Natural History, Genetics, and Pathophysiology of Systemic Juvenile Idiopathic Arthritis, Adult-Onset Still's Disease, and Related Conditions

Study Description: The purpose of this protocol is to study the natural history?natural history A study that follows how a condition changes over time without assigning an experimental treatment. It may involve study visits and tests, and is often used to plan future trials., genetics and pathophysiology of systemic juvenile idiopathic arthritis (sJIA), adult-onset Still s disease (AOSD) and related inflammatory conditions. One of seven subtypes of juvenile idiopathic arthritis (JIA), sJIA contributes disproportionately to the morbidity and mortality of JIA and is considered by many to be the most severe JIA subtype. sJIA typically presents with fever of unknown origin and arthritis, together with evanescent skin rash, serositis, hepatosplenomegaly and lymphadenopathy. It is strongly associated with macrophage activation syndrome (MAS), which has a high fatality rate when untreated. AOSD is phenotypically similar to sJIA in presentation, progression and association with MAS, however it develops after the 16th birthday. The causes sJIA and AOSD are poorly understood. sJIA and AOSD are diagnoses of exclusion and there are often delays in their diagnosis due to the stringency of their classification criteria. There is no diagnostic test for sJIA/AOSD and there exists significant overlap with other conditions. The manifestations and severity of disease can differ among patients, further delaying the diagnosis. There is also considerable variability in both patient response to therapy and long-term outcomes, and there exist no therapeutic or prognostic biomarkers?biomarkers Something measurable in the body, such as a blood test result or an imaging finding, that indicates how a condition or treatment is behaving. to guide treatment. Given our limited understanding of the causes, treatments and prognostic factors of sJIA, we developed this protocol to longitudinally follow patients with sJIA/AOSD and investigate these topics. The specific goals of this protocol include: 1) Establishing a cohort of patients with sJIA/AOSD and assembling a detailed set of longitudinal clinical information; 2) Identifying genetic factors that cause or influence susceptibility to sJIA/AOSD; 3) Determining the functional relevance of genes and variants that influence sJIA/AOSD; and 4) Developing a molecular library of patient biological samples which may be used to further investigate sJIA/AOSD. Patients enrolled in this protocol will undergo screening history, physical examination and laboratory evaluation. At times, we may ask for permission to evaluate additional family members. We will collect peripheral blood samples for genetic and functional studies from affected patients, unrelated healthy volunteers and in some cases patients' family members. We will ask permission to perform whole genome/exome sequencing. We also may ask some patients to undergo skin biopsy for research purposes. This study aims to elucidate genetic factors that contribute to sJIA/AOSD and related conditions and to determine their implications on inflammatory pathophysiology. By so doing, we hope to identify novel therapeutic targets for inflammatory disease. Objectives: The intent of this natural history protocol is to recruit a cohort of patients with sJIA, AOSD and related inflammatory conditions to prospectively follow, who over the course of several years will help us to better understand the potential triggers for disease development, relapse?relapse A condition that improved with treatment and has since returned or worsened., and worsening. Over time, we will test many hypotheses. Specifically, we will aim to identify genetic polymorphisms in the sJIA and AOSD population which may influence disease susceptibility. We also hope to identify differential expression and function of these susceptibility genes and in so doing, explain disease pathogenesis. The information collected may also be helpful in identifying biomarkers to help diagnose disease. With this protocol, we also aim to identify possible therapeutic targets for treatment of disease. Given the large amount of clinical data generated, it may be possible to identify distinct subclasses of sJIA and AOSD which can be used to further classify patients and thereby better predict prognosis and tailor the most appropriate treatment plan. This cohort will be invaluable for further research as well by providing a molecular library of biological material and cell lines which can be used for future research projects. Specific objectives are as follows:

• To gather a robust group of sJIA, AOSD, and patients with a similar phenotype through referrals to the NIH clinical center, from which we can collect and analyze clinical, and laboratory. We will follow many of these patients over time, which will give us invaluable longitudinal data. Most patients will be evaluated in the outpatient department. Given the widely differing trajectories of disease, this will help us to potentially identify phenotypic characteristics which may serve as predictors of disease course. It will also allow us to match detailed phenotypic information with the patient's genotype--something that is lacking in present studies. We anticipate evaluating 1-2 new patients every 2 weeks.
• To perform genotyping and/or sequencing analysis on DNA samples from patients, affected and unaffected family members, and healthy volunteers. We will use this information to identify genetic variants that could be potential causative variants that confer disease. We will also evaluate to see if genetic variants can be used as predictors of disease course.
• Based upon identified genetic variants, to undertake molecular, cellular, immunological, and biochemical functional studies to identify the relevance of the genetic variations in disease pathogenesis. We will also use this information to help identify possible biomarkers. The activity of these genetic variants will be analyzed using fresh and stored samples, and cell lines will be established in the laboratory.
• To establish a molecular library comprised of sera and biological samples obtained from patients which can be used for future research studies.

To identify patients with sJIA, AOSD, and similar phenotypes for possible entry into future treatment protocols