Intense Itching Research Articles

308 Incremental improvements after switching from dupilumab (DUPI) to upadacitinib (UPA) in the Heads Up open-label extension (OLE) study

Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by eczematous morphology and intense itch. Heads Up was a phase 3b, randomized, double-blind, double-dummy clinical trial comparing the efficacy and safety of DUPI vs UPA in adults with moderate-to-severe AD over 24 weeks; in the Heads Up OLE, all patients received UPA 30 mg orally once daily for an additional 52 weeks. This analysis characterized the incremental changes in Eczema Area and Severity Index (EASI) and Worst Pruritus Numerical Rating Scale (WP-NRS) scores during the Heads Up OLE in patients who switched from DUPI to UPA after 24 weeks of DUPI treatment.

LB1041 Machine learning-based single cell analysis of prurigo nodularis identifies a unique population of CD14+pERK+ macrophages correlating with itch intensity

Prurigo nodularis (PN) is a chronic inflammatory skin disease characterized by intense itch and predominantly affects African Americans (AA). Little is known about its pathogenesis and there are currently no FDA approved therapies for PN. To further characterize single cell interactions in the skin we performed imaging mass cytometry (IMC) from prospectively collected formalin-fixed, paraffin-embedded skin biopsies of 12 PN patients and 4 healthy controls (HC). Sections were stained with a panel of 19 isotopic antibodies against immune and epithelial markers. Machine learning was used to segment cells via the bodenmiller pipeline with analysis done in histoCAT. Unsupervised clustering revealed PN patients have unique populations of CD14+ macrophages, keratinocytes (KC), CD11C+CD14+ myeloid dendritic cells (mDC), CD3+ T cells, sMA+ endothelial smooth muscle cells (ESM), CD63+ cells, CD33+ cells, and CD15+ myeloid cells. PN also had an increase in CD15+ myeloid cells (50±87 vs 21±19, p=0.02), CD14+ macrophages expressing pERK1/2 (47±60 vs 9±5, p=0.002), and CD14+KCs (331±565 vs 21±33, p=0.008). Both percentage and absolute number of circulating blood eosinophils correlated positively with CD3+ cells (r=0.955, p=0.003; r=.8929, p=0.01) and negatively with vimentin (r=-0.8469, p=0.02; r=-0.8214, p=0.03) and pERK (r=-0.8108, p=0.04; r=-0.7857, p=0.05). Neighborhood-based single cell analysis revealed CD14+ KCs interacting with CD14+ macrophages and ESM interacting with CD14+ macrophages, CD63+ cells, and CD11C+CD14+ mDCs (p<0.05). Itch intensity positively correlated with frequencies of CD14+ pERK macrophages (r=0.861, p=0.006). The discovery of CD14+ pERK macrophages correlating with itch and interacting with activated KCs may serve as a target for future therapies in PN.

Clinical observations of complex therapy of atopic dermatitis of moderate severity

Atopic dermatitis (AD) is more common in children, but can also occur in adults. Doctors of different specialties, including pediatricians, dermatologists, allergists-immunologists, gastroenterologists and infectious disease specialists deal with this problem. Despite the efforts of pediatricians, the problem of AD remains pressing. The progressive growth of this disease among children and increased persistence in adulthood make it important to study the mechanisms of AD not only for dermatology, but also for the health care system as a whole. The presence of pruritus is an obligatory manifestation of AD, which entails an inevitable decrease in the quality of life of patients. Thus, there are prerequisites for the emergence of new concepts of pathogenesis and the search for the most effective therapeutic methods of treatment. Currently, AD is considered as an interaction of endogenous (impaired immune response, insufficient function of the epidermal barrier) and exogenous factors (exposure to allergens, chemical or physical irritants, microorganisms). The work presents clinical cases of topical calcineurin inhibitor use in the treatment of moderate-to-severe AD. We presented patients with complaints of rashes accompanied by intense itching, on the skin of the extensor surfaces of the limbs, on the skin of the face and torso. Application of topical cal-cineurin inhibitor resulted in reduction of severity of subjective and objective symptoms of various forms of atd. The efficacy of topical calcineurin inhibitors in the treatment of atd with a pronounced anti-inflammatory and antipruritic effect was confirmed. Long-term staggered scheme of their use is the most pathogenetically justified and safe method of treatment of moderate forms of AD.

