Giant Cell Arteritis

I. What every physician needs to know.

Giant cell arteritis (GCA), also known as temporal arteritis, is a chronic vasculitis of large and medium sized vessel that should be considered in individuals older than 50 who present with new onset of headache, visual dysfunction, polymyalgia rheumatica or systemic inflammatory symptoms.

Giant cell arteritis is commonly associated with cranial symptoms and acute phase inflammatory response, but large vessel involvement is frequent and can lead to severe complications such as visual loss, stroke, limb claudication or aortic aneurysm.

II. Diagnostic Confirmation: Are you sure your patient has giant cell arteritis?

GCA should be considered in a patient over the age of 50 who is found to have any of the following:

new headaches
tenderness or decreased pulse of the temporal artery
visual disturbances
symptoms of polymyalgia rheumatica
jaw claudication
unexplained fever or anemia
elevated ESR(greater than 50 mm/h) or c-reactive protein

If there is sufficient clinical suspicion of GCA, a temporal artery biopsy should be performed to confirm the diagnosis.The biospy would reveal a necrotizing arteritis with a predominance of mononuclear cells or a granulomatous process with multinucleated giant cells, should the patient have GCA.

A. History Part I: Pattern Recognition:

The diagnostic category of GCA encompasses multiple variants , but there are four predominant clinical scenarios:

Cranial arteritis

localized new headache
visual loss is due to ischemia of the optic nerve or its tracts
claudication of jaw or tongue
stroke or CNS ischemia
scalp tenderness

Polymyalgia rheumatica

pain in shoulder and pelvic girdle muscles
stiffness

Large vessel vasculitis

claudication of the extremities
decreased or absent pulses
Raynaud’s phenomenon
aortic aneurysm

Nonspecific systemic inflammatory disease:

fever and chills
anorexia,weight loss
night sweats
weakness
depression

B. History Part 2: Prevalence:

GCA is the most common primary systemic vasculitis and occurs almost exclusively in people over the age of 50, with incidence rates reaching 15-25 cases per 100,000. Women are more likely than men to be affected and people of Northern European and Scandinavian countries have the highest prevalence.

C. History Part 3: Competing diagnoses that can mimic giant cell arteritis:

Large cell vasculitis

Takayasu arteritis may have the same radiological and histopathologic findings as GCA, but typically begins before the age of 40 years and visual loss is unusual in Takayasu.

Small and medium vessel vasculitis

Microscopic polyangiitis, Wegener’s granulomatosis and polyarteritis nodosa share the systemic symptoms with GCA, but they usually have a different vascular distribution and distinctive hystopathology.

Central nervous system vasculitis

The two disorders can be separated by the fact that ischemic events in GCA do not cause intracranial symptoms.

Nonvasculitic conditions

Nonarteritic anterior ischemic optic neuropathy(NAAION) can mimic vision loss in GCA,but occurs in older individuals.

D. Physical Examination Findings.

Thickened and tender temporal arterial branches. On physical examination, involved vessels are nodular and tender, pulses are reduced or absent.
Cranial nerve involvement: ranges from vision loss/amaurosis fugax (fleeting visual blurring) to diplopia and pupillary defects. Loss of vision is usually sudden,painless and permanent.On ophtlamologic examination, anterior ischemic optic neuropathy is recognized by optic disc edema followed by optic atrophy, with optic disc cupping.
Intermittent claudication of the masseter and temporalis muscles caused by compromised blood flow in the extracranial branches of the carotid artery.

E. What diagnostic tests should be performed?

The gold standard for diagnosing giant cell arteritis is a temporal artery biopsy. If there is a clinical suspicion of giant cell arteritis (see #II-Diagnostic confirmation above), a temporal artery biopsy should be performed, generally on an outpatient basis, by a vascular surgeon, an ophthalmologist, general surgeon or other surgical subspecialist.

The biopsy should be performed on the same side as the symptoms or abnormal findings on physical exam. Patients who manifest only symptoms of polymyalgia rheumatica(PMR) do not require biopsy. However, these patients should be questioned carefully about headache, jaw or arm claudication, visual symptoms, and any pain in the face, throat or tongue, suggestive of giant cell arteritis.

