Abstract
Background and Aims
Rituximab is a proven effective induction and remission-maintenance treatment in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Studies have identified hypogammaglobulinemia, infection, and late-onset neutropenia as potential adverse events. There is limited data on long-term outcomes following extended periods of B-cell depletion therapy with rituximab in AAV cohorts. We conducted a retrospective study to examine the safety profile of repeated rituximab treatment in AAV.
Method
All patients with AAV treated with rituximab between 1st January 2008 and 31st December 2018 were identified through local dispensary database. Patients were stratified into low (≤4g), medium (>4g to ≤8g) and high (>8g) dose groups according to the cumulative rituximab dose received until 1st October 2019. Baseline characteristics and events including death, opportunistic and severe infections (defined as infections required hospitalization and/or intravenous antibiotic administration), neutropenia (neutrophil count ≤1.5x109/L), hypogammaglobulinemia (IgG level≤5.0), infusion reactions and malignancy diagnosed post-rituximab treatment were examined and compared between the groups.
Results
364 patients (49% male, 52 year old mean age) received rituximab for treatment of active disease or remission maintenance. 49%(n=175) had repeat rituximab treatments (267/513 treatment courses for relapsing disease and 247/513 for remission maintenance). There were 262 (72%), 70(19%) and 32(9%) patients in low-, medium- and high-dose groups respectively. The median cumulative rituximab dose for each group was 2g, 6g and 12g (p<0.001). Low-dose group patients were older (59 and 40 years, p<0.001) and more likely to have renal-limited disease compared to high-dose groups (19%vs4%; p<0.05). Conversely, there were more ear-nose-throat (ENT) /ocular limited (41% and 13%; p<0.05) and antiproteinase 3 (PR3)-ANCA positive disease (56% vs 38%, p<0.05) in high-dose compared to low-dose group. The overall median duration of follow up was 72 months (QR: 28-135months)(Table1).
Outcomes (Table2):
Infections: no difference in serious or opportunistic infection rate between groups (1.2 vs 0.1 vs 0.1infections/patient/year; p=0.18). 77% of opportunistic infections across all groups were related to herpesvirus (e.g. Cytomegalovirus/Herpes Zoster/Herpes Simplex) reactivation.
Hypogammaglobulinemia: incidence was comparable between groups (9.7% vs 10% vs 9%, p=0.91). Overall median time to event was 5 months from first rituximab.
Neutropenia: 101 patients had recorded neutropenia after rituximab (Low-dose: 32%; medium-dose 16% and High-dose: 22%, p<0.05). All were related to concurrent immunosuppressants (e.g. Azathioprine, cyclophosphamide or mycophenolate) or infection. Events resolved after withdrawal or reduction of concurrent immunosuppressant or treatment of underlying infection.
Cancer: No difference in malignancy rate between groups (6% vs 14% vs 3%, p=0.22). 39 malignancies reported in 32 patients post rituximab treatment. The two commonest reported cancers were skin (36%) and breast cancer (21%)
Deaths: 58 patients died during the study period. Mortality rate in the low and medium-dose groups were comparable (82% survival at 30 month after last rituximab). Conversely, there were no deaths in the high-dose group.
Conclusion
In this large, single-centre cohort of patients with AAV, we did not observe an increased incidence of adverse events with increasing cumulative rituximab exposure. This likely reflects physician bias in patient selection for repeat treatment and suggests that in selected patients, extended periods of rituximab treatment might be safe. The superior survival seen in high-dose group was likely related to higher proportion of ENT/ocular limited vasculitis.
Differential effects of 2C9*3 and 2C9*2 variants of cytochrome P-450 CYP2C9 on sensitivity to acenocoumarol
