Paired Rheumatoid Arthritis Synovial Biopsies From Small and Large Joints Show Similar Global Transcriptomic Patterns With Enrichment of Private Specificity TCRB and TCR Signaling Pathways

Abstract

ObjectivesWe explored histological and transcriptomic profiles of paired synovial biopsies from rheumatoid arthritis (RA) patients, in order to assess homogeneity in synovial tissue at the individual level.MethodsSynovial biopsies were performed simultaneously in one small and one large joint per patient using needle-arthroscopy for the knee and ultrasound-guided biopsy for the hand or wrist. Synovium from individuals with osteoarthritis was used as controls. Paraffin-embedded samples were stained for CD3, CD20, and CD68. Total RNA was hybridized on high-density microarrays. TCRB variable sequences were obtained from synovial and blood RNA samples.ResultsTwenty paired biopsies from 10 RA patients with active disease were analyzed. Semi-quantification of histological markers showed a positive correlation for synovial hyperplasia, inflammatory infiltrates and CD3-positive T cells between pairs. Pairwise comparison of transcriptomic profiles showed similar expression of RA-related molecular pathways (TCR signaling, T cell costimulation and response to TNFα). T cells clonotypes were enriched in all but one joints compared to blood, regardless of the magnitude of T cell infiltration. Enriched clonotypes were shared between pairs (23–100%), but this was less the case in pairs of joints displaying weaker T cell signatures and more pronounced germinal center-like transcriptomic profiles.ConclusionCellular and molecular alterations in RA synovitis are similar between small and large joints from the same patient. Interindividual differences in magnitude of T cell infiltrates and distribution of enriched T cell clonotypes support the concept of distinct synovial pathotypes in RA that are associated with systemic versus local antigen-driven activation of T cells.

Common Transcriptomic Effects of Abatacept and Other DMARDs on Rheumatoid Arthritis Synovial Tissue

“…This is in line with previous observations showing that low-inflammatory synovitis is associated with poor response to bDMARDs targeting TNFa (19). Nevertheless, it is unclear whether low-inflammatory synovitis represents a distinct disease (sub) entity, or simply an extreme of a phenotypic continuum (11,12,20,21). Predominant lymphoid versus myeloid immune features have been proposed to distinguish between independent, even disparate entities in RA (11,17).…”

“…This is in line with previous observations showing that low-inflammatory synovitis is associated with poor response to bDMARDs targeting TNFα ( 19 ). Nevertheless, it is unclear whether low-inflammatory synovitis represents a distinct disease (sub) entity, or simply an extreme of a phenotypic continuum ( 11 , 12 , 20 , 21 ).…”

Impact of synovial biopsy procedures and disease-specific aspects on synovial tissue outcome: a systematic literature review informing the EULAR points to consider for the minimal reporting requirements in synovial tissue research in rheumatology

“…In addition, correlations were found for CD68 +macrophages, CD3 +T cells, CD138 +plasma cells and IL-6 expression and CD68 +macrophages and CD3 +T cells in the ST sublining of both small and large joints 17. As far as the synovial lining layer is concerned, significant correlations were found between small and large joints for lining layer hyperplasia, inflammatory infiltrate in H&E staining 19. The same transcripts were shown to be overexpressed in both small and large joints, and the same T-cell clone repartition was observed in small and large and right and left joints of the same individuals with RA 18 19…”

“…Two studies with high RoB17 18 and one with unclear RoB19 assessed the impact of the joint biopsied on either cell infiltrate,17 19 transcriptomics19 or T-cell repertoire (TCR), deemed to be particularly relevant in ST arthritis of autoimmune mechanisms 18 19. Of interest, when comparing outcomes from tissues retrieved in small versus large joints from the same patients with rheumatoid arthritis (RA), the authors could not identify any difference in immune cell infiltrate and IL-6 expression assessed by non-parametric paired analysis 17.…”

Modelling rheumatoid arthritis: A hybrid modelling framework to describe pannus formation in a small joint

“…This initial model is not yet at a stage where direct comparisons to clinical and experimental data can be made. However, once extended to contain appropriate levels of complexity and validated with more accurate data the model could be used to investigate the patterns of cell populations within joints affected by RA, such as those seen within studies that image the progression of RA [1, 2, 4, 14, 96].…”