Ankylosing Spondylitis (AS) is highly heritable and a largely under-diagnosed condition. Our initial efforts were to define the gap in genetic susceptibility risk beyond HLA B-27 positivity, which only accounts for about 50 percent of the hereditability of AS. Worldwide over the past 10 years, we have identified and followed a cohort of approximately 1,500 fully characterized AS patients with assessments for disease activity, disease progression and disease severity. Aberrant and progressive bone formation characterizes these patients and contributes to their disability; we have been exploring biomarker and genetic risks for this aspect of disease progression. These studies will inform us about pathways that could lead to impactful interventions.
New, highly effective, almost life-changing treatments have been available for AS since 1999, and diagnosing AS in its early stages is imperative. Since the true prevalence of this condition is not known in the U.S., we have worked with the U.S. Centers for Disease Control and Prevention (CDC) to develop a population-based tool to identify inflammatory back pain. Coupled with B-27 testing in the most recent National Health and Nutrition Examination Survey (NHANES) (2009-2010), which we initiated and funded, we now have identified the prevalence of inflammatory back pain patients and of axial spondyloarthritis (axial SpA) in a true population-based sample. Finally, it has long been recognized that there is important clinical overlap (the long-suspected bone and gut connection) between AS and patients with inflammatory bowel disease (ulcerative colitis and Crohn’s disease). Over the past four years, we have collaborated with the Division of Gastroenterology to identify clinical, genetic and imaging overlap between these two conditions in an attempt to understand the environmental triggers, as well as biomarker and genetic pathways that will inform us of the evolution of each individual phenotype.
Achievements in Ankylosing Spondylitis
Our AS international consortium over the past five years (called "TASC," or "Triple A-Australian-Anglo-American-Spondylitis Consortium") has identified and confirmed the following AS non-MHC Genes/Loci — IL23R, ERAP 1, 2p15, 21q22, KIF21B, RUNX3, ANTXR2, CARD9, TBKBP1, PTGER4, IL1R2, IL12B and LTBR— with five others either highly likely or probable. The demonstration that the ERAP1 association is restricted to HLA-B27-positive cases reveals a gene-gene interaction and implicates peptide presentation as the likely mechanism underlying the association of HLA-B27 with ankylosing spondylitis. We have published these results in three Nature Genetics papers, with Cedars-Sinai supplying the largest U.S. share of genetic and clinical material.
From our outcome studies of almost 1,500 AS cases over the past five years, we have learned the following: functional disability is multifactorial, treatable and even reversible regardless of X-ray damage; some occupational physical activities may be detrimental and even cause X-ray damage; and AS patients have a highly impaired quality of life. In addition: gender differences do exist, but the causes are unexplained; juvenile onset disease course and outcome is unique; progressive bone fusion is not the rule in AS (suggesting genetic differences); African Americans have a higher individual disease burden despite their less common prevalence of AS; and the role of genetic factors in radiographic outcome appears substantial, but the exact mechanisms need to be identified.
To understand the complexities of the relationship between AS and Inflammatory Bowel Disease (IBD), and since serologic activity representing loss of tolerance to microbial antigens is present in IBD, we studied 80 AS subjects compared with controls and found an increased individual antibody response to I-2 and ASCA, strongly suggesting that mucosal dysregulation could play a role in AS pathogenesis. Further supporting this concept is another study performed with fecal calprotectin (f-Cal), a marker of bowel inflammation in IBD. We found f-Cal to occur at high levels in AS subjects (without symptoms or prior diagnosis of IBD) compared with controls. This evidence of subclinical bowel inflammation present in AS again points to mucosal dysregulation as a key feature and a possible trigger for the disease.
Following the creation, validation and publication of our inflammatory back pain instrument, we were able to collaborate with the CDC and NHANES to determine the first national estimate of HLA-B27, inflammatory back pain and axial spondyloarthritis (SpA) in the U.S. Our three publications have shown that (1) HLA-B27 prevalence averages 7 percent and declines with age (2) using published case definition criteria, SpA may affect up to 1 percent of U.S. adults, greater than the prevalence reported for rheumatoid arthritis, and (3) inflammatory back pain prevalence ranges between 5 and 6 percent in U.S. adults. HLA-B27 declining with age suggests a strong genetic risk factor for mortality; this connection needs further exploration.
Program Interactions in Ankylosing Spondylitis
- National Institute of Arthritis and Musculoskeletal and Skin Diseases — Michael Ward, MD
- University of Texas Health Science Center at Houston — John Reveille, MD
- University of California, San Francisco — Lianne Gensler, MD
- Stanford University — Eswar Krishnan, MD
- University of Oregon — Atul Deodar, MD
- University of Toronto — Robert Inman, MD
- University of Alberta — Walter Maksymowych, MD
- University of Queensland — Matthew Brown, MD