Testing different doses of delgocitinib cream for the treatment of chronic hand eczema

Chronic hand eczema (CHE) causes intense itching and dry skin. It is a common disease and affects around 10% of the population at some time during a year.

National Saudi Consensus Statement on the Management of Atopic Dermatitis (2021).

Atopic dermatitis (AD) is a chronic inflammatory skin disease with an increasing prevalence regionally and globally. It is characterized by intense itching and recurrent eczematous lesions. With the increase in the availability of treatment options for healthcare practitioner and patients, new challenges arise for treatment selection and approach. The current consensus statement has been developed to provide up-to-date evidence and evidence-based recommendations to guide dermatologists and healthcare professionals managing patients with AD in Saudi Arabia. By an initiative from the Ministry of Health (MOH), a multidisciplinary work group of 11 experts was convened to review and discuss aspects of AD management. Four consensus meetings were held on January 14, February 4, February 25, and March 18 of 2021. All consensus content was voted on by the work group, including diagnostic criteria, AD severity assessment, comorbidities, and therapeutic options for AD. Special consideration for the pediatric population, as well as women during pregnancy and lactation, was also discussed. The present consensus document will be updated as needed to incorporate new data or therapeutic agents.

GPR15L is an epithelial inflammation-derived pruritogen.

Itch is an unpleasant sensation that often accompanies chronic dermatological conditions. Although many of the itch receptors and the neural pathways underlying this sensation are known, the identity of endogenous ligands is still not fully appreciated. Using an unbiased bioinformatic approach, we identified GPR15L as a candidate pruritogen whose expression is robustly up-regulated in psoriasis and atopic dermatitis. Although GPR15L was previously shown to be a cognate ligand of the receptor GPR15, expressed in dermal T cells, here we show that it also contributes to pruritogenesis by activating Mas-related G protein–coupled receptors (MRGPRs). GPR15L can selectively stimulate mouse dorsal root ganglion neurons that express Mrgpra3 and evokes intense itch responses. GPR15L causes mast cell degranulation through stimulation of MRGPRX2 and Mrgprb2. Genetic disruption of GPR15L expression attenuates scratch responses in a mouse model of psoriasis. Our study reveals unrecognized features of GRP15L, showing that it is a potent itch-inducing agent.

How to decrease systemic corticosteroids in pemphigus patients under rituximab.

How to decrease systemic corticosteroids in pemphigus patients under rituximab.

Hypothalamic response with PKA/CREB signaling is associated with direct cerebroventricular administration of bombesin-induced scratching

Bombesin (BN) is an itch-specific mediator that causes intense itch-scratching activity in mammals. Although most examinations of BN-induced itch processing have focused on the spinal cord, the involvement of central nervous system mechanisms remains unclear. Here, we investigated how relationships among hypothalamic regions regulate BN-mediated itch-scratch processes. We found that intracerebroventricular (i.c.v.) administration of BN (0.04–4 μg) elicited intense itch scratching in mice, whereas BN (0.4–400 μg) administered via intravenous tail injection failed to evoke a scratching response. Additionally, nalfurafine had no significant effects on BN-induced scratching behavior, indicating that central modulation of BN is distinct from histamine-mediated histaminergic itch and chloroquine-mediated non-histaminergic itch signaling pathways. We labeled BN with a fluorescent tag, 7-nitrobenz-2-oxa-1 (NBD), and traced its fluorescence in the hypothalamus for 30 min following i.c.v. NBD-BN administration. Accordingly, we confirmed that i.c.v. administration of BN enhanced c-Fos expression in the dorsal medial nucleus of the hypothalamus, where neuromedin B receptors and gastrin-releasing peptide receptors are highly expressed. Interestingly, in situ injection of BN into the hypothalamus immediately and robustly induced itch-scratching behavior. Moreover, gene transcripts and western blot assay revealed that BN receptor-dependent PKA/CREB signaling was upregulated in the hypothalamus after i.c.v. administration of BN. Consistently, pretreatment with a PKA inhibitor, Rp-cAMP, significantly reduced BN-induced scratching behavior. Our results indicate that the dorsal medial nucleus of the hypothalamus may be a key nucleus in mediating BN-mediated itch and hypothalamic PKA/CREB signaling is involved in regulating BN-mediated itch.

