A basophil-neuronal axis promotes itch.

Itch is an evolutionarily conserved sensation that facilitates expulsion of pathogens and noxious stimuli from the skin. However, in organ failure, cancer, and chronic inflammatory disorders such as atopic dermatitis (AD), itch becomes chronic, intractable, and debilitating. In addition to chronic itch, patients often experience intense acute itch exacerbations. Recent discoveries have unearthed the neuroimmune circuitry of itch, leading to the development of anti-itch treatments. However, mechanisms underlying acute itch exacerbations remain overlooked. Herein, we identify that a large proportion of patients with AD harbor allergen-specific immunoglobulin E (IgE) and exhibit a propensity for acute itch flares. In mice, while allergen-provoked acute itch is mediated by the mast cell-histamine axis in steady state, AD-associated inflammation renders this pathway dispensable. Instead, a previously unrecognized basophil-leukotriene (LT) axis emerges as critical for acute itch flares. By probing fundamental itch mechanisms, our study highlights a basophil-neuronal circuit that may underlie a variety of neuroimmune processes.

Interleukin-33-activated neuropeptide CGRP-producing memory Th2 cells cooperate with somatosensory neurons to induce conjunctival itch.

Allergic conjunctivitis is a chronic inflammatory disease that is characterized by severe itch in the conjunctiva, but how neuro-immune interactions shape the pathogenesis of severe itch remains unclear. We identified a subset of memory-type pathogenic Th2 cells that preferentially expressed Il1rl1-encoding ST2 and Calca-encoding calcitonin-gene-related peptide (CGRP) in the inflammatory conjunctiva using a single-cell analysis. The IL-33-ST2 axis in memory Th2 cells controlled the axonal elongation of the peripheral sensory C-fiber and the induction of severe itch. Pharmacological blockade and genetic deletion of CGRP signaling in vivo attenuated scratching behavior. The analysis of giant papillae from patients with severe allergic conjunctivitis revealed ectopic lymphoid structure formation with the accumulation of IL-33-producing epithelial cells and CGRP-producing pathogenic CD4+ T cells accompanied by peripheral nerve elongation. Thus, the IL-33-ST2-CGRP axis directs severe itch with neuro-reconstruction in the inflammatory conjunctiva and is a potential therapeutic target for severe itch in allergic conjunctivitis.

The Cytokine TGF-ß Induces Interleukin-31 Expression from Dermal Dendritic Cells to Activate Sensory Neurons and Stimulate Wound Itching.

Cutaneous wound healing is associated with the unpleasant sensation of itching. Here we investigated the mechanisms underlying this type of itch, focusing on the contribution of soluble factors released during healing. We found high amounts of interleukin 31 (IL-31) in skin wound tissue during the peak of itch responses. Il31-/- mice lacked wound-induced itch responses. IL-31 was released by dermal conventional type 2 dendritic cells (cDC2s) recruited to wounds and increased itch sensory neuron sensitivity. Transfer of cDC2s isolated from late-stage wounds into healthy skin was sufficient to induce itching in a manner dependent on IL-31 expression. Addition of the cytokine TGF-ß1, which promotes wound healing, to dermal DCs in vitro was sufficient to induce Il31 expression, and Tgfbr1f/f CD11c-Cre mice exhibited reduced scratching and decreased Il31 expression in wounds in vivo. Thus, cDC2s promote itching during skin would healing via a TGF-ß-IL-31 axis with implications for treatment of wound itching.

Activation of Mast-Cell-Expressed Mas-Related G-Protein-Coupled Receptors Drives Non-histaminergic Itch.

