Defining the natural history of sarcoidosis in a retrospective cohort to inform design of clinical trials

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Project Summary/Abstract (Project Description). Sarcoidosis is a rare multi-system inflammatory disease that affects less than 185,000 patients in the United States per year with significant morbidity. It is an orphan disease with an unclear natural history and no known curative treatment. While a number of drugs are used clinically, none have proven efficacy in randomized clinical trials. This lack of progress in intervention trials is likely because 1) there is a flaw in subject selection since half of patients will resolve naturally, and 2) currently used primary outcome measures may not be the best indicator of drug efficacy. In order to select individual patients that would benefit from enrollment into clinical trials, determine the timing and type of outcomes that would reflect meaningful change, and to establish sample sizes that adequately show effect with the least amount of patients, it is critical to first understand the natural history of sarcoidosis. Our objective is to establish a large, inclusive, retrospective cohort of sarcoidosis patients and define the natural history of sarcoidosis in this population, including a comprehensive study of healthcare utilization and a longitudinal analysis of clinical outcomes. The central hypothesis is patients with sarcoidosis can be segregated into three cohorts (worsening, chronic, or improving) that reflect disease course at different times in the natural history of sarcoidosis. In order to design the most efficient clinical trials with the ability to show an effect size, the key is to predict which patients will have a worsening course, earlier in the natural history, to show the largest effect of an intervention. The rationale for this study is that, by defining the natural history of sarcoidosis, we can better predict at diagnosis the subset of patients who will clinically worsen and be the most appropriate candidates for intervention trials. The aims are the following: Aim 1. Build and validate a retrospective cohort of patients with sarcoidosis in a large population-based dataset. Using a multi-center retrospective dataset, our objective is to establish a cohort of at least 1500 sarcoidosis patients with linked claims and clinical data. A secondary goal is to better define the case definition of sarcoidosis with degrees of confidence based on claims codes, imaging results, and biopsy data. Aim 2. Establish the natural history of sarcoidosis based on health care utilization and clinical data prior to diagnosis of disease and thereafter. The objective is to define characteristics that distinguish between patients who are at differing points in the natural history and to define factors earlier the natural history of sarcoidosis that predict for disease worsening. Aim 3. Based on the change in outcomes of patients with worsening severity, calculate the sample size necessary to determine an effect on outcomes in clinical trials. By assessing change over time for various outcome measures, we will determine effect size, time course, and sample size for each outcome. Our long term objective of this study is that by defining the natural history of sarcoidosis randomized controlled studies can be more effectively designed for treatments.