Boon and bane of remission induction with rituximab in ANCA-associated vasculitis: lessons learned from the RAVE-ITN follow-up study

*Corresponding author: Dr. Andreas Kronbichler, Medical University Innsbruck, Department of Internal Medicine IV, Nephrology and Hypertension, Anichstraße 35, 6020 Innsbruck, Austria. E-mail: [email protected] Randomized controlled trials have revolutionised the treatment options in small vessel vasculitis. From large genome wide association studies we have learned that granulomatosis with polyangiitis (Wegener’s) and microscopic polyangiitis are distinct diseases (1). These findings have not been introduced in the design of newer clinical trials examining the efficacy of immunosuppressive therapies. Rituximab (RTX), a monoclonal chimeric antibody targeting CD20 bearing B-cells, has been approved by the FDA and the EMEA for induction of remission in ANCA-associated vasculitis. The trials leading to the approval have been published with the aim to show non-inferiority of RTX when compared to cyclophosphamide (CYC). Both studies, the RAVE-ITN trial (2) and the RITUXVAS trial (3), included a divergent study population. In the RAVE-ITN trial patients had a well preserved renal function at the time of study enrolment (2), whereas patients in the RITUXVAS trial had severe renal insufficiency (3). Whereas RAVE-ITN recruited nearly 100 patients in each treatment arm (2), RITUXVAS assigned 33 patients to the treatment arm and 11 patients to the control arm (3). In RITUXVAS, patients received an initial course of CYC prior to receiving RTX infusions (3). Both trials reported distinct remission rates. In the RAVE-ITN trial, remission after six months of follow-up could be achieved in 64% of patients treated with RTX, while 53% of the patients receiving CYC were in remission. The primary efficacy end point was defined as a disease activity consistent with remission, which is defined as a BVAS [Birmingham vasculitis activity score (4)] of zero as well as a completion of prednisone tapering (2). RITUXVAS assessed prolonged remission rates at month 12 of follow up. There was no significant difference in the remission rate between both groups (76% in the RTX group and 82% in the CYC group) (3). In the RAVE-ITN trial subgroup analysis revealed that patients in the control group with newly diagnosed ANCA-associated vasculitis achieved higher remission rates than patients with RTX therapy (63% vs. 61%), although these differences did not reach significance (2). One has to emphasize the fact that a large proportion of patients with relapsing disease were included in the RAVE-ITN trial. Of these, a majority of patients in the control group received CYC to induce remission before. In the interpretation of these data, we have to be aware that these patients have failed to achieve a sustained remission following induction therapy. Thus, inclusion of these patients may have led to a selection bias. The RAVE-ITN study population was further followed over a period of 18 months. The results revealed that a single course of RTX along with a 6 month regimen of steroids is as effective as CYC followed by azathioprine (AZA, standard of care) for the induction and maintenance of remission in ANCA-associated vasculitis. Remission could be maintained in 39% of the patients receiving RTX and in 33% of patients with CYC followed by AZA (5). These results are somehow surprising and need to be http://journalrip.com DOI: 10.12861/jrip.2014.05