Article Text

Safety of synthetic and biological DMARDs: a systematic literature review informing the 2019 update of the EULAR recommendations for the management of rheumatoid arthritis
  1. Alexandre Sepriano1,2,
  2. Andreas Kerschbaumer3,
  3. Josef S Smolen3,4,
  4. Désirée van der Heijde1,
  5. Maxime Dougados5,6,
  6. Ronald van Vollenhoven7,
  7. Iain B McInnes8,
  8. Johannes W Bijlsma9,
  9. Gerd R Burmester10,
  10. Maarten de Wit11,
  11. Louise Falzon12,
  12. Robert Landewé13,14
  1. 1 Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands
  2. 2 NOVA Medical School, Universidade Nova de Lisboa, Lisboa, Portugal, Lisboa, Portugal
  3. 3 Division of Rheumatology, Department of Medicine 3, Medical University of Vienna, Vienna, Austria
  4. 4 2nd Department of Medicine, Hietzing Hospital, Vienna, Austria
  5. 5 Department of Rheumatology, Hôpital Cochin. Assistance Publique - Hôpitaux de Paris, Paris, France
  6. 6 Clinical Epidemiology and Biostatistics, INSERM U1153, Paris, France
  7. 7 Department Rheumatology and Clinical Immunology, Amsterdam University Medical Centres, Amsterdam, The Netherlands
  8. 8 Institute of Infection, Immunity and Inflammation, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
  9. 9 Department of Rheumatology, University Medical Centre Utrecht, Utrecht, The Netherlands
  10. 10 Department of Rheumatology and Clinical Immunology, Charité Universitätsmedizin Berlin, Berlin, Germany
  11. 11 EULAR Standing Committee of People with Arthritis/Rheumatism in Europe, Zurich, Switzerland
  12. 12 Center for Personalized Health, Feinstein Institute for Medical Research, Northwell Health, New York, New York, USA
  13. 13 Amsterdam University Medical Center (ARC), Amsterdam, The Netherlands
  14. 14 Department of Rheumatology, Zuyderland Medical Center, Heerlen, The Netherlands
  1. Correspondence to Dr Alexandre Sepriano, Leiden University Medical Center, Leiden, Zuid-Holland, Netherlands; alexsepriano{at}


Objectives To perform a systematic literature review (SLR) concerning the safety of synthetic (s) and biological (b) disease-modifying anti rheumatic dugs (DMARDs) to inform the 2019 update of the EULAR recommendations for the management of rheumatoid arthritis (RA).

Methods An SLR of observational studies comparing safety outcomes of any DMARD with another intervention for the management of RA. A comparator group was required for inclusion. For treatments still without registry data (eg, sarilumab and the Janus kinase (JAK) inhibitors baricitinib, upadacitinib), randomised controlled trials (RCTs) and long-term extensions (LTEs) were used. Risk of bias (RoB) was assessed according to standard procedures.

Results Forty-two observational studies fulfilled the inclusion criteria, addressing safety outcomes with bDMARDs and sDMARDs. Nine studies showed no difference in the risk of serious infections across bDMARDs and two studies (high RoB) showed an increased risk with bDMARDs compared with conventional synthetic (cs) DMARDs (adjusted incidence rate ratio 3.1–3.9). The risk of Herpes zoster infection was similar across bDMARDs, but one study showed an increased risk with tofacitinib compared with abatacept (adjusted HR (aHR) 2.0). Five studies showed no increased risk of cancer for bDMARDs compared with csDMARDs. An increased risk of lower intestinal perforation was found for tocilizumab compared with csDMARDs (aHR 4.5) and tumour necrosis factor inhibitor (TNFi) (aHR 2.6–4.0). Sixty manuscripts reported safety data from RCTs/LTEs. Overall, no unexpected safety outcomes were found, except for the possibly increased risk of venous thromboembolism (VTE) with JAK inhibitors.

Conclusion Data obtained by this SLR confirm the known safety profile of bDMARDs. The risk of VTE in RA, especially in patients on JAK inhibitors, needs further evaluation.

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

Statistics from

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

Supplementary materials

  • Supplementary Data

    This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.


  • Handling editor Dimitrios T Boumpas

  • Contributors All authors contributed and finally approved the current manuscript.

  • Funding European League Against Rheumatism. AS is supported by a doctoral grant from “Fundação para 12 a Ciência e Tecnologia” (SFRH/BD/108246/2015).

  • Competing interests AS: Honoraria as speaker: Novartis. AK: Bristol-Myers Squibb, Celgene, Merck Sharp & Dohme and Pfizer. JS: Grants from Abbvie, AstraZeneca, Janssen, Lilly, Novartis, Roche and honoraria from Abbvie, Amgen, AstraZeneca, Astro, BMS, Celgene, Celltrion, Chugai, Gilead, ILTOO, Janssen, Lilly, MSD, Novartis-Sandoz, Pfizer, Roche, Samsung, Sanofi and UCB. DvdH: Received consulting fees from AbbVie, Amgen, Astellas, AstraZeneca, BMS, Boehringer Ingelheim, Celgene, Daiichi, Eli-Lilly, Galapagos, Gilead, GlaxoSmithKline, Janssen, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi, Takeda and UCB Pharma and is Director of Imaging Rheumatology bv. MD: Received research grants from and honorarium fees for his participation at advisory boards and/or symposium organised by Pfizer, UCB, AbbVie, Lilly, Novartis, BMS, Roche and Merck. RvV: Research support and grants: BMS, GSK, Lilly, Pfizer, UCB Pharma. Consultancy, honoraria: AbbVie, AstraZeneca, Biotest, Celgene, GSK, Janssen, Lilly, Novartis, Pfizer, Servier and UCB. IMcI: grants from AstraZeneca, UCB, BMS, Janssen, GSK, Compugen, Boehringer, Celgene and honoraria from Abbvie, BMS, Janssen, Novartis, UCB, AstraZeneca, Celgene, Causeway, Lilly, Leo and Novimmune. JB: Honoraria as speaker and for consulting: Abbvie, Lilly, MSD, Roche, Sanofi and SUN. GRB: Honoraria as speaker and for consulting: Abbvie, BMS, Gilead, Lilly, MSD, Pfizer, UCB, Roche and Sanofi. MdW: Over the last two years, Stichting Tools has received fees for lectures or consultancy for contributions of Maarten de Wit from Abbvie, Celgene, Eli Lilly, Janssen-Cilag and Pfizer. LF: None. RL: Received consulting fees from AbbVie, BMS, Celgene, Eli-Lilly, Galapagos, Gilead, GlaxoSmithKline, Janssen, Merck, Novartis, Pfizer, Roche and UCB and is Director of Rheumatology Consultancy bv.

  • Patient consent for publication Not required.

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

Linked Articles