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Update on the diagnosisUpdate on the diagnosisand management ofand management of

Takayasus arteritisTakayasus arteritis

CSPT Case StudiesCSPT Case Studies

Dr. Esther OviedoDr. Rosa Jordana

Internal Medicine ServiceCSPT. Hospital de Sabadell. Sabadell (Barcelona)

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Summary:

Clinical cases

Introduction Diagnosis

Treatment

Management

Prognosis

Case studies at the Parc Taul Conclusions

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Case 1 Physical examination:

Difference in BP >10 mmHg between arms.

Rhythmic heart tones. 2-3/6 systolic murmurs in aortic,pulmonary amb mitral foci. Bilateral carotid bruit. Asymmetric pulses:

Right arm: radial and cubital pulses present. Left arm: no radial, cubital, humeral or axillary pulse. Lower limbs: correct pulses without femoral bruit.

Diagnostic tests: Laboratory:

Hemogram: Hb 10.5 g/dl. Biochemistry: ESR 54 mm. CRP 1.8 mg /dl.

Transferrin saturation 3.6%. Normal basic coagulation tests.

Transthoracic echocardiogram: Normal

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Case 1 MR angiogram of the

supraaortic trunks:

Complete prevertebralobstruction of the leftsubclavian artery with

postvertebral recanalization

Stenosis of the descendingaorta

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Case 1 Abdominal CT angiogram

Diffuse thickening of the arterialwall of the aortic arch, and of thethoracic and abdominal aorta.

Stenosis of the prevertebral leftsubclavian artery with postvertebral

recanalization. Diffuse stenosis of the proximal

portion of the left common carotidartery.

Significant stenosis of the celiactrunk and superior mesentericartery; slight stenosis of the rightrenal artery.

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Case 1

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Case 2 A 44-year-old woman was referred to our hospital because of

dyspnea.

History: Ex-smoker (quit two years prior)

1997: diagnosed with hypertension, currently intreatment; stable until two months prior.

Dyslipemia.

1997: diffuse scleritis in both eyes with left eyeamaurosis, treated with immunosuppressive drugs.

2004: studied for suspected systemic disease withinconclusive results.

2005: upper limb arthritis, treated with corticosteroids.

2007: left ear neurosensory deafness. Normal cranial CT.

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Case 2 Current disease:

Detection of Hypertension atenolol treatment is started Dizziness with loss of consciousness atenolol discontinued One week later: dyspnea and orthopnea

Physical examination:

BP: 170/50 HR: 115 bpm Sat O2 86%. Afebrile. RF 34 cpm.Hyperkinetic apex. Rhythmic heart tones with 3/6 diastolic murmur.Hyperkinetic carotid pulses and diminished left pedal and leftposterior tibial artery pulses.Rales in both lung bases.

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Case 2 Diagnostic tests:

Chest X-ray: Cardiomegaly and signs of left heart failure. ECG: Sinus rythm at 100/min. QRS axis 0. Lack of R-wave

progression and negative T-waves in leads V1-V4.

Laboratory:

Hemogram: Hb 88 g/L. MCV 72.7. Biochemistry: ESR 92mm; CRP 8.4 mg/dL.

Coagulation: normal.

Urine sediment: normal

Transthoracic echocardiogram: dilated left ventricle.Interventricular septum 11mm. EF 61%. Left atrium46mm. Severe aortic regurgitation. Normal right chambers.

Doppler US of the supraaortic trunks: Normal

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Case 2 Chest-abdominal CT

angiography

Concentric thickening ofthe aortic arch, descendingaorta, and abdominal aorta

Thickening of the proximal

left subclavian artery. Dilation ( 36mm) of a 10

cm length of the descendingaorta at the level of thediaphragm

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Case 2 Abdominal MR

angiography

Aneurysm of the abdominalaorta

Critical stenoses of theproximal celiac trunk, superiormesenteric, and inferiormesenteric arteries.

Critical stenoses of the iliacarteries at the level of thebifurcation.

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Takayasus arteritisTakayasus arteritis

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Introduction First described by Mikito Takayasu (Japanese ophthalmologist) in 1905

Chronic inflammatory disease of unknown etiology affectingmedium- and large-caliber arteries.

