IN THE NAME OF GOD

Gholamrezapoor, MD, resident of internal medicine

&Sasan Fallahi, MD, rheumatologist, Kerman

University of Medical Sciences

Three cases of Behcet`s disease with vascular involvement

CASE PRESENTATION

FIRST CASE

A 48 years old female

HISTORY

• Chief complaintPain and swelling of the left lower limb• Present illness Patient’s problem has been started from four weeks ago,

initially she had pain and subsequently swelling of the left lower limb.

Swelling appeared initially in distal side of leg and then extended to proximal side of the left thigh.

She also had history of fever, especially at the evening.No dyspnea, chest pain and hemoptysis.

HISTORY

• Past Historyshe did not have any previous history of known

illness, except admission for PID, 7 years ago. She also, had an abortion.No history of recent surgery, trauma, bed ridden or

traveling.She used Prednisolone(5mg daily),Omeprazol,

Doxepin and Loratadin since 4 weeks ago, but she did not used OCP.

HISTORY

• Family HistoryThere was no significant point.• Personal and Social HistoryShe was not smoker and opium addict.

HISTORY• Review of SystemsOral painful lesions

– Since 8 years ago– Interval 20 days– Duration 10-15 days– At the time of physical examination, the lesion was present.

Genital painful lesions– Since 4 years ago– Interval several months– Duration 5-7 days– At the time of physical examination, the lesion was not present.

Dysuria– When genital lesion was present

HISTORY

• Review of SystemsRed eye, tearing and Pain in left eye since 20 years

ago intermittently.No history of visual lossSkin lesion in both lower limbs since 15 days ago No history of headache and seizure No history of GI problems such as abdominal pain

or diarrheaNo history of arthralgia or arthritis

PHYSICAL EXAMINATION

• General SurveyPatient is a middle age female, awake and

oriented, without any distress, she was thin and pale.

• Vital SignsPR:80 RR:15 BP:90/60 AxilaryT:37

PHYSICAL EXAMINATION• Head & Neck-Mild conjunctivitis and tearing in left eye was noted(red eye).-Aphthous lesions in right and left side of tongue were noted -Trachea and thyroid were normal- No adenopathy • Chest & Cardiac & AxillaryNL• Abdomen Prominent veins were visible in epigastric zone, with flow

from down to up.There was no distention, tenderness, hepatomegaly,

splenomegaly and ascites.

PHYSICAL EXAMINATION

• Upper extremities-No skin lesion-Bilateral radial arteries pulsation were normal

and symmetric .-Active and passive motion of joints were

normal.Force of proximal and distal muscles were near

to normal for her sex and age

PHYSICAL EXAMINATION• Lower extremities-Swelling and pitting edema in left lower limb, specially in

foot, ankle and distal side of leg -Size difference between circumference of two legs was about

2.5cm.-Red brownish colored nodule with tenderness (1.5 * 1.5 cm )

on lateral side and anterior surface of the left leg compatible with erythema nodosum

-Dorsalis pedis and posterior tibialis arteries pulsation in left side were palpable but weaker than right side.

Active and passive motion of joints were normal.Force of proximal and distal muscles were near to normal.

DUPPLER SONOGRAPHY

• Thrombosis in CFV and SFV were noted.• Venous thrombosis was extended to the left

iliac vein and IVC.• SMA, SMV, Portal vein and hepatic arteries

were normal.

DIANOSIS

DVT

LABORATORY TEST

• CBCWBC:7500RBC:3790000HG:9.2HCT:31.3MCV:82.6MCH:24.3MCHC:24.4Plat:360000

ESR:104CRP:+3RF: Neg

LABORATORY TEST• BiochemistryBS:86Urea:15Creat:0.89AST:18ALT:12Al Ph:255Bil Total:0.6Bil Direct:0.16LDH:435

• ElectrolyteNa:135K:3.9Ca:8.5P:4.5• CoagulativePTT:41PT:15INR:1

LABORATORY TEST

• PBSHypochromic:+1Anisocytosis:MildPoychilocytosis:+1Ovalucytosis:MildTeardrop:MildHelmet:Mild

• Urine analysisSG:1015PH:7Others: NL

ECHOCARDIOGRAPHY

• EF:60%• PAP:NL• There was no abnormal finding.

ABDOMINOPELVICE SONOGRAPHY

• Liver, biliary tract, pancreas and urinary tract were normal

GYNECOLOGICAL CONSULT

• No aphthous, active lesion or scar in genital area

OPHTHALMOLOGICAL CONSULT

• There was naso-lacrimal duct stenosis in left eye.

• No evidence of uveitis or retinal vasculitis

SECOND CASE

A 36 years old male

HISTORY

• Chief complaintPain and swelling of the right lower limb since

two weeks ago• Present illness -Swelling has been appeared initially in right

foot and then extended to the right leg and thigh.

