Clinical and dermoscopic features of nail unit melanoma in an Australian nail clinic cohort.

Nail unit melanoma carries diagnostic challenges conferring with its poor prognosis. This audit aims to characterise both clinical and dermoscopic features of nail unit malignant lesions and compare them with biopsied benign lesions. It focuses on informing future practice by aiding in the stratification and recognition of malignant diagnostic patterns in the Australian context.

CSL324, a granulocyte colony-stimulating factor receptor antagonist, blocks neutrophil migration markers that are upregulated in hidradenitis suppurativa.

BACKGROUND: Neutrophils have been shown to contribute to the pathophysiology of hidradenitis suppurativa (HS), a chronic, painful and debilitating inflammatory skin disease, yet their exact role remains to be fully defined. Granulocyte colony-stimulating factor (G-CSF), a major regulator of neutrophil development and survival, can be blocked by the novel, fully human anti-G-CSF receptor (G-CSFR) monoclonal antibody CSL324. OBJECTIVES: We investigated the activation and migration of neutrophils in HS and the impact of blocking G-CSFR with CSL324. METHODS: Biopsy and peripheral blood samples were taken from participants of two studies: 2018.206, a noninterventional research study of systemic and dermal neutrophils and inflammatory markers in patients with neutrophilic skin diseases, and CSL324_1001 (ACTRN12616000846426), a single-dose ascending and repeated dose, randomized, double-blind, placebo-controlled study to assess the safety, pharmacokinetics and pharmacodynamics of CSL324 in healthy adult subjects. Ex vivo experiments were performed, including neutrophil enumeration and immunophenotyping, migration, receptor occupancy and transcriptome analysis. RESULTS: The number of cells positive for the neutrophil markers myeloperoxidase (MPO) and neutrophil elastase (NE) was significantly higher in HS lesions compared with biopsies from healthy donors (HDs) (P < 0.0001 and P = 0.0223, respectively). In peripheral blood samples, mean neutrophil counts were significantly higher in patients with HS than in HDs (2.98 vs. 1.60 × 109 L-1, respectively; P = 8.8 × 10-4). Neutrophil migration pathways in peripheral blood were increased in patients with HS and their neutrophils demonstrated an increased migration phenotype, with higher mean CXCR1 on the surface of neutrophils in patients with HS (24453.20 vs. 20798.47 for HD; P = 0.03). G-CSF was a key driver of the transcriptomic changes in the peripheral blood of patients with HS and was elevated in serum from patients with HS compared with HDs (mean 6.61 vs. 3.84 pg mL-1, respectively; P = 0.013). Administration of CSL324 inhibited G-CSF-induced transcriptional changes in HDs, similar to those observed in the HS cohort, as highlighted by expression changes in genes related to neutrophil migratory capacity. CONCLUSIONS: Data suggest that neutrophils contribute to HS pathophysiology and that neutrophils are increased in lesions due to an increase in G-CSF-driven migration. CSL324 counteracted G-CSF-induced transcriptomic changes and blocked neutrophil migration by reducing cell-surface levels of chemokine receptors.

Efficacy and safety of Oleogel-S10 (birch triterpenes) for epidermolysis bullosa: results from the phase III randomized double-blind phase of the EASE study.

