Background/Purpose: The MANDARA trial (NCT04157348) demonstrated that after two years of anti-interleukin-5/receptor (anti-IL-5/R) therapy over 60% of patients with relapsing or refractory eosinophilic granulomatosis with polyangiitis (EGPA) without active organ- or life-threatening disease manifestations achieved remission, and more than 40% discontinued oral glucocorticoids (OGCs). The clinical presentation of EGPA may vary with anti-neutrophil cytoplasmic antibodies (ANCA) status. ANCA-positive patients may exhibit more “vasculitic” features, such as glomerulonephritis, while ANCA-negative patients may tend toward manifestations thought driven by eosinophilic inflammation, such as cardiomyopathy, although there is some overlap of symptoms. Consequently, both ANCA-positive and ANCA-negative patients with EGPA can present with a range of disease manifestations. This analysis evaluated the efficacy of anti-IL-5/R therapies in patients with EGPA according to ANCA status over the combined double-blind (DB) and first year of the ongoing open-label extension (OLE) period in MANDARA.

Methods: Following the 52-week DB period, eligible patients entered the OLE, where they either continued benralizumab or switched from mepolizumab to benralizumab. Remission was defined as Birmingham Vasculitis Activity Score (BVAS) = 0 and oral glucocorticoid (OGC) ≤4 mg/day. The OGC-sparing capacity of the anti-IL-5/R therapies was also assessed, as was disease activity (BVAS and Vasculitis Damage Index [VDI]). Data from both study phases were pooled to evaluate remission and OGC reduction over two years (up to Week 104) according to patients’ ANCA status. ANCA-positive patients were defined as those positive for myeloperoxidase (MPO)-ANCA and/or proteinase 3 (PR3)-ANCA at study screening or with a historical record of ANCA-positivity.

Results: Of the 128 patients that entered the OLE 35 (27.3%) were ANCA-positive and 93 (72.7%) were ANCA-negative at the beginning of the double-blind period of the study (baseline). BVAS and VDI scores were similar between the ANCA-positive and -negative groups at baseline, whereas the proportion of patients who had an ACQ-6 score ≥1.5 was higher, and the time since diagnosis was shorter in the ANCA-positive versus -negative group (Table 1). At Week 104, the proportion of patients achieving remission was similar regardless of ANCA status (ANCA-positive: 65.7%, ANCA-negative: 64.5%; difference: 3.18; 95% confidence interval [CI]: –15.19, 21.56, p=0.7341) (Figure 1). During Weeks 101 through 104, 65.7% and 69.9% in the ANCA-positive and -negative groups, respectively, had a reduction in OGC dose of ≥50% from baseline, and 45.7% versus 43.0%, respectively, were fully withdrawn from OGCs. The proportion of patients with ≥1 relapse was similar between ANCA-positive (37.1%) and ANCA-negative groups (44.1%). Most patients had ≤3 or no relapses (ANCA-positive: 97.1%; ANCA-negative: 93.5%).

Conclusion: This analysis demonstrated that in patients without active organ- or life-threatening EGPA, historic or baseline ANCA status is not associated with response to treatment with anti-IL-5/R therapies.

Figure 1. Efficacy endpoints by ANCA status

Table 1. Baseline characteristics by ANCA status of patients with eosinophilic granulomatosis with polyangiitis in the MANDARA open-label extension phase

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/two-year-efficacy-of-anti-interleukin-5-receptor-therapies-according-to-anti-neutrophil-cytoplasmic-antibodies-status-in-patients-with-eosinophilic-granulomatosis-with-polyangiitis/