CLICK TO PRINT this page for your recordsFor General Information Research

by Medical Professionals & Sufferers

(information researched, collected & compiled by a long term chronic Behçet's disease sufferer)

 

 

 

 

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World Wide Web www.behcets.info

 

Description

"Behçet’s disease is a multisystem inflammatory disorder characterised by recurrent oral ulcers, genital ulcers and ocular inflammation, and which frequently involves the joints, skin, central nervous system (CNS) and gastrointestinal tract. Classified as a systemic vasculitis, it can involve both the arteries and veins of almost any organ. The aetiology of Behçet’s disease remains unknown, but the most widely held hypothesis of disease pathogenesis is that a profound inflammatory response is triggered by an infectious agent in a genetically susceptible host".

(Sara E. Marshall MB BCh, MRcp (Ire), MRcPath (UK), PhD Senior Lecturer in Immunology Wright Fleming Institute, Imperial College School of Medicine, Norfolk Place, London W2 1PG, UK)


An Introduction to this Web-site

I have suffered from Behçet's Disease  since circa 1982 - in those days it was generally referred to as Behçet's Syndrome (correctly pronounced Beh-chets [ info. ]. The incorrect pronunciation seems to be widespread amongst the medical fraternity in the UK & other English speaking parts of the World - perhaps being a primary indicator of most Doctor's general depth of knowledge of this rare & debilitating disease.

The purpose of this web page is not to highlight general medical ignorance about the condition, or to point to inadequacies among individual health care professionals, to the contrary, it is to provide a good basic knowledge to the reader (both medical professionals and sufferers alike) about  Behçets Disease in the hope that it will aid the professional in providing quicker diagnosis and treatment with corresponding  faster, and equally importantly, more efficient relief from the symptoms for any sufferer.

On numerous occasions during my medical treatments (for various ailments over the years but mostly associated with Behçets) I have been habitually confronted with Doctors & other medical staff who are hampered by their inadequate basic knowledge of this disease. Consequently a lot of their time, my time and the important time needed for quick diagnosis and correct treatment (because the vascular and sometimes neurological involvement of BD can be significant and life-threatening, so diagnosing and treating vascular involvement early is vital) has been inefficiently used because - quite rightly -  Doctors cannot be solely guided by the information given to them verbally by a patient who is usually a medical lay-person. Due to this, tests are often carried out unnecessarily and often periodically repeated by others, because  Doctors do not have the confidence to eliminate certain likelihoods from their diagnosis because of a degree of ignorance about the manifestations of this disease. Armed with a little more detailed knowledge, many of the processes of elimination in the diagnostic procedure stages could be done away with. It is my belief that many other sufferers of this disease also experience the same problem. I have a perennial debate with new doctors that I have contact with, because - as an example - they often insist that what they are witnessing is an infection rather than inflammation! Invariably treatment starts with antibiotics. When a course of antibiotics fails to resolve the problem (often with the reverse effect of aggravating the inflammation) the patient is finally administered an anti-inflammatory preparation! Of course not all the problems that I, or other sufferers have, originate with Behçet's Disease. I have my fair perceived need for antibiotics prescriptions, like all others seem to have in the western hemisphere's medical practices, however it is important for the medical practitioner who treats me (or others like me) to understand the mechanisms of this disease, and be able to attribute certain symptoms to it when treating a patient who has the disease.

I have taken the initiative to compile this web-site and publish it on the Internet in order for any medical people who want more detailed in depth  information to be able to access it via the information collected here from various specialist sources and my own personal research over three decades.

Following a constructive discussion some years ago with my very helpful and supportive GP at the time, who has now retired from his practice, I agreed to his suggestion that I should construct this web-site and that the site's URL address be included in my medical file so that it is easily accessible to anyone who may treat me in the future. This site may also be accessed by fellow sufferers, who may find it helpful to understand their condition, and if they so choose, can pass the site's URL address on to their own GPs, hospital medical staff or any other medical practitioner who may benefit from the contents. Please feel free to use the information at will and to circulate references to it as you see fit. There are no copyright restrictions - as long as credits are attributed to authors of any information that is written or published by the users of the material provided here.

The remainder of this web-site is made up of information - as I have previously said - I've researched and documented over the years. Where appropriate, references have been made to source material and there is a table of useful links to other websites that contain similar information that you may wish to research yourself. Simply click the 'links' tab at the head of this page.

Before browsing the remainder of this web-page it is recommended that the reader downloads and reads a PDF document containing an excellent paper authored by Sara E. Marshall MB BCh, MRcp (Ire), MRcPath (UK), PhD Senior Lecturer in Immunology, Wright Fleming Institute, Imperial College School of Medicine, Norfolk Place, London W2 1PG, UK - a small excerpt from that document has been reproduced as an introduction at the top of this page.


The download document requires your computer to have a PDF 'Reader' programme installed on it. If you have this software already installed the document will open automatically. If you do not currently have this type of software installed you can download & install it now for free by clicking on the 'Get Adobe Reader' icon on the right:


Audio/ Visual Information About Behçet's Disease

Please click on the "PodCast" icon on the right to hear a joint talk in the form of a question and answer session given by Drs. Yusuf Yazici, MD (hosting) and Hasan Yazici, MD. This talk was given  at the Behcet's Syndrome Centre in New York City - in November, 2006. You may download & save the file which is in MP3 format. It can also be played directly on your  using any media player software. Playing time is approx. 30mins.


 

Please view these videos on the right that explain the symptoms, diagnosis & care required for Behçet's sufferers.

They are real life accounts from people who suffer with Behçet's Disease. Dr. Yusuf Yazici (one of the leading doctors involved in the field of Behçet's & who is also featured in the pod cast above) gives a commentary in the Sanya Richards video.

Some sufferers have chronic symptoms others have milder initial symptoms (like Sanya Richards). In all cases Behçet's can be a truly serious, painful and dangerous condition as by it's very nature it can attack virtually any organ in the body. Whilst fatalities due to the symptoms are relatively rare, although complications due to the symptoms (especially the neurological and cardio vascular manifestations of the disease) can cause mortality.

Even when not life threatening, Behçet's disease can severely handicap people who suffer with it. Many chronic sufferers cannot execute simple daily tasks and often require 'carers' in order to function on a daily basis. Others who have milder symptoms may be more fortunate. As with many autoimmune system disorders, huge problems arise when the condition 'flares' up.

In the UK there are three NHS centres of excellence, where specialists in various associated fields of medicine have chosen to focus specifically on Behçet's disease. There is more information below. It would be in your interests - if you are a diagnosed sufferer - to draw your GP's attention to this web-site and make them aware of these centres of excellence. I have personally attended the centre in London (Bart's Health Trust).and can vouch for the excellent service and support it provides.

Unfortunately, due to the disease's rarity these centres of excellence are far and few between. Funding and research resources are also woefully inadequate - if Behçet's disease had a prevalence akin to cancer or heart disease, undoubtedly it's causes and a cure would by now have been found. Sadly as things currently stand, we have to concentrate on easing the symptoms, rather than finding a cure.


The Behçets Syndrome Centres of Excellence (UK)

These were set up in three NHS Trusts in Birmingham, Liverpool and London in April 2012 to provide care for patients with Behcet’s disease.

The Behcets Centres of Excellence offer care in the form of multi-disciplinary clinics and help patients to access high cost drugs.

The aim of the Centres of Excellence is to ensure that patients with Behcet’s disease can access timely diagnosis and receive optimal treatment across the country. They provide a “one stop” service, aiming to provide the best care from diagnosis for this rare, chronic disease.

The Centres are based in City Hospital, Birmingham, Aintree University Hospital, Liverpool and the Royal London Hospital, London. Each hospital has specialists with relevant expertise and provides multidisciplinary teams that work together within each hospital and with the other Centres to further improve the care of Behcets syndrome patients.

They are funded by the NHS after a successful bid by the Clinical Leads of each Centre of Excellence and the Behcets Syndrome Society.

Birmingham Centre

 

Birmingham HospitalThe Birmingham Centre of Excellence is situated in the Birmingham and Midland Eye Centre, part of Sandwell and West Birmingham Hospitals NHS Trust. Their clinical lead is Dr Deva Situnayake.

Clinics consist of dedicated consultants from ophthalmology, rheumatology and oral medicine, as well as a psychologist and a lead nurse. They also have access to dermatology, neurology and other disciplines if needed.

 

Liverpool Centre

 

Liverpool Hospital

Photo by MyCoy Wynne

The lead consultant is Professor Robert Moots who has been treating patients with Behçet's disease in his general rheumatology clinics for many years. Alongside him they have specialists in ophthalmology, oral medicine, neurology, gynaecology and soon, dermatology. Other members of the team include a Specialist Nurse, Clinical Psychologist and Support Worker.

They anticipate further clinics starting in the not too distant future with the appointment of a new rheumatologist.

London Centre

 

Royal London Hospital

The London Behçet's Centre of Excellence is situated in the Royal London Hospital (Barts Health Trust), in Whitechapel.

Their Clinical Lead is Professor Farida Fortune, who was a driving force in ensuring the Behçet's Syndrome Centres of Excellence were established. Our clinics take place in the newly built hospital which opened in 2012. Their multi-disciplinary team consists of Consultants in Oral Medicine, Immunology, Ophthalmology, Rheumatology, Neurology as well as a Psychologist, and dedicated Behçet's nurses.

They currently care for over three hundred patients with Behçet's and the numbers increase each week.

 

General Introduction

The disease referred to as Behçets is rare in the UK. It is sometimes referred to as the "Silk Route" or "Silk Road Disease" (from the Mediterranean basin to Japan), suggesting perhaps that an as-yet-unknown genetically determined factor was spread via the migration of old nomadic tribes.

Consequently, (through absolutely no fault of their own), many in the medical profession in this country are not familiar with it and consequently have a very basic knowledge of it's manifestations, symptoms and treatment, due mainly to it's rare occurrence in the UK.

