2011 Clinical Research Grant Recipients
Jacquelyn Dosal, MD - University of Miami, Department of Dermatology
Study sponsor: Jonette Keri, MD, PhD, FAAD
Project title: Effect of Tetracyclines on the Development of Vascular Disease in Veterans with Acne or Rosacea
Abstract: Acne and rosacea are two chronic diseases that can be socially debilitating for patients. Systemic treatment with tetracyclines is quite effective for both conditions. In addition to their antibacterial properties, tetracyclines are increasingly being used for other non-antibacterial properties, for instance their anti-inflammatory properties. These qualities may have secondary benefits and a protective effect on other organ systems, such as the cardiovascular system. In this study, we will test the hypothesis that anti-inflammatory medications such as doxycycline or minocycline in acne and rosacea patients have secondary benefits on the cardiovascular system. Our specific aim is to determine whether use of doxycycline or minocycline in acne and rosacea patients correlates with a decreased development of vascular diseases. We will perform a retrospective cohort study to analyze the electronic records at all medical centers of the Veterans Integrated Service Network-8, and determine whether there is a correlation between long-term (>3 months) use of doxycycline or minocycline for acne or rosacea and the incidence of vascular diseases (cardiovascular disease, cerebrovascular disease, atherosclerosis, and development of aortic aneurysms). Veterans will be searched according to ICD-9 codes for acne, rosacea, and cardiovascular disease. Patients will be subdivided according to those who received a tetracycline and those that did not. Confounding conditions such as diabetes mellitus, dyslipidemia, and hypertension will be accounted for in the analysis. Acne and rosacea patients will be analyzed separately.
Luis Garza, MD, PhD - Johns Hopkins School of Medicine, Department of Dermatology
Study sponsor: Sewon Kang, MD, FAAD
Project title: Effects of Antibiotics and Acne on the Skin Microbiome
Abstract: Classic means of determining microbial flora are dependent on biased culture methods. Recent insights into the diversity of skin flora have been made using novel techniques of microbial 16S rRNA amplification, sequencing, and unbiased speciation of resident microbes. The aim of this study is to use this novel technique to investigate hypotheses regarding the changes in P. acnes and commensal skin flora before, during, and after antibiotic therapy for acne. Specifically, we hypothesize that Propionibacterium acnes and commensal skin flora will decrease with antibiotic treatment. We also hypothesize that return of baseline flora will be delayed in appearance and altered in composition after the cessation of antibiotics. We will quantify this lag time before commensals recover, and the alterations in diversity after antibiotic use. Based on paired clinical histories, we will search for correlations between acne status and microbiome changes. These results will improve our understanding of acne pathogenesis and suggest optimum treatments.
Emmy Graber, MD - Boston University School of Medicine
Study sponsor: Diane Thiboutot, MD, FAAD
Project title: Patient and Parent Attitudes towards Isotretinoin: Both Before and After Treatment
Abstract: Oral isotretinoin is the most effective acne medicine available and is the only available medicine to cure patients of acne. Despite this truth, patients and their parents are often leery to start isotretinoin, even more so with the media stories reporting the negative side effects of isotretinoin. Many of these stories are based on rare, isolated incidents and do not reflect the typical patient's experience with isotretinoin. Regulatory committees have also shown their concern over isotretinoin. Due to the teratogenicity of isotretinoin, the US Food and Drug Administration has recently required strict regulation of the drug through the iPledge system. Isotretinoin induced fetal harm and anecdotal reports of possibly unrelated adverse events may promopt tighter federal regulation or market withdrawal of isotretinoin. The loss of isotretinoin would be devastating, as patients would no longer have a cure for their acne.
Studies have been performed to attempt to negate the link between isotretinoin and negative side effects. While these studies are important, other studies are needed to demonstrate the positive experience that the majority of patients have with isotretinoin. The aims of this study, in addition to trying to disprove the negative side effects, are to prove the positive aspects of isotretinoin by quantifying patient and parent attitudes toward isotretinoin before and after treatment. Demonstrating high patient and parent satisfaction rate with isotretinoin will: 1) encourage future patients to seek treatment and 2) dissuade regulatory committees to potentially withdraw isotretinoin from the market. This will be accomplished by giving both patients and their parents questionnaires to complete at the visit in which patients are enrolled in the iPledge program. This questionnaire will capture feelings and thoughts regarding isotretinoin and the source of information by which patients and parents obtained these ideas. Questionnaires will also be completed once the isotretinoin course has been finished. With this questionnaire, patients and parents will be asked about any side effects encountered and their satisfaction with the treatment.
Laura Marinelli, PhD - UCLA David Geffen School of Medicine, Division of DermatologyProject title: Characterizing the Mechanisms of Lysis and Lysogeny in Propionibacterium acnes Bacteriophages
Abstract: Acne vulgaris affects more than 45 million people, and over 80% in the US report suffering from acne and some point in their lives. Severe acne has significant psychological effects and has been linked with increased mental health problems and suicidal ideation in teenagers. There are several lines of evidence implicating the Gram-positive skin commensal, Propioinibacterium acnes, in the pathogenesis of acne, specifically by eliciting a host inflammatory response. Although antibiotics have demonstrated efficacy for acne treatment, up to 60% of clinical isolates are resistant to those drugs currently in use. This fact, combined with growing concerns regarding the safety of retinoid-based therapies, has created an opportunity for research aimed at developing safer and more effective anti-acne therapeutic agents. To this end, the objective of this study is to characterize the bacteriophages that infect P. acnes and elucidate the mechanisms by which these viruses interact with, and kill, their host bacteria. Bacteriophages are prevalent in the environment, and P. acnes phages can be readily isolated from human skin. Despite this, there is only one complete published genome of a P. acnes phage, and little is known about their role in the skin microbiome. In order to better characterize these entities, we isolated P. acnes phages from the sebaceous follicles of acne patients and healthy donors. Four of these have been completely sequenced and display striking genetic identity (~90%) with one another and the published phage sequence, PA6. The phages in our repertoire also display a broad host range against both lab and clinical strains of P. acnes.
Through the experiments outlined in this proposal, we plan to isolate and sequence additional phages in order to gain a better appreciation of the full extent of genetic diversity present within this population, as well as to uncover genes involved in critical processes, such as host range determination and bacterial killing. The development of improved genetic tools for P. acnes and its phages will facilitate functional genomic studies to confirm their function. We further plan to determine whether any of these phages has the ability to enter into a stable lysogenic relationship with its bacterial host, as understanding of this process and how it is regulated will be critical to the design and development of phage-based acne treatments. Our initial sequencing efforts have already uncovered P. acnes phage genes, known as endolysins, with the potential to be exploited for therapeutic purposes. The third part of this proposal will therefore involve exploring the proposed antibacterial activity of these proteins by assaying their activity in vivo and in vitro. We hypothesize that further characterization of P. acnes bacteriophages, both genetically and phenotypically, will provide the necessary information to effectively manipulate and exploit their ability to efficiently and successfully kill P. acnes. Ultimately, we hope that information gleaned from these studies will facilitate the development of safe and effective phage-based antimicrobial therapies for the treatment of acne.