Background/Purpose:

RITAZAREM (ClinicalTrials.gov: NCT01697267) is an international, randomized, controlled trial comparing rituximab with azathioprine as maintenance therapy after induction of remission with rituximab and glucocorticoids for relapsing ANCA-associated vasculitis (AAV). Since all patients receive rituximab for induction, the RITAZAREM trial is also the largest prospective study of the use of rituximab in patients with relapsing AAV.

Methods:

188 patients with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) were enrolled and received remission-induction therapy with rituximab (4 x 375 mg/m²) and a higher- or lower-dose glucocorticoid regimen, depending on physician choice: reducing from either prednisone (or prednisolone) 1 mg/kg/day or 0.5 mg/kg/day to 10 mg/day by 4 months. Severe disease was defined as an organ- or life-threatening manifestation. Patients who achieved remission (BVAS/WG ≤1 and prednisone ≤10 mg daily) by month 4 were randomized to either repeat dose rituximab (1 g every 4 months) or azathioprine (2 mg/kg/day) for a total treatment period of 24 months. Preliminary results of the 4-month induction phase are reported.

Results:

95/188 (51%) subjects were male, median age 59 years (interquartile range (IQR) 47.5-68.0), disease duration of 5.0 years (IQR 1.85-10.15). 149/188 (79%) had previously received cyclophosphamide and 67/188 (36%) had previously received rituximab. 137/188 (73%) had PR3-ANCA positive disease, and 51/188 (37%) MPO-ANCA positive disease. 118/188 (63%) of relapses were severe, 56/188 (30%) received the higher-dose glucocorticoid regimen and 132/188 (70%) received the lower-dose glucocorticoid regimen (Table 1). The median BVAS/WG at enrollment was 5, maximum 14.

Data on responses at month 4 was available on 181 patients. 165/181 (91.2%) of patients achieved remission. 11/181 (6.0%) patients failed to achieve remission: 9/11 had PR3-ANCA positive disease; 9/11 had ear, nose, and throat involvement at baseline; 7/11 had severe disease at enrollment; and 9/11 received the lower (0.5 mg/kg) glucocorticoid dosing regimen. 5 (2.8%) patients died in the induction phase; causes of death included: pneumonia (2), cerebrovascular accident (1), alveolar hemorrhage/respiratory failure (1), and colon cancer (1).

53 severe adverse events (SAEs) occurred in 30 patients during the induction phase; 15/53 (28%) SAEs were severe infections. 52/188 (28%) patients developed an IgG level <5g/l in the induction phase.

Conclusion:

Data from the first phase of RITAZAREM, the largest reported cohort of patients with relapsing AAV, demonstrates that rituximab, in conjunction with glucocorticoids, is highly effective at re-inducing remission in patients with AAV who have relapsed, with an acceptable safety profile. The maintenance phase of the RITAZAREM trial is ongoing.