Course Authors

Peter Barland, M.D.

Dr. Barland reports no commercial conflict of interest.

Estimated course time: 1 hour(s).

Albert Einstein College of Medicine – Montefiore Medical Center designates this enduring material activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

In support of improving patient care, this activity has been planned and implemented by Albert Einstein College of Medicine-Montefiore Medical Center and InterMDnet. Albert Einstein College of Medicine – Montefiore Medical Center is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.

 

Learning Objectives

Upon completion of this Cyberounds^®, you should be able to:

• List the cells and mediators of the inflammatory reaction in giant cell arteritis

• Discuss the major clinical manifestations of giant cell arteritis

• Describe the diagnostic tests available for giant cell arteritis

• Discuss the therapeutic options for giant cell arteritis.

 

Giant cell arteritis (GCA) is an inflammatory disorder of the branches of the aorta and, occasionally, the ascending aorta itself. The inflammatory response appears to begin as a reaction to an antigen in the artery which activates cytotoxic (TH1) lymphocytes that enter the vessel wall through the vasa vasorum in the adventia of the arteries.(1) These activated TH1 cells release cytokines, especially IL-6 and interferon gamma, which, in turn, activate macrophages. The macrophages produce proteolytic enzymes and toxic oxygen radicals that cause destruction of the internal elastic membrane and damage the media of the artery as well. The macrophages fuse their membranes to become the pathognomic giant cells of the disorder (Figure 1). These giant cells appear to produce growth factors, which lead to fibrosis of the intima of the vessels as well as neovascularization.

While the nature of the antigen remains unknown, there is some evidence to support actinic (i.e., resulting from UV light) damage to the internal elastic membrane of the temporal and ciliary retinal arteries as being an important initiator of the process.(2) Other investigators have focused on a possible infectious agent acting as an antigen or altering the normal endogenous antigens so as to create autoantigens. In support of this theory has been the recent report of Parvovirus DNA in the walls of temporal arteries from patients with GCA. The branches of the external carotid artery are most frequently affected in GCA. Though less frequent, the vertebral, subclavian and coronary arteries have all been the target of the inflammatory process in this disorder and may give rise to symptoms of ischemia in the tissues that they supply. In addition, the ascending aorta may be a site of inflammation, leading to aortic dissection, aortic rupture and aortic valvular insufficiency. While thrombosis of the vessel lumen is seen in some pathological specimens, the rapid reversibility of some of the ischemic manifestations, including visual loss, suggests that there is an element of vasospasm involved as well.

Clinical Presentation

Headache is the most common presenting symptom in GCA. However, headaches are extremely common (bordering on universal) and their causes are very numerous, ranging from such benign conditions as emotional tension, sinusitis and migraine to potentially life threatening conditions such as malignant hypertension and brain tumors. It is, therefore, very understandable that most physicians do not undertake an extensive work up in every patient with a new headache of only a few days duration. It is equally understandable that most physicians do not always think immediately about giant cell arteritis (formerly known as temporal arteritis) when confronted with a patient complaining of a headache. While most of the time, this approach is correct, both clinically and economically, on occasion this can have devastating consequences because undiagnosed and untreated GCA can cause irreversible visual loss early in its course.

Epidemiology and Symptoms

Giant cell arteritis occurs exclusively in patients over the age of 50 and its incidence increases with aging. Giant cell arteritis is uncommon in Blacks, though there have been several well-documented cases in elderly Black patients so this is a relative protective factor. While the disease is more common in females and in fair skinned individuals of northern European extraction, these are only weak factors and are not very helpful in the individual patient.

Physicians can greatly reduce their chances of missing GCA, while still practicing good cost-effective medical care, by recognizing some of the cardinal signs and symptoms of GCA:(3)

1. The headache of GCA is unilateral and usually localized in the distribution of the temporal artery. The headache is often described as sharp or burning and not pulsatile, as one might intuitively suspect from the fact that it is associated with inflammation of medium sized cranial arteries. Visible swelling and redness over the temporal arteries may accompany the headache. Patients will usually be able to recognize this headache as very different from their previous headaches that they have may have experienced from hypertension, sinusitis, migraine or other causes.
2. Sudden monocular blindness, a catastrophic complication of GCA, usually occurs very early in the course of the disease and can be the presenting manifestation of the disease. It is extremely important to begin treatment with high doses of intravenous methylprednisolone within 24 hours of visual loss because such treatment has been reported to restore vision in a small number of patients. In addition, loss of vision in the second eye is most frequently seen in first several days after the involvement of the first eye.
3. New onset of diplopia in an elderly patient, with or without a headache, may be caused by GCA and is also correlated with impending visual loss.
4. Unilateral pain in the temporal muscles brought on by chewing is seen in approximately one fifth of patients with biopsy proven GCA. This symptom, referred to as jaw claudication, is important to recognize because it appears to be present early in the course of GCA and is highly correlated with the risk of visual loss.
5. The presence of painless areas of dark atrophic skin over the temples represent scalp necrosis (Figure 2, below) and, when present, are important signs of GCA.

   Figure 2. An Area of Healing Scalp Necrosis.

