behçet disease its differential diagnosis › congres2018 › conference › 6avr › seance5 ›...
TRANSCRIPT
Behçet Disease and
Its Differential Diagnosis:From Bench to Bedside
Ahmet GulIstanbul University
Istanbul Faculty of Medicine
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Disclosures
• Disclosures: – Consulting fees from MSD, AbbVie, Pfizer, Novartis,
Servier, UCB, Roche
– Research grants from MSD, Novartis, Xoma (US) LLC, UCB
Outline
• Original definition of the disease and diagnostic challenges
• Update on the pathogenesis based on genetic findings• Translation of genetic findings as potential treatment
targets
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Description of the disease by Hulusi Behçet
• Patients with recurrent– Oral aphthous ulcers– Genital ulcers– Uveitis
Dermatologische Wochenschrift 1937; 105:1152-7
• A distinct disease– Viral etiology?
– Role of focal infectionsin oral cavity?
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• Variable recurrence rates– Usually self limited and heal without scarring– Can cause permanent tissue damage
Behçet’s Disease – Recurrent Inflammatory Manifestationswww.samidz.com
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Behçet’s disease as a systemic disease
• Different subsets of patients - target organ associations with factor analysis shows:– Oral ulcers, genital ulcers, and erythema nodosum– Papulopustular skin lesions and joint involvement– Uveitis– Superficial and deep vein thrombosis, dural sinus
thrombosis
• More severe disease course in males and in those aged <25 at disease onset
Tunc et al. J Rheumatol 2002; 29: 2393-6
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JEADV 2014, 28, 338–347
Behçet Disease – Classification / Diagnostic Criteria
• A set of manifestations – The right combination ?...
• Possibility of classifying some overlapping conditions is higher in patients with only mucocutaneous manifestations– Circular problems in criteria development due to definition of cases
by a heterogeneous group of experts
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Behçet disease – A Multisystem Disorder with Recurrent Manifestations
Mucocutaneous
Non-aphthous beginning in 15-20%Smoking may suppress oral ulcers
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• Aphthous ulcers ?• Bipolar ?
Oral and Genital Ulcers
Letsinger JA, et al. J Am AcadDermatol 2005;52:500-8.Keogan MT. Clin Exp Immunol 2009; 156: 1–11 with modification
– Behçet disease– MAGIC syndrome– Crohn disease– Sweet syndrome– Erythema multiforme– Gluten enteropathy– Mevalonate kinase disease
(Hyper-IgD syndrome)– HA20
– Immunodeficiencies– Bullous skin disorders– Drug eruptions– CMV and HSV infections– Cyclic neutropenia– Trisomy 8– Erosive lichen planus– Idiopathic complex aphthosis
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Behçet disease – A Multisystem Disorder with Recurrent Manifestations
MucocutaneousOcular
Deutsche Medixinische Wochenschrift 1926; 36:1503-5
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• Bilateral posterior / panuveitis
Tugal-Tutkun I, et al. Ocular Immunology & Inflammation 2013; 21: 337–350
Behçet disease – ocular findingswww.samidz.com
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Haploinsufficiency for A20 and Behçet-like Disease
Zhou et al. Nat Genet 2016;48:67-73
• Monogenic disease with Behçet disease-like manifestations– Increased NF-κB and NLRP3 activation– Good response to IL-1 and TNF blockade
Stoffels M, Kastner DL. Annu Rev Genomics Hum Genet 2016;17:245-72.
“Is there any better way to advance the proper practice of medicine than to give our minds the discovery of the usual law of nature, by careful investigation of cases of rarer forms of disease?Sir William Harvey (1578–1657)
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• Differential diagnosis with Behçet disease
Aeschlimann FA, et al. Ann Rheum Dis 2018;0:1–8.
Haploinsufficiency for A20 and Behçet-like Diseasewww.samidz.com
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Behçet disease – A Multisystem Disorder with Recurrent Manifestations
Mucocutaneous
Arthritis
Ocular
Gastrointestinal
Neurologic
Vascular
Pathergy
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Behçet’s disease as a systemic vasculitis• Variable vessel vasculitis
– Venous involvement > Arterial involvement
Jennette JC, et al. Arthritis Rheum 2013; 65: 1-11.
