Generalized pustular psoriasis—Dawn of a new era in targeted immunotherapy

Generalized pustular psoriasis (GPP) is a rare, inflammatory skin disease characterized by recurrent flares of pustulation accompanied by systemic symptoms. Due to its acuteness, sufficient diagnosis and treatment are essential, but often face challenges. We recently overviewed various treatment options of GPP utilizing established therapies in psoriasis vulgaris (PsO). Although there is a pathogenic relation to PsO, more and more evidence suggests a predominant involvement of the innate immune system in GPP. Recent discoveries on the genetic background of GPP with underlying mutations in IL36RN, CARD14, AP1S3 and SERPINA3 contributed to a better understanding of the pathogenesis and provide major opportunities in the development of innovative, targeted therapies. The proposed umbrella term “autoinflammatory keratinization diseases” (AIKD) helps to categorize this heterogeneous disease. Finally, we address the problem of insufficient standardized assessment tools and propose a reproducible scoring system also capturing the systemic features of GPP. In summary, GPP is a prototype disease to demonstrate both obstacles and progress in dermatology—currently insufficient definition and diagnostic tools on the one hand side, yet major advances in dissecting disease heterogeneity, opportunities for novel diagnostic techniques and therapeutic decision‐making based on molecular events on the other side.


| INTRODUC TI ON
Generalized pustular psoriasis (GPP) is a chronic, non-communicable inflammatory skin disease which can involve multiple organs and potentially lead to a fatal outcome. GPP is characterized by acute, recurrent flares of sterile pustular lesions on erythematous skin with signs of systemic inflammation also affecting extracutaneous organs. It can be associated with a pre-existing plaque psoriasis or develop independently. Due to its low prevalence, it is defined as an orphan disease. [1][2][3] In our review article of 2018 "Generalized pustular psoriasis-a model disease for specific targeted immunotherapy," we presented the concept that GPP is an ideal disease to illustrate current problems in the field of inflammatory skin diseases-starting from a precise definition of this heterogeneous disease overlapping with other types of pustular diseases, 4 advances in understanding the | 1089 NEUHAUSER Et Al. pathogenesis of GPP, over standardized diagnostic approaches and ultimately targeted therapies. We concluded that there was no consensus whether GPP is to be regarded a variant of psoriasis vulgaris (PsO) or a distinct clinical entity with overlapping pathological findings to PsO. Moreover, we discussed how the lack of standardized clinical criteria for diagnosis challenged the classification of GPP.
We summarized that in accordance with the pathogenetic overlap to PsO, several targeted immunotherapies including anti-TNF α, anti-IL23/12 or anti-IL17 were investigated with good success in GPP.
In this viewpoint essay, we discuss how this approach has continued in the last 2 years-with novel insights into genetics and the pathogenesis of GPP, a proposed classification system, a new diagnostic assessment tool and new as well as ongoing clinical trials.
Today, GPP stands exemplary for an autoinflammatory disease with high unmet medical need for disease stratification and identification of biomarkers on the way to personalized medicine.

| NE W L AB EL FOR G PP-AN AUTOINFL AMMATORY KER ATINIZ ATION DISE A SE
In our review of 2018, we discussed the problematic definition of GPP, regarded as a subtype of psoriasis by some authors versus as a distinct clinical entity by others. We summarized that the pathogenesis of GPP partly overlaps with typical pathways of PsO, but exhibits a pronounced activation of the innate immune system.
Therefore, cytokines such as IL17A, IL22, IL23, TNF and interferons are found to be elevated in both PsO and GPP. However, GPP lesions showed higher IL-1 and IL-36 expressions compared to PsO lesions. 5,6 In 2011, Marrakchi et al laid the foundation on a new autoinflammatory perspective of GPP by discovering an underlying genetic mutation of the IL36 receptor antagonist (IL 36RN) in several cases of familiar GPP which led to the term DITRA (deficiency of IL36 receptor antagonist). 7 This missense mutation of the IL36RN results in a deficiency of IL36 receptor antagonist, an anti-inflammatory cytokine of the IL1-family, which normally antagonizes the binding of IL-36 cytokines (IL-36α, IL-36β and IL-36γ), mainly derived from keratinocytes, to the receptor and therefore inhibits downstream inflammatory pathways via NF-κB. The dis-inhibition leads to an uncontrolled binding of IL-36 to the IL36 receptor resulting in enhanced signal transduction of pro-inflammatory cytokines, for example IL-8, which is essential for the migration of neutrophils ( Figure 1). 5  More recently, a subtype of pityriasis rubra pilaris (PRP), a papulosquamous skin disease, was included to the category of autoinflammatory diseases due to the identification of three different homozygous mutations in CARD14, a known activator of the pro-inflammatory nuclear factor kappa B (NF-κB). 9,14 Previously, similar mutations were identified in a subset of familial psoriasis. 14,15 The first description of a CARD14 mutation in a child with sporadic, early-onset generalized pustular psoriasis was followed by identifying a significant association between CARD14 and GPP with concomitant PsO in a small Japanese cohort in 2014. 15,16 Today, we know that a gain-of-function mutation in caspase recruitment domain family 14 (CARD14) is an underlying mutation occurring in up to 21.1% of GPP patients with concomitant PsO. 16,17 CARD14 is mainly expressed in the epidermal layers of the skin and consequently leads to an activation of the NF-κB and mitogen-activated protein kinase (MAPK) signalling pathways which subsequently induces neutrophilic inflammation in the skin via IL-8. 9,15 Another mutation associated with autoinflammation found in GPP patients involves the adaptor-related protein complex 1 encoding the complex subunit sigma-3 (AP1S3). This mutation results in a reduction of toll-like receptor 3 (TLR3) trafficking, therefore leading to a decreased expression of IFN-β, which normally downregulates the production of IL-1. Genetic studies indicate a prevalence of around 6% in GPP patients. 18 More recently, a rare loss-of-function mutation in SERPINA3 has been detected in a minority of GPP patients, which also leads to an activation of neutrophils ( Figure 1). 19 However, a recent study demonstrated that known susceptibility genes can only be identified in 36% of GPP patients. 11 In general, due to the low prevalence of GPP, genetic data are based on only small numbers of patients and often include an inhomogeneous distribution of investigated ethnicities. Therefore, currently identified mutations in GPP cannot explain the full range of GPP endotypes. 10 The

