Lichen sclerosus: The 2023 update.

Lichen sclerosus (LS) is an underdiagnosed inflammatory mucocutaneous condition affecting the anogenital areas. Postmenopausal women are predominantly affected and, to a lesser extent, men, prepubertal children, and adolescents. The etiology of LS is still unknown. Hormonal status, frequent trauma and autoimmune diseases are well-known associations for LS, yet infections do not seem to be clear risk factors. LS pathogenesis involves factors such as a genetic predisposition and an immune-mediated Th1-specific IFNγ-induced phenotype. Furthermore, there is a distinct expression of tissue remodeling associated genes as well as microRNAs. Oxidative stress with lipid and DNA peroxidation provides an enabling microenvironment to autoimmunity and carcinogenesis. Circulating IgG autoantibodies against the extracellular matrix protein 1 and hemidesmosome may contribute to the progression of LS or simply represent an epiphenomenon. The typical clinical picture includes chronic whitish atrophic patches along with itching and soreness in the vulvar, perianal and penile regions. In addition to genital scarring, and sexual and urinary dysfunction, LS may also lead to squamous cell carcinoma. Disseminated extragenital LS and oral LS are also reported. The diagnosis is usually clinical; however, a skin biopsy should be performed in case of an unclear clinical picture, treatment failure or suspicion of a neoplasm. The gold-standard therapy is the long-term application of ultrapotent or potent topical corticosteroids and, alternatively, topical calcineurin inhibitors such as pimecrolimus or tacrolimus. Collectively, LS is a common dermatological disease with a so far incompletely understood pathogenesis and only limited treatment options. To foster translational research in LS, we provide here an update on its clinical features, pathogenesis, diagnosis and (emerging) treatment options.

Morphea: The 2023 update.

Morphea, also known as localized scleroderma, is a chronic inflammatory connective tissue disorder with variable clinical presentations, that affects both adults and children. It is characterized by inflammation and fibrosis of the skin and underlying soft tissue, in certain cases even of the surrounding structures such as fascia, muscle, bone and central nervous system. While the etiology is still unknown, many factors may contribute to disease development, including genetic predisposition, vascular dysregulation, TH1/TH2 imbalance with chemokines and cytokines associated with interferon-γ and profibrotic pathways as well as certain environmental factors. Since the disease may progress to permanent cosmetic and functional sequelae, it is crucial to properly assess the disease activity and to initiate promptly the adequate treatment, thus preventing subsequent damage. The mainstay of treatment is based on corticosteroids and methotrexate. These, however, are limited by their toxicity, especially if applied long-term. Furthermore, corticosteroids and methotrexate often do not sufficiently control the disease and/or the frequent relapses of morphea. This review presents the current understanding of morphea by discussing its epidemiology, diagnosis, management and prognosis. In addition, it will describe recent pathogenetic findings, thus proposing potential novel targets for therapeutic development in morphea.

Risk factors and sequelae of epidermolysis bullosa acquisita: A propensity-matched global study in 1,344 patients.

Identification of risk factors and sequelae of any given disease is of key importance. For common diseases, primary prevention and disease management are based on this knowledge. For orphan diseases, identification of risk factors and sequelae has been challenging. With the advent of large databases, e.g., TriNetX, this can now be addressed. We used TriNetX to identify risk factors and sequelae of epidermolysis bullosa acquisita (EBA), a severe and orphan autoimmune disease. To date, there is only enigmatic information on EBA comorbidity. We recruited 1,344 EBA patients in the Global Collaborative Network of TriNetX. Using the "explore outcomes" function we identified 55 diagnoses with a different prevalence between EBA and no-EBA patients. We next performed propensity-matched, retrospective cohort studies in which we determined the risk of EBA development following any of the identified 55 diseases. Here, 31/55 diseases were identified as risk factors for subsequent EBA. Importantly, the highest risk for EBA were other chronic inflammatory diseases (CID), especially lupus erythematosus and lichen planus. Lastly, we determined the risk to develop any of the identified diseases after EBA diagnosis. Here, 38/55 diseases were identified as sequelae. Notably, EBA patients showed an increased risk for metabolic and cardiovascular disease, and thrombosis. Furthermore, the risk for CIDs, especially lupus erythematosus and lichen planus, was elevated. These insights into risk factors and sequelae of EBA are not only of clinical relevance, e.g., optimizing cardiovascular disease risk, but in addition, point to shared pathogenetic pathways between EBA and other inflammatory diseases.

Peritoneal dialysate-range hypertonic glucose promotes T-cell IL-17 production that induces mesothelial inflammation.

