Localized scleroderma (LS) is a disfiguring autoimmune disease of the skin and underlying tissue mainly affecting the pediatric population. Unbalanced disease activity leads to fibrosis and atrophy, causing physical and psychological disability that continues throughout childhood into adulthood. Available therapies for LS have had variable effects and are associated with morbidity themselves. A better understanding of the pathophysiology of LS, especially during the active inflammatory phase, would lead toward more directed and efficacious therapies. T-helper (Th) cells and their associated cytokines have been found to contribute significantly to the pathophysiology of systemic sclerosis (SSc), the other form of scleroderma, supported by the presence of cytokines from these lineages in the sera, peripheral blood cells, and tissue. This concept in LS has only been partially investigated, with studies primarily conducted on the serum of adults, evaluating only two of the three Th cell lineages, and not examined in reference to disease activity. The proposed study intends to fill this fundamental knowledge gap of LS pathophysiology by evaluating the role of all three Th cell lineages (Th1, Th2, Th17) in a pediatric LS cohort in context to disease activity in both the serum and skin as these lineages have not been previously explored in pediatric LS.
Specific aim 1 evaluates the serum cytokine profile in healthy children compared with LS patients in a cross-sectional manner using luminex and ELISA assays.
Specific Aim 2 analyzes the shift in LS serum cytokine profile in a longitudinal manner as the disease transitions from active to inactive and comparing it to simultaneously collected clinical features of disease activity/inactivity.
Specific Aim 3 determines the tissue cytokine profile of LS lesions using IHC cytokine identification and compares it to the histological grade of activity and damage. This information will also allow for the comparison of cytokines detected in the serum vs. tissue during different diseases stages, providing further insight into disease pathogenesis. The identification of certain cytokines as biomarkers of disease activity and/or as future therapeutic targets for LS are also possible outcomes of this proposal. Based on our preliminary studies, we hypothesize that in LS Th1 associated cytokines, assessed in both the serum and skin, will be predominant during the clinically active phase of disease, while over time with treatment the Th2 associated cytokines will increase representing the fibrotic damage that remains. The long-term goal of my research path is to provide better treatment options for LS by targeting immune mediators associated with the active phase of the disease to prevent long-term tissue damage. This is of particular interest to me as a pediatric rheumatologist witnessing the deformities and physical limitations of my LS patients. The resources available at the University of Pittsburgh combined with the mentorship and training supported through this application will provide me with the necessary foundation to accomplish these goals.

Public Health Relevance

Localized scleroderma (LS) is disfiguring and sometimes debilitating autoimmune disease which deserves more attention, especially in the pediatric community. Studying the inflammatory proteins in the serum and skin of patients with LS may be the key to a better understanding of why this disease occurs. Findings from the proposed study may also support the development of more effective therapies in LS, which will lead to improved outcomes with less physical and psychological disability for these patients.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Mentored Patient-Oriented Research Career Development Award (K23)
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Arthritis and Musculoskeletal and Skin Diseases Special Grants Review Committee (AMS)
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Tseng, Hung H
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University of Pittsburgh
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Stevens, Brandi E; Torok, Kathryn S; Li, Suzanne C et al. (2018) Clinical Characteristics and Factors Associated With Disability and Impaired Quality of Life in Children With Juvenile Systemic Sclerosis: Results From the Childhood Arthritis and Rheumatology Research Alliance Legacy Registry. Arthritis Care Res (Hoboken) 70:1806-1813
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