Giant cell arteritis

Giant cell arteritis (GCA) is a type of autoimmune vasculitis that causes chronic inflammation of large and medium-sized arteries, in particular the carotid arteries, its major branches, and the aorta. GCA is most common in women over the age of 50 and of northern European descent, and approximately 50% of patients also have polymyalgia rheumatica. Patients usually present with constitutional symptoms (e.g., fever, weight loss, night sweats, fatigue, and malaise), new-onset headache, a tender, hardened temporal artery, jaw claudication, or amaurosis fugax. If there is strong clinical suspicion for GCA, glucocorticoids should be administered immediately, even prior to diagnostic workup if needed, to reduce the risk of permanent vision loss and cerebral ischemia. Laboratory studies typically show signs of inflammation (e.g., elevated erythrocyte sedimentation rate and CRP), and temporal artery biopsy and/or imaging (e.g., Duplex ultrasound) should be performed to confirm the diagnosis. The classic histopathological findings are mononuclear infiltration of the vessel wall and formation of giant cells. Patients should be referred to rheumatology for follow-up because most patients require long-term therapy with glucocorticoids (≥ 2 years).

• Sex: : ♀ > ♂ ^[1]
• Peak incidence: : 70–79 years (rarely seen in patients < 50 years) ^[2]

Women of advanced age are particularly prone to the disease.

Epidemiological data refers to the US, unless otherwise specified.

• Unknown; possible contributing factors include:
  • Genetic predisposition (e.g., human leukocyte antigen HLA-DR4) ^[3]
  • Viral infections (e.g., parvovirus B19) ^[4]
• Association with polymyalgia rheumatica (PMR): up to 50% of patients with giant cell arteritis also have PMR. ^[5]

Giant cell arteritis is thought to be due to a cell-mediated immune response to endothelial injury. However, the initiating factors are not fully understood.

1. Inflammation
   • Activation of dendritic cells in the adventitia of blood vessel walls → dendritic cells recruit Th1 cells, CD8+ T cells, and monocytes
   • Monocytes differentiate into macrophages and giant cells, which produce cytokines (e.g., IL-6, TNF-α) that augment the inflammatory response → focal granulomatous inflammation
2. Local vascular damage
   • Macrophages produce metalloproteinases → destruction of vessel wall structures (e.g., internal elastic lamina)
   • Most commonly involves external carotid artery branches (especially temporal artery), as well as the aorta and vertebral arteries
3. Concentric intimal hyperplasia: macrophages and giant cells produce PDGF and VEGF → stimulate intimal proliferation → reduced blood flow and ischemia

• Constitutional symptoms
  • Fever, weight loss, night sweats
  • Symptoms of anemia: fatigue and malaise
  • Myalgia, arthralgia (mainly of the shoulder and hip joints)
• Clinical features of arterial inflammation
  • Cranial giant cell arteritis: involves the extracranial branches of the common carotid, internal carotid, and external carotid arteries (the temporal artery is the most commonly affected vessel)
    • New-onset unilateral (or bilateral) headache
      • Can be pulse-synchronous, throbbing, dull
      • Typically located over the temples
    • Hardened and tender temporal artery
    • Jaw claudication: jaw pain when chewing
    • Vision loss: due to inflammation and occlusion of the ophthalmic artery and its branches
      • Scintillating scotoma
      • Amaurosis fugax or permanent loss of vision due to anterior ischemic optic neuropathy (AION)
    • Diplopia
  • Large-vessel giant cell arteritis: less common; involves the aorta and its primary branches ^[6][7][8]
    • Angina pectoris, acute coronary syndrome
    • Abdominal pain
    • Limb claudication
    • Asymmetrical pulses, asymmetrical blood pressure
    • Vascular bruits, aortic regurgitation murmur
    • Features of AAA, TAA, aortic dissection
• Symptoms of polymyalgia rheumatica (if both diseases are present)

About 50% of patients with giant cell arteritis also have polymyalgia rheumatica.

