Key Points
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To date, >40 genetic variants have been identified that influence the risk of developing ankylosing spondylitis (AS), including HLA alleles such as HLA-B27, among other, non-HLA alleles
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Genetic studies have also provided strong evidence of a role for the IL-23 pathway in AS pathogenesis
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Other pathways associated with AS include peptide handling prior to HLA presentation, innate and adaptive immune cell differentiation and activation, and bacterial sensing in the gut
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The demonstration that patients with AS have a distinct gut microbiome is consistent with theories that AS is caused by IL-23-dependent interactions between the gut microbiome and the host immune system
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Data on AS genetics have provided preliminary support for the use of therapies targeting the IL-23 pathway and identified other potential targets, including aminopeptidases and the gut microbiome
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Studies performed to date have uncovered less than one-third of the overall genetic risk in AS; new, larger studies should help define the immunopathogenesis of AS and related diseases
Abstract
Ankylosing spondylitis (AS), an immune-mediated arthritis, is the prototypic member of a group of conditions known as spondyloarthropathies that also includes reactive arthritis, psoriatic arthritis and enteropathic arthritis. Patients with these conditions share a clinical predisposition for spinal and pelvic joint dysfunction, as well as genetic associations, notably with HLA-B*27. Spondyloarthropathies are characterized by histopathological inflammation in entheses (regions of high mechanical stress where tendons and ligaments insert into bone) and in the subchondral bone marrow, and by abnormal osteoproliferation at involved sites. The association of AS with HLA-B*27, first described >40 years ago, led to hope that the cause of the disease would be rapidly established. However, even though many theories have been advanced to explain how HLA-B*27 is involved in AS, no consensus about the answers to this question has been reached, and no successful treatments have yet been developed that target HLA-B27 or its functional pathways. Over the past decade, rapid progress has been made in discovering further genetic associations with AS that have shed new light on the aetiopathogenesis of the disease. Some of these discoveries have driven translational ideas, such as the repurposing of therapeutics targeting the cytokines IL-12 and IL-23 and other factors downstream of this pathway. AS provides an excellent example of how hypothesis-free research can lead to major advances in understanding pathogenesis and to the development of innovative therapeutic strategies.
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Brown, M., Kenna, T. & Wordsworth, B. Genetics of ankylosing spondylitis—insights into pathogenesis. Nat Rev Rheumatol 12, 81–91 (2016). https://doi.org/10.1038/nrrheum.2015.133
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