Introduction
Background
Giant cell arteritis (GCA), also known as temporal arteritis or cranial arteritis (coined by Horton et al1 ) is a systemic, inflammatory, vascular syndrome that predominantly affects the temporal arteries. Giant cell arteritis is commonly associated with polymyalgia rheumatica (PMR). About half of persons with giant cell arteritis have underlying polymyalgia rheumatica, whereas about 15% of individuals with polymyalgia rheumatica develop giant cell arteritis.
In 1957, Barber described polymyalgia rheumatica as an aching syndrome that was not associated with other defined rheumatic, infectious, or neoplastic disorders and that usually occurred in elderly persons with constitutional symptoms and an elevated erythrocyte sedimentation rate (ESR).2 In the late 19th century, Jonathan Hutchinson described a man who had difficulty wearing a hat because of his tender temporal arteries. Since then, the clinical spectrum of giant cell arteritis has been growing.
Pathophysiology
The etiology of giant cell arteritis is unknown, but the pathogenesis involves a chronic inflammatory process, predominantly of large arteries, resulting in the elaboration of various cytokines.
The specific cytokine production by the involved tissues may influence how a disease presents clinically. Cytokine profiles for giant cell arteritis and polymyalgia rheumatica are different. In giant cell arteritis, inflamed temporal arteries contain the T-lymphocyte products interferon-gamma (IFN-gamma) and interleukin (IL)–2. Giant cell arteritis also contains the macrophage products IL-1-beta, IL-6, and transforming growth factor-beta (TGF-beta). In polymyalgia rheumatica, temporal arteries contain transcripts for TGF-beta, IL-1, and IL-2 but not IFN-gamma.
Patients with giant cell arteritis, who present with fever of unknown origin and who do not have ischemic symptoms, typically have low IFN-gamma levels. Arteries that express high IFN-gamma levels typically have multinucleated giant cells (MGCs). Unlike macrophages, MGCs have important secretory functions and do not only remove debris. MGCs secrete platelet-derived growth factor (PDGF), which stimulates intimal hyperplasia. MGCs also secrete vascular endothelial growth factor (VEGF), a critical mediator of angiogenesis in the arterial wall.
Researchers recently described the topography of inflammatory cells in different regions of the artery, as follows:
* Adventitial macrophages produce IL-1 and IL-6.
* Medial macrophages produce metalloproteinase-2, PDGF, and VEGF.
* Intimal macrophages produce nitric oxide synthetase-2 and TGF-beta.
* Adventitial T lymphocytes produce IFN-gamma.
* T lymphocytes may enter the arterial wall through the vasa vasorum, which exist in the adventitia.
* The adventitia is the likely site of initial immunologic injury and is considered the immunological center in the pathogenesis of giant cell arteritis.
Concentric intimal hyperplasia is an important underlying pathologic lesion in giant cell arteritis. Researchers assume that intimal hyperplasia occurs when the blood vessel wall responds to injury and that it is a repair mechanism. PDGF is important in stimulating intimal hyperplasia. PDGF derives from macrophages and giant cells, distinguishing giant cell arteritis from other vasculopathies. For example, resident smooth muscle cells, rather than monocytes, produce most of the PDGF in atherosclerotic disease. In giant cell arteritis, the media is the main site of injury. The medial macrophages release the tissue-destroying enzymes and mediate tissue repair by secreting factors (eg, PDGF, VGEF), resulting in a hyperplastic intima that obstructs the blood vessel lumen.
The intima and media layers are the histological center in the pathogenesis of giant cell arteritis. Cell adhesion molecules influence the pathogenesis, and endothelial cells play a pivotal role. Inflammation is an important process that influences the endothelium and causes neovascularization. This process occurs mainly at the intima-media junction and at the adventitial layer. Adhesion molecules are far more intensely expressed on these neovessels than in the vessel lumen. Using immunochemical staining, Cid et al (2000) demonstrated that different adhesion molecules might regulate how leukocytes and endothelial cells interact in different temporal artery layers.3
A study by Maugeri et al (2009) showed that patients with giant cell arteritis had increased expression of platelets expressing P-selectin, of platelet-Nph and platelet-Mo aggregates, and of Nph and Mo expressing tissue factor.71 Activated platelets and white cells could cause vessel inflammation and thromboembolic events.4
Systemic manifestation is likely related to the inflammatory process and cytokine elaboration, while end organ involvement is related to vascular occlusion.
