B Cell Synovitis and Clinical Phenotypes in Rheumatoid Arthritis: Relationship to Disease Stages and Drug Exposure

Objective To define the relationship of synovial B cells to clinical phenotypes at different stages of disease evolution and drug exposure in rheumatoid arthritis (RA). Methods Synovial biopsy specimens and demographic and clinical data were collected from 2 RA cohorts (n = 329), one of patients wit...

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Published in:	Arthritis & rheumatology (Hoboken, N.J.) Vol. 72; no. 5; pp. 714 - 725
Main Authors:	Rivellese, F., Humby, F., Bugatti, S., Fossati‐Jimack, L., Rizvi, H., Lucchesi, D., Lliso‐Ribera, G., Nerviani, A., Hands, R. E., Giorli, G., Frias, B., Thorborn, G., Jaworska, E., John, C., Goldmann, K., Lewis, M. J., Manzo, A., Bombardieri, M., Pitzalis, C., McInnes, Iain B., Buckley, Chris, Taylor, Peter C., Choy, Ernest, Pratt, Arthur, Edwards, Christopher, Gendi, Nagui, Ho, Pauline, Dasgupta, Bhaskar, Durez, Patrick, Fonseca, João Eurico, Sainaghi, Pier Paolo, Bellan, Mattia, Isaacs, John, Cañete, Juan D., Cauli, Alberto, Congia, Mattia, Reynolds, Piero, Moots, Robert, Ng, Nora, Montecucco, Carlomaurizio, Verschueren, Patrick
Format:	Journal Article
Language:	English
Published:	United States Wiley Subscription Services, Inc 01-05-2020 John Wiley and Sons Inc
Subjects:	Adult Aged Antibodies Arthritis Arthritis, Rheumatoid - complications Arthritis, Rheumatoid - drug therapy B-Lymphocytes Biopsy CD20 antigen Cell lineage Citrulline Cohort Studies Correlation analysis Digital imaging Disease Progression Exposure Female Humans Image analysis Image processing Lymphocytes B Male Medical imaging Middle Aged Original Phenotype Phenotypes Rheumatoid Arthritis Rheumatoid factor Ribonucleic acid RNA Synovitis Synovitis - complications Synovitis - genetics Synovitis - immunology Transcription
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Summary:	Objective To define the relationship of synovial B cells to clinical phenotypes at different stages of disease evolution and drug exposure in rheumatoid arthritis (RA). Methods Synovial biopsy specimens and demographic and clinical data were collected from 2 RA cohorts (n = 329), one of patients with untreated early RA (n = 165) and one of patients with established RA with an inadequate response to tumor necrosis factor inhibitors (TNFi‐IR; n = 164). Synovial tissue was subjected to hematoxylin and eosin and immunohistochemical staining and semiquantitative assessment for the degree of synovitis (on a scale of 0–9) and of CD20+ B cell infiltrate (on a scale of 0–4). B cell scores were validated by digital image analysis and B cell lineage–specific transcript analysis (RNA‐Seq) in the early RA (n = 91) and TNFi‐IR (n = 127) cohorts. Semiquantitative CD20 scores were used to classify patients as B cell rich (≥2) or B cell poor (<2). Results Semiquantitative B cell scores correlated with digital image analysis quantitative measurements and B cell lineage–specific transcripts. B cell–rich synovitis was present in 35% of patients in the early RA cohort and 47.7% of patients in the TNFi‐IR cohort (P = 0.025). B cell–rich patients showed higher levels of disease activity and seropositivity for rheumatoid factor and anti–citrullinated protein antibody in early RA but not in established RA, while significantly higher histologic synovitis scores in B cell–rich patients were demonstrated in both cohorts. Conclusion We describe a robust semiquantitative histologic B cell score that closely replicates the quantification of B cells by digital or molecular analyses. Our findings indicate an ongoing B cell–rich synovitis, which does not seem to be captured by standard clinimetric assessment, in a larger proportion of patients with established RA than early RA.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 The views expressed are those of the authors and not necessarily those of the MRC, Versus Arthritis, NHS, the NIHR, or the Department of Health and Social Care. Supported by the MRC, Versus Arthritis, and the NIHR. The Pathobiology of Early Arthritis Cohort (PEAC) was supported by the MRC (grant 36661). The Response–Resistance to Rituximab versus Tocilizumab in Rheumatoid Arthritis (R4RA) trial (EudraCT database no. 2012‐002535‐28) was supported by the NIHR Efficacy and Mechanism Evaluation Programme (grant 11/100/76). Versus Arthritis provided funding infrastructure support (grant 20022). Dr. Rivellese's work was supported by an NIHR Transitional Research Fellowship (TRF‐2018‐11‐ST2‐002). 1F. Rivellese, MD, PhD, F. Humby, MD, PhD, L. Fossati‐Jimack, PhD, D. Lucchesi, PhD, G. Lliso‐Ribera, MD, A. Nerviani, MD, PhD, R. E. Hands, PhD, G. Giorli, MSc, B. Frias, PhD, G. Thorborn, PhD, E. Jaworska, MSc, C. John, PhD, K. Goldmann, MSc, M. J. Lewis, MD, PhD, M. Bombardieri, MD, PhD, C. Pitzalis, MD, PhD: Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK; 2S. Bugatti, MD, PhD, A. Manzo, MD, PhD: IRCCS Policlinico San Matteo Foundation/University of Pavia, Pavia, Italy; 3H. Rizvi, MD: Barts Health NHS Trust, London, UK. Drs. Rivellese and Humby contributed equally to this work. No potential conflicts of interest relevant to this article were reported.
ISSN:	2326-5191 2326-5205
DOI:	10.1002/art.41184