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 <i>STAT4</i> 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 <i>STAT4</i> 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, <i>STAT4</i> 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 <i>STAT4</i> overexpression exhibited higher IFN-γ and IL-23 levels. IL-12 differences persisted among GC/GC carriers regardless of <i>STAT4</i> expression status. In conclusion, these exploratory findings suggest potential interactions among <i>STAT4</i> 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.