Interleukin 23 Expression in Pyoderma Gangrenosum and Targeted Therapy With Ustekinumab

Abstract

Background: Interleukin (IL)-23 is involved in the pathogenesis of the chronic inflammatory Crohn disease. Pyoderma gangrenosum (PG) is often associated with and can even be the first manifestation of this disease and has abundant neutrophilic infiltration. Because IL-23 plays a critical role in driving inflammation associated with IL-17 production and especially neutrophil recruitment, we suspect that PG might be driven by a pathogenetic mechanism similar to that of inflammatory bowel diseases or psoriasis. Observations: Tissue sample analysis showed highly elevated expression of IL-23 on both transcriptional and protein level in a recalcitrant PG lesion. On the basis on these data, a treatment targeting the p40 subunit of the heterodimeric IL-23 with the monoclonal antibody ustekinumab was started. Therapy with ustekinumab resulted in a significant decrease of IL-23 expression in PG and healing after 14 weeks of treatment. No relapse occurred in a 6-month follow-up period. Conclusions: Our data provide evidence of an IL-23dominated inflammatory infiltrate in PG. This might specify a new concept for PG pathophysiology and suggests a possibility for using ustekinumab as a therapeutic agent in this disease.

Pyoderma gangrenosum: challenges and solutions

“…17 However, in a more recent case, IL17 was not significantly elevated in PG, whereas IL23, responsible for driving T cells into the Th17 phenotype, was elevated and was considered the support for therapy with ustekinumab, a monoclonal antibody that binds the shared p40 subunit of IL23 and IL12. 17,18 The mechanisms responsible for the clinical heterogeneity of skin lesions in neutrophilic disorders -ulcers in PG, skin plaques in SS and folliculitis and aphthous ulcers in …”

“…PG may be associated with malignancy, which sometimes precedes the diagnosis; therefore, immunosuppressors, as well as biological agents, can be risky. 18 It is not uncommon for PG to have secondary wound infection, documented by a positive culture from smear, and clinically suspected by CRP elevation and signs such as erythema and swelling. In these cases, antibiotic treatment should be promptly initiated, and except in sepsis, immunosuppression should be maintained to prevent progression.…”

Management of pyoderma gangrenosum

“…Treatment of a patient with the anti-IL-23 monoclonal antibody ustekinumab resulted in complete healing of her PG. 15 Neutrophils may also play a role in PG through sustained inappropriate generation of reactive oxygen species (ROS) promoting angiogenesis in ulcers. In samples from PG lesions, hypoxia inducible factor 2-alpha (HIF2a) and vascular endothelial growth factor (VEGF) were constitutively highly expressed.…”

Gene Therapy for Pyoderma Gangrenosum: Optimal Transfection Conditions and Effect of Drugs on Gene Delivery in the HaCaT Cell Line Using Cationic Liposomes

“…The majority of these may be involved in wound healing, such as keratinocyte growth factor [59], epidermal growth factor, or members of the fibroblast growth factor family [60]. Genes involved in immune regulation may also be investigated, after increasing evidence of an immune aetiology for PG [3,61,62,63,64,65,66]. Particular immune targets may include genes encoding cell surface proteins involved in neutrophil trafficking, such as integrins CR3 and CR4 [63], and encoding interleukin-8, which recruits neutrophils to sites of infection and has been found to be overexpressed in PG ulcers and may be implicated in disease pathogenesis [62,64].…”