Background Psoriatic arthritis is an inflammatory disease associated with joint damage, impaired function, pain, and reduced quality of life. Methotrexate is a disease-modifying anti-rheumatic drug (DMARD) commonly prescribed to alleviate symptoms, attenuate disease activity, and prevent progression of disease. Objectives To assess the benefits and harms of methotrexate for psoriatic arthritis in adults. Search methods We searched CENTRAL, MEDLINE, Embase, the WHO International Clinical Trials Registry Platform, and www.clinicaltrials.gov for relevant records. We searched all databases from inception to 29 January 2018. We handsearched included articles for additional records and contacted study authors for additional unpublished data. We applied no language restrictions. Selection criteria We included all randomised controlled trials (RCTs) and quasi-RCTs that compared methotrexate versus placebo, or versus another DMARD, for adults with psoriatic arthritis. We reported on the following major outcomes: disease response (measured by psoriatic arthritis response criteria (PsARC)), function (measured by the Health Assessment Questionnaire for Rheumatoid Arthritis (HAQ)), health-related quality of life, disease activity (measured by disease activity score (28 joints) with erythrocyte sedimentation rate (DAS28-ESR)), radiographic progression, serious adverse events, and withdrawals due to adverse events. Data collection and analysis Two review authors independently reviewed search results, assessed risk of bias, extracted trial data, and assessed the quality of evidence using the GRADE approach. We undertook meta-analysis only when this was meaningful. Main results We included in this review eight RCTs conducted in an outpatient setting, in Italy, the United Kingdom, the United States of America, China, Russia, and Bangladesh. Five studies compared methotrexate versus placebo, and four studies compared methotrexate versus other DMARDs. The average age of participants varied across studies (26 to 52 years), as did the average duration of psoriatic arthritis (one to nine years). Doses of methotrexate varied from 7.5 mg to 25 mg orally per week, but most studies administered approximately 15 mg or less orally per week. Risk of bias was generally unclear or high across most domains for all studies. We considered only one study to have low risk of selection and detection bias. The main study informing results of the primary comparison (methotrexate vs placebo up to six months) was at low risk of bias for all domains except attrition bias and reporting bias. We restricted reporting of results to the comparison of methotrexate versus placebo for up to six months. Low-quality evidence (downgraded due to bias and imprecision) from a single study (221 participants; methotrexate dose 15 mg orally or less per week) informed results for disease response, function, and disease activity. Disease response, measured by the proportion who responded to treatment according to PsARC (response indicates improvement), was 41/109 in the methotrexate group and 24/112 in the placebo group (risk ratio (RR) 1.76, 95% confidence interval (CI) 1.14 to 2.70). This equates to an absolute difference of 16% more responders with methotrexate (4% more to 28% more), and a number needed to treat for an additional beneficial outcome (NNTB) of 6 (95% CI 5 to 25). Mean function, measured by the HAQ (scale 0 to 3; 0 meaning no functional impairment; minimum clinically important difference 0.22), was 1.0 points with placebo and 0.3 points better (95% 0.51 better to 0.09 better) with methotrexate; absolute improvement was 10% (3% better to 17% better), and relative improvement 30% (9% better to 51% better). Mean disease activity as measured by the DAS28-ESR (scale of 0 to 10; lower score means lower disease activity; minimum clinically important difference unknown) was 3.8 points in the methotrexate group and 4.06 points in the placebo group; mean difference was -0.26 points (95% CI -0.65 to 0.13); absolute improvement was 3% (7% better to 1% worse), and relative improvement 6% (16% better to 3% worse). Low-quality evidence (downgraded due to risk of bias and imprecision) from three studies (n = 293) informed our results for serious adverse events and withdrawals due to adverse events. Due to low event rates, we are uncertain if methotrexate results show increased risk of serious adverse events or withdrawals due to adverse events compared to placebo. Results show 1/141 serious adverse events in the methotrexate group and 4/152 in the placebo group: RR 0.26 (95% CI 0.03 to 2.26); absolute difference was 2% fewer events with methotrexate (5% fewer to 1% more). In all, 9/141 withdrawals in the methotrexate group were due to adverse events and 7/152 in the placebo group: RR 1.32 (95% CI 0.51 to 3.42); absolute difference was 1% more withdrawals (4% fewer to 6% more). One study measured health-related quality of life but did not report these results. No study measured radiographic progression. Authors' conclusions Low-quality evidence suggests that low-dose (15 mg or less) oral methotrexate might be slightly more effective than placebo when taken for six months; however we are uncertain if it is more harmful. Effects of methotrexate on health-related quality of life, radiographic progression, enthesitis, dactylitis, and fatigue; its benefits beyond six months; and effects of higher-dose methotrexate have not been measured or reported in a randomised placebo-controlled trial.
