British Journal of Dermatology最新文献

Background: The main conventional systemic treatments for atopic dermatitis (AD) are methotrexate (MTX) and ciclosporin (CyA). Dupilumab was the first novel systemic agent to enter routine clinical practice. There are no head-to-head randomized controlled trials or real-world studies comparing these agents directly. Network meta-analyses provide indirect comparative efficacy and safety data and have shown strong evidence for dupilumab and CyA.

Objectives: To compare the real-world clinical effectiveness and safety of CyA, dupilumab and MTX in AD.

Methods: We compared the effectiveness and safety of these systemic agents in a prospective observational cohort study of adult and paediatric patients recruited into the UK-Irish Atopic eczema Systemic TherApy Register (A-STAR). Treatment effectiveness measures included Eczema Area and Severity Index (EASI), Patient-Oriented Eczema Measure (POEM), Peak Pruritus Numerical Rating Scale (PP-NRS), Dermatology Life Quality Index (DLQI) and children's DLQI (cDLQI). The minimum duration of treatment was 28 days and follow-up was 12 months. Adjusted Cox-regression analysis was used to compare the hazard ratios of achieving EASI-50, EASI-75 and EASI-90 over time, and linear mixed-effects models were used to estimate changes in efficacy scores. Treatment safety was assessed by examining adverse events (AEs) at follow-up visits.

Results: We included 488 patients (311 adults and 177 children/adolescents) on dupilumab (n = 282), MTX (n = 149) or CyA (n = 57). CyA and MTX were primarily used as the first-line treatment, while dupilumab was mainly a second-line systemic treatment as per UK National Institute of Clinical and Care Excellence (NICE) recommendations. EASI-50, EASI-75 and EASI-90 were achieved more rapidly in the dupilumab and CyA groups compared with MTX. After adjustment for previous severity, the reduction in EASI, POEM, PP-NRS and DLQI was greater for patients treated with dupilumab compared with MTX. In patients with severe disease the reduction in EASI, POEM and PP-NRS was even greater with CyA. The incidence rates of AEs were similar across groups (734, 654 and 594 per 10 000 person-month on CyA, dupilumab and MTX, respectively).

Conclusions: This real-world comparison of CyA, dupilumab and MTX in AD suggests that dupilumab is consistently more effective than MTX and that CyA is most effective in very severe disease within 1 year of follow-up.

Background: Research suggests that a high proportion of melanoma in situ (MIS) may be overdiagnosed, potentially contributing to overtreatment, patient harm and inflated costs for individuals and healthcare systems. However, Australia-wide estimates of the magnitude of melanoma overdiagnosis are potentially outdated and there has been no estimation of the cost to the healthcare system.

Objectives: To estimate the magnitude and cost of overdiagnosed MIS and thin invasive melanomas in Australia.

Methods: Using two different methods to calculate lifetime risk, we used routinely collected national-level data to estimate overdiagnosed MIS and thin invasive melanomas (stage IA) in Australia in 2017 and 2021, separately for men and women. We multiplied the number of overdiagnosed melanomas by the estimated annual cost of a MIS or thin invasive melanoma, to quantify the financial burden of melanoma overdiagnosis to the Australian healthcare system in the year following diagnosis.

Results: We estimated that 67-70% of MIS were overdiagnosed in 2017, rising to 71-76% in 2021, contributing to between 19 829 [95% confidence interval (CI) 19 553-20 105] and 20 811 (95% CI 20 528-21 094) cases of overdiagnosed MIS. In 2021, the estimated costs in Australia ranged between $17.7 million Australian dollars (AUD; 95% CI 17.4-17.9 million) and AUD$18.6 million (95% CI 18.3-18.8 million). We estimated that 22-29% of thin invasive melanomas were overdiagnosed in 2017, rising to 28-34% in 2021, contributing to between 2831 (95% CI 2726-2935) and 3168 (95% CI 3058-3279) overdiagnosed thin invasive melanomas. In 2021, the estimated costs from thin invasive melanoma overdiagnoses ranged between AUD$2.5 million (95% CI 2.4-2.6 million) and AUD$2.8 million (95% CI 2.7-2.9 million).

