1. 馬偕過敏免疫風溼病例討論會 A 4 y/o boy with skin nodules and recurrent oral ulcer
9, 21, 2003
F2 梁恬綺/V.S楊曜旭醫師/江伯倫教授

2. 4Y male
History
Intermittent fever up to °C noted for over 2 wks before admission in 中國醫藥學院(91/10/2-91/10/18 )
1 Multiple furuncle or carbuncle-like erythematous nodules progress from feet to legs
2 Multiple recurrent oral ulceration (+)
3 Intermittent abdominal pain(+)
4 delay healing of needle punture wound
Treatment: Acyclovir & cefazolin  zinacef and GM

3. Study at 中國醫藥學院 WBC 26K Seg/lym 84.5/9.8 HB/HT 9.91/29.7 PLT 740K
Ig A 405 Ig M 133 Ig G 1380
lymphocyte subset: CD4/CD
CD3=72% CD19=22% CD4=24% CD8= 43%
C C CRP 4.07
Skin biopsy at 中國醫藥學院
Ulcer with granulomatous tissue, infiltration with lymphocyte, plasma cell and neutrophil without definite diagnosis
Transfer to NTUH: admission on
91/10/30~91/11/8

5. What is your differential diagnosis?

6. Initial Diagnosis R/O CGD R/O LAD R/O autoimmune disease
-> Behçet’s disease

7. Initial workup for diagnosis
11/1-Abdominal echo: three target or doughnut lesions (fixed bowel loop) in the RLQ of abdomen, compatible with segmental enterocolitis
11/4 skin biopsy: inflammation lesion in subcutaneous tissue, no evidence of vasculitis
11/5 LGI :WNL
11/5 consult oph: no uveitis or retinitis

8. T IgG 1320
B IgA 312
NK IgM 142
CD3/CD C3 149
CD C
Naïve 11
Memory 17
CD11b/18 95
NBT test : 96% activated: 1% baseline
ANA: 1:40(-)
Anti-ENA: all negative

9. Mitogen response PHA CONA PWM ALPHA CD3/28 P’T 9.2 41.38 25.76 7.96
(SI) (T) (T) (T&B)
P’T
CON

10. Diagnosis: Behçet’s disease
11/8~ OPD F/U with medication: prednislone 1mg/kg/d, imuran 2mg/kg/d-> discontinuation of medication themselves for 2 weeks due to travel to Japan-> fever, oral ulcer and skin lesions again

11. Second admission-911231~920124 12/31 1/10 1/13 1/17 1/22
12/ / / / /22
WBC Hb
Plt K K 719K 652K K
Seg/Lym / /5.2 77/ /31
CRP
CsA level

12. Treatment Unasyn 911231~920113 Zithromax 920108~920110
Prednisolone mg/kg/d(iv)~
->1/5 1mg/kg/d(iv)~->1/23 oral form
Imuran #~->1/13 2/3#
Colchicine 1#qd 1/8~1/15
CsA 1/14~1/17:3mg/kg/d->1/17~: 4.5mg/kg/d

13. Discussion

14. Behçet’s disease
1937: Turkish dermatologist Hulusi Behçet described the syndrome consists of triad- aphthous stomatitis, genital ulceration, uveitis

15. Behçet’s disease
Behçet's disease is an inflammatory disorder of unknown cause
Behçet's disease is not a chronic, persistent inflammatory disease, but rather one consisting of recurrent attacks of acute inflammation.
Definition: varies- several sets of diagnostic criteria have been proposed for Behçet’s disease

16. Criteria of the international study group

21. Clinical manifestations
Mucocutanous: skin-ulceration, erythema nodosum, erythema multiforme and other rash including psoriasis , pathergy test: mostly commonly (50-70%) in patients from the Middle East
Ocular disease-
classic is acute uveitis, which is almost always bilateral and involves both the anterior and posterior uveal tracts
severe uveitis may lead to blindness
corneal ulceration, retinal vasculitis and detachment are rare events

22. Clinical manifestations
Musculoskeletal disease- often oligoarthritis, 1/3 is polyarthritis, most commonly affects the knees, ankles, wrists and elbows
GI system: ulceration may from mouth to the anus
CNS system disease- encephalomyelitis, aseptic meningitis, benign intracranial hypertension, organic psychiatric disturbance
Vascular diseases: superficial or deep venous thromboses are common in adults but only 5 to 15 percent of children
Uncommon: cardiac complication, pulmonary hemorrage, renal disease (GN)

23. Clinical manifestations
Bahçet’s disease is characterized by recurrent oral aphthous ulcers, genital ulcers, uveitis, and skin lesions. All these common manifestations are self-limiting except for the ocular attacks. Repeated attacks of uveitis can cause blindness.
Involvement of the gastrointestinal tract, central nervous system, and large vessels is less frequent, although it can be life-threatening.