BACKGROUND: Epidermolysis bullosa (EB) is a heterogeneous group of rare, difficult-to-treat, inherited multisystem diseases affecting epithelial integrity. Patients with EB are affected by mechanical fragility of epithelial surfaces including the skin and, as a result, extensive recurrent blistering is a characteristic of the condition. Chronic wounds predispose patients with EB to the development of squamous cell carcinoma, which is a major cause of premature death. OBJECTIVES: EASE was a double-blind, randomized, vehicle-controlled, phase III study to determine the efficacy and safety of the topical gel Oleogel-S10 (birch triterpenes) in EB. EASE was funded by Amryt Research Limited. METHODS: Patients with dystrophic EB, junctional EB or Kindler EB and a target partial-thickness wound lasting ≥ 21 days and < 9 months that was 10-50 cm2, were enrolled and randomized via computer-generated allocation tables 1 : 1 to Oleogel-S10 or control gel - both with standard-of-care dressings. Study gel was applied to all wounds at least every 4 days. The primary endpoint was the proportion of patients with first complete closure of target wound within 45 days. RESULTS: A total of 223 patients were enrolled and treated (109 treated with Oleogel-S10, 114 with control gel). The primary endpoint was met; Oleogel-S10 resulted in 41·3% of patients with first complete target wound closure within 45 days, compared with 28·9% in the control gel arm (relative risk 1·44, 95% confidence interval (CI) 1·01-2·05; P = 0·013). Adverse events (AEs) occurred with similar frequency for Oleogel-S10 (81·7%) compared with control gel (80·7%). AEs were predominantly of mild-to-moderate intensity (4·6% were severe). CONCLUSIONS: Oleogel-S10 is the first therapy to demonstrate accelerated wound healing in EB. Oleogel-S10 was well -tolerated.

Study protocol: Australasian Registry of Severe Cutaneous Adverse Reactions (AUS-SCAR).

INTRODUCTION: Severe cutaneous adverse reactions (SCAR) are a group of T cell-mediated hypersensitivities associated with significant morbidity, mortality and hospital costs. Clinical phenotypes include Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS) and acute generalised exanthematous pustulosis (AGEP). In this Australasian, multicentre, prospective registry, we plan to examine the clinical presentation, drug causality, genomic predictors, potential diagnostic approaches, treatments and long-term outcomes of SCAR in Australia and New Zealand. METHODS AND ANALYSIS: Adult and adolescent patients with SCAR including SJS, TEN, DRESS, AGEP and another T cell-mediated hypersensitivity, generalised bullous fixed drug eruption, will be prospectively recruited. A waiver of consent has been granted for some sites to retrospectively include cases which result in early mortality. DNA will be collected for all prospective cases. Blood, blister fluid and skin biopsy sampling is optional and subject to patient consent and site capacity. To develop culprit drug identification and prevention, genomic testing will be performed to confirm human leukocyte antigen (HLA) type and ex vivo testing will be performed via interferon-γ release enzyme linked immunospot assay using collected peripheral blood mononuclear cells. The long-term outcomes of SCAR will be investigated with a 12-month quality of life survey and examination of prescribing and mortality data. ETHICS AND DISSEMINATION: This study was reviewed and approved by the Austin Health Human Research Ethics Committee (HREC/50791/Austin-19). Results will be published in peer-reviewed journals and presented at relevant conferences. TRIAL REGISTRATION NUMBER: Australian New Zealand Clinical Trials Registry (ACTRN12619000241134).

Clinical and histopathological features of onychopapilloma in an Australian setting: A case series of 50 patients.

Onychopapilloma is an uncommon tumour of the nailbed and the distal nail matrix. To date, only 19 case reports and case series have been reported in the literature. This article includes literature review on all reported cases and provides the first case series of onychopapilloma in an Australian population, evaluating the clinical features and histopathological diagnosis of patients with onychopapilloma in an Australian subspecialty nail clinic.

[Management of bullous pemphigoid and mucous membrane pemphigoid]. / Management von bullösem Pemphigoid und Schleimhautpemphigoid.

BACKGROUND: Bullous pemphigoid (BP) is the most common blistering autoimmune dermatosis and, as an age-associated disease, is also the bullous dermatosis with the highest increase in incidence in recent years due to demographic developments. Mucous membrane pemphigoid (MMP), which is less common, is a clinically and immunopathologically heterogeneous blistering autoimmune dermatosis characterized by blisters and erosions on mucous membranes. OBJECTIVE: This work summarizes the manifold clinical characteristics of both diseases and provides an up-to-date overview of diagnostics and therapy of BP and SHP. MATERIALS AND METHODS: A selective literature search was carried out. RESULTS: While eczematous, urticarial, or bullous lesions on the integument are typical for BP, MMP is characterized by pronounced, erosive mucosal changes orally, ocularly, genitoanally, tracheally or esophageally and, at most, only minor skin involvement. For diagnosis, the combination of histology, direct immunofluorescence microscopy, and serological detection of autoantibodies against the hemidesmosomal proteins BP180 and BP230 and, in MMP, also against laminin 332 is important. New pathophysiological findings and therapeutics have recently significantly expanded the range of treatment options. CONCLUSION: Due to the comorbidities of the usually elderly BP patients and the often multiple affected mucous membranes in MMP, with the risk of developing irreversible complications such as strictures and synechiae, interdisciplinary diagnosis and therapy is often required.

