Rituximab treatment seen to lower relapse risk in AAV patients in trial

Therapy works better than daily oral azathioprine in relapsing disease

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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People with relapsing ANCA-associated vasculitis (AAV) who achieved remission with rituximab and glucocorticoids have less than half the risk of experiencing a new relapse if they continue on rituximab treatment than if they start daily oral azathioprine.

That’s according to the full results of the Phase 3 RITAZAREM clinical trial (NCT01697267), whose initial data — which had suggested similar findings — were originally shared at a 2019 meeting.

“These data extend previous reports on the efficacy of rituximab for induction of remission for relapsing disease and confirms the place of rituximab as the standard of care for maintenance therapy,” the researchers wrote.

The study, “Rituximab versus azathioprine for maintenance of remission for patients with ANCA-associated vasculitis and relapsing disease: an international randomized controlled trial,” was published in the Annals of the Rheumatic Diseases.

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Rituximab Treatment Effective in Disease Remission in AAV: Study

Trial compared rituximab versus azathioprine

AAV occurs when self-reactive antibodies prompt a type of immune cells called neutrophils to turn against the lining of healthy blood vessels, causing inflammation and damage. This results in various symptoms that can occur anywhere throughout the body.

Rituximab, sold as Rituxan in the U.S., MabThera in Europe, and also available as biosimilars, is an antibody that reduces the number of B-cells, a type of immune cells that make antibodies, including those that drive AAV.

It is approved both as an induction and maintenance therapy for the most common types of AAV — granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA). However, “the optimal strategy to maintain remission following induction of remission with rituximab, especially for treatment of relapse, remains unclear,” the researchers wrote.

The Phase 3 RITAZAREM trial, launched in 2018, assessed how well repeat-dose rituximab prevented relapses versus daily oral azathioprine. The study involved 170 AAV patients — 86 females and 84 males — who were brought into remission with rituximab and glucocorticoids.

The participants were recruited from seven different countries between April 2013 and November 2016. Their mean age was 57.8 years, they had a diagnosis of either GPA or MPA, and they had lived with the disease for a mean of seven years.

Four months after they began induction therapy, the patients were randomly assigned to receive maintenance therapy with either 1,000 mg of rituximab, given every four months for a total of five doses, or 2 mg/kg of azathioprine, taken daily for up to two years.

All patients remained on a 10 mg/day dose or less of the glucocorticoid prednisolone during maintenance therapy. This dose was tapered over time until suspension at month 20 (nearly two years), except if patients experienced a relapse.

The results showed that while on maintenance therapy, rituximab-treated patients had a 65% lower risk of experiencing a new relapse than those on azathioprine. At two years, 85% of patients on rituximab were free of relapses compared with 61% of those on azathioprine.

After maintenance therapy, patients were taken off rituximab or azathioprine and followed for up to two years. During follow-up, patients in the rituximab group had a 55% lower risk of experiencing a new relapse, with half continuing to be in remission at four years versus 22% of those in the azathioprine group.

During the two periods combined, the risk of relapse was 59% lower among rituximab-treated patients than among those on azathioprine.

However, 15% of patients still experienced relapses while on rituximab maintenance treatment, and relapse risk persisted in the follow-up phase, when patients were off the therapy.

During maintenance therapy and follow-up combined, 38 rituximab-treated patients (45%) experienced 52 relapses — 11 major and 41 minor. Meanwhile, 60 azathioprine-treated patients (71%) experienced 89 relapses, 28 of which were major and 61 minor.

Also, the median cumulative dose of prednisolone during the maintenance phase was comparable between groups, but a smaller proportion of patients in the rituximab group were still receiving glucocorticoids at two years (29% vs. 46%).

These data extend previous reports on the efficacy of rituximab for induction of remission for relapsing disease and confirms the place of rituximab as the standard of care for maintenance therapy.

While there were no new safety concerns, nearly one-quarter (22%) of patients on rituximab experienced at least one serious side effect versus 31 (36%) of azathioprine-treated patients.

There were no group differences in the rates of infection and hypogammaglobulinemia, or abnormally low levels of infection-fighting antibodies — two known side effects of rituximab.

These findings highlight that rituximab is superior to azathioprine at maintaining remission in people with relapsing AAV. However, “despite a higher dose rituximab regimen than previously studied, relapses still occurred, and this, together with the increased risk of relapse after stopping rituximab, and the associated safety risks, illustrate the need for newer therapeutic agents for AAV,” the team wrote.

“Future treatment strategies for AAV may necessitate a more individualized approach, taking into account the risk of relapse balanced against the risk of adverse events with extended treatment,” they added.

The trial was funded by Arthritis Research UK, the U.S. National Institutes of Health, and Roche and its subsidiary Genentech, which market Rituxan and MabThera.