Les atteintes vasculaires au cours de la maladie de Behcet

Les atteintes vasculaires au cours de la maladie de Behcet

Vital emergencies and Behçet’s disease:
vascular injury, pulmonary aneurysm
Tazi Mezalek Zoubida
Internal medicine departement
Mohamed V University
Ibn Sina hospital – Rabat – Morocco
Recurrent oral aphtae
Genital ulcers
Hypopion uveitis
Young males
Behçet H. Derm Wschr 1937
Thrombophlebitis is the 4th
symptom of hypopion uveitis.
Adamantiades B. Ann Occulist 1946
Major vessels involvement
in Behcet’s disease
Main cause of mortality
New concept of « vasculo-Behçet »
Need for early recognition and aggressive
treatment
Vascular mortality in Behçet’s
disease
Saadoun et al.
41 deaths / 44% vascular
n=817
Kural Seyahi E et al.
42 deaths / 41% vascular
n=387
3 cases
Pulmonary arteries
aneurisms
9 cases
4 cases
Budd chiari
syndrom
3 cases
4 cases
Aortic
aneurisms
1 cases
4 cases
Vena cava/ pulmonary
thrombosis
4 cases
Arthritis Rheum 2010
Clin Exp Rheumatol 2008 /Medicine 2003
Clinical description of Behçet’s
vascular disease
France : 35%
Spain : 28-33%
Italy : 25%
Israel - Lebanon: 15-25%
Turkey : 17-30%
Korea – Japan : 5-15%
Morocco : 30-45%
Tunisia : 25-45%
Algeria : 23-30%
Prevalence of vascular disease
in Behcet’s disease
Vascular Behçet’s disease
General presentation
Venous disease
15-40%
Arterial disease
8 -18 %
Sexe ratio
3-5/1
7-8/1
Age of diagnosis (years)
25-40
30-50
Diagnosis delay (years)
5 first years
7-10 first years
none
Trauma/puncture
Smoking ?
Risk factors
Inaugural
10-30%
Large vessels / tendency of recurrence
Systemic symptoms/Inflammatory syndrom
Topographic distribution of
Behçet’s vascular disease
10-20%
25%
75%
PAA: 5%
20%
20%
25%
25%
lower limbs
15%
45%
45%
large veins
cerebral veins
30%
55-70%
other
•Caval thrombosis
•Splanchnic thrombosis
•Pulmonary embolism
Tascilar K et al. Rheumatology in press/AC. Desbois et al Arthritis Rheum 2012/
Sarica-Kucukoglu R et al. Int J Dermatol 2006/Saadoun et al. Medicine 2011
Urgent presentations of
vascular disease in Behçet’s
Lower extremities vein
thrombosis Behcet’s disease
• Superficial thrombophlebitis (15%)
– Migratory / recurrent
– Following venipuncture
– Risk factor for future vascular events
• Deep vein thrombosis (55-70%)
– Extensive / Bilateral
– No risk factor
– First vascular event in 80% of patients
• Chronic venous insufficiency
Cerebral vein thrombosis
7-10%
•
•
•
•
•
30% of neurologic manifestations
First 5 years
Increased intracranial pressure symptoms
15% of blindness  optic atrophy
Strong association with legs DVT (62%)
Yesilot N et al. J Neurol 2009
Saadoun D et al. Arthritis Rheum 2009
Caval thrombosis (5-10%)
Behcet’s disease
• Inferior and superior vena cava thrombosis
frequently associated
• Extension from lower limbs thrombosis ++
• Variable clinical presentations
–
–
–
–
Asymptomatic
Collaterals
Caval syndrom
Chylothorax / chylopericardium
Houman H et al. Ann Med Int 1999
Budd-Chiari syndrom (3-5%)
Behcet’s disease
• Severe presentation
– Ascites / hepatomegaly / abdominal pain / icterus
– Acute hepatic insufficiency ++++
• Diagnosis : echography/CT-scan/MRI
• Mostly extend from inferior vena cava thrombosis
