Giant Cell Arteritis

Giant cell arteritis (GCA), commonly referred to as temporal arteritis, is a chronic, idiopathic granulomatous vasculitis of medium- to large-sized vessels.^1,2 Initially GCA was considered a vasculitis affecting the carotid and vertebral artery branches only but was later redefined to include all medium and large vessels when autopsies showed involvement of large vessels in 80% of cases.^1,3 In countries where GCA is known to occur, it is the most frequent primary vasculitis and may be a medical emergency in some individuals.⁴

Epidemiology

Typically, GCA presents after age 50 and the mean age of onset is 70 years.⁵ The prevalence of GCA is highest in people of northern European ancestry, specifically Scandinavian descent.^4,6 The incidence is much lower in southern Europe and the Mediterranean regions, and GCA is especially rare in Latin America, South Asia, and Africa, although these areas lack large-scale epidemiologic studies such that GCA may not be properly identified.^4,5 The reported annual incidence ranges from 1.6 to 32.8 cases per 100,000 people age 50 or more.^1,4-6 The worldwide occurrence of GCA is expected to increase with the aging population. Some estimates predict that GCA may affect up to 3 million people by 2050, and up to 500,000 will be severely affected, with visual impairment being among the most dangerous morbidities.⁴

Women are affected by GCA 2 to 6 times more often than men with a total lifetime risk of 1%.^5,6 Some reports suggest that almost 65% to 70% of cases occur in women.² Human leukocyte antigen (HLA) gene polymorphisms associated with GCA have been identified and when present, appear to increase the frequency of complications.² The most commonly HLA polymorphism associated with GCA in whites is HLA Br1*04, which has also been shown to confer a higher risk of steroid resistance. Polymorphisms in nonHLA genes protein tyrosine phosphatase, nonreceptor type 22 (PTPN22), leucine-rich repeat-containing 32 (LRRC32), interleukin 17A (IL17A), and interleukin 33 (IL33) are associated with GCA.⁵

Pathophysiology

Inflammation of the large size arteries is thought to be the cause of GCA. Histopathology is considered positive for GCA if there are CD4⁺ T lymphocytes and histiocytes in the artery wall. These inflammatory cells can form multinucleated giant cells that can surround fragmented elastic lamina, although these giant cells are not a requirement for diagnosis.⁷ Inflammation can cause smooth muscle layer injury and intima layer hyperplasia, which sometimes causes vessel occlusion that can, in turn, lead to stroke and other vascular complications.⁸ How and why the inflammation develops or what antigen initiates inflammation are unknown. The inflammatory response of GCA includes CD4⁺ T lymphocytes, macrophages, myofibroblast proliferation, and interleukin production.⁹ Several patterns of inflammation have been described. Panarteritis is inflammation in all the layers of the vessel wall. Inflammation may also be in the intima and adventitia but not the media or confined only to the adventitia or extending from the adventitia into the media.⁷

Clinical Features

The presentation of GCA varies depending on which artery is affected.^1,10 The onset is often insidious with weeks or even months of gradually increasing symptoms that may wax and wane before becoming more severe or permanent. Headaches occur in 70% to 80% of cases. Other symptoms include scalp tenderness, jaw claudication, and vision loss in people with cranial involvement.^5,10

Headache and scalp tenderness tend to be among the first symptoms.^5,6,10 Headaches may be described as a dull pain that can be diffuse or localized, most commonly temporal. The pain may also be described as severe, sharp, or burning and can also be localized to the occipital, parietal, or periorbital regions. The pain and scalp tenderness can be resistant to analgesic treatment and so severe that it may interfere with sleep or wearing glasses, owing to scalp tenderness.¹⁰ A person over age 50 with new-onset headache and elevations in their erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) level should have an expedited evaluation for GCA.²

Unilateral or bilateral vision loss occurs in approximately 30% of cases and is usually a later finding. Arteritic anterior ischemic optic neuropathy (AION) can result from GCA via occlusion of the short posterior ciliary arteries or the ophthalmic artery. The resultant optic nerve ischemia causes permanent vision loss in 10% to 20% of people affected. Central retinal artery occlusion (CRAO) and extraocular motor palsies have also been seen with GCA. The opposite eye may become affected within hours or days of initial vision loss or visual complaints. Additional visual symptoms that may be painless include amaurosis fugax, brief visual blurring with exercise, and diplopia in 2% to 15% of cases. On examination, pale disc edema or an afferent pupillary defect may be seen.^2,5,10

Extracranial artery involvement may present with an aortic arch syndrome affecting the upper extremities and presenting as limb weakness, wasting syndrome, or fever of unknown origin.⁷ Extracranial artery involvement may be first identified on vascular imaging ordered because of constitutional symptoms (eg, weight loss, night sweats, fever of unknown origin, and malaise), scalp tenderness, or treatment-resistant polymyalgia rheumatica.^4,10 Polymyalgia rheumatica in the form of muscle weakness and morning stiffness, typically affects large shoulder and pelvic muscles and occurs in more than 50% of cases.^2,5 Other findings may include sore throat (from ischemia of the pharynx), tongue pain or claudication, trismus, choking sensations, syndrome of inappropriate antidiuretic hormone (SIADH), and microangiopathic hemolytic anemia. In some cases, the large-vessel involvement may cause limb claudication, myocardial infarction, transient ischemic attack (TIA), vertebrobasilar insufficiency, stroke, mesenteric ischemia, or aortic rupture. Sudden-onset weakness, dizziness, balance abnormalities, vertigo, and ocular muscle palsies may occur and there can be significant morbidity and even death.^2,5,10

