Background: Rheumatoid arthritis (RA) in its early phase (duration <2 years, termed AR-RI) displays variable synovitis patterns that predict structural damage and therapeutic outcomes. Histological classification systems like the Krenn index enable precise synovitis grading, with higher scores reflecting organized inflammation, stromal activation, and erosive potential. Previous studies link high Krenn grades to sustained disease activity and poor prognosis, underscoring the need for integrated multi-modal profiling including ultrasound and serum proteomics to define aggressive phenotypes and prognostic markers.

Objectives: 1) To evaluate a prospective cohort of early RA patients stratified by Krenn index, integrating baseline clinical assessments, musculoskeletal ultrasound (MSUS), synovial histopathology, and high-throughput serum proteomics. 2) Identifying clinicopathological correlations, defining a Krenn-associated proteomic signature with synovial relevance, and assessing its prognostic value for ultrasound progression at 6 and 12 months post-biopsy.

Methods: Twenty-nine consecutive early RA patients (disease duration ≤2 years) fulfilling 2010 ACR/EULAR criteria underwent ultrasound-guided synovial biopsy from an actively inflamed joint (primarily knee or wrist), alongside clinical evaluation, laboratory tests, and serum collection at baseline. Patients were stratified into low (≤3) and high (>3) Krenn index groups. Clinical parameters included demographics, disease duration, DAS28-CRP, CRP, ESR, RF/ACPA status and titers. MSUS assessed gray-scale synovitis, power Doppler signal, tenosynovitis, and erosions using EULAR-OMERACT scoring. Histology evaluated lining thickness, stromal cellularity, inflammation, and aggregation per Krenn criteria. Serum proteomics employed the Olink Target 96 Inflammation panel to identify differentially expressed proteins. Follow-up MSUS occurred at 6 and 12 months. Groups were compared using t-tests/Mann-Whitney U and chi-square/Fisher exact tests; correlations employed Spearman rho; proteomic analysis used multivariate regression adjusted for confounders.

Results: High Krenn patients (n=13) were comparable to low Krenn (n=12) in sex distribution and disease duration but younger, with greater disease activity (higher DAS28-CRP, p<0.05), systemic inflammation (elevated CRP, p<0.05; ESR trend), and autoantibody burden (RF/ACPA positivity; higher ACPA titers). Ultrasonographically, high Krenn associated with tenosynovitis, moderate gray-scale synovial hypertrophy, and erosions, but not power Doppler intensity. Histologically, high Krenn showed trends toward thicker lining (p=0.07), significantly increased stromal cellularity (moderate-high), inflammation (moderate-high), and aggregation scores (grade 2-3), confirming stromal and organized inflammation dominance. Proteomically, 12 proteins were upregulated in high Krenn sera (FDR<0.05; e.g., TGFA, Beta-NGF, AXIN1, SIRT2, STAMBP, DNER for stromal fibroblast proliferation; MMP1 for matrix degradation/erosiveness; TNFSF14, EN-RAGE, CASP8, SULT1A1 for persistent inflammation/aggregation; CXCL10 for interferon-driven lymphocyte chemotaxis). This signature correlated with baseline clinical (CRP/ESR), ultrasound (tenosynovitis/erosions), and histological Krenn components (all p<0.05). Prognostically, baseline EN-RAGE, Beta-NGF, AXIN1, SIRT2, and STAMBP levels predicted 6/12-month ultrasound progression (ΔDoppler/erosions).

Conclusions: In early RA, elevated Krenn index delineates a clinically aggressive synovitis phenotype marked by heightened disease activity, autoantibody positivity, ultrasound tenosynovitis/erosions, stromal hypercellularity, and organized inflammation. The associated 12-protein serum signature reflects synovial pathobiology—stromal activation, matrix remodeling, and sustained inflammation—and links to baseline features while exhibiting prognostic utility for structural progression.

REFERENCES: NIL.

Acknowledgments: NIL.

Disclosure of Interests: None declared.