Addition of Fibroblast-Stromal Cell Markers to Immune Synovium Pathotypes Better Predicts Radiographic Progression at One Year in Active Rheumatoid Arthritis

Background: Current synovial assessments mainly focus on the infiltrated immune cells. Whether addition of fibroblast-stromal cell markers to a classification of synovial pathotypes improves their predictive value on clinical outcomes in rheumatoid arthritis (RA) remains unknown. Methods: Active RA patients with a knee needle synovial biopsy at baseline and finished one-year follow-up were recruited from a real-world prospective cohort. Positive staining for CD20, CD38, CD3, CD68, CD31 and CD90 were scored semi-quantitatively (0-4). The primary outcome was radiographic progression defined as a minimum increase of 0.5 units of the modified total Sharp score from baseline to one year. Findings: Among 159 recruited RA patients, 123 (77.4%) had qualified synovial tissue. Higher scores of CD20+ B cells, sublining CD68+ macrophages, CD31+ endothelial cells and CD90+ fibroblasts were associated with less decrease in disease activity and greater increase in radiographic progression. A new fibroblast-based classification of synovial pathotypes giving more priority to myeloid and stromal cells classified samples as myeloid-stromal (57.7%, 71/123), lymphoid (31.7%, 39/123), and pauci-cellular pathotypes (10.6%, 13/123). RA patients with myeloid-stromal pathotype showed the highest rate of radiographic progression (43.7% vs. 23.1% vs. 7.7%, P =0.011), and the lowest rate of Boolean remission at 3, 6, 12 months. Baseline myeloid-stromal pathotype independently predicted radiographic progression at one year (3.199, 95% CI: 1.278, 8.010). Similar results were obtained in a subgroup analysis of treatment-naive RA. Interpretation: This novel myeloid-stromal pathotype could predict radiographic progression at one year in active RA which may contribute to the shift of therapeutic decision in RA. Funding Statement: This work including data collection and conduct of experiments was supported by National Natural Science Foundation of China (81801606, 81971527 and 82001731), Guangdong Natural Science Foundation (2018A030313541 and 2018A030313690), Guangdong Medical Scientific Research Foundation (A2018062 and A2021065), Science and Technology Program of Guangzhou (201904010088 and 202102010188), and Guangdong Basic and Applied Basic Research Foundation (2019A1515011928, 2019A1515110125 and 2020A1515110061). Declaration of Interests: The authors declare no conflicts of interest. Ethics Approval Statement: Ethical approval was provided by the Medical Ethics Committee of Sun Yat-sen Memorial Hospital (SYSEC-2009-06 and SYSEC-KY-KS-012). All patient consents were obtained before biopsy and collection of clinical data.