Genetic polymorphisms and Methotrexate response in patients with rheumatoid arthritis

: In the context of rheumatoid arthritis (RA) treatment, Methotrexate (MTX) plays a crucial role in preventing joint damage and bone erosion (BE). RA is characterized by elevated levels of matrix metalloproteinase 2 (MMP2), an enzyme responsible for extracellular matrix degradation, which contributes to joint damage and inflammation. Tissue inhibitor of metalloproteinase 2 (TIMP2) counteracts MMP2, and an imbalance between the two can exacerbate BE. Inosine triphosphatase (ITPA) is an enzyme involved in regulating inosine triphosphate levels, potentially linked to RA susceptibility. Genetic variations in ITPA, MMP2, and TIMP2 genes can influence MTX's efficacy. A study of 122 RA patients on MTX monotherapy assessed its effectiveness using Disease Activity Score (DAS28) changes over 6 months following EULAR response criteria. Genotyping, including MMP2 (rs243866, rs2285053), TIMP2 (rs2277698), and ITPA (rs1127354) polymorphisms, was performed. Among the patients, 87.7% were responders, 63.9% experienced BE, and 24.6% encountered adverse events. Notably, patients with the MMP2 (rs243866) GG genotype were the only ones reporting nausea (p=0.025). Patients with both the MMP2 (rs2285053) CC and TIMP2 (rs2277698) CT genotypes had a lower incidence of BE compared to those lacking this combination (p=0.048). The TIMP2 (rs2277698) CC genotype was associated with a higher baseline DAS28 score (p=0.035). In summary, this study suggests that specific MMP2/TIMP2 genotype combinations may serve as predictors for BE development in RA patients undergoing MTX monotherapy.