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A. Characteristics

  1. Multisystem disorder with recurrent aphthous oral and genital ulcers
  2. Arthritis, thrombophlebitis and uveitis
  3. Onset usually age 20-40
  4. Prevalence varies greatly across world
    1. Turkey has highest prevalence: 80-370 cases per 100,000
    2. Japan, Korea, China, Iran, Saudia Arabia: 13.5-20 cases per 100,000
    3. United Kingdom: 0.64 per 100,000
    4. United States: 0.12-0.33 per 100,000
    5. Behcet's is rare in Japanese immigrants in Hawaii and California
  5. This disease is likely a variant of medium vessel vasculitis

B. Diagnostic Criteria [3]

  1. Must have:
    1. Recurrent aphthous oral ulcerations at least 3 attacks/year AND
    2. Any two of the following symptoms or signs:
  2. Recurrent aphthous genital ulcers
  3. Ocular Disease
    1. Uveitis, posterior or anterior; and/or
    2. Vitreous cells on slit lamp; and/or
    3. Retinal vasculitis
  4. Skin Disease
    1. Erythema nodosum
    2. Pseudo-folliculitis
    3. cneiform nodules
  5. Positive Pathergy Test
    1. #25ga needle pricked to 5mm depth
    2. Positive Test: 2mm erythema 1-2d post needle stick
    3. Test is positive in ~30%

C. Etiology

  1. Basic underlying pathological process is vasculitis and perivasculitis
    1. Vascular injury
    2. Neutrophil hyperfunction
    3. Autoimmune T lymphocyte activation
  2. Ulcerations
    1. Lymphocytes and plasma cells invade dermoepidermal junction leads to necrosis
    2. Type 1 T helper cell responses likely involved
    3. Tumor necrosis factor alpha (TNFa) may play a critical role in ulcerations and uveitis
    4. TNFa blockade can have excellent therapeutic effects [14]
  3. Leukocytoclastic vasculitis with palpable purpura can be seen
  4. Neutrophil motility and superoxide production is usually increased in disease
  5. Early CNS lesions show perivascular infiltrates
  6. ESR, C Reactive Protein (CRP), and immune complexes may be increased
  7. HLA-B51 Association
    1. Significant only in patients who live along "Slik Road" (mainly Asian)
    2. Risk of Behcet's in HLA-B51+ persons is 6.7 fold in Japan
    3. Risk is only 1.3 fold in USA
  8. Many cases have P-ANCA autoantibodies

D. Symptoms (see above)

  1. Recurrent Ulceration
    1. Oral: minor or major aphthous ulcers, or herpetiform ulcers (100% of cases)
    2. Genital: aphthous ulceration or scarring (~80% of cases)
  2. Eye Lesions
    1. Anterior or posterior uveitis (~70% of cases)
    2. Retinal vasculitis
  3. Skin Lesions (60%): erythema nodosum, pseudofolliculitis, papules
  4. Arthritis
    1. Monoarthritis or polyarthritis in ~50% of patients
    2. Knees most frequently affected
    3. Wrists, ankles and elbows also affected
  5. CNS Involvement
    1. Chronic, progressive involvement in 10-20% of patients
    2. Headaches are common
    3. Meningitis (symptomatic or asymptomatic) ~20% by Lumbar Puncture (LP)
    4. Focal deficits less common (10%)
    5. Magnetic resonance imaging (MRI) should be performed on all patients
  6. Major vessel stenosis or aneurysm ~25% of patients
  7. Thrombosis [16]
    1. Venous system most often involved
    2. Superficial thrombophlebitis, often recurrent (50%)
    3. Deep thrombosis (10%)
    4. Elevated levels of various thrombophilic factors in Behcet's versus normal e No differences in thrombophilic factors in Behcet's with or without thrombosis
    5. Etiology is most likely associated with direct vessel damage
  8. Pulmonary Disease (5%)
  9. Gastrointestinal Disease [9]
    1. Uncommon (~1%)
    2. When occurs, >50% of patients can have bowel perforation
    3. Abdominal pain, diarrhea, melena can also occur

