## 3 Therapeutic Management of EGPA
### Anti-IL-5-Targeted Therapies
#### 3.2.1. Mepolizumab  
To date, only mepolizumab has obtained indication for relapsing/remitting or refractory EGPA [20]. In fact, following reports of encouraging results primarily in small series [21; 22; 23; 24], a multicenter, double-blind, parallel-group, phase 3 randomized trial was eventually carried out to evaluate the efficacy and safety of mepolizumab in patients with refractory or relapsing EGPA on stable oral steroid treatment [25]. Relapses considered by the investigators included active vasculitis (Birmingham Vaculitis Activity Score [BVAS] >0 [26]), active asthma symptoms or signs, or active nasal or sinus disease, prompting  
Figure 3: Mechanism of action of IL-5-targeted monoclonal antibodies. (**a**) Blocking IL-5 by mepolizumab and reslizumab prevents eosinophil maturation, proliferation, recruitment, survival, priming, and activation (the latter shown here); (**b**) benzlizumab binds to the IL-5 receptor on eosinophils, thus inhibiting cytokine-mediated cell stimulation; in addition, the Fc fragment of benzlizumab is able to mediate eosinophil killing by NK cells through antibody-dependent cell cytotoxicity. an increase in the glucocorticoid dose, an initiation of or increase in immunosuppressive therapy, or hospitalization. Relapses could be of more than one type. The study confirmed the effectiveness of mepolizumab in maintaining remission throughout the study duration and in delaying major relapses when compared with placebo, with no significant between-group differences in adverse events [25]. Specifically, the study met the two primary endpoints, i.e., (1) the accrued weeks of remission (28% vs. 3%, mepolizumab vs. placebo, respectively, with the treated group showing 24+ weeks of remission) plus prednisone daily dose \(\leq\)4 mg over 52 weeks (44% successfully lowering the dose to \(\leq\)4 mg and 18% discontinuing prednisone vs. 7% and 3%, mepolizumab vs. placebo, respectively) and (2) the proportion of patients in remission at weeks 36 and 48 (32% vs. 3%, mepolizumab vs. placebo, respectively). Rates of relapses were as follows (mepolizumab vs. placebo, respectively): vasculitis 43% vs. 65%; asthma 37% vs. 60%; sinusitis 35% vs. 51%. Overall, 20% of the patients had a vasculitis relapse only, while 54% had a combined vasculitis and asthmatic/sinonasal relapse. Finally, a subgroup analysis revealed that patients with an absolute eosinophil count greater than 150 cells/mm\({}^{3}\) at baseline were more likely to experience a greater efficacy when compared with patients with a lower value of eosinophils, who did not actually obtain a significant benefit from treatment [25]. This observation clearly paves the way for a more effective selection of EGPA patients likely responding to IL-5 therapeutic inhibition in future studies. Therefore, based on these results, the Food and Drug Administration (FDA) licensed mepolizumab in the USA in 2017 as an add-on therapy with a steroid-sparing effect in adult patients with relapsing or refractory EGPA, at a dose of 300 mg subcutaneously (s.c.) every 4 weeks. Subsequent reports from real-world clinical practice confirmed the safety and efficacy of mepolizumab in small series of patients with relapsing or refractory EGPA. Specifically, [PERSON] et al. [27] treated 16 patients, all of them with comorbid asthma, for one year with the licensed 300 mg dose. At the 12-month assessment, mepolizumab treatment resulted in a decreased disease activity, a remission rate of 75%, a glucocorticoid-sparing effect, and a reduced number of patients using concomitant immunosuppressants. The retention rate was excellent (100% of patients). Respiratory symptoms improved immediately after starting mepolizumab, with only 2 patients still complaining of chest discomfort at the 12-month evaluation. Only three patients had an infection. The same authors also retrospectively compared the effectiveness of mepolizumab (300 mg/monthly) with i.v. cyclophosphamide pulse therapy for remission induction in EGPA patients [28].