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Transcriptional Profiling of Synovial Macrophages Using Minimally Invasive Ultrasound-Guided Synovial Biopsies in Rheumatoid Arthritis

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Mandelin AM 2nd1, Homan PJ1, Shaffer AM1, Cuda CM1, Dominguez ST1, Bacalao E1, Carns M1, Hinchcliff M1, Lee J1, Aren K1, Thakrar A1, Montgomery AB1, Bridges SL Jr2, Bathon JM3, Atkinson JP4, Fox DA5, Matteson EL6, Buckley CD7, Pitzalis C8, Parks D4, Hughes LB2, Geraldino-Pardilla L3, Ike R5, Phillips K5, Wright K6, Filer A7, Kelly S8, Ruderman EM1, Morgan V1, Abdala-Valencia H1, Misharin AV1, Budinger GS1, Bartom ET1, Pope RM1, Perlman H1, Winter DR1. Arthritis Rheumatol. 2018 Jun;70(6):841-854. doi: 10.1002/art.40453. Epub 2018 May 3.

Abstract

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1 Northwestern University Feinberg School of Medicine, Chicago, Illinois.

2 University of Alabama at Birmingham.

3 Columbia University, New York, New York.

4 Washington University School of Medicine, St. Louis, Missouri.

5 University of Michigan School of Medicine, Ann Arbor.

6 Mayo Clinic College of Medicine and Science, Rochester, Minnesota.

7 University of Birmingham Research Laboratories, Queen Elizabeth Hospital Birmingham, Birmingham, UK.

8 William Harvey Research Institute and Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.

Abstract

OBJECTIVE: 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, since a reduction in the numbers of sublining synovial macrophages remains the most reproducible biomarker. Thus, a clinically actionable method for the collection of synovial tissue, which can be analyzed using high-throughput strategies, must become a reality. This study was undertaken to assess the feasibility of utilizing synovial biopsies as a precision medicine-based approach for patients with RA.

METHODS: Rheumatologists at 6 US academic sites were trained in minimally invasive ultrasound-guided synovial tissue biopsy. Biopsy specimens obtained from patients with RA and synovial tissue from patients with osteoarthritis (OA) were subjected to histologic analysis, fluorescence-activated cell sorting, and RNA sequencing (RNA-seq). An optimized 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 in RA patients.

RESULTS: Patients with RA reported minimal adverse effects in response to synovial biopsy. Comparable RNA quality was observed from synovial tissue and isolated macrophages between patients with RA and patients with 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 different subpopulations of patients and identified 6 novel transcriptional modules that were associated with disease activity and therapy.

CONCLUSION: Performance of synovial tissue biopsies by rheumatologists in the US is feasible and generates high-quality samples for research. Through the use of cutting-edge technologies to analyze synovial biopsy specimens in conjunction with corresponding clinical information, a precision medicine-based approach for patients with RA is attainable.