- Email: [email protected]
The use of immunosuppressive drugs in IBD: RAND or random choice?
Digestive and Liver Disease 37 (2005) 391–393
Commentary
The use of immunosuppressive drugs in IBD: RAND or random choice? S. Vermeire ∗ University Hospital Gasthuisberg, Division of Gastroenterology, Herestraat 49, 3000 Leuven, Belgium Available online 9 March 2005 See related article on pages 407–417
Patients with inflammatory bowel disease (IBD) often need extensive treatment as a consequence of the chronic nature of their disease. Although many novel biological therapies have been introduced in the last decennium, the older immunosuppressive drugs azathioprine (AZA), 6-mercaptopurine (6-MP), methotrexate (MTX) and cyclosporine (CyA) are still widely prescribed for Crohn’s disease (CD) or ulcerative colitis (UC). Their use in several indications is supported by solid controlled studies, however, for a number of other scenarios, only few and uncontrolled studies exist and these indications still form a matter of debate. In the study by Caprilli et al. [1], a panel of Italian IBDexperts assessed the appropriateness of immunosuppressive drugs in the treatment of IBD by using the RAND method. This method consists of a combination of evidence obtained from the literature together with experts’ opinion, with the assumption that scientific evidence is superior over experts’ opinion. A list of 2781 clinical scenarios or indications was grouped into 13 major categories. Each indication was scored individually on a scale from 1 (=extremely inappropriate) to 9 (=extremely appropriate). A scenario was rated as appropriate if the median score of the individual panellists was 7–9 (without disagreement) and inappropriate if the median score was 1–3 (without disagreement). Overall, 76.8% of scenarios were graded as either appropriate (7.6%) or inappropriate (69.2%). Disagreement, defined as the presence of both low scores (1–3 or inappropriate) and high scores (7–9 or appropriate) for the same scenario was seen in 5% (138/1211) of all indications and was not related to any category in particular. It is not clear what the experts did when there was disagreement. Was a compromise reached or did they agree upon the final decision of the promoter centre?
∗
Tel.: +32 16 34 42 18; fax: +32 16 34 43 99. E-mail address: [email protected].
The authors need to be congratulated for the considerable amount of work. The conclusions reached by the experts were evidence-based and were supplemented by experts’ opinion where no scientific evidence was available. The overall conclusion from this study was that only AZA, 6-MP and MTX are appropriate in the treatment of IBD. CyA was rated appropriate only in the treatment of severe UC after failure of steroids and in some rare cases of extra-intestinal manifestations as pyoderma gangrenosum. Besides the above-mentioned immunosuppressive drugs, thalidomide, tacrolimus (FK506) and mycophenolate mofetil (MMF) were also evaluated, but were rated as inappropriate by the experts. Although the RAND method gives an additive value to simple evidence-based guidelines, there are certain aspects to take into account. Since expert’s opinion is mainly dependent on the experts themselves, these experts should be selected from different backgrounds and should be representative in this case for the Italian gastroenterologists. The physicians that took part in the RAND panel consisted of IBD-specialists from non-academic as well as from academic centres from the different geographical regions in North and South of Italy. Therefore, the conclusions should reflect the opinion of the Italian GI community. One can only speculate if the guidelines would have been more favourable for certain indications (e.g. MTX use) if the same assignment was given to a different (e.g. Canadian?) panel of IBDspecialists. An example of experts’ opinion is provided in the scenario for severe CD. The experts rate AZA and 6-MP appropriate in severe CD regardless of previous infliximab use or outcome. MTX on the other hand is rated appropriate in this indication only if previous IFX was successful. This difference between both immunosuppressive drugs is based on experts’ opinion mainly since only very few studies exist that compare AZA with MTX. However, an Italian study performed by some of
1590-8658/$30 © 2005 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.dld.2005.02.002
392
S. Vermeire / Digestive and Liver Disease 37 (2005) 391–393
the co-authors of the present manuscript evaluated the efficacy and safety of MTX in comparison with AZA in patients with chronic active CD [2]. All patients were given methylprednisolone and were randomised to MTX 25 mg/week IV or AZA 2 mg/(kg day) orally, for a 6-month follow-up period. After 3 months, MTX was switched to oral administration maintaining the same dose. In the 54 patients assigned to MTX (n = 27) or AZA (n = 27), no statistically significant difference was found between the two treatment regimens with respect to remission rate after 6 months (MTX 56%, AZA 63%, p = 0.39, 95% CI: 0.187–0.335). To come back to the proposed guidelines, the large randomised ACCENT studies and the Targan and Present trials on infliximab also did not show a difference between concomitant therapy with AZA or MTX [3–6]. There are a number of indications, which have been given rather