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Safety of synthetic and biological DMARDs: a systematic literature review informing the 2013 update of the EULAR recommendations for management of rheumatoid arthritis
  1. Sofia Ramiro1,2,
  2. Cécile Gaujoux-Viala3,
  3. Jackie L Nam4,5,
  4. Josef S Smolen6,7,
  5. Maya Buch4,5,
  6. Laure Gossec8,
  7. Désirée van der Heijde9,
  8. Kevin Winthrop10,
  9. Robert Landewé1,11
  1. 1Department of Clinical Immunology & Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
  2. 2Department of Rheumatology, Hospital Garcia de Orta, Almada, Portugal
  3. 3Department of Rheumatology, Nîmes University Hospital, EA 2415, Montpellier I University, Nimes, France
  4. 4Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Chapel Allerton Hospital Leeds, Leeds, UK
  5. 5NIHR Leeds Musculoskeletal Biomedical Research Unit, Leeds Teaching Hospitals NHS Trust, Leeds, UK
  6. 6Division of Rheumatology, Department of Medicine 3, Medical University of Vienna, Vienna, Austria
  7. 72nd Department of Medicine, Hietzing Hospital Vienna, Vienna, Austria
  8. 8Department of Rheumatology, UPMC Univ Paris 06, GRC-UPMC 08 (EEMOIS), AP-HP, Pitié Salpêtrière Hospital, Paris, France
  9. 9Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands
  10. 10Oregon Health and Science University, Portland, Oregon, USA
  11. 11Department of Rheumatology, Atrium Medical Center, Heerlen, The Netherlands
  1. Correspondence to Dr Sofia Ramiro, Department of Clinical Immunology & Rheumatology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, Amsterdam 1105 AZ, The Netherlands; sofiaramiro{at}gmail.com

Abstract

Objectives To update the evidence for the safety of synthetic disease-modifying antirheumatic drugs (sDMARDs), glucocorticoids (GC) and biological DMARDs (bDMARDs) in patients with rheumatoid arthritis (RA) to inform the European League Against Rheumatism (EULAR) recommendations for the management of RA.

Methods Systematic literature review (SLR) of observational studies (including registries). Interventions were any bDMARD (anakinra, infliximab, etanercept, adalimumab, rituximab, abatacept, tocilizumab, golimumab or certolizumab pegol) or sDMARD (methotrexate, leflunomide, hydroxychloroquine, sulfasalazine, gold/auranofin, azathioprine, chlorambucil, chloroquine, cyclosporin, cyclophosphamide, mycophenolate, minocycline, penicillamine, tacrolimus or tofacitinib) and a comparator was required. Information on GCs was collected from the included studies. All safety outcomes were included.

Results Forty-nine observational studies addressing diverse safety outcomes of therapy with bDMARDs met eligibility criteria. Substantial heterogeneity precluded meta-analysis of any of the outcomes. Patients on tumour necrosis factor inhibitors (TNFi) compared to patients on conventional sDMARDs had a higher risk of serious infections (adjusted HR (aHR) 1.1–1.8), a higher risk of tuberculosis, and an increased risk of infection by herpes zoster cannot be excluded. Patients on TNFi did not have an increased risk for malignancies in general, lymphoma or non-melanoma skin cancer, but the risk of melanoma may be slightly increased (aHR 1.5). From the studies identified on conventional sDMARDs, no new safety signals were found.

Conclusions The findings from this SLR confirm the known safety pattern of sDMARDs and bDMARDs for the treatment of RA.

Keywords
  • Rheumatoid arthritis
  • DMARDs (biologic)
  • DMARDs (synthetic)
  • anti-TNF
  • outcomes research

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