The association between genetic characteristics and treatment failure when switching from biologic disease-modifying antirheumatic drugs/Janus kinase inhibitors in patients with rheumatoid arthritis

Genetic polymorphisms in several genes can determine the response to therapy with biologic disease-modifying antirheumatic drugs (bDMARDs) and Janus kinase inhibitors (JAKi) in rheumatoid arthritis (RA).

Objective: to determine the association between polymorphisms of genes of IL-6 (rs1800795), IL-6R (rs2228145), TNFAIP3 (rs10499194, rs6920220), TNFα (rs1800629), CTLA-4 (rs231775), TNFSF13B (BAFF) (rs9514828), KCNS1 (rs734784), COMT (rs4633), IL-10 (rs1800872) and STAT4 (rs7574865) and inadequate response when switching RA patients from an ineffective bDMARD and/or JAKi to another bDMARD or JAKi.

Material and methods. The study group consisted of 94 patients with RA (85.1% women, mean age 47.2±13.8 years) with moderate or high disease activity that persisted despite therapy with a bDMARD/JAKi. All patients were switched to another bDMARD or JAKi, including 12 (12.8%) to a tumor necrosis factor-α inhibitor, 27 (28.7%) to an interleukin-6 inhibitor, 46 (48.9%) to rituximab and 9 (9.6%) to a JAKi. After six months, RA activity was assessed using the DAS28-CRP, SDAI and CDAI indices. Two groups of patients were identified: those who responded to treatment (n=47), achieved remission or low activity (DAS28-CRP ≤3.2, SDAI ≤11, CDAI < 10), and those who did not respond to treatment (n=47) and had moderate/high activity according to the aforementioned indices. All patients underwent genotyping of the polymorphisms of the indicated genes using the polymerase chain reaction method.

Results and discussion. Carrying the mutant T allele (TT + CT) of the TNFAIP3 polymorphism (rs10499194) and the T allele (GT + TT) of STAT4 (rs7574865) independently increased the risk of bDMARD/JAKi inefficiency (TT + CT vs. CC: odds ratio, OR 2.84; 95% confidence interval, CI 1.23–6.56; p=0.013; GT + TT vs. GG: OR 3.18; 95% CI 1.36–7.46; p=0.007). The presence of T minor alleles of TNFSF13B (BAFF) (rs9514828) and G (AG + GG) KCNS1 (rs734784) gene polymorphisms was independently associated with a lower risk of treatment failure (CC vs. CT + TT: OR 0.25; 95% CI 0.10–0.66; p=0.004; AA vs. AG + GG: OR 0.29; 95% CI 0.12–0.74; p=0.008, respectively). For the TNFA gene polymorphism (rs1800629), the multiplicative model was statistically significant (G vs. A: OR 3.12; 95% CI 1.1–9.03; p=0.037), and for the CTLA-4 gene (rs231775), the super-dominant model was statistically significant (AA + GG vs. AG: OR 2.6; 95% CI 1.14–6.25; p=0.022).

Conclusion. Six genetic predictors of treatment failure in bDMARDs/JAKi switching were identified: TNFAIP3 (rs10499194), STAT4 (rs7574865), TNFA (rs1800629), TNFSF13B (BAFF) (rs9514828), KCNS1 (rs734784) and CTLA-4 (rs231775).

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