Dermatology
Welcome to Sheffield Dermatology Research (SDR)
Innovative Dermatology research transforming patient’s lives.
Sheffield Dermatology Research (SDR) is focused on research to develop and bring-to-clinic, new treatments for atopic dermatitis - synonym: atopic eczema (AD). Our research spans from the prevention of AD to the development and testing (clinical trials) of innovative new medicines to treat atopic dermatitis.
SDR has a special interest in the prevention of atopic dermatitis. This involves both mechanistic studies and large collaborative clinical trials. We investigate how the environment of a baby interacts with their skin to induce the development of atopic dermatitis. A major focus is on how topical wash products, emollients, oils and water itself, affect the skin barrier and how this leads to the development of atopic dermatitis. This is helping to identify treatment approaches with the optimum effect on the development and maintenance of the skin barrier.
We specialise in treating children and adults with the most severe atopic dermatitis and see patients from anywhere in the UK. At Sheffield Children’s Hospital we have developed an integrated atopic dermatitis – allergy/immunology – psychiatry service, designed to manage the most complex patients. We lead clinical trials of new treatments for atopic dermatitis at the Clinical Research Facilities at Sheffield Children’s Hospital (SCH) for children and at Sheffield Teaching Hospitals (STH) Royal Hallamshire Hospital for adults. SDR is the lead site in the UK for many of the trials for new biologics, small molecules and topicals for atopic dermatitis.
SDR has created a dedicated clinical research facility for skin barrier and biomarker-driven research. The Skin Barrier Team has established a unique combination of techniques to assess how topical wash products, emollients and topical/systemic pharmaceutical agents affect the integrity of the skin barrier and inflammation in normal and AD skin. Biomarkers obtained using these techniques provide novel non-invasive tools for quantifying the effects of treatments on the skin. These atopic dermatitis biomarkers are being used in experimental medicine clinical trials to stratify patients according to clinical response and safety parameters. This information can be used to determine how long a treatment should be used for, the optimum dose, the effect on some comorbidities and inform health economic evaluations.
Coping with eczema: Looking at how to live with the skin condition, eczema.
Could a new drug treatment help those with the condition?
Courtesy of BBC North, Inside Out Yorkshire and Lincolnshire: Release date: 3 October 2017 (Duration: 10m 15s)
- Research interests
- Clinical trials
- Case study conference presentations
- Research group members
- The Skin Barrier Facility
Research interests:
- Gene-Environment Interactions In the Development of Atopic Dermatitis
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Atopic eczema/dermatitis (AD) is a multifactorial, heterogenous, disease that arises as a consequence of the interaction between genetic and environmental factors. Genetic variants found within several groups of genes have been associated with the development of a defective skin barrier including protease, protease inhibitor and structural genes. Loss-of-function mutations affecting the structural protein filaggrin in particular are a high risk factor for predisposing to AD. One common consequence expected of these ‘genetic factors’ is an increase in protease activity and decreased synthesis of lipid lamellae, leading to skin barrier breakdown.
The use of soap and other detergents enhances this by raising stratum corneum pH, resulting in the inhibition of lipid biosynthesis and the activation of degradatory proteases. Exogenous proteases from sources including Staphylococcus aureus and house dust mite also contribute to degradation of the barrier. The combination of these environmental factors with genetic factors appears to result in varying degrees of skin barrier breakdown, which is dependent on the ‘dosage’ of each. Ultimately the breakdown of the skin barrier can permit the penetration of allergens, with subsequent Th2 switching, the first step along the so-called atopic march. The interaction between genetic and environmental factors can therefore be considered the initial event in the development of AD. [Prof Michael Cork; Dr. Simon Danby]
- Development of Treatments for Atopic Dermatitis
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Atopic eczema/dermatitis (AD) is a chronic, inflammatory disease of the skin, which is characterized by xerosis, pruritus and erythematous lesions with increased trans-epidermal water loss (TEWL). The prevalence of AD is high, affecting 15-30% of children and 2 to 10% of adults. AD develops as a non-atopic condition associated with a skin barrier defect, and later, in about 60-80% of cases progresses to true atopic dermatitis. Furthermore AD is thought to be the first step along the atopic march leading to asthma and allergic rhinitis.