P207 KOUNIS SYNDROME TYPE 2: A COLD CASE

Abstract Case Report A 61–year–old man, smoker and family history of cardiovascular diseases, started oral antibiotic therapy with amoxicillin / clavulanic acid following the appearance of a dental abscess. About 30 minutes after taking the antibiotic, he complained of widespread erythema in the limbs, followed by intense itching and dyspnea. Upon arrival of the medical staff, IV cortisone and antihistamine therapy was performed with gradual and progressive resolution of the symptoms. Despite the doctors’ invitation, the patient refused access to the emergency room for fear of a possible hospital infection with SARS–CoV–2. Almost two months later, due to the onset of exertional dyspnea, he is persuaded to go to the hospital for further tests. The ECG showed signs of diffuse anterolateral necrosis (Figure 1). Echocardiography showed severe left ventricular dysfunction (FE 35%) with extensive akinesia of the mid–distal SIV, apex, and anterior mid–distal wall. Myocardiocytolysis indices were negative and allergy tests positive for beta–lactam antibiotics. Subsequently he underwent coronary angiography which showed proximal occlusion of an intermediate branch (Figure 2) treated with angioplasty and drug stent release. Cardiac MRI was then performed with evidence of a large area of ischemic necrosis (subendocardial / transmural) of the antero–septal, anterior and anterolateral wall with FE 35% (Figure 3). Comment Kounis syndrome is a clinical emergency characterized by the appearance of an acute coronary syndrome during an anaphylactic–type reaction. A correct diagnosis is of fundamental importance to limit the extent of myocardial damage as much as possible. In Kounis type 2, the mediators of the allergic reaction can cause not only vasospasm but also the activation of metalloproteases that induce the degradation of collagen with consequent rupture of pre–existing atheromatous plaques, as in our patient. Failure to perform an ECG during first aid leaves doubts about the possible allergic genesis of the episode, which however cannot be excluded with certainty. We have decided to report this clinical case to emphasize the importance of always taking into consideration the possibility of being compared with a case of Kounis when assisting a patient with an anaphylactic type reaction.

A Case Study on Pompholyx (Dyshidrotic Eczema) w.s.r. to Vicharchika

Besides the miraculous achievement of modern medical science, humanity is passing through a horror of disease and drug phobia, particularly in developing countries like India, where poverty and illiteracy account for the man’s ignorance towards the principles of health care. Skin is one of the five ‘Gyanindriyas’ as described in Ayurvedic texts. It is responsible for ‘Sparsha Gyan’ or touch sensation; therefore it plays a great role in physical and mental well-being of any individual. The skin is highly complex organ which plays a vital role in the body’s general working. The unbroken skin is the nature’s dressing over the body’s it acts as an effective barrier against the entry of diseases and its damage results in a whole host problems. Approximately 15% of all patients who visits the doctors to do for care of the skin as the wise saying ‘skin patients never cured and never die. When a skin disorder occurs it is rooted in tissues like fat, blood etc. Skin disorders occur due to aggravated Pitta Dosha. The built up toxins due to imbalanced Pitta cause Pompholyx. Pompholyx is a type of eczema, in which intensely itchy blisters that develop on the edges of the fingers, toes, palms and soles of feet appear. It may be acute or chronic and it affects teenagers and adults. In the present case 42yrs old female patient, who presented with complaints of rash over palm of left hand associated with intense itching, deep seated oozing wound and burning sensation has been presented here. She was treated with Ayurvedic treatment regimen for 40 days and she recovered fully with no symptoms left.

Adolescent Scalp Dermatitis Associated with Dermatophagoides spp. (Acariformes; Pyroglyphidae) Mite

Dermatophagoides spp. (Acariformes; Pyroglyphidae), house dust-mite well known as the causative agent of atopic hypersensitivity and allergy could potentially cause severe dermatitis. Herein we report an uncommon case of scalp dermatitis associated with the presence of Dermatophagoides spp. A 17-year old male presented with patchy alopecia on the scalp without intense peeling or itching, surround by unchanged skin and hair. Initially, superficial fungal infection was suspected; however, parasitological examination revealed the presence of live mites. All the anatomical measurements and parameters from the specimens were compatible with Dermatophagoides spp. Dermatophagoides spp. are not yet confirmed as causative agents of parasitic infestation, but the presence of these mites could have caused an allergic reaction followed by dermatitis with mild-to-moderate clinical manifestations. However, true parasitism as well as phoresy could also be considered. The clinical manifestations caused by house-dust mite cannot be easily recognized and the lack of diagnostic tools is a hindrance that often leads to misdiagnosis and inadequate therapy.

