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Silk Road Disease (Behçet's Disease)

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* Disease Genes That Followed the Silk Road Identified by Science Daily

Excerpt: Researchers with the National Institutes of Health have found susceptibility to Behcet's disease, a painful, inflammatory condition, to be associated with genes involved in the body's immune response.

Although the Greek physician Hippocrates described Behcet's disease (pronounced BET'-chet's), more than 2,000 years ago, the condition existed in relative obscurity until the early 20th century. Named for the Turkish physician who first classified it in 1937, Behcet's disease is found almost exclusively in populations with origins along the Silk Road, a trading route that stretched from Europe to the Far East. Marco Polo was among the most famous travelers along the Silk Road....

* 嘴巴常破皮? 當心絲路之病 by 劉婉君

* Silk Road Disease, Behcet's & Ulcerations of the Mouth by Christine Cadena

Excerpt: Ulcers in and around the mouth are often misdiagnosed by family healthcare providers. For many adults, the complication is diagnosed as a condition related to the herpes virus. For some, however, this diagnosis may be inaccurate and the mouth ulcers, instead, may be associated with a rare disorder known as Behcet's disease....

 

• Celiac Disease
• Bamboo Spine
• Silk Road Disease
• Lactose Intolerance
• Stevens-Johnson Syndrome
• Nasopharyngeal Carcinoma
• Esophageal Cancer

Behçet disease is named after Hulusi Behçet (1889–1948), the Turkish dermatologist and scientist who first recognized the syndrome in one of his patients in 1924.

 

Essential Guide to Behcet's Disease by Joanne Zeis

 

You Are Not Alone: 15 People with Behcet's by Joanne A Zeis

 

Behcet's Disease: A Contemporary Synopsis by Gary R. Plotkin

 

Pathogenesis: The etiology is not well-defined, but it is primarily characterized by auto-inflammation of the blood vessels. Although sometimes erroneously referred to as a "diagnosis of exclusion," the diagnosis can sometimes be reached by pathologic examination of the affected areas.

The primary mechanism of the damage is an overactive immune system that seems to target the patient's own body. The primary cause is not well known. In fact, as of now, no one knows why the immune system starts to behave this way in Behçet's disease. There does however seem to be a genetic component involved, as first degree relatives of the affected patients are often affected in more than expected proportion for the general population.

Excerpts from Wikipedia.org

Behçet's disease (絲路病, 貝賽特氏症; Sometimes called Behçet's syndrome, Adamantiades’ syndrome, Morbus Behçet, or Silk Road disease) is a rare immune-mediated systemic vasculitis that often presents with mucous membrane ulceration and ocular involvements. As a systemic disease, it can also involve visceral organs such as the gastrointestinal tract, pulmonary, musculoskeletal, and neurological systems. This syndrome can be fatal, due to ruptured vascular aneurysms, or severe neurological complications.

Diagnosis: There is no specific pathological testing or technique available for the diagnosis of the disease, although the International Study Group criteria for the disease are highly sensitive and specific, involving clinical criteria and a pathergy test. Behçet's disease has a high degree of resemblance to diseases that cause mucocutaneous lesions such as Herpes simplex labialis, and therefore clinical suspicion should be maintained until all the common causes of oral lesions are ruled out from the differential diagnosis.

Visual acuity, or color vision loss with concurrent mucocutaneous lesions and/or systemic Behçet's symptoms should raise suspicion of optic nerve involvement in Behçet's disease and prompt a work-up for Behçet's disease if not previously diagnosed in addition to an ocular work-up. Diagnosis of Behçet's disease is based on clinical findings including oral and genital ulcers, skin lesions such as erythema nodosum, acne, or folliculitis, ocular inflammatory findings and a pathergy reaction. Inflammatory markers such ESR, and CRP may be elevated. A complete ophthalmic examination may include a slit lamp examination, optical coherence tomography to detect nerve loss, visual field examinations, fundoscopic examination to assess optic disc atrophy and retinal disease, fundoscopic angiography, and visual evoked potentials, which may demonstrate increased latency. Optic nerve enhancement may be identified on Magnetic Resonance Imaging (MRI) in some patients with acute optic neuropathy. However, a normal study does not rule out optic neuropathy. Cerebrospinal fluid (CSF) analysis may demonstrate elevated protein level with or without pleocytosis. Imaging including angiography may be indicated to identify dural venous sinus thrombosis as a cause of intracranial hypertension and optic atrophy.

Diagnostic Guidelines: According to the International Study Group guidelines, for a patient to be diagnosed with Behçet's disease, the patient must have oral (aphthous) ulcers (any shape, size or number at least 3 times in any 12 months period) along with 2 out of the following 4 "hallmark" symptoms:

• genital ulcers (including anal ulcers and spots in the genital region and swollen testicles or epididymitis in men)
• skin lesions (papulo-pustules, folliculitis, erythema nodosum, acne in post-adolescents not on corticosteroids)
• eye inflammation (iritis, uveitis, retinal vasculitis, cells in the vitreous)
• pathergy reaction (papule >2 mm dia. 24-48 hrs or more after needle-prick). The pathery test has a specificity of 95% to 100%, but the results are often negative in American and European patients

Despite the inclusive criteria set forth by the International Study Group, there are cases where not all the criteria can be met and therefore a diagnosis cannot readily be made. There is however a set of clinical findings that a physician can rely upon in making a tentative diagnosis of the disease; essentially Behçet's disease does not always follow the International Study Group guidelines and so a high degree of suspicion for a patient who presents having any number of the following findings is necessary:

• mouth ulcers
• arthritis/arthralgia
• nervous system symptoms
• stomach and/or bowel inflammation
• deep vein thrombosis
• superficial thrombophlebitis
• epididymitis
• cardio-vascular problems of an inflammatory origin
• inflammatory problems in chest and lungs
• problems with hearing and/or balance
• extreme exhaustion
• changes of personality, psychoses
• any other members of the family with a diagnosis of Behçet disease.

