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Psoriatic Arthritis

The development of a spondyloarthropathy phenotype is the result of a complex interaction between environmental triggers acting on a genetically susceptible individual. 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.

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.

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.

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.

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. We’ve 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.

The most easily recognizable form of this disease is the combination of arthritis.

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 patients with spondyloarthropathies in the first six months of the disease. What is distribution of the findings? Well, in this graph you can see the relative frequency of _ and spondyloarthropathies. This is a group of all the spondyloarthropathies. And you can see in the gray column what happens at six months, and then at 12 months and then at 10 years. The frequency of the _higher, the higher is in the tarsal area, then becomes the plantar fascia, the Achilles tendon, then the iliac crest very rarely. We don’t see upper limb involvement in general.

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 don’t 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 symptoms are different. Children with ankylosing spondylitis present with peripheral arthritis. Adults most of the time present with actual involvement. This is also an example. This is a group of patients with ankylosing spondylitis. All of them have got the same disease but they develop actual symptoms at different times. Some of them have got juvenile ankylosing spondylitis, some of them have got adult ankylosing spondylitis. And this is happening in many racial and geographic areas in the world. So the most common form of the onset of this disease, as mentioned before, C syndrome. Actual disease becomes 5-10 years after onset.