Persistent Cutaneous Lesions of Darier Disease and Second-Hit Somatic Variants in ATP2A2 Gene.

Importance: Darier disease (DD) is a rare genetic skin disorder caused by heterozygous variants in the ATP2A2 gene. Clinical manifestations include recurrent hyperkeratotic papules and plaques that occur mainly in seborrheic areas. Although some of the lesions wax and wane in response to environmental factors, others are severe and respond poorly to therapy. Objective: To investigate the molecular mechanism underlying the persistency of skin lesions in DD. Design, Setting, and Participants: In this case series, DNA was extracted from unaffected skin, transient and persistent lesional skin, and blood from 9 patients with DD. Genetic analysis was used using paired-whole exome sequencing of affected skin and blood or by deep sequencing of ATP2A2 of affected skin. Chromosomal microarray analysis was used to reveal copy number variants and loss of heterozygosity. All variants were validated by Sanger sequencing or restriction fragment length polymorphism. Interventions or Exposures: Paired whole-exome sequencing and deep sequencing of ATP2A2 gene from blood and skin samples isolated from persistent, transient lesions and unaffected skin in patients with DD. Main Outcomes and Measures: Germline and somatic genomic characteristics of persistent and transient cutaneous lesions in DD. Results: Of 9 patients with DD, all had heterozygous pathogenic germline variants in the ATP2A2 gene, 6 were female. Participant age ranged from 40 to 69 years on enrollment. All 11 persistent skin lesions were associated with second-hit somatic variants in the ATP2A2 gene. The somatic variants were classified as highly deleterious via combined annotation-dependent depletion (CADD) scores or affect splicing, and 3 of them had been previously described in patients with DD and acrokeratosis verruciformis of Hopf. Second-hit variants in the ATP2A2 gene were not identified in the transient lesions (n = 2) or the normal skin (n = 2). Conclusions and Relevance: In this study, persistent DD lesions were associated with the presence of second-hit somatic variants in the ATP2A2 gene. Identification of these second-hit variants offers valuable insight into the underlying mechanisms that contribute to the lasting nature of persistent DD lesions.

A Prospective, Multicenter, Open-label Study to Evaluate the Safety and Efficacy of a Cream Containing Xyloglucan, Pea Protein, and Opuntia ficus-indica Extract Versus Calcipotriol/Betamethasone in Adult Patients with Mild-to-moderate Psoriasis.

Objective: Psoriasis is a chronic, inflammatory skin disease, requiring local and systemic drugs according to disease severity. This study aims to investigate the efficacy and safety of a topical treatment containing xyloglucan, pea proteins and Opuntia ficus-indica extracts (XPO) compared to calcipotriol 50mcg/betamethasone 0.5mg ointment (CB). Methods: Forty-two patients diagnosed with mild-to-moderate plaque psoriasis were assigned 1:1 to XPO treatment or CB for 28 days. Disease status was assessed at baseline (V1), monitored every two weeks (V2, V3), and at follow-up (V4). Disease severity was assessed by PASI (Psoriasis Area and Severity Index), PGA (Physician's Global Assessment), and VAS (Visual Analog Scale for itching). Photos were taken before and after XPO treatment. Treatment efficacy was determined by comparing psoriasis severity at baseline to V3. Tolerability was assessed by monitoring the occurrence of adverse events. Results: Both groups showed a statistically significant difference in PASI score from V1 to V2 (p=0.001, XPO; p=0.008, CB) and to V3 (p=0.001, XPO; p=0.004, CB). XPO achieved a PASI 50 score of 24 percent at V2 and 52 percent at V3 compared to CB (0% at V2 and 19% at V3). At V3, PGA was significantly reduced in both groups (p=0.003, XPO; p=0.001 CB). Both treatments significantly reduced itching at V2 (p=0.001, XPO; p=0.003, CB) and V3 (p=0.001, XPO; p=0.0005, CB). Conclusion: XPO showed similar efficacy to CB, significantly reducing disease severity, erythema, itching, induration, and scaling with an excellent tolerability profile.

Generalized Pustular Psoriasis, Acute Generalized Exanthematous Pustulosis, and Other Pustular Reactions: A Clinical Review.

Generalized pustular rashes have various etiologies and can be challenging to diagnose and manage at first presentation. The authors provide an in-depth analysis of common pustular skin eruptions including generalized pustular psoriasis (GPP) and acute generalized exanthematous pustulosis, focusing on their pathophysiology, triggers, clinical presentation, diagnostic challenges, and management strategies. The article also highlights recent advances in genetic research and biologic therapies for GPP and the future directions in personalized medicine and prevention strategies.

