Background/Purpose: Our recent study characterized immune endotypes in psoriatic arthritis (PsA) patients using mass cytometry of peripheral blood1. We identified an endotype characterized by high levels of CD4+ central and effector memory T cells (cluster 1), which was associated with higher levels of sonographic musculoskeletal inflammation and lower response to biologic therapy compared with the other two endotypes (cluster 2: innate immune cells (ILC) and cluster 3: terminal effector/Th1 cells). Further characterization of these clusters may enhance our understanding of PsA phenotypes. We aim to characterize the proteomic profile of the CD4+ memory T cell endotype in comparison with the other two immune endotypes and identify key proteins and biological pathways associated with disease severity and treatment outcomes.

Methods: A total of 30 patients initiating advanced therapies for active PsA were analyzed (9 patients in cluster 1, 11 in cluster 2, and 10 in cluster 3). For each patient, we measured 6402 different serum proteins using an aptamer-based platform. Differential expression analysis was performed between cluster 1 vs. cluster 2 and cluster 1 vs. cluster 3, with significance as p < 0.05. Pathway enrichment was performed reusing pathDIP v5, using literature-curated pathways from all 12 database sources. Protein-pathway networks of the shared pathways between cluster 1 vs. cluster 2 and cluster 1 vs. cluster 3 were created using NAViGaTOR v3.

Results: Differential analysis identified 285 proteins in cluster 1 vs. cluster 2 (176 upregulated and 109 downregulated in cluster 2) and 349 in cluster 1 vs. cluster 3 (160 upregulated and 189 downregulated in cluster 1). Pathways shared between these two comparisons (differentially expressed in cluster 1) included WNT signalling, platelet activation, VEGF, PI3K-AKT-MTOR, and MAPK signalling (Figure 1A-C). Additionally, WNT signalling appeared most distinct to the CD4+ memory cell endotype, containing the highest number of DEPs unique to this pathway, whereas other pathways shared multiple proteins. Among the deregulated proteins in the WNT pathway, DKK2, WNT5b, ROR2, FZD7, FZD8, and FZD2, were all proteins upregulated in the CD4+ memory cell endotype and correlated with disease activity measures (Figure 1D).

Conclusion: Given that WNT signalling is known to play a role in PsA pathogenesis, its activity in the CD4+ memory cell endotype may underlie the poorer response to advanced therapy observed in these patients. Overall, these results provide new insights into the biological mechanisms driving PsA and help to define distinct patient subgroups with shared clinical and biological features. 1 Eder L, Li X, Thib S, Ganatra D, Diao L, Chandran V. Deep Cellular Immune Profiling in Psoriatic Arthritis Correlates with Imaging Phenotypes and Response to Targeted Advanced Therapy [abstract]. Arthritis Rheumatol. 2023; 75 (suppl 9). https://acrabstracts.org/abstract/deep-cellular-immune-profiling-in-psoriatic-arthritis-correlates-with-imaging-phenotypes-and-response-to-targeted-advanced-therapy/. Accessed May 12, 2025.

Pathway enrichment and network visualization of differentially expressed proteins across clusters. (A) Pathways enriched in cluster 1 vs. cluster 2 and (B) pathways enriched in cluster 1 vs. cluster 3 ranked in descending order based on gene ratio; (C) Protein-pathway network plot of the shared enriched pathways characterizing cluster 1 vs. cluster 2 and 3. Coloured diamond nodes = shared pathways, blue circular node = DEPs in C1C2, red = DEP in C1C3 and green = DEP in both comparisons. An olive circular highlight = downregulated protein in C1, pink circular highlight = upregulated protein in C1; (D). Correlation matrix of the relationship between DEPs belonging to the WNT signalling pathway and PsA disease features.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/serum-proteomic-analysis-of-cellular-immune-clusters-in-psoriatic-arthritis/