Individualized Rituximab Treatment in ANCA-Associated Vasculitides
A recent ancillary study conducted as part of the MAINRITSAN 2 trial has shed light on the interindividual variability in response to rituximab treatment in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides. The study aimed to explore the relationship between rituximab plasma concentration, genetic polymorphisms in candidate genes related to pharmacokinetics (PK) and pharmacodynamics (PD), and clinical outcomes in these patients.
In the MAINRITSAN 2 trial, patients were randomly assigned to receive either a fixed-schedule infusion of 500 mg rituximab or an individually-tailored regimen. The study assessed rituximab plasma concentrations at month 3 (CM3) and genotyped DNA samples from a subset of patients for single nucleotide polymorphisms in 88 candidate genes associated with PK/PD. Logistic linear regression analysis was performed to examine the relationship between PK/PD outcomes and genetic variants.
The findings of the study revealed interesting insights. Patients in the fixed-schedule group had a significantly lower frequency of underexposed individuals (CM3 <4 μg/mL) compared to those in the tailored-infusion group (2.0% vs. 18.0%; p = 0.02). Importantly, low rituximab plasma concentration at 3 months (CM3 <4 μg/mL) emerged as an independent risk factor for major relapse at month 28 (M28) (odds ratio = 6.56; 95% CI 1.26–34.09; p = 0.025). Survival analysis further confirmed CM3 <4 μg/mL as an independent risk factor for both major relapse (Hazard ratio [HR] = 4.81; 95% CI 1.56–14.82; p = 0.006) and relapse (HR = 2.70; 95% CI 1.02–7.15; p = 0.046) in these patients. Furthermore, genetic variants STAT4 rs2278940 and PRKCA rs8076312 showed significant associations with CM3, indicating their potential influence on rituximab plasma concentration. However, these genetic variants were not directly associated with the onset of major relapse at M28.
The study's findings highlight the potential benefits of individualizing rituximab treatment based on drug monitoring. The identification of a correlation between low rituximab plasma concentration and an increased risk of major relapse emphasizes the importance of maintaining adequate drug levels for optimal therapeutic outcomes. Moreover, the impact of genetic polymorphisms on rituximab plasma concentration underscores the need for further exploration in tailoring treatment strategies.
In summary, the MAINRITSAN 2 trial ancillary study provides valuable insights into the individualized treatment of ANCA-associated vasculitides using rituximab. Monitoring rituximab plasma concentration and considering genetic factors may help optimize treatment outcomes and reduce the risk of relapse in these patients.
Reference:
Khoudour N, Delestre F, Jabot-Hanin F, Jouinot A, Nectoux J, Letouneur F, Izac B, Vidal M, Guillevin L, Puéchal X, Charles P, Terrier B, Blanchet B. Association between plasma rituximab concentration and the risk of major relapse in antineutrophil cytoplasmic antibody-associated vasculitides during rituximab maintenance therapy. Arthritis Rheumatol. 2023 May 3. doi: 10.1002/art.42556. Epub ahead of print. PMID: 37134130.
Tags: vasculitis, GPA