Table 1 Studies included in our review and characteristics of study populations
Author, year | Study location | Study design | Sample size | Main patient characteristics | Treatment groups | Outcomes | Study duration (weeks) |
|---|---|---|---|---|---|---|---|
Braun, 2008 [34] | Germany | RCT, Multicenter, Double-blind, Parallel | 384 | Disease duration 2.3 months, Active disease, Naïve to MTX, Folic acid. | A: Oral MTX 15 mg/week with dosage adjustment after 16 weeks based on efficacy; B: SC MTX 15 mg/week with dosage adjustment after 16 weeks based on efficacy Concomitant treatment with systemic corticosteroids and NSAIDs was permitted under certain conditions, but not DMARDs or biological agents | Primary: ACR20; ESR; CRP; physician’s global assessment of disease activity; patient’s global assessment of disease activity; patient’s assessment of pain; HAQ. Secondary: ACR50; ACR70. Safety: AEs; SAEs; discontinuations due to AEs; clinical laboratory test abnormalities | 24 |
India | RCT, Single centre, Open-label, Parallel | 100 | Disease duration 4.75 years, Active disease, 11% previously taken MTX, Folic acid. | A: Oral MTX 7.5 mg/week; B: Oral MTX 15 mg/week Concomitant treatement with steroids (prednisolone = < 7.5 mg/d) and other DMARDs was allowed | Primary: DAS28-3v. Secondary: Withdrawals due to any cause; withdrawals due to intolerance; patients with cytopenia or transaminitis. | 12 | |
Furst, 1989 [37] | United States | RCT, Single-center, Double-blind, Parallel | 52 | Active disease, Naïve to MTX, Failed DMARDs (gold, D-penicillamine). | A: Oral MTX 5 mg/m2/week; B: Oral MTX 10 mg/m2/week; C: Oral MTX 20 mg/m2/week NR concomitant treatment allowed | Diameter of the 2nd through 5th proximal interphalangeal joints of the hands; modified RAI; duration of morning stiffness; average of the last 2 of 3 grip strength; time in walk 75’ on the level; physician’s global assessment of patient’s sense of wellbeing; patient global sense of wellbeing; patient pain assessment (VAS); patient’s ability to complete 18 activities of daily living | 18 |
Hobl, 2012 [38] | Germany | RCT, Single-center, Double-blind, Parallel | 19 | Active disease, Naïve to MTX, Folic acid. | A: Oral MTX 15 mg/week (standard group); B: Oral MTX 25 mg/week (accelerated group) Concomitant treatment with NSAIDs and corticosteroids was allowed. | DAS-28; swollen joint count; tender joint count; duration of morning stiffness; Patient Global Assessment; Evaluator Global Assessment; mHAQ; intensity of pain and fatigue (VAS) | 16 |
Verstappen, 2007 [35] | Netherlands | RCT, Multicenter, Open-label | 299 | Naïve to DMARDs. | A: Oral MTX 7.5 mg/week, + 5 mg/month (Intensive strategy group); B: Oral MTX 7.5 mg/week + 5 mg/3 months (conventional strategy group) Concomitant treatment with NSAIDs was allowed, but not intra-articular injections or oral glucocorticoids | ESR; number of swollen joints; number of tender joints; VAS for pain; VAS general well-being; morning stiffness; HAQ17 | 52 |
Islam, 2013 [32] | India | RCT, Single centre, Parallel | 92 | Disease duration 4.1 years, Active disease. | A: Oral MTX; B: SC MTX NR concomitant treatment allowed | ACR20; ACR50; ACR70; AE | 24 |
Jain, 2021 [36] | India | RCT, Multicenter, Open-label, Parallel | 178 | Disease duration 1.85 years, Active disease, Naïve to MTX, Folic acid. | A: Oral MTX 15 mg/week, + 5 mg/4 weeks (usual escalation group); B: Oral MTX 15 mg/week, + 5 mg/2 weeks (fast escalation group) Concomitant treatment with hydroxychloroquine, low- dose prednisolone or NSAIDs was allowed | Primary: DAS28; CRP. Secondary: DAS28- CRP; AEs and laboratory abnormalities (cytopaenias or transaminitis). | 16 |
Lambert, 2004 [39] | United Kingdom | RCT, Single-center, Double-blind, Parallel | 54 | Disease duration 9.65 years, Active disease, Failed DRMARDs, and oral MTX 15–20 mg/week. | A: Oral MTX to IM 15 mg/week for 6 weeks, then: MTX IM + 5 mg/4 weeks up to 45 mg (escalation group); B: Oral MTX to IM 15 mg/week for 6 weeks, then: IM MTX 15 mg/week (control group) Concomitant treatment with 2 intraarticular steroid injections of 40 mg methylprednisolone acetate was allowed (prohibited within the final 6 weeks of the trial), but not DMARDs | Primary: DAS28 of < 3.2. Secondary: DAS28 improved by > 1.2; ACR20; % of patients achieving a good response, a moderate response, or no response; the change in the ACR core set disease activity measures; SF-12. | 22 |
Luis, 1999 [40] | Mexico | RCT, Single-center, Single-blind, Parallel | 51 | Disease duration 2,0.82 years, RA in remission disease, No naïve to MTX. | A: Oral low dose MTX weekly (mean MTX dose 7.0 mg); B: Oral low dose MTX every-other-weekly (mean MTX dose 7.01 mg) Concomitant treatment with stable dosages of chloroquine or low-dose steroids was acceptable | Tender and swollen joint counts; RAI; duration of morning stiffness; HAQ; Disability Index; ACR functional class, pain (VAS); physician’s and patient’s global health assessment; AEs | 24 |
United States | RCT, Multicenter, Open-label, Cross-over | 37 | Disease duration 13.3 years, Active disease, No naïve to MTX. | A: Oral MTX (10,15,20 and 25 mg/week); B: SC MTX into the abdomen; (10,15,20 and 25 mg/week); C: SC MTX into the thigh (10,15,20 and 25 mg/week) Concomitant treatment with additional medications, including DMARDs, that could interfere with PK outcome measurements was not allowed. NSAIDs were not permitted within ± 12 h of MTX administration | AUC from time 0 to the last measurable concentration (AUC0–t); or extrapolating to infinity (AUC0–inf ); maximum observed concentration (Cmax) | 8 | |
Schnabel, 1994 [41] | Germany | RCT, Single centre, Open-label, Parallel | 185 | Active disease, Naïve to MTX, With or without DMARDs failure. | A: Oral MTX 15 mg/week orally with dosage adjustment based on efficacy after 3 months; B: Oral MTX 25 mg/week orally with dosage adjustment based on efficacy after 3 months Concomitant treatment with analgesics, NSAIDs and low-dose methylprednisolone was allowed. | AEs; complete blood cell count; creatinine; AST; ALT and alkaline phosphatase; MTX discontinuations; withdrawals | 52 |
Tsutsumino, 2017 [33] | Japan | RCT, Single centre, Parallel | 115 | Active disease, Naïve to MTX, tacrolimus, or biologics. | A: Oral MTX, + 0.25 mg/kg/week up to maximum tolerable dose; B: Oral MTX (conventional treatment group) NR concomitant treatment allowed | Primary: % of patients achieving SDAI remission and Boolean remission | 24 and 48 |