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Ankylosing Spondylitis

The development of a spondyloarthropathy phenotype is the result of a complex interaction between environmental triggers acting on a genetically susceptible individual ankylosing spondylitis, ankelosing spondylitis, spondilitis, ankalosing. The striking specificity of these diseases for individuals with B-27 remains the single most striking genetic clue to the etiology and the pathogenesis, however it is also quite clear that there are many other genes involved in determining susceptibility. For example, twin studies have shown that HLA-B 27 positive monozygotic twins have a concordance rate of about 75% for disease, whereas this drops to about 25% in B 27 positive dizygotic twins. Again, emphasizing the role of other genes. It’s also been suggested in the past few years that the contribution that B 27 makes to the overall susceptibility is somewhere around 20% or less. There are currently genome-wide surveys going on to try to identify other genes that are involved in susceptibility ankylosing spondylitis.

With regard to environmental triggers, there is the obvious well known triggering action of bacterial pathogens, particularly JRAM negative organisms. But there are some rather recent variance modeling studies to suggest that the majority of the susceptibility is actually genetic, implying that whatever the environmental triggers are they are probably relatively ubiquitous.

The predominant hypothesis in the last decade or so to explain the role that HLA-B 27 plays in disease pathogenesis argues that it is a result of its peptide binding specificity. So it is hypothesized that B 27 can select and present arthritogenic peptides and these peptides presumably are arthritogenic because they resemble in some way a pathogen derived peptide and thus can stimulate the proliferation of auto-reactive B 27 restricted T cells. This hypothesis has really not been proven, in fact to date there are no arthritogenic peptides that have been identified and studies looking for auto-reactive CD-8 positive B 27 restricted T cells are fairly limited.

Immuno-histochemical analyses of very early sacroiliac lesions in patients with ankylosing spondylitis reveal a preponderance of CD-4 positive T cells. Lots of CD-14 positive or activated macrophages and increased levels of messenger RNA for TNF alpha, interferon gamma and IL-4. Thus neither a TH-1 or a TH-2 profile. In comparison, peripheral joint fluid more typically will show similar numbers of CD-4 and CD-8 positive T cells and more of a TH-2-like pattern with IL-4 and IL-10.

So what about transgenic animal models? Well, there are three systems where expression of HLA-B 27 in rodents can lead to an inflammatory arthropathy. I really don’t have time to go into each of these model systems in any great detail, so I call your attention to relatively recent review articles for those of you who are interested in further reading on this subject. I do want to make a couple of important points about the model systems. Where it’s been looked at, it does appear that T cells are mediating the disease process. However, in both spontaneous inflammatory disease.

So I emphasize right now that this is theoretical, although clearly HLA-B 27 miss-folds, the consequences are unknown and their relation to pathogenesis is unknown. But the main point that I want to leave you with is that miss-folding presents an alternative to the arthritogenic peptide hypothesis and may be important.

So there are some elements in common that we can take for a concept of these disorders and these elements are: that this is a group of HLA-B 27 associated clinical conditions, syndromes and diseases that mainly affect synovium of the joints, the _ sheaths and bursa. Predominantly involving the lower limbs. There are some less common elements and these are the sacroiliac joint and the spinal joint involvement throughout the course of the disease, that happen in proportion of cases. That some of them get infections, especially enteric infections at three years of their initial symptoms. There is also wide spectrum of articular manifestations. These are the data that we can take to conceptualize what are spondyloarthropathies.

Let’s take them one by one. First the isolated conditions I mentioned before. The more common presentation of these disorders are arthritis, peripheral arthritis and these pose special problems for many years, because patients with arthritis were diagnosed as JRA. That’s because they fulfill the diagnosis criteria or JRA. That was because _ is not a diagnostic exclusion in the list of exclusions of the diagnosis. And as I mentioned before, 66% - 75% of these patients with B 27 have got ankylosing spondylitis. This is exemplified in one this paper, this is one of our papers from 1995. Most of these cases are initially diagnosed as ankylosing spondylitis, ankelosing spondylitis, spondilitis, ankalosing

There are two other isolated conditions which are readily seen. These are emphacitis, this has been described as effecting the antithesis of the feet. Also tenosynovitis. What they found that they are manifestations of patients who later on develop all the features of spondyloarthropathies. But I think these are rare forms of the disease. More rarely seen is uveitis as an initial manifestation of a spondylus without particular symptoms.

The most easily recognizable form of this disease is the combination of arthritis and emphacitis. This was first described by Rosenberg and Petty in 1982 and in fact they presented their first report in this city in 1981. They studied 39 Canadian and Amerindian children who had arthritis and emphacitis. At that time there were some that had already a definite diagnosis of new treatments