Giant cell arteritis (GCA), or temporal arteritis, is a systemic inflammatory vasculitis of unknown etiology that occurs in older persons and can result in a wide variety of systemic, neurologic, and ophthalmologic complications.[1] GCA is the most common form of systemic vasculitis in adults. Other names for GCA include arteritis cranialis, Horton disease, granulomatous arteritis, and arteritis of the aged.
GCA is classified as a large-vessel vasculitis[2] but typically also involves medium and small arteries, particularly the superficial temporal arteries—hence the term temporal arteritis. In addition, GCA most commonly affects the ophthalmic, occipital, vertebral, posterior ciliary, and proximal vertebral arteries. Medium- and large-sized vessels that may be involved include the aorta and the carotid, subclavian, and iliac arteries.[3]
Histopathologically, GCA is marked by transmural inflammation of the intima, media, and adventitia of affected arteries, as well as patchy infiltration by lymphocytes, macrophages, and multinucleated giant cells. Mural hyperplasia can narrow the arterial lumen, resulting in distal ischemia. (See Pathophysiology.)
Age and female sex are established risk factors for GCA, a genetic component seems likely, and infection may have a role (see Etiology). One school of thought considers GCA and polymyalgia rheumatica to be different manifestations of the same disease process, while others see them as closely related but different diseases.[4, 5]
Common signs and symptoms of GCA reflect the involvement of the temporal artery and other medium-sized arteries of the head and the neck and include visual disturbances, headache, jaw claudication, neck pain, and scalp tenderness. Constitutional manifestations, such as fatigue, malaise, and fever, may also be present. (See Presentation.)
GCA should always be considered in the differential diagnosis of a new-onset headache in patients 50 years of age or older with an elevated erythrocyte sedimentation rate. Temporal artery biopsy remains the criterion standard for diagnosis of this granulomatous vasculitis (see the image below). However, increasing evidence supports the use of imaging studies for diagnosis in patients at high clinical risk.
View Image | Hematoxylin- and eosin-stained superficial temporal artery biopsy specimen, cross section. The hallmark histologic features of GCA shown here include .... |
Visual loss is one of the most significant causes of morbidity in GCA. Permanent visual impairment may occur in as many as 20% of patients, and, in some cases, GCA can cause bilateral blindness.[6] Newly recognized GCA should be considered a true neuro-ophthalmic emergency.
Prompt initiation of treatment may prevent blindness and other potentially irreversible ischemic sequelae of GCA.[7] Corticosteroids are the mainstay of therapy. In steroid-resistant cases, drugs such as tocilizumab, cyclosporine, azathioprine, or methotrexate may be used as steroid-sparing agents. The typical patient with GCA remains on steroid therapy for roughly 2 years. (See Treatment and Medication.)
Giant cell arteritis (GCA) is primarily a disease of cell-mediated immunity, which is thought to arise as a maladaptive response to endothelial injury. Actinic damage to the temporal artery from chronic sun exposure has been proposed as one source of the injury.[8] The adventitia is the likely site of initial immunologic injury and is considered the immunological center of the disorder, while the intima and media are the histological center.
The primary inflammatory response involves the activation of dendritic cells in the adventitia of arteries by an unknown antigen, with production of chemokines that recruit CD4+T helper cells. Activated CD4+ T helper cells polarize into Th1 cells (producing interferon gamma) and Th17 cells (producing interleukin 17).
Interferon gamma causes endothelial cells and vascular smooth muscle to recruit more Th1 cells, CD8+ T cells, and monocytes.The monocytes differentiate into macrophages and the characteristic giant cells that produce growth factors, other interleukins and proteolytic enzymes that progressively narrow and obstruct the vessel wall.[9] The inflammation tends to occur in a segmental or patchy manner, although long portions of arteries may be involved.[10]
Systemic manifestations are likely related to the inflammatory process and cytokine elaboration. End-organ involvement relates to hyperplasia and occlusion of the arteries serving those organs.
Concentric intimal hyperplasia is an important underlying pathologic lesion in GCA. Intimal hyperplasia presumably occurs as a repair mechanism in response to injury of the blood vessel wall.
Platelet-derived growth factor (PDGF) is important in stimulating intimal hyperplasia. In GCA, PDGF derives from macrophages and giant cells, and this distinguishes GCA from other vasculopathies. In atherosclerotic disease, for example, PDGF is produced mostly by resident smooth muscle cells rather than monocytes.
