BOTTOM LINE

Takayasu arteritis (TAK) is a large-vessel vasculitis affecting the aorta and its primary branches, occurring more often in women <40 years old and Asians (but all ethnicities are affected). Patients may present sub-acutely with prodromal systemic symptoms followed by arm/leg claudication and abnormal blood pressures, absent/asymmetric pulses, and bruits on exam. Other arterial involvement – including renal, mesentery, coronary or carotid arteries – presents with hypertension, abdominal or chest pain, and carotidynia, respectively. ESR or CRP may sometimes be elevated, though vessel imaging with CT or MRI is necessary to establish the diagnosis. Treatment starts with steroids; steroid-sparing therapies are added, though little evidence exists to guide therapy
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EPIDEMIOLOGY

• Prevalence
  • Difficult to assess; rare disease
  • 1-40/1,000,000 (higher prevalence reported in Japan)
• Incidence
  • 1-2/1,000,000 annually
• Ethnicity
  • More common in Asia and South America
  • Less common in Caucasian and African populations
  • Prevalent worldwide
• Age:
  • ~10-40 years-old, peak incidence in 30 years-old
    • Adults: age up to 50-years reported
    • Pediatric: age before 5-years reported
  •  Adult-onset TAK
    • More commonly presents with pulse loss/pulse deficit or claudication (particularly of the upper limbs).
    • Cluster 2 or 3 angiography more common (aortic arch and branches; focal vascular disease)
  • Pediatric TAK:
    • More commonly presents with constitutional features, hypertension, cardiomyopathy, elevated serum creatinine, and abdominal pain
    • Cluster 1 angiography more common (abdominal predominant vascular disease)
• Sex
  • F > M, (1.5:1 to 8:1)
    • Females may have more supradiaphragmatic vessel involvement
    • Men may have more abdominal vessel involvement
• Genetics
  • HLA loci: HLA-B*52 (an HLA-B serotype more prevalent in Asian populations)
  • Non-HLA loci: SVEP1, CFL2, VPS8, chr13q2

CLINICAL MANIFESTATIONS

CLINICAL PHENOTYPES

—Clinical Phases

Historically, TAK was thought to have a “triphasic” progression of disease, though this is challenged in contemporary cohorts

• Early phase:
  • Systemic symptoms: subacute fever, arthralgias/myalgias, weight loss
• Vascular inflammation phase:
  • Vessel pain, tenderness
• Fibrotic phase:
  • Bruits, ischemia

—Clinical Presentation Groups

Clinical presentation at diagnosis of TAK can be divided into 5 different groups

• Group 1: Constitutional symptoms
  • Fever, weight loss
• Group 2: Carotidynia
  • Pain and tenderness of carotid artery
• Group 3: Vascular symptoms (most common presentation at diagnosis)
  • Other than carotidynia, including: limb claudication, vascular headaches, positional light-headedness, postprandial abdominal pain
• Group 4: Major ischemic event
  • TIA, CVA, retinal ischemia, MI, renovascular hypertension, mesenteric ischemia
• Group 5: Asymptomatic
  • Incidental finding on vascular imaging
    

—Angiographic clusters

Arterial damage in TAK occurs in 3 angiographic clusters

• Cluster 1: Abdominal predominant vascular disease
  • Hypertension, lower limb claudication, mesenteric ischemia, childhood onset of disease
• Cluster 2: Aortic arch predominant vascular disease
  • Carotidynia, stroke, upper limb claudication, lightheadedness, less treatment responsive
• Cluster 3: Focal vascular disease
  • Asymmetrical arterial involvement, fewer involved arteries, less likely to have arterial occlusion

