The Behcet's disease (Turkish pronunciation: bɛhtʃæt , beHtschett '(audible "h"), and Behcet's disease , Adamantiades-Behçet disease ( ABD ) or malignant aphthous called) is a systemic, autoimmune inflammation of the blood vessels ( vasculitis ). It belongs to the rheumatic group of forms . Small veins and capillaries in particular are affected, but in principle all blood vessels of any size can be affected. Since the inflammation can occur in any organ system, a wide range of symptoms is possible in Behçet's disease. The combination of aphthae in the mouth and in the genital area and inflammation of structures of the eye are typical . The main goal of therapy is to prevent consequential damage, which can be particularly serious if the eyes, brain and large vessels are involved. For this purpose, the activity of the immune system is dampened with immunosuppressants .
The cause of the disease is unknown. According to current knowledge, with certain genetic conditions (especially the presence of HLA type B51), contact with an external factor (for example contact with a virus or bacterium ) leads to an overreaction of the immune system and uncontrolled inflammation. The disease occurs primarily in the countries of the historic Silk Road , but is also more common in Europe and North America due to migration. The gender ratio of the sick varies from region to region. The peak of disease worldwide is between 20 and 40 years. The disease runs in waves with phases of stronger and weaker activity, but generally subsides with increasing duration of the disease.
The disease is named after the Turkish dermatologist Hulusi Behçet (1889–1948) and the Greek ophthalmologist Benediktos Adamantiades (1875–1962), who described the symptoms of the disease independently of one another in the 1930s.
Behçet's disease is particularly common along the Silk Road in the Near and Middle East and in East Asia. Due to migration , the disease is also more common in Europe and North America. There are different information on frequency for the individual countries. The country with the highest prevalence is Turkey with 20 to in some places 420 patients per 100,000 inhabitants. In Iran the prevalence is 17–68 per 100,000 and in Japan 7–14 per 100,000. For Germany there are figures between 0.6 and 1.5 per 100,000 inhabitants. Studies on migrants revealed the following findings: Armenians living in Istanbul have a significantly lower risk of developing the disease than the general population in Turkey. Turks living in Germany have a significantly higher risk of disease than the general German population, but the prevalence among Turks living in Germany is lower than the prevalence in Turkey.
The gender ratio differs regionally. In some countries women are more likely to be affected, the difference is particularly clear in Scotland , the United States and Spain . Women also predominate in Israel , Sweden , Korea and Japan. Countries in which men are more frequently affected include Turkey (although there is only a slight overhang here), Germany, Italy , France and Iran. The difference is very strong in Iraq , Saudi Arabia , Russia and Kuwait .
In most countries, the mean age of onset is in the third decade of life. The range is between 20 years in Ireland and 40 years in Brazil . In Turkey and Germany, the mean age of onset is 25 to 26 years. In the USA and Asian countries, patients become ill over the age of 30.
Genetic prerequisites and environmental factors can be assumed as causes of the development of the disease ( etiology ) , which is derived in particular from the findings of the studies on people with a history of migration. One way of gene variants to be identified associated with the disease in compound (associated) are genome-wide association studies .
Human leukocyte antigen (HLA) is the name for proteins thatsiton the surface of cells and present parts of other proteins produced in the cell to the immune system. If the presented parts do not correspond to the usual blueprint, the immune system recognizes this as "foreign" and attacks the cell. There are many variants of HLA proteins, some of which are associated with the development of autoimmune diseases. Behçet's disease is most closely related to HLA-B51. This HLA type is found in up to 60% of the sick. In addition, other HLA types and variants of genes that are important for the function of the immune system have been identified. Among them is the gene for interleukin-10 , an anti-inflammatory messenger substance, and the receptor for interleukin-23 .
So far, no infectious trigger has been detected. Streptococcus sanguis , herpes simplex viruses , the Epstein-Barr virus and cytomegaloviruses were discussed . It has been shown that the immune system of Behçet patients reacts more strongly to antigens from Streptococcus sanguis , but a direct link to the disease has not been shown.
