Objective 1: To define clinical, laboratory (including biomarkers) and imaging features that predict axial involvement in children and young adults with SpA. In initial studies we have analyzed clinical and laboratory features in an inception cohort of ERA patients compared with retrospective cohorts and patients with other subtypes of JIA. Thirty-nine patients satisfying the ILAR criteria for ERA from 5 pediatric rheumatology centers were studied at presentation. Median time from disease onset was 7.3 months;patients were predominantly male (79%) with a median age of 12 years. HLA-B27 was present in 59%, ANA in 41%. Markers of inflammation (ESR/CRP) were not elevated. The median active joint count was 3.5 and active enthesis count was 3.8. Only 1 patient had x-ray evidence of sacroiliitis and 1 had acute anterior uveitis. Interestingly, serum TGF-βlevels were elevated (p<0.01), while IL-22 and GM-CSF were decreased (p<0.04), relative to healthy controls. Other Th17 and Th1 cytokines were unchanged. TGF-βlevels were higher in patients with symptoms of gastrointestinal distress. Consistent with TGF-βelevation, our previous studies have shown evidence of a TGF-βgene expression signature in the peripheral blood of these subjects. We are currently analyzing genes whose differential expression correlates the strongest with TGF-βlevels and thus best represent this signature, so that a more refined signature can be followed in a longitudinal analysis. In collaboration with Pam Weiss (CHOP), we have found that being classified with ERA, and/or having enthesitis, is a consistent predictor for high CHAQ (Childhood Health Assessment Questionnaire), HRQOL (Health Related Quality of Life), and VAS pain scores in a large cohort of JIA patients (2,571) enrolled in the CARRANet Registry, reflecting the health burden of this disease. In collaboration with Lianne Gensler (UCSF) we are analyzing biomarkers associated with axial SpA in adults. We plan to apply what we have learned from these studies to early disease in children. In a study of 160 subjects, we found that matrix metalloproteinase-3 (MMP-3) is elevated in AS (n=110) compared to control groups, including individuals with undifferentiated SpA (n=37;p<0.05) and mechanical back pain (n=13;p<0.02), even when adjusted for age, gender, ethnicity, disease duration, HLA-B27 status, and CRP levels. Interestingly, analyzing the 147 SpA patients we found that bone alkaline phosphatase (BAP), a marker of bone formation, is significantly higher in individuals with grade IV sacroiliitis (vs.
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