Epidemiology

  • Prevalence is 0.3-6.6 cases per 100,000 population. The prevalence is highest in the Middle East, China and Japan.

  • Most common among patients from their third decade on. An age of onset younger than 25 years is associated with a higher prevalence of eye disease and active clinical disease.

  • Males are affected more commonly than females.

  • Behçet's disease is associated with HLA-B51. Familial cases have been reported, but inheritance is probably not Mendelian. See OMIM (Online Mendelian Inheritance in Man) Johns Hopkins University

For the remainder of this page  an article by Marjan Yousefi, MD, (Department of Dermatology, Geisinger Medical Centre) has been reproduced

This article has been chosen as it contains quite an extensive study of the disease with detailed information that covers the disease in some depth. Slight adaptations have been made to reflect figures that correspond to UK statistics for the disease as opposed to the American statistics used by Marjan Yousefi.

Also the drug category tables have been removed and included in a separate page dedicated solely to that subject. A link to that page can be found at the top of this page under the tab "drugs".  Bookmark navigation and an altered document format has been introduced to aid the ease of reading and to help in locating specific headings & sub headings. The content material has not been changed or altered in any way from the author's original input.

In addition to Dr. Marjan Yousefi's article below, there is an additional paper at the foot of this page by Prof. Erkan Alpsoy entitled New Evidence-Based Treatment Approach in Behçet's Disease .

Information

 

 

 

 


Article Bookmarks (Dr. Marjan Yousefi's article)

 

Main Headings

| Background | Pathophysiology | Frequency | Mortality/Morbidity | Sex | Age | History | Physical | Causes |

| Histologic Findings | Medical Care | Consultations | Prognosis | Photographic Examples |

 

Physical   Manifestations (sub headings)

| Oral | Genital | Cutaneous | Ocular | Vascular | Gastrointestinal | Joint | Neurological | Pregnancy-associated |

| Other organ | Pathergy |

 

Causes (sub headings)

| Immunogenetics | Viral and bacterial infection | Immunological abnormalities | Endothelial & vascular dysfunctions |  

 

Other Problems to be Considered  (sub heading)

| Crohn disease |

 

Medical Care (sub headings)

| Local therapy | Systemic therapy | Surgical Care |

Background

Behçet disease (BD) was named in 1937 after the Turkish dermatologist Hulusi Behçet, who first described the triple-symptom complex of recurrent oral aphthous ulcers, genital ulcers, and uveitis.

This complex, multisystemic disease includes involvement of the mucocutaneous, ocular, cardiovascular, renal, gastrointestinal, pulmonary, urologic, and central nervous systems and the joints, blood vessels, and lungs.

It is characterized by oral aphthae and by at least 2 of the following: (1) genital aphthae, (2) synovitis, (3) posterior uveitis, (4) cutaneous pustular vasculitis, (5) meningoencephalitis, (6) recurrent genital ulcers, and (7) uveitis in the absence of inflammatory bowel disease or collagen vascular disease.

Pathophysiology

The cause of BD is not known; however, immunogenetics, immune regulation, vascular abnormalities, or bacterial and viral infection may have a role in its development.

Frequency

UK

BD is not common in the UK, with an estimated prevalence of approximately 2 cases  in 100,000  that is, about 2000 people.

International

BD is most prevalent (and more virulent) in the Mediterranean region, Middle East, and Far East, with an estimated prevalence of 1 case per 10,000 persons.

Mortality/Morbidity

  • Chronic morbidity is typical; the leading cause is ophthalmic involvement, which can result in blindness. The effects of the disease may be cumulative, especially with neurologic, vascular, and ocular involvement.

  • The mortality rate is low, but death can occur from neurologic involvement, vascular disease, bowel perforation, cardiopulmonary disease, or as a complication of immunosuppressive therapy.

Sex

  • Men are affected more often, and with more severe disease, than women in some Mediterranean areas. In Iran, for example, the male-to-female ratio was 24:1 among 1712 patients. In Turkey, the ratio was 16:1 among 427 patients.

Age

  • Onset can occur at any age, but is it most common during the third decade of life.

History

Signs and symptoms, which may be recurrent, may precede the onset of the mucosal membrane ulcerations by 6 months to 5 years.

  • Prior to the onset of BD, patients may experience a variety of symptoms.

    • Malaise

    • Anorexia

    • Weight loss

    • Generalized weakness

    • Headache

    • Perspiration

    • Decreased or elevated temperature

    • Lymphadenopathy

    • Pain of the substernal and temporal regions

  • A history of repeated sore throats, tonsillitis, myalgias, and migratory erythralgias without overt arthritis is common.

  • A diagnosis of BD is based on clinical criteria because of the absence of a pathognomonic laboratory test. The period between the appearance of an initial symptom and a major or minor secondary manifestation can be up to a decade in many cases.

  • The number of different criteria or classification systems that have been introduced over the past 25 years reflects the failure of any single one to meet clinical demands. The revised 1987 criteria of the Japanese group (Mizushima) have been widely applied.

  • More recently, the diagnostic criteria of the International Study Group for Behçet Disease have been applied to establish a firmer diagnosis.

  • The major limitation of these criteria is the fact that recurrent oral ulceration is the characteristic symptom for the diagnosis of BD. For example, patients with uveitis and genital ulcers, without oral aphthosis, would not be considered to have BD, although this is, in fact, a far-advanced form of the disease.

  • Therefore, the authors recommend that both sets of criteria be applied concurrently until a more exact system is devised.

  • Diagnostic criteria from the Behçet syndrome research committee of Japan (1987 revision) are as follows:

    • Major features

      • Recurrent aphthous ulceration of the oral mucous membrane

      • Skin lesions - Erythema nodosum–like lesions, subcutaneous thrombophlebitis, folliculitis (acnelike lesions), cutaneous hypersensitivity

      • Eye lesions - Iridocyclitis, chorioretinitis, retinouveitis, definite history of chorioretinitis or retinouveitis

      • Genital ulcers

    • Minor features

      • Arthritis without deformity and ankylosis

      • Gastrointestinal lesions characterized by ileocecal ulcers

      • Epididymitis

      • Vascular lesions

      • Central nervous system symptoms

    • Diagnosis

      • Complete - Four major features

      • Incomplete - (1) 3 major features, (2) 2 major and 2 minor features, or (3) typical ocular symptom and 1 major or 2 minor features

      • Possible - (1) 2 major features or (2) 1 major and 2 minor features

  • International criteria for the classification of BD (1990) are as follows:

    • Recurrent oral ulceration - Minor aphthous or major aphthous or herpetiform ulceration observed by a physician or reported reliably by a patient that recurs at least 3 times in one 12-month period plus 2 of the following:

      • Recurrent genital ulceration - Recurrent genital aphthous ulceration or scarring, especially males, observed by a physician or reliably reported by a patient

      • Eye lesions - (1) Anterior uveitis, posterior uveitis, and cells in vitreous upon slit-lamp examination or (2) retinal vasculitis observed by physician (ophthalmologist)

      • Skin lesions - (1) Erythema nodosum–like lesions observed by physician or reliably reported by a patient, pseudofolliculitis, and papulopustular lesions or (2) acneiform nodules consistent with BD, observed by a physician, and in postadolescent patients not receiving corticosteroids

      • Positive pathergy test - An erythematous papule larger than 2 mm at the prick site 48 hours after the application of a 20- to 22-gauge sterile needle, which obliquely penetrated avascular skin to a depth of 5 mm as read by a physician at 48 hours

  • Findings are applicable if no other clinical explanation is present.

Physical

  • Oral ulcers

    • Oral aphthae that occur in patients with BD are indistinguishable from common aphthae (canker sores).

    • Aphthae may be more extensive, more painful, more frequent, and evolve quickly from a pinpoint flat ulcer to a large sore.

    • Lesions can be shallow or deep (2-30 mm in diameter) and usually have a central, yellowish, necrotic base and a punched-out, clean margin.

    • They can appear singly or in crops, are located anywhere in the oral cavity, persist for 1-2 weeks, and subside without leaving scars.

    • The most common sites are the tongue, lips, buccal mucosa, and gingiva; the tonsils, palate, and pharynx are less common sites.

    • The interval between recurrences ranges from weeks to months.

    • Oral ulcers can be classified into 3 types.

      • Minor ulcer: This consists of 1-5 small, moderately painful ulcers persisting for 4-14 days .

      • Major ulcer: This is 1-10 very painful ulcers, measuring 10-30 mm, persisting up to 6 weeks, and possibly leaving a scar upon healing.

      • Herpetiform ulcer: This is a recurrent crop of as many as 1000 small and painful ulcers.

  • Genital manifestations

    • Genital ulcers resemble their oral counterparts but may cause greater scarring. They have been found in 56.7-97% of cases, but their appearance is mostly a secondary symptom that accompanies oral ulcers.

    • In males, the ulcers usually occur on the scrotum, penis, and groin.

    • In females, they occur on the vulva, vagina, groin, and cervix.

    • Ulcers have also been found in the urethral orifice and perianal area.

    • Epididymitis may arise and is a minor diagnostic criterion for the disease according to the Behçet Disease Research Committee of Japan.

    • An additional genital symptom is orchiepididymitis, observed in 10.8% of men.

 

  • Cutaneous manifestations

    • A variety of skin lesions may appear in patients with BD (58.6-97%), including the following:

      • Erythema nodosum–like lesions, which are most common

      • Papulopustular eruptions

      • Erythema multiforme–like lesions

      • Thrombophlebitis

      • Ulcers

      • Lesions resembling Sweet syndrome

      • Bullous necrotizing vasculitis

      • Pyoderma gangrenosum

    • Nonspecific skin inflammatory reactivity to any scratches or intradermal saline injection is a common and specific manifestation of these lesions, ie, pathergy (see Image 9).

