fetching data ... 
Background: The analysis of synovial biopsies provides valuable insights into the molecular mechanisms underlying Rheumatoid Arthritis (RA). However, their invasive nature restricts their routine clinical application. Therefore, the identification of serum biomarkers derived from synovial tissue offers a less invasive and promising alternative for diagnosing and monitoring RA. This approach could address current challenges and enable the implementation of precision medicine in RA management.
Characterize synovial tissue-secreted proteins in early RA patients that contribute to serum inflammatory profiles based on immune cell infiltration.
Identify RA patient subsets with distinctive serum levels of these proteins and associate them with disease activity and early clinical response to conventional DMARDs.
Methods: Histomorphological features of synovial explants obtained via ultrasound (US)-guided biopsies from 19 early RA patients were assessed, including lining thickness, inflammation, fibrosis, and immune cell infiltration (T and B lymphocytes, plasma cells, and macrophages identified with anti-CD3, anti-CD20, anti-CD138, and anti-CD68 antibodies, respectively). These tissues were cultured in vitro for 24 hours to profile secreted proteins using proximity extension assay (PEA) technology (Olink), targeting 92 inflammation-related proteins. Proteomic profiles were also evaluated in serum samples from the same subjects, and correlation studies were conducted. The identified protein signatures were validated in an independent cohort of 83 early-stage RA patients to explore their association with clinical response to conventional DMARDs.
Results: Histopathological examination revealed a predominance of lympho-histiocytic inflammation in the synovium of patients with early RA, characterized by the significant presence of CD3+ and CD68+ infiltrating cells. This was associated with heightened inflammation, increased lining thickness, and decreased fibrosis. Seven synovial-secreted proteins (IL-1α, MCP-1, CXCL10, CXCL9, CSF-1, IL-10 and FGF-5) exhibited significant correlation with serum levels in RA patients. Clinically, higher levels of this inflammatory signature were observed in RA patients with active disease, elevated acute-phase reactants and positivity for autoantibodies (ACPAs and RF). Additionally, significant correlations were also found between these synovial-secreted proteins and increased infiltration of CD3+ and CD20+ cells, suggesting that immune cells are a primary source of these secreted proteins. Unsupervised clustering in an independent cohort of 83 early-stage RA patients treated with conventional DMARDs, identified two patient groups with distinctive baseline serum protein profiles. The group with higher inflammatory signature levels exhibited higher disease activity and a better response to conventional DMARDs after three months of treatment.
Conclusion: This study identifies a protein signature secreted by synovial tissue that contributes to the circulating inflammatory and the clinical profile in RA patients. These proteins are strongly associated with immune infiltration in the synovium and correlate with clinical features and early response to conventional DMARDs. These results highlight the potential of serum biomarkers that reflect the molecular characteristics of synovial tissue in guiding personalized treatment strategies, advancing precision medicine in RA management.
REFERENCES: NIL.
Acknowledgements: Supported by the EU/EFPIA Innovative Medicines Initiative Joint Undertaking 3TR, ISCIII (PI24/00959, CD21/00187 and RICOR-21/0002/0033), and RYC2021-033828-I; co-financed by European Union).
Disclosure of Interests: None declared.
© The Authors 2025. This abstract is an open access article published in Annals of Rheumatic Diseases under the CC BY-NC-ND license (