BEHCET’S DISEASE AND ITS
Moderator : Dr. Puneet Bhargava
• First described in 1937 by Hulusi Behcet,
• As classic trisymptom complex of hypopyon, iritis, and
• Greek physician Adamantiades had reported disease 6
years earlier, as Adamantiades Behcet disease.
• First description probably predates both of these by 2500
years. Hippocrates (460–377 BC) describes an endemic
disease in Asia Minor characterised by “aphthous
ulcerations,” “deﬂuxions about genital parts,” “watery
ophthalmies of a chronic character and “large herpetic
• Chronic, relapsing-remitting, occlusive vasculitis
affecting multiple organ systems
• Characterized by oral and genital ulcerations
(sores), uveitis, skin
rashes, arthritis, thrombophlebitis, colitis, and
• Histologically, there is a combination of a perivascular
neutrophilic or lymphocytic infiltration, endothelial
cell damage or swelling, fibrinoid necrosis coupled
with a pro-thrombotic tendency
• Prevalence and expression vary geographically, much
higher in latitudes between 30° and 45° North,
• Around Mediterranean basin extending through
Middle East and Orient
• Striking similarity of distribution to ancient Silk Road
• Suggests that an inherited tendency to develop BD was
spread by merchants who traveled these trading
• Turkey has the highest prevalence: 80 to 370 cases per
• Japan, Korea, China, Iran, and Saudi Arabia ranges
from 13.5 to 20 cases per 100,000
• Much lower in Western countries.
• United States 0.33 per 100,000
• Predominant age: 3rd to 4th decades
• Predominant sex: M > F and with more severe
disease in some Mediterranean areas.
• In Iran, M:F ratio was 24:1 among 1712 patients.
• In Turkey, ratio was 16:1 among 427 patients.
• Genetics: One report in a mother and newborn (A.
Fam, Ann Rheumatic Dis 1981; 40:509-512). Very rarely
• Chronic morbidity is typical; leading cause is
ophthalmic involvement, which can result in
• Effects of disease may be cumulative, especially with
neurologic, vascular, and ocular involvement.
• Mortality rate is low, but death can occur from
neurologic involvement, vascular disease, bowel
perforation, cardiopulmonary disease, or as a
complication of immunosuppressive therapy.
• Cause is not known
• Immunogenetics, immune regulation, vascular
abnormalities, or bacterial and viral infection may
have a role
BD is associated with multiple hereditary and
environmental risk factors.
HLA-B51 and the Silk Road
• A heritable risk factor first identified in 1982
• HLA-B*5 locus includes family of HLA-B51 and HLA-
• In majority of racial groups, greatest heritable risk
factor for disease and severity, is HLA B51.
• 21 different alleles may exist at HLA-B*51 locus (B*5101,
• Both B*5101 and B*5108 are associated.
• HLA-B*52, which differs from HLA-B*51 by only two
amino acids in peptide binding groove, is not
associated with BD in any population, suggesting
selective peptide binding
• Geographical distribution of HLA-B*51 among healthy
subjects roughly corresponds with global disease
• But 1/3 of patients, even in countries with a high
disease prevalence, do not possess this gene.
• In Japanese series prevalence of HLA B51 is only 57%
(Mizuki et al., 1997).
• There is some evidence that HLA B51, as well as B12,
B15, B27, B57, DR2, and DR7 may bear a relationship
• A possible explanation for these data is that HLA-B*51
molecule expresses Bw4 motif, which itself may be
causally related to disease,
Global distribution of HLA-B51 among healthy ethnic control groups
with reference to the Silk Road and early demographic movements.
1. HLA-B51 or its B101 allele is significantly associated
2. MICA allele
• Polymorphic MHC class I–related A gene (MICA) family.
• Significantly associated with BD (74%), compared with controls
(45.6%) in Japan.
• A recent study of 23 Japanese patients showed a strong association
• Association b/w MICA6 and BD may be a secondary phenomenon
related to HLA-B51
3. MEFV gene mutations,
Seen in persons with Mediterranean fever, found associated with
Human MHC on short arm of chromosome 6.
TAP = transporter of antigenic peptides; 21-OH = steroid 21-hydroxylase enzyme; Bf =
properdin factor B of the alternate complement pathway; LT = lymphotoxin.
