Pruritus In Atopic Dermatitis Research Articles

299 IL-31/IL-31 receptor alpha interaction augments IL-4-induced Ccl 17 and Ccl 22 production in dendritic cells

One of characteristic features of atopic dermatitis (AD) is severe pruritus that is closely related to disease activity. Recent studies have shown that IL-31 is one of key determinants of pruritus in AD. Furthermore, anti-IL-31 receptor alpha (IL-31RA) antibody treatment has been reported to show a clinical improvement of pruritus. Therefore, IL-31 has been thought to be an important cytokine to regulate pruritus and disease activity in AD; however, how IL-31 is involved in the immune response in AD has been largely unknown. Epidermal Langerhans cells (LCs) and dermal dendritic cells (DCs) derived from bone marrow cells have been reported to play a critical role in the pathogenesis of AD. LCs and DCs produce Ccl 17 and Ccl 22 that chemoattracts Th2 cells, which leads to the development of AD. Therefore, we aimed to clarify how IL-31/IL-31RA interaction affects functions of DCs including production of Ccl 17 and Ccl 22. To investigate this, we analyzed murine bone marrow derived-DCs (BMDCs) stimulated with IL-4. We found that IL-31RA expression was upregulated by IL-4 stimulation in a dose-dependent manner in BMDCs. Furthermore, IL-4 upregulated production of Ccl 17 and Ccl 22, which was enhanced by IL-31, whereas IL-31 alone did not produce them. These data suggest that IL-4 mediates IL-31RA expression and IL-31/IL-31RA interaction augments production of Ccl 17 and Ccl 22 in BMDC, which promotes Th2-deviated immune response in AD. Since we have previously reported that soy bean tar Glyteer, an aryl hydrocarbon receptor (AHR) ligand, impairs IL-4/Stat 6 signaling in BMDCs, we examined whether Glyteer affected IL-31RA expression induced by IL-4 stimulation. Glyteer inhibited upregulation of IL-31RA expression induced by IL-4 in a dose-dependent manner. Also, Glyteer inhibited production of Ccl 17 and Ccl 22 induced by IL-4 and IL-31. Taken together, these data suggest a possibility that treatment using AHR activators such as Glyteer and anti- IL-31RA antibody may synergistically improve pruritus and disease activitity of AD.

560 KPL-716, anti-Oncostatin M receptor beta antibody, reduced pruritus in atopic dermatitis

560 KPL-716, anti-Oncostatin M receptor beta antibody, reduced pruritus in atopic dermatitis

Dietary habits in adult Japanese patients with atopic dermatitis.

Dietary habits can modulate the pathogenesis of atopic dermatitis. We evaluated these habits in adult Japanese patients with atopic dermatitis using a validated, brief-type self-administered diet history questionnaire and compared the results to those of age- and sex-matched healthy controls. Patients with atopic dermatitis showed higher intakes of carbohydrate and potatoes and lower intakes of alcohol, niacin, meat and oils/fats compared with those of the healthy controls. The results of logistic regression analysis showed that the intake of alcohol was negatively associated with atopic dermatitis (odds ratio, 0.905; 95% confidence interval, 0.832-0.983; P=0.0181). The intakes of vitamin B6 and fruit were positively correlated with the severity scoring of atopic dermatitis. Multiple regression analysis revealed that vitamin B6 intake was a predictor of the severity scoring of atopic dermatitis (β=26.98508709, t=2.3995292, P=0.01933781). The intakes of vegetable fat, n-6 polyunsaturated fatty acid, and confections were lower in the severe atopic dermatitis group (severity scoring of atopic dermatitis, ≥33) than those in the mild group. Atopic dermatitis is negatively associated with alcohol intake, and intake of vitamin B6 is a predictor of severity scoring of atopic dermatitis. The intake of n-6 polyunsaturated fatty acid is lower in the severe atopic dermatitis group than that in the mild group. Further study is warranted on the relationships of these results with abnormal immune responses, impaired skin barrier or pruritus in atopic dermatitis.

