Dermatology Consultation Clinic and Clinical Research

皮肤科会诊服务评估和帮助管理患者的全身疾病的皮肤表现。我们还评估和管理患者在实验药物或与NIH内部协议相关的干预措施上经历的皮肤不良反应。因此，我们在识别新的治疗药物和/或干预措施的不良反应方面发挥着重要作用，将这些不良反应与正在治疗的疾病的表现区分开来。我们帮助其他小组描述各种遗传和/或综合征条件的皮肤表现，这些正在NIH进行深入研究。这对于建立正在研究的综合征的临床表型是重要的。我们有时也被要求处理与方案无关的患者皮肤疾病的急性恶化。咨询服务所照顾的大多数患者都患有罕见疾病和/或正在参加创新的1期或2期试验。因此，在诊所遇到的皮肤问题往往是不寻常的，往往是复杂的。时间的聚类和患者的新颖性为教育和临床研究提供了丰富而独特的资源。我和考恩医生平分咨询部的工作。我直接指导孔医生进行光毒性和局部沉积肽试验。由于会诊服务繁忙，协同临床研究非常活跃。虽然目前大多数的合作项目都有我参与，但Cowen博士将越来越多地参与其中，因为他也参与了咨询服务的工作。合作项目包括继续研究家族性肾细胞癌患者的皮肤表现，如纤维滤泡瘤和平滑肌瘤。我们也描述了可能与几种罕见的遗传性骨髓衰竭综合征相关的皮肤病变，包括Diamond-Blackfan、Fanconis贫血和先天性角化不良患者。我们继续研究原发性免疫缺陷患者的皮肤表现和治疗并发症，如慢性肉芽肿病、高ige综合征（乔布斯综合征）和NEMO基因突变相关的免疫缺陷。在几种周期性发热综合征患者中新发现的pyrin基因突变，以及对由此产生的自身炎症性疾病有效的生物疗法的可用性，将一组新的患者引入了临床。我们现在正在系统地描述这些患者的皮肤表现，并评估对治疗的反应。我们还评估了青少年皮肌炎患者的全身膜炎和钙沉积之间的关系，并评估了强化全身治疗在预防阴燃肌肉疾病和最终钙化方面的益处。Cowen博士和我积极参与了NCI乃至全国范围内多学科慢性移植物抗宿主病（GVHD）联盟的持续运作。我们已经设计并推广了一种用于表征和测量GVHD皮肤受累的仪器。该评估工具可用于测量皮肤疾病的程度、进展/消退以及对治疗的反应。直到最近，人们才认识到慢性GVHD会严重影响女性生殖道。我在外阴阴道疾病方面的专业知识使我能够研究外阴阴道GVHD的表现和治疗。hwang博士和我参与了一个多学科皮肤t细胞淋巴瘤（CTCL）兴趣小组，得出了关于缺乏评估工具的类似结论。我们正在评估我们已经使用了几年的当前工具的有用性。特别是，我们将尝试确定当前评估工具的哪些部分可以简化，以便非皮肤科医生和皮肤科医生都可以使用，并将被参与多中心试验的校外研究人员所接受和实施。皮肤科分部发起的项目由分部的首席研究员带头。Hwang博士正在通过一项名为“皮肤t细胞淋巴瘤的发病机制和病程”（04-C-0081）的方案评估CTCL患者。Drs。Hwang和Cowen已经确定，在肿瘤期CTCL （03-C-0228）患者中可以识别血清蛋白质组学特征。他们的论文是最近发表的，可以在出版物列表中看到。Jonathan Vogel博士和我合作评估了由太阳模拟器产生的致红紫外线辐射对正常人类志愿者皮肤基因表达谱的波长依赖性（04-C-0120B）。手稿正在准备中。作为旨在确定暴露于太阳模拟器后基因表达谱的研究的后续，孔博士和我刚刚开始招募另一项研究，以确定摄入增加对晒伤敏感性的药物（多西环素）后暴露于太阳模拟器的皮肤的基因表达谱。本研究的另一个部分探讨了药物遗传学，即药物代谢与遗传背景的关系，以及这如何具体影响对重要的全身抗真菌药物伏立康唑的光毒性药物反应的发生。我们最新的方案是一项试点研究，旨在确定一种新的局部治疗早期CTCL的毒性。CTCL是一种相对罕见的疾病，但它有很长的皮肤期，有效的局部治疗是不可用的。另外，今年我还参与了人类微生物组计划（HMP），该计划旨在建立一个正常个体中存在于人体各个部位的细菌库。这项倡议是美国国立卫生研究院路线图的一部分，皮肤将是将要研究的5个器官之一。有许多临床迹象表明，常驻微生物在某些疾病的发生或延续中起着重要作用。建立这个文库之后，就可以将这些疾病中的微生物菌群与正常情况下的微生物菌群进行比较。我们将与NHGRI的Julie Segre博士合作，提出一项探索特应性皮炎（AD）微生物菌群的方案。AD是一种相当普遍的皮肤病，由于皮肤上存在金黄色葡萄球菌（葡萄球菌a）而加重和延续。抗生素的使用也能使它平静下来。这种相互关系是如何起作用的，以及如何在不需要长期抗生素治疗的情况下改变它，这只是我们打算追求的一些问题。在未来，我们计划探索为什么晚期CTCL患者会受到皮肤葡萄球菌感染，以至于它即使不是最常见的死亡原因，也是非常常见的原因

The Dermatology Branch consultation service evaluates and helps manage patients with cutaneous manifestations of their systemic diseases. We also evaluate and manage the cutaneous adverse reactions experienced by patients on experimental drugs or interventions that are associated with protocols within intramural NIH. Thus, we play an important role in the recognition of adverse reactions to new therapeutic agents and/or interventions differentiating these from manifestations of the diseases for which they are being treated. We aid other groups in the delineation of the cutaneous manifestations of the various herditary and/or syndromic conditions that are being intensively studied at the NIH. This is important in establishing the clinical phenotype of the syndromes under study. We are also at times, called upon to manage acute exacerbations of skin diseases in patieints that are not protocol-related. Most patients cared for by the consultation service have rare diseases and/or are participating in innovative Phase 1 or 2 trials. Thus, skin problems encountered in the clinic tend to be unusual and are often complicated. The clustering in time and the novelty of patients that are seen provide a rich and unique resource for both educational and clinical research endeavors. Dr. Cowen and I share coverage of the Consult Service equally. I directly supervise Dr. Kong in the phototoxicity and topical depsipeptide protocols. Collaborative clinical research is extremely active by virtue of the busy consultation service. Although most of the collaborative projects currently involve me, Dr. Cowen will become increasingly involved now that he shares in the coverage of the Consultation Service. Collaborative projects include continuing studies of cutaneous findings such as fibrofolliculomas and leiomyomas in patients with familial renal cell carcinoma. We are also characterizing cutaneous lesions that may be associated with several rare inherited bone marrow failure syndromes, including patients with Diamond-Blackfan, Fanconis anemia, and dyskeratosis congenita. We continue to study cutaneous manifestations and complications of therapy that are encountered in patients with primary immunodeficiencies such as chronic granulomatous disease, hyper-IgE syndrome (Jobs syndrome), and immunodeficiency related to mutations in the NEMO gene. The newly discovered mutations in pyrin genes in patients with several periodic fever syndromes, and the availability of biologic therapies that