ΔNp63-Senataxin circuit controls keratinocyte differentiation by promoting the transcriptional termination of epidermal genes.

SignificanceΔNp63 is a master regulator of skin homeostasis since it finely controls keratinocyte differentiation and proliferation. Here, we provide cellular and molecular evidence demonstrating the functional role of a ΔNp63 interactor, the R-loop-resolving enzyme Senataxin (SETX), in fine-tuning keratinocyte differentiation. We found that SETX physically binds the p63 DNA-binding motif present in two early epidermal differentiation genes, Keratin 1 (KRT1) and ZNF750, facilitating R-loop removal over their 3' ends and thus allowing efficient transcriptional termination and gene expression. These molecular events translate into the inability of SETX-depleted keratinocytes to undergo the correct epidermal differentiation program. Remarkably, SETX is dysregulated in cutaneous squamous cell carcinoma, suggesting its potential involvement in the pathogenesis of skin disorders.

How to integrate surgery and targeted therapy with biologics for the treatment of hidradenitis suppurativa: Delphi consensus statements from an Italian expert panel.

Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease characterized by recurrent and painful nodules and abscesses in intertriginous skin areas, which can progress to sinus tract formation, tissue destruction, and scarring. HS is highly debilitating and severely impairs the psychological well-being and quality of life of patients. The therapeutic approach to HS is based on medical therapy and surgery. First-line medical therapy includes topical antibiotics, systemic antibiotics, and biologics. Main surgical procedures include deroofing, local excision, and wide local excision. Despite the availability of multiple therapeutic options, the rates of disease recurrence and progression continue to be high. In recent years, the possibility of combining biologic therapy and surgery has raised considerable interest. In a clinical trial, the perioperative use of adalimumab has been associated with greater response rates and improved inflammatory load and pain, with no increased risk of postoperative infectious complications. However, several practical aspects of combined biologic therapy and surgery are poorly defined. In June 2022, nine Italian HS experts convened to address issues related to the integration of biologic therapy and surgery in clinical practice. To this purpose, the experts identified ten areas of interest based on published evidence and personal experience: 1) patient profiling (diagnostic criteria, disease severity classification, assessment of response to treatment, patient-reported outcomes, comorbidities); 2) tailoring surgery to HS characteristics; 3) wide local excision; 4) pre-surgery biologic treatment; 5) concomitant biologic and surgical treatments; 6) pre- and post-surgery management; 7) antibiotic systemic therapy; 8) biologic therapy after radical surgery; 9) management of adverse events to biologics; 10) management of postoperative infectious complications. Consensus between experts was reached using the Estimate-Talk-Estimate method (Delphi Method). The statements were subsequently presented to a panel of 27 HS experts from across Italy, and their agreement was assessed using the UCLA Appropriateness Method. This article presents and discusses the consensus statements.

Gliptin-associated bullous pemphigoid shows peculiar features of anti-BP180 and -BP230 humoral response: Results of a multicenter study.

BACKGROUND: Recently, several case-control studies demonstrated an association between gliptins and bullous pemphigoid (BP) occurrence. However, data on the clinical and immunologic features of gliptin-associated bullous pemphigoid (GABP) are controversial. OBJECTIVE: This study aimed to clinically and immunologically characterize a large cohort of GABP patients to get an insight into the pathophysiology of this emerging drug-induced variant of BP. METHODS: Seventy-four GABP patients were prospectively enrolled and characterized from 9 different Italian dermatology units between 2013 and 2020. RESULTS: Our findings demonstrated the following in the GABP patients: (1) a noninflammatory phenotype, which is characterized by low amounts of circulating and skin-infiltrating eosinophils, is frequently found; (2) immunoglobulin (Ig)G, IgE, and IgA humoral responses to BP180 and BP230 antigens are reduced in frequency and titers compared with those in patients with idiopathic BP; (3) IgG reactivity targets multiple BP180 epitopes other than noncollagenous region 16A. LIMITATIONS: A limitation of the study is that the control group did not comprise only type 2 diabetes mellitus patients with BP. CONCLUSION: GABP patients show peculiar features of anti-BP180 and -BP230 humoral responses, laying the foundation for diagnostic improvements and getting novel insights into understanding the mechanism of BP onset.