Immunologic mechanisms intervene at a cellular level: Inflammation Wall thickening Fibrosis Stenosis Occlusion (40%-50 %) Thrombosis Aneurysmatic dilation (5%)

Most commonly affected territory: the aorta and its branches Subclavian 85%-88% Carotids 37%-54% Abdominal aorta (Renal artery) 25%-63%

Women > men. 3rd-4th decade of life. Worldwide distribution, more prevalent in Asia

Estimated incidence 150 cases/million inhabitants /year (Japan)vs 1 - 3 cases/million/year (Europe, America)

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Classification criteria1990 American College of Rheumatology (ACR):

1. Age at onset 40 years

2. Limb claudication

3. Diminished brachial pulse

4. Difference of > 10 mmHg systolic pressure between arms5. Bruit over the subclavian artery or aorta

6. Abnormal angiogram

A patient has Takayasu arteritis if 3 criteria arepresent (Sensitivity: 90.5%, Specificity: 97.8 %)

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Clinical presentation Physical examination:

80%-94%Audible bruits(aorta, subclavian, carotid )

5%-20%Retinopathy

10%-37%Secondary hypertension

(Renal artery stenosis)

75%-80%BP difference > 10 mmHg

84%-94%Decreased, asymmetric, orabsent pulse

Park M et al. Clinical characteristics and outcomes of Takayasus arteritis: analysis of 108 patients using standardized criteria for diagnosis, activity

assessment,and angiographic classification. Scand J Rheumatol 2005; 34(4): 284-92.

Mwipatayi B et al. Takayasu arteritis: clinical features and management: report of 272 cases. ANZ J Surg 2005; 75(3):

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Laboratory findings Acute phase reactants: CRP / ESR

Normochromic-normocytic anemia

Negative autoantibodies

NOT VERY SENSITIVEand

NOT VERY SPECIFIC

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Imaging tests Most common lesions:

Subclavian artery territory

Initial phase vascular wall thickening Advanced phase Changes in (63%-97% stenosis; 25%

occlusions; 10% aneurysms)

Most common: Type I (36%-50%); Type V 33%New angiographic classification of Takayasu arteritis

Takayasu Conference 1994

Moriwaki R, Noda M, Yajima M, et al. Takayasu arteritis Clinical manifestations of TA in India and Japan-New classification of angiographic findings. Angiology 1997; 48: 369-79

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Imaging testsClassically...

Arteriography: gold standard Limitations:

Invasive

Requires high doses of ionizing radiation

Technical difficulties significant stenoses and/orcalcification

Detects changes in the of the lumen; cannot detectchanges in vessel walls.

risk of ischemic phenomena after the procedure

Useful prior to angioplasty or stenting

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Imaging tests Doppler

Ultrasonography:(supraaortic trunks)

Advantages:

1. Noninvasive/ convenient

2. Can identify occlusivechanges & dilation

3. Can measure post-stenosisflow velocity

4. Can detect arterial wallthickening

Limitations:

1. Subjectiveinterpretation

2. Not very specific forwall thickening

3. The thoracic aorta canonly be seen intransesophagealultrasonography

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Imaging testsCT/CT angiography:

Advantages:

1. Useful for early diagnosis(wall thickening)

2.

Identifies chronic changes(stenosis/occlusion)

Limitations:

1. Needs iodinated contrast(limitation for allergicpatients & those withrenal failure)

2. Ionizing radiation

3. Contraindicated inpregnancy

4. Not apt for follow-up

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Imaging testsMRI /MR angiography: Advantages:

1. Useful in the early phase

2. Noninvasive

3. Might be useful for follow-up

4.

MR angiography: provides detailed information

Michael B. Philip, A. Aroz, Thanila A. AMcedo. Imaging Findings in Takayasus Arteritis. AJR: 184, June 2005

J Andrews et al. Non-invasive imagining in the diagnosis and management of Takayasus arteritis, Ann Rheum Dis 2004; 63:995-1000

Marcio V. Nastri; MD Luciana P.S Baptista, MD, Ronaldo HGadolinium-enhanced Three-dimensional MR Angiography of TakayasuArteritis. Radiographics 2004; 2773

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Imaging testsMRI /MR angiography: Limitations:

1. Claustrophobia

2. Metallic implants(pacemaker/ICD)

3. Expensive

4. Renal failure (GFR

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Imaging tests

FDG-PET: Noninvasive metabolic imaging test Glucose consumption in inflammed vessels ( > 4mm)

FDG uptake suggestive of vasculitis

Can measure inflammation early phase diagnosis

In a single study imaging of all the vascular tree

CONTROVERSIES Sens 92%/ Spec 100% in older series

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Imaging tests

P = 0.56+5/7 cases

(71.4 %)

Wall edema

P = 0.73+10/23 cases

(43.5 %)

Stronggadolinium

uptake

P = 0.23+14/ 25 cases

(56%)

Wallthickening

Statisticalsignificance

PETTypicallesions MR

angiography

(ACR09) Retrospective study, 40 PETS (n = 28)

Comparison PET /MR angiography

ESR: P = 0.34

RCP: P = 0.82

Increased acutephase reactants

Specif= 69.2%

Sensit= 33.3 %

P = 0.08

Clinical activity

PET

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Treatment and management NIH criteria for inflammatory activity (relapse) 2:

Systemic symptoms

Increased ESR and CRP Symptoms of vascular insufficiency

New imaging findings in new territories (no stenosis or dilationprogression of disease)

Criteria for remission: Absence of symptoms and normal inflammatory parameters in

the absence of new imaging findings.