Immune mediators and therapies for pruritus in atopic dermatitis and psoriasis

AbstractAtopic dermatitis (AD) and psoriasis (Pso) are two common inflammatory skin diseases which are symptomatically characterized by pruritus to variable degrees. Whereas AD is nearly always associated with pruritus, only 50%‐70% of patients with Pso suffer from itching. Within the last decade, the development of biologic agents targeting specific cytokines or cytokine receptors has led to tremendous progress in suppressing inflammation (and thus improving quality of life) in these two diseases. While suppressing inflammation would generally reduce pruritus in these inflammatory diseases, pruritus is still recalcitrant for treatment in some patients due to relative lack of therapeutics that specifically inhibit pruritus signaling. There is abundant evidence that certain cytokines and neuropeptides‐ion channels signaling mediate pruritus that is independent of inflammation in AD and psoriasis. Of note, Janus kinase (JAK) and nerve growth factor (NGF)‐tropomyosin receptor kinase A (TrkA)‐transient receptor potential vanilloid 1 (TRPV1) signaling partially regulates pruritus in AD and psoriasis. JAK kinases inhibitors decrease the extent of itch in patients with AD and psoriasis. In clinical trials, topical inhibitors of TrkA and TRPV1 have been reported to reduce pruritus in patients with Pso and AD, respectively. In this article, we review recent literature knowledge regarding the mechanisms underlying pruritus in AD and Pso, providing hypotheses for why pruritus may be more common in AD than in Pso. In light of the different mechanisms underlying these two diseases, the current and developing therapeutics, either in human clinical trials or animal studies, for targeting pruritus are also discussed.

A novel hydrocortisone-ethanol gel ointment for treating atopic dermatitis (eczema) in children: A double blind, randomized, controlled clinical trial

Importance: Current treatments for moderate to severe atopic dermatitis (AD) in children are limited by incomplete efficacy, long time to benefit, and parental concerns about safety. This study evaluated a novel ointment for treating AD containing 0.83% hydrocortisone and 17% dispersed ethanol gel micro bubbles. Observations:20 children with moderate to severe AD participated in a one-week double blind, randomized, and controlled clinical trial. They were randomly assigned to apply BID either an ointment with 1% hydrocortisone ointment (HC) or a novel ointment containing 1% hydrocortisone and dispersed ethanol gel droplets (HC-EG). The primary endpoint was superiority of HC-EG over HC ointment in SCORAD score improvement during therapy. A secondary endpoint was improvement in pruritus score during therapy. Both the primary and secondary endpoints were reached in this study. SCORAD score improved 74% on average with HC-EG ointment vs 41% with HC ointment (p=.02). Pruritus score improved 68% on average with HC-EG ointment vs 37% with HC ointment (p=.009). No toxicity requiring stopping therapy was observed in either treatment group. Conclusions and Relevance: Inthis small controlled study HC-EG ointment was superior to HC ointment both in improving visible rash and pruritus of AD. Parents felt HC-EG ointment was safe because it contains no prescription corticosteroids, prescription immunosuppressants, or antibiotics. Independent larger studies would be a next step in evaluating further this new way to treat AD.

Correlation between Serum Interleukin-31 Level and the Severity of Atopic Dermatitis in Children

Background: Atopic dermatitis (AD) is a chronic inflammatory skin disease, characterized by intense itch, typical localization and a specific image of skin lesions. Pathogenesis of pruritus in AD is not fully understood, but recent studies emphasize the role of interleukin-31 (IL-31). This relatively recently described cytokine is considered to be a potential mediator inducing pruritus in AD. Aim of the Work: was to assess the correlation of serum IL-31 level and the disease severity in children with AD. Patients and Methods: a case control study. Sera were obtained from 50 AD children and 30 healthy volunteers. IL-31 levels were measured using ELISA with standard kits from EIAab R&D Systems. Serum IL-31 levels were correlated with AD disease activity. Disease severity in children with AD was assessed using the SCORAD (Severity scoringof atopic dermatitis) index. Results: Serum IL-31 level was significantly higher in AD children (Mean ± SD 99.73 ± 75.93) than in healthy children (Mean ± SD 54.01 ± 57.36), (p-value = 0.019). Serum IL-31 levels correlated positively with the calculated severity score (SCORAD index), (rs = 0.480, p- value <0.001) Conclusion: The results of this study confirm the importance of IL-31 in AD pathophysiology. Serum IL-31 level is an objective reliable marker of AD severity in children. It may represent a novel target for antipruritic drug development.