Putative role of MICA molecules and HSP expressed on mucosal epithelial cells. *MHC
class I chain related (MIC) gene locus is situated adjacent to HLA-B domain. MICA is
expressed at gastrointestinal epithelial surfaces in response to bacterial infection. γδ T
cells and NK cells are upregulated, recognise and kill MICA transfected cells. MICA
ligand for NKG2D, also expressed on γδ T cells and NK cells.
4. Levels of TNF-alpha reported significantly elevated
• Park et al analyzed TNF-alpha haplotypes in promoter response
element that affect binding affinity of certain transcription factors.
• Showed TNF-alpha -1031*C, -863*A, -857*C, and -308*G alleles
significantly associated and useful in identifying more susceptibles
5. ERAP1 variant
Associated with BD processes microbial proteins in such a way
that they can be loaded onto HLA-B51 molecule to trigger an
abnormal immune response
6. A significant association of BD with variants near CCR1,
KLRC4, AND STAT4 gene also found
7. Single nucleotide polymorphism (SNP)
• Gene encoding protein tyrosine phosphatase type 22 (PTPN22
620W) has an inverse relationship with BD
6. Killer inhibitory receptors (KIR)
• TCRs, expressed mainly by NK cells and γδ TCR+ T cells
• Inhibit cell mediated toxicity.
• Binds to molecular sequences which are also found in some
HLA class I molecules, including HLA-B51.
• An expansion of CD8+ cells, γδ TCR+ cells, and NK cells has
• This has led to suggestion that host MHC class I haplotype
(HLA-B*51) may “fine tune” the regulation of KIR expression.
Viral and bacterial infection
• Aetiology of BD have focused predominantly on herpes
simplex virus infection, streptococcal infection, and
autoimmunity or cross-reactivity b/w microbial and oral
• Behcet suggested HSV as a causative agent
• PCR studies have remarkably improved diagnostic
significance of viral infections, especially HSV.
• HSV DNA has been detected in saliva, genital ulcers, and
intestinal ulcers in BD Pts.
• BD–like symptoms have been induced in an Institute for
Cancer Research mouse after inoculation of HSV into its
• Acquired hypersensitivity to
streptococcal antigens plays
an important role in
etiopathology of BD
• 65-kd microbial HSP, shows
significant homology with
human 60-kd mitochondrial
• Uncommon serotypes
sanguis found in BD, cross-
react with 65-kd HSP, which
also shares antigenicity with
an oral mucosal antigen.
Role of bacterial and human heat shock
protein (HSP) 60/65 as T cell antigens in BD
•T cell responses
against retinal S-
Ag are present in
various types of
An immunological model for role of cross reactive
retinal-S antigen (S-Ag) and HLA-B27/51 derived
peptides in chronic posterior uveitis of BD
T-cell epitope mapping has identified 4 peptides derived
from sequence of 65-kd HSP that specifically stimulates
TCR+ lymphocytes from patients with BD.
• These peptides (111-125, 154-172, 219-233, and 311-325) show
significant homology with corresponding peptides (136-150, 179-
197, 244-258, 336-351) derived from human 60-kd HSP.
• B-cell epitopes within mycobacterial HSP65 or human HSP60
overlap with T-cell epitopes, and both IgG and IgA antibodies have
• Among 4 T- and B-cell epitopes, peptide 336-351 of 60-kd HSP is
significantly associated with BD in Britain, Japan, and Turkey.
• HSP60/65 found significantly increased in epidermal cells of BD
• Antibody levels to HSP65 were significantly elevated in CSF
• Th1 cytokine IFN-y level is elevated in serum, in skin T cells, and
• IL–12 is generated by the stimulation of CD4 -T cells with HSP
• IL-12 can also be secreted by neutrophils
• Th2 cytokine IL-6 is also increased in active disease
• Stimulation with S sanguis (KTH-1) of T-cell lines generated from
patients with BD suggests that Th1-type mRNA is induced (IL-2
• Investigations of intracellular IFN and IL-4 suggest that
polarization toward Th1 type of cells occurs in patients with active
BD b/c of a significant increase in intracellular IFN that was not
observed with IL-4.