Combining experience from the treatment of AD in the clinic and basic laboratory research into the mechanisms of skin barrier disruption in AD we are actively involved in the development and formulation of new and existing treatments for AD. At the forefront of this research is our investigation of skin protease inhibitors as novel treatments for AD. Elevated protease activity in the SC is a key mechanism linking genetic and environmental factors in the breakdown of the epidermal barrier. [Prof Michael Cork; Dr. Simon Danby]
- The improvement of neonatal skincare
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When we are born our skin appears fully developed, however its function as a barrier to the potentially harmful external environment does not reach maturity for a number of months-years. The rate and level of maturation of the skin barrier is dependent on our genetics: genetic changes within the FLG gene for instance predispose to reduced skin barrier function. This means that the neonate is extremely vulnerable to irritants, allergens and potentially pathogenic bacteria. A combination of genetic changes and negative environmental challenges lead to the development of a defective skin barrier, and atopic dermatitis (AD), the first signs of which coincide with the period of skin barrier optimization. For some infants this is the first step along the Atopic March: the development of one or more of food allergy, allergic asthma, and allergic rhinitis. This has led to the idea that there is a window of opportunity in the first few months of an infants life to modify the environment the skin is exposed to in order to prevent the breakdown of the skin barrier, the development of AD and the atopic march. We are committed to improving neonatal skincare with a view to preventing the development of AD through evidence-based research. Together with our collaborators we have now been involved in several major clinical trials in neonates to assess early skincare practices. Currently we are a recruiting centre for the NIHR HTA-funded Barrier Enhancement Eczema Prevention (BEEP) trial led by Prof Hywel Williams (Nottingham Centre for Evidence Based Dermatology) and the Skin Testing for Atopic eczema Risk (STAR) study led by our team. [Prof Michael Cork; Dr. Simon Danby]
- Interaction of Topical Pharmaceutical and Cosmetic Agents with the Skin Barrier
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Atopic Dermatitis (AD) has historically been considered a disorder of immune dysfunction, however a growing body of evidence supports a primary role for the epidermal skin barrier. Genetic variants within genes encoding key epidermal barrier structural proteins are strongly associated with the development of AD. Furthermore environmental insults including the use of harsh surfactants and/or exogenous proteases from colonising bacteria and house dust mite for example interact with the existing skin barrier defect to exacerbate the condition. We believe that an understanding of gene-environment interactions in the development of AD can lead to the better use of some topical products, avoidance of others, and the future development of products that can repair the skin barrier.
Our aim is to investigate the interaction of topical pharmaceutical and cosmetic agents with the skin barrier. We study the effect of these agents, including emollients, anti-inflammatory treatments and massage oils for example, by designing and conducting comprehensive functional mechanistic studies. These studies, conducted at our Skin Barrier Research Facility, involve the use of a range of biophysical diagnostic tests and biochemical assays to determine the structure and function of the skin barrier in human volunteers. [Prof Michael Cork; Dr. Simon Danby]
- Genetics of Skin Diseases
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Our group has been involved in dissecting the genetics of some complex skin diseases such as psoriasis, atopic dermatitis, alopecia areata and vitiligo. For each disease, candidate genes within susceptibility loci are screened for single nucleotide polymorphisms (SNPs) and the distribution of each SNP is then compared between cases and controls.
We also use genome-wide association studies using SNPs to identify the major genetic variants contributing to the pathogenesis of the disease, which might lead to the identification of potentially novel targets for therapeutic intervention in the treatment of these diseases. [Prof Michael Cork; Dr. Rachid Tazi-Ahnini]
- The Vitamin A Metabolic Pathway and Hyper-Proliferative Disorders of the Skin
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Several diseases are characterised by cellular hyper-proliferation and an altered state of differentiation. These include cancer, psoriasis and cutaneous viral infections. Psoriasis is a common, genetically determined, inflammatory disease of the skin characterised by red scaly, raised areas of skin (plaques). The condition can arise at any age but appears most often between the ages of 15 and 40. Psoriasis affects about 2% of the world’s population, (ranging from 0.5% in Japan up to 2.5 % in Scandinavia) and causes enormous distress to those affected by it.
Treatment with retinoids has been found to be effective in controlling psoriasis (Mendonça and Burden, 2003), some cancers (Freemantle et al., 2003) and acne vulgaris (Webster 2002). Despite the beneficial effects of retinoid treatment; its use is limited by potentially serious adverse effects including hepatotoxicity, alopecia and teratogenicity (Kemmet & Hunter, 1988). These effects are related to the pharmacological dosages needed to achieve a therapeutic response.
We have shown that it is possible to mimic the desirable physiological effects of retinoids on hyper-proliferative cells (i.e. reduced proliferation and/or enhanced differentiation) without exposing these cells to pharmacological doses of retinoids. We can produce the same response by reducing the endogenous level of retinoic acid in hyper-proliferative cells. This is because retinoids exert their effects on cell growth and differentiation at both above and below physiological levels.
