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Behçet's disease
  1. V Kontogiannis,
  2. R J Powell
  1. Clinical Immunology Unit, University Hospital, Queens Medical Centre, Nottingham NG7 2UH, UK
  1. Dr Powell

Abstract

Behçet's disease is a systemic vasculitis of unknown aetiology characteristically affecting venules. Onset is typically in young adults with recurrent oral and genital ulceration, uveitis, skin manifestations, arthritis, neurological involvement, and a tendency to thrombosis. It has a worldwide distribution but is prevalent in Japan, the Middle East, and some Mediterranean countries. International diagnostic criteria have been proposed, however diagnosis can be problematical, particularly if the typical ulcers are not obvious at presentation. Treatment is challenging, must be tailored to the pattern of organ involvement for each patient and often requires combination therapies.

  • Behçet's disease
  • oral ulcers
  • uveitis
  • immunosuppressants

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History

Remarkably this condition was recognised in the 5th century BC by Hippocrates,1 redescribed by the Greek Adamantiades in 1931,2 but in 1937 the classical triad of oral and genital ulceration with ocular inflammation was reported by the Turk Hulusi Behçet.3 Further clinical features including cutaneous, neurological, vascular, gastrointestinal, and arthritis have since been identified. Until recently Behçet's disease was classified as a spondyloarthropathy4 but now is considered to be a systemic vasculitis.

Epidemiology

Onset of disease in the third decade of life is typical but it can occur at any age. Behçet's disease is most common in the so-called “silk route” countries, around the Mediterranean and in Japan, with prevalence rates per 100 000 of population being 80–300 in Turkey5 and 13.6 in Japan.6 It is much less common in Northern Europe: 0.55 in Germany,7 0.27–0.64 in Britain,8 9 and in the USA is even more uncommon at 0.13.10

The male to female ratio is even in both northern Europe and Japan6 11 but increases significantly (1.5–5:1) in certain Mediterranean countries and the Middle East.11-14Familial cases, although unusual, are also reported,15particularly among Middle Eastern populations.16

Clinical presentation

Behçet's disease has a very wide spectrum of clinical features and it is characterised by unpredictable exacerbations and remissions.

Oral ulcers are a defining feature (97%–100% of cases)17 and are the initial symptom in most cases but not necessarily the presenting symptom5 18and can be minor, major, or herpetiform. Minor ulcers have a diameter <10 mm, are shallow, covered by a grey membranous slough, surrounded by an erythematous halo, and heal without scarring in 1–2 weeks. Major ulcers are morphologically similar but larger (>10 mm), deeper, more painful, and heal in 10–30 days or more often with scarring and tissue loss. Increased sensitivity of the area and even a mucosal nodule are frequently noted by patients before the ulceration develops. In herpetiform ulceration, numerous (10–100), 1–2 mm yellowish, papular lesions become confluent and form larger plaques and can heal with scarring.19 Ulcers frequently occur at the sites of trauma20 and can be difficult to differentiate from recurrent oral aphthosis on the basis of severity, duration, and frequency. In Behçet's disease, increased number of ulcers (more than six at the same time), varying size and location (soft palate, oropharynx) are useful distinguishing features.18Recurrent oral ulceration is often reported in other members of the patient's family. The favourable effect of smoking on recurrent oral ulceration,19 also appears to be evident in Behçet's disease.21

Genital ulcers are less common than oral ulcers occurring in 60%–80% of cases.6 17 They can be painful leading to problems both sitting down and walking, pain on intercourse, and dysuria. Morphologically, they are similar to mouth ulcers and their appearance can be preceded by a tender nodule. The scrotum is the most frequently involved site in males but ulcers on the shaft and glans penis are notable. In females, the ulcers most commonly occur on the labia but the vagina and cervix can be affected. Deep ulcers may scar and those in the vagina may be complicated by bladder or urethral fistulae.22 Groin, perineal, and perianal ulcers are reported. A lymphocytic and monocytic infiltrate in the dermis, particularly around the small vessels, typifies both oral and genital ulcers.

