Transcript Moyle EACS 2005

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 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 InvolvementMucocutaneous
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
A patient who presented with seizures and
hemiparesis due to cortical vein thrombosis with
infarction
Axial T2-weighted images in acute stage of neuroBehcet disease showing diffuse enlargement of the
pons (A) with edema extending to the midbrain and
right internal capsule (B). Six years later, axial T2weighted 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).
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
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
1
Vascular lesions (arterial and venous
thrombosis, aneurysm)
1
Pathergy phenomenon (Test)
1
Genital aphthosis
2
Ocular Lesions
2
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. 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
IL10
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
THANK YOU FOR YOUR ATTENTION
Questions??