The ALDH4A1/anti-ALDH4A1 axis as a novel player of atherosclerosis in rheumatoid arthritis

ObjectivesCardiovascular risk excess in rheumatoid arthritis (RA) cannot be explained by traditional risk factors alone. Recent experimental data have identified ALDH4A1 as a mitochondrial self-antigen implicated in atherosclerosis, yet its clinical significance in human autoimmunity remains unexplored. We aimed to characterize ALDH4A1 and anti-ALDH4A1 antibody levels in early RA, and evaluate their associations with atherosclerosis burden and lipoprotein traits. MethodsALDH4A1 and anti-ALDH4A1 antibodies (IgM, IgG, IgA, and IgG subclasses) were measured in early RA (n=82), clinically suspect arthralgia (n=14), healthy controls (n=70), and a validation cohort of established RA. A prospective cohort (n=13) explored therapeutic modulation under TNF blockade. Associations with atherosclerosis burden, lipid/lipoprotein profiles, oxylipin signatures, proteomics, and cell-free DNA were assessed. ResultsALDH4A1 serum levels were associated with apoptotic-related proteomic pathways, cell-free DNA and lipidomic signatures in early RA. Reduced anti-ALDH4A1 antibodies were found, although divergent patters were noted across isotypes. These differences were confirmed in a validation cohort. IgG (predominantly IgG3) anti-ALDH4A1 correlated with favourable lipoprotein traits and cardiometabolic risk factors. Increased ALDH4A1 and reduced IgM/IgG anti-ALDH4A1 antibodies independently predicted atherosclerosis and improved risk stratification beyond mSCORE, most notably for IgG. ALDH4A1 tracked with TNF dynamics under TNF blockade, whereas increases in IgG antibodies occurred in responders and paralleled changes in lipoprotein features. ConclusionsThe ALDH4A1/anti-ALDH4A1 axis emerges as a novel player bridging lipid disturbances and atherosclerosis along the RA spectrum, hence highlighting the involvement of mitochondrial targets. These components hold promise as functional players, clinical tools and therapeutic targets.