Recent studies have shown a possible association between Toll-like receptor 4 gene polymorphism and susceptibility to biopsy-proven giant cell arteritis.79
Frequency
United States
Polymyalgia rheumatica affects approximately 1 per 1000 persons older than 50 years. The true incidence of giant cell arteritis is unknown, but researchers suggest the rate is 33% that of polymyalgia rheumatica. In the United States, the approximate incidence of giant cell arteritis ranges from 0.49-27.3 cases per 100,000 population among persons older than 50 years.4 Salvarani et al (1995) found that the incidence of giant cell arteritis in Olmsted County, Minnesota, was about 17.8 per 100,000 persons older than 50 years.5
International
The incidence of giant cell arteritis is increased in northern latitudes, especially in Scandinavian countries. Smeeth et al (2006) found that the incidence of giant cell arteritis in the United Kingdom from 1990-2001 was 2.2 cases per 10,000 person-years.6 Giant cell arteritis is much less common in Saudi Arabia than in Europe or the United States.7
Mortality/Morbidity
* The morbidity of polymyalgia rheumatica relates to the treatment complications associated with long-term steroid therapy (eg, osteoporosis, hypertension, diabetes, cataract formation, increased infection risk). Patients with giant cell arteritis also experience steroid-related complications; however, they are also at risk for blindness. Ischemic optic retinopathy develops in approximately 26% of patients with giant cell arteritis, leading to permanent visual loss in approximately 7%-14%.8
* In very rare cases, giant cell arteritis involves the CNS, producing seizures, cerebral vascular accidents, or abnormal mental status. This is despite the fact that giant cell arteritis, for the most part, occurs only in vessels with an elastica, a finding that is not present with intradural blood vessels. However, involvement of the aortic arch vessels, including the subclavian arteries, can lead to subclavian steal syndrome and brain ischemia. Rarely, intracranial vessels are involved. The frequency of giant cell arteritis leading to significant ischemic CNS disease is not known because the intracranial vessels are relatively inaccessible and arteriosclerotic vascular disease is prevalent in older patients. Peripheral nerve involvement is also rare.
* Studies show that giant cell arteritis is a basis for aneurysms, dissections, stenotic lesions of the aorta, and stenotic lesions of the major branches of the aorta. Isolated cases of coronary artery disease and various aortic arch syndromes are evident secondary to giant cell arteritis. Involvement of the abdominal aorta, similar to that of the thoracic aorta, can produce symptoms secondary to aortic aneurysms and intestinal infarction. Some clear-cut examples of arm or leg claudication are reported secondary to giant cell arteritis.
Race
* Both polymyalgia rheumatica and giant cell arteritis are much less common in African Americans than in whites. Giant cell arteritis is rare in the Hispanic population.9
Sex
* Polymyalgia rheumatica and giant cell arteritis are twice as common in women as in men.
Age
* Most persons with polymyalgia rheumatica or giant cell arteritis present after their sixth decade of life, and the peak incidence occurs in patients aged 60-80 years. However, studies show that polymyalgia rheumatica, usually in association with giant cell arteritis, can occur in younger patients, as early as the fifth decade of life, but this is rare. Therefore, consider an alternative diagnosis in patients younger than 50 years.
* Recent studies have found age-based differences in the clinical spectrum of giant cell arteritis. Polymyalgia rheumatica, cerebrovascular accidents (CVAs), peripheral neuropathy, and high alkaline phosphatase values were more common in patients younger than 70 years than in older patients. However, there were no age-based differences in the visual ischemic complications.72
Clinical
History
The following are criteria for giant cell arteritis (GCA) issued by the American College of Rheumatology in 1990 (the presence of ≥3 yields a diagnostic sensitivity of 93.5% and specificity of 91.2%):10
* Age 50 years or older
* Newly onset localized headache
* Temporal artery tenderness or decreased temporal artery pulse
* ESR of at least 50 mm/h
* Abnormal artery biopsy specimen characterized by mononuclear infiltration or granulomatous inflammation
Giant cell arteritis is a strikingly heterogeneous systemic inflammatory disorder. Presentation varies from fever of unknown origin to visual loss and limb claudication. Arterial lesions may be widespread; therefore, the varied expression of giant cell arteritis can be analyzed according to the anatomical pattern of the arteries affected. Polymyalgia rheumatica and giant cell arteritis may represent two parts of a single disease spectrum, with giant cell arteritis at the more severe end. They share certain constitutional symptoms, eg, fatigue, weight loss, and fever. Approximately 50% of patients with giant cell arteritis have features of polymyalgia rheumatica, ie, proximal stiffness, soreness, and pain. Earlier descriptions of giant cell arteritis emphasize manifestations that were attributable to involvement of the ophthalmic artery and branches of the external carotid system, but arterial lesions may be widespread.
* Constitutional symptoms
o Patients with giant cell arteritis or polymyalgia rheumatica frequently report malaise and fatigue. They are usually mildly febrile. The fever associated with giant cell arteritis may reach 102°F in some cases. Night sweats may occur. Thus, the presentation of fever of unknown origin is much more common with giant cell arteritis than polymyalgia rheumatica.
o Anorexia and weight loss may be prominent features, suggesting a malignancy, in which case an age-appropriate malignancy evaluation is recommended.
* Proximal myalgias and stiffness
o Polymyalgia rheumatica is characterized by symmetric proximal joint and muscle aching, soreness, and stiffness. These symptoms are most prominent in the shoulder, neck, and pelvic girdles and may involve the distal joints and muscle groups. The onset of symptoms may be abrupt or insidious over weeks to months.
o Aching and stiffness are worse in the morning and with exertion, and they may be severe and incapacitating. Muscles may be tender, disuse may lead to atrophy, and contractures may develop. Muscle strength (usually normal) is often difficult to evaluate because of pain.
o Polymyalgia rheumatica often coexists with giant cell arteritis. In some series, 10-15% of patients with pure polymyalgia rheumatica had associated giant cell arteritis based on findings from biopsy of the temporal artery. Conversely, 50-70% of patients with giant cell arteritis had associated polymyalgia rheumatica.
o Even when treating patients for isolated polymyalgia rheumatica, instruct the patient to report the development of headache or visual symptoms that could be caused by occult giant cell arteritis.