 troncular thrombosis of major hepatic veins
E. Kural-Seyahi et al. Medicine 2003
D. Saadoun et al. Arthritis Rheum 2011
Budd-Chiari syndrom (3-5%)
Behcet’s disease
• Associations
– 2-30% portal vein thrombosis
– 70-90% inferior vena cava thrombosis
• Prognosis
– 10% deaths of BD
– 30-50% mortality 1st year
2014
E. Kural-Seyahi et al. Medicine 2003
D. Saadoun et al. Arthritis Rheum 2011
20% mortality
(5 years)
A. Desbois et al. Orphanet J Rare Dis 2014, in press
Pulmonary embolism 
Pulmonary artery thrombosis
– Peripheral vein thrombosis in BD
 no pulmonary embolism
 adherent thrombus on inflamed vessels
– « in situ » pulmonary artery thrombosis
– Symptoms : hemoptysis, chest pain, fever…
– Significant associations
• Peripheral vein thrombosis
• Pulmonary artery aneurisms
O. Uzun et al. CHEST 2005; E. Seyahi et al. Medicine 2012
Pulmonary arteries
aneurisms
• Rare but classical (1-2%)
• Inaugural : 10-15%
• Almost exclusively men
Hemoptysis
May be asymptomatic
Normal chest radioG
 Systematic CT scan
Cumulative survival of
patients with BD disease
and PAA (201 cases)
O. Uzun et al. CHEST 2005
Pulmonary arteries
aneurisms
• Main pulmonary arteries or lobar branches
• Bilateral / Multi-location : 45-50%
• Significant associations :
• Pulmonary arteries thrombosis
• Peripheral veins thrombosis
• Intracardiac thrombosis
Pulmonary vascular
involvement (5-7%)
Pulmonary arterial
thrombosis
20%
2nd most common
direct cause of
death
Pulmonary arterial
aneurisms
75-85%
Lower limbs thrombosis (70%)
Dural sinus thrombosis (30%)
Intracardiac thrombosis (33-75%)
Caval/splanchnic thrombosis (25%)
Less
ocular
disease
O. Uzun et al. CHEST 2005; E. Seyahi et al. Medicine 2012
Systemic arterial disease
Behcet’s disease
• Clinical prevalence : 5-15%
Koç. J Rheumatol 1992,
Le Thi Huong. J Rheumatol 1995
• Autopsy studies
– Prevalence : 34-44%
– Asymptomatic : 30%
S. Lakhanpal et al. Hum Pathol 1985
• Stenosis / occlusion / aneurysms
• Emergency presentation (75%)
95%
75%
Risk of rupture of aneurysms
 mortality ++
Saadoun D et al, Medicine 2012
Systemic arterial aneurisms
Behcet’s disaese
• Clinical presentation
– Pulsatile mass / pain / huge size
• Relapse : 30% first year
• Multiple : 30%
• Co-existance with venous thrombosis +/-
Vasculo-Behçet
concept
Behçet’s syndrom
Oral ulcers
Acne, arthritis,
enthesopathy
Uveitis
enterocolopathy
Neurological
parenchymal lesions
KT. Calamia et al. Cur Opi Rheum atol 2010
H. Yazici et al. Clinic Rev Allerg Immunol 2012
Vasculo-Behçet
Deep vein thrombosis
PAA/PAT
Major vein thrombosis
Dural sinus thrombosis
Arterial aneurisms
Vasculo-Behçet
Diagnostic criteria
• No vascular disease in ISG criteria
• Vasculo-Behcet : inaugural in 10-30%
Melikoglu M et al. Clin Rev Allergy Immunol 2008
Sarica-Kucukoglu R et al. Int J Dermatol 2006
• 5% patients don’t fulfilled the
diagnostic criteria (isolate oral ulcers)
Young males
Endemic area
Large vessels
Scrotum scar
Pathogenesis of vascular disease
Behcet’s syndrom
Neutrophilic vasculatis
Vaso vasorum
CD3+, CD4+,
NK cells
Pathogenesis of thrombosis
in Behçet’s disease
Age
Immobilisation
Trauma
Respiratory failure
Heart failure
Cancer
………….