Classical itch studies have focused on immunoglobulin E (IgE)-mediated mast cell activation and histamine release. Recently, members of the Mas-related G-protein-coupled receptor (Mrgpr) family have been identified as mast cell receptors, but their role in itch is unclear. Here, we report that mast cell activation via Mrgprb2 evoked non-histaminergic itch in mice independently of the IgE-Fc epsilon RI (FcεRI)-histamine axis. Compared with IgE-FcεRI stimulation, Mrgprb2 activation of mast cells was distinct in both released substances (histamine, serotonin, and tryptase) and the pattern of activated itch-sensory neurons. Mrgprb2 deficiency decreased itch in multiple preclinical models of allergic contact dermatitis (ACD), a pruritic inflammatory skin disorder, and both mast cell number and PAMP1-20 concentrations (agonist of the human Mrgprb2 homolog, MRGPRX2) were increased in human ACD skin. These findings suggest that this pathway may represent a therapeutic target for treating ACD and mast-cell-associated itch disorders in which antihistamines are ineffective.

Single-cell profiling of prurigo nodularis demonstrates immune-stromal crosstalk driving profibrotic responses and reversal with nemolizumab.

BACKGROUND: Prurigo nodularis (PN) is a chronic neuroimmune skin disease characterized by bilaterally distributed pruritic hyperkeratotic nodules on extremities and trunk. Neuroimmune dysregulation and chronic scratching are believed to both induce and maintain the characteristic lesions. OBJECTIVES: This study sought to provide a comprehensive view of the molecular pathogenesis of PN at the single-cell level to identify and outline key pathologic processes and the cell types involved. Features that distinguish PN skin from the skin of patients with atopic dermatitis were of particular interest. We further aimed to determine the impact of the IL31RA antagonist, nemolizumab, and its specificity at the single-cell level. METHODS: Single-cell RNA-sequencing of skin from 15 healthy donors and nonlesional and lesional skin from 6 patients each with PN and atopic dermatitis, combined with spatial-sequencing using the 10x Visium platform. Integration with bulk RNA-sequencing data from patients treated with nemolizumab. RESULTS: This study demonstrates that PN is an inflammatory skin disease characterized by both keratinocyte proliferation and activation of profibrotic responses. This study also demonstrates that the COL11A1+ fibroblast subset is a major contributor to fibrosis and is predominantly found in the papillary dermis of PN skin. Activation of fibrotic responses is the main distinguishing feature between PN and atopic dermatitis skin. This study further shows the broad effect of nemolizumab on PN cell types, with a prominent effect driving COL11A1+ fibroblast and keratinocyte responses toward normal. CONCLUSIONS: This study provides a high-resolution characterization of the cell types and cellular processes activated in PN skin, establishing PN as a chronic fibrotic inflammatory skin disease. It further demonstrates the broad effect of nemolizumab on pathological processes in PN skin.

IL-33 potentiates histaminergic itch.

BACKGROUND: Itch is a common symptom that can greatly diminish quality of life. Histamine is a potent endogenous pruritogen, and while antihistamines are often the first-line treatment for itch, in conditions like chronic spontaneous urticaria (CSU), many patients remain symptomatic while receiving maximal doses. Mechanisms that drive resistance to antihistamines are poorly defined. OBJECTIVES: Signaling of the alarmin cytokine IL-33 in sensory neurons is postulated to drive chronic itch by inducing neuronal sensitization to pruritogens. Thus, we sought to determine if IL-33 can augment histamine-induced (histaminergic) itch. METHODS: Itch behavior was assessed in response to histamine after IL-33 or saline administration. Various stimuli and conditional and global knockout mice were utilized to dissect cellular mechanisms. Multiple existing transcriptomic data sets were evaluated, including single-cell RNA sequencing of human and mouse skin, microarrays of isolated mouse mast cells at steady state and after stimulation with IL-33, and microarrays of skin biopsy samples from subjects with CSU and healthy controls. RESULTS: IL-33 amplifies histaminergic itch independent of IL-33 signaling in sensory neurons. Mast cells are the top expressors of the IL-33 receptor in both human and mouse skin. When stimulated by IL-33, mouse mast cells significantly increase IL-13 levels. Enhancement of histaminergic itch by IL-33 relies on a mast cell- and IL-13-dependent mechanism. IL-33 receptor expression is increased in lesional skin of subjects with CSU compared to healthy controls. CONCLUSIONS: Our findings suggest that IL-33 signaling may be a key driver of histaminergic itch in mast cell-associated pruritic conditions such as CSU.

