Bacterial Skin Dysbiosis in Darier Disease.

INTRODUCTION: Darier disease is a rare inherited disease with dominant skin manifestations including keratotic papules and plaques on sebaceous and flexural areas. Secondary infection of skin lesions is common, and Staphylococcus aureus commonly colonizes these lesions. The aim of the study was to characterize the bacterial microbiome of cutaneous Darier lesions compared to normal-looking skin and disease severity. METHODS: All patients with a history of Darier followed up at Emek Medical Center were invited to participate in the study. Patients that did not use antibiotics in the past month and signed informed consent had four skin sites sampled with swabs: scalp, chest, axilla, and palm. All samples were analyzed for bacterial microbiome using 16S rDNA sequencing. RESULTS: Two hundred and eighty microbiome samples obtained from lesional and non-lesional skin of the scalp, chest, axilla, and palm of 42 Darier patients were included in the analysis. The most abundant bacterial genera across all skin sites were Propionibacterium, Corynebacterium, Paracoccus, Micrococcus, and Anaerococcus. Scalp and chest lesions featured a distinct microbiome configuration that was mainly driven by an overabundance of Staphylococci species. Patients with more severe disease exhibited microbiome alterations in the chest, axilla, and palm compared with patients with only mild disease, driven by Peptoniphilus and Moryella genera in scalp and palmar lesions, respectively. CONCLUSION: Staphylococci were significantly associated with Darier lesions and drove Darier-associated dysbiosis. Severity of the disease was associated with two other bacterial genera. Whether these associations also hold a causative role and may serve as a therapeutic target remains to be determined and requires further investigation.

Adult Henoch-Schönlein Purpura: Comprehensive Assessment of Demographic, Clinical, and Histopathological Features as Predictors for Systemic Involvement.

BACKGROUND: Henoch-Schönlein purpura (HSP) is a small-vessel IgA-predominant vasculitis. A major challenge in managing adult HSP is the difficulty assessing the risk of systemic involvement. There is currently a paucity of data in this area. OBJECTIVE: The objective of this study was to determine demographic, clinical, and histopathological features associated with systemic involvement in adult HSP. METHODS: In this retrospective study, we reviewed demographical features and clinical and pathology data of 112 adult HSP patients seen at Emek Medical Center between January 2008 and December 2020. RESULTS: Of these patients, 41 (36.6%) had renal involvement, 24 (21.4%) had gastrointestinal tract involvement, and 31 (27.7%) had joint involvement. Age >30 years (p = 0.006) at diagnosis was an independent predictor of renal involvement. Platelet count (<150 K/µL) (p = 0.020) and apoptosis of keratinocytes on skin biopsy (p = 0.031) were also associated with renal involvement. History of autoimmune disease (p = 0.001), positive c-antineutrophil cytoplasmic antibody (p = 0.018), positive rheumatoid factor (p = 0.029), and elevated erythrocyte sedimentation rate (p = 0.04) were associated with joint involvement. Female sex (p = 0.003), Arab race (p = 0.036), and positive pANCA (p = 0.011) were associated with gastrointestinal tract involvement. LIMITATIONS: This study is retrospective. CONCLUSION: These findings may serve as a guide to stratify risk in adult HSP patients so that those at higher risk can be monitored more closely.

A Review of Bullous Dermatologic Adverse Events Associated with Anti-Cancer Therapy.

The rapid evolution of anti-cancer therapy (including chemotherapy, targeted therapy, and immunotherapy) in recent years has led to a more favorable efficacy and safety profile for a growing cancer population, and the improvement of overall survival and reduction of morbidity for many cancers. Anti-cancer therapy improves outcomes for cancer patients; however, many classes of anti-cancer therapy have been implicated in the induction of bullous dermatologic adverse events (DAE), leading to reduced patient quality of life and in some cases discontinuation of life-prolonging or palliative therapy. Timely and effective management of adverse events is critical for reducing treatment interruptions and preserving an anti-tumor effect. Bullous DAE may be limited to the skin or have systemic involvement with greater risk of morbidity and mortality. We present the epidemiology, diagnosis, pathogenesis, and management of bullous DAE secondary to anti-cancer therapies to enable clinicians to optimize management for these patients.

Risk of Melanoma in Patients with Basal Cell Carcinoma: A Population-based Cohort Study.

