Journal of Crohn's and Colitis, 2015, 303–304 doi:10.1093/ecco-jcc/jjv038 Editorial Editorial Methotrexate in IBD: The Return of the Prodigal Son Twenty years ago, Brian Feagan and colleagues proved the efficacy of parenteral methotrexate [MTX; 25 mg per week] as an induction therapy in steroid-dependent Crohn’ disease [CD].1 Five years later, they showed that MTX also maintains remission in patients who had reached remission with this drug.2 Since then, the efficacy of MTX has been somewhat eclipsed by the compelling advent of biologics. However, safety and cost of CD therapies remain key issues. Biologics are cost-prohibitive and have a strong impact on healthcare expenditures. In this context, there is a need for alternative, safe and inexpensive drugs in CD as well as in ulcerative colitis [UC]. In these respects, MTX is competitive. MTX has been used for decades in the treatment of Wegeners’ disease, psoriasis, and rheumatoid arthritis. Its safety profile is well known. Side effects of MTX include nausea, vomiting, fatigue, diarrhea leukopenia, liver fibrosis, hypersensitivity pneumonitis, and teratogenicity. Oral folic acid [5 mg per week] can reduce the severity of side effects, particulary leukopenia and gastrointestinal symptoms. Yet, it is fair to say that many patients have nausea and fatigue, even after the maintenance dose has been reduced and split. Nonetheless, severe side effects are rare. The risk of cancer associated with methotrexate therapy has been assessed in patients with rheumatoid arthritis [RA] and most studies have found that it was not increased.3 These results compare favorably with those observed with thiopurines (alone or combined with anti-tumor necrosis factor [anti-TNF]),4,5 which increase the risk of lymphoma, non-melanoma skin cancer, and acute myeloid leukemias and myelodysplastic syndromes.6,7,8 Methotrexate is inexpensive. Inflammatory bowel disease [IBD] incidence continues to rise, particularly in countries of southern and eastern Europe as well as in the Middle East, North Africa, India, and Brazil.9,10,11,12 Not all these countries will be able to afford the cost of biologics. Recent papers, including two published in this issue of JCC, and ongoing studies renew the interest in MTX in IBD. The paper by Haisma et al. is based upon a multicenter retrospective cohort of 130 paediatric patients who had failed thiopurines and were prescribed MTX as a maintenance therapy. Twelve months after initiation of MTX, 52% of the patients were relapse free, decreasing to 29% after 24 months. There was no difference in efficacy between children who were intolerant and those who failed to respond to thiopurines. The paper by Colman et al. is based upon a retrospective chart review of 88 IBD patients who received a combination therapy consisting in anti-TNF and methotrexate at a dose of 15–25 mg/week or less than ≤ 12.5 mg/week. The 46 patients who had reached clinical remission were followed up. The relapse rate was significantly higher in patients who had received the low dose as compared with those who had received the high dose of MTX. The rate of adverse events leading to discontinuation of MTX was similar in the two groups. Analogous results have been observed in rheumatoid arthritis.13 The recently published COMMIT trial compared the efficacy of infliximab + placebo versus infliximab + MTX in patients with CD. There was no difference between the two groups as regard to clinical efficacy [primary endpoint].14 It is possible that the highdose steroids prescribed in all included patients confounded the beneficial effect of combotherapy. Yet, COMMIT did show that patients randomized to the MTX + infliximab arm had a lower rate of immunogenicity and higher trough levels of infliximab. Prevention of immunization against the drug is crucial in patients who receive anti-TNF. Most studies concerning MTX in inflammatory bowel disease were performed in CD patients, and very few were conducted in UC. Until recently, no controlled trial had tested parenteral MTX at the dose of 25 mg/week in UC patients. The METEOR trial (NCT00498589), a European prospective, placebo-controlled, randomized trial, did so in steroid-dependent patients. The study has been completed and the results will be