Although a randomized, controlled trial involving patients with severe ANCA-associated vasculitis that compared cyclophosphamide head to head with another agent had long been deemed unethical,30
uncontrolled studies have suggested that rituximab has efficacy for remission induction in ANCA-associated vasculitis.21-23
Those promising results led to the current study, which suggests that rituximab plus glucocorticoids provides similar results to cyclophosphamide plus glucocorticoids for induction of remission.
The observed treatment effects were consistent across all measures of clinical efficacy. A higher percentage of rituximab-treated patients reached the primary end point (64% vs. 53%); the difference exceeded the prespecified noninferiority margin by 31%. In addition, in a prespecified subgroup analysis,31
patients who presented with relapsing disease and who received rituximab fared substantially better than did those with relapsing disease who received cyclophosphamide. Among patients with severe renal disease or alveolar hemorrhage, the outcomes were similar with the two treatment regimens.
The likelihood of remission at 6 months is affected by whether glucocorticoids have been tapered and discontinued entirely, as well as by the specific definition of remission.32-35
Several differences in trial design may explain why the remission rates in this trial were lower than those in some other vasculitis trials.10,11,32-35
Particularly important is the fact that in other vasculitis trials, patients have generally been permitted to continue to receive glucocorticoids for 1 year or longer. In addition, some of the patients in other trials who were classified as being in remission had the continuation of one or more minor BVAS items (i.e., a score higher than 0).
We anticipated lower rates of certain adverse events in the rituximab group, but we did not observe major differences between the two groups in overall adverse events. There are several possible reasons for this finding. First, adverse events, by their definition, include both disease and treatment complications, including those related to glucocorticoid use. Second, 6 months may have been too short a period in which to detect some of the cyclophosphamide-associated adverse events (e.g., infertility). Third, rigorous monitoring of all patients in our trial may have reduced the incidence of cyclophosphamide-induced leukopenia, which may occur in clinical practice if blood counts are not checked every 2 weeks.
Our trial had certain limitations. We enrolled only patients with severe ANCA-associated vasculitis who were ANCA-positive. Thus, it is not clear whether the treatment effects extend to patients with limited Wegener’s granulomatosis or those who are ANCA-negative.6
Patients with alveolar hemorrhage severe enough to require ventilatory support and those with advanced renal dysfunction (serum creatinine level, >4.0 mg per deciliter [354 μ
mol per liter]) were excluded. Thus, the comparative efficacy of these two regimens is uncertain in such patients.
Our study focused exclusively on remission induction but did not address the question of retreatment with rituximab. Rituximab was not re-administered after the return of peripheral-blood B cells (anticipated by 9 to 12 months). Longer follow-up in the present trial is important to understand the benefits and risks of rituximab therapy for ANCA-associated vasculitis. Evaluations of patients followed for a minimum of 18 months will explore issues such as the need for retreatment, particularly in the context of peripheral B-cell reconstitution. The finding that loss of proteinase 3–ANCA production occurred more frequently with rituximab therapy than with cyclophosphamide therapy suggests that these two treatment strategies modulate proteinase 3–producing cells differently. Since the ANCA response was not associated with the primary end point, it is possible that the clinical efficacies of both rituximab and cyclophosphamide are due to mechanisms beyond autoantibody suppression.
In conclusion, our data suggest that treatment with rituximab and glucocorticoids is not inferior to the standard regimen in patients with severe ANCA-associated vasculitis of recent onset. Moreover, the regimen may be superior to the standard regimen of cyclophosphamide and glucocorticoids for remission induction in severe relapsing ANCA-associated vasculitis.