Generalized Pustular Psoriasis and Systemic Organ Dysfunctions

Abstract

This review explores the intricate relationship between generalized pustular psoriasis (GPP) and various systemic diseases, shedding light on the broader impacts of this severe skin condition beyond its primary dermatological manifestations. GPP is identified as not only a profound contributor to skin pathology but also a significant risk factor for systemic diseases affecting cardiovascular, hepatic, renal, pulmonary, and skeletal systems, as well as associated with an increased incidence of anemia, depression, anxiety, and arthritis. The research highlights the complex interplay of cytokines, particularly IL-17 and IL-36, which are central to the pathophysiology of GPP and implicated in the exacerbation of systemic conditions. Key findings indicate a higher incidence of cardiovascular events in GPP patients compared to those with other severe forms of psoriasis, notably with a stronger correlation between myocardial infarction history and GPP development. Liver disturbances, frequently reversible upon psoriasis remission, suggest a cytokine-mediated link to hepatic health. Renal dysfunction appears elevated in GPP sufferers, with IL-17 and IL-36 potentially driving renal fibrosis. Similarly, interstitial lung disease and osteoporosis in GPP patients underscore the systemic reach of inflammatory processes initiated in the skin. The associations with anemia, depression, anxiety, and arthritis further complicate the clinical management of GPP, requiring a multidisciplinary approach. The study concludes that managing GPP effectively requires a holistic approach that addresses both the cutaneous and systemic dimensions of the disease, advocating for continued research into the mechanisms that connect GPP with broader health implications to refine therapeutic strategies.

Keywords: IL-36; generalized pustular psoriasis; systemic organ dysfunctions.

Figure 1

The pathogenesis of GPP. The interleukin-36 (IL-36) pathway is key in generalized pustular psoriasis (GPP), marked by genetic mutations and high levels of IL-36 proteins in GPP lesions. GPP triggers “autoinflammatory” responses through changes in the innate immune system. Neutrophils, a core part of this system, contribute to inflammation by causing oxidative stress, releasing enzymes, and forming neutrophil extracellular traps (NETs). IL-36 cytokines, belonging to the IL-1 family, are uniquely activated outside of cells by proteases from neutrophils and keratinocytes. This activation is critical for starting other inflammation-related pathways involving MYD88, NF-kB, and MAPK. The process is tightly regulated by inhibitors like SERPINA1 and SERPINA3, highlighting the complex control of inflammation in GPP.

Figure 2

The interplay of GPP and systemic organ dysfunctions. This schema displays the connections between generalized pustular psoriasis (GPP) and various systemic diseases, showing how GPP significantly affects the cardiovascular, liver, renal, pulmonary, and skeletal systems, as well as depression, anxiety, and arthritis. GPP-derived IL-36 and associated IL-17 cytokines show interplay in the development of systemic organ dysfunctions.