Treatments for severe ANCA-associated vasculitis show equal efficacy

For patients with severe antineutrophil cytoplasmic antibody–associated vasculitis, a single 4-week course of rituximab proved to be noninferior to conventional continuous immunosuppression at inducing and maintaining remission for 18 months, according to a report published Aug. 1 in the New England Journal of Medicine.

There were no differences between the two regimens in overall adverse events, except that patients who received rituximab for 1 month had fewer cases of leukopenia and pneumonia than did those who received a standard regimen of cyclophosphamide and azathioprine for 18 months, said Dr. Ulrich Specks of the Mayo Clinic Foundation, Rochester, Minn., and his associates in the RAVE-ITN (Rituximab in ANCA-Associated Vasculitis–Immune Tolerance Network) Research Group.

"Rituximab effectively induced B-cell depletion in all patients, but nearly all the patients showed reconstitution of peripheral-blood B cells by 18 months," the researchers noted.

This reflects "the reality of this disease, which is that relapses are common when the effects of immunosuppressive therapy wear off." However, the results also "point the way to more effective, long-term disease control through intermittent retreatment," they said.

The researchers previously published the short-term (6-month) results of their randomized, double-blind, multicenter RAVE study (N. Engl. J. Med. 2010;363:221-32) and now report the long-term (18-month) results for the 197 patients in the study. They assigned 99 patients to receive an infusion of rituximab at 375 mg/m² of body surface area once a week for 4 weeks and a cyclophosphamide placebo followed by 17 months of a placebo, and 98 patients to receive cyclophosphamide at 2 mg/kg daily (adjusted for renal insufficiency) and infusions of a rituximab placebo for 3-6 months, depending on if and when remission was achieved, followed by azathioprine at 2 mg/kg for the balance of the 18-month treatment period. Patients stopped taking prednisone after 5.5 months if they were in remission.

A total of 64% of the rituximab group had a complete remission by 6 months, which was maintained in 48% at 12 months. The corresponding percentages for conventional immunosuppression were slightly lower at 53% at 6 months and 39% at 12 months.

At 18 months, complete remission was maintained in 39% of patients who had received rituximab and 33% of those who had received cyclophosphamide-azathioprine, which met the criterion for noninferiority but not for superiority, the investigators reported (N. Engl. J. Med. 2013 Aug. 1 [doi: 10.1056/NEJMoa1213277]).

There were no significant differences between the two study groups in any efficacy measure, including the duration of remission; the number, rate, and severity of relapses; or scores on measures of vasculitis damage and quality of life.

Rituximab was found superior to conventional immunosuppression in the subgroup of 101 patients who had relapsing rather than new-onset disease at enrollment in the study. In that subgroup, patients who received rituximab showed complete remission rates of 67% at 6 months, 49% at 12 months, and 37% at 18 months. The corresponding rates were significantly lower with cyclophosphamide-azathioprine at 42%, 24%, and 20%, respectively.

Rituximab’s efficacy was comparable to that of conventional immunosuppression in another important subgroup of patients: those who had major renal disease at baseline. Among the 102 patients with major renal disease at baseline, remission occurred at some point before 18 months in 75% with rituximab and 76% with cyclophosphamide-azathioprine, and the magnitude of improvement in mean estimated creatinine clearance levels was judged to be comparable between the groups.

Also at 18 months, there were no significant differences between the two study groups in the numbers or rates of total adverse events, serious adverse events, or non–disease-related adverse events. There were two deaths in each group.

In particular, the study groups had similar rates of infections of grade 3 or higher and similar serum levels of IgG, IgA, and IgM. No additional cancers developed during follow-up in either group.

However, patients who received rituximab had fewer episodes of moderate or severe leukopenia (5 vs. 23 cases) and required fewer dose adjustments or interruptions.

This study was supported by the National Institute of Allergy and Infectious Diseases, the Juvenile Diabetes Research Foundation, Genentech, Biogen Idec, the National Center for Research Resources, the National Institute of Arthritis and Musculoskeletal and Skin Diseases, and the Arthritis Foundation. Dr. Specks reported receiving an honorarium and travel reimbursement from Roche (Genentech is a member of the Roche Group), and some of his associates reported ties to Genentech, Biogen Idec, and other companies.