SYSTEMIC MANIFESTATIONS

• Systemic
  • Weight loss, low-grade fever, fatigue
• Head/neck, ocular
  • Carotidynia (10-30%), bruits
  • Retinal involvement, transient visual changes or visual loss (4-8%) due to carotid involvement
  • Subclavian steal: subclavian stenosis proximal to origin of vertebral artery decreases posterior cerebral blood flow, especially with upper limb exercise; syncope and neuro symptoms
• Extremity
  • Arm claudication from subclavian involvement or leg claudication from abdominal involvement common
  • Unequal blood pressures (>10-20mmHg difference), weak/asymmetric distal pulses, bruits, rarely causes digital gangrene
• Cardiac
  • Aortic root dilatation, aortic regurgitation and murmur
  • Angina due to coronary artery ostial narrowing or coronary arteritis
• Respiratory
  • Chest pain, dyspnea, hemoptysis, pulmonary arteritis in ~55% which can lead to pulmonary hypertension
• Renal
  • Renovascular hypertension from renal artery involvement
• GI
  • Abdominal pain, ischemic colitis, bruits
• MSK
  • Arthralgias/myalgias (13-41%), peripheral inflammatory arthritis and sacroiliitis is reported in up to 10-20%
• Dermatological
  • Erythema nodosum, pyoderma gangrenosum, erythema induratum and ulcerative lesions
• Comorbid Spondyloarthropathies
  • Associations with IBD (2.6%), psoriasis, and ankylosing spondylitis

Physical exam should include 4 extremity BP, auscultation for murmurs and bruits (carotid, subclavian, renal, abdominal, femoral arteries), palpation of temporal, carotid, brachial, femoral and dorsal pedal arteries

INVESTIGATIONS

• CBC
  • May show leukocytosis and/or thrombocytosis from inflammation
  • May show anemia of chronic inflammation or from GI bleeding
• ESR/CRP
  • May be elevated in active disease, though not reliably so (can be normal in ~30-50% despite active disease on imaging)
• Imaging: Stenotic lesions in >90% of patients; aneurysms in 25%
  MR angiogram is preferred first imaging test, assuming high expertise and prompt availability.
  
  • MR–angiogram (MRA)
    • Sensitivity 92%, Specificity 92% (1.5T MRI) for diagnosis
    • Smoothly tapered circumferential luminal narrowing, dilation, stenosis, occlusion; vessel wall thickening, edema, or wall enhancement
    • Limited resolution for distal aortic branches, may not discriminate versus atherosclerotic plaque
  • CT-angiogram (CTA)
    • Sensitivity 95%, Specificity 100% for diagnosis
    • Smoothly tapered circumferential luminal narrowing, dilation, stenosis, occlusion; vessel wall thickening, enhancement and “low attenuation ring” on delayed phase images.
    • More ability to image calcification and plaque
    • Limited resolution for distal aortic branches, risk from radiation and IV contrast
  • ¹⁸FDG-PET ± CT/CTA
    • Increased metabolic activity in arterial wall suggests disease activity
    • PET scan alone provides no information of arterial wall morphology
    • Atherosclerosis can cause some degree of inflammation on PET, access may be limited
  • Ultrasound with colour Doppler
    • Sensitivity 81%, Specificity 100% for diagnosis
    • May show common carotid and proximal subclavian circumferential vessel wall thickening and luminal narrowing, wall elasticity measures, calcium/plaque imaging
    • Limited imaging of aorta/proximal subclavian, no direct measure of inflammation, technician dependent
    • Not suitable to assess thoracic aorta

Conventional catheter- based dye angiography can better image vascular lumen, determine central blood pressures, and help for surgical planning; however it cannot provide information about vessel wall inflammation and is invasive. Conventional angiography is generally not recommended.

Repeat imaging may be helpful to assess suspected flare, but is not routinely recommended to for patients in clinical and biochemical remission. Serial repeat imaging could be used to follow structural damage (stenosis, occlusion, dilation, aneurysm) on a case by case basis.

