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Safety of synthetic and biological DMARDs: a systematic literature review informing the 2016 update of the EULAR recommendations for management of rheumatoid arthritis
  1. Sofia Ramiro1,
  2. Alexandre Sepriano1,2,
  3. Katerina Chatzidionysiou3,
  4. Jackie L Nam4,5,
  5. Josef S Smolen6,7,
  6. Désirée van der Heijde1,
  7. Maxime Dougados8,
  8. Ronald van Vollenhoven9,
  9. Johannes W Bijlsma10,
  10. Gerd R Burmester11,
  11. Marieke Scholte-Voshaar12,13,
  12. Louise Falzon14,
  13. Robert B M Landewé9,15
  1. 1Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands
  2. 2CEDOC, Nova Medical School, Universidade Nova de Lisboa, Lisboa, Portugal
  3. 3Unit for Clinical Therapy Research, Inflammatory Diseases (ClinTRID), The Karolinska Institute, Stockholm, Sweden
  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. 7Department of Medicine, Hietzing Hospital, Vienna, Austria
  8. 8Department of Rheumatology, Paris Descartes University, Cochin Hospital, Assistance Publique-Hôpitaux de Paris, INSERM (U1153): Clinical Epidemiology and Biostatistics, Paris, France
  9. 9Department of Clinical Immunology & Rheumatology, Amsterdam Rheumatology Center, Amsterdam, The Netherlands
  10. 10Department of Rheumatology, University Medical Center Utrecht, Utrecht, The Netherlands
  11. 11Department of Rheumatology and Clinical Immunology, Charité—University Medicine Berlin, Berlin, Germany
  12. 12Department of Psychology, Health and Technology, University of Twente, Enschede, The Netherlands
  13. 13EULAR Standing Committee of People with Arthritis/Rheumatism in Europe
  14. 14Center for Behavioral Cardiovascular Health, Columbia University Medical Center, New York, USA
  15. 15Department of Rheumatology, Zuyderland Medical Center, Heerlen, The Netherlands
  1. Correspondence to Dr Sofia Ramiro, Department of Rheumatology, Leiden University Medical Center, Albinusdreef 2, PO Box 9600, Leiden 2300 RC, The Netherlands; sofiaramiro{at}


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.

  • Rheumatoid Arthritis
  • DMARDs (biologic)
  • DMARDs (synthetic)
  • Anti-TNF
  • Outcomes research
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  • Contributors All authors contributed and finally approved the current manuscript.

  • Competing interests JS, Amgen, AbbVie, AstraZeneca, Astro, BMS, Celgene, GlaxoSmithKline, ILTOO, Janssen, Merck-Serono, MSD, Novartis-Sandoz, Pfizer, Roche-Chugai, Samsung, UCB. DvdH, AbbVie, Amgen, Astellas, AstraZeneca, BMS, Celgene, Daiichi, Eli-Lilly, Galapagos, Gilead, Merck, Novartis, Pfizer, Roche, Sanofi-Aventis, UCB, 5, Director of Imaging Rheumatology BV. MD, AbbVie, Pfizer, Novartis, MSD. RvV, AbbVie, Bristol-Myers Squibb, GlaxoSmithKline, Pfizer, Roche, UCB Pharma, Biotest, Janssen, Eli-Lilly, Merck, Vertex. JWB, Roche, AbbVie, Bristol-Myers Squibb, Merck Sharp & Dohme, Pfizer and UCB. GB, UCB, 2, AbbVie, BMS, Hexal, Janssen, Eli-Lilly, MSD, Medimmune, Novartis, Pfizer, Sanofi-Aventis, Roche. RL, AbbVie, Amgen, Centocor, Novartis, Pfizer, Roche, Schering-Plough, UCB, Pfizer, Ablynx, Amgen, AstraZeneca, Bristol-Myers Squibb, Celgene, Janssen (formerly Centocor), Galapagos, GlaxoSmithKline, Novartis, Novo-Nordisk, Merck, TiGenix, Rheumatology Consultancy BV.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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