Conclusions: Melanoma overdiagnosis is a growing clinical and public health problem in Australia, producing significant economic costs in the year following overdiagnosis. Limiting melanoma overdiagnosis may prevent unnecessary healthcare resource use and improve financial sustainability within the Australian healthcare system.

Background: The structured expression of several keratins in the skin is associated with differentiation status of the epidermal layers, whereas other keratins are upregulated only during wound healing, in skin disorders and in cancers. One of these stress keratins, K17, is correlated with poor prognosis in various cancer types and its loss has been shown to decelerate tumour growth. K17 expression can also be detected in cutaneous squamous cell carcinomas, where ultraviolet irradiation and infection with cutaneous human papillomaviruses are important cofactors. It was previously reported that K17 is upregulated in papillomavirus (PV)-induced benign skin lesions in mice and induces an immunological status that is beneficial for tumour growth.

Objectives: In order to investigate whether K17 upregulation is induced by PVs, we analysed K17 levels in skin tumour specimens of different animal models and humans.

Methods: Various immunofluorescence stainings were performed to identify K17 expression as well as levels of E-cadherin, vimentin and CD271. Tissues were further analysed by polymerase chain reaction (PCR), quantitative (q)PCR and enzyme-linked immunosorbent assay to control for PV activity. K17 knockdown cells were generated and effects on viral life cycle were investigated by infection assays, qPCR and Western blotting.

Results: We showed that K17 is commonly expressed in skin tumours and that its presence is not directly linked to viral oncoprotein expression. Rather, K17 expression seems to be a marker of epithelial differentiation and its absence in tumour tissue is associated with an epithelial-to-mesenchymal transition. We further demonstrated that the absence of K17 in skin tumours increases markers of cancer stem-like cells and negatively affects viral protein synthesis.

Conclusions: Collectively, our data indicate that K17 expression is a common feature in skin tumorigenesis. While K17 is not primarily targeted by PV oncoproteins, our in vivo and in vitro data suggest that it is an important regulator of epithelial differentiation and thus may play a role in controlling viral protein synthesis.

Background: Cutaneous melanoma incidence varies consistently across body sites between men and women, but the underlying causes of these differences remain unclear. To date, no prospective studies have examined risk factors for melanoma separately for men and women according to body site.

Objectives: We aimed to examine the association between identified constitutional, genetic and environmental risk factors for invasive melanoma of different body sites among men and women.

Methods: We compared the association between constitutional, genetic and environmental risk factors for invasive melanoma on different body sites separately for men and women in a population-based prospective cohort study of 17 774 men and 21 070 women aged between 40 and 69 years who were residents of Queensland, Australia at baseline in 2011. Participants were followed until December 2021. We examined risk factors including hair colour, tanning ability, naevus density and proxies for high cumulative sun exposure, all self-reported at baseline. We also examined polygenic risk score (PRS) derived from summary statistics from a melanoma genome-wide association study meta-analysis.

Results: During a median 10.4 years of follow-up, 455 men and 331 women developed an incident invasive melanoma; the mean age at diagnosis was lower in women than in men (62.6 vs. 65.0 years). The most common body site was the trunk in men (45.1%), and the upper (36.8%) and lower limbs (27.4%) in women. High naevus density and proxy measures of high cumulative sun exposure were similarly associated with melanoma at all sites in men and women. In both sexes, high genetic risk was associated with melanoma on all body sites except the head and neck. We observed differences between men and women in the association between PRS and melanoma of the trunk [highest vs. lowest tertile of PRS: hazard ratio (HR) 2.78, 95% confidence interval (CI) 1.64-4.69 for men; HR 1.55, 95% CI 0.63-3.80 for women] and nonsignificant but large differences for the lower limbs (HR 5.25, 95% CI 1.80-15.27 for men; HR 1.75, 95% CI 0.88-3.47 for women).

Conclusions: While there are a number of potential explanations for these findings, this raises the possibility that genetic factors other than those related to pigmentation and naevus phenotypes may play a role in the predilection for melanoma to arise on different sites in men and women.