NIAMS Pediatric Dermatology Roundtable Discussion Summary
Tuesday, December 6, 2011
NIH Campus, Building 31, Room 6C06
9:00 AM — 4:00 PM
The overall goal of all NIAMS roundtables is to discuss scientific and clinical needs, and to listen to the concerns and challenges facing the scientific community. These sessions provide a valuable source of input for the NIAMS planning process. This specific roundtable focused on pediatric dermatology, and explored research opportunities and needs for skin diseases affecting children.
Significant recent advances in the fundamental understanding of skin biology provide the basis for studies that focus on skin diseases that affect children. For many rare skin diseases, we now know the genes involved and have a better understanding of disease pathogenesis. Despite these promising therapeutic advances, much work remains to be done to increase the number of approved drugs for pediatric dermatologic diseases.
In advance of the meeting, participants were encouraged to consult with colleagues on several questions, including:
- What are the most pressing clinical needs in pediatric dermatology?
- Are there specific high priority/high impact clinical trials that need to be done immediately?
- Are there special infrastructure needs for the conduct of clinical trials in pediatric dermatology?
- What are the gaps in knowledge for safe use of existing drugs in pediatric populations?
- What gaps in training have delayed progress in critical research areas?
- What recent scientific advances in pediatric skin diseases are ready for translation to clinical application? What are the barriers to translation of these advances?
Although only a subset of these topics were discussed in depth, NIAMS leadership and the appropriate program staff read each comment. The NIAMS greatly appreciates the community’s input on these questions.
Current Clinical Research Needs
A major focus of the meeting was improved treatments for pediatric skin disorders, as this is the driving force in pediatric dermatology research. New drugs and other therapies are urgently needed and most existing, approved drugs are used in children “off-label,” i.e., without sufficient knowledge of the appropriate dose, safety, or efficacy in a pediatric population. More clinical trials are required to provide the data for evidence-based medicine in pediatric dermatology. However, organizing and funding these clinical trials has been a challenge.
Under the Best Pharmaceuticals for Children Act (BPCA), the NIH can sponsor off-patent drug trials to provide data that can be submitted to the FDA to support drug label changes. However, treatments for skin diseases and dermatological conditions have not received significant attention in the BPCA Prioritization Process. Epidemiologic data to establish the impact of pediatric skin diseases and the need for pediatric treatments could justify the development of clinical trials and therapies. This information may be used to educate the FDA about pediatric dermatology needs, and to involve other stakeholders, such as pharmaceutical companies and clinical dermatology societies.
The pediatric dermatology community recognizes the value of and need for clinical trials networks and multi-center trials, to:
- facilitate the design and conduct of clinical research;
- share research resources; and
- garner sufficient cohorts to study these relatively rare pediatric skin diseases.
The Childhood Arthritis and Rheumatology Research Alliance (CARRA) is a successful example of a pediatric disease clinical trials network. At the time of its inception in 2002, several existing models were considered before adopting the design of the Children’s Oncology Group. By 2012, CARRA intends to have every pediatric rheumatology patient in the United States enrolled in a clinical research protocol. However, all pediatric rheumatologists need access to the widespread sites that participate in the CARRA network.
CARRA has centralized repositories and data management services, and holds annual meetings. The network has also found tremendous value in the interactions between researchers and patient families. CARRA conducts investigator-initiated clinical trials, and there is a separate pediatric rheumatology network, in which all of the CARRA investigators participate, that carries out industry-sponsored studies. The recommendation to new networks is to create one organization with two arms: investigator-initiated studies and industry-sponsored trials. Adoption of central institutional review boards (cIRBs) to evaluate human subjects protection in clinical research protocols would greatly improve the efficiency of initiating multi-center clinical trials. Greater involvement of clinical coordinators in trial enrollment would also facilitate the conduct of clinical trials.
