Adamantiades-Behçet’s Disease: Demographic and clinical comparison between Iranian and multinational German populations

, Adamantiades-Behçet’s disease (ABD) is a chronic, recurrent inflammatory disease with an unclear aetiology. Major and minor clinical signs characterize ABD. Major signs generally comprise oral and genital aphthae and skin and eye manifestations. Minor signs include joint, neurological, and gastrointestinal symptoms and vascular involvement. This work aims to compare the prevalence and clinical manifestations of ABD using available study results from Iran and Germany.This report is based on statistical data from Iran and Germany. A long-term study over 35 years from the Rheumatology Research Center, Shariati Hospital, Tehran University of Medical Sciences, and a large German epidemiological study dealing with data from the German Registry for ABD and data on the disease in Europe are the information sources. Additionally, data from recent ABD studies listed in PubMed are used.Although the prevalence of ABD in Iran, with 80 patients per 100,000 inhabitants, is markedly higher than in Germany, with 4.2 patients per 100,000 inhabitants, the male-to-female ratio and age of onset are similar in the two populations. In Iran, the male-to-female ratio is 1.3:1, and the average onset age is 26 ± 11.3 years. In Germany, the male-to-female ratio is 1.4:1, and the average onset age is 27.7 ± 11.6 years. The incidence of the disease is decreasing, both in Iran and other parts of the world.Recurrent oral aphthae were the most common onset manifestation in patients of both Iran (82.7%) and Germany (84.5%), with ocular manifestations more common onset signs in Iran (8.7%) than in Germany (5.1%). Except for recurrent genital ulcers, which were more common in women in both countries, all other clinical signs – except oral aphthae – were more common in male patients in both countries. Minor clinical signs differed.A markedly different prevalence was observed in the study populations of Iran and Germany, with the disease being more common in Iran. However, despite the different origins, demographics and major clinical signs of ABD were similar in both countries. ABD is most frequently detected in young patients.


Introduction
Adamantiades-Behçet's diseas (ABD) is a chronic inflammatory disease with characteristic clinical symptoms and an unclear aetiology.According to the general viewpoint, it is a vascular disease.Epidemiological studies have confirmed that environmental factors act as triggers in genetically susceptible patients, and microbial agents are the main environmental factors [1][2][3].The geographic area of ABD distribution is mostly from 30°-45° north latitude.This corresponds to the course of the ancient Silk Road, which led from China via the Far East and the Mediterranean countries to Europe.Because of this epidemiological aspect, ABD has also been called "Silk Road disease" [4,5].Iran is located on the ancient Silk Road and is considered among the countries with the highest ABD prevalence worldwide.Historians say the high prevalence of ABD in Iran is due to Turkic tribes from China.This is due to the associated genetic mixing of Iran's immigrant and indigenous populations [5,6].Turkey, with up to 420 cases per 100,000 inhabitants [7], exhibits the highest ABD prevalence in the world.Iran stands at 68-80 cases per 100,000 [7,8] after Turkey, Israel with 146 per 100,000 [9], and China with 110 cases per 100,000 inhabitants [10], in the fourth place.As a result of globalization, incidence and prevalence rates in Western industrialized countries, including Germany, have increased due to Asian and South-eastern European immigration.As a result, physicians in Europe are increasingly confronted with ABD [1,11].Germany's nationwide prevalence of ABD is 0.9 per 100,000 inhabitants [11].Conversely, Berlin, as a city with one of the largest Turkish communities in Germany and a high proportion of migrants, has a prevalence of 1.47 per 100,000 inhabitants [12].The clinical diagnosis of the disease is made according to the criteria of the "International Team for the Revision of the International Criteria for Behçet's Disease (ICBD) (Table1) [13].Therapy is carried out according to international standards, mainly with corticosteroids, often in combination with immunosuppressants, depending on the organ(s) involved and the patient's condition [14,15].[7,16,17].In 1990, the Deutsches Register Morbus Adamantiades-Behçet (DR-MAB) was founded under Prof.Dr. Christos Zouboulis' presidency in the Department of Dermatology, University Hospital Benjamin Franklin, Freie Universität Berlin [1].Since November 2005, Staedtisches Klinikum Dessau has been the DR-MAB administrative headquarters.This organization currently coordinates the cooperation of over 30 medical departments in Germany on this topic [4,11].For different reasons, Iran and Germany have developed over the years well-organized clinical registries on ABD with their standardized questionnaire This study compared clinical data from these two registries.