poor attention. One of these is fistulising CD. Management of fistulising CD differs greatly. Whereas a simple and low perianal fistula can easily be treated by antibiotics (±fistulotomy) and does not require immunosuppressive therapy, severe complex fistulas almost always need placement of setons, and treatment with immunosuppressive drugs and infliximab. This distinction is not entirely clear from reading the manuscript. Second, although other immunosuppressive drugs were rated inappropriate for this indication, there are studies supporting a role for tacrolimus, MTX or CyA. The recent placebo-controlled study by Sandborn et al. [7] randomised 48 patients with perianal or enterocutaneous fistulas to treatment with oral tacrolimus 0.2 mg/(kg day) or placebo for 10 weeks. Forty-three percent of patients treated with tacrolimus showed fistula improvement compared to only 8% in the group treated with placebo (p = 0.004). However, it must be said that side effects (neftrotoxicity, headache, insomnia, paresthesias and tremor) are at this moment still an obstacle for the use of tacrolimus. Given that side effects in most cases can easily be managed with dose reduction, lower doses need to be studied. A number of open non-controlled studies have also been performed with CyA, showing improvement in up to 80–90% of patients [8–12]. However, early relapses are seen in almost all patients upon discontinuation. Last, there is also evidence that MTX would be appropriate for the treatment of fistulas [13]. In a case series of 16 patients with fistulas, 56% of patients showed a complete (25%) or partial (31%) response to MTX therapy and all had failed or were intolerant to 6-MP. Therefore, MTX and tacrolimus might be appropriate in selected cases of fistulas refractory to AZA and/or infliximab and the appropriateness of these drugs maybe better rated as uncertain until more controlled studies are available. Another comment relates to the indication AZA-intolerant or -resistant patients. The definition of drug failure according to the manuscript was defined as either intolerance to AZA or no response to treatment. If a patient develops a severe side effect to AZA, this is of course a true failure. However, it is not entirely clear how strict the definition of no response was? A patient who did not receive the appropriate dose or
was not given the drug long enough cannot be called a failure. Further, the fact that 6-MP was rated inappropriate in AZA intolerant patients may not be true for all patients. A large number of patients intolerant to AZA (especially because of gastrointestinal side effects) will tolerate 6-MP. There is no discussion that the use of 6-MP in patients experiencing other side effects to AZA as pancreatitis is inappropriate. CyA was rated appropriate only in the treatment of severe UC after failure of steroids. D’Haens et al. [14] previously showed that cyclosporine in monotherapy is also efficacious in severe UC. In this study, patients with a severe attack of UC were randomised to receive cyclosporine IV or methylprednisolone 40 mg/day. After 1 week, 8/15 (53%) of patients who received methylprednisolone showed improvement versus 9/14 (64%) of patients receiving cyclosporine. At 12 months, 7/9 (78%) initially controlled with cyclosporine maintained their remission versus 3/8 (37%) initially treated with methylprednisolone. Therefore, there might be an indication to start CyA first-line in severe UC in selected patients who show substantial side effects to steroids. A final comment includes the appropriateness of thalidomide. Thalidomide is a strong anti-emetic and sedative drug, which was prescribed in the late 1950s to pregnant women for the treatment of morning sickness. The drug was withdrawn from the market in 1961 after reports of teratogenicity and birth defects. Thalidomide has thereafter generated new interest due to its immunomodulatory properties including an anti-TNF␣ effect and an anti-angiogenic action. The efficacy of thalidomide in IBD is not proven in controlled studies but there have been several open label studies, which have included more than 50 patients in total [15–17]. The response observed with thalidomide in these studies mounts to more than 80%. There have also been several reports on the efficacy of thalidomide in patients with serious aphtous stomatitis [18]. The optimal dose of thalidomide still needs to be defined in order to minimise side effects (peripheral neuropathy and deep vein thrombosis in particular). In conclusion, although thalidomide cannot be rated as appropriate at this moment given the lack of controlled studies, the drug may however be useful in a selected subgroup of patients. In conclusion, this is a solid and comprehensible work that is useful and helpful for gastroenterologists, internists and surgeons when dealing with the management of IBD patients. Nevertheless, it can be anticipated that the position of these immunosuppressive drugs will need to be updated in a couple of years given the rapid developments in medicine and the introduction of novel treatments. AZA, 6-MP and MTX have proven their efficacy already. For other immunosuppressive drugs as thalidomide and tacrolimus, their position remains uncertain at this moment but these drugs might be useful in selected patients. Conflict of interest statement None declared.
