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.

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.

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.

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.

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.

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.

The frequency of mucosal-associated invariant T cells is selectively increased in dermatitis herpetiformis.

BACKGROUND/OBJECTIVES: Mucosal-associated invariant T (MAIT) cells are a novel subset of innate-like T-cells that are enriched in mucosal tissues. Their presence in human skin has only recently been recognised. We describe the expression of skin-tropic molecules on human skin MAIT cells at steady state and investigate their contribution to various dermatoses with known T-cell involvement. METHODS: To examine the expression of skin-tropic molecules by MAIT cells at steady state, we performed a flow cytometric analysis of blood and skin samples from healthy donors. To investigate any potential wider contribution of MAIT cells to skin disease, we examined psoriasis, alopecia areata and dermatitis herpetiformis biopsies using immunofluorescent staining to identify the proportion of T-cells expressing MAIT cell surface markers. RESULTS: We found that MAIT cells constituted a small population of T-cells in normal human skin, similar to the percentage found in peripheral blood. Like other skin T-cells, skin MAIT cells expressed high levels of the skin-associated markers, cutaneous lymphocyte antigen and CD103. In psoriasis and alopecia areata the proportion of MAIT cells was similar to that found in normal skin, but in dermatitis herpetiformis it was significantly elevated. CONCLUSIONS: The expression of skin-tropic molecules by skin MAIT cells is consistent with their resident status in normal human skin. Our results suggest that MAIT cells may play a role in the pathogenesis of dermatitis herpetiformis.

Concomitant extraspinal hyperostosis and osteoporosis in a patient with congenital ichthyosis.

Ichthyosiform dermatosis is a term referred to a group of disorders that have as their basis a disorder of keratinization (1). These conditions which are present at birth result in a generalized dry, scaly skin without any inflammation. There are several types of ichthyosis based on their clinical presentation and mode of inheritance. The most common types are: ichthyosis vulgaris, X-linked recessive ichthyosis, epidermolytic hyperkeratosis (bullous), lamellar ichthyosis and non-bullous ichthyosiform erythroderma. Lamellar ichthyosis, which is inherited in an autosomal recessive pattern, shows genetic heterogeneity with the most severe type being due to mutations in the transglutaminase-1 gene. This condition presents with skin changes at birth and cases are referred to as collodion babies. Initially, the stratum corneum is smooth and appears as though it is covered with cellophane. This layer is discarded a few days after birth, leaving a generalized inflamed and scaly appearance. The skin is tight at this stage and may cause ectropion, and difficulties in feeding and temperature regulation. Lamellar ichthyosis is characterized by plate-like scales that last for life and can significantly impact the patient's quality of life (2). We report here a case of multiple extraspinal hyperostoses concomitant with marked osteoporosis and vitamin D deficiency in a patient taking acitretin for 20 years due to severe congenital lamellar ichthyosis.

Molecular and functional analysis of the C-terminal region of human erythroid-specific 5-aminolevulinic synthase associated with X-linked dominant protoporphyria (XLDPP).

Frameshift mutations in the last coding exon of the 5-aminolevulinate synthase (ALAS) 2 gene were described to activate the enzyme causing increased levels of zinc- and metal-free protoporphyrin in patients with X-linked dominant protoporphyria (XLDPP). Only two such so-called gain-of-function mutations have been reported since the description of XLDPP in 2008. In this study of four newly identified XLDPP families, we identified two novel ALAS2 gene mutations, a nonsense p.Q548X and a frameshift c.1651-1677del26bp, along with a known mutation (delAGTG) found in two unrelated families. Of relevance, a de novo somatic and germinal mosaicism was present in a delAGTG family. Such a phenomenon may explain the high proportion of this mutation in XLDPP worldwide. Enhancements of over 3- and 14-fold in the catalytic rate and specificity constant of purified recombinant XLDPP variants in relation to those of wild-type ALAS2 confirmed the gain of function ascribed to these enzymes. The fact that both p.Q548X and c.1651-1677del26bp are located in close proximity and upstream from the two previously described mutations led us to propose the presence of a large gain-of-function domain within the C-terminus of ALAS2. To test this hypothesis, we generated four additional nonsense mutants (p.A539X, p.G544X, p.G576X and p.V583X) surrounding the human XLDPP mutations and defined an ALAS2 gain-of-function domain with a minimal size of 33 amino acids. The identification of this gain-of-function domain provides important information on the enzymatic activity of ALAS2, which was proposed to be constitutively inhibited, either directly or indirectly, through its own C-terminus.

An unusual urticarial eruption: Familial cold autoinflammatory syndrome.

This is a case of a 26-year-old Caucasian woman with a lifelong history of an episodic urticaria associated with arthralgia, precipitated by exposure to cold. She had no other significant past medical history. She reported several family members with a history of very similar episodic eruptions without definitive diagnoses. An examination showed an urticarial eruption over her limbs with no other systemic findings. A baseline full blood examination, serology and autoimmune screen were normal. A skin biopsy was consistent with urticaria, with dermal oedema and a perivascular infiltrate. Following genetic testing, she was found to be heterozygous for a mutation, p.Ala439Val in the NLRP3 gene, known to cause familial cold autoinflammatory syndrome (FCAS), which typically presents with urticaria, conjunctivitis and arthralgia, as described in this patient. FCAS is one subtype of a group of conditions known as cryopyrin-associated periodic syndromes (CAPS). CAPS are rare, autosomal dominant inherited conditions with a spectrum of phenotypes, characterised by increased interleukin-1ß release with subsequent local and systemic proinflammatory and pyrogenic effects.

Halo naevi and café au lait macule regression in a renal transplant patient on immunosuppression.

A case of halo naevi and café au lait macule regression in a renal transplant patient receiving long-term immunosuppressive therapy is described. We propose the direct transfer of an auto-reactive antibody, CD8 T-cells or tumour necrosis factor α from the transplant donor to the recipient as a possible cause. We have also considered insufficient immunosuppressive therapy as a possible mechanism.

A rare cause of petechial rash in the 21st century.

Scurvy was first described by Hippocrates (460-370 BC) as a condition characterised by poor dental health, bruising, bleeding and fragile skin. Despite the widespread availability of foods rich in vitamin C in Australia, scurvy continues to afflict certain high-risk subgroups of the population. Cutaneous signs may be the only manifestation of the disease, as in the case presented below, and therefore scurvy continues to be relevant to dermatologists.