Molecular and cellular heterogeneity in the Rheumatoid Arthritis synovium: Clinical correlates of synovitis

Townsend, Michael J.

doi:10.1016/j.berh.2014.10.024

Cited by 33 publications

(30 citation statements)

References 78 publications

(62 reference statements)

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“…Our observation that TSPO is expressed on all major cell groups in RA pannus could explain why TSPO PET has been found to be a highly sensitive indicator of synovitis, being superior to MRI in detecting subclinical joint inflammation (41). The histologic heterogeneity of RA synovial tissue is increasingly recognized, with the cellular components changing as the disease advances and differing between individuals regardless of disease activity (48,49). The ability of TSPO PET to detect all major cell groups in pannus means that the technique may be highly sensitive in detecting synovitis, as it will not depend on a single pattern of synovial histology.…”

Section: Discussionmentioning

confidence: 94%

Translocator Protein as an Imaging Marker of Macrophage and Stromal Activation in Rheumatoid Arthritis Pannus

et al. 2018

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PET radioligands targeted to translocator protein (TSPO) offer a highly sensitive and specific means of imaging joint inflammation in rheumatoid arthritis (RA). Through high expression of TSPO on activated macrophages, TSPO PET has been widely reported in several studies of RA as a means of imaging synovial macrophages in vivo. However, this premise does not take into account the ubiquitous expression of TSPO. This study aimed to investigate TSPO expression in major cellular constituents of RA pannus-monocytes, macrophages, fibroblastlike synoviocytes (FLS cells), and CD4-positive (CD4+) T lymphocytes (T cells)-to more accurately interpret TSPO PET signal from RA synovium. Three RA patients and 3 healthy volunteers underwent PET of both knees using the TSPO radioligandC-PBR28. Through H-PBR28 autoradiography and immunostaining of synovial tissue in 6 RA patients and 6 healthy volunteers, cellular expression of TSPO in synovial tissue was evaluated. TSPO messenger RNA expression andH-PBR28 radioligand binding was assessed using in vitro monocytes, macrophages, FLS cells, and CD4+ T cells. C-PBR28 PET signal was significantly higher in RA joints than in healthy joints (average SUV, 0.82 ± 0.12 vs. 0.03 ± 0.004; < 0.01). Further, H-PBR28-specific binding in synovial tissue was approximately 10-fold higher in RA patients than in healthy controls. Immunofluorescence revealed TSPO expression on macrophages, FLS cells, and CD4+ T cells. The in vitro study demonstrated the highest TSPO messenger RNA expression andH-PBR28-specific binding in activated FLS cells, nonactivated M0 macrophages, and activated M2 reparative macrophages, with the least TSPO expression being in activated and nonactivated CD4+ T cells. To our knowledge, this study was the first evaluation of cellular TSPO expression in synovium, with the highest TSPO expression and PBR28 binding being found on activated synovial FLS cells and M2 macrophages. TSPO-targeted PET may therefore have a unique sensitivity in detecting FLS cells and macrophage-predominant inflammation in RA, with potential utility for assessing treatment response in trials using novel FLS-cell-targeted therapies.

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Section: Discussionmentioning

confidence: 94%

Translocator Protein as an Imaging Marker of Macrophage and Stromal Activation in Rheumatoid Arthritis Pannus

et al. 2018

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“…Different cytokine/cell pathway targets and associations between synovial tissue pathobiological subtype, associated genes and response to bDMARD have been suggested 28. The role of both innate and adaptive drivers of disease, and observation of autoinflammatory phenotype with/without coexistent typical autoantibody-mediated disease29 provides an additional basis for refractory subgroups.…”

Section: Mechanisms Underlying Refractory Ra Diseasementioning

confidence: 99%

Defining refractory rheumatoid arthritis

2018

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While biologic disease-modifying antirheumatic drugs (bDMARDs) have transformed outcomes of people with rheumatoid arthritis (RA), a proportion of patients are refractory to multiple bDMARDs. Definitions of refractory RA thus far have been arbitrary, and outcome data and impact of such cohorts remain limited. Extrapolation from randomised controlled trial and some real-life data suggest approximately 20% progress onto a third bDMARD with a more modest proportion failing additional bDMARDs. This viewpoint discusses an opinion of refractory RA disease and proposes key principles to accurately identify refractory cohorts. These include demonstrating presence of persistent inflammation despite multiple therapies and acknowledging development of antidrug antibody. Potential basis of refractory disease is summarised, and suggestions for an initial approach in the future evaluation of refractory disease are offered. Specific investigation of refractory RA disease is necessary to inform the clinical need and provide a basis for robust investigation of underlying mechanisms.