S. Vermeire / Digestive and Liver Disease 37 (2005) 391–393
References [1] Caprilli RE, Angelucci A, Cocco A, Viscido V, Annese S, Ardizzone L, et al. Appropriateness of immunosuppressive drugs in inflammatory bowel diseases assessed by RAND method: Italian Group for IBD (IG-IBD) position statement. Dig Liver Dis 2005;37:407– 17. [2] Ardizzone S, Bollani S, Manzionna G, Imbesi V, Colombo E, Bianchi Porro G, et al. Comparison between methotrexate and azathioprine in the treatment of chronic active Crohn’s disease: a randomised, investigator-blind study. Dig Liver Dis 2003;35:619–27. [3] 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. [4] 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. [5] Hanauer SB, et al., ACCENT I Study Group. Maintenance infliximab for Crohn’s disease: the ACCENT I randomised trial. Lancet 2002;359:1541–9. [6] Sands BE, Anderson FH, Bernstein CN, Chey WY, Feagan BG, Fedorak RN, et al. Infliximab maintenance therapy for fistulizing Crohn’s disease. N Engl J Med 2004;350:876–85. [7] Sandborn WJ, Present DH, Isaacs KL, Wolf DC, Greenberg E, Hanauer SB, et al. Tacrolimus for the treatment of fistulas in patients with Crohn’s disease: a randomized, placebo-controlled trial. Gastroenterology 2003;125:380–8. [8] Hanauer SB, Smith MB. Rapid closure of Crohn’s disease fistulas with continuous intravenous cyclosporine A. Am J Gastroenterol 1993;88:646–9. [9] Present DH, Lichtiger S. Efficacy of cyclosporine in treatment of fistula of Crohn’s disease. Dig Dis Sci 1994;39:374–80.
393
[10] Hinterleitner TA, Petritsch W, Aichbichler B, Fickert P, Ranner G, Krejs GJ. Combination of cyclosporine, azathioprine and prednisolone for perianal fistulas in Crohn’s disease. Z Gastroenterol 1997;35:603–8. [11] Egan LJ, Sandborn WJ, Tremaine WJ. Clinical outcome following treatment of refractory inflammatory and fistulizing Crohn’s disease with intravenous cyclosporine. Am J Gastroenterol 1998;93: 442–8. [12] Markowitz J, Grancher K, Mandel F, Daum F. Immunosuppressive therapy in pediatric inflammatory bowel disease: results of a survey of the North American Society for Pediatric Gastroenterology and Nutrition. Subcommittee on immunosuppressive use of the pediatric IBD collaborative research forum. Am J Gastroenterol 1993;88:44–8. [13] Mahadevan U, Marion JF, Present DH. Fistula response to methotrexate in Crohn’s disease: a case series. Aliment Pharmacol Ther 2003;18:1003–8. [14] D’Haens G, Lemmens L, Geboes K, Vandeputte L, Van Acker F, Mortelmans L, et al. Intravenous cyclosporine versus intravenous corticosteroids as single therapy for severe attacks of ulcerative colitis. Gastroenterology 2001;120:1323–9. [15] 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. [16] 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. [17] 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 fistulising refractory Crohn’s disease. Aliment Pharmacol Ther 2002;16:1117–24. [18] Eisen D, Lynch DP. Selecting topical and systemic agents for recurrent aphtous stomatitis. Cutis 2001;68:201–6.
