This study will explore how genes may influence the severity of ankylosing spondylitis, a form of arthritis that affects the spine. Patients have inflammation of the joints of the spine, which may cause the bones of the spine to fuse, resulting in difficulty performing daily activities.

Patients who developed ankylosing spondylitis after age 16 may be eligible for this study. The onset of disease is dated to the first appearance of symptoms of inflammatory low back pain or restricted spinal motion. Patients with a spondyloarthropathy other than AS may not participate. Candidates will be screened with a medical history and physical examination, blood test, and review of their medical records. They will also complete a questionnaire about their disease symptoms and medical history.

Those enrolled in the study will return to the NIH Clinical Center at 6, 12, 18, 24, 30, 36, 42, 48, 54, and 60 months after screening for examination of the joints, measurement of flexibility of the spine, and a blood test. They will also complete symptoms assessment and coping questionnaires. At the first study visit (screening visit), x-rays will be taken of the pelvis, lower back, and neck, if recent X-rays (within 1 year) are not available. These x-ray studies will be repeated on all patients every two years during the study (at 24 and 48 months after screening).

The susceptibility to ankylosing spondylitis (AS) is largely genetically determined. Recent studies suggest that the severity of AS is also influenced by genetic factors. The goal of this study is to identify genes that influence the severity of AS. We hypothesize that genetic markers of susceptibility, including human leukocyte antigen (HLA) polymorphisms, and genes that regulate inflammation and bone formation, influence the severity of AS.

In this prospective longitudinal study, we will test the association of several genetic markers with the severity of AS. Approximately 700 patients will be included. Measures of AS severity will be patient-reported pain and stiffness, functional disability, patient and physician global assessments, joint counts, number of tender entheses, spinal mobility, and laboratory measures of inflammation. These measures will be assessed every 6 months for 5 years. We will also evaluate new laboratory tests as measures of the activity of AS.

Identifying genetic markers that are associated with differences in the severity of active inflammation in AS will enhance our understanding of the pathogenesis of this disease by suggesting mechanisms and pathways involved in the development of long-term damage. In a separate but related protocol, we will assess genetic markers associated with spinal fusion and long-term functional disability in patients with AS.

• Boyer GS, Templin DW, Bowler A, Lawrence RC, Everett DF, Heyse SP, Cornoni-Huntley J, Goring WP. A comparison of patients with spondyloarthropathy seen in specialty clinics with those identified in a communitywide epidemiologic study. Has the classic case misled us? Arch Intern Med. 1997 Oct 13;157(18):2111-7.
• Mau W, Zeidler H, Mau R, Majewski A, Freyschmidt J, Stangel W, Deicher H. Clinical features and prognosis of patients with possible ankylosing spondylitis. Results of a 10-year followup. J Rheumatol. 1988 Jul;15(7):1109-14.
• Amor B, Santos RS, Nahal R, Listrat V, Dougados M. Predictive factors for the longterm outcome of spondyloarthropathies. J Rheumatol. 1994 Oct;21(10):1883-7.

• INCLUSION AND EXCLUSION CRITERIA:

Participants will:

1. have been diagnosed with AS by the modified New York criteria.
2. be able to read English.

Potential participants will be excluded if:

1. onset of AS was at age 16 or younger.
2. have a spondyloarthropathy other than AS.
3. are unable to provide informed consent.
4. anticipate not being available or able to comply with the schedule of study visits.

Study entry is not limited by sex or ethnic origin. Children will necessarily be excluded because spondyloarthropathy developing before age 16 is considered a form of juvenile idiopathic arthritis, and because different age-appropriate measures of functional disability and pain would be needed. English literacy is required because the functional status questionnaires used in the study have not been developed and validated in many languages other than English. In particular, the HAQ-S has been validated in only English, Dutch, and Finnish. The BASFI has been validated in English, Dutch, Finnish, Swedish, German, and French. Each of these validation studies consists of a single report. Monolingual speakers of these languages are likely to be rare in our area.

Participants will be recruited by physician referral and self-referral. Information about the study will be mailed to local rheumatologists and posted on the NIH website. Notices will also be sent to local chapters of the Arthritis Foundation and the Spondylitis Association of America. Former participants in our AS protocols will be notified of this study by letter.

Study of first-degree relatives:

Participants will be:

1. Parent, sibling, or child (age 18 or older) of an enrolled subject.
2. Able to provide informed consent.

Family members may by asymptomatic or have signs or symptoms of AS or a condition in the spondyloarthropathy family. There is no requirement for a minimum number of members per family to be eligible for participation.

The accrual ceiling will be unlimited. Approximately 700 patients will be enrolled from all study sites. Approximately 150 patients will be recruited at the NIH. Other sites participating in this study are Cedars-Sinai Medical Center, Los Angeles, CA; and University of Texas-Houston Health Sciences Center. To ensure a sufficient sample of patients with active inflammation, enrollment in the study will be monitored so that at least 80 patients will be included who have an ESR of 40 mm/hr or higher at the screening visit or visit 1, or who have an elevated serum C-reactive protein level at visit 1.