Rituximab for refractory Wegener's granulomatosis: report of a prospective, open-label pilot trial

Abstract

Rationale: Standard therapy for Wegener's granulomatosis is fraught with substantial toxicity and not always effective. B lymphocytes have been implicated in the pathogenesis of Wegener's granulomatosis. Their depletion has been proposed as salvage therapy for refractory disease. Earlier encouraging reports are confounded by concomitant immunosuppressive medications and include only limited available biomarker data.

Objectives: To evaluate the efficacy and safety of rituximab for remission induction in refractory Wegener's granulomatosis.

Methods: A prospective open-label pilot trial was conducted with 10 patients monitored for 1 yr. Included were patients with active severe antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, ANCA positivity, and resistance to (or intolerance of) cyclophosphamide. The remission induction regimen consisted of oral prednisone (1 mg/kg/d) and four weekly infusions of rituximab (375 mg/m(2)). Prednisone was tapered and discontinued over 5 mo. Failure to achieve remission, a clinical flare in the absence of B lymphocytes, and inability to complete the glucocorticoid taper were considered treatment failures.

Main results: Three women and seven men (median age, 57 yr; range, 25-72 yr) were enrolled. All had ANCA reacting with proteinase-3. The median activity score at enrollment was 6 (range, 5-10). All patients tolerated rituximab well, achieved swift B-lymphocyte depletion and complete clinical remission (activity score, 0) by 3 mo, and were tapered off glucocorticoids by 6 mo. Five patients were retreated with rituximab alone for recurring/rising ANCA titers according to protocol. One patient experienced a clinical flare after B lymphocyte reconstitution.

Conclusion: In this cohort, rituximab was a well-tolerated and effective remission induction agent for severe refractory Wegener's granulomatosis.

Figure 1.

Response to treatment. (A) All 10 patients experienced a prompt decline in the Birmingham Vasculitis Activity Score for Wegener's granulomatosis (BVAS/WG). By 3 mo all patients had achieved complete remission with a BVAS/WG of 0. Only one patient experienced a clinical flare at 9 mo. This flare responded promptly on repeating the remission induction regimen. (B) Rituximab therapy resulted in peripheral blood B-lymphocyte depletion in all patients, and B-lymphocyte recovery occurred between 6 and 12 mo. (C) Monthly proteinase-3–antineutrophil cytoplasmic antibody (PR3-ANCA) levels measured in all patients. IQR = interquartile range.

Figure 2.

(A) Renal function remained stable or improved in all seven patients with active renal involvement at enrollment. Shown are mean (± SD) serum creatinine levels at enrollment and at 6 mo. Patients with high serum creatinine all had chronic renal insufficiency as a result of previous episodes of disease activity. (B) Reduction in sedimentation rate and (C) C-reactive protein levels occurred in all patients, but only the mean differences in erythrocyte sedimentation rate were statistically significant.