Natural History and Development of Spondyloarthritis

The purpose of this protocol is to study the natural history of spondyloarthritis (SpA) in
children and adults. Spondyloarthritis encompasses a spectrum of immune-mediated inflammatory
diseases that exhibit overlapping features, but differ from other types of inflammatory
arthritis in genetic predisposition, pathogenesis, and outcome. Ankylosing spondylitis (AS),
the most common form of SpA, frequently begins in an undifferentiated form with back pain and
stiffness in adults, and leads to aberrant ossification and ankylosis (fusion) of the spine.
In children, SpA rarely presents with back pain, but instead often begins with pain and
stiffness in the hips and knees due to arthritis. Enthesitis, or inflammation where tendons
and ligaments connect to bones, is more common in children. Our ability to recognize early
forms of AS involving the axial skeleton, particularly in children, and our understanding of
the cause and progression of this disease, is limited.

The goals of this natural history protocol are to establish a cohort of pediatric and adult
patients with SpA to prospectively evaluate the signs and symptoms, magnetic resonance
imaging (MRI) and X-ray findings, and bone and inflammatory biomarkers associated with axial
disease. We will study pathogenic mechanisms including the role of AS susceptibility genes
and their variants in causing disease, and will identify patients for possible entry into
future treatment studies.

Patients enrolled in this protocol will undergo a history, physical examination, imaging
studies, and laboratory evaluation. When clinically indicated, patients may also be evaluated
for extra-articular manifestations such as acute anterior uveitis, psoriasis or other skin
problems, and inflammatory bowel disease. Peripheral blood samples will be collected from
affected patients, unrelated healthy volunteers, and in some cases unaffected family members
to help identify and study the genes involved in SpA and their functions. We may ask some
patients to undergo skin biopsy or bone marrow aspiration for research purposes. For a small
number of patients and family members, we may ask permission to perform whole genome or exome
sequencing. Fibroblasts and/or peripheral blood cells obtained from patients will be induced
to become pluripotent stem cells that can be maintained indefinitely in culture and
differentiated into cell types that are relevant to pathogenesis. Successful completion of
these studies will allow rheumatologists to better recognize early SpA with axial
involvement, particularly in children, and will improve our understanding of disease
pathogenesis.

- INCLUSION CRITERIA:

Subjects with known or suspected SpA 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 SpA will not be followed.

Patients with signs and symptoms of SpA will be classified as outlined in #1 and #2 below
(see Appendix 10.1 for Classification Criteria):

1. Patients less than 16 years of age will be considered to have SpA if they meet the
ILAR criteria for ERA (without or with psoriasis or a positive family history of
psoriasis), or modified NY criteria for AS.

2. Patients 16 years of age or older will be considered to have SpA if they have
previously met ILAR criteria for ERA, or currently meet ESSG or Amor criteria for
USpA, ASAS criteria for Axial SpA, or modified NY criteria for AS.

3. Family members of individuals included under items 1 and 2. Family members will not be
asked to submit to bone marrow aspiration or interruption of therapy.

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 be 6 years of age or older, and not pregnant.

5. Minor healthy volunteers undergoing imaging (SI and/or WB MRI) must be old enough to
complete the procedure without sedation. Generally this requires that they be at least
6 years of age, so no healthy volunteers under age 6 will be enrolled.

EXCLUSION CRITERIA:

1. Inability to provide informed consent or, 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 comply with the schedule for follow-up visits.