Basal cell carcinoma is the most prevalent cancer in Caucasians worldwide. The aim of this study was to examine the overall risk of melanoma among patients diagnosed with basal cell carcinoma. This population-based retrospective cohort study included data from January 2010 to December 2018 from the databases of the Clalit Health Maintenance Organization and 2 major pathology laboratories in North District, Israel. The incidence and hazard ratio of melanoma in patients with a diagnosis of basal cell carcinoma were determined. Of 466,700 participants, 51% were women and the mean (standard deviation) follow-up was 6.7 (2.9; range 1-9) years. A total of 3,338 patients were diagnosed with basal cell carcinoma during the study period, 82 of whom subsequently developed melanoma. Patients with basal cell carcinoma had a significantly higher incidence of melanoma than patients without basal cell carcinoma (2.46% vs 0.37%; p < 0.0001). Univariate Cox regression analysis revealed a hazard ratio of 6.6 (95% confidence interval: 3.6-12.1; p < 0.0001) for melanoma in patients with a diagnosis of basal cell carcinoma. In conclusion, a diagnosis of basal cell carcinoma confers a significant risk of melanoma.

Acral peeling in Nagashima type palmo-plantar keratosis patients reveals the role of serine protease inhibitor B 7 in keratinocyte adhesion.

Acral peeling skin syndrome (APSS) is a heterogenous group of genodermatoses, manifested by peeling of palmo-plantar skin and occasionally associated with erythema and epidermal thickening. A subset of APSS is caused by mutations in protease inhibitor encoding genes, resulting in unopposed protease activity and desmosomal degradation and/or mis-localization, leading to enhanced epidermal desquamation. We investigated two Arab-Muslim siblings with mild keratoderma and prominent APSS since infancy. Genetic analysis disclosed a homozygous mutation in SERPINB7, c.796C > T, which is the founder mutation in Nagashima type palmo-plantar keratosis (NPPK). Although not previously formally reported, APSS was found in other patients with NPPK. We hypothesized that loss of SERPINB7 function might contribute to the peeling phenotype through impairment of keratinocyte adhesion, similar to other protease inhibitor mutations that cause APSS. Mis-localization of desmosomal components was observed in a patient plantar biopsy compared with a biopsy from an age- and gender-matched healthy control. Silencing of SERPINB7 in normal human epidermal keratinocytes led to increased cell sheet fragmentation upon mechanical stress. Immunostaining showed reduced expression of desmoglein 1 and desmocollin 1. This study shows that in addition to stratum corneum perturbation, loss of SERPINB7 disrupts desmosomal components, which could lead to desquamation, manifested by skin peeling.

Parental mosaic cutaneous-gonadal GJB2 mutation: From epidermal nevus to inherited ichthyosis-deafness syndrome.

Ichthyosis and deafness syndrome is a group of devastating genodermatoses caused by heterozygous mutations in GJB2, encoding the gap junction protein connexin 26. These syndromes are characterized by severe skin disease, hearing loss, recurrent infections, and cutaneous neoplasms. Cutaneous somatic mutations in the same gene are associated with porokeratotic eccrine ostial dermal duct nevus. Here we report a family in which a parent presented with localized epidermal nevus and his child suffered with hystrix-like ichthyosis with deafness. Histologic examination of the parent's cutaneous lesion revealed verrucous epidermal nevus without features of porokeratotic eccrine ostial dermal duct nevus. Genetic analysis identified the same pathogenic variant, GJB2 c.148G>A (p.D50N), in DNA extracted from the parent's cutaneous lesion and the child's leukocytes, but not in the parent's leukocytes. This study expands the phenotypic heterogeneity of GJB2 mosaic variants in addition to porokeratotic eccrine ostial dermal duct nevus, and emphasizes the importance of molecular diagnosis of mosaic skin diseases considering the risk of severe inherited diseases in the offspring.

Concomitant variants in NF1, LZTR1 and GNAZ genes probably contribute to the aggressiveness of plexiform neurofibroma and warrant treatment with MEK inhibitor.

