Itch In Atopic Dermatitis Research Articles

Immune regulation in pathophysiology and targeted therapy for itch in atopic dermatitis

Abstract Itch is an unpleasant perception that provokes one to desire to scratch. It results from the activation of free nerve endings by noxious stimuli in the skin. Atopic dermatitis (AD) is a prototypic inflammatory skin disease that always occurs with an intense itch. AD involves many components of skin-associated lymphoid tissue (SALT). As a disease with polarized T helper 2 cell activation, AD involves eosinophil infiltration and immunoglobulin E, interleukin (IL)-2, IL-4, IL-13, and IL-31 production. As a disease involving an impaired skin barrier, AD is characterized by the enhanced transepidermal entry of allergens and the production of thymic stromal lymphopoietin (TSLP) from epidermal keratinocytes, which worsen atopic march and disease progression. Both immune and epidermal events interact with cutaneous nerve components, including transient receptor potential (TRP) channels and opioid receptors, causing both the perception and propagation of itch from the skin to the brain. In addition to treating itch through TRP channels and opioid receptors, it might be possible to target the various cellular components of SALT, including keratinocytes, eosinophils, and soluble factors, such as IL-31, IL-4, IL-13, IL-31, and TSLP.

The imagined itch: brain circuitry supporting nocebo-induced itch in atopic dermatitis patients.

Psychological factors are known to significantly modulate itch in patients suffering from chronic itch. Itch is also highly susceptible to both placebo and nocebo (negative placebo) effects. Brain activity likely supports nocebo-induced itch, but is currently unknown. We collected functional MRI (fMRI) data from atopic dermatitis (AD) patients, in a within-subject design, and contrast brain response to nocebo saline understood to be allergen vs open-label saline control. Exploratory analyses compared results to real allergen itch response and placebo responsiveness, evaluated in the same patients. Nocebo saline produced greater itch than open saline control (P < 0.01). Compared to open saline, nocebo saline demonstrated greater fMRI response in caudate, dorsolateral prefrontal cortex (dlPFC), and intraparietal sulcus (iPS) - brain regions important for cognitive executive and motivational processing. Exploratory analyses found that subjects with greater dlPFC and caudate activation to nocebo-induced itch also demonstrated greater dlPFC and caudate activation, respectively, for real allergen itch. Subjects reporting greater nocebo-induced itch also demonstrated greater placebo reduction of allergen-evoked itch, suggesting increased generalized modulation of itch perception. Our study demonstrates the capacity of nocebo saline to mimic both the sensory and neural effects of real allergens and provides an insight to the brain mechanisms supporting nocebo-induced itch in AD, thus aiding our understanding of the role that expectations and other psychological factors play in modulating itch perception in chronic itch patients.

Dietary deficiencies of unsaturated fatty acids and starch cause atopic dermatitis-like pruritus in hairless mice.

Hairless mice fed with a special diet (named HR-AD) show atopic dermatitis (AD)-like pruritic skin inflammation that is almost completely resolved with the supplementation of an unsaturated fatty acid (UFA), the linoleic acid (LA). This suggests that the dietary deficiency of LA is the key cause of this dermatitis. However, because there is no appropriate control diet for HR-AD, the involvement of other dietary ingredients cannot be ruled out. Furthermore, it has not yet been tested whether only UFA deficiency can cause such AD-like pruritus. In this study, using semi-purified custom diets, we attempted to reproduce this syndrome. Four-week-old hairless mice were maintained on a widely used standard diet American Institute of Nutrition-76A (AIN-76A), its modifications, or HR-AD. Several modifications of fat and carbohydrate components revealed that dietary deficiency of both UFAs and cornstarch was required to induce severe skin barrier dysfunction as typically occurred in HR-AD-fed mice. An UFA- and cornstarch-deficient diet caused severe AD-like pruritus comparable to HR-AD, despite weak Th2 immune responses and absence of immunoglobulin E production. On the other hand, a diet lacking UFAs but containing cornstarch significantly alleviated the development of pruritic dermatitis. Furthermore, the supplementation of wheat starch similarly improved skin barrier function. In conclusion, this study showed that a lack of certain starches might also be the cause of diet-induced AD. Our findings could help to reproduce the diet-induced AD itch model and also provide evidence that certain starches can have protective and ameliorative effects on AD-like pruritus.

