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Safety of synthetic and biological DMARDs: a systematic literature review informing the 2022 update of the EULAR recommendations for the management of rheumatoid arthritis
  1. Alexandre Sepriano1,2,
  2. Andreas Kerschbaumer3,
  3. Sytske Anne Bergstra2,
  4. Josef S Smolen3,4,
  5. Désirée van der Heijde2,
  6. Roberto Caporali5,6,
  7. Christopher J Edwards7,
  8. Patrick Verschueren8,9,
  9. Savia de Souza10,
  10. Janet Pope11,
  11. Tsutomu Takeuchi12,13,
  12. Kimme Hyrich14,15,
  13. Kevin L Winthrop16,
  14. Daniel Aletaha3,
  15. Tanja Stamm17,18,
  16. Jan W Schoones19,
  17. Robert B M Landewé20,21
  1. 1CHRC Campus Nova Medical School, Lisboa, Portugal
  2. 2Rheumatology, Leiden University Medical Center, Leiden, The Netherlands
  3. 3Division of Rheumatology, Department of Medicine, Medical University of Vienna, Wien, Austria
  4. 42nd Department of Medicine, Hietzing Hospital, Wien, Austria
  5. 5Department of Clinical Sciences and Community Health, ASS G. Pini, University of Milan, Milano, Italy
  6. 6Department of Rheumatology, ASST PINI-CTO, Milan, Italy
  7. 7NIHR Southampton Clinical Research Facility, University Hospital Southampton NHS Foundation Trust, Southampton, UK
  8. 8Rheumatology, KU Leuven University Hospitals, Leuven, Belgium
  9. 9Engineering Research Centre, Lueven, Belgium
  10. 10Patient Research Partner Network, European Alliance of Associations for Rheumatology, Zurich, Switzerland
  11. 11Medicine, Division of Rheumatology, University of Western Ontario Schulich School of Medicine & Dentistry, London, Ontario, Canada
  12. 12Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine Graduate School of Medicine, Shinjuku-ku, Japan
  13. 13Saitama Medical University, Iruma-gun, Japan
  14. 14Centre for Epidemiology Versus Arthritis, The University of Manchester, Manchester, UK
  15. 15NIHR Manchester Biomedical Research Centre, Manchester, UK
  16. 16School of Public Health, Oregon Health & Science University, Portland, Oregon, USA
  17. 17Section for Outcomes Research, Centre for Medical Statistics, Informatics, and Intelligent Systems, Medical University of Vienna, Wien, Austria
  18. 18Institute for Arthritis and Rehabilitation, Ludwig Boltzmann, Vienna, Austria
  19. 19Walaeus Library, Leiden University Medical Center, Leiden, The Netherlands
  20. 20Amsterdam Rheumatology Center, Amsterdam University Medical Centres, Amsterdam, The Netherlands
  21. 21Rheumatology, Zuyderland Medical Centre Heerlen, Heerlen, The Netherlands
  1. Correspondence to Dr Alexandre Sepriano, CHRC Campus Nova Medical School, Lisboa, 1169-056, Portugal; alexsepriano{at}


Objectives To perform a systematic literature review (SLR) concerning the safety of synthetic(s) and biological (b) disease-modifying antirheumatic drugs (DMARDs) to inform the 2022 update of the EULAR recommendations for the management of rheumatoid arthritis (RA).

Methods SLR of observational studies comparing safety outcomes of any DMARD with another intervention in RA. A comparator group was required for inclusion. For treatments yet without, or limited, registry data, randomised controlled trials (RCTs) were used.

Results Fifty-nine observational studies addressed the safety of DMARDs. Two studies (unclear risk of bias (RoB)) showed an increased risk of serious infections with bDMARDs compared with conventional synthetic (cs)DMARDs. Herpes zoster infections occurred more with JAKi than csDMARDs (adjusted HR (aHR): 3.66) and bDMARDs (aHR: 1.9–2.3) (four studies, two low RoB). The risk of malignancies was similar across bDMARDs (five studies) and with tofacitinib compared with bDMARDs (one study, low RoB). The risk of major adverse cardiovascular events (MACE) was similar with bDMARDs and tofacitinib (two studies, one low RoB). Thirty studies reported safety from RCTs, with one, designed to evaluate safety, showing that malignancies (HR (95% CI): 1.48 (1.04 to 2.09)) and MACE (HR (95% CI): 1.33 (0.91 to 1.94)) occurred numerically more frequently with tofacitinib (5 mg and 10 mg doses combined) than with TNFi in patients with cardiovascular risk factors. In this study, the risk of venous thromboembolism (VTE) was higher with tofacitinib 10 mg than with TNFi.