Pathology and Disease Development
A microscopic examination of diseased blood vessels reveals what is known as leukocytoclastic vasculitis. This means that leukocytes (white blood cells, the immune cells) migrate into the tissue and destroy it. The types of leukocytes that are found vary depending on the type of vessel. Diffuse necroses and transudates are often found in the inflamed vessel walls. Edema and accumulations of macrophages appear in the surrounding tissue .
There is still no conclusive model of disease development. It is certain that both parts of the immune system are involved in the disease process, because there are signs of the innate and the adaptive immune response . The disease is probably mediated by T helper cells , which are part of the adaptive immune system. Antigens are presented to these immune cells by other cells . It is your job to decide whether these are “foreign” antigens and whether an immune response is initiated. In Behçet patients with their corresponding genetic requirements, the T H 1 lymphocytes (a type of T helper cells that activate the innate immune system) react too strongly to activation. In doing so, they set in motion a self-sustaining signal cascade that leads to an uncontrolled response from the innate immune system.
The classification of Behçet's disease is not easy: It is not considered an autoimmune disease (such as Graves' disease ), as no autoantibodies directed against the body's own structures are known. It cannot be assigned to the autoinflammatory diseases (which include Crohn's disease and familial Mediterranean fever). The innate immune system would be the culprit here, but the typical genetic conditions and symptoms such as recurring fever attacks are missing.
|Place of manifestation||Frequency in percent|
|Oral aphthous ulcers||47-86|
Since Behçet's disease is a systemic disease that can potentially affect any organ system, the clinical picture is very variable. The triad (the appearance of three symptoms) consisting of aphthae in the mouth and in the genital area as well as uveitis is typical for the disease .
Oral and genital ulcers
The most common early symptom of Behcet's disease are recurrent aphthous ulcers in the mouth. They are observed in all patients in the course of the disease. They occur singly or in clusters and mostly affect the lining of the cheek, gums , lips and tongue . The palate and throat are less affected. Smaller aphthae (<1 cm diameter) usually heal within 4 to 14 days, larger ones take longer.
Ulcers in the genital area are also common. They are usually deeper and more painful than oral canker sores and heal with scarring . In women, they occur on the vulva , vagina, and cervix . In men mainly on the scrotum , the penis is rarely affected. In both sexes, the ulcers can occur on the perineum , around the anus or in the groin region .
In around 10% of patients, one eye is the first organ affected. The spectrum of manifestations is wide: Typically, uveitides occur, the external feature of which is often an accumulation of pus in the anterior chamber ( hypopyon ). In addition, inflammation of the retina , sclera , cornea and optic nerve can occur. Symptoms include pain in the eyes, impaired vision, photophobia and increased tearing. In general, eye involvement is more likely to be found in men and is associated with a more severe course of the disease.
The involvement of the skin can manifest itself in papelike changes , erythema nodosum -like lesions , acneiform rashes, pyoderma gangrenosum or, less often, in erythema multiforme -like rashes. Under pathergy means a hyperreactivity of the skin. This reacts to small injuries such as needle sticks with a delayed papulopustular rash. This phenomenon can be used for diagnostics, but does not only occur in Behçet's disease.
45 to 60% of patients have manifestations on the joints. This results in joint pain or inflammation in one or more joints. Usually knees, ankles, elbows, and wrists are affected. The inflammations are not damaging to the joints. Fibromyalgia syndrome can develop in the course of the disease, especially in women . Some studies also found inflammation of the sacrum-iliac joint and ankylosing spondylitis in Behçet patients. In specialist books, however, these symptoms are not counted among the Behçet manifestations.
Involvement of the cardiovascular system
Since Behçet's disease is an inflammation of the vessels, this also causes direct damage. Veins are the most commonly affected blood vessels. Inflammation ( phlebitis ) often causes blood clots to form . Depending on the location of the inflamed veins, thrombophlebitides (in superficial veins) or deep vein thromboses (in the deep veins of the arms and legs) appear. Thromboses in the vena cava , the dural nerve or the hepatic veins rarely occur .
A disease of the arteries is rare and likely to be found in men. It causes bulging of the artery walls (aneurysms), vasoconstriction and also thromboses. Torn aneurysms cause bleeding, which can have serious consequences depending on the location (for example, bulging in the pulmonary arteries , which is very rare).
