Michael J. Cork

A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1

To identify new susceptibility loci for psoriasis, we undertook a genome-wide association study of 594,224 SNPs in 2,622 individuals with psoriasis and 5,667 controls. We identified associations at eight previously unreported genomic loci. Seven loci harbored genes with recognized immune functions (IL28RA, REL, IFIH1, ERAP1, TRAF3IP2, NFKBIA and TYK2). These associations were replicated in 9,079 European samples (six loci with a combined P < 5 × 10−8 and two loci with a combined P < 5 × 10−7). We also report compelling evidence for an interaction between the HLA-C and ERAP1 loci (combined P = 6.95 × 10−6). ERAP1 plays an important role in MHC class I peptide processing. ERAP1 variants only influenced psoriasis susceptibility in individuals carrying the HLA-C risk allele. Our findings implicate pathways that integrate epidermal barrier dysfunction with innate and adaptive immune dysregulation in psoriasis pathogenesis.

Epidermal barrier dysfunction in atopic dermatitis.

Atopic dermatitis (AD) is a multifactorial, heterogenous disease that arises as a result of the interaction between both environmental and genetic factors. Changes in at least three groups of genes encoding structural proteins, epidermal proteases, and protease inhibitors predispose to a defective epidermal barrier and increase the risk of developing AD. Loss-of-function mutations found within the FLG gene encoding the structural protein, filaggrin, represent the most significant genetic factor predisposing to AD identified to date. Enhanced protease activity and decreased synthesis of the lipid lamellae lead to exacerbated breakdown of the epidermal barrier. Environmental factors, including the use of soap and detergents, exacerbate epidermal barrier breakdown, attributed to the elevation of stratum corneum pH. A sustained increase in pH enhances the activity of degradatory proteases and decreases the activity of the lipid synthesis enzymes. The strong association between both genetic barrier defects and environmental insults to the barrier with AD suggests that epidermal barrier dysfunction is a primary event in the development of this disease. Our understanding of gene-environment interactions should lead to a better use of some topical products, avoidance of others, and the increased use and development of products that can repair the skin barrier.

Emollient enhancement of the skin barrier from birth offers effective atopic dermatitis prevention

Background Atopic dermatitis (atopic eczema) is a chronic inflammatory skin disease that has reached epidemic proportions in children worldwide and is increasing in prevalence. Because of the significant socioeconomic effect of atopic dermatitis and its effect on the quality of life of children and families, there have been decades of research focused on disease prevention, with limited success. Recent advances in cutaneous biology suggest skin barrier defects might be key initiators of atopic dermatitis and possibly allergic sensitization. Objective Our objective was to test whether skin barrier enhancement from birth represents a feasible strategy for reducing the incidence of atopic dermatitis in high-risk neonates. Methods We performed a randomized controlled trial in the United States and United Kingdom of 124 neonates at high risk for atopic dermatitis. Parents in the intervention arm were instructed to apply full-body emollient therapy at least once per day starting within 3 weeks of birth. Parents in the control arm were asked to use no emollients. The primary feasibility outcome was the percentage of families willing to be randomized. The primary clinical outcome was the cumulative incidence of atopic dermatitis at 6 months, as assessed by a trained investigator. Results Forty-two percent of eligible families agreed to be randomized into the trial. All participating families in the intervention arm found the intervention acceptable. A statistically significant protective effect was found with the use of daily emollient on the cumulative incidence of atopic dermatitis with a relative risk reduction of 50% (relative risk, 0.50; 95% CI, 0.28-0.9; P = .017). There were no emollient-related adverse events and no differences in adverse events between groups. Conclusion The results of this trial demonstrate that emollient therapy from birth represents a feasible, safe, and effective approach for atopic dermatitis prevention. If confirmed in larger trials, emollient therapy from birth would be a simple and low-cost intervention that could reduce the global burden of allergic diseases.

Comparison of parent knowledge, therapy utilization and severity of atopic eczema before and after explanation and demonstration of topical therapies by a specialist dermatology nurse.

