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. 2020 Jun;79(6):760-770.
doi: 10.1136/annrheumdis-2019-216653. Epub 2020 Feb 7.

Safety of synthetic and biological DMARDs: a systematic literature review informing the 2019 update of the EULAR recommendations for the management of rheumatoid arthritis

Alexandre Sepriano  1   2 , Andreas Kerschbaumer  3 , Josef S Smolen  3   4 , Désirée van der Heijde  5 , Maxime Dougados  6   7 , Ronald van Vollenhoven  8 , Iain B McInnes  9 , Johannes W Bijlsma  10 , Gerd R Burmester  11 , Maarten de Wit  12 , Louise Falzon  13 , Robert Landewé  14   15
Affiliations

Safety of synthetic and biological DMARDs: a systematic literature review informing the 2019 update of the EULAR recommendations for the management of rheumatoid arthritis

Alexandre Sepriano et al. Ann Rheum Dis. 2020 Jun.

Abstract

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.

Keywords: DMARDs (biologic); DMARDs (synthetic); anti-TNF; outcomes research; rheumatoid arthritis.

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Conflict of interest statement

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.

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