 

 

Epidemiology

The Silk Road was a network of trade routes across the Asian continent that connected East, South, and Western Asia with the Mediterranean world, as well as North and Northeast Africa, and Europe. It began in central China and the Indian subcontinent, stopping somewhere near the Mediterranean Sea. China traded silk, spices, teas, and porcelain; while India traded ivory, textiles, precious stones, and pepper. The main trade routes in the Indian subcontinent were by sea or through areas in the north. In recent years, both the maritime and overland Silk Routes are again being used, often closely following the ancient routes.

Behçet disease is considered more prevalent in the areas surrounding the old silk trading routes in the Middle East and in Central Asia. Thus, it is sometimes known as Silk Road Disease. However, this disease is not restricted to people from these regions. A large number of serological studies show a linkage between the disease and HLA-B51. HLA-B51 is more frequently found from the Middle East to South Eastern Siberia, but the incidence of B51 in some studies was 3 fold higher than the normal population. However, B51 tends not to be found in disease when a certain SUMO4 gene variant is involved, and symptoms appear to be milder when HLA-B27 is present. At the current time, a similar infectious origin has not yet been confirmed that leads to Behçet's disease, but certain strains of Streptococcus sanguinis has been found to have a homologous antigenicity.

Vasculitis resulting in occlusion of the vessels supplying the optic nerve may be the cause of acute optic neuropathy and progressive optic atrophy in Behçet's disease. Histological evaluation in a reported case of acute optic neuropathy demonstrated substitution of the axonal portion of the optic nerve with fibrous astrocytes without retinal changes. CNS involvement in Behçet's may lead to intracranial hypertension most commonly due to dural venous sinus thrombosis and subsequent secondary optic atrophy.

The syndrome is rare in the United States, but is common in the Middle East and Asia, suggesting a possible cause endemic to the tropical areas. It is not associated with cancer, and links with tissue-types (which are under investigation) are not certain. It also does not follow the usual pattern for autoimmune diseases. However, one study has revealed a possible connection to food allergies, particularly to dairy products. An estimated 15,000 to 20,000 Americans have been diagnosed with this disease. In the UK, it is estimated to have about 1 case for every 100,000 people. Globally, males are affected more frequently than females. In the United States, more females are affected than males.

In an epidemiologic study by Krause et al., 56% of patient’s with Behçet's disease developed ocular involvement at a mean age of 30. Ocular involvement was the first manifestation of Behçet's disease in 8.6% of patients.] Ocular Behçet's with involvement of the optic nerve is rarely reported. Among patients with ocular Behçet's disease funduscopic findings of optic atrophy, and optic disc paleness have been identified with a frequency of 17.9% and 7.4%, respectively. Other fundoscopic findings include vascular sheathing (23.7%), retinal hemorrhage (9%), macular edema (11.3%), branch retinal vein occlusion (5.8%), and retinal edema (6.6%). However, optic atrophy was the most significant cause of visual impairment identified in 54% of patients with ocular Behçet's disease and permanent visual impairment.

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HLA-B51

HLA-B51 (B51) is an HLA-B serotype. The serotype identifies the more common HLA-B*51 gene products.

B51 is a split antigen of the broad antigen B5, and is a sister serotype of B52. There are a large number of alleles within the B*51 allele group. B51 is associated with several diseases, including Behçet's disease.

Alleles: There are 71 alleles, 57 amino acid sequence variants in B51 of which 4 are nulls. Of these only 9 are frequent enough to have been reliably serotyped. B*5101 is the most common, but others have a large regional abundance.

Disease Associations: Bw51 was associated with Behçet's disease, in endemic (versus epidemic) mucocutaneous lymph node syndrome, susceptibility to the virus that causes German measles infection.

In Behçet's Disease: Adamanitiades-Behçet's disease (ABD) is an inflammation of the wall of blood vessels that can involve the eyes, skin, and the rest of the body. Several alleles of B51 (B*5101, B*5108, B*5105, and B*5104) are found in disease, and linkage to markers, D6S285, in the HLA locus was strong (P>0.005). Homozygotes of B51 showed considerably high risk for disease indicating a possible gene-dose effect. B51 is capable of distinguishing several varieties of disease. HLA-B51 is found more frequently in disease that has an eye involvement. However it is less common in some regions when there is increased neurological involvement. The MICA*009 allele has been found to also associated with ABD when B51 is also present, IL-8 and other cytokines may also be involved. Sister chromatid exchange has also been observed more frequently in B51(+) ABD.

However, B51 tends not to be found in ABD when a certain SUMO4 gene variant is involved, and symptoms appear to be milder when HLA-B27 is present.

 

HLA B*5101 Frequencies

Population	(%)
Bulgaria	20.9
Georgia Tibilisi Georgians	15.7
India Tamil Nadu Nadar	15.6
China North Han	14.8
Georgia Tibilisi Kurds	12.1
India Andhra Pradesh Golla	12.0
China Qinghai Hui	11.4
India New Delhi	9.8
Madeira	9.7
South Africa Natal Tamil	9.2
USA Hawaii Okinawa	8.7
Cape Verde Northwestern Islands	8.1
Cape Verde Southeastern Islands	7.3
India Mumbai Marathas	6.8
Russia Tuva pop 2	6.1
Israel Arab Druse	6.0
China Inner Mongolia	5.9
Czech Republic	5.7
Finland	5.6
Iran Baloch	8.1
Brazil	5.1
Mexico Guadalajara Mestizos	4.9
New Mexico Canoncito Navajo	4.9
China South Han	4.6
India North Hindus	3.8
Thailand	3.1
Ivory Coast Akan Adiopodoume	2.3
Singapore Chinese Han	2.3
Singapore Javanese Indonesians	2.0
Taiwan Saisiat	2.0
Kenya	1.7
Cameroon Yaounde	1.6
Senegal Niokholo Mandenka	1.6
Guinea Bissau	1.5
USA Arizona Pima	1.1
Venezuela Perja Mountain Bari	1.1
Taiwan Pazeh	0.9
China Guangdong Meizhou Han	0.5
Israel Ashk. & Non Ashk. Jews	0.5
Singapore Thai	3.0
Iran Baloch	1.0

HLA B*5102 Frequencies

Population	(%)
Mexico Sonora Seri	1.5
Thailand	1.4
Singapore Chinese	1.3
Hong Kong Chinese	1.0
USA Natives	0.8
Mexico Zaptotec Oaxaca	0.7
South Korea pop 3	0.6
Shijiazhuang Tianjian Han	0.5
China Guangxi Maonan	0.5
Japan (5)	0.4

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

* Behçet’s Disease, the Silk Road and HLA-B51: Historical and geographical perspective by D.H. Verity, et al.