Therapeutic Interventions for Itch in AD

Atopic dermatitis (AD) is characterized by severe pruritus, which has a negative impact on the quality of life of patients. AD pruritus is usually of high intensity, occurs predominantly during the night and leads to severe scratching. Thus, the therapy has to focus not only on the suppression of the symptom but also on improvement of sleep and therapy of scratch lesions. Today, the therapy of AD pruritus is mainly based on conventional topical and systemic anti-inflammatory drugs and off-label application of mu-opioid receptor antagonists, the antidepressant mirtazapine, and – without evidence from controlled studies – the neurokinin-1 receptor antagonist aprepitant. The pathophysiology of AD-associated pruritus is still not fully understood; however, recent identification of several key mediators and mechanisms might enable development of novel therapies such as receptor antagonists for neurokinin 1, histamine 4, interleukin 31, thymic stromal lymphopoietin (TSLP), and nerve growth factor (NGF). Controlled studies that are currently being carried out can be expected to pave the way for improved treatment options in AD pruritus.

Itch in atopic dermatitis: from pathogenesis to treatment

For allergists, itch is the most important symptom of atopic dermatitis (AD), and at the same time, the most difficult-to-manage complaint of atopic patient. Rather than just one symptom of AD, itch has more profound clinical significance in the following sense: itch, as a key component of so-called ‘itch-scratch’ vicious-cycle, plays a central role in the development and persistence of AD, thus, treating itch is not just alleviating one symptom of AD, but stopping genesis and progress of AD. In other words, itch is AD in itself. Pathomechanism underlying development of itch in AD could be summarized as follows: First, exogenous triggering factors penetrate impaired barrier, leading to allergic skin inflammation. Resulting characteristic itch of AD is amplified through the ‘itch → scratch → inflammation → (again) → itch → …’ vicious-cycle. Thus, pathomechanism-based management strategy could be provided accordingly-avoidance of triggering factor, repair of impaired barrier, control of skin inflammation, and decreasing desire for itch/scratch. Among them, controlling inflammation is thought to be most effective measure based on the clinical experiences, for skin inflammation, as one of key components in ‘itch-scratch-inflammation’ vicious-cycle, at the same time, is a crucial connecting link between OUTSIDE and INSIDE. However, individualized approach should be taken for patient per se. Finally, following topics may be future topics for doctors always hungry for new weapon against AD and patients suffering from this out-of-place (a-top-y) disease: central itch pathway-emerging new hero; neural sensitization - still in the Dark-Ages in terms of diagnosis and management; and scratch-just in its infancy. (Allergy Asthma Respir Dis 2014;2:8-15)

TRPA1-Dependent Pruritus in IL-13–Induced Chronic Atopic Dermatitis

Chronic debilitating pruritus is a cardinal feature of atopic dermatitis (AD). Little is known about the underlying mechanisms. Antihistamines lack efficacy in treating itch in AD, suggesting the existence of histamine-independent itch pathways in AD. Transient receptor potential ankyrin 1 (TRPA1) is essential in the signaling pathways that promote histamine-independent itch. In this study, we tested the hypothesis that TRPA1-dependent neural pathways play a key role in chronic itch in AD using an IL-13-transgenic mouse model of AD. In these mice, IL-13 causes chronic AD characterized by intensive chronic itch associated with markedly enhanced growth of dermal neuropeptide-secreting afferent nerve fibers and enhanced expression of TRPA1 in dermal sensory nerve fibers, their dorsal root ganglia, and mast cells. Inhibition of TRPA1 with a specific antagonist in these mice selectively attenuated itch-evoked scratching. Genetic deletion of mast cells in these mice led to significantly diminished itch-scratching behaviors and reduced TRPA1 expression in dermal neuropeptide containing afferents in the AD skin. Interestingly, IL-13 strongly stimulates TRPA1 expression, which is functional in calcium mobilization in mast cells. In accordance with these observations in the AD mice, TRPA1 expression was highly enhanced in the dermal afferent nerves, mast cells, and the epidermis in the lesional skin biopsies from patients with AD, but not in the skin from healthy subjects. These studies demonstrate a novel neural mechanism underlying chronic itch in AD and highlight the complex interactions among TRPA1(+) dermal afferent nerves and TRPA1(+) mast cells in a Th2-dominated inflammatory environment.

