BEHCET SYNDROME

BEHCET SYNDROME - Bruce M. Rothschild, MD
BASICS
DESCRIPTION
• Rare multisystem, chronic disease characterized by oral and genital mucocutaneous ulcerations, skin rashes, arthritis, thrombophlebitis, uveitis, colitis, and neurologic symptoms (1-6)[A]
• Endemic in Japan and Northeastern Mediterranean region
• Synonym(s): Ucocutaneous ocular syndrome; Franceschetti-Valero syndrome
ALERT
Geriatric Considerations
Rare
Pediatric Considerations
Rare
Pregnancy Considerations
• Thalidomide contraindicated in pregnancy
• Possible increase in thrombosis and fetal demise
GENERAL PREVENTION
Avoid English walnuts
EPIDEMIOLOGY
• Predominant age: 3rd to 4th decades
• Predominant sex: Male > Female frequently twice as often, whereas as some studies suggest equal frequency
Prevalence (6,8)[A]
• 1/100,000 prevalence in the United States
• In other countries, per 100,000
- Japan: 10
- Iran: 16-100
- Germany: 2
- Saudi Arabia: 20
RISK FACTORS
See "Etiology"
Genetics
• One report in a mother and newborn (9)
• Very rarely familial
ETIOLOGY (2-6)[A], (9)[A]
Unknown:
• Classified as vasculopathy or autoimmune
• HLA-B5 alloantigen relationship
• Possible environmental toxin: Heavy metals, pesticides
• Possibly English walnuts or Ginkgo nuts
• Fibrinolysis abnormality
• 1 report associated with HIV infection (10)
ASSOCIATED CONDITIONS
• Amyloid
• Sweet syndrome


DIAGNOSIS
SIGNS AND SYMPTOMS (2-6)[A], (8)[A]
• Aphthous stomatitis
• Genital ulcers: Painful in the male, usually painless in the female
• Dermal: Papulovesicular, erythema nodosum, pathergy, erythema multiforme, vasculitis, pyoderma
• Ocular: Liritis, iridocyclitis, chorioretinitis, hypopyon, hemorrhage, papilledema, optic atrophy (8)[A]
• Morning stiffness: In 1/3 of patients
• Polyarthritis: Self-limited and predominantly affecting lower extremities
• Thrombophlebitis: Peripheral, pulmonary, cerebral, Budd Chiari syndrome (11)[A]
• Neurologic: Cranial nerve palsy, hemiplegia, intracranial hypertension, meningomyelitis and recurrent meningitis, confusional state (12)[A], (13)[A]
• GI: Aphthous ulcers, colitis, melena
• Pulmonary infiltratespossibly related to thrombosis
• Myopathy/myositis: Rare
• Peripheral gangrene: Rare
• Epididymitis
• Glomerulonephritis: Rare
TESTS (2-6)[A], (8)[A]
• Erythrocyte sedimentation rate elevation, but can be normal
• Immune complexes detected by Raji cell and C1q solid phase assays, but not clinically useful
• Cryoglobulin
• Hypergammaglobulinemia
• Circulating anticoagulation (rare)
• Depression of plasma antithrombin III levels with active disease
• Increased fibrinolytic activity during attacks
• Antineutrophil cytoplasmic antigen antibodies, perinuclear variety
• Demyelinating antibodies in neuro-Behcet syndrome
• Anticardiolipin antibodies (rare), lupus anticoagulants
• Antiendothelial antibodies
• Pathergy
Diagnostic Procedures/Surgery
• Careful history and physical and frequent reevaluation
• Synovial fluid: Inflammatory effusion
• Arteriography: For aneurysms or thrombosis
Pathological Findings
• May be no recognizable changes
• Mononuclear perivascular infiltration
• Mononuclear infiltrate in synovium
• Endothelial cell swelling
• Partial obliteration of vascular lumen
• Neutrophilic dermatitis (Sweet syndrome) (rarely)
DIFFERENTIAL DIAGNOSIS
• Reiter syndrome and other forms of spondyloarthropathy
• Inflammatory bowel disease (Crohn disease and ulcerative colitis)
• Syphilis
• Erythema nodosum
• Aphthous stomatitis
• Herpes simplex
• Stevens-Johnson syndrome
• Vasculitis
• Multisystem disease
• Thrombophlebitis related to coagulation factor deficiency
• Mollaret meningitis
TREATMENT
STABILIZATION
• Usually outpatient
• Inpatient usually required for neurologic complications
GENERAL MEASURES
According to body system involved
Diet
No special diet
Activity
As tolerated
MEDICATION (DRUGS)
First Line (2-6)[A], (14-15)[A], (16)[B]
• Colchicine: 0.6 mg b.i.d.
