Safety of synthetic and biological DMARDs: a systematic literature review informing the 2025 update of the EULAR recommendations for the management of rheumatoid arthritis

<b>Objectives</b><br/>To perform a systematic literature review (SLR) concerning the safety of synthetic(s) and biological (b) disease-modifying antirheumatic drugs (DMARDs) to inform the 2025 update of the EULAR recommendations for the management of rheumatoid arthritis (RA).<br/><br/><b>Methods</b><br/>Medline, EMBASE, Cochrane CENTRAL and Web of Science were searched for observational and randomized controlled trials (RCTs) with a primary endpoint of DMARD safety on conventional-synthetic, biological, and targeted-synthetic DMARDs (csDMARDs, bDMARDs, tsDMARDs respectively), as well as glucocorticoids (GC) and biosimilars, published between January 14, 2022 and January 22, 2025. Additionally, separate searches on DMARD monitoring were conducted from database inception to January 22, 2025. The SLR of observational studies focussed on comparing safety outcomes of any DMARD with another intervention in RA. A comparator group was mandatory to be included in the SLR. For treatments with limited or absent registry data, randomised controlled trials (RCTs) were used. The risk of bias (RoB) of each included study was assessed using the ‘Hayden-tool’ for observational studies and The Cochrane Collaboration’s tool for RCTs (RoB 2). <br/><br/><b>Results</b><br/>3837 articles were identified with 3502 screened following de-duplication (335 removed before screening); in total 321 were identified for full text screening and assessed for eligibility. 71 articles were included that studied the safety of DMARDs in RA. Serious infections were more common with bDMARDs than csDMARDs, while Janus Kinase inhibitors (JAKi) showed higher herpes zoster risk than bDMARDs. Tuberculosis risk was not increased with JAKis compared to tumour necrosis factor inhibitors (TNFi) or bDMARDs, while the risk was raised with infliximab and adalimumab compared to etanercept. Increased non-malignant skin cancer was noted in RA patients using DMARDs compared to the general population, but was not linked to specific drug class. No consistent evidence of increased MACE risk with JAKi compared to bDMARDs was identified in observational studies. VTE risk appeared elevated with JAKi compared to bDMARDs; some reports suggested this was secondary to pulmonary embolism events and not driven by deep vein thrombosis.<br/><br/><b>Conclusion</b><br/>This SLR, along with the SLR on efficacy of DMARDs, informed the 2025 update of the EULAR recommendations for management of RA with synthetic and biological DMARDs. <br/><br/>