Epidermal Nerve Fibers Modulate Keratinocyte Growth via Neuropeptide Signaling in an Innervated Skin Model

Atopic eczema is a chronic inflammatory skin disease characterized by cutaneous nerve fiber sprouting and epidermal hyperplasia, pointing to an involvement of the peripheral nervous system in cutaneous homeostasis. However, the interaction of sensory neurons and skin cells is poorly understood. Using an innervated skin model, we investigated the influence of sensory neurons on epidermal morphogenesis. Neurons induced the proliferation of keratinocytes, resulting in an increase in the epidermal thickness. Inhibition of calcitonin gene-related peptide (CGRP), but not substance P (SP) signaling, reversed this effect. Human CGRP enhanced keratinocyte proliferation and epidermal thickness in skin models, demonstrating a key role of CGRP in modulating epidermal morphogenesis, whereas SP had only a moderate effect. Innervated skin models composed of atopic skin cells showed increased neurite outgrowth, accompanied by elevated CGRP release. As atopic keratinocytes were sensitized to CGRP owing to higher expression levels of the CGRP receptor components, receptor activity-modifying protein 1 (RAMP1) and receptor component protein (RCP), atopic innervated skin models displayed a thicker epidermis than did healthy controls. We conclude that neural CGRP controls local keratinocyte growth. Our results show that the crosstalk of the cutaneous peripheral nervous system and skin cells significantly influences epidermal morphogenesis and homeostasis in healthy and atopic skin.

The effects of treatment on itch in atopic dermatitis

Pruritus causes significant impairment in the quality of life of patients suffering from atopic dermatitis. Treatments for itch in atopic dermatitis range from simple avoidance of pruritus triggers to more complicated systemic therapy. Several treatments aim to target specific mediators of itch in atopic dermatitis, whereas others improve pruritus by reducing inflammation. Currently the most effective treatments for atopic dermatitis-associated itch are primarily topical or systemic anti-inflammatory agents. Better management of pruritus in atopic dermatitis is an important goal and necessitates the development of novel targeted treatments as well as efficient use of current therapies.

The Role of Transient Receptor Potential Ankyrin-1 (TRPA1) in Chronic Itch in Atopic Dermatitis (AD)

The Role of Transient Receptor Potential Ankyrin-1 (TRPA1) in Chronic Itch in Atopic Dermatitis (AD)

A Novel Topical Formulation Containing Strontium Chloride Significantly Reduces the Intensity and Duration of Cowhage-Induced Itch

The aim of this double-blinded, vehicle-controlled study was to test the antipruritic efficacy of topical strontium to relieve a nonhistaminergic form of itch that would be clinically relevant for chronic pruritic diseases. Itch induced with cowhage is mediated by PAR2 receptors which are considered to play a major role in itch of atopic dermatitis and possibly other acute and chronic pruritic conditions. The topical strontium hydrogel formulation (TriCalm®) was tested in a head-to-head comparison with 2 common topical formulations marketed as antipruritics: hydrocortisone and diphenhydramine, for their ability to relieve cowhage-induced itch. Topically-applied strontium salts were previously found to be effective for reducing histamine-induced and IgE-mediated itch in humans. However, histamine is not considered the critical mediator in the majority of skin diseases presenting with chronic pruritus. The current study enrolled 32 healthy subjects in which itch was induced with cowhage before and after skin treatment with a gel containing 4% SrCl2, control vehicle, topical 1% hydrocortisone and topical 2% diphenhydramine. Strontium significantly reduced the peak intensity and duration of cowhage-induced itch when compared to the control itch curve, and was significantly superior to the other two over-the-counter antipruritic agents and its own vehicle in antipruritic effect. We hereby show that a 4% topical strontium formulation has a robust antipruritic effect, not only against histamine-mediated itch, but also for non-histaminergic pruritus induced via the PAR2 pathway, using cowhage.

OA08.04. Brain circuitry subserving acupuncture relief of itch in atopic dermatitis: an fMRI study

Purpose Chronic itch is a prevalent symptom of many inflammatory skin disorders, including atopic dermatitis (AD). While conventional systemic approaches to reduce AD itch have shown limited efficacy and/or significant side effects, several recent studies have demonstrated effectiveness of acupuncture for reducing itch in healthy adults and AD. We sought to evaluate the brain circuitry underlying acupuncture reduction of itch.

