An Overview of Behçet's Disease

**3**

**Chapter 1**

**Abstract**

Behçet's Disease

is of great importance in the diagnosis.

International Criteria for Behçet's disease

genital ulceration, and iridocyclitis with hypopyon [4].

**1. Introduction**

**eponym)**

The History and Diagnosis of

Behçet's disease (BD) is a multisystemic vasculitis of unknown aetiology, initially reported by Turkish dermatologist Hulusi Behçet in 1937. Hulusi Behçet presented the disease as a triple symptom complex with recurrent aphthosis, genital ulceration and recurrent hypopyon uveitis. But subsequent studies have shown that it can affect many organs with wide clinical spectrum. It is challenging to make a definite diagnosis because there is no pathognomic laboratory test to diagnose Behçet's disease. The diagnosis is based on variable group of clinical manifestations. Many new diagnostic/classification criteria have been developed through the years. International Study Group (ISG) Criteria and the International Criteria for Behçet's Disease (ICBD) are the most commonly acceptable criteria for the diagnosis of BD. However, due to the broad clinical spectrum of Behçet's disease, there will always be Behçet's patients who do not complete the criteria. Therefore, the experience of the physician and evaluation of the findings with a good clinical anamnesis

**Keywords:** Hulusi Behçet, Behçet's disease, International Study Group criteria,

Behçet's disease (BD) is a multisystemic vasculitis according to the 2012 Revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides [1]. The autoimmune process, which is triggered by the environmental and infectious factors on the basis of the genetic factors, is held responsible for the formation of the disease [2]. The definition of the disease dates back to ancient times until the time of Hippocrates [3]. However, for the first time in modern medicine in 1937, Prof. Dr. Hulusi Behçet described it as a separate entity consisting of oral aphthosis,

**2. Hulusi Behçet: a life dedicated to dermatology (the person behind the**

Hulusi Behçet was born on 20 February 1889 in Istanbul. Hulusi Behçet was raised by his grandmother after his mother's death when he was young and he had a difficult childhood. He settled in Damascus because of his father's work. He studied at a French school and learned French, Latin, and German. In 1906, he started Kuleli Military Medical School when he was only 16 years old and graduated in 1910.

*Müzeyyen Gönül, Arzu Kılıç and Bilgen Gençler*

#### **Chapter 1**

## The History and Diagnosis of Behçet's Disease

*Müzeyyen Gönül, Arzu Kılıç and Bilgen Gençler*

#### **Abstract**

Behçet's disease (BD) is a multisystemic vasculitis of unknown aetiology, initially reported by Turkish dermatologist Hulusi Behçet in 1937. Hulusi Behçet presented the disease as a triple symptom complex with recurrent aphthosis, genital ulceration and recurrent hypopyon uveitis. But subsequent studies have shown that it can affect many organs with wide clinical spectrum. It is challenging to make a definite diagnosis because there is no pathognomic laboratory test to diagnose Behçet's disease. The diagnosis is based on variable group of clinical manifestations. Many new diagnostic/classification criteria have been developed through the years. International Study Group (ISG) Criteria and the International Criteria for Behçet's Disease (ICBD) are the most commonly acceptable criteria for the diagnosis of BD. However, due to the broad clinical spectrum of Behçet's disease, there will always be Behçet's patients who do not complete the criteria. Therefore, the experience of the physician and evaluation of the findings with a good clinical anamnesis is of great importance in the diagnosis.

**Keywords:** Hulusi Behçet, Behçet's disease, International Study Group criteria, International Criteria for Behçet's disease

#### **1. Introduction**

Behçet's disease (BD) is a multisystemic vasculitis according to the 2012 Revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides [1]. The autoimmune process, which is triggered by the environmental and infectious factors on the basis of the genetic factors, is held responsible for the formation of the disease [2]. The definition of the disease dates back to ancient times until the time of Hippocrates [3]. However, for the first time in modern medicine in 1937, Prof. Dr. Hulusi Behçet described it as a separate entity consisting of oral aphthosis, genital ulceration, and iridocyclitis with hypopyon [4].

#### **2. Hulusi Behçet: a life dedicated to dermatology (the person behind the eponym)**

Hulusi Behçet was born on 20 February 1889 in Istanbul. Hulusi Behçet was raised by his grandmother after his mother's death when he was young and he had a difficult childhood. He settled in Damascus because of his father's work. He studied at a French school and learned French, Latin, and German. In 1906, he started Kuleli Military Medical School when he was only 16 years old and graduated in 1910.

#### *Different Aspects of Behçet's Disease*

After his specialization training on skin and venereal diseases in Gulhane Military Hospital, he worked in Edirne Military hospital for 4 years. Afterwards, he went to Europe and worked in Budapest and Berlin for a short time and returned to his country. He worked as a freelance doctor for a while, and then he worked at Haskoy Venereal Diseases Hospital and Guraba Hospital after that in 1933; he became the head of the Department of Skin and Venereal Diseases of Istanbul University and continued this position until 1947 [5, 6].

He is interested in many different areas of dermatology such as syphilis, leishmaniasis**,** dermatitis *Figus carcia*, parasitosis, and mycosis, but he is mostly known for his studies on Behçet's disease, which is named after him. He presented his research in many national and international meetings and congresses and published 126 articles between 1921 and 1940 [5, 6].

Studies on Behçet's disease began with a patient he first saw in 1924.The patient had recurrent hypopyon uveitis accompanied by ulcerations in the mouth and scrotum, painful nodules on the legs, fever, and joint pain and was variously diagnosed in Istanbul and Vienna and was followed by Hulusi Behçet later on for many more years [5–7].

In 1930, he conducted a study on a female patient with recurrent ocular symptoms and oral and genital lesions and in 1936 on a male patient with oral pemphigus-like wounds, acneiform lesions on the back, scrotal ulcer, night fever, abdominal pain, and ocular symptoms [5–7].

As a result of his research on these three patients, Hulusi Behçet first suggested in 1937 that recurrent oral aphthous lesions, genital ulceration, and recurrent hypopyon uveitis were the symptoms of a single disease as a triple symptom complex [4]. He wrote this view in 1937 in the journal *Dermatologische Wochenschrift* and presented it to his colleagues at a congress in France in the same year. At the same congress, it was suggested that viruses may play a role in the etiology of this condition, especially those of dental origin [5, 6, 8] (**Figure 1**).

**5**

*The History and Diagnosis of Behçet's Disease DOI: http://dx.doi.org/10.5772/intechopen.89927*

Behçet" [5, 6].

Behçet.

affect many organs [1, 13].

2006, and the revised ICBD in 2014 [18–32].

neurological manifestations, and epididymitis [24].

In 1938, *Dermatologische Wohenschrift* published his thoughts in more detail. In the following years, new case reports came from different countries. While ophthalmologists accepted this new disease, dermatologists believed it to be a symptom of another existing skin disease. However, as a result of the new articles published in different parts of the world, the disease was accepted to be a separate entity. At the international medical congress in Geneva, with the suggestion of Prof. Mischner from Zurich Medical Faculty, this newly diagnosed disease was called "Morbus

In 1930, Dr. Benedictos Adamantiades (1875–1962), a Greek ophthalmologist, reported a patient with recurrent hypopyonic irritation accompanied by mucocutaneous lesions and arthritis [9]. In later years, he wrote new case reports, but he did not interpret this as a triple complex; focusing only on the eye, he suggested that hypopyonic iridocyclitis was a separate clinical disease by itself [10–12]. Undoubtedly, although his colleagues from many parts of the world contributed to the acceptance of Behçet's disease as a separate clinical entity, the first person to describe the triple triad and to present it to the world through his articles and presentations is our esteemed professor, doctor Hulusi

**3. The diagnosis and classification criteria of Behçet's disease**

a good clinical anamnesis is of great importance in the diagnosis [14].

Firstly, although Behçet's disease is accepted as a triple symptom complex with recurrent aphthosis, genital ulceration, and recurrent hypopyon uveitis, subsequent studies have shown that it is a multisystemic chronic inflammatory disease that can

Although it is a relatively young disease, many different diagnostic/classification criteria have been developed. The first one was created by Curth in 1946 [15]. In 1969, Hewitt et al. presented the diagnostic criteria and revised and reformed them in 1971 [16, 17]. Many new diagnostic criteria have been established in the light of the studies that have been carried out until today. The main ones are Mason and Barnes in 1969, Japan criteria in 1972, Hubault and Hamza in 1974, O'Duffy in 1974, Chen in 1980, Dilsen et al. in 1986, Japan revised criteria in 1988, International Study Group (ISG) in 1990, Iran in 1993, Classification Tree in 1993, Dilsen revised in 2000, Korea in 2003, the International Criteria for Behçet's Disease (ICBD) in

The Japan Research Committee for Behçet's Disease created the Japanese criteria in 1972. There are four major symptoms according to these criteria: oral aphthosis, genital aphthosis, skin lesions, and ocular findings. In the presence of an ocular lesion, one different major finding is sufficient for the diagnosis. If there are no ocular findings, the presence of the other three major findings is essential for the diagnosis. It is called "complete form" if there are four major findings, and it is called "incomplete form" if there are fewer findings [19]. Japan criteria were revised in 1988. Five minor findings were added to the major findings, and two minor findings were suggested to replace one missing major finding. These minor findings include arthritis/arthralgia, gastrointestinal manifestations, vascular thrombosis,

There is no pathognomic laboratory test to diagnose Behçet's disease. The disease's wide clinical spectrum, its showing ethnical and geographical differences, and the differences that it shows in the time of onset of symptoms and its courses with different findings in each patient are the factors that make it difficult to diagnose. Therefore, the experience of the physician and evaluation of the findings with

**Figure 1.** *Hulusi Behçet MD (1889–1948).*

*The History and Diagnosis of Behçet's Disease DOI: http://dx.doi.org/10.5772/intechopen.89927*

*Different Aspects of Behçet's Disease*

continued this position until 1947 [5, 6].

126 articles between 1921 and 1940 [5, 6].

abdominal pain, and ocular symptoms [5–7].

tion, especially those of dental origin [5, 6, 8] (**Figure 1**).

years [5–7].

After his specialization training on skin and venereal diseases in Gulhane Military Hospital, he worked in Edirne Military hospital for 4 years. Afterwards, he went to Europe and worked in Budapest and Berlin for a short time and returned to his country. He worked as a freelance doctor for a while, and then he worked at Haskoy Venereal Diseases Hospital and Guraba Hospital after that in 1933; he became the head of the Department of Skin and Venereal Diseases of Istanbul University and

He is interested in many different areas of dermatology such as syphilis, leishmaniasis**,** dermatitis *Figus carcia*, parasitosis, and mycosis, but he is mostly known for his studies on Behçet's disease, which is named after him. He presented his research in many national and international meetings and congresses and published

Studies on Behçet's disease began with a patient he first saw in 1924.The patient had recurrent hypopyon uveitis accompanied by ulcerations in the mouth and scrotum, painful nodules on the legs, fever, and joint pain and was variously diagnosed in Istanbul and Vienna and was followed by Hulusi Behçet later on for many more

As a result of his research on these three patients, Hulusi Behçet first suggested

In 1930, he conducted a study on a female patient with recurrent ocular symptoms and oral and genital lesions and in 1936 on a male patient with oral pemphigus-like wounds, acneiform lesions on the back, scrotal ulcer, night fever,

in 1937 that recurrent oral aphthous lesions, genital ulceration, and recurrent hypopyon uveitis were the symptoms of a single disease as a triple symptom complex [4]. He wrote this view in 1937 in the journal *Dermatologische Wochenschrift* and presented it to his colleagues at a congress in France in the same year. At the same congress, it was suggested that viruses may play a role in the etiology of this condi-

**4**

**Figure 1.**

*Hulusi Behçet MD (1889–1948).*

In 1938, *Dermatologische Wohenschrift* published his thoughts in more detail. In the following years, new case reports came from different countries. While ophthalmologists accepted this new disease, dermatologists believed it to be a symptom of another existing skin disease. However, as a result of the new articles published in different parts of the world, the disease was accepted to be a separate entity. At the international medical congress in Geneva, with the suggestion of Prof. Mischner from Zurich Medical Faculty, this newly diagnosed disease was called "Morbus Behçet" [5, 6].

In 1930, Dr. Benedictos Adamantiades (1875–1962), a Greek ophthalmologist, reported a patient with recurrent hypopyonic irritation accompanied by mucocutaneous lesions and arthritis [9]. In later years, he wrote new case reports, but he did not interpret this as a triple complex; focusing only on the eye, he suggested that hypopyonic iridocyclitis was a separate clinical disease by itself [10–12]. Undoubtedly, although his colleagues from many parts of the world contributed to the acceptance of Behçet's disease as a separate clinical entity, the first person to describe the triple triad and to present it to the world through his articles and presentations is our esteemed professor, doctor Hulusi Behçet.

#### **3. The diagnosis and classification criteria of Behçet's disease**

Firstly, although Behçet's disease is accepted as a triple symptom complex with recurrent aphthosis, genital ulceration, and recurrent hypopyon uveitis, subsequent studies have shown that it is a multisystemic chronic inflammatory disease that can affect many organs [1, 13].

There is no pathognomic laboratory test to diagnose Behçet's disease. The disease's wide clinical spectrum, its showing ethnical and geographical differences, and the differences that it shows in the time of onset of symptoms and its courses with different findings in each patient are the factors that make it difficult to diagnose. Therefore, the experience of the physician and evaluation of the findings with a good clinical anamnesis is of great importance in the diagnosis [14].

Although it is a relatively young disease, many different diagnostic/classification criteria have been developed. The first one was created by Curth in 1946 [15]. In 1969, Hewitt et al. presented the diagnostic criteria and revised and reformed them in 1971 [16, 17]. Many new diagnostic criteria have been established in the light of the studies that have been carried out until today. The main ones are Mason and Barnes in 1969, Japan criteria in 1972, Hubault and Hamza in 1974, O'Duffy in 1974, Chen in 1980, Dilsen et al. in 1986, Japan revised criteria in 1988, International Study Group (ISG) in 1990, Iran in 1993, Classification Tree in 1993, Dilsen revised in 2000, Korea in 2003, the International Criteria for Behçet's Disease (ICBD) in 2006, and the revised ICBD in 2014 [18–32].