Systemic Collagen VII Replacement Therapy for Advanced Recessive Dystrophic Epidermolysis Bullosa.

Recessive dystrophic epidermolysis bullosa (RDEB) is a genetic skin blistering disease associated with progressive multiorgan fibrosis. RDEB is caused by biallelic mutations in COL7A1 encoding the extracellular matrix protein collagen VII (C7), which is necessary for epidermal‒dermal adherence. C7 is not simply a structural protein but also has multiple functions, including the regulation of TGFß bioavailability and the inhibition of skin scarring. Intravenous (IV) administration of recombinant C7 (rC7) rescues C7-deficient mice from neonatal lethality. However, the effect on established RDEB has not been determined. In this study, we used small and large adult RDEB animal models to investigate the disease-modulating abilities of IV rC7 on established RDEB. In adult RDEB mice, rC7 accumulated at the basement membrane zone in multiple organs after a single infusion. Fortnightly IV injections of rC7 for 7 weeks in adult RDEB mice reduced fibrosis of skin and eye. The fibrosis-delaying effect was associated with a reduction of TGFß signaling. IV rC7 in adult RDEB dogs incorporated in the dermal‒epidermal junction of skin and improved disease by promoting wound healing and reducing dermal‒epidermal separation. In both species, IV C7 was well-tolerated. These preclinical studies suggest that repeated IV administration of rC7 is an option for systemic treatment of established adult RDEB.

A comparison study of outcome measures for epidermolysis bullosa: Epidermolysis Bullosa Disease Activity and Scarring Index (EBDASI) and the Instrument for Scoring Clinical Outcomes of Research for Epidermolysis Bullosa (iscorEB).

BACKGROUND: The success of clinical trials in Epidermolysis Bullosa (EB) is dependent upon the availability of a valid and reliable scoring tool that can accurately assess and monitor disease severity. The Epidermolysis Bullosa Disease Activity and Scarring Index (EBDASI) and Instrument for Scoring Clinical Outcomes of Research for Epidermolysis Bullosa (iscorEB) were independently developed and validated against the Birmingham Epidermolysis Bullosa Severity Score but have never been directly compared. OBJECTIVE: To compare the reliability, convergent validity, and discriminant validity of the EBDASI and iscorEB scoring tools. METHODS: An observational cohort study was conducted in 15 patients with EB. Each patient was evaluated using the EBDASI and iscorEB-clinician scoring tools by 6 dermatologists with expertise in EB. Quality of life was assessed using the iscorEB-patient and Quality of Life in EB measures. RESULTS: The intraclass correlation coefficients for interrater reliability were 0.942 for the EBDASI and 0.852 for the iscorEB-clinician. The intraclass correlation coefficients for intrarater reliability was 0.99 for both scores. The two tools demonstrated strong convergent validity with each other. CONCLUSION: Both scoring tools demonstrate excellent reliability. The EBDASI appears to better discriminate between EB types and disease severities.

Mouse models for dominant dystrophic epidermolysis bullosa carrying common human point mutations recapitulate the human disease.

