Pruritus In Atopic Dermatitis Research Articles

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 nonpharmaceutical 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, nonsedating 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.

Higher-order sensorimotor circuit of the whole-brain functional network involved in pruritus regulation in atopic dermatitis.

Little is known about the neural mechanisms underlying pruritus regulation in Atopic dermatitis (AD). To investigate the functional changes of the resting-state whole brain network of AD participants and the mechanisms by which they were involved in pruritus regulation. Based on the functional magnetic resonance imaging data from 19 AD participants and 37 healthy controls (HC), a graph-theoretical measure of degree centrality (DC) conjoined with a voxel-level seed-based functional connectivity (FC) method was used to identify abnormal higher-order nodes and the functionally relevant circuit in AD participants compared to healthy controls (HC). Of 64 participants screened, 19 AD participants (12M/7F, median [IQR] age, 27 [14] years) and 36 HCs (13M/23F, median [IQR] age, 20 [1] years) were enrolled. DC values of the left superior frontal gyrus (LSFG) increased in AD participants and exhibited a negative correlation with the SCORAD score (r = -0.561, p = 0.012) compared with HC. In the FC analysis with LSFG as the seed, FC values of several sensory and motor regions increased in AD participants, highly overlapping with the anatomical distribution of the inferior fronto-occipital fascicle (IFOF). AD participants with severe pruritus exhibited lower levels of DC (T = -2.316, p = 0.033) and FC between the LSFG and left insula (T = -2.203, p = 0.042) than those with mild-to- moderate pruritus. LSFG was involved in pruritus regulation in AD by forming a high-order sensorimotor circuit through the IFOF, a white matter fascicle that proved to provide multimodal integration in motor control and sensory information processing. These results offer more mechanism-guided treatment targets for severe pruritus in AD.

Interleukin-31 in serum and cerebrospinal fluid of dogs with syringomyelia

BackgroundSyringomyelia is a spinal cord cavity containing cerebrospinal fluid (CSF)-like fluid. If syringomyelia asymmetrically involves the dorsal horn grey matter of the spinal cord, affected dogs show increased signs of dysesthesia and neuropathic pain, like increased itching behaviour. In the dorsal horn, amongst others, receptors for Interleukin-31 (IL-31) can be found. IL-31 is one of the main cytokines involved in the pathogenesis of pruritus in atopic dermatitis in different species. This study investigates suspected elevated levels of IL-31 in serum and CSF of dogs showing signs of pain or increased itching behaviour related to syringomyelia. The IL-31 were measured in archived samples (52 serum and 35 CSF samples) of dogs with syringomyelia (n = 48), atopic dermatitis (n = 3) and of healthy control dogs (n = 11) using a competitive canine IL-31 ELISA.ResultsMean serum IL-31 level in dogs with syringomyelia was 150.1 pg/ml (n = 39), in dogs with atopic dermatitis 228.3 pg/ml (n = 3) and in healthy dogs 80.7 pg/ml (n = 10). Mean CSF IL-31 value was 146.3 pg/ml (n = 27) in dogs with syringomyelia and 186.2 pg/ml (n = 8) in healthy dogs. Individual patients with syringomyelia (especially dogs with otitis media or otitis media and interna or intervertebral disc herniation) showed high IL-31 levels in serum and CSF samples, but the difference was not statistically significant. IL-31 serum and CSF levels did not differ significantly in dogs with syringomyelia with or without itching behaviour and with or without signs of pain.ConclusionBased on this study, increased IL-31 levels seem not to be correlated with itching behaviour or signs of pain in dogs with syringomyelia, but might be caused by other underlying diseases.

Blockade of HMGB1 Reduces Inflammation and Pruritus in Atopic Dermatitis by Inhibiting Skin Fibroblasts Activation