The Japan Research Committee for Behçet's Disease created the Japanese criteria in 1972. There are four major symptoms according to these criteria: oral aphthosis, genital aphthosis, skin lesions, and ocular findings. In the presence of an ocular lesion, one different major finding is sufficient for the diagnosis. If there are no ocular findings, the presence of the other three major findings is essential for the diagnosis. It is called "complete form" if there are four major findings, and it is called "incomplete form" if there are fewer findings [19]. Japan criteria were revised in 1988. Five minor findings were added to the major findings, and two minor findings were suggested to replace one missing major finding. These minor findings include arthritis/arthralgia, gastrointestinal manifestations, vascular thrombosis, neurological manifestations, and epididymitis [24].

In the Fourth International Conference on Behçet's Disease, which was held in London in 1985, it was planned to establish a diagnostic criterion with high sensitivity and specificity. Therefore, the International Behçet's Disease Study Group was established [25, 33]. In 7 countries (France, Iran, Japan, Tunisia, Turkey, the UK, and the USA) and in 12 separate institutions, 912 Behçet patients together with 308 control patients were included in a study and followed up. Twenty-eight patients without oral ulceration were excluded from the study [25]. In the light of the data obtained, "International Behçet's Disease Study Group Classification Criteria" was established and published in 1990. ISG classification criteria consist of five items. The first criterion is recurrent oral ulceration at least three times a year and is a sine qua non. The other four criteria consist of recurrent genital ulceration, eye lesions (anterior uveitis, posterior uveitis, retinal vasculitis), skin lesions (erythema nodosum, pseudofolliculitis, or papulopustular lesions), and positive pathergy test. In addition to the major criterion oral aphthosis, the existence of two of the four findings is enough for the diagnosis of Behçet's disease [25, 34] (**Table 1**).

The sensitivity and specificity of ISG classification criteria were found to be 92 and 97%, respectively [25]. Although it is one of the most widely used criteria to date, several concerns about its sensitivity have arisen. In fact, many studies have been performed that measure the performance of diagnostic/classification criteria for Behçet's disease. Because of the high specificity of ISG, the risk of another disease being misdiagnosed and classified as BD is very low. However, many Behçet's disease patients go undiagnosed due to its low sensitivity [35]. Another controversial issue is that oral aphthosis is an indispensable finding in ISG, but it has been shown that oral aphthosis may not be in 1–10% of BD patients [36]. Behçet patients with severe, specific symptoms such as vascular involvement can also go without diagnosis with these criteria, and thus the concern of delay in treatment has arisen [37, 38].

In 1993, Iran presented the ISG criteria in an international conference by modifying them to overcome the problem of low sensitivity and low accuracy. According to these criteria, it consisted of five items similar to ISG, but oral aphthosis was not mandatory. Oral aphthosis was given 2 points, and other lesions were given 1 point, and 3 points were sufficient to diagnose BD [26].

In 1993, Iran released a new classification system, using the Classification and Regression Tree method, called the classification tree. The presence of one of the five subgroups in the patient alone is sufficient to diagnose BD. These subgroups are as follows: oral aphthosis + genital aphthosis, oral aphthosis + skin lesions + positive

**7**

*\**

**Table 2.**

*The History and Diagnosis of Behçet's Disease DOI: http://dx.doi.org/10.5772/intechopen.89927*

other findings [29].

if necessary [35].

**Sign/symptom points**

the USA.

and positive pathergy test + ocular findings [27].

findings, thrombophlebitis, and positive pathergy test [28].

pathergy test, oral aphthosis + ocular findings, genital aphthosis + ocular findings,

In 2003, Korea established its own diagnostic criterion for BD. This criterion contains six items: oral aphthosis, genital ulceration, skin lesions, ocular findings, positive pathergy test, and gastrointestinal involvement. Three points and above is sufficient to diagnose BD with three points for genital ulceration and one point for

In 2003 the First International Workshop of Behçet's Disease was held in Austria.

In this workshop, it was decided that a team of eight countries would prepare a proposal to develop the ISG criteria and to establish new criteria for Behçet's disease

Greece, India, Iran, Iraq, Israel, Italy, Japan, Jordan, Libya, Morocco, Pakistan, Portugal, Russia, Saudi Arabia, Singapore, Spain, Taiwan, Thailand, Tunisia, and

of ICBD was 94.8 and 90.5%, respectively [30–32] (**Table 2**).

*2-A patient scoring 4 points or above was classified as having Beh***ç***et's disease.*

*The international criteria for Behçet's disease (ICBD)—point-score system.*

In the 11th International Conference on Behçet's Disease in Antalya (Turkey) in 2004, the International Team for the Revision of the ISG criteria was created which was composed of clinicians from 27 countries. Among these countries, in the first place comes Turkey, and the rest were Austria, Azerbaijan, China, Egypt, France, Germany,

Between January 2005 and June 2006, 2556 BD and 1163 control patients were included in a study who were selected by expert opinion, rather than a classification system. The International Criteria for Behçet's Disease included a new scoring system for the diagnosis of Behçet's disease. It consisted of six items: genital ulceration and ocular findings with 2 points and oral aphthosis, skin lesions, vascular lesions, and pathergy test with 1 point. A score of 3 or more was sufficient for the diagnosis of BD. In 2010, ICBD criteria were revised and presented at the 14th International Conference on Behçet's Disease in London. In 2014, these criteria were published in the *Journal of the European Academy of Dermatology and Venereology*. The differences from the classical form were the addition of neurological findings as 1 point and the increase of oral aphthosis to 2 points. Pathergy test was optional but 1 point should be added at its presence. Four points and above was sufficient for the diagnosis of Behçet's disease. The sensitivity and specificity

Oral aphthosis 2 Genital ulceration 2 Ocular lesions 2 Skin lesions 1 Vascular manifestations 1 Neurological manifestations 1 Positive pathergy test\* 1

*1-Pathergy test is optional. However, when it is performed, one extra point may be assigned for a positive result.*

In 2000, the original criteria were revised by Dilsen, suggesting that three of the six diagnostic criteria were sufficient to diagnose BD. These criteria are oral aphthosis, genital ulceration, skin lesions (pseudofolliculitis, erythema nodosum), ocular

#### **Table 1.**

*International study group (ISG) criteria for the diagnosis of Behçet's disease.*

#### *The History and Diagnosis of Behçet's Disease DOI: http://dx.doi.org/10.5772/intechopen.89927*

*Different Aspects of Behçet's Disease*

treatment has arisen [37, 38].

Recurrent oral ulceration

Recurrent genital ulceration

Plus any two of the following criteria

and 3 points were sufficient to diagnose BD [26].

Positive pathergy test Read by physician at 24–48 hours.

*Findings applicable only in the absence of other clinical explanations.*

*International study group (ISG) criteria for the diagnosis of Behçet's disease.*

In the Fourth International Conference on Behçet's Disease, which was held in London in 1985, it was planned to establish a diagnostic criterion with high sensitivity and specificity. Therefore, the International Behçet's Disease Study Group was established [25, 33]. In 7 countries (France, Iran, Japan, Tunisia, Turkey, the UK, and the USA) and in 12 separate institutions, 912 Behçet patients together with 308 control patients were included in a study and followed up. Twenty-eight patients without oral ulceration were excluded from the study [25]. In the light of the data obtained, "International Behçet's Disease Study Group Classification Criteria" was established and published in 1990. ISG classification criteria consist of five items. The first criterion is recurrent oral ulceration at least three times a year and is a sine qua non. The other four criteria consist of recurrent genital ulceration, eye lesions (anterior uveitis, posterior uveitis, retinal vasculitis), skin lesions (erythema nodosum, pseudofolliculitis, or papulopustular lesions), and positive pathergy test. In addition to the major criterion oral aphthosis, the existence of two of the four findings is enough for the diagnosis of Behçet's disease [25, 34] (**Table 1**).

The sensitivity and specificity of ISG classification criteria were found to be 92 and 97%, respectively [25]. Although it is one of the most widely used criteria to date, several concerns about its sensitivity have arisen. In fact, many studies have been performed that measure the performance of diagnostic/classification criteria for Behçet's disease. Because of the high specificity of ISG, the risk of another disease being misdiagnosed and classified as BD is very low. However, many Behçet's disease patients go undiagnosed due to its low sensitivity [35]. Another controversial issue is that oral aphthosis is an indispensable finding in ISG, but it has been shown that oral aphthosis may not be in 1–10% of BD patients [36]. Behçet patients with severe, specific symptoms such as vascular involvement can also go without diagnosis with these criteria, and thus the concern of delay in

In 1993, Iran presented the ISG criteria in an international conference by modifying them to overcome the problem of low sensitivity and low accuracy. According to these criteria, it consisted of five items similar to ISG, but oral aphthosis was not mandatory. Oral aphthosis was given 2 points, and other lesions were given 1 point,

In 1993, Iran released a new classification system, using the Classification and Regression Tree method, called the classification tree. The presence of one of the five subgroups in the patient alone is sufficient to diagnose BD. These subgroups are as follows: oral aphthosis + genital aphthosis, oral aphthosis + skin lesions + positive

> Minor or major aphthous ulceration or herpetiform ulceration observed by physician or patient (at least three occurrences within a 12-month period)

Aphthous ulceration or scarring observed by the physician or patient

papulopustular lesions or acneiform nodules observed by the physician in postadolescent patients (not receiving corticosteroid treatment)

Eye lesions Anterior uveitis, posterior uveitis, or cells in vitreous on slit-lamp examination or retinal vasculitis detected by an ophthalmologist Skin lesions Erythema nodosum observed by physician or patient, pseudofolliculitis, or

**6**

*\**

**Table 1.**

pathergy test, oral aphthosis + ocular findings, genital aphthosis + ocular findings, and positive pathergy test + ocular findings [27].

In 2000, the original criteria were revised by Dilsen, suggesting that three of the six diagnostic criteria were sufficient to diagnose BD. These criteria are oral aphthosis, genital ulceration, skin lesions (pseudofolliculitis, erythema nodosum), ocular findings, thrombophlebitis, and positive pathergy test [28].

In 2003, Korea established its own diagnostic criterion for BD. This criterion contains six items: oral aphthosis, genital ulceration, skin lesions, ocular findings, positive pathergy test, and gastrointestinal involvement. Three points and above is sufficient to diagnose BD with three points for genital ulceration and one point for other findings [29].

In 2003 the First International Workshop of Behçet's Disease was held in Austria. In this workshop, it was decided that a team of eight countries would prepare a proposal to develop the ISG criteria and to establish new criteria for Behçet's disease if necessary [35].

In the 11th International Conference on Behçet's Disease in Antalya (Turkey) in 2004, the International Team for the Revision of the ISG criteria was created which was composed of clinicians from 27 countries. Among these countries, in the first place comes Turkey, and the rest were Austria, Azerbaijan, China, Egypt, France, Germany, Greece, India, Iran, Iraq, Israel, Italy, Japan, Jordan, Libya, Morocco, Pakistan, Portugal, Russia, Saudi Arabia, Singapore, Spain, Taiwan, Thailand, Tunisia, and the USA.

Between January 2005 and June 2006, 2556 BD and 1163 control patients were included in a study who were selected by expert opinion, rather than a classification system. The International Criteria for Behçet's Disease included a new scoring system for the diagnosis of Behçet's disease. It consisted of six items: genital ulceration and ocular findings with 2 points and oral aphthosis, skin lesions, vascular lesions, and pathergy test with 1 point. A score of 3 or more was sufficient for the diagnosis of BD. In 2010, ICBD criteria were revised and presented at the 14th International Conference on Behçet's Disease in London. In 2014, these criteria were published in the *Journal of the European Academy of Dermatology and Venereology*. The differences from the classical form were the addition of neurological findings as 1 point and the increase of oral aphthosis to 2 points. Pathergy test was optional but 1 point should be added at its presence. Four points and above was sufficient for the diagnosis of Behçet's disease. The sensitivity and specificity of ICBD was 94.8 and 90.5%, respectively [30–32] (**Table 2**).

*\* 1-Pathergy test is optional. However, when it is performed, one extra point may be assigned for a positive result. 2-A patient scoring 4 points or above was classified as having Beh***ç***et's disease.*

#### **Table 2.**

*The international criteria for Behçet's disease (ICBD)—point-score system.*

#### **4. Differential diagnosis of Behçet's disease**

Since Behçet's disease has a broad clinical spectrum, many diseases are included in the differential diagnosis. Although many diagnostic criteria have been developed, it can still be difficult to diagnose Behçet's disease, and it may be necessary to exclude diseases that show similar findings in the differential diagnosis.

#### **4.1 Differential diagnosis of mucocutaneous findings**

#### *4.1.1 Oral aphthosis*

Recurrent aphthous stomatitis (RAS), viral infections such as herpes simplex virus and Coxsackievirus infections, nutritional deficiencies such as vitamin B and iron, recurrent erythema multiform, oral erosive lichen planus, autoimmune bullous diseases, fixed drug eruption, Stevens-Johnson syndrome, toxic epidermal necrolysis, inflammatory bowel diseases (IBD), Reiter syndrome, systemic lupus erythematosus, celiac disease, mouth and genital ulcers with inflamed cartilage (MAGIC) syndrome, must be Periodic Fever, Aphthous Stomatitis, Pharyngitis, Adenitis (PFAPA) syndrome, hematologic malignancies, and trauma [39–42].

#### *4.1.2 Genital ulceration*

Herpes simplex infection; erosive lichen planus; autoimmune bullous dermatoses; sexually transmitted infectious diseases, especially syphilis; and fixed drug eruption [41, 43].

#### *4.1.3 Skin lesions*

Papulopustular lesions can be confused with acne and bacterial folliculitis [14, 44].

#### **4.2 Differential diagnosis of systemic findings**

The diseases of the similar systemic findings with BD are inflammatory bowel diseases, seronegative arthropathies, sarcoidosis, lupus erythematosus and other systemic vasculitis, multiple sclerosis as neurological involvement, and stroke of the young adult [14, 45].

