title: Folic acid and folinic acid for reducing side effects in patients receiving methotrexate for rheumatoid arthritis.
abstract: OBJECTIVE
  To perform a systematic review of the benefits and harms of folic acid and folinic acid in reducing the mucosal, gastrointestinal, hepatic, and hematologic side effects of methotrexate (MTX); and to assess whether folic or folinic acid supplementation has any effect on MTX benefit.
  
  
  METHODS
  We searched the Cochrane Library, MEDLINE, EMBASE, and US National Institutes of Health clinical trials registry from inception to March 2012. We selected all double-blind, randomized, placebo-controlled clinical trials in which adult patients with rheumatoid arthritis (RA) were treated with MTX (dose ≤ 25 mg/week) concurrently with folate supplementation. We included only trials using low-dose folic or folinic acid (a starting dose of ≤ 7 mg weekly) because the high dose is no longer recommended or used. Data were extracted from the trials, and the trials were independently assessed for risk of bias using a predetermined set of criteria.
  
  
  RESULTS
  Six trials with 624 patients were eligible for inclusion. Most studies had low or unclear risk of bias for key domains. The quality of the evidence was rated as "moderate" for each outcome as assessed by the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) working group, with the exception of hematologic side effects, which were rated as "low." There was no significant heterogeneity between trials, including where folic acid and folinic acid studies were pooled. For patients supplemented with any form of exogenous folate (either folic or folinic acid) while receiving MTX therapy for RA, a 26% relative (9% absolute) risk reduction was seen for the incidence of gastrointestinal side effects such as nausea, vomiting, or abdominal pain (RR 0.74, 95% CI 0.59 to 0.92; p = 0.008). Folic and folinic acid also appear to be protective against abnormal serum transaminase elevation caused by MTX, with a 76.9% relative (16% absolute) risk reduction (RR 0.23, 95% CI 0.15 to 0.34; p < 0.00001), as well as reducing patient withdrawal from MTX for any reason [60.8% relative (15.2% absolute) risk reduction, RR 0.39, 95% CI 0.28 to 0.53; p < 0.00001].
  
  
  CONCLUSIONS
  The results support a protective effect of supplementation with either folic or folinic acid for patients with RA during treatment with MTX. There was a clinically important significant reduction shown in the incidence of GI side effects and hepatic dysfunction (as measured by elevated serum transaminase levels), as well as a clinically important significant reduction in discontinuation of MTX treatment for any reason.
authors.affiliation: From the Bruyère Research Institute (BRI); Centre for Global Health, Institute of Population Health, University of Ottawa, Ottawa, ON, Canada; Epidemiological Research Center, National Academy of Medicine, Buenos Aires, Argentina; Rheumatology Division, Department of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand; Cochrane Musculoskeletal Group, Ottawa; Institute for Work and Health, Toronto; Department of Epidemiology and Community Medicine, and the Department of Medicine, Faculty of Medicine, University of Ottawa; Ottawa Hospital Research Institute, Clinical Epidemiology Program; Institute of Population Health and Department of Epidemiology and Community Medicine, University of Ottawa, Ottawa, ON, Canada.B. Shea, PhD, MSc, RN, BRI, Department of Epidemiology and Community Medicine, University of Ottawa; M.V. Swinden, MBBS; E. Tanjong Ghogomu, MD, MSc, Centre for Global Health, Institute of Population Health, University of Ottawa; Z. Ortiz, MD, MSc, Epidemiological Research Center, National Academy of Medicine; W. Katchamart, MD, FRCP, MSc, Rheumatology Division, Department of Medicine, Siriraj Hospital, Mahidol University; T. Rader, MLIS, Cochrane Musculoskeletal Group; C. Bombardier, MD, FRCPC, Institute for Work and Health; G.A. Wells, PhD, MSc, Department of Epidemiology and Community Medicine, University of Ottawa; P. Tugwell, MD, FRCPC, MSc, Department of Medicine, Faculty of Medicine, Institute of Population Health and Department of Epidemiology and Community Medicine, University of Ottawa; and Ottawa Hospital Research Institute, Clinical Epidemiology Program. bevshea@uottawa.ca.
