Eficácia comparada do rtuximab, abatacept e tocilizumab em pacientes com artrite reumatóide refratária ao metotrexato ou agentes Anti-TNF: uma revisão sistemática e meta-análise em rede

Abstract

Background: Although disease-modifying antirheumatic drugs (DMARD), including synthetic ones, such as methotrexate (MTX), and biological ones (bDMARD), such as tumor necrosis-factor inhibitors (anti-TNF agents), have unquestionably improved the quality of life of individuals with rheumatoid arthritis (RA), at least one third of individuals do not respond to these treatments. Rituximab, abatacept, and tocilizumab are bDMARD options available, but it is unclear whether any of these drugs is superior to the others. Objective: To compare the efficacy of rituximab, tocilizumab, and abatacept in individuals with RA refractory to treatments with MTX or anti-TNF agents as general objectives and to systematically review the literature through randomized clinical trials and indirectly compare treatments for RA between rituximab, tocilizumab and abatacept; to evaluate the impact of treatments for RA with rituximab, tocilizumab and abatacept on ACR response as specific objectives. Data sources: PubMed, Cochrane Library, Embase, Web of Science, Scopus, LILACS and Gray Literature (Opengrey and Academic Google) until July 18, 2020. Study selection: Phase 2-4 randomized controlled trials (RCTs) evaluating patients with RA refractory to MTX or anti-TNF therapy treated with rituximab, abatacept, and tocilizumab (intervention arm) compared to controls. Data extraction: Study characteristics, quality, and data were independently assessed by two investigators. The primary outcome was a 70% reduction in disease activity according to the American College of Rheumatology response criteria (ACR70). A revisão foi registrada na base International Prospective Register of Systematic Reviews do Centre for Reviews and Dissemination / University of York (PROSPERO). Número do registo: CRD42020167953. Data synthesis: The meta-analysis included 19 RCTs, with 7,835 patients randomized to the intervention vs. control arms and a mean study duration of 1.2 years. The mean age was 52.3 years, 77.2% of individuals were women, and the mean disease duration was 8.7 years. The drugs rituximab, tocilizumab and abatacept were compared with placebo in 13 clinical trials and with active comparator (anti-TNF) in 6 clinical trials as adjuvant treatment. The hazard ratios (HRs) for achieving an ACR70 response at six months were not different among the bDMARDs when compared to placebo, however, there was a high heterogeneity. Three factors showing a critical imbalance among the bDMARD classes were identified: baseline HAQ (Health Assessment Questionaire) score, study duration, and frequency of anti-TNF treatment in the control arm. These explanatory variables were chosen based on their association with ACR70 response in univariate regressions and the presence of imbalance between treatment arms with respect to these characteristics. To better understand the heterogeneity among RCTs, multivariate meta-regression adjusted to these three factors were conducted for the relative risk (RR) for achieving an ACR70 response during the study follow-up. Thus, heterogeneity was attenuated (I2 = 24%, p for heterogeneity = 0.27) and the explanatory power of the model increased (R2 = 85%). In this model, rituximab did not modify the chance of achieving an ACR70 response compared to abatacept (RR = 1.773, 95% CI 0.113–10.21, p = 0.765). In contrast, abatacept was associated with a RR = 2.217 (95% CI 1.554–3.161, p < 0.001) for ACR70 compared to tocilizumab. Conclusion: In the network meta-analysis, there was no significant difference among tocilizumab, abatacept, and rituximab in achieving an ACR70 response, there being a low inconsistency, but high heterogeneity among studies. Based on the result of multivariate meta-regressions, if the conditions of the RCTs were similar, we estimate that abatacept could increase the chance of reaching an ACR70 response by 2.2-fold compared to tocilizumab.