Differential functional and lipidomic impact of tofacitinib and other disease-modifying antirheumatic drugs on HDL in rheumatoid arthritis

High-density lipoprotein (HDL) presents atheroprotective functions that can be impaired in patients with chronic inflammatory disease, such as rheumatoid arthritis (RA). We investigated the effects of different disease-modifying antirheumatic drugs (DMARDs) on HDL composition and functions in RA patients. Serum was collected from patients with active RA at baseline, 3 and 6 months of treatment with methotrexate (n = 10), biologic DMARDs (anti-TNFα, n = 10; and abatacept, n = 30) or the JAK inhibitor tofacitinib (n = 21). HDL cholesterol efflux and antioxidant capacities, paraoxonase-1 (PON1) activity, and serum amyloid A1 (SAA1) levels were measured. LC-MS/MS was performed to analyze the HDL lipidome, before and at 6 months of tofacitinib treatment. Disease activity was assessed by the Disease Activity Score in 28 joints (DAS28). HDL-SAA1 levels correlated positively with DAS28 across the combined cohort. Tofacitinib resulted in improvement of all HDL atheroprotective parameters assessed and induced favorable HDL lipidomic remodeling, with changes in specific lipid species correlating with functional improvement. HDL-associated ether lipids and specific sphingomyelin species, known for their atheroprotective properties, showed a negative correlation with DAS28. Anti-TNFα agents resulted in improvement of only HDL-PON1 activity and HDL-SAA1 levels, while methotrexate and abatacept had no significant effect. We showed a differential effect of DMARDs on HDL atheroprotective properties in RA patients. Tofacitinib comprehensively improved HDL's atheroprotective functions and favorably altered its lipidome, with distinct lipid species emerging as potential biomarkers of treatment response. Whether the observed improvements in HDL-related parameters could be associated with reduced cardiovascular risk warrants investigation in larger prospective studies.