authors.forename: Beverley
authors.initials: B
authors.lastname: Shea
authors.affiliation: From the Bruyère Research Institute (BRI); Centre for Global Health, Institute of Population Health, University of Ottawa, Ottawa, ON, Canada; Epidemiological Research Center, National Academy of Medicine, Buenos Aires, Argentina; Rheumatology Division, Department of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand; Cochrane Musculoskeletal Group, Ottawa; Institute for Work and Health, Toronto; Department of Epidemiology and Community Medicine, and the Department of Medicine, Faculty of Medicine, University of Ottawa; Ottawa Hospital Research Institute, Clinical Epidemiology Program; Institute of Population Health and Department of Epidemiology and Community Medicine, University of Ottawa, Ottawa, ON, Canada.B. Shea, PhD, MSc, RN, BRI, Department of Epidemiology and Community Medicine, University of Ottawa; M.V. Swinden, MBBS; E. Tanjong Ghogomu, MD, MSc, Centre for Global Health, Institute of Population Health, University of Ottawa; Z. Ortiz, MD, MSc, Epidemiological Research Center, National Academy of Medicine; W. Katchamart, MD, FRCP, MSc, Rheumatology Division, Department of Medicine, Siriraj Hospital, Mahidol University; T. Rader, MLIS, Cochrane Musculoskeletal Group; C. Bombardier, MD, FRCPC, Institute for Work and Health; G.A. Wells, PhD, MSc, Department of Epidemiology and Community Medicine, University of Ottawa; P. Tugwell, MD, FRCPC, MSc, Department of Medicine, Faculty of Medicine, Institute of Population Health and Department of Epidemiology and Community Medicine, University of Ottawa; and Ottawa Hospital Research Institute, Clinical Epidemiology Program.
authors.forename: Michael V
authors.initials: MV
authors.lastname: Swinden
authors.affiliation: From the Bruyère Research Institute (BRI); Centre for Global Health, Institute of Population Health, University of Ottawa, Ottawa, ON, Canada; Epidemiological Research Center, National Academy of Medicine, Buenos Aires, Argentina; Rheumatology Division, Department of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand; Cochrane Musculoskeletal Group, Ottawa; Institute for Work and Health, Toronto; Department of Epidemiology and Community Medicine, and the Department of Medicine, Faculty of Medicine, University of Ottawa; Ottawa Hospital Research Institute, Clinical Epidemiology Program; Institute of Population Health and Department of Epidemiology and Community Medicine, University of Ottawa, Ottawa, ON, Canada.B. Shea, PhD, MSc, RN, BRI, Department of Epidemiology and Community Medicine, University of Ottawa; M.V. Swinden, MBBS; E. Tanjong Ghogomu, MD, MSc, Centre for Global Health, Institute of Population Health, University of Ottawa; Z. Ortiz, MD, MSc, Epidemiological Research Center, National Academy of Medicine; W. Katchamart, MD, FRCP, MSc, Rheumatology Division, Department of Medicine, Siriraj Hospital, Mahidol University; T. Rader, MLIS, Cochrane Musculoskeletal Group; C. Bombardier, MD, FRCPC, Institute for Work and Health; G.A. Wells, PhD, MSc, Department of Epidemiology and Community Medicine, University of Ottawa; P. Tugwell, MD, FRCPC, MSc, Department of Medicine, Faculty of Medicine, Institute of Population Health and Department of Epidemiology and Community Medicine, University of Ottawa; and Ottawa Hospital Research Institute, Clinical Epidemiology Program.
authors.forename: Elizabeth Tanjong
authors.initials: ET
authors.lastname: Ghogomu
authors.affiliation: From the Bruyère Research Institute (BRI); Centre for Global Health, Institute of Population Health, University of Ottawa, Ottawa, ON, Canada; Epidemiological Research Center, National Academy of Medicine, Buenos Aires, Argentina; Rheumatology Division, Department of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand; Cochrane Musculoskeletal Group, Ottawa; Institute for Work and Health, Toronto; Department of Epidemiology and Community Medicine, and the Department of Medicine, Faculty of Medicine, University of Ottawa; Ottawa Hospital Research Institute, Clinical Epidemiology Program; Institute of Population Health and Department of Epidemiology and Community Medicine, University of Ottawa, Ottawa, ON, Canada.B. Shea, PhD, MSc, RN, BRI, Department of Epidemiology and Community Medicine, University of Ottawa; M.V. Swinden, MBBS; E. Tanjong Ghogomu, MD, MSc, Centre for Global Health, Institute of Population Health, University of Ottawa; Z. Ortiz, MD, MSc, Epidemiological Research Center, National Academy of Medicine; W. Katchamart, MD, FRCP, MSc, Rheumatology Division, Department of Medicine, Siriraj Hospital, Mahidol University; T. Rader, MLIS, Cochrane Musculoskeletal Group; C. Bombardier, MD, FRCPC, Institute for Work and Health; G.A. Wells, PhD, MSc, Department of Epidemiology and Community Medicine, University of Ottawa; P. Tugwell, MD, FRCPC, MSc, Department of Medicine, Faculty of Medicine, Institute of Population Health and Department of Epidemiology and Community Medicine, University of Ottawa; and Ottawa Hospital Research Institute, Clinical Epidemiology Program.
