Our prior work established the foundation for discovering novel insights into the genetic susceptibility and severity of ankylosing spondylitis (AS) as well as genetic-associated mechanistic pathways driving outcomes in this disease. During the renewal of Project 2, we will: 1) expand those insights by combining with another North American cohort of similar size (from Toronto and Edmonton, Canada) that we have already genotyped and followed with almost identical measures (Aim 1);2) assess and improve cun-ent radiographic scoring systems and determine the characteristics of radiographic progression (Aim 2);and 3) examine a critical association between cardiovascular outcomes and premature mortality in AS while concurrently exploring a relationship between chronic gut inflammation, cardiac morbidity, and AS outcome and mortality (Aim 3). The rationale for Aim 1 comes from the need to examine a robust spectrum of disease phenotype from the very early years of AS through later stage disease. This combined cohort is critical to the analyses of radiographic progression, cardiovascular risk, and gut inflammation addressed in Aims 2 and 3. The rationale for Aim 2 is that the most widely used radiographic scoring system - the modified Stokes Ankylosing Spondylitis Spinal Score (mSASSS), a scoring system that includes measures of erosions, sclerosis, squaring, syndesmophytes, and ankylosis - has several theoretical and methodological limitations for measuring bone formation and disease progression. The rationale for Aim 3 comes from emerging data that the frequency of HLA-B27 in adults from 20-69 years of age declines with increasing age and that unchecked inflammation, presumably from gut ongin, may be responsible for the premature cardiovascular morbidity and mortality that occurs in AS patients relative to the general population. The ability to address these issues during the renewal of Project 2 will allow us to significantly contribute to the understanding of disease initiation, progression, and outcomes in AS.

Public Health Relevance

AS patients have a large variation in outcomes;some patients fuse their spine completely while others do not. Many have premature heart disease and in some cases, early death. Our studies are designed to discover the genetic as well as the environmental predictors of these individual outcomes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Program Projects (P01)
Project #
5P01AR052915-08
Application #
8722434
Study Section
Special Emphasis Panel (ZAR1)
Project Start
Project End
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
8
Fiscal Year
2014
Total Cost
Indirect Cost
City
Houston
State
TX
Country
United States
Zip Code
77225
Kehl, Amy S; Corr, Maripat; Weisman, Michael H (2016) Review: Enthesitis: New Insights Into Pathogenesis, Diagnostic Modalities, and Treatment. Arthritis Rheumatol 68:312-22
Robinson, Philip C; Claushuis, Theodora A M; Cortes, Adrian et al. (2015) Genetic dissection of acute anterior uveitis reveals similarities and differences in associations observed with ankylosing spondylitis. Arthritis Rheumatol 67:140-51
Cortes, Adrian; Pulit, Sara L; Leo, Paul J et al. (2015) Major histocompatibility complex associations of ankylosing spondylitis are complex and involve further epistasis with ERAP1. Nat Commun 6:7146
Robinson, Philip C; Costello, Mary-Ellen; Leo, Paul et al. (2015) ERAP2 is associated with ankylosing spondylitis in HLA-B27-positive and HLA-B27-negative patients. Ann Rheum Dis 74:1627-9
Cortes, A; Maksymowych, W P; Wordsworth, B P et al. (2015) Association study of genes related to bone formation and resorption and the extent of radiographic change in ankylosing spondylitis. Ann Rheum Dis 74:1387-93
Reveille, John D (2015) Spondyloarthropathies: EULAR recommendations reflect advances in imaging. Nat Rev Rheumatol 11:388-9
Kiltz, U; van der Heijde, D; Boonen, A et al. (2015) Development of a health index in patients with ankylosing spondylitis (ASAS HI): final result of a global initiative based on the ICF guided by ASAS. Ann Rheum Dis 74:830-5
Reveille, John D (2015) Biomarkers for diagnosis, monitoring of progression, and treatment responses in ankylosing spondylitis and axial spondyloarthritis. Clin Rheumatol 34:1009-18
Thom, Nicole; Ritchlin, Christopher T; Zhang, Xiao et al. (2015) Prevalence of chronic axial pain, inflammatory back pain, and spondyloarthritis in diagnosed psoriasis. Arthritis Care Res (Hoboken) 67:829-35
Reveille, John D (2014) An update on the contribution of the MHC to AS susceptibility. Clin Rheumatol 33:749-57

Showing the most recent 10 out of 51 publications