title: Risk of serious infection in biological treatment of patients with rheumatoid arthritis: a systematic review and meta-analysis.
abstract: BACKGROUND
  Serious infections are a major concern for patients considering treatments for rheumatoid arthritis. Evidence is inconsistent as to whether biological drugs are associated with an increased risk of serious infection compared with traditional disease-modifying antirheumatic drugs (DMARDs). We did a systematic review and meta-analysis of serious infections in patients treated with biological drugs compared with those treated with traditional DMARDs.
  
  
  METHODS
  We did a systematic literature search with Medline, Embase, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov from their inception to Feb 11, 2014. Search terms included "biologics", "rheumatoid arthritis" and their synonyms. Trials were eligible for inclusion if they included any of the approved biological drugs and reported serious infections. We assessed the risk of bias with the Cochrane Risk of Bias Tool. We did a Bayesian network meta-analysis of published trials using a binomial likelihood model to assess the risk of serious infections in patients with rheumatoid arthritis who were treated with biological drugs, compared with those treated with traditional DMARDs. The odds ratio (OR) of serious infection was the primary measure of treatment effect and calculated 95% credible intervals using Markov Chain Monte Carlo methods.
  
  
  RESULTS
  The systematic review identified 106 trials that reported serious infections and included patients with rheumatoid arthritis who received biological drugs. Compared with traditional DMARDs, standard-dose biological drugs (OR 1.31, 95% credible interval [CrI] 1.09-1.58) and high-dose biological drugs (1.90, 1.50-2.39) were associated with an increased risk of serious infections, although low-dose biological drugs (0.93, 0.65-1.33) were not. The risk was lower in patients who were methotrexate naive compared with traditional DMARD-experienced or anti-tumour necrosis factor biological drug-experienced patients. The absolute increase in the number of serious infections per 1000 patients treated each year ranged from six for standard-dose biological drugs to 55 for combination biological therapy, compared with traditional DMARDs.
  
  
  CONCLUSIONS
  Standard-dose and high-dose biological drugs (with or without traditional DMARDs) are associated with an increase in serious infections in rheumatoid arthritis compared with traditional DMARDs, although low-dose biological drugs are not. Clinicians should discuss the balance between benefit and harm with the individual patient before starting biological treatment for rheumatoid arthritis.
  
  
  BACKGROUND
  Rheumatology Division at the University of Alabama at Birmingham.
authors.affiliation: Birmingham Veterans Affairs Medical Center, Birmingham, AL, USA; Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, AL, USA; Department of Orthopedic Surgery, Mayo Clinic College of Medicine, Rochester, MN, USA. Electronic address: jasvinder.md@gmail.com.
authors.forename: Jasvinder A
authors.initials: JA
authors.lastname: Singh
authors.affiliation: School of Epidemiology, Public Health and Preventive Medicine, University of Ottawa, ON, Canada; University of Ottawa Heart Institute, Ottawa, ON, Canada.
authors.forename: Chris
authors.initials: C
authors.lastname: Cameron
authors.affiliation: American University, Washington, DC, USA.
authors.forename: Shahrzad
authors.initials: S
authors.lastname: Noorbaloochi
authors.affiliation: Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Tyler
authors.initials: T
authors.lastname: Cullis
authors.affiliation: Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Tucker
authors.affiliation: Musculoskeletal Statistics Unit, The Parker Institute, Department of Rheumatology, Copenhagen University Hospitals, Bispebjerg and Frederiksberg, Denmark.
authors.forename: Robin
authors.initials: R
authors.lastname: Christensen
authors.affiliation: School of Epidemiology, Public Health and Preventive Medicine, University of Ottawa, ON, Canada.
authors.forename: Elizabeth Tanjong
authors.initials: ET
authors.lastname: Ghogomu
authors.affiliation: School of Epidemiology, Public Health and Preventive Medicine, University of Ottawa, ON, Canada.
authors.forename: Doug
authors.initials: D
authors.lastname: Coyle
authors.affiliation: School of Epidemiology, Public Health and Preventive Medicine, University of Ottawa, ON, Canada.
authors.forename: Tammy
authors.initials: T
authors.lastname: Clifford
authors.affiliation: School of Epidemiology, Public Health and Preventive Medicine, University of Ottawa, ON, Canada.
authors.forename: Peter
authors.initials: P
authors.lastname: Tugwell
authors.affiliation: School of Epidemiology, Public Health and Preventive Medicine, University of Ottawa, ON, Canada; University of Ottawa Heart Institute, Ottawa, ON, Canada.
authors.forename: George A
authors.initials: GA
authors.lastname: Wells
mesh_terms: D018501:Antirheumatic Agents / Q000009:adverse effects*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy*; D001685:Biological Factors / Q000009:adverse effects*; D006801:Humans; D009894:Opportunistic Infections / Q000139:chemically induced*; D016032:Randomized Controlled Trials as Topic; D012307:Risk Factors
chemical_list: D018501:Antirheumatic Agents; D001685:Biological Factors