* Joint symptoms
o Most patients have poorly localized tenderness over the joints, especially the shoulders and hips.
o Synovitis was once excluded as a feature of giant cell arteritis, but moderate bland effusions can develop in the knees and occasionally other joints (eg, shoulders, wrists).
o Carpal tunnel syndrome and peripheral synovitis may be present in patients with polymyalgia rheumatica, potentially causing diagnostic confusion.
* Symptoms related to vasculitis involving branches of the external carotid artery
o Headache and scalp pain are probably the most common symptoms of giant cell arteritis, occurring in 50-75% of patients. Headache is often the first manifestation and is described as extracranial, dull, boring, and burning. Persistent and prominent temporal headaches represent a typical symptom. Patients with occipital artery involvement may have occipital pain and difficulty combing their hair or discomfort from the pressure of a pillow on the head.
o Involvement of the posterior auricular artery may manifest as pain in the ear canal, pinna, or parotid gland.
o Jaw claudication and pain (predominantly in the masseter muscles with chewing) are highly specific symptoms of giant cell arteritis and occur in nearly 50% of patients. Patients with involvement of the maxillary or lingual arteries may have jaw or tongue pain when chewing or talking, and tongue gangrene has been reported.
o Unilateral and bilateral scalp necrosis has been reported in patients with giant cell arteritis and is associated with an increased likelihood of visual complications.78,80
o Rare cases of tongue necrosis have been reported in patients with giant cell arteritis.81
* Symptoms related to vasculitic involvement of the ophthalmic artery and its branches
o In patients with giant cell arteritis, decreased vision secondary to arteritis is the most common serious consequence. This occurs in 20-50% of patients who present to ophthalmologists and is the presenting symptom at diagnosis in 60% of patients with giant cell arteritis who develop visual loss.
o A careful history from most patients who present with sudden visual loss reveals that headache, constitutional symptoms, and polymyalgia rheumatica (usually specific enough to suggest diagnosis) precede blindness in approximately 40% of patients. Even the evolution of the visual loss is often staggered, with a partial field defect progressing to complete blindness over days. If giant cell arteritis remains untreated, the second eye may become affected within 1-2 weeks.
o Ocular manifestations vary according to the pattern of arterial branch involvement.
o The posterior ciliary arteries are the arteries most frequently involved in giant cell arteritis; thus, ischemic optic neuritis is the most common lesion.
o The central retinal artery supplies the retina, which is the terminal branch of the ophthalmic artery. Occlusion of the central retinal artery or its branches occurs in fewer than 10% of patients with eye involvement; therefore, retinal changes (eg, exudates, hemorrhages, vasculitis) are uncommon.
o Amaurosis fugax occurs in approximately 10% of patients with giant cell arteritis, and, if not treated, 80% of those patients develop permanent visual loss.
o The posterior ciliary arteries that supply the optic nerve and the muscular branches that supply the extraocular muscles also derive from the ophthalmic artery. Thus, diplopia or ptosis, observed in 5% of patients with giant cell arteritis, may precede visual loss.
o Note that the visual abnormality that occurs can be a composite of many ischemic events occurring together in the optic nerve, extraocular muscles, chiasm, and the brain itself.
* Symptoms related to large artery involvement
o These symptoms are related to involvement of the aortic arch and thoracic aorta. Limited pathologic studies show giant cell arteritis in vessels with bruits; however, the frequency of aortic and aortic root involvement in giant cell arteritis, based on clinical evidence, varies between 9% and 18%.11
o Certain clinical characteristics distinguish large vessel from cranial giant cell arteritis. Approximately 88% of large vessel involvement occurs in women. Patients typically have a younger age at onset, fewer constitutional symptoms, and a longer interval until diagnosis. Thoracic aneurysms with giant cells in the tissue can develop as late as 15 years after the diagnosis and successful treatment of giant cell arteritis. These patients are less likely to have positive temporal artery biopsy findings, headache, jaw claudication, or visual changes and are more likely to have arm claudication at disease onset.
o The major symptoms are arm or leg claudication. Occasionally, symptoms related to intermittent or persistent brain ischemia develop and are related to a subclavian steal syndrome or narrowing of other aortic arch vessels or, rarely, even intracerebral vascular disease.
o Abdominal aortic aneurysms can occur. Giant cell arteritis can manifest as symptoms of aortic aneurysms and intestinal infarction. For unknown reasons, renal involvement is rare.
Physical
In polymyalgia rheumatica, a striking paucity of findings is encountered during the physical examination relative to the severity of the symptoms. The same may be true for giant cell arteritis, although ocular and funduscopic evidence of ischemic disease is present in symptomatic patients.
* Patients may present with fever.
* Muscles may be tender.
* Joints are tender, especially over the shoulder and pelvic girdles. Mild peripheral synovitis may be present in patients with polymyalgia rheumatica.
* Temporal arteries are prominent, beaded, tender, and pulseless; however, a totally normal appearance of these vessels in no way excludes a diagnosis of giant cell arteritis.
* Funduscopic examination findings are typically normal, although optic atrophy or ischemic optic neuropathy may be observed in patients with symptoms of visual loss.
