Exanthem with Cryopyrin Associated Periodic Syndromes and Consideration of IL-1 Targeted Therapy for Neutrophilic Predominant Urticaria

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The article by Kambe et al. 1 is an excellent review on the potential role of the inflammasome in skin disorders.As one of the investigators involved in the discovery of the cryopyrin mutation, I felt compelled to comment on the exanthem associated with cryopyrinassociated periodic syndromes (CAPS), i.e.Familial Cold Auto-Inflammatory Syndrome, Muckle-Wells Syndrome, and Neonatal Onset Multi-System Inflammatory Disorder, referred to as NOMID.This exanthem is not true urticaria 2 as: (1) it is erythematous, macular-papular; (2) it is non-pruritic; (3) it can remain in situ for more than 24 hours; (4) it has dermal infiltration primarily with neutrophils; ( 5) it has no histo-pathological evidence of mast cell degranulation; and ( 6) it is non-responsive to anti-histamines.I suggest that typical urticaria is not a manifestation of CAPS, and in lieu of this terminology, I would recommend use of nomenclature, such as macular-papular exanthem or urticaria-like exanthem, to differentiate from true urticaria associated with vasoactive mediator release secondary to mast cell degranulation.The authors make an important commentary that the cytoplasm of mast cells contain the NLRP-3 inflammasome.The NLRP-3 inflammasome can be stimulated by pathogen-associated molecular patterns (PAMPs) and danger associated membrane patterns (DAMPs), such as urate crystal formation, free ATP, hypokalemia that can develop from catabolic tissue injury.PAMPs and DAMPs can in turn stimulate a cascade of events leading to extracellular secretion of IL-1 cytokines.These cytokines can cause neutrophilic chemotaxis by various immune pathways 3 that could explain skin biopsy proven perivascular neutrophilic predominant urticaria, as described by Tharp. 4 This particular type of urticaria is often less responsive to anti-histamines.Assuming the inflammasome is involved, there may be rationale to consider IL-1 targeted therapy in conjunction with optimal antihistamine treatment for management of these conditions.Moreover, clinicians frequently witness outbreaks of urticaria in association with viral infections and consequently this aforementioned inflammasome mediated mechanism may explain some of the pathobiology associated with infectious-induced urticaria.

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