LPS exacerbates TRPV4-mediated itch through the intracellular TLR4-PI3K signalling.

Pruritus is often accompanied with bacterial infections, but the underlying mechanism is not fully understood. Although previous studies revealed that lipopolysaccharides (LPS) could directly activate TRPV4 channel and TRPV4 is involved in the generation of both acute itch and chronic itch, whether and how LPS affects TRPV4-mediated itch sensation remains unclear. Here, we showed that LPS-mediated TRPV4 sensitization exacerbated GSK101-induced scratching behaviour in mice. Moreover, this effect was compromised in TLR4-knockout mice, suggesting LPS acted through a TLR4-dependent mechanism. Mechanistically, LPS enhanced GSK101-evoked calcium influx in mouse ear skin cells and HEK293T cells transfected with TRPV4. Further, LPS sensitized TRPV4 channel through the intracellular TLR4-PI3K-AKT signalling. In summary, our study found a modulatory role of LPS in TRPV4 function and highlighted the TLR4-TRPV4 interaction in itch signal amplification.

The COL6A5-p.Glu2272* mutation induces chronic itch in mice.

Pruritus is a common irritating sensation that provokes the desire to scratch. Environmental and genetic factors contribute to the onset of pruritus. Moreover, itch can become a major burden when it becomes chronic. Interestingly, the rare Collagen VI alpha 5 (COL6A5) gene variant p.Glu2272* has been identified in two families and an independent patient with chronic neuropathic itch. These patients showed reduced COL6A5 expression in skin and normal skin morphology. However, little progress has been made until now toward understanding the relationships between this mutation and chronic itch. Therefore, we developed the first mouse model that recapitulates COL6A5-p.Glu2272* mutation using the CRISPR-Cas technology and characterized this new mouse model. The mutant mRNA, measured by RT-ddPCR, was expressed at normal levels in dorsal root ganglia and was decreased in skin. The functional exploration showed effects of the mutation with some sex dysmorphology. Mutant mice had increased skin permeability. Elevated spontaneous scratching and grooming was detected in male and female mutants, with increased anxiety-like behavior in female mutants. These results suggest that the COL6A5-p.Glu2272* mutation found in patients contributes to chronic itch and induces in mice additional behavioral changes. The COL6A5-p.Glu2272* mouse model could elucidate the pathophysiological mechanisms underlying COL6A5 role in itch and help identify potential new therapeutic targets.

Astrocytes in chronic pain and itch.

Astrocytes are critical for maintaining the homeostasis of the CNS. Increasing evidence suggests that a number of neurological and neuropsychiatric disorders, including chronic pain, may result from astrocyte 'gliopathy'. Indeed, in recent years there has been substantial progress in our understanding of how astrocytes can regulate nociceptive synaptic transmission via neuronal-glial and glial-glial cell interactions, as well as the involvement of spinal and supraspinal astrocytes in the modulation of pain signalling and the maintenance of neuropathic pain. A role of astrocytes in the pathogenesis of chronic itch is also emerging. These developments suggest that targeting the specific pathways that are responsible for astrogliopathy may represent a novel approach to develop therapies for chronic pain and chronic itch.

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.

The CysLT2R receptor mediates leukotriene C4-driven acute and chronic itch.