E. Treatment [1]

  1. Glucocorticoids
    1. Topical steroids for ulcerations - triamcinolone
    2. Oral prednisone may be needed for other symptoms and resistant disease
  2. Other agents for first line therapy
    1. Dapsone - 100mg/d po, caution in G6PD deficiency
    2. Pentoxyfylline - reduces neutrophil activation; effective in early studies 600mg bid [5]
    3. Thalidomide - (see below)
    4. Colchicine may be effective for ulcers, arthritis, and pseuofolliculitis (0.5-1.5mg/d)
    5. Colchicine combination with interferon and penicillin is effective (see below) [13]
    6. Infliximab (anti-TNFa antibody) effective in two patients with severe panuveitis [14,15]
  3. Heparin or warfarin for phlebitis
  4. Interferon Alpha [8,9]
    1. Mainly for resistant Behcet's, has shown good efficacy
    2. Dose is 6,000 IU sc x 14 days, then 3,000 IU three times weekly
    3. Has shown efficacy for oral and skin ulcers, and eye disease [9,10]
  5. Azathioprine (Imuran®) [12]
    1. Recently shown to control the progression of the syndrome
    2. However, not as effective for initial severe disease as chlorambucil (alkylating agent)
    3. May be combined with prednisone and cyclosporine [7]
    4. Dose is 100mg/d po (or up to 4mg/kg)
  6. Cyclosporine
    1. High doses (10mg/kg/d) may suppress ocular disease [2]
    2. Lower doses (3-5mg/kg/d) may suppress myositis [7]
    3. May be used as mouthwash for resistant oral lesions
    4. Creatinine clearance should be done, and renal function monitored (even with oral agent)
    5. Contraindicated in acute or chronic progressive CNS lesions
  7. Chlorambucil
    1. Used for posterior uveitis, retinal vasculitis, CNS disease
    2. Dose is 5mg/d or 0.1mg/kg/d (for ~2.5 years) po
    3. Incidence of acute leukemia is increased with this agent compared to normal controls
  8. Cyclophosphamide
    1. For acute or chronic disease control; may be used in place of chlorambucil
    2. Dose for chronic disease is 50-100mg/d po
    3. For acute retinal vasculitis, CNS disease, arteritis, venous thrombosis
    4. Dose for acute disease is 700-1000mg/month IV
  9. Methotrexate
    1. Relatively well tolerated maintenance therapy
    2. Dose is 7.5-15mg po (or IM) each week
  10. Thalidomide [4,11]
    1. May have efficacy in resistant cases, especially for aphthous ulcers
    2. Inhibits TNF alpha production and angiogenesis
    3. Clearly reduces mucocutaneous ulcers
    4. Increases erythema nodosum lesion numbers initially, with decreases after 8 weeks
    5. Has shown efficacy for HIV associated aphthous ulcers, but increased viral load [6]
    6. Polyneuropathy is the major side effect, with mild decreases in libido
    7. US FDA information number for obtaining agent: 301-827-2335
    8. Dose is 100-300mg po qd (approved for leprosy)
  11. Interferon Alpha Combination Therapy [13]
    1. Dose 3 million units qod for 6 months
    2. Combination therapy with penicillin and colchicine
    3. Particularly reduced ocular disease by ~80%
    4. Arthritis, vascdular events, and mucocutaneous lesions also reduced
  12. Topical lidocaine may also be useful for ulcers

References

  1. Kaklamani VG, Vaiopoulos G, Kaklamanis PG. 1998. Semin Arthritis Rheum. 27:197 abstract
  2. Masuda K, et al. 1989. Lancet. 333:1093
  3. International Study Group. 1990. Lancet. 335:1078 abstract
  4. Thalidomide. 1996. Med Let. 38(968):15 abstract
  5. Yasui K, Ohta K, Kobayashi M, et al. 1996. Ann Intern Med. 124(10):891 abstract
  6. Jacobson JM, Greenspan JS, Spritzler J, et al. 1997. NEJM. 336(21):1487 abstract
  7. Lingenfelser T, Duerk H, Stevens A, et al. 1992. Ann Intern Med. 116(8):651 abstract
  8. Koetter I, Eckstein A, Stubinger N, et al. 1996. Arthritis Rheum. 39:227
  9. Grimbacher B, Wenger B, Deibert P, et al. 1997. Lancet. 350(9094):1818 (Case Report) abstract
  10. Feron EJ, Rothova A, van Hagen PM, et al. 1994. Lancet. 343:1428 abstract
  11. Hamuryudan V, Mat C, Saip S, et al. 1998. Ann Intern Med. 128(6):443 abstract
  12. Yazici H, Pazarli H, Barnes C, et al. 1990. NEJM. 322(5):281 abstract
  13. Demiroglu H, Ozcebe O, Barista I, et al. 2000. Lancet. 355(9204):605 abstract
  14. Sfikakis PP, Theodossiadis PG, Katsiari CG, et al. 2001. Lancet. 358(9278):295 abstract
  15. Weale R. 2001. Lancet. 358(9293):1644 abstract
  16. Espinosa G, Font J, Tassies D, et al. 2002. Am J Med. 112(1):37 abstract