title: Randomized controlled trial comparing 2 different starting doses of methotrexate in rheumatoid arthritis.
abstract: OBJECTIVE
  Methotrexate (MTX) remains the gold standard disease-modifying antirheumatic drug for the treatment of rheumatoid arthritis (RA). Few studies have compared different starting doses of MTX in RA. We hypothesized that starting with a higher MTX dose may be more effective but associated with more adverse effects. We compared a starting dose of 7.5 versus 15 mg per week of MTX followed by similar fast escalation.
  
  
  METHODS
  This was an open-label (blinded assessor), parallel-group, randomized controlled trial that included RA patients aged 18 to 65 years, not on MTX, and having active disease (Disease Activity Score for 28 joints using 3 variables [DAS28(3)] ≥5.1). Patients were randomized to receive MTX at a starting dose of 7.5 mg (group 1) or 15 mg (group 2) per week. The dose of MTX was escalated by 2.5 mg every 2 weeks to a maximum of 25 mg. Patients were seen every 4 weeks, and dose escalation was continued if DAS28(3) was >2.6 and there were no laboratory abnormalities (transaminitis [>2 × upper limit of normal] or cytopenia). The primary endpoint was change in disease activity at 12 weeks (assessed by using the DAS28[3]). Secondary endpoints were patient withdrawals and episodes ofcytopenia or transaminitis. Adverse effects were ascertained by using a questionnaire. Both intention-to-treat and per-protocol analyses were performed.
  
  
  RESULTS
  We enrolled 100 patients (female:male ratio, 78:22) with a mean (SD) age of 43.6 (10.8) years and a disease duration of 4.7 (4.8) years. At baseline, patients had a mean DAS28(3) of 6.2 (0.7) and a Health Assessment Questionnaire score of 1.3 (0.6). Group 1 (7.5 mg) and group 2 (15 mg) included 47 and 53 patients, respectively, with no significant differences in baseline characteristics. At 12 weeks, the mean dose of MTX reached was 17.3 (4.6) mg in group 1 and 23.6 (3.0) mg in group 2 (P < 0.001). The 2 groups had a similar number of patient withdrawals. The mean change in DAS28(3) at 12 weeks in group 1 (-0.47 [0.86]) and group 2 (-0.55 [0.79]) was not significantly different (P = 0.60). The change in the Health Assessment Questionnaire score was also similar in the groups. The frequency of episodes of transaminitis (6 and 7; P = 0.8) and cytopenia (1 and 2; P = 0.9) did not differ significantly between groups 1 and 2, respectively. Results remained the same according to the per-protocol analysis. Among adverse effects, nausea was more common in group 2 compared with group 1 (relative risk, 1.6 [95% CI, 1.1-2.2]).
  
  
  CONCLUSIONS
  There were no significant differences in efficacy between the 2 starting doses of MTX. The fast escalation of dose in both groups may have blunted any advantage of starting at a higher dose. Nausea occurred more commonly in patients started on 15 mg of MTX. We suggest longer trials to confirm our findings. ClinicalTrials.gov identifier: NCT01404429.
authors: Department of Internal Medicine (Rheumatology Unit), Post Graduate Institute of Medical Education and Research, Chandigarh, India. Electronic address: varundhir@gmail.com.
authors: Varun
authors: V
authors: Dhir
authors: Department of Internal Medicine (Rheumatology Unit), Post Graduate Institute of Medical Education and Research, Chandigarh, India.
authors: Mandeep
authors: M
authors: Singla
authors: Department of Internal Medicine (Rheumatology Unit), Post Graduate Institute of Medical Education and Research, Chandigarh, India.
authors: Nidhi
authors: N
authors: Gupta
authors: Department of Internal Medicine (Rheumatology Unit), Post Graduate Institute of Medical Education and Research, Chandigarh, India.
authors: Palvi
authors: P
authors: Goyal
authors: Department of Internal Medicine (Rheumatology Unit), Post Graduate Institute of Medical Education and Research, Chandigarh, India.
authors: Vinay
authors: V
authors: Sagar
authors: Department of Internal Medicine (Rheumatology Unit), Post Graduate Institute of Medical Education and Research, Chandigarh, India.
authors: Aman
authors: A
authors: Sharma
authors: Department of Internal Medicine (Rheumatology Unit), Post Graduate Institute of Medical Education and Research, Chandigarh, India.
authors: Shefali
authors: S
authors: Khanna
authors: Department of Internal Medicine (Rheumatology Unit), Post Graduate Institute of Medical Education and Research, Chandigarh, India.
authors: Surjit
authors: S
authors: Singh
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D018501:Antirheumatic Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage* / Q000627:therapeutic use; D008875:Middle Aged; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D018501:Antirheumatic Agents; D008727:Methotrexate
keywords: methotrexate; randomized controlled trial; rheumatoid arthritis; starting dose