Acute and chronic itch are burdensome manifestations of skin pathologies including allergic skin diseases and atopic dermatitis, but the underlying molecular mechanisms are not well understood. Cysteinyl leukotrienes (CysLTs), comprising LTC4, LTD4, and LTE4, are produced by immune cells during type 2 inflammation. Here, we uncover a role for LTC4 and its signaling through the CysLT receptor 2 (CysLT2R) in itch. Cysltr2 transcript is highly expressed in dorsal root ganglia (DRG) neurons linked to itch in mice. We also detected CYSLTR2 in a broad population of human DRG neurons. Injection of leukotriene C4 (LTC4) or its nonhydrolyzable form NMLTC4, but neither LTD4 nor LTE4, induced dose-dependent itch but not pain behaviors in mice. LTC4-mediated itch differed in bout duration and kinetics from pruritogens histamine, compound 48/80, and chloroquine. NMLTC4-induced itch was abrogated in mice deficient for Cysltr2 or when deficiency was restricted to radioresistant cells. Itch was unaffected in mice deficient for Cysltr1, Trpv1, or mast cells (WSh mice). CysLT2R played a role in itch in the MC903 mouse model of chronic itch and dermatitis, but not in models of dry skin or compound 48/80- or Alternaria-induced itch. In MC903-treated mice, CysLT levels increased in skin over time, and Cysltr2-/- mice showed decreased itch in the chronic phase of inflammation. Collectively, our study reveals that LTC4 acts through CysLT2R as its physiological receptor to induce itch, and CysLT2R contributes to itch in a model of dermatitis. Therefore, targeting CysLT signaling may be a promising approach to treat inflammatory itch.

Pain and itch processing by subpopulations of molecularly diverse spinal and trigeminal projection neurons.

A remarkable molecular and functional heterogeneity of the primary sensory neurons and dorsal horn interneurons transmits pain- and or itch-relevant information, but the molecular signature of the projection neurons that convey the messages to the brain is unclear. Here, using retro-TRAP (translating ribosome affinity purification) and RNA sequencing, we reveal extensive molecular diversity of spino- and trigeminoparabrachial projection neurons. Among the many genes identified, we highlight distinct subsets of Cck+ -, Nptx2+ -, Nmb+ -, and Crh+ -expressing projection neurons. By combining in situ hybridization of retrogradely labeled neurons with Fos-based assays, we also demonstrate significant functional heterogeneity, including both convergence and segregation of pain- and itch-provoking inputs into molecularly diverse subsets of NK1R- and non-NK1R-expressing projection neurons.

Difelikefalin suppresses itch and reduces scratching independent of inflammation in a murine model of atopic dermatitis.

BACKGROUND: Therapies specifically targeting nonhistaminergic pruritus are largely lacking. Difelikefalin (DFK) has been found to reduce itch in various chronic pruritic conditions, including atopic dermatitis (AD). OBJECTIVE: We sought to investigate the ability of DFK to impact scratching behavior, inflammatory mediators, and neuronal signaling in a murine model of AD. METHODS: The ears of C57BL/6 mice were topically treated with MC903 for 12 consecutive days to induce AD-like inflammation and itch. Before MC903 treatment, mice were treated with either DFK (0.5 mg/kg, intraperitoneal injection twice daily) or vehicle (saline). Skin ear thickness, histological analysis, flow cytometry, RNA-sequencing, and differential gene expression analyses of mouse ear skin were used to examine the effect of DFK on skin inflammation. Scratching behavior was quantified to measure itch behavior in mice that were topically treated with MC903 for 6 consecutive days; then, mice received a single injection of either DFK (1.0 mg/kg, intraperitoneal injection) or saline. Calcium imaging and single-cell RNA-sequencing were used in mouse dorsal root ganglia neurons to determine the size of the neurons activated with DFK treatment. Statistical significance was determined by Mann-Whitney test, unless otherwise noted. RESULTS: DFK rapidly suppressed itch without altering AD-like skin inflammation in MC903 (calcipotriol)-treated mice. In vitro Ca2+ influx trace of dorsal root ganglia suggested that a major target for DFK is the larger-diameter mechanoreceptors (eg, Aꞵ-fibers), rather than small-diameter pruriceptive C-fibers. CONCLUSIONS: These studies support a potential neuromodulatory role of DFK for reducing itch associated with AD in mice.