* Bruits may be heard over the carotid, axillary, or brachial arteries.
Causes
The cause of polymyalgia rheumatica and giant cell arteritis is unknown. Environmental and genetic factors likely play a significant role.
* Genetic factors
o Polymyalgia rheumatica and giant cell arteritis may aggregate in families.12
o Polymyalgia rheumatica and giant cell arteritis are more common among individuals of European descent and less common among African Americans.
o In polymyalgia rheumatica and giant cell arteritis, the frequency of the human leukocyte antigen DR4 is approximately twice that of normal controls in some series and may be an important susceptibility factor.
o An infectious etiology has been speculated to trigger giant cell arteritis.Differential Diagnoses
Atherosclerosis
Rheumatoid Arthritis
Atherosclerotic Disease of the Carotid Artery
Takayasu Arteritis
Cluster headache
Trigeminal neuralgia
Fever of Unknown Origin
Wegener Granulomatosis
Granulomatous angiitis of the CNS
Migraine headache
Polymyalgia rheumatica
Other Problems to Be Considered
Sinusitis
Dental problems
Workup
Laboratory Studies
* Blood studies
o The laboratory hallmark of polymyalgia rheumatica and giant cell arteritis (GCA) is an elevation in the acute-phase reactants, ie, ESR and C-reactive protein (CRP). The ESR usually exceeds 50 mm/h and may exceed 100 mm/h. However, an ESR in the low 30s or 20s does not exclude polymyalgia rheumatica or giant cell arteritis if other characteristic clinical or, in the case of giant cell arteritis, pathological, features are present.14,75
o Lopez-Diaz et al (2008) found that visual ischemic events were more common in patients with an ESR in the range of 70-100 mm/h at the time of diagnosis.73
o Normocytic normochromic anemia and thrombocytosis occur in approximately 50% of patients with polymyalgia rheumatica and are good guides to the state of inflammation. These findings are also common in giant cell arteritis. Anemia has been shown to have a good negative predictive value for severe ischemic complications in giant cell arteritis.74
o In both polymyalgia rheumatica and giant cell arteritis, the frequency of rheumatoid factor, antinuclear antibodies, and other autoreactive antibodies is not higher than that of age-matched controls. Complement levels are normal, and cryoglobulins and monoclonal immunoglobulins are absent.
o Findings from liver function tests, especially the alkaline phosphatase level, may be elevated in approximately one third of patients, most commonly in giant cell arteritis rather than pure polymyalgia rheumatica.
o Muscle enzyme levels (eg, creatine kinase, aldolase) are normal in both polymyalgia rheumatica and giant cell arteritis.
Imaging Studies
* Researchers have recently explored the role of color duplex ultrasonography in the diagnosis of giant cell arteritis. A hypoechoic halo around the temporal artery lumen on color duplex sonograms was reported in 22 of 30 patients (73%) with biopsy-proven giant cell arteritis.15 The halo was observed bilaterally in 17 of these patients and disappeared at a mean of 16 days after the initiation of corticosteroid therapy. The presence of the halo had a sensitivity of 73% and was 100% specific for giant cell arteritis. The halo represents edema in the artery wall. Although some centers consider this finding a major decision-maker in their diagnostic equation, others do not believe that such a halo is definitive for giant cell arteritis. Superficial temporal artery biopsy remains the standard for diagnosis of giant cell arteritis (see Procedures).
* Thoracic or abdominal ultrasonography may be helpful for diagnosing and monitoring patients with aortic aneurysms.
* In giant cell arteritis, temporal artery arteriography has no diagnostic value and does not aid in predicting the proper biopsy site for the temporal artery.
* Polymyalgia rheumatica has no characteristic imaging abnormalities. However, recent MRI findings of tendinitis and bursitis in the shoulders of patients with polymyalgia rheumatica support the soft tissues as significant sites of inflammation and sources of symptoms in polymyalgia rheumatica.
* Positron emission tomography (PET) scan is showing promise in the diagnosis of giant cell arteritis in some case reports.82
Other Tests
* Electromyographic studies
o Results are within normal limits.
o This study is rarely needed in patients with a clinical presentation of polymyalgia rheumatica.
* Synovial fluid and tissue studies
o Leukocyte counts in joint fluid, which are rarely available for study, range from 1000-8000/µL, with a preponderance of mononuclear cells.
o Synovial biopsy findings, when available, reveal mild synovial proliferation with slight lymphocytic infiltration.16
Procedures
* Muscle biopsy
o Histology findings are not diagnostic in polymyalgia rheumatica; type II muscle fiber atrophy probably represents disuse.
o This study is not indicated because patients with polymyalgia rheumatica do not present with weakness or muscle enzyme abnormalities.