There has been an effort in recent years to build pediatric dermatology clinical trials networks, but these organizations are still in their infancy. They include the Hemangioma Investigator Group (HIG), the Pediatric Dermatology Research Alliance, (PeDRA), and the Epidermolysis Bullosa Clinical Research Consortium (EBCRC). Even with the advantage of multiple sites for recruiting patients, the EBCRC must carefully plan studies around enrollment constraints, because the epidermolysis bullosa (EB) patient population is very limited. The HIG and others in the community have considered developing an umbrella organization for pediatric skin disease research. The Dermatology Foundation, which has provided some funding to the HIG, and the American Academy of Dermatology have been identified as potential partners.
Intra-institutional, but especially inter-institutional infrastructure, is a critical concern as the supply of research dollars is reduced. Although the NIH-funded Clinical and Translational Science Awards (CTSAs) and NIAMS-funded Skin Disease Research Centers (SDRCs) have typically served their home institutions, multi-institutional sharing of these resources would benefit the research community at large.
Repositories and databases are important for assembling multi-center efforts. The HIG has started a database, funded by the NIAMS through the American Recovery and Reinvestment Act, for the classification of hemangiomas. The database will facilitate clinical trial design by stratifying patients according to clinical severity, lesion characteristics, complications, quality of life impact, and other factors. The NIAMS, with the participation of the National Center for Research Resources, also supported the establishment of the National Epidermolysis Bullosa Registry, but another registry is currently under development with private funding. This new tool will capture quality of life and burden of disease information that the pharmaceutical industry will use to guide drug development. The NIAMS supported the creation of an alopecia areata registry that includes more than 1,000 children. The pediatric dermatology community is not involved yet, but there is potential for future participation.
Genotyping is more common in Europe than in the United States, which creates an imbalance in research capabilities. New technologies are reducing the price of genotyping significantly, to facilitate discovery work, but there are still cost barriers for clinical-grade genotyping that can be applied to clinical trials.
The lack of pediatric dermatologists and pediatric dermatology researchers is a notable burden on the field. In contrast with other fellowships in pediatric specialties, which last three years, most pediatric dermatology fellowships have been reduced recently from two years to one year. As a result, the focus is on clinical work, with no time for clinical research training. There is a perception in the community that there is no clear funding structure for pursuing such training outside of the fellowship program. On the other hand, laboratory research related to skin biology is currently robust and productive.
Current Clinical Needs
Atopic dermatitis (AD) is recognized as the top need among clinicians. Eighty-five percent of AD patients are children and, although the majority of cases resolve before adulthood, severe AD may be accompanied by severe asthma. Greater understanding of pediatric AD subphenotypes, the natural history of asthma development, and other aspects of severe AD is necessary for early intervention, predicting outcomes, and tracking comorbidities.
Acne is often ignored in physician training, and would benefit from more serious clinical attention. Itch is a widespread symptom of many skin diseases, and improvements in understanding and treating it would have a tremendous effect on patient quality of life for numerous conditions. Psoriasis, EB, and other pediatric dermatology conditions require coordinated care, such as the effects of diet and hormones, quality of life and psychosocial issues, and treatment adherence and costs. Drug delivery strategies also need attention, particularly effective skin barrier penetration of topical compounds.
Translational Research Needs and Opportunities
Multidisciplinary collaborations are cited as essential to current research efforts. Frequent interactions between bench scientists, bioinformaticians, engineers, clinicians, and industry would support advancement of pediatric dermatology research. In addition, translational research needs to be driven by clinical needs. Professional societies, such as the Society for Investigative Dermatology (SID) or the Society for Pediatric Dermatology (SPD), could create an electronic forum for scientists and clinicians to announce what they have to share, or specific topics for collaboration. Some of the CTSAs have helped create multidisciplinary, translational research clusters, but such activities are institution-specific. However, some joint efforts and a greater focus on pediatrics are developing across the CTSA network, which is composed of 60 sites nationwide.
Basic scientists need access to patient samples, which could be facilitated through closer communication with clinicians, as well as the involvement of patient advocacy groups and private foundations. Because most pediatric skin diseases are rare, virtual repositories, linked with information from multiple sources, would be extremely beneficial. The NIH Office of Rare Diseases Research is developing a data repository that might help pediatric dermatology researchers locate samples.