Pediatric Hidradenitis Suppurativa: A Cross-Sectional Study on Clinical Features and Treatment Approaches.

BACKGROUND: Hidradenitis suppurativa is uncommon in patients of pediatric age, and differentiation with adult-onset disease is controversial. Treatment of pediatric hidradenitis suppurativa is scarcely standardized, and specific guidelines are lacking. OBJECTIVE: We report the clinical features, relevant risk-factors, comorbidity profile, and treatment patterns of a hospital-based cohort of pediatric hidradenitis suppurativa. METHODS: In a cross-sectional study data on patients' demographics, disease-specific characteristics, early/pre-pubertal onset of disease, comorbidities, and treatment management were retrieved. Reference population data and clinical data from the national hidradenitis suppurativa disease registry were used for comparison. RESULTS: From a database of 870 patients with hidradenitis, 71 (15 males and 56 females) patients aged <18 years (mean age: 15.3 years; range 8-17 years), with mild (Hurley I, 45.1%) and moderate-severe disease (Hurley II-III, 54.9%), were retrieved. Smoking (23.9%) and overweight/obese frequencies (59.2%) were higher than reference population standards. Patient's older age at baseline (OR 1.43, 95% CI: 1.01 to 2.02) and higher BMI (OR 1.26, 95% CI: 1.07-1.48) were the only factors associated with moderate-severe disease. Family history and early/pre-pubertal onset of disease were not associated with severity or extent of disease. Sebaceous-follicular comorbid conditions were associated with cigarette smoking (P = .002). Among 81 treatment courses, clindamycin-based and zinc-sulphate-based combination regimens were most frequently used (59.3%). Female preponderance, family history of disease and extensive involvement were significantly different from the general hidradenitis suppurativa population. CONCLUSIONS: Pediatric hidradenitis suppurativa presents a clinical spectrum comparable to adult-onset disease. Increased preventive measures should target obesity and smoking in this population.

Multiple Roles for Cytokines in Atopic Dermatitis: From Pathogenic Mediators to Endotype-Specific Biomarkers to Therapeutic Targets.

Atopic dermatitis (AD) is one of the most common chronic inflammatory skin diseases, which generally presents with intense itching and recurrent eczematous lesions. AD affects up to 20% of children and 10% of adults in high-income countries. The prevalence and incidence of AD have increased in recent years. The onset of AD mostly occurs in childhood, although in some cases AD may persist in adult life or even manifest in middle age (adult-onset AD). AD pathophysiology is made of a complex net, in which genetic background, skin barrier dysfunction, innate and adaptive immune responses, as well as itch contribute to disease development, progression, and chronicization. One of the most important features of AD is skin dehydration, which is mainly caused by filaggrin mutations that determine trans-epidermal water loss, pH alterations, and antigen penetration. In accordance with the "outside-inside" theory of AD pathogenesis, in a context of an altered epidermal barrier, antigens encounter epidermal antigen presentation cells (APCs), such as epidermal Langerhans cells and inflammatory epidermal dendritic cells, leading to their maturation and Th-2 cell-mediated inflammation. APCs also bear trimeric high-affinity receptors for immunoglobulin E (IgE), which induce IgE-mediated sensitizations as part of pathogenic mechanisms leading to AD. In this review, we discuss the role of cytokines in the pathogenesis of AD, considering patients with various clinical AD phenotypes. Moreover, we describe the cytokine patterns in patients with AD at different phases of the disease evolution, as well as in relation to different phenotypes/endotypes, including age, race, and intrinsic/extrinsic subtypes. We also discuss the outcomes of current biologics for AD, which corroborate the presence of multiple cytokine axes involved in the background of AD. A deep insight into the correlation between cytokine patterns and the related clinical forms of AD is a crucial step towards increasingly personalized, and therefore more efficient therapy.

