Background/Purpose: Therapeutic advances in RA have introduced effective treatments, including b/tsDMARDs such as Baricitinib. However, its cardiovascular safety profile remains unclear, partly due to the limited scope of existing studies, limiting its optimal positioning within treatment strategies. This study’s objective was to conduct clinical-molecular analyses to elucidate the effects of Baricitinib (4mg/day) on the proinflammatory, prothrombotic, and cardiovascular risk profiles of RA patients, in comparison with TNF inhibitors (TNFi) and cDMARDs

Methods: A longitudinal, prospective study was conducted in three RA patient cohorts (n=25 each) who received standard-dose treatment with cDMARDs, TNFi or Baricitinib. All had moderate-severe disease activity (DAS28≥3.2), inadequate response to methotrexate and were naïve to b/tsDMARDs. A control group of 25 age- and sex- matched healthy donors was included. Clinical-demographic data were collected at baseline and after 6 and 12 months. Carotid ultrasound evaluated atherothrombotic risk.Blood samples were obtained to isolate serum, plasma and monocytes prior to and after treatment. Consequent analyses included: screening for hypercoagulability-associated polymorphisms (Factor V Leiden and prothrombin); quantification of prothrombotic markers (D-dimer, prothrombin F1+2 and TAT complex); transcriptomic monocyte profiling via RNA-seq;and serum proteomic analysis of 276 inflammation- and CV-related proteins using proximity extension assay (Olink/Cobiomic)

Results: At baseline, disease activity was comparable across groups. All treatments led to significant improvements at 6-12 months, although Baricitinib demonstrated superior clinical efficacy, achieving the highest remission rates at both timepoints. Patients exhibited a baseline hypercoagulable state, although all therapies reduced D-dimer levels supporting their capacity to attenuate prothrombotic activity. Genetic hypercoagulability variants were infrequent, while carotid plaque prevalence and traditional CV risk factors were similar among cohorts.Transcriptomic analysis showed that each therapy induced distinct gene expression changes, with shared effects on inflammation, interferon response and cell metabolism. Proteomic profiling revealed broad molecular shifts, with Baricitinib altering 68 proteins, TNFi 38, and sDMARDs 39. Common changes involved inflammation and vascular remodeling, while Baricitinib uniquely regulated 51 proteins related to cytokine signaling, angiogenesis, and matrix remodeling. Several modulated genes and proteins were linked to known CV risk markers. However, the unique molecular shifts highlight the differential impact of each treatment on CV risk

Conclusion: Baricitinib showed superior clinical efficacy, with higher rates of sustained remission beyond one year. Molecular studies suggest it not only does not increase CV risk but may confer beneficial effects by normalizing gene and protein profiles linked to elevated CV risk.Funded by Instituto de Salud Carlos III (ISCIII), co-funded by European Union. Supported by Lilly (I4V-NS-0032), ISCIII (PI23/00027, PI24/00959, CD21/00187, RICORS: 24/0007/0019), and RYC2021-033828-I

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/impact-of-baricitinib-on-cardiovascular-health-in-biologic-naive-rheumatoid-arthritis-patients-a-comparative-study-with-tnf-inhibitors-and-conventional-dmards/