Kingsley 2012.

Methods	Study design: double‐blind, randomised, placebo‐controlled trial of methotrexate vs placebo Duration of study: 6 months Run‐in period: none Location: United Kingdom Number of study centres: 22 Study setting: outpatient Withdrawals: 70 ‐ missing data were imputed by multiple imputation using chained equations with 20 cycles Dates of study: January 2003 to July 2008
Participants	Randomised: n = 221 Methotrexate ‐ n = 109 Placebo ‐ n = 112 Completed: n = 151 Methotrexate ‐ n = 74 Placebo ‐ n = 77 Baseline characteristics Mean age (SD): Methotrexate ‐ 46 years (±13) Placebo ‐ 51 years (±11) Sex: Methotrexate ‐ 56 males; 53 females Placebo ‐ 68 males; 44 females Mean disease duration (IQR): Methotrexate ‐ 1 year (1 to 5) Placebo ‐ 1 year (1 to 6) Mean function (95% CI) (HAQ) Methotrexate ‐ 0.9 (95% CI 0.8 to 1.1) Placebo ‐ 1.2 (95% CI 1.02 to 1.28) Health‐related quality of life (SF‐36) Not reported for either group Disease activity (DAS28‐ESR) Not reported for either group Mean pain (95% CI) (VAS 100 mm) Methotrexate ‐ 40.5 (95% CI 36.2 to 44.8) Placebo ‐ 46.4 (95% CI 41.8 to 50.9) Mean skin disease (95% CI) (PASI) Methotrexate ‐ 3.76 (95% CI 2.84 to 4.78) Placebo ‐ 3.79 (95% CI 2.79 to 4.78) Mean patient global assessment (95% CI) (VAS 100 mm) Methotrexate ‐ 49.8 (95% CI 45.1 to 54.4) Placebo ‐ 49.7 (95% CI 45.1 to 54.4) Mean physician global assessment (95% CI) (VAS 100 mm) Methotrexate ‐ 41.1 (95% CI 37.7 to 44.5) Placebo ‐ 43.7 (95% CI 40.2 to 47.2) Mean swollen joint count (95% CI) (66 joints) Methotrexate ‐ 8.7 (95% CI 7.2 to 10.1) Placebo ‐ 8.0 (95% CI 6.5 to 9.5) Mean tender joint count (95% CI) (68 joints) Methotrexate ‐ 11.9 (95% CI 9.8 to 14.0) Placebo ‐ 13.6 (95% CI 11.6 to 15.7) Severity of condition: not reported Diagnostic criteria: rheumatologist‐diagnosed PsA Inclusion criteria: Clinically apparent psoriasis (skin or nails) and active inflammatory synovitis involving at least 1 peripheral joint Constant level of NSAID therapy for at least 1 month Previous DMARD therapy discontinued for at least 1 month Willingness and ability to give informed consent Exclusion criteria: Other inflammatory arthropathies or arthritis mutilans Systemic steroid therapy provided currently or within the last 3 months Previous or current treatment with methotrexate Other serious medical disorders including liver, renal, and cardiac disease Women of childbearing potential not taking adequate contraceptive precautions Abnormal full‐blood counts and liver function tests or other contraindications to methotrexate therapy
Interventions	Methotrexate group: methotrexate tablets 7.5 mg weekly for 4 weeks, 10 mg for 4 weeks, and 15 mg ongoing. Dose could be increased to 20 mg at 4 months and 25 mg at 4 months at the discretion of the clinician Placebo group: matching placebo tablet Concomitant medications: Folic acid 5 mg weekly Anti‐emetic therapy as needed Current NSAIDs and analgesics could continue at unchanged dosage from baseline Only 1 IA steroid was allowed Excluded medications: oral or intramuscular steroids were not used
Outcomes	Time points: 6 months Major: Disease response (PsARC) ‐ measured as response achieved/not achieved, with response achieved indicating benefit ‐ absolute numbers of PsARC responders provided by study authors for valid compliant completers only (i.e. not provided for ITT cohort) PsARC ‐ composite outcome based on 4 assessment measures: patient self‐assessment, physician assessment (improvement = decrease by 1 category; worsening = increase by 1 category), tender and swollen joint counts (improvement = decrease by 30%; worsening = increase by 30%). Treatment response is defined as improvement in at least 2 out of 4 measures, 1 of which must be tender or swollen joint counts, and there can be no worsening in any measure Function (HAQ) ‐ scale 0 to 3 (no units); 0 = no impairment of function, 3 = severe impairment of function (higher scores indicate worse function) ‐ SD calculated from