For patients with severe antineutrophil cytoplasmic antibody–associated vasculitis, a single 4-week course of rituximab proved to be noninferior to conventional continuous immunosuppression at inducing and maintaining remission for 18 months, according to a report published Aug. 1 in the New England Journal of Medicine.

There were no differences between the two regimens in overall adverse events, except that patients who received rituximab for 1 month had fewer cases of leukopenia and pneumonia than did those who received a standard regimen of cyclophosphamide and azathioprine for 18 months, said Dr. Ulrich Specks of the Mayo Clinic Foundation, Rochester, Minn., and his associates in the RAVE-ITN (Rituximab in ANCA-Associated Vasculitis–Immune Tolerance Network) Research Group.

"Rituximab effectively induced B-cell depletion in all patients, but nearly all the patients showed reconstitution of peripheral-blood B cells by 18 months," the researchers noted.

This reflects "the reality of this disease, which is that relapses are common when the effects of immunosuppressive therapy wear off." However, the results also "point the way to more effective, long-term disease control through intermittent retreatment," they said.

The researchers previously published the short-term (6-month) results of their randomized, double-blind, multicenter RAVE study (N. Engl. J. Med. 2010;363:221-32) and now report the long-term (18-month) results for the 197 patients in the study. They assigned 99 patients to receive an infusion of rituximab at 375 mg/m² of body surface area once a week for 4 weeks and a cyclophosphamide placebo followed by 17 months of a placebo, and 98 patients to receive cyclophosphamide at 2 mg/kg daily (adjusted for renal insufficiency) and infusions of a rituximab placebo for 3-6 months, depending on if and when remission was achieved, followed by azathioprine at 2 mg/kg for the balance of the 18-month treatment period. Patients stopped taking prednisone after 5.5 months if they were in remission.

A total of 64% of the rituximab group had a complete remission by 6 months, which was maintained in 48% at 12 months. The corresponding percentages for conventional immunosuppression were slightly lower at 53% at 6 months and 39% at 12 months.

At 18 months, complete remission was maintained in 39% of patients who had received rituximab and 33% of those who had received cyclophosphamide-azathioprine, which met the criterion for noninferiority but not for superiority, the investigators reported (N. Engl. J. Med. 2013 Aug. 1 [doi: 10.1056/NEJMoa1213277]).

There were no significant differences between the two study groups in any efficacy measure, including the duration of remission; the number, rate, and severity of relapses; or scores on measures of vasculitis damage and quality of life.

Rituximab was found superior to conventional immunosuppression in the subgroup of 101 patients who had relapsing rather than new-onset disease at enrollment in the study. In that subgroup, patients who received rituximab showed complete remission rates of 67% at 6 months, 49% at 12 months, and 37% at 18 months. The corresponding rates were significantly lower with cyclophosphamide-azathioprine at 42%, 24%, and 20%, respectively.

Rituximab’s efficacy was comparable to that of conventional immunosuppression in another important subgroup of patients: those who had major renal disease at baseline. Among the 102 patients with major renal disease at baseline, remission occurred at some point before 18 months in 75% with rituximab and 76% with cyclophosphamide-azathioprine, and the magnitude of improvement in mean estimated creatinine clearance levels was judged to be comparable between the groups.

Also at 18 months, there were no significant differences between the two study groups in the numbers or rates of total adverse events, serious adverse events, or non–disease-related adverse events. There were two deaths in each group.

In particular, the study groups had similar rates of infections of grade 3 or higher and similar serum levels of IgG, IgA, and IgM. No additional cancers developed during follow-up in either group.

However, patients who received rituximab had fewer episodes of moderate or severe leukopenia (5 vs. 23 cases) and required fewer dose adjustments or interruptions.

This study was supported by the National Institute of Allergy and Infectious Diseases, the Juvenile Diabetes Research Foundation, Genentech, Biogen Idec, the National Center for Research Resources, the National Institute of Arthritis and Musculoskeletal and Skin Diseases, and the Arthritis Foundation. Dr. Specks reported receiving an honorarium and travel reimbursement from Roche (Genentech is a member of the Roche Group), and some of his associates reported ties to Genentech, Biogen Idec, and other companies.

