Spesolimab: a comprehensive review on the anti-IL-36 receptor antibody in dermatology.

Interleukin-36 (IL-36) cytokines contribute to the pathogenesis of various inflammatory skin conditions and are potential therapeutic targets. Spesolimab is a monoclonal antibody that inhibits IL-36 signaling recently approved by the Food and Drug Administration for the management of generalized pustular psoriasis flares in adults. Clinical trials are evaluating the efficacy of this monoclonal antibody in a few other dermatological conditions. Here, this review comprehensively summarizes the safety and efficacy of spesolimab treatment in various dermatological conditions.

Rash and Poor Wound Healing After Mastectomy.

A patient who had recently undergone bilateral mastectomy had erythema, edema, pain, pruritus, serous fluid drainage at the incision sites, and an erythematous papulovesicular rash on the trunk and extremities. A skin swab bacterial culture result was negative, and the skin findings did not improve with antibiotics. What is the diagnosis and what would you do next?

Angiogenesis in Chronic Inflammatory Skin Disorders.

Angiogenesis, the growth of new blood vessels from preexisting vessels, is associated with inflammation in various pathological conditions. Well-known angiogenetic factors include vascular endothelial growth factor (VEGF), angiopoietins, platelet-derived growth factor, transforming growth factor-ß, and basic fibroblast growth factor. Yes-associated protein 1 (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) have recently been added to an important angiogenic factor. Accumulating evidence indicates associations between angiogenesis and chronic inflammatory skin diseases. Angiogenesis is deeply involved in the pathogenesis of psoriasis. VEGF, angiopoietins, tumor necrosis factor-a, interleukin-8, and interleukin-17 are unregulated in psoriasis and induce angiogenesis. Angiogenesis may be involved in the pathogenesis of atopic dermatitis, and in particular, mast cells are a major source of VEGF expression. Angiogenesis is an essential process in rosacea, which is induced by LL-37 from a signal cascade by microorganisms, VEGF, and MMP-3 from mast cells. In addition, angiogenesis by increased VEGF has been reported in chronic urticaria and hidradenitis suppurativa. The finding that VEGF is expressed in inflammatory skin lesions indicates that inhibition of angiogenesis is a useful strategy for treatment of chronic, inflammatory skin disorders.

Epidermal PPARγ Is a Key Homeostatic Regulator of Cutaneous Inflammation and Barrier Function in Mouse Skin.

Both agonist studies and loss-of-function models indicate that PPARγ plays an important role in cutaneous biology. Since PPARγ has a high level of basal activity, we hypothesized that epidermal PPARγ would regulate normal homeostatic processes within the epidermis. In this current study, we performed mRNA sequencing and differential expression analysis of epidermal scrapings from knockout mice and wildtype littermates. Pparg-/-epi mice exhibited a 1.5-fold or greater change in the expression of 11.8% of 14,482 identified transcripts. Up-regulated transcripts included those for a large number of cytokines/chemokines and their receptors, as well as genes associated with inflammasome activation and keratinization. Several of the most dramatically up-regulated pro-inflammatory genes in Pparg-/-epi mouse skin included Igfl3, 2610528A11Rik, and Il1f6. RT-PCR was performed from RNA obtained from non-lesional full-thickness skin and verified a marked increase in these transcripts, as well as transcripts for Igflr1, which encodes the receptor for Igfl3, and the 2610528A11Rik receptor (Gpr15). Transcripts for Il4 were detected in Pparg-/-epi mouse skin, but transcripts for Il17 and Il22 were not detected. Down-regulated transcripts included sebaceous gland markers and a number of genes associated with lipid barrier formation. The change in these transcripts correlates with an asebia phenotype, increased transepidermal water loss, alopecia, dandruff, and the appearance of spontaneous inflammatory skin lesions. Histologically, non-lesional skin showed hyperkeratosis, while inflammatory lesions were characterized by dermal inflammation and epidermal acanthosis, spongiosis, and parakeratosis. In conclusion, loss of epidermal Pparg alters a substantial set of genes that are associated with cutaneous inflammation, keratinization, and sebaceous gland function. The data indicate that epidermal PPARγ plays an important role in homeostatic epidermal function, particularly epidermal differentiation, barrier function, sebaceous gland development and function, and inflammatory signaling.