• Converse was found in another investigation by stimulating
peripheral blood mononuclear cells, with increased Th2
cytokines (IL-10 and decreased IL-2 or IFN) in active Behçet
• Intracellular adhesion molecule 1 was enhanced in human
dermal microvascular endothelial cells after treatment with
serum from patients with BD, and this may have induced
increased adhesion of T cells to endothelial cells.
• Levels of proinflammatory cytokines TNF– alpha, TNF
receptor 1, IL-1, and IL-8 are elevated and remain unregulated
in peripheral blood mononuclear cells and neutrophils
• Levels of IL-10 and IL-13 may also be elevated.
• IL-23 p19 mRNA has been detected in erythema nodosum-
like lesions of BD
• Plasma levels of vascular endothelial growth factor is
• Neopterin (marker of cellular immune activation)
• Produced by human monocytes and macrophages in response to
interferon-gamma (IFN-gamma) released from activated T cells
• Kose et al showed that serum levels of neopterin were significantly
higher in active and inactive BD patients than in controls.
• Polymorphisms in toll-like receptor 4 have been associated
Endothelial and vascular dysfunctions
• Vascular changes leading to vasculitis and thrombosis are
important pathological feature
• A recent study proposes that immunoglobulin to carboxy-
terminal subunit of Sip1 (Sip1 C-ter) may be a useful novel
• Level was elevated in 41% of BD patients, and in 45% of
primary vasculitis patients, pointing at endothelial dysfunction
• Antiendothelial cell antibodies significantly increased
• T cells (mostly CD4 cells), B cells, and neutrophils are
• Esmat et al showed much higher serum lipoprotein(a) levels in
patients with vascular complications and lower levels of serum
nitrites during disease activity.[
• Association of factor V Leiden and G20210A prothrombin
mutation with thrombosis in BD patients is also seen
• Prostanoid synthesis in endothelial cells or vessel walls is
impaired, whereas von Willebrand factor, thromboxane, and
thrombomodulin are increased.
• Level of endothelin 1 and 2 is increased in patients with
• Endothelial cell–dependent vasodilator function is
• Thrombin activatable fibrinolysis inhibitor levels are higher,
possibly contributing to increased thrombosis
• Signs and symptoms may be recurrent, may precede onset of mucosal
membrane ulcerations by 6 months to 5 years.
• Prior to onset of disease, patients may experience a variety of
• Weight loss
• Generalized weakness
• Decreased or elevated temperature
• Pain of the substernal and temporal regions
• A history of repeated sore throats, tonsillitis, myalgias, and migratory
erythralgias without overt arthritis is common.
spectrum of organ involvement in behçet’s disease.
Diagnostic criteria from the Behçet syndrome research
committee of Japan (1987 revision)
a) Complete –
Four major features
b) Incomplete –
(1) 3 major features,
(2) 2 major and 2 minor
(3) Typical ocular symptom
and 1 major or 2 minor
c) Possible –
(1) 2 major features
(2) 1 major and 2 minor
• Major features
• Recurrent aphthous ulceration of oral mucous
• Skin lesions -Erythema nodosum – like lesions,
subcutaneous thrombophlebitis, folliculitis
(acnelike lesions), cutaneous hypersensitivity
• Eye lesions - Iridocyclitis, chorioretinitis,
retinouveitis, definite history of chorioretinitis
• Genital ulcers
• Minor features
• Arthritis without deformity and ankylosis
• Gastrointestinal lesions characterized by
• Vascular lesions
• Central nervous system symptoms
• Recurrent oral ulceration - Minor aphthous or major aphthous or
herpetiform ulceration observed by a physician or reported reliably by a
patient that recurs at least 3 times in one 12-month period plus 2 of the
• Recurrent genital ulceration –
Recurrent genital aphthous ulceration or scarring, especially males, observed by a
physician or reliably reported by a patient
• Eye lesions –
(1) Anterior uveitis, posterior uveitis, and cells in vitreous upon slit-lamp
examination or (2) retinal vasculitis observed by physician (ophthalmologist)
• Skin lesions –
(1) Erythema nodosum–like lesions observed by physician or reliably reported by a
patient, pseudofolliculitis, and papulopustular lesions or (2) acneiform nodules
consistent with Behçet disease, observed by a physician, and in postadolescent
patients not receiving corticosteroids
• Positive pathergy test –
An erythematous papule larger than 2 mm at prick site 48 hours after application
of a 20- to 22-gauge sterile needle, which obliquely penetrated avascular skin to a
depth of 5 mm as read by a physician at 48 hours
Findings are applicable if no other clinical explanation is present.