Peritoneal dialysis (PD) employs hypertonic glucose to remove excess water and uremic waste. Peritoneal membrane failure limits its long-term use. T-cell cytokines promote this decline. T-cell differentiation is critically determined by the microenvironment. We here study how PD-range hypertonic glucose regulates T-cell polarization and IL-17 production. In the human peritoneal cavity, CD3+ cell numbers increased in PD. Single cell RNA sequencing detected expression of T helper (Th) 17 signature genes RORC and IL23R. In vitro, PD-range glucose stimulated spontaneous and amplified cytokine-induced Th17 polarization. Osmotic controls l-glucose and d-mannose demonstrate that induction of IL-17A is a substance-independent, tonicity dose-dependent process. PD-range glucose upregulated glycolysis and increased the proportion of dysfunctional mitochondria. Blockade of reactive-oxygen species (ROS) prevented IL-17A induction in response to PD-range glucose. Peritoneal mesothelium cultured with IL-17A or IL17F produced pro-inflammatory cytokines IL-6, CCL2, and CX3CL1. In PD patients, peritoneal IL-17A positively correlated with CX3CL1 concentrations. PD-range glucose-stimulated, but neither identically treated Il17a-/- Il17f-/- nor T cells cultured with the ROS scavenger N-acetylcysteine enhanced mesothelial CX3CL1 expression. Our data delineate PD-range hypertonic glucose as a novel inducer of Th17 polarization in a mitochondrial-ROS-dependent manner. Modulation of tonicity-mediated effects of PD solutions may improve membrane survival.

Ultraviolet radiation induces Melan-A-expressing cells in interfollicular epidermis in wild-type mice.

Adult wild-type mice are not supposed to be proper models for ultraviolet radiation (UVR)-induced melanoma since melanocytes are confined to hair follicles and cannot be sufficiently reached by UVR. On the other hand, in mutated mouse models used for melanoma research limitations, including an altered immune system and selection of affected pathways, lead to tumors phenotypically quite different from naturally occurring melanomas. We compared the distribution of epidermal melanocytes in UVR and not-UVR-exposed wild-type C57BL/6 mice. Starting at the age of 8 weeks, mice were exposed to physiologic doses of UVR three times weekly over 16 weeks. Back skin biopsies were taken 4, 8, 12 and 16 weeks after initiation of exposure, and stained for Melan-A, representing a highly selective marker for melanocytes. Surprisingly, after exposure to UVR, Melan-A positive cells were detected also in the interfollicular epidermis of C57BL/6 mice. We conclude that UVR is capable of inducing interfollicular epidermal melanocytes in wild-type mice.

A study of skin disease spectrum occurring in Angola phototype V-VI population in Luanda.

BACKGROUND: Prevalence of skin diseases in Luanda (Angola) is unknown, and publications are barely found in the literature. We aim to describe, for the first time, the frequency of skin disease spectrum in phototype V-VI Angolan population in Luanda City. METHODS: We included Fitzpatrick phototype V-VI Angolan patients who consulted the Dermatology Unit in Luanda Medical Center during a 1-year period. Medical information was recovered from the electronic database, and diagnoses were based on ICD-10. Only the main complaint was registered, and the results were classified according to age and sex. Criteria exclusion consisted of incomplete clinical records, Fitzpatrick phototype I-IV Angolan, or foreign patients from the study. RESULTS: From a total of 3938 patients, 3554 met the inclusion criteria, of which 2742 were adults 13 years or older. In this group, acne (23.6%), dermatophytosis (11.0%), and pityriasis versicolor (8.6%) were the main complaints. On the other hand, in the pediatric population (n = 812), atopic dermatitis (29.4%), tinea capitis (13.7%), and molluscum contagiosum (12.5%) were the most frequent disorders. In adult females, acne (31.3%) was the main condition, while in adult males, dermatophytosis (13.5%). In children, the frequency of atopic dermatitis was comparable: 29.1% and 28.6% in girls and boys, respectively. CONCLUSIONS: We published for the first time the frequency of the skin disease spectrum in Fitzpatrick phototype V-VI Angolan population in Luanda City, highlighting the prevalence of acne, dermatophytosis, and atopic dermatitis.

Serie parasitosis en dermatología: tungiasis / Dermatology iconography: tungiasis

La tungiasis es una ectoparasitosis causada por la penetración en la piel de la pulga hembra Tunga penetrans. Esta enfermedad no es específica del hombre y se distribuye en regiones cálidas y secas alrededor del mundo. Se adquiere por contacto directo con el suelo en donde habitan los parásitos adultos. En zonas endémicas, su alta prevalencia se asocia a pobreza y falta de acceso al sistema de salud. Además es frecuente entre viajeros que visitan regiones endémicas y que regresan a sus lugares de origen. Presentamos un caso típico de tungiasis en un paciente 39 años que había realizado un viaje reciente a zona endémica. (AU)

