Long-term maintenance therapy using rituximab-induced continuous B-cell depletion in patients with ANCA vasculitis

Abstract

Background and objectives: Remission in the majority of ANCA vasculitis patients is not sustained after a single course of rituximab, and risk of relapse warrants development of a successful strategy to ensure durable remission.

Design, setting, participants, & measurements: A retrospective analysis of ANCA vasculitis patients who underwent maintenance therapy using rituximab-induced continuous B-cell depletion for up to 7 years was performed. Maintenance therapy with rituximab was initiated after achieving remission or converting from other prior maintenance therapy. Continuous B-cell depletion was achieved in all patients by scheduled rituximab administration every 4 months. Disease activity, serologic parameters, adverse events, and survival were examined.

Results: In the study, 172 patients (mean age=60 years, 55% women, 57% myeloperoxidase-ANCA) treated from April of 2006 to March of 2013 underwent continuous B-cell depletion with rituximab. Median remission maintenance follow-up time was 2.1 years. Complete remission (Birmingham Vasculitis Activity Score [BVAS] = 0) was achieved in all patients. Major relapse (BVAS ≥ 3) occurred in 5% of patients and was associated with weaning of other immunosuppression drugs. Remission was reinduced in all patients. Survival mirrored survival of a general age-, sex-, and ethnicity-matched United States population.

Conclusion: This analysis provides evidence for long-term disease control using continuous B-cell depletion. This treatment strategy in ANCA vasculitis patients also seems to result in survival rates comparable with rates in a matched reference population. These findings suggest that prospective remission maintenance treatment trials using continuous B-cell depletion are warranted.

Figure 1.

Ancillary immunosuppression use in ANCA vasculitis patients undergoing continuous B-cell depletion. Heat maps depict use of prednisone, cyclophosphamide (CYC), azathioprine (AZA), mycophenolate mofetil (MMF), and methotrexate (MTX) throughout the study period. Each square represents maximum daily medication dose in milligrams for prednisone, CYC, AZA, and MMF and weekly medication dose in milligrams for MTX during each 90-day period. Squares from left to right represent each 90-day time period. Squares from top to bottom represent each individual patient. Gray squares within study period represent missing data, and each individual patient row becomes gray at the end of study period.

Figure 2.

ANCA titers in ANCA vasculitis patients undergoing continuous B cell depletion. (A) Myeloperoxidase (MPO)-ANCA and (B) proteinase 3 (PR3)-ANCA titers were measured in each patient throughout the study duration. The dashed line represents the lower limit of a positive test, which is 2.8 and 20 units for MPO- and PR3-ANCA, respectively. Error bars represent median and interquartile range. Titers were significantly lower at all time points compared with the 0- to 90-day time period for all time periods with greater than five samples (*P<0.05).

Figure 3.

Minor and major relapse-free survival of ANCA vasculitis patients undergoing continuous B-cell depletion. Kaplan–Meier curves comparing major (circles) and minor (triangles) relapse-free remission and survival.

Figure 4.

Survival of ANCA vasculitis patients undergoing continuous B-cell depletion compared with survival of the general population. Kaplan–Meier survival curves comparing cumulative survival of the cohort (diamonds) with the survival of an age-, sex-, and ethnicity-matched general United States population (dashes) based on data retrieved from National Vital Statistics Reports. There was no statistically significant difference in survival over time (P=0.94).