FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Infusions of rituximab proved superior to the standard of care, daily oral azathioprine, at maintaining remission of ANCA-associated vasculitis in a randomized trial.
At final follow-up after 28 months, the rate of major relapse was 5% for rituximab, compared with 29% for standard azathioprine maintenance. Rates of severe adverse events were similar in the two study groups, Dr. Loic Guillevin of Hôpital Cochin, Paris, and his associates reported in the New England Journal of Medicine.
Despite the decrease in major relapse rate with rituximab and no increase in the rate of severe adverse events, Dr. David Jayne wrote in an editorial accompanying the report that these still remain worrisome, and patients will still require prolonged observation after rituximab withdrawal. The duration of follow-up after the last rituximab dose was short in this study at only 10 months, and previous research indicates that at least half of patients will relapse after a 2-year maintenance course of the drug. Thus, the long-term risk of relapse also requires prolonged patient observation, said Dr. Jayne of the University of Cambridge (England) ( N. Engl. J. Med. 2014;371:1839-40 ).
Dr. Guillevin and his colleagues performed the trial because maintenance of remission is still “a major challenge” in these patients, and serial rituximab infusions have not been thoroughly assessed in prospective studies. They chose to study a relatively low 500-mg dose of the drug. That dose is “lower than that used for induction or maintenance in other conditions, such as rheumatoid arthritis. We opted for this dose because enrolled patients were in remission – that is, already B-cell depleted – and with the aim of limiting the risk of infection,” they wrote.
The study participants were 115 adults who had granulomatosis with polyangiitis (87 patients), microscopic polyangiitis (23 patients), or renal-limited antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (5 patients) and were in complete remission after combined therapy using glucocorticoids plus pulsed cyclophosphamide. They were randomly assigned to receive either the experimental therapy of rituximab infusions at days 0 and 14 and at 6-month intervals for 18 months (57 patients) or the control therapy of azathioprine at 2 mg/kg per day for 12 months, then 1.5 mg/kg per day for 6 months, and finally 1 mg/kg per day for 4 months (58 patients). All patients also further tapered their prednisone dose, which was then kept low at about 5 mg/day for 18 months.
These participants were followed until month 28, which was 10 months after completing rituximab infusions or 6 months after completing oral azathioprine. The primary endpoint of the study – the percentage of patients who experienced a major relapse until the end of follow-up – was 5% for rituximab, which was significantly better than the 29% in the control group (hazard ratio, 6.61; 95% confidence interval, 1.56-27.96; P = .002). The number needed to treat with rituximab rather than azathioprine to avoid a major relapse was only 4, Dr. Guillevin and his associates reported ( N. Engl. J. Med. 2014;371:1771-80 ).
Six patients (11%) who received rituximab and nine (16%) who received azathioprine had minor relapses.
There were no significant differences between the two groups in decreases in total immunoglobulin, IgG, or IgM levels. A total of 25 patients in each group developed at least one severe adverse event. Severe adverse infections developed in 11 patients who received rituximab (19%) and in 8 in the control group (14%). Cancers developed in one patient on rituximab and in two in the control group. There were two patient deaths, both in the control group: one from sepsis and one from pancreatic cancer.
This trial was supported by the French Ministry of Health. Hoffmann-La Roche provided rituximab for the study. Dr. Guillevin reported serving on an advisory board for GlaxoSmithKline and receiving lecture fees from Roche, Actelion, and other companies. His associates reported ties to numerous industry sources. Dr. Jayne reported ties to Sanofi/Genzyme, Roche/Genentech, and other companies.