Skin lesions occur in about 80% of patients and can be divided into two main types—namely, erythema nodosum and the papulopustular/acneiform lesions. The erythema nodosum-like lesions are most commonly seen on the legs, they do not ulcerate and resolve leaving hyperpigmented areas. Histology shows a focal small vessel vasculitis/perivascular lymphocytic infiltrate involving particularly the venules with panniculitis.23 Another cause of painful, erythematous nodules on the lower extremities is superficial thrombophlebitis which can be migratory and should be differentiated clinically from erythema nodosum. Acneiform and papulopustular lesions can occur at any site; they are sterile and morphologically very similar to adolescent acne. Histologically they are characterised by a leucocytoclastic vasculitis (neutrophil infiltrate) with fibrinoid necrosis.24 Pyoderma gangrenosum,25 26Sweet's syndrome,27 28 and erythema multiforme29 have all been described with Behçet's disease.

The pathergy reaction represents hyper-reactivity in the skin following trauma, including minor injury (shaving, venepuncture sites, etc). The formal pathergy test involves intradermal pricking of the skin with a needle and it is considered positive if an erythematous papule or a pustule develops at the prick site within 48 hours. Histology reveals epidermal thickening, cell vacuolisation, subcorneal pustules, and a dense infiltrate of T lymphocytes and macrophages is present in the dermis especially around vessels.30 The suppression of the reaction after surgical cleaning of the skin31 suggests a possible role of bacteria or skin products. Pathergy is highly specific for Behçet's disease, therefore has been included in the diagnostic criteria for the disease.32 A positive pathergy test has been reported in healthy individuals,33 rarely in spondyloarthropathies,34 and up to a quarter of patients with chronic myeloid leukaemia treated with interferon-α.35 More than 60% of Turkish36and Middle Eastern37 patients and 44% of the Japanese6 demonstrate pathergy. Pathergy is uncommon in individuals living in Britain and USA,10 38 39 which reduces its diagnostic value in these countries.

The possibility of compromised wound healing in the presence of pathergy has recently been addressed by a study from Turkey which revealed that although skin wounds in Behçet's disease are associated with increased inflammation, healing is not impaired.40

Ocular involvement is bilateral in the majority of cases, although the severity may be asymmetrical.41 Characteristically, it occurs within the first 2–3 years of the onset of Behçet's disease42being the presenting feature in approximately 20% of patients.43 Its frequency varies from 40%–70% among different populations6 44 45 and visual loss occurs in up to 25% of the affected patients.46 The clinical pattern of the eye disease is characteristically recurrent and explosive in nature with episodes lasting 2–4 weeks followed by periods of quiescence. Isolated anterior uveitis is a frequent and relatively benign lesion when isolated and although hypopyon is considered to be a characteristic sign of Behçet's disease, it is only observed in one third of cases.43 Concurrent involvement of the posterior chamber is commonly seen47and can lead to blindness. This retinal disease is characterised by occlusion of arteries and veins with retinal haemorrhages, oedema, and neovascularisation as well as inflammation of the vitreous. Fluorescein angiography is particularly useful in revealing the extent and nature of the inflammation. The end stage disease is characterised by retinal and optic atrophy with attenuated retinal vessels and complications include glaucoma, cataract, and retinal detachment.47

Milder forms of ocular disease such as episcleritis and conjunctivitis can also occur.

Typically a non-erosive, non-deformingarthritis is seen in about 50% of the patients with an oligoarticular or monoarticular pattern. The arthritis/arthralgias are usually transient in nature with episodes lasting from a few days to weeks involving peripheral joints, particularly the knees, ankles, and wrists.48 Synovial fluid appears cloudy with an increased number of polymorphonuclear cells and good mucin clot formation, however synovial histology is not diagnostic.49

Fatigue is a common symptom of Behçet's disease, which correlates with disease activity,50 but must be distinguished from that associated with fibromyalgia which can co-occur, particularly females.31

A widespread vasculitis is the primary lesion in Behçet's disease and vessels of all sizes, both arteries and veins, may be involved in 9%–25% of patients depending on the population studied.6 8 51 A tendency for both superficial and deep vein thrombosis is well recognised, the veins of the lower extremities being the most commonly affected sites, however subsequent pulmonary embolism is uncommon.51 52Thrombosis in the dural sinuses, superior and inferior vena cava and Budd-Chiari syndrome carry a poor prognosis.53 Reduced synthesis of prostacyclin by the endothelial cells,54defective fibrinolytic activity,55 and increased levels of endothelin-156 have all been reported in patients with Behçet's disease but these data do not correlate with clinical thrombosis.

