Background: Psoriatic arthritis (PsA) is associated with marked alterations in systemic metabolism, including dyslipidemia, changes in fatty acid composition, and disturbances in amino acid metabolism, contributing to increased cardiometabolic risk. Chronic inflammation induces immunometabolic reprogramming, affecting both, immune cell function and circulating metabolic profiles. Although TNF inhibitors effectively reduce disease activity, their impact on underlying immunometabolic alterations and their relationship with clinical and inflammatory response remain incompletely understood.

Objectives: To characterize longitudinal changes in circulating metabolites following anti-TNF therapy in psoriatic arthritis and to assess their association with changes in disease activity and systemic inflammation.

Methods: Plasma samples from 45 PsA patients were collected before initiation of anti-TNF therapy and after 6 months of treatment. Metabolic profiling was performed using a high-throughput nuclear magnetic resonance (NMR) platform (Nightingale Health), quantifying lipoprotein subclasses, fatty acids, amino acids, and inflammatory markers. Paired t-tests were used to identify metabolites significantly modulated by therapy. Changes in disease activity and inflammation were assessed using the DAPSA and CRP, respectively. Associations between changes in DAPSA or CRP and changes in metabolite levels were evaluated using correlation analyses.

Results: After 6 months of anti-TNF therapy, PsA patients exhibited extensive immunometabolic remodeling. Longitudinal analysis identified 71 circulating metabolites significantly modulated by treatment, with 68 metabolites showing increased levels and 3 showing decreased levels after six months of treatment. Modulated metabolites predominantly involved lipid-related pathways, including increases in total cholesterol, cholesterol esters, and extensive remodeling of LDL and VLDL subclasses, together with changes in fatty acid composition. In parallel, levels of several amino acids, including histidine and branched-chain amino acids, increased, while the inflammatory glycoprotein marker GlycA decreased following therapy. Importantly, metabolic changes were closely linked to both clinical and inflammatory response. Greater improvement in disease activity (larger reduction in DAPSA) was associated with increases in glutamine, histidine and albumin, as well as higher phospholipid content of small HDL particles, consistent with resolution of systemic inflammation and partial restoration of HDL functionality. In contrast, poorer clinical response was associated with increases in lactate, GlycA and cholesterol-enriched large HDL particles. Similarly, increases in CRP were positively associated with GlycA levels and enlargement of HDL particles enriched in cholesterol and phospholipids, whereas reductions in CRP correlated with higher levels of anti-inflammatory amino acids, albumin and small, lipid-poor HDL particles.

Conclusions: Anti-TNF therapy in psoriatic arthritis is associated with broad immunometabolic remodeling, with significant modulation of 71 circulating metabolites over 6 months of treatment. These findings suggest that effective TNF inhibition rapidly influences systemic metabolic pathways beyond clinical disease activity, leading to coordinated changes in amino acid availability, inflammatory markers and lipoprotein composition. The observed metabolomic shifts are consistent with a partial attenuation of inflammation-driven metabolic disturbances and may reflect a trend towards a less pro-inflammatory and potentially less atherogenic metabolic profile. Although longer-term studies are required to determine the clinical relevance of these changes, our results highlight the close interplay between inflammation and systemic metabolism in PsA and support the use of metabolomic profiling to capture early biological effects of anti-inflammatory therapy.

REFERENCES: NIL.

Acknowledgments: NIL.

Disclosure of Interests: None declared.