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 of vasculitis. 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 of age (typically seen in individuals aged ≥ 50 years) ^[2][3]

Older women are particularly prone to GCA.

Epidemiological data refers to the US, unless otherwise specified.

• Unknown; possible contributing factors include:
  • Genetic predisposition (e.g., human leukocyte antigen HLA-DR4) ^[4]
  • Viral infections (e.g., parvovirus B19) ^[5]
• Association with polymyalgia rheumatica (PMR): up to 50% of patients with giant cell arteritis also have PMR. ^[6]

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, CD4+ 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

Nonspecific symptoms

• Constitutional symptoms (e.g. fever, weight loss, and night sweats)
• Symptoms of anemia (e.g., fatigue and malaise)
• Musculoskeletal pain and morning stiffness in the shoulders and/or neck
• Clinical features of polymyalgia rheumatica (if both diseases are present)

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

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 ^[7][8][9]
  • 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

Limb or jaw claudication, temporal artery abnormalities (e.g., tenderness, thickening, or loss of pulses), and/or signs of AION in a patient ≥ 50 years of age should prompt further evaluation for GCA. ^[10]

Approach ^[2]

• Obtain ESR and CRP levels.
• Perform imaging studies and/or a biopsy to confirm the presence of medium- or large-vessel vasculitis.
• Once vasculitis is established, apply the ACR/EULAR classification criteria to assess for GCA.

If clinical suspicion for GCA is high, initiate high-dose glucocorticoids before the diagnostic workup to minimize the risk of complications such as vision loss or stroke. ^[11]

Laboratory studies ^[2][7][12]

• Inflammatory markers: initial laboratory study in suspected GCA
  • ↑ ESR (≥ 50 mm/hour): due to rouleaux formation of RBCs ^[13][14]
  • ↑ CRP (≥ 10 mg/L)
• Additional laboratory studies
  • CBC: normal or mild thrombocytosis, leukocytosis, or normochromic anemia
  • Liver chemistries: normal or ↑ ALP, ↑ transaminases, or ↓ albumin
  • Coagulation studies: normal or ↑ fibrinogen

Elevated inflammatory markers (e.g., ESR, CRP) and/or thrombocytosis increase the likelihood of GCA. ^[10]

Confirmatory studies ^[15]

All patients require imaging studies and/or a temporal artery biopsy to confirm the diagnosis of vasculitis. ^[2][16][17]

Temporal artery biopsy (gold standard)

• Indications
  • Consider in all patients with suspected GCA ^[18]
  • High clinical suspicion for GCA despite inconclusive findings on imaging
• Findings: See “Pathology.”
• Important considerations
  • Biopsy samples should be > 1 cm in length. ^[15]
  • Histopathology may be falsely negative due to skip lesions. ^[14][19]

Temporal artery biopsy with histopathology is the only study that can definitively confirm GCA and should be considered in all patients, especially if GCA cannot be ruled out with imaging. ^[15][18]

Duplex ultrasound ^[20][21][22]

• Indications
  • Duplex ultrasound of the temporal arteries (with/without the axillary arteries): first-line imaging technique in suspected GCA ^[2][16][17]
  • Duplex ultrasound of other cranial arteries and extracranial arteries: consider if duplex ultrasound of the temporal and axillary arteries is inconclusive ^[18][20]
• Supportive findings ^[18][20]
  • Edema and thickening of the vessel wall (halo sign)
  • Noncompressible artery (compression sign)
  • Stenosis and occlusion ^[23]
• Disadvantages ^[22]
  • Operator-dependent
  • Less sensitive in detecting thoracic aortic involvement

Additional imaging studies ^{[2][7][24][25]}

• Indications
  • High clinical suspicion for GCA despite inconclusive duplex ultrasound ^[20]
  • 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 in large arteries (e.g., the aorta and its branches)

GCA classification ^[2]

These criteria establish the diagnosis of GCA in patients with medium- or large-vessel vasculitis confirmed with imaging or biopsy.

• 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.”

The differential diagnoses listed here are not exhaustive.

Approach ^[7][15]

Consult rheumatology for all patients.

• Start high-dose glucocorticoid therapy for patients with newly diagnosed or recurrent GCA.
• Consider adding glucocorticoid-sparing therapy for all patients.
• Obtain urgent specialist consults as needed for complications. ^[26][27]
  • Visual symptoms: ophthalmology
  • Neurological symptoms: neurology
  • Large-vessel involvement: vascular surgery
• Taper glucocorticoid therapy to a maintenance dose once clinical remission has been achieved.

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

Glucocorticoid therapy ^[7][15]

This is the mainstay of treatment for patients with GCA.

Initial high-dose therapy (induction therapy) ^[15]

• Ischemic organ damage (e.g., vision loss, cerebrovascular ischemia): high-dose IV glucocorticoids (e.g., methylprednisolone; ) followed by high-dose oral glucocorticoids ^[15]
• No cranial symptoms (e.g., vision loss, amaurosis fugax, stroke): high-dose oral glucocorticoids (e.g., prednisone ) ^[15]

Maintenance therapy ^[15][16][28]

• Initiate after remission has been achieved.
• Slowly taper glucocorticoids to the lowest dose needed to control symptoms. ^[28]
• If symptoms recur, revert to the dose before the recurrence and reattempt tapering after 4–8 weeks.
• Treatment duration: no consensus (generally, ≥ 2 years) ^[16]
• Initiate measures to prevent complications of glucocorticoid therapy as needed.

Adjunctive therapy ^[15][28]

• Glucocorticoid-sparing therapy
  • Indications
    • Consider in all patients with newly diagnosed GCA.
    • Patients with glucocorticoid-related adverse effects
    • Patients with GCA relapse
  • Options include:
    • Tocilizumab (IL-6 receptor antagonist)
    • Methotrexate ^[15]
    • Abatacept if other agents are not effective ^[29]
  • Glucocorticoid-sparing therapy is typically tapered after glucocorticoid therapy has been discontinued. ^[16]
• Low-dose aspirin
  • Not routinely recommended
  • Consider in patients with critical stenosis of vertebral or carotid arteries. ^[15]

Follow-up ^[15]

• Clinical remission typically occurs after 2–4 weeks of treatment. ^[7]
• For patients without clinical remission, consider adding a glucocorticoid-sparing agent or switching the existing agent until remission is achieved.
• Patients in remission require long-term monitoring, including:
  • Imaging studies, and inflammatory markers
  • Monitoring for complications of immunosuppressive therapy

• 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 adding glucocorticoid-sparing therapy (e.g., tocilizumab or methotrexate) for all patients with newly diagnosed GCA.

Begin treatment as soon as GCA is suspected. Do not wait for diagnostic confirmation.

• Permanent vision loss: ∼ 20–30% if giant cell arteritis is left untreated ^[30]
• Cerebral ischemia (e.g., transient ischemic attack and stroke): < 2% of cases ^[31]
• Aortic aneurysm and/or dissection: ∼ 12% of patients ^[32]

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