title: Comparison of two different folic acid doses with methotrexate--a randomized controlled trial (FOLVARI Study).
abstract: BACKGROUND
  There is reasonable evidence that folic acid 5-10 mg per week leads to reduction in methotrexate (MTX) toxicity in rheumatoid arthritis (RA). However, this is based on studies conducted with lower MTX dosage than used currently. It is unclear whether higher doses of folic acid may be better in reducing toxicity.
  
  
  METHODS
  This was a double-blind randomized controlled trial of 24 weeks duration. To be eligible, patients should have rheumatoid arthritis (1987 American College of Rheumatology criteria), be 18-75 years of age, not be on MTX and have active disease as defined by 'Modified Disease Activity Score using three variables' (DAS28(3)) > 3.2. MTX was started at 10 mg/week and escalated to 25 mg/week by 12 weeks. Folic acid was given at a dose of 10 mg (FA10) or 30 mg per week (FA30). Co-primary endpoints were incidence of toxicity (undesirable symptoms and laboratory abnormalities) and change in disease activity by 24 weeks. Intention-to-treat and per-protocol analyses were performed.
  
  
  RESULTS
  Among 100 patients enrolled, 51 and 49 were randomized to FA10 and FA30 respectively. By 24 weeks, there were 6 patient withdrawals in either group and mean(±SD) dose of MTX was 22.8 ± 4.4 and 21.4 ± 4.6 mg per week (p = 0.1). Frequency of patients with undesirable symptoms was non-significantly lower by 7.4% (95% confidence interval -27.4 to 12.7%) in FA10 compared to FA30. There was also no difference in frequency of transaminitis (>Upper limit of normal (ULN)) (42.6, 45.7%, p = 0.7) or transminitis as per primary endpoint (>2xULN) (10.6, 8.7%, p = 1.0) or cytopenias (4.3, 4.3%, p = 0.9). There was no difference in the primary end-point of occurrence of any adverse effect (symptom or laboratory) in FA10 and FA30 (46.8, 54.3%, p = 0.5). At 24 weeks, DAS28(3) declined in both groups by a similar extent (-1.1 ± 1.0, -1.3 ± 1.0, p = 0.2) and 'European League Against Rheumatism' good or moderate response occurred in 56.9 and 67.4% (p = 0.3).
  
  
  CONCLUSIONS
  Even with the high doses of MTX used in current practice, there was no additional benefit (or harm) of a higher dose of folic acid (30 mg/week) over a usual dose (10 mg/week).
  
  
  BACKGROUND
  Clinicaltrials.gov NCT01583959 Registered 15 March 2012.
authors.affiliation: Department of Internal Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, 160020, India. varundhir@gmail.com.
authors.forename: Varun
authors.initials: V
authors.lastname: Dhir
authors.affiliation: Department of Internal Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, 160020, India. sandhu.amit90@gmail.com.
authors.forename: Amit
authors.initials: A
authors.lastname: Sandhu
authors.affiliation: Department of Biochemistry, Government Medical College and Hospital, Sector 32, Chandigarh, India. jasbinderkaur1961@gmail.com.
authors.forename: Jasbinder
authors.initials: J
authors.lastname: Kaur
authors.affiliation: Department of Internal Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, 160020, India. benzeeta@gmail.com.
authors.forename: Benzeeta
authors.initials: B
authors.lastname: Pinto
authors.affiliation: Department of Internal Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, 160020, India. dphani.mbbs@gmail.com.
authors.forename: Phani
authors.initials: P
authors.lastname: Kumar
authors.affiliation: Department of Internal Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, 160020, India. prabhdeep.kaur88@gmail.com.
authors.forename: Prabhdeep
authors.initials: P
authors.lastname: Kaur
authors.affiliation: Department of Internal Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, 160020, India. nidhigupta504@gmail.com.
authors.forename: Nidhi
authors.initials: N
authors.lastname: Gupta
authors.affiliation: Department of Internal Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, 160020, India. anki16nov@gmail.com.
authors.forename: Ankita
authors.initials: A
authors.lastname: Sood
authors.affiliation: Department of Internal Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, 160020, India. sharma.aman@pgimer.edu.in.
authors.forename: Aman
authors.initials: A
authors.lastname: Sharma
authors.affiliation: Department of Internal Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, 160020, India. sharma.shefali@pgimer.edu.in.
authors.forename: Shefali
authors.initials: S
authors.lastname: Sharma
mesh_terms: D000328:Adult; D018501:Antirheumatic Agents / Q000008:administration & dosage* / Q000009:adverse effects*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D005492:Folic Acid / Q000008:administration & dosage*; D006801:Humans; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage / Q000009:adverse effects*; D008875:Middle Aged
chemical_list: D018501:Antirheumatic Agents; D005492:Folic Acid; D008727:Methotrexate