Abstract: Behçet’s disease (BD), also known as the Silk Road disease, is a blinding inflammatory disorder of young adults found predominantly between the Mediterranean basin and the Orient, and is strongly associated with the major histocompatibility complex (MHC) antigen HLA-B51. In this article we review the history of Behçet’s disease since its first description by Hippocrates, the development of the trading routes collectively known as the Silk Road and the effect of population movement on the distribution of HLA-B51. The global distribution of this antigen among healthy control populations bears a striking similarity both to the ancient trading routes and the distribution of Behçet’s disease, suggesting a genetic risk that migrated in parallel with population movement between the Mediterranean and Asia. However, certain indigenous Amerindian peoples have a high prevalence of HLA-B51 but no reported cases of BD. Furthermore, a clear genealogical relationship exists between eastern, but not central, Siberian populations with the Amerindians. Since a high level of recombination within the MHC is known to have occurred in these eastern populations before their migration into Beringia, we suggest that disruption of genetic loci in linkage disequilibria with HLA-B51 may be one reason for the absence of disease in these high HLA-B51-bearing populations. However, a contributory influence of environmental factors is not excluded by this data, and the wide variation that exists in relative risk of HLA-B51 even within Europe would support other non-genetic risk factors on the Silk Road which may be absent, or non-contributory to disease, in the Americas.

 

* Behçet’s Disease: A Review by L.M. Al-Otaibi, et al.

Excerpt: The mean age at onset of BD is most commonly in the third decade, although the age at time of final diagnosis usually is in the fourth decade. Both genders can be affected, although both male and female predominance has been described in studies of affected patients from different geographic regions of the world. A higher prevalence of BD has been observed in adult females in Korea, Israeli Jews, Singapore, and Camas village of Turkey, while a higher prevalence of BD in males has been found in the West Indies, Spain, Israeli Arabs, London , Japan , Jordan, Iran and Turkey, India, Lebanon, Saudi Arabia, and Kuwait.

Behçet’s disease has a worldwide distribution, although it has a higher prevalence in countries of the ancient Silk Route (from the Mediterranean basin to Japan), suggesting perhaps that an as-yet-unknown genetically determined factor was spread via the migration of old nomadic tribes.

BD is most common in Turkey, where the reported prevalence ranges from 80/100,000 in nine villages near Istanbul to 370/100,000 in Camas village, and may be least common in the USA, where the incidence is about 1/300,000/year.

BD has also been reported in many countries such as Israel (prevalence, 120/100,000), Japan (prevalence, 15/100,000), Germany (prevalence, 2.26/100,000), Iran (prevalence, 16.7/100,000) , Iraq (prevalence, 17/100,000) , and Spain (prevalence, 0.66/100,000) ). Of interest, it was recently found that the frequency of BD in the Afro-Caribbean population of Guadeloupe (French West Indies) was at least 3/100,000)—a rate higher than those reported in some Caucasian populations (and in a population unrelated to the aforementioned Silk Route). ...

The clinical manifestations of BD may show geographic variation. For example, the pathergy reaction occurs in 57–65% of patients from the Middle East and Turkey, but has lower frequency in Western European countries Likewise, gastrointestinal disease, which occurs in about one-third of patients from Taiwan and a quarter of patients from Spain, rarely occurs in those from Jordan, Saudi Arabia, and Turkey.In childhood BD, neurological and gastrointestinal disease may be more common in patients from France and Saudi Arabia, whereas cutaneous disease occurs more frequently in Turkey....

 

* Unraveling a Silk Road Disease Mystery by National Institutes of Health

Excerpt: The distinctive distribution of Behçet's disease led researchers to suspect a hereditary component. However, even the most strongly associated genetic factor to date—HLA-B51—accounts for less than 20% of the genetic risk for the disease. To look for other factors, researchers led by Dr. Elaine F. Remmers of NIH’s National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), in collaboration with Dr. Ahmet Gul's group at Istanbul University, performed a large genome-wide association study (GWAS) of people from Turkey. The researchers examined the genomes of more than 1,200 Behçet's patients and 1,200 people without the disease, looking for tiny differences, called single nucleotide polymorphisms (SNPs), between the groups.

In the advance online edition of Nature Genetics on July 11, 2010, the scientists confirmed the association of HLA-B51 with the disease. The team also identified HLA-A as another region associated with Behçet's disease. Both HLA-A and HLA-B51 are found in a section of the genome known as the major histocompatibility complex (MHC). The MHC contains a large number of immune-related genes.

The researchers also found other potential links. To better evaluate these, they exchanged data with another group of investigators that independently performed a large GWAS for Behçet's disease in a Japanese population. That group's paper appeared in the same edition of Nature Genetics. The NIAMS researchers analyzed genetic data from 5 additional groups as well, which included populations from Turkey, the Middle East, Europe and Asia.

The researchers found associations with Behçet's disease in a known variant of the IL10 gene and in a variant located between the IL23R and IL12RB2 genes. Interestingly, the variants associated with disease in the Turkish population were identical to those in the Japanese population. This finding lends credence to a genetic link between 2 disparate populations separated by thousands of miles but tied together by the ancient trading route.

IL-10 protein is known to decrease inflammation. IL10 variants have been tied to other autoimmune and autoinflammatory diseases, including ulcerative colitis, type 1 diabetes and juvenile rheumatoid arthritis. The researchers found that people who had 2 copies of the IL10 variant produced significantly lower levels of IL-10 protein than those with normal versions of the gene.