Correlation between Serum Interleukin-31 Level and the Severity of Atopic Dermatitis in Children

Background: Atopic dermatitis (AD) is a chronic inflammatory skin disease, characterized by intense itch, typical localization and a specific image of skin lesions. Pathogenesis of pruritus in AD is not fully understood, but recent studies emphasize the role of interleukin-31 (IL-31). This relatively recently described cytokine is considered to be a potential mediator inducing pruritus in AD. Aim of the Work: was to assess the correlation of serum IL-31 level and the disease severity in children with AD. Patients and Methods: a case control study. Sera were obtained from 50 AD children and 30 healthy volunteers. IL-31 levels were measured using ELISA with standard kits from EIAab R&D Systems. Serum IL-31 levels were correlated with AD disease activity. Disease severity in children with AD was assessed using the SCORAD (Severity scoringof atopic dermatitis) index. Results: Serum IL-31 level was significantly higher in AD children (Mean ± SD 99.73 ± 75.93) than in healthy children (Mean ± SD 54.01 ± 57.36), (p-value = 0.019). Serum IL-31 levels correlated positively with the calculated severity score (SCORAD index), (rs = 0.480, p- value <0.001) Conclusion: The results of this study confirm the importance of IL-31 in AD pathophysiology. Serum IL-31 level is an objective reliable marker of AD severity in children. It may represent a novel target for antipruritic drug development.

Synergistic Effect of H1-Antihistamines on Topical Corticosteroids for Pruritus in Atopic Dermatitis: A Systematic Review and Meta-Analysis

BackgroundAlthough oral antihistamines (H1-histamine receptor antagonists) are the main treatment option for pruritus in general skin dermatosis, their effect in treating pruritus of atopic dermatitis (AD) has not yet been established.ObjectiveWe conducted a systematic review and meta-analysis to evaluate the effectiveness of combined therapy of H1-antihistamines and topical steroids.MethodsWe systematically searched MEDLINE, Embase, and CENTRAL databases for articles published from 1967 to 2015. We identified 1,206 studies and assessed their titles, abstract, and full-text. Random effects meta-analysis was used to calculate mean differences (MD) with 95% confidence intervals (CI).ResultsTwo studies satisfying the inclusion criteria of antihistamine therapy with mandatory topical steroid use were selected. Comparing antihistamine monotherapy with combination therapy, patients treated with the addition of antihistamine to topical corticosteroids showed a statistically significant clinical improvement (standard MD, −0.24; 95% CI, −0.42 to −0.05; p=0.01).ConclusionH1-antihistamines may have a synergistic effect when combined with topical steroids by influencing various associative factors of chronic pruritus in AD.

Barbiturates enhance itch-associated scratching in atopic dermatitis mice: A possible clue to understanding nocturnal pruritus in atopic dermatitis

In chronic pruritic diseases such as atopic dermatitis, pruritus is exacerbated during nocturnal sleep; however, the underlying mechanism remains unclear. We previously demonstrated that acute administration of the sedative-hypnotics ethanol markedly enhanced itch-associated spontaneous scratching in a diet-induced mouse model of atopic dermatitis. In the present study, to expand our previous finding and provide a general mechanism for the central modulation of chronic itch, we examined whether other hypnotic drugs, such as barbiturates and benzodiazepines, also enhance scratching, and further investigated the underlying mechanism. Barbiturates markedly enhanced spontaneous scratching in the atopic dermatitis model but not controls. However, unexpectedly, benzodiazepines only slightly increased scratching, and the selective γ-aminobutyric acid type A (GABAA) receptor agonist, muscimol, had no effect. Local injection studies have demonstrated that barbiturates act at the supraspinal level to enhance scratching. Barbiturate-induced scratching was inhibited not only by GABAA receptor antagonists but also by an L-type voltage-dependent calcium channel (L-VDCC) agonist and an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor agonist. An intracisternally injected AMPA receptor antagonist alone or in combination with an L-VDCC antagonist sufficiently enhanced scratching. Barbiturate-induced scratching enhancement was observed in another atopic dermatitis model, NC/Nga, but not in histamine-induced acute itch model in normal healthy mice. Overall, our results suggest that a synergistic effect among AMPA receptor inhibition, GABAA receptor activation, and L-VDCC inhibition in the brain mediates barbiturate-induced scratching in atopic dermatitis mice. This observation may provide a novel clue to understanding a supraspinal itch mechanism in chronic diseases such as atopic dermatitis.