Arterial aneurysms and occlusions are less common and are associated with the presence of venous thromboses.57 Arteries of all sizes and sites may be affected51 52 and in particular pulmonary arterial aneurysms are a serious and potentially lethal complication seen on chest radiography as characteristic nodular shadows. These pulmonary aneurysms occur in approximately 1% of patients, almost exclusively males and the main presenting symptom is typically massive haemoptysis.57

Neuro-Behçet's occurs in approximately 5% of cases. In parenchymal disease the brain stem is most frequently involved but the hemispheres, meninges, and spinal cord can also be affected either individually or in combination and during the course of the disease brain atrophy may develop.58 Clinical presentations include bilateral pyramidal symptoms, mental changes, hemiparesis, cranial nerve palsies, sphincter disturbances, and brain stem symptoms in the majority of patients. Sensory signs are characteristically absent. Headaches should be regarded as part of central nervous system involvement only when other neurological signs and symptoms are also present. Isolated psychiatric symptoms and peripheral nerve involvement are rare.59 Cerebrospinal fluid can be normal or show pleocytosis (neutrophils with or without lymphocytes), increased protein, and raised pressure. Magnetic resonance imaging (MRI) is more sensitive than computed tomography revealing mass-like lesions, isolated brain stem and basal ganglia lesions, multiple small white matter lesions, or lesions in the spinal cord.58

Surprisingly frequent are the audiovestibular abnormalities in Behçet's disease which have been demonstrated in more than half of the patients. Bilateral, symmetrical, sensorineural hearing loss of the cochlear type and unilateral peripheral vestibular dysfunction are the most common findings, although central deficits can develop.60

Brain involvement secondary to arterial occlusions/aneurysms and dural sinus thromboses can also develop.

The prevalence of gastrointestinalinvolvement varies among different populations being particularly common in Japanese patients.6 Ulcers predominantly occur in the ileocaecal region,9 but can be seen throughout the intestinal tract, including the oesophagus, causing dysphagia, abdominal pain, and diarrhoea, which is occasionally bloody, and intestinal perforation and perianal fistulae can result.

Various other features are associated with Behçet's disease without being characteristic for this disease. Self limitingepididymitis is seen in 5%–10% of patients.45

Although Behçet's disease is a systemic vasculitis, the kidneys are characteristically spared. Benign, mild proteinuria and microscopic haematuria may occur in some patients but only a few cases of biopsy proved glomerulonephritis have been reported.61 62 The kidneys can also be affected in cases complicated by amyloid deposits or renal vein thrombosis.63 Systemic amyloidosis of the AA type is a very rare complication that can occur any time in the course of Behçet's disease,64 but it should be considered in cases presenting with nephrotic syndrome particularly in patients of Mediterranean origin.

Cardiac involvement is unusual in Behçet's disease but cases of pericarditis,65 valvular involvement,66coronary thrombosis and aneurysms,67 68 right ventricular thrombosis,51 and endomyocardial fibrosis69have all been documented. A recent study found mitral valve prolapse and dilatation of the proximal aorta in 50% and 30% of patients respectively.70

Juvenile Behçet's disease is uncommon, accounting for 3%–7% of all cases,11 71 but only a few neonatal cases have been reported. Clinically, juveniles may have a less severe course,72 but an increased incidence and severity of ocular disease is reported in a single study.71

Pregnancy does not consistently alter the activity of the disease and equally, no increased incidence of miscarriages or other pregnancy complications have been identified among pregnant women suffering from Behçet's disease.73

Diagnosis—disease activity

There are no diagnostic investigations for the disease the diagnosis relying solely on the clinical picture. Despite published diagnostic criteria32 (table 1), problems still arise as features may not be present at the same time and incomplete forms of the condition can occur.

Table 1

Criteria for diagnosis of Behçet's disease

Objective assessment of disease activity is problematical as erythrocyte sedimentation rate and C reactive protein are not consistently raised. The complement component C9 is reported to be raised during active disease,29 but its discriminant value has not been assessed.