Skin signs in eating disorders: a literature review.

PURPOSE: To summarize and describe the available knowledge on dermatological manifestation of eating disorders: anorexia nervosa, bulimia nervosa, binge eating disorder and eating disorder not otherwise specified, diagnosed according to Diagnostic and Statistical Manual of Mental Disorders IV-TR and 5th edition. METHODS: We searched in PubMed, Scopus and Web of Science databases from January 1, 1980 through May 1, 2020 for papers in English language on the skin manifestation of eating disorders. Results were screened using the PRISMA tool. RESULTS: The study yielded 207 results. According with PRISMA guidelines, 26 papers were included in the review. More than 73% of screened papers (19/26) were case reports. Cross-sectional studies represented the 19.2% of screened papers (5/26). Each eligible study has been screened and analyzed. CONCLUSION: Huge heterogeneity of skin signs of eating disorders were identified. The number of controlled studies available is very limited, and most papers of interest are case reports or narrative review articles. Larger, more methodologically rigorous studies to evaluate the presence of dermatological issue in eating disorder patients are needed. LEVEL OF EVIDENCE: Level IV. Evidence obtained from multiple time series analysis such as case studies.

Alexithymia, Psychological Distress, and Social Impairment in Patients with Hidradenitis Suppurativa.

BACKGROUND: Hidradenitis suppurativa (HS) is a rare, chronic, inflammatory skin disease characterized by deep-seated nodules, abscesses, and draining fistulas. HS has a substantial adverse impact on patients' lives. Only a few studies investigated the relationship between health-related quality of life, psychological distress, and emotional dysregulation in patients with HS. Alexithymia, namely the difficulty in describing or recognizing emotions, has been associated with various psychological disorders, such as anxiety, depression, and psychological distress. OBJECTIVE: The aim of this study was to examine the prevalence of alexithymia in patients with HS and its association with demographic and clinical variables, quality of life indices, and psychological distress. METHODS: Ninety outpatients with HS completed the 20-item Toronto Alexithymia Scale, the 12-item General Health Questionnaire (GHQ-12), the Dermatology Life Quality Index, the Skindex-17, and the 36-Item Short-Form Health Survey. Information on sociodemographic and clinical variables was retrieved from clinical records. RESULTS: Alexithymia or borderline alexithymia was observed in 44.4% of patients with HS, with a higher prevalence of the alexithymic trait in women than in men (51.7 vs. 31.2%). We did not find any association between alexithymia and clinical variables. Of the entire sample analyzed, 46.1% reported high psychological distress; among them, 78% reported alexithymia or borderline alexithymia compared to 16.7% among GHQ noncases. Furthermore, HS patients with alexithymia or borderline alexithymia showed significantly higher scores on the Skindex-17 psychosocial scale and the Dermatology Life Quality Index, and a lower score on the mental component of the 36-item Short-Form Health Survey, than nonalexithymic patients. CONCLUSIONS: Dermatologists should consider alexithymia in the diagnosis and treatment of HS patients, given its important role in psychological and psychosocial distress.

Sex Differences in Health-related Quality of Life in Patients with Keratinocyte Carcinomas.

The difference between men and women in the impact of keratinocyte carcinomas on quality of life has not been widely studied. This study of 364 patients with keratinocyte carcinoma, measured quality of life using the self-administered 12-item Short Form Health Survey (SF-12) and Skindex-29. Results for both the physical and the mental components of SF-12 were worse in women than in men. For the mental component, women had significantly lower scores compared with men in almost all subgroups, based on demographic and clinical variables. The Skindex-29 emotions mean score was worse in women than in men. Women reported significantly higher level of worry that the disease could get worse and of developing scars, and more depression. On the other hand, men reported lower quality of sleep. The impact of keratinocyte carcinomas on quality of life is generally higher in women than in men. Such data may be important for tailored management of the disease in different categories of patients.