    • Lesions often occur in combination (eg, erythema nodosum–like lesions and papulopustular eruptions).

    • Follicle-based pustules or acne lesions are not considered specific lesions of BD.

 

  • Ocular manifestations

    • Ocular involvement is the major cause of morbidity and the most dreaded complication because it occasionally progresses rapidly to blindness. It is reported in 47-65% of patients with BD. Childhood-onset Behçet uveitis is more common in males (Tugal, 2003).

    • The most diagnostically relevant lesion is posterior uveitis, ie, retinal vasculitis. Other lesions include anterior uveitis, iridocyclitis, chorioretinitis, scleritis, keratitis, vitreous hemorrhage, optic neuritis, conjunctivitis, retinal vein occlusion, and retinal neovascularization. Hypopyon, which was considered the hallmark of BD, is now uncommon.

    • Eye disease is usually present from the outset but also may develop within the first few years. Decreased visual acuity is a result of secondary glaucoma, cataracts, or vitreous hemorrhage. Blindness has been reported to occur within 4-5 years from the onset of ocular symptoms. Retinal vein thrombosis leading to sudden blindness is not rare.

 

  • Vascular involvement

    • This occurs in 7-29% of patients, mostly men.

    • Histologic findings include media thickening, elastic fiber splitting, and perivascular round cell infiltration.

    • The 4 types of vascular lesions recognized in persons with BD are arterial occlusions, venous occlusions, aneurysms, and varices.

    • Venous involvement is usually limited to occlusion, with the varices rarely affected.

    • Affected sites of the venous system are the superior vena cava, inferior vena cava, deep femoral vein, and subclavian vein.

    • Arterial complications account for 7% of cases. Aneurysm and occlusion are most common.

    • The subclavian artery and pulmonary artery are the most common arteries occluded. Depending on the site, arterial occlusions can have different clinical presentations. Pulseless disease is due to subclavian artery occlusion.

    • Hypertension can originate from renal artery stenosis.

    • Femoral artery stenosis and intermittent claudication cause avascular necrosis of the femoral head.

    • Pulmonary vasculitis can produce dyspnea, chest pain, cough, or hemoptysis.

    • Aneurysm formation accounts for most vascular deaths. Common sites of aneurysms are the abdominal aorta, femoral artery, and thoracic artery.

    • Because the vascular involvement of BD can be significant and life-threatening, diagnosing and treating vascular involvement early is vital.

 

  • Gastrointestinal involvement

    • The clinical spectrum of gastrointestinal effects is enormously varied and occurs in more than 10% of patients with BD.

    • Anorexia, vomiting, dyspepsia, diarrhea, abdominal distention, and abdominal pain all may occur.

     

  • Joint manifestations

    • More than half the patients develop signs or symptoms of synovitis, arthritis, and/or arthralgia during the course of the disease.

    • The most frequent minor feature in childhood-onset BD is reported to be arthritis, occurring in 11 of 40 patients.

    • Multiple-joint involvement is common.

    • Clinical features have been reported as pain, tenderness, swelling, limitation of joint movement, warmth, and morning stiffness.

     

  • Neurological manifestations

    • The rate of neurologic involvement in persons with BD varies from 3.2-49% according to the reports of different populations.

    • Neurologic involvement may present (in various combinations) as meningoencephalitis, a multiple sclerosis–like illness, acute myelitis, stroke, or pseudotumor cerebri.

    • Three categories of neurologic involvement are (1) brain stem syndrome, (2) meningomyelitis syndrome, and (3) organic confusional syndrome.

    • Neurologic involvement is one of the most serious complications, leading to severe disability and a high fatality rate. Neurologic manifestations usually occur within 5 years of disease onset.

    • Severe headache is the most frequent initial neurological symptom.

     

  • Pregnancy-associated manifestations

    • Pregnant women with BD may experience more severe symptoms during the course of the pregnancy, especially in the first trimester. Overall, pregnancy does not seem to markedly affect the course of BD (Uzun, 2003).

    • Close follow-up is necessary to monitor the health of the mother and baby.

 

  • Other organ manifestations

    • Myocarditis and cardiac vessel disease may occur.

    • Major hemoptysis may result from pulmonary vascular thrombosis, aneurysms, or vasculitis.

    • Cases with renal involvement, such as mild asymptomatic glomerulonephritis, have also been reported. However, most patients have been asymptomatic.

 

  • Pathergy (skin hyperreactivity)

    • The presence of pathergy strongly suggests the diagnosis of BD.

    • Following a needle prick or intradermal injection with saline or dilute histamine, the puncture site becomes inflamed and develops a small sterile pustule from hyperactivity of the skin to any intracutaneous insult.

    • The pustular reaction of the skin is thought to denote increased neutrophil chemotaxis.

    • Higher positivity (84-98%) is found in Mediterranean areas and the Middle East than in the Far East (40-70%), with Western countries having significantly lower positivity than the other regions.

 

Causes

  • Immunogenetics

    • HLA-B51 or its B101 allele is significantly associated with BD in Japan, Korea, Turkey, and France and with ocular manifestations in Britain. Although HLA-B51 transgenic mice do not develop any manifestations of BD, their neutrophils show excessive function.

    • The MICA allele is a polymorphic MHC class I–related A gene (MICA) family. The MICA6 allele has recently been shown to be significantly associated with BD (74%), compared with controls (45.6%) in Japan. The relationship between MICA6 and BD was confirmed in France. The MICA6 allele is thought to be in linkage disequilibrium with HLA-B51; consequently, the search for genes related to BD continues. A recent study of 23 Japanese patients showed that the MICA6 allele had no significant association with BD, but it showed a strong association with HLA-B51; therefore, the association between MICA6and BD may be a secondary phenomenon related to HLA-B51 (Nishiyama, 2006).

    • MEFV gene mutations, seen in persons with Mediterranean fever, are increased in persons with BD. This mutation has been associated with vascular BD (Atagunduz, 2003).

    • Levels of tumor necrosis factor-alpha (TNF-alpha) have been reported to be significantly elevated in BD patients; thus, reports of TNF-alpha blockers having therapeutic benefits have been reported. Park et al analyzed TNF-alpha haplotypes in the promoter response element that affect the binding affinity of certain transcription factors. Their study showed that TNF-alpha -1031*C, -863*A, -857*C, and -308*G alleles were significantly associated with BD. TNF-alpha haplotypes in the promoter response elements may be useful in identifying those more susceptible to BD (Park, 2006).

 

  • Viral and bacterial infection

    • Investigations of the etiology of BD have focused predominantly on herpes simplex virus infection, streptococcal infection, and autoimmunity or cross-reactivity between microbial and oral mucosal antigens.

    • Behçet suggested the herpes simplex virus as a causative agent in his first report. Polymerase chain reaction studies have remarkably improved the diagnostic significance of viral infections, especially herpes simplex virus. Herpes simplex virus DNA has been detected in saliva, genital ulcers, and intestinal ulcers of patients with BD. BD-like symptoms have been induced in an Institute for Cancer Research mouse after inoculation of herpes simplex virus into its earlobe.

    • Acquired hypersensitivity to streptococcal antigens plays an important role in the etiopathology of BD.

    • The multiplicity of etiologic factors may have a common denominator in the 65-kd microbial heat shock protein (HSP), which shows significant homology with the human 60-kd mitochondrial HSP. Indeed, the uncommon serotypes of Streptococcus sanguis found in BD cross-react with the 65-kd HSP, which also shares antigenicity with an oral mucosal antigen.

    • T-cell epitope mapping has identified 4 peptides derived from the sequence of the 65-kd HSP that specifically stimulates T-cell receptor (TCR+) lymphocytes from patients with BD.

      • These peptides (111-125, 154-172, 219-233, and 311-325) show significant homology with the corresponding peptides (136-150, 179-197, 244-258, 336-351) derived from the human 60-kd HSP.

      • B-cell epitopes within mycobacterial HSP65 or human HSP60 overlap with the T-cell epitopes, and both immunoglobulin G and immunoglobulin A antibodies have been identified.

      • Among the 4 T- and B-cell epitopes, peptide 336-351 of the 60-kd HSP is significantly associated with BD in Britain, Japan, and Turkey. HSP60/65 was also found to be significantly increased in the epidermal cells of BD skin lesions, and antibody levels to HSP65 were significantly elevated in the cerebrospinal fluid from patients with neurological manifestations of BD.

      • An experimental model of BD uveitis was established in rats, in which subcutaneous immunization with peptide 336-351 and adjuvants elicited uveitis in approximately 80% of Lewis rats. Furthermore, a mucosal model of induction of uveitis was developed in rats by oral or nasal administration of peptide 336-351 without an adjuvant, and this is consistent with the oral onset of ulceration in more than 90% of patients with BD.

 

  • Immunological abnormalities

    • In persons with BD, the Th1 cytokine interferon (IFN) level is elevated in serum, in skin T cells, and cerebrospinal fluid, and interleukin (IL)–12 is generated by the stimulation of CD4+ T cells with the HSP peptide 336-351, although IL-12 can also be secreted by neutrophils in persons with BD. However, the concentration of the Th2 cytokine IL-6 is also increased in the serum of patients with BD, especially in the active stage, as was also found with IL-10 upon stimulation of the peripheral blood mononuclear cell.

    • Stimulation with S sanguis (KTH-1) of T-cell lines generated from patients with BD suggests that Th1-type mRNA is induced (IL-2 and IFN).

    • Investigations of intracellular IFN and IL-4 suggest that polarization toward the Th1 type of cells occurs in patients with active BD because of a significant increase in the intracellular IFN that was not observed with IL-4. However, the converse was found in another investigation by stimulating peripheral blood mononuclear cells, with increased Th2 cytokines (IL-10 and decreased IL-2 or IFN) in active BD.

