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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 J2, Aren K1, Thakrar A1, Montgomery AB1, Louis Bridges S Jr.3, Bathon JM4, Atkinson JP5, Fox DA6, Matteson EL7, Buckley CD8, Pitzalis C9, Parks D5, Hughes LB3, Geraldino-Pardilla L4, Ike R6, Phillips K6, Wright K7, Filer A8, Kelly S9, Ruderman EM1, Morgan V1, Abdala-Valencia H1, Misharin AV10, Budinger GS10, Bartom ET11, Pope RM1, Perlman H1, Winter DR1. Arthritis Rheumatol. 2018 Feb 13. doi: 10.1002/art.40453. [Epub ahead of print]

Abstract

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1 Department of Medicine, Division of Rheumatology, Northwestern University Feinberg School of Medicine Chicago, IL.

2 Department of Preventive Medicine, Northwestern University Feinberg School of Medicine Chicago, IL.

3 Department of Medicine, Division of Clinical Immunology and Rheumatology, University of Alabama, Birmingham, AL.

4 Department of Medicine, Division of Rheumatology, Columbia University, College of Physicians and Surgeons, New York, NY.

5 Department of Medicine, Division of Rheumatology, Washington University School of Medicine, Saint Louis, MO.

6 Department of Internal Medicine, University of Michigan, Division of Rheumatology and Clinical Autoimmunity Center of Excellence, University of Michigan School of Medicine, Ann Arbor, MI.

7 Department of Internal Medicine, Division of Rheumatology, Mayo Clinic College of Medicine and Science, Rochester, MN.

8 Rheumatology Research Group, Institute of Inflammation and Ageing, University of Birmingham Research Laboratories, Queen Elizabeth Hospital Birmingham, Edgbaston, Birmingham, UK.

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

10 Department of Medicine, Division of Pulmonary and Critical Care, Northwestern University Feinberg School of Medicine Chicago, IL.

11 Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine Chicago, IL.

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 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 analyzed 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 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 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.

CONCLUSION: Performance of synovial tissue biopsies by rheumatologists in the United States is feasible and generates high-quality samples for research. By utilizing cutting-edge technologies on synovial biopsies with corresponding clinical information, a precision-based medicine approach for patients with RA is attainable.