International criteria for the classification of Behçet disease (1990)
• Oral ulcers (100%)
• Indistinguishable from common aphthae (canker sores).
• Aphthae may be more extensive, more painful, more
frequent, and evolve quickly from a pinpoint flat ulcer to a large
• Lesions can be shallow or deep (2-30 mm in diameter) and
usually have a central, yellowish, necrotic base and a punched-
out, clean margin.
• Appear singly or in crops, located anywhere in the oral
cavity, persist for 1-2 weeks, and subside without leaving scars.
• M/c sites - tongue, lips, buccal mucosa, and gingiva;
• Tonsils, palate, and pharynx are less common sites.
• Interval b/w recurrences ranges from weeks to months.
• 3 types:
Consists of 1-5 small, moderately
painful ulcers persisting for 4- 14
1-10 very painful ulcers,
measuring 10-30 mm, persisting
up to 6 weeks, and possibly
leaving a scar upon healing
Recurrent crop of as many as
1000 small and painful ulcers
• Genital ulcers (90%, M>F)
resemble their oral
counterparts but cause greater
• In males, usually occur on
scrotum, penis, and groin.
• In females, occur on vulva,
vagina, groin, and cervix
• Ulcers may found in urethral
orifice and perianal area.
• Epididymitis may arise in men
• Orchiepididymitis,10.8% of
A variety of skin lesions may appear,
eruptions (55-83%, M>F)
lesions (44-62%, F>M)
• Erythema multiforme–like lesions
• Bullous necrotizing vasculitis
• Pyoderma gangrenosum
• Pathergy reaction
• Erythematous papule larger than 2
mm develops at prick site after 48
• Higher positivity (84-98%) is found
in Mediterranean areas and Middle
East than in Far East (40-70%),
• Western countries having
significantly lower positivity
pathergy reaction at
• Eye disease is usually present from outset but also may
develop within first few years.
• Major cause of morbidity and most dreaded complication
b/c it occasionally progresses rapidly to blindness.
• Childhood-onset Behçet uveitis is more common in males.
• Most diagnostically relevant lesion is posterior uveitis, ie,
• Other include anterior uveitis, iridocyclitis, chorioretinitis,
scleritis, keratitis, vitreous hemorrhage, optic neuritis,
conjunctivitis, retinal vein occlusion, and retinal
• Hypopyon, considered hallmark of BD, is now uncommon.
• Decreased visual acuity is a result of secondary glaucoma,
cataracts, or vitreous hemorrhage.
• Blindness has been reported to occur within 4-5 years from
onset of ocular symptoms.
• Retinal vein thrombosis leading to sudden blindness is not
• Saadoun et al found that cerebral venous thrombosis
(CVT) was present in 7.8% of a large cohort of patients
• Main complication of CVT was severe visual loss from optic
Inflammatory retinal vein occlusion with
associated vitritis and retinal vasculitis
before (A) and after (B) treatment with high
dose oral steroid.
Anterior segment complications of retinal
vein occlusion: retinal ischaemia with
secondary rubeosis iridis.
(A) Acute branch retinal vein occlusion. (B)
Total vascular obliteration and optic atrophy
secondary to recurrent vascular occlusion.
Ocular involvement showing
HYPOPYON – pus in the
anterior chamber associated with
• Occurs in 30-50%, mostly men.
• H/P- media thickening, elastic fiber splitting, and
perivascular round cell infiltration.
• 4 types of vascular lesions –
• Aterial and venous occlusions, aneurysms, and varices.
• Venous inv. M/C occlusion, rarely varices.
• M/C sites - SVC,IVC, deep femoral vein, and
• Arterial complications, 7% , M/C Aneurysm and occlusion
• Subclavian and pulmonary artery, M/Cly occluded.
• Different clinical presentations A/t site
• Pulseless disease -subclavian artery occlusion.
• Hypertension - renal artery stenosis.
• Femoral artery stenosis - intermittent claudication, AVN of
• Pulmonary vasculitis- dyspnea, chest pain, cough
• Aneurysm accounts for most vascular deaths.