Prurigo Nodularis: Pathogenesis and the Horizon of Potential Therapeutics.

Chronic pruritus that lasts for over 6 weeks can present in various forms, like papules, nodules, and plaque types, with prurigo nodularis (PN) being the most prevalent. The pathogenesis of PN involves the dysregulation of immune cell-neural circuits and is associated with peripheral neuropathies, possibly due to chronic scratching. PN is a persistent and challenging condition, involving complex interactions among the skin, immune system, and nervous system. Lesional skin in PN exhibits the infiltration of diverse immune cells like T cells, eosinophils, macrophages, and mast cells, leading to the release of inflammatory cytokines and itch-inducing substances. Activated sensory nerve fibers aggravate pruritus by releasing neurotransmitters, perpetuating a vicious cycle of itching and scratching. Traditional treatments often fail, but recent advancements in understanding the inflammatory and itch transmission mechanisms of PN have paved the way for innovative therapeutic approaches, which are explored in this review.

Cutaneous Immune-Related Adverse Events Secondary to Immune Checkpoint Inhibitors and Their Management.

Immune checkpoint inhibitors (CPIs) are highly effective in the treatment of various cancers. Immunotherapy enhances antitumor activity by relieving inhibition of T cells responsible for immune surveillance. However, overactivation of T cells leads to immune-related adverse events (irAE), of which cutaneous adverse events are the most common. Examples include pruritus and maculopapular eruption most commonly, psoriasis and bullous dermatoses less commonly, and, rarely, severe, life-threatening eruptions such as Stevens-Johnson Syndrome or Toxic Epidermal Necrolysis. Many of these are autoimmune in nature, and these may present de novo or as recurrence of pre-existing disease. In order to maximize the therapeutic potential of CPIs, it is essential to recognize and effectively manage cutaneous irAE, which can otherwise lead to treatment interruption or discontinuation. This review summarizes the presentation and management of dermatologic adverse events secondary to immune dysregulation as a result of immune checkpoint inhibitor therapy, including the most common (maculopapular eruption, pruritus, lichenoid dermatitis, and vitiligo), less common (psoriasis, bullous pemphigoid, erythema multiforme, eczematous dermatitis, alopecia areata, and granulo-matous and neutrophilic dermatoses), and severe (acute generalized exanthematous pustulosis [AGEP], drug reaction with eosinophilia and systemic symptoms [DRESS], and Stevens-Johnson syndrome or toxic epidermal necrolysis [SJS/TEN]), as well as exacerbation of pre-existing cutaneous autoimmune disease (subacute cutaneous lupus erythematosus, dermatomyositis, eosinophilic fasciitis, leukocytoclastic vasculitis, and scleroderma-like reaction).

Curcumin inhibits the pruritus in mice through mast cell MrgprB2 receptor.

BACKGROUND: Curcumin is a diketone compound extracted from the rhizomes of some plants in the Zingiberaceae and Araceae family. It possesses a variety of biological activities, including antioxidant, anti-inflammatory and anti-cancer properties. However, the cellular and molecular antipruritic mechanisms of curcumin remain to be explored. OBJECTIVE: Our objective was to study the role of curcumin in pruritus and determine whether its antipruritic effect is related to MrgprB2 receptor. METHODS: The effect of curcumin on pruritus in mice was examined by scratching behavior test. The antipruritic mechanism of curcumin was explored by using transgenic mice (MrgprB2-/- mice, MrgprB2CreTd/tomato mice), histological analysis, western blot and immunofluorescence. In addition, the relationship between curcumin and MrgprB2/X2 receptor was studied in vitro by using calcium imaging, plasmid transfection and molecular docking RESULTS: In the current study, we found that curcumin had obvious antipruritic effect. Its antipruritic effect was related to the regulation of MrgprB2 receptor activation and mast cells tryptase release. In vitro, mouse peritoneal mast cells activated by compound 48/80 could be inhibited by curcumin. In addition, curcumin was also found to suppress the calcium flux in MrgprX2 or MrgprB2-overexpression HEK cells induced by compound 48/80, substance P, and PAMP 9-20, displaying the specific relation with the MrgprB2/X2 receptor. Moreover, molecular docking results showed that curcumin had affinity to MrgprX2 protein. CONCLUSIONS: Overall, these results indicated that curcumin has the potential to treat pruritus induced by mast cell MrgprB2 receptor.