The disease can also affect the heart directly, but this is rare. In addition to damage to the coronary arteries , manifestations also include inflammation of the pericardium ( pericarditis ), the heart muscle ( myocarditis ) and the inner lining of the heart ( endocarditis ), as well as damage to the heart valves .
Some years after the onset of the disease, around 10% of patients develop a disease of the nervous system, which is also known as Neuro-Behçet . It usually affects the central nervous system and rarely the peripheral nervous system . Usually the Neuro-Behçet is divided into two forms: the parenchymal and the non-parenchymal form. The parenchymal form is not an inflammation of the blood vessels, but of the brain tissue around the blood vessels (a so-called perivasculitis). The non-parenchymal form, on the other hand, is the inflammation of the blood vessels of the brain (i.e. the vasculitis underlying Behçet's disease). The majority of patients with Neuro-Behçet suffer from the parenchymal form. It presents as meningoencephalitis (inflammation of the brain and meninges) with migraine- like headaches. It often hits the brain stem and basal ganglia . The substance may cause motor , sensory and cognitive limitations (such as difficulty concentrating). The consequences of the non-parenchymal form include thrombosis in the dural sinuses and cerebral veins, aneurysms of the arteries, and increased intracranial pressure. Ischemic strokes are rare. Typically, a neuro-behçet develops in men and is associated with a period of increased disease activity.
Inflammation of the gastrointestinal tract is mainly seen in patients in Japan, but is a rarer manifestation of Behçet's disease in other regions of the world. Ulcers can appear anywhere in the gastrointestinal tract. Most often they arise in the end section of the small intestine (ileum, ileitis ) and in the appendix (cecum). Signs of gastrointestinal involvement include abdominal pain, loss of appetite , vomiting, diarrhea, and tarry stools . The ulcers rarely break through (perforation).
In men, epididymitis can also be a sign of the disease. The kidneys are rarely affected in the form of glomerulonephritis or amyloidosis . When the urinary bladder is involved , urination disorders occur. Recurrent cartilage inflammation in connection with other Behçet symptoms has been described in some patients ( MAGIC syndrome : inflammation of the cartilage of the nose and auricles with oral and genital aphthae).
The diagnosis is made difficult by the wide range of possible symptoms, the variable presentation of the disease and the lack of biomarkers . Diagnosis must therefore be based on clinical symptoms while excluding other possible causes. There are three classification systems in use. The oldest are the criteria of the International Study Group from 1990. In this system, the main symptom of oral aphthae and two secondary symptoms (genital aphthae, eye or skin symptoms or a pathergy reaction after injection of 0.5 ml saline solution into the skin) must be met be. The International Criteria for Behçet's Disease (ICBD) was published in 2006 and revised in 2014. Each symptom is assigned a point value. The point values of the symptoms that have occurred are added up; when a certain point value is reached, the presence of Behçet's disease can be assumed. The pathognomonic phenomenon is the cutaneous pathergy phenomenon , in which pustules appear in the flare-up at the injection site of a 0.9 percent NaCl solution. The test is performed both cutaneously (on the inside of a forearm) and orally (on the inside of the lower lip).
Differential diagnoses are diseases that show similar symptoms and therefore have to be excluded in the diagnostic process. In Behçet's disease, these are primarily other systemic rheumatic diseases such as vasculitides , systemic lupus erythematosus and sarcoid . Different diseases can be used for differential diagnosis for the individual forms of manifestation:
- Oral aphthous ulcers of Behçet's disease must be differentiated from a severe form of benign aphthosis, with aphthosis of the Mikulicz type, of the Sutton type and of the Cooke type, with equally painful but harmless aphthous ulcers without systemic disease. In addition, infections with herpes simplex oralis and aphthous ulcers due to deficiencies (as can occur with celiac disease or chronic bowel disease) can be considered.
- Sexually transmitted diseases can be the cause of genital aphthae .
- The eye involvement in the form of uveitis can have numerous other causes, including infections with viruses , bacteria and fungi , or a symptom of another systemic disease (see Uveitis: Secondary Forms )
- If the digestive system is affected, Crohn's disease in particular must be excluded.
- Neuro-Behçet must be differentiated from multiple sclerosis .
- Manifestations on the skeletal system must be distinguished from other joint diseases : ankylosing spondylitis , rheumatoid arthritis without an increase in the typical laboratory parameters ( seronegative arthritis) and psoriatic arthritis (also a seronegative arthritis).
