0.1–0.2 mg/kg per day and adjusted in order to achieve levels of 5–10 ng/ml; only mesalazine was continued concomitantly. Steroids and total parenteral nutrition were tapered when appropriate. Median treatment was 27.3 months. Only one patient withdrew from the study due to adverse events. CDAI score decreased significantly after 6 months in 11 patients, for being maintained at 1 year in nine of them, and at 7 years in two of them. The IBD life-quality (IBDQoL) questionnaire score significantly increased over the same periods. A marked drop in hospitalisations was also recorded. In three out of six patients, complete closure of fistulas was achieved. Tacrolimus allowed total parenteral nutrition to be withdrawn in three out of five patients. Supplementation with low-dose steroids was required in five patients. Two patients underwent surgery [98]. In a prospective, open-label, non-controlled trial, tacrolimus was used in IBD patients. Inclusion criteria were perianal CD (PCD), CD in rectal stump, pouchitis and cuffitis with severely impaired function of the ileoanal pouch, and proven refractoriness to other therapies. Clinical assessment included Hughes’ classification (PCD), Oresland index (OI) in IPAA, endoscopy–biopsy and Quality of life (QoL) using the Spanish version of the IBDQ. Response was determined as complete (CR), partial (PR) or non-existent (NR). Tacrolimus was administered orally at a dose of 0.1 mg/kg per day (levels 5–15 g/l) to the 19 patients entered in the study. Mean duration of treatment was 9.6 ± 6.3 months. In PCD, CR was achieved in 66% of cases and PR in 33%, with disappearance of inflammation, stenosis and ulcers. In patients with pouchitis and cuffitis, 77% presented either CR or PR. The OI scores and QoL improved significantly after treatment (P < 0.006 and P < 0.002, respectively). Adverse effects were minor and controlled by regulating the treatment dose [99]. In an open-label, multicentre trial, oral tacrolimus was evaluated in 14 patients with steroid-refractory severe colitis. Patients not responding to conventional therapy received tacrolimus, 0.1 mg/kg per dose given twice a day, and the dosage was adjusted to achieve blood levels between 10 and 15 ng/ml. Response was defined as an improvement in a num-

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ber of clinical parameters (including abdominal pain, diarrhoea, rectal bleeding and cessation of transfusions). Patients who responded by 14 days continued to receive tacrolimus, and 6-MP or AZA was added as a steroid-sparing agent, 4–6 weeks after the tacrolimus was commenced. One patient elected to withdraw after 48 h. Of the 13 remaining, 9 (69%) responded and were discharged. Tacrolimus was continued for 2–3 months in the responders, except in one patient who received tacrolimus for 11 months. At 1-year follow-up, only five (38%) patients were receiving maintenance therapy; the other four responders had undergone colectomy. Although tacrolimus is effective induction therapy for severe UC or CD, fewer than 50% of treated patients will successfully achieve long-term remission [100]. 5.4. Side-effects Until now, the use of tacrolimus in CD has been limited to a few cases and for a short time period as a “bridge” to other immunosuppressants. Tacrolimus has an adverse effect profile similar to CyA, and may cause renal insufficiency.

6. MMF MMF is an ester prodrug of mycophenolic acid that inhibits inosine monophosphate dehydrogenase and potently suppresses lymphocyte proliferation [101]. The drug is routinely used in clinical transplantation but several studies have suggested it could be useful in various autoimmune diseases including rheumatoid arthritis, psoriasis, refractory uveitis, IgA nephrophaty, retroperitoneal fibrosis and pemfigus vulgaris. There is conflicting evidence regarding the response to MMF of IBD patients [102]. To date, several clinical trials, including of two RCTs, have provided contradictory results in the case of IBD. 6.1. Meta-analysis and systematic reviews No meta-analysis or systematic review has been published. 6.2. RCTs In the only randomised prospective trial, 70 chronically active CD patients were treated with prednisolone and either MMF (15 mg/kg per day) or AZA (2.5 mg/kg per day) and thereafter, these patients were followed for 6 months. MMF and AZA had a comparable impact on disease activity, although in a subgroup of patients with more severe disease (CDAI > 300), MMF appeared to decrease the clinical activity more rapidly than AZA. Treatment with MMF/cortisone was associated with some adverse effects [103].

