Jasvinder A Singh, Alomgir Hossain, Amy S Mudano, Elizabeth Tanjong Ghogomu, Maria E Suarez-Almazor, Rachelle Buchbinder, Lara J Maxwell, Peter Tugwell, George A Wells

Biologic disease-modifying anti-rheumatic drugs (biologics) are highly effective in treating rheumatoid arthritis (RA), however there are few head-to-head biologic comparison studies. We performed a systematic review, a standard meta-analysis and a network meta-analysis (NMA) to update the 2009 Cochrane Overview. This review is focused on the adults with RA who are naive to methotrexate (MTX) that is, receiving their first disease-modifying agent. To compare the benefits and harms of biologics (abatacept, adalimumab, anakinra, certolizumab pegol, etanercept, golimumab, infliximab, rituximab, tocilizumab) and small molecule tofacitinib versus comparator (methotrexate (MTX)/other DMARDs) in people with RA who are naive to methotrexate. In June 2015 we searched for randomized controlled trials (RCTs) in CENTRAL, MEDLINE and Embase; and trials registers. We used standard Cochrane methods. We calculated odds ratios (OR) and mean differences (MD) along with 95% confidence intervals (CI) for traditional meta-analyses and 95% credible intervals (CrI) using a Bayesian mixed treatment comparisons approach for network meta-analysis (NMA). We converted OR to risk ratios (RR) for ease of interpretation. We also present results in absolute measures as risk difference (RD) and number needed to treat for an additional beneficial or harmful outcome (NNTB/H). Nineteen RCTs with 6485 participants met inclusion criteria (including five studies from the original 2009 review), and data were available for four TNF biologics (adalimumab (six studies; 1851 participants), etanercept (three studies; 678 participants), golimumab (one study; 637 participants) and infliximab (seven studies; 1363 participants)) and two non-TNF biologics (abatacept (one study; 509 participants) and rituximab (one study; 748 participants)).Less than 50% of the studies were judged to be at low risk of bias for allocation sequence generation, allocation concealment and blinding, 21% were at low risk for selective reporting, 53% had low risk of bias for attrition and 89% had low risk of bias for major baseline imbalance. Three trials used biologic monotherapy, that is, without MTX. There were no trials with placebo-only comparators and no trials of tofacitinib. Trial duration ranged from 6 to 24 months. Half of the trials contained participants with early RA (less than two years' duration) and the other half included participants with established RA (2 to 10 years). Biologic + MTX versus active comparator (MTX (17 trials (6344 participants)/MTX + methylprednisolone 2 trials (141 participants))In traditional meta-analyses, there was moderate-quality evidence downgraded for inconsistency that biologics with MTX were associated with statistically significant and clinically meaningful benefit versus comparator as demonstrated by ACR50 (American College of Rheumatology scale) and RA remission rates. For ACR50, biologics with MTX showed a risk ratio (RR) of 1.40 (95% CI 1.30 to 1.49), absolute difference of 16% (95% CI 13% to 20%) and NNTB = 7 (95% CI 6 to 8). For RA remission rates, biologics with MTX showed a RR of 1.62 (95% CI 1.33 to 1.98), absolute difference of 15% (95% CI 11% to 19%) and NNTB = 5 (95% CI 6 to 7). Biologics with MTX were also associated with a statistically significant, but not clinically meaningful, benefit in physical function (moderate-quality evidence downgraded for inconsistency), with an improvement of HAQ scores of -0.10 (95% CI -0.16 to -0.04 on a 0 to 3 scale), absolute difference -3.3% (95% CI -5.3% to -1.3%) and NNTB = 4 (95% CI 2 to 15).We did not observe evidence of differences between biologics with MTX compared to MTX for radiographic progression (low-quality evidence, downgraded for imprecision and inconsistency) or serious adverse events (moderate-quality evidence, downgraded for imprecision). Based on low-quality evidence, results were inconclusive for withdrawals due to adverse events (RR of 1.32, but 95% confidence interval included possibility of important harm, 0.89 to 1.97). Results for cancer were also inconclusive (Peto OR 0.71, 95% CI 0.38 to 1.33) and downgraded to low-quality evidence for serious imprecision. Biologic without MTX versus active comparator (MTX 3 trials (866 participants)There was no evidence of statistically significant or clinically important differences for ACR50, HAQ, remission, (moderate-quality evidence for these benefits, downgraded for imprecision), withdrawals due to adverse events,and serious adverse events (low-quality evidence for these harms, downgraded for serious imprecision). All studies were for TNF biologic monotherapy and none for non-TNF biologic monotherapy. Radiographic progression was not measured. In MTX-naive RA participants, there was moderate-quality evidence that, compared with MTX alone, biologics with MTX was associated with absolute and relative clinically meaningful benefits in three of the efficacy outcomes (ACR50, HAQ scores, and RA remission rates). A benefit regarding less radiographic progression with biologics with MTX was not evident (low-quality evidence). We found moderate- to low-quality evidence that biologic therapy with MTX was not associated with any higher risk of serious adverse events compared with MTX, but results were inconclusive for withdrawals due to adverse events and cancer to 24 months.TNF biologic monotherapy did not differ statistically significantly or clinically meaningfully from MTX for any of the outcomes (moderate-quality evidence), and no data were available for non-TNF biologic monotherapy.We conclude that biologic with MTX use in MTX-naive populations is beneficial and that there is little/inconclusive evidence of harms. More data are needed for tofacitinib, radiographic progression and harms in this patient population to fully assess comparative efficacy and safety.