Permanent organ damage should be excluded from any current activity assessment and symptoms related to fibromyalgia or other conditions must not be attributed to active Behçet's disease.

Differential diagnosis

A detailed history is essential to reveal the existence of other clinical features of Behçet's disease. Isolated recurrentoral and genital ulceration (bipolar aphthosis Neumann)74 does not fulfil the diagnostic criteria and may be a forme fruste of Behçet's disease.

Sarcoidosis can present with erythema nodosum, uveitis, and arthralgia but the presence of mouth ulcers, chest radiography findings and the chronic non-explosive course of uveitis47 are useful distinguishing features.

Oral and genital lesions can occur in Reiter's syndrome where the arthritis is typically erosive with sacroiliac joint involvement and circinate balanitis and urethritis are not features of Behçet's disease.

Stevens-Johnson's syndrome involves the skin and mucosal surfaces with conjunctival inflammation but skin lesions are annular and posterior uveitis is not a feature.

Inflammatory bowel disease associated with oral ulcers and uveitis represents a diagnostic problem but in inflammatory bowel disease uveitis does not have such an explosive nature and retinal vasculitis is absent.

Multiple sclerosis can be difficult to distinguish from neuro-Behçet's, in the absence of other features of Behçet's disease.

The Vogt-Koyanagi-Harada syndrome is a granulomatous panuveitis associated with variable occurrence of poliosis, vitiligo, alopecia, auditory, and central nervous system signs. It is associated with HLA-DR4, is often complicated by cataracts and glaucoma and it is very responsive to steroid treatment.75

PFAPA syndrome(Periodic Fever,Aphthous stomatitis,Pharyngitis, and cervicalAdenitis) is a condition that affects children with a relapsing, benign course which may respond to short courses of steroids or cimetidine.76 77

There are sporadic reports of patients with symptoms both of Behçet's disease and relapsing polychondritis, the so-calledMAGIC syndrome. 78

See figs 1-8 for diagnostic features.

Aetiology/pathogenesis

It is a vasculitic condition of unknown aetiology but it is not a typical autoimmune disease having no female preponderance, no association with other autoimmune diseases or classically autoimmune associated HLA antigens (A1, B8, DR3, DR4) or autoantibodies. The geographic distribution of the disease favours an infective or environmental cause, although occasional familial cases occur.

GENETICS

Several studies have confirmed a strong association with HLA-B51 particularly in patients from Japan79 (B51 and DRw52), Mediterranean, and Middle Eastern countries37 42 70 80 81 whereas this is not mirrored in patients from Northern Europe and England.42 82 83However in Northern Europe, HLA-B51 is more common in males than females and seems to be associated with uveitis.11 In particular, the HLA-B*5101 allele in Japanese84 and Greek85 patients and both B*5101 and B*5108 in a population of European patients86 seems to be important.

Recent studies suggest that MICA (major histocompatibility complex class I chain related gene A) which is located near the B51, may be the pathogenetic gene, as it occurs in a higher frequency than B51 in Japanese87 and Caucasoids,88 although this was not confirmed in Middle Eastern patients.89 Further studies from Japan suggest that the susceptibility locus for Behçet's disease may be located between the MICA and HLA-B genes.90

Familial cases of Behçet's disease are uncommon therefore is difficult to attribute the pathogenesis solely to genetic factors. Although the above findings are sometimes conflicting and their biological significance is not clearly understood, there could be two explanations for these associations (as in any HLA related disease): (1) only B51 may be able to express a critical peptide and (2) B51 may be responsible for the deletion of a T cell modulatory for the disease process.

Furthermore, the classical neutrophil hyper-reactivity notable in Behçet's disease has been strongly associated with HLA-B51 positivity. However this association applies regardless whether the individual suffers from Behçet's disease or not.91 92

INFECTIVE

The geographic distribution and differences in the manifestations of the disease in different countries favour an infectious agent possibly acting as a trigger factor.