Neurofibromatosis 1 (NF1) is caused by germline mutations in the NF1 gene and manifests as proliferation of various tissues, including plexiform neurofibromas. The plexiform neurofibroma phenotype varies from indolent to locally aggressive, suggesting contributions of other modifiers in addition to somatic loss of NF1. In this study, we investigated a life-threatening plexiform neurofibroma in a 9-month-old female infant with NF1. Germline mutations in two RASopathy-associated genes were identified using whole-exome sequencing-a de novo pathogenic variant in the NF1 gene, and a known pathogenic variant in the LZTR1 gene. Somatic analysis of the plexiform neurofibroma revealed NF1 loss of heterozygosity and a variant in GNAZ, a gene encoding a G protein-coupled receptor. Cells expressing mutant GNAZ exhibited increased ERK 1/2 activation compared to those expressing wild-type GNAZ. Taken together, we suggest the variants in NF1, LZRT1 and GNAZ act synergistically in our patient, leading to MAPK pathway activation and contributing to the severity of the patient's plexiform neurofibromatosis. After treatment with the MEK inhibitor, trametinib, a prominent clinical improvement was observed in this patient. This case study contributes to the knowledge of germline and somatic non-NF1 variants affecting the NF1 clinical phenotype and supports use of personalized, targeted therapy.

An Update on the Cutaneous Manifestations of Darier Disease.

BACKGROUND: Knowledge about the clinical features of Darier disease, an orphan autosomal-dominant genetic disorder, is sparse and has been evaluated only in few studies. OBJECTIVES: To investigate the clinical features of a large group of patients with Darier disease, and to explore for associations between disease characteristics and severity of the disease. METHODS: Seventy-six individuals with Darier disease were evaluated utilizing a structured questionnaire-based interview, a physical examination, and a retrospective assessment of their medical records. RESULTS: The most frequent locations of lesions were hands (99%) and fingernails (93%). Wart-like lesions on the hands were more visible after soaking them in water for 5 minutes, we therefore named this phenomenon the "wet hand sign". Oral involvement was found in 43% of patients, while 48% of women and 16% of men showed genital lesions. Patients with severe Darier disease had a tenfold greater risk of developing genital lesions than those with mild disease (P = .01). Most patients (88%) in our study exhibited a combination of the four types of the disease patterns of distribution (flexural, seborrheic, nevoid, and acral). CONCLUSIONS: Documentation of disease on the hands and fingernails provides a highly sensitive means to aid in the diagnosis of Darier disease. It is important to evaluate mucosal lesions including genital and oral mucosa.

Ophthalmic Assessment in Patients With Darier Disease.

PURPOSE: To assess the prevalence of ophthalmic findings in patients with Darier disease, an autosomal dominant genetic skin disorder, in an effort to evaluate the need for eye examinations in the management of the disease. DESIGN: Prospective observational case series. METHODS: Thirty-six individuals with Darier disease were evaluated by both ocular assessment questionnaire and a comprehensive ophthalmic examination (visual acuity, refraction, external examination, and slit-lamp examination) with emphasis on the eyelids, conjunctiva, and cornea. In addition, questionnaire-based medical interview and skin examination were conducted. RESULTS: According to the medical questionnaire, 39% of patients reported eye problems, 36% dry eye, and 42% eye fatigue after prolonged reading. Ocular examination revealed Darier disease lesions on the eyelids in 55% of the patients, blepharitis in 44%, conjunctival hyperemia in 28%, and short tear film break-up time in 83%. There was no significant relationship between any of these ophthalmic findings and systemic retinoid therapy, sex, or age. CONCLUSIONS: The high prevalence of blepharitis and dry eye highlights the importance of ophthalmologic evaluation of patients with Darier disease.

Retrospective Study of Patients With SJS/TEN Treated at a Tertiary Burn Unit in Canada: Overview of 17 Years of Treatment.

BACKGROUND: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are adverse drug reactions. OBJECTIVES: To learn about the clinical characteristics of patients with SJS/TEN including treatments provided, outcomes, and mortality. METHODS: We conducted a retrospective chart review of patients who were hospitalized with the diagnosis of SJS/TEN at the Ross Tilley Burn Center between the years 1999 and 2015. RESULTS: A total of 43 patients were identified with a mean age of 54 ± 19 (58, 18-85). The most common offending medications were allopurinol and carbamazepine. The overall mortality rate in our study is 21% with the most common causes of death being multiorgan failure and sepsis. The majority of our patients had oral (84%), ocular (79%), and genital (60%) involvement during hospitalization. Our data revealed that combination treatment involving oral corticosteroids with intravenous immunoglobulin (IVIG) had the highest mortality rate in our study since 55% (6/11) of patients who were treated in this manner passed away compared to 11% (2/18) of patients passing away who were treated with solely IVIG and 33% (1/3) who were treated with only supportive care. Our study also demonstrates the addition of etanercept and cyclosporine treatment in the second time period we studied: 2008-2015 versus the earlier time period of 1999-2007. None of the patients in our study who were treated with therapies including cyclosporine and/or etanercept passed away. CONCLUSIONS: Our study sheds light on a possible beneficial role of cyclosporine and etanercept for the treatment of SJS and TEN and reinforces the necessity of a multidisciplinary care team for patients.