Material and Methods
In this study, the patient data and the frequencies of recorded clinical symptoms were documented using the standardized questionnaire in the participating centers.From 1975 to October 2014, 7,187 patients from all over Iran were referred to the ABD center of the RRC of the Tehran University of Medical Sciences as part of a longitudinal study.This study from 2016 [7] shows that 6,075 patients were older than 16 years, of which 3,403 (56.0%) were male and 2,671 (44.0%) were female.A multidisciplinary team diagnosed rheumatology, dermatology, and ophthalmology specialists.Specific classifications or diagnostic criteria were not considered for diagnosis.Nonetheless, 96.8% of the patients met the ICBD [13].One hundred and five items were systematically examined for each patient in the registry [7].In the 2016 analysis, the statistical analysis included a 95% confidence interval (CI), a standard deviation (SD) (SD) for the mean, and the percentages for each item [7].Since establishing the DR-MAB in 1990 in the Department of Dermatology, University Hospital Benjamin Franklin, the Free University of Berlin until October 1997, 218 patients with ABD have been registered.Of these, 130 (59.6%) were male and 88 (40.4%) were female.This cohort included 89 (40.8%)German-origin patients, 100 (45.9%) of Turkish origin, and 29 (13.3%) of other origins.Of these patients, 196 met the RICBD [13].By 2015, 747 patients were recorded in this registry [12].Of the 747 patients, 434 (58.1%) were male and 313 (41.9%) were female [12].The statistical methods of the German study from 1997 were described as follows: Data are presented either as median values with minimum and maximum values shown in brackets or as mean values ± one standard deviation.The Wilcoxon performed statistical comparisons matched pairs test, Mann-Whitney-U test, or Kruskal-Wallis test.A chisquare test or two-tailed exact Fisher test compared clinical findings frequencies.Differences were defined as statistically significant at P < 0.05 [1].This article utilizes patient data collected from both ABD registries.This paper is a systematic descriptive study of the literature from 1995 to 2017 and compares ABD studies from Germany and Iran.A systematic literature search was performed on Medline's electronic biomedical database via PubMed.

Demographic data
The COPCORD study reported a prevalence of 80 per 100,000 inhabitants in Iran in 2016 [7] (Table 2).In Germany, a prevalence of 0.9 per 100,000 inhabitants was reported in 2012 [11], but a new study reported a prevalence of 4.2 per 100,000 inhabitants in 2015 [12] (Table 2).In 2016, out of the 6075 patients in Iran, 3403 (56%) were male and 2671 (44%) were female [7].The male-to-female ratio was 1.3, and the average onset age was 28.3 years for both sexes.Until 2012, the DR-MAB had 721 patients registered in Germany, of whom 35.8% were of German origin, and 42.7% were of Turkish origin; among them, 422 were male (58.5%) and 299 female (41.5%) [11].For the population of Turkish origin in Berlin, the prevalence of 77.4 per 100,000 inhabitants was similar to that of the European part of Turkey [11].In contrast, for German origin inhabitants, the prevalence of 0.4 per 100,000 inhabitants was comparable to that in Great Britain and the USA [11].The male-to-female ratio was 1.4:1.The average onset age was 27.4-27.7 years (Table 3) in 2012 and 2015 [11,12].Table 3 shows the reported data on average; the first disease manifestation occurs at similar ages in Iran and Germany (average age of first manifestation -Iran: 28.3 years; Germany: 27.7 years) [7,11].There was a non-significant difference in the average age of disease manifestation for patients of Turkish and German origin (patients of Turkish origin: 27 years; German origin: 28.8 years) [11].Furthermore, Table 3 shows that the ratio between male and female patients was also similar in Iran and Germany (Iran: 1.3:1, Germany: 1.4:1) [7,11].This statement only applies to the overall German study population.Among the subgroup of German patients, ABD was more common among women than men.In the subgroup of Turkish and Iranian patients, ABD was observed more among men than women.
Table 4 and Figure 1 compare the onset manifestations extracted from the Iranian study results in 2016 with the German study results from 2012.
German study from 1997 showed that epididymitis had an incidence of 15.9% [1].In 2010, an international study from Iran reported that epididymitis frequency was 8.8% in Germany and 5.6% in Iran [21].In another German study in 2012, epididymitis was reported in 10.8% of the overall study population.In comparison, prostatitis/epididymitis was twice as common in patients of German origin (15.3%) than in patients of Turkish origin (7.4%) [11].An Iranian study from 2016 shows that epididymitis frequency was lowest among Iranian patients (4.6%) [7].information on epididymitis.Recurrent oral aphthus ulcer were found in a German study from 1995 in over 80% of patients on the tongue (80%), lips (79%), and buccal mucosa (74%), with involvement in almost two-thirds of the gingiva (60%) and less than one-third on the tonsils (30%), palate (28%), and pharynx (25%) [22] (Table 7).The study results from 2016 show that 97.5% of Iranian patients suffer from oral aphthus ulcer [7].Recurrent genital aphthous ulcerations can range from millimeters to centimeters in size and heal after ten days to 4 weeks with or without scarring.They usually occur simultaneously with -but less often than -oral aphthae.In men, twothirds of aphthae were located on the scrotum and penis, and in women, more than 80% were on the vulva, with almost half of the cases on the vaginal mucosa (Table 8) [22].Table 8 displays the study results from Germany from 1995 that compare the frequency and localization of genital aphthous ulcers among the two sexes.This study from Germany also showed that genital aphthae are more common in women in the vulva area than in the cervix.They are also more common in men in the scrotum and penis than in the inguinal area.
Furthermore, 2016 study results showed that 97.5% of Iranian patients suffer from oral aphthae.Moreover, in a study from 2016 from Iran, 70.5% of male and 57.1% of female patients suffered from skin lesions.In a study from 2015 from Germany, 84.2% of male and 74% of female patients suffered from skin lesions [7,12].Table 9 compares the results of an Iranian study from 2016 with those of a German study from 2012 regarding the different skin lesions and their frequencies [7,11].Table 9 shows that skin lesions occur more frequently in Germans than in Iranian subjects.The Iranian study provided no data regarding superficial thrombophlebitis and pyoderma [7,11].10 [7,11] and Figure 4 compare ocular manifestations reported in international studies from Iran and Germany.Compared with Germany, anterior uveitis was more common in Iran (Germany 13.9%; Iran 41.1%) [7,11].The frequency of panuveitis in Germany is 67.8%.The classic ocular lesion in ABD, panophthalmitis involving all these three parts, was seen in 21.2% (CI: 1.1) of Iranian patients.Panuveitis was present in 12% (CI: 0.9).Therefore, the total frequency of panuveitis would be 33.2% in Iranian patients [31].
Retinal vasculitis occurs twice as often in Iranian patients (33.6%) as in German patients (16%).In Iranian ABD patients, cataracts were reported at 24.4% and conjunctivitis at 6.3%.No studies are available regarding the frequency of cataracts and conjunctivitis in German ABD patients since these clinical signs are not considered associated with ABD.The frequency of papillitis among German ABD patients was reported to be 0.7%, while no studies were found regarding the frequency of papillitis among Iranian ABD patients.