Heterozygous missense mutations in the human COL7A1 gene - coding for collagen VII - lead to the rare, dominantly inherited skin disorder dominant dystrophic epidermolysis bullosa (DDEB), which is characterised by skin fragility, blistering, scarring and nail dystrophy. To better understand the pathophysiology of DDEB and develop more effective treatments, suitable mouse models for DDEB are required but to date none have existed. We identified the two most common COL7A1 mutations in DDEB patients (p.G2034R and p.G2043R) and used CRISPR-Cas9 to introduce the corresponding mutations into mouse Col7a1 (p.G2028R and p.G2037R). Dominant inheritance of either of these two alleles results in a phenotype that closely resembles that seen in DDEB patients. Specifically, mice carrying these alleles show recurrent blistering that is first observed transiently around the mouth and paws in the early neonatal period and then again around the digits from 5-10 weeks of age. Histologically, the mice show micro-blistering and reduced collagen VII immunostaining. Biochemically, collagen VII from these mice displays reduced thermal stability, which we also observed to be the case for DDEB patients carrying the analogous mutations. Unlike previous rodent models of epidermolysis bullosa, which frequently show early lethality and severe disease, these mouse models, which to our knowledge are the first for DDEB, show no reduction in growth and survival, and - together with a relatively mild phenotype - represent a practically and ethically tractable tool for better understanding and treating epidermolysis bullosa. This article has an associated First Person interview with the first author of the paper.

De-escalation of anti-CD20 monoclonal antibody (Rituximab) protocols in Pemphigus Vulgaris - a systematic review.

Introduction: This review assesses current evidence supporting dose de-escalated rituximab therapy in pemphigus vulgaris, compared to standard protocols. Primary outcome measures were remission and relapse rates. Adverse effects, cumulative steroid dosages, and serological markers of disease activity were also reported.Areas covered: A literature search was performed to look for reports describing the use of de-escalated rituximab therapy in pemphigus vulgaris. Results from heterogenous studies showed a large variation in remission and relapse rates. Complete remission rates from de-escalated treatment ranged from 41.7 to 100.0%, while rates in the control groups ranged from 60.0 to 90.9%. Relapse rates varied from 8.0 to 81.3% in the de-escalated group and from 0.0 to 72.4% in the control group. Of the 165 patients included in this report, only two major adverse effects were reported.Expert Opinion: Overall, dose de-escalated rituximab protocols reported to date appear effective and safe. However, it is unclear if treatment effect parallels that of standard regimens in regard to disease control in the long term. A lower limit of effective dosing for rituximab in pemphigus vulgaris has not yet been reached or defined. The role for and timing of repeated cycles of low-dose rituximab therapy require further exploration.

Successful management of treatment resistant nail psoriasis with tildrakizumab.

Nail psoriasis significantly impacts quality of life and is notoriously difficult to treat. Tildrakizumab, an IL-23 inhibitor, has shown significant clinical improvement in the treatment of moderate-to-severe chronic plaque psoriasis. We report 2 cases of treatment resistant nail psoriasis which showed marked improvement with the use of off-label tildrakizumab. The dosing regimen utilised was consistent with that used to treat chronic plaque psoriasis, with 100 mg subcutaneously at Day 0 and Week 4, and maintenance dosing of 100 mg every 12 weeks thereafter. Significant improvement at 6 and 12 months, as per the modified Nail Psoriasis Severity Index (mNAPSI) and Dermatology Life Quality Index (DLQI), was seen. There have been no tildrakizumab related side effects observed to date. Tildrakizumab appears to be an effective option in managing treatment resistant nail psoriasis.

Comparison of the EUROIMMUN Dermatology Profile ELISA to the novel BIOCHIP Mosaic 7 for the diagnosis of immunobullous skin disease.