Daily Lifestyle and Inflammatory Skin Diseases.

Throughout life, it is necessary to adapt to the Earth's environment in order to survive. A typical example of this is that the daily Earth cycle is different from the circadian rhythm in human beings; however, the ability to adapt to the Earth cycle has contributed to the development of human evolution. In addition, humans can consume and digest Earth-derived foods and use luxury materials for nutrition and enrichment of their lives, as an adaptation to the Earth's environment. Recent studies have shown that daily lifestyles are closely related to human health; however, less attention has been paid to the fact that obesity due to excessive energy intake, smoking, and alcohol consumption contributes to the development of inflammatory skin diseases. Gluten or wheat protein, smoking and alcohol, sleep disturbance, and obesity drive the helper T (Th)1/Th2/Th17 immune response, whereas dietary fiber and omega-3 fatty acids negatively regulate inflammatory cytokine production. In this review, we have focused on daily lifestyles and the mechanisms involved in the pathogenesis of inflammatory skin diseases.

Central opioid receptors mediate morphine-induced itch and chronic itch via disinhibition.

Opioids such as morphine are mainstay treatments for clinical pain conditions. Itch is a common side effect of opioids, particularly as a result of epidural or intrathecal administration. Recent progress has advanced our understanding of itch circuits in the spinal cord. However, the mechanisms underlying opioid-induced itch are not fully understood, although an interaction between µ-opioid receptor (MOR) and gastrin-releasing peptide receptor (GRPR) in spinal GRPR-expressing neurons has been implicated. In this study we investigated the cellular mechanisms of intrathecal opioid-induced itch by conditional deletion of MOR-encoding Oprm1 in distinct populations of interneurons and sensory neurons. We found that intrathecal injection of the MOR agonists morphine or DAMGO elicited dose-dependent scratching as well as licking and biting, but this pruritus was totally abolished in mice with a specific Oprm1 deletion in Vgat+ neurons [Oprm1-Vgat (Slc32a1)]. Loss of MOR in somatostatin+ interneurons and TRPV1+ sensory neurons did not affect morphine-induced itch but impaired morphine-induced antinociception. In situ hybridization revealed Oprm1 expression in 30% of inhibitory and 20% of excitatory interneurons in the spinal dorsal horn. Whole-cell recordings from spinal cord slices showed that DAMGO induced outward currents in 9 of 19 Vgat+ interneurons examined. Morphine also inhibited action potentials in Vgat+ interneurons. Furthermore, morphine suppressed evoked inhibitory postsynaptic currents in postsynaptic Vgat- excitatory neurons, suggesting a mechanism of disinhibition by MOR agonists. Notably, morphine-elicited itch was suppressed by intrathecal administration of NPY and abolished by spinal ablation of GRPR+ neurons with intrathecal injection of bombesin-saporin, whereas intrathecal GRP-induced itch response remained intact in mice lacking Oprm1-Vgat. Intrathecal bombesin-saporin treatment reduced the number of GRPR+ neurons by 97% in the lumber spinal cord and 91% in the cervical spinal cord, without changing the number of Oprm1+ neurons. Additionally, chronic itch from DNFB-induced allergic contact dermatitis was decreased by Oprm1-Vgat deletion. Finally, naloxone, but not peripherally restricted naloxone methiodide, inhibited chronic itch in the DNFB model and the CTCL model, indicating a contribution of central MOR signalling to chronic itch. Our findings demonstrate that intrathecal morphine elicits itch via acting on MOR on spinal inhibitory interneurons, leading to disinhibition of the spinal itch circuit. Our data also provide mechanistic insights into the current treatment of chronic itch with opioid receptor antagonist such as naloxone.

Knowledge Gaps in the Etiology and Pathophysiology of Incontinence-Associated Dermatitis: A Scoping Review.

