1. BEHCET’S DISEASE
Eldad Ben-Chetrit

2. BEHCET’S DISEASE
A rare multisystem, chronic disease characterized by oral and genital mucocutaneous ulcerations, skin rashes, arthritis, thrombophlebitis, uveitis, colitis, and neurologic symptoms.

3. Endemic in Japan and Northeastern Mediterranean region (Turkey & Iran)
“Silk Road Disease”
Endemic in Japan and Northeastern Mediterranean region (Turkey & Iran)

4. Hulusi Behçet was a Turkish dermatologist from Istanbul (1889–1948).
Described the syndrome in 1936

5. Other names of the syndrome
Adamantiades’ syndrome – 1930
Behçet's disease – 1936
Adamantiades-Behçet syndrome
Gilbert's syndrome

6. EPIDEMIOLOGY Incidence/Prevalence: In USA 1/100, 000
In Japan - 670/100,000 (during the last years there is a significant decrease in this rate)
In Turkey /100,000

7. EPIDEMIOLOGY Predominant age: 3rd to 4th decades
Predominant sex: Male > Female; as frequently to twice as often. Some studies suggest equal frequency.

8. Etiology Unknown Various bacteria and viruses suggested
(No good evidence to suggest any of them)
Tumor necrosis factor (TNF) thought to be important
Genetic factors (HLA-B51, SNPs in IL-1)

9. Systemic Involvement- Mucocutaneous
Oral aphthous ulceration – 100%

10. Oral Aphthae

12. BEHÇET’S DISEASE Systemic Involvement
Genital ulceration – %

13. BEHÇET’S DISEASE Systemic Involvement
Skin lesions – 80%
Erythema Nodosum
Pyoderma gangrenosum

14. Acneiform pustulosis & folliculitis

15. “Spontaneous” pathergy test

16. Pulmonary aneurysms

17. Systemic Involvement blood vessels
Major vessels eg superior Vena cava obstruction

18. CNS involvement – strokes, fits
Axial T2-weighted images in acute stage of neuro-Behcet disease showing diffuse enlargement of the pons (A) with edema extending to the midbrain and right internal capsule (B). Six years later, axial T2-weighted image shows advanced atrophy of the brainstem (C), and axial T1-weighted image with gadolinium enhancement shows a small area of enhancement in the caudal midbrain (D).
A patient who presented with seizures and hemiparesis due to cortical vein thrombosis with infarction

19. Ocular Features Uveitis 70% (inflam. of iris, ciliary body or choroid)
Acute iritis
Recurrent hypopyon
(Fluid level of WBC)
The red or white eye

20. HYPOPYON – pus in the anterior chamber associated with uveitis

21. Intestinal BD Intestine
Presentation similar to Crohn’s disease (CD). In pt with intestinal BD, other stigmata of BD may appear later
Rectal and anal involvement rare
Ileocecal involvement common to Japan & Turkey. Colonic involvement common in Europe & N. America

22. Intestinal BD cont..
Morphology of lesions: aphthous ulcers or deep round or oval ulcers with punched-out appearance. Longitudinal ulcers rare
Ulcers localize and appear in clusters

23. The Esophagous in Behcet’s disease

24. Small intestine in Behcet’s Disease

25. Differential Diagnosis
Reactive arthritis and other forms of spondyloarthropathy
Inflammatory bowel disease (Crohn's disease and ulcerative colitis)
Syphilis

26. Differential Diagnosis
Herpes simplex
Stevens-Johnson syndrome
Vasculitides
Thrombophlebitis related to coagulation factor deficiency

27. Complications Death (rupture of pulmonary aneurysm) Blindness
Paralysis
Embolism/thrombosis - pulmonary, vena cava, peripheral
Amyloidosis

