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.

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.

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.

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 case of multicentric reticulohistiocytosis responsive to azathioprine in a patient with no underlying malignancy.

Multicentric reticulohistiocytosis (MRH), a rare histiocytic systemic condition characterized by mutilating arthritis and multiple cutaneous nodules, has been associated with malignancy including that of the breast, thyroid and colon. An unsubstantiated link with infectious agents such as mycobacterium tuberculosis has been described. Many treatments have been used with varying success. We describe the case of a 60-year-old man with MRH and no underlying malignancy who initially responded well to azathioprine and whose disease recurred upon cessation. A second course of azathioprine administered in conjunction with antituberculous treatment resulted in disease control. Broader associations and features of this rare disease are discussed.

Photodynamic therapy for Basal cell carcinoma in recessive dystrophic epidermolysis bullosa.

A 22-year-old male with recessive dystrophic epidermolysis bullosa with a large superficial and nodular basal cell carcinoma on his right forehead was treated with photodynamic therapy. The treatment was well tolerated, and the site healed well. Patients with epidermolysis bullosa are at increased risk of developing skin cancers, particularly squamous cell carcinomas. However, basal cell carcinomas are rare in recessive dystrophic epidermolysis bullosa. As patients with epidermolysis bullosa have recurrent blistering and poor wound healing, surgery may not be the optimal choice in treating skin cancers. We present this case to highlight that photodynamic therapy may be a helpful and safe technique in the treatment of superficial skin cancers in patients with epidermolysis bullosa, as an alternative to more radical methods.

Border detection in dermoscopy images using hybrid thresholding on optimized color channels.

Automated border detection is one of the most important steps in dermoscopy image analysis. Although numerous border detection methods have been developed, few studies have focused on determining the optimal color channels for border detection in dermoscopy images. This paper proposes an automatic border detection method which determines the optimal color channels and performs hybrid thresholding to detect the lesion borders. The color optimization process is tested on a set of 30 dermoscopy images with four sets of dermatologist-drawn borders used as the ground truth. The hybrid border detection method is tested on a set of 85 dermoscopy images with two sets of ground truth using various metrics including accuracy, precision, sensitivity, specificity, and border error. The proposed method, which is comprised of two stages, is designed to increase specificity in the first stage and sensitivity in the second stage. It is shown to be highly competitive with three state-of-the-art border detection methods and potentially faster, since it mainly involves scalar processing as opposed to vector processing performed in the other methods. Furthermore, it is shown that our method is as good as, and in some cases more effective than a dermatology registrar.

Epidemiology of epidermolysis bullosa in the antipodes: the Australasian Epidermolysis Bullosa Registry with a focus on Herlitz junctional epidermolysis bullosa.

OBJECTIVE: To present epidemiologic and clinical data from the Australasian Epidermolysis Bullosa (EB) Registry, the first orphan disease registry in Australia. DESIGN: Observational study (cross-sectional and longitudinal). SETTING: Australian private dermatology practice, inpatient ward, and outpatient clinic. PATIENTS: Systematic case finding of patients with EB simplex, junctional EB (JEB), and dystrophic EB and data collection were performed throughout Australia and New Zealand from January 1, 2006, through December 31, 2008. Patients were consecutively enrolled in the study after clinical assessment and laboratory diagnosis. Medical records were retrospectively examined, and physicians involved in EB care were contacted to obtain patient history. A Herlitz JEB case series was prepared from registry data. MAIN OUTCOME MEASURES: Demographics and prognosis of patients with Herlitz JEB. RESULTS: A total of 259 patients were enrolled in the study: 139 with EBS, 91 with dystrophic EB, 28 with JEB, and 1 with Kindler syndrome. Most enrollees were Australian citizens (n = 243), with an Australian prevalence rate of 10.3 cases per million. The age range in the registry was birth to 99 years, with a mean and median age of 24.1 and 18.0 years, respectively. Ages were similar in patients with EBS and dominant dystrophic EB but were markedly lower in patients with JEB. Patients with Herlitz JEB (n = 10) had the highest morbidity and mortality rates, with a mean age at death of 6.8 months. Sepsis, failure to thrive, and tracheolaryngeal complications were the leading causes of death. CONCLUSIONS: The Australasian EB registry is the first registry in Australia and New Zealand to provide original data on age, sex, ethnicity, and geographical and disease subtype distribution. The Australasian Herlitz JEB cohort witnessed a high infant mortality rate and poor prognosis overall.

Spontaneous resolution of facial papular mucinosis in a transplant patient.

A 37-year-old male developed facial papules 6 months post renal-pancreatic transplant. Histological findings were consistent with localized papular mucinosis; electrophoresis showed no paraprotein. A trial of erbium and aura lasers, at ablative doses, produced no improvement. Independent treatments with oral doxycycline, itraconazole, acitretin, and isotretinoin also had no effect. The facial papules improved spontaneously, 2 years after first presentation and 8 months after treatment ceased. The patient remains clear of lesions.

A pilot study to determine the short-term effects of a low glycemic load diet on hormonal markers of acne: a nonrandomized, parallel, controlled feeding trial.