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6.3. Uncontrolled studies An open-label prospective and uncontrolled multicentre 6-month trial of MMF in combination with steroids was carried out on 24 chronic active IBD patients. The treatment consisted of a steroid pulse and tapering protocol in combination with MMF (2 g/day). A prednisone dose of 5 mg/day was maintained for 4–6 months. The primary end-point was induction and maintenance of remission. Only 10 out of 24 patients had achieved remission after 3 months. All but one CD patient had relapsed by the end of the study at 6 months. In conclusion, MMF 2 g/day was unable to induce and maintain remission for a period of 6 months in 23 out of 24 chronic active IBD patients [104]. In a multicentric and retrospective trial, the efficacy and tolerance of MMF was assessed in 20 patients with refractory CD. All had been treated with AZA and/or MTX. The daily dose of MMF was 750 mg to 2 g for a median period of 4 months (range: 4 days–21 months). Response to MMF was determined according to the Harvey-Bradshaw index <4 and the possibility to taper steroids. In this small cohort of 20 patients with refractory CD, either intolerant or non-responders to AZA or MTX, treatment with MMF resulted in only 20% success. Intolerance to MMF was observed in 25% of patients [105]. In a randomised open study, comparison of the efficacy and safety of treatment with MMF/prednisolone versus standard immunosuppressive treatment with AZA/prednisolone was evaluated in patients with chronic active UC. In this study, 24 patients with active UC (Rachmilewitz score ≥ 6 points) were randomly assigned to the MMF (20 mg/kg)/prednisolone or AZA (2 mg/kg)/prednisolone group. The rates of remission were higher in the AZA/prednisolone group (n = 12) than in the MMF/prednisolone group (n = 12) throughout the study. Remission rates were 92% versus 67% after 4 weeks, 92% versus 67% after 3 months, 92% versus 67% after 6 months, 83% versus 78% after 9 months, and 100% versus 88% after 1 year. The number of patients not requiring steroids was higher in the AZA/prednisolone group than in the MMF/prednisolone group. In the MMF/prednisolone group, two severe adverse events were observed (recurrent upper airway infections, bacterial meningitis) [106]. 6.4. Side-effects It is important to recognise the toxicity of this drug. MMF has primarily adverse gastrointestinal effects. In the near future, the therapeutic efficacy needs to be confirmed by prospective randomised double-blind trials. 7. Thalidomide The use of thalidomide has been abandoned since the 1960s due to its teratogenic effects [107]. Over the last few years the drug has been reproposed on account of its efficacy in the treatment of several inflammatory and autoimmune

disorders, including erythema nodosum leprosum, Bechet’s syndrome [108], rheumathoid arthritis [109], discoid lupus erythematosus and CD. It is also effective in the treatment of graft versus host disease in bone marrow transplantation and aphthous ulceration in HIV infection. Thalidomide is believed to exert its anti-inflammatory effects, at least in part, by inhibiting TNF-␣ production by monocytes and by the degradation of its mRNA. Thalidomide is also known to inhibit angiogenesis, and it has several other well-described immunomodulatory properties. Today, it has become a promising drug in a wide variety of disorders in which TNF-␣ seems to play a pivotal role, including IBD. There are no controlled studies. In this field, several case reports and clinical trials [110–115] have demonstrated that thalidomide is emerging as an effective alternative in the treatment of selected patients with refractory CD. Previously, refractory CD patients respond to thalidomide, and many enter clinical remission. The beneficial results are usually evident within 4 weeks. Thalidomide also has steroid-sparing properties, and is particularly useful in treating oral and fistulous complications of CD. Although it is usually well tolerated, careful monitoring is recommended to avoid toxicity, such as birth defects and peripheral neuropathy. 7.1. Uncontrolled studies In an open-label trial [110], 22 patients with refractory CD (CDAI > 200 and/or draining perianal disease) were treated with thalidomide 200 mg (18 patients) or 300 mg (four patients) at bedtime for ≤12 weeks. The mean CDAI in this study population at entry was 371. Of the 22 patients, 9 had luminal disease and 15 had perianal disease. A total of 14 patients (5 luminal and 9 perianal) completed 12 weeks of therapy and all were classified as responders. Nine patients achieved clinical remission, three patients in the luminal group and six in the fistula group. The median CDAI score was 175. Three patients (21%) were able to discontinue steroid therapy. In another American open-label trial [111], 12 adult male CD patients with CDAI scores of ≥250 and ≤500 despite ≥20 mg prednisone/day were enrolled: the first six patients received 50 mg thalidomide every night; the next six received 100 mg every night. The steroid doses were stable during the first 4 weeks of treatment, then tapered over weeks 5–12. The median CDAI at the start of thalidomide therapy was 322. Ten of the 12 patients completed the 12-week course of treatment. Disease activity improved in all patients during weeks 1–4: 58% response, 17% remission. During weeks 5–12, the clinical improvement was generally maintained. All patients were able to reduce steroids by ≥50%, while 44% of patients discontinued steroids. Seven out of 10 (70%) patients were responders at 12 weeks, and two of these patients achieved remission (20%). No apparent dose–response was noted between the higher- and lower-dose thalidomide groups.

