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

Arthur M. Mandelin, Philip J. Homan, Alexander M. Shaffer, Carla M. Cuda, Salina T. Dominguez, Emily Bacalao, Mary Carns, Monique Hinchcliff, Jungwha Lee, Kathleen Aren, Anjali Thakrar, Anna B. Montgomery, S. Louis Bridges, Joan M. Bathon, John P. Atkinson, David A. Fox, Eric Lawrence Matteson, Christopher D. Buckley, Costantino Pitzalis, Deborah ParksLaura B. Hughes, Laura Geraldino-Pardilla, Robert Ike, Kristine Phillips, Kerry Wright, Andrew Filer, Stephen Kelly, Eric M. Ruderman, Vince Morgan, Hiam Abdala-Valencia, Alexander V. Misharin, G. Scott Budinger, Elizabeth T. Bartom, Richard M. Pope, Harris Perlman, Deborah R. Winter

Research output: Contribution to journalArticle

14 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)841-854
Number of pages14
JournalArthritis and Rheumatology
Volume70
Issue number6
DOIs
StatePublished - Jun 1 2018
Externally publishedYes

Fingerprint

Rheumatoid Arthritis
Macrophages
Biopsy
RNA Sequence Analysis
Osteoarthritis
Biomarkers
Precision Medicine
Synovial Membrane
Libraries
Flow Cytometry
RNA
Technology
Therapeutics
Research

ASJC Scopus subject areas

  • Immunology and Allergy
  • Rheumatology
  • Immunology

Cite this

Mandelin, A. M., Homan, P. J., Shaffer, A. M., Cuda, C. M., Dominguez, S. T., Bacalao, E., ... Winter, D. R. (2018). Transcriptional Profiling of Synovial Macrophages Using Minimally Invasive Ultrasound-Guided Synovial Biopsies in Rheumatoid Arthritis. Arthritis and Rheumatology, 70(6), 841-854. https://doi.org/10.1002/art.40453

Transcriptional Profiling of Synovial Macrophages Using Minimally Invasive Ultrasound-Guided Synovial Biopsies in Rheumatoid Arthritis. / Mandelin, Arthur M.; Homan, Philip J.; Shaffer, Alexander M.; Cuda, Carla M.; Dominguez, Salina T.; Bacalao, Emily; Carns, Mary; Hinchcliff, Monique; Lee, Jungwha; Aren, Kathleen; Thakrar, Anjali; Montgomery, Anna B.; Bridges, S. Louis; Bathon, Joan M.; Atkinson, John P.; Fox, David A.; Matteson, Eric Lawrence; Buckley, Christopher D.; Pitzalis, Costantino; Parks, Deborah; Hughes, Laura B.; Geraldino-Pardilla, Laura; Ike, Robert; Phillips, Kristine; Wright, Kerry; Filer, Andrew; Kelly, Stephen; Ruderman, Eric M.; Morgan, Vince; Abdala-Valencia, Hiam; Misharin, Alexander V.; Budinger, G. Scott; Bartom, Elizabeth T.; Pope, Richard M.; Perlman, Harris; Winter, Deborah R.

In: Arthritis and Rheumatology, Vol. 70, No. 6, 01.06.2018, p. 841-854.