Introduction: Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by relapsed eczema and serious pruritus. High-mobility group box 1 protein (HMGB1) is a nuclear-binding protein and serves as an alarmin to promote inflammatory responses. Methods: In this study, we established an AD mouse model by topical use of MC903 on ears and then used a specific HMGB1-binding peptide cIY8 and a HMGB1 inhibitor of glycyrrhizin to investigate HMGB1 on fibroblast activation in the pathogenesis of AD-like symptoms. Results: Topical use of cIY8 and oral use of glycyrrhizin significantly improved the MC903-induced AD-like symptoms and pathological changes of the ears and scratching behavior in an AD mouse model; cIY8 treatment inhibited the higher mRNAs of IL-1α, IL-4, IL-5, IL-13, and IL-31 in the ears. In human fibroblasts, HMGB1 caused nuclear translocation of NF-kB, and the nuclear translocation could be inhibited by pre-treatment of HMGB1 with cIY8, suggesting that NF-κB signaling pathway participates in the HMGB1-induced inflammation of AD in fibroblasts and that cIY8 effectively impedes the function of HMGB1. Glycyrrhizin inhibited the Ca²⁺ signaling induced by ionomycin in mouse primary fibroblasts. The fibroblast-related proteins of α-SMA, Hsp47, and vimentin and the pruritus-related proteins of IL-33 and periostin were increased in the ears of the AD mouse model, the ratio of EdU incorporation became higher in mouse fibroblasts treated with MC903, and the higher proliferation and inflammatory responses of the fibroblasts could be reversed by glycyrrhizin treatment. Conclusions: Fibroblast activation by HMGB1 is one of the critical processes in the development of inflammation and pruritus in the AD mouse model. The specific HMGB1-binding peptide cIY8 and the HMGB1 inhibitor glycyrrhizin inactivate skin fibroblasts to alleviate the inflammation and pruritus in the AD mouse model. Peptide cIY8 may be topically used to treat AD patients in the future.

Selection of Nemolizumab Clinical Dosage for Atopic Dermatitis.

Nemolizumab is a monoclonal antibody directed against the interleukin-31 receptor A subunit, which is involved in the pathogenesis of pruritus and inflammation in atopic dermatitis (AD). Clinical trial results were combined with population PK (popPK) and pharmacokinetic/ pharmacodynamic (PK/PD) models to optimize nemolizumab dosing. Phase 1 and 2a clinical studies indicated that weight-based nemolizumab dosing reduced pruritus in patients with moderate-to-severe AD with good safety and tolerability even at the highest dose (3 mg/kg single dose and 2 mg/kg multiple doses). Nemolizumab PK profile was characterized by a slow absorption with peak serum concentrations reached 4.5-9.2 days post-dose, and a long terminal half-life ranging from 12.6 to 16.5 days. A change from weight-based dosing to flat dose was supported by an additional phase 2b study sponsored by Galderma. Flat dosing provides several practical advantages, including ease of preparation for self- or auto-injection and reduced chance of dosing errors. Doses of 10, 30, and 90 mg were selected based on popPK and PK/PD simulations to result in nemolizumab serum concentrations sufficient to achieve efficacy. Loading doses were administrated at the 2 lower doses in order to achieve target systemic concentrations from the first injection. The efficacy of Nemolizumab in improving cutaneous signs of inflammation and pruritus in AD and its safety profile, combined with popPK and PK/PD analyses, supported selection of the flat-dose regimen of 30 mg (with a 60 mg loading dose) given every 4 weeks subcutaneously for 16 weeks in the phase 3 ARCADIA studies sponsored by Galderma. J Drugs Dermatol. 2023;22(10):1017-1020 doi:10.36849/JDD.7437R1.

English version of Japanese guidance for biologics in treating atopic dermatitis.

This is the English version of the Japanese guidance for biologics in treating atopic dermatitis (AD). The signaling pathway mediated by interleukin (IL)-4 and IL-13 contributes to type 2 inflammatory responses and plays an important role in the pathogenesis of AD. IL-31 is a cytokine mainly produced by activated T cells and is known to be involved in the pruritus of AD. Biologics for AD have been approved, including dupilumab, an anti-IL-4 receptor α antibody that was approved for expanded use in AD in 2018. In 2022, nemolizumab, an anti-IL-31 receptor α antibody, was approved for pruritus of AD, and tralokinumab, an anti-IL-13 antibody, was approved for AD. Physicians who intend to use these drugs should sufficiently understand and comply with the contents of the guidelines prepared by the Japanese Ministry of Health, Labour, and Welfare to promote the optimal use of the drugs. In treatment with biologics, it is important to consider disease factors (activity and severity), treatment factors (dosage and administration as well as the efficacy and safety), and patients' background characteristics (age and comorbidities) and share this information with patients when choosing treatment options. This guidance was developed for board-certified dermatologists who specialize in treating AD, and for promoting the proper use of biologics, taking into account the variety of factors in individual patients.