* Temporal artery biopsy
o Consider this biopsy if a patient with polymyalgia rheumatica has symptoms or signs suggestive of giant cell arteritis or is unresponsive to 15 mg prednisone daily. It may also be indicated in the workup of an elderly patient with fever of unknown origin with a high ESR in whom infection and malignancy testing has been unrevealing.
o Temporal artery biopsy can be performed on an ambulatory basis and, if findings are positive, can dramatically diminish the diagnostic studies otherwise needed in evaluating systemically ill patients with an elevated ESR.
o Several clinical studies demonstrate that the likelihood of positive findings after temporal artery biopsy in patients with giant cell arteritis polymyalgia rheumatica is greatly enhanced if temporal artery pulses are absent or diminished, even in the absence of other localizing signs. The presence of a headache and jaw claudication may also increase the yield.76
o No difference is evident in the degree of ESR elevation, the presence of minor visual symptoms, sex, age, or the duration of symptoms among patients with polymyalgia rheumatica who do not have giant cell arteritis; furthermore, approximately 10% of patients with polymyalgia rheumatica and localized temporal artery signs have negative biopsy findings.
o Strategies for planning temporal artery biopsies in patients suggested to have giant cell arteritis include the following:
+ Always perform the biopsy on the temporal artery on the symptomatic side of the head.
+ If a specific part of the artery is tender, beaded, or inflamed, include that area in the biopsy. No information exists on whether the artery trunk or a distal branch specimen is best. Take at least 2-3 cm of the artery. Make multiple sections because the process may be segmental.
+ Studies performed during the 1970s and 1980s show that bilateral temporal artery biopsies can increase the sensitivity of diagnosing giant cell arteritis by 11-60%. However, recent studies have found that bilateral biopsies do not increase the diagnostic yield in the vast majority of patients (99%).17,18 However, questions have been raised about the use of steroid treatment for giant cell arteritis in the absence of positive biopsy results.19
+ Results of temporal artery biopsies remain positive for characteristic giant cell arteritis pathology after as long as 4 weeks while high doses of corticosteroids are administered. Thus, the physician should never delay the institution of steroids because of fear of ruining the chances of finding an inflamed artery on a biopsy sample.
Histologic Findings
An inflammatory infiltrate, predominantly of mononuclear cells, usually involves the entire vessel wall (ie, panarteritis). Fragmentation of the internal elastic lamina is characteristic. Fibrinoid necrosis is not a feature of the lesion. Giant cells are commonly present, and they often seem to engulf parts of the internal elastic lamina. The giant cells are difficult to find in some cases, and their absence does not exclude the diagnosis. Intimal proliferation is often marked, is a nonspecific feature in this age group, and does not suggest past or present arteritis if found alone. When giant cell arteritis involves larger vessels, the lesions are indistinguishable from those observed in Takayasu arteritis.Treatment
Medical Care
Both polymyalgia rheumatica and giant cell arteritis (GCA) are clinical diagnoses, with laboratory tests and temporal artery biopsies functioning as supporting, not definitive, data. Thus, the diagnosis should not be held hostage to the finding of an elevated ESR or positive temporal artery biopsy results in the setting of a clinical picture that overwhelmingly supports the diagnosis. Thus, do not withhold corticosteroid therapy pending the results of a temporal artery biopsy, as such an action could leave a patient with giant cell arteritis open to developing irreversible vision loss.
* Corticosteroid therapy is discussed as follows:
o Prednisone is the preferred therapy for giant cell arteritis and polymyalgia rheumatica. The starting dose is usually 60-80 mg/d for giant cell arteritis and 10-15 mg/d for polymyalgia rheumatica. Start patients on parenteral methylprednisolone at doses of 250-1,000 mg intravenously daily for 3 days when acute visual changes secondary to giant cell arteritis are present. Alternate-day therapy is not effective in preventing vision loss.
o Do not offer empirical treatment with high-dose steroid regimens appropriate for giant cell arteritis to patients with polymyalgia rheumatica who do not have symptoms of giant cell arteritis or who do not demonstrate histologic arteritis. On the other hand, do not delay treatment in patients with visual symptoms or signs (eg, amaurosis fugax, partial or complete visual loss) when giant cell arteritis is strongly suggested. The confirmatory biopsy can be performed after treatment is started, without major alteration in the diagnostic histology for up to 10 days.
o Usually, symptoms of giant cell arteritis (eg, polymyalgia rheumatica, headache, lethargy) disappear in 36-72 hours. The ESR elevation and ischemic manifestations (eg, temporal headache, jaw claudication, localized temporal artery inflammation) diminish in several days. The temporal artery pulse may not return, and visual loss may be permanent.
o A prompt and dramatic clinical response to low-dose prednisone (<15 mg/d) is a key feature of polymyalgia rheumatica, and most symptoms resolve in 48-72 hours.
o After 2-4 weeks, the ESR, anemia, and thrombocytosis usually normalize. If the patient shows no significant improvement in a week, consider an alternative diagnosis, which may include one of the aforementioned disorders or a companion systemic disorder (eg, giant cell arteritis that may require a higher steroid dose).
* Even in patients with known giant cell arteritis, do not use steroids to treat large vessel disease without evidence that vasculitis, rather than atheromatous disease, is responsible. Because cases of aortic aneurysms caused by giant cell arteritis may develop many years after the patient no longer requires steroid therapy, follow-up chest radiographs and thoracic or abdominal ultrasound may be needed over time.
