GSTT1 Null Genotype as a Pharmacogenetic Risk Marker for Infection During Cyclophosphamide Induction Therapy in Systemic Lupus Erythematosus

Abstract Cyclophosphamide (CYC) remains an important induction therapy for severe systemic lupus erythematosus (SLE), but infection risk varies considerably among patients. This prospective study evaluated associations of pharmacokinetic and pharmacogenetic factors with infection in patients with SLE receiving intravenous CYC induction therapy. Thirty patients underwent pharmacokinetic sampling and 24-week follow-up. Infection occurred in 12 patients (40.0%). The GSTT1 null genotype was associated with increased infection risk (RR = 3.455; BH-FDR-adjusted p = 0.040) and remained associated with infection after adjustment for baseline absolute lymphocyte count (ALC) (adjusted RR = 2.824; p = 0.033). Exploratory discrimination analysis showed the highest discrimination with combined baseline ALC and GSTT1 genotype. The 6-hour plasma concentration after initiation of infusion (C 6 ) showed the strongest correlation with AUC 0−24 (R 2 = 0.987). Each 1,000 ng/mL increase at C 6 or C 8 was associated with a lower risk of infection (RR = 0.908 and 0.880; BH-FDR-adjusted p = 0.027 and 0.018, respectively). Higher CYC clearance (CL) was associated with an early reduction in lymphocytes. These findings highlight the GSTT1 null genotype as a potential genetic marker of infection risk in SLE. Integrating lymphocytes, CYC pharmacokinetics, and pharmacogenetics may support infection-risk stratification and could prevent the serious infection from CYC over-suppression.