PURPOSE: Incontinence-associated dermatitis (IAD) due to the prolonged exposure of the skin to urinary, fecal, or double incontinence represents a major clinical practice challenge. The aim of this review was to identify and critically appraise the results of published studies on the etiology and pathophysiology of IAD and highlight the current gaps in empirical evidence. METHODS: Scoping literature review. SEARCH STRATEGY: The electronic databases PubMed, Cumulative Index to Nursing and Allied Health Literature, MEDLINE, and Embase were searched for relevant articles published from 1996 to April 2018. Thirteen studies and review articles related to the etiology and pathophysiology of IAD were identified in our initial review, and 3 studies published subsequent to our initial review were evaluated and included in our final review. FINDINGS: These studies suggest that several etiologic factors contribute to the development of IAD including exposure to urine, stool, or a combination of these substances (dual incontinence), the duration and frequency of exposure, frequent cleaning, and inflammatory responses. Results from the current scoping review showed that despite the increasing interest in IAD, evidence related to the underlying mechanisms causing IAD remains sparse. This paucity represents a clear gap in knowledge and indicates a need for additional research. IMPLICATIONS: Future studies should aim at elucidating: (1) the role of urine and its inherent pH on skin integrity, (2) the role of stool, specific digestive enzymes, and fecal bacteria on skin integrity, (3) the permeability and susceptibility of the skin to damage following frequent cleansing activities and occlusion, and (4) the specific inflammatory response triggered following exposure to urine and fecal matter.

[Pathophysiology of autoinflammatory dermatoses]. / Pathophysiologie der autoinflammatorischen Dermatosen.

Autoinflammation leads to inflammation that mostly occurs without any clinically obvious reason. It can be so severe that organ damage with relevant tissue damage occurs. Inflammasomes are the drivers of autoinflammation. Although IL­1 beta and the inflammasomes as its critical regulators are very important in autoinflammation, not all patients respond to inhibition of this signalling pathway. Several autoinflammatory diseases were associated with mutations in proteasome-immunoproteasome components. Autoinflammatory diseases caused by highly relevant genetic variants are mostly hereditary. Usually in childhood but not always. The coming years will show whether inflammatory dermatoses will be increasingly treated with suppression of the innate immune system in addition to inhibition of adaptive immunity.

Alcohol-Related Dermatitis: A Review.

: Wine, beer, liquor, and spirits are widely consumed in many cultures across the globe, and for some individuals, ingestion, cutaneous contact, or other exposure can lead to dermatologic findings. However, there currently exist no comprehensive reviews on alcohol-related dermatitis. Herein, we will provide an overview of alcohol-related dermatitis and contact urticaria, including the epidemiology and clinical manifestations, potential allergens found in alcoholic beverages, testing approaches, and strategies for allergen avoidance.

Dermatitis actínica crónica / Chronic actinic dermatitis

RESUMEN La dermatitis actínica crónica (DAC) - dermatitis por fotosensibilidad, reacción solar persistente o su variante extrema el reticuloide actínico- es una fotodermatosis crónica, propia del adulto más frecuente en el sexo masculino provocada por rayos ultravioletas (UVB), (UVA) y luz visible. El diagnóstico es clínico, caracterizado por placas eccematosas y liquenificadas pruriginosas en aéreas expuestas al sol. Se cree que el DAC se debe a la fotosensibilización secundaria de un antígeno endógeno de la piel.

ABSTRACT Chronic actinic dermatitis (ACD) - photosensitivity dermatitis, persistent solar reaction or its extreme variant actinic reticuloid - is a chronic photodermatosis, typical of the adult male caused by ultraviolet (UVB), (UVA) and visible light. The diagnosis suggested by clinical researchers, characterized by eczematous and lichenified pruritic plaques in areas exposed to the sun. It is believed that DAC is due to the secondary photosensitization of an endogenous skin antigen.

Cutaneous inflammation differentially regulates the expression and function of Angiotensin-II types 1 and 2 receptors in rat primary sensory neurons.

