Background/Purpose: Lipid metabolism plays a key role in immune cell plasticity, influencing activation, differentiation and function. Inflammation alters this metabolism, contributing to disease progression. Extensive analyses of these profiles in Rheumatoid Arthritis (RA) using high throughput metabolomics may improve disease characterization.This study objectives were to analyze circulating lipid and inflammatory profiles of RA patients, explore their association with disease activity and their modulation by b/tsDMARDs and identify mechanisms underlying altered lipid metabolism.

Methods: Clinical data and blood samples were collected from 362 RA patients and age- and sex-matched healthy donors (HDs). Serum lipid profiles were analyzed using Nightingale’s NMR spectroscopy ( >200 lipid markers). Inflammatory proteins were measured by proximity extension assay (Olink/Cobiomic). A 6-month follow-up was performed in active RA patients treated with TNFi (n=80), IL6Ri (n=27), or JAK inhibitors (n=46). In vitro studies in HepG2 liver cells treated with serum from active RA patients included Bodipy staining for lipid accumulation and PCR assays for lipid metabolism gene expression.

Results: Patients were classified as high (n=97) and moderate-low (n=265) disease activity (DAS28). Around 100 lipid markers differed significantly between groups. High activity was associated with reduced levels of most lipids, including apolipoproteins, fatty acids, phospholipids, and total lipid, cholesterol, and triglyceride content. Notably, LDL and VLDL-related proatherogenic markers were reduced. Many lipids negatively correlated with CRP, ESR, ACPAs, RF, cardiovascular risk, and liver enzymes (AST, ALT, GGT). Some proinflammatory proteins-cytokines, chemokines, and growth factors-were increased in high activity. These also correlated with clinical parameters and the altered lipids identified, indicating a shared dysregulation in high disease activity. At 6-month follow-up, treatment significantly reversed the altered lipid markers and inflammatory proteins, paralleling clinical improvements, including common and specific molecules modulated by each drug.In vitro HepG2 cells treated with active RA serum showed altered lipid accumulation and dysregulated gene expression compared to HDs. Genes related to lipolysis, β-oxidation, lipid transport and scavenger receptors were over expressed in active RA, whereas genes related to lipogenesis and cholesterol homeostasis were under expressed. These changes were partially reversed by TNFi, IL6Ri or JAKi mirroring in vivo effects.

Conclusion: Active RA is characterized by reduced circulating lipids and proinflammatory dysregulation. These changes are partially reversed by biologics and JAKi in parallel with clinical improvement. In vitro findings suggest an adaptive hepatic response to inflammation favoring energy mobilization over lipid synthesis, potentially contributing to metabolic dysfunction and CV risk, which may be mitigated by targeted therapies. Ongoing studies aim to further clarify these mechanisms.Supported by ISCIII (PI21/0591, PI24/00959, CD21/00187 and RICOR-24/0007/0019), and RYC2021-033828-I; co-financed by European Union.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/integrative-metabolomic-and-inflammatory-profiling-in-rheumatoid-arthritis-disease-activity-therapeutic-modulation-and-underlying-hepatic-mechanisms/