Jaw claudication or limb claudication, temporal artery abnormalities (e.g., tenderness, thickening, or loss of pulses), and signs of AION have a positive likelihood ratio (LR+) > 2 for GCA and should prompt further evaluation. ^[9]

Demonstration of arterial inflammation on imaging and/or histopathology is required to make a diagnosis of GCA. In patients with features of cranial GCA, the ACR classification criteria for GCA can be used to differentiate GCA from other forms of vasculitis. ^[6][10][11]

If GCA is highly suspected, diagnostics should not delay the initiation of high-dose glucocorticoids to minimize the risk of vision loss. ^[12]

Laboratory studies ^[6][10]

• Inflammatory markers: initial laboratory test in suspected GCA
  • ↑ ESR, specifically ≥ 50 mm/h (due to Rouleaux formation of RBCs) ^[13][14]
  • ↑ CRP
• Additional laboratory tests
  • CBC: normal or mild thrombocytosis, leukocytosis, or normochromic anemia
  • Liver chemistries: normal or ↑ ALP, ↑ transaminases, or ↓ albumin
  • Coagulation studies: normal or ↑ fibrinogen

ESR > 60 mm/h and platelets > 400,000/μL have an LR+ > 2 for GCA. ESR < 60 mm/h and a normal CRP make the diagnosis less likely. ^[9]

Confirmatory diagnostic studies

All patients require imaging and/or a temporal artery biopsy to confirm the diagnosis. ^{[6][11][15][16]}

Temporal artery biopsy (gold standard)

• Indications
  • Consider in all patients with suspected GCA ^[11]
  • High clinical suspicion for GCA despite inconclusive findings on imaging
• Findings: See “Pathology.”
• Important considerations
  • The minimum length of biopsy is 1.5 cm. ^[17]
  • Histopathology may be falsely negative due to skip lesions ^[14][18]

Do not delay therapy for TAB results in patients with a high clinical suspicion of GCA.

Temporal artery biopsy (TAB) with histopathology is the only test that can definitively confirm GCA and should be considered in all patients, especially if GCA cannot be ruled out with imaging. ^[11]

Duplex ultrasound (US) ^[19][20][21]

• Indications
  • Duplex US of the temporal arteries (with/without the axillary arteries): first-line imaging technique in suspected GCA ^[6][11][22]
  • Duplex US of other cranial arteries and extracranial arteries: consider if duplex US of the temporal and axillary arteries is inconclusive ^[11][19]
• Supportive findings ^[11][19]
  • Edema and thickening of the vessel wall (halo sign)
  • Noncompressible artery (compression sign)
  • Stenosis and occlusion ^[23]
• Disadvantages ^[21]
  • Operator-dependent
  • Less sensitive in detecting thoracic aortic involvement

Additional imaging studies ^[6][24][25]

• Indications
  • High clinical suspicion for GCA despite inconclusive duplex US ^[19]
  • Suspected large-vessel GCA
• Modalities
  • For suspected cranial and/or extracranial involvement: high-resolution MRI; MRA
  • For suspected predominant extracranial involvement: CTA or FDG-PET scan
• Findings
  • Similar to ultrasound findings (see above)
  • CTA/MRA: contrast enhancement of the vessel wall; also detects stenotic or aneurysmal segments
  • FDG-PET scan: increased tracer uptake by the vessel wall

The characteristic diagnostic findings in GCA are raised inflammatory markers in combination with evidence of vascular inflammation on imaging and/or histopathology.

• Panarteritis of the large and medium-sized arteries
• Proliferation of the intima (and subsequent stenosis of the artery)
• Necrosis of the media
• Fragmentation of the internal elastic lamina
• Predominantly mononuclear infiltration of the vessel wall with formation of giant cells

Differential diagnoses of GCA

• Polymyalgia rheumatica
  • Giant cell arteritis and polymyalgia rheumatica often occur simultaneously and share common features (e.g., elevated ESR, constitutional symptoms).
  • Shoulder girdle, pelvic stiffness, and pain are more common rather than ocular or cerebral findings.
• Other vasculitides
  • Takayasu arteritis
  • Polyarteritis nodosa
  • Granulomatosis with polyangiitis
  • Systemic lupus erythematosus
  • Rheumatoid arthritis
• Other causes of monocular vision loss
  • Carotid artery disease
  • Thromboembolism
  • Retinal vein occlusion
• Other causes of constitutional symptoms
  • Infections (e.g., tuberculosis, endocarditis, hepatitis, HIV infection)
  • Hyperthyroidism
  • Malignancy
  • Fibromyalgia
  • Multiple myeloma
• Other causes of headache: See “Differential diagnoses of headache.”