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In an Italian study on children and young adults [112], thalidomide was administered to five male CD patients, intolerant or resistant to conventional medical treatment or as the last medical resort before surgery. The drug was given at night at a dose of 1.5–2 mg/kg per day. Disease activity decreased consistently in four out of five patients after 3 months of treatment. Steroid treatment (mean dose, 35 mg before treatment) was tapered and then discontinued in four patients within 1–3 months. Four patients were in remission after 19–24 months of treatment. In an Australian study [113], 11 patients (nine males, mean age 33 years) with IBD (six CD, four UC and one indeterminate colitis) symptomatic despite standard medical therapy received a daily dose of thalidomide for 12 weeks in an open-label protocol. Nine patients completed the 12 weeks of treatment with eight (five CD, two UC and one IC) showing a marked clinical response, while one CD patient had no response. The mean CDAI decreased from 117 to 48. Endoscopic inflammatory and histological grade, C-reactive protein and erythrocyte sedimentation rate (ESR) all decreased significantly (P = 0.011, P = 0.03, P = 0.023 and P = 0.044, respectively). In a French study [114], 15 CD patients with severe refractory disease (10 females, five males; mean age, 40 years; seven out of 15 with fistulising disease) were started on thalidomide (100 mg/day), 29 ± 10 days after responding to infliximab (5 mg/kg infusions). The median follow-up period was 238 days (range 10–458) from the start of thalidomide. The median CDAI scores were 322, 119 and 35 before infliximab, at the start of thalidomide and at the end of follow-up, respectively. Remission rates on thalidomide were 92, 83 and 83% at 3, 6 and 12 months, respectively, after the last infliximab infusion. In an American open-label study [115], four CD patients (two with fistulae) received 200 mg of thalidomide every night. One patient with a single perirectal fistula achieved complete closure by 4 weeks; the other showed a marked improvement in 5 perianal fistulae at 4 weeks. In one luminal patient CDAI decreased by 250 points in 4 weeks. Two patients (one luminal, one fistula) continued thalidomide after the 3-month study period and remained in remission at 5 and 7 months. 7.2. Side-effects In an open-label trial [110], three patients had to discontinue thalidomide on account of severe adverse effects, including one with a diffuse rash and two with excessive sedation. All patients reported sedative side-effects and indeed nine patients required a dose reduction on account of sedation. Other side-effects included constipation, mild hypertension, seborrhoea and neuropathy. In another American open-label trial [111], withdrawal of thalidomide was not necessary due to an adverse event in any of the patients. Drowsiness was the most common adverse event occurring in 7 out of 12 patients. Other adverse events

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included peripheral neuropathy (five patients), oedema (two patients) and dermatitis (one patient). In an Italian study [112], only one out of five CD patients discontinued thalidomide after 1 week of treatment due to distal paresthesia. In an Australian study [113], two patients withdrew at 3 weeks on account of mood disturbances. Side-effects included mild sedation, xerostomia and skin dryness in all, constipation in three, and minor abnormalities in nerve conduction in one patient. In a French study [114], four CD patients (two in remission) stopped thalidomide for suspected adverse effects. Sideeffects (drowsiness, rash and peripheral neuropathy) were mild and mostly transient. In an American open-label study [115], one CD patient withdrew secondary to sedation after only one week of treatment. Side-effects reported were sedation (four out of four patients), hypertension (one out of four), and peripheral neuropathy (one out of four). Despite reports of relatively mild side-effects in these studies, with increased use of this drugs and less careful surveillance side-effects could likely increase in frequency and severity with the possibility of an unexpected pregnancy and the potentially devastating consequences [116]. Conflict of interest statement None declared.

Acknowledgements We are indebted with the following members of the Italian Group for Inflammatory Bowel Disease (IG-IBD) for their comments and suggestions in the preparation of this review. V. Annese (S. Giovanni Rotondo, FG), S. Ardizzone (Milano), L. Biancone (Roma), F. Castiglione (Napoli), M. Cottone (Palermo), G. Meucci (Milano), P. Paoluzi (Roma), C. Papi (Roma), G. Sturniolo (Padova), M. Vecchi (Milano).

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