-No fever, dyspnea, chest pain and hemoptysis

HISTORY

• Past History-known case of DM since six months, ago-No history of recent surgery, trauma or bed

rest, but he had a trip by bus , 45 days ago.

HISTORY

• Family HistoryNo significant point.• Personal and Social HistoryNo smoking and opium addiction

HISTORY• Review of SystemsOral painful lesions

– The first time appeared at 1375 and continued for 2 weeks and then disappeared for 5 years

– Further started from 1380 – Interval 20 days– Duration about 15 days– At the time of physical examination, the lesion was present.

Genital painful lesions– The first time appeared at 1380And reoccurred several times .– Duration 3-5 days– At the time of physical examination, there was no lesion or scar.

HISTORY

• Review of Systems-45 days, ago a few skin pustular lesions appeared on

right leg. only two small brownish papule remained. -No history of erythema nodosum-Swelling of right testis one month, ago-No history of visual loss, red eye and ocular pain-No history of headache and seizure -No history of GI problems such as abdominal pain or

diarrhea-No history of arthralgia or arthritis

PHYSICAL EXAMINATION

Patient is a young male, awake and oriented, without any distress.•Vital SignsPR:84 RR:14 BP:120/80 AxillaryT:37.4

PHYSICAL EXAMINATION• Head & Neck-An aphthous lesion in anterior side of tongue was

noted.-Trachea and thyroid were normal.-No adenopathy • Chest & Cardiac & AxillaryNL• Abdomen -No distention, tenderness, hepatomegaly,

splenomegaly and ascites

PHYSICAL EXAMINATION

• Upper extremities-No skin lesion-Bilateral radial arteries pulsation were normal

and symmetric. -Active and passive motion of joints were

normal.-Force of proximal and distal muscles were

normal.

PHYSICAL EXAMINATION• Lower extremities-Swelling and pitting edema in right lower limb, specially in

foot, ankle and distal side of leg -Size difference between circumference of two legs was about

1.5cm.-Two skin lesions (brownish colored pigmentation with 3 *

3mm in size )were visible on lateral side of the right leg (scars of pseudofolliculitis).

Bilateral dorsalis pedis and posterior tibialis arteries pulsation were palpable, normal and symmetric.

-Active and passive motion of joints were normal.-Force of proximal and distal muscles were normal .

DUPPLER SONOGRAPHY

• Thrombosis in popliteal vein• CFV and SFV were normal.• SMA, SMV, portal vein and IVC were normal.

DIAGNOSIS

DVT

LABORATORY TEST• CBCWBC:7400RBC:5180000HG:14.3HCT:45MCV:87MCH:28MCHC:32.1Plat:374000

• BiochemistryBS:207Urea:31Creat:1AST:14ALT:13Al Ph:234Bil Total:0.75Bil Direct:0.16Uric acid:4.8

LABORATORY TEST

• ElectrolyteNa:137K:4.2Ca:9.2P:3.5• CoagulativePTT:31PT:13INR:1.1

Pathergy test

THIRD CASE

34 years old male

HISTORY

-Diplopia and visual loss since Farvardin, 1390 due tothrombosis of cerebral venous sinuses, increase of ICP and optic disk atrophy.-8 months, ago he had DVT in left lower limb for which Warfarin started.-Post prandial abdominal pain 6 months, ago

HISTORY

-Abdomino-pelvice CT scan: vascular aneurysm was suspected.-CT Angiography showed aneurysm in abdominal aorta and right common iliac artery. -Operation was done and Prednisolone,60mg daily and Cyclophosphamide, monthly were started.

HISTORY

• Review of system-Oral aphthous since the age of eight-No history of genital lesions-No history of erythema nodozum or

pseudofolliculitis-No history of arthritis

THE FIRST CASE

Oral aphtous+

Erythema nodosum+

DVT+

Positive pathergy test

Behcet’s disease

THE SECOND CASE

Oral aphtous+

Pseudofolliculitis Lesions+

DVT+

Positive pathergy test

Behcet’s disease

THE THIRD CASE

Oral aphtous+

Increased ICP, Cerebral venous sinus thrombosis and lower limb DVT

+Arterial aneurysm

+Positive pathergy test

Behcet’s disease

VIRCHOW'S TRIAD

• Proposes that VTE occurs as a result of1.Alterations in blood flow (stasis)2.Vascular endothelial injury3.Alterations in the constituents of the blood

(inherited or acquired hypercoagulable state)