IL-20 promotes cutaneous inflammation and peripheral itch sensation in atopic dermatitis.

Atopic dermatitis (AD) is a chronic skin disease, which is associated with intense itch, skin barrier dysfunction and eczematous lesions. Aberrant IL‐20 expression has been implicated in numerous inflammatory diseases, including psoriasis. However, the role of IL‐20 in AD remains unknown. Here, RNA‐seq, Q‐PCR, and immunocytochemistry were utilized to examine disease‐driven changes of IL‐20 and its cognate receptor subunits in skin from healthy human subjects, AD patients and murine AD‐models. Calcium imaging, knockdown and cytokine array were used to investigate IL‐20‐evoked responses in keratinocytes and sensory neurons. The murine cheek model and behavioral scoring were employed to evaluate IL‐20‐elicited sensations in vivo. We found that transcripts and protein of IL‐20 were upregulated in skin from human AD and murine AD‐like models. Topical MC903 treatment in mice ear enhanced IL‐20R1 expression in the trigeminal sensory ganglia, suggesting a lesion‐associated and epidermal‐driven mechanism for sensitization of sensory IL‐20 signaling. IL‐20 triggered calcium influx in both keratinocytes and sensory neurons, and promoted their AD‐related molecule release and transcription of itch‐related genes. In sensory neurons, IL‐20 application increased TLR2 transcripts, implicating a link between innate immune response and IL‐20. In a murine cheek model of acute itch, intradermal injection IL‐20 and IL‐13 elicited significant itch‐like behavior, though only when co‐injected. Our findings provide novel insights into IL‐20 function in peripheral (skin‐derived) itch and clinically relevant intercellular neuron‐epidermal communication, highlighting a role of IL‐20 signaling in the pathophysiology of AD, thus forming a new basis for the development of a novel antipruritic strategy via interrupting IL‐20 epidermal pathways.

Therapeutic Targets in Allergic Conjunctivitis.

Allergic conjunctivitis (AC) is a common condition resulting from exposure to allergens such as pollen, animal dander, or mold. It is typically mediated by allergen-induced crosslinking of immunoglobulin E attached to receptors on primed conjunctival mast cells, which results in mast cell degranulation and histamine release, as well as the release of lipid mediators, cytokines, and chemokines. The clinical result is conjunctival hyperemia, tearing, intense itching, and chemosis. Refractory and chronic cases can result in ocular surface complications that may be vision threatening. Patients who experience even mild forms of this disease report an impact on their quality of life. Current treatment options range from non-pharmacologic therapies to ocular and systemic options. However, to adequately control AC, the use of multiple agents is often required. As such, a precise understanding of the immune mechanisms responsible for this ocular surface inflammation is needed to support ongoing research for potential therapeutic targets such as chemokine receptors, cytokine receptors, non-receptor tyrosine kinases, and integrins. This review utilized several published articles regarding the current therapeutic options to treat AC, as well as the pathological and immune mechanisms relevant to AC. This review will also focus on cellular and molecular targets in AC, with particular emphasis on potential therapeutic agents that can attenuate the pathology and immune mechanisms driven by cells, receptors, and molecules that participate in the immunopathogenesis and immunopathology of AC.

Management of Atopic Dermatitis with Individualised Homoeopathic Treatment

AbstractSkin being an important protective organ of body has its own functional and cosmetic values. Atopic dermatitis (AD) is a disease comprising of heterogenous skin manifestations with intense itching. AD affects people of all age groups and ethnicities and has psychosocial impact on the patient. Being the leading cause of global burden of skin disease, this disease also enhances the chances of developing food allergy, allergic asthma etc. Moreover, due to poor hygiene and decreased protective barrier function, AD often gets infected by certain pathogens (Staphylococcus aureus, Malassezia, Molluscum etc.), as a result of which patient suffers from life-threatening complications. Absence of specific diagnostic test with gradual escalation in the disease burden makes it one of the chief concerns for the health care workers. For dermatological diseases, homoeopathy stands out as a prime choice for many patients. In this case, a 72-year-old male patient presented with symptoms of dry, itchy eruptions on right hand for the last 2 years. He also developed similar itching eruptions in and around navel. The patient was clinically diagnosed with AD and treated with individualised homoeopathic treatment. Initially, he was prescribed Tuberculinum which improved the patient and finally he was cured by Sulphur.

