Ankylosing Spondylitis - Pathophysiology

Pathophysiology

Ankylosing spondylitis (AS) is a systemic rheumatic disease, meaning it affects the entire body. Approximately 90% of AS patients express the HLA-B27 genotype, meaning there is a strong genetic association. However, only 5% of individuals with the HLA-B27 genotype contract the disease. Tumor necrosis factor-alpha (TNF α) and IL-1 are also implicated in ankylosing spondylitis. Autoantibodies specific for AS have not been identified. Antineutrophil cytoplasmic antibodies ANCA are associated with AS, but do not correlate with disease severity. In a study of 40 patients with AS, ANCA was an infrequent finding, being present in only six patients.

The association of AS with HLA-B27 suggests the condition involves CD8 T cells, which interact with HLA-B. This interaction is not proven to involve a self antigen, and at least in the related Reiter's syndrome (reactive arthritis), which follows infections, the antigens involved are likely to be derived from intracellular microorganisms. There is, however, a possibility that CD4 T cells are involved in an aberrant way, since HLA-B27 appears to have a number of unusual properties, including possibly an ability to interact with T cell receptors in association with CD4 (usually only cytotoxic T lymphocytes with CD8 react with HLAB antigen as it is a MHC class 1 antigen).

There has been a longstanding claim that AS arises from a cross-reaction between HLA-B27 and antigens of the Klebsiella bacterial genus (Tiwana et al. 2001). The problem with this idea is no such cross reactivity with B27 has been found (i.e. although antibody responses to Klebsiella may be increased, there is no antibody response to B27, so there seems to be no cross reactivity). Particular authorities argue elimination of the prime nutrients of Klebsiella (starches) would decrease antigenemia and improve the musculoskeletal symptoms. However, as Khan (2002) argues, evidence for a correlation between Klebsiella and AS is circumstantial so far, and the efficacy of low-starch diets has not yet been scientifically evaluated. Studies on low-starch diet and AS could be difficult to fund, while new biologics developed by the pharmaceutical industry may demonstrate efficacy, as well as financial benefit to the industry (whereas changing the diet would not). A randomized controlled trial in Turkey demonstrated that 12-week therapy with moxifloxacin (which would kill Klebsiella) resulted in "significant and sustained improvement" in inflammatory symptoms in patients with ankylosing spondylitis.

Toivanen (1999) found no support for the role of Klebsiella in the etiology of primary AS.