A longitudinal cohort study uncovers plasma protein biomarkers predating clinical onset and treatment response of rheumatoid arthritis

Siyu He, Chenxi Zhu, Yi Liu, Zhiqiang Xu, Rui Sun, Bin Yang, Xin Guo, Martin Herrmann I, Luis E. Muñoz, Inger Gjertsson, Rikard Holmdahl, Lunzhi Dai () and Yi Zhao ()
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Siyu He: Sichuan University
Chenxi Zhu: Sichuan University
Yi Liu: Sichuan University
Zhiqiang Xu: Sichuan University
Rui Sun: Sichuan University
Bin Yang: Sichuan University
Xin Guo: Sichuan University
Martin Herrmann I: Sichuan University
Luis E. Muñoz: University Hospital Erlangen, and Deutsches Zentrum für Immuntherapie; Friedrich-Alexander Universität Erlangen-Nürnberg (FAU)
Inger Gjertsson: University of Gothenburg
Rikard Holmdahl: Karolinska Institute
Lunzhi Dai: Sichuan University
Yi Zhao: Sichuan University

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract Rheumatoid arthritis (RA) is a systemic inflammatory condition posing challenges in identifying biomarkers for onset, severity and treatment responses. Here we investigate the plasma proteome in a longitudinal cohort of 278 RA patients, alongside 60 at-risk individuals and 99 healthy controls. We observe distinct proteome signatures in at-risk individuals and RA patients, with protein levels alterations correlating with disease activity, notably at DAS28-CRP thresholds of 3.1, 3.8 and 5.0. The combination of methotrexate (MTX) and leflunomide (LEF) modulates proinflammatory pathways, whereas MTX plus hydroxychloroquine (HCQ) impact energy metabolism. A machine-learning model is trained for predicting responses, and achieves average receiver operating characteristic (ROC) scores of 0.88 (MTX + LEF) and 0.82 (MTX + HCQ) in the testing sets. The efficiency of these models is further validated in independent cohorts using enzyme-linked immunosorbent assay data. Overall, our study unveils distinct plasma proteome signatures across various stages and subtypes of RA, providing valuable biomarkers for predicting disease onset and treatment responses.

Date: 2025
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DOI: 10.1038/s41467-025-62032-1

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