Investigation of this phenomenon has led to the identification of novel vitamin A pathway inhibitors for the treatment of hyper-proliferative disorders, including psoriasis and malignant melanoma. [Prof Michael Cork; Dr. Simon Ward; Dr. Simon Danby] - Alopecia Areata
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The research into alopecia areata and androgenetic alopecia is at the forefront internationally; the RHH Hair Clinic involves both clinical and academic research and is a resource for pathobiology and clinical trials. Academic work concentrates on autoantibodies and investigation into the role of environmental factors in bald pattern hair loss and scarring alopecia. [Prof. Andrew Messenger; Dr. Rachid Tazi-Ahnini; Dr. Andrew McDonagh]
The autoimmune regulator gene in the pathogenesis of alopecia areata
In addition to sporadic cases, alopecia areata (AA) occurs with very high frequency (>50%) in APS-1 patients. This is a rare disease characterised by hyperparathyroidism, Addison’s disease and chronic candidiasis, with a variety of autoimmune disorders present as secondary manifestations. The disease is caused by loss of function mutations in the autoimmune regulator (AIRE) gene that encodes a 57.7-kDa protein. AIRE is expressed in the thymus, particularly in thymic medullary epithelial cells (mTEC’s), and is required for the ectopic expression of a diverse range of peripheral tissue antigens (PTAs) by mTECs, conferring on them the ability to perform the negative selection of T cells. The role of the autoimmune regulator (AIRE) gene is fundamental to alopecia areata (AA) arising in the autoimmune polyendocrine syndrome type 1 (APS-1). We are using a cellular model of thymic cell gene expression to demonstration that autoantigens identified in AA cases unassociated with APS-1 are also regulated by the AIRE gene would strongly support the role of AIRE in the pathogenesis of AA. [Dr Rachid Tazi-Ahnini, Dr Andrew McDonagh, Dr Helen Kemp and Prof Anthony Weetman]
- Contact Dermatitis and Pigment Cell Research
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The contact dermatitis and pigment cell research also has an international reputation. The work is currently targeted at getting narrow band UVB operational and to develop research into T-cell mediated autoimmunity in pigment cell disease. [Prof. David Gawkroger]
Clinical trials:
- An Investigation of the Genetics and Skin Barrier Function in Atopic Eczema and Related Diseases
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Site Investigators: Michael J Cork
Status: Recruitment open
Reference: 04/MRE04/70 and STH13839
Contact Details: Les Hunter on +44 (0) 114 215 9576 or dermatologyresearch@sheffield.ac.uk - A longitudinal investigation of skin barrier development from birth and the validation of early predictors of atopic eczema risk: The Skin Testing for Atopic eczema Risk (STAR) study
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Site Investigators: Simon G Danby, John Chittock, Alison Cook, Tina Lavender, Michael J Cork
Status: Recruitment open
Reference: 16/NW/0848 and STH19479
Contact Details: The STAR study team on 07834392439 or starstudy@sheffield.ac.uk - A Randomized Controlled Trial of Gentle Touch/Early Massage with a New Wash and Lotion Regimen for Improved Skin Barrier Strength, Parental Bonding, and Physical Development in Newborn Babies: The Barrier Optimizing Skincare and Newborn Development (BOND) Trial
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Site Investigators: Michael J Cork, Simon G Danby, Shatha Shibib, Tina Lavender
Status: In set-up
Reference: STH19623
Contact Details: The BOND study team on 07834392439 or BOND@sheffield.ac.uk - A Comparison between Optical Coherence Tomography (OCT) determined basal cell carcinoma (BCC) margins against surgeon excision margins and histology – an observational pilot study
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Site Investigators: Anna-Victoria Giblin, Poonam Valand, Michael J Cork, Simon Danby, Stephen Matcher
Status: Recruitment open
Reference: STH19474
Contact Details: Poonam Valand, valandpoonam@gmail.com - Open-label Study of Dupilumab (REGN668/SAR231893) in Patients With Atopic Dermatitis
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Site Investigators: Michael J Cork
Status: Recruitment open
Reference: NCT01949311 - A Randomised Controlled Trial Assessing the Effectiveness, Safety and Cost-effectiveness of Methotrexate versus Ciclosporin in the Treatment of Severe Atopic Dermatitis in Children: The TREatment of Severe Atopic Dermatitis Trial (TREAT)
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Site Investigators: Michael J Cork, Ruth Murphy
Status: In set-up
Reference: ISRCTN15837754
Contact details: Heather Chisem/Stuart Gormley on +(0) 114 305 3136 or website http://www.treat-trial.org.uk/ - Barrier Enhancement for Eczema Prevention – BEEP
