Giant cell arteritis

Synonyms: giant cell arteritis, cranial arteritis

What is giant cell arteritis?

Giant cell arteritis is a granulomatous medium and large-vessel vasculitis. It is the most common form of systemic vasculitis. Giant cell arteritis mainly affects the external cranial branches of the aorta.¹

What causes giant cell arteritis? (aetiology)¹

The actual cause of temporal arteritis is unknown.

Polymyalgia rheumatica (PMR) is considered by some to be a variant of giant cell arteritis, where overt vasculitis has either not commenced or is possibly prevented by an unknown inhibiting mechanism. 40-60% of people with temporal arteritis also have PMR, conversely 16-21% with PMR have temporal arteritis, perhaps resulting from sharing of genetic risk factors and pathogenesis.

Temporal arteritis should be considered in PMR patients with marked constitutional symptoms and/or elevated acute phase reactants, and where there is an inadequate response to glucocorticoids or relapse.

There is a significant increased risk of peripheral arterial disease in people with giant cell arteritis.

The classical paradigm of giant cell arteritis, focused on cranial artery involvement, has evolved towards a model incorporating cranial as well as extra-cranial (large-vessel) arterial inflammation. Extra-cranial large vessel involvement is particularly associated with systemic symptoms, such as fever and weight loss.³

How common is giant cell arteritis? (Epidemiology)⁴³

• Giant cell arteritis occurs in people over the age of 50. Cases in under-50s have been reported, but are exceptionally rare.⁵ In some diagnostic criteria, an age above 50 years is considered an absolute requirement for diagnosis.⁶ The mean age at onset is approximately 70.

• Giant cell arteritis is 2.5 times more likely to occur in women than in men, with lifetime risk at 1% for women and 0.5% for men.

• It is also more likely to occur in Northern European countries and those of northern Europe ancestry with incidence rate of 20 per 100,000. The incidence of giant cell arteritis is much lower in southern Europe and Mediterranean and quite rare in patients of African and Asian descent.

• The HLA gene most commonly associated with giant cell arteritis in white people is HLA Br1*04. Those with this gene are at higher risk for developing temporal arteritis, higher risk for complications of giant cell arteritis such as visual loss, and higher risk of resistance to glucocorticoids.

Giant cell arteritis symptoms^{4 7 8 9}

The onset may be acute or insidious. Typical symptoms include headaches, scalp tenderness and jaw claudication but constitutional symptoms are also common, including malaise, fatigue, weight loss, anorexia and low-grade fever.

Headaches are typically severe, may be unilateral or bilateral, and are usually located in the temporal area. Patients typically describe the pain as sharp, burning and severe. Scalp tenderness usually precedes the headaches by a few weeks. Headaches and scalp tenderness tend to occur prior to the onset of visual loss, which occurs in about 30% of patients and is permanent in about 10-15%.

Giant cell arteritis should be suspected if the person is aged 50 years or older and presents with at least one of:

• New-onset headache: headache occurs in about two thirds of people with giant cell arteritis. It is usually temporal but location may vary.

• Temporal artery abnormality -eg, tenderness, thickening, or nodularity - is present in up to 30% of people with giant cell arteritis. Overlying skin is occasionally red and pulsation may be reduced or absent.

• Visual disturbances such as loss of vision, diplopia, or changes to colour vision. Up to 30% of people with giant cell arteritis develop visual loss that may be transient or permanent. In unilateral visual loss there is a 20-50% chance of the other eye also being affected. Double vision, visual field defects, or changes to colour vision may also occur.

• Fundoscopic findings are not specific, but may include pallor and oedema of the optic disc, and 'cotton-wool' patches and small haemorrhages in the retina (these features are usually seen following loss of vision).

• Scalp tenderness occurs in about 50% of people, in particular over the temporal and occipital arteries. Scalp necrosis may occur but is less common.

• Intermittent jaw claudication occurs in nearly half of people with giant cell arteritis, causing pain in the jaw muscles (typically over the masseter after minutes of chewing). Occasionally, intermittent claudication affects the tongue, or the muscles involved in swallowing.

• Systemic features such as fever (usually low-grade), fatigue, anorexia, weight loss, and depression are often present.

  • Systemic features may be the only symptoms in patients with GCA who have predominantly extra-cranial large vessel vasculitis; symptoms of cranial involvement may be absent.³

• Features of polymyalgia rheumatica (PMR), such as proximal muscle pain, stiffness, and tenderness) are present in about 40% of people with giant cell arteritis.

• Neurological features occur in about 30% of people and include:

  • Mononeuropathy or polyneuropathy of the arms or legs.

  • Transient ischaemic attack or stroke in the distribution of the carotid or vertebrobasilar arteries.

  • Upper cranial nerve palsies.

• Giant cell arteritis may occasionally present with audio-vestibular symptoms or respiratory symptoms such as cough, sore throat, and hoarseness.

• Features associated with extra-cranial large vessel involvement include bruits (eg, carotid artery), decreased arterial pulsation/blood pressure difference between arms, intermittent arm/limb claudication (due to stenosis), and back or chest pain (due to aortitis or aortic dissection).

As clinical features are not specific for giant cell arteritis, other possible causes of symptoms should be considered. Features suggestive of another cause include neurological deficits, severe systemic features, and localised ear, nose, and throat signs.

Differential diagnosis

• Migraine.

• Tension-type headache.

• Trigeminal neuralgia.

• Takayasu's arteritis.

• Polyarteritis nodosa.

• Polymyositis.

Diagnosing giant cell arteritis (investigations)⁷

Giant cell arteritis is a medical emergency. Same-day secondary care referral should be made (usually to a rheumatologist) for an urgent specialist opinion and consideration of further investigations.

