Epidemiology of Adamantiades-Behçet's DiseaseBy Christos C. ZOUBOULIS (Germany)
Adamantiades-Behçet's disease is a universal rare disorder with varying prevalence. It occurs endemically in the Eastern Mediterranean area and in Central and East Asia. The spread of these geographic areas along the old silk route and associated immunogenetic data support the hypothesis of distribution through the immigration of old nomadic tribes. Transfer of genetic material and/or of exogenous agent(s) may have been responsible for the expansion of the disease.
The highest prevalence of the disease has been reported in Northeastern Turkey (370 patients per 100,000 inhabitants), while the overall prevalence in Asia is 20- to 30-fold lower and in Europe and the U.S.A. more than 150-fold lower. Single or a few cases have been reported in all continents.
In countries with several ethnic populations, certain ethnic groups are mainly affected. In Taiwan, all 103 patients diagnosed between 1970 and 1988 were Chinese. In Iran, Turks presented a significantly higher prevalence than Caucasians and Semites, while no patient was found among Zoroastrians, who are isolated-living Caucasians. In Kuwait, Kuwaiti Bedouins were not affected, whereas 1.35:100,000 non-Arab Kuwaiti were diseased. In Berlin-West, the prevalence among Turks was 20.75:100,000 inhabitants of Turkish origin compared to only 0.42:100,000 Germans in 1989.
In ethnic populations the prevalence of the disease seems to be strongly dependent on the geographic area of their residence. The prevalence in Turks was calculated to decrease up to 18-fold by moving from Eastern Turkey to Germany. The prevalence of the disease in Japan decreased up to 30-fold by moving from northern to southern Japan and was annihilated in Japanese living in Hawaii and in the U.S.A. These data indicate that environmental factor(s) possibly trigger(s) the onset or the development of the disease in genetically determined populations.
Long-time studies have found a throughout increasing prevalence, which may be due to the chronic character of the disease. In Japan, there were 6.3-8.5 patients per 100,000 inhabitants in 1972 and 13.5:100,000 in 1991. In Berlin-West, 0.65 patients per 100,000 inhabitants were detected in 1984 and 2.26:100,000 in 1994. In Rome, Adamantiades-Behçet's disease was found responsible for 3% of uveitis cases between 1968 and 1977, but for as much as 7.5% between 1978 and 1987.
Data on the incidence of the disease are sparse and ambiguous. In Japan, a country with well organized registration of patients with Adamantiades-Behçet's disease, 0.89 new cases per 100,000 inhabitants have been diagnosed in the year 1984. In 1990, 0.75 new cases:100,000 have been registered indicating the reaching of a plateau after a rapid increase of incidence since 1972. In Taiwan, 5 patients/year visited 6 major medical centers for the first time from 1979 to 1983 and 14 patients/year from 1984 to 1988.
Age of Onset
The disease usually occurs around the third decade of life. An average age of onset of 31.7 years was recorded in East Asian countries, 26.5 years in Arab countries, 25.6 years in Turkey, 19.9 years in Israel, 25.9 years in Europe and 28.3 years in the Americas. Cases of early and late onset have also been reported (months to 72 years). Juvenile disease was estimated in France to be 0.17 patients per 100,000 inhabitants and reported in 1.5 to 20.8% of patients in different countries.
In contrast to old reports about androtropism, current studies register an approximately equal male-to-female ratio in several populations. Androtropism is still observed in Arab countries, while gynaecotropism is evident in some northern European countries and in the U.S.A.. Japanese studies has shown that there is a real increase in the numbers of female patients which is associated with a trend towards a milder disease.
Familial occurrence is more frequent in Korean (15.4%) than Japanese or Chinese (2.2-2.6%) families (p < 0.001). Also Arabs, Israeli and Turks presented higher frequencies of familial cases (2.0-18.2%) than Europeans (0.0-4.5%; p <0.001). Juvenile patients exhibit higher familial occurrence rates than adult ones.
Oral aphthous ulcers represent the onset feature of the disease in the majority of the patients worldwide (47-86%). Genital ulcerations (0-18%), skin lesions (0-27%) - especially erythema nodosum (0-19%) -, ocular lesions (0-35%), arthropathy (0-24%), neurological features (0-12%) and vascular involvement (0-3%) can also occur as onset lesions. The high frequencies of mucocutaneous and ocular lesions as onset lesions confirm the importance of these clinical features for diagnosis. Highly recurrent oral aphthosis is a warning signal for Adamantiades Behçet's disease. Fifty-two per cent of 67 prospectively evaluated patients with recurrent oral aphthosis (in average 10 recurrences per year) in Korea developed Adamantiades Behçet's disease in 8 years after development of oral aphthous ulcers.
Oral aphthous ulcers (92-100%), genital ulcerations (57-93%), skin lesions (38-99%), ocular lesions (29-100%) and arthropathy (16-84%) are the most frequent features of the disease. Sterile pustules (28-66%) and erythema nodosum (15-78%) are the most frequent skin lesions. A positive pathergy test has been reported in 6-71% of the different patients groups. Lower rates of positive pathergy test were assessed in European, U.S. American and Brazilian patients (32%) than in patients in the rest of the world (54%, p <0.001) and higher rates of arthropathy in Europeans, U.S. Americans and Brazilian (62%) than in the latter group (41%; p<0.001). Gastrointestinal features were assessed more frequent in Japanese and European (16%) than in Korean and Turkish patients (3%, p < 0.001). Ocular lesions in south-eastern European patients (Italian and Greek) were significantly more common than in south-western as well as northern European patients.
HLA-B51 is significantly associated with Adamantiades-Behçet's disease. However, none of the functional correlates appear to be restricted by HLA-B51. Current evidence indicates that HLA-B51 is not involved directly in the etiology of the disease but might be closely linked to disease-related gene(s). On the other hand, HLA-B51 was found to be a marker for unfavorable prognosis, especially for an earlier development of the disease, for ocular lesions and vessel involvement. HLA-B5-positive German individuals as well as from other northern European countries were detected to present a lower relative risk for the disease compared to southern Europeans. The relative risk of HLA-B51 individuals for the disease does not follow the world-wide distribution of HLA-B51; it is increased in a small geographic area which well correlates with the major trade routes of the antiquity.
Course and Prognosis
Adamantiades-Behçet's disease is usually diagnosed with a delay of 1-15 years after the appearance of the first symptom. The disease exhibits a potentially severe course with mortality rates of 0 to 6.3%, mostly involving male patients. The real increase of female cases in Japan are associated with a decrease of the mortality rate, namely from 1% in 1972 to 0.4% in 1991. Central nervous system, pulmonary as well as large vessel involvement and bowel perforation are the major life-threatening manifestations. Blindness and the consequences of central nervous system involvement are the most disabling features. There is evidence that a lethal outcome is often due to delayed diagnosis and treatment. HLA-B51 positivity, male gender and early development of systemic features are considered markers of severe prognosis. Spontaneous remission of certain or of all manifestations have been observed in a part of patients several years after the onset of the disease.