Single-cell RNA-seq reveals abnormal differentiation of keratinocytes and increased inflammatory differentiated keratinocytes in atopic dermatitis.

BACKGROUND: Atopic dermatitis (AD) is a chronic and recurrent inflammatory skin disease characterized by severe pruritus and eczematous lesions. Heterogeneity of AD has been reported among different racial groups according to clinical, molecular and genetic differences. OBJECTIVE: This study aimed to conduct an in-depth transcriptome analysis of AD in Chinese population. METHODS: We performed single-cell RNA sequencing (scRNA-seq) analysis of skin biopsies from five Chinese adult patients with chronic AD and from four healthy controls, combined with multiplexed immunohistochemical analysis in whole-tissue skin biopsies. We explored the functions of IL19 in vitro. RESULTS: ScRNA-seq analysis was able to profile a total of 87,853 cells, with keratinocytes (KCs) in AD manifesting highly expressed keratinocyte activation and pro-inflammatory genes. KCs demonstrated a novel IL19+ IGFL1+ subpopulation that increased in AD lesions. Inflammatory cytokines IFNG, IL13, IL26 and IL22 were highly expressed in AD lesions. In vitro, IL19 directly downregulated KRT10 and LOR in HaCaT cells and activated HaCaT cells to produce TSLP. CONCLUSION: Abnormal proliferation and differentiation of keratinocytes contribute immensely to the pathogenesis of AD, whereas AD chronic lesions have witnessed significant presence of IL19+ IGFL1+ KCs, which may be involved in the disruption of the skin barrier, the connection and magnification of Th2 and Th17 inflammatory responses, and mediation of skin pruritus. Furthermore, progressive activation of multiple immune axes dominated by Type 2 inflammatory reaction occur in AD chronic lesions.

Electromagnetic Sensing Techniques for Monitoring Atopic Dermatitis-Current Practices and Possible Advancements: A Review.

Atopic dermatitis (AD) is one of the most common skin disorders, affecting nearly one-fifth of children and adolescents worldwide, and currently, the only method of monitoring the condition is through an in-person visual examination by a clinician. This method of assessment poses an inherent risk of subjectivity and can be restrictive to patients who do not have access to or cannot visit hospitals. Advances in digital sensing technologies can serve as a foundation for the development of a new generation of e-health devices that provide accurate and empirical evaluation of the condition to patients worldwide. The goal of this review is to study the past, present, and future of AD monitoring. First, current medical practices such as biopsy, tape stripping and blood serum are discussed with their merits and demerits. Then, alternative digital methods of medical evaluation are highlighted with the focus on non-invasive monitoring using biomarkers of AD-TEWL, skin permittivity, elasticity, and pruritus. Finally, possible future technologies are showcased such as radio frequency reflectometry and optical spectroscopy along with a short discussion to provoke research into improving the current techniques and employing the new ones to develop an AD monitoring device, which could eventually facilitate medical diagnosis.

Efficacy and Microbiota Modulation Induced by LimpiAL 2.5%, a New Medical Device for the Inverse Psoriasis Treatment.

