Case report: Dupilumab: a promising treatment option for adult linear IgA bullous dermatosis with severe pruritus.

Linear IgA bullous dermatosis (LABD) is an acquired autoimmune subepidermal blistering disorder. Diagnosis always relies on skin pathology and direct immunofluorescence (DIF), with typical linear deposits of IgA along the basement membrane zone (BMZ). The typical clinical manifestation is tense bullae arranged like the "string of pearls" companied with severe pruritus. Dapsone is often considered first-line therapy for LABD, and it is necessary to test the HLA-B*1301 gene to prevent the occurrence of dapsone-induced hypersensitivity syndrome (DHS). Here we report a case of LABD resistant to corticosteroid and sulfasalazine, while waiting for HLA-B*1301 gene test results, dupilumab was used to control severe pruritus.

Eosinophils in hidradenitis suppurativa patients exhibit pro-inflammatory traits, implicating a potential pathogenic role in the disease.

Hidradenitis suppurativa (HS) is an inflammatory skin disease characterized by painful nodules, abscesses and purulent secretions in intertriginous regions. Intense pruritus frequently accompanies HS lesions, adding further discomfort for patients. While Th17 pathway activation is implicated in HS pathogenesis, disease mechanisms are still not fully understood, and therapeutics are lacking. Previous reports raise a potential role for eosinophils in HS, showing a strong association of eosinophil levels with disease severity. To investigate eosinophils in HS, we recruited patients and matched healthy controls and then performed flow-cytometry studies, eosinophil stimulation assays, and lesional skin staining for eosinophils. We found that HS patients reported similar levels of pain and itch. Compared to matched controls, HS blood exhibited decreased mature eosinophils and increased numbers of immature eosinophils, coupled with a significant increase in dermal eosinophilic infiltrates. Additionally, IL-17RA+ eosinophils were highly and significantly correlated with multiple HS-related clinical scores. In both stimulated and unstimulated conditions, HS eosinophils showed an inflammatory phenotype versus controls, including an increase in costimulatory T- and B-cell markers (e.g. CD5 and CD40) following all stimulations (TNFα/IL-17A/IL-17F). These findings highlight the significance of pruritus in HS and suggest a higher turnover of eosinophils in HS blood, potentially due to the consumption of eosinophils in skin lesions. Our data delineate the features and functions of eosinophils in HS and suggest that eosinophils participate in disease pathogenesis, advancing Th17-related inflammation. Further studies are needed to investigate eosinophils' response to current HS treatments and their potential as a therapeutic target in the disease.

Immunoexpression of IL-33 in the different clinical aspects of canine atopic dermatitis.

Canine atopic dermatitis (CAD) is a chronic and inflammatory skin condition with a multifaceted origin, involving genetic factors, skin barrier abnormalities, immune responses, and hypersensitivity to various allergens. Interleukin 33 (IL-33), released by keratinocytes upon cellular injury, plays a crucial role in atopic dermatitis pathogenesis by inducing Th2 lymphocyte-mediated immune responses. This study aimed to evaluate IL-33 expression in dogs with atopic dermatitis and compare it to a control group. Forty-nine dogs were included, with 39 having atopic dermatitis, subdivided into groups based on clinical characteristics, and ten in the control group. Lesion and pruritus scores were assessed, and incisional biopsies were analyzed for dermatopathological characteristics. IL-33 expression was evaluated using immunohistochemistry, the analyses were blinded, based on the measurement of immunostaining areas using Image Pro-Plus software, version 4.5, relying on a semi-automatic color segmentation method, where the tissue immunostaining area for each biomarker was artificially delimited and quantified. Statistically significant differences in IL-33 immunostaining were found among groups (P=0.0005). Lichenified dogs (group 4) exhibited higher immunostaining compared to erythema (group 3) (P=0.0006), alesional pruritus (group 2) (P=0.0261), and the control group (group 1) (P=0.0079). IL-33 immunostaining increased with lesion progression, strongly correlating with lesion scores (P<0.0001), particularly in patients with chronic lesions characterized by erythema and lichenification. These findings suggest IL-33's significant role in canine atopic dermatitis pathogenesis and its association with lesion and inflammation scores during the chronic phase. This suggests potential therapeutic interventions targeting IL-33 or its receptors, though further studies are needed to explore these possibilities.