RISK FACTORS FOR VENOUS THROMBOSIS

• Inherited thrombophilia1. Factor V Leiden mutation2. Prothrombin gene

mutation3. Protein S deficiency4. Protein C deficiency5. Antithrombin (AT)

deficiency 6. Rare disorders

Dysfibrinogenemia

RISK FACTORS FOR VENOUS THROMBOSIS

• Acquired disorders1. Malignancy 2. Surgery, especially

orthopedic 3. Trauma 4. Pregnancy 5. Oral contraceptives 6. Immobilization 7. Antiphospholipid antibody

syndrome 8. Myeloproliferative

disorders – Polycythemia vera – Essential thrombocythemia

9) Presence of a central venous catheter

10) Congestive failure 11) Hormone replacement

therapy 12) Tamoxifen, Thalidomide,

Lenalidomide13) PNH14) IBD15) Nephrotic syndrome16) Behcet disease

SCREENING FOR HYPERCOAGULABLE STATE

• Screening for a hypercoagulable state is not generally recommended unless the results are likely to change subsequent therapy for the patient or family members

• There is currently no consensus regarding who to test for inherited thrombophilia

SCREENING FOR HYPERCOAGULABLE STATE

Only patients with one or more of the following:1.Initial thrombosis occurring prior to age 50 without an immediately identified risk factor (ie, idiopathic or unprovoked venous thrombosis)2.A family history of venous thromboembolism (ie, first-degree relatives with VTE prior to age 50)3.Recurrent venous thrombosis4.Thrombosis occurring in unusual vascular beds such as portal, hepatic, mesenteric, or cerebral veins5.A history of warfarin-induced skin necrosis, which suggests protein C deficiency

THROMBOPHILIA WORK-UP

1. Antithrombin 2. Protein C3. Protein S 4. Factor VIII level5. Factor V Leiden6. Antiphospholipid antibodies7. Lupus anticoagulant8. Prothrombin gene mutation

Hypercoagulable disorder for testing

Confounding Factors

Acute thrombosisHeparin therapyCoumadin therapy

Antithrombin (deficiency)

Can be loweredLoweredNC; Rarely increased

Antiphospholipid antibodies

NCNCNC

Factor V LeidenNCNCNC

Factor VIII levelAcute phase reactant. Do not test while inflammation is still present.

Lupus anticoagulantNCCannot measureFalse positives possible

Protein C (deficiency) Can be lowered*NCCannot measure•

Protein S (deficiency)Can be lowered*NCCannot measure•

Prothrombin gene mutation

NCNCNC

Thrombophilia workup:Effects of anticoagulant therapy and acute thrombosis

BEHCET’S DISEASE

DEFINITION

• Behcet's disease is a multisystem autoimmune disorder presenting with recurrent oral and genital ulcerations as well as ocular involvement.

EPIDEMIOLOGY

• Affects young males and females• Males and females are affected equally• Males often have more severe disease• Mediterranean region, the Middle East, and the

Far East• Prevalence ranges from 13.5 to 20 per 100,000• Prevalence in the United States and Europe have

ranged from 0.12 to 7.5 per 100,000

PATHOGENESISThe etiology and pathogenesis of this syndrome remain obscure•Increase of circulating autoantibodies – Anti-Enolase of endothelial cells– Anti-Selenium binding protein – Anti-Saccharomyces cerevisiae antibodies

•Association of Behcet's disease with HLA-B*5, HLA-B*51 and the MHC Class I region is confirmed•An association with ILI0 and the IL23R-ILI2RB2 locus were also observed•Perhaps infectious acts as a immune activity trigger

PATHOLOGY

The classic Behçet’s lesion is 1. Necrotizing leukocytoclastic obliterative

perivasculitis 2. Venous thrombosis 3. Lymphocytic infiltration of capillaries, veins and

arteries of all sizes• Cellular infiltration is often neutrophils and CD4+ T

lymphocytes

1.In some patients, diffuse inflammatory disease, involving all layers of large vessels and resulting to formation of pseudoaneurysms, suggests vasculitis of vasa vasorum.

CLINICAL FEATURES

Mucocutaneous1.The recurrent aphthous ulcerations– Are a sine qua non for the diagnosis – The ulcers are usually painful – Are shallow or deep with a central yellowish necrotic base – Appear singly or in crops – Are located anywhere in the oral cavity – Less than 10 mm in diameter are seen in 85% of patients,

while large or herpetiform lesions are less frequent– The ulcers persist for 1-2 weeks and subside without

leaving scars

CLINICAL FEATURES

2. The genital ulcers – Are less common but more specific – Painful – Do not affect the glans penis or urethra– Produce scrotal scars

3. Pseudofolliculitis 4. Erythema nodosum 5. Acne-like exanthem

CLINICAL FEATURESEye involvement•Occurring in 50% of patients•Is usually present at the onset but may also develop within the first few years•Includes

1. Anterior uveitis (Iritis )2. Posterior uveitis3. Bilateral pan uveitis with scarring

• Is the most dreaded complication, since it occasionally progresses rapidly to blindness.