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 to 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 Anearococcus. 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 drive 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.

Management of Adult Patients With Drug Reaction With Eosinophilia and Systemic Symptoms: A Delphi-Based International Consensus.

Importance: Drug reaction with eosinophilia and systemic symptoms (DRESS) is a rare but potentially fatal drug hypersensitivity reaction. To our knowledge, there is no international consensus on its severity assessment and treatment. Objective: To reach an international, Delphi-based multinational expert consensus on the diagnostic workup, severity assessment, and treatment of patients with DRESS. Design, Setting, and Participants: The Delphi method was used to assess 100 statements related to baseline workup, evaluation of severity, acute phase, and postacute management of DRESS. Fifty-seven international experts in DRESS were invited, and 54 participated in the survey, which took place from July to September 2022. Main Outcomes/Measures: The degree of agreement was calculated with the RAND-UCLA Appropriateness Method. Consensus was defined as a statement with a median appropriateness value of 7 or higher (appropriate) and a disagreement index of lower than 1. Results: In the first Delphi round, consensus was reached on 82 statements. Thirteen statements were revised and assessed in a second round. A consensus was reached for 93 statements overall. The experts agreed on a set of basic diagnostic workup procedures as well as severity- and organ-specific further investigations. They reached a consensus on severity assessment (mild, moderate, and severe) based on the extent of liver, kidney, and blood involvement and the damage of other organs. The panel agreed on the main lines of DRESS management according to these severity grades. General recommendations were generated on the postacute phase follow-up of patients with DRESS and the allergological workup. Conclusions and Relevance: This Delphi exercise represents, to our knowledge, the first international expert consensus on diagnostic workup, severity assessment, and management of DRESS. This should support clinicians in the diagnosis and management of DRESS and constitute the basis for development of future guidelines.

SNG100, a novel topical treatment for moderate atopic dermatitis, in patients aged 6 years or older: A randomised, double-blind, active-controlled trial.

Background: Atopic dermatitis (AD) is one of the most common inflammatory skin diseases. It is associated with significant itch and impaired quality of life. Systemic treatments are efficient but associated with side effects. Novel topical treatments with a favourable safety profile are needed. SNG100 is a novel composition of hydrocortisone 1% in a cream base comprising sulphated polysaccharide (SPS; extracted from in-house cultivated Porphyridium Cruentum unicellular algae), a well-known hydrating, moisturising and a skin barrier repairing agent. Objectives: To assess the safety, usability and efficacy of SNG100 cream in patients aged ≥6 years with moderate AD. Methods: In this proof of concept phase I, double-blind, randomised trial, participants received one of three treatments for 14 days: SNG100 twice daily (BID), hydrocortisone 1% BID or mometasone furoate once daily (QD). The primary endpoint was the safety and tolerability of SNG100 cream compared to hydrocortisone 1% and mometasone furoate. The secondary endpoint was the subject's usability of SNG100. Exploratory efficacy endpoints included percent change from baseline in SCOring AD (SCORAD), Eczema Area and Severity Index, Patient-Oriented Eczema Measure, Dermatology Life Quality Index, pruritus Numerical Rating Score (NRS), peak pruritus-NRS and Investigator's Global Assessment. Subjects were also followed up without any treatment for additional 14 days. Results: Overall, 66 participants were screened, and 60 patients were randomised. SNG100 demonstrated a high safety profile, similar to marketed products hydrocortisone 1% and mometasone furoate 0.1%, with no unanticipated drug safety related events. SNG100 and mometasone furoate 0.1% cream achieved almost similar and statistically significant greater percentage reductions from baseline in SCORAD as compared to hydrocortisone 1% cream. SNG100 demonstrated significant improvement in NRS as compared to hydrocortisone 1% cream. Remarkably, SNG100 led to a lasting effect with only 29.4% of subjects returning to IGA3 during the follow-up period compared to 50% and 38.9% in the hydrocortisone 1% and in mometasone furoate treatment arms, respectively. Conclusions: Topical SNG100 is an effective, safe, and well-tolerated innovative treatment for moderate AD. Trial registration number: NCT04615962 (Topical Cream SNG100 for Treatment in Moderate AD Subjects).

Updates in SJS/TEN: collaboration, innovation, and community.

Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis (SJS/TEN) is a predominantly drug-induced disease, with a mortality rate of 15-20%, that engages the expertise of multiple disciplines: dermatology, allergy, immunology, clinical pharmacology, burn surgery, ophthalmology, urogynecology, and psychiatry. SJS/TEN has an incidence of 1-5/million persons per year in the United States, with even higher rates globally. One of the challenges of SJS/TEN has been developing the research infrastructure and coordination to answer questions capable of transforming clinical care and leading to improved patient outcomes. SJS/TEN 2021, the third research meeting of its kind, was held as a virtual meeting on August 28-29, 2021. The meeting brought together 428 international scientists, in addition to a community of 140 SJS/TEN survivors and family members. The goal of the meeting was to brainstorm strategies to support the continued growth of an international SJS/TEN research network, bridging science and the community. The community workshop section of the meeting focused on eight primary themes: mental health, eye care, SJS/TEN in children, non-drug induced SJS/TEN, long-term health complications, new advances in mechanisms and basic science, managing long-term scarring, considerations for skin of color, and COVID-19 vaccines. The meeting featured several important updates and identified areas of unmet research and clinical need that will be highlighted in this white paper.

Efficacy and Tolerability of a Novel Topical Treatment Containing Pea Protein and Xyloglucan in the Management of Atopic Dermatitis in Children: A Prospective, Multicenter Clinical Study.

INTRODUCTION: Atopic dermatitis (AD) is a chronic disease that occurs mainly in children. Topical corticosteroids are the main treatment for mild to moderate AD, although they can induce side effects. The efficacy and tolerability of xyloglucan and pea protein (XG-PP) was compared with hydrocortisone in pediatric patients with AD as a steroid-sparing solution. METHODS: A prospective, multicenter, comparative study enrolled 42 patients (age 0.5-12 years) with mild-to-moderate AD, assigned 1:1 to XG-PP or hydrocortisone ointment. Treatments were applied twice daily for 14 consecutive days and assessed at baseline, day 8, and day 15. Efficacy endpoints were AD Severity Index (ADSI) score, Scoring Atopic Dermatitis (SCORAD) index, and Patient-Oriented Eczema Measure (POEM). Tolerability was assessed by the occurrence of adverse events (AEs). RESULTS: Both treatments significantly improved ADSI mean score from baseline to day 15; in the XG-PP arm, ADSI score decreased from 10.55 to 4.15 (p = 0.00001), and in the hydrocortisone arm, from 10.65 to 4.30 (p = 0.0001). In the XG-PP arm, the mean SCORAD score decreased from 65.86 to 30.26 (p = 0.00001) and in the hydrocortisone arm from 68.84 to 31.19 (p = 0.0001) at day 15. An overall decrease from moderate to mild AD for both arms (p = 0.0001) was observed with POEM. For all the three indexes evaluated, no statistical significant differences between the study arms evolution from baseline to day 8 or to day 15 were found. No AEs were reported. CONCLUSION: XG-PP provided a comparable efficacy to hydrocortisone ointment in managing AD, thus representing a safe and effective steroid-sparing alternative in pediatric patients with AD. TRIAL REGISTRATION: Retrospectively registered on 24 November 2021 in the ISRCTN registry: 11118799.

Dupilumab significantly improves sleep in adults with atopic dermatitis: results from the 12-week placebo-controlled period of the 24-week phase IV randomized double-blinded placebo-controlled DUPISTAD study.

BACKGROUND: Sleep disturbance is a prominent symptom of atopic dermatitis (AD) and can result in insomnia, daytime fatigue, drowsiness, reduced productivity and impaired quality of life (QoL). OBJECTIVES: The Dupilumab Effect on Sleep in AD Patients (DUPISTAD) phase IV randomized double-blinded placebo-controlled study evaluated the impact of dupilumab treatment on sleep and other patient- and physician-reported outcomes. METHODS: Adults with moderate-to-severe AD were randomized 2 : 1 to dupilumab 300 mg once every 2 weeks (q2w) or placebo for 12 weeks; concomitant topical corticosteroids were permitted. Patients subsequently entered an open-label phase and received dupilumab 300 mg q2w for a further 12 weeks. The primary endpoint was the percentage change in sleep quality from baseline to week 12, assessed using a novel numeric rating scale (NRS). Secondary and exploratory endpoints included percentage change in peak pruritus NRS (PP NRS), change in SCORing Atopic Dermatitis (SCORAD), SCORAD sleep visual analogue scale (VAS), Eczema Area and Severity Index, Patient-Reported Outcomes Measurement Information System (PROMIS) sleep-related impairment T-score and the Epworth Sleepiness Scale. Sleep diary and wrist actigraphy measurements were recorded throughout the study. RESULTS: In total, 127 patients received dupilumab and 61 patients received placebo. Demographic and baseline disease characteristics were balanced between groups. Sleep quality NRS significantly improved in patients treated with dupilumab by week 12 vs. placebo [least squares mean of the difference (LSMD) -15.5%, P < 0.001]. PP NRS (LSMD -27.9%, P < 0.001), SCORAD (LSMD -15.1, P < 0.001), SCORAD sleep VAS (LSMD -2.1, P < 0.001) and PROMIS T-score (LSMD -3.6, P < 0.001) were also significantly improved at week 12 with dupilumab vs. placebo. The overall percentage of patients reporting treatment-emergent adverse events was lower in the dupilumab group (56.7%) than in the placebo group (67.2%). CONCLUSIONS: Dupilumab significantly improved sleep quality and perception of sleep continuity, itch, metrics of AD severity and QoL in adults with moderate-to-severe AD, with an acceptable safety profile compared with placebo.

