Progress of Pruritus Research in Atopic Dermatitis

Abstract

-Atopic dermatitis is a common skin disease affecting up to 10% of children and approximately 2% of adults. Atopic dermatitis exhibits four major symptoms, including intense itching, dry skin, redness and exudation. The "itch-scratch-itch" cycle is one of the major features in atopic dermatitis. The pathophysiology and neurobiology of pruritus is unclear. Currently there are no single and universally effective pharmacological antipruritic drugs for treatment of atopic dermatitis. Thus, controlling of itch is a very important unmet need in patients suffering from atopic dermatitis. This article will update progress during the past 10 years of research in the field of pruritus of atopic dermatitis, focusing on aspects of pruritogens (including inflammatory lipids, histamine, serotonin, proteinases, proteinase-activating receptors, neurotransmitters, neuropeptides, and opioid peptides), antipruritic therapies, and emerging new targets. Based on recent progress, researchers expect to identify exciting possibilities for improved treatments and to develop new antipruritic drugs acting through novel targets, such as histamine H4 receptor, gastrin-releasing peptide receptor, MrgprA3, thromboxane A2 receptor and the putative SPC receptor. Keywords: Pruritus, Atopic dermatitis, Pruritogen, Antipruritic therapy, New targetAtopic dermatitis (AD) is a common skin disease that affects up to 10% of children and approximately 2% of adults in the general population (Leung and Soter, 2001). The socio-economic losses resulting from the disease are high; the cost of illness to the third-party payer for AD ranges from US $0.9 billion to US $3.8 billion (Ellis et al., 2002). The quality-of-life is remarkably lowered by AD. The genetic background, in combination with several environmental factors, results in this chronic remittent skin disease. AD exhibits four major symptoms including intense itching (pruritus), dry skin (xerosis), redness (erythema) and exudation. The "itch-scratch-itch" cycle is a common feature of AD. Scratching can cause bleeding, secondary infection (bacterial, fungal and/or viral) and thickening of the skin (lichenification) (Lewis-Jones, 2005). Itching is the predominant symptom of AD and is also an important diagnostic feature of systemic disease (Malekzad et al., 2009).The pathophysiology and neurobiology of pruritus are unclear. Therefore it is not surprising that anti-pruritus therapy is not well established and the choice of therapeutic agents is limited. However, recent progress over the past 10 years has provided insights into the neurophysiology of pruritus and is opening up exciting possibilities for development of new antipruritic drugs (Yosipovitch and Papoiu, 2008;Liu et al., 2009;Sun et al., 2009).Itch can be regarded as a cutaneous sensory perception, which requests excitation of specialized itch receptors in the skin. Increased amounts of neurofilament-, protein gene product (PGP) 9.5-, calcitonin gene-related peptide (CGRP)-, and substance P (SP)-positive nerve fibres have been observe...

Commiphora myrrha inhibits itch‑associated histamine and IL‑31 production in stimulated mast cells

“…The majority of drugs used for the treatment of itch, particularly in AD, have been demonstrated to be ineffective. This is due to the sole targeting of the histamine pathways for which histamine is not the only mediator of itch (15). As such, there is an urgent requirement to develop drugs that will target histamine-dependent and histamine-independent itch in AD.…”

“…small red/purple spots, small and dilated blood vessels on the surface of the skin and skin thinning, atrophy (14). Chronic itch is difficult to treat as current therapeutic options are frequently ineffective, which emphasizes the requirement for more effective therapeutic approaches (15). Furthermore, difficulties are experienced due to the failure of most antihistamines used in AD treatment, as histamine is not the sole mediator of itch (16).…”

The Implications of Pruritogens in the Pathogenesis of Atopic Dermatitis

“…PAF amplifies the immune response by triggering degranulation, chemotaxis, and adhesion of immune cells, such as eosinophils and MCs [34]. Intradermal injection of PAF can induce wheal and itch, which is related to histamine release from MCs via a neurogenic response because it can be blocked by nerve blocks [35][36][37]. A post hoc analysis in a Japanese study showed that rupatadine, an H1 antihistamine with a PAF antagonist improved total pruritus score in patients with AD [11].…”

Neuroimmunological Mechanism of Pruritus in Atopic Dermatitis Focused on the Role of Serotonin

“…A group of pruritogens including inflammatory lipids, cytokines, neuropeptides, neurotransmitters such as histamine and serotonin (5-hydroxytryptamine, 5-HT), proteases, proteinase-activating receptors, and opioid peptides appears to be related to pruritus in AD (Darsow et al , 1997; Steinhoff et al , 2006; Ständer et al , 2008; Lee, 2010). Among these factors, histamine has been the most well-known pruritogen.…”

“…Because of the multifactorial pathogenesis of AD, no specific, universally effective and well-tolerated antipruritic agent for AD has been developed yet (Lee, 2010). Until now, management of pruritus in AD is mainly confined to imunomodulators such orgas glucocorticoids, cyclosporin A and topical calcineurin inhibitors (tacrolimus and pimecrolimus) (Wahlgren et al , 1990; Hoare et al , 2000; Hanifin et al , 2001; Luger et al , 2001).…”