Background/Purpose: Patients with rheumatoid arthritis (RA) have a high risk of suffering cardiovascular disease. The analysis of the cardiovascular and cardiometabolic proteome in RA patients may provide disease biomarkers and insights into the biological pathways that contribute to the cardiovascular risk.

Objectives: 1) To evaluate the changes in the cardiometabolic and cardiovascular serum proteome in two cohorts of active RA patients: new diagnosed (naïve-treated) and well-established disease and its association with the clinical characteristics and 2) to analyze the modulation of the levels of these proteins by methotrexate and tofacitinib.

Methods: 1) Cross-sectional study in two cohorts of RA: patients at diagnosis (evolution time <2 years, n=25) and patients with established disease (evolution time>25 years, n=25), age and sex-matched with healthy donors (n=25). 2) Longitudinal study was performed on 25 RA patients treated with methotrexate and 25 RA patients treated with Tofacitinib combined with DMARDs for 6 months. Clinical and analytical variables were recorded. Proteomic profiling of 184 proteins (cardiometabolic and cardiovascular II panels) was performed in the serum using Olink Proteomics technology.

Results: There were no statistical differences between the RA at diagnosis and RA established disease groups in age and DAS28. The evolution time mean in the RA established disease group was 37.48 ±11.79 years. One hundred and seven proteins were significantly increased in the serum of RA patients at diagnosis versus healthy donors, among these 47 proteins were elevated in RA patients with established disease. The PCA analysis showed that the alteration of these proteins could discriminate between RA patients and healthy donors. The molecules more significantly increased in the RA at diagnosis group were SAA4, ST6GAL1, CCL18, TNC, IGLC2, IL6, SORT1, TNFRSF10A, AGRP, and CD4. In addition, the top ten molecules significantly elevated in RA patients with established disease were SAA4, CCL18, ST6GAL1, CRTAC1, ANGPTL3, TNFRSF10A, LEP, Gal-9, SORT1, and TRAIL-R2. The increase of these proteins was associated with the inflammation shown by the correlation with C reactive protein (CRP) levels and DAS28. The elevated levels of SAA4 (serum amyloid A protein-4) discriminated between RA patients and healthy donors with high sensitivity and specificity (AUC=0.95).

Treatment with methotrexate in RA patients at diagnosis reduced the levels of 64 proteins (50% of the altered proteins) while tofacitinib modulated the expression of 30 proteins (50% of the altered proteins) in RA patients with established disease after 6 months. These reductions were associated with the decrease in CRP and DAS28 levels.>

Conclusion: 1) The cardiovascular and cardiometabolic serum proteome is altered in RA patients at diagnosis and after a long time of the disease evolution and chronic treatments, 2) SAA4 may represent a biomarker for the diagnosis of RA with a high sensitivity and specificity, 3) Methotrexate and tofacitinib specifically modulate the alteration on the serum proteome after six months of treatment alongside the reduction of clinical inflammatory and disease activity markers.

Funded by Pfizer-IRS-Aspire 2019.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/alteration-of-the-cardiometabolic-and-cardiovascular-proteome-in-rheumatoid-arthritis-modulation-by-methotrexate-and-tofacitinib/