馬偕馬偕過敏免疫風溼病例討過敏免疫風溼病例討論會論會

A 4 y/o boy with skin nodules aA 4 y/o boy with skin nodules and recurrent oral ulcernd recurrent oral ulcer

馬偕馬偕過敏免疫風溼病例討過敏免疫風溼病例討論會論會

A 4 y/o boy with skin nodules aA 4 y/o boy with skin nodules and recurrent oral ulcernd recurrent oral ulcer

9, 21, 20039, 21, 2003F2 F2 梁恬綺梁恬綺 /V.S/V.S 楊曜旭醫師楊曜旭醫師 // 江伯倫教授江伯倫教授

4Y maleHistory• Intermittent fever up to 38.5-39°C noted for ove

r 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 woundTreatment: Acyclovir & cefazolin zinacef and G

M

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/CD8 0.56 CD3=72% CD19=22% CD4=24% CD8= 43%• C3 175 C4 42.4 CRP 4.07• Skin biopsy at 中國醫藥學院 Ulcer with granulomatous tissue, infiltration with ly

mphocyte, plasma cell and neutrophil without definite diagnosis

Transfer to NTUH: admission on 91/10/30~91/11/8

What is your differential diagnosis?

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

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

• T 74 IgG 1320 B 21 IgA 312 NK 2 IgM 142 CD3/CD8 43 C3 149 CD4 28 C4 41.2 Naïve 11 Memory 17 CD11b/18 95

• NBT test : 96% activated: 1% baseline• ANA: 1:40(-)• Anti-ENA: all negative

Mitogen response• PHA CONA PWM ALPHA CD3/28(SI) (T) (T) (T&B)

P’T 9.2 41.38 25.76 7.96

CON15.9 8.63 10.6 14

• Diagnosis: Behçet’s disease• 11/8~ OPD F/U with medication: pred

nislone 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

Second admission-911231~920124

12/31 1/10 1/13 1/17 1/22• WBC 21480 17120 26520 18490 15660 • Hb 10.9 9.6 10.9 9.8 11.8• Plt 612K 619K 719K 652K 742K• Seg/Lym 75.5/19.6 93.7/5.2 77/18 64/31• CRP 4.52 2.24 0.32 1.37• CsA level 26.46 33.08

Treatment• Unasyn 911231~920113• Zithromax 920108~920110• Prednisolone 911231 2mg/kg/d(iv)~ ->1/5 1mg/kg/d(iv)~->1/23 oral form• Imuran 911231 0.5#~->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

Discussion

Behçet’s disease• 1937: Turkish dermatologist Hulusi B

ehçet described the syndrome consists of triad- aphthous stomatitis, genital ulceration, uveitis

Behçet’s disease• Behçet's disease is an inflammatory disord

er 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

Criteria of the international study group

Clinical manifestations• Mucocutanous: skin-ulceration, erythema nodosum, er

ythema 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

Clinical manifestations• Musculoskeletal disease- often oligoarthritis, 1/3 is polyar

thritis, most commonly affects the knees, ankles, wrists and elbows

• GI system: ulceration may from mouth to the anus• CNS system disease- encephalomyelitis, aseptic meningiti

s, 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)

Clinical manifestations• Bahçet’s disease is characterized by recurre

nt 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.

Epidemiology• Cases of Behçet's disease cluster along the ancien

t 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.

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

Epidemiology• The frequency within families is 2 to 5 perc

ent, 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

Behçet’s disease in childhood

Etiology and pathogenesis

• Poorly understood• Genetic background: HLA-B51, an important contributor of risk i

n 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.

Etiology and pathogenesis

• Infectious precipitant: HSV type 1, hepatitis C virus and parvovirus B19 St

reptococcal oralis and Streptococcus sanguis In fact, the results of a series of studies led to the h

ypothesis that ubiquitous antigens, including heat shock protein of microorganisms, may trigger cross-reactive autoimmune responses in patients with Behçet's disease.

Etiology and pathogenesis

• Immunological aspect: Neutrophils from patients with Behçet's disease have incr

eased 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- , 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

Pathology• Aseptic infiltration of tissue with neutrophil

s, 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

Laboratory examination

• No lab finding is diagnostic• Acute phase reactant: generalized increased • ANA(-), RF(-)• Anticardiolipin Ab may positive (rare): presenc

e may correlate with the presence of retinal vascular disease

• Abnormalities of T cells and cytokines: increase serum levels of TNF- and soluble TNF- receptor

Treatment• The choice of the treatment depends on th

e patient's clinical manifestations • Colchicine• Thalidomide• Corticosteroid• Immunosuppressant drug: azathioprine, cy

closporin, cyclophosphamide, chlorambucil

Mucocutanous lesion

Treatment• Recent trials of interferon alfa for Behçet's disease ha

ve 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.

Course of the disease and prognosis

• Long, relapsing course• The young child who presents with only recurren

t 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%.