Criteria for sustained remission: Above conditions and at least 6 months with corticoid doses

< 10 mg /day.

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Drug therapy Individual decision: inflammatory activity (NIH Criteria):

PREDNISONE (1mg/kg/day)

Very good initial response : 80%-90% REMISSION

Rate of sustained remission < 10%.

> 80% relapse with gradual reduction in corticoids.

69%-75% IMMUNOSUPRESSORS (Methotrexate, Azathioprine)

Enable the dose of corticoids and their adverse effects to bereduced.

Increase the rate of sustained remission

Hoffman GS et al. 1994 Treatment of glucocorticoid-resistant or relapsing Takayasu arteritis withMethotrexate. Arthritis Rheum 37:578-582

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Drug therapy

Mycophenolate mofetil:Retrospective study 2003-2006N= 10 patients; Follow-up = 2 years

5 received other immunosuppressors first

5 received MMF as a first-line drug

Objective:

Response in refractory disease

Reduce the dose of corticoids

Avoid adverse effects

Not evaluated withimaging tests

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Drug therapy Anti TNF:

(INFLIXIMAB/ETANERCEPT)

Retrospective study

N= 25 patients, Follow-up: 7 years10 sustained remissions 1-3.3 years

Randomized studiesto evaluate toxicity

and sustained remission

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Surgical treatment 40% require revascularization 25% reinterventions

Location Renal artery and subclavian artery

Indication In stable phase of disease

Hypertension due to renal artery stenosis Limiting limb claudication Cerebrovascular ischemia Moderate-severe aortic insufficiency Myocardial ischemia

Type:1. Angioplasty and stenting: 36%- 70% Restenosis 70%-80%

2. Reconstructive surgery: Bypass 30%-60 % Restenosis 36%

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Surgical treatment: Retrospective study

n=42 surgically treated patients.

Restenosis 37% Follow-up24 months

1 year: 50%

2 year: 44% 5 year: 12%

Location:Subclavian carotid

Less restenosis if: Performed in stable phase

(p< 0.039)

Immunosuppressor treatmentafter surgery (p< 0.044)

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Monitoring patientsDifficult management NIH activity criteria:

Clinical, Laboratory, Imaging

High correlation inflammatory activity Acute phasereactants (ESR)

25%-30% with normal acute phase reactants are in theinflammatory phase (determined by histologic study ofsurgical specimens, new lesions at imaging...)

Normal acute phase reactants ischemic claudication

n=108

Predictive factors

of remission

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Monitoring patients

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PrognosisChronic, relapsing, progressivemorbidity severe lesions (vital organs)

Type I or V Early diagnosis

Complications

Survival:

1 year: 98.1% 3 year: 95.3% 5 year: 92.9% 10 year: 87.2%

5%-20%TIA/stroke

10%-17%AMI

22%-25%Aort. Ins.

19%-25%CHF

10%-50%Hyperten.

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Final.Case 1Type V Takayasus arteritis:

Begin Prednisone 70 mg/day (11/13/2008) 1st week No new symptoms. Acute phase reactants

normal. At 1 month Corticoids to 20 mg/day

At 8 months:

Clinical stability + imaging follow-up ( thickening)+ minimal APR without anemia:

NO criteria of inflammatory activity (1)

Treatment: Corticoids < 10 mg + BP control

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Case 2Summary. 44-year-old woman

+Asymmetric pulses + carotid bruit

+

Hypertension + bilateral episcleritis and neurosensorydeafness

+

Aortic insufficiency and HF

+

Acute phase reactants+

Lesions at imaging

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Final... Case 2Cogan syndrome (Takayasu-like Type V)

Neurosensory deafness + HF due to aortitis +Necrotizing episcleritis

Begin: Corticoids + Azathioprine (methotrexate toxicity) Relapse with corticoid reduction < 10 mg/d.

Severe side effects with corticoids:

weight + Cushing + Sleep apnea syndrome (CPAP)

Due to relapse & impossibility of lowering corticoids Mycophenolate mofetil started

2-year follow-up: elevated APR, clinical stability, nochanges at MR angiography or PET.

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Descriptive analysis of the

CSPTs cases

ComorbiditySymptoms and signsDiagnosticAge/yearPatient

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---Asthenia, weight loss, febricula. Limb claudication, chest painand dyspnea. Abdominal pain and diarrhea.

Decreased asymmetric pulses. Audible bruits.

15 months40

2006

8/ Woman

Autoimmune

Hypothyroidism

Asthenia, right upper limb claudication.

