Mind and Skin - the Neurocutaneous Axis in Atopic Eczema

Study Overview
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Brief Summary
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'Mind and Skin': A prospective cohort study evaluating the impact of inflammation, itch and sleep disturbance on the brain, mental health and cognition, in patients with severe atopy.

Detailed Description
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Atopic eczema is an intensely itchy skin disease which often starts in infancy or early childhood. It can have profound effects on patients' quality of life and cause long-lasting psychological impairment. Sleep may be very disturbed. More severe disease often requires oral/injectable immuno-modulatory treatments (i.e. medications which control symptoms by influencing the immune system). There is an association between eczema, impaired cognitive functioning and mental health disorders, but the underlying mechanisms are not clearly defined. This projects examines the links between inflammation-driven itching and disturbed sleep, and how this might be causally responsible for systemic and brain inflammation, disturbance of cognitive functioning and mental health problems. The investigators will also study potential changes occurring following an improvement in eczema when patients are treated with systemic immuno-modulators. Key investigations will include: i) Home-based sleep studies using a commercially available sleep devices (for example DREEM headband, Philips Actiwatch, oximetry) ii) Structural and functional magnetic resonance imaging (MRI) of the brain, iii) Blood tests to quantify systemic inflammation iv) Genetic analyses, particularly related to the immune system, circadian rhythm (the internal 24-hour clock), skin barrier function and the risk of developing eczema or associated diseases, v) Assessments of the skin's barrier function vi) Stool samples and skin swabs to study the gut and skin microbiome. The investigators will utilise existing anonymised data for comparative purposes (e.g. from patients with Attention Deficit Hyperactivity Disorder (ADHD) and healthy controls who previously had brain imaging.) The investigators will explore eczema patients' and families' perception of their disease, in particular itch and the resulting sleep loss, through focus groups, to better understand the sociological impact of eczema, and how these patients' interactions with the external world and society are affected by eczema. Importantly, this will include exploration of family dynamics, as patients with eczema often have profound sleep disturbance from early life, which can impact on their caregivers' sleep and quality of life.

Official Title
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'Mind and Skin': A Prospective Cohort Study Evaluating the Impact of Inflammation, Itch and Sleep Disturbance on the Brain, Mental Health and Cognition, in Patients With Severe Atopy

Conditions
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Atopic Dermatitis

Intervention / Treatment
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* Drug: Methotrexate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients aged 5 years or above with atopic eczema (groups 1 and 2), which has been diagnosed by a Consultant Dermatologist. Patients with atopic eczema warranting systemic immuno-modulatory therapy or patients with atopic eczema on topical therapy or healthy controls. Written informed consent for study participation obtained from the patient or from the parent(s) / legal guardian, with assent as determined by the patient's age and level of understanding. Willingness to comply with all study requirements. Competent use of English language, according to patient's age (patients will be required to understand the written questionnaires and complying with instructions during MRI scanning). Exclusion Criteria: Insufficient understanding of the study by the patient and/or parent/guardian. Any clear contra-indication to MRI scanning. In particular this would be due to the presence of any implanted devices or metal from previous surgery or accident. This would be fully assessed with a standardised safety questionnaire by a radiographer prior to MRI scanning. Any condition deemed by the Investigator to limit a patient's ability to undertake MRI components of the study, for example significant claustrophobia. Diagnosed by a sleep medicine specialist with a formal sleep disorder, requiring systemic medication. Sleep disturbance from co-morbid illness (including physical and/or mental/psychological illness) other than atopic eczema, deemed by the Investigator to significantly impact on sleep components of the study. Previous and/or current substance misuse. Patients who take medications that would, in the investigator's opinion, impact on quality of sleep studies.