Neuropathic and inflammatory pain results from cellular and molecular changes in dorsal root ganglion (DRG) neurons. The type-2 receptor for Angiotensin-II (AT2R) has been involved in this type of pain. However, the underlying mechanisms are poorly understood, including the role of the type-1 receptor for Angiotensin-II (AT1R). Here, we used a combination of immunohistochemistry and immunocytochemistry, RT-PCR and in vitro and in vivo pharmacological manipulation to examine how cutaneous inflammation affected the expression of AT1R and AT2R in subpopulations of rat DRG neurons and studied their impact on inflammation-induced neuritogenesis. We demonstrated that AT2R-neurons express C- or A-neuron markers, primarily IB4, trkA, and substance-P. AT1R expression was highest in small neurons and co-localized significantly with AT2R. In vitro, an inflammatory soup caused significant elevation of AT2R mRNA, whereas AT1R mRNA levels remained unchanged. In vivo, we found a unique pattern of change in the expression of AT1R and AT2R after cutaneous inflammation. AT2R increased in small neurons at 1 day and in medium size neurons at 4 days. Interestingly, cutaneous inflammation increased AT1R levels only in large neurons at 4 days. We found that in vitro and in vivo AT1R and AT2R acted co-operatively to regulate DRG neurite outgrowth. In vivo, AT2R inhibition impacted more on non-peptidergic C-neurons neuritogenesis, whereas AT1R blockade affected primarily peptidergic nerve terminals. Thus, cutaneous-induced inflammation regulated AT1R and AT2R expression and function in different DRG neuronal subpopulations at different times. These findings must be considered when targeting AT1R and AT2R to treat chronic inflammatory pain. Cover Image for this issue: doi: 10.1111/jnc.14737.

[Adhesion problems of stoma accessories due to peristomal dermatitis]. / Slecht hechtende stomaplak door dermatitis.

Peristomal dermatitis is a frequent problem in stoma patients. This causes problems with the adhesion of stoma material. Not being able to rely on a leak-free stoma plaque has major social consequences for stoma patients. In this article we discuss the differential diagnosis, pathophysiology and therapy based on a patients case. If the dermatitis is based on an irritating contact dermatitis due to the stoma adhesive, the dermatitis should be treated with a local corticosteroid, preferably in the form of a nasal spray.

Paciente con dermatitis y artritis durante sus embarazos / A patient with dermatitis and arthritis during her two pregnancies

Paciente femenina que presentó durante sus dos embarazos eritema nodoso, úlceras nasales y artritis. Debido a la persistencia del eritema nodoso después del segundo parto, se practicó determinación de ANA y anti-DNA ­ IF, resultando este último positivo, por lo que se plantea el diagnóstico de lupus eritematoso y es referida al Centro Nacional de Enfermedades Reumáticas, (CNER) donde se le practicó biopsia de piel que resultó compatible con lepra: borderline o dimorfa (BB-BL) en estado reaccional tipo II (eritema nodoso leproso: ENL). Se discuten algunos de aspectos de la lepra haciendo especial énfasis en síntomas que presentó la paciente y la exacerbación de los mismos durante los embarazos, posiblemente en relación con algunos cambios inmunológicos adaptativos que son generados para mantener la tolerancia materno fetal(AU)

Female young patient with erythema nodosum, nasal ulcers and arthritis during her two pregnancies. Due to the persistence of the erythema nodosum after the second delivery, ANA and anti-DNA - IF determination were done, the latter being positive, and she was diagnosed with lupus erythematosus and was referred to the National Center for Rheumatic Diseases, where skin biopsy showed to be compatible with leprosy: borderline or dimorphic (BB-BL) in type II reactional state (leprous erythema nodosum: LEN). Some aspects of leprosy are discussed with special emphasis on symptoms that the patient presented and their exacerbation during pregnancies, possibly in relation to some adaptive immunological changes that was generated to maintain maternal fetal tolerance(AU)

Diagnóstico y tratamiento del síndrome de piel sensible: un algoritmo para la práctica clínica habitual / Diagnosis and Treatment of Sensitive Skin Syndrome: An Algorithm for Clinical Practice

Tradicionalmente, la piel sensible se ha considerado como un problema cosmético o como una alteración puramente psicosomática con un fuerte componente subjetivo. Sin embargo, diversos estudios científicos sobre sus procesos fisiopatológicos y su etiopatogenia han demostrado que se trata de una entidad compleja que ya diversos autores consideran un síndrome neurodermatológico. Sus características hacen que su diagnóstico y tratamiento puedan resultar complicados en la práctica clínica habitual, siendo necesarias herramientas sencillas que se puedan usar de rutina, tanto para identificar esta entidad, que puede presentarse acompañada de otra patología, como para su manejo independiente. En este trabajo realizamos una revisión práctica de los avances científicos más recientes el campo de la piel sensible que justifican su consideración individual y ofrecen herramientas para identificarla y tratarla. Proponemos algoritmos de diagnóstico y de tratamiento basados en las evidencias de la literatura y en la opinión de los expertos que firman este artículo