Observational evidence suggests that dietary glycemic load may be one environmental factor contributing to the variation in acne prevalence worldwide. To investigate the effect of a low glycemic load (LGL) diet on endocrine aspects of acne vulgaris, 12 male acne sufferers (17.0 +/- 0.4 years) completed a parallel, controlled feeding trial involving a 7-day admission to a housing facility. Subjects consumed either an LGL diet (n = 7; 25% energy from protein and 45% from carbohydrates) or a high glycemic load (HGL) diet (n = 5; 15% energy from protein, 55% energy from carbohydrate). Study outcomes included changes in the homeostasis model assessment of insulin resistance (HOMA-IR), sex hormone binding globulin (SHBG), free androgen index (FAI), insulin-like growth factor-I (IGF-I), and its binding proteins (IGFBP-I and IGFBP-3). Changes in HOMA-IR were significantly different between groups at day 7 (-0.57 for LGL vs. 0.14 for HGL, p = 0.03). SHBG levels decreased significantly from baseline in the HGL group (p = 0.03), while IGFBP-I and IGFBP-3 significantly increased (p = 0.03 and 0.03, respectively) in the LGL group. These results suggest that increases in dietary glycemic load may augment the biological activity of sex hormones and IGF-I, suggesting that these diets may aggravate potential factors involved in acne development.

IgE food sensitization in infants with eczema attending a dermatology department.

OBJECTIVES: Because community-based studies, which report IgE food sensitization (IgE-FS) in more than 80% of infants with moderate atopic eczema, may be influenced by referral bias, we assessed the prevalence of IgE-FS in a cohort of infants with moderate atopic eczema attending a dermatology department clinic. STUDY DESIGN: Consecutive infants (n = 51, 39 males; median age, 34 weeks; range, 20 to 51 weeks) with moderate atopic eczema referred to a university-affiliated dermatology department were studied prospectively. Clinical history and eczema severity were documented. IgE-FS was assessed by the skin prick test (SPT; n = 51) and food-specific serum IgE antibodies (CAP-FEIA test; n = 41). IgE-FS was diagnosed if the SPT or CAP-FEIA level exceeded the >95% predictive reference cutoff for positive food challenges. RESULTS: Based on SPT, 44 of 51 infants (86%; 95% confidence interval [CI] = 74% to 94%) had IgE-FS (cow's milk, 16%; egg, 73%; peanut, 51%). Using age-specific 95%-predictive cutoff values, CAP-FEIA identified 34 of 41 infants (83%; 95% CI = 68% to 93%) with IgE-FS (cow's milk, 23%; egg, 80%). Forty-six (90%) infants had IgE-FS to at least 1 food item by either SPT or CAP-FEIA. CONCLUSIONS: Atopic eczema was found to be closely associated with IgE-FS in infants attending a dermatology department.

The transcription factors c-rel and RelA control epidermal development and homeostasis in embryonic and adult skin via distinct mechanisms.

Determining the roles of Rel/NF-kappaB transcription factors in mouse skin development with loss-of-function mutants has been limited by redundancy among these proteins and by embryonic lethality associated with the absence of RelA. Using mice lacking RelA and c-rel, which survive throughout embryogenesis on a tumor necrosis factor alpha (TNF-alpha)-deficient background (rela(-/-) c-rel(-/-) tnfalpha(-/-)), we show that c-rel and RelA are required for normal epidermal development. Although mutant fetuses fail to form tylotrich hair and have a thinner epidermis, mutant keratinocyte progenitors undergo terminal differentiation to form an outer cornified layer. Mutant basal keratinocytes are abnormally small, exhibit a delay in G(1) progression, and fail to form keratinocyte colonies in culture. In contrast to the reduced proliferation of mutant keratinocytes during embryogenesis, skin grafting experiments revealed that the mutant epidermis develops a TNF-alpha-dependent hyperproliferative condition. Collectively, our findings indicate that RelA and c-rel control the development of the epidermis and associated appendages during embryogenesis and regulate epidermal homeostasis in a postnatal environment through the suppression of innate immune-mediated inflammation.

Topical diclofenac in hyaluronan gel for the treatment of solar keratoses.

This randomized, double-blind, placebo-controlled study assessed the efficacy and safety of a topical gel containing 3% diclofenac in 2.5% hyaluronan in 150 patients with solar keratoses (SK). The active treatment was compared with the vehicle only, hyaluronan gel, as placebo over a 12-week period. Patients in both groups applied the active treatment or placebo to a targeted area of skin (0.25 g b.d.). At 12 weeks the mean lesion-count reduction in the targeted area was not significantly different between treatments. However, at post-termination follow up (16 weeks), there was a highly significant decrease in the number of lesions, 6.2 +/- 7.5 standard deviations (SD) (56.1% reduction) in the active treatment group compared with 2.4 +/- 4.3 SD (23.6% reduction) in the placebo group (P < 0.001). Other efficacy measures (complete lesion resolution, >50% lesion reduction) were also significantly different (P < 0.01) between treatments at 16 weeks. In conclusion, topical 3% diclofenac in 2.5% hyaluronan gel was effective and well tolerated in this study, suggesting a role for this therapy in the treatment of SK.