submitted soon. The MEthotrexate Response In Treatment of Ulcerative Colitis trial (MERIT-UC [NCT01393405]) is a US prospective, placebo-controlled, randomized trial that tests the efficacy of MTX as a maintenance treatment in UC patients who have responded to MTX. The study is still enrolling patients. MTX is a safe and inexpensive drug. In CD patients, it is an efficient drug in monotherapy and it prevents immunization when associated with an anti-TNF. It can be prescribed to CD patients who have failed or become intolerant to thiopurines. It is now recommended as a first-line immunosuppressive therapy in Epstein-Barr virus- [EBV-] naive CD patients [ECCO malignancy consensus 2015, in preparation]. Due to its safety profile, it can also be employed as the first-line immunosuppressive, either alone or in combination with biologics, in women and men who do not wish to conceive. Results concerning UC patients will be published soon. Thibaut Vaysse and Franck Carbonnel Service de Gastroentérologie, Hôpital universitaire de Bicêtre, Université Paris Sud, Assistance Publique-Hôpitaux de Paris, le Kremlin Bicêtre, Paris, France Corresponding author: Franck Carbonnel; Email: fcarbonnel7@ gmail.com Conflict of interest None declared. Copyright © 2015 European Crohn's and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: [email protected] 303 304 References 1. Feagan BG, Rochon J, Fedorak RN, et al. Methotrexate for the treatment of Crohn’s disease. The North American Crohn’s Study Group Investigators. N Engl J Med 1995;332:292–9. 2. Feagan BG, Fedorak RN, Irvine EJ, et al. A comparison of methotrexate with placebo for the maintenance of remission in Crohn’s disease. North American Crohn’s Study Group Investigators. N Engl J Med 2000;342:1627–32. 3. Mariette X, Cazals-Hatem D, Warszawki J, et al. Lymphomas in rheumatoid arthritis patients treated with methotrexate: a 3-year prospective study in France. Blood 2002;99:3909–15. 4. Nyboe Andersen N, Pasternak B, Basit S, et al. Association between tumor necrosis factor-α antagonists and risk of cancer in patients with inflammatory bowel disease. JAMA 2014;311:2406–13. 5. Osterman MT, Sandborn WJ, Colombel J-F, et al. Increased risk of malignancy with adalimumab combination therapy, compared with monotherapy, for Crohn’s disease. Gastroenterology 2014;146:941–9. 6. Beaugerie L, Brousse N, Bouvier AM, et al. Lymphoproliferative disorders in patients receiving thiopurines for inflammatory bowel disease: a prospective observational cohort study. Lancet 2009;374:1617–25. 7. Peyrin-Biroulet L, Khosrotehrani K, Carrat F, et al. Cesame Study Group. Increased risk for nonmelanoma skin cancers in patients who receive thiopurines for inflammatory bowel disease. Gastroenterology 2011;14:1621–8 T. Vaysse and F. Carbonnel 8. Lopez A, Mounier M, Bouvier AM, et al. CESAME Study Group. Increased risk of acute myeloid leukemias and myelodysplastic syndromes in patients who received thiopurine treatment for inflammatory bowel disease. Clin Gastroenterol Hepatol 2014;12:1324–9 9. Ng SC, Bernstein CN, Vatn MH, et al. Geographical variability and environmental risk factors in inflammatory bowel disease. Gut 2013;62:630– 49. 10.Baumgart DC, Bernstein CN, Abbas Z, et al. IBD around the world: comparing the epidemiology, diagnosis, and treatment: proceedings of the World Digestive Health Day 2010 Inflammatory Bowel Disease Task Force meeting. Inflamm Bowel Dis 2011;17:639–44. 11.Ahuja V, Tandon RK. Inflammatory bowel disease in the Asia-Pacific area: a comparison with developed countries and regional differences. J Dig Dis 2010;11:134–47. 12.Parente JML, Coy CSR, Campelo V, et al. Inflammatory bowel disease in an underdeveloped region of Northeastern Brazil. World J Gastroenterol 2015;21:1197–206. 13.Burmester G-R, Kivitz AJ, Kupper H, et al. Efficacy and safety of ascending methotrexate dose in combination with adalimumab: the randomised CONCERTO trial. Ann Rheum Dis 2014; Feb 18. doi: 10.1136/annrheumdis-2013-204769. [Epub ahead of print]. 14.Feagan BG, McDonald JWD, Panaccione R, et al. Methotrexate in combination with infliximab is no more effective than infliximab alone in patients with Crohn’s disease. Gastroenterology 2014;146:681–8.
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