Ages Eligible for Study
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Minimum Age: 5 Years
Maximum Age: 18 Years

Sexes Eligible for Study
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All

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Severe eczema<br>Patients aged 5-18 who have been diagnosed with atopic eczema and require starting systemic therapy. | Drug: Methotrexate<br>* As per usual standard of care<br>|
| Less severe eczema<br>Patients aged 5-18 who have been diagnosed with atopic eczema and require topical steroid therapy only. | |
| Healthy controls<br>Patients ages 5-18 who do not have atopic eczema. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Eczema Area and Severity Index (EASI) Score | Clinical assessment of atopic dermatitis disease activity. Range 0-72 (72 being the most severe outcome) | 6 months | 
| Peak Pruritus Numerical Rating Score | Patient reported itch severity. Range 0-10 (10 being the worst outcome) | 6 months | 
| Transepidermal water loss (TEWL) | Skin barrier function measurement using a device which measures the amount of water that passively evaporates through skin to the external environment due to water vapor pressure gradient on both sides of the skin barrier | 6 months | 
| Skin surface pH | Skin barrier function measurement using a pH measuring device. | 6 months | 
| Metabolome swab | Skin metabalome analysis using a skin swab | 6 months | 
| Skin ELISA (enzyme-linked immunosorbent assay) and serum ELISA | Immunoassay detection and quantification | 6 months | 
| RNA sequencing of blood serum | To detect transcript isoforms, gene fusions and single nucleotide variants. | 6 months | 
| Pediatric Sleep Questionnaire | Sleep questionnaire. Score 18-126 (126 being the worst clinical outcome) | 6 months | 
| Morningness-Eveningness Questionnaire | Sleep questionnaire. Score 16-86 assesses individual differences in morningness and eveningness - the degree to which respondents are active and alert at certain times of day. | 6 months | 
| Patient-Reported Outcomes Measurement Information System (PROMIS) | Sleep questionnaire. Score 0-20 (0 being the worst clinical outcome) | 6 months | 
| Pittsburgh Sleep Quality Index | Sleep questionnaires. Score 0-21 (21 being the worst clinical outcome) | 6 months | 
| Dreem headband electroencephalogram monitoring | Sleep study - Measures brain activity to assess sleep cycles | 6 months | 
| Polysomnography | Sleep study incorporating electroencephalogram, electro-oculogram, electromyogram, electrocardiogram, and pulse oximetry, as well as airflow and respiratory effort, to evaluate for underlying causes of sleep disturbances. | 6 months | 
| Actigraphy Watch analysis | Watch is worn by participant which records movement during sleep to analyse sleep pattern | 6 months | 
| EMFIT mattress analysis | Mattress sensor which records movement during sleep to analyse sleep pattern to analyse sleep pattern | 6 months | 
| Wechsler Abbreviated Scale of Intelligence Second Edition (WASI-II) Score | Intelligence Quotient Test. Score 40-160 (40 being the worst clinical outcome) | 6 months | 
| Go/No-GO Task | The Go/No-go task requires participants to respond by pressing a button when they see a go signal, and not respond when they see the no-go signal. The key behaviour measured with this experiment is the participants' ability to withhold a response on No-go trials. This is scored as a fraction of correct responses. | 6 months | 
| Simon Task | In this task participants are asked to respond to visual stimuli by making a rightward response to one stimulus (e.g. a circle) and a leftward response to another (e.g. a square). This is scored as a fraction of correct responses. | 6 months | 
| Continuous Performance Task | In this task participants are asked to only respond to a specific sequence of visual stimuli. This is scored as a fraction of correct responses. | 6 months | 
| Time Discrimination Task | In this task participants are ask to decide which stimuli stayed on screen for the longest duration. This is scored as a fraction of correct responses. | 6 months | 
| Vigilance Task (Mackworth Clock) | In this task participants are asked to watched a clock hand that moves every second around the clock. From time to time the hand skips a second and participants need to respond to this. This is scored as a fraction of correct responses. | 6 months | 
| Performance on Working Memory Task | Completed in functional MRI | 6 months | 
| Performance on Sustained Attention Task | Completed in functional MRI | 6 months | 
| Resting Brain State | Measured in functional MRI | 6 months | 
| Structural Changes in the Brain | Structure of the brain is measured in MRI | 6 months |