Clinical characterizations of itch in atopic dermatitis and chronic urticaria

Clinical characterizations of itch in atopic dermatitis and chronic urticaria

Acupuncture compared with oral antihistamine for type I hypersensitivity itch and skin response in adults with atopic dermatitis – a patient‐ and examiner‐blinded, randomized, placebo‐controlled, crossover trial

Itch is the major symptom of atopic dermatitis (AD). Acupuncture has been shown to exhibit a significant effect on experimental itch in AD. Our study evaluated acupuncture and antihistamine itch therapy (cetirizine) on type I hypersensitivity itch and skin reaction in AD using a patient and examiner-blinded, randomized, placebo-controlled, crossover trial. Allergen-induced itch was evaluated in 20 patients with AD after several interventions in separate sessions: preventive (preceding) and abortive (concurrent) verum acupuncture (VAp and VAa), cetirizine (10mg, VC), corresponding placebo interventions (preventive, PAp, and abortive, PAa, placebo acupuncture; placebo cetirizine pill, PC) and a no-intervention control (NI). Itch was induced on the forearm and temperature modulated over 20min, using our validated model. Outcome parameters included itch intensity, wheal and flare size and the D2 attention test. Mean itch intensity (SE: 0.31 each) was significantly lower following VAa (31.9) compared with all other groups (PAa: 36.5; VC: 36.8; VAp: 37.6; PC: 39.8; PAp: 39.9; NI: 45.7; P<0.05). There was no significant difference between VAp and VC (P>0.1), although both therapies were significantly superior to their respective placebo interventions (P<0.05). Flare size following VAp was significantly smaller (P=0.034) than that following PAp. D2 attention test score was significantly lower following VC compared with all other groups (P<0.001). Both VA and cetirizine significantly reduced type I hypersensitivity itch in patients with AD, compared with both placebo and NI. Timing of acupuncture application was important, as VAa had the most significant effect on itch, potentially because of counter-irritation and/or distraction. Itch reduction following cetirizine coincided with reduced attention.

Involvement of leukotriene B4 in spontaneous itch-related behaviour in NC mice with atopic dermatitis-like skin lesions

To elucidate the mechanisms of severe itch in atopic dermatitis, we investigated the role of leukotriene B(4) , a potent itch mediator, in spontaneous itch-related behaviour in NC mice with atopic dermatitis-like skin lesions. Topical application of the BLT leukotriene B(4) receptor antagonist ONO-4057 inhibited spontaneous itch-related behaviour. The concentration of leukotriene B(4) was significantly increased in the lesional skin. The expression levels of 5-lipoxygenase were also elevated in the lesional skin, yet present throughout the epidermis of both healthy and lesional skin. These results suggest a role for leukotriene B(4) in chronic dermatitis-related itch. Sphingosylphosphorylcholine (SPC) was increased in the epidermis of the lesional skin. Moreover, intradermal injection of SPC elicited itch-related behaviours in healthy mice. Because SPC induces itch-related responses through the production of leukotriene B(4) in keratinocytes (J Invest Dermatol, 129, 2009, 2854), these results suggest that an increase in SPC induces leukotriene B(4) -mediated itching in chronic dermatitis. BLT1 receptor and 5-lipoxygenase in the skin may be effective pharmacological targets for the treatment of itch in atopic dermatitis.

Management of Itch in Atopic Dermatitis

Atopic dermatitis is a common, pruritic, inflammatory skin disorder. Chronic, localized, or even generalized pruritus is the diagnostic hallmark of atopic dermatitis, and its management remains a challenge for physicians. The threshold for itch and alloknesis is markedly reduced in these patients, and infections can promote exacerbation and thereby increase the itch. Modern management consists of anti-inflammatory, occasionally antiseptic, as well as antipruritic therapies to address the epidermal barrier as well as immunomodulation or infection. Mild forms of atopic dermatitis may be controlled with topical therapies, but moderate-to-severe forms often require a combination of systemic treatments consisting of antipruritic and immunosuppressive drugs, phototherapy, and topical compounds. In addition, patient education and a therapeutic regimen to help the patient cope with the itch and eczema are important adjuvant strategies for optimized long-term management. This review highlights various topical, systemic, and complementary and alternative therapies, as well as provide a therapeutic ladder for optimized long-term control of itch in atopic dermatitis.

Contagious itch in humans: a study of visual ‘transmission’ of itch in atopic dermatitis and healthy subjects

Anecdotal evidence suggests that 'contagious' itch occurs in daily life when we see other people itch and scratch. This phenomenon has not previously been studied systematically, and factors which can amplify itch perception were unknown. We investigated whether exposure to visual cues of itch can induce or intensify itch in healthy subjects and patients with atopic dermatitis (AD). Participants received histamine or a saline control delivered to the forearm and were asked to watch short video clips of people scratching. Spontaneous scratching induced by visual cues was monitored and analysed. Patients with AD reported a higher itch intensity and scratched more frequently while watching itch videos, even in the presence of mock itch stimuli. Human susceptibility to develop itch when exposed to visual cues is confirmed; it appears to be amplified in patients with AD. These findings suggest that interpersonal social cues can dramatically alter the subjective sensory experience of itch.

