Background: Spondyloarthritis (SpA) and psoriatic arthritis (PsA) are chronic inflammatory disorders that, despite being traditionally classified as separate clinical entities, display substantial overlap in clinical presentation as well as genetic and immunological characteristics. Metabolomics, which enables comprehensive profiling of metabolites in biological samples, offers a powerful approach to uncover biochemical pathway alterations associated with disease states.

Objectives: To characterize disease-specific and shared metabolic signatures in PsA and SpA patients and to investigate their molecular similarities using an unsupervised analytical approach, thereby improving the understanding of common pathogenic mechanisms.

Methods: A cross-sectional metabolomic analysis was performed including 124 patients with PsA, 291 patients with SpA (284 with axial involvement and 7 with peripheral involvement), and 116 control subjects presenting with musculoskeletal complaints. Serum concentrations of 250 metabolites were quantified. An unsupervised clustering analysis was initially conducted across all participants. Subsequently, metabolite levels in each disease group were compared with those of controls. Differentially expressed metabolites were identified as either disease-specific or shared across conditions. Pathway enrichment analyses were then carried out to determine the metabolic pathways most significantly affected in each group.

Results: Unsupervised clustering identified three distinct metabolic clusters. The majority of PsA patients were assigned to cluster 3, whereas most SpA patients, including both axial and peripheral forms, clustered predominantly in cluster 1. Notably, 35.8% of axial SpA patients also grouped within cluster 3, indicating a closer metabolic resemblance to PsA. A total of 59 metabolites were uniquely altered in PsA, 24 in axial SpA, and 2 in peripheral SpA, while 8 metabolites were commonly dysregulated across all disease groups. PsA and axial SpA shared the largest number of altered metabolites (n = 14). Pathway enrichment analyses highlighted disruptions in lipid metabolism and pathways related to systemic inflammation. Metabolites specific to PsA were associated with increased cardiovascular and metabolic risk, those linked to axial SpA reflected immunometabolic inflammation without accompanying hypertriglyceridemia, and peripheral SpA metabolites were related to mitochondrial dysfunction and low-grade inflammation.

Conclusions: This study identifies a shared metabolic signature between psoriatic arthritis and spondyloarthritis, primarily involving alterations in lipid metabolism and systemic inflammatory pathways, alongside distinct metabolic profiles that differentiate clinical subtypes. The observed clustering pattern underscores a notable metabolic overlap between PsA and axial SpA. The identification of both shared and disease-specific metabolites, associated with cardiovascular risk in PsA, immunometabolic inflammation in axial SpA, and mitochondrial stress in peripheral SpA, supports the utility of metabolomics in disentangling the biological complexity of these conditions. These findings may contribute to the development of more personalized diagnostic tools and targeted therapeutic strategies.

REFERENCES: NIL.

Acknowledgments: NIL.

Disclosure of Interests: None declared.