provided 95% confidence interval Health‐related quality of life (SF‐36) ‐ abstract only (not extractable; could not clarify with study authors) Disease activity (DAS28‐ESR) ‐ ITT analysis requested and provided by study authors; SD estimated from SE provided by study authors Serious adverse events ‐ measured as events/no events, with events indicating harm ‐ provided upon request from study authors Withdrawals due to adverse events ‐ measured as events/no events, with events indicating harm Minor: Disease response (ACR20) ‐ measured as response achieved/not achieved, with response achieved indicating benefit ‐ absolute numbers of ACR20 responders provided by study authors for valid compliant completers only (i.e. not provided for ITT cohort) ACR20 ‐ composite outcome based on 7 assessment measures: tender and swollen joint counts, patient and physician global assessments, pain (VAS), ESR or CRP, and results on a functional questionnaire (HAQ). Treatment response is defined by improvement of 20% in both tender and swollen joint counts, and in 3 out of 5 other measures Pain (VAS 100 mm) ‐ 0 mm for no pain, 100 mm for maximum pain ‐ SD calculated from provided 95% confidence interval Skin disease (PASI) ‐ scale 0 to 72 (no units), with 0 indicating no psoriasis and 72 indicating very severe psoriasis covering > 90% body surface area ‐ provided upon request from study authors; SD estimated from SE provided by study authors Total adverse events ‐ measured as events/no events, with events indicating harm Patient global assessment (VAS 100 mm) ‐ 0 mm for no disease activity; 100 mm for maximum disease activity Physician global assessment (VAS 100 mm) ‐ 0 mm for no disease activity; 100 mm for maximum disease activity Swollen joint count (66 joints) ‐ 0 = no swollen joints; 66 = 66 swollen joints ‐ SD calculated from provided 95% confidence interval Tender joint count (68 joints) ‐ 0 = no tender joints; 68 = 68 tender joints ‐ SD calculated from provided 95% confidence interval
Notes	Clinical trials registration: ISRCTN54376151 Funding: Arthritis Research UK, London South Comprehensive Local Research Network of the National institute for Health Research, Wyeth (UK) (supplied tablets), UKMRC, King's College Declarations of interest: single author (NJM) received honoraria from Abbott and Pfizer
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"Allocation sequence was generated by the trial statistician using random number tables"
Allocation concealment (selection bias)	Low risk	"Metrologists and trial coordinator were unaware of the allocation sequence. Treatment assignments were in a locked cabinet in the co‐ordinating centre pharmacy for emergency access"
Blinding of participants and personnel (performance bias) All outcomes	Low risk	"The MTX and placebo were identical in appearance. Each patient received the treatment in the corresponding pre‐packed container"
Blinding of outcome assessment (detection bias) All outcomes	Low risk	"Metrologists were unaware of the allocation sequence"
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	We considered attrition of 35 participants in each group (total attrition 32%) to be high; however missing data were imputed "All missing data were imputed regardless of the reason(s) the data were missing…Assuming unobserved measurements were missing at random, we imputed missing data by multiple imputation using chained equations with 20 cycles, where at the end of the cycle one imputed data set is created and process was repeated to create 20 imputed data sets"
Selective reporting (reporting bias)	High risk	The number of events was not reported for ITT analysis (e.g. for PsARC outcome) but was reported for completers. Also, study authors measured but did not report quality of life
Other bias	Low risk	Minor differences in baseline characteristics were evident; co‐intervention use and compliance were similar between groups. This trial was judged as having low risk of bias for these outcomes