New analysis identifies phase-specific relapse risks in AAV treatment
Study finds relapse predictors differ during maintenance, off-treatment phases
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Risk factors for relapse in ANCA-associated vasculitis (AAV) appear to differ depending on treatment phase, with higher levels of inflammation and immune activity linked to a greater risk of relapse after maintenance therapy is stopped.
That’s according to a new, non-prespecified analysis of data from the Phase 3 RITAZAREM trial (NCT01697267), which compared rituximab with the immunosuppressant azathioprine in more than 100 people with relapsing AAV.
“Monitoring markers of inflammation and immune reconstitution may identify patients at risk for relapse, particularly after treatment withdrawal,” the researchers wrote.
The findings were detailed in the study “Risk factors for relapse in ANCA-associated vasculitis among patients with relapse after induction of remission with rituximab,” which was published in Arthritis & Rheumatology.
Understanding AAV and why relapse remains a concern
AAV refers to a group of diseases marked by inflammation and damage to small blood vessels, which can lead to injury in multiple organs. Most cases involve the production of self-reactive antibodies known as ANCAs.
Rituximab, marketed as Rituxan and available as biosimilars, is approved — when used with corticosteroids — to both induce and maintain remission in people with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA), the most common types of AAV. However, relapses remain common, particularly among patients with a history of prior relapse.
In the RITAZAREM study, rituximab was more effective than azathioprine at maintaining remission in people with relapsing AAV who had first achieved remission using rituximab and standard corticosteroids. Compared with azathioprine, rituximab reduced the risk of relapse by more than half. The trial was sponsored by Genentech, a member of the Roche Group, which co-markets Rituxan in the U.S. with Biogen.
The current analysis, conducted after completion of the clinical trial, examined why some patients relapse after their disease is controlled with rituximab and maintenance treatment is later withdrawn. Identifying these risk factors may help clinicians determine which patients need closer monitoring or longer-term treatment.
RITAZAREM trial data used to examine relapse risk
The analysis included data from 170 participants in the RITAZAREM trial. At the start of the study, participants had a median age of 59 and had been living with AAV for a median of five years.
Participants who achieved remission four months after induction treatment with rituximab plus corticosteroids were randomly assigned to receive maintenance treatment with either rituximab or azathioprine for up to two years. After maintenance therapy ended, participants were followed for an additional two years without treatment.
Relapses were evaluated during two periods: while patients were receiving maintenance treatment and after all treatment had stopped. In total, 99 relapses were recorded — 46 during the maintenance phase and 53 during the off-treatment phase. The likelihood of relapse increased over time during follow-up.
Statistical analyses adjusted for potential influencing factors revealed that during the maintenance phase, having muscle or joint involvement at baseline was significantly associated with a nearly three times higher chance of relapse by the next study visit. Higher patient global assessment scores, reflecting greater patient-reported disease activity, during follow-up were significantly linked to a 10% higher risk of relapse.
By contrast, treatment with rituximab was the strongest protective factor during maintenance therapy, being associated with about a 70% lower chance of relapse.
During the off-treatment phase, higher blood levels of inflammatory markers, including C-reactive protein and immunoglobulin A — as well as larger increases over time in inflammatory marker levels, platelet counts, and immune cell counts — were significantly linked to a higher likelihood of relapse by the next visit.
Testing positive for ANCAs, converting from ANCA-negative to ANCA-positive status, and the presence of CD19-positive B-cells — the antibody-producing immune cells targeted by rituximab — were each significantly linked to a two- to three-times higher risk of relapse.
Different predictors emerge after treatment ends
In analyses adjusted for potential influencing factors, only rituximab treatment and a higher percent change in immunoglobulin A, platelets, and immune cells during follow-up remained independent risk factors of relapse in the off-treatment phase.
“While not all of these factors were retained in the final … model, likely in part due to the inter-relatedness of these measures as markers of inflammation and immune activity and a lack of granular assessments of B-cell populations and ANCA levels over time, these findings provide further support that markers of immune reconstitution and inflammation are associated with short-term relapse risk,” the team wrote.
Overall, the analysis showed that relapse risk factors in AAV differ depending on whether patients are still on maintenance treatment or discontinued treatment.
“This study identified that among patients with AAV, markers of inflammation and immune reconstitution are associated with disease relapse within 3-6 months during the period of observation off treatment after completion of a regimen to maintain remission,” the researchers wrote. “These data support monitoring of these laboratory tests at regular intervals to help identify patients with AAV at risk for relapse after withdrawal of treatment.”
