Generalized Pustular Psoriasis: Divergence of Innate and Adaptive Immunity

Abstract

Generalized pustular psoriasis (GPP) is a severe, relapsing, immune-mediated disease characterized by the presence of multiple sterile pustules all over the body. The exact pathomechanisms behind GPP remain elusive, although increased interest in the genetic basis and immunological disturbances have provided some revealing insights into the underlying signaling pathways and their mutual interaction. The genetic background of GPP has been thoroughly investigated over the past few years. The conducted studies have identified genetic variants that predispose to pustular forms of psoriasis. The loss-of-function mutation of the interleukin 36 receptor antagonist gene, along with rare gain-of-function mutations in the gene that encodes the keratinocyte signaling molecule (CARD14), are examples of the uncovered abnormalities. Interleukin 36 (IL-36), along with neutrophils, is now considered a central cytokine in GPP pathogenesis, with IL-36 signaling providing a link between innate and adaptive immune responses. More recently, a new concept of inflammation, caused by a predominantly genetically determined abnormal activation of innate immune response and leading to inflammatory keratinization, has arisen. GPP is currently considered a representative of this novel group of skin conditions, called autoinflammatory keratinization diseases. As no therapeutic agents have been approved for GPP to date in the United States and Europe, the novel anti-IL-36R antibodies are particularly promising and may revolutionize management of the disease.

Flare‐up of generalized pustular psoriasis combined with systemic capillary leak syndrome after coronavirus disease 2019 mRNA vaccination

“…Generalized pustular psoriasis is a rare, chronic, highly inflammatory, and potentially life-threatening variant of psoriasis; acute flare-ups are associated with significant morbidity and mortality if not adequately treated. 6 GPP onset or flare-up are frequently induced by infection, pregnancy, and medications including systemic corticosteroids. However, flare-ups induced by vaccination are very rare.…”

Antibodies to watch in 2022

“…Spesolimab (BI 655130) is a humanized IgG1ҡ antibody that blocks activation of the IL-36 receptor, which is involved in the pathogeneses of neutrophilic skin diseases such as generalized pustular psoriasis (GPP), 125 palmoplantar pustulosis (PPP) and hidradenitis suppurativa (HS). The FDA granted spesolimab Orphan Drug designation for the treatment of GPP in October 2018.…”

Types of Psoriasis and Their Effects on the Immune System

“…Inflammation is now thought to be brought on by an aberrant innate immune response that is primarily genetically determined and results in an inflammatory kind of keratinization. Currently, generalized pustular is regarded as a representative of this newly discovered class of skin disorders known as autoinflammatory keratinization disease [ 11 ].…”