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.

Epidemiology of eczema in South-Eastern Australia.

BACKGROUND/OBJECTIVES: Eczema is a common chronic debilitating skin condition in childhood. Data on the epidemiology and natural history of eczema across the life course are lacking. This analysis aimed to describe these epidemiological features in Australian children and adults. METHODS: Data collected on eczema from four Australian cohort studies were analysed: namely HealthNuts, Melbourne Atopic Cohort Study (MACS), Tasmanian Longitudinal Health Study (TAHS) and the Australian arm of the European Community Respiratory Health Survey (ECRHS). RESULTS: Among children aged under 6 years, 28.8%-35.6% have ever-had eczema, and 16.7%-26.6% had 'current eczema'. Among those aged 6-12 years, 14.6%-24.7% had 'current eczema' with 12.0%-18.5% of those at ages of 6 and 10 years classified as having moderate-to-severe eczema according to the Scoring of Atopic Dermatitis (SCORAD) index. In adults, the prevalence of 'eczema ever' ranged between 13.8% and 48.4%. The 12-month period prevalence of eczema was 15.1% at age 18, while current eczema was 8.5% at an average age of 51, and 8.8% at an average age 53 years. Eczema was more common among young boys, but this difference became non-significant for older children and early adolescents. In contrast, eczema was more common for adult women than men. CONCLUSIONS: Eczema is common both in children and adults. The proportion of severe eczema in children was substantial.

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.

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.

The association of mycophenolate mofetil and human herpes virus infection.

Purpose: Mycophenolate mofetil (MMF) is a steroid-sparing immunosuppressant used extensively to treat both common and rare dermatological conditions. Its lymphocyte specificity makes it a favorable therapeutic option particularly for patients who cannot tolerate alternative immunosuppressants. However, the side effect profile of MMF has not been extensively evaluated. This review presents current evidence regarding increased risk of human herpesvirus infection (HHV) with MMF therapy.Methods: The electronic database Medline (OVID) was searched on January 2018 for relevant English-language articles regarding the evaluation of incidence/prevalence of HHV infection in patients taking MMF, identifying 24 studies.Results: The majority of available studies were conducted on solid organ transplant recipients receiving complex immunosuppressive treatment including the MMF. Cytomegalovirus is the most well studied of the HHV. A positive association with cytomegaloviruses was found with MMF when compared to alternative immunosuppressants and studies to date suggest dose-dependent effect.Conclusion: MMF is a commonly used steroid-sparing agent used to treat dermatological conditions. This review highlights that MMF is positively associated with cytomegalovirus infection. The presented studies were heterogeneous in study design and detection method, with the majority completed on renal transplant patients. Further studies are needed to shed light on the association of MMF with HHV.

PEBBLES study protocol: a randomised controlled trial to prevent atopic dermatitis, food allergy and sensitisation in infants with a family history of allergic disease using a skin barrier improvement strategy.

INTRODUCTION: The skin is an important barrier against environmental allergens, but infants have relatively impaired skin barrier function. There is evidence that impaired skin barrier function increases the risk of allergic sensitisation, atopic dermatitis (AD) and food allergy. We hypothesise that regular prophylactic use of emollients, particularly those that are designed to improve skin barrier structure and function, will help prevent these conditions. With the aim of determining if application of a ceramide-dominant emollient two times per day reduces the risk of AD and food allergy, we have commenced a multicentre phase III, outcome assessor blinded, randomised controlled trial of this emollient applied from birth to 6 months. METHODS AND ANALYSIS: Infants (n=760) with a family history of allergic disease will be recruited from maternity hospitals in Melbourne. The primary outcomes are as follows: the presence of AD, assessed using the UK Working Party criteria, and food allergy using food challenge, in the first 12 months of life as assessed by a blinded study outcome assessor. Secondary outcomes are as follows: food sensitisation (skin prick test), skin barrier function, AD severity, the presence of new onset AD after treatment cessation (between 6 and 12 months) and the presence of parent reported AD/eczema. Recruitment commenced in March 2018. ETHICS AND DISSEMINATION: The PEBBLES Study is approved by the Human Research Ethics Committees of the Royal Children's Hospital (RCH) (#37090A) and the Mercy Hospital for Women (2018-008). Parents or guardians will provide written informed consent. Outcomes will be disseminated through peer-reviewed publications and presented at scientific conferences. TRIAL REGISTRATION NUMBERS: ACTRN12617001380381 and NCT03667651.

Baseline patients' characteristics as predictors for therapeutic survival and response in patients with psoriasis on biological treatments.

BACKGROUND/OBJECTIVES: Biological agents provide a relatively safe and promising long-term therapeutic option for patients with moderate to severe psoriasis in whom conventional treatment has failed. However, these agents are not effective in all patients. We aimed to examine the association of baseline patients' characteristics with the short-term efficacy and the long-term survival of biological therapies in patients with moderate to severe psoriasis. METHODS: We performed a retrospective observational study of all patients who received biological treatment for psoriasis at the Royal Melbourne Hospital (N = 146). We extracted data on the patients' characteristics and medical history. The outcomes we measured included a 75% reduction in psoriasis area and severity index (PASI) score at 12 and 24 weeks, the total duration of drug survival and dermatology life quality index (DLQI) scores. We used regression modelling to assess the association between each baseline patient's characteristic and outcome measures. RESULTS: An increase in baseline body mass index was associated with a reduced likelihood of achieving PASI75 at 12 and 24 weeks (P = 0.014) and also correlated with reduced long-term therapeutic survival (P = 0.03). High rates of treatment termination were noted in patients with greater baseline DLQI (P = 0.038). CONCLUSION: Greater body mass index at the initiation of biological treatment for psoriasis may contribute to its decreased short-term efficacy. Similarly, a high body mass index or DLQI at baseline was associated with a relatively short duration of biological treatment retention.