A case report of bullous pemphigoid treated with homoeopathy

This is a case of 20 years female having multiple vesicles filled with fluid present on her both hands since 4 months, having various sizes from pin point to very large accompanied with intense itching and burning. Systematic case taking followed by repertorisation was done according totality of symptoms by Synthesis Repertory using RADAR software in order to select the individualised homoeopathic remedy where Ranunculus bulbosus, Rhus Toxicodendron, Phosphorus, and Sulphur were shortlisted. The patient responded well to the individualised homoeopathic treatment in a very short period of time.

Anaphylaxis for COVID-19 Pfizer-BioNTech mRNA vaccination in a person with previous allergy to the vaccine: a case report

Protection from COVID-19 infection has been a major challenge and priority to protect the health and life of people around the globe. In clinical trials, vaccination has shown to protect people from severe COVID-19 infection and reduce both morbidity and mortality. At the time of writing this article, mRNA-based vaccines were being used as new form of vaccination against the COVID-19 infection. As this is a new method of vaccination, full information about managing cases with allergy to the vaccine was not clearly available. So, any form of allergic response was considered contraindication for the future doses of the mRNA based COVID-19 vaccines. A 35 years old female received 2nd dose COVID-19 mRNA vaccine as per vaccination plan in a healthcare center. She developed features of allergic reaction and anaphylaxis including urticarial rash, intense itching of whole body, tightness in the chest, hypotension, reduced central pulse volume, decreased level of consciousness and grunting. Immediate anaphylaxis diagnosis with level 1 certainty of Brighton Anaphylaxis scoring and management with Epinephrin, Hydrocortisone and IV fluids was undertaken. Patient was stabilized and transferred to secondary care for further management. The use of mRNA vaccines for COVID-19 had initial uncertainties about allergic reactions, severity of allergic reactions, the patients for future allergic reaction and dealing with these patients about future vaccine doses. We presented a case with history of previous immediate mild rash to 1st COVID-19 mRNS vaccine dose and subsequent anaphylaxis following 2nd dose of the same mRNS vaccine.

Role of ERK Pathway in the Pathogenesis of Atopic Dermatitis and Its Potential as a Therapeutic Target.

Atopic dermatitis (AD) is an eczematous skin disorder characterized by type 2 inflammation, barrier disruption, and intense itch. In addition to type 2 cytokines, many other cytokines, such as interferon gamma (IFN-γ), interleukin 17 (IL-17), and interleukin 22 (IL-22), play roles in the pathogenesis of AD. It has been reported that the extracellular signal-regulated kinase (ERK) is downstream of such cytokines. However, the involvement of the ERK pathway in the pathogenesis of AD has not yet been investigated. We examined the expression of p-ERK in mouse and human AD skin. We also investigated the effects of the topical application of an ERK inhibitor on the dermatitis score, transepidermal water loss (TEWL), histological change, and expression of filaggrin, using an AD-like NC/Nga murine model. The effects of an ERK inhibitor on filaggrin expression in normal human epidermal keratinocytes (NHEKs) and on chemokine production from bone marrow-derived dendritic cells (BMDCs) were also evaluated. p-ERK was highly expressed in mouse and human AD skin. Topical application of an ERK inhibitor alleviated the clinical symptoms, histological changes, TEWL, and decrease in expression of filaggrin in the AD-like NC/Nga murine model. The ERK inhibitor also restored the IL-4 induced reduction in the expression of filaggrin in NHEK, and inhibited chemokine production from BMDC induced by IL-4. These results indicate that the ERK pathway is involved in the pathogenesis of AD, and suggest that the ERK pathway has potential as a therapeutic target for AD in the future.

