THU0095 Cadherin-11 Gene is Aberrantly Expressed in the Peripheral Blood of Patients with Rheumatoid Arthritis and Strongly Correlates with Multiple Joint Inflammation

Abstract

Background In immunodeficient mice the subcutaneous implantation of synovial fibroblasts (SFs) derived from patients with rheumatoid arthritis (RASFs) revealed an active movement via the vasculature to the naive cartilage that led to damage, thus supporting the idea that RASFs may facilitate and drive the progression from oligo- to polyarticular disease in RA (Nat Med. 2009;15:1414). On the other hand, RASFs hyper-express cadherin-11 and anti-cadherin-11 therapy may have potential as a novel RA therapy. This adhesion molecule, which is required for synovial lining formation, is involved in tumor invasion and metastasis, and signal transduction. Objectives By considering that cadherin-11 can serve as a marker of possibly circulating RASFs and since it is not thought to be expressed in hematopoietic tissues, we tested the hypothesis that cadherin-11 gene is aberrantly expressed in the peripheral blood of RA patients with active inflammation in multiple joints. Methods Total RNA extracted from 3 ml peripheral blood samples from 70 consecutive patients with RA, 56 healthy blood donors and 47 other joint disease-control patients was subjected to quantitative real time RT-PCR for analysis of cadherin-11 gene expression. Flow-cytometry was also performed in selected RA blood samples. Inflammatory synovial fluid samples served as positive controls. Results Cadherin-11 mRNA transcripts were found in all 5 synovial fluid samples examined, as well as in the peripheral blood of 71% of those patients with active, established RA, versus 14% of healthy blood donors (p<0.0001) and 14% of those RA patients in remission. Among patients with active, established RA, cadherin-11 was expressed in 24/30 and 10/21 patients with poly- and oligoarthritis, respectively (80% versus 48%, p:0.016). The positive correlation between cadherin-11 expression and the extent of joint inflammation was confirmed in 75 % of serial samples obtained from RA patients at different disease activity phases. Cadherin-11 gene expression was not associated with ESR or CRP levels, autoantibodies, or treatment modalities. Comparable to RA results were also obtained from patients with or without active, chronic joint inflammation in the context of other connective tissue diseases (SLE/Sjogren’s/SSc, n=20) or spondylarthropathies (n=16). In contrast, cadherin-11 was not expressed in blood samples derived from 9 of 11 patients with infectious or crystal arthropathies, or osteoarthritis. By flow cytometry, cells co-expressing surface cadherin-11 and CD90(Thy-1)/CD106(VCAM-1), probably representing RASFs, were found in all synovial fluids examined. Such rare circulating cells, either or not expressing the pan-haematolymphoid marker CD45, were also identified in the peripheral blood of patients with active RA. Conclusions Cadherin-11 mRNA transcripts are frequently found in the peripheral blood of RA patients with active disease and may serve as biomarker of (auto)immune-mediated joint inflammation. These results will have important prognostic and therapeutic ...