Serum interleukin-31 level and pruritus in atopic dermatitis: A Meta-analysis.

To investigate associations of interleukin-31 (IL-31) and pruritus in atopic dermatitis (AD) with Meta-analysis. Methods: Materials were extracted from the citations listed in the following databases: PubMed, Science Direct, Web of Science and Cochrane. Key search terms included: atopic dermatitis, pruritus, and IL-31. The Meta-analysis was used to analyze the correlation between pruritws in AD and IL-31 expression level. Results: The Meta-analysis showed that serum IL-31 levels were higher in AD patients than those in the healthy controls. The levels of IL-31 were higher in severe AD patients than those in the mild and moderate AD patients. Moreover, a positive correlation between serum IL-31 levels and severity of pruritus was identified. Conclusion: Increased serum levels of IL-31 generally exist in the AD patients, and it may accelerate the pruritus in the AD patients.

New aspects in systemic treatment of atopic dermatitis

In severe cases of atopic dermatitis (AD) systemic treatment is indicated. So far, cyclosporine and systemic glucocorticosteroids represented the only systemic treatment options approved for the indications of AD in Germany; however, from clinical practice there is increasing evidence for beneficial therapeutic effects in AD by other immunosuppressive or immunomodulatory substances, such as mycophenolate, methotrexate, alitretinoin and ustekinumab. Beyond this, ongoing research activities focus on abetter understanding of genetic and immunological aspects of this chronic inflammatory skin disease. Regarding treatment with mycophenolate, genetic polymorphisms in AD patients could be identified that might predict responsiveness to this medication. Moreover, several new substances specifically targeting inflammation in AD are currently being studied and the first promising treatment effects on skin condition and pruritic symptoms of AD could be observed. As an exceptional result of this development in September 2017 in Europe and therefore in Germany the first biologic as first-line treatment was approved for the indication of moderate to severe AD in adults. Dupilumab is ahuman monoclonal IgG4 antibody that blocks asubunit of the interleukin (IL)-4 and IL-13 receptors, thus inhibiting the proinflammatory effects of these cytokines. Furthermore, the cytokine IL-13 itself, the IL-31 receptor, which is of particular relevance for pruritus in AD, the histamine-4-receptor and Janus kinases represent further promising targets currently being investigated in clinical trials for the treatment of AD.

Serum 25-hydroxyvitamin D levels in patients with skin diseases including psoriasis, infections, and atopic dermatitis.

ABSTRACTThe pathogenetic role of vitamin D as well as its clinical correlation in inflammatory skin diseases is still uncertain. This study aimed to compare serum levels of 25(OH) vitamin D (calcidiol) in outpatients suffering from different skin diseases using the same laboratory method in one study. In routine serum samples of 1,532 patients from the previous 12 months we identified retrospectively 180 (mean age 49.4 years, 80 female, 100 male) and 205 (mean age 36.3 years, 116 female, 89 male) patients with psoriasis (PSO) and atopic dermatitis (AD), respectively. Clinical disease activity and quality of life was evaluated using Physicians Global Assessment Scores (PGA), Dermatology Life Quality Index (DLQI), and a Visual Analog Scale for pruritus in AD, respectively. The median 25(OH)D serum level of all patients (22.97 ng/mL, range 2.61–96.0, n = 1,461) was significantly lower in comparison to healthy controls (41.6 ng/mL, range 16.9–77.57, p < 0.0001, n = 71). In PSO and AD we measured 21.05 ng/mL (44% < 20 ng/mL) and 22.7 ng/mL (39% < 20 ng/mL), respectively (p = 0.152). Among all subgroups, patients with severe acute or chronic infectious skin diseases had the lowest median 25(OH)D serum levels (17.11 ng/mL, n = 94, 66% <20 ng/mL, p < 0,001 vs. AD, p = 0,007 vs. PSO). For PSO and AD there was no significant correlation between 25(OH)D levels and PGA scores and DLQI values, respectively, or the extent of pruritus in AD. 25(OH)D serum levels in inflammatory skin diseases might correlate more with the type of disease and the degree of inflammation than with clinical activity itself.