    • The intracellular adhesion molecule 1 was enhanced in human dermal microvascular endothelial cells after treatment with serum from patients with BD, and this may have induced increased adhesion of T cells to the endothelial cells.

    • Levels of the proinflammatory cytokines tumor necrosis factor (TNF)–alpha, TNF receptor 1, IL-1, and IL-8 are elevated in the serum of persons with BD and remain unregulated in peripheral blood mononuclear cells and neutrophils of patients with BD (Duzgun, 2005). Levels of IL-10 and IL-13 may also be elevated (Aridogan, 2003).

    • Plasma levels of vascular endothelial growth factor, a proinflammatory cytokine, is significantly higher in persons with active BD (Cekmen, 2003).

    • Neopterin is produced by human monocytes and macrophages in response to interferon-gamma (IFN-gamma) released from activated T cells; thus, it serves as a marker for cellular immune activation. Kose et al showed that serum levels of neopterin were significantly higher in active and inactive BD patients than in controls. Those with active disease had higher levels than those with inactive disease (Kose, 2006).

 

  • Endothelial and vascular dysfunctions

    • Vascular changes leading to vasculitis and thrombosis are important pathological features of BD.

    • A recent study proposes that immunoglobulin to carboxy-terminal subunit of Sip1 (Sip1 C-ter) may be a useful novel autoantigen in BD. Interestingly, this autoantigen level was not only elevated in 41% of BD patients, but also in 45% of those patients with primary vasculitis, thus this marker may also point at endothelial dysfunction in vasculitis (Delunardo, 2006).

    • Antiendothelial cell antibodies are detected in diseases with immune-mediated vascular damage and show significantly increased prevalence in BD.

    • T cells (mostly CD4 cells), B cells, and neutrophils are infiltrated perivascularly.

    • Esmat et al showed much higher serum lipoprotein(a) levels in patients with vascular complications and lower levels of serum nitrites during disease activity (Esmat, 2006).

    • Another study demonstrated an association of factor V Leiden and G20210A prothrombin mutation with thrombosis in BD patients (Ricart, 2006).

    • Prostanoid synthesis in endothelial cells or vessel walls is impaired, whereas von Willebrand factor, thromboxane, and thrombomodulin are increased.

    • The level of endothelin 1 and 2 is increased in patients with BD vascular involvement.

    • Endothelial cell–dependent vasodilator function is significantly impaired in patients with BD and is demonstrated by high-resolution ultrasound imaging.

 

Other Problems to be Considered

Inflammatory bowel disease (Crohn disease)

Lab Studies

  • BD cannot be confirmed through clinical laboratory results.

    • Mild anemia and leukocytosis are observed in some patients with chronic disease.

    • The erythrocyte sedimentation rate, C-reactive protein value, and other acute phase reactants may be elevated during the active stage of BD, but they do not correlate well with the clinical activity.

    • An increase in alpha-2 globulins is often observed. Serum immunoglobulin levels, especially immunoglobulin A, may be elevated.

    • Circulating immune complexes are often present.

    • Rheumatoid factor and antinuclear antibodies are absent.

    • Antineutrophil cytoplasmic antibody and antiphospholipid antibody test results are usually negative.

Histologic Findings

The etiology and pathogenesis of BD remain obscure, although many reviews describe a lymphocytic vasculitis.

Vasculitis is thought to affect vessels of all sizes; the various skin lesions are thought to be secondary to small vessel vasculitis.

The histopathology is variable, dependent upon the type of lesion. Pathergic lesions are characterized by a heavy neutrophilic infiltrate without fibrin within the vessel walls. Folliculitis, acneiform lesions, and dermal abscesses have been described in BD.

The erythema nodosum–like lesions show a perivascular lymphocytic infiltrate of lymphocytes in the deep dermis and septa with a lymphocytic vasculitis but lack the histiocytic granulomas of typical erythema nodosum.

The aphthous ulcers have a nonspecific pathology with a variable infiltrate of lymphocytes, macrophages, and neutrophils at the base of the ulcer.

T-cell subsets with a preponderance of helper-inducer cells over T suppressor-cytotoxic cells have been observed in lesions.

Electron microscopic observations

Examination of erythema nodosum–like lesions shows microvascular changes and lymphocyte-mediated fat cell lysis. Additionally, small dermal blood vessels embolized by thrombi are observed at the sites of the needle prick reaction (pathergy) and at the erythema nodosum–like lesions.

The early changes in fat cells may be caused by vascular changes brought about by the specific degeneration of endothelial cells and vascular stenosis associated with the delayed-type hypersensitivity reaction.

Medical Care

Although multiple therapeutic modalities have been used, treatment is far from satisfactory. Treatment of BD seems to be symptomatic and empiric. Therapeutic efficacy has been difficult to evaluate because of the variable course of the disease and the limited number of cases for clinical investigation.

 

  • Local therapy

    • Tetracycline remains the drug of choice for aphthous stomatitis and oral ulcers of BD.

    • The patient dissolves the contents of a 250-mg tetracycline capsule in 5 mL of water or flavored syrup and holds the solution in the mouth for approximately 2 minutes before swallowing. This is repeated 4 times daily.

    • Topical corticosteroids are effective for oral or genital ulcerations if they are applied during the prodromal stage of ulceration.

    • Other useful drugs include lidocaine gel (2%), sucralfate suspension, and 5% amlexanox.

  • Systemic therapy

    • No single drug has proven effective.

    • Corticosteroids are the mainstay of treatment for all the various clinical manifestations. Although they have a beneficial effect on acute manifestations, no definite evidence indicates they are effective for controlling progression.

    • The adverse effects of long-term steroid therapy must be considered.

    • Mucocutaneous lesions and arthritis have been treated with nonsteroidal anti-inflammatory drugs, zinc sulfate, levamisole, colchicine, dapsone, or sulfapyridine and thalidomide (use is strictly limited because of its teratogenicity). Immunosuppressive therapy with azathioprine, chlorambucil, or cyclophosphamide has been used.

    • Uveitis and central nervous system involvement is treated with systemic corticosteroids, azathioprine, or cyclosporine.

    • Anticoagulants are given to patients with thromboses.

    • Recent therapeutic approaches have included cyclosporine, IFN alfa, IFN gamma, acyclovir, high-dose corticosteroids or cyclophosphamide pulse therapy, and FK506 (tacrolimus, an immunosuppressive agent similar to cyclosporine).

    • FK506 (tacrolimus) has been particularly noteworthy. The Japanese FK506 study group reported that FK506 was effective in treating refractory uveitis in a dosage-dependent manner. Adverse effects were renal impairment (28.3%), neurologic symptoms (20.8%), gastrointestinal symptoms (18.9%), and hyperglycemia (13.2%). The study group also noted the need for further clinical investigations on FK506 before more widespread application.

    • Subcutaneous IFN alfa-2a therapy has resulted in reduced ulcers and eye disease. Flulike symptoms were the most common adverse effect. Leukopenia, hair loss, and development of antinuclear and antithyroid antibodies were reported less commonly (Alpsoy, 2003; Kotter, 2003).

    • With the possible role of TNF-alpha in the pathogenesis of BD, infliximab, a chimeric monoclonal immunoglobulin G antibody that inhibits TNF-alpha, and etanercept, a TNF receptor blocker, have steroid-sparing effects and have decreased the frequency of attacks in patients with BD (Sfikakis, 2002). Case reports describe treatment of patients with recalcitrant disease or those in whom conventional immunosuppressive agents have failed (Katsiari, 2003; Ohno, 2004; Tugal-Tutkun, 2005. Etanercept has been used at 25 mg twice a week (Melikoglu, 2005). Infliximab has resulted in responses after etanercept failed (Estrach, 2002). Infliximab infusions of 5-10 mg/kg have been used with variable dosing schedules. Tuberculosis was a reported adverse effect of infliximab infusion in one BD patient (Ohno, 2004).

Surgical Care

Surgical therapy becomes necessary in serious conditions, including the following:

  • Gastrointestinal perforation

    • Enterocutaneous fistula formation

    • Spontaneous arterial aneurysm formation

    • Thrombotic obstruction in large-caliber vessels

    • Cardiac involvement

  • Proper timing for surgical treatment is important.

  • Delayed wound healing or inflammation at operative sites may be related to pathergy.

Consultations

  • Dermatologist - For evaluation of mucocutaneous lesions (ie, oral ulcer, genital ulcer, skin lesions)

  • Ophthalmologist - For evaluation of eye involvement

  • Rheumatologist or orthopedic surgeon - For evaluation of joint involvement

  • Neurologist or psychiatrist - For evaluation of CNS involvement

  • Internal medicine specialist - For evaluation of gastrointestinal, pulmonary, renal, or endocrine involvement

  • General surgeon - For evaluation of gastrointestinal involvement

  • Chest surgeon or cardiologist - For evaluation of cardiovascular involvement

  • Ear, nose, and throat specialist or dentist - For evaluation of oral cavity

The goals of pharmacotherapy are to reduce morbidity and to prevent complications. Corticosteroids have been used for all of the various clinical manifestations of BD. Anti-inflammatory and immunosuppressive agents are used to treat mucocutaneous lesions and arthritis associated with this disease. Anticoagulants are administered to patients with thromboses.

Prognosis

 

  • The clinical course of BD is variable, even in the early stages, making determinations of the long-term prognosis difficult.

  • Men appear to have a poorer prognosis.

  • The disease usually runs a protracted course, with attacks generally lasting for several weeks and recurring more frequently early in the disease.

  • Mucocutaneous and arthritic involvement usually occur early.

  • Chronic morbidity is usual; the leading cause is ophthalmic involvement, which can result in blindness. The effects of the disease may be cumulative, especially for neurologic, vascular, and ocular involvement.

  • Mortality is low, but patients may die from neurologic involvement, vascular disease, bowel perforation, cardiopulmonary disease, or as a complication of immunosuppressive therapy.