Large veins
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• 882 patients with vascular involvement among 5970 patients (14.7%)– Isolated deep vein thrombosis is the most common form of
major vascular disease (67.1%) in Behçet’s disease
Taşçılar et al. Rheumatology 2014;53:2018-22
Vascular involvement in Behçet’s diseasewww.samidz.com
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Vascular involvement in Behçet’s disease
Posterior 3D image demonstrating the left main pulmonary artery stump
Endarterectomy material
• Inflammatory venous thrombus– Sticky rock-hard in situ thrombi– Low risk for thromboembolism
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• Patients with extrapulmonary artery involvement (EPAI) were significantly older than those with venous and pulmonary artery involvement (PAI).
Taşçılar et al. Rheumatology 2014;53:2018-22
Vascular involvement in Behçet’s diseasewww.samidz.com
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Behçet’s disease as a systemic vasculitis – Pathology
• Vasculitis / vasculopathy with a mixed cellular perivascular infiltrate and a tendency for thrombosis– Pseudoaneurysms and severe perivascular inflammation
destroying surrounding tissues– Vasa vasorum vasculitis
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Behçet’s disease – Neurologic Involvement
• It is seen in about 5% to 10% of patients. • Subacute brainstem syndrome is the most common form.
– Focal or multifocal inflammatory parenchymal disease in the brainstem and diancephalon with pyramidal signs, ataxia, hemiparesis, behavioral changes, and sphincter disturbance
– CSF analysis reveals pleocytosis including neutrophils and lymphocytes, elevated protein and interleukin-6 (IL-6) levels, with normal glucose.
a- T2 b- T1
Courtesy Prof Gülşen Akman Demir
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Behçet’s disease – Neurologic Involvement
• Much less frequently (10–20%), patients may present with isolated vascular findings as cerebral venous sinus thrombosis causing intracranial hypertension and papilledema. – This vascular group has a better prognosis.
Taşçılar et al. Rheumatology 2014;53:2018-22
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Behçet Disease
Behçet Disease vs Crohn Disease
Oral aphthous ulcers
Genital aphthous ulcers
Papulopustular or EN-like
Uveitis
Arthritis /SpA
Uveitis
Oral aphthous ulcers
Genital aphthous ulcers
Arthritis /SpA
Papulopustular or EN-like
Intestinal involvement Intestinal involvement
Crohn Disease
Vascular involvementNeurologic involvement? Pathergy reaction
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• Innate immune response– Non-specific hyperreactivity
• Pathergy phenomenon– Increased expression of
proinflammatory cytokines– Neutrophil-rich inflammation(DDx with Sweet Syndrome and PG)
• Adaptive immune response– CD8 and CD4 T cells, γδ T cells– Th1 type polarization– Th17 response
• Triggers of inflammatory attacks– Viral triggers ?
• Herpes simplex ?, novel ?, others
– Bacterial triggers• Steptococci, others
Behçet disease – inflammatory disorder
Dermatologische Wochenschrift 1937; 105:1152-7
Sohn S, et al. Eur J Dermatol 1998; 8: 21-3.
Kaneko et al. Genet Res Int 2014:581468
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Behçet disease – Significant host predispositionFamilial Aggregation
λs = 11.4-52.5Gul et al. Ann Rheum Dis 2000; 59: 622-5
Geographic Distribution
Verity et al. Br J Ophthalmol 2003; 87: 1175-83.
HLA-B*51 Association
Ohno et al. Lancet 1973.
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Behçet disease – Association with MHC Class I Region
Remmers et al. Nat Genet 2010; 42: 698-702 Mizuki et al. Nat Genet 2010; 42: 703-6
• HLA-B*51 is an essential element of the BD-associated HLA-B/MICA extended haplotype
Ombrello MJ, et al. PNAS 2014
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A B
β2-microglobulin
Antigen binding groove
Antigen binding groove
NK receptor binding site
Asp63
Phe67
Antigen
HLA-B*51 heavy chain
Possible HLA-B*51 – related pathogenic mechanisms in Behçet disease
Gul A. Semin Immunopathol 2015;37:413-8.