Intimal macrophages also produce vascular endothelial growth factor (VEGF), which promotes intimal proliferation. Medial macrophages generate metalloproteinases, leading to the destruction of vascular elements, including the internal elastic lamina.[11] Adventitial macrophages produce interleukin-6, augmenting the inflammatory response. This results in inflammation with local vascular damage and intimal hyperplasia, leading to stenosis and occlusion.[12]
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 demonstrated that different adhesion molecules might regulate how leukocytes and endothelial cells interact in different temporal artery layers.[13]
A study by Maugeri et al showed that patients with GCA had increased expression of platelets expressing P-selectin, of platelet-Nph and platelet-Mo aggregates, and of Nph and Mo expressing tissue factor.[14] Activated platelets and white cells could cause vessel inflammation and thromboembolic events.[15]
A cellular immune reaction to elastin has been implicated in the pathogenesis of GCA.[16] In support of the hypothesis that elastin is the inciting antigen, disease severity has been shown to correlate with the amount of elastic tissue within the vessels.[17] For example, intracranial arteries lack an internal elastic lamina, and GCA does not cause a widespread intracranial cerebral vasculitis.
This hypothesis also is supported by histopathologic findings of a disrupted, fragmented internal elastic lamina in affected vessels and the presence of characteristic giant cells, which may contain elastic fiber fragments, close to the internal elastic lamina. Along with elevated serum levels of neutrophil elastase, deposition of elastase along the damaged internal elastic lamina has been described.
The superficial temporal artery is involved in most patients, providing a convenient biopsy site, but this is only the "tip of the iceberg." GCA commonly affects arteries in the following pattern:
The most common cause of vision loss in GCA is anterior ischemic optic neuropathy (AION). This results from ischemia of the optic nerve head, which is supplied mainly by the posterior ciliary arteries.
Finally, numerous studies now suggest that GCA consists of various clinical subsets rather than one uniform disease. Variable expression of different cytokine profiles likely determines the clinical manifestations. Tumor necrosis factor (TNF) and, more recently, interleukin 6, have been recognized to play a major role in the pathophysiology of temporal arteritis.[20]
A close relationship exists between GCA and polymyalgia rheumatica.[21, 22, 23] About 50% of patients with GCA have underlying polymyalgia rheumatica, and about 15% of individuals with polymyalgia rheumatica develop GCA. The precise nature of this association is poorly understood. Several authors have suggested that these 2 diseases are actually different stages of the same disease process.
The exact etiology of giant cell arteritis (GCA) remains unknown. Despite increased understanding of the inflammatory cascade responsible for the disease process, the initial event that triggers the cascade remains uncertain. Genetic, environmental, and autoimmune factors have been identified.
Reports of familial aggregation,[24] association with the HLA-DR4 haplotype, and an apparent higher frequency of these conditions in northern Europe and in persons in the United States with similar ethnic backgrounds suggest a genetic or hereditary predisposition. GCA is less common among African Americans. A possible association between Toll-like receptor 4 gene polymorphism and susceptibility to biopsy-proven GCA has been found.[25]
Epidemiological observations, reports, and studies using DNA detection techniques have implicated Chlamydia pneumoniae, Mycoplasma pneumoniae, parvovirus B19, and varicella zoster as the impetus for the destructive inflammation.[26, 27, 28] Nevertheless, it is generally accepted that these infectious agents are only "innocent bystanders."
The immune system (both cellular and humoral) has been implicated in the pathogenesis of GCA. The granulomatous histopathology of GCA has suggested the presence of an antigen-driven disease with local T-cell and macrophage activation in or near elastic tissue in the arterial walls with an important role of the proinflammatory cytokines.[29, 30] It may begin as a foreign body giant cell attack on calcified internal elastic membrane in the arteries and on calcified atrophic parts of the aortic media.
The reported incidence of GCA ranges from approximately 0.5 to 27 cases per 100,000 people aged 50 years or older.[15] The annual incidence is higher in northern areas of the United States.
A review from Olmsted County, Minnesota identified 125 cases over a period of 42 years, representing an average annual incidence rate of 17.8 cases per 100,000 population aged 50 years and older and a prevalence of persons with active or remitted GCA of 200 cases per 100,000 population aged 50 years or older. A regular cyclical pattern in incidence over 20 years was noted.[31]
The prevalence of GCA depends heavily on the number of individuals aged 50 years or older; the mean age of onset is 75 years. Countries with a lower life expectancy have a lower prevalence. Incidence figures reporting biopsy-proven GCA may be lower than those that include clinically diagnosed cases of GCA.
The annual incidence in northern European countries has been reported to be more than 20 cases per 100,000 people over the age of 50 years. A United Kingdom study reported an incidence of 22 per 100,000 in that age group.[32] Scandinavian countries report the highest incidence of GCA—up to 32.4 per 100,000 individuals over the age of 50 years.
The annual incidence in southern European countries has been reported to be less than 12 cases per 100,000 people. In Lugo, Spain, the average annual incidence for the population aged 50 years and older was 10 cases per 100,000 people.