Differential diagnosis of BD from IBD may be challenging for clinicians because findings of both two diseases include gastrointestinal manifestations, fever, oral aphthosis, pyoderma gangrenosum, erythema nodosum, Sweet syndrome like dermatosis, neutrophilic lobular panniculitis, ocular involvement, arthritis, vasculitis, and thrombotic events. Moreover, the manifestations of intestinal BD are similar to IBD. There are no diagnostic laboratory tests or endoscopic findings for the differential diagnosis of both diseases. Endoscopic findings of Behçet's disease demonstrate single or few, large, round, or oval-shaped ulcerations. Longitudinal ulcers in a discontinuous distribution and cobblestone appearance are endoscopic features of IBD. However, neurologic involvement is not observed in IBD [46–50].

Bowel-associated dermatosis-arthritis syndrome (BADAS) is a recurrent neutrophilic dermatosis which is associated with bowel bypass surgery and gastrointestinal disorders like IBD and diverticulitis [51, 52]. The syndrome should be distinguished from BD, due to the similar findings such as oral aphthosis, vesiculopustular dermatosis, erythema nodosum, neutrophilic lobular panniculitis, fever, vasculitis, and arthritis. The other cutaneous findings of BD and ocular and

**9**

**Author details**

Müzeyyen Gönül1

\*, Arzu Kılıç2

2 Dermatology Department, Balıkesir University, Turkey

\*Address all correspondence to<EMAIL_ADDRESS>
Education and Research Hospital, Turkey

provided the original work is properly cited.

and Bilgen Gençler1

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

1 Dermatology Clinic, University of Health Sciences, Dışkapı Yıldırım Beyazıt

*The History and Diagnosis of Behçet's Disease DOI: http://dx.doi.org/10.5772/intechopen.89927*

also negative in the BADAS patients [50].

neurologic involvement are not expected findings for BADAS. The pathergy test is

Although many criteria have been developed for the diagnosis of Behçet's disease, there are still a number of difficulties to establish a definitive diagnosis and for making differential diagnosis. Therefore, newly defined molecular markers and

universal criteria with high sensitivity and specificity are needed.

#### *The History and Diagnosis of Behçet's Disease DOI: http://dx.doi.org/10.5772/intechopen.89927*

*Different Aspects of Behçet's Disease*

*4.1.1 Oral aphthosis*

*4.1.2 Genital ulceration*

eruption [41, 43].

*4.1.3 Skin lesions*

young adult [14, 45].

not observed in IBD [46–50].

**4. Differential diagnosis of Behçet's disease**

**4.1 Differential diagnosis of mucocutaneous findings**

**4.2 Differential diagnosis of systemic findings**

Since Behçet's disease has a broad clinical spectrum, many diseases are included in the differential diagnosis. Although many diagnostic criteria have been developed, it can still be difficult to diagnose Behçet's disease, and it may be necessary to

Recurrent aphthous stomatitis (RAS), viral infections such as herpes simplex virus and Coxsackievirus infections, nutritional deficiencies such as vitamin B and iron, recurrent erythema multiform, oral erosive lichen planus, autoimmune bullous diseases, fixed drug eruption, Stevens-Johnson syndrome, toxic epidermal necrolysis, inflammatory bowel diseases (IBD), Reiter syndrome, systemic lupus erythematosus, celiac disease, mouth and genital ulcers with inflamed cartilage (MAGIC) syndrome, must be Periodic Fever, Aphthous Stomatitis, Pharyngitis, Adenitis (PFAPA) syndrome, hematologic malignancies, and trauma [39–42].

Herpes simplex infection; erosive lichen planus; autoimmune bullous dermatoses; sexually transmitted infectious diseases, especially syphilis; and fixed drug

Papulopustular lesions can be confused with acne and bacterial folliculitis [14, 44].

The diseases of the similar systemic findings with BD are inflammatory bowel diseases, seronegative arthropathies, sarcoidosis, lupus erythematosus and other systemic vasculitis, multiple sclerosis as neurological involvement, and stroke of the

Differential diagnosis of BD from IBD may be challenging for clinicians because findings of both two diseases include gastrointestinal manifestations, fever, oral aphthosis, pyoderma gangrenosum, erythema nodosum, Sweet syndrome like dermatosis, neutrophilic lobular panniculitis, ocular involvement, arthritis, vasculitis, and thrombotic events. Moreover, the manifestations of intestinal BD are similar to IBD. There are no diagnostic laboratory tests or endoscopic findings for the differential diagnosis of both diseases. Endoscopic findings of Behçet's disease demonstrate single or few, large, round, or oval-shaped ulcerations. Longitudinal ulcers in a discontinuous distribution and cobblestone appearance are endoscopic features of IBD. However, neurologic involvement is

Bowel-associated dermatosis-arthritis syndrome (BADAS) is a recurrent neutrophilic dermatosis which is associated with bowel bypass surgery and gastrointestinal disorders like IBD and diverticulitis [51, 52]. The syndrome should be distinguished from BD, due to the similar findings such as oral aphthosis, vesiculopustular dermatosis, erythema nodosum, neutrophilic lobular panniculitis, fever, vasculitis, and arthritis. The other cutaneous findings of BD and ocular and

exclude diseases that show similar findings in the differential diagnosis.

**8**

neurologic involvement are not expected findings for BADAS. The pathergy test is also negative in the BADAS patients [50].

Although many criteria have been developed for the diagnosis of Behçet's disease, there are still a number of difficulties to establish a definitive diagnosis and for making differential diagnosis. Therefore, newly defined molecular markers and universal criteria with high sensitivity and specificity are needed.

### **Author details**

Müzeyyen Gönül1 \*, Arzu Kılıç2 and Bilgen Gençler1

1 Dermatology Clinic, University of Health Sciences, Dışkapı Yıldırım Beyazıt Education and Research Hospital, Turkey

2 Dermatology Department, Balıkesir University, Turkey

\*Address all correspondence to<EMAIL_ADDRESS>
© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

#### **References**

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[2] Greco A, De Virgilio A, Ralli M, Ciofalo A, Mancini P, Attanasio G, et al. Behçet's disease: New insights into pathophysiology, clinical features and treatment options. Autoimmunity Reviews. 2018;**17**(6):567-575

[3] Feigenbaum A. Description of Behçet's syndrome in the hippocratic third book of endemic diseases. The British Journal of Ophthalmology. 1956;**40**:355-357

[4] Behçet H. Uber rezidivierende aphthosa, durch ein Virus verüsachte Geschewüre am Mund, am Auge und an den Genitalien. Dermatologische Wochenschrift. 1937;**109**:1152-1157

[5] Saylan T. Life story of Dr. Hulusi Behçet. Yonsei Medical Journal. 1997;**38**(6):327-332

[6] Tüzün Y. Hulusi Behçet MD: February 20, 1889 to March 8, 1948. Clinics in Dermatology. 2006;**24**(6):548-550

[7] Evereklioglu C. Behçet's disease or Adamantiades-Behçet disease? An evidence-based historical survey. Medical Science Monitor. 2010;**16**(6):136-142

[8] Behçet H, Gözcü N. Üç Nahiyede Nüksi Tavazzular Yapan ve Hususi Bir Virus Tesiri ile Umumi İntan Hasıl Ettiğine Kanaatimiz Artan Entite Morbide Hakkında. Deri Hastalıkları ve Frengi Kliniği Arşivi. 1938;**5**:1863-1873

[9] Adamantiades B. A case of recurrent hypopyon iritis. Proceedings of the Medical Society of Athens. 1930:586-593 [10] Adamantiades B. La thrombophlébite comme quatrième symptôme de l'iritis récidivante à hypopyon. The Annales d'Oculistique et de Gynecologie (Paris). 1946;**179**:143-148

[11] Adamantiades B. Le symptôme complexe de l'uvéite récidivante à hypopyon (the complex syndrome of recurrent uveitis with hypopyon). The Annales d'Oculistique et de Gynecologie (Paris). 1953;**186**(9):846-856

[12] Adamantiades B. Severe complications of the central nervous system in the syndrome of relapsing iritis with hypopyon (in Greek). Deltion Ellikinis Ophthalmologikis Etairias. 1958;**26**:199-202

[13] Alpsoy E. Behçet's disease: A comprehensive review with a focus on epidemiology, etiology and clinical features, and management of mucocutaneous lesions. The Journal of Dermatology. 2016;**43**(6):620-632

[14] Boyvat A. Behçet Hastalığında Tanı ve Ayırıcı Tanı. Turkiye Klinikleri Dermatology-Special Topics. 2017;**10**(4):315-320

[15] Curth HO. Recurrent genito-oral aphthosis with hypopion (Behçet's syndrome). Archives of Dermatology;**54**:179-196

[16] Hewitt J, Escande JP, Laurent PH, Perlemuter L. Criteres de prevision du syndrome de Behçet. Bulletin de la SocieteFrancaise de Dermatology et de Syphiligraphie. 1969;**76**:565-568

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**11**

*The History and Diagnosis of Behçet's Disease DOI: http://dx.doi.org/10.5772/intechopen.89927*

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[22] Cheng SP, Zhang X-Q. Some special clinical manifestations of Behçet's disease—Report of illustrative cases and review of literature (author's transl). The Chinese Journal of Internal

[23] Dilsen N, Konice M, Aral O. Our diagnostic criteria of Behçet's disease—An overview. In: Lehner T, Barnes CG, editor. Recent Advances in Behçet's Disease. Vol. 103. International Congress and Symposium Series. London, UK: London Royal

Society of Medicine Services; 1986.

[24] Mizushima Y. Recent research into Behçet's disease in Japan. International

[26] Davatchi F, Shahram F, Akbarian M, et al. Accuracy of existing diagnosis criteria for Behçet's disease. In:

Wechsler B, Godeau P, editors. Behçet's

Disease. Vol. 1037. Amsterdam,

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1990;**335**(8697):1078-1080

[19] Behçet's Disease Research Committee of Japan. Behçet's disease guide to the diagnosis of Behçet's disease (1972). Japanese Journal of Ophthalmology. 1974;**18**:291-294

1974. pp. 43-55

1974;**36**:2371-2379

Medicine;**19**:15-22

pp. 177-180

1988;**10**:59-65

*The History and Diagnosis of Behçet's Disease DOI: http://dx.doi.org/10.5772/intechopen.89927*

[18] Mason RM, Barnes CG. Behçet's syndrome with arthritis. The Annals of the Rheumatic Diseases;**28**:95-103

[19] Behçet's Disease Research Committee of Japan. Behçet's disease guide to the diagnosis of Behçet's disease (1972). Japanese Journal of Ophthalmology. 1974;**18**:291-294

[20] Hubault A, Hamza M. La maladie de Behçet en 1974. In: de Sezeet S et al., editors. L'actualit'e Rhumatologique 15. Paris, France: Expension Scientifique; 1974. pp. 43-55

[21] O'Duffy JD. Crit'eres propos'es pour le diagnostique de la maladie de Behçet et notes therapeutiques. Revista Médica. 1974;**36**:2371-2379

[22] Cheng SP, Zhang X-Q. Some special clinical manifestations of Behçet's disease—Report of illustrative cases and review of literature (author's transl). The Chinese Journal of Internal Medicine;**19**:15-22

[23] Dilsen N, Konice M, Aral O. Our diagnostic criteria of Behçet's disease—An overview. In: Lehner T, Barnes CG, editor. Recent Advances in Behçet's Disease. Vol. 103. International Congress and Symposium Series. London, UK: London Royal Society of Medicine Services; 1986. pp. 177-180

[24] Mizushima Y. Recent research into Behçet's disease in Japan. International Journal of Tissue Reactions. 1988;**10**:59-65

[25] International Study Group for Behçet's Disease. Criteria for diagnosis of Behçet's disease. Lancet. 1990;**335**(8697):1078-1080

[26] Davatchi F, Shahram F, Akbarian M, et al. Accuracy of existing diagnosis criteria for Behçet's disease. In: Wechsler B, Godeau P, editors. Behçet's Disease. Vol. 1037. Amsterdam,

The Netherlands: Excerpta Medica International Congress Series; 1993. pp. 225-228

[27] Davatchi F, Shahram F, Akbarian M, et al. Classification tree for the diagnosis of Behçet's disease. In: Wechsler B, Godeau P, editors. Behçet's Disease. Vol. 1037. Amsterdam, The Netherlands: Excerpta Medica International Congress Series; 1993. pp. 245-248

[28] Dilsen N. About diagnostic criteria for Behçet's disease: Our new proposal. In: Bang D, Lee ES, Lee S, editors. Behçet's Disease. Seoul, Korea: Design Mecca Publishing; 2000. pp. 101-104

[29] Chang HK, Kim SY. Survey and validation of the criteria for Behçet's disease recently used in Korea: A suggestion for modification of the international study group criteria. Journal of Korean Medical Science;**18**:88-92

[30] International Team for the Revision of the International Criteria for Behçet's Disease. Evaluation of the international criteria for Behçet's disease (ICBD). Clinical and Experimental Rheumatology. 2006;**24**(42):13

[31] International Team for the Revision of the International Criteria for Behçet's disease. Revision of the international criteria for Behçet's disease (ICBD). Clinical and Experimental Rheumatology. 2006;**24**(42):14-15

[32] International Team for the Revision of the International Criteria for Behçet's disease (ITR-ICBD), Davatchi F, Assaad-Khalil S, Calamia KT, et al. The International Criteria for Behçet's Disease (ICBD): A collaborative study of 27 countries on the sensitivity and specificity of the new criteria. Journal of the European Academy of Dermatology and Venereology. 2014, 2014;**28**:338-347

[33] Evaluation of Diagnostic (Classification) Criteria in Behçet's

**10**

*Different Aspects of Behçet's Disease*

**References**

[1] Davatchi F, Chams-Davatchi C, Shams H, Shahram F, Nadji A, Akhlaghi M, et al. Behçet's disease: Epidemiology, clinical manifestations, and diagnosis. Expert Review of Clinical [10] Adamantiades B. La

et de Gynecologie (Paris).

The Annales d'Oculistique et de Gynecologie (Paris). 1953;**186**(9):846-856

[12] Adamantiades B. Severe

Etairias. 1958;**26**:199-202

mucocutaneous lesions. The Journal of Dermatology.

