Ankylosing Spondylitis (AS) is one of the major forms of chronic inflammatory arthritis and is the prototypical example of the spondyloarthropathies, a group of chronic autoimmune joint diseases. Ankylosing Spondylitis has a global distribution, though rarer in Africans. It is characterised by arthritis affecting the spine and pelvis. It specifically involves the sacroiliac joint and initially causing pain and reversible stiffness (stiffness in the mornings that goes away later in the day with exercise) but leads to progressive joint fusion and irreversible stiffness and deformity in a number of cases.
Twin studies have confirmed that susceptibility to AS is genetically determined. There is a strong association with the HLA class I molecule HLA-B27, found in upwards of 90% of patients. Association of AS to B27 is amongst the strongest genetic associations with a common disease, although the mechanism of action remains uncertain. Ankylosing Spondylitis is thought to be triggered by exposure to a common environmental pathogen. Proposed mechanisms include the ‘arthritogenic peptide’, ‘molecular mimicry’ and endoplasmic reticulum stress due to B27 misfolding and accumulation. The arthritogenic peptide theory proposes that disease results from an HLA-B27 restricted cytotoxic T cell response to a peptide or peptides found only in joints and other affected tissues. The molecular mimicry theory proposes that some invading pathogens share antigenic determinants with native cell surface antigens in the joint resulting in an autoimmune response.
Different B27 alleles have different strengths of association with AS, making genetic testing useful over and above serological testing. HLA-B*27:02 and B*27:05 are strongly associated. Until recently B*27:06 and B*27:09 were thought to be protective but a number of AS cases have now been reported in patients carrying these alleles, making these alleles protective only relative to the strongly associated alleles.
Family studies suggest that less than 50% of the overall genetic risk is due to HLA-B27. HLA-B27 is found in 8 – 10% of the population with only a minority of carriers going on to develop the disease. It is likely that other genes both within and outside the MHC are involved. Other MHC genes which have shown some association in studies include HLA-B*40:01, B*52 and B*38. One haplotype study looking at the HLA-B – DRB1 haplotype has suggested the existence of non B27 genes in AS carried by both B27 positive and B27 negative individuals though the actual association was not identified. A number of non HLA genes have been shown, through genome wide association studies, to be associated with AS. These include the Interleukin-23 Receptor (IL23R) and the protein cleaving enzyme Endoplasmic Reticulum Aminopeptidase 1 (ERAP1).
The strong association of HLA-B27 with AS makes B27 testing a useful component of the diagnostic work up which includes a physical examination, use of X rays MRI and a check for family history of AS. Waiting for a patient to fulfil all the classification criteria for a diagnosis of AS may been too late in that the damage to joints would already have happened. The value of B27 testing is that it allows a presumptive diagnosis and early treatment in patients showing some of the symptoms.
Do you or someone you know suffer from Ankylosing Spondylitis or are you a researcher working in this area? Please join the conversation. Leave a comment. Thanks.
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