# Pustular psoriasis: From Pathophysiologyology to Treatment
## 3 Pathogenesis
### Pathophysiology of Generalized Forms  
Immunological pathways in GPP and PV are thought to be partly overlapping, with a more prominent role of the innate immune system, IL-1 and IL-36 in GPP pathogenesis. However, TNF-\(\alpha\) and IL-17A also seem to be involved [62; 90]. A gene expression study on lesional skin revealed a significant overexpression of IL-17A, TNF, IL-1, IL-36 and interferons in both PV and GPP with a significantly greater abundance of transcripts for IL-18, IL-36\(\alpha\) and -\(\gamma\) in GPP versus PV lesions [62]. The pathogenic landscape of IH is poorly understood [91; 92; 32] and a key issue is the relationship with GPP. During pregnancy, immune responses shift towards an overall Th2 polarization, although emerging evidence indicates a much more nuanced immunological rewiring. Recent research hints at a regulatory role for IL-36 cytokines in the immunology of reproduction [93] providing a conceptual framework for the understanding of PP during pregnancy, which could represent the result of deranged IL-36 cytokines physiologic changes in the setting of a predisposing genetic background. Annular PP-like lesions have been reported in few cases of hereditary lactate dehydrogenase M-subunit deficiency, that is responsible for an imbalance between oxidized and reduced forms of nicotinamide adenine dinucleotide (NAD/NADH), leading to dysregulation of intracellular calcium. [PERSON] et al. hypothesized that calcium dysregulation may lead to epidermal infiltration by neutrophils and elevated serum levels of IL-8, two hallmarks of PP [94]. Annular PP was observed in an individual with Noonan syndrome, supporting a putative shared pathomechanism involving the RAS/MAPK signaling pathway [95]. As concerns genetic factors in GPP, a list of the main genes involved in GPP pathogenesis is summarized in Table 2[1; 69; 96; 97; 98; 99; 100]. Loss-of-function pathogenic variants of the _IL36 RN_ gene, encoding IL-36 Ra, have been found with a frequency close to 24% in GPP [1; 12]. More specifically, mutations in _IL36 RN_ have been shown to be associated with GPP without PV and with an earlier age of disease onset [69; 101; 102]. Deficiency of IL-36 Ra (DITRA) has been classified as a subgroup of GPP with a specific monogenetic defect [103] consisting in null mutations of _IL36 RN_, associated with severe clinical phenotypes. Hypomorphic variants with decreased or unchanged protein expression have also been found and may account for clinical heterogeneity of GPP [104]. _IL36 RN_ variants have been detected also in IH, and, in particular, East Asian founder mutations might be implicated in IH pathogenesis [105]. Curiously, identical _IL36 RN_ mutations led to both isolated IH and IH with a preceding history of GPP and/or PV. Recently, _CARD14_ causal variants have been linked to GGP. Heterozygous gain-of-function variants in _CARD14_ occur in up to 21% of GPP patients with concomitant PV [1; 97] while a homozygous gain-of-function _CARD14_ variant has been described in a mild case of IH [106]. Accordingly, _IL36 RN_-related pustulosis and _CARD14_-mediated PP have been classified within the spectrum of autoinflammatory keratinization diseases, a group of inflammatory keratinization disorders with autoinflammatory pantomechanisms [107]. _AP1S3_ is another gene recently associated with GPP [108]. _AP1S3_ pathogenic variants are mainly found in Europeans and rarely in East Asians [69]. _AP1S3_ mutations can be co-inherited with _IL36 RN_ genetic changes, modifying the phenotypic effect of the latter [98]. The mutational analysis of _IL36 RN_, _CARD14_, and _AP1S3_ genes in a group of 61 GPP patients showed that almost two-thirds of them did not carry variants in any of the three genes, reiterating the complexity of GPP pathogenesis [102]. Additional genetic factors might contribute to GPP pathogenesis (Table 2), like _SERPINA3_[109], _TNIP1_[110; 111], and _MPO_[63; 112] variants.