2016;**43**(6):620-632

2017;**10**(4):315-320

[13] Alpsoy E. Behçet's disease: A comprehensive review with a focus on epidemiology, etiology and clinical features, and management of

[14] Boyvat A. Behçet Hastalığında Tanı ve Ayırıcı Tanı. Turkiye Klinikleri

genito-oral aphthosis with hypopion (Behçet's syndrome). Archives of

[16] Hewitt J, Escande JP, Laurent PH, Perlemuter L. Criteres de prevision du

de la SocieteFrancaise de Dermatology et de Syphiligraphie. 1969;**76**:565-568

[17] Hewitt J, Escande JP, Manesse S. Revision of the diagnostic criteria of Behçet's syndrome. La Presse Médicale.

Dermatology-Special Topics.

[15] Curth HO. Recurrent

Dermatology;**54**:179-196

1971;**79**:901

syndrome de Behçet. Bulletin

complications of the central nervous system in the syndrome of relapsing iritis with hypopyon (in Greek). Deltion Ellikinis Ophthalmologikis

1946;**179**:143-148

thrombophlébite comme quatrième symptôme de l'iritis récidivante à hypopyon. The Annales d'Oculistique

[11] Adamantiades B. Le symptôme complexe de l'uvéite récidivante à hypopyon (the complex syndrome of recurrent uveitis with hypopyon).

Immunology. 2017;**13**(1):57-65

Reviews. 2018;**17**(6):567-575

1956;**40**:355-357

1997;**38**(6):327-332

2006;**24**(6):548-550

2010;**16**(6):136-142

[3] Feigenbaum A. Description of Behçet's syndrome in the hippocratic third book of endemic diseases. The British Journal of Ophthalmology.

[4] Behçet H. Uber rezidivierende aphthosa, durch ein Virus verüsachte Geschewüre am Mund, am Auge und an den Genitalien. Dermatologische Wochenschrift. 1937;**109**:1152-1157

[5] Saylan T. Life story of Dr. Hulusi Behçet. Yonsei Medical Journal.

[6] Tüzün Y. Hulusi Behçet MD: February 20, 1889 to March 8, 1948. Clinics in Dermatology.

[7] Evereklioglu C. Behçet's disease or Adamantiades-Behçet disease? An evidence-based historical survey. Medical Science Monitor.

[8] Behçet H, Gözcü N. Üç Nahiyede Nüksi Tavazzular Yapan ve Hususi Bir Virus Tesiri ile Umumi İntan Hasıl Ettiğine Kanaatimiz Artan Entite Morbide Hakkında. Deri Hastalıkları ve Frengi Kliniği Arşivi. 1938;**5**:1863-1873

[9] Adamantiades B. A case of recurrent hypopyon iritis. Proceedings of the Medical Society of Athens. 1930:586-593

[2] Greco A, De Virgilio A, Ralli M, Ciofalo A, Mancini P, Attanasio G, et al. Behçet's disease: New insights into pathophysiology, clinical features and treatment options. Autoimmunity Disease: Toward Internationally Agreed Criteria. International Study Group for Behçet's Disease. In: O'Duffy JD, Komken E, editors. Behçet's Disease. Papers Presented at the Fifth International Conference on Behçet's Disease. New York: Marcel Dekker Inc; 1991. pp. 11-39

[34] Wechsler B, Davatchi F, Mizushima Y, Hamza M, Dilsen N, Kansu E, et al. International Study Group for Behçet's Disease. Evaluation of diagnostic ('classification') criteria in Behçet's disease-toward internationally agreed criteria. British Journal of Rheumatology. 1992;**31**:299-308

[35] Davatchi F, Sadeghi Abdollahi B, Chams-Davatchi C, Shahram F, Shams H, Nadji A, et al. The saga of diagnostic/ classification criteria in Behçet's disease. International Journal of Rheumatic Diseases. 2015;**18**(6):594-605

[36] Davatchi F, Shahram F, Chams-Davatchi C, et al. Behçet's disease: From east to west. Clinical Rheumatology. 2010;**29**:823-833

[37] Mignogna MD, Fedele S, Lo Russo L. International diagnostic criteria and delay of diagnosis in Behçet's disease. The Journal of Rheumatology. 2000;**27**(11):2725

[38] Dilsen N. The importance of the manifestations besides the ones included in international criteria for Behçet's disease. Advances in Experimental Medicine and Biology. 2003;**528**:105-108

[39] Muñoz-Corcuera M, Esparza-Gómez G, González-Moles MA, Bascones-Martínez A. Oral ulcers: Clinical aspects. A tool for dermatologists. Part I. Acute ulcers. Clinical and Experimental Dermatology. 2009;**34**(3):289-294

[40] Femiano F, Lanza A, Buonaiuto C, Gombos F, Cirillo N. Oral aphthous-like lesions, PFAPA syndrome: A review.

Journal of Oral Pathology and Medicine. 2008;**37**(6):319-323

[41] Köse O. Behçet hastalığında tanı ve ayırıcı tanı. Türkderm. 2009;**43** (Suppl 2):87-91

[42] Talacko AA, Gordon AK, Aldred MJ. The patient with recurrent oral ulceration. Australian Dental Journal. 2010;**55**(Suppl 1):14-22

[43] Roett MA, Mayor MT, Uduhiri KA. Diagnosis and management of genital ulcers. American Family Physician. 2012;**85**(3):254-262

[44] Kalkan G, Karadag AS, Astarci HM, Akbay G, Ustun H, Eksioglu M. A histopathological approach: When papulopustular lesions should be in the diagnostic criteria of Behçet's disease? Journal of the European Academy of Dermatology and Venereology. 2009;**23**(9):1056-1060

[45] Siva A, Altintas A, Saip S. Behçet's syndrome and the nervous system. Current Opinion in Neurology. 2004;**17**(3):347-357

[46] Baptista B, Marto N, Tavares JG, Horta AB, Cunha E Sá D, Gerardo G, et al. Behçet syndrome and Crohn's disease: What are the differences? The European Journal of Case Reports in Internal Medicine. 2019;**6**(3)

[47] Ye JF, Guan JL. Differentiation between intestinal Behçet's disease and Crohn's disease based on endoscopy. Turkish Journal of Medical Sciences. 2019;**49**(1):42-49

[48] Jung YS, Cheon JH, Park SJ, Hong SP, Kim TI, Kim WH. Longterm clinical outcomes of Crohn's disease and intestinal Behçet's disease. Inflammatory Bowel Diseases. 2013;**19**(1):99-105

[49] Valenti S, Gallizzi R, De Vivo D, Romano C. Intestinal Behçet

**13**

*The History and Diagnosis of Behçet's Disease DOI: http://dx.doi.org/10.5772/intechopen.89927*

and Crohn's disease: Two sides of the same coin. Pediatric Rheumatology Online Journal. 2017;**15**(1):33

[50] Davis MDP, Moschella SL. Behçet's syndrome. In: Bolognia JL, Schaffer JV, Cerroni L, editors. Dermatology. 4th ed. Philadelphia: Elsevier; 2017. pp. 463-466

[51] Oldfield CW, Heffernan-Stroud LA, Buehler-Bota TS, Williams JV. Bowelassociated dermatosis-arthritis syndrome (BADAS) in a pediatric patient. JAAD Case Reports.

Vano-Galvan S, Jaen P. Bowel-associated

2016;**2**(3):272-274

2013;**52**(12):1596-1598

[52] Truchuelo MT, Acantara J,

dermatosis-arthritis syndrome: Another cutaneous manifestation of inflammatory intestinal disease. International Journal of Dermatology. *The History and Diagnosis of Behçet's Disease DOI: http://dx.doi.org/10.5772/intechopen.89927*

and Crohn's disease: Two sides of the same coin. Pediatric Rheumatology Online Journal. 2017;**15**(1):33

*Different Aspects of Behçet's Disease*

Papers Presented at the Fifth

[34] Wechsler B, Davatchi F, Mizushima Y, Hamza M, Dilsen N, Kansu E, et al. International Study Group for Behçet's Disease. Evaluation of diagnostic ('classification') criteria in Behçet's disease-toward internationally agreed criteria. British Journal of Rheumatology. 1992;**31**:299-308

1991. pp. 11-39

Disease: Toward Internationally Agreed Criteria. International Study Group for Behçet's Disease. In: O'Duffy JD, Komken E, editors. Behçet's Disease.

Journal of Oral Pathology and Medicine.

[41] Köse O. Behçet hastalığında tanı ve

Aldred MJ. The patient with recurrent oral ulceration. Australian Dental Journal. 2010;**55**(Suppl 1):14-22

Uduhiri KA. Diagnosis and management of genital ulcers. American Family Physician. 2012;**85**(3):254-262

[44] Kalkan G, Karadag AS, Astarci HM, Akbay G, Ustun H, Eksioglu M. A histopathological approach: When papulopustular lesions should be in the diagnostic criteria of Behçet's disease? Journal of the European Academy of Dermatology and Venereology.

[45] Siva A, Altintas A, Saip S. Behçet's syndrome and the nervous system. Current Opinion in Neurology.

[46] Baptista B, Marto N, Tavares JG, Horta AB, Cunha E Sá D, Gerardo G, et al. Behçet syndrome and Crohn's disease: What are the differences? The European Journal of Case Reports in

Internal Medicine. 2019;**6**(3)

[47] Ye JF, Guan JL. Differentiation between intestinal Behçet's disease and Crohn's disease based on endoscopy. Turkish Journal of Medical Sciences.

[48] Jung YS, Cheon JH, Park SJ, Hong SP, Kim TI, Kim WH. Longterm clinical outcomes of Crohn's disease and intestinal Behçet's disease.

Inflammatory Bowel Diseases.

[49] Valenti S, Gallizzi R, De

Vivo D, Romano C. Intestinal Behçet

ayırıcı tanı. Türkderm. 2009;**43**

[42] Talacko AA, Gordon AK,

[43] Roett MA, Mayor MT,

2009;**23**(9):1056-1060

2004;**17**(3):347-357

2019;**49**(1):42-49

2013;**19**(1):99-105

2008;**37**(6):319-323

(Suppl 2):87-91

International Conference on Behçet's Disease. New York: Marcel Dekker Inc;

[35] Davatchi F, Sadeghi Abdollahi B, Chams-Davatchi C, Shahram F, Shams H, Nadji A, et al. The saga of diagnostic/ classification criteria in Behçet's disease. International Journal of Rheumatic Diseases. 2015;**18**(6):594-605

[36] Davatchi F, Shahram F, Chams-Davatchi C, et al. Behçet's disease: From east to west. Clinical Rheumatology. 2010;**29**:823-833

[37] Mignogna MD, Fedele S, Lo Russo L. International diagnostic criteria and delay of diagnosis in Behçet's disease. The Journal of Rheumatology. 2000;**27**(11):2725

[38] Dilsen N. The importance of the manifestations besides the ones included in international criteria for Behçet's disease. Advances in Experimental Medicine and Biology. 2003;**528**:105-108

Esparza-Gómez G, González-Moles MA,

[40] Femiano F, Lanza A, Buonaiuto C, Gombos F, Cirillo N. Oral aphthous-like lesions, PFAPA syndrome: A review.

[39] Muñoz-Corcuera M,

2009;**34**(3):289-294

Bascones-Martínez A. Oral ulcers: Clinical aspects. A tool for dermatologists. Part I. Acute ulcers. Clinical and Experimental Dermatology.

**12**

[50] Davis MDP, Moschella SL. Behçet's syndrome. In: Bolognia JL, Schaffer JV, Cerroni L, editors. Dermatology. 4th ed. Philadelphia: Elsevier; 2017. pp. 463-466

[51] Oldfield CW, Heffernan-Stroud LA, Buehler-Bota TS, Williams JV. Bowelassociated dermatosis-arthritis syndrome (BADAS) in a pediatric patient. JAAD Case Reports. 2016;**2**(3):272-274

[52] Truchuelo MT, Acantara J, Vano-Galvan S, Jaen P. Bowel-associated dermatosis-arthritis syndrome: Another cutaneous manifestation of inflammatory intestinal disease. International Journal of Dermatology. 2013;**52**(12):1596-1598

**15**

**Chapter 2**

**Abstract**

immunomodulators.

**1. Introduction**

Behçet's Disease: An Enigmatic

*Shamaz Mohamed and Abhilash R. Krishnan*

Malady with Plethoric Expressions

Behçet's disease (BD) is a chronic, inflammatory, repetitive, debilitating systemic vasculitis with conglomerate system involvement of uncharted aetiology portrayed by the triad of oral ulcers, genital ulcers and cutaneous lesions. Behçet's disease has a universal distribution with a predominance among populace with higher prevalence of human leukocyte antigen (HLA) B5 and its split, HLA-B51, in the Mediterranean basin, the Middle East and Far East. This ailment is presently acknowledged to be a multisystem disorder with mucocutaneous, ocular, intestinal, articular, vascular, urogenital, musculoskeletal, cardiopulmonary and neurologic systems and hence bears significant organ sinistering morbidity and mortality. The diagnosis of Behçet's disease relies on scrupulous history, identification of its emblematic clinical countenance as per the diagnostic criteria construed by the International Study Group (ISG) and examination of all pertinent systems and excluding other systemic rheumatic diseases. However, there is a lag in diagnosis because of its plethoric presentations and a dearth of specific biomarkers. The multiple organ and tissue involvement of Behçet's disease necessitates an interdisciplinary approach from various health specialities since a general and an organspecific approach is mandatory. Prime concern is to control the active periods of the disease which is achieved by different anti-inflammatory drugs, steroids or

**Keywords:** Behçet's disease, triple symptom complex, Adamantiades-Behçet's disease,

Behçet's disease (BD) is described as a severely debilitating chronic, recurrent, multisystem vascular inflammatory disorder characterised by the triad of oral and genital ulceration and ocular lesions. This exemplary presentation would have been probably first identified by Hippocrates [1, 2]. Even though Behçet's disease was first identified by the father of medicine in the fifth century BC, there were no literature representations for this entity till 1930, and then a Greek ophthalmologist Benediktos Adamantiades presented one of his case of relapsing eye lesions associated with genital ulceration and arthritis in a 20-year-old male; since then entity has been added with a synonym "Adamantiades-Behçet's disease" [3–6]. Further to its classic expression of orogenital ulceration and ocular lesions, the conditions seem to involve the musculoskeletal system, nervous system, gastrointestinal tract, vascular beds, urogenital tract and cardiopulmonary system, so Behçet's disease have a high

morbidity and mortality particularly in males with early age onset [7, 8].

oral ulcers, aphthous stomatitis, vasculitis, silk road disease

#### **Chapter 2**

## Behçet's Disease: An Enigmatic Malady with Plethoric Expressions

*Shamaz Mohamed and Abhilash R. Krishnan*

#### **Abstract**

Behçet's disease (BD) is a chronic, inflammatory, repetitive, debilitating systemic vasculitis with conglomerate system involvement of uncharted aetiology portrayed by the triad of oral ulcers, genital ulcers and cutaneous lesions. Behçet's disease has a universal distribution with a predominance among populace with higher prevalence of human leukocyte antigen (HLA) B5 and its split, HLA-B51, in the Mediterranean basin, the Middle East and Far East. This ailment is presently acknowledged to be a multisystem disorder with mucocutaneous, ocular, intestinal, articular, vascular, urogenital, musculoskeletal, cardiopulmonary and neurologic systems and hence bears significant organ sinistering morbidity and mortality. The diagnosis of Behçet's disease relies on scrupulous history, identification of its emblematic clinical countenance as per the diagnostic criteria construed by the International Study Group (ISG) and examination of all pertinent systems and excluding other systemic rheumatic diseases. However, there is a lag in diagnosis because of its plethoric presentations and a dearth of specific biomarkers. The multiple organ and tissue involvement of Behçet's disease necessitates an interdisciplinary approach from various health specialities since a general and an organspecific approach is mandatory. Prime concern is to control the active periods of the disease which is achieved by different anti-inflammatory drugs, steroids or immunomodulators.

