Rapid Downregulation of Innate Immune Cells, Interleukin-12 and Interleukin-23 in Generalized Pustular Psoriasis with Infliximab in Combination with Acitretin

Abstract

Background: Generalized pustular psoriasis (GPP) is a severe inflammatory disease characterized by recurrent eruptions of sterile pustules on erythematous skin. Although tumor necrosis factor (TNF) antagonists may lead to a rapid resolution of GPP, the mechanism of action of these agents remains to be investigated. Here, we sought to evaluate markers of immune response in the skin of a patient who experienced a rapid amelioration of GPP after treatment with infliximab and acitretin. Methods: A skin biopsy was obtained before and 72 h after initiation of treatment. Immunohistochemical stainings were performed to characterize alterations of the infiltrates, the apoptosis marker caspase 3 and key cytokines like TNFα, interleukin (IL)-12, IL-23 and the chemokine CXCL8/IL-8. Results: Parallel with clinical improvement, a striking decline of neutrophils, myeloid and plasmacytoid dendritic cells, M1 macrophages and partly of CD4+ T cells was observed. There was no evidence of increased apoptosis mediated through the caspase-3 pathway. A marked reduction particularly of IL-12 and IL-23 and, to a lesser degree, of TNFα and CXCL8/IL-8 was observed. Conclusion: A swift clinical improvement of GPP by infliximab and acitretin is associated with a marked reduction particularly of innate and partially of the acquired immune cells as well as IL-12 and IL-23.

Generalized pustular psoriasis – a model disease for specific targeted immunotherapy, systematic review

“…Only three reports with a total of 5 cases provide significant follow‐up data (>3 months) for the time after discontinuation of treatment with infliximab. Within those cases a relapse has been observed in two patients, while in three GPP remained stable, although two needed continuous treatment with acitretin …”

“…The onset of action seems to be particularly quick in patients receiving infliximab, exhibiting a pustule clearance of 1‐3 days. Anti‐TNF treatment seems also to be effective in patients having IL36RA deficiency, achieving a clinical response in 7 of 8 reported DITRA positive patients . Only three reports with a total of 5 cases provide significant follow‐up data (>3 months) for the time after discontinuation of treatment with infliximab.…”

Acrodermatitis Continua of Hallopeau Treated Successfully with Ustekinumab and Acitretin after Failure of Tumour Necrosis Factor Blockade and Anakinra

“…IL-23 induces development of Th17 cells and secretion of IL-17 [22]. IL-17 causes neutrophil influx and is involved in neutrophil-mediated inflammatory responses [23]; IL-17 mRNA levels (assessed by quantitative PCR) in lesional skin samples of psoriasis have been found to be higher in pustular psoriasis than in other clinical subtypes [23]; this may explain why ustekinumab has been successfully used once in generalized pustular psoriasis [24]; moreover, it has been shown that successful treatment of generalized pustular psoriasis by infliximab + acitretin was followed by a marked reduction of IL-12 and IL-23 expression in the skin (evaluated by immunohistochemistry) [25]. …”

Childhood Generalized Pustular Psoriasis: Longtime Remission With Combined Infliximab and Methotrexate Treatment

“…Generalized pustular psoriasis (GPP, or von Zumbusch psoriasis) in childhood is a rare and potentially life‐threatening disease characterized by acute onset of sterile pustular eruptions on erythematous skin with general ill health . In severe cases, conventional established agents such as cyclosporine, methotrexate, and retinoids may be ineffective and toxic to certain organs . Infliximab, a chimeric monoclonal antibody against tumor necrosis factor α (TNF‐α), has been used beneficially in several cases of GPP refractory to other treatment in adults and in one child .…”