Background: Dermatomyositis (DM), Anti-Synthetase Syndrome (ASS), and Immune-Mediated Necrotizing Myositis (IMNM) are rare systemic autoimmune myopathies characterized by muscle weakness, systemic inflammation, and multi-organ involvement, particularly cardiovascular and pulmonary systems. Despite advances in treatment, these diseases are associated with significant morbidity and mortality, particularly in refractory cases. Traditional therapies such as methotrexate, azathioprine, intravenous immunoglobulin (IVIG), rituximab, and mycophenolate mofetil have been the standard of care, but they often fail to control disease activity and prevent complications in many patients. Janus Kinase (JAK) inhibitors have emerged as a promising alternative, offering targeted immunomodulation that may address gaps in current treatment options effects. However, the long-term effects of JAK inhibitors, particularly on cardiovascular health and disease outcomes, remain poorly understood in these populations, highlighting the urgent need for further investigation.

Objectives: To evaluate the impact of JAK inhibitors versus standard therapies on mortality, major adverse cardiovascular events (MACE), malignancy, disease activity (measured by creatine kinase [CK] levels), and other clinical outcomes in patients with DM, ASS, and IMNM over a three-year follow-up.

Methods: This retrospective cohort study utilized the TriNetX global collaborative network, which electronic health records from 142 healthcare organizations. Patients aged above 18 years with diagnosed of DM, ASS, or IMNM were included. Diagnoses and treatments were identified using international coding standards. The cohorts were defined by treatment exposure: patients receiving JAK inhibitors (tofacitinib, ruxolitinib, abrocitinib, upadacitinib, filgotinib, or baricitinib) were compared to those receiving standard therapies (methotrexate, azathioprine, IVIG, rituximab, or mycophenolate mofetil). Propensity score matching (PSM) was used to balance the cohorts based on demographics, preexisting comorbidities, laboratory parameters (e.g., CK levels), and concurrent medication use, including cardiovascular and diabetes therapies, statins, and corticosteroids. Patients with preexisting outcomes were excluded. Outcomes assessed over three years included all-cause mortality, MACE, coronary artery disease (CAD), heart failure, stroke, thrombosis, atherosclerotic vascular disease, malignancy (solid tumors), and CK-based disease activity.

Results: Following propensity score matching, 2,071 patients were included in each cohort, ensuring comparability of baseline characteristics. Over a three-year follow-up, patients receiving JAK inhibitors had higher all-cause mortality (15.5% vs. 9.5%; HR: 1.71, 95% CI: 1.42–2.06, p < 0.001). However, JAK inhibitors were associated with lower rates of MACE (12.2% vs. 15.1%; HR: 0.81, 95% CI: 0.69–0.96, p = 0.013), stroke (3.4% vs. 4.7%; RR: 0.72, 95% CI: 0.53–0.97, p = 0.03), CAD (6.1% vs. 9.9%; RR: 0.61, 95% CI: 0.49–0.77, p < 0.001), and heart failure (7.8% vs. 10.2%;RR: 0.76, 95% CI: 0.62–0.92, p = 0.005). The incidence of thrombosis was also lower among JAK inhibitor users (5.3% vs. 7.2%; RR: 0.73, 95% CI: 0.58–0.93, p = 0.012), as was atherosclerotic vascular disease (4.8% vs. 8.9%; RR: 0.54 (0.43–0.67), p < 0.001). Regarding disease activity, the JAK inhibitor cohort demonstrated fewer cases of severely elevated CK levels (>1,000 U/L; 10.1% vs. 15.3%; RR: 0.68, 95% CI: 0.52–0.88, p = 0.005), along with higher rates of CK normalization (22.3% vs. 14.8%; RR: 1.51, 95% CI: 1.29–1.77, p < 0.001). Additionally, malignancy rates were significantly lower among JAK inhibitor users (1.2% vs. 2.1%; RR: 0.72, 95% CI: 0.56–0.91, p = 0.02), indicating a potential protective effect against solid tumors.

Conclusion: JAK inhibitors demonstrated significant benefits in reducing MACE, stroke, CAD, heart failure, thrombosis, vascular disease, malignancy, and CK-based disease activity in patients with DM, ASS, and IMNM compared to standard therapies. However, these advantages, the higher all-cause mortality observed in the JAK inhibitor cohort underscores the importance of careful risk stratification and close monitoring. These findings highlight the therapeutic potential of JAK inhibitors in refractory myopathies, warranting further investigation in randomized controlled trials to validate these results and refine treatment strategies for inflammatory myopathies.

REFERENCES: NIL.

Acknowledgements: NIL.

Disclosure of Interests: None declared.

© The Authors 2025. This abstract is an open access article published in Annals of Rheumatic Diseases under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ). Neither EULAR nor the publisher make any representation as to the accuracy of the content. The authors are solely responsible for the content in their abstract including accuracy of the facts, statements, results, conclusion, citing resources etc.