## 4 Discussion  
In this multicentre study, we describe the clinical characteristics and severity of a series of consecutive patients experiencing a flare of GPP, defined according to the ERASPEN criteria. The major findings of the study include that the flare affects more frequently females with a M:F ratio of 0.47 (21/45), aged between 50 and 60 years, which is consistent with different Asian, European, and American series [6; 7; 8; 9; 21; 22; 23; 24; 25; 26; 27; 28; 29; 30; 31; 32]. For example, in recent Turkish study of 156 GPP patients by [PERSON] et al. a M:F ratio of 0.6 was estimated [13]. Although GPP can occur in children, it typically emerges in adulthood and according to the existing literature the onset age can range from 20 years to 58 years. In our sample, we found an average of 58.1 \(\pm\) 14.9 years, which is consistent with previous studies [21; 22; 23; 24; 25; 26; 27; 28; 29; 30; 31; 32]. The history of plaque psoriasis in GPP patients broadly varies between 30-70.4%, usually preceding GPP of some years [21; 22; 23; 24; 25; 26; 27; 28; 29; 30; 31; 32]. In the present study, 39 out of 66 (59%) patients had a personal history of chronic plaque psoriasis. No significant differences were found in clinical features of disease (i.e., onset age and severity) between patients with personal history of plaque psoriasis vs. those without. Accumulating genetic, transcriptomic, and clinical evidence supports the idea that GPP and plaque psoriasis are distinct diseases, but they can coexist [33]. Both European and Japanese diagnostic criteria highlight the relapsing nature of GPP, which can be triggered by several events [1]. Triggers act mainly by dysregulated the IL-36 axis in epidermal keratinocytes through IL-17C [34]. In this study, the precipitating factor was identified in 37.8% (25/66) of the cases, including infections in 15.2% (10/66), drugs in 10.6% (7/66), stressful events in 7.6% (5/66), corticosteroids withdrawal in 3.0% (2/66), hypocalcaemia in 1.5% (1/66), and pregnancy in 1.5% (1/66). Among drugs, antibiotics, terbinafine, TNF-alpha inhibitors, and corticosteroids withdrawal have been reported [13; 35]. Different infections, including upper respiratory infections and COVID-19 have been associated with GPP exacerbation. The role of stressful life events in triggering GPP is still controversial [36]. The novelty of our study is the assessment of GPP disease severity at flare through GPPASI, which was on average 22.8 \(\pm\) 13.5, with an involvement of almost half BSA, including nail and genitals involvement, with moderate-to-severe itch and skin pain (VAS > 6). Our result confirms the significant impact of GPP on the quality of life, as we found a mean DLQI of 21.0 \(\pm\) 4.9. There have been few studies evaluating the quality of life in GPP patients. [PERSON] et al. reported DLQI lower scores (11.4 \(\pm\) 9.8) [13]. Extensive cutaneous involvement, itch and pain, and systemic symptoms and comorbidities, contribute to the negative impact of quality of life. The flare presentation in our series was characterized by high fever of 39.4% and leukocytosis in 59.1% (data not shown in tables). In the literature, high fever has been reported in 24-96% of patients during GPP flare and leukocytes (with neutrophil) in 30-70%. Systemic inflammation can be also associated with fatigue, malaise, diarrhoea, laboratory abnormalities (raised C-reactive protein and erythrocyte sedimentation rate), and extracutaneous neutrophil inflammatory involvement, including cholestasis, arthritis, interstitial pneumonia, oral lesions, and acute renal failure [1; 2; 3; 4]. Interestingly enough, patients with severe disease showed more frequent flares. In detail, almost 80% of the patients had recurrent flares, but only less than 10% had more than one single episode per year. Few studies assessed the GPP course in terms of frequency of flares. A study using the French National Health Data System database showed that most patients with GPP had no flare or only one episode per year [7].