Pharmacological control of itch cholinergic constituent in atopic dermatitis patients

The aim of the study. To study pharmacological efficacy of antihistamines with both M-holino- and H-histaminoreceptors activity and with electoral effect on H1- histaminoreceptors on acetylholine - induced itch in atopic dermatitis (AD) patients. Materials and methods. 60 AD patients were investigated. All patients were divided on 2 groups. The 1-st group took chloropiramine hydrochloride 25 mg three times daily for 7 days. The 2-d group took cetirizine hydrochloride 10 mg once daily for 7 days. Microcirculation in two symmetric sites of the intact skin area of forearms was estimated with laser doppler flowmetry in standard conditions. Then 20 µIΛ of 0,5 M acetylholine (ACH) solution was injected intracutaneously into a back surface of the left forearm (for control the same volume of 0,9% NaCl solution was injected into a symmetric point of the right forearm) and during 20 minutes the skin reaction was measured with microcirculation index (1sm proximately ACH injection) and local sensation was estimated by means of visual analog scale before treatment, on 7th day of antihistamines treatment and 3d day after treatment. Also index SCORAD, intensity of itch, facts of diary self-control was estimated before treatment, on 7th day of antihistamines treatment and 3d day after treatment. Results. AD patients felt an itch in the ACH injection site before the beginning of antihistamines administration. All patients from the lgroup and patients with mild and moderate dermatitis on the 3-rd day after antihistamines treatment felt ACH-induced tingling and burning. All patients from the 2 group and severe AD patients from the 1 group felt a weak itch in the ACH injection site at the 7-th day of administration and at the 3-rd day after antihistamines treatment completion. Intracutaneous ACH-injection increased cutaneous blood-flux, weal and flare reactions in mild and moderate AD; in severe AD there was no increasing of cutaneous blood-flux, weal and flare reactions, but a significant increased intensity and duration of itch. During chloropiramine and cetirizine treatment the recovery of normal reaction of skin was established. Chloropiramine demonstrated long-term reduction of itch at the 3-d day after the treatment completion as compared with cetirizine. Conclusions: Administration of lgeneration antihistamines with anthicholinergic activity in complex therapy of AD patients is more preferable to reduce itch.

Mechanisms of itch in atopic dermatitis

Pruritus is a constant and principal symptom of atopic dermatitis (AD), because of it's impact on quality of life. There fore studying of itch mechanisms is actual and could substantiate the ways of AD management. The present review is devoted to consideration of the modern data on this problem.

Analysis of the Mechanism for the Development of Allergic Skin Inflammation and the Application for Its Treatment: Mechanisms and Management of Itch in Atopic Dermatitis

Although the identification of neural pathways for histamine-induced itch was a breakthrough in itch research, other pathways also seem to be involved in itch. In regard to itch of atopic dermatitis, neural sensitization complicates its mechanisms. Inflammatory mediators such as bradykinin that, normally, do not induce itch can function as pruritogens under neural sensitization, which also affects the treatment to a considerable extent. Complete inhibition of skin inflammation is, for now, the most effective way to suppress itching in atopic dermatitis, since there might be countless potential mediators inducing itch. Centrally acting anti-pruritic drugs as well as drugs against neural sensitization are prospective treatments for itch of atopic dermatitis.

Itch characteristics in atopic dermatitis: results of a web-based questionnaire

Itch significantly impairs the quality of life of patients with atopic dermatitis. However, only a few previous studies have examined the specific characteristics of itch in atopic dermatitis. To examine the frequency, intensity and perceived characteristics of pruritus among individuals with atopic dermatitis. Questionnaire reliability and validity were established in pilot testing. Survey participants completed the comprehensive, web-based 'Characteristics of itch' questionnaire. Participants provided anonymous demographic information and answered questions regarding itch intensity, frequency, timing, duration, location, associated symptoms and itch descriptors. A total of 304 individuals with atopic dermatitis completed the web-based questionnaire. Itch occurred at least once daily in 91% of the individuals surveyed. Of the 32 itch descriptors rated by survey participants, 31 demonstrated a statistically significant positive correlation with the participants' ratings of itch intensity (P < 0.001). More than half the survey participants reported pain (59%) and heat sensation (53%) associated with itch. The questionnaire was found to be a useful tool in characterization of itch. Pain appears to be an important component of atopic dermatitis. The strong correlation between itch descriptors and itch intensity suggests that such descriptors serve as strong indicators of the symptomatology in atopic dermatitis.