Rheumatology · Medical Literature
LAP-defined hepatic steatosis and cardiometabolic risk in rheumatoid arthritis: a post-hoc analysis of the FRANCIS randomized trial.
Abstract
Rheumatoid arthritis (RA) is a chronic autoimmune disease associated with metabolic dysfunction-associated steatotic liver disease (MASLD), which may contribute to cardiovascular (CV) risk. This study aimed to examine the association between hepatic steatosis, measured by a non-invasive test, and CV risk markers in RA patients. This post-hoc analysis used cross-sectional and longitudinal data from the Franciscus Rheumatoid Arthritis and Cardiovascular Intervention Study (FRANCIS), an open-label randomized controlled trial of intensive CV risk management in patients with rheumatoid arthritis without cardiovascular disease (CVD) or type 2 diabetes. Hepatic steatosis was assessed using the Lipid Accumulation Product (LAP) with sex-specific thresholds for rule-in and rule-out of severe steatosis. Associations between hepatic steatosis and carotid intima-media thickness (cIMT) were assessed using linear regression analysis. Crude associations were first evaluated in unadjusted models, followed by multivariable models adjusting for age, sex, BMI, and systolic blood pressure. Longitudinal changes in cIMT over 3 years were analyzed according to LAP-defined steatosis and treatment strategy. Among 236 RA patients (66% female; mean age 54 ± 10 years), those with LAP-defined steatosis had a more adverse cardiometabolic profile, including higher blood pressure, fasting glucose, and a more atherogenic lipid profile (all p < 0.05). Mean cIMT tended to be higher in the steatosis group (0.61 ± 0.10 vs. 0.57 ± 0.11 mm). In crude regression, LAP-defined steatosis showed a non-significant trend toward higher cIMT (B = 0.036, 95% CI - 0.003-0.076), which was no longer observed after multivariable adjustment (B = - 0.016, 95% CI - 0.050-0.019). Over 3 years, intensive treatment reduced cIMT progression compared with standard treatment in patients without LAP-defined steatosis (ΔcIMT 0.03 ± 0.07 vs. 0.06 ± 0.12 mm; p = 0.013), whereas no treatment effect was observed in patients with LAP-defined steatosis (ΔcIMT 0.05 ± 0.05 vs. 0.04 ± 0.05 mm; p = 0.696). Intensive treatment also produced greater improvements in lipid parameters, including reductions in total cholesterol and apoB in both groups, and increased apoAI mainly in participants with LAP-defined steatosis, while glycemic, hepatic, and inflammatory markers remained largely unchanged. In this exploratory post-hoc analysis, LAP-defined hepatic steatosis identified RA patients with a more adverse cardiometabolic profile. An unadjusted association with subclinical vascular burden was observed but was attenuated after adjustment for established CV risk factors. Intensive CV risk management was associated with lower cIMT progression in patients without LAP-defined steatosis, while no clear vascular effect was observed in those with LAP-defined steatosis. No evidence of differential treatment effects according to LAP-defined steatosis was found.
Clinical relevance
Rheumatoid arthritis confers independent cardiovascular risk, and the co-occurrence of metabolic dysfunction-associated steatotic liver disease (MASLD) may further amplify that risk through atherogenic dyslipidemia and insulin resistance. This post-hoc analysis of the FRANCIS RCT addresses a clinically important gap by evaluating whether a non-invasive, bedside-applicable index (LAP) can stratify subclinical atherosclerosis burden and predict differential response to intensive CV risk management in RA patients free of established CVD or type 2 diabetes. Identifying RA patients with concurrent hepatic steatosis who may respond suboptimally to standard CV interventions is directly actionable for rheumatologists and cardiologists co-managing this population.
Key findings
1. Among 236 RA patients (66% female; mean age 54 ± 10 years), those with LAP-defined hepatic steatosis demonstrated a significantly more adverse cardiometabolic profile, including higher blood pressure, elevated fasting glucose, and a more atherogenic lipid panel (all p < 0.05). 2. Mean carotid intima-media thickness (cIMT) was numerically higher in the LAP-defined steatosis group versus the non-steatosis group (0.61 ± 0.10 mm vs. 0.57 ± 0.11 mm), suggesting greater subclinical vascular burden. 3. In unadjusted linear regression, LAP-defined steatosis showed a non-significant trend toward higher cIMT (B = 0.036, 95% CI −0.003 to 0.076), which was fully attenuated after multivariable adjustment for age, sex, BMI, and systolic blood pressure (B = −0.016, 95% CI −0.050 to 0.019), indicating that conventional CV risk factors mediate the observed association. 4. Over 3 years, intensive CV risk management significantly reduced cIMT progression compared with standard treatment in patients WITHOUT LAP-defined steatosis (ΔcIMT 0.03 ± 0.07 vs. 0.06 ± 0.12 mm; p = 0.013). 5. In patients WITH LAP-defined steatosis, no significant treatment effect on cIMT progression was observed with intensive versus standard management (ΔcIMT 0.05 ± 0.05 vs. 0.04 ± 0.05 mm; p = 0.696). 6. Intensive treatment improved lipid parameters in both groups (reductions in total cholesterol and apoB); apoAI increases were observed predominantly in the LAP-defined steatosis subgroup, while glycemic, hepatic enzyme, and inflammatory markers remained largely unchanged across groups.
Practice implications
Rheumatologists should consider routine LAP calculation (derived from waist circumference and fasting triglycerides, using sex-specific thresholds) in RA patients without established CVD or type 2 diabetes, as it identifies a subgroup with a markedly more atherogenic cardiometabolic profile who may warrant earlier or more aggressive multidisciplinary cardiovascular risk evaluation. Clinicians should be aware that RA patients with LAP-defined hepatic steatosis may derive attenuated vascular benefit from intensive CV risk management strategies alone, suggesting that concurrent MASLD-directed interventions — such as lifestyle modification targeting visceral adiposity and insulin resistance — may need to be integrated into their CV risk reduction plan. Given the exploratory, post-hoc, and cross-sectional limitations of this analysis, formal interaction testing did not confirm differential treatment effects by LAP status; these findings are hypothesis-generating and should be validated in prospective trials powered to assess MASLD as an effect modifier of CV risk interventions in RA.