Some of the investments in basic research have begun to pay off through the development of promising therapeutics for pediatric skin diseases. The aforementioned National Epidermolysis Bullosa Registry included a clinical data and biospecimen repository. Through this resource, and the active participation of collaborative scientists and a strong patient advocacy group (that convened meetings and contributed to the repository), the gene defects in EB were identified. As a result of these efforts, several clinical trials which involve gene or protein replacement are either underway or are scheduled to start soon. Some of the research findings may be applicable to wound healing (e.g., chronic ulcers), in conditions that affect larger numbers of people.
In order to harness the advances in genetic technology for improved understanding and, potentially, treatment of genetic disorders, enhanced interaction between scientists and clinicians would help to link genetic variants with specific disease phenotypes. Exome and genome sequencing may improve genetic diagnoses, and, in turn, more knowledge about the gene defects in skin diseases would provide insights into disease pathogenesis, as well as the basic biology of skin.
The identification of filaggrin defects in the stratum corneum that are associated with skin barrier disruption in AD and ichthyoses is a significant breakthrough, but there are likely other factors involved in these complex diseases; immunoglobulin E levels are very high in AD, which indicates a systemic allergic response, and filaggrin defects in a mouse model have an enhanced epicutaneous sensitization with a protein antigen. The skin microbiota also have an important role in barrier disruption conditions. Understanding of immune system effects is incomplete, particularly in pediatric forms of these diseases. However, there is substantial characterization of immune cell subsets and their respective role in adult AD and psoriasis, and a large body of evidence on drug effects on these immune cell subsets to support immune-related investigations in pediatric skin diseases. Insights into skin barrier function can inform vaccine development and drug delivery efforts, in addition to understanding and treating conditions such as AD.
The role of innate immunity in acne is an emerging field, including studies on the effects of small molecules on toll-like receptor activity. The lack of a good animal model for acne hampers research and drug development in this area.
The effects of lipid components in healthy and diseased skin have been studied in adults, but not in children. Lipids can affect the skin microbiome and barrier function, and there is growing interest in their potential role in signal transduction.
Clinical knowledge of pediatric hemangiomas is directing some investigations of pathogenic mechanisms, such as their clinical risk factors (hypoxia, prematurity, low birth rate families) and the therapeutic efficacy of beta-blockers, which are primarily used for treatment of hypertension. However, hemangiomas can be quite heterogeneous, and there are persistent questions about the variable response across the patient population to beta-blockers, and potential markers or predictors of clinical course. Hemangioma research is hampered by the lack of an adequate animal model and the limited amounts of biospecimens that can be obtained from infant patients.
Clinical needs in pediatric dermatology are creating additional areas of research and development opportunities that include, but are not limited to, the following:
- Linking genetic diagnoses to specific phenotypes is the basis for further functional genomics studies
- Elucidating pathways in rare pediatric skin diseases can provide insights into biological mechanisms and more common diseases
- Assays are needed for defects in epidermal permeability in diseases such as AD and ichthyoses
- Better non-invasive imaging technologies would reduce the burden on pediatric research participants (e.g., multiple biopsies, potential risks associated with anesthesia for lengthy imaging sessions)
- Novel approaches to immortalizing keratinocytes will allow expansion of cell resources derived from limited biospecimens
- Optimization of cell-based therapies includes selection of specific cell types to be corrected and improved delivery methods
- Microneedles and other technologies developed for drug delivery may also be useful in fluid sampling through different layers of skin
- Skin is commonly used to test nanotechnology drug delivery strategies, as well as new sampling methods (e.g., measuring blood sugar through the skin with nanofibers)
The pediatric dermatology community also cites critical clinical studies and trials to be conducted in the near future:
- Pathogenesis-based approaches to treatment
- Ancillary mechanism-of-action studies in efficacy trials, such as beta-blockers for hemangiomas
- Comparative effectiveness trials, such as penetration and efficacy of active ingredients in topical medications
- Prospective studies on the impact of diet and hormones on diseases such as acne
- Pruritus interventions, such as opiate antagonists
The discussion yielded many ripe opportunities for moving forward, collectively, to improve understanding and treatment for pediatric skin diseases.