LEKTI domain 6 displays anti-inflammatory action in vitro and in a murine atopic dermatitis model.

BACKGROUND: Lympho-epithelial Kazal-type-related inhibitor (LEKTI) is a serine protease inhibitor consisting of multiple domains. A loss of function mutation is described in Netherton patients that show severe symptoms of atopic lesions and itch. OBJECTIVES: LEKTI domain 6 (LD6) has shown strong serine protease-inhibitory action in in vitro assays and thus it was tested in vitro and in vivo for potential anti-inflammatory action in models of atopic skin disease. METHODS: Human skin equivalents were treated with LD6 and an inflammatory reaction was challenged by kallikrein-related endopeptidase 5 (KLK5). Furthermore, LD6 was tested on dorsal root ganglia cells stimulated with KLK5, SLIGRL and histamine by calcium imaging. The effect of topically administered LD6 (0.4-0.8%) in lipoderm was compared to a topical formulation of betamethasone-diproprionate (0.1%) in a therapeutic setting on atopic dermatitis-like lesions in NC/Nga mice sensitized to house dust mite antigen. Endpoints were clinical scoring of the mice as well as determination of scratching behaviour. RESULTS: KLK5 induced an upregulation of CXCL-8, CCL20 and IL-6 in skin equivalents. This upregulation was reduced by pre-incubation with LD6. KLK5 as well as histamine induced calcium influx in a population of neurons. LD6 significantly reduced the calcium response to both stimuli. When administered onto lesional skin of NC/Nga mice, both LD6 and betamethasone-dipropionate significantly reduced the inflammatory reaction. The effect on itch behaviour was less pronounced. CONCLUSION: Topical administration of LD6 might be a new therapeutic option for treatment of lesional atopic skin.

Immunologic Profiling of Immune-Related Cutaneous Adverse Events with Checkpoint Inhibitors Reveals Polarized Actionable Pathways.

PURPOSE: Immune-related cutaneous adverse events (ircAE) occur in ≥50% of patients treated with checkpoint inhibitors, but the underlying mechanisms for ircAEs are poorly understood. EXPERIMENTAL DESIGN: Phenotyping/biomarker analyses were conducted in 200 patients on checkpoint inhibitors [139 with ircAEs and 61 without (control group)] to characterize their clinical presentation and immunologic endotypes. Cytokines were evaluated in skin biopsies, skin tape strip extracts, and plasma using real-time PCR and Meso Scale Discovery multiplex cytokine assays. RESULTS: Eight ircAE phenotypes were identified: pruritus (26%), maculopapular rash (MPR; 21%), eczema (19%), lichenoid (11%), urticaria (8%), psoriasiform (6%), vitiligo (5%), and bullous dermatitis (4%). All phenotypes showed skin lymphocyte and eosinophil infiltrates. Skin biopsy PCR revealed the highest increase in IFNγ mRNA in patients with lichenoid (P < 0.0001) and psoriasiform dermatitis (P < 0.01) as compared with patients without ircAEs, whereas the highest IL13 mRNA levels were detected in patients with eczema (P < 0.0001, compared with control). IL17A mRNA was selectively increased in psoriasiform (P < 0.001), lichenoid (P < 0.0001), bullous dermatitis (P < 0.05), and MPR (P < 0.001) compared with control. Distinct cytokine profiles were confirmed in skin tape strip and plasma. Analysis determined increased skin/plasma IL4 cytokine in pruritus, skin IL13 in eczema, plasma IL5 and IL31 in eczema and urticaria, and mixed-cytokine pathways in MPR. Broad inhibition via corticosteroids or type 2 cytokine-targeted inhibition resulted in clinical benefit in these ircAEs. In contrast, significant skin upregulation of type 1/type 17 pathways was found in psoriasiform, lichenoid, bullous dermatitis, and type 1 activation in vitiligo. CONCLUSIONS: Distinct immunologic ircAE endotypes suggest actionable targets for precision medicine-based interventions.

Levels of IgE sensitization drive symptom thresholds in allergic rhinitis.