   

   There are areas of alopecia and post-infarction atrophy and hyperpigmentation.

6. Almost all patients with GCA have evidence of an acute phase response in their blood. This is most easily demonstrated by an elevated Westegren sedimentation rate (ESR) - usually over 50 mm/hour. While the specificity of an elevated ESR for GCA in an elderly patient is not very high, the sensitivity of the test is better than 90% and, therefore, represents an excellent cost-effective screening test for GCA.(4) In addition to the ESR, the C-reactive protein (CRP) levels are usually greatly elevated. The acute phase response in this disease is believed to be caused by interleukin-6 (IL-6) produced by activated T lymphocytes in the walls of the inflamed arteries acting on hepatocytes. Recently, it has been reported that the circulating levels of IL-6 are elevated in GCA and more accurately predict flares of the disease than the ESR.
7. While many patients with GCA have stiffness and pains in their pectoral and pelvic muscles consistent with polymyalgia rheumatica, this symptom complex carries a relatively low risk of visual loss and does not, in itself, constitute a reason for an invasive work up, such as a temporal artery biopsy.
8. Once the carotid and vertebral arteries penetrate the dura mater, they are rarely subject to the inflammatory attack of GCA. As a result, cerebral infarction is not a common sign of GCA. However, involvement of the vertebral and basilar arteries, prior to their penetration of the dura, can lead to infarction of the posterior portions of the brain - typically, the posterior lobes, cerebellum and, occasionally, the medulla. Therefore, ischemia of these areas of the CNS in a normotensive elderly patient, who is in normal sinus rhythm and has a high ESR (vide infra), should lead to a work up for GCA.
9. While many patients with GCA are febrile, anorectic and depressed, these symptoms are so nonspecific and have such low specificity as to make them relatively useless in raising the suspicion of GCA in an individual patient with a headache.
10. Other unusual signs and symptoms of GCA are listed in Table 1. In an elderly patient with an unexplained high ESR and one of these findings, a temporal artery biopsy is a reasonable consideration.

Diagnosis

The diagnosis of GCA is best established by a biopsy of a temporal artery that demonstrates the inflammatory and proliferative changes noted above. Because a positive biopsy is the gold standard for the diagnosis of GCA, it is not possible to ascertain the sensitivity of the test itself. It is generally agreed, however, that the biopsy may be falsely negative in anywhere from 10 to 25 percent of patients who otherwise have the disorder. Negative biopsies have been blamed on skip lesions in the arteries, though this has not been proven in any controlled study. Another possible explanation for a false negative biopsy is that the pathology has been altered by steroid treatment.

A number of strategies have been proposed for increasing the sensitivity of the temporal artery biopsy:

1. Performing biopsies on the side that the patient has arteritic symptoms.
2. Performing biopsies within 72 hours of the institution of corticosteroid therapy.
3. Including periarterial lymphocytic foci as criteria for a pathological diagnosis.
4. Using magnetic resonance angiography of the temporal arteries to localize the site of arteritis.
5. Using high-resolution ultrasonography of the temporal arteries to localize the site of arteritis.
6. Using positron (PET) scanning in a similar fashion.

From a practical standpoint, only the first two suggestions help to increase the yield of positive biopsies. An extension of these observations is that, in a patient with a clinical picture highly suggestive of GCA, treatment should be continued in the face of a negative biopsy.

Treatment

Patients with suspected GCA should be started on 80 mg of prednisone (or an equivalent dose of methylprednisolone) daily. This should be continued for a minimum of three weeks and, then, gradually tapered by no more than five mg decrements every five days until the patient reaches 40 mg per day, at which point the interval between five mg decrements should be extended to every ten days. Patients with very recent visual loss should receive 500 mg of intravenous methylprednisolone every six hours for the first two days. Patients should be concomitantly treated with medications such as bisphosphonates together with calcium and vitamin to prevent rapid bone resorption and some experts recommend the routine use of an H2 antagonist or a proton pump inhibitor for these patients while they are on high doses of corticosteroids. Patients should also be monitored for the development of hyperglycemia and hypertension, both of which should be treated with appropriate oral medications.(5)

Dapsone, azathioprine, methotrexate have been advocated as steroid sparing agents, but have not yet been shown to be efficacious in prospective controlled studies. An immediate fall in the ESR, after initiating corticosteroid therapy, is often helpful in confirming the diagnosis and reassures the treating physician that the patient is receiving an appropriate dose. However, it is probably not a good idea to use the ESR as a guide to therapy. This is because patients have been known to flare up without a rise in the ESR and the ESR can increase from a number of intercurrent problems other than GCA - most notably infection, for which additional corticosteroids would be contraindicated. Based on recently published observations, patients with GCA may have persistently elevated IL-6 levels in the face of normal ESR, indicating ongoing subclinical inflammation.(6) This ongoing inflammation may contribute to some of the late vascular complications of the disorder, such as aortic rupture and dissection.

In conclusion, GCA is a serious condition of the elderly that can usually be diagnosed and treated successfully when the physician is attuned to the cardinal manifestations of the disease. A current review of GCA and polymyalgia rheumatica has recently been published.(7)