Background: Diagnosing psoriatic arthritis (PsA) can be challenging. Uncovering novel biomarkers via proteomic approaches is essential to provide more accurate and early detection methods. In this scenario, individuals with related musculoskeletal manifestations, yet without a diagnosed PsA, are pivotal for identifying specific disease biomarkers. In addition, employing clustering based on molecular patterns offers insights into disease heterogeneity, identifying potential subtypes, and guiding personalized therapeutic strategies.

Objectives: 1 ) To discover novel proteins involved the pathogenesis of PsA, 2 ) to identify potential candidate biomarkers for diagnosing PsA, and 3 ) to uncover molecular phenotypes of PsA patients associated with clinical features through unsupervised analysis.

Methods: A cohort of 154 individuals participated in this study, 104 patients diagnosed with PsA according to CASPAR criteria and 50 subjects with musculoskeletal manifestations but definitive no diagnosis of any rheumatic disease, serving as the control group. A comprehensive analysis of 384 proteins in peripheral blood mononuclear cells (PBMCs) was conducted using Olink technology. The enriched R platform facilitated the exploration of biological functions associated with the identified altered proteins. The self-organizing map algorithm was employed in this study to elucidate unsupervised molecular clusters.

Results: patients with PsA exhibited an average disease duration of 7 ± 5 years, accompanied by moderate disease activity. Notably, these patients displayed significantly elevated levels of acute phase reactants compared to the control group. Furthermore, a noteworthy prevalence of clinical manifestations, such as dactylitis, enthesitis, and onychopathy. Molecular analyses enabled the detection of 338 out of 384 proteins in PBMCs, with 73 exhibiting significant alterations in PsA compared to the control group. Notably, the identified proteins displayed significant enrichment in processes related to inflammatory response, immune system function, as well as osteoclast differentiation and osteoclast precursor cells. This enrichment encompassed various immune cell types, such as dendritic cells, monocytes, and macrophages. Of the significantly altered proteins, seven demonstrated individual discriminatory capacity, achieving an area under the curve (AUC) above 0.75 to distinguish PsA patients from the control group. Notably, their combined analysis yielded an impressive AUC of 0.9, underscoring their collective potential as biomarkers for diagnosing PsA. Notably, ANGPTL-2, CCL-17, CXCL-12, MEGF-10, and TREM-2 exhibited significant associations with disease activity, while ANXA-11 and PREB were notably linked to the presence of dactylitis. Ultimately, unsupervised analyses unveiled three PsA clusters characterized by distinct molecular patterns defined by proteins enriched in the regulation of MAP kinase cascades, with enriched cell types like fibroblasts and immune cells such as B cells and monocytes, including DAPP1, CCN2, SPRY2, WAS, PTX3, LILRB4, TIMP3, CCL17, CEP164 and BANK1. Remarkably, PsA patients in one cluster exhibited significantly higher levels of C-reactive proteins and monocytes compared to the other clusters.

Conclusion: 1) High-throughput proteomic analysis of PBMCs revealed novel protein alterations in PsA predominantly linked to inflammatory response, immune system modulation, and osteoclast function, 2) this study also unveiled distinct molecular clusters associated with crucial clinical features and immune cell subtypes, and 3) our study pinpointed a distinct set of proteins with promising discriminatory potential between PsA patients and individuals exhibiting musculoskeletal manifestations without a PsA diagnosis, paving the way to validation study to solidify the identified proteins as robust molecular biomarkers, heralding a new era in the diagnosis of PsA.Supported the “Instituto de Salud Carlos III” (PMP21/00119 and RICOR-RD21/0002/0033) co-financed by the European Union and “Junta de Andalucia” (PI-0243-2022).

REFERENCES: NIL.

Acknowledgements: Supported the “Instituto de Salud Carlos III” (PMP21/00119 and RICOR-RD21/0002/0033) co-financed by the European Union and “Junta de Andalucia” (PI-0243-2022).

Disclosure of Interests: None declared.