Pilot Study on Cellular and Molecular Impact of Neuroimmune Interactions in Atopic Dermatitis
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- 入组人数
- 8
- 试验地点
- 4
- 主要终点
- Percentage change in EASI scores at Day 28 as compared to baseline.
研究概览
简要总结
The purpose of this study is to understand cellular and molecular interactions in the skin of participants with mild-to-moderate AD, and how botulinum toxin alters these interactions.
详细描述
Atopic dermatitis is a debilitating chronic inflammatory disease with substantial health and economic impact, affecting 10-20% of the U.S. population with an estimated annual direct health care cost of $13 billion. There is much to still discover regarding the dysfunctional skin barrier underlying AD and its effects on quality of life, highlighting a critical health care cap. AD manifests as erythematous and pruritic plaques often in flexural regions of the body, but may also be widespread as well. AD patients suffer from high rates of mental health disorders and often report a poor quality of life (QoL).
The pathogenesis of AD is multifactorial, involving both genetic and environmental components. Specifically, a defect in the filaggrin gene is a common etiology. Moreover, it is thought that decreased levels of ceramides within the epidermis allow for an abnormal amount of transepidermal water loss leading to an increased Th2 response and subsequently, overexpression of proinflammatory cytokines IL-4 and IL-5. Additionally, scratching of the epidermis promotes increased levels of IL-1, IL-6 and TNF-alpha from keratinocytes.
The objective of this pilot study is to determine whether cutaneous neurons are required for the maintenance of atopic dermatitis (AD) lesions. The significance derives from the potential to reveal novel neuro-immune pathways that could provide suitable targets for future therapeutic approaches for this disease. Specifically, the investigators hypothesize that neurotransmitters released from cutaneous neurons are required for the persistence of AD lesions. This is supported by a prior report showing that injection of botulinum toxin which prevents vesicular fusion in neurons and hence neurotransmitter release led to clinical improvement and resolution of AD lesions. Similar findings have been reported with Psoriasis. The investigators approach will analyze biopsy samples from AD patients treated with botulinum toxin using spatial single cell imaging.
The project will be performed in 2 phases. Phase 1a will include a pilot run of spatial single cell imaging performed on normal skin and with atopic dermatitis. In Phase 1b, the investigators will administer intradermal botulinum toxin in AD lesions to determine the kinetics of the clinical response when neurotransmitter release is inhibited using standardized clinical outcome assessments, including Physician Global Assessment (PGA) and Eczema Area and Severity Index (EASI). The kinetics, or time, to reduction of lesion severity, as determined in Phase 1b, will be used in Phase 2 to determine the biopsy visits.
Phase 2 will test the hypothesis that botulinum toxin therapy alters the cellular and molecular state of AD lesions, specifically by blocking neuroimmune interactions with a specific emphasis of cytokine and chemokine interactions. In Phase 2, botulinum toxin will be injected into multiple lesions in a small cohort of AD patients. Based on the results of Phase 1b, skin biopsies will be harvested at 3 different times and analyzed using spatial single cell imaging.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Other
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients 18 years or older at time of consent
- •Mild-to-Moderate AD, defined as:
- •BSA ≤ 10%
- •No past biologic therapy
- •No systemic therapy for 3 months
- •No topical therapy for treatment of AD for 4 weeks
- •Patients 18 years or older at time of consent
- •Mild-to-Moderate AD, defined as:
- •BSA ≤ 10%
- •At least one patch of eczema of at least 5 cm in diameter
- •No past biologic therapy
- •No systemic therapy for 3 months
- •No topical therapy for treatment of AD for 4 weeks
排除标准
- •Age less than 18 years old
- •Pregnant or breastfeeding
- •Has medical comorbidity such as end stage congestive heart failure or coagulopathy that is a relative contradiction to skin biopsy procedure
- •Has had prior exposure to biologic treatments or has had prior treatment with systemic non-biologics (e.g. methotrexate) within 12 weeks
- •Has used topical therapy for treatment of AD within 4 weeks
- •Patients enrolled in Phase 1
- •Age less than 18 years old
- •Pregnant or breastfeeding
- •Has medical comorbidity such as end stage congestive heart failure or coagulopathy that is a relative contradiction to skin biopsy procedure
- •Has had prior exposure to biologic treatments or has had prior treatment with systemic non-biologics (e.g. methotrexate) within 12 weeks
- •Has used topical therapy for treatment of AD within 4 weeks
研究组 & 干预措施
Onabotulinum Toxin Type A - Phase 1b
Onabotulinum toxin administered to two lesions.
干预措施: Onabotulinum Toxin Type A - Phase 1b (Drug)
Onabotulinum Toxin Type A - Phase 2
Onabotulinum toxin administered to three lesions.
干预措施: Onabotulinum Toxin Type A - Phase 2 (Drug)
结局指标
主要结局
Percentage change in EASI scores at Day 28 as compared to baseline.
时间窗: At Day 28
Eczema Area and Severity Index (EASI) total score from 0-72, with higher score indicating more severity. The EASI index assigns proportionate values to 4 body regions. Each region is assigned a score of 0 to 3, indicating none, mild, moderate, and severe clinical expression. The percentage of area involved is also assigned an eruption proportional score from 0 to 6. The total body score for each body region is obtained by multiplying the sum of the severity scores by the area score, then multiplying the result by the constant weighted value assigned to that body region. The sum of these scores gives the EASI total from 0-72.
Percentage change in PGA at Day 28 as compared to baseline.
时间窗: At Day 28
The Physician's Global Assessment (PGA) is a clinician-reported measure used to assess the overall severity of atopic dermatitis (AD) at a single time point. It utilizes a scale of 5-points; total scale ranging from 0 (clear) to 5 (severe disease). The PGA score represents overall disease severity based on clinical signs including erythema, induration/papulation, lichenification, and oozing/crusting. Higher scores indicate greater disease severity.
次要结局
- Percentage change in transcriptional mRNA in immune and non-immune cells in skin biopsies, up to Day 28, as compared to baseline.(Until last biopsy, up to Day 28)
- Percentage change in spatial distribution of specific cell types in skin biopsies, up to Day 28, as compared to baseline.(Until last biopsy, up until Day 28)
研究者
Daniel Kaplan
Professor
University of Pittsburgh