BACKGROUND: Allergic rhinitis (AR) is a common respiratory disease encompassing a variety of phenotypes. Patients can be sensitized to 1 or more allergens. There are indications that polysensitization is associated with more severe disease. However, the extent to which the level of sensitization is associated with clinical disease variability, underlying the distinct nature of AR from AR+ conjunctivitis or AR+ asthma, is not known. OBJECTIVE: To evaluate phenotypical differences between monosensitized and polysensitized patients with AR and to quantify their symptomatic variability. METHODS: A total of 565 patients with a confirmed diagnosis of AR were included in this cross-sectional study. Of those, 155 were monosensitized and 410 were polysensitized. Interactions between sensitization levels and the reporting of different symptoms of AR and co-morbidities, disease duration, and impact were assessed. Furthermore, patients were stratified into monosensitized, oligosensitized, and polysensitized to assess whether the effect of sensitization on the phenotype was ranked. RESULTS: Polysensitized patients reported itchy eyes significantly more often (P = .001) and had a higher number of ocular (P = .005), itch-related (P = .036), and total symptoms (P = .007) than monosensitized patients. In addition, polysensitized adults and children more often reported wheeze (P = .015) and throat-clearing (P = .04), respectively. Polysensitization was associated with more burdensome AR based on a visual analog scale (P = .005). Increased sensitization level was reflected in more itchy eyes, a higher number of ocular, itch-related, and total number of symptoms, and disease burden. CONCLUSION: With an increasing number of sensitizations, patients with AR experience an increased diversity of symptoms. Multimorbidity-related symptoms increase with sensitization rank, suggesting organ-specific thresholds.

Staphylococcus aureus: The Bug Behind the Itch in Atopic Dermatitis.

Pruritus or itch is a defining symptom of atopic dermatitis (AD). The origins of itch are complex, and it is considered both a defense mechanism and a cause of disease that leads to inflammation and psychological stress. Considerable progress has been made in understanding the processes that trigger itch, particularly the pruritoceptive origins that are generated in the skin. This perspective review discusses the implications of a recent observation that the V8 protease expressed by Staphylococcus aureus can directly trigger sensory neurons in the skin through activation of protease-activated receptor 1. This may be a key to understanding why itch is so common in AD because S. aureus commonly overgrows in this disease owing to deficient antimicrobial defense from both the epidermis and the cutaneous microbiome. Increased understanding of the role of microbes in AD provides increased opportunities for safely improving the treatment of this disorder.

Dominant dystrophic epidermolysis bullosa is associated with glycolytically active GATA3+ T helper 2 cells which may contribute to pruritus in lesional skin.

BACKGROUND: Dominant dystrophic epidermolysis bullosa (DDEB) is characterized by trauma-induced blisters and, in some individuals, intense pruritus. Precisely what causes itch in DDEB and optimal ways to reduce it have not been fully determined. OBJECTIVES: To characterize DDEB skin transcriptomes to identify therapeutic targets to reduce pruritus in patients. METHODS: Using bulk RNA sequencing, we evaluated affected and unaffected skin biopsy samples from six patients with DDEB (all with the very itchy pruriginosa subtype) and four healthy individuals. Single-cell transcriptomes of affected (n = 2) and unaffected (n = 1) DDEB skin and healthy skin (n = 2) were obtained. Dupilumab treatment was provided for three patients. RESULTS: The skin bulk transcriptome showed significant enrichment of T helper (Th)1/2 and Th17 pathways in affected DDEB skin compared with nonlesional DDEB skin and healthy skin. Single-cell transcriptomics showed an association of glycolytically active GATA3+ Th2 cells in affected DDEB skin. Treatment with dupilumab in three people with DDEB led to significantly reduced visual analogue scale (VAS) itch scores after 12 weeks (mean VAS 3.83) compared with pretreatment (mean VAS 7.83). Bulk RNAseq and quantitative polymerase chain reaction showed that healthy skin and dupilumab-treated epidermolysis bullosa (EB) pruriginosa skin have similar transcriptomic profiles and reduced Th1/Th2 and Th17 pathway enrichment. CONCLUSIONS: Single-cell RNAseq helps define an enhanced DDEB-associated Th2 profile and rationalizes drug repurposing of anti-Th2 drugs in treating DDEB pruritus.

