title: Methotrexate Is Not Superior to Placebo for Inducing Steroid-Free Remission, but Induces Steroid-Free Clinical Remission in a Larger Proportion of Patients With Ulcerative Colitis.
abstract: OBJECTIVE
  Parenteral methotrexate is an effective treatment for patients with Crohn's disease, but has never been adequately evaluated in patients with ulcerative colitis (UC). We conducted a randomized controlled trial to determine its safety and efficacy in patients with steroid-dependent UC.
  
  
  METHODS
  We performed a double-blind, placebo-controlled trial to evaluate the efficacy of parenteral methotrexate (25 mg/wk) in 111 patients with corticosteroid-dependent UC at 26 medical centers in Europe from 2007 through 2013. Patients were given prednisone (10 to 40 mg/d) when the study began and were randomly assigned to groups (1:1) given placebo or methotrexate (intramuscularly or subcutaneously, 25 mg weekly) for 24 weeks. The primary end point was steroid-free remission (defined as a Mayo score ≤2 with no item >1 and complete withdrawal of steroids) at week 16. Secondary endpoints included clinical remission (defined as a Mayo clinical subscore ≤2 with no item >1) and endoscopic healing without steroids at weeks 16 and/or 24, remission without steroids at week 24, and remission at both weeks 16 and 24.
  
  
  RESULTS
  Steroid-free remission at week 16 was achieved by 19 of 60 patients given methotrexate (31.7%) and 10 of 51 patients given placebo (19.6%)--a difference of 12.1% (95% confidence interval [CI]: -4.0% to 28.1%; P = .15). The proportion of patients in steroid-free clinical remission at week 16 was 41.7% in the methotrexate group and 23.5% in the placebo group, for a difference of 18.1% (95% CI: 1.1% to 35.2%; P = .04). The proportions of patients with steroid-free endoscopic healing at week 16 were 35% in the methotrexate group and 25.5% in the placebo group--a difference of 9.5% (95% CI: -7.5% to 26.5%; P = .28). No differences were observed in other secondary end points. More patients receiving placebo discontinued the study because of adverse events (47.1%), mostly caused by UC, than patients receiving methotrexate (26.7%; P = .03). A higher proportion of patients in the methotrexate group had nausea and vomiting (21.7%) than in the placebo group (3.9%; P = .006).
  