Fc Epsilon RI-Neuroimmune Interplay in Pruritus Triggered by Particulate Matter in Atopic Dermatitis Patients.

Atopic dermatitis (AD) is the most common chronic relapsing neuroinflammatory skin disease that is characterized by a complex and multifactorial pathophysiology. It reflects a profound interplay between genetic and environmental factors, and a recently disclosed neuroimmune dysregulation that drives skin barrier disruption, pruritus, and microbial imbalance. In terms of the key external environmental players that impact AD, air quality and itch severity linkage have been thoroughly researched. The impact of ambient air pollutants including particulate matter (PM) and AD pruritic exacerbation has been recorded despite reductions in air pollution levels in in developed countries. The developing countries have, on the contrary, experienced significant urbanization and industrialization with limited environmental protection standards in the past decades. This unprecedented construction, petrochemical industry utilization, and increment in population counts has been paired with consistent exposure to outdoor PM. This may present a key cause of AD pruritic exacerbation supported by the fact that AD prevalence has intensified globally in the past 50 years, indicating that environmental exposure may act as a trigger that could flare up itch in vulnerable persons. At the molecular level, the impact of PM on severe pruritus in AD could be interpreted by the toxic effects on the complex neuroimmune pathways that govern this disease. AD has been recently viewed as a manifestation of the disruption of both the immune and neurological systems. In light of these facts, this current review aims to introduce the basic concepts of itch sensory circuits in the neuroimmune system. In addition, it describes the impact of PM on the potential neuroimmune pathways in AD pathogenesis with a special focus on the Fc Epsilon RI pathway. Finally, the review proposes potential treatment lines that could be targeted to alleviate pruritus based on immune mediators involved in the Fc Epsilon signaling map.

Alternative clinical approaches to the treatment of pruritus related with canine atopic dermatitis

Canine atopic dermatitis (CAD) is a genetically inheritable, inflammatory and pruritic skin disease with characteristic clinical features, most commonly associated with IgE antibodies to environmental allergens. Itching is the most prominent clinical finding. Depending on the allergens involved, seasonal or non-seasonal pruritus may occur. 
 In the first active phase of pruritus treatment, which consists of two stages, acute exacerbations should be controlled by drugs with active ingredients such as corticosteroids, oclacitinib, lokivetmab, etc. In the proactive pruritus treatment, it is aimed to prevent exacerbations and prolong the pruritus-free period with maintenance treatment. For this purpose, in addition to active phase of the therapy, different treatment options such as cyclosporine, tacrolimus, antihistamines, essential fatty acids, Palmitoylethanolamide (PEA), topical drugs and shampoos can be used to repair the skin barrier.
 Due to the side effects and costs of the drugs used in the treatment of pruritus in atopic dermatitis, researches on alternative treatment methods are still continuing. Applications such as mesenchymal stem cell therapy, recombinant canine gamma-interferon, luteolin, vitamin D, vitamin E, lactoferricin/verbascoside, mastinib, cannabidiol (CBD), probiotics and vaccination against IL-31 are the alternative treatment options for atopic dermatitis in dogs. However, more studies are needed before their inclusion in our routine clinical practices and added to the guidelines. In this review, it is aimed to provide information about new treatments used for pruritus in CAD and to encourage their use in routine veterinary clinical practice.

Mast cells in type 2 skin inflammation: Maintenance and function.

Mast cells (MCs) are immune cells residing in tissues and playing indispensable roles in maintaining homeostasis and inflammatory states. Skin lesions associated with atopic dermatitis (AD) and type 2 skin inflammation display an increment in MCs, which have both pro- and anti-inflammatory effects. The direct and indirect activations of skin MCs by environmental factors such as Staphylococcus aureus can instigate type 2 skin inflammation in AD with poorly understood mechanisms. Furthermore, both IgE-dependent and -independent degranulation of MCs contribute to pruritus in AD. Conversely, MCs suppress type 2 skin inflammation by promoting Treg expansion through IL-2 secretion in the spleen. Moreover, skin MCs can upregulate gene expression involved in skin barrier function, thus mitigating AD-like inflammation. These functional variances of MCs in AD could stem from differences in experimental systems, their localization, and origins. In this review, we will focus on how MCs are maintained in the skin under homeostatic and inflammatory conditions, and how they are involved in the pathogenesis of type 2 skin inflammation.

