title: Adverse effects of biologics: a network meta-analysis and Cochrane overview.
abstract: BACKGROUND
  Biologics are used for the treatment of rheumatoid arthritis and many other conditions. While the efficacy of biologics has been established, there is uncertainty regarding the adverse effects of this treatment. Since serious risks such as tuberculosis (TB) reactivation, serious infections, and lymphomas may be common to the biologics but occur in small numbers across the various indications, we planned to combine the results from biologics used in many conditions to obtain the much needed risk estimates.
  
  
  OBJECTIVE
  To compare the adverse effects of tumor necrosis factor blocker (etanercept, adalimumab, infliximab, golimumab, certolizumab), interleukin (IL)-1 antagonist (anakinra), IL-6 antagonist (tocilizumab), anti-CD28 (abatacept), and anti-B cell (rituximab) therapy in patients with any disease condition except human immunodeficiency disease (HIV/AIDS).
  
  
  METHODS
  Randomized controlled trials (RCTs), controlled clinical trials (CCTs) and open-label extension (OLE) studies that studied one of the nine biologics for use in any indication (with the exception of HIV/AIDS) and that reported our pre-specified adverse outcomes were considered for inclusion. We searched The Cochrane Library, MEDLINE, and EMBASE (to January 2010). Identifying search results and data extraction were performed independently and in duplicate. For the network meta-analysis, we performed mixed-effects logistic regression using an arm-based, random-effects model within an empirical Bayes framework.
  
  
  RESULTS
  We included 163 RCTs with 50,010 participants and 46 extension studies with 11,954 participants. The median duration of RCTs was six months and 13 months for OLEs. Data were limited for tuberculosis (TB) reactivation, lymphoma, and congestive heart failure. Adjusted for dose, biologics as a group were associated with a statistically significant higher rate of total adverse events (odds ratio (OR) 1.19, 95% CI 1.09 to 1.30; number needed to treat to harm (NNTH) = 30, 95% CI 21 to 60) and withdrawals due to adverse events (OR 1.32, 95% CI 1.06 to 1.64; NNTH = 37, 95% CI 19 to 190) and an increased risk of TB reactivation (OR 4.68, 95% CI 1.18 to 18.60; NNTH = 681, 95% CI 143 to 14706) compared to control.The rate of serious adverse events, serious infections, lymphoma, and congestive heart failure were not statistically significantly different between biologics and control treatment. Certolizumab pegol was associated with significantly higher risk of serious infections compared to control treatment (OR 3.51, 95% CI 1.59 to 7.79; NNTH = 17, 95% CI 7 to 68). Infliximab was associated with significantly higher risk of withdrawals due to adverse events compared to control (OR 2.04, 95% CI 1.43 to 2.91; NNTH = 12, 95% CI 8 to 28). Indirect comparisons revealed that abatacept and anakinra were associated with a significantly lower risk of serious adverse events compared to most other biologics.  Although the overall numbers are relatively small, certolizumab pegol was associated with significantly higher odds of serious infections compared to etanercept, adalimumab, abatacept, anakinra, golimumab, infliximab, and rituximab; abatacept was significantly less likely than infliximab and tocilizumab to be associated with serious infections.  Abatacept, adalimumab, etanercept and golimumab were significantly less likely than infliximab to result in withdrawals due to adverse events.
  
  
  CONCLUSIONS
  Overall, in the short term biologics were associated with significantly higher rates of total adverse events, withdrawals due to adverse events and TB reactivation. Some biologics had a statistically higher association with certain adverse outcomes compared to control, but there was no consistency across the outcomes so caution is needed in interpreting these results.There is an urgent need for more research regarding the long-term safety of biologics and the comparative safety of different biologics. National and international registries and other types of large databases are relevant sources for providing complementary evidence regarding the short- and longer-term safety of biologics.
authors.affiliation: Department of Medicine, Birmingham VA Medical Center, Faculty Office Tower 805B, 510 20th Street South, Birmingham, USA, AL 35294.
authors.forename: Jasvinder A
authors.initials: JA
authors.lastname: Singh
authors.forename: George A
authors.initials: GA
authors.lastname: Wells
authors.forename: Robin
authors.initials: R
authors.lastname: Christensen
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Tanjong Ghogomu
authors.forename: Lara
authors.initials: L
authors.lastname: Maxwell
authors.forename: John K
authors.initials: JK
authors.lastname: Macdonald
authors.forename: Graziella
authors.initials: G
authors.lastname: Filippini
authors.forename: Nicole
authors.initials: N
authors.lastname: Skoetz
authors.forename: Damian
authors.initials: D
authors.lastname: Francis
authors.forename: Luciane C
authors.initials: LC
authors.lastname: Lopes
authors.forename: Gordon H
authors.initials: GH
authors.lastname: Guyatt
authors.forename: Jochen
authors.initials: J
authors.lastname: Schmitt
authors.forename: Loredana
authors.initials: L
authors.lastname: La Mantia
authors.forename: Tobias
authors.initials: T
authors.lastname: Weberschock
authors.forename: Juliana F
authors.initials: JF
authors.lastname: Roos
authors.forename: Hendrik
authors.initials: H
authors.lastname: Siebert
authors.forename: Sarah
authors.initials: S
authors.lastname: Hershan
authors.forename: Michael Pt
authors.initials: MP
authors.lastname: Lunn
authors.forename: Peter
authors.initials: P
authors.lastname: Tugwell
authors.forename: Rachelle
authors.initials: R
authors.lastname: Buchbinder
mesh_terms: D006801:Humans; D000911:Antibodies, Monoclonal / Q000009:adverse effects; D001688:Biological Products / Q000009:adverse effects; D007155:Immunologic Factors / Q000009:adverse effects; D010352:Patient Dropouts / Q000706:statistics & numerical data; D016032:Randomized Controlled Trials as Topic
chemical_list: D000911:Antibodies, Monoclonal; D001688:Biological Products; D007155:Immunologic Factors