Presentation of “the peptides” to cytotoxic CD8+ T cells
ADAPTIVE
Interaction with receptors On NK cells, CD8+cells, γδ+ T cells
INNATE AND ADAPTIVE
Folding problems and ER stressINNATE
AUTOINFLAMMATION
Tissue specific“Peptides”
No association with KIR3DL1/DS1polymorphism
B*51/Bw4-independentKIR3DS1 association in ocular subsetGenes Immun 2016
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Kirino et al. Nat Genet 2013;45:202-7
Peptides derived from degraded self proteins
and other cytoplasmic proteins in each tissues
CytosoleProtesomeImmunoproteasome
X X Y X X X X X X XEndoplasmic ReticulumERAP1ERAP2
HLA Class I
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HLA-B*51 and Other HLA Class I Alleles
Ombrello MJ, et al. PNAS 2014
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MHC-I-opathies ?
HLA-A
Tissue-specificPeptidomeERAP1 haplotypesand others
HLA-C
HLA-B
McGonagle et al. Nat Rev Rheumatol 2015;11:731-40
Overall risk assessment using Bayesian approach is under progress
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• Genetic predisposition for low IL-10 expression is associated with Behçet’s disease
Behçet Disease – Association with IL10
Remmers et al. Nat Genet 2010; 698-702
PBMCTurkish healthy donorsLPS, 24 h
MonocytesAmerican healthy donorsMDP + PAM3Cys , 24 h
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Behçet disease – Association with IL23R-IL12RB2
Remmers et al. Nat Genet 2010; 698-702
• IL23R / IL12RB2 association– Associated with the IL23R block
• Non-genomewide association with IL12A– Confirmed in Immunochip analysis
• STAT4 mRNA expression was higher in individuals carrying the risk allele A
Kirino et al. Nat Genet 2013;45:202-7.
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• Association with TLR4, NOD2 and MEFV (M694V) variantsBehçet disease – Association of with rare autoinflammatory variants
Kirino et al. Proc Natl Acad Sci U S A 2013;110:8134-9
• Relative protection from intestinal inflammation– Exaggerated inflammatory reaction against microbial antigens (BD)
vs Defective clearance of certain microbial infections (CD)
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• Shared inflammatory pathways with spondyloarthritis, autoinflammatory disorders, and microbe-host interactions
Behçet’s disease – Complex Autoinflammatory Disease
Gül A. Curr Opin Rheumatol 2014
Phenotype definition
Triggers
Inflammatoryfeatures
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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 20 22
12
10
8
6
4
2
0
-log P
19 21 Chromosome
IL10
IL1A-IL1B
CCR1
IL12A
IRF8
MHC
IL23R-IL12RB2
KLRC4
FUT2
ADO-EGR2
RIPK2
LACC1
CEBPB-PTPN1
74
72
70
ERAP1
Behçet disease – Immunochip Results
Takeuchi et al. Nat Genet 2017
Locus Behçet's disease IBD Pso CeD MS AS PBC SLE RA T1D SSc SJO JIA CDa UCa LeprosyMHC Class I HLA-B*51
IL1A-IL1B rs3783550/rs4402765
MEFV p.Met694Val
KLRC4 rs2617170
CEBPB-PTPN1 rs913678 rs913678
CCR1 rs7616215/rs13092160 rs13098911
RIPK2 rs2230801
LACC1b rs2121033 rs3764147 rs3764147 rs9567307
FUT2 rs681343/rs601338/rs1047781 rs516246 rs516246 rs516246
ADO-EGR2 rs1509966/rs7075773/rs224127 rs10761659 rs10761659 rs10761659
ERAP1 rs17482078 rs1363907 rs27432 rs30187 rs1363907
IL10 rs1518111/rs1800871
IRF8 rs11117433/rs7203487/rs142105922 rs11117433
IL12A rs76830965/rs17810546 rs17810546
IL23R-IL12RB2 rs924080/rs1495965
TNFAIP3 rs9494885
STAT4 rs7574070/rs897200
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Behçet disease – Treatment• Treatment aims
– to control inflammatory findings of an acute attack• Early treatment is critical in ocular, vascular, neurologic and GI
manifestations– to prevent recurrent flares
• Corticosteroids (topical, oral, IV, intraarticular, intravitreal)• Colchicine
– Mucocutaneous and articular manifestations– Others (thalidomide, dapsone, etc)
• Azathioprine, – Ocular, vascular, articular, GI, neurologic, and refractory mucocutaneous
• Cyclosporine A– Ocular– May exacerbate neurologic involvement
• Cyclophosphomide– Serious vascular and neurologic manifestations
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• Translation of the genetic findings to define treatment targets?