- The Hughes-Stovin syndrome is a disease associated with thrombosis and aneurysms associated pulmonary arteries. However, it is unclear whether it is a separate disease or a manifestation of Behçet's disease.
In Western countries, Crohn's disease and seronegative arthritis are the main differential diagnoses of Behçet's disease. In particular, when there is only one form of manifestation, the distinction can be impossible.
The basic building block of drug therapy is influencing the immune system. The therapy depends on the symptoms that occur. In general, inflammations of the retina, arterial aneurysms and the Neuro-Behçet are treated more aggressively because of their potentially serious consequences. To suppress the immune system ( immunosuppression ), glucocorticoids such as prednisolone and other immunosuppressants such as azathioprine , mycophenolate mofetil , ciclosporin and methotrexate , TNF blockers such as infliximab and other monoclonal antibodies such as rituximab and alemtuzumab are used. In the absence of high-quality therapy studies, the recommendations are based on expert opinions . In addition to the immunosuppressive therapy, which depends on the severity of the disease, other measures such as pain therapy or the local treatment of skin symptoms and aphthae can be useful. There are currently some drugs that are still in clinical trials. Of these, apremilast deserves special mention, as it is the only one of these drugs to have been tested in a phase II study and to show effectiveness. For use also come cyclophosphamide , colchicine , interferons and dapsone . In the case of serious complications, i.e. rapidly growing aneurysms and the consequences of fistulas and perforations in the gastrointestinal tract, surgical interventions may be necessary. These should be accompanied by strong immunosuppression.
Course and prognosis
The disease has a wavy course with phases of increasing and decreasing disease activity. Basically, it subsides the longer the disease lasts.
Many Behçet manifestations heal without permanent damage. Men and those who are sick at a young age have more severe courses and a higher mortality rate . Young men diagnosed between the ages of 14 and 24 have the highest mortality rate. Over time, however, their mortality also decreases. The main causes of death are neuro-behçet, gastrointestinal involvement and aneurysms of the pulmonary arteries, which lead to death within five years of every fifth person affected (5-year mortality 20%). Occlusions in the liver veins, the Budd-Chiari syndrome , also have a poor prognosis. Eye involvement is associated with a high risk of blindness - around 25 to 50% of affected patients lose their eyesight. Overall, however, the prognosis, especially the risk of blindness, has improved significantly in recent years.
Even in less severe cases, the disease has a significant impact on the physical and mental well-being of those affected. Although the disease does not directly affect fertility , it is influenced by the effects of genital ulcers and the psychological stress of the disease. There is no evidence that the condition has a negative impact on pregnancy .
The disease is named after the Turkish dermatologist Hulusi Behçet , who in 1937 published the three symptoms of oral and genital aphthae with iris inflammation with hypopyon as a syndrome and thus regarded it as an independent clinical picture. However, as early as 1930 , the Greek ophthalmologist Benediktos Adamantiades described a case of iritis with recurrent hypopyon and the typical oral and genital aphthae. He suggested viewing the symptoms observed as a syndrome. In the 1950s he added other symptoms such as thrombophlebitis to the symptom complex . In his honor and because of this work, the disease was later entered as Adamantiades-Behçet's disease in the German and Greek registers as well as in the National Registry for Rare Disorders (NORD) in the USA ( English Adamantiades-Behçet Disease (ABD) ) .
Apart from these descriptions, in the history of medicine there are always descriptions of cases of illness that can be assigned to Behçet's disease. The oldest probably comes from the ancient world of Hippocrates of Kos .
- S2k guidelines (long version), diagnosis and treatment options for aphthae and aphthoid lesions of the oral and pharyngeal mucosa , Working Group of the Scientific Medical Societies in Germany (AWMF), as of November 2016. Accessed on November 11, 2017.
- Website of the University of Tübingen on Behçet's disease
- Behçet's syndrome at whonamedit.com (English)
- Case report of a long-unrecognized M. Behçet: Merinopoulos D, Saada J, et al .: Pattern recognition is a sequential process — accurate diagnosis and treatment 20 years after presentation. Oxford Medical Case Reports 2019 (7), July 2019, DOI: 10.1093 / omcr / omz058, with German-language processing of the case at SPIEGEL online
- Ina Kötter: Behçet's disease. In: H.-H. Peter, WJ Pichler, U. Müller-Ladner (Ed.): Clinical Immunology. Urban & Fischer , Munich 2012, p. 399 ff.