Photographic Examples

1:  Minor aphthous ulcer.

 

Click to see larger picture

2:  Major aphthous ulcer.

 

Click to see larger picture

3:  Herpetiform oral ulcer.

 

Click to see larger picture

4:  A characteristic genital ulcer on scrotum.

Click to see larger picture

 

5:  A single ulcer on vulva.

 

Click to see larger picture

6:  Erythema nodosum–like lesions on skin.

Click to see larger picture

7:  Papulopustular eruptions.

 

Click to see larger picture

8:  Sweet syndrome–like lesion.

 

Click to see larger picture

 

9:  Typical positive pathergy reaction at injection site.

 

Click to see larger picture

10:  Ocular involvement showing posterior uveitis.

 

 

Click to see larger picture

Additional Photos & Note by web-page author:

Below is this web-site author's previous leg inflammation. Taken 16th June 2008 at Bronglais General Hospital, Aberystwyth, Wales. The condition was treated as Cellulitis - due to similarities in the outward appearance of the condition, (which was in fact a Erythema nodosum-like flare up of BD). The treatment insisted on was an IV infusion of antibiotics despite the author's suggestion to the doctors that it was not an infection but inflammation due to BD! Hence one of the reasons for this web-page.

 

 

 


 

New Evidence-Based Treatment Approach in Behçet's Disease

click on the photo of Prof. Alpsoy for more information  . . . .

Erkan Alpsoy

Professor in Dermatology and Venereology

Psoriasis, Behçet's disease, Vasculitis, Immunodermatology

Verified email at akdeniz.edu.tr

Pathology Research International
Volume 2012 (2012), Article ID 871019, 11 pages
http://dx.doi.org/10.1155/2012/871019
Review Article

Department of Dermatology and Venerology, Akdeniz University School of Medicine, 07059 Antalya, Turkey

Received 20 June 2011; Accepted 1 August 2011

Academic Editor: Ümit Tursen

Copyright © 2012 Erkan Alpsoy. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


Article Bookmarks (Prof. Erkan Alpsoy's article)

Main Headings

| Introduction | Treatment | Evidenced-Based Algorithmic Treatment Approach | Mucutaneous Disease | Articular Disease | Ocular Disease | Severe Disease | References (83) |

Treatment (sub headings)

| Topical Treatment | Systemic Treatment | Surgical Treatment |

Systemic Treatment (sub headings)

 | Cordicosteroids  |  Colchicine  |  Benzathine Penicillin  |  Rebamipide  | Zinc Sulphate | Dapsone | Thalidomide | Azathioprine | Cyclophosphamide | Cyclosporin A | Interferon-α | Anti-TNF-α Agents | Rituximab | Other Systemic Treatment Approaches |

Severe Disease (sub headings)

| Large Vessel Involvements | Neurologic Involvements | Gastrointestinal Disease |


 

Abstract

Behçet's disease (BD) is a chronic, relapsing, and debilitating systemic vasculitis of unknown aetiology with the clinical features of mucocutaneous lesions, ocular, vascular, articular, neurologic, gastrointestinal, urogenital, and pulmonary involvement. The disease is much more frequent along the ancient “Silk Route” extending from Eastern Asia to the Mediterranean basin, compared with Western countries. The disease usually starts around the third or fourth decade of life. Male sex and a younger age of onset are associated with more severe disease. Although the treatment has become much more effective in recent years, BD is still associated with severe morbidity and considerable mortality. The main aim of the treatment should be the prevention of irreversible organ damage. Therefore, close monitoring, early, and appropriate treatment is mandatory to reduce morbidity and mortality. The treatment is mainly based on the suppression of inflammatory attacks of the disease using immunomodulatory and immunosuppressive agents. In this paper, current state of knowledge regarding the therapeutic approaches is outlined. To provide a rational framework for selecting the appropriate therapy along the various treatment choices, a stepwise, symptom-based, evidence-based algorithmic approach was developed.

1. Introduction

Behçet's disease (BD) is a chronic, relapsing, and debilitating systemic vasculitis of unknown aetiology with the clinical features of mucocutaneous lesions, ocular, vascular, articular, neurologic, gastrointestinal, urogenital, and pulmonary involvement [1]. BD usually starts around the third or fourth decade of life. Recent epidemiologic surveys [2–4] suggest that sex distribution is roughly equal. The disease is particularly prevalent in “Silk Route” populations but has global distribution. The pravelance of the disease is 14–20 per 100 000 along the Silk route [5]. Turkey has the highest prevalence. Azizlerli et al. from Istanbul reported the prevalence of the disease to be nearly 1/250 of the population aged 12 or older [2]. BD is rarely seen in western countries. The pravelance of the disease in England is less than 1/100 000 [5, 6]. This marked geographic variation of BD can be explained by the genetic basis of the disease and/or environmental triggers. The diagnosis is based on clinical criteria, as there is no pathognomonic test. Although several immunological abnormalities have been demonstrated, the exact mechanism of the inflammatory changes occurring remains to be elucidated. The most probable hypothesis is that of an inflammatory reaction set off by infectious agents such as herpes simplex virus 1 or Streptococcus spp. or by an autoantigen such as heat shock proteins in genetically predisposed individuals [7–9].

Mucocutaneous lesions figure prominently in the presentation and diagnosis and may be considered the hallmarks of BD. Oral ulcers (OUs), genital ulcers (GUs), and cutaneous lesions together with ocular lesions and arthropathy are the most frequent features of the disease in all countries. Mucocutaneous lesions often precede other manifestations. Therefore, their recognition may permit earlier diagnosis and treatment, with salutary results [5]. OUs are characterized by recurrent and painful ulcerations of the oral mucosa. They are identical to aphthae in appearance, but they tend to be more frequent and multiple. The most common sites are the mucous membranes of the lips, buccal mucosa, tongue, and soft palate. GUs are similar in appearance and course to OUs, but may not recur as often. They are usually deeper than the OUs and have a scarring tendency. The labia is the most frequently involved site in females and scrotum in males. Relapsing bipolar oral and genital ulcers are strongly evocative of BD [5]. Papulopustular lesions (PPLs) are sterile, folliculitis, or acne-like lesions on erythematous base which appear as a papule and in the course of a 24–48 hours become pustule. Trunk and the lower limbs are the most common locations [10]. Erythema nodosum (EN) is mostly seen in females and occur in about one-third of all patients. They have a typical clinical presentation with bilateral, pretibial, painful, and hot erythematous nodules. Other cutaneous lesions such as Sweet’s syndrome-like, pyoderma gangrenosum-like, erythema multiforme-like lesions, extragenital ulcers, and palpable purpura can be seen during the course of the disease [1, 5, 11]. The skin pathergy test is a nonspecific skin hyperreactivity, induced by needle prick. The test positivity is defined as the development of a papule or pustule at the needle-prick site at 48 h. It is more strongly positive among males. Test positivity varies between geographic areas and has been reported to be high especially in Japan and the Mediterranean Sea countries (50–70%) [5].

Ocular involvement is a serious complication of BD and is characterized by repeated, explosive inflammatory attacks that may lead to visual loss in almost 15% of eyes. Panuveitis is the most frequent ocular lesion in BD. Anterior uveitis, posterior uveitis, and retinal vasculitis are the other main ocular manifestations. They are bilateral in most of the patients [12]. Articular involvement is characterized by nonerosive and nondeforming arthritis which often presents with monoarticular pattern, although asymmetrical polyarthritis can occur. The articular involvement is usually transient in nature with episodes lasting from a few days to weeks [13]. The disease is a systemic vasculitis affecting arteries and veins of various sizes. Venous system is the major affected site, and subcutaneous thrombophlebitis is, indeed, the most frequent type of venous involvement. Thromboses of the inferior vena cava and superior vena cava, dural sinuses, and Budd-Chiari syndrome can also be seen and are associated with poor prognosis. Pulmonary arterial aneurysm is rare; however, it is important cause of mortality [14]. Neurological involvement is relatively rare, but one of the most serious complications of the disease due to its grave prognosis. Parenchymal involvement including brainstem involvement, hemispheric manifestations, spinal cord lesions, and meningoencephalitis is seen in the majority of patients (%80). Dural sinus thrombi presenting with headaches and papilledema appear in 20% of patients with neurological involvement and have a more bening course [15]. Gastrointestinal involvement is characterized by aphthous-like mucosal ulcers occuring predominantly in the iliocaecal region, although it can occur throughout the gastrointestinal tract [16].

BD runs a chronic course with unpredictable exacerbations and remissions. In a recent multicenter study [17], we aimed retrospectively to determine the occurrence of the symptoms in chronologic order. We also evaluated the influence of the treatment and followup on the clinical severity and tried to obtain the factors determining the severe organ involvement in 661 patients. OUs were the most common manifestation (100%) followed by GUs (85.3%), PPLs (55.4%), EN (44.2%), skin pathergy reaction (37.8%), and articular (33.4%) and ocular involvement (29.2%). OUs were the most common onset manifestation (88.7%) which was followed by GUs (14.2%), EN (5.7%), and ocular involvement (4.2%). The duration between the onset symptom and the fulfilment of diagnostic criteria was calculated to be 4.3 ± 5.7 years. The frequency of ocular involvement and GUs was significantly higher in patients whose disease onset was less than 40 years. GUs, ocular involvement, PPLs, thrombophlebitis, and skin pathergy reaction were found to be significantly higher in males. The clinical severity of the disease showed a significant increase in noncompliant treatment group compared with compliant group with the passage of time. Our study showed that mucocutaneous lesions are the hallmarks of the disease, and especially OUs precede other manifestations. Male sex and a younger age of onset are associated with more severe disease.

