Background/Purpose: Human rheumatoid arthritis synovial fibroblasts (RASF) implanted subcutaneously in immunodeficient mice trans-migrate through the vasculature and drive the progression from oligo– to poly-articular disease. On the other hand, RASFs overexpress the mesenchymal cadherin-11, an adhesion molecule involved in tumor invasion and metastasis and cadherin-11 therapeutics prevent and reduce experimental arthritis. We tested the hypothesis that aberrant expression of cadherin-11, deriving from possibly circulating RASFs with pathogenic potential, can be identified in the peripheral blood of patients with active RA.

Methods: Cadherin-11 mRNA was quantified by real-time reverse transcription-PCR in peripheral blood (3ml) from 100 consecutive RA patients (15 studied serially) and 70 healthy controls. Western blotting and flow cytometry were performed in synovial fluid and peripheral blood using an anti-cadherin-11 antibody that decorated RASFs in synovial tissue’s immunohistochemistry.

Results: Cadherin-11 mRNA was detected in 69.2% of moderately or severely active disease, versus 31.8% of patients with low disease activity or clinical remission (p=0.001), versus 17.1 % of healthy controls (p<0.0001). Repeated measurements after 2-4 months confirmed these findings. Disease duration was significantly longer in cadherin-11 positive versus negative patients, whereas rheumatoid factor, ESR, CRP levels and treatment modalities were comparable.  Notably, among patients with established RA (disease duration longer than one year) cadherin-11 mRNA was detectable in 88.4% of those with active polyarthritis (5 or more tender and swollen joints at the time of sampling) versus 48.3% in those with oligo– or monoarthtitis (p<0.0001). Western blotting experiments were not sensitive enough to reveal cadherin-11 expression at the protein level in either synovial fluid or peripheral blood samples. However, rare cells expressing surface cadherin-11, together, or not, with the pan-hematopoietic marker CD45 were consistently present in RA-derived synovial fluid. Such rare cells were also identified in peripheral blood from 5/6 versus 1/6 patients with established or early, respectively, poly-articular RA.

Conclusion: Cadherin-11 mRNA transcripts in the peripheral blood may serve as the first biomarker of active polyarthritis in established RA.  Rare circulating cells expressing surface cadherin-11 in patients with RA could possibly represent macrophages and RASFs; the latter could enter the circulation as the synovium transforms into an hyperplastic, invasive tissue with new vessel formation. Taken together, these data further identify cadherin-11 as a potential therapeutic target in RA.