• Common sites- abd. aorta, femoral and thoracic artery.
• Gastrointestinal involvement (>10%)
• Clinical spectrum is enormously varied
• Anorexia, vomiting, dyspepsia, diarrhea, abdominal
distention, and abdominal pain
• Cardiac manifestations (5-17%)
• Coronary vasculitis and thrombosis, pericarditis,
myocarditis, endocarditis with granulomatous changes
or fibrosis, regurgitation, and diastolic dysfunction
• Lung involvement (up to 18%)
• Pulmonary vasculitis, hypertension, pleural effusions
Joint manifestations (30 - 40%)
• More than half patients develop signs or symptoms of
synovitis, arthritis, and/or arthralgia during course of
• Most frequent minor feature in childhood-onset BD is
reported to be arthritis, occurring in 11 of 40 patients.
• Multiple-joint involvement is common.
• Clinical features have been reported as pain,
tenderness, swelling, limitation of joint movement,
warmth, and morning stiffness.
Neurologic manifestations (3.2-49%)
• May present as meningoencephalitis, a multiple sclerosis–like illness,
acute myelitis, stroke, or pseudotumor cerebri.
• Most serious, leading to severe disability and a high fatality rate.
• Usually occur within 5 years of disease onset.
• Severe headache is most frequent initial symptom.
• Three categories (Pallis and Fudge (1956) and Wadia and Williams (1957)
(1) Brain stem syndrome,
A/w fever, arthralgia and skin eruption; brainstem signs developes
subacutely with evolving cranial neuropathies, ocular motor
dysfunction, nystagmus and gaze palsies, dysarthria and ataxia, bulbar
muscle weakness, Headache with meningism, CSF pleocytosis and high
(2) Meningomyelitis syndrome,
Meningitis with spinal cord and hemisphere signs (Silfverskiold, 1951)
(3) Organic confusional syndrome,
Meningoencephalitis without focal neurological signs, some times
chronic and progressive, resulting ultimately in dementia,
Parkinsonism, pseudobulbar palsy and quadriparesis
• Pregnant women may experience more severe
symptoms during first trimester.
• Overall, pregnancy does not seem to markedly affect
the course of BD.
• Close follow-up is necessary to monitor the health of
mother and baby.
• Mild anemia and leukocytosis in chronic disease.
• ESR, C-reactive protein value, and other acute phase
reactants may be elevated during the active didease, but
they do not correlate well with clinical activity.
• IgA, IgG, alpha-2 globulin, IgM, and immune complexes
are occasionally elevated.
• Rheumatoid factor and antinuclear antibodies are absent.
• Antineutrophil cytoplasmic antibody and antiphospholipid
antibody test results are usually negative.
• Vasculitis is thought to affect vessels of all
sizes; various skin lesions are thought to be
secondary to small vessel vasculitis.
• H/P is variable, dependent upon type of
• Pathergic lesions:- Characterized by a heavy
neutrophilic infiltrate without fibrin within
• Erythema nodosum–like lesions:- Show a
perivascular lymphocytic infiltrate in deep
dermis and septa with a lymphocytic
vasculitis but lack histiocytic granulomas of
typical erythema nodosum.
• Aphthous ulcers have a nonspecific
pathology with a variable infiltrate of
lymphocytes, macrophages, and neutrophils
at base of ulcer.
• T-cell subsets with a preponderance of
helper-inducer cells over T suppressor-
cytotoxic cells have been observed in
Histology of ulcers revealing neutrophilic
infiltrate and vasculitis
Electron microscopic observations
• Erythema nodosum–like lesions shows microvascular
changes and lymphocyte-mediated fat cell lysis.
• Small dermal blood vessels embolized by thrombi are
observed at sites of needle prick reaction (pathergy)
and at erythema nodosum–like lesions.
• Early changes in fat cells may be caused by vascular
changes brought about by the specific degeneration of
endothelial cells and vascular stenosis a/w delayed-
type hypersensitivity reaction.
