Prof. Ohno began his talk with an acknowledgement to
Hyppocrates, Zong-Zing-Zang, and Dr. Hulusi
Behcet, who recorded the disease in Greece 2400 years ago, in China 1800 years ago and in Turkey
about sixty years ago respectively.
Prof. Ohno began his talk with an acknowledgement to
Hyppocrates, Zong-Zing-Zang, and Dr. Hulusi
Behcet, who recorded the disease in Greece 2400 years ago, in China 1800 years ago and in Turkey
about sixty years ago respectively.
"Main ocular lesions usually occur in the uveil tissue as well as in the retina. Of course, in the late stages optic nerves may also be involved, but the main area is uveil tissues, such as iris, ciliary body and cornea, as well as retina and optic nerves.
There are five minor symptoms. There is arthritis or arthropathies, epididymitis, ileo-caecal ulcers, vascular lesions and Central Nervous System symptoms, but another specialist will talk about these regions.
In 1964, when Prof. Bietti in Rome university reported the incidence of BD in the world, Japan had the most - 412 reports, followed by Italy, Greece, Turkey, and so on. So even at that time the researchers felt that this disease may have some world distribution, that is not equal in the world. When I put his data on a map, they showed quite biased geographical distribution in the world. There are very few reports from European countries and from the United States, but the number is much much lower than what we have in this area. In Korea they also have many many patients. In China, of course the population is so huge, there are many patients. The number is still increasing. I'm sure not only in Turkey and Japan, but also in many areas between the latitude 30-45degrees north we have many patients. There are many patients, not only in Egypt, Tunisia, Algeria and Morocco, but also in southern parts of Spain and Portugal. You can easily see that this disease has quietly biased geographical distribution, between Japan and Morocco or Portugal. And most of these countries are situated between the latitude 30-45degrees north. You can easily imagine this area that used to be "The Silk-Road" for thousands of years. That's why I thought that the nick-name for this disease may be "Silk-Route Disease" or "Silk-Road Disease".
So to understand better the true idiopathology of this disease we should think something in the history- there are maybe some things in the history, I think. Of course if we didn't get BD we may be happier, but I'm sure there maybe some other advantageous genetic affects. Probably our ancestors have succeeded in coming all the way from western Asia to Japan, so there may be some advantages, genetically or others. So, anyway, I would like to look for positive aspects, not negative aspects.
Another interesting thing - In 1972 I first found the close association of HLA B-51 with Behcet's Disease. There are many many succeeding reports just the same as our data in other countries, especially along the silk-road. Anyway, the same HLA B-51 association has been found not only in Japan, but also other countries, where there are many patients with BD. But this is just a genetic predisposition. Almost all of them with B-51 will never develop BD. Another factor is needed for this disease. The genetic blocker for controlling HLA B-51 positive E or negative E is controlled by this gene, located on the short arm of chromosome number six.
It's apparent that BD is often seen in areas where there are higher frequencies of HLA B-51. But another important factor is that, although there are more than one million Japanese-Brazilians populating San-Paulo, there are no patients with Behcet's Disease at all. Neither in Hawaii, nor in California. So the genetic factor is just one of the factors predisposing to BD, not all of them.
In Behcet's patients who have anterior segment ocular inflammation, such as anterior uveitis, their retina, their optic nerve may be in tact, not involved, so visual prognosis is usually much better in this type of patients. However, in those who have posterior segment involvement especially retina or optic nerve, their visual prognosis may be much worse. In BD most of the anterior segment involvement may be iritis or iridocyclitis. They may sometimes exhibit hypopyon in the arterial chamber. They may sometimes exhibit hypopyon or iridocyclitis. But if they have no involvement in the posterior segment, their visual prognosis can be usually much better. However if there are secondary cataract or secondary glaucoma, they may sometime have worse visual prognosis. So you should be careful. If they have only anterior segment involvement, all they need is usually dilating drops and corticosteroids eye-drops. They may not have to take systemic drugs.
In the patient with posterior segment involvement they may have vitreous opacities, retinitis, retinal vasculitis, retinal pigmentary uveitis, choroiditis and optic neuritis.
Unfortunately, most of the patients with BD have both anterior segment as well as posterior segment inflammation. That's why the visual prognosis is usually much-much worse than other types of uveitis.
There may sometimes be very severe retinitis or retinal choroiditis. Although before these ocular attacks they have 20/20 vision, after this ocular exacerbation, their best visual acuity may be sometimes 20/40 or 20/100 and they may never come back to normal. They may often exhibit this type of hyper permeability in the retinal vessels, so they often develop Crowning Retinal Edema, and then this may also cause decreased vision.
In this patient the retinal vessels are almost all obliterated, and diffuse retinal atrophy as well as optic atrophy are seen in this case, and in this situation it may be very difficult for us to recover of lesion again.
In this graph, the patients' visual acuity was around 20/50 or 20/60, and in eight years their average visual acuity was only 2200 (0.1). Although all of them are given cyclosporine A, sometimes FF5 or 6, colchicin, corticosteroids and everything we can get, still this disease shows very bad visual prognosis. Although there are many new immunosuppressive drugs available for the treatment of Behcet's Disease, this disease is still challenging, and we are not satisfied with the drugs.
There are many complicated epimechanisms involving neutrophilic leukocytes, inflammatory cells and so on. Colchicin is effective for the suppression of polymorpho-nuclear leukocytes. Cyclosporine A is effective for the suppression of TH1 cells, helper T-cells. We still need much-much more investigation. For example, TNF-alpha. Of course, the TNF-alpha is regularly produced even in healthy controls, but in the case of patients with aphthae inflammation, their TNF-alpha production is significantly increased, enhanced. So we thought we may be able to suppress this disease by decreasing the TNF-alpha production. We started an early pilot clinical trial last year from August, using mouse-human chimeric antibody, monoclonal antibody, against TNF-alpha. This is the first time I can release this information, the first discovery in the world utilising anti TNF-alpha monoclonal antibody.
This is the first case in the world, who was a 47yo man, and he had repeated ocular attacks in January, March, April, June and July 1999. Although he was taking cyclosporine A, colchicin and so on, he was losing vision in his second eye rapidly, so we thought that he may also lose his only vision in the right eye, and we decided to try this new monoclonal antibody with his informed consent. He got four intravenous treatments. And fortunately, this new trial was quite effective. We were very much surprised.
This is the second case. He also responded to this new trial. This is the third case. She also responded well to this new trial.
Anyway, we have many other possible immunotherapies for the treatment of Behcet's Disease, and we are hoping some of them may be very applicable in the clinical situation for the treatment of Behcet's Disease.
This is Behcet's Disease written in Arabic. The father of Dr. Behcet was originally an Arab. He moved to Turkey at the age of Kemal-Ata-Turk. So he is originally an Arabic man, so Behcet is originally an Arabic word, not a Turkish word. And what I am going to tell you is that the meaning of Behcet is HAPPINESS. So I can translate that Behcet's Disease is a Disease of Happiness. You don't think so, yeah, I really don't. But we have to accept it. Ironically, this disease can be translated in English - Disease of Happiness. I cannot understand, I don't understand it either, but this is it. I completely agree with you that you may never be able to accept this is a disease of happiness, but this is the true meaning, and I sincerely hope that you will continue your fight against Behcet's Disease.
Thank you very much." (Prof. Shigeaki Ohno, May 2000)