Background  The failure of patients to take medicines in a way that leads to clinical benefit is a major challenge. A consensus has emerged that, on average, compliance sufficient to obtain therapeutic objectives occurs about half the time, with noncompliance contributing to therapeutic failure in the other half. These figures refer to simple oral regimens. There has been little work assessing compliance/concordance with complex treatment regimens for atopic eczema. Asthma schools led by specialist nurses have been shown to improve knowledge, use of therapies and clinical outcome.

Cyclosporin for severe childhood atopic dermatitis: short course versus continuous therapy.

Cyclosporin (CyA) has been shown to be highly effective and well tolerated in the short‐term treatment of severe childhood atopic dermatitis; however, there is limited experience in its longer‐term use. The aim of this study was to compare multiple short courses of CyA with continuous therapy for 1 year, with respect to efficacy, safety, tolerability and quality of life. Children aged 2–16 years, with a diagnosis of severe atopic dermatitis refractory to topical steroid therapy, were randomly assigned to receive short course therapy (multiple courses of 12 weeks) or continuous therapy. The starting dose and maximum dose for all patients was 5 mg/kg per day. Disease activity was monitored using the Six Area Six Sign Atopic Dermatitis score and the ‘Rule of Nines’ area score. Pruritus, sleep disturbance and irritability were measured using visual analogue scales, and topical therapy was monitored. Safety measurements included monitoring of serum creatinine, blood pressure and adverse events. Forty patients were included in the efficacy analysis, 21 of whom were randomized to the short course group (of whom six were withdrawn) and 19 to the continuous group (of whom five were withdrawn). Significant improvements were seen in all efficacy parameters at every time‐point. There were no significant differences between groups, although the improvement was more consistent in the continuous arm. In the short course arm, 7 out of 21 patients could be managed by at least two short courses. The remaining 14 patients includes 12 who could not be controlled by at least two short courses, one patient who failed to return after week 12 and another patient who was withdrawn at week 4 due to an adverse event. Quality of life improved for both the children and their families. Tolerability was considered good or very good in at least 80% of the patients at week 12 and at the end of the study. No clinically significant change was seen in mean serum creatinine and no change was seen in mean blood pressure in either group. CyA is effective in controlling severe atopic dermatitis in children over a 1‐year period and is well tolerated. More consistent control is achieved with continuous treatment; however, short course therapy was adequate for some patients, indicating that treatment should be tailored to the individual patient’s needs. Short course treatment may produce prolonged remission in some cases and reduce the cumulative exposure to the drug.

Cyclosporine in severe childhood atopic dermatitis: A multicenter study

BACKGROUND Severe atopic dermatitis (AD) remains difficult to treat. Cyclosporine is effective in adults but has not previously been investigated in children with AD. OBJECTIVE The aims were to investigate the efficacy, safety, and tolerability of cyclosporine in severe refractory childhood AD. METHODS Subjects 2 to 16 years of age were treated for 6 weeks with cyclosporine, 5 mg/kg per day, in an open study. Disease activity was monitored every 2 weeks by means of sign scores, visual analogue scales for symptoms, and quality-of-life questionnaires. Adverse events were monitored. Efficacy and tolerability were assessed with five-point scales. RESULTS Twenty-seven children were treated. Significant improvements were seen in all measures of disease activity. Twenty-two showed marked improvement or total clearing. Quality of life improved for both the children and their families. Tolerability was considered good or very good in 25 subjects. CONCLUSION Cyclosporine may offer an effective, safe, and well-tolerated short-term treatment option for children with severe AD.

Interleukin 1 receptor antagonist gene polymorphism association with lichen sclerosus

Cytokines play key roles in immune responses, inflammation and fibrosis. The balance between levels of cytokines, their receptors and specific inhibitors controls inflammatory reactions in tissues. The pathogenesis of lichen sclerosus is unknown but probably involves cytokine mediators such as interleukin 1 (IL-1) and interleukin 1 receptor antagonist (IL-1ra). The IL-1ra is a competitive inhibitor of IL-1α and IL-1β, and therefore is a powerful endogenous anti-inflammatory molecule. The gene encoding IL-1ra (designated IL-1RN) has a variable number tandem repeat polymorphism in intron 2. There are five alleles of the gene corresponding to 2, 3, 4, 5 and 6 repeats of an 86-bp sequence. We have determined allele frequencies in a control population and a group of 78 patients with lichen sclerosus. The frequency of one of the alleles is related to increasing disease severity. Thus, IL-1RN may be a candidate gene or severity factor for lichen sclerosus or may possibly be a linked marker to another, as yet undefined, gene.