  
  CONCLUSIONS
  In a randomized controlled trial, parenteral methotrexate was not superior to placebo for induction of steroid-free remission in patients with UC. However, methotrexate induced clinical remission without steroids in a significantly larger percentage of patients, resulting in fewer withdrawals from therapy due to active UC. ClinicalTrials.gov ID NCT00498589.
authors.affiliation: CHU de Bicêtre, Service de Gastroentérologie, APHP-Université Paris Sud, Le Kremlin Bicêtre, France; CHU de Besançon, Hôpital Jean Minjoz, Service de Gastroentérologie, Besançon, France. Electronic address: fcarbonnel7@gmail.com.
authors.forename: Franck
authors.initials: F
authors.lastname: Carbonnel
authors.affiliation: Helmsley Inflammatory Bowel Disease Center, Icahn Medical School of Medicine at Mount Sinai, New York, New York.
authors.forename: Jean Frédéric
authors.initials: JF
authors.lastname: Colombel
authors.affiliation: CHU de Nice, Hôpital de l'Archet 2, Service de Gastroentérologie et Nutrition Clinique, Nice, France.
authors.forename: Jérome
authors.initials: J
authors.lastname: Filippi
authors.affiliation: Department of Gastroenterology, School of Medical Sciences, University of Ioannina, Ioannina, Greece.
authors.forename: Konstantinos H
authors.initials: KH
authors.lastname: Katsanos
authors.affiliation: Inserm U954 and Department of Gastroenterology, Université de Lorraine, Vandoeuvre-les-Nancy, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Peyrin-Biroulet
authors.affiliation: Hôpital Saint-Louis, Service d'Hépato-Gastroentérologie, APHP-Université Paris VII, Paris, France.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Allez
authors.affiliation: CHU de Besançon, Hôpital Jean Minjoz, Service de Gastroentérologie, Besançon, France; CHRU de Lille, Hôpital Claude Huriez, Service des Maladies de L'Appareil Digestif-Endoscopie Digestive, Lille, France.
authors.forename: Maria
authors.initials: M
authors.lastname: Nachury
authors.affiliation: Medizinische Universität Wien, Universitätsklinik für Innere Medizin III Klinische Abteilung für Gastroenterologie und Hepatologie, Währinger Gürtel, Wien, Austria.
authors.forename: Gottfried
authors.initials: G
authors.lastname: Novacek
authors.affiliation: Department of Gastroenterology Istituto Clinico Humanitas, Rozzano, Milan, Italy.
authors.forename: Silvio
authors.initials: S
authors.lastname: Danese
authors.affiliation: CHU Cochin, Service de Gastroentérologie, APHP-Paris, France.
authors.forename: Vered
authors.initials: V
authors.lastname: Abitbol
authors.affiliation: Division of Gastroenterology, Casa Sollievo della Sofferenza Hospital IRCCS, San Giovanni Rotondo, Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Bossa
authors.affiliation: CHU de Toulouse, Hôpital Rangueil, Service de Gastro-Entérologie et Nutrition, Toulouse, France.
authors.forename: Jacques
authors.initials: J
authors.lastname: Moreau
authors.affiliation: CHU Clermont-Ferrand, Service Hépatologie-Gastro-Entérologie, Clermont-Ferrand, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Bommelaer
authors.affiliation: CHU de Nantes, Hôtel-Dieu, Hépato-Gastroentérologie, Institut des Maladies de l'Appareil Digestif, Nantes, France.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Bourreille
authors.affiliation: CHU Amiens, Hôpital Nord, service d'Hépato-Gastroentérologie, Amiens, France.
authors.forename: Mathurin
authors.initials: M
authors.lastname: Fumery
authors.affiliation: CHU de Saint-Etienne, Hôpital Nord, Service de Gastro-Entérologie et Hépatologie, Saint-Etienne, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Roblin
authors.affiliation: Medizinische Universität Wien, Universitätsklinik für Innere Medizin III Klinische Abteilung für Gastroenterologie und Hepatologie, Währinger Gürtel, Wien, Austria; Department of Internal Medicine, McMaster University, Hamilton Ontario, Canada.
authors.forename: Walter
authors.initials: W
authors.lastname: Reinisch
authors.affiliation: Hôpital Beaujon, Gastroentérologie, MICI et Assistance Nutritive, APHP-Université Paris VII, Clichy, France.
authors.forename: Yoram
authors.initials: Y
authors.lastname: Bouhnik
authors.affiliation: Hôpital Robert Debré, Service de Gastroentérologie, Reims, France.
authors.forename: Hedia
authors.initials: H
authors.lastname: Brixi
authors.affiliation: Hôpital St-Antoine, Service de Gastroentérologie, Paris, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Seksik
authors.affiliation: Université Paris Descartes-Sorbonne Paris Centre, Gastroenterology Department, Hôpital Européen Georges Pompidou APHP, Paris, France.
authors.forename: Georgia
authors.initials: G
authors.lastname: Malamut
authors.affiliation: Helsinki University, and Helsinki University Central Hospital, Clinic of Gastroenterology, Helsinki, Finland.
authors.forename: Martti
authors.initials: M
authors.lastname: Färkkilä
authors.affiliation: Service de Gastro-Entérologie, Centre Hospitalier d' Avignon, Avignon, France.
authors.forename: Baya
authors.initials: B
authors.lastname: Coulibaly
authors.affiliation: UCL Saint Luc, Service de Gastroentérologie, Brussels, Belgium.
authors.forename: Olivier
authors.initials: O
authors.lastname: Dewit
authors.affiliation: Department of Gastroenterology, University Hospital CHU of Liège, Liège, Belgium.
authors.forename: Edouard
authors.initials: E
authors.lastname: Louis
authors.affiliation: Université Lille, CHRU Lille, Inserm, Lille, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Deplanque
authors.affiliation: Gastroenterology La Source-Beaulieu and Division of Gastroenterology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
authors.forename: Pierre
authors.initials: P
authors.lastname: Michetti
authors.affiliation: Public Health, Epidemiology and Economic Health, Registre Epimad, Maison Régionale de la Recherche Clinique and Biostatistics Unit and Lille Inflammation Research International Center LIRIC, Université Lille, Lille, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Sarter
authors.affiliation: CHU de Bordeaux, Hôpital Haut-Lévêque, Service d'Hépato-Gastroentérologie, Université Bordeaux, Laboratoire de Bactériologie, Bordeaux, France.
authors.forename: David
authors.initials: D
authors.lastname: Laharie
mesh_terms: D000305:Adrenal Cortex Hormones / Q000009:adverse effects / Q000627:therapeutic use*; D000328:Adult; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D003093:Colitis, Ulcerative / Q000175:diagnosis / Q000188:drug therapy*; D003106:Colon / Q000187:drug effects* / Q000473:pathology; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005060:Europe; D005260:Female; D005765:Gastrointestinal Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D007273:Injections, Intramuscular; D007279:Injections, Subcutaneous; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D008875:Middle Aged; D012074:Remission Induction; D013997:Time Factors; D016896:Treatment Outcome; D014945:Wound Healing / Q000187:drug effects
chemical_list: D000305:Adrenal Cortex Hormones; D000893:Anti-Inflammatory Agents; D005765:Gastrointestinal Agents; D008727:Methotrexate
keywords: Clinical Trial; Drug; IBD; Methotrexate