Glucocorticoid therapy should be started if there is a clinical suspicion of giant cell arteritis, and should not be delayed whilst waiting for diagnostic imaging or a temporal artery biopsy.³

Investigations include:

• Blood tests. These may provide evidence in support of, or against, the diagnosis:

  • Blood inflammatory markers (ESR and CRP) are usually elevated, and raised levels support the diagnosis.⁶

    • Less than 5% of patients with giant cell arteritis have normal inflammatory markers.¹⁰

    • Normal inflammatory markers therefore make giant cell arteritis less likely as a diagnosis, and should prompt consideration of alternative diagnoses, although they do not definitively rule it out.³

    • ESR and CRP are highly correlated, and most patients will have elevations in both. However, non-concordance can sometimes be seen,¹¹ making it prudent to measure both.³

  • A full blood count may show a normocytic anaemia, leukocytosis, and thrombocytosis.³

  • Liver function tests are abnormal in up to 30% of patients.³

• Ultrasound imaging or biopsy:³

  • Historically, a temporal artery biopsy was considered the 'gold standard' for confirming a diagnosis of giant cell arteritis.

  • This has a very high specificity (up to 100%), but a lower sensitivity, as vascular lesions in giant cell arteritis typically show a segmented pattern, which may be missed in a biopsy of a single part of the vessel.

  • It should be performed within 4 weeks of the initiation of glucorticoids (and ideally earlier), as steroid therapy can lead to a resolution of the vascular inflammatory infiltrate.

  • More recently, ultrasound of the temporal artery has emerged as a diagnostic surrogate for temporal artery biopsies, as a non-invasive test that can often be performed more quickly.

  • The presence of the halo sign on temporal artery ultrasound is highly specific for giant cell arteritis, and now appears in diagnostic criteria. A positive temporal artery ultrasound may obviate the need for a biopsy.⁶

  • Glucocorticoids progressively reduce the sensitivity of temporal artery ultrasound, and so ultrasound should be performed within one of week of starting steroids.³

• FDG-PET/CT is increasingly important as part of the diagnostic workup, as it aids in ruling out alternative diagnoses and can detect extra-cranial large vessel involvement.³

• Magnetic resonance angiography, CT angiography, and axillary artery ultrasound may also be used to evaluate for large vessel involvement.⁸

Giant cell arteritis treatment and management

• Steroids:

  • Once the diagnosis is suspected, treat with high-dose corticosteroid immediately:¹²

    • 40 mg prednisolone daily unless the patient has ischaemic symptoms (jaw or tongue claudication, or visual symptoms).

    • Claudication symptoms: give 60 mg prednisolone daily.

    • If the patient has visual symptoms, they are likely to require intravenous methylprednisolone, although 60-100 mg of prednisolone for up to three days is an alternative if this is not possible.⁷

  • Symptoms should improve rapidly after initiation of corticosteroids; if they do not, an alternative diagnosis should be considered.

  • Once symptoms and abnormal test results resolve, prednisolone should be gradually tapered to zero over the next 12 to 18 months, providing there is no relapse of symptoms, signs, or laboratory markers of inflammation.⁸

  • Flare-ups and relapses usually respond to corticosteroid increases to the level at which symptoms previously were controlled. Protracted courses of therapy are often necessary.¹³

• Glucocorticoid therapy leads to significant toxicity in over 80% of the patients. Osteoporosis prophylaxis is required for patients on long-term steroid treatment.¹⁴

• Tocilizumab (a monoclonal antibody against the interleukin-6 receptor) is an effective glucocorticoid-sparing therapy, demonstrating sustained glucocorticoid-free remission in 56% of patients receiving weekly tocilizumab compared with 18% of patients receiving a 52-week prednisone taper.¹⁵

  • Tocilizumab was originally approved by the National Institute for Health and Care Excellence (NICE) in 2018 for relapsing or refractory giant cell arteritis only.¹⁶

  • Its use has expanded, however, and is used more widely in the initial treatment of giant cell arteritis (alongside corticosteroids), especially in patients who are at a high risk of glucocorticoid toxicity.⁸

• Methotrexate is a potential alternative to tocilizumab as a glucocorticoid-sparing therapy to reduce relapse risk.³

Complications of giant cell arteritis¹⁷

• Loss of vision. Permanent visual loss, partial or total, occurs in up to 20% of patients and is often the first manifestation of the disease.¹⁸

• Aneurysms, dissections and stenotic lesions of the aorta and its major branches.

• Central nervous system disease: seizures, cerebral vascular accidents. SSS and brain ischaemia. Intracranial vessels are involved only rarely. Peripheral nerve involvement is also rare.

• Steroid-related complications are common; morbidity from steroid therapy is often worse than the underlying disease. Potential steroid-related complications include osteoporosis, corticosteroid myopathy, bruising, emotional symptoms (eg, insomnia, restlessness, hypomania, depression), hypertension, diabetes, elevated cholesterol and fluid retention.¹³

Prognosis⁷

• Visual damage is often irreversible. Partial or complete loss of vision occurs in about 15-20% of patients. Severe sight impairment in both eyes is rare.¹³

• Most people with giant cell arteritis respond rapidly to treatment with glucocorticoids. However, relapses are common and occur in up to 50% despite appropriate treatment.

• Treatment with glucocorticoids is usually needed for 1-2 years, and, in some cases, continued low-dose prednisolone may be needed for several years.

• Overall survival is similar to that of the general population but the risk of developing large vessel complications such as aortic aneurysm is increased..