Janus-kinase Inhibitors in Pathogenesis and Management of Chronic Urticaria: A Review of the Literature

Background: Chronic urticaria is a long-lasting condition, sometimes with serious comorbidities, severely affecting the quality of life, which makes the patients seek efficient therapies to achieve sustained remissions. The complex nature of urticaria greatly complicates the patients’ responses to appropriate treatments. Objectives: This review was conducted to focus on the Janus kinase (JAK) pathway, evaluate its role as a new biomarker, and discover the efficacy of its inhibitors as novel therapeutic agents in the treatment of refractory chronic urticaria. Methods: Electronic databases of PubMed and SCOPUS were searched to find and evaluate all the reports describing “Janus kinase,” “JAK-STAT pathway,” “chronic urticaria,” “JAK inhibitors,” and “pruritus.” Because itching is the most annoying symptom of chronic urticaria and due to the scarcity of articles conducted on the use of JAK inhibitors in the treatment of this disease, we also reviewed quite a few articles performed on applying JAK inhibitors in the treatment of dermatologic disorders and also pruritus in atopic dermatitis. Results: From the initially retrieved articles, only five were exclusively about the use of JAK inhibitors in the treatment of chronic urticaria. Conclusions: Although JAK inhibitors are widely known as effective therapies in the treatment of some dermatological diseases, we found out that there are not currently sufficient eligible studies confirming the role of JAK inhibitors in the treatment of chronic urticaria. There is therefore a need for more studies regarding the efficacy and safety of these medications in the treatment of refractory chronic urticaria.

Non-Neuronal Kappa Opioid Pathway Profiling in the Skin of Different Chronic Pruritus–Associated Dermatoses

Recent studies argue for an important role of peripheral opioidergic signaling including cutaneous pathways in inflammation, neurons and itch ( Ádám et al., 2022 Ádám D Arany J Tóth KF Tóth BI Szöllősi AG Oláh A Opioidergic Signaling—A Neglected, Yet Potentially Important Player in Atopic Dermatitis. Int J Mol Sci. MDPI. 2022; Google Scholar ). Signal transduction induced by synthetic opiates and endogenous opioid peptides takes place via three types of opioid receptors (OR), the μ-OR (MOR), δ-OR (DOR) and the κ-OR (KOR) ( Tominaga et al., 2007 Tominaga M, Ogawa H, Takamori K. Possible Roles of Epidermal Opioid Systems in Pruritus of Atopic Dermatitis. Journal of Investigative Dermatology. Elsevier Masson SAS; 2007;127(9):2228–2235 Available from: https://linkinghub.elsevier.com/retrieve/pii/S0022202X15335387 Google Scholar ). A specific agonist/receptor combination is usually preferred for activation of the signaling cascade, e.g. morphine/MOR and dynorphin/KOR ( Snyder et al., 2018 Snyder LM, Chiang MC, Loeza-Alcocer E, Omori Y, Hachisuka J, Sheahan TD, et al. Kappa Opioid Receptor Distribution and Function in Primary Afferents. Neuron. Elsevier Inc.; 2018;99(6):1274-1288.e6 Available from: https://doi.org/10.1016/j.neuron.2018.08.044 Google Scholar ). The nervous system is the predominant site of opioid receptor expression including their endogenous agonists (Rogers 2020). However, these can also be found in non-neuronal peripheral cells of the skin ( Kupczyk et al., 2017 Kupczyk P Reich A Hołysz M Gajda M Wysokińska E Kobuszewska A et al. Opioid receptors in psoriatic skin: Relationship with itch. Acta Derm Venereol. 2017; 97: 564-570 Crossref PubMed Scopus (30) Google Scholar ). So far, little is known about the cutaneous expression and function of endogenous opioid peptides and their receptors. This includes the κ-opioidergic system, which is in the current focus of the itch research and already resulted in the first approved peripherally acting KOR agonist difelikefalin. ( Fishbane et al., 2020 Fishbane S Jamal A Munera C Wen W Menzaghi F A Phase 3 Trial of Difelikefalin in Hemodialysis Patients with Pruritus. New England Journal of Medicine. 2020; 382: 222-232 Crossref PubMed Scopus (0) Google Scholar ; Inan et al., 2019 Inan S Huerta A Jensen L Dun N, Cowan A. Nalbuphine, a kappa opiod receptor agonist and mu opioid receptor antagonist attenuates pruritus, decreases IL-31, and increases IL-10 in mice with contact dermatitis. Eur J Pharmacol. 2019; : 864 Google Scholar ) . Interestingly, OPRK1 expression found to be reduced in lesional pruritic skin areas compared to non-lesional, non-pruritic skin areas in patients, with keratinocytes as predominant expression site. Based on these data, itch induced by a cutaneous imbalance in KOR expression with stable expression of MOR has been discussed, forcing the importance of KOR ( Kupczyk et al., 2017 Kupczyk P Reich A Hołysz M Gajda M Wysokińska E Kobuszewska A et al. Opioid receptors in psoriatic skin: Relationship with itch. Acta Derm Venereol. 2017; 97: 564-570 Crossref PubMed Scopus (30) Google Scholar ; Phan et al., 2012 Phan NQ Lotts T Antal A Bernhard JD Ständer S Systemic kappa Opioid receptor agonists in the treatment of chronic pruritus: A literature review. Acta Derm Venereol. 2012; 92: 555-560 Crossref PubMed Scopus (100) Google Scholar ). Therefore, we investigated the KOR, MOR and dynorphin expression in skin biopsies from patients with chronic pruritus-associated inflammatory skin diseases with different pathophysiology and different epidermal pathology. We selected the entities of atopic dermatitis (AD), psoriasis (PSO), chronic nodular prurigo (CNPG), lichen planus (LP), mastocytosis (MAST) and healthy controls.