DIAGNOSIS

Suspect TAK in patient, typically 10-40 years old and more often female, presenting with subacute systemic features of aortic main-branch claudication — particularly carotidynia, extremity claudication, hypertension, unequal blood pressures/pulses, anginal chest pain, or bruits. ESR or CRP may be elevated, but is not sensitive. Vessel imaging should be obtained (ideally MR angiogram), which should show smooth circumferential narrowing of the aorta and major branches with wall thickening. If “aortitis” was discovered incidentally on CT, seek supportive evidence of vasculitis by imaging other regions of aorta and primary branches with MRA or CTA or PET; carefully consider differential or comorbid atherosclerosis to explain imaging findings. Recognition and diagnosis can be delayed by months to years due to subacute presentation. Often, consequences of arterial disease is the first sign noticed at presentation.

DIFFERENTIAL DIAGNOSIS

• Rheumatological
  • GCA (affects older patients, higher predilection for cranial branches of aorta)
  • Behcets: commonly has mucosal ulcers, skin rash, uveitis
  • IgG4-related disease: may IgG4-RD involving other organs (ex: retroperitoneal fibrosis, peri-aortitis) and atopy
  • Cogan’s syndrome: typically presents with vestibuloauditory dysfunction and keratitis
  • PAN: affects aortic branches, unlikely to cause aortitis
  • Kawasaki disease (paediatric)
• Infectious
  • Syphilis, Salmonella, Staph/strep, tuberculosis
• Genetic
  • Collagen disorders: Marfan, Ehlers-Danlos syndrome, Loeys-Dietz
  • Turner syndrome
  • Fibromuscular dysplasia
• Atherosclerosis
  • Can cause degree of vessel wall edema on MR or PET, but usually with shorter segment non-circumferential vessel wall narrowing
• Other
  • Post-radiation arteritis, fibromuscular dysplasia, Erdheim Chester disease

CLASSIFICATION CRITERIA

TAK is a clinical diagnosis. Classification criteria are not meant as diagnostic criteria to diagnose disease in a single specific patient. Classification criteria are a standardized way of recruiting a well-defined homogenous population of patients in research studies in order to ensure comparability across studies of a heterogenous disease.

2022 ACR/EULAR CRITERIA

Criteria should be applied to classify Takayasu arteritis after a diagnosis of medium or large vessel vasculitis has been made. Alternate diagnoses mimicking vasculitis should first be excluded. Sum scores for 10 items, if present. Classification criteria met if total score ≥5

Absolute Requirement

• Age ≤60 years at time of diagnosis
• Evidence of vasculitis on imaging¹

Additional Clinical Criteria

Female Sex	+1
Angina or ischemic cardiac pain	+2
Arm or leg claudication	+2
Vascular bruit2	+2
Reduce pulse in upper extremity3	+2
Carotid artery abnormality4	+2
Systolic blood pressure difference in arms ≥20mmHg	+1

Additional Imaging Criteria

Number of affected arteries5 · 1 arterial territory · 2 arterial territories · 3+ arterial territories	+1 +2 +3
Symmetric involvement of paired arteries6	+1
Abdominal aorta involvement with renal or mesenteric involvement7	+3

1. Evidence of vasculitis in the aorta or branch arteries must be confirmed by vascular imaging (ex: CTA, MRA, Ultrasound, PET)
2. Bruit detected by auscultation of large artery including aorta, carotid, subclavian, axillary, brachial, renal, or iliofemoral
3. Reduction or absence of pulse by physical exam of axillary, brachial, or radial arteries
4. Reduction or absence of pulse of the carotid artery or tenderness of the carotid artery
5. Number of arterial territories with luminal damage (ex: stenosis, occlusion, aneurysm) detected by angiography or ultrasonography from the following 9 territories: thoracic aorta, abdominal aorta, mesenteric, left/right carotid, left/right subclavian,  left or right renal arteries.
6. Bilateral luminal damage (stenosis, occlusion, or aneurysm) detected by angiography or ultrasonography involving the abdominal aorta and either the renal or mesenteric arteries
7. Luminal damage (stenosis, occlusion, aneurysm) detected by angiography or ultrasonography involving the abdominal aorta and either the renal or mesenteric arteries

TREATMENT

Little evidence exists to guide therapy. Glucocorticoid combined with cs/b/ts-DMARDs are typically used. Drug-free remission is uncommon

Target: Absence of new symptoms, of an inflammatory syndrome, and absence of radiological progression

—Glucocorticoid

• Prednisone 0.5-1.0mg/kg/d for 2-4 weeks tapering over 6-12 months with similar schedule to GCA

—Non-glucocorticoid

Addition of nonglucocorticoid immunosuppressive agent is recommended over monotherapy glucocorticoid for patients with active TAK.