Commentary
The use of immunosuppressive drugs in IBD: RAND or random choice? S. Vermeire ∗ University Hospital Gasthuisberg, Division of Gastroenterology, Herestraat 49, 3000 Leuven, Belgium Available online 9 March 2005 See related article on pages 407–417
Patients with inflammatory bowel disease (IBD) often need extensive treatment as a consequence of the chronic nature of their disease. Although many novel biological therapies have been introduced in the last decennium, the older immunosuppressive drugs azathioprine (AZA), 6-mercaptopurine (6-MP), methotrexate (MTX) and cyclosporine (CyA) are still widely prescribed for Crohn’s disease (CD) or ulcerative colitis (UC). Their use in several indications is supported by solid controlled studies, however, for a number of other scenarios, only few and uncontrolled studies exist and these indications still form a matter of debate. In the study by Caprilli et al. [1], a panel of Italian IBDexperts assessed the appropriateness of immunosuppressive drugs in the treatment of IBD by using the RAND method. This method consists of a combination of evidence obtained from the literature together with experts’ opinion, with the assumption that scientific evidence is superior over experts’ opinion. A list of 2781 clinical scenarios or indications was grouped into 13 major categories. Each indication was scored individually on a scale from 1 (=extremely inappropriate) to 9 (=extremely appropriate). A scenario was rated as appropriate if the median score of the individual panellists was 7–9 (without disagreement) and inappropriate if the median score was 1–3 (without disagreement). Overall, 76.8% of scenarios were graded as either appropriate (7.6%) or inappropriate (69.2%). Disagreement, defined as the presence of both low scores (1–3 or inappropriate) and high scores (7–9 or appropriate) for the same scenario was seen in 5% (138/1211) of all indications and was not related to any category in particular. It is not clear what the experts did when there was disagreement. Was a compromise reached or did they agree upon the final decision of the promoter centre?
∗
Tel.: +32 16 34 42 18; fax: +32 16 34 43 99. E-mail address: [email protected].
The authors need to be congratulated for the considerable amount of work. The conclusions reached by the experts were evidence-based and were supplemented by experts’ opinion where no scientific evidence was available. The overall conclusion from this study was that only AZA, 6-MP and MTX are appropriate in the treatment of IBD. CyA was rated appropriate only in the treatment of severe UC after failure of steroids and in some rare cases of extra-intestinal manifestations as pyoderma gangrenosum. Besides the above-mentioned immunosuppressive drugs, thalidomide, tacrolimus (FK506) and mycophenolate mofetil (MMF) were also evaluated, but were rated as inappropriate by the experts. Although the RAND method gives an additive value to simple evidence-based guidelines, there are certain aspects to take into account. Since expert’s opinion is mainly dependent on the experts themselves, these experts should be selected from different backgrounds and should be representative in this case for the Italian gastroenterologists. The physicians that took part in the RAND panel consisted of IBD-specialists from non-academic as well as from academic centres from the different geographical regions in North and South of Italy. Therefore, the conclusions should reflect the opinion of the Italian GI community. One can only speculate if the guidelines would have been more favourable for certain indications (e.g. MTX use) if the same assignment was given to a different (e.g. Canadian?) panel of IBDspecialists. An example of experts’ opinion is provided in the scenario for severe CD. The experts rate AZA and 6-MP appropriate in severe CD regardless of previous infliximab use or outcome. MTX on the other hand is rated appropriate in this indication only if previous IFX was successful. This difference between both immunosuppressive drugs is based on experts’ opinion mainly since only very few studies exist that compare AZA with MTX. However, an Italian study performed by some of
1590-8658/$30 © 2005 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.dld.2005.02.002
392
S. Vermeire / Digestive and Liver Disease 37 (2005) 391–393
the co-authors of the present manuscript evaluated the efficacy and safety of MTX in comparison with AZA in patients with chronic active CD [2]. All patients were given methylprednisolone and were randomised to MTX 25 mg/week IV or AZA 2 mg/(kg day) orally, for a 6-month follow-up period. After 3 months, MTX was switched to oral administration maintaining the same dose. In the 54 patients assigned to MTX (n = 27) or AZA (n = 27), no statistically significant difference was found between the two treatment regimens with respect to remission rate after 6 months (MTX 56%, AZA 63%, p = 0.39, 95% CI: 0.187–0.335). To come back to the proposed guidelines, the large randomised ACCENT studies and the Targan and Present trials on infliximab also did not show a difference between concomitant therapy with AZA or MTX [3–6]. There are a number of indications, which have been given rather poor attention. One of these is fistulising CD. Management of fistulising