- Jagdish R. Nair, Robert J. Moots: Behçet's Disease. In: Clinical Medicine. 17, No. 1, 2017, PDF file; 126 kB ). , pp. 71-77 (
- Adnan Al-Araji, Desmond P. Kidd: Neuro-Behçet's Disease: epidemiology, clinical characteristics, and management. In: Lancet Neurology. No. 8, 2009, pp. 192-204. ( PDF , English).
- Gulen Hatemi et al .: 2018 update of the EULAR recommendations for the management of Behçet's syndrome. In: Annals of the Rheumatic Diseases. No. 77, 2018, pp. 808-818. ( online , PDF )
- Marc C. Hochberg, Alan J. Silman, Josef S. Smolen, Michael E. Weinblatt, Michael H. Weisman: Rheumatology . 6th edition. tape 2 . Mosby / Elsevier, Philadelphia 2015, ISBN 978-0-323-09138-1 , pp. 1276 .
- Marc C. Hochberg, Alan J. Silman, Josef S. Smolen, Michael E. Weinblatt, Michael H. Weisman: Rheumatology . 6th edition. tape 2 . Mosby / Elsevier, Philadelphia 2015, ISBN 978-0-323-09138-1 , pp. 1328 .
- Fereydoun Davatchi: Behcet's disease. In: International Journal of Rheumatic Diseases. 17, 2014, p. 355, doi: 10.1111 / 1756-185X.12378 .
- Jagdish R. Nair, Robert J. Moots: Behçet's Disease. In: Clinical Medicine. 17, No. 1, 2017, PDF file; 126 kB ). , p. 71 (
- Marc C. Hochberg, Alan J. Silman, Josef S. Smolen, Michael E. Weinblatt, Michael H. Weisman: Rheumatology . 6th edition. tape 2 . Mosby / Elsevier, Philadelphia 2015, ISBN 978-0-323-09138-1 , pp. 1328 .
- University Hospital Tübingen - Behcet's disease. Retrieved November 10, 2017 .
- Mohamad J. Zeidan, David Saadoun, Marlene Garrido, David Klatzmann, Adrien Six: Behçet's disease physiopathology: a contemporary review . In: Auto-Immunity Highlights . tape 7 , no. 1 , February 12, 2016, ISSN 2038-0305 , doi : 10.1007 / s13317-016-0074-1 , PMID 26868128 , PMC 4751097 (free full text).
- Ina Kötter: Behçet's disease. In: H.-H. Peter, WJ Pichler, U. Müller-Ladner (Ed.): Clinical Immunology. Urban & Fischer, Munich 2012, p. 401.
- Zeidan, Saadoun, Garrido, Klatzmann, Six, Cacoub: Behçet's disease physiopathology: a contemporary review. In: Autoimmunity Highlights. 7, No. 4 2016. PMC 4751097 (free full text), last accessed on September 21, 2017.
- Sakane, Takedo, Suzuki, Inaba: Behçet's Disease. In: The New England Journal of Medicine 341, 1999, pp. 1284-1291. (online) , not freely accessible, last accessed on September 21, 2017.
- Jagdish R. Nair, Robert J. Moots: Behçet's Disease. In: Clinical Medicine. 17, No. 1, 2017, PDF file; 126 kB ). , p. 72 (
- MA Ait Badi, M. Zyani, S. Kaddouri, R. Niamane, A. Hda: Les manifestations articulaires de la maladie de Behçet. Speaking of 79 cas . In: La Revue de Médecine Interne . tape 29 , no. 4 , p. 277-282 , doi : 10.1016 / j.revmed.2007.09.031 .
- Marc C. Hochberg, Alan J. Silman, Josef S. Smolen, Michael E. Weinblatt, Michael H. Weisman: Rheumatology . 6th edition. tape 2 . Mosby / Elsevier, Philadelphia 2015, ISBN 978-0-323-09138-1 , pp. 1330 .
