Simon Tarp1, Daniel E Furst2, Anna Dossing3, Mikkel Østergaard4, Tove Lorenzen5, Michael S Hansen6, Jasvinder A Singh7, Ernest H Choy8, Maarten Boers9, Maria E Suarez-Almazor10, Lars E Kristensen3, Henning Bliddal3, Robin Christensen3. 1. Musculoskeletal Statistics Unit, The Parker Institute, Bispebjerg og Frederiksberg Hospital, The Capital Region, Copenhagen, Denmark. Electronic address: simon.tarp@regionh.dk. 2. Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA. 3. Musculoskeletal Statistics Unit, The Parker Institute, Bispebjerg og Frederiksberg Hospital, The Capital Region, Copenhagen, Denmark. 4. Copenhagen Center for Arthritis Research, Center for Rheumatology and Spine Diseases, Glostrup Hospital, Copenhagen, Denmark; Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark. 5. Department of Rheumatology, Diagnostic Centre, Silkeborg Regional Hospital, Copenhagen, Denmark. 6. ReumaKlinik Roskilde, Roskilde, Denmark; Gildhøj Privathospital, Brøndby, Denmark. 7. Medicine Service and Center for Surgical Medical Acute care Research and Transitions, VA Medical Center, Birmingham, AL; Department of Medicine at School of Medicine, Division of Epidemiology at School of Public Health, University of Alabama, Birmingham, AL; Department of Orthopedic Surgery, Mayo Clinic College of Medicine, Rochester, MN. 8. Section of Rheumatology, Arthritis Research UK and Health and Care Research Wales CREATE Centre, Cardiff University School of Medicine, Cardiff, UK. 9. Department of Epidemiology & Biostatistics, VU University Medical Center, Amsterdam, The Netherlands; Amsterdam Rheumatology and Immunology Center, VU University Medical Center, Amsterdam, The Netherlands. 10. Section of Rheumatology and Clinical Immunology, University of Texas MD Anderson Cancer Center, Houston, TX.
Abstract
OBJECTIVES: To summarize and compare the benefits and harms of biological agents used as monotherapy for rheumatoid arthritis (RA) in order to inform decisions for patients who are intolerant to conventional DMARD therapy. METHODS: We searched MEDLINE, EMBASE, CENTRAL, and other sources for randomised trials that compared biological monotherapy with methotrexate, placebo, or other biological monotherapies. Primary outcomes were ACR50 and the number of patients who discontinued due to adverse events. Our network meta-analysis was based on mixed-effects logistic regression, including both direct and indirect comparisons of the treatment effects, while preserving the randomised comparisons within each trial. PROSPERO identifier: CRD42012002800. RESULTS: The analysis comprises 28 trials (8602 patients), including all nine biological agents approved for RA. Eight trials included "DMARD-naïve", and 20 "DMARD-Inadequate responder" (DMARD-IR) patients. All agents except anakinra and infliximab were superior (p < 0.05) to placebo (i.e., no DMARD treatment) with regard to ACR50. Etanercept and rituximab were superior to anakinra (p = 0.018 and p = 0.049, respectively). Tocilizumab was superior to adalimumab (p = 0.0082), anakinra (p = 0.0083), certolizumab (p = 0.037), and golimumab (p = 0.049). No differences among etanercept, tocilizumab, and rituximab were found (p > 0.52). However, because rituximab was evaluated in just 40 patients, our confidence in the estimates is limited. When including only DMARD-IR trials, the same statistical pattern emerged; in addition etanercept and tocilizumab were superior to abatacept. At recommended doses, both etanercept and tocilizumab were superior to adalimumab and certolizumab. No statistically significant differences among biological agents were found with respect to discontinuation due to adverse events (p > 0.068). CONCLUSIONS: Evidence from randomised trials suggests that most biological agents are effective as monotherapy. Although our confidence in the estimates is limited, etanercept or tocilizumab may be the optimal choice for most patients who need treatment with biological monotherapy. However, given our limited confidence in the estimates including possibility of bias, it is appropriate to strongly weight patients׳ preferences and values in the final treatment choice.
OBJECTIVES: To summarize and compare the benefits and harms of biological agents used as monotherapy for rheumatoid arthritis (RA) in order to inform decisions for patients who are intolerant to conventional DMARD therapy. METHODS: We searched MEDLINE, EMBASE, CENTRAL, and other sources for randomised trials that compared biological monotherapy with methotrexate, placebo, or other biological monotherapies. Primary outcomes were ACR50 and the number of patients who discontinued due to adverse events. Our network meta-analysis was based on mixed-effects logistic regression, including both direct and indirect comparisons of the treatment effects, while preserving the randomised comparisons within each trial. PROSPERO identifier: CRD42012002800. RESULTS: The analysis comprises 28 trials (8602 patients), including all nine biological agents approved for RA. Eight trials included "DMARD-naïve", and 20 "DMARD-Inadequate responder" (DMARD-IR) patients. All agents except anakinra and infliximab were superior (p < 0.05) to placebo (i.e., no DMARD treatment) with regard to ACR50. Etanercept and rituximab were superior to anakinra (p = 0.018 and p = 0.049, respectively). Tocilizumab was superior to adalimumab (p = 0.0082), anakinra (p = 0.0083), certolizumab (p = 0.037), and golimumab (p = 0.049). No differences among etanercept, tocilizumab, and rituximab were found (p > 0.52). However, because rituximab was evaluated in just 40 patients, our confidence in the estimates is limited. When including only DMARD-IR trials, the same statistical pattern emerged; in addition etanercept and tocilizumab were superior to abatacept. At recommended doses, both etanercept and tocilizumab were superior to adalimumab and certolizumab. No statistically significant differences among biological agents were found with respect to discontinuation due to adverse events (p > 0.068). CONCLUSIONS: Evidence from randomised trials suggests that most biological agents are effective as monotherapy. Although our confidence in the estimates is limited, etanercept or tocilizumab may be the optimal choice for most patients who need treatment with biological monotherapy. However, given our limited confidence in the estimates including possibility of bias, it is appropriate to strongly weight patients׳ preferences and values in the final treatment choice.
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