If HLA-B27 is necessary in the great majority of patients to get the disease, which other factors are needed? There is evidence that bacterial infections or bacterial exposure is an important, if not essential, trigger. First of all, this comes from the relationship between AS with reactive arthritis (ReA) and with inflammatory bowel disease. ReA can occur shortly after a preceding bacterial infection of the gut with enterobacteriae or the urogenital tract with Chlamydia trachomatis. 20-40% of these patients develop the full clinical picture of AS 10-20 years after the initial infection, if they are positive for HLA-B27 . Such a relationship between bacterial infections and AS is also supported by older indirect data. In the 1940s and 1950s arthritis associated with urogenital infections was associated with the development of ankylosing spondylitis in Sweden in a higher percentage than 20 to 30
years later . Only consequent and long-term antibiotic treatment later on was the main difference in the management of these patients. Similarly, AS and related diseases were more severe in lower social classes with less hygiene (without a refrigerator) when investigated in North Africa , and AS starts at an earlier age and runs a more severe course in countries such as Mexico , China , and North Africa  when compared with Western Europe, suggesting that frequent and repeated bacterial infections play an important role for first disease manifestation at young age and for severity of disease.
Although only less than 10% of AS patients recall an earlier reactive arthritis, many of the gut or urogenital infections preceding the clinical manifestation of ReA can be asymptomatic. Especially infections with Chlamydia trachomatis or Yersinia enterocolitica go often along with no or only a few clinical symptoms. Indeed Chlamydia trachomatis has been detected in synovial fluid or synovial membrane of patients with so-called undifferentiated oligoarthritis (without clear clinical or laboratory evidence of a preceding infection) in up to 30% .
Despite the fact that IBD cannot be seen as a bacterial infection stimulation of the immune system by local gut bacteria as a consequence of lesions in the gut mucosa serves most probably a similar purpose. Patients with IBD who are positive for HLA-B27 have an especially high risk to develop AS. In one large study 54% HLA-B27-positive Crohn's patients developed AS, while AS could be diagnosed only in 2.6% of HLA-B27-negative Crohn's patients . Although again less than 10% of patients with primary AS do have clinical evidence of IBD it has become clear that in up to 50% of patients with so-called idiopathic AS macroscopic or microscopic mucosal chronic lesions resembling Crohn's disease can be detected in the gut by colonoscopy . Thus, probably in most, if not all, of the AS patients a bacterial trigger is essential in the pathogenesis of the disease. These patients normally have to be positive for HLA-B27.
This is further supported by the B27-transgenic rat model for AS/SpA. HLA-B27 transgenic rats develop features of SpA including gut inflammation, peripheral arthritis, and psoriasiform skin and nail changes. The importance of environmental factors in this animal model is emphasised by the observation that many of these features, including gut inflammation and arthritis, do not develop in HLA-B27 transgenic rats born and bred in a germ-free environment . Germ-free animals rapidly develop inflammatory disease on removal from the sterile environment. This can be partially prevented by treatment with antibiotics .
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