BP diff>10mmHg. Asymmetric decreased pulses, audiblebruits.

4 months36

2008

7/ Woman

Erythema

nodosum

Asthenia, weight loss, vertigo, headache.

Hypotension, BP diff >10mmHg, decreased weak pulses, audiblebruits.

12 months34

2004

6/ Woman

---Vertigo, headacheHypertension, BP diff> 10mmHg. asymmetric decreasedpulses, audible bruits.

6 weeks2420085/ Woman

---Asthenia, febricula, weight loss,. limb claudication, ischemiculcers, abdominal pain.

Hypertension, decreased asymmetric pulses.

---25

1984

4/ Woman

AutoimmuneHypothyroidism

Vertigo, orthostatism, headache, convulsions, stroke.Hypotension, BP diff >10 mmHg, asymmetric decreased pulses,

audible bruits.

3 weeks212007

3/ Woman

Crohns diseaseAsthenia, limb claudication, subclavian steal, dyspnea.

Vertigo, orthostatism, and headache.

Hypertension, BP diff>10mmHg,. decreased pulses, audiblebruits.

5 months30

1993

2/ Woman

Cogan synd.

Sleep apneasyndrome

Asthenia, arthralgias, vertigo, orthostatism, and syncope.

HF.Hypertension, BP diff >10mmHg, decreased asymmetric pulses,

audible bruits.

10 months44

2007

1/ Woman

ComorbiditySymptoms and signsDiagnostic

delay

Age/yeardiagnosis

Patient

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Results

Decreased pulse : 8 patientsAsymmetric pulses: 7 patientsAudible bruits : 7 patientsHypertension: 4 patientsBlood pressure differences between limbs >10 mmHg:4 patients

Physicalexam.

Systemic: 6 cases (fever, asthenia)Cardiovascular: 5 cases (intermittent claudication,subclavian steal)

Neurologic: 6 cases (Carotid-vertebral : vertigo -orthostatism)

Digestive : 1 case (abdominal pain and diarrhea)Heart failure due to aortic insufficiency: 1 case

Clinical

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Results

1st imaging examination MR angiography 3 (2 chest-abdominal, 1 SA trunks)

CT angiography 4 (2 chest-abdom., 1 chest, 1 SA trunks)

Doppler US SA trunks 1

Most frequent location: subclavian, carotid.

Lesions at imaging: Wall thickening 5 (inflammatory activity)

Stenosis/occlusion 5 Dilation/aneurysm + stenosis/occlusion 3

Classification: I:3; IIb: 1; IV:1 ; V: 3

Echocardio (TT) : 5 (3 N; 1 aort. insuf.; 1 Ao. An.)

PET:4 all normal ( 3 in clinically & radiol. stable

phase; 1 pretreatment assessment)

Imaging

Elevated acute phase reactants: 7 patients

Normochromic-normocytic: 6 patients

Antinuclear antibodies + : 3 patients

Laboratory

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Results

Medical treatment:

Corticoids + Immunosuppressors: 5 patients(2 Methotrexate, 2 Azathioprine, 1 Mycophenolate)

Only corticoids: 2 patients.

Without treatment: 1 patient.

Revascularization:

2 bypasses (subclavian-carotid, aortic-carotid +

aortobifemoral). 1 PTCA + celiac trunk stent.

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Evolution. 2 patients lost to follow-up (1 transferred, Crohns disease)

1 normal imaging tests, normal APR. No symptoms No treatment.5 years follow-up without symptoms

1 initial constitutional symptoms and elevated APR (15 months)Diagnosed due to symptoms of ischemia, acute phase reactants

PTCA and celiac trunk stent Restenosis intestinal ischemia parenteral nutrition at home.

4 patients high dose corticoids (+immunosuppressors in 2) remission of symptoms and laboratory signs

1 relapse at 14 months (symptoms, lab. signs) corticoids + azathioprine Cushing & sleep apnea synd (CPAP) mycophenolate

1 relapse at 3 months (lab. signs) Improved w/ corticoids 2 sustained remissions Corticoids

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Conclusions1. Chronic, active, relapsing, with a progressive course

high morbidity

2. Heterogeneous, nonspecific clinical presentation:constitutional symptoms diagnostic delay.

3. Lack of specific criteria for inflammatory activity:comprehensive monitoring Imaging, lab, and clinical.

4. 80% relapse with high dose corticoids frequent relapses often need immunosuppressors

5. Use of mycophenolate and anti-TNF as alternatives inrefractory cases to conventional treatment or withcorticoid adverse effects.

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Conclusions6. CT angiography and MR angiography early diagnosis

and follow-up

7. New surgical treatments improve the prognosis in thesepatients

8. A multidisciplinary approach is best.

9. Available treatments should be tested in largerrandomized trials with longer follow-up.