**Keywords:** Behçet's disease, triple symptom complex, Adamantiades-Behçet's disease, oral ulcers, aphthous stomatitis, vasculitis, silk road disease

#### **1. Introduction**

Behçet's disease (BD) is described as a severely debilitating chronic, recurrent, multisystem vascular inflammatory disorder characterised by the triad of oral and genital ulceration and ocular lesions. This exemplary presentation would have been probably first identified by Hippocrates [1, 2]. Even though Behçet's disease was first identified by the father of medicine in the fifth century BC, there were no literature representations for this entity till 1930, and then a Greek ophthalmologist Benediktos Adamantiades presented one of his case of relapsing eye lesions associated with genital ulceration and arthritis in a 20-year-old male; since then entity has been added with a synonym "Adamantiades-Behçet's disease" [3–6]. Further to its classic expression of orogenital ulceration and ocular lesions, the conditions seem to involve the musculoskeletal system, nervous system, gastrointestinal tract, vascular beds, urogenital tract and cardiopulmonary system, so Behçet's disease have a high morbidity and mortality particularly in males with early age onset [7, 8].

The self-limiting inflammation and the relapsing episodes of clinical manifestations are the hallmark of Behçet's disease [9]. Frequency and span of regression are uncertain and show no distinguishable pattern of onset.

Although Behçet's disease has a worldwide distribution, it is more rampant in Turkish population, where the prevalence is about 421 cases per 100,000 and 13 to 20 cases per 100,000 population in China, Korea, Japan and the Middle East [10, 11]. Behçet's disease is most commonly diagnosed in the second and third decades of life especially during the reproductive years and shows a female predilection among Europeans. Behçet's disease rarely occurs prior to puberty and after the fifth decade of life. Behçet's disease developing in early age has shown to have severe clinical manifestations and mortality. Familial occurrences have been reported in various literatures but are unusual, and the aetiology of Behçet's disease remains cryptic [12–18]. The widely accepted hypothesis is that of an inappropriate inflammatory response provoked by an infectious agent in a genetically liable host [19].

Diagnosis of Behçet's disease is based on the criteria developed by the International study group (ISG) in 1990 and International Criteria for Behçet's Disease (ICBD) [20]. The ICBD was developed with the intention of bettering the ISG criteria that did not consist of nervous system, vascular and gastrointestinal involvement that are severe but rather infrequent complications of Behçet's disease. A recent study conducted in the United Kingdom has compared the efficacy of ISG and ICBD diagnostic criteria among their patients with Behçet's disease and concluded that the sensitivity was higher for ICBD than ISG criteria, but the specificity of ICBD was much lower than the ISG criteria [20–22].

Management is aimed to alleviate symptoms, resolve inflammation, restrain tissue damage, dwindle frequency and severity and avoid lethal complications. A multitude of treatment modalities have been proposed for managing Behçet's disease ranging from anti-inflammatory to immunomodulators and biologic monoclonal antibodies. Detrimental ramifications are a main concern since it requires long-term medication [8].

#### **2. Epidemiology**

Behçet's disease is observed to have a worldwide distribution. However, it is seen commonly among the inhabitants of the historic Silk Road, which was supposed to be an old trading route that linked Japan and China in the Far East to the Mediterranean Sea, including countries such as Turkey and Iran. Therefore, Behçet's disease is also known by the synonym "Silk Road disease" [23]. Behçet's disease has a highest prevalence rate in Turkey, where the estimated prevalence is about 421 per 100,000 population followed by Iran, Israel and Japan [24]. It is rarely reported in African countries and the USA [23] as well as Australia, where the prevalence remains unknown but with an annual incidence of 0.6% (**Table 1**) [25].

Two studies conducted in Korea and Turkey in 2016 and 2017 reported the prevalence of Behçet's disease. A study conducted in Korea estimated the prevalence of Behçet's disease, and change in prevalence rate over time from the Korean healthcare big data that consists of medical institution claims data concerning diagnosis, prescription medicines and surgical treatment and represents the total population. The database was reviewed for patients diagnosed to have Behçet's disease during the year 2011 and 2015. The diagnosis was based on the Korean Standard Classification of Diseases (KCD). The estimated prevalence was about 35.0 per 100,000 population which was a little more than the previously reported prevalence of 30.2 per 100,000 in Korea. The change in prevalence rate was also estimated during the time period of 2011 and 2015 and concluded that there is a creeping

**17**

*Behçet's Disease: An Enigmatic Malady with Plethoric Expressions*

**Prevalence per one lakh population Country** Turkey 421 Iran 80 Saudi Arabia 20 Iraq 17 Israel 15.2 Japan 13.5 France 7.1 USA 5.2 Sweden 4.9 Germany 2.26 Portugal 1.53 UK 0.64

escalation in the annual prevalence rate between 2011 and 2015. The prevalence rate was 32.8 per 100,000 in 2011, 34.0 per 100,000 in 2012, 34.6 per 100,000 in 2013, 35.5 per 100,000 in 2014 and 35.7 per 100,000 in 2015. The prevalence would have been more since patients with milder form of the disease have not come for treatment. Females had a higher prevalence, with a female-to-male ratio of 1:0.54 in

Another study conducted in Northern Turkey showed a prevalence of Behçet's disease in 600/100,000 population who have crossed their second decade of life and is considered as the highest prevalence reported in the literature so far [27]. Nonetheless this conclusion seems to be biased since there are methodological errors. Patients were randomly selected from the 52 urban and 33 rural general practices of a city and are invited for an examination and interview by three dermatologists. As per the authors, the invited sample would well represent the whole population since all individuals are recorded in general practices. Eye examination and pathergy test were performed in suspected individuals. Individuals compatible to ISG criteria were diagnosed as Behçet's disease. However, the total number of individuals who were invited for interview was not mentioned. Authors reported that 2325 of 2428 individuals interviewed were included in the study, of which 1290 were females and 1035 were males. Symptomatic individuals may have responded to the invitation, which might have led to a higher prevalence estimate. Authors have also reported increased prevalence of Behçet's disease in females (860/100,000) compared to males (140/100,000) (p = 0.022) which does not correlate with the previous studies conducted in Turkey, since they concluded no significant gender predilections [27]. A recent meta-analysis that included 45 prevalence studies suggested that even though there was clearly a wide variation across countries, the overall prevalence of Behçet's disease were 10.3/100,000. The estimated prevalence was 119.8/100,000 for Turkey, 31.8/100,000 for the Middle East, 4.5/100,000 for Asia and 3.3/100,000 for Europe [28]. A meta-regression analysis showed that classification criteria, study period or reference type had hardly any effect and study design was the deciding factor for Behçet's disease prevalence in these studies. The authors have also suggested that true geographic variations and different study methods are the possible factors responsible for the large variation in Behçet's disease prevalence across countries.

*DOI: http://dx.doi.org/10.5772/intechopen.86863*

2011 and 1:0.56 in 2015 [26].

*Worldwide prevalence of Behçet's disease [24].*

**Table 1.**

*Behçet's Disease: An Enigmatic Malady with Plethoric Expressions DOI: http://dx.doi.org/10.5772/intechopen.86863*

#### **Table 1.**

*Different Aspects of Behçet's Disease*

The self-limiting inflammation and the relapsing episodes of clinical manifestations are the hallmark of Behçet's disease [9]. Frequency and span of regression are

Although Behçet's disease has a worldwide distribution, it is more rampant in Turkish population, where the prevalence is about 421 cases per 100,000 and 13 to 20 cases per 100,000 population in China, Korea, Japan and the Middle East [10, 11]. Behçet's disease is most commonly diagnosed in the second and third decades of life especially during the reproductive years and shows a female predilection among Europeans. Behçet's disease rarely occurs prior to puberty and after the fifth decade of life. Behçet's disease developing in early age has shown to have severe clinical manifestations and mortality. Familial occurrences have been reported in various literatures but are unusual, and the aetiology of Behçet's disease remains cryptic [12–18]. The widely accepted hypothesis is that of an inappropriate inflammatory response provoked by an infectious agent in a genetically liable host [19]. Diagnosis of Behçet's disease is based on the criteria developed by the International study group (ISG) in 1990 and International Criteria for Behçet's Disease (ICBD) [20]. The ICBD was developed with the intention of bettering the ISG criteria that did not consist of nervous system, vascular and gastrointestinal involvement that are severe but rather infrequent complications of Behçet's disease. A recent study conducted in the United Kingdom has compared the efficacy of ISG and ICBD diagnostic criteria among their patients with Behçet's disease and concluded that the sensitivity was higher for ICBD than ISG criteria, but the specificity

Management is aimed to alleviate symptoms, resolve inflammation, restrain tissue damage, dwindle frequency and severity and avoid lethal complications. A multitude of treatment modalities have been proposed for managing Behçet's disease ranging from anti-inflammatory to immunomodulators and biologic monoclonal antibodies. Detrimental ramifications are a main concern since it requires long-term

Behçet's disease is observed to have a worldwide distribution. However, it is seen commonly among the inhabitants of the historic Silk Road, which was supposed to be an old trading route that linked Japan and China in the Far East to the Mediterranean Sea, including countries such as Turkey and Iran. Therefore, Behçet's disease is also known by the synonym "Silk Road disease" [23]. Behçet's disease has a highest prevalence rate in Turkey, where the estimated prevalence is about 421 per 100,000 population followed by Iran, Israel and Japan [24]. It is rarely reported in African countries and the USA [23] as well as Australia, where the prevalence

remains unknown but with an annual incidence of 0.6% (**Table 1**) [25].

Two studies conducted in Korea and Turkey in 2016 and 2017 reported the prevalence of Behçet's disease. A study conducted in Korea estimated the prevalence of Behçet's disease, and change in prevalence rate over time from the Korean healthcare big data that consists of medical institution claims data concerning diagnosis, prescription medicines and surgical treatment and represents the total population. The database was reviewed for patients diagnosed to have Behçet's disease during the year 2011 and 2015. The diagnosis was based on the Korean Standard Classification of Diseases (KCD). The estimated prevalence was about 35.0 per 100,000 population which was a little more than the previously reported prevalence of 30.2 per 100,000 in Korea. The change in prevalence rate was also estimated during the time period of 2011 and 2015 and concluded that there is a creeping

uncertain and show no distinguishable pattern of onset.

of ICBD was much lower than the ISG criteria [20–22].

**16**

medication [8].

**2. Epidemiology**

*Worldwide prevalence of Behçet's disease [24].*

escalation in the annual prevalence rate between 2011 and 2015. The prevalence rate was 32.8 per 100,000 in 2011, 34.0 per 100,000 in 2012, 34.6 per 100,000 in 2013, 35.5 per 100,000 in 2014 and 35.7 per 100,000 in 2015. The prevalence would have been more since patients with milder form of the disease have not come for treatment. Females had a higher prevalence, with a female-to-male ratio of 1:0.54 in 2011 and 1:0.56 in 2015 [26].

Another study conducted in Northern Turkey showed a prevalence of Behçet's disease in 600/100,000 population who have crossed their second decade of life and is considered as the highest prevalence reported in the literature so far [27]. Nonetheless this conclusion seems to be biased since there are methodological errors. Patients were randomly selected from the 52 urban and 33 rural general practices of a city and are invited for an examination and interview by three dermatologists. As per the authors, the invited sample would well represent the whole population since all individuals are recorded in general practices. Eye examination and pathergy test were performed in suspected individuals. Individuals compatible to ISG criteria were diagnosed as Behçet's disease. However, the total number of individuals who were invited for interview was not mentioned. Authors reported that 2325 of 2428 individuals interviewed were included in the study, of which 1290 were females and 1035 were males. Symptomatic individuals may have responded to the invitation, which might have led to a higher prevalence estimate. Authors have also reported increased prevalence of Behçet's disease in females (860/100,000) compared to males (140/100,000) (p = 0.022) which does not correlate with the previous studies conducted in Turkey, since they concluded no significant gender predilections [27].

A recent meta-analysis that included 45 prevalence studies suggested that even though there was clearly a wide variation across countries, the overall prevalence of Behçet's disease were 10.3/100,000. The estimated prevalence was 119.8/100,000 for Turkey, 31.8/100,000 for the Middle East, 4.5/100,000 for Asia and 3.3/100,000 for Europe [28]. A meta-regression analysis showed that classification criteria, study period or reference type had hardly any effect and study design was the deciding factor for Behçet's disease prevalence in these studies. The authors have also suggested that true geographic variations and different study methods are the possible factors responsible for the large variation in Behçet's disease prevalence across countries.