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Site Investigators: Michael J Cork
Status: Closed to recruitment - in follow-up
Reference: ISRCTN21528841
Contact details: Heather Chisem/Stuart Gormley on +44 (0) 114 305 3136 or website http://www.nottingham.ac.uk/research/groups/cebd/projects/1eczema/beep-maintrial.aspx - A Study to Determine the Safety and Tolerability of Dupilumab (REGN668/SAR231893) in Patients Aged ≥6 to <18 Years With Atopic Dermatitis (Eczema)
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Site Investigators: Michael J Cork and Ruth Murphy
Status: Closed - follow up complete
Reference: NCT02407756
Contact details: Heather Chisem/Stuart Gormley on +44 (0) 114 305 3136 - A Study to Assess the Long-term Safety of Dupilumab (REGN668/SAR231893) Administered in Patients 6 to <18 Year of Age With Atopic Dermatitis (AD)
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Site Investigators: Michael J Cork and Ruth Murphy
Status: Closed to recruitment - In follow up
Reference: NCT02612454
Contact details: Heather Chisem/Stuart Gormley on +44 (0) 114 305 3136 - Identification of Susceptibility Genes for Eczema & Food Allergy
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Site Investigators: Michael J Cork
Status: Closed - follow up complete
Reference: NIHR Portfolio Study ID: 10226
Contact details: Heather Chisem/Stuart Gormley on +44 (0) 114 305 3136 - A Study to Assess the Efficacy and Safety of Dupilumab in Patients With Severe Atopic Dermatitis (AD) That Are Not Controlled With Oral Cyclosporine A (CSA) or for Those Who Cannot Take Oral CSA Because it is Not Medically Advisable (CAFÉ)
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Site Investigators: Michael J Cork
Status: Recruitment closed
Reference: NCT02755649 - A Study to Confirm the Efficacy and Safety of Different Dupilumab Dose Regimens in Adults With Atopic Dermatitis (AD) (SOLO-Continue)
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Site Investigators: Michael J Cork
Status: Recruitment closed
Reference: NCT02395133 - Study of Dupilumab (REGN668/SAR231893) Monotherapy Administered to Adult Patients With Moderate-to-Severe Atopic Dermatitis (SOLO 2)
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Site Investigators: Michael J Cork
Status: Recruitment closed
Reference: NCT02277769
Case Study Conference Presentations
- Quantification of Natural Moisturising Factors at the skin surface using a portable Infrared spectrometer device: a pilot calibration model
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10th Georg Rajka International Symposium on Atopic Dermatitis 2018, Utrecht, Netherlands
Background: Attenuated Total Reflectance (ATR) Fourier Transform Infrared Spectroscopy (FTIR) is a useful technique for the molecular analysis of surfaces, including the skin, with promising translational clinical potential. Skin surface levels of Natural Moisturising Factors (NMF) are a biomarker of filaggrin (FLG) status (both inherited and acquired) and skin dryness. FLG-related Atopic Dermatitis (AD) is associated with more severe/persistent disease.
- Characterizing the microcirculation of atopic dermatitis using angiographic optical coherence tomography
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67th Annual meeting of the British Microcirculation Society 2017, Birmingham, UK
Background: The microcirculation within localised skin lesions often presents a unique morphology when compared to that of healthy skin. In the case of inflammatory conditions such as atopic dermatitis (AD), epidermal thickening is likely to influence both the depth and shape of the underlying vessels. Optical coherence tomography (OCT) provides a non-invasive view into the tissue, however structural measures of epidermal hyperplasia (thickening) are made challenging due to the lack of a delineated dermal-epidermal junction in AD patients. Instead, angiographic extensions to OCT may allow for direct measurement of vascular depth, potentially presenting a more robust method of estimating the degree of subclinical inflammation.
- Innovating imaging techniques to understand Atopic Dermatitis skin
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9th Georg Rajka International Symposium on AD 2016, Sao Paulo, Brazil
Background: Atopic dermatitis (AD) is a chronic relapsing condition that is commonly observed in primary care. The characteristics of such a condition is itching and redness of the skin, associated with breakdown of the skin barrier. Efforts to estimate the prevalence of AD are complicated due to the presence of few studies in the literature. Optical coherence tomography (OCT) provides a fast and non-invasive method of studying the skin barrier and the effects of treatments on it.
