Background:Rheumatoid arthritis (RA) is a heterogeneous disease with variable prognosis. The cellular composition in synovium is the driving force of joint destruction in RA, and the predictive values of histopathological assessments on the clinical outcomes of RA have been identified. However, current synovial histopathological assessments mainly focus on the infiltrated immunocytes to distinguish RA synovium into different synovial pathotypes. Whether addition of stromal cells improve the accuracy of histopathological assessments remains unknow.Objectives:To distinguish synovial pathotypes of RA based on intercellular connection and explore their predictive value on one-year radiographic progression.Methods:Active RA patients who underwent needle synovial biopsy at baseline were recruited from a real-world prospective cohort. Clinical data were evaluated at baseline and 1, 3, 6, 12 months. Histopathologic assessments included Krenn synovitis score and semiquantitative score of immunohistochemical staining for CD20, CD38, CD4, CD8, CD68, CD31 and CD90. Cluster analysis was used to distinguish synovial pathotypes. The primary outcome was one-year radiographic progression defined as a change in total Sharp/van der Heijde modified score≥0.5 units.Results:1. Among 134 RA patients who received synovial biopsy at baseline and finished one-year follow-up, 105 had qualified synovial tissue. The mean age was 50.2±13.3 years with 77.1% female. The median disease duration was 24 (9-120) months. All patients were active RA, and 64.8%, 26.7% and 8.6% patients in high, moderate and low disease activity, respectively. There were 41 (39%) patients who have never been treated with corticosteroids or disease-modifying anti-rheumatic drugs.2. During one-year follow-up, there were 48.6%, 63.8%, 71.4%, and 69.5% patients achieved CDAI LDA target, and 12.4%, 30.5%, 34.3%, and 32.4% patients achieved CDAI remission after 1, 3, 6, and 12 months, respectively. A total of 33 (31.4%) patients had radiographic progression.3. All patients were divided into three clusters using cluster analysis based on the seven synovial cellular scores. Patients in cluster 1 (n=50, 47.6%) had higher scores of sublining CD68+ macrophages, CD31+ endothelial cells and CD90+ fibroblasts, thus named as myeloid-stromal pathotype. Patients in cluster 2 (n=26, 24.8%) had higher scores of CD20+ B cells, CD38+ plasma cells, CD4+ T cells and CD8+ T cells, thus named as lymphoid pathotype. Patients in cluster 3 (n=29, 27.6%) had lower scores of all seven cell types, thus named as pauci-cellular pathotype (Figure 1).4. RA patients with baseline synovial myeloid-stromal pathotype showed higher rate of one-year radiographic progression versus lymphoid and pauci-cellular pathotypes (48% vs. 16.4%, P<0.001), whereas there was no difference between lymphoid and pauci-cellular pathotypes (11.5% vs. 20.7, P=0.475). Adjusted for confounding factors including age, sex, smoking, disease duration, RF status, ACPA status, CDAI, HAQ-DI and mTSS at baseline, multivariate logistic regression analysis showed that baseline synovial myeloid-stromal pathotype independently predicted one-year radiographic progression (AOR=3.602, 95%CI:1.257-10.324, P=0.017, Table 1).Conclusion:Baseline synovial myeloid-stromal pathotype in RA can predict one-year radiographic progression.Funding:This work was supported by National Natural Science Foundation of China (no. 81971527, 81801606 and 81801605), Guangdong Natural Science Foundation (no. 2018A030313541 and 2018A030313690), Guangdong Medical Scientific Research Foundation (no. A2018062), Guangdong Basic and Applied Basic Research Foundation (no. 2019A1515011928 and 2020A1515110061), and Science and Technology Program of Guangzhou (no. 201904010088).Acknowledgements:We thank all subjects and medical staff who generously contributed to this study.Disclosure of Interests:None declared
Immunohistological assessment of the synovial tissue in small joints in rheumatoid arthritis: validation of a minimally invasive ultrasound-guided synovial biopsy procedure