Granulomatous Cutaneous Drug Eruptions: A Systematic Review.

BACKGROUND: Granulomatous drug eruptions are rare entities, where granuloma formation occurs as an attempt to contain an exogenous or endogenous inciting agent. Granulomatous drug eruptions may be localized to the skin or may include major systemic involvement, and their characteristics depend both on the properties of the causative irritant and host factors. Because of the overlapping features amongst noninfectious granulomatous diseases, granulomatous drug eruptions are challenging to diagnose and distinguish both histologically and clinically. OBJECTIVE: The objective of this article is to provide a review and summary of the current literature on the five major types of cutaneous granulomatous drug eruptions: interstitial granulomatous drug reaction, drug-induced accelerated rheumatoid nodulosis, drug-induced granuloma annulare, drug-induced sarcoidosis, and miscellaneous presentations. METHODS: A systematic review was conducted through PubMed using the search terms "granulomatous drug eruption" and "cutaneous" or "skin". English full-text studies that included human subjects experiencing a cutaneous reaction comprising granulomatous inflammation as the direct result of a drug were included. Of 205 studies identified, 48 articles were selected after a full-text review. Evidence was evaluated using the Tool for evaluating the methodological quality of case reports and case series. RESULTS: Polypharmacy and a prolonged lag period from drug ingestion to rash onset may create diagnostic challenges. Ruling out tuberculosis is imperative in the endemic setting, particularly where anti-tumor necrosis factor therapy is the presumed cause. Interstitial granulomatous drug reactions and granuloma annulare are often localized to the skin whereas accelerated rheumatoid nodulosis and sarcoidosis may sometimes be associated with systemic features as well. Granulomatous drug eruptions typically resolve on discontinuing the offending medication; however, the decision for drug cessation is dependent on a risk-benefit assessment. In some situations, supplementation of an additional agent to suppress the reaction may resolve symptoms. In some cases, granulomatous drug eruptions may be pivotal in the successful outcome of the drug, as in cases of melanoma treatment. In all situations, the decision to continue or withdraw the drug should be carefully based on the severity of the eruption, necessity of continuing the drug, and availability of a suitable alternative. CONCLUSIONS: Granulomatous drug eruptions should always be considered in the differential diagnosis of noninfectious granulomatous diseases of the skin. Further research examining dose-response relationships and the recurrence of granulomatous drug eruptions on the rechallenge of offending agents is required. Increased awareness of granulomatous drug eruption types is important, especially with continuous development of new anti-cancer agents that may induce these reactions. CLINICAL TRIAL REGISTRATION: PROSPERO registration number CRD42020157009.

[PIGMENTED BASAL CELL CARCINOMA AND IONIZING RADIATION].

AIMS: This study aimed at demonstrating whether the histological and clinical manifestations of pigmented basal cell carcinoma are different among those who were previously treated with ionizing radiation for ringworm infection. BACKGROUND: Ionizing radiation is known to cause increased morbidity among those who are chronically exposed. Basal cell carcinoma in known to be related to ionizing radiation however, the characteristics of pigmented BCC in relation to ionizing radiation are poorly described. METHODS: The study included the demographics and characteristics of 23 patients with pigmented BCC who were treated for ringworm with ionization radiation and a control group of 21 patients that had not been treated with ionizing radiation. All the cases treated between the years 2005-2015 were included in the study. The data was analyzed with a SPSS program. RESULTS: Among the patients who were treated with ionizing radiation the percentage of the tumors that were well differentiated was 34.8%, much higher than those who were not treated with ionizing radiation - 14.3%. In addition, the average age for those who were treated with ionizing radiation was 66 compared to 73 in the group that weren't treated with radiation. DISCUSSION: Pigmented basal cell carcinoma is a rare variant of BCC and it has characteristics that are quite dissimilar among patients treated with ionizing radiation. However, more studies are needed in order to strengthen the results.

[SYSTEMIC REVIEW OF EOSINOPHILIC DERMATOSES PATIENTS TREATED WITH TNF-Α INHIBITORS AND USTEKINUMAB].

