Genetic and Functional Characterization of STAT4 in Rheumatoid Arthritis Patients with Distinct Disease Activity

Rheumatoid arthritis (RA) is characterized by chronic inflammation mediated by the JAK/STAT pathway. Variants in STAT4 have been associated with autoimmune susceptibility, but their functional role in RA remains unclear. The aim of this study was to genetically and functionally characterize STAT4 in RA patients with varying disease activity by analyzing two variants, mRNA expression, phosphorylated STAT4 (pSTAT4), and inflammatory cytokines (IL-12, IL-23, and IFN-γ). Sixty-three Mexican patients with RA were stratified into remission/low and moderate/high activity groups. Genotyping, STAT4 mRNA expression, pSTAT4 quantification, cytokine profiling, and treatment analyses were conducted. Patients receiving methotrexate, hydroxychloroquine, and sulfasalazine had higher IL-12 concentrations compared with those on other regimens. In remission/low activity patients, GC/GC carriers exhibited increased IL-12, PBMC levels, and anti-CCP antibodies, while GC/TT carriers in the moderate/high activity group showed distinct ESR values. Secondary analyses revealed that TT/TT carriers with STAT4 overexpression exhibited higher IFN-γ and IL-23 levels. IL-12 differences persisted among GC/GC carriers regardless of STAT4 expression status. In conclusion, these exploratory findings suggest potential interactions among STAT4 haplotypes, expression status, and treatment regimens influencing cytokine and inflammatory profiles in RA. However, due to the small subgroup sizes, the observed associations should be interpreted with caution and considered hypothesis-generating until validated in larger cohorts.