Rheumatology

Giant Cell Arteritis (Temporal Arteritis)

Does this patient have giant cell arteritis (temporal arteritis)?

Giant cell arteritis (GCA), also known as temporal arteritis, is an uncommon form of granulomatous vasculitis that affects primarily the large and medium-sized arteries. GCA is a disease that affects elderly patients and rarely occurs in subjects under 50 years of age. The prevalence of GCA for subjects over the age of 50 years is 24.2 per 100,000 in women and 8.2 per 100,000 in men. The incidence of GCA increases with age. GCA is a disease that has a predilection for people of Scandinavian descent. The cause of GCA is not known but some investigators postulate it is caused by an infection.

Herpes zoster has been implicated as the cause of GCA by some investigators but subsequent studies have failed to confirm this finding. So far, no single infectious organism has been consistently found as a cause for GCA. Patients with GCA appear to have a higher rate of respiratory, urinary tract, and other types of infections prior to the diagnosis of GCA. These data suggest that changes in one’s immune system or the development of multiple infections could increase a patient’s risk of developing GCA.

Inflammation of large and medium-sized arteries may lead to either stenosis, aneurysm formation or dissection of affected arteries. Patients with GCA have a higher risk of developing an aortic aneurysm than the general population. Vessel stenoses and aneurysms can interrupt blood flow to distal organs leading to ischemic signs and symptoms or rarely cause bleeding. Patients may describe symptoms including:

  • Headache, unilateral or bilateral. The superficial temporal artery is commonly inflamed causing head pain or scalp tenderness. Parietal and occipital regions of the scalp may also be painful if arteries supplying these areas become inflamed. The headache is often described as insidious but may be acute in onset. The pain is often described as dull or less commonly as the worse headache of one's life, although a "thunderclap" pattern headache is not typical.

  • Claudicatory jaw pain, often described as a dull pain in the masseter muscle, usually begins after initiating food mastication. The pain intensifies with chewing solid foods such as meat and improving with rest. Patients may also describe weakness in mastication or an inability to open their mouth widely.

  • Diplopia caused by extraocular muscle ischemia.

  • Blindness due to ischemia or occlusion of arteries supplying the eye.

  • Stroke is uncommon.

  • Polymyalgia rheumatica (PMR) which includes symptoms of proximal shoulder and thigh pain often associated with dramatic early morning axial muscle stiffness.

Physical exam findings in patients with GCA may include the following:

  • Weight loss

  • Fever

  • Asymmetric blood pressures in arms or legs may occur if inflammation causes stenosis of the subclavian, axillary, iliac or femoral arteries.

  • Scalp tenderness or prominent and pulseless temporal arteries sometimes associated with bitemporal muscle wasting.

  • Decreased or absent carotid, radial, dorsalis pedis or posterior tibial artery pulses.

  • Bruits over major arteries such as the carotids, vertebrals, subclavians, axillary, iliac/femoral arteries.

  • Murmur of aortic regurgitation caused by aortic root dilation secondary to inflammation of the aortic root.

The diagnosis of GCA is suspected based upon history and physical exam and often confirmed by biopsy of the superficial temporal artery. Advanced imaging using CTA or MRA of the great vessels may show artery wall thickening, vessel stenosis or aneurysm formation. No blood test exists that is diagnostic of GCA but elevations in blood inflammatory markers such as sedimentation rate (ESR) or C-reactive protein (CRP) are suggestive of the disease in the appropriate clinical setting. However, up to 22.5 % of patients may have a ESR of less than 40 mm/h. Biopsy of the superficial temporal artery showing vasculitis is extremely valuable when positive, but may be negative in subjects with GCA. Other diseases may mimic the symptoms of GCA and/or cause inflammation of the temporal artery.

PMR is a disease that can exist alone or be a part of the symptomatology of subjects with GCA. Other vasculitides such as polyarteritis nodosa, granulomatosis with polyangiitis (GPA, Wegener's), microscopic polyangiitis (MPA), or eosinophilic granulomatosis with polyangiitis (eGPA) and Takayasu arteritis rarely cause vasculitis of the superficial temporal artery. Severe atherosclerosis of the carotid arteries or its branch arteries can cause artery stenosis and headache. Noninflammatory vasculopathies such as fibromuscular dysplasia or segmental arterial mediolysis may cause artery wall thickening/stenosis or dissection.

Paget's disease, varicella zoster, and some malignancies may cause headaches and elevations in ESR and CRP. Acute glaucoma can also cause diagnostic confusion at times. Infections such as meningitis/encephalitis or strokes caused by hemorrhage, thrombosis or embolism should also be ruled out.

