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

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 38.5-39°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/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 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 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

9. 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

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 • 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

12. 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

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 unknowncause • Behçet's diseaseis not a chronic, persistent inflammatory disease, but ratherone 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, genitalulcers, uveitis, and skin lesions. All these common manifestationsare self-limiting except for the ocular attacks. Repeated attacksof uveitis can cause blindness. • Involvementof the gastrointestinal tract, central nervous system, and largevessels is less frequent, although it can be life-threatening.

24. Epidemiology • Cases of Behçet's disease cluster along the ancient SilkRoad, which extends from eastern Asia to the Mediterranean basin. • Turkey has the highest prevalence: 80 to 370 cases per 100,000population. • 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 UnitedKingdom and 0.12 to 0.33 per 100,000 in the United States.

25. Epidemiology • Onset age: varies,typically inthe 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 familiesis 2 to 5 percent, except in Middle Eastern countries, whereit is 10 to 15 percent. Although the rate of concordance amongtwins is not known, one pair of monozygotic twins who were concordant and two pairs who were discordant for Behçet's diseasehave been described

27. Behçet’s disease in childhood

28. Etiology and pathogenesis • Poorly understood • Genetic background: HLA-B51, an importantcontributor of risk in areasin which the disease is prevalent but not in Western countries • The prevalence of the HLA-B51 allele is high among patientswith Behçet's disease who live in areas along the SilkRoad (up to 81 percent of Asian patients have the allele) butnot among white patients who live in Western countries (13 percent). In Japan, the relativerisk among carriers of HLA-B51, as compared withthat among noncarriers, is 6.7 in Japan, whereas it is only1.3 in the United States. • The allele also affects the severity of disease, since it ismore common among patients with posterior uveitis or progressivecentral nervous system disease than among those with milderdisease. More than 55 percent of patients with centralnervous 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 tothe hypothesis that ubiquitous antigens, including heat shockprotein of microorganisms, may trigger cross-reactive autoimmuneresponses in patients with Behçet's disease.

30. Etiology and pathogenesis • Immunological aspect: Neutrophils from patientswith Behçet's disease have increased superoxide production,enhanced chemotaxis, and excessive production of lysosomal enzymes,indicating that the neutrophils are overactive, which leadsto tissue injuries Levels of circulating tumor necrosisfactor-a , interleukin-1ß, and interleukin-8 have beenreported 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 clinicalmanifestations • Colchicine • Thalidomide • Corticosteroid • Immunosuppressant drug: azathioprine, cyclosporin, cyclophosphamide, chlorambucil Mucocutanous lesion

35. Treatment • Recent trials of interferon alfa for Behçet's diseasehave shown encouraging results. In one study, 95 percentof the patients with ocular involvement had a response to therapywith interferon alfa. Interferon alfa-2a is most effectivefor ocular symptoms: in one study, it resulted in complete remissionof the ocular symptoms in 67 percent of the patients withinfour months. • Intravenous infusions of immune globulin, plasmapheresis, andgranulocytapheresis have also been tried in small numbers ofpatients, 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%.