• Topical ocular steroids
• Prednisone: 1 mg/kg for severe involvement, especially central nervous system
• Azathioprine: 2-3 mg/kg/d PO
• Methotrexate: Use lowest possible dose; perhaps 7.5 mg per week
• Cyclosporine: 1-4 mg/kg, but monitor liver function, creatinine, magnesium, and lipids every 2 weeks for 3 months, then every month (17)[A]
• Resistant cases may require
- Tacrolimus (FK 506) 0.09-0.15 mg/kg/d
- Thalidomide 300 mg/d
- Interferon alpha (15)[A]
- Anticoagulants for patients with anticardiolipin antibodies: Warfarin (Coumadin) to establish PT international normalized ratio 3.0 to 3.5.
• Contraindications
- Thalidomide contraindicated during pregnancy
- Refer to manufacturer's literature
• Precautions
- Refer to manufacturer's literature
- Absorption of drugs such as amitriptyline, diazepam, carbamazepine, phenytoin, and acetaminophen may be reduced in Behcet syndrome. (14)[A]
• Significant possible interactions: Refer to manufacturer's literature.
Second Line
• Levamisole: 100-150 mg 2 days per week
• Chlorambucil: But concern with respect to toxicity, especially its malignant potential
• Cyclophosphamide: 50-100 mg per day in morning.
• The patient should drink 8-10 glasses of water per day and report any blood in the urine.
• Tumor necrosis factor inhibitors (18)[A]
• Stem cell transplantation (19)[B]
• Anti-CD52 antibody (16)[B]
FOLLOW-UP
PROGNOSIS
• Normal life expectancy, except with neurologic involvement
• Possible vision impairment
COMPLICATIONS (2-6), 8[A]
• Death
• Blindness
• Paralysis
• Embolism/thrombosispulmonary, vena cava, peripheral
• Aneurysms
• Amyloidosis
• Thrombotic events, especially when anticardiolipin antibodies present
PATIENT MONITORING
Dependent on severity of system involvement and medication monitoring
REFERENCES
1. International diagnostic study group for Behcet's disease. Evaluation of ("classification") criteria in Behcet's diseaseTowards internationally agreed criteria. Br J Rheumatol. 1992;31:299-308.
2. Kaklamani VG, et al. Behcet's disease. Semin Arthritis Rheu. 1998;27:197-217.
3. Lockwood CM, Hale G, Waldman H, Jayne DR. Remission induction in Behcet's disease following lymphocyte depletion by the anti-CD52 antibody CAMPATH 1-H. Rheumatology (Oxford). 2003;42:1539-1544.
4. Pacor ML, et al. Cyclosporin in Behcet's disease. J Rheumatol. 1994;13:224-227.
5. Shimizu T, et al. Behcet disease. Semin Arthritis Rheu. 1979;8:223-260.
6. Zouboulis CC, Vaiopoulos G, Marcomichelakis N, et al. Onset signs, clinical course, prognosis, treatment and outcome of adult patients with Adamantiades-Behcet's disease in Greece. Clin Exp Rheumatol. 2003;21(suppl 30):19-26.
7. Sushan JJ, Sela EY, Ozcan C. Behcet's disease and pregnancy. Acta Obstet Gynecol Scand 2005;84:939-944 [B].
8. Yoshida A, Kawashima H, Motoyama Y, et al. Comparison of patients with Behcet's disease in the 1980's and 1990's. Ophthalmology 2004;111:810-815 [A].
9. Fam A. Neonatal Behcet syndrome in an infant of a mother with the disease. Ann Rheumatic Dis. 1981;40:509-512.
10. Stein C. J Rheumatol. 1991;18:1427-1428.
11. Huong DL, et al. Arterial lesions in Behcet's disease. J Rheumatol. 1995;22:2103-2113.
12. Akman-Demir G, et al. Seven-year follow-up of neurologic involvement in Behcet syndrome. Arch Neurol. 1996;53:691-768.
13. Gerber S, et al. Long-term MR follow-up of cerebral lesions in neuro-Behcet's disease. Neuroradiology. 1996;38:761-768.
14. Chaleby K. Decreased drug absorption in a patient with Behcet's syndrome. Clin Chem. 1987;33:1679-1681.
15. Hamuryudan V, et al. Systemic interferon alpha-2b treatment in Behcet syndrome. J Rheumatol. 1994;21:1098-1100.
16. Mauer B, Hensel M, Max R, et al. Autologous haematopoietic stem cell transplantation for Behcet's disease with pulmonary involvement: Analysis after 5 years of followup. Ann Rheumatic Dis. 2006;65:127-129 [B].
17. Sakane T, Takeno M, Suzuki N, Inaba G. Behcet's disease. N Engl J Med. 1999;341:1284-1291.
18. Hassard PV, Binder SW, Nelson V, Vasiliauskas EA. Anti-tumor necrosis factor monoclonal antibody therapy for gastrointestinal Behcet's disease: a case report. Gastroenterology. 2001;120:995-999.
19. Melikoglu M, Fresko I, Mat C, et al. Short-term trial of etanercept in Behcet's disease: A double blind, placebo controlled study. J Rheumatol 2005;32:98-105 [B].
20. O'Duffy JD. Behcet's disease. Curr Opin Rheumatol. 1994;6:39-43.