Sensitive skin has traditionally been viewed as a cosmetic problem or as a purely psychosomatic alteration with a major subjective component. Different studies of its pathophysiologic etiology, however, have shown it to be a complex entity that several authors now consider to be a neurodermatological syndrome. Because of this complexity, skin sensitivity can be difficult to diagnose and treat, particularly considering that it may present with another disease. Simple tools applicable to clinical practice are thus necessary to identify and manage this disease as an independent entity. In this study, we perform a practical review of the most recent scientific advances in the area of sensitive skin that justify it being considered an individual entity, and provide tools for its identification and treatment. We propose diagnostic and treatment algorithms based on evidence from the literature and our experience and expertise

Blau syndrome with a rare mutation in exon 9 of NOD2 gene.

Blau syndrome is an autosomal dominant rare disease caused by mutations in NOD2 gene. Less than 200 patients published with Blau Syndrome Worldwide. We reported a 41-year old female Turkish patient diagnosed as Blau syndrome. Granulomatous dermatitis and severe headache, as well as recurrent chest and pelvic pain have been present since she was 8 years old. Arthritis started when she was teenage, hypertension diagnosed when she was 20 and other symptoms also occurred during the lifetime (severe preeclampsia, ischemic stroke, recurrent hemiparesis, recurrent-transient-vision-loss and renal-artery-stenosis). Genomic DNA was isolated from peripheral blood and 12 genes sequenced in Autoinflammatory panel on IonTorrent-S5-NGS platform with Parseq-VariFind™AIPassay. NGS analysis showed 107 variants in in the index case, mainly benign with no strong association with Blau syndrome. Additionally, we identified one very rare missense mutation in NOD2 gene (c2803G>A, p.Val935Met) and in silico assessment of the mutation indicated possible pathogenic significance and strong association with Blau syndrome. In addition, we analyzed family members of the index case and identified the same mutation in NOD2 gene. The segregation analysis shows the presence of the same mutant allele in NOD2 gene in the index case affected sister, as well as in her son with arthralgia, while in her non affecter brother we didn't detect the Val935Met mutation in NOD2 gene. Blau Syndrome is known as a very rare disease, mainly caused by mutations in NOD2 gene. Missense mutation diagnosed in our case could be responsible for the phenotype of the index case. Our results indicate the importance of NGS testing and its major role in the detection of rare mutations that may responsible for the onset of autoinflammatory disorders.

Exploring Incontinence-Associated Dermatitis in a Single Center Intensive Care Unit: A Longitudinal Point Prevalence Survey.

PURPOSE: The purpose of this study was to provide longitudinal prevalence rates of incontinence-associated dermatitis (IAD) in patients in an intensive care unit (ICU) and to identify patient characteristics associated with IAD development. DESIGN: Prospective observational. SUBJECTS AND SETTING: The sample comprised 351 patients aged 18 years and older in a major metropolitan public hospital ICU in Queensland, Australia. METHODS: All consenting, eligible participants at risk of developing IAD underwent weekly skin inspections to determine the presence of IAD. Data were collected weekly for 52 consecutive weeks. Descriptive statistics described the study sample and logistic regression analysis was used to identify patient characteristics associated with development of IAD. RESULTS: The weekly IAD prevalence ranged between 0% and 70%, with IAD developing in 17% (n = 59/351) of ICU patients. The odds of IAD developing increased statistically significantly with increasing age (odds ratio [OR]: 1.029, 95% confidence interval [CI]: 1.005-1.054, P = .016), time in the ICU (OR = 1.104; 95% CI: 1.063-1.147, P < .001), and Bristol Stool chart score (OR = 4.363, 95% CI: 2.091-9.106, P < .001). Patients with respiratory (OR = 3.657, 95% CI: 1.399-9.563, P = .008) and sepsis (OR = 3.230, 95% CI: 1.281-8.146, P = .013) diagnoses had increased odds of developing IAD. CONCLUSIONS: These data show the high variability of IAD prevalence over a 1-year period. Characteristics associated with the development of IAD in patients in the ICU included older age, longer lengths of ICU stay, incontinent of liquid feces, and having respiratory or sepsis diagnoses.