28. DIAGNOSIS International Study Group Criteria 1990

29. INTERNATIONAL CRITERIA
ITR-ICBD
INTERNATIONAL CRITERIA
Classification Tree
2006

30. Revision of the International Criteria for Behcet’s Disease (ICBD 1,2,3,)
- Austria (M. Schirmer, M Baltaci), Azerbaijan (A. Isayeva), China (Y. Dong, Z. Zhang), Egypt ) S. Assaad-Khalil), France (B. Wechsler), Germany (C.C. Zouboulis, A. Altenburg), Greece (Ph. Kaklamanis), India (A. Kumar), Iran (F. Davatchi, B. Sadeghi-Abdollahi, F. Shahram, A. Nadji, C. Chams-Davatchi, H. Shams, N. Zia’I, M. Akhlagi, A.R. Jamshidi, A.K. Haghdoost), Iraq) K. Sharquie, R. Hayani ,Israel (Eldad Ben-Chetrit), Italy (I. Olivieri, C. Salvarani, N. Pipitone), Japan (Sh. Ohno, K. Namba), Jordan (W. Madanat (Libya (K. Elmuntaser( Morocco (S. Benamour), Pakistan (A. Ali), Portugal (J. Crespo, T Tribolet, C Vasconcelos, J Correia, L Carvalho, M Bastos, MJ Serra, C Resende, F Ramos, M Rosa, V Queirós, J Vedes, C. Dias, J.V. Patto, FP Duarte), Russia (Z. Alekberova, A. Elonakov), Saudi Arabia (A. Al Dalaan), Singapore (C. Yew Kuang), Spain (G. Grana Gil), Taiwan (W.C. Chen), Thailand (A. Emvalee), Tunisia (H. Houman, I. Ben Ghorbel, M. Sliti-Khanfir), Turkey (A. Boyvat), USA (K. Calamia). Coordinator: F. Davatchi. Data collection and analysis: Rheumatology Research Center, Tehran University for Medical Sciences

31. Table 2: Traditional format criteria
Points
Oral aphthosis 1
Skin manifestations
Vascular lesions (arterial and venous thrombosis, aneurysm)
Pathergy phenomenon (Test)
Genital aphthosis 2
Ocular Lesions
Behcet’s Disease: 3 or more points

32. Prognosis Normal life expectancy, except with neurologic involvement
Possible vision impairment
Improvement with age

33. Genetics of Behcet’s disease
Familial aggregation
Familial clustering is more frequent among juvenile onset (<16 Y).
Geographic distribution – endemic areas overlap with the ancient Silk Road
BD is strongly associated with class I MHC allele, HLA-B51

34. Genome wide associated study

35. Genome-wide association study identifies variants in the MHC class I, IL10, and IL23R-IL12RB2 regions associated with Behçet’s disease Elaine F Remmers, Fulya Cosan, Yohei Kirino, Michael J Ombrello, Neslihan Abaci, Colleen Satorius, Julie M Le, Barbara Yang, Benjamin D Korman, Aris Cakiris, Oznur Aglar, Zeliha Emrence, Hulya Azakli, Duran Ustek, Ilknur Tugal-Tutkun, Gulsen Akman-Demir, Wei Chen, Christopher I Amos, Michael B Dizon, Afet Akdag Kose, Gulsevim Azizlerli, Burak Erer, Oliver J Brand, Virginia G Kaklamani, Phaedon Kaklamanis, Eldad Ben-Chetrit, Miles Stanford, Farida Fortune, Marwen Ghabra, William E R Ollier, Young-Hun Cho, Dongsik Bang, John O’Shea, Graham R Wallace, Massimo Gadina, Daniel L Kastner & Ahmet Gül Nat Genet 2010

36. Figure 1 Behçet’s disease genome-wide association results
Figure 1 Behçet’s disease genome-wide association results. The −log10 P values (allelic χ2 test) for association of 311,459 autosomal SNPs in 1,215 Behçet’s disease cases and 1,278 controls from Turkey are shown segregated by chromosome and sorted by genomic position.
HLA-B51
IL-10 1
CPLX-1 6

37. The difference in expression of the gene between the disease-associated haplotype and normal haplotypes – was tested

38. These data suggest that genetic variants contributing to low IL-10 expression may be a risk factor for Behçet’s disease.

39. This observation may suggest IL-10 as an additional therapeutic measure.

40. Behcet’s disease – treatment
Azathioprine
Steroids
Chlorambucil
Colchicine
Cyclophosphamide
Cyclosporine
Tacrolimus
IFN – α
Thalidomide
MTX
Mycophenolate mofetil
Anti – TNFα:
Infliximab
Etanercept

42. Year 1998 Systematic Review:
Conclusions
32 studies were reviewed
679 Behcet’s patients
No difference between placebo and colchicine – aphthous stomatitis
Local interferon is not effective in ulcers
Cyclosporin is better than colchicine for oral ulcers.