have efficacy in the resulting autoinflammatory diseases have introduced a new group of patients to the clinic. We are now systematically characterizing cutaneous manifestations in these patients and assessing responses to treatment. We are also evaluating the relationship between panniculitis and calcium deposition in patients with juvenile dermatomyosistis and assessing the benefit of intensive systemic therapy in the prevention of smoldering muscle disease and eventual calcification. Dr. Cowen and I are actively involved in the continuing operation of the multidisciplinary chronic graft versus host disease (GVHD) consortium not only within NCI but nationally. We have devised and propagated the use of an instrument meant to characterize and measure skin involvement in GVHD. This assessment tool can be used to measure extent and progression/regression of cutaneous disease and response to therapy. Only lately has it been recognized that chronic GVHD results in significant involvement in the female genital tract. My expertise in vulvovaginal diseases has enabled me to study the manifestations and treatment of vulvovginal GVHD. Dr. Hwangs and my participation in a multidisciplinary cutaneous T-cell lymphoma (CTCL) interest group has led to similar conclusions regarding the lack of assessment tools. We are in the process of assessing the usefulness of the current tool that we have been using for several years. In particular, we will try to determine which portions of the current assessment tool can simplified so that they can be utilized by non-dermatologists as well as dermatologists and that will be embraced and implemented by extramural investigators participating in multi-center trials. Dermatology Branch-initiated projects are spearheaded by Branch principal investigators. Dr. Hwang is evaluating CTCL patients via a protocol entitled Pathogenesis and course of cutaneous T-cell lymphoma (04-C-0081). Drs. Hwang and Cowen have determined that serum proteomic signatures can be identified in patients who have tumor stage CTCL (03-C-0228). Their paper was published recently and can be seen in the list of publications. Dr. Jonathan Vogel and I collaborated on on the assessment of wavelength-dependence of erythemogenic solar simulator-derived UV radiation on gene expression profiles in skin of normal human volunteers (04-C-0120B). The manuscript is in preparation. As a sequel to the study aimed at the determination of the gene expression profile following exposure to a solar simulator, Dr. Kong and I have just started recruitment for another study, to determine the gene expression profile of skin exposed to a solar simulator after ingesting a drug (doxicycline) that increases sensitivity to sunburn. Another arm of this study explores pharmacogenetics, that is, the relationship of drug metabolism to genetic background and how this, specifically impacts on the occurrence of a phototoxic drug reaction to an important systemic antifungal agent, voriconazole. Our newest protocol is a pilot study aimed at determination of toxicity of a novel topical therapy for early CTCL. CTCL is a relatively rare disease but it has a long cutaneous phase for which effective topical therapy is not available. Also new this year is my participation in the Human Microbiome Project (HMP) which aims to establish a library of the bacteria present on various parts of the human body, in normal individuals. This initiative is part of the NIH Roadmap and the skin will be one of the 5 organs that will be studied. There are many clinical indications that resident microbes play a major role in the initiation or perpetuation of certain diseases. Establishment of this library will then allow comparisons to be made between the microbial flora in those diseases versus that in normals. In collaboration with Dr. Julie Segre of NHGRI, we are about to present a protocol that will explore the microbial flora in atopic dermatitis (AD). AD is a fairly prevalent skin disease that appears to be exacerbated and perpetuated by the presence of staphylococcus aureus (staph a)on the skin. It also is calmed by the administration of antibiotics. How this interrelationship works and how it can be altered without the need for long-term antibiotic therapy are just some of the questions that we intend to pursue. In the future, we plan to explore why patients with late CTCL are subject to skin staph a infections such that it is a very common if not the most common cause their death