The scientific focus of this research proposal is patient-oriented research (POR) in two serious autoimmune skin diseases, lupus erythematosus (LE), where they have been investigating etiology and genetics, and pemphigus vulgaris (PV), where they are investigating therapeutics.
Aim 1 : Role of the -308A TNFa promoter polymorphism in photosensitive LE. They recently reported that the -308A polymorphism of the TNFct promoter, unlike the wild-type (-308G) allele, is strongly associated with a photosensitive form of LE and mediates markedly increased transcription in vitro in response to UVB. They now propose to a) expand their survey of cutaneous LE patients for the -308A polymorphism and related HLA haplotypes, to increase the numbers of patients and better evaluate the role of DR3 linkage dysequlibrium; b) phototest patients with LE, including measurement of TNFa in blister fluid obtained from UVB-irradiated regions, and correlate their findings with the presence of the -308A or G polymorphisms; and c) evaluate molecular mechanisms for the exaggerated response of the -308A promoter to UVB, by examining differential binding of transcription factors to the area of the polymorphism. The results of these studies are intended to advance the pathophysiologic understanding and may suggest new treatments for patients with cutaneous LE.
Aim 1 : Evidence-based evaluation of a glucocorticoid (GC)-sparing agent in PV. Because of her tertiary referral practice, Dr. Werth has published several POR projects related to PV, particularly involving therapeutic interventions to minimize GC-induced osteoporosis. They have recently begun enrolling patients into the first multicenter therapeutic trial for PV, a potentially fatal autoimmune blistering disease. Moreover, this trial is prospective, double-blinded, and placebo-controlled. The trial evaluates the role of dapsone, an off-patent sulfone, as a GC-sparing drug in the maintenance phase of PV. The overall goal is to systematically study and improve the treatment of severe blistering disease, by developing a model for collaborative trials that have not existed in this area to date and by using this trial in the training of individuals mentored under the K24 program. Dr. Werth has been involved in the mentoring and training of students, resident, and junior faculty in POR. She is committed to expanding these efforts with a medical dermatology fellowship. This K24 translational grant is intended to permit the P.I. greater time to focus on patient-based scientific studies and will provide an infrastructure for Dr. Werth to pursue and mentor in POR.
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