24. Epidemiology
Cases of Behçet's disease cluster along the ancient Silk Road, which extends from eastern Asia to the Mediterranean basin.
Turkey has the highest prevalence: 80 to 370 cases per 100,000 population.
The prevalence in Japan, Korea, China, Iran, and Saudi Arabia : 13.5 to 20 cases per 100,000
In Western countries: 0.64 per 100,000 in the United Kingdom and 0.12 to 0.33 per 100,000 in the United States.

25. Epidemiology
Onset age: varies,typically in the third or fourth decade of life
Childhood onset: 4-8%~26%
Boys and girls are of equal frequency
in adults, male are two times frequent than female

26. Epidemiology
The frequency within families is 2 to 5 percent, except in Middle Eastern countries, where it is 10 to 15 percent. Although the rate of concordance among twins is not known, one pair of monozygotic twins who were concordant and two pairs who were discordant for Behçet's disease have been described

27. Behçet’s disease in childhood

28. Etiology and pathogenesis
Poorly understood
Genetic background: HLA-B51, an important contributor of risk in areas in which the disease is prevalent but not in Western countries
The prevalence of the HLA-B51 allele is high among patients with Behçet's disease who live in areas along the Silk Road (up to 81 percent of Asian patients have the allele) but not among white patients who live in Western countries (13 percent).
In Japan, the relative risk among carriers of HLA-B51, as compared with that among noncarriers, is 6.7 in Japan, whereas it is only 1.3 in the United States.
The allele also affects the severity of disease, since it is more common among patients with posterior uveitis or progressive central nervous system disease than among those with milder disease. More than 55 percent of patients with central nervous system lesions are positive for HLA-B51.

29. Etiology and pathogenesis
Infectious precipitant:
HSV type 1, hepatitis C virus and parvovirus B19 Streptococcal oralis and Streptococcus sanguis
In fact, the results of a series of studies led to the hypothesis that ubiquitous antigens, including heat shock protein of microorganisms, may trigger cross-reactive autoimmune responses in patients with Behçet's disease.

30. Etiology and pathogenesis
Immunological aspect:
Neutrophils from patients with Behçet's disease have increased superoxide production, enhanced chemotaxis, and excessive production of lysosomal enzymes, indicating that the neutrophils are overactive, which leads to tissue injuries
Levels of circulating tumor necrosis factor-a , interleukin-1ß, and interleukin-8 have been reported to be elevated
Ab-mediated, abnormal T cell function (gamma-delta T cell), both innate and adaptive immune system activated

31. Pathology
Aseptic infiltration of tissue with neutrophils, together with infiltration of mononuclear cells
Occlusive vasculitis in arteriole and veins: intraluminal aggregation of leucocytes are often seen within blood vessels-> intravascular leucocyte activation and/or enhanced leukocyte traffic into the tissues

32. Laboratory examination
No lab finding is diagnostic
Acute phase reactant: generalized increased
ANA(-), RF(-)
Anticardiolipin Ab may positive (rare): presence may correlate with the presence of retinal vascular disease
Abnormalities of T cells and cytokines: increase serum levels of TNF-a and soluble TNF-a receptor

33. Treatment
The choice of the treatment depends on the patient's clinical manifestations
Colchicine
Thalidomide
Corticosteroid
Immunosuppressant drug: azathioprine, cyclosporin, cyclophosphamide, chlorambucil
Mucocutanous lesion

35. Treatment
Recent trials of interferon alfa for Behçet's disease have shown encouraging results. In one study, 95 percent of the patients with ocular involvement had a response to therapy with interferon alfa. Interferon alfa-2a is most effective for ocular symptoms: in one study, it resulted in complete remission of the ocular symptoms in 67 percent of the patients within four months.
Intravenous infusions of immune globulin, plasmapheresis, and granulocytapheresis have also been tried in small numbers of patients, but the data are quite limited.

36. Course of the disease and prognosis
Long, relapsing course
The young child who presents with only recurrent oral mucocutaneous lesions may develop genital ulcerations and GI tract disease during adolescence
Potentially fatal lesions include occlusion or aneurysms of arteries supplying the CNS or heart, pulmonary hemorrage and bowel perforation
In a series of 65 patients, the mortality rate was 3%.