BD needs multidisciplinary approach
• Dermatologist - For evaluation of mucocutaneous lesions (ie, oral
ulcer, genital ulcer, skin lesions)
• Ophthalmologist - For evaluation of eye involvement
• Rheumatologist or orthopedic surgeon - For evaluation of joint
• Neurologist or psychiatrist - For evaluation of CNS involvement
• Internal medicine specialist - For evaluation of gastrointestinal,
pulmonary, renal, or endocrine involvement
• General surgeon - For evaluation of gastrointestinal involvement
• Chest surgeon or cardiologist - For evaluation of cardiovascular
• Ear, nose, and throat specialist or dentist - For evaluation of oral cavity
• Treatment of BD symptomatic and empiric.
• Choice of treatment depends on site and severity of
• mild diet, avoidance of irritating agents,
• Caustic solutions (silver nitrate, 1%-2%; tinctura myrrha, 5%-10%
weight/volume; H202,0.5%; methylviolet,0.5%) 1-2xld
• Antiseptic and anti-inflammatory preparations (amlexanox, 5% in
oral paste; triclosan, 0.1% mouthwash solution and in toothpaste ), 3%
diclofenac in 2.5% hyaluronic acid, tetracycline mouthwash
• Corticosteroids (triamcinolone mucosal ointment, dexamethasone
mucosal paste, betamethasone pastilles) 4 x/day or during night
(ointment / paste) or intrafocal infiltrations with triamcinolone
suspension 0.1-0.5 mL per lesion
• Anaesthetics (lidocaine - 2%-5%; mepivacaine - 1.5%, tetracaine -
0.5%-1% gels or mucosal ointments) 2-3 x/day
• 5-Aminosalicylic acid (5% cream) 3 x/day (reduces the duration of
lesions and the pain
• Sucralfate suspension, 5 mL x 4/day (for oral aphthous and genital
• Topical tacrolimus, nicotine patches, and topical G-CSF
Genital ulcers and skin lesions,
• Corticosteroid and antiseptic creams for 7 days.
• Painful genital ulcerations topical anaesthetics in
• Corticosteroid injections (triamcinolone, 0.1 to 0.5
ml/lesion) in recalcitrant ulcerations.
• Mainstay for all clinical manifestations.
• Have a beneficial effect on acute manifestations, no definite
evidence effectiveness in controlling progression.
• Adverse effects of long-term therapy must be considered.
• Mucocutaneous lesions and arthritis:-
• NSAIDs, zinc sulfate, levamisole, colchicine, dapsone, or
sulfapyridine and thalidomide. Immunosuppressive therapy
with azathioprine, chlorambucil, or cyclophosphamide
• Uveitis and CNS involvement:-
• Systemic corticosteroids, azathioprine, or cyclosporine, MTx
• In CNS involvement, risks and benefits of cyclosporine
need to be considered b/c of neurological side effects.
• Anticoagulants are given to patients with thromboses.
• Other therapeutic approaches
• IFN alfa, IFN gamma, acyclovir, high-dose corticosteroids or
cyclophosphamide pulse therapy, and tacrolimus
• Japanese tacrolimus study group reported that
tacrolimus was effective in treating refractory uveitis in a
• Adverse effects were renal impairment (28.3%), neurologic
symptoms (20.8%), gastrointestinal symptoms (18.9%), and
• Subcutaneous IFN alfa-2a therapy
• resulted in reduced ulcers and eye disease.
• Flulike symptoms were most common adverse effect.
• Leukopenia, hair loss, and development of antinuclear and
antithyroid antibodies were reported less commonly.
• A patient presenting with oral ulcers resistant to
prednisone, azathioprine, colchicine, dapsone, and
cyclosporin responded well to lenalidomide.
• A patient with Behçet disease with ocular involvement,
dependant on corticosteroids and refractory to
azathioprine, showed improvement with addition of
• A case of Behçet disease resistant to prednisolone,
cyclosporin, azathioprine, infliximab with
methotrexate, and colchicine has been successfully
treated with anakinra.
• infliximab, and etanercept, have decreased frequency of
• Etanercept has been used at 25 mg twice a week.
• Pediatric case responding to infliximab has been reported.
• Infliximab has resulted in responses after etanercept failed.
• Infliximab infusions of 5-10 mg/kg have been used with
variable dosing schedules.
• Several patients not responding to infliximab have been
treated with adalimumab.
Behcet’s Disease: Prognosis
• Behcet's disease has an undulating course of
exacerbations and remissions, and may become less
severe after approximately 20 years.
• Appears to be more severe in young, male, and Middle
Eastern or Far Eastern patients.