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.

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.

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.

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.

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.

Epidemiology of severe drug hypersensitivity.

Epidemiological studies of severe drug hypersensitivities are important to understanding the morbidity and mortality of this heterogeneous group of disorders. These insights also allow greater identification of at-risk patient groups. However, epidemiological studies of drug hypersensitivity reactions are challenging due to the variable diagnostic criteria applied and incomplete data sets studied. We review the epidemiology of severe drug hypersensitivity reactions with a particular focus on severe cutaneous adverse reactions (SCARs). SCAR diseases include: Stevens-Johnson syndrome, toxic epidermal necrolysis, drug rash eosinophilia and systemic symptoms, serum-sickness-like reaction and acute generalized exanthematous pustulosis.

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.

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.

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.

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.