European experience with methotrexate treatment in Crohn’s disease: a multicenter retrospective analysis Uri Kopylov a,b, *, Konstantinos H. Katsanos d, *, Christien Janneke van der Woude h , Konstantinos Karmiris e , Vicent Hernandez i , Selwyn Odes c , Konstantinos Papamichael f , Ioannis E. Koutroubakis g , Daniela Bojic j,k , Ioannis Kaimakliotis l , Gionata Fiorino m , Neofytos Papageorgiou a,b , Juan R. Pineda i , Konstantina Strongili b , Luciano Sanroman i , Gerassimos J. Mantzaris f , Njegica Jojic j,k , Gregorios Paspatis e , Dimitrios K. Christodoulou d , Shomron Ben-Horin a,b and Epameinondas V. Tsianos d Introduction Methotrexate (MTX) has been utilized for the treatment of Crohn’s disease (CD) for decades. Nevertheless, current data provide equivocal evidence on the efficacy of MTX in CD. The aims of this study were to describe the efficacy of MTX for maintenance of remission in CD and to identify the factors associated with the probability of steroid-free clinical remission in a multicenter European referral center cohort. Patients and methods This was a retrospective cohort analysis. Consecutive patients treated with MTX for CD were included from 11 referral centers. Patients receiving concomitant treatment with tumor necrosis factor inhibitors or thiopurines were excluded. The main outcome was steroid-free clinical remission; the secondary outcomes included the rate of complications leading to MTX discontinuation and duration of relapse-free survival in patients achieving the main outcome. Results Between July 1992 and January 2012, 118 patients were identified for inclusion. MTX administration route was oral for induction in 31.4% and for maintenance in 49.1% of the patients. Steroid-free remission was achieved in 44/118 (37.2%) patients and was maintained relapse free by 28/44 (63.6%) for a median of 12 (3.5–18.5) months. At least one adverse effect was reported by 28.9% of the patients. No clinical or demographic factors were associated with either likelihood of achieving a clinical response or duration of relapse-free survival. Conclusion MTX treatment induced steroid-free clinical remission in over a third of CD patients and maintained it for a year in almost two-thirds of the responders. MTX should be considered a viable therapeutic option in CD patients refractory to other therapies. Eur J Gastroenterol Hepatol 00:000–000 Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved. Introduction Methotrexate (MTX) is an analog of folic acid; MTX acts mainly by the inhibition of dihydrofolate reductase, the enzyme involved in the de-novo synthetic pathway for purines and pyrimidines [1,2]. Over the last 25 years, multiple studies have described the efficacy of MTX in the treatment of Crohn’s disease (CD). The first major study to show the efficacy of intramuscular MTX for induction of remission in both CD and ulcerative colitis was published by Kozarek et al. [3]. A first small randomized-controlled trial [4] failed to show the superiority of low-dose oral MTX over mercaptopurine or placebo. In a large rando- mized multicenter study, intramuscular MTX (25 mg/ week) was superior to placebo for induction of remission and reduction of prednisone requirements [5]. A recent Cochrane group review suggested that intramuscular MTX (25 mg/week) provides a benefit for induction of remission and complete withdrawal of steroids in patients with refractory CD, whereas lower dose oral MTX does not appear to provide any significant benefit over placebo [6]. For maintenance treatment, this review suggested that intramuscular MTX at a dose of 15 mg/week is superior to placebo for maintenance of remission in CD, whereas low- dose oral MTX (12.5–15 mg/week) does not appear to be effective [7]. Despite our extensive experience with MTX, the data are still relatively sparse and more studies are required to elucidate its role in the management of CD patients in the biologic era. The aim of the current study was to describe our experience with MTX for CD in a large multicenter European referral center cohort. a Department of Gastroenterology, Sheba Medical Center, Ramat Gan, b Sackler Medical School, Tel-Aviv University, Tel-Aviv, c Department of Gastroenterology and Hepatology, Ben-Gurion University of the Negev, Beer Sheva, Israel, d Division of Gastroenterology, University of Ioannina, Ioannina, e Department of Gastroenterology, Venizeleio General Hospital, Heraklion, f First Department of Gastroenterology, Evangelismos Hospital, Athens, g Department of Gastroenterology, University Hospital Heraklion, Crete, Greece, h Department of Gastroenterology and Hepatology, Erasmus MC, Rotterdam, The Netherlands, i Department of Gastroenterology, Instituto de Investigacion Biomedica Ourense- Pontevedra-Vigo, Xerencia Xestion Integrada de Vigo, Spain, j Department of Gastroenterology and Hepatology, Zvezdara University Clinical Centre, Zvezdara, k Medical Faculty, University of Belgrade, Belgrade, Serbia, l Central IBD Clinic, Nicosia, Cyprus and m IBD Center, Department of Gastroenterology, Humanitas Research Hospital, Milan, Italy *Uri Kopylov and Konstantinos H. Katsanos contributed equally to the writing of this article. Correspondence to Uri Kopylov, MD, Department of Gastroenterology, Sheba Medical Center, Tel-Hashomer, Ramat Gan, 5296100 Israel Tel: +97235303660; fax: +97235302661; e-mail: ukopylov@gmail.com Received 7 December 2015 Accepted 14 January 2016 European Journal of Gastroenterology & Hepatology 2016, 00:000–000 Keywords: Crohn’s disease, methotrexate, steroid-free remission ’ Original article 0954-691X Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved. DOI: 10.1097/MEG.0000000000000609 1 Copyright r 2016 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.