Behçet's syndrome is a systemic vasculitis characterized by recurrent oral and genital ulcers, skin lesions, uveitis, and arterial, venous, or neurological involvement. It is most common along the ancient Silk Road trade route. Diagnosis requires recurrent oral ulcers plus two of the other main symptoms. Treatment involves immunosuppressants such as colchicine, azathioprine, and TNF-antagonists, which can help control symptoms but the underlying cause remains unknown. Prognosis is generally good if major vessel or neurological involvement can be prevented.

1. Beh ç et’s syndrome

2. Beh ç et’s syndrome 5th C BC Description by Hippocrates 19th C Early European literature 1930 Benedictos Adamantiades 1937 Hulusi Beh ç et

3. 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

4. Epidemiology of Behçet’s syndrome “ The Silk Route disease” Japan 1:10,000 Turkey 3-8:10,000 UK ? about 2000 cases

5. 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

6. Differential diagnosis of oral ulceration Benign recurrent oral ulceration Deficiencies (haematinics, B group vitamins) GIT disease (coeliac disease, IBD) Rheumatological (Beh ç et’s, Reiter’s, SLE) Infection (EBV, HSV, HIV) Neutropenia (drugs, cyclic) Imuune-deficiency (eg IgA)

7. Skin Papules and pustules Ulcers and Pyoderma Erythema nodosum / nodular vasculitis Pathergy

8. PATHERGY Inappropriate excessive response to injury Very suggestive of Beh çet’s syndrome Low sensitivity in UK Probably associated with disease severity/activity

9. 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

10. neurological manifestations Headaches - + migraine - Intracranial hypertension Meningoencephalitis Space occupying lesions Stroke syndrome - Cortical - Brain-stem - Spinal cord Audiovestibular

11. headaches : 7 year follow-up Presented with headache only 27 No neurologic involvement 18 Silent involvement 7 Neurologic attack 2 Objective neurologic involvement 15 Stationary 7 Progressive 8 Akman-Demir et al 1996 Arch Neurol 53:691

12. 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 H 2 0 Aged 42 Represented with intermittent headaches Bilateral optic atrophy CSF opening pressure 57 cms H 2 0 Deteriorating vision resulted in R optic nerve fenestration Temporary lumbo-peritoneal shunt

13. 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

14. vascular manifestations Venous Superficial thrombophlebitis Thrombosis Systemic artery Thrombosis and stenosis Aneurysm Pulmonary artery Thrombosis Aneurysm

15. 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

16. Gastrointestinal involvement Ulceration (oral to anal) Abdominal pain Diarrhoea Bleeding Pancreatitis

17. Beh ç et’s arthritis Asymmetrical Flitting and usually non-erosive Oligoarticular Knees, ankles, wrists, elbows

18. REITER’S BEHCET’S Oral ulcers “ painless” painful Urogental prostatitis urethritis ulcers epididymitis Skin keratoderma psoriasiform lesions pustules nodules ulcers Arthritis persistent, erosive axial and peripheral transient peripheral

19. REITER’S BEH Ç ET’S Nervous system rare 20% Large vessels aortitis thrombophlebitis aneurysms Eye conjunctivitis anterior uveitis panuveitis retinal vasculitis HLA Class I B27 B51

20. Beh ç et’s syndrome Oral and genital ulcers Ocular inflammation Skin lesions Arthralgias, arthritis Vascular lesions Neurological lesions Gastrointestinal Urogenital Systemic features

21. non-specific features Fatigue Joint pains Muscle pains Headaches Fevers

22. routine investigations modest  WCC modest  CRP and ESR modest  immunoglobulins normal complement usually no autoantibodies

23. Behçet’s syndrome Autoimmunity Genetic Vascular dysfunction Prolonged inflammation Thrombosis Ulceration

24. Evidence for cell mediated autoimmunity in Beh çet’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)

25. 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

26. problems with treatment Uncertain aetiology and pathogenesis Heterogeneity of manifestations Rarity Few laboratory indices of activity

27. Management of oral ulceration Oral hygiene Chlorhexidine mouth washes Topical steroids Beclomethasone inhaler Triamcinolone (Adcortyl) in Orabase Hydrocortisine lozenges (Corlan) Betamethasone (500  g) and doxycycline (100mg) in 10 ml water as mouth wash Systemic corticosteroids other

28. 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

29. Immunosuppressants Azathioprine Mycophenolate mofetil Methotrexate Cyclosporin A Tacrolimus Rapamycin

30. 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

31. Hamuryudan, V. et. al. Ann Intern Med 1998;128:443-450 Thalidomide 100mg/300mg daily vs placebo placebo 300mg/day 100mg/day treatment

32. 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)

33. 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

34. Caution Dentistry Invasive investigations Surgery

35. References 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.