Chronic pruritus in atopic dermatitis – mechanisms and different ways of treatment, affect on quality of life

Introduction: Pruritus in atopic dermatitis is one of the main symptoms of the disease and the one that causes a significant impact on quality of life. It is important to control itching because it’s not only an unplesant sense. Scratching topically deepen the dermatitis, damages the epidermal barrier causing additional infections possible and makes it harder to acheive a remission of the disease. It is also highly associated with stress and has an impact on mental health of the patient. In this article we present a summary of how pruritus affects the quality of life, mechanisms of pruritus and possible treatment.
 Materials and methods: Our work is based on the articles published in PubMed, medical books and websites. We were looking for the key words such as ‘stress and itch’, ‘pruritus treatment’, ‘chronic itch in atopic dermatitis’, ‘itch and quality of life’.
 Results: Patients with atopic dermatitis should come under miltidisciplinar treatment to acheive the best possible control of symptoms. This will result in higher quality of life and better mental health of the patient.
 Conclusions: There is a high need to develop new targeted medications as contemporary medicine knows a lot more about the mechanism of pruritus. Many new types of treatment are being studied and soon we may have more options to choose in systemic and topical therapy. We should also concetrate more on a mental side of the disease.

Itch and Janus Kinase Inhibitors

Itch is a common skin symptom, with complex aetiology and pathogenesis. It is mediated by 2 pathways, the histaminergic and non-histaminergic pathways. Chronic itch is understood to be processed by the latter and is difficult to treat with traditional pruritus therapies. The Janus kinase and signal transducer and activator of transcription pathway is a signalling mechanism that regulates gene expression through various cytokines. Janus kinase inhibitors, which have been tested and used for several autoimmune diseases, have also been shown to be effective for itch through clinical trials and case reports. Janus kinase inhibitors could be a good choice for pruritus in atopic dermatitis, psoriasis, and other diseases, such as prurigo nodularis and lichen planus, with rapid itch relief compared with conventional treatments. The most common adverse effects reported include nasopharyngitis, acne, and elevated blood creatine phosphokinase levels. Janus kinase inhibitors are currently prescribed with warnings about a potential increase in malignancies and cardiovascular diseases and usage in people of older ages. This review aims to provide knowledge about itch and the Janus kinase and signal transducer and activator of transcription pathway and to analyse the current evidence for itch relief by Janus kinase inhibitors.

Lidocaine alleviates inflammation and pruritus in atopic dermatitis by blocking different population of sensory neurons.