– Monoclonal anti-TNFs: Infliximab, adalimumab• For all refractory cases with ocular, GI, neurologic, articular and mucocutaneous findings
– Interferon alpha: increased IL-1Ra and IL-10, decreased Th17 response
• A higher potential to induce remission in ocular disease?
Behçet disease – Complex inflammatory features
N Engl J Med 2015;372:1510-8.
− Apremilast (PDE4 inhibitor): decreased TNF, increased IL-10Effective in refractory oral ulcers
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Refractory Behçet disease uveitis – Anti-IL-1β• Favorable results in acute exacerbation with IV infusion of
gevokizumab without any increase in corticosteroid dosage and despite discontinuation of immunosuppressive drugs
• SC gevokizumab was not successful in the prevention of recurrent attacks compared to placebo on top of immunosuppressive drugs in Phase 3 trial
• Favorable results with anakinra and canakinumab in several refractory casesVitali et al. IMAJ 2016; 18: 171–6
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Refractory Behçet disease uveitis – Anti-IL-17
Hueber et al. Sci Transl Med. 2010 Oct 6;2(52):52ra72.
Pilot trialSingle 10mg/kg IV infusion
SC SecukinumabIV Secukinumab
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Refractory Behçet disease – Ustekinumab
Mirouse A, et al. J Autoimmun 2017;82:41-46.
• It binds to p40 subunit of IL-12 and IL-23• Pilot, open-label trial for oral ulcers in 14 patients
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Behçet’s Disease – Anti-IL-6
• Few favorable and negative case reports– Good response in ocular and neurologic manifestations– Exacerbation of mucocutaneous features ?
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• Behçet disease is a unique multifactorial inflammatory disease– It has distinctive clinical features in patients with ocular,
vascular and parenchymal neurologic involvements
– MHC Class I-associated phenotype and tissue-specific inflammatory response is important in its pathogenesis
• Different HLA Class I / ERAP1 combinations
– Deregulated host-microbial interactions plays a critical role• Different responses to PAMPs and DAMPs
– Findings of deregulated inflammatory response can be seen in both innate and adaptive immunity.
• Hyper-reactive innate inflammatory response• Th1/Th17 type of adaptive immune response
Behçet disease – Complex inflammatory features
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Genetic SusceptibilityHLA-B*51, other HLA alleles, non-HLA
polymorphisms
Environmental TriggersStreptoccocal antigens, viruses, trauma
Hyper-Inflammatory ResponseInnate Immunity
Activation of neutrophils, monocytes, NK cells and innate lymphocytes
Adaptive Immunity
Th1 polarizationTh17 polarization
MucocutaneousAphthous ulcers
Papulopustular lesionsNodular lesions
OcularPosterior/Panuveitis
Endothelial Activation
ThrombosisVasa vasorum vasculitis
Clinical Manifestations
VascularSuperficial thrombophlebitis
Deep vein thrombosisArterial aneurysms and occlusions
NeurologicParenchymal
Vascular
MusculoskeletalArthritis
GastrointestinalAphthous ulcers
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Istanbul UniversityIstanbul Faculty of MedicineDepartment of Internal Medicine, Division of RheumatologyAhmet Gül, Murat Inanc, Lale Öcal, Orhan AralDepartment of OphthalmologyIlknur Tugal Tutkun Department of NeurologyGulsen Akman Demir (now moved to Bilim University)DETAE, Department of GeneticsDuran Üstek, Fulya Cosan, Neslihan Abacı, Zeliha Emrence, Aris Cakiris, Sema Ekmekçi, and othersCerrahpaşa Faculty of MedicineHasan Yazıcı, Emire Seyahi, Yılmaz Özyazgan, Serdal Ugurlu
Koç UniversityBurak Erman
NIH, NHGRIDan Kastner, Elaine Remmers, Yohei Kirino, Mike Ombrello, Masaki Takeuchi, George Bertsias, and others
Other collaboratorsJapan Yoshiaki Ishigatsubo, Nobuhisa Mizuki, Shigeaki Ohno, and othersOthers Wei Chen, Cristopher Amos, Graham Wallace, Oliver J. Brand, Eldad Ben-Chetrit, Phedon Kaklamanis, Dongsik Bang, Fereydoun Davatchi, Farhad Shahram, Bahar Sadeghi Abdollahi, Abdolhadi Nadji, NiloofarMojarad Shafiee, Fahmida Ghaderibarmi, Sofia A. Oliveira
Acknowledgments
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