## 4 Discussion
In particular, 79.4% had only 1 flare and 17.6% had 2 to 4 flares. Flare duration ranged broadly from few weeks to persistent forms in 30% of the cases, probably reflecting disease severity, timing, treatment efficacy, and comorbidities. In a large retrospective cohort study based on electronic records in US, patients with GPP flares had 34% higher mean CCI score (\(2.80\pm 3.11\) vs. \(2.09\pm 2.52\)) compared to those without. In addition, they had higher inpatients and emergency department visits and higher use of all treatment [37]. In our study, we found a mean CCI score of 2.2 \(\pm\) 1.9, reflecting a similar comorbidity burden. The rarity of GPP makes clinical trials challenging and treatment recommendations are based on insufficient evidence [38]. These include corticosteroids, cyclospor, methotrexate, retinoids, and infliximab [2; 36; 38]. A mean of 2.4 \(\pm\) 1.1 different systemic treatments (range 1-5) were prescribed to manage the flare in our case series, generally starting with systemic corticosteroids and/or retinoids. To our knowledge, data about the proportion of multi-failure GPP are scarce. In a Turkish cross-sectional study, 36% of the patients with GPP flare were lesion-free under treatment [13]. Phase 3 studies in Japanese patients showed the efficacy of target biological therapies targeting IL-17 and IL-23 (namely, ixezizumab, secukinumab, brodalumab, guselkumab, and risankizumab) in GPP [39; 40; 41; 42; 43; 44]. Nonetheless, it was estimated that up to 10% may not respond to treatment [45]. Emerging therapies targeting IL-36R, such as spesolimab and insidolimab, showed promising results in clinical trials in terms of efficacy and safety and may improve the management of GPP in the future [46]. In fact, approximately 20% of the flares needed hospitalization due to complications, with a mortality rate of 1.6%. It was estimated that a patient with GPP will require hospitalization for a flare at least once every 5 years, with a duration of stay of 10 to 14 days [21]. According to published data, the mortality rate ranges between 0% to 16%. Our low rate could be associated with the high efficacy of new target therapies, as confirmed also by [PERSON] et al. that found no mortality rate in a large group of 156 patients with GPP flare [13]. The study has some limitations and strengths. The retrospective design resulted in recall bias, the longitudinal follow-up is relatively short to address properly the disease course and causative inferences between treatments and disease course cannot be drawn and the sample size relatively small. Finally, we did not test for the presence of genetic mutations (IL36 RN, CARD14, and AP1S3). In fact, a recent Malaysian study found that IL36 RN disease alleles are associated with a severe and early onset clinical phenotype [47]. [PERSON] et al. also found that patients with true PPP hardly ever had IL36 RN mutations, while ACH is common in patients with IL36 RN [47]. Nonetheless, this was a multicentre study collecting GPP cases according to the ERASPEN criteria definition and emphasizing their flare phase. Future longitudinal studies are needed to better understand GPP disease course and its burden of comorbidities. In conclusion, GPP flares can be severe and cause severe pain and itch with significant impact on the quality of life. A proportion of patients may have persistent disease and complications requiring hospitalization. Given the rarity of GPP and the unpredictable course of the disease, a better understanding of GPP flare is crucial to achieve the optimal management strategy. Conceptualization, methodology, software, validation, formal analysis, investigation, resources, data curation F.B., P.G., A.V.M., S.P., C.D.S., G.D., G.A., M.V., P.D., A.C. ([PERSON]), M.M., F.P., M.B., F.S., A.C. ([PERSON]), E.P., M.R., A.C. ([PERSON]) and G.G. Writing--original draft preparation F.B. and P.G.