Evaluation of cutaneous, oral and intestinal microbiota in patients affected by pemphigus and bullous pemphigoid: A pilot study.

BACKGROUND: Significant alterations of the cutaneous microbiota (CM) have been recently demonstrated in bullous pemphigoid (BP). Microbiome data of both oral cavity (OM) and gut (GM) from patients affected by bullous disease are not available yet and, further consistent studies focused on the role of such microbial populations are still missing. OBJECTIVE: Objective: In this pilot study we characterized and compared GM, OM and CM of patients affected by pemphigus vulgaris (PV) and BP to investigate a distinctive microbiome composition in this two rare dermatological disorders. METHODS: High-throughput sequencing of the V1-V3 hyper-variable regions of 16S rRNA was used to compare the bacterial community composition of stool, skin and oral mucosae swabs in a cohort of PV and BP patients. A dedicated bioinformatics software coupled with in-house pipeline was implemented to analyse and compare diseases dataset. RESULTS: GM samples of both PV and BP patients were principally characterized by Firmicutes and Bacteroidetes phyla. Interestingly, the Firmicutes phylum and Staphylococcus genus were mainly represented in cutaneous samples. The diversity of phyla in oral mucosae was higher than those of gut and skin samples and, Bacteroidetes phylum was significantly underrepresented in all PV samples. CONCLUSION: Firmicutes phylum and Staphilococcus genus were the most represented in OM and CM swabs of PV and BP microbial populations. Moreover, we argue the quantitative imbalance linked to the decrease of Bacteriodetes in the oral cavity of PV patients might be associated to disease typical fetor. To shed light on this peculiar feature further studies are still required.

Intralesional ultrasound-guided combined treatment with triamcinolone plus lincomycin in hidradenitis suppurativa: A pilot study.

Hidradenitis suppurativa (HS) is a chronic, inflammatory, disease of the hair follicle. Intralesional corticosteroid treatment in HS patients has been reported, and while several data described this route of administration as an efficient delivery system, its efficacy is still debated. The aim of this study was to explore the clinical efficacy and the effect on quality of life (QoL) of an innovative intralesional treatment in HS patients. This was an interventional prospective study. The treatment consisted of two intralesional ultrasound-guided injections of triamcinolone plus lincomycin, at baseline and after 2 weeks. Lesions and QoL were evaluated at baseline and at 4 weeks following intralesional therapy. All clinical variables of 36 HS patients significantly improved after 4 weeks. Mean values of the visual analog scale (VAS) pain decreased from 4.6 to 1.5, P = .027. The Bodily Pain (BP) scale of the Short-Form Health Survey (SF-36) significantly improved from 36.2 at baseline to 53.9 at 4-week follow-up (P < .001). On a scale from 0 to 10, over 90% of the patients gave a satisfaction score of 8 or more. This combination of corticosteroids and antibiotics delivered intralesionally seems to be effective, as it improved both patient- and physician-reported outcomes.

Correlation between Depression, Quality of Life and Clinical Severity in Patients with Hidradenitis Suppurativa.

Depression is frequent in patients with hidradenitis suppurativa. However, its relationship with quality of life and clinical severity needs further investigation. In this cross-sectional study, 341 adult, consecutive patients with hidradenitis suppurativa completed the 12-item General Health Questionnaire (GHQ-12), which has been shown to be able to identify cases of major depressive disorder in dermatological patients. The frequency of depression in hidradenitis suppurativa patients was 29.0%. In patients with depression, severity (International Hidradenitis Suppurativa Severity Score System (IHS4)), quality of life (Skindex-17; Dermatology Life Quality Index (DLQI)), and health status (36-item Short Form Health Survey (SF-36)) were significantly worse compared with patients with no depression. The highest linear correlation was observed between GHQ-12 and the psychosocial scale of the Skindex-17 and the SF-36 mental scale. In contrast, correlation between GHQ-12 and clinical severity was poor. Depression is an important comorbidity in hidradenitis suppurativa, which is strongly associated with impairment in quality of life, but not linearly correlated with clinical severity.