Each or any combination of mucocutaneous, articular, and ocular symptoms of the disease may have significant pain or loss in function, or both. Besides considerable morbidity, the disease confers an increased mortality, mainly due to large vessel (especially pulmonary arterial) and neurologic involvement as well as bowel perforation. In general, mortality ratios as well as mucocutaneous and articular manifestations tend to decrease significantly with the passage of time. Both the onset of eye disease and its greatest damage are usually within the first few years of disease onset. A recent study [14] has shown that neurologic and large vessel involvements are exceptions, and they can have their onset late (5–10 years) during the disease course. In our multicenter study [17], in addition to these involvements, gastrointestinal involvement was also found to be a late manifestation of the disease. Therefore, all these results stress the importance of vigilance in long-term surveillance of patients with BD. Close monitoring and appropriate treatments are mandatory to decrease the morbidity and mortality of the disease since the disease shows a continuous activity.

2. Treatment

Treatment of the disease has become much more effective in recent years because of advances in understanding the pathogenesis the underlying disease and availability of a wide spectrum of therapeutic agents. Although several effective treatments currently exist, none of them result in a cure of the disease and some are associated with significant side effects. The choice of treatment is generally based on the clinical presentation and the site affected. However, the main aim of the treatment should be the prevention of irreversible organ damage, especially, during the early, active phase of the disease. Close monitoring and appropriate treatment may control and change the course of the disease. It is wise to remember that especially male patients and those with early onset disease are associated with more severe presentations including major vessel disease, ocular, gastrointestinal, and neurological involvement and, therefore, require more aggressive treatment [18].

This paper overviews the current state of knowledge regarding the therapeutic approaches for BD. Based on the mainly controlled studies and personal experience in clinical practice and basic research in this field, a stepwise, symptom-based, evidence-based algorithmic approach for the management of BD was proposed. This approach might enable clinicians to rationalize and further increase the selection of the most appropriate therapy among numerous treatment options [18].

2.1. Topical Treatment

The majority of experience in the treatment of OUs comes from the studies performed in patients with recurrent aphthous stomatitis (RAS). As we mentioned before, OUs of BD are identical to RAS in appearance. Therefore, therapeutic remedies related with RAS, to some extent, can be applied to OUs of BD.

Although controlled studies are still lacking, the efficacy of topical corticosteroids is indisputable based on their favorable and widespread use. Topical corticosteroids suppress the inflammation associated with the formation of aphthae, and they are effective on both OUs and GUs especially when they are used in the early stage of these lesions. They reduce the pain severity and healing duration. Triamcinolone acetonide as cream 0.1% in Orabase or spray, prednisolone tablets in 20 mL water as rinse four times daily like those of dexamethasone elixir (0,5 mg/5 mL) can be used for OUs. Potent corticosteroid creams alone or in conjunction with antiseptics are also effective in GUs. Major OUs or GUs can be treated by intralesional triamcinolone, 5–10 mg/mL. Topically applied corticosteroid eye drops may also be used in mild attacks of anterior and intermediate uveitis together with mydriatics or cycloplegic agents [19]. Antimicrobial agents including antiseptic agents and antibiotics are used to control microbial load [1]. Two controlled studies with antiseptic agents, listerine mouth rinse [20], and chlorhexidine gel [21] in RAS noted the effectiveness on the pain severity and duration. Triclosan, a broad-spectrum antibacterial agent has been shown to reduce the number of aphthous ulcers in a double-blind cross-over study in RAS patients [22]. Antibiotics, especially tetracycline has been widely used in OUs of BD for years. Tetracycline mouthwash (250 mg capsules dissolved in 5 mL of water or flavored syrup and held in the mouth for about 2 minutes before swallowing four times daily) decrease pain severity and duration of OUs. A double-blind trial of tetracycline suspension showed significant reductions in ulcer duration, size, and pain in RAS patients [23]. A recent study [24] assessed 0.2 percent minocycline and 0.25 percent tetracycline aqueous solution mouthwash in patients with RAS in a clinical randomized crossover trial. Minocycline mouthwashes as compared to topical tetracycline rinses resulted in significantly improved pain control, by reducing the severity and duration of pain. Cephalexin [25] and penicillin G [26] have also been reported to be effective antibiotics. Sucralfate (1 g/5 mL), 4 times daily, for 3-month duration as mouthwash, decreases significantly the frequency, healing time, and pain of OUs and healing time and pain of GUs. The effectiveness of the sucralfate on the OUs frequency and healing time continue during the posttreatment period in decreasing order [27]. This compound binds to ulcerated tissue and forms a barrier and augments ulcer healing. Recent controlled studies suggest that pimecrolimus, a topical immunomodulator, twice a day seems to be safe and efficient in the treatment of genital ulcers, by accelerating the healing process and shortening the pain duration [28, 29]. Amlexanox accelerate the healing and decreases the pain severity of oral ulcers. It has anti-inflammatory and antiallergic activities [30, 31]. Amlexanox is used in oral paste (5%) 4 times daily (after meals and at bedtime) for 4–10 days. Anti-inflammatory agents (benzydamine, diclofenac), anaesthetics (lidocaine 2–5%, mepivacaine 1.5%, tetracaine 0.5–1% gels, or mucosal ointments), and silver nitrate, in general reduce the pain severity of aphthous lesions [5, 32, 33]. Recently, beneficial effects of colony stimulating factor on the healing duration and pain severity of OUs and GUs have been reported by our group [34].

In addition to the above-mentioned treatment approaches to OUs, patients should be advised to maintain good daily oral hygiene [35]. These patients should avoid irritating agents such as acid, crusty, hard, spicy, or salty nutrients and alcoholic beverages. EN is treated topically like classic EN. Wet dressings such as aluminium acetate 3–5% (Burow’s solution) can be applied in early stage of these lesions. This approach is also helpful for the treatment of superficial thrombophlebitis. All therapy should be combined with rest in bed.

2.2. Systemic Treatment
2.2.1. Corticosteroids

Corticosteroids have been widely used almost for all lesions of the disease. The compound is an effective choice especially in mucocutaneous lesions, acute uveitis, and neurologic disease. They can be given as monotherapy or in combination with other drugs such as colchicine, interferon (IFN)-α, cyclosporine, or azathioprine. However, in a recent randomized, placebo-controlled study of 86 patients who had active mucocutaneous lesions without eye and major organ involvement, low dose depot steroid (40 mg of methylprednisolone acetate every 3 weeks) was only found to be helpful in controlling EN, especially among females [36]. However, this result does not mean the compound is not effective in daily and/or higher doses. On the other hand, the well-known side effect profile limits their long-term use, and more corticosteroids do not improve the long-term outcome.

2.2.2. Colchicine

Colchicine inhibits the enhanced chemotactic activity of neutrophils. Promising results with colchicine (0.5–2 mg/d p.o.) have been reported especially in mucocutaneous and articular findings. The first placebo-controlled study suggested that the drug is effective only for EN and arthralgia [37]. Yurdakul et al., in a randomized placebo-controlled study [38], revisited the issue and have shown that colchicine reduces the occurrence of GUs, EN, and arthritis among women and the occurence of arthritis among men. Although oligozoospermia, amenorrhea, or dysmenorrhea, malaise, hair loss, gastrointestinal complaints (nausea, vomiting, diarrhea), and hematologic side effects are recorded as the main adverse effects of colchicine, Yurdakul et al. [38] reported no significant difference between the groups.

Recently, Davatchi et al. [39], in a large cohort of BD patients (169 patients without major organ involvement), reevaluated the efficacy of colchicine. In this randomized, double-blind, controlled crossover trial, the overall disease activity index and OUs, GUs, PPLs, and EN improved significantly with colchicine. There was not any significant difference between the results for males and females.

2.2.3. Benzathine Penicillin

Calguneri et al. [40] have found that the combined use of colchicine and benzathine penicillin (1.2 MU/3 weeks) treatment more effective than colchicine alone. Combined treatment was effective in reducing frequency and duration of OUs and EN and the frequency of GUs. Combined treatment also significantly reduced the number of arthritis episodes and prolonged the duration of episode-free time compared with the colchicine-alone group. Recently Al-Waiz et al. [41] showed that combined use of colchicine (1 g/d) and benzathine penicillin (1.2 MU/m) is more effective in decreasing clinical manifestation index, the numerical sum of the clinical features, than in either drug alone.

2.2.4. Rebamipide

In a double-blind, placebo-controlled study of 35 BD patients, having as the main symptom OUs, Matsuda et al. [42] used rebamipide (300 mg/day) for 3 to 6 months. They reported that the rate of moderate or marked improvement in OUs count and pain was 36% in the placebo group and 65% in the drug group. Authors concluded that rebamipide may be useful in the treatment and prevention of recurrences of OUs. No significant adverse effect has been reported.

2.2.5. Zinc Sulphate

In a recent controlled study of 32 patients, Sharquie et al. [43] evaluated the efficacy of zinc sulfate in a double-blind, crossover study and reported an improvement in the clinical manifestations index of mucocutaneous lesions without any side effect.

2.2.6. Dapsone

Dapsone also inhibits the enhanced chemotactic activity of neutrophils and can be used as an alternative compound to colchicine. In a double-blind, crossover study of 20 patients, Sharquie et al. reported significant reductions in the number, duration, and frequency of OUs and number of GUs in dapsone-treated patients. This compound also showed a significant decrease in the frequency of EN and PPLs. Arthritis and epididymitis were also significantly supressed by dapsone, but the effect of the compound on arthralgia failed to reach the level of statistical significance [44]. Hemolytic anemia and methemoglobinemia, which can be severe in patients with glucose-6-phosphate dehydrogenase deficiency, are the main side effects, which may significantly limit their use.

Despite the encouraging results of the last three studies, a limited number of patients included, and a relatively short follow-up periods were the main limitations.

