Has anyone found ones for two dosage protocol? This sounds pretty much by the book approach my doctors used for me in 2010. I wonder if the protocol has changed some since?
Rituximab in Granulomatosis with Polyangiitis (Wegener's) and Microscopic Polyangiitis
MAY 6, 2011
On April 19, 2011 the FDA approved rituximab (Rituxan) combined with glucocorticoids for the treatment of adult patients with granulomatosis with polyangiitis (GPA; Wegener’s granulomatosis) or microscopic polyangiitis (MPA). This new indication for rituximab provided the first ever FDA-approved therapy for these two diseases and the first alternative to cyclophosphamide (CYC) for the treatment of severe disease in almost 40 years.
The combination of CYC and glucocorticoids was introduced for the treatment of GPA in 1973 and has been the foundation of therapy since that time. While it has been proven to prolong survival and induce disease remission, this regimen is associated with substantial toxicity and does not prevent relapse. Rituximab, a chimeric anti-CD20 monoclonal antibody previously approved in 1997 for non-Hodgkin's lymphoma and in 2006 for rheumatoid arthritis had shown promise as a remission-induction agent in GPA/MPA from uncontrolled studies. This evidence supported the conduct of a randomized controlled trial comparing rituximab to CYC (the Rituximab in Antineutrophil Cytoplasmic Antibody (ANCA)-Associated Vasculitis trial, the RAVE trial). This trial was designed as a pivotal trial and the results formed the basis of the FDA approval of rituximab for the treatment of patients with GPA (Wegener’s granulomatosis) or MPA.
Clinical Trial Results:
197 patients with active severe GPA or MPA were treated in a randomized, double-blind, double-dummy, active controlled, non-inferiority study. Patients were randomized in a 1:1 ratio to receive either rituximab 375 mg/M2 once weekly for 4 weeks or oral CYC 2 mg/kg daily for 3 to 6 months. Patients in both arms received 1000 mg of intravenous (IV) methylprednisolone per day for 1 to 3 days followed by oral prednisone (1 mg/kg/day, not exceeding 80 mg/day) with pre-specified tapering. Once remission was achieved or at the end of the 6 month remission induction period, the CYC group received azathioprine to maintain remission. The rituximab group did not receive additional therapy to maintain remission.
The primary endpoint was a Birmingham Vasculitis Activity Score for Wegener’s granulomatosis (BVAS/WG) of 0 and prednisone dose =0 at 6 months. 63 patients who received rituximab (64%) reached the primary endpoint as compared with 52 (53%) in the CYC group, which met the criterion for non-inferiority (P< 0.001). Of those who entered the trial with relapsing disease, rituximab was more efficacious than CYC with 34 of 51 (67%) in the rituximab group reaching the primary endpoint as compared to 21 of 50 in the CYC arm (42%)(p=0.01).
Limitations of these data include:
- The duration of follow-up has thus far been insufficient to determine relapse rate, although 16 severe relapses (6 in the rituximab group) had occurred by the time of publication.
- As patients with a serum creatinine of > 4.0 mg/dL or respiratory insufficiency requiring ventilator support were excluded, there are insufficient data to determine the comparative efficacy of CYC versus rituximab in the most fulminantly ill patients.
- This trial enrolled only patients with severe disease who were ANCA-positive and thus it is unclear whether these results are generalizable to those who are ANCA-negative or have mild disease.
- The primary endpoint focused on remission induction and did not address the question of retreatment with rituximab.
Safety:
There were no significant differences between the CYC and rituximab groups in the number of total adverse events, serious adverse events, or non-disease-related events. This may have been influenced by the inclusion of disease and treatment related complications, including those related to glucocorticoids, the short study duration of 6 months during which time CYC toxicity might not have emerged, the limited duration of CYC exposure consistent with past studies of changing from CYC to azathioprine within 3-6 months, and a rigorous schedule of blood count monitoring to prevent CYC-induced leucopenia.
Serious infections (> grade 3) occurred equally in each group. The most common infections in the rituximab-treated patients were upper respiratory tract and urinary tract infections, and herpes zoster. Among patients with exposure to rituximab during the trial, malignant conditions developed in 5% as compared to 1% of those without exposure (p=0.26). Three patients (2%) died during the trial (1 received rituximab).
Practical issues:
The approved rituximab dosage for GPA/MPA is 375mg/M2 by IV infusion once weekly for 4 weeks. Glucocorticoids given as methylprednisolone 1000mg IV per day for 1-3 days followed by prednisone 1 mg/kg/day with subsequent taper are recommended for severe vasculitis. Pneumocystis prophylaxis is recommended during treatment and for at least 6 months following the last rituximab infusion.
The Bottom Line:
Rituximab is the first ever FDA approved treatment for GPA/MPA and represents an alternative to CYC for remission induction of severe disease.
- Rituximab combined with glucocorticoids is as effective as CYC to induce remission of severe GPA/MPA.
- The rate of adverse events in patients with severe GPA/MPA who receive rituximab and glucocorticoids remains high.
- Use of concomitant or sequential immunosuppressives other than glucocorticoids given with rituximab has not been adequately studied to determine safety or efficacy.
- There are insufficient data to determine the comparative efficacy of CYC versus rituximab in fulminantly ill patients (creatinine > 4.0 mg/dL, requirement of mechanical ventilation).
- Further studies are needed to determine the rate of relapse, the long term side effect profile, and the safety and efficacy of subsequent courses of rituximab versus maintenance therapies with other conventional immunosuppressive agents (e.g., azathioprine or methotrexate) in GPA/MPA.
- Fauci AS, Wolff SM. Wegener’s granulomatosis: studies in 18 patients and a review of the literature. Medicine (Baltimore) 1973, 52:535-561.
- Hoffman GS, et al. Wegener granulomatosis: an analysis of 158 patients. Ann Intern Med 1992, 116:488-498.
- Stone JH, et al. Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N Engl J Med 2010, 363:221-232.
Hotline author: Carol A. Langford, MD MHS, Director Center for Vasculitis Care and Research, Cleveland Clinic
Hotline Editors: Arthur Kavanaugh, MD, and Eric Ruderman, MD
Disclosures: Dr. Langford is an investigator member of the Rituximab in ANCA-Associated Vasculitis-Immune Tolerance Network (RAVE-ITN) Research Group. Dr. Ruderman and Dr. Kavanaugh have nothing to disclose.
In addition to review by the editors, this Hotline has been reviewed by all members of the ACR Executive Committee, Communications and Marketing Committee and Drug Safety Committee.
The ACR Hotline is provided by the ACR Communications and Marketing Committee as a service to members. This Hotline reflects the views of the author(s) and does not represent a position statement of the American College of Rheumatology.
Bookmarks