Dominant dystrophic epidermolysis bullosa (DDEB) is a rare inherited skin disease that causes fragile skin that blisters easily, often triggered by minor injuries. These blisters are accompanied by intense itching, which can be distressing. The underlying cause of DDEB lies in genetic mutations in a gene called COL7A1. This gene encodes 'type VII collagen', a protein crucial for attaching the outer skin layer (epidermis) to the layer beneath (dermis). Although the genetic basis of DDEB is understood, the causes of itch are not known. As well as this, effective treatments for DDEB are lacking, which has driven scientists to explore innovative approaches like repurposing existing drugs. Drug repurposing involves using medications that have already been approved for other health conditions. One such drug is dupilumab, which is used for severe atopic dermatitis (eczema). Dupilumab targets immune cells called Th2 cells, which play a role in inflammation and allergies. While dupilumab has shown promise in relieving DDEB itching, the way it works in this condition is unclear. This study, carried out by a group of researchers in Taiwan, looked at gene expression in DDEB-affected and unaffected skin, and compared it to gene expression in healthy skin samples. We found heightened activity in Th2 immune cells and abnormal gene signals related to itching, similar to atopic dermatitis. These findings support using dupilumab and other anti-inflammatory drugs to alleviate itching in DDEB. Clinical trials will be crucial to evaluate the effectiveness of these drugs for managing DDEB symptoms. This research opens doors for enhanced treatment options and improving the quality of life of people living with DDEB.

Atopic Dermatitis Itch: Scratching for an Explanation.

Chronic pruritus is a cardinal symptom of atopic dermatitis (AD). The mechanisms underlying atopic itch involve intricate crosstalk among skin, immune components, and neural components. In this review, we explore these mechanisms, focusing on key players and interactions that induce and exacerbate itch. We discuss the similarities and differences between pruritus and pain in patients with AD as well as the relationship between pruritus and factors such as sweat and the skin microbiome. Furthermore, we explore novel targets that could provide significant itch relief in these patients as well as exciting future research directions to better understand atopic pruritus in darker skin types.

The EGR1-Artemin Axis in Keratinocytes Enhances the Innervation of Epidermal Sensory Neurons during Skin Inflammation Induced by House Dust Mite Extract from Dermatophagoidesfarinae.

Epidermal hyperinnervation is a critical feature of pruritus during skin inflammation. However, the mechanisms underlying epidermal hyperinnervation are unclear. This study investigates the role of the transcription factor EGR1 in epidermal innervation by utilizing wild-type (Egr1+/+) and Egr1-null (Egr1‒/‒) mice topically applied Dermatophagoides farinae extract from dust mite. Our findings revealed that Egr1‒/‒ mice exhibited reduced scratching behaviors and decreased density of epidermal innervation compared with Egr1+/+ mice. Furthermore, we identified artemin, a neurotrophic factor, as an EGR1 target responsible for Dermatophagoides farinae extract-induced hyperinnervation. It has been demonstrated that Dermatophagoides farinae extract stimulates toll-like receptors in keratinocytes. To elucidate the cellular mechanism, we stimulated keratinocytes with Pam3CSK4, a toll-like receptor 1/2 ligand. Pam3CSK4 triggered a toll-like receptor 1/2-mediated signaling cascade involving IRAK4, IκB kinase, MAPKs, ELK1, EGR1, and artemin, leading to increased neurite outgrowth and neuronal migration. In addition, increased expression of EGR1 and artemin was observed in the skin tissues of patients with atopic dermatitis. These findings highlight the significance of the EGR1-artemin axis in keratinocytes, promoting the process of epidermal innervation and suggesting it as a potential therapeutic target for alleviating itch and pain associated with house dust mite-induced skin inflammation.

Peripheral Mechanisms of Mechanical Itch.

Mechanical itch, which is defined as an itch sensation caused by innocuous mechanical force, may warn of the potential risk in the skin. The increased mechanosensitivity in sensory neurons may cause scratch-induced itch and promote the transition from acute itch to chronic itch. Recent studies have not only expanded our knowledge about the neuronal circuits in the CNS but have also highlighted the importance of the peripheral epithelia-immune-neuronal crosstalk in the development of mechanical itch. In this review, we will summarize related findings about the molecular and cellular mechanisms of mechanical itch in the skin.