title: Risk of serious adverse effects of biological and targeted drugs in patients with rheumatoid arthritis: a systematic review meta-analysis.
abstract: To determine possible differences in serious adverse effects among the 10 currently approved biological and targeted synthetic DMARDs (b/ts-DMARDs) for RA.
  
  
  
  Systematic review in bibliographic databases, trial registries and websites of regulatory agencies identified randomized trials of approved b/ts-DMARDs for RA. Network meta-analyses using mixed-effects Poisson regression models were conducted to calculate rate ratios for serious adverse events (SAEs) and deaths between each of the 10 drugs and control (i.e. no b/ts-DMARD treatment), based on subjects experiencing an event in relation to person-years. Confidence in the estimates was assessed by applying the Grading of Recommendations Assessment, Development and Evaluation approach (GRADE).
  
  
  
  A total of 117 trials (47 615 patients) were included. SAEs were more common with certolizumab compared with abatacept (rate ratio = 1.58, 95% CI: 1.18, 2.14), adalimumab (1.36, 95% CI: 1.02, 1.81), etanercept (1.60, 95% CI: 1.18, 2.17), golimumab (1.45, 95% CI: 1.00, 2.08), rituximab (1.63, 95% CI: 1.16, 2.30), tofacitinib (1.44, 95% CI: 1.03, 2.02) and control (1.45, 95% CI: 1.13, 1.87); and tocilizumab compared with abatacept (1.30, 95% CI: 1.03, 1.65), etanercept (1.31, 95% CI: 1.04, 1.67) and rituximab (1.34, 95% CI: 1.01, 1.78). No other comparisons were statistically significant. Accounting for study duration confirmed our findings for up to 6 months' treatment but not for longer-term treatment (6-24 months). No differences in mortality between b/ts-DMARDs and control were found. Based on the GRADE approach, confidence in the estimates was low due to lack of head-to-head comparison trials and imprecision in indirect estimates.
  
  
  
  Despite low confidence in the estimates, our analysis found potential differences in rates of SAEs. Our data suggest caution should be taken when deciding among available drugs.
  
  
  
  PROSPERO CRD42014014842.
authors.affiliation: Musculoskeletal Statistics Unit, The Parker Institute, Copenhagen University Hospital at Bispebjerg and Frederiksberg, Copenhagen, Denmark.
authors.forename: Simon
authors.initials: S
authors.lastname: Tarp
authors.affiliation: David Geffen School of Medicine, University of California Los Angeles, CA.|Division of Rheumatology, University of Washington, Seattle, WA, USA.|Division of Rheumatology, University of Florence, Florence, Italy.
authors.forename: Daniel
authors.initials: D
authors.lastname: Eric Furst
authors.affiliation: Department of Epidemiology and Biostatistics.|Amsterdam Rheumatology and Immunology Center, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Maarten
authors.initials: M
authors.lastname: Boers
authors.affiliation: Department of Biostatistics, Bioinformatics, and Biomathematics, Georgetown University Medical Center, Washington, DC, USA.
authors.forename: George
authors.initials: G
authors.lastname: Luta
authors.affiliation: Musculoskeletal Statistics Unit, The Parker Institute, Copenhagen University Hospital at Bispebjerg and Frederiksberg, Copenhagen, Denmark.
authors.forename: Henning
authors.initials: H
authors.lastname: Bliddal
authors.affiliation: Department of Rheumatology, Aarhus University Hospital, Aarhus N.
authors.forename: Ulrik
authors.initials: U
authors.lastname: Tarp
authors.affiliation: Department of Rheumatology, Copenhagen University Hospital at Bispebjerg and Frederiksberg, Copenhagen.
authors.forename: Karsten
authors.initials: K
authors.lastname: Heller Asmussen
authors.affiliation: Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus N.
authors.forename: Birgitte
authors.initials: B
authors.lastname: Brock
authors.affiliation: Musculoskeletal Statistics Unit, The Parker Institute, Copenhagen University Hospital at Bispebjerg and Frederiksberg, Copenhagen, Denmark.
authors.forename: Anna
authors.initials: A
authors.lastname: Dossing
authors.affiliation: Musculoskeletal Statistics Unit, The Parker Institute, Copenhagen University Hospital at Bispebjerg and Frederiksberg, Copenhagen, Denmark.
authors.forename: Tanja
authors.initials: T
authors.lastname: Schjødt Jørgensen
authors.affiliation: Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Steffen
authors.initials: S
authors.lastname: Thirstrup
authors.affiliation: Musculoskeletal Statistics Unit, The Parker Institute, Copenhagen University Hospital at Bispebjerg and Frederiksberg, Copenhagen, Denmark.
authors.forename: Robin
authors.initials: R
authors.lastname: Christensen
mesh_terms: D000069594:Abatacept / Q000009:adverse effects; D000068879:Adalimumab / Q000009:adverse effects; D000911:Antibodies, Monoclonal / Q000009:adverse effects; D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects; D018501:Antirheumatic Agents / Q000009:adverse effects*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy*; D001688:Biological Products / Q000009:adverse effects*; D000068582:Certolizumab Pegol / Q000009:adverse effects; D000068800:Etanercept / Q000009:adverse effects; D006801:Humans; D010880:Piperidines / Q000009:adverse effects; D016012:Poisson Distribution; D011743:Pyrimidines / Q000009:adverse effects; D011758:Pyrroles / Q000009:adverse effects; D012044:Regression Analysis; D012306:Risk; D000069283:Rituximab / Q000009:adverse effects
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D001688:Biological Products; D010880:Piperidines; D011743:Pyrimidines; D011758:Pyrroles; D000069283:Rituximab; D000069594:Abatacept; C479163:tofacitinib; C529000:golimumab; D000068879:Adalimumab; C502936:tocilizumab; D000068800:Etanercept; D000068582:Certolizumab Pegol
keywords: biological agents; indirect comparison; meta-analysis; mortality; network meta-analysis; rheumatoid arthritis; serious adverse events; systematic review; targeted synthetic disease-modifying antirheumatic drugs