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 Psoriasis. In GPP, the innate immune system seems to play a more significant role, with the interleukin (IL)-36 pathway being fundamentally involved. Spesolimab and imsidolimab, 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.

The immunopathogenesis of HS is partially understood and exhibits features of an autoinflammatory disease; it is associated with the potential involvement of B cells and the contribution of Th1 or Th17 cell subsets. Recently, the pathogenic role of both innate immunity and IL-1 family cytokines in HS has been deeply investigated. Several agents targeting the IL-1 family pathway at different levels are currently available and under investigation for the treatment of HS. HS is still characterized by unmet clinical needs and represents an expanding field in the current scientific research. The aim of this narrative review is to describe the pathological dysregulation of IL-1 family members in HS and to provide an update on therapeutic strategies targeting IL-1 family cytokine signaling. Further clinical and preclinical data may likely lead to the enrichment of the therapeutic armamentarium of HS with IL-1 family cytokine antagonists.

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The interleukin-1 (IL-1) family is involved in the correct functioning and regulation of the innate immune system, linking innate and adaptative immune responses. This complex family is composed by several cytokines, receptors, and co-receptors, all working in a balanced way to maintain homeostasis. Dysregulation of these processes results in tissue inflammation and is involved in the pathogenesis of common inflammatory dermatoses such as psoriasis, hidradenitis suppurativa, and atopic dermatitis. Therefore, therapeutic targeting of IL-1 pathways has been studied, and several monoclonal antibodies are currently being assessed in clinical trials. So far, promising results have been obtained with anti-IL-36R spesolimab and imsidolimab in pustular psoriasis, and their efficacy is being tested in other conditions.

Generalized pustular psoriasis (GPP) is a rare yet severe variant of psoriasis, characterized by the eruption of superficial sterile pustules that appear suddenly and widely distributed, potentially life-threatening. It more commonly presents through recurrent acute flares triggered by stress, corticosteroid withdrawals, pregnancy, or infections. The pathogenesis of this disease is yet to be fully understood. Nevertheless, studies have suggested an important role of an IL-1 subfamily of cytokines, due to an imbalance of the IL-36 axis favoring of pro-inflammatory activity. The therapeutic intervention for this condition is still a challenge as its rarity and scarce available information contribute to the absence of specific treatment. Current options stand on small, open-label trials or follows standard treatment for plaque psoriasis. Spesolimab and imsidolimab are two IL-36 receptor inhibitors which completed phase 1 and 2 trials with a good efficacy and safety profile in the treatment of this disease, including in the fast control of its acute flares. The most common adverse events reported with spesolimab were mild to moderate infections, and imsidolimab was well tolerated. GPP clinical trials remain to have their small sample size as a major limitation, but IL-36 receptor inhibitors are promising therapeutic options currently under investigation.

UNASSIGNED: IL-36 cytokines are members of the IL-1 superfamily. Increasing evidence in the IL-36 pathway demonstrates their potential as a therapeutic target for treating inflammatory skin diseases, such as generalized pustular psoriasis (GPP).
UNASSIGNED: A narrative review was written to further study preclinical and clinical evidence for the role of IL-36 in psoriasis, atopic dermatitis (AD), hidradenitis suppurativa (HS), acne, autoimmune blistering diseases, and neutrophilic dermatoses.
UNASSIGNED: IL-36 has important downstream effects such as inducing expression of inflammatory cytokines, antimicrobial peptides, and growth factors. Increased expression of IL-36 cytokines has been observed in the lesional skin of patients with psoriasis. Studies of other inflammatory skin diseases have also noted similar findings, albeit to a lesser extent. IL-36 inhibition has been shown to be effective in GPP and is currently being studied for other inflammatory skin diseases.
UNASSIGNED: The IL-36 pathway contributes to pathogenesis of many inflammatory skin diseases and is a promising therapeutic target.

Unmet needs in the treatment of psoriasis call for novel therapeutic strategies. Pustular psoriasis and psoriatic arthritis often represent a therapeutic challenge. Focus on IL-36 cytokines offers an interesting approach, as the IL-36 axis has been appointed a critical driver of the autoinflammatory responses involved in pustular psoriasis. Two IL-36R blocking antibodies, imsidolimab and spesolimab, are currently undergoing phase II and III clinical trials, with promising results.

Introduction: IL-1 family cytokines play an important role in the innate immune system and their uncontrolled activation and expression can initiate a pathologic inflammatory response. Their role in psoriasis, pustular psoriasis, and psoriatic arthritis has been studied, and they offer potential interest as therapeutic targets.Areas covered: This review focuses on the role that interleukin (IL)-1 family cytokines play in psoriasis pathogenesis, with a special focus on pustular psoriasis, and how these cytokines can be used as therapeutic targets. Using PubMed, we review the literature for articles related to IL-1 family cytokines and psoriasis, focusing on pustular psoriasis, and including pathogenesis, genetics and therapeutic targets.Expert opinion: IL-1 and IL-36 cytokines act as critical drivers of the autoinflammatory responses involved in pustular psoriasis. Studies on the specific role of each IL-1 cytokine are needed, as well as of their regulatory pathways. Targeting of IL-1 family cytokines has been used in pustular psoriasis, with IL-1 and IL-36 R blockade showing promising results.