2.2.7. Thalidomide

The drug selectively inhibits TNF-α synthesis. In a randomised, double blind, placebo-controlled study with 63 patients, a remission of OUs, GUs, and PPLs was detected in 22% of the patients over 8 weeks. During the 6-month treatment 30% of the patients remained free of lesions. Thalidomide therapy, however, was associated with exacerbation of EN [45]. In addition, the effects of the drug are temporary, and discontinuation of the treatment results in recurrence of the OUs and GUs. The effectiveness of the thalidomide is lost about 20 days after discontinuation of the drug. Neurological side effects and teratogenic risc of thalidomide limit the clinical application.

2.2.8. Azathioprine

Azathioprine, an important disease-modifying compound, shows an anti-inflammatory effect by suppressing both cellular and humoral immune responses. In a randomised, double-blind, placebo-controlled study [46] of 73 patients, azathioprine has been found to be an effective choice in OUs and GUs besides ocular inflammation and arthritis. Azathioprine was significantly better than placebo in preventing the development of new eye disease. Therefore, the authors concluded that the drug can be used prophylactically to prevent the eye involvement in young, male patients presenting with severe mucocutaneous lesions. Myelotoxicity, gastrointestinal complaints, immunosuppression, opportunistic infections, and hepatotoxicity are the main side effects.

2.2.9. Cyclophosphamide

Cyclophosphamide is the fast-acting alkylating agent. It has been found as a beneficial therapeutic agent for eye disease and systemic vasculitis (neurologic involvement and arterial aneurysms). In a double-blind crossover study [47], it has been shown that the combination of cyclophosphamide and corticosteroid therapy is superior to corticosteroid therapy alone in eye involvement. Myelosuppression, pulmonary fibrosis, renal toxicity, hemorrhagic cystitis, infertility, malignancy, and alopecia are the major adverse effects of cyclophosphamide. Due to the severe toxicity, cyclophosphamide should be selected in cases with clinically significant disease who are refractory to other agents.

2.2.10. Cyclosporin A

Cyclosporin A (CyA) is an immunosuppressant agent which selectively inhibits T lymphocytes. The drug is capable of markedly ameliorating uveitis as well as mucocutaneous lesions. CyA is still one of the most effective agents for the treatment of uveitis which reduces the frequency of ocular exacerbations and improves visual acuity. In a conrolled study of 96 patients with recurrent uveitis, CyA (10 mg/kg/d) has been shown to be superior to colchicine (1 mg/d) in decreasing frequency and severity of ocular attacks [48]. In the study of BenEzra et al. [49], CsA was more effective than conventional therapy (prednisolone, chlorambucil) in decreasing the active ocular inflammatory processes and arresting the deterioration of visual acuity. However, conventional therapy was superior to CsA in controlling OUs, GUs, and arthritis. Elidan et al. [50] reported that CyA is significantly better than conventional therapy (prednisolone, chlorambucil) at improving hearing loss. Five of 20 Behçet patients under CyA therapy demonstrated improvement in their hearing loss. In a comparative study [51], a significant improvement in visual acuity during the first 6 months in CyA (5 mg/kg/d) group compared with cyclophosphamide (1000 mg/mo) was observed. However, this favorable effect of CyA was not sustained in the followup of patients up to 24 months. In another controlled trial [52], 26 patients treated with CyA with a dose of 5 mg/kg/d have been compared with 50 patients receiving conventional therapy, systemic corticosteroid alone or combined with azathioprine. CyA treatment was found to be more effective in reducing OUs, GUs, cutaneous lesions, thrombophlebitis as well as articular symptoms and neurologic symptoms. Therefore, CyA is also an effective alternative for mucocutaneous lesions; however, it should be reserved for the most severe cases because of its significant long-term adverse effects such as renal failure, hypertension, neurologic toxicity, and hirsutism. It is wise to remember that neurological manifestations occur more frequently in BD patients under CyA treatment [53].

2.2.11. Interferon-α

In recent years, the increasing evidence suggests that interferon (IFN)-α is an effective alternative in the treatment of BD. The mode of action of IFN-α in BD is still unknown. However, their antiviral and immunomodulatory effects appear to be the possible mechanisms. In a randomised, double-blind, placebo-controlled study [54], we have shown that IFN-α 2a treatment is an effective alternative particularly for the management of mucocutaneous lesions, and its effect decreases gradually after the cessation of treatment. IFN-α 2a treatment decreased significantly the duration and pain of OUs and the frequency of GUs and PPLs. Although not significant, the mean frequency and duration of EN, thrombophlebitis, and articular symptoms also showed a decrease. Hamuryudan et al. [55], in their 48-week open, self-controlled trial, reported that IFN-alpha 2b significantly reduced the mean number of arthritis attacks.

IFN-α has also been employed in cases of sight-threatening refractory uveitis with promising results. Kötter et al. in their open-label, prospective study [56] used IFN-α 2a in 50 patients at a dose of 6 million IU (MIU) daily, tapered according to a preset schedule. The authors concluded that IFN-α 2a is effective in ocular BD, leading to significant improvement of vision and complete remission of ocular vasculitis in the majority of the patients. Tugal-Tutkun et al. [57] evaluated the IFN-α treatment in 44 patients with uveitis unresponsive to conventional immunosuppressive therapy. Although the overall response rate was 91%, complete response rate (36.4%) was lower than that of the study of Kötter et al. In a newer study, Onal et al. [58] investigated the long-term efficacy and safety of low dose (3.0 MIU daily for 14 days, maintenance dose, 3 MIU 3 times per week for 24 months) therapy of IFN-α 2a in 37 patients with refractory Behçet panuveitis unresponsive to conventional immunosuppressive therapy. During maintenance therapy, IFN-α 2a controlled uveitis in 35 patients (95%). In 15 patients (41%), a maintenance dosage of 3 MIU 3 times per week controlled uveitis without any relapse. Remission rate after discontinuation of IFN-α 2a therapy was 76% by 3 months. Therapeutic response rate differences of ocular BD with IFN-α treatment among the respected studies might have been caused by the different patient populations studied and the different dose schedules. Nevertheless, taken together, IFN-α 2a seems to be able to control and achieve remission of uveitis in most patients with refractory ocular BD.

The primary side effects of IFN-α therapy are flulike symptoms (fever, chills, headache, fatigue, myalgia, etc.) that start a few hours after the initiation of the therapy and continue less than a day. We use oral acetaminophen (paracetamol) 1000 mg orally before injections and 500 mg after 6 hours during the first weeks of the therapy to decrease these side effects. Nausea, vomiting, anorexia, diarrhea, loss of weight, hematologic changes, transient raising of hepatic transaminases are seen less frequently. Psychiatric side effects and depression are limiting factors for use of IFN-α.

2.2.12. Anti-TNF-α Agents

Several pieces of evidence indicate that TNF-α plays a critical role in the pathogenesis of BD, and so far, three anti-TNF-α compounds, infliximab, adalimumab, and etanercept, have shown favourable results on preliminary tests. Almost all trials reported encouraging results for recalcitrant mucocutaneous lesions besides ocular and gastrointestinal symptoms, arthritis, and cerebral vasculitis. Anti-TNF-α treatment suppresses almost all manifestations of the disease with an immediate and dramatic response. It also reduces the dosage of immunosuppressors. Therefore, when the disease is associated with vital organ involvement, especially in young male patients, anti-TNF-α agents can also be used because of their potential to improve the survival and prognosis.

The majority of current data related with infliximab comes from the uncontrolled, open studies, small case series, and case reports. The main 3 prospective studies performed by Sfikakis et al. [59], Ohno et al. [60], and Tugal-Tutkun et al. [61] concentrated on the eye disease and reported promising results. Besides these studies, many small case series and case reports suggest that patients with mucocutaneous lesions, gastrointestinal symptoms, arthritis and cerebral vasculitis exhibit rapid and good responses to infliximab [62]. Recently, adalimumab, a fully humanised anti-TNF-α antibody, has also been reported to be an effective alternative [63].

Melikoglu et al. [64] conducted the first controlled study of anti-TNF-α compound, etanercept. In a double-blind, placebo-controlled study of 40 male patients, authors reported that etanercept (25 mg twice a week for 4 week) is effective in suppressing most of the mucocutaneous lesions. The drug had a clear effect on OUs and nodular lesions, and the response was as early as the first week. There was a significant decrease in the mean numbers of OUs and nodular lesions as well as PPLs.

A recent position paper concluded that infliximab is recommended as an add-on therapy for severe BD, refractory or intolerant to traditional immunosuppressive regimens. Moreover, a single infusion of infliximab (5 mg/kg) can be used as a first-line agent for sight-threatening, bilateral posterior eye segment inflammation, because the fast onset of response is critical to prevent fixed retinal lesions, and therefore, permanent visual loss. In case when ocular relapses are not controlled by azathioprine and/or cyclosporin, maintenance therapy with 5 mg/kg doses of infliximab every 6–8 weeks could be used for 2 years, provided no relapses occur between intervals [62].

However, the high cost, the need for injections, troublesome toxic side effects, and the inability to cure the disease are the main limitations for widespread acceptance of anti-TNF-α as a first-line choice for the management of BD. Optimal dosage and the long-term consequences are still important questions for anti-TNF-α agents to be answered. It still needs further controlled studies in large series.

Adverse effects of anti-TNF-α agents include infection (sinusitis, pharyngitis, bronchitis, and urinary tract infections, reactivation of tuberculosis), autoimmune reactions (e.g., lupuslike syndrome), lymphoproliferative disorders, delayed hypersensitivity reactions, and neurologic, cardiac, and gastrointestinal symptoms.

