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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Midcareer Investigator Award in Patient-Oriented Research (K24)
Project #
1K24AR002207-01
Application #
6226996
Study Section
Special Emphasis Panel (ZAR1-JRL-C (O1))
Program Officer
Moshell, Alan N
Project Start
2001-07-25
Project End
2006-06-30
Budget Start
2001-07-25
Budget End
2002-06-30
Support Year
1
Fiscal Year
2001
Total Cost
$97,008
Indirect Cost
Name
University of Pennsylvania
Department
Dermatology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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Ang, C C; Anyanwu, C O; Robinson, E et al. (2017) Clinical signs associated with an increased risk of interstitial lung disease: a retrospective study of 101 patients with dermatomyositis. Br J Dermatol 176:231-233
Alves, Paul; Bashir, Muhammad M; Wysocka, Maria et al. (2017) Quinacrine Suppresses Tumor Necrosis Factor-? and IFN-? in Dermatomyositis and Cutaneous Lupus Erythematosus. J Investig Dermatol Symp Proc 18:S57-S63
Chansky, P B; Mittal, L; Werth, V P (2017) Dermatological evaluation in patients with skin of colour: the effect of erythema on outcome measures in atopic dermatitis. Br J Dermatol 176:853-854
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Tiao, Janice; Feng, Rui; Carr, Kasey et al. (2016) Using the American College of Rheumatology (ACR) and Systemic Lupus International Collaborating Clinics (SLICC) criteria to determine the diagnosis of systemic lupus erythematosus (SLE) in patients with subacute cutaneous lupus erythematosus (SCLE). J Am Acad Dermatol 74:862-9
Pomerantz, Hyemin; Hogan, Daniel; Eilers, David et al. (2015) Long-term Efficacy of Topical Fluorouracil Cream, 5%, for Treating Actinic Keratosis: A Randomized Clinical Trial. JAMA Dermatol 151:952-60
Murrell, Dedee F; Marinovic, Branka; Caux, Frederic et al. (2015) Definitions and outcome measures for mucous membrane pemphigoid: recommendations of an international panel of experts. J Am Acad Dermatol 72:168-74
Schultz, Heather Y; Dutz, Jan P; Furukawa, Fukumi et al. (2015) From pathogenesis, epidemiology, and genetics to definitions, diagnosis, and treatments of cutaneous lupus erythematosus and dermatomyositis: a report from the 3rd International Conference on Cutaneous Lupus Erythematosus (ICCLE) 2013. J Invest Dermatol 135:7-12
Robinson, E S; Feng, R; Okawa, J et al. (2015) Improvement in the cutaneous disease activity of patients with dermatomyositis is associated with a better quality of life. Br J Dermatol 172:169-74

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