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“…There are also some links between pathobiology and DMARD-specific treatment responses. Furthermore, TNFα inhibitors seem to be superior in patients with a CD68-positive macrophage-dominated synovium (9) and are most effective in reducing erosive joint damage in RA (15). Furthermore, TNFα inhibitors seem to be superior in patients with a CD68-positive macrophage-dominated synovium (9) and are most effective in reducing erosive joint damage in RA (15).…”

Section: Introductionmentioning

confidence: 99%

Responses to Cytokine Inhibitors Associated with Cellular Composition in Models of Immune‐Mediated Inflammatory Arthritis

Nielsen

Lomholt

Mellemkjær

et al. 2019

ACR Open Rheumatology

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Objective. Immune-mediated inflammatory arthritis (IMIA) is a heterogeneous group of diseases including rheumatoid arthritis (RA), psoriatic arthritis (PsA), and spondyloarthritis (SpA). Disease-modifying antirheumatic drugs (DMARDs) target very different cellular components of the disease processes. Characterization of the pathobiological subtypes of IMIA could provide more specific treatment approaches for each disease. For example, RA has been proposed to consist of at least three synovial pathotypes (lymphoid, myeloid, and fibroid), and only a subgroup of RA patients have erosive disease. The objective of this study was to evaluate the effects of various DMARDs on different synovial cell subsets using human ex vivo models of IMIA.Methods. Synovial fluid and blood samples were obtained from a study population consisting of patients with RA, PsA, or peripheral SpA with at least one swollen joint (n = 18). The DMARDs used in this study were methotrexate, adalimumab, etanercept, tocilizumab, anakinra, ustekinumab, secukinumab, tofacitinib, and baricitinib. Paired synovial fluid mononuclear cells (SFMCs), peripheral blood mononuclear cells (PBMCs), and fibroblast-like synovial cells (FLSs) were used in three different previously optimized ex vivo models.Results. In SFMCs cultured for 48 hours, all DMARDs except anakinra decreased the production of monocyte chemoattractant protein (MCP)-1. In SFMCs cultured for 21 days, only the two tumor necrosis factor alpha (TNFα) inhibitors adalimumab and etanercept decreased the secretion of tartrate-resistant acid phosphatase (P < 0.01, P < 0.001). In the FLS and PBMC 48-hour co-cultures, only tocilizumab (P < 0.001) and the two Janus kinase inhibitors tofacitinib and baricitinib (both P < 0.05) decreased the production of MCP-1 by around 50%.Conclusion. TNFα inhibition was effective in preventing inflammatory osteoclastogenesis, whereas tocilizumab, tofacitinib, and baricitinib had superior efficacy in cultures dominated by FLSs. Taken together, this study reveals that responses to cytokine inhibitors associate with cellular composition in models of IMIA. In particular, this study provides new evidence on the differential effect of DMARDs on leukocytes compared with stromal cells.

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Molecular and cellular heterogeneity in the Rheumatoid Arthritis synovium: Clinical correlates of synovitis

Cited by 33 publications

References 78 publications

Translocator Protein as an Imaging Marker of Macrophage and Stromal Activation in Rheumatoid Arthritis Pannus

Translocator Protein as an Imaging Marker of Macrophage and Stromal Activation in Rheumatoid Arthritis Pannus

Defining refractory rheumatoid arthritis

Responses to Cytokine Inhibitors Associated with Cellular Composition in Models of Immune‐Mediated Inflammatory Arthritis

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