Management of Itch in Atopic Dermatitis.

Atopic dermatitis (AD) is the most common itchy dermatosis that affects millions of children and adults worldwide. Chronic itch in this condition has significant impact on measures of quality of life, such as sleep. Treating itch in AD has been challenging for decades, but new drugs have emerged in the last year with significant anti-pruritic effect. The optimal treatment regimen for atopic itch addresses barrier dysfunction, inflammation, neural hypersensitivity, and the itch-scratch cycle. Topical moisturizers remain the foundation of treatment and should be used by all patients with AD-associated pruritus. Step-wise therapy, from topical anti-inflammatory creams to systemic monoclonal antibodies and immunosuppressants, is recommended. There are multiple adjuvant therapies that can be used, especially to target itch in the setting of minimal skin inflammation. Finally, patient education, sleep management, and stress relief are important components to optimize outcomes. This review assesses the latest advances and treatment recommendations for pruritus in AD. Finally, suggested therapeutic ladders and emerging treatments are discussed.

Validation of the Severity of Pruritus Scale for the Assessment of Pruritus in Atopic Dermatitis

Abstract Not Available

Emerging role of interleukin-31 and interleukin-31 receptor in pruritus in atopic dermatitis.

Atopic dermatitis (AD) is a chronic or chronically relapsing, eczematous, severely pruritic skin disorder associated with skin barrier dysfunction. The lesional skin of AD exhibits T helper 2 (TH 2)-deviated immune reactions. Interleukin-31 (IL-31), preferentially produced from TH 2 cells, is a potent pruritogenic cytokine, and its systemic and local administration induces scratching behavior in rodents, dogs and monkeys. Recent clinical trials have revealed that administration of an anti-IL-31 receptor antibody significantly alleviates pruritus in patients with AD. In this review, we summarize recent topics related to IL-31 and its receptor with special references to atopic itch.

House Dust Mites Induce Production of Endothelin-1 and Matrix Metalloproteinase-9 in Keratinocytes via Proteinase-Activated Receptor-2 Activation

Background: Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by skin barrier dysfunction and abnormal immune response. House dust mites (HDM) are a major source of allergens, some of which have cysteine and serine protease activities. Keratinocytes stimulated by HDM-derived proteases have been suggested to contribute to the pathogenesis of AD by producing various cytokines. However, whether keratinocytes contribute to the induction of pruritus in AD, especially by producing pruritus-related mediators upon stimulation with HDM-derived proteases, has not been fully elucidated. Methods: We examined whether the production of endothelin-1 (ET-1), matrix metalloproteinase (MMP)-2, and MMP-9 in keratinocytes can be induced by stimulation with Dermatophagoides farinae extracts, and if so, whether pretreatment with a protease inhibitor or proteinase-activated receptor-2 (PAR-2) antagonist affects the production of these mediators in keratinocytes. Results: Although MMP-2 levels were undetectable in the culture supernatants, the production of ET-1 and MMP-9 was increased upon stimulation with HDM extracts in a concentration- and time-dependent manner and suppressed by pretreatment of HDM extracts with serine protease inhibitor, but not with cysteine protease inhibitor. Mite-derived serine proteases also induced ET-1 and MMP-9 production in a concentration- and time-dependent manner. Moreover, pretreatment with a PAR-2 antagonist inhibited the production of ET-1 and MMP-9 in keratinocytes. Conclusion: These results suggest that the activation of PAR-2 on keratinocytes by HDM-derived serine proteases induces the production of ET-1 and MMP-9, and may contribute to the induction of pruritus in AD.

Different therapeutic effects between topical corticosteroid and tacrolimus application on pruritus in atopic dermatitis

Different therapeutic effects between topical corticosteroid and tacrolimus application on pruritus in atopic dermatitis

Atopic Dermatitis: Managing the Itch.