A viral aetiology was suggested by Behçet in his original publication, based on his observation of inclusion bodies in the ulcers.3 Particular attention has been drawn to herpes simplex virus type 1 (HSV1). HSV1 genome has been identified by hybridisation in peripheral blood lymphocytes and monocytes of patients with Behçet's disease.93 94 Serum antibodies to HSV1 were found in a higher proportion in patients with Behçet's disease than in healthy controls, however viral DNA was not detected in biopsy samples taken from oral ulcers.95 HSV1 DNA was found using the polymerase chain reaction in biopsy samples taken from genital ulcers of patients but not in biopsies from normal controls.96 HSV1 DNA was found in all biopsy specimens of seven patients with Behçet's disease who had intestinal ulcers but only in two of 13 with Crohn's disease.97 Although the results of the above studies are interesting, they need confirmation in larger studies.

The possible role of bacteria in the aetiopathogenesis of Behçet's disease is also interesting. Serum antibody titres and delayed type hypersensitivity of patients with Behçet's disease against streptococcal antigens were found to be significantly higher than in controls and higher prevalence of an unusual type ofStreptococcus sanguis was found in the oral flora of these patients.98 It has been observed that dental treatment and streptococcal antigen skin testing can induce severe symptoms in stable Behçet's disease patients99and a higher incidence of tonsillitis and dental caries has been found in the presymptomatic period of patients with Behçet's disease.100 101 Furthermore, the pathergy reaction is significantly suppressed after surgical cleaning of the skin which results in the removal of bacterial organisms.102

Production of inflammatory cytokines (interleukin (IL)-1, IL-6, IL-8, interferon gamma, and tumour necrosis factor-alpha (TNF-α)) by peripheral blood mononuclear cells and T lymphocytes is enhanced after in vitro stimulation of these cells with streptococcus related antigens suggesting that hypersensitivity to streptococcal strains may play a part in the pathogenesis of Behçet's disease.103 104

Increased levels of IgA antibodies to the mycobacterial 65 kD heat shock protein (HSP), which cross reacts with strains ofS sanguis, have been described in the serum of patients with Behçet's disease105 and significant lymphoproliferative responses have been elicited after stimulation of T cells with the same HSP and four peptides derived from the 60 kD human HSP sequence.106 One of the above HSP 60 kD peptides, which is also uveitogenic in experimental rats,107 yielded vigorous proliferation in T cells of patients with Behçet's disease in comparison both with those with rheumatoid arthritis and healthy controls. The latter finding could indicate that the T cells were expanded oligoclonally (in an antigen specific manner) even before stimulation with the HSP.104 However, another study documented hyper-responsiveness of T cells to superantigens and suggested that T cell hypersensitivity is a consequence of intrinsic T cell abnormalities.

The finding that the 60 kD HSP peptides have been found to stimulate predominantly γδ-T cells has been suggested as a laboratory test for the diagnosis of the disease108 but this test has not been widely adopted. Increased numbers of γδ-T cells have also been observed in the cerebrospinal fluid of neuro-Behçet's patients.109 The precise role of γδ-T cells in Behçet's disease is not clearly understood but they may produce cytokines essential for the development of the disease, such as TNF-α.

Circulating immune complexes have been detected in 40%–60% of patients and were closely associated with disease activity110 but no deposition of immune complexes has been observed in the lesional biopsies.82 Other observations include reduced number of CD4+ cells111, decreased activity of NK cells during active disease,112 increased soluble IL-2 receptors113 and interferon gamma.90 Levels of IL-10, IL-2, and sTNFR-75 (soluble TNF receptor-75) are raised in Behçet's disease and sTNFR-75 levels are reported to correlate with disease activity.114

Management

The diversity of clinical features demands the collaboration between various organ specialists and treatment must be tailored to the organ involvement and degree of severity of the individual patient.

TOPICAL TREATMENT

Oral ulceration can often be managed with soluble prednisolone mouthwashes (5 mg in 20 ml of water, four times a day, not to be swallowed) and corticosteroid pastes may be useful for deeper ulcers. Potent corticosteroid creams are useful for genital ulceration, although long term use may be complicated by skin atrophy. Intra-articular corticosteroid injections are usually very effective in cases of severe joint involvement. Local mydriatics/steroids are useful during acute ocular attacks the former to prevent synechiae formation.

SYSTEMIC TREATMENT

The treatment of Behçet's disease is highly problematical and one often has to resort to combinations of drugs in an attempt to control the various clinical manifestations. Only a few controlled trials are available and these will be denoted by an asterisk (*).

Non-steroidal anti-inflammatory drugs can be useful for symptom relief during attacks of arthritis.