 

* Genetic Susceptibility to Behcet's Disease: Role of genes belonging to the MHC region by Piga M, et al.

Abstract

Objective: To review the progress in the field of MHC-related genetic susceptibility to Behçet's disease (BD).

Method: Systematic review of the English literature between 1 January 1980 and 31 January 2010 using Medline. Case-control, population-based, observational cohort studies investigating the association between BD and HLA-B*51 subtypes, classical and non-classical HLA alleles and other HLA-related genes were selected. The geographical distribution of BD and these susceptibility genes was also taken into consideration. Case and familial case reports were excluded except for case series with more than two patients.

Results: Ninety articles plus 17 obtained from other sources were included in the systematic review. We have found high evidence that a core component of genetic susceptibility to BD is within the MHC region being primarily related to an HLA-B*51 subtype: HLA-B*5101/B*510101. Moreover, HLA-A*26, HLA-B*15, HLA-B*5701 and TNF-α -1031C were independently associated with BD. Data suggest that other HLA (HLA-C, HLA-DR) and HLA-related [MHC Class I chain-related gene A (MIC-A), TNF-α] genes may play a role in BD co-susceptibility or pathogenesis. Finally, the distinctive geographical distribution of BD suggested an evolutionary selection of HLA-B*51 subtypes as the major susceptibility factors for BD.

Conclusion: Further studies must be addressed to clarify the functional relevance of the different genes found to be associated with disease susceptibility and the potential interactions between genes located within and outside the MHC region.

* Genetics of Behçet Disease Inside and Outside the MHC by Meguro A, et al.

Abstract

Background: Behçet disease (BD) is a rare, chronic, systemic, inflammatory disorder characterised by recurrent ocular, genital and skin lesions. Although its aetiology is still uncertain, an intricate interplay between the environment (eg, viruses) and the host seems to initiate and/or perpetuate the disease, although the mechanism remains speculative. Since the identification of HLA-B*5101 (and more recently of MICA) as a susceptibility locus for BD, the identification of additional genetic locus/loci, whether inside, or perhaps more importantly outside the MHC has clearly stalled.

Objective: To carry out a genome-wide association study (GWAS) of BD.

Methods: 300 Japanese patients with BD and an equal number of controls were recruited. The samples were screened using a dense panel of 23 465 microsatellites (MS) covering the entire genome.

Results: The six best (of a total of 147) positively associated MS with BD were identified. Of these six, two were located within the human leucocyte antigen (HLA) class I region itself. Although one of these was clearly reminiscent of the association with HLA-B, the second, not in linkage disequilibrium with the former, was in the telomeric side of the class I region and remained to be formally identified. HLA genotyping and haplotype analysis conclusively led to the deciphering of a dual, independent, contribution of two HLA alleles to the pathogenesis of BD: HLA-B*5101 and HLA-A*26.

Conclusions: This GWAS highlights the premier genetic susceptibility locus for BD as the major histocompatibility complex itself, wherein reside two independent loci: HLA-B and HLA-A.

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Taiwan

 

貝賽特氏症（Behçet's disease），或稱貝賽特氏症候群，因好發於絲路國家，亦稱絲路病、貝歇氏病，是一種血管炎，會造成潰瘍及各種損傷，好發在20至40歲的青壯年人身上。

它肇因於基因問題引起的自體免疫異常。，主要症狀為：反覆性口腔潰瘍(recurrent oral ulcers)、反覆性生殖部位潰瘍(recurrent genital ulcers)、葡萄膜炎(uveitis)，絕大部分的患者最後會失明。

此病在中緯度地區有較高的發生率，例如土耳其一帶，為此疾病命名的醫師即為土耳其人，日本的發生率亦較其他國家來得高。目前台灣的全民健保將此一疾病列為重大傷病之一。此一疾病與基因HLA-B51有較高的相關性。

 

 

* 絲路病貝塞特氏症候群 by 蔡文展

Excerpt: 一九三七年，一位土耳其的醫師貝塞特描述他所看到一些病人的特徵並發表於醫學文獻上，從此揭開了貝塞特氏症的臨床研究；口腔長期且反覆性的潰瘍是這個病的主要病徵，除此之外，病人常合併有生殖道潰瘍、皮膚病變及關節疼痛等，嚴重的病人則會侵犯到眼睛而造成失明；另外少數的病人亦會有中樞神經的侵犯而造成昏迷甚或死亡。

說也奇怪，這個病好發的地區正好沿著古代「絲路」散布，東邊從日本韓國，經中國的北方、西藏、新疆、土耳其、中東而到達西邊的希臘；因此亦有人將此病稱為「絲路病」。貝塞特氏症在這些國家不但較為盛行，其後果也較為嚴重，病人常有失明之虞，以及大血管的栓塞、血管瘤等變化。

 

* 貝歇氏症 (Behcet’s Disease) by 中山醫學大學

前言: 貝歇氏症是個古老的疾病，好發的區域分布在中東和地中海沿線，絲綢之路沿線，特別是土耳其，中東、新疆、日本也不少，台灣也有。病人有反覆性的嘴巴潰瘍、泌尿道潰瘍、皮疹或是眼睛紅紅的發炎(如虹彩炎)等。所以經常嘴巴潰瘍、又多又大又深不要只認為那是“火氣大”哦!