Two studies conducted in Korea reported on the clinical manifestations of Behçet's disease patients according to gender [29, 30]. The first study was carried out by a rheumatology department of a university hospital in Turkey, which assessed the prevalence between male and female with Behçet's disease in a retrospective chart review of 329 patients [29]. The study included patients who fulfilled the ISG criteria. Data on demographic features of the patients, family history, age of onset, manifestations of Behçet's, positive pathergy test and HLA-B51 were retrieved from patient charts. Among the 329 patients, 199 (60.4%) were males. A family history of Behçet's disease was reported by 9.7% of the patients and a family history of oral ulcers by 22.5%. Early onset was observed in patients with a positive family history; this phenomenon is termed as genetic anticipation which had already been seen in previous studies [31]. Female patients had an early onset compared to males (23.0 vs. 25.2 years, p < 0.05). Eye lesions were more common among males (42.2 vs. 29.2%, p = 0.014). Vascular involvement was also more common among in males (44.7 vs. 15.3%, p < 0.001), whereas joint involvement and headache were common among women (70.0 vs. 49.2%, p < 0.001 for joint involvement and 60.0 vs. 36.2%, p < 0.001 for headache). Frequency of genital ulcers, nodular lesions, papulopustular lesions and nervous system involvement was similar among males and females. Pathergy test was positive in 48.7% of the patients (52.4% among male and 43.4% among female, p = 0.316). HLA-B51 was positive in 44.1% of Behçet's disease patients, and the frequency was lower among men, but the difference was not that significant (38.8 vs. 50.6%, p = 0.106). The second study was conducted in Korea, which was a retrospective chart review of 193 patients, which analysed gender, age of onset of Behçet's disease and HLA-B51 [30]. The study showed that there is an increased prevalence in females (67%), whereas other parameters like the mean age at onset, the mean disease duration, positive pathergy test and positive HLA-B51 were similar in both males and females. Genital ulcers, peripheral joint involvement and inflammatory back pain were more common in females, while skin lesions were more frequent in males. In total, major organ involvement was present in 39% of the patients (uveitis, 27%; nervous system involvement, 7%; vascular involvement, 4% and gastrointestinal involvement, 11%), with similar frequency in both the genders. When clinical findings were compared based on onset of disease, patients with late onset (>40 years) had more nervous system involvement than those with an early onset (15.9 vs. 4.2%, p = 0.007).

Like the previous study, HLA-B51 positive patients had a history of early disease onset, but less nervous system (17.2 vs. 2.5%, p = 0.02) and gastrointestinal system (20.7 vs. 2.5%, p = 0.01) involvement than patients with negative HLA-B51 [32, 33].

A Japanese study conducted in 2015 analysed the change in disease phenotype over time among Behçet's disease patients treated in seven hospitals in a district in mid-Japan between 1991 and 2015. Patients fulfilled the 1987 revised diagnostic criteria of the Behçet's disease research committee; the Ministry of Health, Labour and Welfare of Japan was included in the study [34, 35]. This criterion classified the manifestations of Behçet's disease into major and minor symptoms. Major symptoms include recurrent aphthous oral ulcers, skin lesions, ocular inflammation and genital ulcers, and minor symptoms include arthritis, intestinal ulcers, epididymitis, vascular lesions and neuropsychiatric disease.

Those who have all four major symptoms during the clinical course are classified as complete, whereas those who have three major symptoms, two major and two minor symptoms, typical recurrent ocular inflammation and one or more major symptoms or typical recurrent ocular inflammation and two minor symptoms are classified as incomplete Behçet's disease. Patients were divided into three groups as group A, diagnosed before 2000; group B, diagnosed between 2000 and 2007; and group C, diagnosed after 2008. Authors observed a decrease in the number of

**19**

**3. Genetics**

*Behçet's Disease: An Enigmatic Malady with Plethoric Expressions*

German population, remains inferior to prevalence in Turkey [38].

among patients of Italian and non-Italian origin living in these areas.

Moroccans is the same as in their countries of origin [39, 40].

with HLA-B15, HLA-B27, HLA-B57 and HLA-A26 [40].

patients with complete disease over time, suggesting a trend for milder disease in more recent years which could be due to usage of newer medicaments and awareness about the disease. The male-to-female ratio and the age of onset of disease were not changed over time, whereas the frequency of genital ulcers and HLA-B51 positivity decreased and gastrointestinal involvement frequency increased [34, 35]. Additionally, individuals migrated from countries with high prevalence of Behçet's disease to countries with less prevalence rate were shown to have less risk of developing disease [36, 37]. Prevalence of Behçet's disease among Turkish individuals in Germany is about 21/100,000, which, although higher than that of the

Although Behçet's disease is rare in Africans, two series have been published recently based on studies conducted in Nigeria and Dakar from the year 2007 to 2011. Based on the observation by Italian authors, the prevalence of Behçet's disease was found to be higher among immigrants when they analysed its prevalence

A study conducted in the Netherlands estimated the prevalence of Behçet's disease in patients with diverse ethnic origins residing in the Rotterdam area showed a prevalence of 1/100,000 population among Dutch Caucasians, 39/100,000 among Moroccans and 71/100,000 among Turks, suggesting that the prevalence among

Peculiar geographical distribution, familial aggregation, polymorphisms in genes that control immune responses and correlation with HLA-B51 class I antigen are the four factors that are considered to contribute to Behçet's disease susceptibility. Ohno in 1973 described the association of BD with HLA-B5 [39]. They demonstrated that HLA-B5 includes HLA-B51 and HLA-B52 as it has a heterogeneous composition. In major histocompatibility locus, HLA-B51 and HLA-B5701 were associated with the pathogenesis of the disease, mainly among populace alongside of ancient Silk Road. Although associations with HLA-A and HLA-C have been described, they are nonspecific and require confirmation. Other MHC genes such as TNF and MHC class I genes (MICA) are under study; the exact mechanism has not been fully understood. The association with HLA-B51 appears to be important in neutrophil activation. However, the presence of HLA-B51 alone is not ample to explain the manifestations of Behçet's disease. A case series of Iranian patients showed association with HLA-B35, HLA-B51, HLA-B52 and HLA-Bw4. Supplementary studies suggest associations

Researches focused on single-nucleotide polymorphisms (SNPs) revealed that SNP which is in the HLA-B region between HLA-B and MICA genes is responsible for the relationship between HLA-B51 and Behçet's disease. The epistatic interactions with endoplasmic reticulum-associated aminopeptidase 1 (ERAP-1) has also been studied, and the authors suggested that the interaction of ERAP-1 and HLA-B has also been consistent, and these cytokines were apparently high in the peripheral blood mononuclear cells of patients with Behçet's disease compared to the control group. Another conclusion was the unbalanced suppressor of cytokine signalling

A Chinese study stated that the polymorphisms of NOS3/rs1799983, a nitric oxide synthase gene, were found to be associated with the disease and the involvement of CD16 and CD11c in Behçet's disease susceptibility. Mutations in the familial Mediterranean fever (MEFV) gene were suggested by a meta-analysis of 8 studies which analysed 2538 patients and 2792 healthy controls. Researches also suggested

expression in patients with Behçet's disease compared to controls [41].

*DOI: http://dx.doi.org/10.5772/intechopen.86863*

*Behçet's Disease: An Enigmatic Malady with Plethoric Expressions DOI: http://dx.doi.org/10.5772/intechopen.86863*

patients with complete disease over time, suggesting a trend for milder disease in more recent years which could be due to usage of newer medicaments and awareness about the disease. The male-to-female ratio and the age of onset of disease were not changed over time, whereas the frequency of genital ulcers and HLA-B51 positivity decreased and gastrointestinal involvement frequency increased [34, 35].

Additionally, individuals migrated from countries with high prevalence of Behçet's disease to countries with less prevalence rate were shown to have less risk of developing disease [36, 37]. Prevalence of Behçet's disease among Turkish individuals in Germany is about 21/100,000, which, although higher than that of the German population, remains inferior to prevalence in Turkey [38].

Although Behçet's disease is rare in Africans, two series have been published recently based on studies conducted in Nigeria and Dakar from the year 2007 to 2011. Based on the observation by Italian authors, the prevalence of Behçet's disease was found to be higher among immigrants when they analysed its prevalence among patients of Italian and non-Italian origin living in these areas.

A study conducted in the Netherlands estimated the prevalence of Behçet's disease in patients with diverse ethnic origins residing in the Rotterdam area showed a prevalence of 1/100,000 population among Dutch Caucasians, 39/100,000 among Moroccans and 71/100,000 among Turks, suggesting that the prevalence among Moroccans is the same as in their countries of origin [39, 40].

#### **3. Genetics**

*Different Aspects of Behçet's Disease*

onset (15.9 vs. 4.2%, p = 0.007).

tis, vascular lesions and neuropsychiatric disease.

Two studies conducted in Korea reported on the clinical manifestations of Behçet's disease patients according to gender [29, 30]. The first study was carried out by a rheumatology department of a university hospital in Turkey, which assessed the prevalence between male and female with Behçet's disease in a retrospective chart review of 329 patients [29]. The study included patients who fulfilled the ISG criteria. Data on demographic features of the patients, family history, age of onset, manifestations of Behçet's, positive pathergy test and HLA-B51 were retrieved from patient charts. Among the 329 patients, 199 (60.4%) were males. A family history of Behçet's disease was reported by 9.7% of the patients and a family history of oral ulcers by 22.5%. Early onset was observed in patients with a positive family history; this phenomenon is termed as genetic anticipation which had already been seen in previous studies [31]. Female patients had an early onset compared to males (23.0 vs. 25.2 years, p < 0.05). Eye lesions were more common among males (42.2 vs. 29.2%, p = 0.014). Vascular involvement was also more common among in males (44.7 vs. 15.3%, p < 0.001), whereas joint involvement and headache were common among women (70.0 vs. 49.2%, p < 0.001 for joint involvement and 60.0 vs. 36.2%, p < 0.001 for headache). Frequency of genital ulcers, nodular lesions, papulopustular lesions and nervous system involvement was similar among males and females. Pathergy test was positive in 48.7% of the patients (52.4% among male and 43.4% among female, p = 0.316). HLA-B51 was positive in 44.1% of Behçet's disease patients, and the frequency was lower among men, but the difference was not that significant (38.8 vs. 50.6%, p = 0.106). The second study was conducted in Korea, which was a retrospective chart review of 193 patients, which analysed gender, age of onset of Behçet's disease and HLA-B51 [30]. The study showed that there is an increased prevalence in females (67%), whereas other parameters like the mean age at onset, the mean disease duration, positive pathergy test and positive HLA-B51 were similar in both males and females. Genital ulcers, peripheral joint involvement and inflammatory back pain were more common in females, while skin lesions were more frequent in males. In total, major organ involvement was present in 39% of the patients (uveitis, 27%; nervous system involvement, 7%; vascular involvement, 4% and gastrointestinal involvement, 11%), with similar frequency in both the genders. When clinical findings were compared based on onset of disease, patients with late onset (>40 years) had more nervous system involvement than those with an early

Like the previous study, HLA-B51 positive patients had a history of early disease onset, but less nervous system (17.2 vs. 2.5%, p = 0.02) and gastrointestinal system (20.7 vs. 2.5%, p = 0.01) involvement than patients with negative HLA-B51 [32, 33]. A Japanese study conducted in 2015 analysed the change in disease phenotype over time among Behçet's disease patients treated in seven hospitals in a district in mid-Japan between 1991 and 2015. Patients fulfilled the 1987 revised diagnostic criteria of the Behçet's disease research committee; the Ministry of Health, Labour and Welfare of Japan was included in the study [34, 35]. This criterion classified the manifestations of Behçet's disease into major and minor symptoms. Major symptoms include recurrent aphthous oral ulcers, skin lesions, ocular inflammation and genital ulcers, and minor symptoms include arthritis, intestinal ulcers, epididymi-

Those who have all four major symptoms during the clinical course are classified as complete, whereas those who have three major symptoms, two major and two minor symptoms, typical recurrent ocular inflammation and one or more major symptoms or typical recurrent ocular inflammation and two minor symptoms are classified as incomplete Behçet's disease. Patients were divided into three groups as group A, diagnosed before 2000; group B, diagnosed between 2000 and 2007; and group C, diagnosed after 2008. Authors observed a decrease in the number of

**18**

Peculiar geographical distribution, familial aggregation, polymorphisms in genes that control immune responses and correlation with HLA-B51 class I antigen are the four factors that are considered to contribute to Behçet's disease susceptibility. Ohno in 1973 described the association of BD with HLA-B5 [39]. They demonstrated that HLA-B5 includes HLA-B51 and HLA-B52 as it has a heterogeneous composition. In major histocompatibility locus, HLA-B51 and HLA-B5701 were associated with the pathogenesis of the disease, mainly among populace alongside of ancient Silk Road. Although associations with HLA-A and HLA-C have been described, they are nonspecific and require confirmation. Other MHC genes such as TNF and MHC class I genes (MICA) are under study; the exact mechanism has not been fully understood. The association with HLA-B51 appears to be important in neutrophil activation. However, the presence of HLA-B51 alone is not ample to explain the manifestations of Behçet's disease. A case series of Iranian patients showed association with HLA-B35, HLA-B51, HLA-B52 and HLA-Bw4. Supplementary studies suggest associations with HLA-B15, HLA-B27, HLA-B57 and HLA-A26 [40].

Researches focused on single-nucleotide polymorphisms (SNPs) revealed that SNP which is in the HLA-B region between HLA-B and MICA genes is responsible for the relationship between HLA-B51 and Behçet's disease. The epistatic interactions with endoplasmic reticulum-associated aminopeptidase 1 (ERAP-1) has also been studied, and the authors suggested that the interaction of ERAP-1 and HLA-B has also been consistent, and these cytokines were apparently high in the peripheral blood mononuclear cells of patients with Behçet's disease compared to the control group. Another conclusion was the unbalanced suppressor of cytokine signalling expression in patients with Behçet's disease compared to controls [41].