BACKGROUND: The BIOCHIP is an indirect immunofluorescence diagnostic investigation which identifies multiple autoantibodies with a mosaic panel of target antigen-specific substrates in a single incubation field. The EUROIMMUN Dermatology Profile ELISA allows simultaneous investigation of the six most important autoantibodies in bullous autoimmune dermatoses. Evaluation of the BIOCHIP Mosaic 7, compared to that of the EUROIMMUN Dermatology Profile ELISA, when used as a diagnostic investigation in pemphigus and pemphigoid, was undertaken in an Australian cohort. METHODS: The serum of 27 patients was analysed including patients with pemphigus vulgaris (n = 10), pemphigus foliaceous (n = 4), bullous pemphigoid (n = 8), mucous membrane pemphigoid (n = 3) and negative controls (n = 2). Results of the BIOCHIP were compared with the EUROIMMUN Dermatology Profile ELISA, as well as with histology, direct immunofluorescence and indirect immunofluorescence. RESULTS: In pemphigus vulgaris, sensitivity & specificity for the BIOCHIP Mosaic 7 were 100% and 94.1%, comparable to that of the EUROIMMUN Dermatology Profile ELISA with 80% sensitivity and 100% specificity. In bullous pemphigoid, sensitivity of the BIOCHIP was 87.5% and sensitivity of the EUROIMMUN Dermatology ELISA profile was 75%, whilst specificities for both diagnostic methods were 100% in our limited cohort. There was substantial or almost perfect concordance between the BIOCHIP Mosaic 7 and EUROIMMUN Dermatology Profile ELISA for pemphigus vulgaris and bullous pemphigoid. CONCLUSION: The BIOCHIP Mosaic 7 is a rapid, reliable diagnostic investigation in pemphigus and bullous pemphigoid. Results indicate it is comparable to the EUROIMMUN Dermatology Profile ELISA, whilst also providing additional testing with salt split skin, on one field.

A casemix study of patients seen within an urban Aboriginal Health Service dermatology clinic over a five-year period.

This is the largest study of Aboriginal and Torres Strait Islander dermatologic presentations to an urban specialist clinic within a community-controlled health organisation. It adds to our understanding of Aboriginal and Torres Strait Islander dermatoepidemiology. Patient files were reviewed over the five-year audit period, with age, gender, Indigenous status, diagnosis, disease category, 'new' or 'review consultation' and 'did not attend' (DNA) data recorded. Our study shows that eczema and benign, pre-malignant or malignant neoplasms are the most common presentations for urban Aboriginal and Torres Strait Islander patients. Lupus erythematosus and cutaneous infections were less prominent in comparison to data from rural and remote populations. Overall, a broad casemix of dermatologic presentations was observed. Similar to other studies, adult male patients were under-represented. Most skin malignancies were diagnosed in this cohort; this, therefore, identifies a possible target for public health intervention. A high ratio of new to review patients is consistent with the clinic offering a consultation model of care facilitated by primary health-care providers' support within Aboriginal Community-Controlled Health Service. DNA rates in this study were lower than hospital outpatient rates in a comparative study and may be attributed to specialist dermatology care being offered in a more culturally sensitive environment. The dermatology clinic at the Victorian Aboriginal Health Services (VAHS) provides a good breadth of specialist dermatology care. The community health-care model could be replicated in centres elsewhere, including interstate, to help overcome barriers to specialist dermatology care experienced by Aboriginal and Torres Strait Islander populations. Additionally, this model improves trainee exposure and understanding of Aboriginal and Torres Strait Islander health.

Intraoral human herpes viruses detectable by PCR in majority of patients.

OBJECTIVES: To identify factors which influence the intraoral prevalence of human herpes viruses (HHVs) using mucosal swabs, saliva samples and qPCR analysis. METHODOLOGY: In this cross-sectional observational study, matched saliva and oral swabs were collected from a total of 115 subjects: 70 immunocompetent subjects with no mucosal abnormalities, 22 with mucosal abnormalities and 23 therapeutically immunocompromised individuals. Extracted DNA was analysed by multiplex qPCR for detection and quantification of HHVs 1-6. RESULTS: At least one human herpes virus was detected in 77.1% of immunocompetent individuals with no mucosal abnormalities, with EBV the most commonly detected at 61.4%. HHV-6 was detected in 17.1%, HSV-1 in 4.3% and CMV in 1.1%. Detection was higher in saliva than in oral swabs. There was no detection of HSV-2 or VZV. Neither presence of oral mucosal abnormality nor therapeutic immunocompromise was related to increased detection of human herpes virus. CONCLUSION: Commensal detection rates of EBV are high, and caution in clinical correlation of positive detection is warranted. Commensal CMV rates are low, and detection is likely to be clinically relevant. This study presents a comprehensive commensal detection rate of HHVs 1-6 by qPCR in saliva and swabs.