Background: Rheumatoid Arthritis (RA) is a systemic autoimmune-inflammatory disorder characterized by autoantibody production, joint damage, and the development of comorbidities, with cardiovascular disease (CVD) being a key contributor to disease severity and prognosis. Over recent years, therapeutic advances have introduced effective treatments, including bDMARDs and tsDMARDs such as Baricitinib. However, the impact of Baricitinib on CV risk remains unclear, partly due to reports of increased thromboembolism risk at higher doses and the limited size and number of existing studies. This uncertainty hinders a comprehensive understanding of its safety and optimal use in disease management.

Objectives: To perform an extensive clinical and molecular analyses to elucidate the specific effects of the JAK-STAT inhibitor Baricitinib (4 mg/day) in comparison to TNF inhibitors (TNFi) and conventional DMARDs on the proinflammatory, prothrombotic, and cardiovascular (CV) risk profiles of RA patients.

Methods: A longitudinal prospective study was performed in three cohorts of patients -25 each- diagnosed with RA according to ACR/EULAR classification criteria (2010), treated with conventional DMARDs, TNFi and Baricitinib for 6 and 12 months, all at standard doses. A cohort of 25 healthy donors (HDs) matched for age and sex was included. Patients ranged from 18 to 75 years of age, with moderate to severe disease activity (DAS28≥3.2), and inadequate response to Methotrexate. All were naïve to b/tsDMARDs. Patients with thrombotic disorders or recent surgery/immobilization were excluded. Clinical and demographic data (including disease activity -DAS28-CRP- and duration, autoantibody status, traditional CV risk factors and events, BMI, medication use, and clinical response following EULAR criteria) were collected before and after 6 and 12 months. Non-invasive carotid ultrasounds assessed atherothrombotic risk through carotid plaque presence. Blood samples were collected to obtain serum, plasma, and monocytes both prior to and following administration of the medication, and were analysed for thrombotic-risk markers: polymorphisms including mutations in Factor V Leiden (rs6025) and prothrombin G20210A (rs1799963) which lead to procoagulant states; D-dimer, prothrombin fragments F1+F2, and thrombin-antithrombin complex, as well as the levels of 92 CV-related proteins using proximity extension assay technology (PEA, Olink/Cobiomic). Statistical and bioinformatic analyses integrated all data.

Results: Baseline disease activity was comparable across treatment groups (DAS28: sDMARDs 4.03 ± 1.46, TNFi 4.66 ± 1.00, Baricitinib 4.64 ± 1.15). All treatments significantly reduced disease activity after 6 months, with Baricitinib achieving the highest rates of remission (75% vs . 58% for TNFi and 42% for sDMARDs). This clinical improvement was sustained, as seen at the 12-month evaluation. The 3 patient groups were also similar at baseline in terms of CV risk parameters: polymorphisms in prothrombotic markers were rare, pathological CIMT (indicating plaque presence) was prevalent in 32-39% of patients across all groups, and traditional CV risk factors were homogeneously distributed. CV risk scores and atherogenic indexes were both low (below 4) and similar among groups. Markers of hypercoagulability (D-dimer, thrombin-antithrombin complex, and F1+F2 fragments) were elevated in RA patients compared to HDs but significantly reduced after treatment in all cohorts. Analysis of the circulating CV proteome revealed changes in 29 proteins with Baricitinib treatment, 26 with TNFi, and 23 with conventional DMARDs. These alterations included both general changes common across therapies and specific molecular shifts unique to each treatment, highlighting their distinct CV molecular effects: 8 proteins were commonly modified by all treatments and were mainly involved in inflammation, vascular remodeling, chemotaxis, and apoptosis. Baricitinib uniquely modulated 21 proteins, interconnected and linked to key processes such as inflammation, cell adhesion/signalling, coagulation, atherosclerosis, and lipid metabolism. This treatment option significantly reduced proteins involved in inflammatory pathways (IL-1RA, IL-4RA, IL-18), and oxidative stress, atherosclerosis development, and vascular inflammation (Gal-9, GLO1, NEMO, TGM2) all closely associated with disease pathogenesis, autoimmunity and CV risk, as they showed significant correlations with key indicators.

Conclusion: All therapies effectively reduced disease activity over 6 months, with Baricitinib showing the greatest clinical efficacy and remission rates. Each treatment favorably modulated CV risk markers, with Baricitinib demonstrating unique molecular benefits, including reduced levels of inflammatory and prothrombotic proteins. These findings highlight its potential as a leading treatment option for RA in patients naïve to b/tsDMARDs, offering robust clinical benefits while maintaining a favorable CV safety profile.

REFERENCES: NIL.

Acknowledgements: Supported by Lilly (I4V-NS-0032), ISCIII (PI21/0591, PI23/00027, PI24/00959, CD21/00187 and RICOR-21/0002/0033), and RYC2021-033828-I; co-financed by European Union.

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.