Adalimumab, etanercept, infliximab, rituximab and abatacept for the treatment of rheumatoid arthritis after the failure of a tumour necrosis factor inhibitor: a systematic review and economic evaluation

Background: Rheumatoid arthritis (RA) is an inflammatory condition that typically causes a symmetrical chronic arthritis. Timely use of disease-modifying antirheumatic drugs (DMARDs) is an essential aspect of disease management, but many patients may not respond even when conventional agents are used optimally. Objective: To assess the clinical effectiveness and cost-effectiveness of adalimumab (ADA), etanercept (ETN), infliximab (IFX), rituximab (RTX) and abatacept (ABT) when used in patients with RA who have tried conventional agents and have failed to improve after trying a first tumour necrosis factor (TNF) inhibitor. Data sources: A systematic review of primary studies was undertaken. Databases searched included the Cochrane Library, MEDLINE (Ovid) and EMBASE up to July 2009. Study selection: Two reviewers assessed titles and abstracts of studies identified by the search strategy, obtained the full text of relevant papers and screened them against inclusion criteria. Study appraisal: Data from included studies were extracted by one reviewer and checked by a second. The quality of included studies was assessed independently by two reviewers, with any disagreements resolved by discussion and consultation with a third reviewer if necessary. Results: Thirty-five studies were included in the systematic review: five randomised controlled trials (RCTs), one comparative study, one controlled study and 28 uncontrolled studies. One RCT (REFLEX) demonstrated the effectiveness of RTX. At 6 months significantly more patients treated with RTX achieved American College of Rheumatology (ACR) 20 [relative risk (RR)=2.85, 95% confidence interval (Cl) 2.08 to 3.91] and ACR70 (RR=12.14, 95% Cl 2.96 to 49.86) compared with those treated with the placebo. Differences between groups in favour of RTX were observed at 6 months for mean change from baseline in Disease Activity Score 28 (DAS28) (mean difference -1.50, 95% Cl -1.74 to -1.26) and mean change from baseline in Health Assessment Questionnaire (HAQ) score (mean difference -0.30, 95% Cl -0.40 to -0.20). One RCT (ATTAIN) demonstrated the effectiveness of ABT. At 6 months significantly more patients treated with ABT achieved ACR20 (RR=2.56, 95% Cl 1.77 to 3.69) and ACR70 (RR=6.70, 95% Cl 1.62 to 27.80) compared with those treated with placebo. Significant differences between groups in favour of ABT were observed at 6 months for mean change from baseline in DAS28 score (mean difference -1.27, 95% Cl -1.62 to -0.93) and mean change from baseline in HAQ score (mean difference -0.34). Twenty-eight uncontrolled studies observed improvement of effectiveness compared with before switching, in patients who switched to ADA, ETN or IFX after discontinued previous TNF inhibitor(s). Four studies were included in the systematic review of cost-effectiveness. Independent economic evaluation undertaken by the assessment group showed that compared with DMARDs, the incremental cost-effectiveness ratios (ICERs) were 34,300 pound [per quality-adjusted life-year (QALY)] for ADA, 38,800 pound for ETN, 36,200 pound for IFX, 21,200 pound for RTX and 38,600 pound for ABT. RTX dominates the TNF inhibitors and the ICER for ABT compared with RTX is over 100,000 pound (per QALY). Limitations: Paucity of evidence from RCTs for assessing the clinical effectiveness of TNF inhibitors and an absence of head-to-head trials comparing the five technologies. Conclusions: Evidence from RCTs suggests that RTX and ABT are more effective than supportive care. Data from observational studies suggest that the use of an alternative TNF inhibitor in patients who exhibit an inadequate response to a first TNF inhibitor may offer some benefit, but there remain uncertainties with regard to the magnitude of treatment effects and their cost-effectiveness. Future research should include head-to-head trials comparing the clinical effectiveness and cost-effectiveness of the technologies against each other and emerging biologics.