Topical preparations for the treatment of psoriasis: a systematic review

Summary Background There is clinical uncertainty about the appropriate use of first‐line topical treatments for psoriasis.

Novel interleukin-1 receptor antagonist exon polymorphisms and their use in allele-specific mRNA assessment

A variable number of tandem repeats (VNTR) polymorphism has been described in intron 2 of the interleukin-1 receptor antagonist gene. Allele 2 of this polymorphism is associated with many chronic inflammatory diseases. Using direct sequencing of polymerase chain reaction products from individuals of known genotype for the VNTR, we have identified four single base change polymorphisms in exons 1c and 2 and one upstream of exon 1ic all of which are probably in linkage disequilibium with the intron 2 VNTR. The exonic polymorphisms do not alter the encoded amino acid sequence. Using the exon 2 polymorphism as a marker for the intron 2 disease-associated allele, we have been able to analyse allele-specific mRNA in heterozygotic keratinocyte cell lines. The disease-associated allele shows no difference from other alleles in this cell type with respect to mRNA accumulation.

Safety and Tolerability of 1% Pimecrolimus Cream Among Infants: Experience With 1133 Patients Treated for Up to 2 Years

Pimecrolimus is a calcineurin inhibitor developed for the topical treatment of atopic dermatitis. During the clinical development of 1% pimecrolimus cream, 1133 patients 3 to 23 months of age with mild to severe atopic dermatitis were treated for up to 2 years. The objective of this review is to discuss the safety and tolerability of 1% pimecrolimus cream among infants, on the basis of the combined results from all studies (4 pharmacokinetic studies and 6 clinical trials) conducted among these patients. Pimecrolimus blood concentrations measured for 35 patients were consistently low (≤1 ng/mL in >80% of samples), irrespective of the disease severity and extent, and remained low during intermittent treatment for up to 1 year. The level of systemic exposure to pimecrolimus among infants was comparable to that observed for older pediatric patients enrolled in the same studies and treated in the same way with 1% pimecrolimus cream, which indicated that young pediatric patients are not at higher risk of significant percutaneous absorption of topically applied pimecrolimus, despite their large skin surface area/body mass ratio. The 6 clinical trials included a total of 1098 infants, who were treated for periods ranging from 4 weeks to 2 years. Most of these patients (60%) had moderate to severe disease at baseline. The most frequently reported adverse events were common childhood disorders such as nasopharyngitis, pyrexia, upper respiratory tract infections, ear infections, and bronchitis. During the double-blind (DB) studies or DB phases of studies, the incidence rates for the most frequently reported adverse events were similar for patients who received 1% pimecrolimus cream and patients who received the vehicle, except for the incidence of teething, which was higher among the pimecrolimus-treated infants (relative risk: 2.02; 95% confidence interval: 1.32–3.27). Treatment with 1% pimecrolimus cream was not associated with an increase in the overall incidence of nonskin infections, compared with the vehicle (relative risk: 1.015; 95% confidence interval: 0.88–1.18). The incidence density (ID) rates for total bacterial, fungal, parasitic, and viral skin infections during the DB studies or DB phases of studies were comparable for patients treated with 1% pimecrolimus cream and patients who received the vehicle. The ID rate of herpes simplex virus infections was 0.8 cases per 1000 patient-months of follow-up monitoring among patients treated with 1% pimecrolimus cream and 1.7 cases per 1000 patient-months of follow-up monitoring among patients who received the vehicle. Considering all 1098 infants treated with 1% pimecrolimus cream in DB trials and open-label studies, the ID rate of clinically diagnosed eczema herpeticum was 1.3 cases per 1000 patient-months of follow-up monitoring. Burning and erythema were the most frequently reported application site reactions, with ID rates of 2.0 and 1.2 cases per 1000 patient-months of follow-up monitoring, respectively. No sign of immunosuppression was found among infants treated intermittently with 1% pimecrolimus cream for up to 2 years; they demonstrated normal immune responses to vaccinations and did not show increases in the incidence of systemic infections or skin infections over time.