title: Comparative effectiveness and safety of biological treatment options after tumour necrosis factor α inhibitor failure in rheumatoid arthritis: systematic review and indirect pairwise meta-analysis.
abstract: BACKGROUND
  Optimal treatment for rheumatoid arthritis (RA) after inadequate response (IR) to tumour necrosis factor α inhibitors (TNFi) remains uncertain.
  
  
  OBJECTIVE
  To compare the efficacy and safety of biological agents after TNFi-IR.
  
  
  METHODS
  A systematic literature search was carried out using Medline and Cochrane databases, as well as http://www.clinicaltrials.gov, and bibliographies of the retrieved literature were searched by hand. Randomised, placebo-controlled trials that enrolled patients with RA with TNFi-IR were included and American College of Rheumatology (ACR) response as primary efficacy outcome and adverse events (AEs), serious adverse events (SAEs) and serious infections (SIs) as safety measures were extracted. An indirect meta-analysis with pairwise comparisons of efficacy and safety data was then carried out using ORs or risk differences (RDs) in a random effects model.
  
  
  RESULTS
  In four randomised controlled trials with 24 weeks' follow-up, direct comparisons of abatacept, golimumab, rituximab and tocilizumab versus placebo showed statistically significant mean ORs of 3.3-8.9 for ACR20, 5.5-10.2 for ACR50 and 4.1-13.5 for ACR70. Risks of AEs, SAEs and SIs versus placebo were non-significant. Indirect pairwise comparisons of the four biological agents showed no significant differences in ACR50 and ACR70. Golimumab had a significantly lower OR (0.56-0.59) for ACR20 but significantly fewer AEs (RD 0.13-0.18). Efficacy after one versus multiple TNFi failures did not differ significantly between the different biological agents.
  
  
  CONCLUSIONS
  In patients refractory to one or more TNFi, new biological agents provide significant improvement with good safety. Lacking head-to-head trials, indirect meta-analysis enables a comparison of effectiveness and safety of biological agents with each other and shows that all biological agents have similar effects.
authors.affiliation: 2nd Department of Internal Medicine, Hietzing Hospital, Vienna, Austria. monika.schoels@chello.at
authors.forename: Monika
authors.initials: M
authors.lastname: Schoels
authors.forename: Daniel
authors.initials: D
authors.lastname: Aletaha
authors.forename: Josef S
authors.initials: JS
authors.lastname: Smolen
authors.forename: John B
authors.initials: JB
authors.lastname: Wong
mesh_terms: D000069594:Abatacept; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use; D058846:Antibodies, Monoclonal, Murine-Derived / Q000627:therapeutic use; D018501:Antirheumatic Agents / Q000627:therapeutic use*; D057915:Drug Substitution; D005260:Female; D006801:Humans; D018796:Immunoconjugates / Q000627:therapeutic use; D016239:MEDLINE; D008297:Male; D008875:Middle Aged; D016032:Randomized Controlled Trials as Topic; D012213:Rheumatic Fever / Q000188:drug therapy*; D000069283:Rituximab; D017211:Treatment Failure; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D058846:Antibodies, Monoclonal, Murine-Derived; D018501:Antirheumatic Agents; D018796:Immunoconjugates; D014409:Tumor Necrosis Factor-alpha; D000069283:Rituximab; D000069594:Abatacept; C529000:golimumab; C502936:tocilizumab