Proteomic landscape of synovial tissue in rheumatoid arthritis and determinants of synovial histological pathotypes

C. Aboo, A. Stensballe, C. Nielsen, H. D. Schrøder, M. E. Thomsen, S. Déjean, H. M. Lindegaard, S. A. Just

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Abstract

Background Pathological mechanisms in the affected synovial joints in rheumatoid arthritis (RA) and factors contributing to synovial histological heterogeneity, which may impact treatment outcomes, remain largely unexplored at the protein level. Mapping the proteomic landscape of RA-affected synovial tissue (ST) and identifying determinants of synovial pathotypes could provide insights into RA’s pathological mechanisms, identify new therapeutic targets, and pave the way for personalized medicine options.

Objectives To map the proteomic landscape and dysregulated biological pathways in ST and plasma at multiple stages of RA. Through this investigation, the study also aims to identify the molecular and cellular determinants of synovial histological pathotypes in early untreated RA patients.

Methods ST and matched plasma samples from patients with early untreated RA (ERA) (n = 20) and longstanding RA (LRA) (n = 20), as well as healthy controls (HC) (n = 16) were collected at baseline and at six months follow-up (RA patients only). ST biopsies were collected from the wrist via an ultrasound-guided synovial biopsy procedure (RA patients), or via arthroscopic guidance (HC). Samples were then characterized using discovery proteomics profiling. Comparisons were made between HC versus ERA or LRA at both timepoints, and proteins were regarded as differentially abundant at 5% FDR and a log2-fold change ±2.0 (ST proteins) or ±1.5 (plasma proteins). Next, the molecular and cellular determinants of synovial histological pathotypes were identified in untreated ERA patients by integrating the ST proteome, plasma proteome, Krenn synovitis score, number of circulating immune cells and scores of CD3 (T cells), CD20 (B cells), CD68 (Macrophages) and CD138 (Plasma cells) synovial immune infiltration.

Results 335 plasma proteins and 3416 ST proteins were identified and quantified. Plasma proteins: CRP and SAA1 were overabundant in ERA compared to HC at baseline, but no proteins were differentially abundant in ERA compared to HC at follow-up (Figure 1 A-B). CRP was overabundant in LRA compared to HC at both timepoints (Figure 1 C-D). Synovial tissue proteins: In ERA patients 243 proteins were differentially abundant at baseline, but only 114 were differentially abundant at follow-up (Figure 1 E-F). In LRA patients, 216 and 284 proteins were differentially abundant at baseline and follow-up, respectively (Figure 1 G-H). Largely the same biological processes were dysregulated in ERA at baseline and in LRA at both timepoints. However, biological processes related to complement cascade, acute inflammatory response, scavenging of heme from plasma among others, tended to be less dysregulated in ERA patients at follow-up. Finally, data integration identified proteomic and cellular signatures underlying synovial pathotypes, that suggests the difference between lymphoid, myeloid, and fibroid pathotypes is a continuous spectrum that is linearly modellable. Proteins involved in negative regulation of: peptidase/protease activity, hemostasis and wound healing were underabundant in the lymphoid pathotype compared to the fibroid pathotype and to a lesser degree, the myeloid pathotype. Proteins that were involved in various aspects of antibody production were overabundant in the lymphoid pathotype compared to the fibroid pathotype and to a lesser degree, the myeloid pathotype.

Conclusion The study revealed new insights into the proteomic landscape of the synovium in RA, elucidating the pathological mechanisms occurring in the synovium at different stages of disease. Additionally, the study identified a linear proteomic and cellular difference between the lymphoid, myeloid, and fibroid synovial pathotypes in untreated ERA patients, rather than distinct signatures for each pathotype.

Original languageEnglish
JournalAnnals of the Rheumatic Diseases
Volume82
Issue numberSuppl. 1
Pages (from-to)210
Number of pages1
ISSN0003-4967
DOIs
Publication statusPublished - Jun 2023
EventEULAR 2023 European Congress of Rheumatology - Milan, Italy
Duration: 31 May 20233 Jun 2023
https://congress.eular.org/index.cfm

Conference

ConferenceEULAR 2023 European Congress of Rheumatology
Country/TerritoryItaly
CityMilan
Period31/05/202303/06/2023
Internet address

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