| A SS E SS ING THE S E VERIT Y OF G PP IS S TILL CHALLENG ING
The diagnosis and management of GPP are still challenging, espe- with a maximum of 9 points. Secondly, the systemic involvement is assessed via pyrexia, white blood cell count, CRP and serum albumin with scores ranging from 2 to 0 (maximum 8 points). The sum of those two categories represents the total JDA severity index score of GPP varying from severe (17-11 points), moderate (10-7 points) to mild (0-6 points). 23 (Table 1).
Stephenson ularizes "skin rash" into pustular, plaque-type with keratinization or unspecified and adds geographic tongue as a single criterion. 24 With further future validation, this specified assessment tool could be used not only to monitor disease activity but also provide a way to measure treatment response in multiple organs.
In our opinion, DITRA/AIKD-AI presents a detailed and comprehensive assessment of symptoms in GPP which might be used within clinical trials, but lacks feasibility in daily practice due to its time-consuming documentation. Adapted scores from PsO lack the evaluation of systemic symptoms in GPP. Therefore, we favour the practicable JDA severity index to be used as a standardized assessment tool in GPP in both clinical routine and clinical trials.

| NOVEL THER APEUTI C OP TI ON S IN G PP
We previously summarized the various treatment options for GPP, emphasizing the role of specific targeted immunotherapies in GPP.
Due to its pathological overlap, we presented well-established   In 2017, guselkumab, an IL23-p19 antibody, was approved for the treatment of PsO. 38 One multicentre, open-label, phase-3 study reports on 10 Japanese GPP patients treated with this monoclonal IL-23 antibody at week 0, 4 and then every 8 weeks. Five out of 10 patients showed successful treatment, defined as improvement of the Global Impression Score within the first week, consecutively leading to a 100% success rate in the patients who completed the study (8/10) at week 52, demonstrating efficacy without safety concerns. 39 Currently, there is an ongoing phase-3 trial investigating the efficacy of risankizumab, another anti-IL23-p19 antibody, in GPP patients. Safety was already proven, but publication of efficacy data is still pending. 40,41 Since the discovery of the IL36RN mutation in GPP, therapies targeting autoinflammation via inhibition of the inflammasome were followed. Initial studies investigated antibodies targeting IL-1β or the  Table 2). Spesolimab is currently investigated in phase-III clinical trials, without published data so far.
Another humanized monoclonal IL-36-receptor antibody, ANB019, is also currently scrutinized in a clinical trial for GPP. 42

| THE FUTURE: D IS E A S E S TR ATIFI C ATI ON BY IDENTIFI C ATI ON OF B IOMARKER S?
Advances in our knowledge of genetic variants of GPP, the interaction of autoinflammation and clinical phenotypes, and numerous therapeutic options to treat GPP set the ground for a future of precision medicine in the field. Today, we have opportunities to treat Although applying those novel, cost-demanding biologics in GPP comes with good chance to relieve the patient almost completely from disease symptoms, selecting the right treatment for an individual patient remains challenging. Due to the lack of specific objective biomarkers, it is currently impossible to predict the therapeutic response of a given biologic in GPP.
In chronic inflammatory skin diseases, numerous efforts are currently undertaken to identify molecular biomarkers for improving diagnostics, assess disease severity and stratify patients according to chances of therapeutic response. [44][45][46] For instance, HLA-C*06:02 genotype has been identified as a biomarker of biologic treatment response in psoriasis predicting the response chances between ustekinumab and adalimumab. 47 In the era of autoinflammatory keratinization diseases, the CARD14 mutation has recently been proposed as a biomarker predicting therapy response to ustekinumab in familial PRP. 48 The oligogenic rather than monogenic inheritance in GPP suggests that even more genetic disorders may underlie the pathogenesis of GPP. This is highlighted by the fact that IL-36 antagonizing In summary, more and more genetic and expression biomarkers are proposed to define GPP, assess its severity, or predict therapeutic response. On the other hand, our understanding of the underlying pathogenesis of GPP improves and numerous therapeutic options are available. Once we succeed to implement biomarkers into our therapeutic strategy at an individual patient's level, GPP can become a driving disease on the way to precision medicine in (auto-) inflammatory skin diseases.

ACK N OWLED G EM ENT
Open access funding enabled and organized by Projekt DEAL.

CO N FLI C T S O F I NTE R E S T
There are no conflicts of interest.

AUTH O R CO NTR I B UTI O N S
Dr(s) RN, KE and AB had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. RN