Conclusion The safety profile of bDMARDs was further demonstrated. Whether the difference in incidence of malignancies, MACE and VTE between tofacitinib and TNFi applies to other JAKi needs further evaluation.

  • Rheumatoid Arthritis
  • DMARDs (biologic)
  • DMARDs (synthetic)
  • Outcomes research

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  • Handling editor David S Pisetsky

  • Twitter @AlexSepriano, @Janetbirdope

  • Collaborators N/A.

  • Contributors AS extracted the data for the SLR; JWS developed the search strategies; AS wrote the first version of the manuscript and all authors revised the manuscript critically for important intellectual content and gave final approval of the version to be published.

  • Funding European Alliance of Associations for Rheumatology.

  • Competing interests AS: received speaker/consulting fees from UCB, Novartis and Lilly AK: Speakers bureau, Consultancy: AbbVie, Amgen, Bristol-Myers Squibb, Eli Lilly, Gilead, Janssen, Merck Sharp and Dohme, Novartis, UCB und Pfizer SAB: received an ASPIRE grant from Pfizer JS received grants from Abbvie, Astra-Zeneca, Janssen, Lilly, Novartis, Roche and honoraria from Abbvie, Amgen, Astra-Zeneca, Astro, BMS, Celgene, Celltrion, Chugai, Gilead, ILTOO, Janssen, Lilly, MSD, Novartis-Sandoz, Pfizer, Roche, Samsung, Sanofi, UCB DvdH: received consulting fees from AbbVie, Amgen, Astellas, AstraZeneca, BMS, Boehringer Ingelheim, Celgene, Daiichi, Eli-Lilly, Galapagos, Gilead, Glaxo-Smith-Kline, Janssen, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi, Takeda, UCB Pharma and is Director of Imaging Rheumatology bv RC received consulting fees from Abbvie, BMS, Amgen, Celltrion, Eli-Lilly, Fresenius-Kabi, Galapagos, Janssen, MSD, Novartis, Pfizer, UCB Pharma. CJE Has received fees from Abbvie, Astra Zeneca, BMS, Celgene, Celltrion, Fresenius Kabi, Gilead, Galapagos, GSK, Janssen, Eli Lilly, Pfizer, Roche, Sanofi for advisory boards, speakers bureau and research support PV received consulting fees from Abbvie, BMS, Celltrion, Eli Lilly, Galapagos, Gilead, Nordic Pharma, Pfizer, Sidekick Health, UCB and speaker’s fees from Eli Lilly, Galapagos, MSD and Roularta. Holds the Pfizer Chair Early RA Management at KU Leuven. SdS: none JEP received research grants from AbbVie, Frensenius Kabi, Mallinckrodt Pharmaceuticals, Pfizer, Seattle Genetics and consulting fees from AbbVie, Amgen, Astra Zeneca, BI, BMS, Celltrion, EMERALD, Frensenius Kabi, Galapagos, GSK, Janssen, Lilly, Mallinckrodt Pharmaceuticals, Medexus, Mitsubishi Tanabe Pharma, Novartis, Pfizer, Roche, Sandoz, Samsung, Sobi, Viatris TT received grants from AbbVie, Asahikasei, AYUMI, Chugai, Eli Lilly Japan, Mitsubishi-Tanabe, Ono, and honoraria from AbbVie, Asahikasei, Astellas, Bristol-Myers Squibb, Chugai., Daiichi Sankyo., Eisai, Eli Lilly Japan, Gilead Sciences, Janssen K.K., Mitsubishi-Tanabe, Pfizer Japan KLH: Honoraria from Abbvie (Speakers’ fees) and Research Grants from Pfizer and BMS KLW received research grants from Pfizer, BMS, and GSK, and scientific consulting fees from UCB, Abbvie, BMS, Galapagos, Gilead, Lilly, GSK, Roche, and Novartis DA received grants, speaker fees, or consultancy fees from Abbvie, Amgen, Lilly, Janssen, Merck, Novartis, Pfizer, Roche, Sandoz, Sanofi, and Sobi TAS has received grant/research support from AbbVie and Roche, has been a consultant for AbbVie and Sanofi Genzyme, and has been a paid speaker for AbbVie, Novartis, Roche, Sanofi, and Takeda JWS: none RBML received consulting fees from AbbVie, BMS, Celgene, Eli-Lilly, Galapagos, Gilead, Glaxo-Smith-Kline, Janssen, Merck, Novartis, Pfizer, Roche, UCB and is Director of Rheumatology Consultancy by JSS, DvdH, KLH, KLW, DA and RBML are members of the Editorial Board of ARD.

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

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