* In refractory cases of polymyalgia rheumatica or giant cell arteritis that require persistent doses of prednisone of more than 5-10 mg/d or in those patients who develop significant steroid-related adverse effects, consider using other anti-inflammatory agents, such as methotrexate20 (RA doses of 15-25 mg/wk PO) or azathioprine21 (2 mg/kg/d PO), as potentially steroid-sparing disease-controlling drugs. These agents may suppress rheumatic symptoms but do not reduce the risk of blindness if giant cell arteritis is present. Adjuvant methotrexate therapy has shown conflicting results.83,84 The newer tumor necrosis factor antagonists are being evaluated in clinical trials for the treatment of giant cell arteritis. Initial studies of infliximab have not shown impressive disease-controlling or steroid-sparing effects.22
* Recent retrospective but impressive data support the use of low-dose aspirin in patients with giant cell arteritis for prevention of visual loss and stroke.23
* Recent studies have shown differential expression of glucocorticoid receptor between polymyalgia rheumatica and giant cell arteritis. Complete remission in giant cell arteritis could be predicted based on the presence of CD-68–positive cells and extent of glucocorticoid receptor staining in chronic inflammation.77
Surgical Care
The temporal artery biopsy site should be monitored.
Consultations
* Consultation with a rheumatologist is helpful.
* Consultation with an ophthalmologist may be useful to help exclude other causes of visual disturbances and to perform temporal artery biopsy.
* Consultation with vascular surgeon may be useful to perform temporal artery biopsy.
* Consultation with neurologist is helpful for excluding other causes of headache.
Medication
Corticosteroid therapy for giant cell arteritis (GCA) is started at high doses with gradual tapering, using clinical manifestations and the ESR to gauge disease activity. In general, prednisone is a safe treatment in patients with the clinical presentation of pure polymyalgia rheumatica, preventing the need for high-dose steroid therapy or routine biopsy. However, instruct all patients with polymyalgia rheumatica to call their physician immediately if they develop headache, visual symptoms, or other manifestations of giant cell arteritis.
The transition from polymyalgia rheumatica to giant cell arteritis is uncommon but can occur within 12-14 months after initial diagnosis. In general, administering low-dose corticosteroids for polymyalgia rheumatica enables protection from visual loss. Some physicians have advocated treating all patients with polymyalgia rheumatica with high-dose corticosteroids to prevent complications of occult giant cell arteritis. This approach leads to unnecessary treatment-related toxicity and is not generally recommended.
Corticosteroids
These agents have anti-inflammatory properties and cause profound and varied metabolic effects. Corticosteroids modify the body's immune response to diverse stimuli.
Prednisone (Sterapred)
DOC; steroids have many physiologic, molecular, and cellular effects. They regulate many CNS, metabolic, and anti-inflammatory functions. With regard to autoimmune diseases, they inhibit many inflammatory and immune pathways. Steroids are potent anti-inflammatory drugs.
* Dosing
* Interactions
* Contraindications
* Precautions
Adult
Giant cell arteritis: 40-60 mg PO qd or divided bid
Polymyalgia rheumatica: 10-15 mg PO qd or divided bid
Intravenous solu-Medrol in high doses for acute visual loss or visual symptoms
Attempt using minimal effective dose; do not stop abruptly; taper gradually
Pediatric
Not established; giant cell arteritis and polymyalgia rheumatica are extremely rare in pediatric patients
* Dosing
* Interactions
* Contraindications
* Precautions
Coadministration with estrogens may decrease clearance; concurrent use with digoxin may cause digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, and rifampin may increase metabolism of glucocorticoids (consider increasing maintenance dose); monitor for hypokalemia when coadministered with diuretics
* Dosing
* Interactions
* Contraindications
* Precautions
No absolute contraindication; documented hypersensitivity; severe bacterial, viral, fungal infection; active peptic ulcer disease; diabetes mellitus
* Dosing
* Interactions
* Contraindications
* Precautions
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Abrupt discontinuation of glucocorticoids may cause adrenal crisis; weight gain, hyperglycemia, edema, cataracts, avascular necrosis, myopathy, dyspepsia, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, and infections may occur with glucocorticoid use
Methylprednisolone (Medrol, Solu-Medrol, Depo-Medrol)
Slightly more potent than prednisone. Same effects as prednisone and decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reversing increased capillary permeability. Four mg of methylprednisolone is equivalent to 5 mg of prednisone.
* Dosing
* Interactions
* Contraindications
* Precautions
Adult
Acute visual changes secondary to giant cell arteritis: 80-100 mg/d IV; taper to prednisone 60 mg/d PO over 7-10 d
Pediatric
Not established; giant cell arteritis and polymyalgia rheumatica are extremely rare in pediatric patients
* Dosing
* Interactions
* Contraindications
* Precautions
Coadministration with digoxin may increase digitalis toxicity secondary to hypokalemia; estrogens may increase levels; phenobarbital, phenytoin, and rifampin may decrease levels (adjust dose); monitor patients for hypokalemia when coadministered with diuretics
* Dosing
* Interactions
* Contraindications
* Precautions
No absolute contraindication; documented hypersensitivity; severe bacterial, viral, fungal infection; active peptic ulcer disease; diabetes mellitus
* Dosing
* Interactions
* Contraindications
* Precautions
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Hyperglycemia, edema, avascular necrosis, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myopathy, and infections are possible complications of glucocorticoid use; all patients should be treated with optimal doses of calcium and vitamin D and bisphosphonates to prevent osteoporosis
Immunosuppressive agents
These agents may have anti-inflammatory properties in giant cell arteritis and result in steroid sparing in relatively resistant cases.
