# Generalized Pustular Soriasis: Divergence of Innate and Adaptive Immunity
## 4 Biologic Therapeutics for GPP in the Light of Novel Genetic and Immunological Findings
The better utilization of the currently available therapies and the development of novel molecules will ensure safe long-term flare control [114]. TNF-\(\alpha\) inhibitors (infliximab, adalimumab, and etanercept) were the first biologic agents to be used as an off-label treatment of GPP; therefore, the available data comprise a considerable number of GPP patients treated with those drugs [26; 115]. The administration of those biologics results in rapid neutralization of TNF-\(\alpha\), which is also upregulated in GPP skin lesions [23]. Infliximab, the most-studied TNF-\(\alpha\) blocking agent in GPP, showed a good response rate in 58% of patients and partial response in 28%. Notably, a quick onset of action was observed (pustule clearance in 1-3 days) [26]. Case report data also showed that infliximab can effectively treat juvenile GPP [116; 117; 118; 119]. Treatment with TNF-\(\alpha\) blockers was also highly effective in patients having IL-36 Ra deficiency [120; 121]. Interestingly, adalimumab has been shown to be a potential alternative treatment option in patients who fail infliximab, as [PERSON] et al. demonstrated significant improvement of GPP lesions in all four of their patients who had previously failed numerous systemic treatments, including infliximab, prior to switching to adalimumab [122]. It needs to be noted that most studies of TNF-\(\alpha\) blocking agents in GPP are case reports. Therefore, further phase II and III clinical trials are necessary to evaluate the benefits and safety of these biologics in this indication. Considering the upregulation of IL-17 and the pronounced neutrophil infiltration in the skin of GPP patients, anti-IL-17 treatment appeared to be a very promising option [33]. Three IL-17 inhibitors (secukinumab, izekizumab, and brodalumab) are currently licensed and approved for the treatment of moderate-to-severe plaque psoriasis [123]. All of the mentioned agents were used in GPP patients, including three open-label phase III clinical trials. Overall, a complete response was demonstrated in approximately two thirds of treated individuals, whereas only one in ten patients exhibited weak to no response [26]. The promising efficacy data for each of those compounds resulted in their approval for the treatment of GPP in Japan. Since IL-23 plays a significant role in the pathogenesis of GPP, vitekinumab, an anti-IL-12/23 p40 monoclonal antibody, has also been successfully utilized in the management of GPP [124]. Out of a total of seven described patients, complete remission has been achieved in six individuals; however, all but one of them were _IL36 RN_-negative [26; 124; 125; 126]. Risankizumab and guselkumab are both highly effective and safe inhibitors of the IL-23 p19 subunit, and which are approved for the treatment of moderate-to-severe plaque psoriasis [127; 128]. Guselkumab was assessed in a phase III open-label study in GPP and was less efficient when compared to IL-17 inhibitors [30]. A phase III clinical trial to evaluate the efficacy and safety of risankizumab in Japanese patients with GPP has been completed but detailed results have to date not been published [129]  
Even though blocking of the TNF-\(\alpha\)/IL-17/IL-23 axis has resulted in some degree of success in GPP, the IL-1/IL-36-chemokine-neutrophil axis appears to be a more promising therapeutic target, especially in the context of the aforementioned immunopathogeniced findings [23]. IL-1 targeting with biologics has been previously performed in GPP patients using the IL-1\(\alpha\) receptor antagonist (IL-1-RA) anakinra and the IL-1\(\beta\) monoclonal antibodies gevokizumab and canakinumab. Anakinra, a recombinant IL-1 receptor antagonist, frequently used in the treatment of other autoin Inflammatory diseases, was also documented to be successfully used in GPP, including a juvenile case [88; 130]. However, further randomized control trials are needed to evaluate the efficacy and safety of anakinra in GPP.