Justus-Liebig-University Gießen Bad Nauheim, Germany
Selina Ohl1, Klaus Frommer2, Markus Rickert3, Stefan Rehart4, Ulf Müller-Ladner5 and Elena Neumann6, 1Department of Rheumatology and Clinical Immunology, Campus Kerckhoff, Bad Nauheim, Germany, 2Justus Liebig University Gießen, Department of Rheumatology and Clinical Immunology, Campus Kerckhoff, Bad Nauheim, Germany, 3Dept. of Orthopaedics and Orthopaedic Surgery, University Hospital Giessen and Marburg, Giessen, Germany, Gießen, Germany, 4Agaplesion Markus Hospital, Dpt of Orthopaedics and Trauma Surgery, Frankfurt, Germany, 5JLU Campus KK, Bad Nauheim, Germany, 6JLU Gießen, Campus Kerckhoff, Bad Nauheim, Germany
Background/Purpose: Rheumatoid arthritis (RA) is a chronic autoimmune disease, whose inflammatory processes in the synovium lead to the destruction of cartilage and bone. Although there are various treatment options, RA cannot yet be cured. Therefore, remission is the therapeutic goal. Since the prognostic outcomes of patients in remission vary widely, a better understanding of remission is necessary. The objective is the characterization of remission in RA by comparison of histological and molecular features in the synovium of patients in remission and those with an active disease.
Methods: RA patients (age 43-81 years, mean 62.2 years) receiving joint replacement surgery were categorized into remission vs. active disease based on clinical (e.g. painful joints, pain degree, medication) and laboratory parameters (e.g. ESR, CRP, leucocytes). To characterize histologically the type and grade of synovitis, the Krenn Score was applied. RA synovial fibroblasts (RASF) of patients in remission and those with an active disease were either stimulated with IL-1 or unstimulated for 24 h in passage 3 followed by RNA sequencing to further characterize remission on RNA level. Evaluation included analysis of differentially expressed genes (DEG) based on a combination of absolute expression, divergence and significance as well as gene set enrichment analysis of the DEGs in order to identify the enriched gene sets or pathways.
Results: Clinical classification of 39 synovial tissues led to the inclusion of 20 active patients and 19 in remission. Patients in remission showed lower synovitis scores. Specifically hyperplasia (P=0.021) and total Krenn score (P=0.022) showed significant differences for patients in remission compared to active disease. Sub-analyses regarding medication (e.g. biologicals, DMARDs, NSAIDs, glucocorticoids) confirmed the observations between remission and active RA for all drugs and indicated an overall reduction of hyperplasia. Especially patients receiving biologics showed a 4.2 fold decrease of hyperplasia in remission. The results of the RNA sequencing indicated homogeneity of the expressed genes and the undergoing pathways between the RASF of patients in remission and those with an active RA. These observations were evident in both, the unstimulated approaches, and the RASF stimulated with IL-1. However, RNAseq identified several differentially expressed genes. These genes include IL-36B (-2.85 fold), cathepsin K (-0.73 fold) and folliculin (active vs. remission: -0.62 fold) which were downregulated in remission and play a crucial role in the progression of RA.
Conclusion: The characterization of synovium after joint replacement surgery was used to compare histological and molecular differences that may help to characterize remission in RA. The histology showed a lower degree of inflammation and, most prominent, hyperplasia for patients in remission, specifically in patients receiving biologics. RNAseq identified several genes showing altered expressions related to the pro-inflammatory and destructive processes during RA which gives insight into the molecular characteristics of remission.
Disclosures: S. Ohl, None; K. Frommer, None; M. Rickert, None; S. Rehart, None; U. Müller-Ladner, Biogen; E. Neumann, None.
