MTHFR risk alleles associate with Th17 immunity and spinal damage in axial spondyloarthritis.

BACKGROUND

MTHFR polymorphisms regulate homocysteine metabolism, yet their role in clinical heterogeneity, immune dysregulation, and treatment outcomes in axial spondyloarthritis (axSpA) remains undefined.

METHODS

This cross-sectional study included 180 axSpA patients and a retrospective TNF inhibitor (TNFi) cohort (n = 50). CD4+ T-cell subsets were profiled by flow cytometry. Patients were stratified by cumulative MTHFR risk allele load into MTHFRR0, MTHFRR1, and MTHFRR2 groups.

RESULTS

Cumulative MTHFR risk allele load showed graded associations with GGT, ALP, mSASSS (p = 0.008, 0.037, 0.038) and Th17/Treg ratio (p = 0.036), all BH-adjusted. In TNFi treatment cohort, the proportion of patients achieving clinically important improvement did not differ significantly across genotype groups.

CONCLUSION

In axSpA, cumulative MTHFR risk allele load associated with metabolic disturbances, Th17 polarization, and spinal damage. Treatment response analyses detected no significant TNFi genotype-response link. These findings support a gene-metabolism-immunity axis requiring prospective validation.