authors.forename: Zulma
authors.initials: Z
authors.lastname: Ortiz
authors.affiliation: From the Bruyère Research Institute (BRI); Centre for Global Health, Institute of Population Health, University of Ottawa, Ottawa, ON, Canada; Epidemiological Research Center, National Academy of Medicine, Buenos Aires, Argentina; Rheumatology Division, Department of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand; Cochrane Musculoskeletal Group, Ottawa; Institute for Work and Health, Toronto; Department of Epidemiology and Community Medicine, and the Department of Medicine, Faculty of Medicine, University of Ottawa; Ottawa Hospital Research Institute, Clinical Epidemiology Program; Institute of Population Health and Department of Epidemiology and Community Medicine, University of Ottawa, Ottawa, ON, Canada.B. Shea, PhD, MSc, RN, BRI, Department of Epidemiology and Community Medicine, University of Ottawa; M.V. Swinden, MBBS; E. Tanjong Ghogomu, MD, MSc, Centre for Global Health, Institute of Population Health, University of Ottawa; Z. Ortiz, MD, MSc, Epidemiological Research Center, National Academy of Medicine; W. Katchamart, MD, FRCP, MSc, Rheumatology Division, Department of Medicine, Siriraj Hospital, Mahidol University; T. Rader, MLIS, Cochrane Musculoskeletal Group; C. Bombardier, MD, FRCPC, Institute for Work and Health; G.A. Wells, PhD, MSc, Department of Epidemiology and Community Medicine, University of Ottawa; P. Tugwell, MD, FRCPC, MSc, Department of Medicine, Faculty of Medicine, Institute of Population Health and Department of Epidemiology and Community Medicine, University of Ottawa; and Ottawa Hospital Research Institute, Clinical Epidemiology Program.
authors.forename: Wanruchada
authors.initials: W
authors.lastname: Katchamart
authors.affiliation: From the Bruyère Research Institute (BRI); Centre for Global Health, Institute of Population Health, University of Ottawa, Ottawa, ON, Canada; Epidemiological Research Center, National Academy of Medicine, Buenos Aires, Argentina; Rheumatology Division, Department of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand; Cochrane Musculoskeletal Group, Ottawa; Institute for Work and Health, Toronto; Department of Epidemiology and Community Medicine, and the Department of Medicine, Faculty of Medicine, University of Ottawa; Ottawa Hospital Research Institute, Clinical Epidemiology Program; Institute of Population Health and Department of Epidemiology and Community Medicine, University of Ottawa, Ottawa, ON, Canada.B. Shea, PhD, MSc, RN, BRI, Department of Epidemiology and Community Medicine, University of Ottawa; M.V. Swinden, MBBS; E. Tanjong Ghogomu, MD, MSc, Centre for Global Health, Institute of Population Health, University of Ottawa; Z. Ortiz, MD, MSc, Epidemiological Research Center, National Academy of Medicine; W. Katchamart, MD, FRCP, MSc, Rheumatology Division, Department of Medicine, Siriraj Hospital, Mahidol University; T. Rader, MLIS, Cochrane Musculoskeletal Group; C. Bombardier, MD, FRCPC, Institute for Work and Health; G.A. Wells, PhD, MSc, Department of Epidemiology and Community Medicine, University of Ottawa; P. Tugwell, MD, FRCPC, MSc, Department of Medicine, Faculty of Medicine, Institute of Population Health and Department of Epidemiology and Community Medicine, University of Ottawa; and Ottawa Hospital Research Institute, Clinical Epidemiology Program.
authors.forename: Tamara
authors.initials: T
authors.lastname: Rader
authors.affiliation: From the Bruyère Research Institute (BRI); Centre for Global Health, Institute of Population Health, University of Ottawa, Ottawa, ON, Canada; Epidemiological Research Center, National Academy of Medicine, Buenos Aires, Argentina; Rheumatology Division, Department of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand; Cochrane Musculoskeletal Group, Ottawa; Institute for Work and Health, Toronto; Department of Epidemiology and Community Medicine, and the Department of Medicine, Faculty of Medicine, University of Ottawa; Ottawa Hospital Research Institute, Clinical Epidemiology Program; Institute of Population Health and Department of Epidemiology and Community Medicine, University of Ottawa, Ottawa, ON, Canada.B. Shea, PhD, MSc, RN, BRI, Department of Epidemiology and Community Medicine, University of Ottawa; M.V. Swinden, MBBS; E. Tanjong Ghogomu, MD, MSc, Centre for Global Health, Institute of Population Health, University of Ottawa; Z. Ortiz, MD, MSc, Epidemiological Research Center, National Academy of Medicine; W. Katchamart, MD, FRCP, MSc, Rheumatology Division, Department of Medicine, Siriraj Hospital, Mahidol University; T. Rader, MLIS, Cochrane Musculoskeletal Group; C. Bombardier, MD, FRCPC, Institute for Work and Health; G.A. Wells, PhD, MSc, Department of Epidemiology and Community Medicine, University of Ottawa; P. Tugwell, MD, FRCPC, MSc, Department of Medicine, Faculty of Medicine, Institute of Population Health and Department of Epidemiology and Community Medicine, University of Ottawa; and Ottawa Hospital Research Institute, Clinical Epidemiology Program.
