Dose-dependent Pharmacological Response to Rituximab in the Treatment of Antineutrophil Cytoplasmic Antibody-associated Vasculitis.

Abstract

Rituximab (RTX) is effective in the induction and maintenance of remission in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). However, uncertainty remains regarding the optimal maintenance dosing regimen. This work evaluates the relationship between variability in RTX dosing and pharmacological response in AAV. A prospective cohort of patients with AAV (n = 28) with either granulomatosis with polyangiitis (n = 23) or microscopic polyangiitis (n = 5) receiving maintenance RTX therapy were followed in a single tertiary care academic medical center over a 2-year period. Patient demographics, RTX dosing information, and trough plasma RTX levels were collected along with laboratory measures of pharmacologic response, including B cell counts and ANCA titers. RTX dosing information from 94 infusions with 59 trough samples were collected with a mean ± SD dose of 640 ± 221 mg, dosing interval of 210 ± 88 days, and trough plasma RTX concentration of 622 ± 548 ng/mL. RTX trough concentrations were associated with RTX dose (ρ = 0.60, <i>P</i> < 0.0001) and dosing interval (ρ = -0.55, <i>P</i> < 0.0001). RTX dosing intensity (mg/d) was associated with RTX trough concentrations (ρ = 0.57, <i>P</i> < 0.0001). Higher dosing intensities were associated with undetectable B cell repopulation (<i>P</i> < 0.0001), but not negative ANCA titers (<i>P</i> = 0.60). Stratification of dosing intensities based on the standard dosing regimen of 500 mg every 6 months (2.4-3.3 mg/d) demonstrated that this regimen was associated with B cell repopulation in 8 of 17 doses (47%) compared to 0 of 23 doses (0%) with the high-dose regimen (> 3.3 mg/d; <i>P</i> < 0.0001). RTX maintenance dosing of 500 mg every 6 months may be inadequate to maintain B cell depletion in the treatment of AAV.