Research output: Contribution to journalArticle

Mandelin, AM, Homan, PJ, Shaffer, AM, Cuda, CM, Dominguez, ST, Bacalao, E, Carns, M, Hinchcliff, M, Lee, J, Aren, K, Thakrar, A, Montgomery, AB, Bridges, SL, Bathon, JM, Atkinson, JP, Fox, DA, Matteson, EL, Buckley, CD, Pitzalis, C, Parks, D, Hughes, LB, Geraldino-Pardilla, L, Ike, R, Phillips, K, Wright, K, Filer, A, Kelly, S, Ruderman, EM, Morgan, V, Abdala-Valencia, H, Misharin, AV, Budinger, GS, Bartom, ET, Pope, RM, Perlman, H & Winter, DR 2018, 'Transcriptional Profiling of Synovial Macrophages Using Minimally Invasive Ultrasound-Guided Synovial Biopsies in Rheumatoid Arthritis', Arthritis and Rheumatology, vol. 70, no. 6, pp. 841-854. https://doi.org/10.1002/art.40453
Mandelin, Arthur M. ; Homan, Philip J. ; Shaffer, Alexander M. ; Cuda, Carla M. ; Dominguez, Salina T. ; Bacalao, Emily ; Carns, Mary ; Hinchcliff, Monique ; Lee, Jungwha ; Aren, Kathleen ; Thakrar, Anjali ; Montgomery, Anna B. ; Bridges, S. Louis ; Bathon, Joan M. ; Atkinson, John P. ; Fox, David A. ; Matteson, Eric Lawrence ; Buckley, Christopher D. ; Pitzalis, Costantino ; Parks, Deborah ; Hughes, Laura B. ; Geraldino-Pardilla, Laura ; Ike, Robert ; Phillips, Kristine ; Wright, Kerry ; Filer, Andrew ; Kelly, Stephen ; Ruderman, Eric M. ; Morgan, Vince ; Abdala-Valencia, Hiam ; Misharin, Alexander V. ; Budinger, G. Scott ; Bartom, Elizabeth T. ; Pope, Richard M. ; Perlman, Harris ; Winter, Deborah R. / Transcriptional Profiling of Synovial Macrophages Using Minimally Invasive Ultrasound-Guided Synovial Biopsies in Rheumatoid Arthritis. In: Arthritis and Rheumatology. 2018 ; Vol. 70, No. 6. pp. 841-854.
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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.",
author = "Mandelin, {Arthur M.} and Homan, {Philip J.} and Shaffer, {Alexander M.} and Cuda, {Carla M.} and Dominguez, {Salina T.} and Emily Bacalao and Mary Carns and Monique Hinchcliff and Jungwha Lee and Kathleen Aren and Anjali Thakrar and Montgomery, {Anna B.} and Bridges, {S. Louis} and Bathon, {Joan M.} and Atkinson, {John P.} and Fox, {David A.} and Matteson, {Eric Lawrence} and Buckley, {Christopher D.} and Costantino Pitzalis and Deborah Parks and Hughes, {Laura B.} and Laura Geraldino-Pardilla and Robert Ike and Kristine Phillips and Kerry Wright and Andrew Filer and Stephen Kelly and Ruderman, {Eric M.} and Vince Morgan and Hiam Abdala-Valencia and Misharin, {Alexander V.} and Budinger, {G. Scott} and Bartom, {Elizabeth T.} and Pope, {Richard M.} and Harris Perlman and Winter, {Deborah R.}",
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T1 - Transcriptional Profiling of Synovial Macrophages Using Minimally Invasive Ultrasound-Guided Synovial Biopsies in Rheumatoid Arthritis

AU - Mandelin, Arthur M.

AU - Homan, Philip J.

AU - Shaffer, Alexander M.

AU - Cuda, Carla M.

AU - Dominguez, Salina T.

AU - Bacalao, Emily

AU - Carns, Mary

AU - Hinchcliff, Monique

AU - Lee, Jungwha

AU - Aren, Kathleen

AU - Thakrar, Anjali

AU - Montgomery, Anna B.

AU - Bridges, S. Louis

AU - Bathon, Joan M.

AU - Atkinson, John P.

AU - Fox, David A.

AU - Matteson, Eric Lawrence

AU - Buckley, Christopher D.

AU - Pitzalis, Costantino

AU - Parks, Deborah

AU - Hughes, Laura B.

AU - Geraldino-Pardilla, Laura

AU - Ike, Robert

AU - Phillips, Kristine

AU - Wright, Kerry

AU - Filer, Andrew

AU - Kelly, Stephen

AU - Ruderman, Eric M.

AU - Morgan, Vince

AU - Abdala-Valencia, Hiam

AU - Misharin, Alexander V.

AU - Budinger, G. Scott

AU - Bartom, Elizabeth T.

AU - Pope, Richard M.

AU - Perlman, Harris

AU - Winter, Deborah R.

PY - 2018/6/1

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N2 - 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.

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