Jasvinder A Singh1, Chris Cameron2, Shahrzad Noorbaloochi3, Tyler Cullis4, Matthew Tucker4, Robin Christensen5, Elizabeth Tanjong Ghogomu6, Doug Coyle6, Tammy Clifford6, Peter Tugwell6, George A Wells2. 1. 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. 2. School of Epidemiology, Public Health and Preventive Medicine, University of Ottawa, ON, Canada; University of Ottawa Heart Institute, Ottawa, ON, Canada. 3. American University, Washington, DC, USA. 4. Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, AL, USA. 5. Musculoskeletal Statistics Unit, The Parker Institute, Department of Rheumatology, Copenhagen University Hospitals, Bispebjerg and Frederiksberg, Denmark. 6. School of Epidemiology, Public Health and Preventive Medicine, University of Ottawa, ON, Canada.
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. FINDINGS: 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. INTERPRETATION: 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. FUNDING: Rheumatology Division at the University of Alabama at Birmingham.
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. FINDINGS: 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. INTERPRETATION: 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. FUNDING: Rheumatology Division at the University of Alabama at Birmingham.
Authors: John P A Ioannidis; Fotini B Karassa; Eric Druyts; Kristian Thorlund; Edward J Mills Journal: Nat Rev Rheumatol Date: 2013-09-03 Impact factor: 20.543
Authors: Tim Bongartz; Alex J Sutton; Michael J Sweeting; Iain Buchan; Eric L Matteson; Victor Montori Journal: JAMA Date: 2006-05-17 Impact factor: 56.272
Authors: Sebastian Schneeweiss; Soko Setoguchi; Michael E Weinblatt; Jeffrey N Katz; Jerry Avorn; Paul E Sax; Raisa Levin; Daniel H Solomon Journal: Arthritis Rheum Date: 2007-06
Authors: Rebecca M Turner; Jonathan Davey; Mike J Clarke; Simon G Thompson; Julian Pt Higgins Journal: Int J Epidemiol Date: 2012-03-29 Impact factor: 7.196
Authors: Cécile Gaujoux-Viala; Jackie Nam; Sofia Ramiro; Robert Landewé; Maya H Buch; Josef S Smolen; Laure Gossec Journal: Ann Rheum Dis Date: 2014-01-06 Impact factor: 19.103
Authors: Sofia Dias; Nicky J Welton; Alex J Sutton; Deborah M Caldwell; Guobing Lu; A E Ades Journal: Med Decis Making Date: 2013-07 Impact factor: 2.583
Authors: Josef S Smolen; Robert Landewé; Ferdinand C Breedveld; Maya Buch; Gerd Burmester; Maxime Dougados; Paul Emery; Cécile Gaujoux-Viala; Laure Gossec; Jackie Nam; Sofia Ramiro; Kevin Winthrop; Maarten de Wit; Daniel Aletaha; Neil Betteridge; Johannes W J Bijlsma; Maarten Boers; Frank Buttgereit; Bernard Combe; Maurizio Cutolo; Nemanja Damjanov; Johanna M W Hazes; Marios Kouloumas; Tore K Kvien; Xavier Mariette; Karel Pavelka; Piet L C M van Riel; Andrea Rubbert-Roth; Marieke Scholte-Voshaar; David L Scott; Tuulikki Sokka-Isler; John B Wong; Désirée van der Heijde Journal: Ann Rheum Dis Date: 2013-10-25 Impact factor: 19.103
Authors: Susan M Goodman; Allina A Nocon; Nicolas A Selemon; Bo Shopsin; Yi Fulmer; Mary E Decker; Sarah E Grond; Laura T Donlin; Mark P Figgie; Thomas P Sculco; Linda A Russell; Michael E Henry; Anne R Bass; Andy O Miller; Peter K Sculco Journal: J Arthroplasty Date: 2019-01-17 Impact factor: 4.757
Authors: Michael D George; Joshua F Baker; Kevin Winthrop; Jesse Y Hsu; Qufei Wu; Lang Chen; Fenglong Xie; Huifeng Yun; Jeffrey R Curtis Journal: Ann Intern Med Date: 2020-09-22 Impact factor: 25.391
Authors: Jorge A Zamora-Legoff; Megan L Krause; Cynthia S Crowson; Jay H Ryu; Eric L Matteson Journal: Clin Rheumatol Date: 2016-07-22 Impact factor: 2.980