SynovialMet: Impact of Metabolic Syndrome on Clinical, Histological, and Cellular Features in Patients with Psoriatic Arthritis

Background and Objectives Psoriatic arthritis (PsA) is a chronic, immune-mediated inflammatory disease characterized by marked clinical heterogeneity and a complex pathogenesis involving immune, stromal, and environmental factors. Among its most relevant comorbidities, metabolic syndrome (MetS) has emerged as a key contributor to disease severity and therapeutic response. MetS is defined by a cluster of cardiometabolic abnormalities, including visceral obesity, insulin resistance, dyslipidaemia, and hypertension, and is associated with chronic low-grade systemic inflammation. The objective of this study was to investigate the impact of MetS on the clinical phenotype, histological features, and cellular mechanisms of PsA, with a particular focus on immunometabolic interactions involving adipose tissue, macrophages, and synovial fibroblasts. Materials and Methods An integrated experimental approach was employed, combining clinical data analysis with in vitro and ex vivo models. Pre-adipocytes (3T3) were differentiated into adipocytes and co-cultured with macrophages polarized into M1 and M2 phenotypes. Serum from patients with PsA and PsA with MetS was used to condition these co-cultures. Supernatants were then applied to synovial fibroblasts isolated from patient synovial tissue. Flow cytometry was used to assess the expression of adhesion molecules (VCAM-1, ICAM-1) and angiogenic markers (VEGFR). ELISA assays and immunohistochemical analyses were performed to evaluate cytokine and adipokine profiles in synovial tissue and fluid. Clinical correlations with disease severity and difficult-to-treat (D2T) phenotype were also assessed. Results Patients with PsA and comorbid MetS exhibited a more severe clinical phenotype and a higher prevalence of difficult-to-treat disease. At the cellular level, adipocyte–macrophage interactions generated a pro-inflammatory microenvironment that significantly enhanced synovial fibroblast activation. This was evidenced by increased expression of VCAM-1, ICAM-1, and VEGFR, indicating enhanced leukocyte recruitment and angiogenic potential. Additionally, distinct alterations in adipokine expression were observed in synovial tissues from PsA+MetS patients, including a dysregulated role of adiponectin. Histological analyses confirmed a specific inflammatory and stromal signature associated with the coexistence of MetS. Conclusions This study demonstrates that metabolic syndrome actively contributes to the pathogenesis of psoriatic arthritis by promoting immunometabolic crosstalk between adipose tissue, immune cells, and synovial fibroblasts. MetS is not merely a comorbidity but a driver of disease severity and chronicity, facilitating the transition toward a stromal-driven inflammatory state. These findings highlight the need for a multidimensional therapeutic approach in PsA that integrates metabolic control with targeted immunological treatment, and they support the development of novel strategies aimed at modulating stromal and metabolic pathways.