The overall goal of this proposal is to improve clinical trial design for early diffuse systemic sclerosis (SSc) patients by using a clinical observational cohort to address three crucial gaps in knowledge. These three critical knowledge gaps include 1) how disease duration should be optimally defined as an inclusion criterion for trials using skin change as a primary outcome, 2) if trial design or analysis should be stratified by SSc-associated autoantibody, and 3) the effect size of mycophenolate mofetil (MMF) on skin thickness score in early diffuse SSc.
Specific Aim 1 will determine the most appropriate definition of disease onset, first non-Raynaud symptom compared to the first SSc-attributable symptom, by which to define disease duration as a clinical trial inclusion criterion.
Specific Aim 2 will then establish if clinical trials may be improved through stratification of trial participants by SSc-associated autoantibody (anti-Scl70 or anti-RNA polymerase 3).
For Specific Aims 1 and 2, the already existing, prospectively collected clinical observational cohort of the University of Pittsburgh Scleroderma Center will be used for analysis.
In Specific Aim 3 an observational cohort of early diffuse SSc patients treated with MMF will be created and made available for future trial use with information on disease characteristics, medication use and skin scores over a one year period. To accomplish this, the pre-existing and prospectively followed cohort of early diffuse SSc patients treated with MMF in the Pittsburgh database will be combined with a newly recruited additional cohort of early diffuse SSc patients treated with MMF to form an observational hybrid cohort. The newly-recruited patients will enrich the follow-up skin score data taken at 3-month time intervals and add samples for skin gene expression. We will perform a matched analysis of the MMF-treated hybrid cohort to our historical non-MMF treated early diffuse SSc patients and assess the effect size of MMF on skin at 6 and 12 months of therapy. Potential applications of a MMF-treated cohort are as a comparator or control group for future open label studies of potential therapeutics for early diffuse SSc or to assess the effect of new investigational drugs in early phase trials when MMF is allowed as ongoing background therapy. The knowledge gained from each of the proposal Aims can be applied to both ongoing early diffuse SSc clinical trials and trials in the planning stage.

Public Health Relevance

Systemic sclerosis is a disease which affects 240 of every million Americans and has the highest case-specific mortality of the rheumatic diseases. To date, there is no FDA-approved therapy for systemic sclerosis. The objective of this proposal is to address specific fundamental questions in early diffuse SSc that can be used to improve current and future clinical trial design for investigational agents to treat the skin manifestations of systemic sclerosis.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Arthritis and Musculoskeletal and Skin Diseases Clinical Trials Review Committee (AMSC)
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Witter, James
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University of Pittsburgh
Internal Medicine/Medicine
Schools of Medicine
United States
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