43. Treatment of mucocutaneous involvement
A double-blind trial of colchicine in Behcet's syndrome. Arthritis Rheum 2001 Nov;44(11):
Double blind study.
116 patients with joint and mucocutaneous involvement only.
Colchicine versus placebo
Significant improvement in treated group in genital ulcers, erythema nodosum and arthritis

44. Most common current treatment
Prednisone
Azathioprine
Methotrexate
Cyclosporin
Interferon

45. What is the treatmet for resistant Behcet’s Disease?
Biologics

46. A patient with severe Behcet’s disease – a therapeutic

47. Patient Rita M.
A 48 year old lady came from Armenia due to severe aphthous stomatitis
A year before she started having recurrent oral and genital ulcers, general weakness, headache, trigeminal neuralgia, an episode of uveitis and elevated ESR and CRP
She was under colchicine treatment continuously

48. Patient (cont.)
She was treated with steroids with mild improvement and even cyclophosphamide (The indication is not really clear)
Local anesthetics and antibiotics were ineffective.

49. Patient (Cont.)
Following 3 weeks her situation deteriorated. She could not eat due to the oral pains which irradiated to her left ear
On physical examination the main findings were 3 severe and large oral ulcers
Some papulo-squamous rash over her scalp

50. Patient (cont.) ESR -70 CRP- 3.7 Hemoglobin 10.8 HLA-B51 positive
ANA and RF – negative
Zeil Nilssen staining negative

51. Patient (cont.) She got fluids Systemic antibiotics
300 mg solumedrol (IV)
No significant improvement.

52. Patient (Cont.)
She got 300 mg Remicade with dramatic improvement.

53. Patient (Cont.)
After a few months (and having discontinued the anti TNF treatment on her own), she was re-hospitalized because of severe pain with a large skin lesion on her left leg.

54. Patient (Cont.) A diagnosis of pyoderma gangrenosum was made.
Topical treatment was ineffective. Therefore the patient was treated with pulse solumedrol 1 gr for two successive days and 500 mg on the third day, and she received 300 mg Remicade intravenously.

55. Again, significant and quick improvement was noted regarding the skin lesion on her calf

57. Patient (cont.)
Recently, she came again to our clinic because of severe mouth and right ear pain with excessive salivation, difficulties in swallowing and mild hoarseness.
The patient was not on Remicade for at least 3 months (she could not obtain this agent for logistic reasons) but instead was treated with Enbrel 25 mg twice a week.

58. Patient (cont.)
On physical examination the main findings through indirect laryngoscopy were narrowing of the larynx with swelling of the epiglottis (mainly on the left side) and fibrinous discharge. The arytenoid was reddish and swollen and the epiglottis was partially bitten.

60. Patient (cont.)
The patient was treated with three doses of solu-medrol (750 mg, 500 mg and 500 mg) and 300 mg Remicade. Following this treatment her condition improved significantly within a week

61. Patient (cont.)
After 12 days the swelling of the arytenoid disappeared and the vocal cord on the same side returned to its place. The pain in the ear and the ipsilateral headache diminished and the excessive salivation improved as well.

62. This case exemplify the potential risks of laryngeal stenosis and the difficulties in treatment – sometimes requiring surgical intervention.

63. Unique characteristics of the case
The present case is unique in several points: First, it describes a patient with unusual resistant Behcet's disease presenting with recalcitrant aphthous stomatitis, later with pyoderma gangrenosum and recently with severe laryngeal involvement.

64. Unique characteristics of the case
None of the previous reports used anti TNF blockers as a treatment for this devastating clinical condition.
Second, it shows the dependency of the disease on anti TNF treatment and its dramatic effect in ameliorating all these clinical conditions.

65. Unique characteristics of the case
Third, it shows that different anti TNF agents have different effects on this pathology. Etanercept was found to be ineffective in treating the severe inflammation and aphthae in the larynx, while infliximab was significantly effective.

66. REMICADE VERSUS ENBREL
Remicade has longer half time
In addition to soluble TNF it binds membrane bound TNF leading to cell – lysis

67. In the future… Anti IL-1 agents Anti IL-6 receptor – Actemra
Anti IL-17 Ab – in phase III trials

68. THANK YOU FOR YOUR ATTENTION Questions??