Behçet’s syndrome

Behçet’s syndrome

• 5th C BC Description by Hippocrates

• 19th C Early European literature

• 1930 Benedictos Adamantiades

• 1937 Hulusi Behçet

1990 International Study Group criteria

Requires oral ulceration with two of

- Uveitis, retinal vasculitis

- Genital ulceration

- Typical skin lesions

- Pathergy

Lancet 1990 335: 1078-80

Epidemiology of Behçet’s syndrome

Japan 1:10,000Turkey 3-8:10,000

UK ? about 2000 cases

“The Silk Route disease”

oral ulcers

• Commonly present in childhood or adolescence then gap of 10-15 years

• Minor (80%), major (10%) and herpetiform (10%)

• Predominantly on non-keratinized mucosa

• May get submandibular LNs

Differential diagnosis of oral ulceration

• Benign recurrent oral ulceration

• Deficiencies (haematinics, B group vitamins)

• GIT disease (coeliac disease, IBD)

• Rheumatological (Behçet’s, Reiter’s, SLE)

• Infection (EBV, HSV, HIV)

• Neutropenia (drugs, cyclic)

• Imuune-deficiency (eg IgA)

Skin

• Papules and pustules

• Ulcers and Pyoderma

• Erythema nodosum / nodular vasculitis

• Pathergy

PATHERGY

Inappropriate excessive response to injury

Very suggestive of Behçet’s syndrome

Low sensitivity in UK

Probably associated with disease severity/activity

Eye involvement

• Anterior uveitis with hypopyon• Posterior uveitis• Retinal vasculitis• Retinal artery or vein occlusion • Optic neuritis leading to optic atrophy• Secondary cataracts, glaucoma, blindness

neurological manifestations

• Headaches - + migraine- Intracranial hypertension

• Meningoencephalitis• Space occupying lesions• Stroke syndrome

- Cortical- Brain-stem - Spinal cord

• Audiovestibular

headaches : 7 year follow-up

• Presented with headache only 27

No neurologic involvement 18Silent involvement 7

Neurologic attack 2

• Objective neurologic involvement 15

Stationary 7

Progressive 8

Akman-Demir et al 1996 Arch Neurol 53:691

intracranial hypertension• Aged 31 recurrent oral and vulval ulcers

• Aged 36 Frontal headache and blurred vision – Acuities normal but papilloedema and R VI palsy– MRI failed to demonstrate venous sinus thrombosis – CSF opening pressure 30 cms H20

• Aged 42 Represented with intermittent headaches – Bilateral optic atrophy– CSF opening pressure 57 cms H20– Deteriorating vision resulted in R optic nerve fenestration– Temporary lumbo-peritoneal shunt

Auditory symptoms : 58%Auditory test abnormalities: 52%Bilateral: 77%Cochlear: 85%Vestibular symptoms: 60%Vestibular test abnormalities: 37%Unilateral: 80%Peripheral: 91%

audio-vestibular manifestations

vascular manifestations

• Venous– Superficial thrombophlebitis– Thrombosis

• Systemic artery – Thrombosis and stenosis– Aneurysm

• Pulmonary artery – Thrombosis – Aneurysm

Assessing risk of DVT

Greater risk of thrombosis if:

• Age less than 31 years• Within two years of diagnosis• Eye disease

Demiroglu et al 1996 Thrombosis Research 84:297

Gastrointestinal involvement

• Ulceration (oral to anal)

• Abdominal pain

• Diarrhoea

• Bleeding

• Pancreatitis

Behçet’s arthritis

• Asymmetrical

• Flitting and usually non-erosive

• Oligoarticular

• Knees, ankles, wrists, elbows

REITER’S BEHCET’S

Oral ulcers “painless” painful

Urogental prostatitisurethritis

ulcersepididymitis

Skin keratodermapsoriasiform lesions

pustulesnodulesulcers

Arthritis persistent, erosiveaxial and peripheral

transientperipheral

REITER’S BEHÇET’S

Nervous system rare 20%

Large vessels aortitis thrombophlebitisaneurysms

Eye conjunctivitisanterior uveitis

panuveitisretinal vasculitis

HLA Class I B27 B51

Behçet’s syndrome• Oral and genital ulcers• Ocular inflammation • Skin lesions• Arthralgias, arthritis• Vascular lesions• Neurological lesions• Gastrointestinal• Urogenital • Systemic features

