LAUSR

Background Despite the many therapies for patients with rheumatoid arthritis (RA), there is little information to guide selection of the most effective treatment for an individual patient. Forty-sixty percent of patients with RA respond (defined by ACR50 response criteria) to conventional disease modifying anti-rheumatic drugs (cDMARDs) or cDMARDs plus anti-tumour necrosis factor (TNF) therapy. Moreover, 20%–40% of subjects in clinical trials never demonstrate even a minimal response (ACR20 response criteria). Based on a population of over 300 million in the United States, a disease prevalence of 0.6%, and a course of 3–4 months per biologic DMARD therapy, as much as $2.5 billion is wasted annually on inadequate therapy. There is a clear need to develop precision-based therapy for patients with RA, whereby clinical information such as novel biomarkers will enhance our ability to predict the therapeutic response and thereby limit ineffective therapy. Objectives Currently, there are no reliable biomarkers for predicting therapeutic response in patients with rheumatoid arthritis (RA). The synovium may unlock critical information for determining efficacy as reduction in numbers of sublining synovial macrophages remains the most reproducible biomarker. Thus, a clinically actionable method for collection of synovial tissue, which can be analysed using high-throughput strategies, must become a reality. Methods Rheumatologists at six United States academic sites were trained in minimally invasive ultrasound-guided synovial tissue biopsy. Histology, fluorescence-activated cell sorting and RNA-seq were performed on biopsy synovial tissue from patients with RA and compared with osteoarthritis (OA) samples. An optimised protocol for digesting synovial tissue was developed to generate high quality RNA-seq libraries from isolated macrophage populations. Associations were determined between macrophage transcriptional profiles and clinical parameters of RA patients. Results Patients with RA reported minimal adverse effects in response to synovial biopsy. Comparable RNA quality was observed between synovial tissue and isolated macrophages from patients with RA and OA. Whole tissue samples from patients with RA demonstrated a high degree of transcriptional heterogeneity. In contrast, the transcriptional profile of isolated RA synovial macrophages highlighted a subpopulation of patients and identified six novel transcriptional modules that were associated with disease activity and therapy. Conclusions Performance of synovial tissue biopsies by rheumatologists in the United States is feasible and generates high-quality samples for research. By utilising cutting-edge technologies on synovial biopsies with corresponding clinical information, a precision-based medicine approach for patients with RA is attainable. Disclosure of Interest None declared