What tests to perform?

  • ESR and CRP are usually elevated in subjects with GCA. Complete blood counts (CBC) may show a mild thrombocytosis. Anemia, usually caused by anemia of inflammation, is common in affected patients. Less common, elevations in liver transaminases or a low serum albumin may occur.

  • Advanced imaging techniques including computerized tomography angiography (CTA) or magnetic resonance angiography (MRA) of the aorta should be considered for all patients diagnosed with or suspected of having GCA. Some investigators have shown that up to 67% of subjects with GCA will have findings of large or medium-sized vasculitis on imaging. These findings may include artery wall thickening, stenosis or aneurysm formation. Particular attention should be made at evaluating the entire aorta and its branch arteries for aneurysm formation or stenosis. Patients with aortic aneurysms may need frequent imaging to watch for expanding aneurysms that may require surgical intervention. No formal recommendations exist as to which imaging modality should be used or how frequently patients should be screened for large or medium-artery disease.

  • Some investigators have reported that ultrasound, MRI or CT of the temporal arteries may be used to diagnosis GCA. These modalities are operator dependent, may only be available at limited institutions and cannot reliably replace biopsy of the temporal artery for diagnosis of GCA. Echocardiogram and chest X-ray may show aortic dilatation but are limited by their poor sensitivity and inability to evaluate the entire aorta and all its branch arteries. CT PET scan is currently being studied as a tool to diagnose GCA and attempt to ascertain activity of disease.

  • Biopsy of a superficial temporal artery should be pursued in patients with symptoms consistent with GCA. The biopsy often shows hyperproliferation of the intima and luminal narrowing. The internal elastic membrane may be fragmented. Inflammatory cells usually involving CD4 T lymphocytes and macrophages may cause a panarteries, inflammation of all layers of the temporal artery wall, or cause inflammation of only the adventitia. The inflammation is usually described as granulomatous. Fibrinoid necrosis is not a prominent feature of GCA and if seen on microscopy should lead one to look for other causes of temporal artery inflammation. Multinucleated giant cells caused by the fusion of macrophages are seen in only 50% of biopsied arteries.

  • Although ESR and CRP are often elevated in patients with GCA, they do not always correlate with disease activity. Approximately 5% of patients may have an ESR less than 40mm/h at the time of diagnosis. Negative temporal artery biopsies in patients with signs and symptoms of GCA should be interpreted with caution. The false negative rate of a temporal artery biopsy in patients with GCA is around 10%. Arterial inflammation often does not affect the entire artery and may cause skip lesions that may be missed on microscopic examination.

  • Controversy remains as to how long a temporal artery specimen should be for adequate analysis. A 2cm biopsy specimen is usually adequate for interpretation but specimens longer in length have a higher yield at giving positive results than shorter specimens. Unilateral biopsies are usually sufficient to provide a diagnosis particularly in patients that have signs or symptoms (jaw pain, vision loss, abnormal temporal artery on exam) that localize to one size of the head. Bilateral biopsies are preferred by some institutions and may increase the yield of obtaining a positive biopsy.

  • Glucocorticoids are unlikely to change the architecture of a temporal artery specimen if a biopsy is performed within two weeks of starting the drug. Thus, glucocorticoids should not be withheld until after a biopsy is performed if the diagnosis is strongly suspected.

How should patients with temporal arteritis be managed?

  • Glucocorticoids remain the gold standard for the treatment of GCA and should be started at the first suspicion of GCA. Studies that evaluate the initial starting dose and length of time patients should remain on prednisone are lacking. In the United States most clinicians agree that prednisone 1 mg/kg/d (40-60 mg/d) is a reasonable starting dose. The dose can be increased if symptoms are not adequately controlled. Initial prednisone doses should be continued for at least two to four weeks before initiating a taper. Signs or symptoms of disease activity should also be gone prior to initiating a taper. Most patients will require up to 12 months of glucocorticoid therapy.

  • One type of prednisone taper to consider is reducing the dose of prednisone to 50 mg/d after two weeks of the initial starting dose of 60 mg/d. Then taper by 10 mg every two weeks until at 40 mg/d. Once at 40 mg/d, taper by 5mg every 2 weeks until at 20 mg/d and then by 2.5 mg every 2 weeks until at 10 mg/d. Since flares are more common to occur at doses of prednisone of 10 mg/d or less, tapering by 1 mg every month until the patient is off prednisone may be attempted.

