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Ann Rheum Dis. 2017 Jun;76(6):1101-1136. doi: 10.1136/annrheumdis-2016-210708. Epub 2017 Mar 15.

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

Author information

Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands.
CEDOC, Nova Medical School, Universidade Nova de Lisboa, Lisboa, Portugal.
Unit for Clinical Therapy Research, Inflammatory Diseases (ClinTRID), The Karolinska Institute, Stockholm, Sweden.
Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Chapel Allerton Hospital Leeds, Leeds, UK.
NIHR Leeds Musculoskeletal Biomedical Research Unit, Leeds Teaching Hospitals NHS Trust, Leeds, UK.
Division of Rheumatology, Department of Medicine 3, Medical University of Vienna, Vienna, Austria.
Department of Medicine, Hietzing Hospital, Vienna, Austria.
Department of Rheumatology, Paris Descartes University, Cochin Hospital, Assistance Publique-Hôpitaux de Paris, INSERM (U1153): Clinical Epidemiology and Biostatistics, Paris, France.
Department of Clinical Immunology & Rheumatology, Amsterdam Rheumatology Center, Amsterdam, The Netherlands.
Department of Rheumatology, University Medical Center Utrecht, Utrecht, The Netherlands.
Department of Rheumatology and Clinical Immunology, Charité-University Medicine Berlin, Berlin, Germany.
Department of Psychology, Health and Technology, University of Twente, Enschede, The Netherlands.
EULAR Standing Committee of People with Arthritis/Rheumatism in Europe.
Center for Behavioral Cardiovascular Health, Columbia University Medical Center, New York, USA.
Department of Rheumatology, Zuyderland Medical Center, Heerlen, The Netherlands.



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.


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.


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).


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.


Anti-TNF; DMARDs (biologic); DMARDs (synthetic); Outcomes research; Rheumatoid Arthritis

[Indexed for MEDLINE]

Conflict of interest statement

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.

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