Circulating and Synovial Pentraxin-3 (PTX3) Expression Levels Correlate With Rheumatoid Arthritis Severity and Tissue Infiltration Independently of Conventional Treatments Response

Abstract

AimsTo determine the relationship between PTX3 systemic and synovial levels and the clinical features of rheumatoid arthritis (RA) in a cohort of early, treatment naïve patients and to explore the relevance of PTX3 expression in predicting response to conventional-synthetic (cs) Disease-Modifying-Anti-Rheumatic-Drugs (DMARDs) treatment.MethodsPTX3 expression was analyzed in 119 baseline serum samples from early naïve RA patients, 95 paired samples obtained 6-months following the initiation of cs-DMARDs treatment and 43 healthy donors. RNA-sequencing analysis and immunohistochemistry for PTX3 were performed on a subpopulation of 79 and 58 synovial samples, respectively, to assess PTX3 gene and protein expression. Immunofluorescence staining was performed to characterize PTX3 expressing cells within the synovium.ResultsCirculating levels of PTX3 were significantly higher in early RA compared to healthy donors and correlated with disease activity at baseline and with the degree of structural damages at 12-months. Six-months after commencing cs-DMARDs, a high level of PTX3, proportional to the baseline value, was still detectable in the serum of patients, regardless of their response status. RNA-seq analysis confirmed that synovial transcript levels of PTX3 correlated with disease activity and the presence of mediators of inflammation, tissue remodeling and bone destruction at baseline. PTX3 expression in the synovium was strongly linked to the degree of immune cell infiltration, the presence of ectopic lymphoid structures and seropositivity for autoantibodies. Accordingly, PTX3 was found to be expressed by numerous synovial cell types such as plasma cells, fibroblasts, vascular and lymphatic endothelial cells, macrophages, and neutrophils. The percentage of PTX3-positive synovial cells, although significantly reduced at 6-months post-treatment as a result of global decreased cellularity, was similar in cs-DMARDs responders and non-responders.ConclusionThis study demonstrates that, early in the disease and prior to treatment modification, the level of circulating PTX3 is a reliable marker of RA activity and predicts a high degree of structural damages at 12-months. In the joint, PTX3 associates with immune cell infiltration and the presence of ectopic lymphoid structures. High synovial and peripheral blood levels of PTX3 are associated with chronic inflammation characteristic of RA. Additional studies to determine the mechanistic link are required.

The Relationship between Plasma Pentraxin 3 and Serum Amyloid P Levels and Disease Activity in Ankylosing Spondylitis

“…In our study, we observed increased levels of both PTX3 and SAP in AS patients, yet we could not demonstrate a relation with disease activity. These results, in accordance with the results of Deniz et al [ 4 ], Boutet et al [ 15 ], and Nisihara et al [ 16 ], may imply that these biomarkers may have diagnostic value in spondyloarthritis, regardless of disease activity.…”

“…Deniz et al [ 4 ] demonstrated increased PTX3 levels in AS patients without any correlation with disease activity. Boutet et al [ 15 ] reported increased PTX3 levels in rheumatoid arthritis patients in comparison to healthy subjects, but again, no relation with active disease was reported. Likewise, Nisihara et al [ 16 ] did not observe any correlation between PTX levels and disease activity in spondyloarthritis patients.…”

Salivary Microbiota and Host-Inflammatory Responses in Periodontitis Affected Individuals With and Without Rheumatoid Arthritis

“…Previous studies investigating the inflammatory mediators in serum of RA-patients, demonstrate a higher level of TWEAK, and Pentraxin-3 compared to controls (Park et al, 2008;Boutet et al, 2021). According to Boutet et al, the serum levels of Pentraxin-3 are correlated with disease activity and may act as a reliable marker of RA activity (Boutet et al, 2021). In addition, expression of IL-19 is also significantly elevated in synovial fluid of patients with RA compared to healthy controls, indicating an involvement of the regulation of synovial inflammation in patients with RA (Alanara et al, 2010).…”

“…Previous studies investigating the inflammatory mediators in serum of RA-patients, demonstrate a higher level of TWEAK, and Pentraxin-3 compared to controls (Park et al, 2008;Boutet et al, 2021). According to Boutet et al, the serum levels of Pentraxin-3 are correlated with disease activity and may act as a reliable marker of RA activity (Boutet et al, 2021).…”

Targeting MyD88 Downregulates Inflammatory Mediators and Pathogenic Processes in PBMC From DMARDs-Naïve Rheumatoid Arthritis Patients

“…This limitation may have affected the gene expression signatures and interfered with the interpretation of the fundamental role of some genes in RA pathogenesis. Only a few studies have considered the analysis of treatment-naïve RA patients to identify gene expression signatures in response to treatment and to characterize better the RA transcriptional profiles obtaining insightful results ( Shchetynsky et al, 2017 ; Boutet et al, 2021 ; Wang et al, 2021 ).…”