Azathioprine (Imuran, Azasan)
Imidazolyl derivative of 6-mercaptopurine. Many biological effects are similar to those of parent compound. Both compounds are eliminated rapidly from blood and are oxidized or methylated in erythrocytes and liver. No azathioprine or mercaptopurine is detectable in urine 8 h after taken.
Antagonizes purine metabolism and inhibits synthesis of DNA, RNA, and proteins. The mechanism whereby azathioprine affects autoimmune diseases unknown. Works primarily on T cells. Suppresses hypersensitivities of cell-mediated type and causes variable alterations in antibody production. Immunosuppressive, delayed hypersensitivity, and cellular cytotoxicity tests are suppressed to a greater degree than antibody responses. Works very slowly; may require 6-12 mo of trial prior to effect. Up to 10% of patients may have idiosyncratic reaction, disallowing use. Do not allow WBC count to drop below 3000/µL or lymphocyte count to drop below 1000/µL.
Available in tab form for PO administration or in 100-mg vials for IV injection.
* Dosing
* Interactions
* Contraindications
* Precautions
Adult
1 mg/kg/d PO for 6-8 wk; increase by 0.5 mg/kg q4wk until response or dose reaches 4 mg/kg/d
Pediatric
Not applicable
* Dosing
* Interactions
* Contraindications
* Precautions
Toxicity increases with allopurinol; concurrent use with ACE inhibitors may induce severe leukopenia; may increase levels of methotrexate metabolites and decrease effects of anticoagulants, neuromuscular blockers, and cyclosporine
* Dosing
* Interactions
* Contraindications
* Precautions
Documented hypersensitivity
* Dosing
* Interactions
* Contraindications
* Precautions
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Increases risk of neoplasia; caution with liver disease and renal impairment; hematologic toxicities may occur; check TPMT level prior to therapy and follow liver, renal, and hematologic function; pancreatitis rarely associated
Methotrexate (Folex PFS, Rheumatrex)
Inhibits dihydrofolate reductase. The precise mechanism of action in giant cell arteritis is unknown but may affect immune function. Ameliorates symptoms of inflammation (eg, pain, swelling, stiffness). Adjust dose gradually to attain satisfactory response.
* Dosing
* Interactions
* Contraindications
* Precautions
Adult
7.5-25 mg PO or SC qwk
Pediatric
Not established; giant cell arteritis and polymyalgia rheumatica are extremely rare in pediatric patients
* Dosing
* Interactions
* Contraindications
* Precautions
Oral aminoglycosides may decrease absorption and blood levels of concurrent oral methotrexate; charcoal lowers levels; coadministration with etretinate may increase hepatotoxicity; indomethacin and phenylbutazone can increase plasma levels; may decrease phenytoin serum levels; probenecid, salicylates, procarbazine, and sulfonamides (including TMP-SMZ) may increase effects and toxicity; may increase plasma levels of thiopurines
* Dosing
* Interactions
* Contraindications
* Precautions
Documented hypersensitivity; alcoholism, hepatic insufficiency, documented immunodeficiency syndromes, preexisting blood dyscrasias (eg, bone marrow hypoplasia, leukopenia, thrombocytopenia, significant anemia)
* Dosing
* Interactions
* Contraindications
* Precautions
Pregnancy
X - Contraindicated; benefit does not outweigh risk
Precautions
Monitor CBC counts monthly and liver and renal function every 1-3 mo during therapy (monitor more frequently during initial dosing, dose adjustments, or when risk of elevated levels [eg, dehydration]); has toxic effects on hematologic, renal, GI, pulmonary, and neurologic systems; discontinue use if significant drop in blood counts; aspirin, NSAIDs, or low-dose steroids may be administered concomitantly (possibility of increased toxicity with NSAIDs including salicylates has not been studied)
Antiplatelet agents
Low-dose aspirin decreases the rate of visual loss and strokes in patients with giant cell arteritis.23
Aspirin (Ecotrin, Bayer Aspirin)
Odorless white powdery substance available in 81 mg, 325 mg, and 500 mg for oral use. When exposed to moisture, aspirin hydrolyzes into salicylic acid and acetic acids.
Stronger inhibitor of both prostaglandin synthesis and platelet aggregation than other salicylic acid derivatives. Acetyl group is responsible for inactivation of cyclooxygenase via acetylation. Aspirin is hydrolyzed rapidly in plasma, and elimination follows zero order pharmacokinetics.
Irreversibly inhibits platelet aggregation by inhibiting platelet cyclooxygenase. This, in turn, inhibits conversion of arachidonic acid to PGI2 (potent vasodilator and inhibitor of platelet activation) and thromboxane A2 (potent vasoconstrictor and platelet aggregate). Platelet-inhibition lasts for life of cell (approximately 10 d). May be used in low dose to inhibit platelet aggregation and improve complications of venous stases and thrombosis. Reduces likelihood of myocardial infarction. Also very effective in reducing risk of stroke. Early administration of aspirin in patients with AMI may reduce cardiac mortality in first month.
