Short Course Rituximab Gives Long-lasting Results in ANCA Vasculitis

Daniel M. Keller
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A single 4-week course of rituximab was as effective as 18 months of standard therapy with daily oral cyclophosphamide (CyP) and azathioprine (AZA) for induction of remission and maintenance therapy of severe anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). The number, rate, and severity of adverse events was similar between the treatment groups, Cees Kallenberg, MD, PhD, professor of clinical immunology at University Medical Center Groningen in Groningen, Netherlands, reported at the 48th Congress of the European Renal Association-European Dialysis and Transplant Association in Prague in June. Rituximab is a monoclonal antibody directed against B lymphocytes.

AAV, an autoimmune disease, affects small blood vessels in multiple organ sites. It can attack the capillaries of the glomeruli, and glomerulonephritis is common in patients with AAV. Left untreated, AAV has a very poor prognosis.

The Rituximab in ANCA-Associated Vasculitis (RAVE) trial tested whether rituximab would be as effective as cyclophosphamide to induce remission of severe AAV. The primary endpoint in the trial was complete remission at 6 months, as measured by a Birmingham vasculitis activity score specific for Wegener’s granulomatosis (BVAS/WG) of 0 and no need for corticosteroids. (WG is one form of AAV.)

Eligible patients had active or severe AAV—either WG or microscopic polyangiitis. The trial design specified that at least half of the participants were to have WG, with a BVAS/WG score of 3 or greater, require cyclophosphamide, and be ANCA-positive at screening. All patients were followed for at least 18 months.

All 200 trial participants initially received 1 to 3 grams of methylprednisolone and were then randomly assigned to a rituximab group or to a CyP/AZA group. The rituximab group received rituximab infusions once weekly for 4 weeks, followed by CyP-placebo for 6 months and AZA-placebo for 12 more months.

The other group took oral CyP daily for 3 to 6 months and rituximab-placebo infusions. For those patients who achieved remission, CyP was replaced by AZA between months 3 and 6 and continued for the remainder of the 18 months. All patients in both groups received daily prednisone, which was tapered over 5.5 months.

If the assigned induction therapy failed, patients were crossed-over to the other treatment. Or if remission was lost for patients while they were taking AZA maintenance therapy, they then received rituximab in an open-label fashion. Analysis of results was on an intention-to-treat basis, meaning participants’ results were analyzed according to the original treatment group to which they were assigned.

The groups were well matched at baseline: two-thirds of the patients were positive for antibodies against proteinase 3 (PR3), one-third for antibodies against myeloperoxidase (MPO), one-quarter had microscopic polyangiitis, and three-quarters had WG. The rituximab (n=99) and CyP/AZA (n=98) groups had similar BVAS/WG scores (5.6–5.7) and scores on the physical and mental components of the SF-36 questionnaire, which profiles functional health and well-being.

Rituximab induced complete remissions at least as well as CyP/AZA

“B cells were undetectable after 2 infusions of rituximab and stayed undetectable during 6 months,” Kallenberg reported. CyP was also effective in reducing B cell counts out to 6 months. Results were the same for patients with either the MPO or PR3 form of ANCA.

At 6 months, “the primary endpoint was reached, which means that rituximab is not inferior to cyclophosphamide for induction of remission,” Kallenberg told the conference attendees. By that time, 64 percent of patients on rituximab and 53 percent receiving CyP had achieved remission (p=0.089).

The proportion of newly diagnosed patients experiencing a remission was about the same in the 2 groups (60 to 65 percent), but for patients with a severe disease flare, rituximab administration was associated with more responses (67 vs. 42 percent; p=0.013). MPO-ANCA patients did as well with either treatment, but for PR3-ANCA, more patients responded in the rituximab group (65 vs. 48 percent; p=0.04).

Short course rituximab effective for 18 months

At 12 and 18 months, fewer patients remained in each treatment arm, but overall, patients continued to respond to the therapies, and there was no significant difference in the proportions of remissions. At 18 months, the rituximab group had 39 out of 47 patients still in remission, compared to 32 out of 38 patients in the CyP/AZA group.

Similarly, the groups did not differ in the number of severe or limited disease flares at either time point. Most treatment failures were because of disease flare or the need for prednisone, usually for conditions other than AAV.

Flares were associated with the return of detectable B cells. Of the 76 patients randomized to rituximab who had achieved complete remission, 16 flares occurred after 6 months and were treated with open-label rituximab. “All these 16 severe flares occurred in the presence of detectable peripheral blood B lymphocytes,” Kallenberg reported.

Adverse events or serious adverse events occurred about equally in the 2 arms, with 2 deaths in each treatment group. Eighteen of 99 rituximab patients developed grade 3 infections, compared to 16 of 98 CyP/AZA patients.

Kallenberg summarized the trial results, saying that both treatments were associated with similar rates of complete remissions at 12 and 18 months, the times to complete remission and to first disease flare were similar, as were the rates of severe and limited flares. Severe flares rarely occurred in the absence of B cells. He concluded, “One course of 4 weekly infusions of rituximab without any maintenance treatments is as effective as 18 months treatment of standard therapy with daily oral cyclophosphamide followed by azathioprine.”

An important issue for the future will be to identify patients who will do best on rituximab as either front-line or rescue treatment, given the expense of the drug. And while the adverse event profile of the RAVE trial looks good, there is still some concern about the potential for infectious complications when rituximab is used.