If one temporal artery is abnormal on clinical exam (swollen or tender), then the biopsy should be taken from that artery. However, when the extracranial arteries are not obviously abnormal, it is important to biopsy a longer segment (minimum length of 20 mm) of the temporal artery,to increase the chance of arterial specimens showing inflammatory changes. The rate of false-negative biopsies can be minimized by taking a sufficient length of biopsy, examining serial sections and removing the contralateral temporal artery in cases in which the first biopsy is free of disease.

Statistical models have been used successfully in predicting a negative temporal artery biopsy. The following combination of findings correlated with a 95 percent probability of a negative temporal artery biopsy:

a normal or mildly elevated ESR
absence of jaw claudication
absence of temporal artery tenderness
the presence of synovitis,which suggests an alternative diagnosis

Typical histopathological findings include a lymphocytic infiltrate with activated macrophages and multinucleated giant cells that infiltrate the vessel, but is only seen in 50% of cases. Giant cells are not necessary for the diagnosis of GCA.

Scheduling of temporal artery biopsy should never interfere with the start of treatment in a patient with a high likelihood of GCA, since the inflammatory infiltrate is still present several weeks or even months after the start of steroid therapy.

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Acute phase reactants

Erythrocyte sedimentation rate (ESR) is elevated in most patients with GCA (>50 mm/h), although as many as 20% of patients with biopsy proven giant cell arteritis have been found to have a normal sedimentation rate before steroid therapy. Therefore, a normal sedimentation rate does not exclude the diagnosis of giant cell arteritis and should not delay its diagnosis and treatment.

C-Reactive protein

C-reactive protein levels parallel those of ESR.In clinical practice it is useful to measure both the ESR and CRP,since disease activity correlates more closely with serum CRP in some patients and with ESR in others.

Interleukin-6

Interleukin-6 is elevated in patients with GCA and is closely correlated with clinical disease activity and risk for relapse

Hematology

As a result of systemic inflammation, the patient may present with normochromic, normocytic anemia, leukocytosis and thrombocytosis.

Hepatic enzymes

Hepatic enzymes may be elevated in 25 to 30 percent of patients and revert to normal with glucocorticoid therapy.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Imaging studies are potentially useful tools in larger vessel vasculitis but are still the subject of controversy.

Doppler ultrasonography

Doppler ultrasonography of the temporal artery has been reported to be helpful in diagnosing GCA,because it shows a halo around the arterial lumen,but the results of various studies are controversial, and the technique is highly operator dependent.Temporal artery biopsy remains the gold standard test for giant cell arteritis, but some have suggested that ultrasound may help with identifying the best site for biopsy.

MRA and computed angiography

MRA and computed angiography have been used for diagnosis and serial monitoring of patients with GCA,since it gives information on vessel wall intensity that reflects inflammation.These tests are not routinely used.

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.

Ultrasonography is neither a substitute for biopsy nor a screening tool for disease.
Arteriography, although accurate, has been replaced by noninvasive imaging studies.

III. Default Management.

1. For patients in whom the diagnostic suspicion of GCA is high, especially if visual changes are present, glucocorticoid treatment should be started immediately.

One study showed the following combination of findings correlated with a 95% probability of a negative temporal artery biopsy:

a normal or mildly elevated ESR(less than 40 mm/h)
absence of jaw claudication
absence of temporal artery tenderness
the presence of synovitis suggests an alternative diagnosis

2. A temporal artery biopsy should be obtained as soon as possible, but treatment should not be whitheld while awaiting biopsy results.

3. If the temporal artery biopsy reveal no evidence of arteritis, but suspicion of GCA remains strong steroid therapy should be continued.

A. Immediate management.

Glucocorticoid therapy

Highly effective in inducing disease remission in patients with GCA and rapid clinical response can be seen within 48 hours, although some patients have a more delayed clinical improvement. There is still a role for obtaining a temporal artery biopsy up to several weeks after steroids are started, as the pathological abnormalities of GCA do not resolve rapidly. Steroids cannot reverse intimal hyperplasia,but reduce ischemic events by reducing tissue edema and may contribute to improved vision.

