## 2 Genetics of Pustular Psoriasis
### TGFBr2  
TGF-\(\beta\) signaling is recognized for its inhibitory effects on cell proliferation and immune system suppression [41]. Thus, the hyperproliferation of keratinocytes in the psoriatic epidermis is consistent with disrupted TGF-\(\beta\) signaling because of heterozygous loss-of-function TGFBR2 mutations. Concomitant with the overexpression of KRT17, there is an increase in keratinocyte proliferation and subsequent recruitment of neutrophils [42]. The overexpression of KRT17 is thus in line with a potential role for diminished TGFBR2 function in both GPP and AOID. Whole-exome sequencing (WES) was carried out on a total of 53 patients, comprising 32 individuals exhibiting pustular psoriasis phenotypes and 21 individuals with AOID presenting with pustular skin reactions [43]. The result showed that 4 Thai patients displaying similar pustular phenotypes, including two diagnosed with GPP and two with AOID, were found to carry the same rare TGFBR2 frameshift mutation. It is concluded that AOID might share pathogenic mechanisms with GPP.  
Mechanistically, TGFBR1 and TGFBR2 are transmembrane serine/threonine kinases [44]. TGFBR2 expression is remarkably reduced or absent in psoriatic skin. As a result, it has been suggested that genetic variations in TGFBR2 could enhance susceptibility to GPP and AOID in some patients.  
Current and Potential Therapeutic Agents Targeting Immune Mediators in Generalized Pustular Psoriasis  
The phenotype and pathogenesis of different psoriasis subtypes are on a spectrum. On the one hand, plaque psoriasis is associated with the overactivation of the adaptive immune system, including T and B cells, and is thought to involve self-perpetuating inflammatory mechanisms through the IL-23/Th17 axis [45]. On the other end, pustular psoriasis has been associated with the stimulation of innate immune responses and the activation of IL-36 cytokine pathways [46]. Based on the pathomechanism, therapeutic agents for patientswho have plaque psoriasis and GPP at the same time need to target not only the adaptive immune pathways but also the innate immune axis [47].  
IL-36 cytokines are members of the IL-1 superfamily, and the IL-1/IL-36-chemokine-neutrophil axis plays a significant role in driving disease pathology in GPP. The first pathogenic variant found to be linked with GPP was a homozygous mutation of the IL36 RN gene [48], and further studies have looked into the distribution over different populations [48; 49].  
Progress in understanding the relationship between autoinflammation and clinical phenotypes has contributed to the development of highly efficacious targeted treatments such as TNF-\(\alpha\), IL-17, IL-23, IL-1\(\alpha/\beta\), or IL-36 inhibitors or receptor blockers, as well as small molecule drugs such as PDE4 inhibitors, JAK inhibitors, and ROR-\(\gamma\)t inhibitors.  
Well-established treatment guidelines for GPP are currently lacking, and multiple biologic and non-biologic treatments exist. Considering the variety of comorbidities and severity associated with GPP, personalized treatments should be tailored. Figure 1 shows a graphical abstract of current and emerging biologic agents for GPP.