Pruritis ani

Pruritis ani is defined as an intense itch in the peri-anal area. About 25% of individuals have no identifiable cause. It presents a diagnostic challenge, due to the multitude of causative factors, and is estimated to affect 5% of the population, more so men than women. Causative factors include faecal soilage and skin infections, however, malignant conditions such as Bowen’s disease have been implicated. It is important to take a thorough and focused history, as symptoms are often abated by removal of causative agents. Physical examination should not be limited to the peri-anal area, as clues may be garnered from peripheral manifestation of systemic conditions. Focus of management involves eliminating risk factors, improving peri-anal hygiene and encouraging compliance to treatment. Novel treatments include capsaicin cream and methylene blue.

Mast cells, cortistatin, and its receptor, MRGPRX2, are linked to the pathogenesis of chronic prurigo

Chronic prurigo (CPG) is characterized by intensive itch and interactions among nerves, neuropeptides, and mast cells (MCs). The role of some neuropeptides such as cortistatin (CST) and its receptor, Mas-related G protein-coupled receptor X2 (MRGPRX2), in CPG remains poorly investigated. We evaluated first whether CST activates human skin MCs, and second whether CST and MRGPRX2 are expressed in the skin of CPG patients, and by which cells. Skin prick tests and microdialysis with CST were performed in 6 and 1 healthy volunteers, respectively. Degranulation of human skin MCs was assessed using β-hexosaminidase and histamine release assays. Skin samples from 10 patients with CPG and 10 control subjects were stained for CST, MCs, and MRGPRX2 (protein and mRNA) using immunohistochemistry, immunofluorescence, and/or in situ hybridization. Flow cytometry was used to assess CST in human skin MCs. MRGPRX2 levels were measured in serum by ELISA. CST induced concentration-dependent degranulation of human skin MCs invivo and exvivo. Skin lesions of CPG patients exhibited markedly higher numbers of CST-expressing cells, CST-expressing MCs, MRGPRX2-expressing cells, and MRGPRX2 mRNA-expressing cells than nonlesional skin. MCs were the main MRGPRX2 mRNA-expressing cells in the lesions of most CPG patients (70%). Stimulation of human skin MCs with anti-IgE led to a release of CST. The number of MRGPRX2-expressing cells correlated with disease severity (r= 0.649, P= .04). MRGPRX2 serum levels in CPG patients correlated with disease severity (r= 0.704, P= .023) and quality-of-life impairment (r= 0.687, P= .028). CST and MRGPRX2 may contribute to the pathogenesis of CPG and should be evaluated in further studies as potential biomarkers and novel therapeutic targets.

Dermatitis herpetiformis Duhring as one of the forms of gluten-associated pathology: a review of the literature and a description of a clinical case

This review presents information on the prevalence, pathogenesis, clinical manifestations, diagnosis and treatment of Duhring’s dermatitis herpetiformis. Although the disease was first clinically described in 1884 by the American dermatologist L.A. Duhring, the study of its pathogenesis and the search for prognostic markers of its occurrence continue. Against the background of a significant expansion of ideas about gluten-dependent diseases and conditions, views on the mechanisms of autoimmune skin damage in dermatitis herpetiformis are detailed. A strong association with hereditary predisposition through the major human leukocyte histocompatibility complex (HLA) DQ2 and DQ8, and a role of epidermal transglutaminase as a major autoantigen in dermatitis herpetiformis are shown. The hypotheses explaining the decline in the incidence of dermatitis herpetiformis in recent decades against the background of increased and more effective serological screening and the resulting earlier diagnosis of celiac disease are commented on. A typical clinical picture of dermatitis herpetiformis, in which erythematous papules, plaques, vesicles are seen, usually clustered on the flexural surfaces of the extremities. Secondary elements are erosions, excoriations and crusts due to rupture of blisters and due to scratching caused by intense itching. A generally favourable prognosis for life and disease is shown with a gluten-free diet and the use of dapsone, glucocorticoids and, if these are ineffective, immunosuppressants. The authors describe a clinical case of the disease in an adolescent girl with a typical clinical history and characteristic rashes on the extensor surfaces of the limbs. The authors show that drug therapy without a gluten-free diet cannot be considered effective, and that the diet for dermatitis herpetiformis, like that for celiac disease, is lifelong. The growing understanding of gluten-associated pathology, which includes dermatitis herpetiformis, in recent decades has led to an intensive search for diagnostic and prognostic markers, as well as the development of ways to correct this group of diseases, including those not related to the lifelong elimination of cereal prolamines.