## 5 Discussion  
Although often limited by small sample sizes, short duration of the therapeutic interventions, the lack of double-blind placebo controls or other comparators, as well as the uncertainty about long-term adverse effects, particularly in case of complete eosinophil depletion, the evidence accumulated thus far appears to support the use of IL-5-targeted therapies in the treatment of EGPA-associated eosinophilic asthma, as well as for other significant disease manifestations. Currently, only prepolizumab may be used for in-label treatment of relapsing/remitting or refractory EGPA [20], while waiting for completion of ongoing studies or start of new investigations addressing the role of benzlizumab and reslizumab in EGPA management. Moreover, given the likely effectiveness of low-dose prepolizumab in the management of refractory/relapsing EGPA [30; 31; 32; 33; 34; 35; 36], studies are also warranted to assess whether 100 mg every 4 weeks may be used as a stable maintenance therapy in patients obtaining initial drug-induced remission. Comparison should be undertaken with the approved 300 mg dose every 28 days, considering as the main outcomes for lung involvement the rates of asthma exacerbations and the daily dose of maintenance oral steroids in the two patient groups. Reslizumab shares the same mechanism of action as prepolizumab, targeting IL-5 directly [18]. Since prepolizumab can only be prescribed in a fixed dose [20], reslizumab may provide an additional advantage due to the i.v. route of administration allowing for weight-based dose adjustments [38], which may be particularly useful in obese patients. Nevertheless, this potential advantage for dose adjustment needs confirmation through design of ad hoc studies, upon preliminary verification of differential responses to prepolizumab treatment between lean and obese EGPA patients. Finally, the ability of benzlizumab to completely deplete circulating eosinophils may theoretically suggest use of this drug in patients with exceedingly high peripheral eosinophils, as in case 2 reported above, or in patients failing prepolizumab (or reslizumab, in case of future indication for EGPA). Again, the hypothetical threshold of the circulating eosinophil count above which the fixed prepolizumab dose may be expected not to be satisfactorily effective needs to be determined through specific studies comparing drug responses in EGPA patients with different levels of eosinophil, and the same holds true with regard to the utility of benzlizumab as a rescue therapy following prepolizumab (or reslizumab) failure. A further issue is represented by how long IL-5-targeted therapies should be continued in patients achieving remission. Relapse rates may be high indeed if EGPA patients in remission on IL-5-targeted therapies are switched to conventional immunosuppression [24]. Therefore, future trials should also investigate whether a minimally effective dose and/or lengthening dosing intervals may be an acceptable trade-off between therapy suspension and relapse rates, as this strategy has been observed to be rewarding in other chronic conditions requiring long-term therapeutic monoclonal antibody administration [49; 50]. Cost-effectiveness may also benefit from this strategy. Meanwhile, further insights on the role of IL-5 targeted therapies in relapsing or refractory EGPA will hopefully be obtained at the completion of the MANDARA trial (NCT04157348), comparing prepolizumab vs. benzlizumab [45].