Diagnostic Criteria

The diagnostic criteria for GCA is based on analysis of 214 cases of GCA compared with a sample of 593 patients with other vasculitis types. The traditional criteria, published in 1990, require 3 of 5 criteria and provide sensitivity and specificity of 93.5% and 91.2%, respectively. Those 5 criteria are age 50 or more, new-onset localized headache, temporal artery tenderness or decreased temporal artery pulse, ESR elevated to 50 mm/hour or more, and a consistent biopsy sample. Alternatively, a classification tree of 6 criteria substitutes jaw claudication and scalp tenderness for elevated ESR and a sensitivity and specificity of 95.3% and 90.7%, respectively.¹¹

A 2017 study assessed the continued validity of the 1990 diagnostic criteria, comparing 1,095 people with primary systemic vasculitis with 415 people who had clinical context-specific comparator conditions and found sensitivity and specificity of the 1990 American College of Radiology (ACR) Criteria for GCA patients of 81.1% and 94.9%, respectively. The authors of the 2017 study suggested the variance is due to greater reliance on diagnostic tools and new modern imaging that have expanded the clinical phenotype.¹²

Diagnosis and Diagnostic Testing

The diagnosis of GCA is made based on history or clinically. There should be a high degree of suspicion in individuals who are more than age 50 and presenting with headache, especially new-onset headache or with visual changes, fevers, jaw claudication, and/or muscle aches. A delay in diagnosis can lead to significant morbidity. Definitive diagnosis of GCA is made with histopathologic analysis of a temporal artery biopsy.⁷

Diagnostic Testing

Blood Tests. The most widely used blood tests to help make the diagnosis are the ESR and CRP, both of which are markers of inflammation, which is typically elevated in arteritis. However, neither is specific to GCA, and both can be elevated with age.¹³ Typically, the combination of ESR and CRP is used together to help make the diagnosis. In some cases, ESR can be normal or only slightly elevated, but this should not exclude the diagnosis, because the risk of vision loss is similar.¹⁴

Biopsy. The standard for diagnosis is histopathology of the temporal artery, which is highly specific and sensitive and can be done in an outpatient setting. The biopsy is usually done on a temporal periauricular artery in the scalp to avoid damaging frontal branches that supply the facial nerve.⁷ Surgeons will usually take 20 to 25 mm of the artery to get good sensitivity. False-negatives can occur because there may be segmental “skip” areas within an affected artery.⁷ The biopsy usually remains positive for 2 to 6 weeks, in most cases even if steroid treatment has been started.¹⁵

Imaging. Color Doppler ultrasound (CDUS) involves imaging the temporal, facial, occipital, vertebral, axillary, and subclavian arteries to a resolution of 0.1 mm. Affected vessels will show the halo sign, a darkened area around the vascular lumen caused by edema. This can turn into the compression sign, in which the area of the vessel remains visible after compression by the ultrasound probe.¹⁶ The sensitivity of this technique is 28.6% to 100% and may be operator dependent. There is evidence that these changes are not visible after treatment with corticosteroids.¹⁷ It is, therefore, still not widely used.

Angiography with MRI and contrast can be used as well. Expected changes with GCA include mural edema. Similar to CDUS, the sensitivity decreases with corticosteroid treatment. A meta-analysis showed approximately 73% sensitivity and 88% specificity for GCA.⁷ Other imaging modalities, include fluorodeoxyglucose positron emission tomography(FDG-PET)/CT, although this also decreases in sensitivity with steroid treatment and the sensitivity and specificity is lower than biopsy.⁷

Treatment

Usually, treatment initiation is recommended before definitive diagnosis in order to avoid potentially devastating complications, including blindness or stroke. The first-line and mainstay treatment for GCA is steroids. For those without vision loss, oral prednisone is tried, commonly 1 mg/kg with a maximum dose of 100 mg/day. The goal is to reverse some symptoms and normalize inflammatory factors, mainly ESR and CRP. Corticosteroid doses may be titrated higher while following lab values. If there is already vision loss or other more dangerous symptoms, a more aggressive approach is usually taken, including intravenous steroids. Methylprednisolone may be used, usually in a monitored setting, although there are no clinical trials for this approach.

Oral steroids are continued for 2 to 4 weeks and then tapered to prevent rebound inflammation once treatment is stopped. If symptoms return or inflammatory markers increase again, the steroid dose is usually increased again. Relapse may occur, usually in the first year.¹⁸ Some individuals may need treatment for up to 5 years. Timely treatment is very important because vision loss is rare if treatment is started before it occurs. Long-term use of steroids, however, comes with many side effects that need to be managed. Almost 90% of treated individuals will experience adverse events, including osteoporosis, bone fractures, peptic ulcers, diabetes, infections, weight gain, or mood disorders.¹⁹

Steroid-Sparing Agents

For people in whom steroids are contraindicated or not well tolerated, other agents can be tried. Methotrexate, an antimetabolite used to treat cancers and autoimmune disorders, may be tried⁷ as an adjunct to steroids, allowing a lower dose of steroids. Methotrexate is only moderately effective as monotherapy. The other most commonly used agent is tocilizumab, which is a monoclonal antibody to the IL-6 receptor.⁷

Summary

A vasculitis of large and medium vessels, GCA typically presents in people who are more than age 50 and of northern European ancestry. Women tend to be affected about 2 to 6 times more than men. The pathophysiology is thought to be inflammation of medium and large vessel arteries. The main clinical features include headache, jaw claudication, polymyalgias, and fevers. There can be complications including vision loss as well as stroke and other morbidities related to vessel inflammation. There are a number of diagnostic criteria, including clinical features and measures of inflammation, although the standard is a temporal artery biopsy. The first line treatment is typically steroids, although there are a number of other steroid-sparing agents that can be used.