Safety of synthetic and biological DMARDs: A systematic literature review informing the 2016 update of the EULAR recommendations for management of rheumatoid arthritis

S. Ramiro, A. Sepriano, K. Chatzidionysiou, J.L. Nam, J.S. Smolen, D. Van Der Heijde, M. Dougados, R. Van Vollenhoven, J.W. Bijlsma, G.R. Burmester, M. Scholte-Voshaar, L. Falzon, R.B.M. Landewé

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Objectives To assess the safety of synthetic (s) and biological (b) disease-modifying antirheumatic drugs (DMARDs) for the management of rheumatoid arthritis (RA) to inform the European League Against Rheumatism recommendations for the management of RA. Methods Systematic literature review (SLR) of observational studies comparing any DMARD with another intervention for the management of patients with RA. All safety outcomes were included. A comparator group was required for the study to be included. Risk of bias was assessed with the Hayden's tool. Results Twenty-six observational studies addressing diverse safety outcomes of therapy with bDMARDs met eligibility criteria (15 on serious infections, 4 on malignancies). Substantial heterogeneity precluded meta-Analysis. Together with the evidence from the 2013 SLR, based on 15 studies, 7 at low risk of bias, patients on bDMARDs compared with patients on conventional sDMARDs had a higher risk of serious infections (adjusted HR (aHR) 1.1 to 1.8)-without differences across bDMARDs-a higher risk of tuberculosis (aHR 2.7 to 12.5), but no increased risk of infection by herpes zoster. Patients on bDMARDs did not have an increased risk of malignancies in general, lymphoma or non-melanoma skin cancer, but the risk of melanoma may be slightly increased (aHR 1.5). Conclusions These findings confirm the known safety pattern of bDMARDs, including both tumour necrosis factor-α inhibitor (TNFi) and non-TNFi, for the treatment of RA. © Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to
Original languageEnglish
Pages (from-to)1093-1101
Number of pages9
JournalAnnals of the rheumatic diseases
Issue number6
Publication statusPublished - Jun 2017


  • Anti-TNF
  • DMARDs (biologic)
  • DMARDs (synthetic)
  • Outcomes research
  • Rheumatoid Arthritis
  • abatacept
  • disease modifying antirheumatic drug
  • etanercept
  • glucocorticoid
  • infliximab
  • rituximab
  • tumor necrosis factor inhibitor
  • antirheumatic agent
  • biological product
  • protein kinase inhibitor
  • tumor necrosis factor
  • Article
  • autoimmune disease
  • cardiovascular disease
  • demyelinating disease
  • disease severity
  • drug efficacy
  • drug safety
  • gastrointestinal disease
  • hematologic disease
  • herpes zoster
  • human
  • kidney disease
  • lymphoma
  • malignant neoplasm
  • medical society
  • non melanoma skin cancer
  • observational study
  • opportunistic infection
  • priority journal
  • rheumatoid arthritis
  • risk assessment
  • risk factor
  • systematic review
  • teratogenicity
  • tuberculosis
  • antagonists and inhibitors
  • Arthritis, Rheumatoid
  • infection
  • Neoplasms
  • practice guideline
  • Antirheumatic Agents
  • Biological Products
  • Humans
  • Infection
  • Observational Studies as Topic
  • Practice Guidelines as Topic
  • Protein Kinase Inhibitors
  • Risk Factors
  • Tumor Necrosis Factor-alpha


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