Plasma Protein Signatures Reveal Damage in Ankylosing Spondylitis

AMONG PATIENTS with ankylosing spondylitis (AS), a validated five-protein plasma signature has been linked to high structural damage, researchers have found, suggesting that plasma protein signatures could complement imaging by capturing biological processes beyond systemic inflammation.

Plasma Protein Signatures Beyond Inflammation

Pathological bone formation in AS is not fully reflected by systemic inflammation, which limits the usefulness of inflammatory markers for assessing structural damage and leaves a need for complementary biomarkers. Researchers therefore sought to identify plasma protein signatures associated with the severity of structural damage in ankylosing spondylitis.

Discovery and Validation Cohorts

Deep plasma proteomics was conducted in a prospective 88-participant discovery cohort comprising 32 normal controls and patients stratified by the SPARCC sacroiliac joint structural score into high (n=25) and low (n=31) structural damage groups.

Age- and sex-adjusted differential expression analysis, WGCNA, and integrated machine learning were used to characterise damage-associated molecular programmes and prioritise biomarkers. Five candidate proteins were then validated by ELISA in an independent 88-participant cohort comprising 32 patients with high damage, 32 with low damage, and 24 normal controls.

Five-Protein Panel Performance

Proteomic profiling identified 536 differentially expressed proteins between the high structural damage group and normal controls.

WGCNA revealed a structural-damage-associated module enriched in platelet activation and cell-matrix adhesion, together with an AS-associated reduction in a module related to RNA processing and translation.

Integrated analysis prioritised a five-protein signature comprising ITGA2B, HSPG2, ITGB1, EPHB2, and SAA2.

In the validation cohort, the combined model achieved an AUC of 0.917 and significantly outperformed individual biomarkers (AUCs: 0.732 to 0.819; all Holm-adjusted P<0.05).

Complementing Imaging-Based Assessment

These findings support a dual-pathway model in which SAA2-marked systemic inflammation and ITGA2B-associated platelet-ECM remodelling appear partially dissociated yet remain biologically interconnected in AS.

The validated five-protein panel provides a noninvasive tool for identifying patients with current high structural damage and may complement imaging-based assessment by capturing biological heterogeneity. Further validation in larger cohorts will be needed to confirm these findings.

Reference

Sun T et al. Plasma proteomics identifies molecular signatures and biomarkers associated with high structural damage in ankylosing spondylitis. Arthritis Rheumatol. 2026;DOI:10.1002/art.70353.