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Reactive Arthritis

The development of a spondyloarthropathy phenotype is the result of a complex interaction between environmental triggers acting on a genetically susceptible individual reactive arthritis, reactive artritis, new treatments. 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. Itís 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 reactive arthritis, reactive artritis, new treatments.

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 reactive arthritis, reactive artritis, new treatments.

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 donít 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 itís been looked at, it does appear that T cells are mediating the disease process. However, in both spontaneous inflammatory disease in rats and spontaneous arthritis in mice it appears that CD-4 positive T cells play a critical role in the disease. In the spontaneous arthritis model in mice, animals that expressed B 27 developed disease in the absence of beta 2 microglobulin. What this means is that cell surface expression of HLA-B 27 in a folded, conformationally correct form that can present peptide, is virtually nonexistent although there are free heavy chains that are expressed. In addition, lack of beta 2 microglobulin causes a defect in the selection of the CD-8 positive T cells. So for example, in this model system, it is extremely unlikely that a straightforward arthritogenic peptide mechanism is working. There are data that support that hypothesis in HLA-B 27 transgenic rats, although there is no direct evidence indicating what the arthritogenic peptides are. There are other components of this system which have not been easily explained. One is the requirement for over-expression of HLA-B 27.

There is sort of a new concept evolving in this field and I want to bring that to your attention today. Normally when class I molecules are synthesized, shortly after the heavy chain is made it folds into a conformation that is capable of binding beta 2 microglobulin and peptide and then makes its way to the cell surface where it can be recognized by T cells. Weíve shown recently that in addition to this normal pathway of B 27 assembly, that B 27 has a tendency to miss-fold. Interestingly this miss-folding is entirely dependent on the B pocket structure and the B pocket of B 27 is critically involved in the peptide selection process, and in fact it is very similar in all of the B 27 subtypes but differs between alleles and has been hypothesized to be critical for the arthritogenicity of HLA-B 27. We have hypothesized that miss-folding may have consequences that are

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 in pathogenesis.

Let me first show you some of the examples that are these diseases. These poor boys got a spondyloarthropathy. All of them are 27 boys. All of them got peripheral arthritis in their initial months of disease and some of them for a few years. Then _ affecting the lower limbs. Throughout the course of their disease they present a series of symptoms that define their final diagnosis. Some of those symptoms were involving the axial joints, specifically the sacroiliac joints and the spinal joints. Some of them 

Another way to look at the importance of these disorders is to look at the prevalence. So the prevalence of these disorders is very high in native populations of some countries. So these are people from Canada, Alan Rosenberg and others. In the U.S. similar groups, and similar groups or ethnic groups in Russia. These forms prevail in those populations. The other way is to look at the population of patients with ankylosing spondylitis and try to look at how many of them got their initial symptoms in

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.

Letís 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. Thatís 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

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 ankylosing spondylitis or IVD or some other spondyloarthropathies. Perhaps the most important message from that paper is that those were the clinical forms at work, recognizable and those were the forms that were differentiated from JRA from the clinical points of view. Twenty-six of their patients had an idiopathic form, or letís say, a syndrome not associated with a definite spondyloarthropathy at that time. We did a follow-up, a ten year follow-up, of 21 patients with this diagnosis. We had patients

So arthritis and endocitis are the clue to recognize this form of diseases. This is comparison of our patients. Those who develop ankylosing spondylitis through the years are in the first column. And the second column are those who have JRA. Those are at six months. This is the most specific sign of spondyloarthropathies. Less commonly we found involvement of the lower spine very very rarely. _ arthritis is sometimes useful at the beginning, and the other thing is that upper limb involvement is rarely seen in reactive arthritis, reactive artritis, new treatments

This form of the disease results from the swelling of the synovial sheaths, involvement of the antithesis of the tarsal area and now we have found that there is some swelling that is becoming around the synovial area and we donít know where it is coming from. This is the posterior view of those feet and those are very characteristic.

Ankylosing spondylitis is the most well-described disease in children but there are some problems. First is name and diagnosis in accordance to adult concept disease parameters. So maybe this is one of the reasons why this disorders were rarely seen in the past, or diagnosed in the past. The diagnosis of ankylosing spondylitis requires the presence of spinal symptoms, radiographic sacroiliac which occur many years before or after peripheral arthritis. Clinical features at onset, severity of disease and some genetic markers, differentiate juvenile and adult onset forms. So this is also important at onset, especially at onset, clinical