Exploring candidate biomarkers for rheumatoid arthritis through cardiovascular and cardiometabolic serum proteome profiling

Front Immunol. 2024 Feb 14:15:1333995. doi: 10.3389/fimmu.2024.1333995. eCollection 2024.

Abstract

Introduction: RA patients are at higher risk of cardiovascular disease, influenced by therapies. Studying their cardiovascular and cardiometabolic proteome can unveil biomarkers and insights into related biological pathways.

Methods: This study included two cohorts of RA patients: newly diagnosed individuals (n=25) and those with established RA (disease duration >25 years, n=25). Both cohorts were age and sex-matched with a control group (n=25). Additionally, a longitudinal investigation was conducted on a cohort of 25 RA patients treated with methotrexate and another cohort of 25 RA patients treated with tofacitinib for 6 months. Clinical and analytical variables were recorded, and serum profiling of 184 proteins was performed using the Olink technology platform.

Results: RA patients exhibited elevated levels of 75 proteins that might be associated with cardiovascular disease. In addition, 24 proteins were increased in RA patients with established disease. Twenty proteins were commonly altered in both cohorts of RA patients. Among these, elevated levels of CTSL1, SORT1, SAA4, TNFRSF10A, ST6GAL1 and CCL18 discriminated RA patients and HDs with high specificity and sensitivity. Methotrexate treatment significantly reduced the levels of 13 proteins, while tofacitinib therapy modulated the expression of 10 proteins. These reductions were associated with a decrease in DAS28. Baseline levels of SAA4 and high levels of BNP were associated to the non-response to methotrexate. Changes in IL6 levels were specifically linked to the response to methotrexate. Regarding tofacitinib, differences in baseline levels of LOX1 and CNDP1 were noted between non-responder and responder RA patients. In addition, response to tofacitinib correlated with changes in SAA4 and TIMD4 levels.

Conclusion: In summary, this study pinpoints molecular changes linked to cardiovascular disease in RA and proposes candidate protein biomarkers for distinguishing RA patients from healthy individuals. It also highlights how methotrexate and tofacitinib impact these proteins, with distinct alterations corresponding to each drug's response, identifying potential candidates, as SAA4, for the response to these therapies.

Keywords: Olink; biomarkers; methotrexate; proximity extension assay (PEA); rheumatoid arthritis; tofacitinib.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antirheumatic Agents* / therapeutic use
  • Arthritis, Rheumatoid* / chemically induced
  • Arthritis, Rheumatoid* / diagnosis
  • Arthritis, Rheumatoid* / drug therapy
  • Cardiovascular Diseases* / diagnosis
  • Cardiovascular Diseases* / drug therapy
  • Humans
  • Methotrexate
  • Proteome

Substances

  • Methotrexate
  • Antirheumatic Agents
  • Proteome

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by grants from the “Instituto de Salud Carlos III” (PI20/00079, PI21/00591, FI21/00039, and RICOR-RD21/0002/0033) co-financed by the European Union; the Andalusian government (1381035-F) co-financed by the European Regional Development Fund (ERDF); MINECO (RyC- 2017-23437, FPU/06329) and Consejería de Conocimiento, Investigación y Universidad, Junta de Andalucía (P20_01367). The authors declare that this study also received funding from Pfizer (IRS-Aspire-2019 grant). The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article, or the decision to submit it for publication. CL-P was supported by a contract from the Junta de Andalucia (Nicolas Monardes program). CP-S was supported by MCIN/AEI/10.13039/501100011033 (RYC2021-033828-I) and the European Union “NextGenerationEU”/PRTR.