Development and Validation of a Novel Score to Predict Mortality in Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis: CRISTEN.

BACKGROUND: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening, severe mucocutaneous adverse reactions. Severity prediction at early onset is urgently required for treatment. However, previous prediction scores have been based on data of blood tests. OBJECTIVE: This study aimed to present a novel score that predicts mortality in patients with SJS/TEN in the early stages based on only clinical information. METHODS: We retrospectively evaluated 382 patients with SJS/TEN in a development study. A clinical risk score for TEN (CRISTEN) was created according to the association of potential risk factors with death. We calculated the sum of these risk factors using CRISTEN, and this was validated in a multinational survey of 416 patients and was compared with previous scoring systems. RESULTS: The significant risk factors for death in SJS/TEN comprised 10 items, including patients' age of ≥65 years, ≥10% body surface area involvement, the use of antibiotics as culprit drugs, the use of systemic corticosteroid therapy before the onset, and mucosal damage affecting the ocular, buccal, and genital mucosa. Renal impairment, diabetes, cardiovascular disease, malignant neoplasm, and bacterial infection were included as underlying diseases. The CRISTEN model showed good discrimination (area under the curve [AUC] = 0.884) and calibration. In the validation study, the AUC was 0.827, which was statistically comparable to those of previous systems. CONCLUSION: A scoring system based on only clinical information was developed to predict mortality in SJS/TEN and was validated in an independent multinational study. CRISTEN may predict individual survival probabilities and direct the management and therapy of patients with SJS/TEN.

Acute Generalized Exanthematous Pustulosis: Clinical Features, Differential Diagnosis, and Management.

Acute generalized exanthematous pustulosis (AGEP) is a rare, acute, severe cutaneous adverse reaction mainly attributed to drugs, although other triggers, including infections, vaccinations, ingestion of various substances, and spider bites, have also been described. AGEP is characterized by the development of edema and erythema followed by the eruption of multiple punctate, non-follicular, sterile pustules and subsequent desquamation. AGEP typically has a rapid onset and prompt resolution within a few weeks. The differential diagnoses for AGEP are broad and include infectious, inflammatory, and drug-induced etiologies. Diagnosis of AGEP depends on both clinical and histologic criteria, as cases of overlap with other disease processes have been reported. Management includes removal of the offending drug or treatment of the underlying cause, if necessary, and supportive care, as AGEP is a self-limited disease. This review aims to provide an overview and update on the epidemiology, pathogenesis, reported precipitating factors, differentials, diagnosis, and management of AGEP.

Epidemiology of adult patients with atopic dermatitis in AWARE 1: A second international survey.

Background: There are gaps in our understanding of the epidemiology of atopic dermatitis (AD) in adults. Objective: To evaluate the prevalence and severity of AD in adults from countries/regions within Asia, Eurasia, Latin America, Middle East, and Russia. Methods: This international, web-based survey was performed in Argentina, Brazil, China, Colombia, Egypt, Hong Kong, Israel, Malaysia, Mexico, Russia, Kingdom of Saudi Arabia (KSA), Singapore, Taiwan, Thailand, Turkey, and United Arab Emirates. Questionnaires were sent to adult members of online respondent panels for determination of AD and assessment of severity. A diagnosis of AD required respondents to meet the modified United Kingdom (UK) Working Party criteria and to self-report they had a physician diagnosis of AD. Severity of AD was determined using Patient-Oriented Scoring of Atopic Dermatitis (PO-SCORAD), Patient-Oriented Eczema Measure (POEM), and Patient Global Assessment (PGA). Results: Among respondents by country/region the prevalence of AD ranged from 3.4% in Israel to 33.7% in Thailand. The prevalence was generally higher in females versus males. Severity varied by scale, although regardless of scale the proportion of respondents with mild and moderate disease was higher than severe disease. PGA consistently resulted in the lowest proportion of severe AD (range 2.4% China - 10.8% Turkey) relative to PO-SCORAD (range 13.4% China - 41.6% KSA) and POEM (range 5.1% China - 16.6% Israel). Conclusions: This survey highlights the importance of AD in adults, with high prevalence and high morbidity among respondents and emphasizes that AD is not just a disease of childhood-there is disease persistence and chronicity in adults.