Paraneoplastic Dermatoses: A Brief General Review and an Extensive Analysis of Paraneoplastic Pemphigus and Paraneoplastic Dermatomyositis.

Skin manifestations of systemic disease and malignancy are extremely polymorphous. Clinicians should be familiarized with paraneoplastic dermatoses in order to perform an early diagnosis of the underlying neoplasm. Lack of familiarity with cutaneous clues of internal malignancy may delay diagnosis and treatment of cancer. In this review, we described several paraneoplastic dermatoses and discussed extensively two paradigmatic ones, namely paraneoplastic pemphigus and paraneoplastic dermatomyositis.

High-resolution melting analysis to screen the ST18 gene functional risk variant for pemphigus vulgaris: The occasion to open a debate on its usefulness in clinical setting.

The ST18 -497-65050 T > C polymorphisms (rs17315309) exhibit a very strong association in the pathogenesis of Pemphigus Vulgaris (PV) and could represent a new potential molecular target for the treatment of disease. The present study aimed to establish a low-cost, sensitive and reliable assay using high-resolution melting curve analysis (HRMA) on magnetic induction rotor-based platform, the Magnetic Induction Cycler (MIC) (Bio molecular Systems). HRMA assay was able to identify easily and unambiguously the c.-497-65050 T > C genotypes evaluating melting curve shape and melting temperature (Tm). The results of HRMA were validated by direct DNA sequencing. The HRMA is rapid, sensitive, low-cost and high-throughput assay to screen the rs17315309 variant and could be used in clinical diagnostic laboratories.

The Broad-Spectrum Impact of Hidradenitis Suppurativa on Quality of Life: A Comparison with Psoriasis.

BACKGROUND/AIM: Hidradenitis suppurativa (HS) is a chronic skin disease with a heavy impact on patients' quality of life (QoL). The aim of this study was to evaluate in detail the QoL impact of HS comparing it with other skin conditions, and in particular with psoriasis. METHODS: Patients with a diagnosis of HS were recruited. QoL was measured using the Skindex-17 questionnaire. RESULTS: Data were available for 69 HS patients. HS had the worst QoL among several skin conditions. Compared to psoriasis the mean symptom score was 69.4 versus 53.7, and the mean psychosocial score was 56.1 versus 32.7. Overall, the scores of patients with HS were higher than those of psoriasis patients on 16 of the 17 items of the Skindex-17. CONCLUSIONS: When compared to many different skin conditions, and in particular to psoriasis, HS was the most impairing condition, even at low levels of clinical severity.

Role of Nicotinamide in Genomic Stability and Skin Cancer Chemoprevention.

Nicotinamide (NAM) is an amide form of vitamin B3 and the precursor of nicotinamide adenine dinucleotide (NAD+), an essential co-enzyme of redox reactions for adenosine triphosphate (ATP) production and for other metabolic processes. As NAD+ status is critical in maintaining cellular energy, vitamin B3 deficiency mainly affects tissues that need high cellular energy causing pellagra and skin sun sensitivity. In animal models, NAD+ deficiency leads to UV sensitivity of the skin, impairs DNA damage response, and increases genomic instability and cancer incidence. Furthermore, NAD+ depletion is associated with human skin aging and cancer. NAM prevents the UV-induced ATP depletion boosting cellular energy and enhances DNA repair activity in vitro and in vivo. Moreover, NAM reduces skin cancer incidence and prevents the immune-suppressive effects of UV in mice. Thus, NAM is involved in the maintenance of genomic stability and may have beneficial effects against skin aging changes and tumor development. Clinical studies showed that topical use of NAM reduces cutaneous aging. Furthermore, oral NAM administration reduces the level of UV-mediated immunosuppression and lowers the rate of non-melanoma skin cancers in high-risk patients. Therefore, NAM replenishment strategy may be a promising approach for skin cancer chemoprevention.