- Jagdish R. Nair, Robert J. Moots: Behçet's Disease. In: Clinical Medicine. 17, No. 1, 2017, PDF file; 126 kB ). , p. 73 (
- Adnan Al-Araji, Desmond P Kidd: Neuro-Behçet's disease: epidemiology, clinical characteristics, and management . In: The Lancet Neurology . tape 8 , no. 2 , 2009, p. 192-204 , doi : 10.1016 / s1474-4422 (09) 70015-8 .
- Marc C. Hochberg, Alan J. Silman, Josef S. Smolen, Michael E. Weinblatt, Michael H. Weisman: Rheumatology . 6th edition. tape 2 . Mosby / Elsevier, Philadelphia 2015, ISBN 978-0-323-09138-1 , pp. 1330 f .
- F. Davatchi, p Assaad-Khalil u. a .: The International Criteria for Behçet's Disease (ICBD): a collaborative study of 27 countries on the sensitivity and specificity of the new criteria. In: Journal of the European Academy of Dermatology and Venereology. 28, 2014, p. 338, doi: 10.1111 / jdv.12107 .
- Rudolf Ott, Wolfgang Krug, Hans-Peter Vollmer: Clinic and Practice Guide Dentistry . Georg Thieme Verlag, 2002, ISBN 3-13-158021-6 , p. 294 ( google.com ).
- Marc C. Hochberg, Alan J. Silman, Josef S. Smolen, Michael E. Weinblatt, Michael H. Weisman: Rheumatology. 6th edition. Volume 2, Mosby / Elsevier, Philadelphia 2015, ISBN 978-0-323-09138-1 , p. 1331.
- Aphthous and aphthoid lesions. In: German Dental Journal . 68 (5), 2013, pp. 264-268. Retrieved November 14, 2017.
- Jagdish R. Nair, Robert J. Moots: Behçet's Disease. In: Clinical Medicine. 17, No. 1, 2017, PDF file; 126 kB ). , pp. 73-76 (
- Gulen Hatemi, Melike Melikoglu, Recep Tunc, Cengiz Korkmaz, Banu Turgut Ozturk: Apremilast for Behçet's Syndrome - A Phase 2, Placebo-Controlled Study . In: New England Journal of Medicine . tape 372 , no. 16 , April 15, 2015, p. 1510–1518 , doi : 10.1056 / nejmoa1408684 ( nejm.org [accessed September 28, 2017]).
- Jagdish R. Nair, Robert J. Moots: Behçet's Disease. In: Clinical Medicine. 17, No. 1, 2017, PDF file; 126 kB ). , p. 74 (
- Jagdish R. Nair, Robert J. Moots: Behçet's Disease. In: Clinical Medicine. 17, No. 1, 2017, PDF file; 126 kB ). , p. 75 (
- Fereydoun Davatchi: Behcet's disease. In: International Journal of Rheumatic Diseases. 17, 2014, p. 355, doi: 10.1111 / 1756-185x.12378 .
- Ina Kötter: Behçet's disease. In: H.-H. Peter, WJ Pichler, U. Müller-Ladner (Ed.): Clinical Immunology. Urban & Fischer, Munich 2012, p. 402.
- Jagdish R. Nair, Robert J. Moots: Behçet's Disease. In: Clinical Medicine. 17, No. 1, 2017, PDF file; 126 kB ) , p. 76. (
- Türkan Saylan : Life Story of Dr. Hulusi Behçet. In: Yonsei Med J. Volume 38, 1997, pp. 327-332.
- CC Zouboulis: Benediktos Adamantiades and his forgotten contributions to medicine. In: European journal of dermatology: EJD. Volume 12, Number 5, Sep-Oct 2002, pp. 471-474. PMID 12370138 .
- Ina Kötter: Behçet's disease. In: H.-H. Peter, WJ Pichler, U. Müller-Ladner (Ed.): Clinical Immunology. Urban & Fischer, Munich 2012, p. 400.
- Kleonikos A. Tsakiris: Bibliography of Benediktos F. Adamantiades. In: Archiwum historii i filozofii medycyny. Volume 79, Winter 2016, pp. 8–15. (on-line)
- Ina Kötter: About Behçet's disease. Retrieved October 8, 2017 .