A Chinese study stated that the polymorphisms of NOS3/rs1799983, a nitric oxide synthase gene, were found to be associated with the disease and the involvement of CD16 and CD11c in Behçet's disease susceptibility. Mutations in the familial Mediterranean fever (MEFV) gene were suggested by a meta-analysis of 8 studies which analysed 2538 patients and 2792 healthy controls. Researches also suggested

the associations of Toll-like receptors 7 (TLR7) and other nucleic acid-sensing genes of innate immunity-like inflammatory pathways such as IFI16 (a dsDNA cytosolic sensor and mediator of the AIM2-dependent inflammatory pathway) found to influence Behçet's disease susceptibility [39]. Epigenetic studies with inverted repeat sequences (IRS) demonstrated that methylation level of IRS elements may influence the pathogenesis of the Behçet's disease. Researches were done on genes related to apoptosis, but the results were not conclusive [41].

#### **4. Pathogenesis**

A multitude of factors that indicate the interaction between environmental, innate and adaptive immunity in the development of the disease has been already discussed in the Genetics section. Various researches have studied about the role of bacterial and viral agents in the development of Behçet's disease, but the results were inconclusive. *Streptococcus sanguinis* and Herpesviridae were suspected as contributing extrinsic factors for the oral presentations in Behçet's disease; the immune response to these microorganisms and bacterial plaque ecology may be affected in Behçet's disease, leading to changes seen in the oral mucosa. However good prognosis was noticed in patients with good oral health status [41]. Recent studies in Behçet's disease patients have demonstrated peculiar dysbiosis of the gut microbial flora with a notable drop in the production of butyrate. Butyrate can initiate the differentiation of regulatory T cells (T-reg), and thus, its decrease would lead to the reduction of regulatory T-cell response and activation of immunopathological T-cell effector responses. Predisposition to insulin resistance and metabolic syndrome in patients and reduction of angiopoietin 1 especially in patients with vascular involvement has been observed in other studies [42]. In an attempt to find out specific Behçet's disease antigen, a Chinese research group demonstrated high IgG reactivity to an endothelial cell autoantigen [41].

Matzinger suggested the danger model, which occurs due to a continuous autoimmune cascade resulting from signals emitted by the affected cells of the host which will override the external stimulus. T cells and other antigen-presenting cells (APC) would command the process, which would be perpetuated on a favourable genetic terrain. Damage by a non-self-entity would trigger permanent aggression by activating an uncontrolled adaptive response. Because of their similarity to other pathogenic proteins, heat shock proteins (HSP60) could be involved. This adaptive reaction to external stimuli would persist in the permanent pathogenic presence via autoantigens that would activate dendritic T cells and B cells [40]. Thus, overexpression of proinflammatory cytokines especially Th1 and Th17 and probably association with genetic susceptibility may be the contributing factor for the increased inflammatory reaction in Behçet's disease. Stimulated lymphocytes would activate neutrophils and endothelial cells, and HSPs would probably trigger innate and adaptive immune responses. Hypersensitivity to *Streptococcus sanguinis* is observed through the innate immune system. Microbial flora along with stress proteins in oral and periodontal tissues could cross-react with host tissues and stimulate the proliferation of autoreactive T-cell clones. HSPs would transfer antigenic peptides to APCs that could be identified by TLRs, triggering an endogenous signal of danger that would lead to the activation of innate and adaptive immune systems. They could also, directly or indirectly, cause increased expression of vascular endothelial growth factor by T cells, causing both endothelial cell damage and vasculitis.

Many studies have demonstrated the presence of IFN-gamma and IL-12 in peripheral blood of Behçet's disease patients suggesting involvement of TH1 cells. Elevated IL-1, IL-6, IL-18, TNF-alpha and chemokines would reflect the activation of innate

**21**

**Table 2.**

*Manifestations of Behçet's disease.*

*Behçet's Disease: An Enigmatic Malady with Plethoric Expressions*

and adaptive immune systems. Neutrophils are hyperactivated with increased phagocytosis, chemotaxis, superoxide and lysosomal enzyme production. Lymphocytes have also shown abnormal functions such as clonal expansion of autoreactive T cells specific for heat shock protein 60 peptides. In addition, gamma-delta T cells are abundant in the blood and mucosal lesions of the affected individuals. Researchers have concluded that the interaction between T cells, neutrophils and antigen-presenting

Behçet's disease is a form of systemic vasculitis which affect almost all vascularized systems (**Table 2**) and is characterised by episodes of relapses and remissions

The triad of oral aphthae, genital ulcers and ocular lesions specifies the disease pattern even though Behçet's disease has other multisystem involvement and several

Children exhibit more frequent perianal ulceration and more severe course of chorioretinitis and less frequent genital ulcers and vascular involvement [44, 45].

A meta-analysis of 18 articles which was performed by Horie et al. to assess the association between HLA-B51 and the ocular manifestations of Behçet's disease among various ethnic group studies from Middle and Far East suggested that there was a strong association between HLA-B51 expression and ocular involvement, whereas studies from North Africa and Europe showed no association [46]. Accorinti et al. investigated demographic and clinical trends of 385 Behçet's disease patients with uveitis seen over 44 years in a referral unit at Sapienza University in Rome, Italy. The cohort was divided into cohort 1, which included the patients seen from 1968 to 1992, and cohort 2 included the patients seen during 1993 and 2011. Compared to the cohort 1, the cohort 2 has more female patients, more patients with milder disease (more frequent isolated anterior uveitis, less frequent hypopyon) and more immunosuppressive use. Ocular complications such as optic atrophy, maculopathy and retinal neovascularisation and retinal detachment

**Manifestation Prevalence Prognosis Comments**

Genital ulcers 57–93% Favourable Lesion will leave a scar

Oral ulcers 47–83% Favourable Appear in all patients during the disease

Ocular lesions 30–70% Poor More frequent in males. Has high morbidity Cutaneous lesions 38–99% Favourable Erythema nodosum more frequent in females Joint involvement 45–60% Favourable Nondeforming and nonerosive Cardiovascular involvement 7–49% Poor More frequent in males, high morbidity and

Neurological involvement 5–10% Poor More frequent in males, high morbidity and

Gastrointestinal involvement 3–26% Poor More frequent among Japanese

course

mortality

mortality

cells probably contributes to the pathogenesis of Behçet's disease [40].

*DOI: http://dx.doi.org/10.5772/intechopen.86863*

**5. Clinical presentations**

clinical manifestations.

**5.1 Eye manifestations**

[9, 43, 44].

and adaptive immune systems. Neutrophils are hyperactivated with increased phagocytosis, chemotaxis, superoxide and lysosomal enzyme production. Lymphocytes have also shown abnormal functions such as clonal expansion of autoreactive T cells specific for heat shock protein 60 peptides. In addition, gamma-delta T cells are abundant in the blood and mucosal lesions of the affected individuals. Researchers have concluded that the interaction between T cells, neutrophils and antigen-presenting cells probably contributes to the pathogenesis of Behçet's disease [40].

### **5. Clinical presentations**

*Different Aspects of Behçet's Disease*

**4. Pathogenesis**

the associations of Toll-like receptors 7 (TLR7) and other nucleic acid-sensing genes of innate immunity-like inflammatory pathways such as IFI16 (a dsDNA cytosolic sensor and mediator of the AIM2-dependent inflammatory pathway) found to influence Behçet's disease susceptibility [39]. Epigenetic studies with inverted repeat sequences (IRS) demonstrated that methylation level of IRS elements may influence the pathogenesis of the Behçet's disease. Researches were done on genes

A multitude of factors that indicate the interaction between environmental, innate and adaptive immunity in the development of the disease has been already discussed in the Genetics section. Various researches have studied about the role of bacterial and viral agents in the development of Behçet's disease, but the results were inconclusive. *Streptococcus sanguinis* and Herpesviridae were suspected as contributing extrinsic factors for the oral presentations in Behçet's disease; the immune response to these microorganisms and bacterial plaque ecology may be affected in Behçet's disease, leading to changes seen in the oral mucosa. However good prognosis was noticed in patients with good oral health status [41]. Recent studies in Behçet's disease patients have demonstrated peculiar dysbiosis of the gut microbial flora with a notable drop in the production of butyrate. Butyrate can initiate the differentiation of regulatory T cells (T-reg), and thus, its decrease would lead to the reduction of regulatory T-cell response and activation of immunopathological T-cell effector responses. Predisposition to insulin resistance and metabolic syndrome in patients and reduction of angiopoietin 1 especially in patients with vascular involvement has been observed in other studies [42]. In an attempt to find out specific Behçet's disease antigen, a Chinese research group demonstrated high

Matzinger suggested the danger model, which occurs due to a continuous autoimmune cascade resulting from signals emitted by the affected cells of the host which will override the external stimulus. T cells and other antigen-presenting cells (APC) would command the process, which would be perpetuated on a favourable genetic terrain. Damage by a non-self-entity would trigger permanent aggression by activating an uncontrolled adaptive response. Because of their similarity to other pathogenic proteins, heat shock proteins (HSP60) could be involved. This adaptive reaction to external stimuli would persist in the permanent pathogenic presence via autoantigens that would activate dendritic T cells and B cells [40]. Thus, overexpression of proinflammatory cytokines especially Th1 and Th17 and probably association with genetic susceptibility may be the contributing factor for the increased inflammatory reaction in Behçet's disease. Stimulated lymphocytes would activate neutrophils and endothelial cells, and HSPs would probably trigger innate and adaptive immune responses. Hypersensitivity to *Streptococcus sanguinis* is observed through the innate immune system. Microbial flora along with stress proteins in oral and periodontal tissues could cross-react with host tissues and stimulate the proliferation of autoreactive T-cell clones. HSPs would transfer antigenic peptides to APCs that could be identified by TLRs, triggering an endogenous signal of danger that would lead to the activation of innate and adaptive immune systems. They could also, directly or indirectly, cause increased expression of vascular endothelial growth factor by T cells, causing both endothelial cell damage and vasculitis.

Many studies have demonstrated the presence of IFN-gamma and IL-12 in peripheral blood of Behçet's disease patients suggesting involvement of TH1 cells. Elevated IL-1, IL-6, IL-18, TNF-alpha and chemokines would reflect the activation of innate

related to apoptosis, but the results were not conclusive [41].

IgG reactivity to an endothelial cell autoantigen [41].

**20**

Behçet's disease is a form of systemic vasculitis which affect almost all vascularized systems (**Table 2**) and is characterised by episodes of relapses and remissions [9, 43, 44].

The triad of oral aphthae, genital ulcers and ocular lesions specifies the disease pattern even though Behçet's disease has other multisystem involvement and several clinical manifestations.

Children exhibit more frequent perianal ulceration and more severe course of chorioretinitis and less frequent genital ulcers and vascular involvement [44, 45].

#### **5.1 Eye manifestations**

A meta-analysis of 18 articles which was performed by Horie et al. to assess the association between HLA-B51 and the ocular manifestations of Behçet's disease among various ethnic group studies from Middle and Far East suggested that there was a strong association between HLA-B51 expression and ocular involvement, whereas studies from North Africa and Europe showed no association [46].

Accorinti et al. investigated demographic and clinical trends of 385 Behçet's disease patients with uveitis seen over 44 years in a referral unit at Sapienza University in Rome, Italy. The cohort was divided into cohort 1, which included the patients seen from 1968 to 1992, and cohort 2 included the patients seen during 1993 and 2011. Compared to the cohort 1, the cohort 2 has more female patients, more patients with milder disease (more frequent isolated anterior uveitis, less frequent hypopyon) and more immunosuppressive use. Ocular complications such as optic atrophy, maculopathy and retinal neovascularisation and retinal detachment

were significantly more common in cohort 1. The visual acuity at final evaluation was better in the second cohort. When considered both the cohorts, more severe findings were observed in males. From the above findings, the authors concluded that timely and aggressive management reduces ocular complications and facilitates better prognosis [47].

Even though uveitis is the common ocular pathology in Behçet's disease, it is not a common cause of uveitis. The highest incidence of uveitis is reported by Mishima S from Japan [48], where it constitutes about 25%, but it is much rarer in other countries such as Brazil, where the incidence is 2% [49], and India, where the incidence is 1% reported by Sen DK from a study conducted in 94 Indian children [50]. The classical feature of Behçet's disease is recurrent, acute anterior uveitis associated with hypopyon. Other ocular manifestations seen in Behçet's disease include necrotizing vascular lesions involving the retina and the optic nerve. These manifestations may be unnoticed because of severity of the anterior segment reaction and commonly include macular oedema, retinal periphlebitis and periarteritis, thrombosis of the vessels and retinal or vitreous haemorrhages which are frequently observed in males with Behçet's disease [51, 52].

#### **5.2 Oral manifestations**

Recurrent oral ulcers are one of the earliest manifestations of Behçet's disease in around 47–86% of patients and are seen in almost all patients during their clinical course [53]. Other symptoms may at times take years to appear after the onset of disease. Oral ulcerative lesions usually manifest as a round- or oval-shaped ulcer with discrete erythematous border with a greyish-white pseudomembrane or a central yellowish fibrinous floor and grow rapidly from a flat ulcer to a deep sore [9]. They may occur as single ulcers or as numerous [9, 53]. Oral ulcers most commonly affect the gingival and buccal mucosa, tongue and lips yet may also appear in the soft and hard palates, pharynx and tonsils [9]. Minor ulcers which are less than 1 cm in diameter heal without scarring over a period of 1 to 2 weeks, whereas major ulcers which are more than 1 cm in diameter are more painful and heal within 2–6 weeks. Herpetiform ulcers occurring in recurrent crops of small ulcers that are 0.2–0.3 cm in diameter are painful and may coalesce to form large ulcers. Treatment is usually symptomatic, and prognosis of oral ulcerations is favourable [18, 53].

#### **5.3 Cutaneous manifestations**

The most commonly seen cutaneous manifestations are erythema nodosum and pseudofolliculitis, in which erythema nodosum is manifested as painful multiple subcutaneous nodules that vary in size and colour, whereas pseudofolliculitis (pustulosis) appears as a dome-shaped sterile pustule on a round reddish edematous base that looks like acne vulgaris [54]. Although these are commonly seen on the lower extremities, it can be seen throughout the body [55]. The pathergy reaction is included in the criteria for the diagnosis of Behçet's disease. Although more than 50% of patients from Turkey and Japan had a positive pathergy test, it is rarely observed in patients from Northern Europe, the USA and Australia [56, 57]. It used to be an important diagnostic criterion for Behçet's disease; however, the frequency of the pathergy phenomenon was reported to decrease during the recent years [58]. Subcutaneous thrombophlebitis is often confused with lesions of erythema nodosum; the former is manifested as tender erythematous nodules with a linear arrangement in most case. The lesions may relocate depending on the vascular segment involved [59].