For patients with severe antineutrophil cytoplasmic antibody–associated vasculitis, a single 4-week course of rituximab proved to be noninferior to conventional continuous immunosuppression at inducing and maintaining remission for 18 months, according to a report published Aug. 1 in the New England Journal of Medicine.

There were no differences between the two regimens in overall adverse events, except that patients who received rituximab for 1 month had fewer cases of leukopenia and pneumonia than did those who received a standard regimen of cyclophosphamide and azathioprine for 18 months, said Dr. Ulrich Specks of the Mayo Clinic Foundation, Rochester, Minn., and his associates in the RAVE-ITN (Rituximab in ANCA-Associated Vasculitis–Immune Tolerance Network) Research Group.

"Rituximab effectively induced B-cell depletion in all patients, but nearly all the patients showed reconstitution of peripheral-blood B cells by 18 months," the researchers noted.

This reflects "the reality of this disease, which is that relapses are common when the effects of immunosuppressive therapy wear off." However, the results also "point the way to more effective, long-term disease control through intermittent retreatment," they said.

The researchers previously published the short-term (6-month) results of their randomized, double-blind, multicenter RAVE study (N. Engl. J. Med. 2010;363:221-32) and now report the long-term (18-month) results for the 197 patients in the study. They assigned 99 patients to receive an infusion of rituximab at 375 mg/m² of body surface area once a week for 4 weeks and a cyclophosphamide placebo followed by 17 months of a placebo, and 98 patients to receive cyclophosphamide at 2 mg/kg daily (adjusted for renal insufficiency) and infusions of a rituximab placebo for 3-6 months, depending on if and when remission was achieved, followed by azathioprine at 2 mg/kg for the balance of the 18-month treatment period. Patients stopped taking prednisone after 5.5 months if they were in remission.

A total of 64% of the rituximab group had a complete remission by 6 months, which was maintained in 48% at 12 months. The corresponding percentages for conventional immunosuppression were slightly lower at 53% at 6 months and 39% at 12 months.

At 18 months, complete remission was maintained in 39% of patients who had received rituximab and 33% of those who had received cyclophosphamide-azathioprine, which met the criterion for noninferiority but not for superiority, the investigators reported (N. Engl. J. Med. 2013 Aug. 1 [doi: 10.1056/NEJMoa1213277]).

There were no significant differences between the two study groups in any efficacy measure, including the duration of remission; the number, rate, and severity of relapses; or scores on measures of vasculitis damage and quality of life.

Rituximab was found superior to conventional immunosuppression in the subgroup of 101 patients who had relapsing rather than new-onset disease at enrollment in the study. In that subgroup, patients who received rituximab showed complete remission rates of 67% at 6 months, 49% at 12 months, and 37% at 18 months. The corresponding rates were significantly lower with cyclophosphamide-azathioprine at 42%, 24%, and 20%, respectively.

Rituximab’s efficacy was comparable to that of conventional immunosuppression in another important subgroup of patients: those who had major renal disease at baseline. Among the 102 patients with major renal disease at baseline, remission occurred at some point before 18 months in 75% with rituximab and 76% with cyclophosphamide-azathioprine, and the magnitude of improvement in mean estimated creatinine clearance levels was judged to be comparable between the groups.

Also at 18 months, there were no significant differences between the two study groups in the numbers or rates of total adverse events, serious adverse events, or non–disease-related adverse events. There were two deaths in each group.

In particular, the study groups had similar rates of infections of grade 3 or higher and similar serum levels of IgG, IgA, and IgM. No additional cancers developed during follow-up in either group.

However, patients who received rituximab had fewer episodes of moderate or severe leukopenia (5 vs. 23 cases) and required fewer dose adjustments or interruptions.

This study was supported by the National Institute of Allergy and Infectious Diseases, the Juvenile Diabetes Research Foundation, Genentech, Biogen Idec, the National Center for Research Resources, the National Institute of Arthritis and Musculoskeletal and Skin Diseases, and the Arthritis Foundation. Dr. Specks reported receiving an honorarium and travel reimbursement from Roche (Genentech is a member of the Roche Group), and some of his associates reported ties to Genentech, Biogen Idec, and other companies.