High serum vitamin D level correlates with better prognostic indicators in primary melanoma: A pilot study.

BACKGROUND/OBJECTIVES: Sunlight is a major risk factor for cutaneous melanoma. However, its interaction with melanoma is complex. In particular, vitamin D is a UVB-derived hormone that has been shown to have anti-cancer effects. In this retrospective pilot study we sought to determine an association between the clinicopathological features of melanoma and the patients' corresponding serum vitamin D level. METHODS: In total, 109 primary melanomas diagnosed between 2001 and 2013 were retrospectively identified from our institutional database with a corresponding 25-hydroxyvitamin D3 level estimated within 6 months of diagnosis. Tumour, clinical (age, sex, tumour location) and pathological (thickness, mitosis, ulceration, Clark level, subtype, metastatic status) parameters were correlated with vitamin D. For statistical analysis, an unpaired Student's t-test and anova was used for categorical variables, and Spearman's correlation for continuous variables. RESULTS: Vitamin D level was inversely associated with Breslow thickness as a dichotomous, categorical and continuous variable. The association remained significant when controlled for patient's age and sex (P = 0.026). Vitamin D was higher in non-ulcerated tumours compared with ulcerated tumours (P = 0.006) and in tumours with mitotic rate <1/mm2 compared with ≥1/mm2 (P = 0.036). A significant association was found between vitamin D level and tumour histological subtype (P = 0.019). On subgroup analysis, significant associations were found between superficial spreading melanoma (SSM) and nodular melanoma (P = 0.026), and SSM and acral lentiginous melanoma (P = 0.007). CONCLUSION: A high vitamin D status may benefit prognosis in patients diagnosed with primary melanoma. A prospective cohort analysis with a large sample and controlled for other vitamin D confounders would validate these findings.

Low-dose rituximab and concurrent adjuvant therapy for pemphigus: Protocol and single-centre long-term review of nine patients.

Pemphigus is an autoimmune B-cell mediated blistering disease associated with significant morbidity and mortality. Rituximab has proven effective for the treatment of steroid-refractory pemphigus, although there is controversy over the optimum dosing protocol. Additionally, effective disease control often requires long-term immunosuppression, even in disease-free periods. We present a case series of a single-centre long-term follow up of nine patients with pemphigus, treated with two 500-mg doses of rituximab separated by 14 days along with concurrent adjuvant therapy. In all these patients, low-dose rituximab resulted in B-cell depletion, along with a reduction in blistering disease. Three of these patients required repeat dosing cycles due to either relapsed disease or incomplete disease control following the first dosing cycle, and have remained disease free up to 154 weeks thus far. Six patients developed minor infections during the course of their treatment, but no major complications were observed.

Improving patient safety: The impact of an outpatients' electronic handover system in a tertiary dermatology department.

BACKGROUND/OBJECTIVES: Electronic medical records (EMR) can improve quality healthcare, patient safety and streamline workflow to improve efficiency of a department. Despite the known benefits and difficulties of EMR systems, there is limited data on the impact and definable effectiveness it can have within a dermatology unit. We present an outpatients' EMR known as an electronic handover system (EHS) from its inception, delivery and audit of its use in evaluating the true impact. METHODS: An audit of the EHS was conducted from 1 March to 31 August 2014. Quantitative data evaluating the type of jobs entered and completed, overdue tasks, patient workload and phone consultations were conducted. Qualitative data was assessed via a pilot survey assessing users' perspectives of the EHS evaluating communication, clinician-patient relationship and administrative tasks. RESULTS: Altogether 754 jobs were entered for 411 dermatology outpatients using the EHS. Most tasks concerned following up bloods and swabs (38%) or biopsies (36%). Overall, 51 jobs were not completed by the specified due dates and 188 phone consultations were performed. Compared with pre-EHS data, clinic review patients fell by 16%, with a modest increase (2%) in the number of new patients seen. The survey results show that most respondents believed that EHS improved communication, did not affect the clinician-patient relationship and they were more confident in their practice knowing there was a recording system for follow up. CONCLUSION: The dermatology EHS has provided a reliable system for following up all outpatient results. The potential benefits range from clinical, organisational and health research, which, from our experience, demonstrates improved patient follow-up care.

Inhibitor of Apoptosis Proteins (IAPs) Limit RIPK1-Mediated Skin Inflammation.

Inhibitor of apoptosis proteins (IAPs) are critical regulators of cell death and survival pathways. Mice lacking cIAP1 and either cIAP2 or XIAP die in utero, and myeloid lineage-specific deletion of all IAPs causes sterile inflammation, but their role in the skin is unknown. We generated epidermal-specific IAP-deficient mice and found that combined genetic deletion of cIAP1 (epidermal knockout [EKO]) in keratinocytes and ubiquitous cIAP2 deletion (cIap1EKO/EKO.cIap2-/-) caused profound skin inflammation and keratinocyte death, lethal by postpartum day 10. To investigate their role in skin homeostasis, we injected an IAP antagonist compound subcutaneously into wild-type and knockout mice. This induced a toxic epidermal necrolysis-like local inflammation, which mirrored the phenotype seen in cIap1EKO/EKO.cIap2-/- mice. Loss of one Ripk1 allele limited lesion formation and significantly extended the lifespan of cIap1EKO/EKO.cIap2-/- mice. cIAP activities are important for recruitment of LUBAC to signaling complexes, and loss of LUBAC component SHARPIN, induces dermatitis in mice. Consistent with this relationship between cIAPs and LUBAC, Ripk1 heterozygosity also protected against development of dermatitis in Sharpin-deficient mice. This work therefore refines our molecular understanding of inflammatory signaling in the skin and defines potential targets for treating skin inflammation.