Atopic dermatitis is a common chronic pruritic inflammatory disease of the skin involving neuro-immune communication. Neuronal mechanism-based therapeutic treatments remain lacking. We investigated the efficacy of intravenous lidocaine therapy on atopic dermatitis and the underlying neuro-immune mechanism. Pharmacological intervention, immunofluorescence, RNA-sequencing, genetic modification and immunoassay were performed to dissect the neuro-immune basis of itch and inflammation in atopic dermatitis-like mouse model and in patients. Lidocaine alleviated skin lesions and itch in both atopic dermatitis patients and calcipotriol (MC903)-induced atopic dermatitis model by blocking subpopulation of sensory neurons. QX-314, a charged NaV blocker that enters through pathologically activated large-pore ion channels and selectivity inhibits a subpopulation of sensory neurons, has the same effects as lidocaine in atopic dermatitis model. Genetic silencing NaV 1.8-expressing sensory neurons was sufficient to restrict cutaneous inflammation and itch in the atopic dermatitis model. However, pharmacological blockade of TRPV1-positive nociceptors only abolished persistent itch but did not affect skin inflammation in the atopic dermatitis model, indicating a difference between sensory neuronal modulation of skin inflammation and itch. Inhibition of activity-dependent release of calcitonin gene-related peptide (CGRP) from sensory neurons by lidocaine largely accounts for the therapeutic effect of lidocaine in the atopic dermatitis model. NaV 1.8+ sensory neurons play a critical role in pathogenesis of atopic dermatitis and lidocaine is a potential anti-inflammatory and anti-pruritic agent for atopic dermatitis. A dissociable difference for sensory neuronal modulation of skin inflammation and itch contributes to further understanding of pathogenesis in atopic dermatitis.

JAK-STAT signaling pathway in the pathogenesis of atopic dermatitis: An updated review.

Atopic dermatitis (AD) is a chronic, inflammatory, pruritic form of dermatosis with heterogeneous manifestations that can substantially affect patients' quality of life. AD has a complex pathogenesis, making treatment challenging for dermatologists. The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway plays a central role in modulating multiple immune axes involved in the immunopathogenesis of AD. In particular, Th2 cytokines, including interleukin (IL)-4, IL-5, IL-13, IL-31, and thymic stromal lymphopoietin, which contribute to the symptoms of chronic inflammation and pruritus in AD, are mediated by JAK-STAT signal transduction. Furthermore, JAK-STAT is involved in the regulation of the epidermal barrier and the modulation of peripheral nerves related to the transduction of pruritus. Targeting the JAK-STAT pathway may attenuate these signals and show clinical efficacy through the suppression of various immune pathways associated with AD. Topical and oral JAK inhibitors with variable selectivity have emerged as promising therapeutic options for AD. Notably, topical ruxolitinib, oral upadacitinib, and oral abrocitinib were approved by the U.S. Food and Drug Administration for treating patients with AD. Accordingly, the present study reviewed the role of JAK-STAT pathways in the pathogenesis of AD and explored updated applications of JAK inhibitors in treating AD.

Potential Natural Biomolecules Targeting JAK/STAT/SOCS Signaling in the Management of Atopic Dermatitis.

Atopic dermatitis (AD) is a chronic inflammatory skin disease caused by the dysregulation of cytokines and other immune mediators. JAK/STAT is a classical signal transduction pathway involved in various biological processes, and its dysregulation contributes to the key aspects of AD pathogenesis. Suppressor of cytokine signaling (SOCS) proteins negatively regulate the immune-related inflammatory responses mediated by the JAK/STAT pathway. JAK/STAT-mediated production of cytokines including IL-4, IL-13, IL-31, and TSLP inhibits the expression of important skin barrier proteins and triggers pruritus in AD. The expression of SOCS proteins regulates the JAK-mediated cytokines and facilitates maintaining the skin barrier disruptions seen in AD. STATs are crucial in dendritic-cell-activated Th2 cell differentiation in the skin, releasing inflammatory cytokines, indicating that AD is a Th2-mediated skin disorder. SOCS proteins aid in balancing Th1/Th2 cells and, moreover, regulate the onset and maintenance of Th2-mediated allergic responses by reducing the Th2 cell activation and differentiation. SOCS proteins play a pivotal role in inflammatory cytokine-signaling events that act via the JAK/STAT pathway. Therapies relying on natural products and derived biomolecules have proven beneficial in AD when compared with the synthetic regimen. In this review, we focused on the available literature on the potential natural-product-derived biomolecules targeting JAK/STAT/SOCS signaling, mainly emphasizing the SOCS family of proteins (SOCS1, SOCS3, and SOCS5) acting as negative regulators in modulating JAK/STAT-mediated responses in AD pathogenesis and other inflammatory disorders.