non-specific features

• Fatigue• Joint pains• Muscle pains• Headaches• Fevers

routine investigations

• modest WCC

• modest CRP and ESR

• modest immunoglobulins

• normal complement

• usually no autoantibodies

Behçet’s syndrome

AutoimmunityGenetic

Vascular dysfunction

Prolonged inflammation

Thrombosis

Ulceration

Evidence for cell mediated autoimmunity in Behçet’s disease

Response to immunosuppressive medication

Presence of T lymphocytes in lesions

Immunogenetic associations

Th1 profile of cytokines released from blood T cells(IFN, IL-2, IL-12)

Autoreactive T cells (eg anti-hsp-60)

Prognosis

Kural- Seyahi et al 2003 Medicine 82:60

• 20 year follow-up of 387 (90%) of cohort of 428 patients (262 M, 125 F) enrolled from 1977-1983• 42 (9.8%; 39 M, 3F) died – from major vessel and neurological disease• Mortality and morbidity decreased with time• Disease burden tends to be greatest in early years and may burn out• ….but major vessel and neurological involvement may occur late

problems with treatment

• Uncertain aetiology and pathogenesis

• Heterogeneity of manifestations

• Rarity

• Few laboratory indices of activity

Management of oral ulceration

• Oral hygiene– Chlorhexidine mouth washes

• Topical steroids– Beclomethasone inhaler – Triamcinolone (Adcortyl) in Orabase– Hydrocortisine lozenges (Corlan)– Betamethasone (500g) and doxycycline (100mg) in 10 ml water

as mouth wash

• Systemic– corticosteroids– other

Colchicine

• Commonly prescribed for mucocutaneous manifestations

• Aktulga et al 1980 – limited usefulness

• Randomised placebo-controlled trial:

– reduced arthritis in men and women

– reduced GU and EN in women only.

Yurdakul et al (2001) Arthritis Rheum 2001; 44:2686

Immunosuppressants

• Azathioprine• Mycophenolate mofetil• Methotrexate • Cyclosporin A• Tacrolimus• Rapamycin

Thalidomide

• May act by inhibiting TNF release

• Randomised placebo-controlled trial showed efficacy for oral ulcers, genital ulcers and pustules

(Hamuryudan et al 1998 Ann Intern Med 128:443)

• May exacerbate nodular vasculitis

• Beware teratogenesis and peripheral neuropathy

Hamuryudan, V. et. al. Ann Intern Med 1998;128:443-450

Thalidomide 100mg/300mg daily vs placebo

placebo300mg/day

100mg/day

treatment

Interferon alpha

• Many case-reports and small open studies

• Randomised placebo-controlled study showed significant benefit for OU, GU, papulopustular lesions - underpowered for ocular inflammation

(Alpsoy et al 2002 Arch Dermatol 138:467)

TNF-antagonists

• Goossens et al 2001 ulceration, retinal vasculitis• Hassard et al 2001 gastrointestinal disease• Munoz-Fernandez et al 2001 uveitis• Sfikakis et al 2001 uveitis• Travis et al 2001 gastrointestinal disease

Caution

• Dentistry

• Invasive investigations

• Surgery

Sakane T, Takeno M, Suzuki N, Inaba G (1999) Behcet's disease. N Engl J Med 341: 1284-91

Pickering MC, Haskard DO. Behcet's Syndrome - a review of 230 referrals. Journal of the Royal College of Physicians 2000; 34(2):169-177.

Hirohata S, Kikuchi H. Behcet's disease. Arthritis Research 2003; 5:139-146.

Yazici H. Behcet's Syndrome: An Update. Current Rheumatolology Reports 2003; 5(3):195-199.

References