Background: Rheumatoid arthritis (RA) and psoriatic arthritis (PsA) are associated with an increased metabolic and cardiovascular risk. Chronic systemic inflammation and associated metabolic comorbidities may contribute to the development of subclinical hepatic alterations, such as steatosis and fibrosis. Transient elastography (FibroScan ^® ) and the controlled attenuation parameter (CAP) a enable non-invasive assessment of liver fibrosis and steatosis. Serum metabolomics represents an advanced tool for the characterization of complex metabolic profiles, providing an integrated approach to the study of lipid metabolism and its potential relationship with hepatic involvement in patients with inflammatory arthritis (IA).

Objectives: 1) To evaluate the presence of liver fibrosis and steatosis using transient elastography in non-obese patients with inflammatory arthritis (RA and PsA) employing FibroScan® and CAP, and 2) To analyse the association between liver fibrosis and steatosis and lipid metabolomic profiles, as well as their relationship with clinical and biochemical variables.

Methods: A cross-sectional study was conducted in a cohort of 88 non-obese patients with IA (RA=49 and PsA=39). Patients were recruited from routine clinical practice at the Rheumatology Department of Reina Sofía University Hospital (Córdoba). Clinical and laboratory parameters, as well as biomarkers of subclinical liver disease, were analysed. In addition, all patients underwent transient liver elastography using FibroScan ^® to assess liver stiffness or fibrosis, together with CAP, a parameter that allows the determination and quantification of the degree of hepatic fat infiltration. Serum lipidomic-metabolomic profiling was performed in all patients using a high-throughput platform to comprehensively characterise lipid and energy metabolism.

Results: Patients with RA and PsA had low disease activity, with a DAS28 of 2.86±1.43 and a DAPSA of 11.22±7.01, respectively, and none of the patients were receiving biologic or targeted synthetic disease-modifying antirheumatic drugs at the time of evaluation. Hepatic steatosis was detected in 48.7% of patients with PsA and in 61.2% of patients with RA. Liver fibrosis was less frequent (12.8% and 4.1%, respectively). Metabolomic analysis performed in all 88 patients identified 74 metabolites that were significantly altered between patients with and without hepatic steatosis. Higher CAP values were associated with increased levels of triglycerides (TG) and triglyceride-rich lipoproteins, particularly large particles, as well as with branched-chain amino acids (valine, leucine and isoleucine), alanine, lactate, and a higher proportion of monounsaturated fatty acids. In contrast, hepatic steatosis was associated with lower concentrations of high-density lipoprotein (HDL) cholesterol, a reduction in large HDL particles, a smaller mean HDL particle size, and a decreased proportion of polyunsaturated fatty acids, together with a reduced polyunsaturated-to-monounsaturated fatty acid ratio. Some of these metabolites were also associated with liver stiffness, showing positive associations with TG and atherogenic lipoproteins, and negative associations with HDL cholesterol and polyunsaturated fatty acids. When comparing patients with and without liver fibrosis, 22 differentially expressed metabolites were identified, predominantly very-low-density lipoprotein (VLDL) subfractions, together with amino acids and metabolites related to energy metabolism. Multivariate analysis using sparse partial least squares discriminant analysis (sPLS-DA) enabled the identification of specific serum metabolomic signatures for hepatic steatosis and fibrosis. The steatosis-associated signature was characterised by hypertriglyceridaemia, increased triglyceride-rich lipoproteins and pathological remodelling of HDL particles, and was independently associated with the presence of hepatic steatosis (adjusting by sex, age, metabolic comorbidities and treatment exposure), with small-HDL-TG (β=0.425; p<0.001; 95% CI 0.007-0.021) and glutamine (β=0.246; p=0.034; 95% CI 0.005-0.131) as key contributing metabolites. Conversely, the metabolomic signature associated with liver fibrosis was mainly characterised by increased TG in VLDL, larger VLDL particle size, an increased TG-to-phosphoglyceride (TG/PG) ratio, and alterations in amino acids involved in energy metabolism, particularly alanine and glutamine, and was independently associated with the presence of liver fibrosis (adjusting by sex, age, metabolic comorbidities and treatment exposure), with alanine (β=0.260; p=0.022; 95% CI 0.008-0.093) showing the strongest associations.

Conclusions: 1) Hepatic steatosis is prevalent in patients with inflammatory arthritis, even in settings of low inflammatory disease activity and absence of obesity. 2) Hepatic steatosis and fibrosis in IA patients are associated with distinct serum metabolomic signatures characterised by profound alterations in lipid and energy metabolism, including hypertriglyceridaemia, increased triglyceride-rich lipoproteins, pathological remodelling of HDL particles, and changes in amino acids involved in energy metabolism. This metabolomic profile might indicate an atherogenic and insulin-resistant phenotype, suggesting that hepatic involvement in inflammatory arthritis may act as a systemic amplifier of cardiovascular risk.

REFERENCES: NIL.

Acknowledgments: NIL.

Disclosure of Interests: None declared.