authors.forename: Claire
authors.initials: C
authors.lastname: Bombardier
authors.affiliation: From the Bruyère Research Institute (BRI); Centre for Global Health, Institute of Population Health, University of Ottawa, Ottawa, ON, Canada; Epidemiological Research Center, National Academy of Medicine, Buenos Aires, Argentina; Rheumatology Division, Department of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand; Cochrane Musculoskeletal Group, Ottawa; Institute for Work and Health, Toronto; Department of Epidemiology and Community Medicine, and the Department of Medicine, Faculty of Medicine, University of Ottawa; Ottawa Hospital Research Institute, Clinical Epidemiology Program; Institute of Population Health and Department of Epidemiology and Community Medicine, University of Ottawa, Ottawa, ON, Canada.B. Shea, PhD, MSc, RN, BRI, Department of Epidemiology and Community Medicine, University of Ottawa; M.V. Swinden, MBBS; E. Tanjong Ghogomu, MD, MSc, Centre for Global Health, Institute of Population Health, University of Ottawa; Z. Ortiz, MD, MSc, Epidemiological Research Center, National Academy of Medicine; W. Katchamart, MD, FRCP, MSc, Rheumatology Division, Department of Medicine, Siriraj Hospital, Mahidol University; T. Rader, MLIS, Cochrane Musculoskeletal Group; C. Bombardier, MD, FRCPC, Institute for Work and Health; G.A. Wells, PhD, MSc, Department of Epidemiology and Community Medicine, University of Ottawa; P. Tugwell, MD, FRCPC, MSc, Department of Medicine, Faculty of Medicine, Institute of Population Health and Department of Epidemiology and Community Medicine, University of Ottawa; and Ottawa Hospital Research Institute, Clinical Epidemiology Program.
authors.forename: George A
authors.initials: GA
authors.lastname: Wells
authors.affiliation: From the Bruyère Research Institute (BRI); Centre for Global Health, Institute of Population Health, University of Ottawa, Ottawa, ON, Canada; Epidemiological Research Center, National Academy of Medicine, Buenos Aires, Argentina; Rheumatology Division, Department of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand; Cochrane Musculoskeletal Group, Ottawa; Institute for Work and Health, Toronto; Department of Epidemiology and Community Medicine, and the Department of Medicine, Faculty of Medicine, University of Ottawa; Ottawa Hospital Research Institute, Clinical Epidemiology Program; Institute of Population Health and Department of Epidemiology and Community Medicine, University of Ottawa, Ottawa, ON, Canada.B. Shea, PhD, MSc, RN, BRI, Department of Epidemiology and Community Medicine, University of Ottawa; M.V. Swinden, MBBS; E. Tanjong Ghogomu, MD, MSc, Centre for Global Health, Institute of Population Health, University of Ottawa; Z. Ortiz, MD, MSc, Epidemiological Research Center, National Academy of Medicine; W. Katchamart, MD, FRCP, MSc, Rheumatology Division, Department of Medicine, Siriraj Hospital, Mahidol University; T. Rader, MLIS, Cochrane Musculoskeletal Group; C. Bombardier, MD, FRCPC, Institute for Work and Health; G.A. Wells, PhD, MSc, Department of Epidemiology and Community Medicine, University of Ottawa; P. Tugwell, MD, FRCPC, MSc, Department of Medicine, Faculty of Medicine, Institute of Population Health and Department of Epidemiology and Community Medicine, University of Ottawa; and Ottawa Hospital Research Institute, Clinical Epidemiology Program.
authors.forename: Peter
authors.initials: P
authors.lastname: Tugwell
mesh_terms: D000328:Adult; D018501:Antirheumatic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000188:drug therapy*; D005260:Female; D005492:Folic Acid / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D002955:Leucovorin / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008727:Methotrexate / Q000009:adverse effects* / Q000627:therapeutic use
chemical_list: D018501:Antirheumatic Agents; D005492:Folic Acid; D002955:Leucovorin; D008727:Methotrexate
keywords: COCHRANE REVIEW; FOLIC ACID; FOLINIC ACID; RHEUMATOID ARTHRITIS