什麼是白塞病病? 這是一种慢性血管炎症性疾病，是自體免疫疾病的一種，主要臨床表現為反覆性的嘴巴潰瘍、泌尿道潰瘍、皮疹或是眼睛紅紅的發炎(如:虹彩炎)等，也可累及血管、神經系统，消化道、關節、肺、腎等器官，为一系统性疾病。大部分患者預後良好，但是若有中樞神經及血管侵犯者則受累者預後不佳。EB病毒、單純泡疹病毒, 鏈球菌, 分支桿菌屬)有關係，以及免疫遺傳因素(HLA-B51)有關。

症狀: 幾乎百分之百都會嘴巴潰瘍，80%會有毛囊炎，50%會有紅色結節，60%會有打針後針孔的地方會長膿包，泌尿道和會陰部潰瘍有80%，關節炎50%，少數會有消化道潰瘍,很容易出血甚至破掉，有的會副睪丸炎，有時候會有靜脈的栓塞和發炎。眼睛的侵犯機率很高，最常見的就是虹彩炎。血管的影響常都是以靜脈為主會血管栓塞，甚至會影響到心冠動脈。在神經系统方面，可以以中風，非細菌性腦膜炎來表現。在關節方面是以2-3個對稱關節炎。在肺方面有時候會有肺栓塞，而腎臟方面有些人會出現腎炎,或是類殿粉導致的腎病變等。

什麼人容易得到貝歇氏症? 年輕人較多，大約20-35歲左右，小孩不常見。，男女一樣多，但在日本和台灣則是看到女生比較多。 貝歇氏症跟HLA-B51基因有關。

 

* Behçet's Disease in Taiwan--A review of 53 cases by Chung YM, et al.

Abstract: Clinical manifestations and immunogenetic aspects of Behçet's disease were investigated in the Veterans General Hospital of the National Yang-Ming Medical College, Taiwan. Diagnosis of Behçet's disease was made according to the diagnostic criteria proposed by the Japanese Research Committee of Behçet's disease. Fifty-three patients including 33 men and 20 women have been diagnosed as having Behçet's disease in the past 10 years; 20 cases with the complete type and 33 cases with the incomplete type. About half of these cases were diagnosed in the past 2 years, predominantly by ophthalmologists. Of the 53 cases, ocular lesions were found in 35 cases, 25 men and 10 women. The ages of the onset of the ocular lesions ranged from 10 to 50 years, with the peak distribution between 20-30 years. Bilateral involvement was seen in 24 men and 8 women, and a total of 67 eyes were affected; 37 eyes (55.2%) had the final visual acuity of 0.1 or lower. Immunogenetic study revealed that the incidence of HLA-B51 was significantly higher in the patients than in the normal population.

 

* A Genetic Study of Behçet's Disease in Taiwan Chinese by Y-M. Chun, et al.

Abstract: The frequency of HLA-A, B and C antigen in 53 patients and HLA-DR, DQ and DN antigen in 31 patients of Behest's disease was studied. All patients were Chinese, and diagnosis was made according to the Japanese Research Committee on Behcet's disease. A significantly increased incidence of HLA-B51 (P <0.001) and a significantly decreased incidence of HLA-B16 (P <0.01) was found. No significant difference was found in HLA-DR, DQ and DN antigens

 

* Estimations of Allele and Haplotype Frequencies of the HLA-A, HLA-B, and HLA-DRB1 Loci Based on the Marrow Donors of TCTMDR by 林雅惠

 

HLA-B (%)	Minnan (N=36774)	Hakka (N=4794)	Mainlander (N=5114)	Aborigines (N=233)	Total (N=46915)
5101	4.2	4.34	4.4	1.29	4.22
5102	1.17	1.62	0.94		1.19
5103	<0.01				<0.01
5104	0.01	0.02	0.01		0.01
5105	<0.01		0.01		<0.01
5106	0.01		0.04		0.01
5107	0.27	0.27	0.14		0.25
5108	<0.01				<0.01
5109	0.01		0.02	0.21	0.01

 

* Clinical Characteristics of Behçet's Disease in Southern Taiwan by Chen YC, et al.

Abstract: A total of 22 patients were found to have Behçet's disease during the period from 1991 through 1999 in the Chang Gung Memorial Hospital in Kaohsiung, Taiwan. Diagnosis of Behçet's disease was made according to the criteria proposed by the International Study Group for Behçet's Disease. Oral lesions were found in all patients, ocular lesions in 55% of patients, genital lesions in 55%, skin lesions in 90.9%, pathergy reaction in 22.7%, arthritis in 31.8%, gastrointestinal involvement in 31.8%, involvement of the central nervous system in 27.2%, and thrombophlebitis in 18%. The mean age was 35.5 years with a biphasic age distribution. The clinical characteristics of patients in this series were different from patients in other Asian countries, which suggests that geographic and genetic factors are important in the pathogenesis of the disease.

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Other Countries

 

* Epidemiology of Behcet's Disease in Thai Patients by Arromdee E, et al.

Abstract

Objective: To describe symptoms, signs, laboratory findings and to compare sensitivity of several classification criteria in Thai patients who were diagnosed with Behcet's disease.

Material and Method: Using medical records from the rheumatology unit, Siriraj hospital, all cases diagnosed with Behcet's disease by our rheumatology staff were identified and reviewed. Demographic data, clinical presentations, and laboratory data were collected. All cases were also reviewed if they had fulfilled any of the following criteria: Iran classification tree, Japanese, Korean, ISG and O'Duffy's criteria. The sensitivity of each criterion was calculated.

Results: Twenty three cases were identified during a 24 year interval (1980-2003). Our population had a mean age of 30.83 years. Common clinical presentations were recurrent oral ulcers 100% (23/23), genital ulcers 69.6% (16/23), eye involvement 52.2% (12/23), skin involvement 60.9% (14/23), GI ulcers 8.7% (2/23), epididymitis 4.3% (1/23), vascular lesions 8.7% (2/23), CNS involvement 8.7% (2/23), fever 60.9% (14/23), and positivity of the pathergy test 33.3% (3/9). The sensitivity of criteria used for diagnosis of our patients with Behcet's disease varied widely. We found that the Iran classification tree criteria had the highest sensitivity followed by those from Japan (82.6%), O'Duffy's (73.9%), ISG (52.2%), and Korean (39.1%) criteria respectively.

Conclusion: Behcet's disease is heterogeneous in its manifestations and clinical constellation of the disease varies widely among different parts of the world. This is the first epidemiologic study describing Thai Behcet's patients. We also found the Iran classification tree criteria had the highest sensitivity for diagnosis of Thai patients.

 

* Behçet's Disease in Southern Chinese Patients by Mok CC, et al.