Discussion
This work compared the demographic data and clinical manifestations of ABD in Iran and Germany.Epidemiological studies have confirmed that geographical as well as environmental factors might contribute to the development of this disease [3].Although these two factors play a major role, possible agents, e.g., viruses and bacteria, as further triggers of thedisease should not be neglected [3].Countries that are located along the Silk Road show a higher ABD prevalence than the rest of the world [5].Interestingly and despite the different origin of patients in these two countries we could detect similar distribution in the majority of extracted data with the exception of the disease prevalence.Reported prevalence in other countries comes from Japan with 13.5-30.5patients per 100,000 inhabitants, Korea with 7.3-30.2,Iraq with 17 [25,26], United States with 8.6 [7,21], France with 7.2 [7,21], Germany with 0.9-4.2/100,000[11,12], Portugal with 1.53 [27], Northern European countries with 1.18 [26][27][28] and UK with 0.64 patients per 100,000 inhabitants [26][27][28].Thus, in Turkey, Israel, China, Iran, Japan, Korea and Iraq the prevalence of ABD is much higher than in Western European countries.In the countries compared in this study, namely Iran and Germany, a significant difference in prevalence, 80 versus 0.9 ABD patients per 100,000 inhabitants, respectively, was shown [7,11].However, the gender distribution was similar with a male-to-female ratio of 1.3:1 in the most recent study from Iran (2016) [7] compared with 1.4:1 in Germany (2012) [11].
The average age of manifestation in the 2016 study from Iran was 28.3 years [7], which is also comparable to the average age in Germany of 27.4 years [12] and the global average of 28.1 years [29].The first clinical manifestation is predominantly found between 20 and 40 years of age with comparable occurrence of oral aphthae (82.7% in Iran, 84.5% in Germany) [7,11] as an onset sign.The occurrence of major clinical signs was also similar in the two countries.A limitation of this study concerns the data of the ABD patients registries and do not reflect the data of all patients with the disease.
Adamantiades-Behçet's disease in Germany and the municipality of Berlin: results of a nationwide survey.Clin Exp Rheumatol 2006;24(5 Suppl

Figure 1 :
Figure 1: Comparison of ABD onset manifestations in Iran and Germany

Figure 2 :
Figure 2: Comparison of major clinical signs between patients from Iran and Germany

Figure 4 :
Figure 4: Frequency distribution of ocular manifestations in Iran and Germany

Table 1 :
Revised International criteria for the diagnosis of ABD

Table 2 :
Prevalence of ABD in Iran and Germany * hospital based referral patients ** community base population.

Table 3 :
Age of onset manifestation and gender distribution in Iran and Germany

Table 4 :
Onset manifestations in Iranian (2016) and German (2012) patients (%) Table 5 and Figure 2 compare the major signs of the Iranian study results from 2010 and 2016 with the German study results from 2012 and 2015.It can be observed that genital

Table 5 :
Comparison of major clinical characters Iranian and German patients (%)

Table 6 compares
Iranian studies from 2010 and 2016 with German results from 2012 and 2015.Figure 3 compares the minor signs in the 2016 Iranian and 2015 German studies.The German study from 2015 contained no

Table 7 :
Localization frequency of oral aphthae in Germany

Table 8 :
Localization of genital aphthous ulcers

Table 9 :
Skin manifestations in comparison between Iranian and German patients * = No data could be determined from Iran in 2016

Table 10 :
Ocular manifestations in comparison between Iranian and German patients