BEHCET’S DISEASE Eldad Ben-Chetrit - 2012
BEHCET’S DISEASE A rare multisystem, chronic disease characterized by oral and genital mucocutaneous ulcerations, skin rashes, arthritis, thrombophlebitis, uveitis, colitis, and neurologic symptoms.
“Silk Road Disease” Endemic in Japan and Northeastern Mediterranean region (Turkey & Iran)
Hulusi Behçet was a Turkish dermatologist from Istanbul (1889–1948). Described the syndrome in 1936
Other names of the syndrome Adamantiades’ syndrome – 1930 Behçet's disease – 1936 Adamantiades-Behçet syndrome Gilbert's syndrome - 1920
EPIDEMIOLOGY Incidence/Prevalence: In USA1/100, 000 In Japan - 670/100,000 (during the last years there is a significant decrease in this rate) In Turkey - 80-320/100,000
EPIDEMIOLOGY Predominant age: 3rd to 4th decades Predominant sex: Male > Female; as frequently to twice as often. Some studies suggest equal frequency.
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)
Systemic Involvement- Mucocutaneous Oral aphthous ulceration – 100%
BEHÇET’S DISEASE Systemic Involvement Genital ulceration – 60-80%
BEHÇET’S DISEASE Systemic Involvement Skin lesions – 80% Erythema Nodosum Pyoderma gangrenosum
Systemic Involvement blood vessels Major vessels eg superior Vena cava obstruction
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
Ocular Features Uveitis 70% (inflam. of iris, ciliary body or choroid) Acute iritis Recurrent hypopyon (Fluid level of WBC) The red or white eye
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
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
Differential Diagnosis Reactive arthritis and other forms of spondyloarthropathy Inflammatory bowel disease (Crohn's disease and ulcerative colitis) Syphilis
Differential Diagnosis Herpes simplex Stevens-Johnson syndrome Vasculitides Thrombophlebitis related to coagulation factor deficiency
Complications Death (rupture of pulmonary aneurysm) Blindness Paralysis Embolism/thrombosis - pulmonary, vena cava, peripheral Amyloidosis
ITR-ICBD INTERNATIONAL CRITERIA Classification Tree 2006
Revision of the International Criteria for Behcet’s Disease (ICBD 1,2,3,) - Austria (M. Schirmer, MBaltaci), 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: RheumatologyResearchCenter, TehranUniversity for Medical Sciences
Table 2: Traditional format criteria Behcet’s Disease: 3 or more points
Prognosis Normal life expectancy, except with neurologic involvement Possible vision impairment Improvement with age
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
Genome-wide association study identifies variants in the MHC class I, IL10, and IL23R-IL12RB2 regions associated with Behçet’s diseaseElaine 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
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
The difference in expression of the gene between the disease-associated haplotype and normal haplotypes – was tested
These data suggest that genetic variants contributing to low IL-10 expression may be a risk factor for Behçet’s disease.
This observation may suggest IL-10 as an additional therapeutic measure.
Behcet’s disease – treatment Azathioprine Steroids Chlorambucil Colchicine Cyclophosphamide Cyclosporine • Tacrolimus • IFN – α • Thalidomide • MTX • Mycophenolate mofetil • Anti – TNFα: • Infliximab • Etanercept
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.
A double-blind trial of colchicine in Behcet's syndrome. Arthritis Rheum 2001 Nov;44(11):2686-92. 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 Treatment of mucocutaneous involvement
Most common current treatment • Prednisone • Azathioprine • Methotrexate • Cyclosporin • Interferon
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
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.
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
Patient (cont.) • ESR -70 • CRP- 3.7 • Hemoglobin 10.8 • HLA-B51 positive • ANA and RF – negative • Zeil Nilssen staining negative