  • Patients with evidence of extraocular muscle ischemia or organ damage due to vasculitis (diplopia, blindness or stroke), methylprednisolone IV (3g divided over 3 days) has been used by some clinicians. Evidence supporting this higher dose is lacking.

  • Antiplatelet therapy such as daily oral aspirin therapy (81 mg/d) should be strongly considered in all patients with GCA since some studies have shown that antiplatelet therapy may reduce the risk of ischemic events such as stroke or blindness.

  • Although controversial, current evidence does not support the use of immunosuppressant medications such as methotrexate or azathioprine or biologic agents such as TNFa inhibitors as glucocorticoid sparing medications.

  • Subcutaneous Tocilizumab, a humanized anti-IL-6R monoclonal antibody, is FDA approved for the treatment of GCA. A phase 2, double-blind study of patients with relapsing or newly diagnosed GCA showed higher remission rates, longer relapse-free survival rates, and reduced cumulative steroid doses in subjects treated with tocilizumab in combination with prednisone compared to subjects receiving tocilizumab-placebo and prednisone. The number of adverse events in each group were similar. Another large controlled study investigating the efficacy of tocilizumab is currently underway.

  • Abatacept, an inhibitor of the T cell costimulatory molecule CD28, has been shown also to reduce the risk of GCA relapses with no increase in adverse events when compared to placebo when used in combination with prednisone. However, its efficacy may not be as good as Tocilizumab, although the two have not been studied in a head to head trial.

  • Oral and IV cyclophosphamide have also been used with success in some patients with treatment-resistant GCA; however, cyclophosphamide should not be considered as first-line therapy.

What happens to patients with temporal arteritis?

  • Untreated GCA may lead to blindness and stroke. Coronary arteries may be involved in rare instances leading to myocardial infarction. Subclavian or iliac arteries with inflammation may become stenotic or occluded leading to arm or leg claudication. An inflamed aorta can dilate and cause an aneurysm leading to dissection or rupture.

  • Untreated patients with GCA may have fevers, weight loss and muscle wasting. Fatigue may occur due to active disease or due to anemia caused by inflammation.

    • GCA may be a self-limited disease in some patients treated with prednisone. Most will eventually be able to discontinue their glucocorticoids.

    • Relapse may occur in up to 70% of patients. Increased doses of prednisone are usually sufficient to treat most relapses. Some patients will require long-term glucocorticoid treatment. Treatment with glucocorticoids for long periods of time will cause side effects in most patients. These side effects include infection, glaucoma, cataracts, skin striae, hypertension, insomnia, osteoporosis and increased risk for fractures. For some patients, tocilizumab or abatacept may be used as initial therapy or as add-on therapy in combination with prednisone. Studies do not support the use of these medications in place of prednisone.

    • Patients with GCA should receive age-appropriate immunizations including influenza and pneumonia vaccinations. Vaccines that use live or attenuated virus should be withheld until after the patient is no longer receiving high dose immunosuppressive medications.

    • Medications that prevent osteoporosis should be considered for all patients expected to receive glucocorticoids for up to 3 months or more. Daily oral calcium and vitamin D as well as oral or IV bisphosphonates may be beneficial.

    • Revascularization procedures such as angioplasty or bypass surgery may be required for some patients. Patients with aortic dilatation or aneurysm may require aortic root replacement and/or aortic valve repair/replacement.

How to utilize team care?

  • Consultation with a surgeon with knowledge in performing superficial temporal artery biopsies.

  • Consultation with a vascular surgeon for patients who have stenotic or occluded arteries requiring revascularization. A consultation with a vascular surgeon or cardiothoracic surgeon may be necessary for subjects with aortic aneurysms or aortic regurgitation caused by aortic root dilatation.

  • Consultation with an ophthalmologist for subjects with visual disturbance or blindness caused by GCA.

  • Consultation with a physician specializing in the treatment of glucocorticoid induced osteoporosis.

  • Consultation with a rheumatologist with expertise in managing GCA.

Are there clinical practice guidelines to inform decision making?

  • GCA should be considered in any patient greater than 50 years of age with new unexplained head pain, amaurosis and/or polymyalgia rheumatica.

  • Patients suspected of having GCA should be started on glucocorticoids while awaiting biopsy of the temporal artery. The use of tocilizumab or abatacept should be made on an individual basis.

  • Advanced imaging (MRA or CTA) should be considered in all patients with GCA to evaluate the entire aorta and its branch arteries for signs of vasculitis.

  • Antiplatelet therapy should be considered in all patients with GCA.

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