aPL  inconsistent data
Hyperhomocysteinemia
-Negative studies
-Positive metaanalysis
Virchow
triad
Genetic thrombophilia
-Negative studies +++
-Positive studies : Turkey
-Factor V Leiden
-Factor II mutation
Endothelium injury
Surgery
Trauma
Sepsis
Vasculitis
ML Regina et al. Arterioscl Thrombo Vasc Biol 2010
Houman H et al. Adv Exp Med Biol 2003,
Ozdemir R et al. Am J Cardiol 2004
Leiba M et al. Ann Rheum Dis 2004
Ates A et al. Pathophysiol Haemost Thromb 2003
Espinosa G et al. Am J Med 2002
Mader R et al. J Rheumatol 1999
Gull et al. Br J Rheumatol 1996; Rheumatol 1999
Therapeutic considerations in
vasculo-Behçet
Management of venous
thrombosis in Behcet’s
No RCT
Observational studies
Retrospective analysis
The EULAR recommandations
Hatemi G et al. Ann Rheum Dis 2008
Corticosteroids +
Immunosuppressive agents
yes
- Bleeding risk +++
30% associated aneurisms
- Low risk of « PE »
inflammatory thrombus
- No thrombophilic factors
- Relapses on VKA
Anticoagulant
« non »
Relapse rate of thrombosis
in Behcet’s patients
Treatment
n=37 [1]
Corticoids +
IS
Anticoagulants + Anticoagulants
corticoids + IS
alone
n=16 12.5% n=17  5.9%
n=4  75%
Relapse risk = 46%
n=96 [2]
OR = 0.2-0.3 ; p=003
OR=0.6; p=0.4
n=292 [3]
--
n=185  20%
n=122  56%
n=131 [4]
29%
27%
91% (p=0.002)
[1] JK. Ahn et al. Clin Rheumatol 2008 / [2] Kahraman O, et al. Arthritis Rheum 2003
[3] AC Debois et al. Arthritis Rheum 2012 / [4] Alibaz O, et al. Arthritis Rheum 2014;
Bleeding risk with anticoagulants
in Behcet’s disease
DVT in Behçet’s  20% aneurisms
• 657 BD patients  62 (9%) DVT
 90% patients treated with VKA  2 bleedings (1 PAA)
Puja Mehta et al. Rheumatology 2010
• 292/807 DVT
 99% under VKA  7 bleeding episodes (2.6%)  1 PAA
• 38 having aneurisms
AC. Debois et al. Arthritis Rheum 2012
Management of pulmonary
arteries aneurisms
• Early diagnosis
+
• Aggressive therapy
Glucocorticoids + IS agents
Embolization (70% success)
survival
80% at 5 years
Hamuryudan V et al. Am J Med 2004
Peripheral artery
aneurisms / surgery
• Surgery
– Mortality :
– Anastomotic relapses:
– Graft thrombosis :
Aggressive medical treatment
Corticosteroids + IS
peri et post-operatory
5-30%
50%
40%
0-10%
10-15%
MC Park et al. Clin Rheumatol 2007
HJ. Ho et al. Clin Exp Rheum 2012
Peripheral artery
aneurisms / endovascular
Meta-analysis : 101 cases
 Recurrences (puncture sites) : 14 - 50%
Aggressive medical treatment
 Thrombosis : 6-40%
Corticosteroids + IS
peri et post-procedure
SS Yang et al. Rheum Int 2013 / CW Liu et al. JVS 2009 / C. Park et al. Radiology 2001
Other medications in
vasculo-Behçet
• Interferon a ?
• Anti-TNFa
More than 50 observations
Good results in the majority of cases
Second line treatment
• Other biologic
A. Arida et al. Semin Arthritis Rheum 2011
Silvestri E, et al. Expert Rev Cardiovasc Ther 2013/2014
Infliximab
or
adalimumab
Pulmonary vascular
involvement
Embolization in case
of active bleeding
second line
treatment
Methylprednisolone pulses (1g/d, 3dys)
+ oral prednisone (1 mg/kg)
Anticoagulant
Cyclophosphamide IV/monthly (1 an)
Maintenance : azathioprine (3-5 years)
« sceening »
aneurisms
TIPPs
for BCS
Major veins thrombosis
BCS/ICT/VCT
Surgery
Endovascular
Systemic arterial
aneurisms
Other deep vein
thrombosis
• Isolated superficial thrombophlebitis
 colchicine + NSAI + corticosteroids (low doses)
• DVT of legs / first relapse / CVT
 screen for aneurisms
YES
Corticosteroids
+ CYC+ ttt of
aneurisms
NO
anticoagulants +
corticosteroids +
AZA (3 to 5 years)
Thrombophlebitis is the 4th
symptom of hypopion uveitis.
Adamantiades B. Ann Occulist 1946
Conclusion
• Vasculo-Behcet  bad outcomes,
• Delay on diagnosis  delay in therapeutics
• The prognosis is considerably better today
compared to 20-30 years ago.
• It is certainly not enough!
 Urgent need for controlled trials
Acknowledgements
• Internal medicine
Rabat/Morocco
Adnaoui M
Harmouche H
Ammouri W
Maamar M
Bourkia M
• Internal medicine /Paris
Cacoub P
Weschler B
Guilevin L
• Vascular surgery
Bensaid Y
Sefiani Y
Lekehel B
• Ophtalmology
Berbich 0
• Neurology
Alaoui FM
Aidi S
• Dermatology
Ismaili N
• Radiology
El Hassani MH