Scabies itch: an update on neuroimmune interactions and novel targets

Abstract

Frequently described as 'the worst itch' one can ever experience scabies itch is the hallmark of Sarcoptes scabiei mite infestation. Notably, the itchiness often persists for weeks despite scabicides therapy. The mechanism of scabies itch is not yet fully understood, and effective treatment modalities are still missing which can severely affect the quality of life.The aim of this review is to provide an overview of the scope of itch in scabies and highlight candidate mechanisms underlying this itch. We herein discuss scabies itch, with a focus on the nature, candidate underlying mechanisms and treatment options. We also synthesize this information with current understanding of the mechanisms contributing to non-histaminergic itch in other conditions. Itch is a major problem in scabies and can lead to grave consequences. We provide the latest insights on host-mite interaction, secondary microbial infection and neural sensitization with special emphasis on keratinocytes and mast cells to better understand the mechanism of itch in scabies. Also, the most relevant current modalities remaining under investigation that possess promising perspectives for scabies itch (i.e. proteaseactivated receptor-2 (PAR-2) inhibitor, Mas-related G protein-coupled receptor X2 (MRGPRX2) antagonist) are discussed. Greater understanding of these diverse mechanisms may provide a rational basis for the development of improved and targeted approaches to control itch in individuals with scabies.

Inhibition of MRGPRX2 but not FcεRI or MrgprB2-mediated mast cell degranulation by a small molecule inverse receptor agonist

“…A unique feature of MRGPRX2 is that in addition to FDA-approved cationic drugs, it can be triggered by a wide range of endogenous agonists such as the neuropeptides substance P (SP), cortistatin, neuromedin, pro-adrenomedullin peptide (PAMP-12), eosinophil-derived major basic proteins and the host defense peptides ( 1 , 7 – 10 ). Furthermore, MRGPRX2 has recently been implicated in the pathogenesis of mastocytosis ( 11 ), neurogenic inflammation ( 12 ), chronic urticaria ( 13 ), chronic prurigo ( 8 ), rosacea ( 14 , 15 ), atopic dermatitis ( 16 ), and allergic contact dermatitis/itch ( 17 ). Thus, given the new and emerging role of MRGPRX2 on the pathogenesis of a variety of cutaneous conditions, the development of high-affinity receptor inhibitors may provide a novel approach for the modulation of these IgE-independent MC-mediated disorders ( 18 ).…”

Tropical parasitic itch in returned travellers and immigrants from endemic areas

“…Our recent study found that scabies-induced pruritus is non-histaminergic, but has several elevated neural receptors (PAR2, TRPA1, TRPV1) as well as type 2 inflammation with IL-31 and periostin. 56,57 The first-line topical treatment for scabies traditionally has been permethrin cream, 55 although a recent systematic review has found that the treatment regimens combination permethrin plus oral ivermectin, topical ivermectin and synergized pyrethrins have the highest cure, lowest risk of persistent itching and lowest adverse events, respectively. 58 Alternative options include topical ivermectin, sulphur, benzyl benzoate and crotamiton.…”

“…Pruritus may also arise from a host immune response to the mite and have contributions from secondary infection. Our recent study found that scabies‐induced pruritus is non‐histaminergic, but has several elevated neural receptors (PAR2, TRPA1, TRPV1) as well as type 2 inflammation with IL‐31 and periostin 56,57 …”

“…58 Alternative options include topical ivermectin, sulphur, benzyl benzoate and crotamiton. [55][56][57][58][59][60][61] For patients who cannot tolerate topical treatments, oral ivermectin alone has shown similar efficacy. 59,60 Treatments that are not recommended are lindane, which has potential neurotoxicity and carcinogenicity, and malathion, which has low cure rates yet high adverse events.…”

“…The first‐line topical treatment for scabies traditionally has been permethrin cream, 55 although a recent systematic review has found that the treatment regimens combination permethrin plus oral ivermectin, topical ivermectin and synergized pyrethrins have the highest cure, lowest risk of persistent itching and lowest adverse events, respectively 58 . Alternative options include topical ivermectin, sulphur, benzyl benzoate and crotamiton 55–61 . For patients who cannot tolerate topical treatments, oral ivermectin alone has shown similar efficacy 59,60 .…”