NK cell cytotoxicity is markedly reduced in younger patients with rheumatoid arthritis treated with JAK inhibitors

Abstract

Objectives This study investigated the impact of Janus kinase inhibitors (JAKi) on natural killer (NK) cell activity and phenotype in patients with rheumatoid arthritis (RA). While JAKi are effective in achieving low disease activity (LDA), preclinical and pharmacokinetic studies suggest potential effects on NK cells, raising concerns about infection and malignancy risks. However, the extent of these effects in RA patients remains unclear. Methods We assessed the cytotoxic activity of peripheral blood NK cells in RA patients with LDA who had been treated with JAKi (n = 85) or TNF inhibitors (TNFi) (n = 131) for more than three months using a 51Cr-release assay. Propensity score matching was used to adjust for confounders, and multivariable logistic regression identified risk factors for low NK cell activity. NK cell maturation and differentiation were evaluated via flow cytometry. Results NK cell activity was significantly lower in the JAKi group compared to the TNFi group (median 50% vs 36%, p = 0.002). The proportion of NK and CD56dim cells was reduced, while CD56bright cells were more abundant in the JAKi group. In the JAKi group, glucocorticoid use (odds ratio [OR] 5.36, 95% confidence interval [CI] 1.10-26.07, p = 0.04) and younger age (<50 years; OR 10.56, 95% CI 2.69-41.45, p < 0.01) were independent risk factors for reduced NK cell activity. Notably, herpes zoster incidence was significantly higher in the low NK cell activity group among RA patients younger than 50 years. Conclusion JAKi treatment significantly impaired NK cell activity and differentiation in RA patients, with age influencing these effects, underscoring important safety concerns.