CD differs greatly. Whereas a simple and low perianal fistula can easily be treated by antibiotics (±fistulotomy) and does not require immunosuppressive therapy, severe complex fistulas almost always need placement of setons, and treatment with immunosuppressive drugs and infliximab. This distinction is not entirely clear from reading the manuscript. Second, although other immunosuppressive drugs were rated inappropriate for this indication, there are studies supporting a role for tacrolimus, MTX or CyA. The recent placebo-controlled study by Sandborn et al. [7] randomised 48 patients with perianal or enterocutaneous fistulas to treatment with oral tacrolimus 0.2 mg/(kg day) or placebo for 10 weeks. Forty-three percent of patients treated with tacrolimus showed fistula improvement compared to only 8% in the group treated with placebo (p = 0.004). However, it must be said that side effects (neftrotoxicity, headache, insomnia, paresthesias and tremor) are at this moment still an obstacle for the use of tacrolimus. Given that side effects in most cases can easily be managed with dose reduction, lower doses need to be studied. A number of open non-controlled studies have also been performed with CyA, showing improvement in up to 80–90% of patients [8–12]. However, early relapses are seen in almost all patients upon discontinuation. Last, there is also evidence that MTX would be appropriate for the treatment of fistulas [13]. In a case series of 16 patients with fistulas, 56% of patients showed a complete (25%) or partial (31%) response to MTX therapy and all had failed or were intolerant to 6-MP. Therefore, MTX and tacrolimus might be appropriate in selected cases of fistulas refractory to AZA and/or infliximab and the appropriateness of these drugs maybe better rated as uncertain until more controlled studies are available. Another comment relates to the indication AZA-intolerant or -resistant patients. The definition of drug failure according to the manuscript was defined as either intolerance to AZA or no response to treatment. If a patient develops a severe side effect to AZA, this is of course a true failure. However, it is not entirely clear how strict the definition of no response was? A patient who did not receive the appropriate dose or
was not given the drug long enough cannot be called a failure. Further, the fact that 6-MP was rated inappropriate in AZA intolerant patients may not be true for all patients. A large number of patients intolerant to AZA (especially because of gastrointestinal side effects) will tolerate 6-MP. There is no discussion that the use of 6-MP in patients experiencing other side effects to AZA as pancreatitis is inappropriate. CyA was rated appropriate only in the treatment of severe UC after failure of steroids. D’Haens et al. [14] previously showed that cyclosporine in monotherapy is also efficacious in severe UC. In this study, patients with a severe attack of UC were randomised to receive cyclosporine IV or methylprednisolone 40 mg/day. After 1 week, 8/15 (53%) of patients who received methylprednisolone showed improvement versus 9/14 (64%) of patients receiving cyclosporine. At 12 months, 7/9 (78%) initially controlled with cyclosporine maintained their remission versus 3/8 (37%) initially treated with methylprednisolone. Therefore, there might be an indication to start CyA first-line in severe UC in selected patients who show substantial side effects to steroids. A final comment includes the appropriateness of thalidomide. Thalidomide is a strong anti-emetic and sedative drug, which was prescribed in the late 1950s to pregnant women for the treatment of morning sickness. The drug was withdrawn from the market in 1961 after reports of teratogenicity and birth defects. Thalidomide has thereafter generated new interest due to its immunomodulatory properties including an anti-TNF␣ effect and an anti-angiogenic action. The efficacy of thalidomide in IBD is not proven in controlled studies but there have been several open label studies, which have included more than 50 patients in total [15–17]. The response observed with thalidomide in these studies mounts to more than 80%. There have also been several reports on the efficacy of thalidomide in patients with serious aphtous stomatitis [18]. The optimal dose of thalidomide still needs to be defined in order to minimise side effects (peripheral neuropathy and deep vein thrombosis in particular). In conclusion, although thalidomide cannot be rated as appropriate at this moment given the lack of controlled studies, the drug may however be useful in a selected subgroup of patients. In conclusion, this is a solid and comprehensible work that is useful and helpful for gastroenterologists, internists and surgeons when dealing with the management of IBD patients. Nevertheless, it can be anticipated that the position of these immunosuppressive drugs will need to be updated in a couple of years given the rapid developments in medicine and the introduction of novel treatments. AZA, 6-MP and MTX have proven their efficacy already. For other immunosuppressive drugs as thalidomide and tacrolimus, their position remains uncertain at this moment but these drugs might be useful in selected patients. Conflict of interest statement None declared.