2.2.13. Rituximab

Rituximab is a chimeric monoclonal antibody against CD20, a B-cell differentiation marker. Recently, Davatchi et al. [65] used rituximab in their randomized single-blind controlled study. Twenty patients were randomized to a rituximab group (in two 1000 mg courses, 15-day interval) or cytotoxic combination therapy group. Patients with rituximab group were also given methotrexate (15 mg/weekly) with prednisolone (0.5 mg/kg per day). The cytotoxic combination therapy group received pulse cyclophosphamide (1000 mg/monthly), azathioprine (2–3 mg/kg per day), and prednisolone (0.5 mg/kg per day). The authors concluded that rituximab was efficient in severe ocular manifestations of BD, and total adjusted disease activity index improved significantly after 6 months with rituximab, but not with cytotoxic combination therapy group.

2.2.14. Other Systemic Treatment Approaches

Several open studies of methotrexate (7.5–20 mg/1x week p.o. over 4 weeks) have reported the induction of an improvement of a severe mucocutaneous involvement [66] as well as neurological [67, 68] and ocular involvement [69]. Methotrexate is not recommended in pregnancy and lactation, and severe bone marrow depression, liver dysfunction, acute infections, renal insufficiency, and mucositis are important side effects of the drug. Mycophenolate mofetil (MMF) was found to be safe and effective in controlling cystoid macular oedema and in reducing the uveitis relapse rate in patients not responding to traditional immunosuppressants [70]. On the other hand, an open study reported no benefit in mucocutaneous disease [71]. MMF is generally well tolerated; the most common side effects involve gastrointestinal and genitourinary symptoms. Other reported less frequent adverse events include neurologic, cutaneous, cardiorespiratory, and metabolic reactions. Rarely, severe leukopenia has also been reported. Autologous hematopoietic stem cell transplantation has recently been reported as a successful treatment option for severe/refractory patients with intestinal [72], pulmonary [73], and neurologic [74] involvements. Open studies with Pentoxifylline reported good results on mucocutaneous symptoms. However, recurrences occurred in all patients after discontinuation of treatment. Pentoxifylline has also been described as alternative treatments for ocular lesions in few patients with BD [75, 76]. Sulfasalazine (2–4 gr/day) was reported to be an effective choice for the treatment of gastrointestinal involvement [77].

2.3. Surgical Treatment

Although various treatment modalities appear, surgical intervention often is indicated for arterial aneurysms. In patients with recurrent or massive hemoptysis, surgery may be necessary. Endovascular treatment for pseudoaneurysms due to BD seems to be an effective choice when the disease activity is strictly controlled with immunosuppressive therapy [78, 79]. In other serious consequences, such as gastrointestinal bowel perforation, enterocutaneous fistula formation, thrombotic obstruction in large-caliber vessels, cardiac involvement, and complications of eye involvement such as glaucoma, vitreous opacities, surgery may also be the only possible remedy [19, 80].

3. Evidenced-Based Algorithmic Treatment Approach in Behçet’s Disease

Activity spectrum of systemic therapeutic agents on BD in randomized, controlled studies is summarized in Table 1. A stepwise, symptom-based, algorithmic approach, mainly based on controlled studies and our clinical experience in this field, is summarized below and in Tables 2–6.

Table 1: Activity spectrum of systemic therapeutic agents on Behçet’s disease in randomized, controlled studies.
Table 2: Summary of evidence-based algorithmic treatment for mucocutaneous Behçet’s disease.
Table 3: Summary of evidence-based algorithmic treatment for articular Behçet’s disease.
Table 4: Summary of evidence-based algorithmic treatment for ocular Behçet’s disease.
Table 5: Summary of evidence-based algorithmic treatment for Vasculo-Behçet disease.
Table 6: Summary of evidence-based algorithmic therapy for Neuro-Behçet's disease.
3.1. Mucocutaneous Disease

Colchicine should be the first choice in the treatment of GUs and/or EN, especially in female patients [38]. If it is not effective or patient is male, colchicine can be combined with benzathine penicillin [40, 41]. In the presence of OUs with or without other mucocutaneous lesions, this combination should also be the starting point.

Short-term corticosteroids in combination with other drugs such as colchicine can be used as alternatives in the treatment of acute attacks of mucocutaneous lesions [18]. Dapsone can also be used at this stage as an effective compound [44]. Patients with severe mucocutaneous disease or those who are unresponsive to the respected treatments can be treated with azathioprine [46]. Thalidomide [45] is an effective choice. However, because of potential side effects, it should be used cautiously in selected patients. It is wise to keep in mind that EN worsens during thalidomide treatment.

Rebamipide [42], zinc sulfate [43], and Pentoxifylline [75] can be used as 3rd-line treatment choices. However, there is still a need for well-organised newer studies for these agents. In severe cases and/or unresponsive cases to the other treatments, methotrexate [66], cyclosporin [52], and biologicals such as IFN [54] and anti-TNF-αagents [62, 64] can be used to control the disease.

Antimicrobial agents [20–26], sucralfate [27] and corticosteroids [19] especially in OUs, and pimecrolimus [28, 29] in GUs can be selected as 1st-line topical treatment choices. Anti-inflammatory agents, amlexanox, anaesthetics, and silver nitrate [30–33] are other alternatives for topical treatment of mucocutaneous lesions. However, it is very important to ensure for clinician that topical treatment, with a great possibility, has only local effects and should almost always be associated with systemic therapy.

Evidenced based algorithmic treatment approach for mucocutaneous Behçet’s disease is summariezed in Table 2.

3.2. Articular Disease

Evidenced-based algorithmic treatment approach for articular Behçet’s disease is summariezed in Table 3.

Colchicine should be the first choice [37, 38]. Additional use of benzathine penicillin or anti-inflammatory analgesics can be the next step [40, 41].

In unresponsive cases, azathioprine [46] can be an alternative. Low dose corticosteroids, and even intraarticular corticosteroid injections in monoarticular involvement, can also be used as 2nd-line treatment [77, 81].

Although controlled studies are still lacking, methotrexate and salazopyrine are used successfully in the clinical practice [77]. IFN-α [55] and anti-TNF-α agents [62] are the other alternatives.

3.3. Ocular Disease

Evidenced-based algorithmic treatment approach for ocular Behçet’s disease is summarized in Table 4.

Ocular involvement requires special attention and usually aggressive treatment since it has the highest morbidity. In mild uveitis such as anterior uveitis, topically applied corticosteroid eye drops together with mydriatics or cycloplegic agents can often control the disease [19]. Systemic corticosteroids should be the next step. It is wise to remember that systemic corticosteroids are also used in acute inflammatory ocular attacks of posterior uveitis, panuveitis, and retinal vasculitis [18]. Systemic corticosteroids should be used in brief courses for long term because of well-known side effect profile. Unresponsive cases, those with posterior uveitis, or those who develop chronic, steroid-dependent intraocular inflammation (given the deleterious effects of chronic steroid administration to the eye) require more aggressive treatment. Immunosuppressives such as azathioprine [46] and cyclosporine [48, 49, 51] are the main choices. Cyclosporine together with corticosteroids can be used effectively. Azathioprine and cyclosporine can also be combined in those patients whose eye disease is refractory to treatment [18].

As we mentioned before, IFN-α or anti-TNF-α treatments can be used in case when the immunosuppressives do not control the disease [82].

Methotrexate, MMF, cyclophosphamide, and rituximab can be used in selected patients as a 3rd-line therapy [47, 65, 69, 70].

In the most severe cases with retinal vasculitis or macular involvement, CyA or anti-TNF-α treatments can be combined with azathioprine and corticosteroids. Cyclophosphamide and IFN-α with or without corticosteroids are other alternatives for the treatment of severe eye disease [18].

3.4. Severe Disease

Although several promising therapies are evolving, the treatment of severe disease is not entirely satisfactory and treatment of those remains predominantly empirical. Severe disease has relatively lower incidence. Because of the limited number of patients enrolled in studies in this area statistical comparisons were usually not made. These factors make recommendation of individual treatments difficult for these involvements.

Evidenced-based algorithmic treatment approach of Behçet’s disease with large vessel, neurologic, and gastrointestinal involvement is summarized in Tables 5–7.

Table 7: Summary of evidence-based algorithmic therapy for gastrointestinal Behçet's disease.
3.4.1. Large Vessel Involvements

In the presence of deep vein thromboses, azathioprine can be used. In severer cases with inferior vena cava or superior vena cava syndrome and Budd-Chiairi syndrome cyclophosphamide as monthly pulse treatment should be added to the treatment. It is unclear the effectiveness of additional use of antiplatelets or anticoagulation [18, 77, 81, 82].

In arterial involvement, corticosteroids together with cyclophosphamide are generally preferred to control the disease. Anticoagulation should not be given in the presence of pulmonary arterial aneurysm because of the danger of bleeding [77, 81, 82]. Anti-TNF-α agents, especially infliximab, can be alternative [18].

Surgery may be necessary in life-threatening conditions such as growing aneurysm, acute rupture [81].

3.4.2. Neurologic Involvements

In parenchymal involvement, corticosteroids (100 mg/d or 1 gx 5 days as pulse treatment) should be the first choice. Azathioprine is usually combined with corticosteroids. In severe or unresponsive cases, cyclophosphamide can be given additionally [83]. Anti-TNF-α agents and IFN-α are other new effective alternative agents [19]. Methotrexate is another treatment alternative [67, 68].

In venous sinus thrombosis corticosteroids with or without immunosuppressives are the main treatment approaches. In this situation additional use of anticoagulation is also suggested [81, 83].

3.4.3. Gastrointestinal Disease

Sulfasalazine and corticosteroids seem to be the 1st-line treatment options [77]. Azathioprine can be used effectively in unresposive cases. Anti-TNF-α treatments, especially infliximab, seem to be new and effective alternative. Surgery should be selected in those patients with perforation and intractable bleeding [18, 81].

In conclusion, treatment of BD has become much more effective in recent years. Due to recent advances in understanding the pathogenesis of the underlying disease and availability of a wide spectrum of therapeutic agents, alleviation of most symptoms, control of the disease, and, even, modification of the course of the disease are now possible.


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