CLICK TO PRINT this page for your recordsFor General Information Research by Medical Professionals & Sufferers

(compiled by Gwilym ab Ioan a long term 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)


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 PC using any media player software. Playing time is approx. 30mins.

Please view this video that explains the symptoms, diagnosis & care required for Behçet's sufferers.

It is based on 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 this 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, this disease can severely handicap people who suffer with it.


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


An Introduction to this Web-page

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, 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 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 involvement of BD can be significant and life-threatening, 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 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 doctors that 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 need of antibiotics like all others seem to have  in the western hemisphere, 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 decided 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. Following a constructive discussion with my GP I have agreed to the suggestion that this web site URL address be included in my medical file so that it is easily accessible to anyone who may treat me in the future. This page may also be accessed by fellow sufferers, who may find it helpful to pass the URL 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.

The remainder of this web-site is made up of information that I have researched 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.

Before browsing the remainder of this web-page it is recommended that the reader downloads and views 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 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 icon opposite: 


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

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.

 


Article Bookmarks

 

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.

 

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2:  Major aphthous ulcer.

 

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3:  Herpetiform oral ulcer.

 

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4:  A characteristic genital ulcer on scrotum.

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5:  A single ulcer on vulva.

 

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6:  Erythema nodosum–like lesions on skin.

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7:  Papulopustular eruptions.

 

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8:  Sweet syndrome–like lesion.

 

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9:  Typical positive pathergy reaction at injection site.

 

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10:  Ocular involvement showing posterior uveitis.

 

 

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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.