S. Vermeire / Digestive and Liver Disease 37 (2005) 391–393
References [1] Caprilli RE, Angelucci A, Cocco A, Viscido V, Annese S, Ardizzone L, et al. Appropriateness of immunosuppressive drugs in inflammatory bowel diseases assessed by RAND method: Italian Group for IBD (IG-IBD) position statement. Dig Liver Dis 2005;37:407– 17. [2] Ardizzone S, Bollani S, Manzionna G, Imbesi V, Colombo E, Bianchi Porro G, et al. Comparison between methotrexate and azathioprine in the treatment of chronic active Crohn’s disease: a randomised, investigator-blind study. Dig Liver Dis 2003;35:619–27. [3] 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. [4] 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. [5] Hanauer SB, et al., ACCENT I Study Group. Maintenance infliximab for Crohn’s disease: the ACCENT I randomised trial. Lancet 2002;359:1541–9. [6] Sands BE, Anderson FH, Bernstein CN, Chey WY, Feagan BG, Fedorak RN, et al. Infliximab maintenance therapy for fistulizing Crohn’s disease. N Engl J Med 2004;350:876–85. [7] Sandborn WJ, Present DH, Isaacs KL, Wolf DC, Greenberg E, Hanauer SB, et al. Tacrolimus for the treatment of fistulas in patients with Crohn’s disease: a randomized, placebo-controlled trial. Gastroenterology 2003;125:380–8. [8] Hanauer SB, Smith MB. Rapid closure of Crohn’s disease fistulas with continuous intravenous cyclosporine A. Am J Gastroenterol 1993;88:646–9. [9] Present DH, Lichtiger S. Efficacy of cyclosporine in treatment of fistula of Crohn’s disease. Dig Dis Sci 1994;39:374–80.
393
[10] Hinterleitner TA, Petritsch W, Aichbichler B, Fickert P, Ranner G, Krejs GJ. Combination of cyclosporine, azathioprine and prednisolone for perianal fistulas in Crohn’s disease. Z Gastroenterol 1997;35:603–8. [11] Egan LJ, Sandborn WJ, Tremaine WJ. Clinical outcome following treatment of refractory inflammatory and fistulizing Crohn’s disease with intravenous cyclosporine. Am J Gastroenterol 1998;93: 442–8. [12] Markowitz J, Grancher K, Mandel F, Daum F. Immunosuppressive therapy in pediatric inflammatory bowel disease: results of a survey of the North American Society for Pediatric Gastroenterology and Nutrition. Subcommittee on immunosuppressive use of the pediatric IBD collaborative research forum. Am J Gastroenterol 1993;88:44–8. [13] Mahadevan U, Marion JF, Present DH. Fistula response to methotrexate in Crohn’s disease: a case series. Aliment Pharmacol Ther 2003;18:1003–8. [14] D’Haens G, Lemmens L, Geboes K, Vandeputte L, Van Acker F, Mortelmans L, et al. Intravenous cyclosporine versus intravenous corticosteroids as single therapy for severe attacks of ulcerative colitis. Gastroenterology 2001;120:1323–9. [15] 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. [16] 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. [17] 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 fistulising refractory Crohn’s disease. Aliment Pharmacol Ther 2002;16:1117–24. [18] Eisen D, Lynch DP. Selecting topical and systemic agents for recurrent aphtous stomatitis. Cutis 2001;68:201–6.