405 Atopic dermatitis patients have decreased epidermal innervation but increased neuronal substance p expression

Severe pruritus in atopic dermatitis (AD) significantly impairs patients’ quality of life, primarily due to relentless itching. Sensory nerves in the epidermis are important in mediating sensation of itch, but there is conflicting evidence whether epidermal nerve density is increased or decreased in lesional skin of AD. Here we measured nerve length, branching, and neurotransmitter expression in epidermis of healthy controls and lesional and non-lesional skin of AD patients. Four millimeter punch biopsies were taken from skin of 8 healthy adult control patients and 8 lesional and non-lesional skin of patients with moderate-to-severe AD.

Tacrolimus suppresses itch-related response in diet-induced atopic dermatitis model mice by reducing chloroquine-sensitive sensory neurons

Introduction: Itch (or pruritus) is a common symptom of atopic dermatitis (AD), which significantly decreases the patient’s quality of life. Tacrolimus ointment reduces pruritus in AD; however, the underlying mechanism is not fully understood. Methods: In the present study, we used a diet-induced AD mouse model to examine the antipruritic mechanism of tacrolimus. After induction of AD symptoms, the tacrolimus-containing ointment was applied once daily for 7 days. Responsiveness of isolated dorsal root ganglion (DRG) cells to various stimuli was examined by monitoring intracellular Ca2+ levels. Results: Repeated application of tacrolimus ointment attenuated spontaneous itch-related responses, even when skin barrier dysfunction, skin inflammation, and epidermal nerve sprouting were not ameliorated. Tacrolimus-treated mice also exhibited reduced scratching behavior induced by several pruritogens, such as histamine, SLIGRL-NH2, and chloroquine (CQ), although capsaicin-induced pain behavior was not affected. DRG cells from tacrolimus-treated mice showed significantly lower Ca2+ responses to CQ. Furthermore, a reduction in CQ-sensitive DRG neurons was observed after in vitro treatment with either tacrolimus or rapamycin. Discussion: CQ-sensitive (MrgprA3-expressing) DRG neurons are implicated as itch-specific sensory neurons. Therefore, topically applied tacrolimus may act directly on itch-signaling neurons, consequently suppressing various itch responses in AD mice.

Neuroimmune communication regulating pruritus in atopic dermatitis

Atopic dermatitis (AD) is a common, chronic-relapsing inflammatory skin disease with significant disease burden. Genetic and environmental trigger factors contribute to AD, activating 2 of our largest organs, the nervous system and the immune system. Dysregulation of neuroimmune circuits plays a key role in the pathophysiology of AD, causing inflammation, pruritus, pain, and barrier dysfunction. Sensory nerves can be activated by environmental or endogenous trigger factors, transmitting itch stimuli to the brain. On stimulation, sensory nerve endings also release neuromediators into the skin, contributing again to inflammation, barrier dysfunction, and itch. In addition, dysfunctional peripheral and central neuronal structures contribute to neuroinflammation, sensitization, nerve elongation, and neuropathic itch, thus chronification and therapy resistance. Consequently, neuroimmune circuits in skin and central nervous system may be targets to treat pruritus in AD. Cytokines, chemokines, proteases, lipids, opioids, and ions excite/sensitize sensory nerve endings, which not only induces itch but further aggravates/perpetuates inflammation, skin barrier disruption, and pruritus as well. Thus, targeted therapies for neuroimmune circuits as well as pathway inhibitors (eg, kinase inhibitors) may be beneficial to control pruritus in AD either in systemic and/or in topical form. Understanding neuroimmune circuits and neuronal signaling will optimize our approach to control all pathological mechanisms in AD, inflammation, barrier dysfunction, and pruritus.

Neuroimmune mechanisms of pruritus in atopic dermatitis

Atopic dermatitis is a chronic hereditary recurrent skin disease. One of the most pronounced symptoms of this dermatosis is itchy skin. Pruritus accompanies atopic dermatitis in more than 80% of cases. This review presents modern data on the mechanisms of pruritus formation in atopic dermatitis. The issues of etiological factors, neuroimmune interactions, peculiarities of skin dysfunction, as well as the role of stress are considered. The relevance of studying the topic is due to the high prevalence of atopic dermatitis among the population, a decrease in the quality of life and the lack of effective therapy. Analysis of the literature indicates the need for a comprehensive assessment of the pathogenetic mechanisms of the development of pruritus in atopic dermatitis. A more in-depth study of the mechanisms of neurogenic inflammation in atopic dermatitis will contribute to the development of new methods of diagnosis and treatment.