* Dosing
* Interactions
* Contraindications
* Precautions
Adult
81-325 mg/d PO
Pediatric
Not established; giant cell arteritis and polymyalgia rheumatica are extremely rare in pediatric patientsFollow-up
Further Outpatient Care
* Symptom control
o Relapse of giant cell arteritis (GCA) is common (25-60%).
o In almost all patients, the steroid dosage can be significantly decreased; however, the dose may need to be briefly increased then decreased again because of the ebb and flow of the inflammatory process.
o The duration of treatment of polymyalgia rheumatica varies significantly among patients, with some needing corticosteroids for only 1 year and others for more than 5 years. In general, polymyalgia rheumatica is a self-limited disorder that lasts approximately 2 years, but some patients may also need low doses of prednisone for a frustratingly longer period. Constantly try to optimally balance the positive and negative effects of steroids in elderly patients with many comorbid disorders.
o Following symptom control, reduce the dosage of corticosteroids to the lowest level required to suppress symptoms because the cumulative morbidity associated with long-term therapy often exceeds that of the underlying disease.
o Increase the dosage of prednisone only if symptoms recur, not based solely on an elevation of the ESR. An elevated ESR without accompanying symptoms or signs of polymyalgia rheumatica or giant cell arteritis could be related to an infection.
o If the patient improves (as expected) but the ESR does not improve or rises after a prior fall, look for another cause of an elevated ESR (eg, infection). Although uncommon, discontinuing steroid therapy after less than 2 years is possible.
o Patients with polymyalgia rheumatica may require low-dose steroids (eg, <5 mg/d of prednisone) for 6 months to 5 years.
o In patients with giant cell arteritis, maintain high-dose steroid therapy only long enough for symptoms to resolve and then taper to a maintenance dosage of prednisone over several months. Both clinical signs and the ESR (or CRP) assist in monitoring the patient's response.
o Patients with visual involvement usually require slower tapering of corticosteroids. While the average patient requires continued maintenance therapy with prednisone for 2 years, some patients may need treatment for as long as 5 years. Because the incidence of new visual damage appears to decrease with disease duration, consider a repeat temporal artery biopsy before restarting corticosteroids in patients who relapse after 18-24 months.
* Long-term therapy
o Narvaez et al retrospectively studied the effect of long-term therapy on patients with polymyalgia rheumatica and patients with giant cell arteritis (ie, 10-y period).24 Among patients with pure polymyalgia rheumatica, 49% were off steroids in a mean duration of 23 months and remained symptom-free at 11 months of follow-up. These patients had a higher remission rate than those with polymyalgia rheumatica associated with giant cell arteritis.
o In the patients with polymyalgia rheumatica associated with giant cell arteritis, 29% were off steroids after a mean duration of 31 months and remained symptom-free at 14 months of follow-up. The median duration of therapy was 56 months for this group; 50% of these patients required treatment for more than 4 years.
o Factors that predict the need for prolonged therapy and increased relapse risk are older age at diagnosis, female sex, higher baseline ESR, and rapid taper of prednisone.
* Prophylactic measures
o Given the high risk of corticosteroid-induced osteoporosis, obtain a baseline bone densitometry value at the start of therapy for polymyalgia rheumatica or giant cell arteritis and administer an aggressive bone-preserving regimen accordingly.
o Ensure that all patients are on 1500 mg of calcium and 800 IU of vitamin D-3 per day.
o Consider adding osteoporosis preventive therapy with bisphosphonates, calcitonin, or hormonal therapy if the baseline bone densitometry findings show osteopenia or osteoporosis.
o Administer age-appropriate vaccinations (eg, influenza vaccinations, pneumococcal vaccine polyvalent [Pneumovax]).
o Low-dose aspirin (81 mg enteric coated) may be used for prevention of visual loss.
Complications
* Loss of vision
* Scalp necrosis (rare)
* Cerebrovascular accidents (rare)
* Aortic aneurysm, dissection, or stenosis
* Aortic arch syndromes (rare)
* Coronary involvement (rare)
* Corticosteroid-related complications
* Synovitis
o The presence of synovitis may complicate differentiation of polymyalgia rheumatica from rheumatoid arthritis. In addition, these disorders may occur in the same patient, adding further confusion.
o Findings from radionuclide scans, imaging studies, and synovial biopsies demonstrate the presence of synovitis in proximal joints.
Prognosis
* Polymyalgia rheumatica: This is generally a self-limited 2-year disorder and rarely progresses to giant cell arteritis.
* Giant cell arteritis: Visual damage is often irreversible. The average duration of treatment is 2 years; however, some patients require treatment for 5 years or more. Morbidity from steroid therapy is often worse than the underlying disease.
Patient Education
* Education is the most important step in allowing the patient to appreciate the clinical facets of this illness, the potential adverse effects of the therapy, and the need for monitoring.
Miscellaneous
Medicolegal Pitfalls
* Failure to consider the following:
o Corticosteroid-related adverse effects
o Long-term use of high-dose corticosteroid therapy due to the treatment of an elevated ESR in an improved patient
o Avascular necrosis, cataracts, or osteoporosis with vertebral or peripheral fracture
* Many physicians (eg, ophthalmologists; ear, nose, and throat specialists; neurologists; primary care physicians) may observe patients with giant cell arteritis, and their failure to diagnose giant cell arteritis because they either do not think about it until too late or feel that a normal or low ESR excludes the possibility may lead to blindness in the patient.