(1) Inverse psoriasis (IP), also known as intertriginous, typically affects the groin, armpits, navel, intergluteal fissure, and external genitalia. Skin lesions are erythematous plaques of inflammatory nature, smooth, well-delimited, non-scaly, and non-infiltrated. Lesions may be accompanied by itching, pain, or burning sensation. The aim of this study is both to investigate the modulation of the skin microbiota induced by IP and, on the other hand, to test the effectiveness of the new biotechnological product LimpiAL 2.5%. (2) Patients affected by IP were recruited in a private practice and treated for 4 weeks with LimpiAL 2.5% exclusively. The clinical effects on the lesion skin were evaluated, and the skin microbiotas before and after treatment were compared. (3) The clinical outcomes reveled a significant beneficial effect of the tested product. At the same time, LimpiAL increased the biological diversity of the skin microbiota and exerted a significant decrease of some Corynebacterium species, and the increase of some Staphylococcus species. (4) Together, the clinical outcomes and the microbiota analysis suggest that LimpiAL treatment improves the skin condition of affected patients, basically restoring the eubiosis conditions of the affected sites and modulating the bacterial composition of the resident microbiota.

Short-Term Efficacy and Safety of Non-Ablative Laser Treatment Alone or with Estriol or Moisturizers in Postmenopausal Women with Vulvovaginal Atrophy.

BACKGROUND: Among treatments for vulvo-vaginal atrophy (VVA), there is a new kind of energy-based device, the non-ablative CO2 laser. AIM: This study aimed to assess the efficacy and safety of the non-ablative CO2 laser in menopausal women with VVA as a monotherapy or in association with vaginal estriol or moisturizer. METHODS: Seventy-five women with VVA received laser treatment (Laser group), laser plus estriol gel (Laser+E) or laser plus moisturizers (Laser+M). The study protocol consisted of 3 monthly laser sessions (t0, t1, t2) and a gynecological examination at baseline and 1 month after last laser treatment (t3). Objective measures included VHI (Vaginal Health Index) and VuHI (Vulvar Health Index); subjective symptoms of VVA (Dryness, Burning, Itching, Dysuria) evaluated via visual analog scales, sexual function evaluated by FSFI (Female Sexual Function Index), FSDS (Female Sexual Distress Score) and MENQOL (Mopause-specific Quality Of Life). Adverse events and discomfort encountered during the procedure were also assessed. OUTCOMES: Primary outcomes were the evaluation of VHI and VuHI and secondary outcomes were changes in VVA symptoms (VAS), sexual function (MENQOL, FSFI, FSDS) and discomfort during the procedure. RESULTS: Seventy-five women (25 in Laser, 25 in Laser+E and 25 in Laser+M group) completed the study. At t3, mean VHI, VuHI, dryness, burning and itching VAS scores improved significantly with no differences between the groups. The lubrication domain of FSFI improved significantly only in the Laser+M group, while the pain domain improved significantly in all women with no differences between the groups. FSFI and FSDS overall scores and MENQOL sexual domain improved in all women with no significant difference between the groups. The mean score of the pain during the procedure was low at t0 and did not change throughout the study. CLINICAL IMPLICATIONS: This study extends knowledge concerning the effectiveness of a new non-ablative CO2 laser in post-menopausal women with VVA. STRENGTHS & LIMITATIONS: This is one of the first studies on this kind of laser and is the first to compare the effectiveness of laser treatment alone or in combination with vaginal estriol or moisturizers. Parameters of VVA and sexual function were evaluated using validated tools. Study limitations include short follow-up time, the limited number of participants and the absence of a sham-controlled group. CONCLUSION: Non-ablative CO2 laser seems to be an effective treatment for VVA in menopausal women. Our preliminary data shows that it can be effective as monotherapy or with adjuvant treatments. Alvisi S, Lami A, Baldassarre M, et al. Short-Term Efficacy and Safety of Non-Ablative Laser Treatment Alone or with Estriol or Moisturizers in Postmenopausal Women with Vulvovaginal Atrophy. J Sex Med 2022;19:761-770.