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

The purpose of this protocol is to study the natural history, 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 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.

- INCLUSION CRITERIA:

Subjects with known or suspected sJIA, AOSD or a similar inflammatory phenotype will
provide informed consent and then be evaluated either in the outpatient or inpatient unit
of the NIH Clinical Center. To be eligible for follow-up visits patients must meet the
Inclusion Criteria, but not the Exclusion Criteria. Subjects determined to not have known
or suspected sJIA or AOSD, or a related

inflammatory phenotype, will not be followed.

Patients with signs and symptoms of sJIA will be classified as outlined in #1, #2 and #3
below:

1. Patients less than 16 years of age will be considered to have sJIA if they meet the
ILAR criteria for sJIA.

2. Patients 16 years of age and older will be considered to have sJIA if they have
previously met ILAR criteria for sJIA.

3. Family members of individuals included under items 1 and 2.

4. Controls for clinical, cellular, molecular, and biochemical assays, and genetic
evaluation will be enrolled. Individuals who undergo phlebotomy specifically to
provide a control specimen will include both pediatric and adult patients and will not
be pregnant.

Patients with signs and symptoms of AOSD will be classified as outlined in #1, #2 and #3
below:

1. Patients 16 years of age and older will be considered to have AOSD if they meet the
Yamaguchi criteria for AOSD (including a negative ANA and RF).

2. Patients may be considered to have a diagnosis of AOSD if they met criteria for
diagnosis in the past but do not still have present evidence of disease.

3. Family members of individuals included under items 1 and 2.

4. Controls for clinical, cellular, molecular, and biochemical assays, and genetic
evaluation will be enrolled. Individuals who undergo phlebotomy specifically to
provide a control specimen will include both pediatric and adult patients and will not
be pregnant.

Patients with suspected sJIA, AOSD or a related inflammatory condition, as indicated by the
presence of episodic fever and/or arthritis, may also be included.

EXCLUSION CRITERIA:

1. In adults, inability to provide informed consent and unavailability of a legally
authorized representative to provide surrogate consent. In the case of minors,
unavailability of a parent or guardian.

2. Presence of any medical condition that would, in the opinion of the investigators,
confuse the interpretation of the study.

3. Unavailability, or inability to adhere with the schedule for follow-up visits.