Atopic dermatitis has a substantial impact on sleep, appearance, psychological well-being, and other qualities of life. The visual appearance of lichenification, cheilitis, hyperpigmentation, ichthyosis, and erythema can be socially stigmatizing, and treatment of these symptoms is challenging. In managing pruritus in patients, practitioners should assess and document pruritus through questionnaires at each routine visit. Initially, practitioners should advise patients to employ non-pharmaceutical treatments such as emollients with wet wraps, elimination of triggers, changing scratching habits, and psychological interventions. If these methods of treatment are not successful or if the disease presentation is severe, pharmacological therapies should be employed. This chapter describes the therapeutic ladder for pruritus in atopic dermatitis and discusses each treatment modality in further detail for practitioners to advise their patients.First-line topical pharmaceutical agents include topical glucocorticoids and topical calcineurin inhibitors. Second-line topical agents include coal tar, menthol, capsaicin, or doxepin. After the use of topical agents has been exhausted, primary systemic agents can be applied. These include sedating antihistamines, non-sedating antihistamines, oral glucocorticoids, or cyclosporine A. Finally, neuromodulating or immunomodulating agents can be attempted, including SSRI/SNRIs, TCAs, immunosuppressants, neural modulators, and opioid receptor modulators. Outside of pharmacological treatments, phototherapy has been shown to provide a dramatic improvement of pruritus in atopic dermatitis and can be used at any stage of treatment including as a first-line agent.

Role of cyclosporine A in inhibitory mechanism of pruritus in atopic dermatitis

Atopic dermatitis (AD) is a chronic inflammatory skin disease caused by eczematous, scratching, and cutaneous sensitization due to skin barrier dysfunction and abnormal immune function. Cyclosporine A (CysA) is an immunosuppressive agent which is used as therapeutic drug in patients with severe AD, although the antipruritic mechanisms are poorly understood. This study aims to reveal the mechanisms of itch inhibition in atopic dermatitis and the dose effectiveness of cyclosporine A in pruritus of atopic dermatitis. In this study, we investigated the antipruritic mechanisms of CysA in AD by using NC/Nga mice by repeated application of Dermatophagoides farinae body (Dfb) ointment to the dorsal skins of the neck of NC/Nga mice. Different doses of CysA were injected intraperitoneally to each Dfb-NC/Nga mouse. Skins and dorsal root ganglion (DRG) cells were collected from each mouse for histological examination and gene expression analyses. As a result, intraperitonial (i.p.) injection of 5 mg/kg CysA reduced number of scratching bouts, dermatitis scores and values of transepidermal water loss (TEWL) as well as reducing increased density of epidermal nerve fibers. Meanwhile, i.p. injection of 1 mg/kg CysA was less effective than 5 mg/kg CysA treated-group. In addition, increased expressions of itch-related genes such as MrgprA3, IL-31ra and NK1R in the DRG cells of Dfb-NC/Nga mice were decreased in the DRG of 5 mg/kg CysA treated-mice compared with those in control mice. In conclusion, 5 mg/kg CysA may have therapeutic efficacy in intractable pruritus of AD through reducing the epidermal nerve density and reducing the increased levels of itch-related genes in the DRG.

Efficacy of Astaxanthin for the Treatment of Atopic Dermatitis in a Murine Model.

Atopic dermatitis (AD) is a common chronic inflammatory skin disease associated with various factors, including immunological abnormalities and exposure to allergens. Astaxanthin (AST) is a xanthophyll carotenoid that has recently been demonstrated to have anti-inflammatory effects and to regulate the expression of inflammatory cytokines. Thus, we investigated whether AST could improve the dermatitis and pruritus in a murine model of AD using NC/Nga mice. In addition to a behavioral evaluation, the effects of AST on the AD were determined by the clinical skin severity score, serum IgE level, histological analyses of skin, and by reverse transcription-PCR and Western blotting analyses for the expression of inflammation-related factors. AST (100 mg/kg) or vehicle (olive oil) was orally administered once day and three times a week for 26 days. When compared with vehicle-treated group, the administration of AST significantly reduced the clinical skin severity score. In addition, the spontaneous scratching in AD model mice was reduced by AST administration. Moreover, the serum IgE level was markedly decreased by the oral administration of AST compared to that in vehicle-treated mice. The number of eosinophils, total and degranulated mast cells all significantly decreased in the skin of AST-treated mice compared with vehicle-treated mice. The mRNA and protein levels of eotaxin, MIF, IL-4, IL-5 and L-histidine decarboxylase were significantly decreased in the skin of AST-treated mice compared with vehicle-treated mice. These results suggest that AST improves the dermatitis and pruritus in AD via the regulation of the inflammatory effects and the expression of inflammatory cytokines.