Tungiasis is an ectoparasitosis caused by penetration into the skin of the female flea Tunga penetrans. This disease is not human-specific and is distributed worldwide in warm, dry regions. It is acquired by direct contact with the soil where the adult parasites live. In endemic areas, its high prevalence is associated with poverty and lack of access to the health system. It is also frequent among travelers visiting endemic regions and returning to their places of origin. We present a typical case of tungiasis in a 39 year old patient who had made a recent trip to an endemic area. (AU)

Vías de señalización celular y su aplicaciónen dermatología / Cell signaling pathways and it application in dermatology

El estudio de las vías de señalización celular permite conocer la fisiología normal de la piel, así como también su rol en la génesis de las enfermedades inflamatorias y de las neoplasias dermatológicas. La vía de MAPK está vinculada con la proliferación normal de la célula, pero su desregulación se asocia al melanoma y a enfermedades congénitas como las rasopatías. La vía PI3K tiene una actividad antiapoptótica y regula el metabolismo celular, pero ante mutaciones pueden aparecer hamartomas y neoplasias como el melanoma. Los nuevos tratamientos del carcinoma basocelular en estadio avanzado están dirigidos a bloquear la vía Hedgehog. En el caso de Wnt, esta vía es indispensable para el desarrollo normal del pelo, pero también se asocia a enfermedades como el liquen plano y la psoriasis y su mutación, al mayor riesgo de metástasis. Los nuevos tratamientos dermatológicos están dirigidos a blancos moleculares específicos, por lo que se requiere estar actualizado para elegir la mejor terapéutica para nuestros pacientes...

Ácidos ribonucleicos no codificantes: hacia la era de la medicina personalizada / Noncoding ribonucleic acids: stepping into the era of personalized medicine

Los ácidos ribonucleicos (ARN) son moléculas que clásicamente transmiten la información codificada en el núcleo celular para traducirse a proteínas con diversas funciones. Sin embargo, existe una gran variedad de ARN (microARN, miARN, LncARN, ácido ribonucleicono codificante) capaces de regular diferentes funciones y bloquear o activar la transcripción celular, pero que no tienen la capacidad de traducirse a proteínas. Estos ARN conocidos como no codificantes, fueron descubiertos en los últimos años y están asociadosa diferentes enfermedades tanto inmunológicas como neoplásicas de forma específica. Además, se plantean como una herramienta de utilidad diagnóstica con alta especificidad, por lo que se espera que revolucionen los métodos actualmente utilizados en elámbito médico.

The ribonucleic acids (RNA) are molecules classically involved in the transmission of theinformation encoded in the nucleus, which are translated to proteins with different functions.However, there is a great variety of RNA (microRNA, miRNA, LncRNA, non-coding-RNA) capable of regulating several cellular mechanisms and blocking or activating thetranscription, but they cannot be translated into proteins. These kind of RNA are known asnon-coding, they were recently discovered and they are related to different immunologicaland neoplastic diseases. Moreover, non-coding-RNAs could become a high specificitydiagnostic tool, so it is expected that they will improve the methods currently used inmedicine.

Los retrovirus endógenos y su rol en el melanoma cutáneo / The role of endogenous retroviruses in cutaneous melanoma

Los retrovirus endógenos son elementos virales ancestrales insertos en el genoma humano desde hace miles de años. Aunque permanecen quiescentes a lo largo de la vida, ciertos estímulos y mutaciones genéticas pueden reactivar estos elementos genéticos. El másestudiado de los retrovirus endógenos, el HERV-K, aporta diferentes proteínas que tienen acción inmunosupresora y alteran la migración y el fenotipo celular, lo que conduce finalmente a una génesis y progresión de diferentes neoplasias, como el melanoma cutáneo. A través dediferentes métodos, pueden detectarse anticuerpos dirigidos contra las proteínas retrovirales, las cuales correlacionan con un pronóstico desfavorable en pacientes con melanoma en diferentes estadios. La terapéutica dirigida contra HERV-K es una de las futuras herramientasen estudio para reducir la morbimortalidad de esta neoplasia cutánea...

Leucemia cutis / Leukemia Cutis

La leucemia cutis se define como la infiltración de células leucémicas a nivel de la piel. Constituye un signo de enfermedad diseminada y en ocasiones es un marcador de recidiva. Su presentación clínica es variable y comprende desde pequeñas pápulas hasta grandes nódulos o tumores. Por lo general las lesiones aparecen en forma posterior al compromiso de sangre periférica. La leucemia cutis se observa con mayor frecuencia en las leucemias monocíticas o mielomonocíticas, y su presencia implica un signo de mal pronóstico. Se presentan tres casos de pacientes con diagnóstico de leucemia mieloide aguda, síndrome mielodisplásico y leucemia mieloide crónica, que presentaron leucemias cutáneas diagnosticadas por histolopatología e inmunohistoquímica.