Colchicine

Colchicine is an inhibitor of neutrophil migration, once a popular choice for any feature of the disease, has been shown to be effective only for erythema nodosum and arthralgia (*),115 and combined treatment with cyclosporin, may reduce the frequency of the ocular attacks.116

Azathioprine

Azathioprine, 2.5 mg/kg/day, reduces the development of new eye disease and the frequency of ocular attacks, has a favourable effect on arthritis, oral and genital ulceration, and thrombophlebitis (*)113and improves the long term prognosis.117

Methotrexate

Methotrexate is reported to slow down the progression of neuropsychiatric disease118 and have a beneficial effect on cutaneous vasculitis.119

Cyclosporin A

Cyclosporin A is an effective, rapidly acting drug not only alleviating acute attacks of uveitis (thus preserving visual acuity), but also reducing the frequency of ocular attacks and extraocular features of the disease120 121 and is reported to have a favourable effect on hearing loss in Behçet's disease.122 Unfortunately relapses on reducing the dose or stopping treatment are often seen.

Tacrolimus

Tacrolimus (FK 506) is an immunosuppressive agent with an activity similar to cyclosporin A, which can suppress active uveitis even when cyclosporin A has failed, and it may better tolerated.123 124 Cyclosporin and tacrolimus are drugs of choice for ocular involvement, however, their use can be limited by renal impairment and/or hypertension and regular monitoring of blood pressure, renal function, and blood trough levels is required.

Pulsed intravenous cyclophosphamide

Pulsed intravenous cyclophosphamide has shown to be as effective as cyclosporin A in the long term treatment of uveitis (*)125 but is also useful in neurological and arterial involvement.57 126 Efficacy of regular, oral chlorambucil is also reported127 128 but controlled studies for both alkylating agents are lacking.

Systemic corticosteroids

Systemic corticosteroids have a role in uveitis and severe attacks of arterial and neurological disease in combination with immunosuppressants/cytotoxics and a synergistic action with cyclosporin A in ocular disease is reported.129 Long term corticosteroids, however, should be avoided and recent evidence for another systemic vasculitis, namely systemic lupus erythematosus, shows that steroids are associated with increased mortality from coronary heart disease.130

Thalidomide

Thalidomide, 100–300 mg/day, is very effective for oral and genital ulcers and folicular lesions of Behçet's disease and possibly prevents new eye disease (*).131 Cases of successfully treated associated pyoderma gangrenosum are also reported.26 132 Although it paradoxically leads to an exacerbation of the erythema nodosum,131 it is an extremely useful alternative for disabling ulceration when other treatments have failed. Because of the risks of teratogenicity and neurotoxicity, a published guideline for its use and dispensing is available.133

Based on the evidence for a bacterial aetiology,penicillin 134 135(*) andminocyclin 104 have been tried in the treatment of Behçet's disease with reported improvement of ulceration, skin lesions, and arthritis.

Anticoagulation for thrombosis is appropriate, however the degree and duration of warfarin therapy is debatable. Despite adequate anticoagulation patients can develop new thromboses presumably related to the underlying vascular inflammation, which also demands specific treatment.

Surgical intervention is required in cases of arterial aneurysms, unfortunately with a high rate of recurrence and mortality136 and in severe intestinal involvement.

Prognosis

Behçet's disease runs a chronic course with unpredictable exacerbations and remissions whose frequency and severity diminish with time.137 Rupture of arterial aneurysms (particularly in young males), extensive thrombotic events, and perforated intestinal ulcers can be causes of death but the overall mortality does not appear to be higher than in general population.34 138 Morbidity, however, is high and ocular and neurological involvement may result in significant disabilities.

References

Figure 1

Aphthous ulcers involving the lip and tongue.

Figure 2

Scrotal ulcer healing with scarring.

Figure 3

Acneiform skin lesion.

Figure 4

Pustular skin lesions remarkably resembling aphthous ulcers.

Figure 6

Typical pyoderma gangrenosum lesion in a young male patient with severe disease.

Figure 7

Superficial thrombophlebitis in the lower leg.

Figure 8

Brain MRI in a patient with neuro-Behçet's showing multiple lesions. The MRI findings in neuro-Behçet's are non-specific.

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