Abstract

Objective: To describe the clinical characteristics of Behçet's disease (BD) in a southern Chinese population and compare them with those reported in other ethnic groups.

Methods: Patients with BD from 4 large regional hospitals in Hong Kong were identified from the hospital information retrieval system. Their records were retrospectively reviewed and the diagnosis was verified by at least 2 rheumatologists using the International Study Group (ISG) criteria. Demographic data and various clinical features of our patients were collected and analyzed.

Results: Between 1978 and 2000, 37 adult patients with definite BD according to the ISG criteria were identified. All patients were ethnic southern Chinese. There were 19 women and 18 men (F:M = 1.1:1). The mean age at diagnosis was 36.2 +/- 10 (18-74) years. Presenting features at diagnosis, in decreasing order of frequency, were oral ulceration (100%), genital ulceration (81%), skin lesions (73%), arthritis/arthralgia (54%), and ocular lesions (35%). Among skin lesions, the commonest manifestations were erythema nodosum (74%), folliculitis (44%), and acneiform nodules (30%). Arthritis was usually polyarticular (75%) and symmetrical, and involved the upper limb joints. Anterior uveitis was the most common ocular complication (77%) and was often bilateral. Involvement of other systems such as the central nervous system, gastrointestinal (GI) tract, and cardiopulmonary system was uncommon. Vascular complications were rare. Only 2 (6%) patients had a positive pathergy test. Our patients were followed for a mean of 59.9 +/- 52 months. Apart from recurrent attacks of orogenital ulceration and uveitis, new systemic features were unusual. One patient died of bowel perforation as a result of active GI disease. Compared with other reported series, our patients had fewer ocular and systemic manifestations, and a significantly lower incidence of the pathergy reaction.

Cconclusions: BD is rare among southern Chinese in Hong Kong and tends to run a more benign course with less systemic involvement and fewer serious ocular complications. Whether the observed difference in clinical manifestations of the disease is related to a different HLA association or environmental factors warrants further studies.

 

* Clinical Characteristics of Behçet's Disease in China by Wang LY, et al.

Abstract: To evaluate the prevalence of clinical findings in Behçet's disease (BD) in Chinese population. The clinical data of 170 consecutive BD patients were, retrospectively, analyzed and compared with previous reports. The mean age at onset was 34.4 years (range 6-72) and the mean age of diagnosis was 39.1 years (range 8-72). Mean delay in diagnosis was 5.7 years. The male to female ratio was 1.3:1. Recurrent aphthous ulceration (64.7%), skin lesion (18.2%), and genital ulceration (8.2%) were the commonest onset-presentations of the disease. During the disease course, the commonest presenting features were oral ulcer (100%), cutaneous involvement (68.2%), genital ulcer (63.5%), arthritis (37.1%), and ocular lesion (14.1%). As for the minor clinical manifestations, gastrointestinal lesion (10.0%), vascular lesion (8.8%), and cardiac lesion (4.7%) occurred occasionally. The pathergy skin test showed positive in 63.5% of the patients and revealed a higher positive rate in the females (76.7%) than in the males (53.6%). Less ocular lesion and genital ulcer were present in Chinese BD patients.

 

* The Clinical Feature of Behçet's Disease in Northeastern China by Shang Y, et al.

Abstract

Purpose: Behçet's disease (BD) is a chronic, relapsing, multi-system vasculitis of unknown aetiology with complicated and diversified clinical features predominantly involving oral and genital ulcers, and ocular and cutaneous lesions. The clinical features of this disease have been described to be different according to geographical areas and gender. We investigated the specific clinical features of BD patients in Northeastern China.

Materials and Methods: 116 patients involved in this study fulfilled the classification criteria of the International Study Group for BD. The clinical manifestations and results of laboratory tests of BD were recorded in each patient.

Results: The onset was typically between 20-39 years with a slight female predominance. Oral ulcers were the most common manifestation, followed by skin lesions, positive pathergy reaction/genital ulcers, and ocular lesions. Vascular lesion and epididymitis were rare in patients with BD. The frequency of erythema nodosum-like lesion and articular involvement were significantly higher in females, while gastrointestinal involvement was significantly higher in males. The results of laboratory tests showed that the human leukocyte antigen (HLA)-B*51 alleles were positive in 30.9% of patients and the immunological abnormities were present in some patients.

Conclusion: The clinical features of BD showed geographical and gender difference. Genetic and immune factors might participate in aetiopathogenesis of BD.

 

* HLA-B*51 Allele Analysis by the PCR-SBT Method and a Strong Association of HLA-B*5101 with Japanese Patients with Behçet's Disease by Mizuki N, et al.

Abstract: Behçet's disease (BD) is known to be associated with human leukocyte antigen (HLA) B51 in many different ethnic groups. An increased incidence of HLA-B51 in the patient group has also been reported in a Japanese population. Recently, the B51 antigen has been identified to comprise 21 alleles, B*5101-B*5121. Further, not only HLA-B*5101 but also HLA-B*5108 were found to be relatively increased in the patient groups among Italian and Saudi Arabian populations. Therefore, we performed HLA-B*51 allele genotyping by the polymerase chain reaction-sequencing based typing (PCR-SBT) method in order to investigate whether there is any correlation of one particular B51-associated allele with Japanese BD. Ninety-six Japanese patients with BD and 132 healthy Japanese volunteers were enrolled in this study. As a result, the phenotype frequency of the B51 antigen was confirmed to be remarkably increased in the patient group as compared to the ethnically matched control group (59.4% in patients vs. 13.6% in controls; Pc=0.0000000000098, R.R.=9.3). In the B*51 allele genotyping, 56 out of 57 B51-positive patients were defined as B*5101 and the remaining one was B*5102. In contrast, all of 18 B51-positive normal controls were B*5101. None of the Japanese patients and healthy controls carried the HLA-B*5108 allele. This study revealed that B*51 allelic distribution in Japanese was different from those in Italian and Saudi Arabian populations, and that the significantly high incidence of the HLA-B51 antigen in the Japanese BD patient group was mostly caused by the significant increase of the HLA-B*5101 allele.