**23**

*Behçet's Disease: An Enigmatic Malady with Plethoric Expressions*

Cardiac involvement is a rare finding in patients with Behçet's disease. Behçet's disease affects arteries, veins as well as the heart. Cardiovascular features have been reported to affect 7–49% of patients, more frequently in males. They occur 3–16 years after the onset of Behçet's disease. Cardiac involvement in Behçet's disease patients was first described by Mirone et al. in 1958 as a case of paroxysmal fibrillation and heart block. In 1963, Oshima et al. described a case of myocardial infarction complicated by incomplete right bundle-branch block [60]. Since then different types of cardiovascular lesions, including pericarditis, atrial thrombus, complex ventricular arrhythmia, myocardial infarction, heart block and sudden death, have been reported in association with Behçet's disease [61]. Dong Soo et al. in 1998 reported a case of superior vena cava syndrome caused by Behçet's disease in a 40-year-old man with recurrent oral aphthous ulcers and skin rashes on the

Neurological involvement in Behçet's disease, the neuro-Behçet's disease, occurs

very rarely and only in 5–10% of patients. It is frequently seen in males [63]. It usually occurs around 5 years after the onset of the disease and is associated with long-term morbidity and mortality [9]. Neuro-Behçet's disease can be parenchymal, nonparenchymal or mixed brain disease, in which the parenchymal brain disease affects the brainstem and/or basal ganglia and is correlated with a poor prognosis, whereas nonparenchymal also known as vasculo-Behçet's disease or angio-Behçet's disease is characterised by subsets of cerebral venous thromboses, dural venous sinus thrombosis, arterial vasculitis and aseptic meningitis and comprises the most devastating symptom category of Behçet's disease with high mortality [63, 64]. A mixed parenchymal and nonparenchymal disease has also been reported but is very rare. Infrequent clinical manifestations like epilepsy, stroke, brain tumour-like neuro-Behçet's disease, acute meningeal syndrome, movement disorders, optic neuropathy, spinal cord involvement and asymptomatic and subclinical neurological involvement have also been reported [65, 66]. Meningitis, neurological deficits including motor disturbances and brainstem symptoms and psychiatric symptoms including personality changes develop in patients with neuro-Behçet's disease are considered as a classic finding [18, 63]. These symptoms are associated with disease exacerbations and gradually cause disability and unfortunately are irreversible [18]. At late stages, dementia develops in approximately one-third of patients with

Gastrointestinal involvement was observed in 3–26% of patients and varies among different populations [38, 39]. It is much more frequent in Japan than in the Middle East and the Mediterranean region [1–3]. Mucosal inflammation and ulceration can occur anywhere in the gastrointestinal tract but typically in the ileocecal region. Other rarely involved sites include the oesophagus, ascending colon and transverse colon [18, 19, 67]. Clinical symptoms include anorexia, vomiting, dyspepsia, diarrhoea, melena, abdominal pain and, less frequently, perforation requiring surgical intervention [68]. Due to the similarity in intestinal and extraintestinal symptoms, it is tough to differentiate Behçet's disease from inflammatory bowel disease; however, the presence of granulomata can be used to confirm inflamma-

*DOI: http://dx.doi.org/10.5772/intechopen.86863*

**5.4 Cardiac manifestations**

anterior chest wall [62].

neuro-Behçet's disease.

tory bowel disease [66].

**5.6 Gastrointestinal manifestations**

**5.5 Neurological manifestations**

#### **5.4 Cardiac manifestations**

*Different Aspects of Behçet's Disease*

observed in males with Behçet's disease [51, 52].

better prognosis [47].

**5.2 Oral manifestations**

favourable [18, 53].

**5.3 Cutaneous manifestations**

were significantly more common in cohort 1. The visual acuity at final evaluation was better in the second cohort. When considered both the cohorts, more severe findings were observed in males. From the above findings, the authors concluded that timely and aggressive management reduces ocular complications and facilitates

Even though uveitis is the common ocular pathology in Behçet's disease, it is not a common cause of uveitis. The highest incidence of uveitis is reported by Mishima S from Japan [48], where it constitutes about 25%, but it is much rarer in other countries such as Brazil, where the incidence is 2% [49], and India, where the incidence is 1% reported by Sen DK from a study conducted in 94 Indian children [50]. The classical feature of Behçet's disease is recurrent, acute anterior uveitis associated with hypopyon. Other ocular manifestations seen in Behçet's disease include necrotizing vascular lesions involving the retina and the optic nerve. These manifestations may be unnoticed because of severity of the anterior segment reaction and commonly include macular oedema, retinal periphlebitis and periarteritis, thrombosis of the vessels and retinal or vitreous haemorrhages which are frequently

Recurrent oral ulcers are one of the earliest manifestations of Behçet's disease in around 47–86% of patients and are seen in almost all patients during their clinical course [53]. Other symptoms may at times take years to appear after the onset of disease. Oral ulcerative lesions usually manifest as a round- or oval-shaped ulcer with discrete erythematous border with a greyish-white pseudomembrane or a central yellowish fibrinous floor and grow rapidly from a flat ulcer to a deep sore [9]. They may occur as single ulcers or as numerous [9, 53]. Oral ulcers most commonly affect the gingival and buccal mucosa, tongue and lips yet may also appear in the soft and hard palates, pharynx and tonsils [9]. Minor ulcers which are less than 1 cm in diameter heal without scarring over a period of 1 to 2 weeks, whereas major ulcers which are more than 1 cm in diameter are more painful and heal within 2–6 weeks. Herpetiform ulcers occurring in recurrent crops of small ulcers that are 0.2–0.3 cm in diameter are painful and may coalesce to form large ulcers. Treatment is usually symptomatic, and prognosis of oral ulcerations is

The most commonly seen cutaneous manifestations are erythema nodosum and pseudofolliculitis, in which erythema nodosum is manifested as painful multiple subcutaneous nodules that vary in size and colour, whereas pseudofolliculitis (pustulosis) appears as a dome-shaped sterile pustule on a round reddish edematous base that looks like acne vulgaris [54]. Although these are commonly seen on the lower extremities, it can be seen throughout the body [55]. The pathergy reaction is included in the criteria for the diagnosis of Behçet's disease. Although more than 50% of patients from Turkey and Japan had a positive pathergy test, it is rarely observed in patients from Northern Europe, the USA and Australia [56, 57]. It used to be an important diagnostic criterion for Behçet's disease; however, the frequency of the pathergy phenomenon was reported to decrease during the recent years [58]. Subcutaneous thrombophlebitis is often confused with lesions of erythema nodosum; the former is manifested as tender erythematous nodules with a linear arrangement in most case. The lesions may relocate depending on the vascular

**22**

segment involved [59].

Cardiac involvement is a rare finding in patients with Behçet's disease. Behçet's disease affects arteries, veins as well as the heart. Cardiovascular features have been reported to affect 7–49% of patients, more frequently in males. They occur 3–16 years after the onset of Behçet's disease. Cardiac involvement in Behçet's disease patients was first described by Mirone et al. in 1958 as a case of paroxysmal fibrillation and heart block. In 1963, Oshima et al. described a case of myocardial infarction complicated by incomplete right bundle-branch block [60]. Since then different types of cardiovascular lesions, including pericarditis, atrial thrombus, complex ventricular arrhythmia, myocardial infarction, heart block and sudden death, have been reported in association with Behçet's disease [61]. Dong Soo et al. in 1998 reported a case of superior vena cava syndrome caused by Behçet's disease in a 40-year-old man with recurrent oral aphthous ulcers and skin rashes on the anterior chest wall [62].

#### **5.5 Neurological manifestations**

Neurological involvement in Behçet's disease, the neuro-Behçet's disease, occurs very rarely and only in 5–10% of patients. It is frequently seen in males [63]. It usually occurs around 5 years after the onset of the disease and is associated with long-term morbidity and mortality [9]. Neuro-Behçet's disease can be parenchymal, nonparenchymal or mixed brain disease, in which the parenchymal brain disease affects the brainstem and/or basal ganglia and is correlated with a poor prognosis, whereas nonparenchymal also known as vasculo-Behçet's disease or angio-Behçet's disease is characterised by subsets of cerebral venous thromboses, dural venous sinus thrombosis, arterial vasculitis and aseptic meningitis and comprises the most devastating symptom category of Behçet's disease with high mortality [63, 64]. A mixed parenchymal and nonparenchymal disease has also been reported but is very rare. Infrequent clinical manifestations like epilepsy, stroke, brain tumour-like neuro-Behçet's disease, acute meningeal syndrome, movement disorders, optic neuropathy, spinal cord involvement and asymptomatic and subclinical neurological involvement have also been reported [65, 66]. Meningitis, neurological deficits including motor disturbances and brainstem symptoms and psychiatric symptoms including personality changes develop in patients with neuro-Behçet's disease are considered as a classic finding [18, 63]. These symptoms are associated with disease exacerbations and gradually cause disability and unfortunately are irreversible [18]. At late stages, dementia develops in approximately one-third of patients with neuro-Behçet's disease.

#### **5.6 Gastrointestinal manifestations**

Gastrointestinal involvement was observed in 3–26% of patients and varies among different populations [38, 39]. It is much more frequent in Japan than in the Middle East and the Mediterranean region [1–3]. Mucosal inflammation and ulceration can occur anywhere in the gastrointestinal tract but typically in the ileocecal region. Other rarely involved sites include the oesophagus, ascending colon and transverse colon [18, 19, 67]. Clinical symptoms include anorexia, vomiting, dyspepsia, diarrhoea, melena, abdominal pain and, less frequently, perforation requiring surgical intervention [68]. Due to the similarity in intestinal and extraintestinal symptoms, it is tough to differentiate Behçet's disease from inflammatory bowel disease; however, the presence of granulomata can be used to confirm inflammatory bowel disease [66].

#### **5.7 Articular manifestations**

Joint involvement is common in patients with Behçet's disease seen in almost half of patients. It presents as an initial manifestation seen long before the commencement of other features of BD [55]. Erosive, non-deforming oligoarthritis typically involving the knees, ankles and wrists is seen in most of the Behçet's disease patients. Rarely, it can present as sacroiliitis or erosive arthritis. Myopathy has also been reported by Arkin in 1980 [69–72].

#### **5.8 Vascular manifestations**

Vasculitis is one of the classic signs in Behçet's disease, and the typical finding is deep vein thrombosis. Thrombophlebitis occurs generally in the first year after onset of Behçet's disease, and relapses are frequent. Vasculitis can affect both the veins and arteries and capillaries although venous involvement is more common [55]. Venous thrombosis may occur at any site and can even involve large vessels like the inferior vena cava, the superior vena cava and the pulmonary artery. [55]. Arterial involvement is seen in 3–5% of cases [73]. Aneurysm formation is found to be the foremost manifestation, and the affected patients can be asymptomatic [74]. Vascular surgery is mandatory, but relapse is a frequent concern [55].

#### **5.9 Pulmonary manifestations**

Pulmonary manifestations are rare in patients with Behçet's disease. Haemoptysis is the only reported manifestation, but it can be massive and fatal [74].

#### **6. Diagnostic criterion and activation markers in Behçet's disease**

The diagnosis of Behçet's disease relies purely on its clinical manifestation since it lacks specific biological test, so diagnosis with clinical symptoms is challenging, especially due to non-concomitant symptoms. Hence different diagnostic criteria have been developed for the determination of Behçet's disease. In 1990, an ISG for Behçet's disease was formed by a group of researchers [21]. The International Study Group developed a set of classification criteria which is designed for research studies, which in many instances is used for diagnosing. The features were defined as the presence of specific symptoms as seen in **Table 3**. Oral ulceration along with any other two symptoms is said to be diagnostic [75]. The capability of the ISG criteria as a diagnostic tool has been questioned [56]. An international team which includes 27 countries was formed to evaluate and reassess the ISG criteria, and a new ICBD was developed that include the major criteria consisting of oral aphthosis, genital aphthosis and ocular lesions which were each given 2 points, whereas 1 point was assigned to the skin lesion, neurological manifestation, vascular manifestation and positive pathergy test (which is optional and not included in the primary criteria due to geographic variation and its declining sensitivity and increased specificity) [58, 75]. Higher sensitivity of the ICBD was reported as it aided in earlier diagnosis and hence earlier treatment and thereby better prognosis [75]. However, the delay between the onsets of major manifestations may be decades needs to be considered [76]. Inflammatory markers such erythrocyte sedimentation rate (ESR) and C-reactive protein have no longer been recognised as accurate or specific for the disease activity (**Table 4**).

Investigations for Behçet's disease include routine total blood count; renal, liver and bone profile; inflammatory markers, including C-reactive protein and erythrocyte sedimentation rate; urine analysis; chest X-ray; coeliac screen; stool sample; autoimmune

**25**

**7. Management**

*Behçet's Disease: An Enigmatic Malady with Plethoric Expressions*

Positive pathergy test Read by a physician at 24–48 hours

*The international study group criteria for Behçet's disease [21].*

*International criteria for Behçet's disease [75].*

Minor aphthous, major aphthous or herpetiform ulceration observed by physician

or patient, which recurred at least three times in one 12-month period

papulopustular lesions or acneiform nodules observed by physician in post

b

Aphthous ulceration or scarring observed by physician or patient

Eye lesion Anterior uveitis, posterior uveitis or cells in vitreous on slit lamp examination or retinal vasculitis observed by ophthalmologist Skin lesions Erythema nodosum observed by physician or patient, pseudofolliculitis or

adolescent patients not on corticosteroid treatment

**Symptoms Points** Oral aphthosis 2 Genital aphthosis 2 Ocular lesion 2 Skin lesion 1 Neurological manifestation 1 Vascular manifestation 1 Positive pathergy test 1