Clinical criteria to differentiate GCA from other forms of vasculitis ^[16][26]

These criteria were developed in 1990 by the American College of Rheumatology (ACR) to differentiate cranial GCA from other forms of vasculitis. They should not be used to diagnose cranial GCA, for which they have low sensitivity and low positive predictive value. ^[7][27][28]

The differential diagnoses listed here are not exhaustive.

Approach ^[6]

• Initial high-dose glucocorticoid therapy for 2–4 weeks is indicated for all patients with newly diagnosed GCA or recurrent GCA symptoms.
• Consults
  • Rheumatology consult for all patients
  • Urgent specialist consults as needed for complications ^[29][30]
    • Visual symptoms: ophthalmology consult
    • Neurological symptoms: neurology consult
    • Large-vessel involvement: vascular surgery consult
• After the completion of high-dose therapy, taper the dose of glucocorticoid therapy to a maintenance dose.

Glucocorticoid therapy ^[6][15][16]

This is the mainstay of treatment for patients with GCA.

Initial high-dose therapy (induction therapy)

• Indication: all patients with new-onset or recurrent GCA
• Important consideration: Initiate before diagnostic workup (e.g., before TAB) if clinical suspicion for GCA is high to minimize the risk of complications such as vision loss or stroke
• Options
  • Uncomplicated disease: oral glucocorticoids, e.g., prednisolone
  • Ischemic organ damage (e.g., impaired vision): Consider initial pulse therapy with IV glucocorticoids before oral glucocorticoids. ^[6][15][16]
    • Pulse therapy with methylprednisolone
    • Oral glucocorticoids (initially, or following pulse therapy), e.g., prednisolone
• Duration: Approx. 2–4 weeks ^[6]

Immediate administration of high-dose glucocorticoids is crucial to lowering the risk of permanent vision loss in patients with giant cell arteritis.

Maintenance therapy ^[6][15][22]

• Initiate after acute symptoms have resolved.
• Slowly taper glucocorticoids to the lowest dose needed to control symptoms. ^[6]
• Length of treatment: no consensus; generally ≥ 2 years ^[15]
• Administer prophylactic measures to prevent complications of glucocorticoid therapy as needed.

Adjunct therapy

• Glucocorticoid-sparing therapy ^[15][22][31]
  • Indications
    • Consider in patients who relapse or are at high risk of complications from long-term glucocorticoid therapy
    • May be used to decrease the dose of glucocorticoids
  • Options
    • Tocilizumab (antagonizes the IL-6 receptor)
    • Methotrexate ^[22][32]
• Low-dose aspirin
  • Not routinely recommended
  • Consider in patients with preexisting cardiovascular or cerebrovascular disease ^[15]

• Start treatment with glucocorticoids immediately.
• Assess inflammatory markers.
• Confirm arterial inflammation via temporal artery biopsy and/or imaging.
• Consider further imaging (extracranial duplex ultrasound, MRI, CTA, or PET scan) if large-vessel involvement is suspected.
• Refer all patients to rheumatology.
• Refer patients with evidence of complications to the appropriate specialists.
• Consider tocilizumab or methotrexate in patients at high risk of complications from long-term glucocorticoid therapy

Begin treatment as soon as GCA is suspected. Do not wait for a biopsy.

• Permanent vision loss: ∼ 20–30% if giant cell arteritis is left untreated ^[33]
• Cerebral ischemia (e.g., transient ischemic attack and stroke): < 2% of cases ^[34]
• Aortic aneurysm and/or dissection: ∼ 12% of patients ^[35]

We list the most important complications. The selection is not exhaustive.