Ankylosing spondylitis (AS) is a chronic inflammatory rheumatic disease characterized by arthritis affecting predominantly the joints of the spine. It is the commonest arthritis affecting the spine and affects 1% of the Canadian population. Uncontrolled inflammation can eventuate in osteoproliferation, with pathologic new bone formation and eventually bony ankylosis of the spine. The cause of AS is unknown and the basic mechanisms underlying chronic inflammation remains undefined. With the advent of genome wide association studies (GWAS), several new genes have been identified and this could potentially open up information of novel pathways and drug targets in AS. Clinical Research: The clinical arm of my research program includes identification of biomarkers and prediction models of severe disease. We recently reported a 70% reduced risk of progression of AS if we start treating these patients early with a class of medicines that target Tumor Necrosis Factor α. This was the first report to suggest that damage in AS can be prevented with appropriate therapy. Currently we are working on identifying patients with spondyloarthritis even before the x-rays become abnormal. We are using MRI techniques and gene expression profiles to develop a prediction model. Translational and Basic Science Research: My laboratory research program involves identifying novel pathogenic pathways in AS. We are currently exploring the role of a new gene 'ERAP1' that was found to be strongly associated with AS in GWAS studies. ERAP1 is an aminopeptidase that clips peptides to be presented on Major Histocompatibility Complex Class-I molecules like HLA-B27. HLA-B27 is present in 90% of AS patients and the ERAP1 association is seen only in HLA-B27 positive patients. Thus there is likely a functional interaction between these two genes that may be pathogenic in AS. We were the first group to report on the receptor shedding function of ERAP1 in AS patients. Subsequently we showed for the first time that AS associated ERAP1 variants cause changes in HLA-B27 expression on monocytes of AS patients. We are looking at the impact of this genetic interaction on several cellular pathways and trying to identify novel targets for the treatment of AS.
Subject Area Themes: Arthritis, Spondyloarthritis, Spine, Ankylosing Spondylitis, ERAP1, HLA-B27
Toronto Western Research Institute (TWRI)
"Everybody wants better healthcare systems. At TRP we learn how to make it happen"
- Anat Segal-Shalev, 2017 Cohort