Frailty and cardiovascular safety of JAK inhibitors versus TNF inhibitors in rheumatoid arthritis: real-world comparative study of drug effects and patients' profile.

Ettore Silvagni¹Alessandra Bortoluzzi¹Giuseppe Occhino²Giuseppe Bellelli^3,4Carlo Garaffoni¹Paolo Delvino⁵Olivia Leoni⁶Maria Grazia Valsecchi^2,7Carlo Alberto Scirè^4,7*Paola Rebora^2,7

• ¹Rheumatology Unit, Department of Medical Sciences, Università degli Studi di Ferrara and Azienda Ospedaliero-Universitaria S.Anna, Cona (FE), Cona (FE), Italy
• ²Bicocca Bioinformatics, Biostatistics and Bioimaging Centre - B4 School of Medicine, University of Milano Bicocca, Milan, Italy, Milan, Italy
• ³Acute Geriatric Unit, IRCCS San Gerardo dei Tintori Foundation, Monza, Italy., Monza, Italy
• ⁴School of Medicine and Surgery, University Milano-Bicocca, Milan, Italy, Milan, Italy
• ⁵Rheumatology Unit, IRCCS San Gerardo dei Tintori Foundation, Monza, Italy ., Monza, Italy
• ⁶General Directorate for Health, Lombardy Region, Milan, Italy., Milan, Italy
• ⁷Unit of Clinical Epidemiology and Biostatistics, IRCCS San Gerardo dei Tintori Foundation, Monza, Italy., Monza, Italy

Objective: to comparatively assess the risk of cardiovascular events (CVEs) in rheumatoid arthritis (RA) patients treated with Janus Kinase inhibitors (JAKis) or tumor necrosis factor inhibitors (TNFis), and to explore interactions with patients’ profile (included age, baseline CV risk, and frailty, a state of decreased physiological reserve assessed using a validated Frailty Index (FI) for healthcare administrative databases (AHDs)).Methods: This retrospective study was based on AHDs of the Lombardy region, Italy (from January 1st, 2020, to December 31st, 2023). Cox regression models, both crude and adjusted, were applied to estimate the association between treatments and outcomes (CVEs, major adverse cardiovascular events (MACEs), and thromboembolic events (TEs)). We tested the interaction between the drug treatment and the regulatory agency prescription rules changes (before or after July 06th, 2021, date of the first EMA pronouncement on tofacitinib safety) or patients’ profile.Results: We identified 7,541 therapeutic courses on 5,563 patients: 2,343 started as TNFis, and 1,443 as JAKis users, while 1,777 started as other drugs (1,459 days of follow-up). The crude incidence rates (IRs) for new CVEs were 16.6 (95% confidence intervals (95%CI) 12.8–21.2) and 18.6 (95%CI 14.2–23.9) per 1000 person-year for TNFi and JAKi users, respectively. Exposure to JAKis was not associated with a significantly increased risk of CVEs (adjusted hazard ratio (HR) 0.92, 95%CI 0.64–1.32), MACEs (0.71, 0.37–1.33), or TEs (1.53, 0.65–3.65) compared to TNFis. Each 0.1-point increment of the FI significantly increased the HR for new CVEs (HR 1.80, 95%CI 1.48-2.19), MACEs (1.66, 1.10-2.51), and TEs (1.69, 1.03-2.78). When assessing the interaction between the period of drug delivery and the treatment with JAKis on the risk of new CVEs, no significant interaction was highlighted (p=0.838), while the interaction was statistically significant for baseline CV risk (p=0.007).Conclusion: RA patients treated with JAKis in the real-world have a risk of developing CVEs no higher than TNFis users, but potential signals remain for TEs, even if the sample was not sufficiently powered. Patients’ profiles, particularly the frailty, have a more substantial impact on the risk of CVEs than the specific DMARD choice.