DESTIN, FLA. – The optimal rituximab dose and dosing intervals for maintenance treatment of granulomatosis with polyangiitis and microscopic polyangiitis are unknown, but the available data do provide some guidance for rituximab use in these diseases, according to Dr. Gary Hoffman.
Findings from the Rituximab in ANCA-Associated Vasculitis (RAVE) trial, for example, suggest that rituximab is an alternative to cyclophosphamide-based therapy. Steroid-free remission induction at 6 months in 197 participants with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) was similar at 64% and 53% in those treated with rituximab or cyclophosphamide/azathioprine, respectively; and 86% of patients overall achieved remission at 6 months when steroid dose was not taken into consideration (N. Engl. J. Med. 2010;363:221-32), said Dr. Hoffman, chairman of the department of rheumatic and immunologic diseases at the Cleveland Clinic and professor of medicine at the Cleveland Clinic’s Lerner College of Medicine.
The recently published 18-month results of the RAVE study indicate that a single, 4-week course of rituximab is similar to a continuous immunosuppression regimen of cyclophosphamide followed by azathioprine in inducing and maintaining remission (N. Engl. J. Med. 2013 Aug. 1 [doi:10.1056/NEJMoa1213277]).
In a retrospective study of 65 patients with various types of antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis who experienced remission with either four once-weekly 375-mg treatments or two biweekly 1-g treatments of rituximab, 80% of patients relapsed within 2 years without maintenance therapy (Arthritis Rheum. 2009;60:2156-68).
"So that begs the question, what if you were to give rituximab repeatedly to prevent relapse?" Dr. Hoffman asked.
In another retrospective study of 73 patients with GPA or MPA, the relapse rate was 12% in 45 patients treated with rituximab every 6 months, compared with 73% in 28 patients treated as needed for relapse (Arthritis Rheum. 2012;64:3760-9).
The groups did not differ with respect to the rate of serious infections (18% and 14%, respectively) or mortality. The rate of malignancy was higher in the regular dosing group (4% vs. 0%) but the numbers were too small to conclude that treatment increases cancer risk, he said at the Congress of Clinical Rheumatology.
On the basis of these data, a large international, randomized controlled trial is now underway to better answer the question about repeat dosing, Dr. Hoffman noted.
In addition, interim findings from a French phase III study (MAINRITSAN), also presented at the annual meeting of the American College of Rheumatology last year as well as at the International Vasculitis and ANCA Workshop in Paris in April, show that a 500-mg dose of rituximab every 6 months is associated with a greater likelihood of staying in remission, compared with maintenance treatment with azathioprine at 2 mg/kg per day for 22 months.
The major relapse rate was 5% vs. 25%, the serious adverse event rate was 51% vs. 50%, and the mortality rate was 5% vs. 0% in the rituximab and azathioprine groups, respectively.
"Pretty compelling," Dr. Hoffman commented.
Based on all of these data, he said he uses rituximab for induction of remission in young women of reproductive age as an alternative to chronic cyclophosphamide, which can cause infertility.
"I don’t think we need to do that anymore, when we have an alternative effective agent," he said, adding: "I would apply the same rule to men who are planning a family, because the risk of infertility in men is also known to be significant."
Dr. Hoffman also uses rituximab to induce remission in patients in whom cyclophosphamide was used in the past for disease with severe relapses, and in those who have had a rituximab-mediated complete remission lasting at least 6 months if they experience relapse with critical organ system involvement for which cyclophosphamide would otherwise be considered.
"It’s the cumulative dose of cyclophosphamide that buys you that long-term toxicity, whether it’s infertility, marrow failure, increased risk of malignancy, cystitis, and so on. We try not to ever give people large cumulative doses of cyclophosphamide anymore," he said.
Patients in whom he would consider automatic maintenance rituximab include those previously treated with cyclophosphamide who have severe critical organ damage that is likely to lead to profound disability or death if the patient is exposed again to cyclophosphamide.
Conversely, he uses methotrexate or azathioprine, if well tolerated, for maintenance in those who have done extremely well on rituximab or cyclophosphamide, he said.
He typically tries to use cyclophosphamide for 3 months followed by the appropriate maintenance therapy. The available data suggest that once a patient is in remission and doing well, treatment should be maintained at a steady dose to prevent relapse unless toxicity mandates a change.