Could consider monotherapy glucocorticoid if very mild TAK or if diagnosis is uncertain.

Consider favouring methotrexate, azathioprine, and TNFi before tocilizumab: efficacy of tocilizumab in TAK is not established and more clinical experience exists with TNFi

• Methotrexate 20-25mg/week
• Azathioprine 2mg/kg/d (max 200mg/d)
• TNF-inhibitors (infliximab 5mg/kg IV q8 weeks)
• Tocilizumab 162mg SC weekly
• Other choices
  • Leflunomide, mycophenolate
  • Cyclophosphamide reported for severe life/organ threatening disease
  • Tofacinib
  • Abatacept, rituximab, ustekinumab

—Surgery

• If possible, revascularization should be avoided during active disease and instead be considered during the chronic fibrotic stage of disease
• May consider revascularization surgery if:
  • Critical organ-threatening ischemia
    • ex: MI, stroke, ischemic optic neuropathy, acute mesenteric ischemia
  • Chronic ischemia affecting quality of life despite optimal medical therapy and lack of sufficient new collateral circulation
    • ex: severe limb claudication, chronic mesenteric ischemia, renovascular hypertension that is refractory to immunosuppressive therapy, subclavian steel
  • Vascular complications
    • ex: severe aortic regurgitation, arterial/aortic aneurysms at risk of rupture
• Endovascular stenting may help for short segment stenoses
• Open surgery with bypass grafting may be necessary for long segment and extensive disease.

—Evaluating Treatment Response

Lack of specific biomarkers and limitations in accessibility and interpretation of imaging make treatment evaluation challenging. Validated tools (ex: VDI, BVAS) are lacking.

• Clinical assessment
  • Regular monitoring of constitutional symptoms, possible improvement in claudication symptoms and signs (usually due to the development of collateral circulation)
• Labs
  • ESR and CRP, but not reliably reflective of disease activity
  • Be wary of escalating therapy based on inflammatory markers alone, particularly if otherwise in clinical remission
• Imaging
  • Baseline MRI or CT
    • MRI is more favourable than CT, due to the radiation/contrast associated with CT
  • May consider regular re-imaging or re-imaging if clinical worsening and suspicion of flare
  • Re-imaging may provide information regarding:
    • Progression or stabilization of structural changes
    • Presence or absence of active vessel wall inflammation, possibly

Consider escalating therapy if clinical evidence of disease activity (ex: symptoms, elevated inflammatory markers, and new abnormalities in vascular imaging).

If a patient is in apparent remission but imaging evidence reveals inflammation in new vascular territories (ex: new stenosis or vessel wall thickening), could consider escalation of immunosuppressive therapy

—Adjunctive therapy

• Optimize cardiovascular risk factors, particularly hypertension
• Hypertension management
  • Assess BP in non-diseased limbs for more accurate BP measurement
  • If bilateral renal artery stenosis or significant aorta stenosis, avoid ACEi/ARB due to concern for decreased renal perfusion
• Consider statin and antiplatelet therapy, particularly if critical cranial or vertebrobasilar involvement
• Age-appropriate vaccination
• Vitamin D, BMD, and pharmacotherapy for osteoporosis as indicated

PROGNOSIS

• Minority may have self-limited course; majority have progressive or relapsing disease requiring long term immunomodulation
  • 50% of the patients relapse or develop a vascular complication within 10 years of diagnosis
• Morbidity substantial:
  • 74% have decreased functional daily activities and 23% unable to work.
• Mortality:
  • US: 94-95% 10-year survival
  • South Korea: 87% 10-year survival
  • Japan: 96.5% 15-year survival

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