A serum proteomic signature predictive of flare during biologic tapering in rheumatoid arthritis

ABSTRACT: Rheumatoid arthritis (RA) is a chronic immune-mediated inflammatory disease characterized by joint inflammation, systemic manifestations, and a heterogeneous clinical course marked by periods of remission and disease flares. The introduction of biologic therapies has revolutionized RA treatment by enabling sustained disease control; however, their long-term use is associated with potential adverse effects and substantial healthcare costs, making treatment tapering an attractive but clinically challenging strategy. Flares remain unpredictable events that limit the safe implementation of biologic dose tapering. In this study, we applied deep quantitative serum proteomics to identify molecular signatures associated with flare susceptibility during therapeutic de-escalation in RA. Baseline serum samples from a randomized clinical trial of biologic tapering (OPTIBIO) were analyzed using data-independent acquisition mass spectrometry, enabling the quantification of 806 circulating proteins. Comparative analysis identified 87 proteins differentially abundant between patients who subsequently flared and those who maintained remission within the tapering arm. Functional enrichment analysis revealed a strong overrepresentation of immune-regulatory and innate immune pathways, including processes related to myeloid cell function and complement regulation. Selected candidates were taken forward for orthogonal validation using immunoassays in the full cohort (n = 194), together with a targeted screening of anti-cytokine autoantibodies. This approach identified V-set immunoglobulin-domain-containing protein 4 (VSIG4) and anti-interferon-γ autoantibodies as serum markers associated with increased flare risk following biologic dose reduction. Integration of these proteomics-derived markers with baseline disease activity measures significantly improved flare prediction compared with clinical parameters alone. Together, these findings demonstrate that deep serum proteomics within a controlled therapeutic perturbation can uncover immune regulatory signatures linked to disease flare in RA. This study highlights the value of proteomics-guided biomarker discovery for developing integrative predictive frameworks to support personalized treatment strategies.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Blood Serum

SUBMITTER: PATRICIA FERNANDEZ PUENTE  

LAB HEAD: Cristina Ruiz Romero

PROVIDER: PXD073940 | Pride | 2026-10-05

REPOSITORIES: Pride