Background/Purpose: The main objective of this study was to conduct extensive clinical and molecular analyses to accurately characterize the specific effects of Baricitinib (4 mg/day) compared with other DMARDs on the pro-inflammatory, pro-thrombotic, and cardiovascular (CV) risk profile of RA patients.

Methods: A longitudinal prospective study was conducted on 75 RA patients divided into 3 groups of 25 individuals, each starting different therapies: conventional DMARDs, TNF-alpha inhibitors (TNFi), and Baricitinib (4 mg/day). A control group of 25 age- and sex-matched healthy donors was included. Patients were naïve to biologic or targeted synthetic DMARDs and those over 65, with BMI >30, thrombotic disorders, or recent surgery/immobilization were excluded.

Clinical and demographic data were comprehensively collected before and after 6 months of treatment. The effects of treatments on hypercoagulability status and CV risk profiles were assessed: 1) Carotid intima-media thickness (cIMT); 2) Thrombotic Activation Molecules: D-dimers, von Willebrand factor (vWf), and thrombin-antithrombin complex (TAT); 3) 92 CV-related proteins using proximity extension assay technology (Olink).

Results: At baseline, patients across all treatment arms exhibited similar disease activity levels (DMARDs: 4.03 ± 1.46; TNFi: 4.66 ± 1.00; Baricitinib: 4.64 ± 1.15). CV risk scores and atherogenic indexes (AI) were low (both below 4) and similar among all three treatment groups, with a prevalence of pathological cIMT around 30-35%.

After six months of treatment, remission rates were 75% for Baricitinib, 58% for TNFi, and 42% for DMARDs. Regarding thrombotic activation molecules, only D-dimers, which were elevated at baseline compared to HD, were significantly reduced in all three treatment groups.

Analysis of the circulating CV proteome revealed changes in 32 proteins with Baricitinib treatment, 26 with TNFi, and 23 with conventional DMARDs. Eight proteins were commonly modified by all treatments, mainly involved in inflammation, vascular remodelling, chemotaxis, and apoptosis. Baricitinib uniquely modulated 21 proteins, related to inflammation, cell adhesion, coagulation, atherosclerosis, lipid metabolism, and cell signalling. Notably, while Baricitinib increased levels of certain pro-atherogenic and pro-inflammatory proteins (e.g., TF, VEGFD, LPL, LEP; without exceeding the levels observed in HDs), it also reduced others that might counterbalanced these effects, including inflammatory cytokines (IL-1RA, IL-4RA, IL-18) and regulators of oxidative stress, atherosclerosis development, and vascular inflammation (Gal-9, GLO1, NEMO, PTX3, TGM2, TNFRSF10A).

Conclusion: 1- Baricitinib demonstrates higher clinical efficacy in treating RA patients naïve to biologic/tsDMARDs, compared to TNF-alpha inhibitors and conventional DMARDs.

2- Baricitinib uniquely modulates the CV proteome by increasing and decreasing specific proteins, balancing CV risk factors.

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

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/clinical-efficacy-and-molecular-cardiovascular-changes-of-baricitinib-in-biologic-naive-patients-with-rheumatoid-arthritis-direct-comparative-analysis-with-tnf-inhibitors-and-conventional-dmards/