 

* Behçet's Disease: The first Mongolian case in literature showing HLA B51, MICA gene type *5/*6 by Chung YL, et al.

Abstract: Behçet's disease is a chronic multi-systemic disease of unknown origin that includes mucocutaneous, ocular, cardiac, vascular, renal, gastrointestinal, neurologic and cutaneous involvement. The disease is spread throughout the world, but it is most prevalent in the eastern Mediterranean region-along the Silk Road-, and in Japan, China, and Korea. Recently, we treated a Mongolian patient who had complete-type Behçet's disease. As far as we know, this case is the first report of a Mongolian with Behçet's disease in the English literature. HLA typing in this patient revealed A2, A24;B51, B35; Cw4, Cw7; DR9, DR11. Study of the MICA genetype showed *5, *6 positive. Our data provided adequate evidence, from an epidemiological aspect, to support the belief that Behçet's disease is most prevalent along the old Silk Road.

 

* Low Prevalence of Juvenile-Onset Behçet’s Disease with Uveitis in East/South Asian People by N Kitaichi, et al.

Abstract

Aim: There is little information on the demographic and clinical characteristics of Behçet’s disease in children in different parts of the world. We sought to provide this information through a questionnaire survey of specialist eye centres.

Methods: Descriptive questionnaires were collected from 25 eye centres in 14 countries. The questionnaire surveyed details of juvenile-onset Behçet’s disease with uveitis. Ethnic groups, clinical features, treatments and prognosis of paediatric-age Behçet’s disease were examined on a worldwide scale.

Results: The clinical data of 135 juvenile-onset and 1227 adult-onset patients with uveitis were collected. The average age of disease diagnosis in the children was 11.7 years old. Of the ethnic groups identified 54% were from Middle East, 43% from Europe, but only 2% from East/South Asian countries. By contrast, 19.2% of adult patients were from East or South Asia. The frequency of genital ulcers in juvenile patients was 38.7%, which was significantly lower than in adult cases (53.5%; p<0.01).

Conclusions: Behçet’s disease with uveitis was less common in children than in adults in East/South Asia. Although the clinical features of the systemic disease were similar in children and adults, there was a lower frequency of genital ulceration in children.

 

* Population-Based Prevalence Study of Behc¸et’s Disease Differences by Ethnic Origin and Low Variation by Age at Immigration by Alfred Mahr, et al.

Objective. To estimate the prevalence of Behc¸et’s disease (BD) in a multiethnic population living in France, with particular focus on disease risk among immigrants.

Methods. The study was conducted in a county in the Paris metropolitan area that is home to 1,094,412 adults (ages >15 years), of whom 26% are of non- European ancestry. Patients with BD living in this area during 2003 were identified using 3 sources (hospitals, community physicians, and the National Health Insurance database), and diagnoses were verified using the International Study Group criteria. Standardized, year-2003 prevalence rates were computed for the overall population and for each ethnic group. Stratified prevalence rates according to age at immigration to France were calculated to investigate the relationship between age at immigration and BD risk.

Results. Seventy-nine subjects fulfilled our search criteria. The overall prevalence per 100,000 adults was 7.1 (95% confidence interval [95% CI] 3.5–14.4), and the prevalence for populations of European, North African, and Asian ancestry was 2.4 (95% CI 0.6–7.2), 34.6 (95% CI 24.4–47.5), and 17.5 (95% CI 10.7–27.2), respectively. Within the migrant population of either North African or Asian ancestry, BD prevalences were similar for residents born in France, residents <15 years old at immigration, and residents >15 years old at immigration.

Conclusion. Our findings indicate that the prevalence of BD among immigrants of North African or Asian ancestry is significantly higher than that in the European-origin population, and comparable with rates reported from North Africa and Asia. Moreover, our results suggest that BD risk is not related to age at immigration. These findings support the hypothesis that BD has a primarily hereditary basis.

 

* Behcet's Disease: from East to West by Davatchi F, et al.

Abstract: Behcet's disease (BD) is classified among vasculitides. There are actually five nationwide surveys of BD: Iran, Japan, China, Korea, and Germany. Among case series, four are on more than 200 cases (Turkey, Morocco, Tunisia, and UK). BD was classically seen around the Silk Route. Now, it is seen everywhere. The male to female ratios were, respectively (in nationwide surveys), 1.19, 0.98, 1.34, 0.63, and 1.40 to 1. The mean age at onset was 26.2, 35.7, 33.8, 29, and 26 years. Major manifestations were seen, respectively, in nationwide surveys: mucous membrane (oral aphthosis in 97%, 98%, 98%, 99%, and 98%; genital aphthosis in 65%, 73%, 76%, 83%, and 64%); skin manifestations (pseudo-folliculitis in 57%, N/A, 31%, N/A, and 62%; erythema nodosum in 22%, N/A, 38%, N/A, and 42%; ocular manifestations in 55%, 69%, 35%, 51%, and 53%). Minor manifestations were seen, respectively, in nationwide surveys: joint manifestations in 33%, 57%, 30%, 38%, and 53%; neurological manifestations in 9%, 11%, 6.5%, 4.6%, and 11%; gastrointestinal manifestations in 7%, 15.5%, 9%, 7.3%, and 12%; vascular involvement in 8.9%, 8.9%, 7.7%, 1.8%, and 13%; pulmonary manifestations in 0.3%, N/A, 2.2%, N/A, and 3.6%; cardiac manifestations in 0.5%, N/A, 4%, N/A, and 3.2%. Laboratory tests are not useful except the pathergy test, which was positive in 54%, 44%, N/A, 40%, and 34% of cases. ESR was normal in many patients. Diagnosis is based upon clinical manifestations. The International Criteria for Behcet's Disease (ICBD, 2006) may be of help, having a sensitivity of 98.2% and a specificity of 95.6% in Iranian patients.

 

* A Strong Association between HLA-B*5101 and Behçet's Disease in Greek Patients by Mizuki N, et al.