Exploring a multi-disciplinary model of supportive cancer care for monoclonal antibody treatment-related dermatological symptoms.

CONTEXT AND OBJECTIVES: The present study examined the perspectives of healthcare providers (HCPs) in designing a multi-disciplinary model of supportive cancer care for the relief of dermatology-related symptoms caused by monoclonal antibody therapies. METHODS: The study employed a mixed research methodology, with qualitative research embedded within a pragmatic prospective study of a registry protocol study. Patients undergoing oncology therapy with MoAB, anti-HER2, and anti-PD-L1 monoclonal antibodies were identified among a cohort of patients referred to an integrative oncology (IO) consultation for symptom relief and improved quality of life (QoL). Case studies with significant dermatology-related concerns were selected and presented to a panel of 6 HCPs trained in medical oncology, oncology nursing, family medicine, supportive cancer care, and IO. HCP narratives were qualitatively analyzed and assessed using ATLAS.Ti software for systematic coding. RESULTS: Of the 924 patients referred to the IO consultation, 208 were treated with monoclonal antibodies, from which 50 were selected for further evaluation. Of these, 7 cases were presented to the HCP team who were asked to identify treatment gaps requiring a multi-disciplinary approach. Qualitative analysis identified 3 major themes: a biophysical perspective; a psycho-social-spiritual perspective; and the implementation of integrated care. DISCUSSION: There is a need for a multi-disciplinary approach when treating patients suffering from monoclonal antibody treatment-related skin toxicities. HCP-reported themes highlight the need to identify patients for whom such an approach is warranted; conditions in which a psycho-social-spiritual perspective should be considered, in addition to a bio-physical approach; and considerations of who should be designated as the patient's primary case manager.

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.

Ectopic Cushing's syndrome in a patient with metastatic Merkel cell carcinoma: A case report.

BACKGROUND: Ectopic Cushing syndrome (ECS) is a rare condition commonly associated with neuroendocrine tumors (NET), mainly bronchial carcinoids. The association of paraneoplastic syndrome with Merkle cell carcinoma (MCC) is limited to individual case reports. CASE SUMMARY: In this article we report an unusual and striking presentation of ECS in a patient with known metastatic MCC. An elderly patient presented with new onset severe hypertension, hyperglycemia and hypokalemia, muscle wasting, and peripheral edema. A diagnosis of adrenocorticotropic hormone dependent, non-pituitary, Cushing syndrome was established. Medical therapy inhibiting adrenal function was promptly started but unfortunately the patient survived only a few days after diagnosis. CONCLUSION: The occurrence of an aggressive form of ECS in patients with NET should be recognized as an ominous event. To our knowledge, the association of this complication in a patient with MCC had not been reported.

Drug Reaction with Eosinophilia and Systemic Symptoms (DReSS)/Drug-Induced Hypersensitivity Syndrome (DiHS)-Readdressing the DReSS.

Drug reaction with eosinophilia and systemic symptoms (DReSS), also known as drug-induced hypersensitivity syndrome (DiHS), is a severe, systemic, T cell mediated drug reaction with combinations of cutaneous, hematologic, and internal organ involvement. Pathogenesis of DReSS is multi-factorial, involving drug-exposure, genetic predisposition through specific human leukocyte antigen (HLA) alleles and metabolism defects, viral reactivation, and immune dysregulation. Clinical features of this condition are delayed, stepwise, and heterogenous, making this syndrome challenging to recognize and diagnose. Two sets of validated diagnostic criteria exist that can be employed to diagnose DReSS/DiHS. Methods to improve early recognition of DReSS and predict disease severity has been a recent area of research focus. In vitro and in vivo tests can be employed to confirm the diagnosis and help identify culprit drugs. The mainstay treatment of DReSS is prompt withdrawal of the culprit drug, supportive treatment, and immunosuppression depending on the severity of disease. We present a comprehensive review on the most recent research and literature on DReSS, with emphasis on pathogenesis, clinical features, diagnosis, confirmatory testing modalities, and treatment. Additionally, this summary aims to highlight the differing viewpoints on this severe disease and broaden our perspective on the condition known as DReSS.