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.

Endemic in Japan and Northeastern Mediterranean region (Turkey & Iran) “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 USA 1/100, 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%

Oral Aphthae

BEHÇET’S DISEASE Systemic Involvement Genital ulceration – 60-80%

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

Acneiform pustulosis & folliculitis

“Spontaneous” pathergy test

Pulmonary aneurysms

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

HYPOPYON – pus in the anterior chamber associated with uveitis

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

The Esophagous in Behcet’s disease

Small intestine in Behcet’s Disease

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

DIAGNOSIS International Study Group Criteria 1990

INTERNATIONAL CRITERIA ITR-ICBD INTERNATIONAL CRITERIA Classification Tree 2006

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

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

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 associated study

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

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

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.

Treatment of mucocutaneous involvement 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

Most common current treatment Prednisone Azathioprine Methotrexate Cyclosporin Interferon

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

A patient with severe Behcet’s disease – a therapeutic

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

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

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

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.

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.

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

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.

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.

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

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.

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

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.

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.

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.

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

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

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