Abstract: Behçet's disease is known to be associated with HLA-B51, one of the split antigens of HLA-B5, among many different ethnic groups. In a Greek population, an increased incidence of HLA-B5 in the patient group has also been reported. Because the B51 antigen has been recently identified to comprise seven alleles, B*5101-B*5107, we performed HLA-B51 allele genotyping by the PCR-SSP method as well as serological HLA-A and -B typing among 31 Greek patients with Behçet's disease to investigate whether there is any correlation between one particular B51-associated allele and Behçet's disease. The frequency of B51 was remarkably high (80.6%) in the patient group as compared to the ethnically matched control group (26.7%). In addition, HLA-A26 was also increased in the patients (29.0%) as compared with the healthy controls (3.3%). B51 allele genotyping revealed that all these B51-positive patients carried B*5101. This study revealed a strong association of Behçet's disease in Greeks with one of the B51 subantigens, providing insight into the molecular mechanism underlying an HLA association with Behçet's disease.

 

* Significant Associations of HLA-B*5101 and B*5108, and Lack of Association of Class II Alleles with Behçet's Disease in Italian Patients by Kera J, et al.

Abstract: Behçet's disease has been known to be strongly associated with human leukocyte antigen (HLA) B51, one of the split antigens of HLA-B5. An increased incidence of HLA-B51 in the patient group has also been reported in an Italian population. Since the B51 antigen has been recently identified to comprise nine alleles, B*5101-B*5109, we performed HLA-B51 allele genotyping by the polymerase chain reaction-sequencing based typing (PCR-SBT) method as well as serological HLA-A and -B typing among 21 Italian patients with Behçet's disease in order to investigate whether there is any correlation of one particular B51-associated allele with Behcet's disease. In addition, HLA class II genotyping was performed by the PCR-restriction fragment length polymorphism (RFLP) method. As a result, only the phenotype frequency of the B51 antigen was found to be significantly increased in the patient group as compared to the ethnically matched control group by the corrected P-value analysis (71.4% in patients vs. 17.9% in controls; chi2 = 14.26, Pc = 0.0042, R.R. = 11.5). In the B51 allele genotyping, 11 out of 15 B51-positive patients were B*5101 and the remaining four were B*5108, whereas all of 5 normal controls were B*5101, showing significant association of each allele with Behçet's disease. No significant difference was observed between the patient and control groups in the HLA class II allelic distribution. This study revealed a strong association of Behçet's disease in Italian with B*5108 as well as B*5101, providing important insight into the molecular mechanism underlying an HLA association with Behçet's disease.

 

* HLA Class I and class II Genotyping in Patients with Behcet's Disease: A regional study of eastern part of Turkey by Pirim I, et al.

Abstract: Class I human leucocyte antigen (HLA)-B51 is well known to be associated with Behcet's disease in many ethnic groups. However, there has been no published paper with respect to its association with HLA class I and class II among the Turkish people who live in the eastern region of Turkey. Moreover, as it is known that B51 antigen is encoded by 21 alleles, B*5101-5121, HLA-B51 allele typing was performed, as well as HLA class I and class II genotyping of 75 patients with the disease and the 54 individuals in the matched control group. The result shows that the HLA-B51 frequency was significantly higher (58.66%) in the patient group, compared to that in the control group (18.51%) (OR = 6.245). In the subtyping of B51 alleles, 44 B51-positive patients possessed B*5101 (45.5%), B*5108 (25%), B*5105 (9.1%) and B*5104 (4.5%). There was no significant difference in the HLA-B51 allelic distribution between the patient group and the control group. However, homozygous carriers of HLA-B51 showed considerably high risk (OR = 2.647) in the patient group, compared to that in the control group. In the genotyping of class II HLA alleles, while HLA-DRB1*04 (45.3%) and HLA-DRB1*07 (24%) were the predominant alleles in the patient group, DRB1*11 (50%) appeared to be more common in the control group.

 

* Allelic Distribution of HLA-B*5 in HLA-B5-Positive Israeli Patients with Behçet's Disease by Paul M, et al.

Abstract: In order to investigate the sub-typing of the B5 antigen in Israeli (Jewish and Arabic) patients with Behçet's disease (BD) allele-specific genotyping of B51 and B52 alleles was performed in Israeli BD patients and healthy controls. Among the HLA-B51-positive BD patients, B*5101 was found to be the predominant allele, identified in 62% of all BD patients and 78% of Jewish BD patients. HLA-B*5101 was also the predominant allele in HLA-B51-positive healthy controls. HLA-B*5108 and B*5104 alleles were identified in 23% and 15% of B51-positive BD patients, respectively. The HLA-B*5201 allele was identified in all HLA-B52-positive patients and controls. Our study suggests that both HLA-B*5101 and HLA-B*5201 are the dominant alleles of HLA-B5 in Israeli BD patients.

 

* HLA Class I Genotyping Including HLA-B*51 Allele Typing in the Iranian Patients with Behçet's Disease by Mizuki N, et al.

Abstract: It is well known that Behçet's disease (BD) is strongly associated with human leukocyte antigen (HLA) B51 in many ethnic groups. However, there has been no published report as yet with respect to this association among the Iranian people. Furthermore, since it is now known that the B51 antigen can be encoded by 21 alleles, B*5101-B*5121, we performed HLA-B*51 allele typing as well as HLA class I genotyping of 48 Iranian patients with this disease. As a result, the frequency of the B*51 allele was significantly higher (62.1%) in the patient group as compared with the ethnically matched control group (31.8%) (Pc=0.067, R.R.=3.51). In the genotyping of B*51 alleles, 33 out of the 36 B*51-positive patients possessed B*5101 and the remaining 3 carried B*5108. This study revealed that Iranian patients with BD also had a strong association with HLA-B51. In addition, this significantly high incidence of HLA-B*51 was found to be caused by an increase in both the HLA-B*5101 and HLA-B*5108 alleles. However, there was no significant difference in the HLA-B*51 allelic distribution between the patient and control groups.