Background: Rheumatoid arthritis (RA) is a systemic immune-mediated disease characterized by chronic inflammation and increased cardiovascular risk. Active RA is paradoxically associated with reduced circulating lipid levels despite enhanced atherosclerotic burden, a phenomenon known as the “lipid paradox”. Although inflammation is known to reshape lipid metabolism, how inflammatory signaling integrates with lipid remodeling and hepatic metabolic responses in RA remains incompletely understood.

Objectives: To characterize the integrated lipidomic and inflammatory proteomic landscape across RA disease activity states.

To evaluate its modulation by biological and targeted-synthetic DMARDs such as TNFi, IL6Ri and JAK inhibitors.

To investigate the functional hepatic consequences of these systemic alterations.

Methods: Serum samples from three RA cohorts with different disease activity were analyzed: low (n=75), moderate (n=191) and high disease activity (n=96) according to DAS28-CRP, together with 25 age- and sex-matched healthy donors (HDs). High-throughput NMR metabolomics (Nightingale Health), profiling >200 lipid metabolites, and proximity extension assay proteomics (Olink/Cobiomic) targeting 96 inflammatory proteins were performed. A longitudinal sub-cohort initiating TNFi (n=80), IL-6Ri (n=27), or JAK inhibitors (n=46) was evaluated at baseline and after 6 months of therapy. Functional relevance was assessed in vitro by exposing HepG2 hepatocytes to patient serum before and after therapy, followed by lipid droplet quantification using Bodipy staining and expression analysis of lipid metabolism-related genes by PCR.

Results: The integrated profiling revealed profound and coordinated alterations in lipid and inflammatory signatures across RA cohorts. A total of 86 lipid metabolites and 26 inflammatory proteins differed significantly among low, moderate, and high disease activity, defining a robust inflammatory-metabolic gradient.

Patients with high activity showed a global reduction in lipid fractions—including cholesterol, cholesteryl esters, apolipoproteins, and multiple LDL/HDL subclasses—along with altered fatty acid composition. In contrast, GlycA, a composite marker of systemic inflammation, increased consistently with disease activity, paralleling elevations in IL-6 and other pro-inflammatory mediators.

Correlation analyses showed that most altered lipid metabolites were negatively associated with CRP, ESR, ACPA, and RF, while inflammatory proteins correlated positively with these and with cardiovascular and hepatic markers (AST, ALT, GGT), linking lipid depletion to cardiometabolic and hepatic involvement. Cross-omic integration revealed extensive inverse associations between proteins and lipids, identifying GlycA and IL-6 as central hubs connecting inflammatory activity with lipid remodeling.

HepG2 hepatocytes exposed to serum from highly active patients displayed reduced lipid accumulation and upregulation of lipid catabolic genes, indicating direct modulation of hepatic metabolism by circulating inflammatory factors.

Longitudinal analyses showed that b/tsDMARD therapy induced both general and drug-specific reprogramming of lipidomic and proteomic profiles. IL-6R and JAK inhibition achieved greater normalization of lipid fractions and inflammatory markers, while TNF blockade primarily modulated protein networks. Responders showed coordinated improvements in lipid and cytokine signatures—most notably after JAK inhibition—whereas non-responders retained active inflammatory and dyslipidemic patterns.

In vitro, post-therapy serum partially reversed lipid-depleting effects, supporting a mechanistic link between inflammatory blockade and hepatic lipid homeostasis restoration.

Conclusions: Integrated lipidomic and proteomic profiling reveals that systemic inflammation in rheumatoid arthritis drives a coordinated remodeling of lipid metabolism, underlying the so-called “lipid paradox.” Active disease is characterized by depleted lipoprotein fractions and enriched inflammatory hubs centered on IL-6 and GlycA, defining a tightly linked inflammatory–metabolic network. Functional assays demonstrate that circulating inflammatory factors directly modulate hepatic lipid handling, supporting a mechanistic link between systemic inflammation and hepatic metabolism. Biological and targeted-synthetic DMARDs, particularly IL-6R and JAK inhibitors, effectively restore lipidomic homeostasis in parallel with inflammatory resolution, highlighting lipid recovery as a dynamic marker of deep immunometabolic remission.

REFERENCES: NIL.

Acknowledgments: NIL.

Disclosure of Interests: None declared.