Initial dose of 1mg/kg (40-60 mg) per day of prednisone is recommended. The initial dose of prednisone is usually maintained for 4 weeks and then decreased slowly. With close monitoring for clinical signs of disease reactivation the dose of steroid can be tapered by 10 percent every one to two weeks. After achieving a a daily dose of 10 mg, the prednisone taper should be slowed substantially, such that patients remain on some prednisone for a total of 12 months. The duration of therapy varies and most patients remain on therapy for at least one year, and some cannot stop it completely without recurrence of symptoms.

Daily dosing is more effective than alternate day dosing, but split dosing(use of multiple doses during a single day) is not more effective than a single daily dose.

In the setting of visual loss in one eye or threatened visual function, some experts advocate high dose parenteral glucocorticoid therapy. Intravenous pulse dose methylprednisolone (500 to 1000mg iv daily) for three days is recommended, followed by oral therapy with 1mg/kg per day prednisone for at least one year.

Because prolonged treatment courses with glucocorticoids are associated with osteoporosis, adequate dietary calcium and vitamin D intake should be encouraged. Depending on clinical scenarion bisphosphonates might also be appropriate. Measuring bone mineral density near the time treatment is initiated may guide prophylaxis and treatment for osteoporosis. All other prophylactic measures related to steroid use apply.

Aspirin

Low dose (80 to 100mg/day) is recommended in addition to steroids to reduce the risk of visual loss, transient ischemic attacks or stroke.

In view of concomitant use of steroids, for prevention of stress ulcer use of misoprostol or a proton pump inhibitor is recommended.

B. Physical Examination Tips to Guide Management.

Disease relapses can occur in up to 60% of patients during the course of treatment. GCA relapse should be suspected when patients experience return of symptoms from their original presentation, or new symptoms compatible with GCA or polymyalgia rheumatica (pain in shoulder and pelvic girdle muscles, stiffness) occur. Symptoms of systemic inflammation (fever, chills, anorexia, weight loss) are frequently seen with disease reactivation, but vascular complication are not usually noted.

C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.

Laboratory testing

Checking ESR, CRP and hemoglobin prior to each decrease in glucocorticoid dose is ideal. At some point ESR or other monitoring tests may rise above normal, leading to concern about recurrence of disease. If elevated ESR or CRP are not accompanied by symptoms or findings suggestive, changes in steroid dosing may prolong glucocorticoid therapy unnecessarily.

Serum IL-6 levels are more sensitive than CRP and ESR measurements in detecting inflammation prior and during steroid therapy. If IL-6 levels remain elevated after discontinuation of therapy, smoldering continuation of disease is likely.

Monitoring for development of aortic aneurysm

Patients with GCA are at risk of developing thoracic aortic aneurysms, involving more often the ascending than the descending aorta. Yearly CXR should be performed for up to ten years to identify patients with thoracic aortic aneurysms prior to rupture or dissection.

If aneurysm identified on CXR, monitoring with CT every 6 to 12 month is recommended. Medical management is indicated for thoracic artery aneurysms of 3 to 5cm diameter, while surgical management is recommended for patients with larger, or rapidly enlarging aneurysms.

D. Long-term management.

The current practice is to measure both the ESR and CRP at a patient’s visit and to identify through longitudinal follow-up which of these measurements appear to reflect disease activity. That being said, the clinician must remember to treat the patient as a whole and not only the laboratory test results, to avoid substantial glucocorticoid morbidity.

E. Common Pitfalls and Side-Effects of Management

None of the immunosuppressants used to manage other rheumatic disease has proved useful in treatment of giant cell arteritis. Methotrexate has been evaluated in three prospective randomized trials with mixed results.It seems that methotrexate lacks steroid sparing activity in GCA.

Similarly, infliximab is not recommended in treatment of patients with giant cell arteritis, because prospective studies have shown no difference in the relapse rate and higher rate on infection in the infliximab group compared to placebo.

Adverse effects of glucocorticoid use in GCA should be anticipated, and the patients should be provided appropriate warnings. Problems with high doses of prednisone include weight gain, glucose intolerance, frank diabetes mellitus, hypertension, opportunistic infection and others. Close follow-up after steroids are started is essential to detecting these potential issues.