# New and Emerging Treatments for Generalized Pustular Psoriasis: Focus on IL-36 Receptor Inhibitors
###### Abstract  
Generalized Pustular Psoriasis (GPP) is a rare and severe subtype of psoriasis that significantly impacts patients' quality of life. Until recently, no specific treatment modalities were available, and treatment for GPP followed the guidelines for the treatment of plaque psoriasis, consisting of conventional treatments, such as retinoids, methotrexate, and even biologics, which although effective in some cases, may be associated with significant side effects, necessitating more effective and safe options. The pathophysiology of Generalized Pustular Psoriasis is complex and not fully understood, but there is some overlap with the pathogenesis of Plaque Psorasis. In GPP, the innate immune system seems to play a more significant role, with the interleukin (IL)-36 pathway being fundamentally involved. Spesolimab and insidolimab, two recently developed therapeutic agents, target the IL-36 inflammatory pathway by binding to the IL-36 receptor (IL-36R). Both biologics have already been evaluated in phase 1 and 2 clinical trials and have shown promising results in terms of safety and efficacy. IL-36 receptor inhibitors demonstrated great efficacy and good safety profile in the management of patients with GPP, demonstrating their potential to emerge as a leading treatment option. This review aims to explore and summarize the current scientific literature on the most recently developed treatments for GPP.  
generalized pustular psoriasis; spesolimab; insidolimab; HB0034; IL-36 receptor inhibitors; treatment +
Footnote †: journal: _pharmaceutics_  
Acute infections, menstruation, and rapid withdrawal of systemic corticosteroids have been proven to trigger acute flares [5].  
Extractaneous manifestations, such as cholangitis and acute renal failure, result from its multisystemic nature and can lead to serious complications [6; 7]. In fact, this condition imposes a heavy burden of morbidity, and potential mortality, significantly impacting patients' quality of life [8].  
Since it was described for the first time in 1910 by [PERSON], finding an adequate treatment for GPP has been a real challenge [1; 6]. Its rarity, which makes clinical trials very scarce and difficult to manage, and the necessity of treatment for both flare control and prevention, are the main obstacles [9]. Until very recently, no specific therapeutic agents or guidelines were available for the treatment of GPP, with treatments commonly following the standard guidelines of plaque psoriasis [1]. Therefore, treatment consisted of conventional options such as retinoids and methotrexate. While they might be effective in favorable courses of GPP, they carry significant side effects and are often insufficient in more severe cases [3; 6; 10].  
With the discovery of new biologic therapies, particularly those approved for the treatment of psoriasis, new therapeutic agents started to be considered for the treatment of GPP, providing new and more adequate options [10]. These new agents targeted cytokines involved in the immune pathways of psoriasis (such as TNF, IL-17, or IL-23), which overlap, at certain points with the GPP pathway, and have demonstrated good effectiveness in people with GPP. However, they must be used with caution, as, paradoxically, they have been reported to induce pushular disease in patients being treated for other conditions [9; 10].  
The discovery of the importance of the IL-36 pathway in the pathogenesis of GPP led to the development of the first specific therapeutic agent for GPP: spesolimab, an IL-36 receptor antagonist. It was recently approved in Japan, the US, and the EU, after demonstrating very positive results. Other similar therapeutic agents are also being evaluated, as this pathway appears to be the main focus for the development of GPP therapies [8; 9; 11].  
This narrative review aims to comprehensively evaluate the development and clinical potential of novel and emerging therapies for GPP.