POSTER - Innovating imaging techniques to understand Atopic Dermatitis skin (pdf 467kb)
ABSTRACT - Innovating imaging techniques to understand Atopic Dermatitis skin (.doc 14kb)
- An investigation of protease activity at non-lesional sites in atopic dermatitis
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British Society for Investigative Dermatology annual meeting 2017, Manchester, UK
Background: Sustained protease hyperactivity within the stratum corneum (SC) is a feature of chronic skin disorders such as Atopic Dermatitis (AD). Animal models have provided a rich source of mechanistic evidence for protease-associated barrier breakdown in AD and related skin diseases, but to date, there is the requirement for further clinical studies in patients. To address this we have developed a simple, non-invasive assay allowing the quantification of a broad-spectrum of proteases at the skin surface. Using this assay we recently identified a subset of neonates at risk of developing AD, with desquamatory protease hyperactivity in normal appearing skin at birth. Here, to extend these findings, a cohort study was designed to investigate protease activity in non-lesional adult skin.
POSTER - An investigation of protease activity at nonlesional sites in Atopic Dermatitis (pdf 639kb)
- Abnormal corneodesmosome distribution in atopic dermatitis and soap-induced xerosis
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15th Skin Forum annual meeting 2016, London, UK
Background: In the stratum corneum (SC), inter-corneocyte cohesion is provided by corneodesmosomes. In healthy skin, corneodesmosomes are distributed uniformly across the corneocyte surface in the basal SC layers, becoming degraded as the corneocyte matures, leaving only peripheral corneodesmosomes at the SC surface. This gradual loss of corneocyte cohesion is regulated by numerous SC proteases to facilitate desquamation. In atopic dermatitis and soap-induced xerosis, there is abnormal corneodesmosome degradation.
- Characterisation of the skin barrier defect in atopic dermatitis using in vivo ATR-FTIR molecular spectroscopy
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9th Georg Rajka International Symposium on AD 2016, Sao Paulo, Brazil.
Background: Attenuated total reflectance (ATR)-Fourier transform infrared (FTIR) spectroscopy is a molecular spectroscopic technique that can be used to investigate the surface properties of human skin in vivo.
- The neonatal epidermal barrier: development of superficial chymotrypsin-like protease activity and natural moisturising factors
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9th Georg Rajka International Symposium on AD 2016, Sao Paulo, Brazil.
Background: The infant stratum corneum (SC) is thinner, and immature in both structure and function compared to adults throughout the first year of life. This vulnerable period coincides with the onset (<1 year of age) of skin manifestations such as atopic dermatitis. From birth, the SC enters a maturation phase of rapid hydration and acid mantle formation. Considering the reported homeostatic action of these functional properties, the observations suggest underdeveloped or transitional mechanisms underlying neonatal epidermal barrier differentiation and desquamation.
- The effect of a humectant emollient cream containing 5% urea compared to a non-humectant emollient on the skin barrier in older people with dry skin
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23rd World Congress of Dermatology 2015, Vancouver, Canada
Background: Xerosis affects between 30 and 75% of older people. The development of xerotic skin conditions, such as atopic dermatitis, asteatotic eczema and winter xerosis, is associated with a skin barrier defect. This defect is characterised by reduced levels of natural moisturising factor (a collection of natural humectants including urea, pyrrolidone carboxylic acid [PCA], and lactate), abnormal intercellular lipid levels in the stratum corneum (SC), and elevated skin surface pH (linked to increased skin barrier breakdown). Emollients are widely used to treat xerosis, however there is limited mechanistic evidence of their effects on the skin barrier.
- Comparing the effect of tacrolimus (0.1%) ointment and betamethasone (0.1%) valerate on the epidermal barrier: a twice-weekly maintenance dose
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23rd World Congress of Dermatology 2015, Vancouver, Canada
Background: The proactive use of topical anti-inflammatories is an effective method of addressing the subclinical inflammation associated with the remission phase of atopic dermatitis (AD). To date, the interaction of this treatment dose with the subclinical epidermal barrier defect in AD is yet to be determined.
Research group members:
Staff:
- Professor Michael J Cork
- Dr. Simon G Danby
- Dr. Robert A. Byers
- Mr Paul V Andrew
- Mrs Kirsty Brown
- Mr John Chittock
- Dr. Linda Kay
- Dr. Abigail Pinnock
- Dr. Rachid Tazi-Ahnini
- Mr Les Hunter
Associates/Honorary:
- Professor Stephen J Matcher
- Dr. Shatha Shibib
PhD students:
- Dr. Oludolapo S Katibi
- Mr Sam Williams