Abstract: 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. 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.

Plain-language summary: We included eight studies published between 1964 and 2014. All studies involved people from rheumatology clinics. Studies were conducted in Italy, United Kingdom, United States of America, China, Russia, and Bangladesh. Five studies compared methotrexate against placebo (345 people), and four studies compared methotrexate against another DMARD (leflunomide (61 people), ciclosporin A (35 people), gold (30 people), and sulfasalazine (24 people)). The average age of people included in these studies varied from 26 to 52 years. The average duration of psoriatic arthritis ranged from one to nine years. The dose of methotrexate consisted of 7.5 mg to 25 mg orally, but for most studies, 15 mg was given orally per week. In most western countries, a dose of 15 mg to 20 mg orally per week is normally used in routine practice. After six months of treatment, comparison with placebo (a fake drug) showed that methotrexate resulted in the following (note that one study measured but did not report quality of life, and no studies measured radiographic progression). Proportion who responded to treatment as measured by the Psoriatic Arthritis Response Criteria 16% more people, or 16 more people out of 100, improved with treatment (4% more to 28% more) 37 out of 100 people taking methotrexate improved 21 out of 100 people taking placebo improved Function (lower scores mean better function) Function was improved by 10% (ranging from 3% better to 17% better), or by 0.30 points (ranging from 0.09 better to 0.51 better) on a 0 to 3 scale (this is expected to be meaningful to patients) People taking methotrexate rated their function as 0.7 point People taking placebo rated their function as 1.0 point Disease activity (lower scores mean less active disease) Disease activity improved by 3% (7% better to 1% worse), or by 0.26 points (0.65 better to 0.13 worse) on a 0 to 10 scale People taking methotrexate had a disease activity score of 3.8 points People taking placebo had a disease activity score of 4.06 points Serious adverse events (more events mean more harm) 2% fewer people, or two fewer people out of 100 (5% fewer to 1% more), reported a serious adverse event with methotrexate One person out of 100 people taking methotrexate had a serious adverse event Three out of 100 people taking placebo had a serious adverse event Withdrawals due to adverse events (more events means more harm) 1% more people, or one more person out of 100 (4% fewer to 6% more), withdrew from treatment with methotrexate Six out of 100 people taking methotrexate withdrew Five out of 100 people taking placebo withdrew Low-quality evidence suggests that methotrexate might lead to slightly greater benefit than placebo for some outcomes (e.g. improving function) but may be no better than placebo for other outcomes (e.g. reducing disease activity). We assessed the quality of the evidence as low due to flawed trial design and imprecision (some results are meaningful to patients and some are not). We are uncertain whether methotrexate causes more harm than placebo due to the small number of reported events.