AIMS: This study aims to critically review the pros and cons of biological drugs as treatments and triggers of eosinophilic dermatoses. BACKGROUND: Eosinophilic dermatoses syndromes are rare diseases with a prominent eosinophilic infiltration mechanism. These syndromes have several known treatments with limited success. Several physicians worldwide suggested possible advantages of using specific biological drugs, which are different from eosinophil targeted biotherapies as treatments for eosinophilic dermatoses syndromes. Others considered these drugs as possible triggers. METHODS: Articles published in the last 30 years containing relevant key words were reviewed using PubMed and Medline. Associations between Infliximab, Adalimumab, Etanercept, TNF alpha inhibitors and Ustekinumab to Eosinophilic Dermatoses syndromes were reviewed. RESULTS: Our search revealed an association between 17 eosinophilic dermatoses patients and the drugs of interest. Out of 5 Wells' syndrome cases, four patients had an outbreak of the disease following treatment and one improved by the treatment. Six cases of Eosinophilic Fasciitis mostly had a positive reaction to the treatment. More associations were found among 4 cases of Churg-Strauss syndrome, one case of Granuloma Faciale and 1 case of Eosinophilic Pustular Folliculitis. CONCLUSIONS: TNF alpha inhibitors and Ustekinumab may have a role in the treatment of eosinophilic dermatosis syndromes. These drugs may act as triggers among Wells' syndrome patients. Further investigation is needed.

The Role of Desmoglein 1 in Gap Junction Turnover Revealed through the Study of SAM Syndrome.

An effective epidermal barrier requires structural and functional integration of adherens junctions, tight junctions, gap junctions (GJ), and desmosomes. Desmosomes govern epidermal integrity while GJs facilitate small molecule transfer across cell membranes. Some patients with severe dermatitis, multiple allergies, and metabolic wasting (SAM) syndrome, caused by biallelic desmoglein 1 (DSG1) mutations, exhibit skin lesions reminiscent of erythrokeratodermia variabilis, caused by mutations in connexin (Cx) genes. We, therefore, examined whether SAM syndrome-causing DSG1 mutations interfere with Cx expression and GJ function. Lesional skin biopsies from SAM syndrome patients (n = 7) revealed decreased Dsg1 and Cx43 plasma membrane localization compared with control and nonlesional skin. Cultured keratinocytes and organotypic skin equivalents depleted of Dsg1 exhibited reduced Cx43 expression, rescued upon re-introduction of wild-type Dsg1, but not Dsg1 constructs modeling SAM syndrome-causing mutations. Ectopic Dsg1 expression increased cell-cell dye transfer, which Cx43 silencing inhibited, suggesting that Dsg1 promotes GJ function through Cx43. As GJA1 gene expression was not decreased upon Dsg1 loss, we hypothesized that Cx43 reduction was due to enhanced protein degradation. Supporting this, PKC-dependent Cx43 S368 phosphorylation, which signals Cx43 turnover, increased after Dsg1 depletion, while lysosomal inhibition restored Cx43 levels. These data reveal a role for Dsg1 in regulating epidermal Cx43 turnover.

Biologic drug survival in Israeli psoriasis patients.

BACKGROUND: Drug survival is defined as the time period of treatment with a certain drug until its cessation. The role of previous exposure to traditional systemic treatments in biologic survival is still unknown. OBJECTIVE: To investigate the drug survival rates of biologic treatments in patients with psoriasis and to identify predictor factors. METHODS: Survival analysis was performed on patients with severe psoriasis who received adalimumab, infliximab, etanercept, and ustekinumab for treatment of psoriasis, drawn from the Clalit Health Services database. Multivariate analysis was performed adjusting for demographic variables; metabolic syndrome and its components; psoriatic arthritis; biologic naivety; coadministration of methotrexate, acitretin, or cyclosporine; and previous standard systemic treatment exposure. RESULTS: Among 907 patients treated with 1575 biologic treatments, ustekinumab had a significantly higher survival rate than tumor necrosis factor inhibitors. Biologic naivety and concomitant methotrexate intake were positive predictors for drug survival, whereas the female sex and the duration of previous systemic treatments were negative predictors. LIMITATIONS: Data regarding disease severity or duration could not be drawn from the Clalit Health Services database. CONCLUSION: Ustekinumab had better retention rates in comparison with other investigated biologics in patients with severe psoriasis, most of whom used it as a third line therapy.