– Retinal vessel occlusions– Optic neuritis

CLINICAL FEATURES

Articular involvement•Seen in a 50% of patients•Non-deforming arthritis or arthralgia•Affects knees and ankles

CLINICAL FEATURESVascular involvement 1.Venous involvement

– SVT or DVT is seen in 30% of patients– The superior vena cava is obstructed occasionally– Pulmonary emboli are a rare complication

2.Arterial involvement 1. Occurs in less than 5% of patients 2. Presents with

• Aortitis • Peripheral arterial aneurysm • Arterial thrombosis • Pulmonary artery vasculitis presenting with dyspnea, cough, chest

pain, hemoptysis, and infiltrates on chest roentgenograms has been reported in 5% of patients

• Behcet’s disease involve blood vessels of all sizes - small, medium, and large - both arteries and veins

CLINICAL FEATURES

Neurologic involvement •5-10%1.Mainly in the parenchymal form (80%) it is associated with brain stem involvement – IL-6 is persistently raised in CSF of these patients

•Dural sinus thrombi (20%) are associated with headache and increased ICP

CLINICAL FEATURES

Gastrointestinal involvement •Is seen more frequently in patients from Japan •Consists of mucosal ulcerations of the gut, resembling Crohn's disease

Genital tract involvement•Epididymitis is seen in 5% of patients

PATHERGY TEST

• Nonspecific skin inflammatory reactivity to any scratches or intradermal saline injection is a common and specific manifestation

• A papule or pustul 2 mm or more in size developing 24 to 48 hours after oblique insertion of a 20 to 25 gauge needle 5mm intra-demal, generally performed on the forearm

DIFFERENTIAL DIAGNOSIS• Differential diagnosis of recurrent oral ulcers includes – Herpes simplex – Benign aphthous ulcers – Inflammatory bowel disease – Stevens-Johnson syndrome– SLE – Dental prosthetics – Oral hygiene products– Medications such as methotrexate can cause oral ulcers – Pemphigoid, pemphigus vulgaris, cicatricial pemphigoid, – Lichen planus– Linear IgA disease

DIFFERENTIAL DIAGNOSIS

• Differential diagnosis of genital ulcers include:– HSV– Syphilis – Chancroid– Lymphogranuloma venereum– Fixed drug reactions – Neoplasms– Trauma

DIFFERENTIAL DIAGNOSIS• Other causes of inflammatory eye disease, neurologic

disease, vascular disease, arthritis, are included– SLE– IBD– Sarcoidosis – Reactive arthritis– Psoriatic arthritis– Ankylosing spondylitis– Juvenile idiopathic arthritis – FMF – MS– Tuberculosis – HIV– Malignancies

DIAGNOSIS

• Diagnosis is clinical and based on internationally agreed diagnostic criteria

• Recurrent oral ulceration plus two of the following:

1.Recurrent genital ulceration2.Eye lesions3.Skin lesions4.Pathergy test

LABORATORY FINDINGS

• Laboratory findings are mainly nonspecific indices of inflammation, such as

1.Leukocytosis 2.Elevated erythrocyte sedimentation rate3.Elevated C-reactive protein levels

TREATMENT

• Mucocutaneouce involvement1. Topical glucocorticoids (triamcinolone) in the form

of mouthwash or paste 2. Topical Sucralfate 1g/5mL four times daily as a

mouthwash3. Colchicine4. In more serious cases, Thalidomide (l00 mg/d)5. Prednisone starting dose is 15 mg/day, with

tapering to 10 mg/day after one week and discontinuation of prednisone entirely over two to three weeks period

TREATMENT

• Uveitis – Prednisone(I mg/kg per day) and azathioprine (2-3

mg/kg per day)

• Sight-threatening uveitis– Cyclosporin (5mg/kg) +/- azathioprine

• Panuveitis refractory or intolerant to other immunosuppressives– Anti-TNF therapy

TREATMENT

• Arthritis 1. Colchicine 1 to 2 mg/day, administered in

divided doses2. NSAIDs3. Prednisone 10 mg/day is an appropriate starting

dose• Joint complaints not controlled by colchicine

TREATMENT

• CNS-Behcet's syndrome – Prednisone(I mg/kg per day) and azathioprine (2-3

mg/kg per day)

PROGNOSIS• Behçet’s disease typically has a waxing and

waning course characterized by exacerbations and remissions

• The disease appears to be more severe in young, male, and Middle Eastern or Far Eastern patients

• The severity of the syndrome usually abates with time

• Apart from the patients with CNS-Behcet's syndrome and major vessel disease, the life expectancy seems to be normal and the only serious complication is blindness

Oral aphthous on tongue

Oral aphthous

Dilated superficial veins

Erythema nodosum

Oral aphthous