Time of Onset to Changes in Skin Condition During Exposure to Synthetic Urine: A Prospective Study.

PURPOSE: The purpose of this study was to evaluate the impact of incontinence on epithelial-moisture barrier function and the subsequent risk for incontinence-associated dermatitis by exposing healthy volunteers to a premium incontinence pad wet with synthetic urine. DESIGN: Prospective, single-group study. PARTICIPANTS AND SETTING: Thirty women 65 years or older participated in the study. Participants had healthy skin of the buttocks, perineal, and perigenital areas and were not incontinent of urine or stool. The study was conducted at a contracted clinical research facility in Southeastern United States. METHODS: Four hundred milliliters of synthetic urine was distributed across the width of a premium incontinence pad with wicking technology containing a superabsorbent polymer core. Participants laid supine for a total of 4 hours, with the wet pad under the buttocks. Skin assessments were conducted at baseline prior to contact with the wet pad, at 15 minutes, 30 minutes, and 1, 2, and 4 hours after exposure to the synthetic urine. Outcome measures were skin moisture content, cutaneous pH, transepidermal water loss (TEWL), mean coefficient of friction values (static and dynamic), and tolerability evaluations (expert clinical grader-assessed erythema and participant-assessed discomfort). RESULTS: Mean moisture content of the skin increased from 46.19 ± 22.1 to 1845.28 ± 542.7 micro-Siemens (µS) after just 15 minutes of exposure and was significantly increased at all time points compared to baseline (P < .001). Cutaneous pH increased from 5.67 ± 0.5 to 6.25 ± 0.1 after 15 minutes; pH was higher at all time points compared to baseline (P < .001). Passive transfer of water through the stratum corneum (TEWL) showed an increase from 9.02 ± 2.2 g/m/h at baseline to 16.83 ± 5.2 g/m/h at 4 hours (P < .001). There was a significant increase from baseline to 4 hours in mean coefficient of static friction (0.32 ± 0.01 vs 0.47 ± 0.03; P < .00001) as well as mean coefficient of dynamic friction (0.29 ± 0.01 vs 0.42 ± 0.02; P < .00001). There was a significant increase in erythema and an increase in participant-assessed discomfort at all time points (P < .005). CONCLUSIONS: Our findings suggest that impairment of the skin's epithelial-moisture barrier function associated with inflammation and development of incontinence-associated dermatitis begins rapidly after an incontinence event, even with the use of a premium pad with wicking technology. Study findings also suggest that prompt attention to incontinence events is needed to prevent moisture-associated skin damage (incontinence-associated dermatitis) even when absorbent pads are used.

Cutibacterium acnes phylotypes diversity loss: a trigger for skin inflammatory process.

BACKGROUND: Acne has long been understood as a multifactorial chronic inflammatory disease of the pilosebaceous follicle, where Cutibacterium acnes (subdivided into six main phylotypes) is a crucial factor. In parallel, the loss of microbial diversity among the skin commensal communities has recently been shown as often accompanied by inflammatory skin disorders. OBJECTIVE: This study investigated the association of C. acnes phylotype diversity loss and the impact on Innate Immune System (IIS) activation. METHODS: The IIS response of skin after incubation with phylotypes IA1, II or III individually and with the combination of IA1 + II + III phylotypes, was studied in an in vitro skin explant system. The inflammatory response was monitored by immunohistochemistry and ELISA assays, targeting a selection of Innate Immune Markers (IIMs) (IL-6, IL-8, IL-10, IL-17, TGF-ß). RESULTS: IIMs were significantly upregulated in skin when being incubated with phylotype IA1 alone compared with the combination IA1 + II + III. In parallel, ELISA assays confirmed these results in supernatants for IL-17, IL-8 and IL-10. CONCLUSION: We identify the loss of C. acnes phylotype diversity as a trigger for IIS activation, leading to cutaneous inflammation. These innovative data underline the possibility to set up new approaches to treat acne. Indeed, maintaining the balance between the different phylotypes of C. acnes may be an interesting target for the development of drugs.