In Canada, the estimated incidence of biopsy-proven GCA for the population aged older than 50 years is 4.9 to 9.4 cases per 100,000 people.[33, 34] A series comprising all adult subjects undergoing autopsy at two hospitals in southern Sweden revealed arteritis in 1.6% of 889 cases, suggesting that GCA may be more common than is clinically apparent.[35]
The incidence of GCA in Saudi Arabia is probably less than in the United States and Western Europe. In 1998, Bosley and Riley reported only 4 positive biopsy results from 72 temporal artery biopsies performed over a 15-year period in Saudi patients.[36]
Although existing epidemiologic studies are limited because they have been performed on predominantly white populations, the results of these studies suggest that GCA primarily affects whites, specifically those of northern European descent. Scandinavians have the highest prevalence. GCA is less common in African Americans and Asians.[37] Although GCA had been considered less common among Hispanic persons,[38] recent evidence has challenged this notion.
The female-to-male ratio in GCA is roughly 3.7:1. Smoking increases the risk 6-fold in women.
Age is the most important risk factor for GCA. The disease is rare in patients younger than 50 years. In those 50 years and older, the incidence increases with age, peaking in the seventh to eighth decade. The age range in one series of 166 biopsy-proven cases was 55-92 years. The median age of onset is 75 years. GCA is the most common systemic vasculitis affecting elderly patients.
With prompt, adequate therapy, full recovery is the rule. Symptoms from temporal arteritis improve within days of treatment. Corticosteroids can usually be tapered within the first 4-6 weeks and eventually discontinued. The reduced rate of neuro-ophthalmologic complications in recent years reflects improved recognition and treatment; blindness is now a rare complication.
Although the overall course of the disease is one of progressive improvement and eventual complete resolution, the clinical course is highly variable. The average duration of treatment is 2 years; however, some patients require treatment for 5 years or more.[16, 12] Morbidity from steroid therapy can be worse than that from the underlying disease, with the exception of blindness. Rarely, patients do not respond to steroid therapy or doses cannot be tapered. Cytotoxic or immunosuppressive drugs have been recommended in such cases, but more data are needed.
Restuccia et al reported that 73 of 131 patients (56%) with biopsy-proven transmural GCA maintained complete clinical remission without elevation of inflammatory markers for at least 1 year after the withdrawal of steroids. Normal hemoglobin levels were significantly positively associated with long-term remission, while polymyalgia at the time of GCA diagnosis was significantly negatively associated with long-term remission.[39]
In a study that included 35 patients with both polymyalgia rheumatic and temporal arteritis, Narváez and colleagues found that no clinical feature was associated with increased risk of relapse. However, they reported that multivariate analysis identified the following as significant risk factors associated with long duration of steroid therapy[40] :
The prognosis for patients with untreated GCA is extremely poor. These patients may suffer blindness, or death from myocardial infarction, stroke, or dissecting aortic aneurysm. Ophthalmic complications are common and include visual disturbances, amaurosis fugax, diplopia, and blindness from involvement of the ophthalmic artery. Visual loss in GCA is often irreversible, but may be temporary; may be partial or complete; and may involve one or both eyes. Blindness usually occurs abruptly and painlessly. Ischemic optic neuropathy with eventual optic atrophy is the most common cause of visual loss and occurs in 15% of patients.
Vision damage that occurs before initiation of therapy is often irreversible,[41] especially in patients who have other ischemic complications.[42] In patients whose vision loss is initially unilateral, the second eye may become affected even after the initiation of treatment (possibly because those vessels have already been affected by arteritis) in 6-13% of patients.[43]
Progression of vision loss despite the initiation of high-dose corticosteroid therapy typically occurs within the first 5-6 days of treatment if therapy is going to fail.[44, 45] Risk factors for progressive visual loss despite steroid therapy include older age, elevated CRP level, and optic disc swelling.[46]
Nervous system alterations are found in as many as 30% of patients; 14% have either mononeuritis or polyneuropathy, and 7% have transient ischemic attacks or strokes.[47] Strokes from GCA may lead to multi-infarct dementia. Solans-Laqué et al report 7 patients with biopsy-proven GCA who presented with stroke or multi-infarct dementia.[48] Rare but serious complications include myocardial infarction (MI) and visceral organ ischemia (eg, small-bowel infarction).[49, 50, 18]
Complications of long-term steroid treatment that may occur in patients with GCA include the following:
An observational cohort study using a United Kingdom primary care database found that GCA is associated with increased risks for MI, stroke, and peripheral vascular disease. The hazard ratios were 2.06 for MI, 1.28 for stroke, and 2.13 for peripheral vascular disease. Hazard ratios were more pronounced in the first month after the diagnosis of GCA.[51]
GCA leads to death by stroke or MI in roughly 2% of cases. As would be expected, the topographic extent and severity of the vasculitis is greater in fatal than in nonfatal cases. More difficult to quantify are the number of patients whose deaths are related directly or indirectly to chronic corticosteroid use and its attendant complications (eg, hip fracture).
A population-based cohort study from South Australia found that mortality rates in patients with biopsy-proven GCA were similar to those in the general population. Cardiovascular disease was the most common cause of death, followed by infection and cancer. An increased risk of death from infection was more common in the first year, which may be related to immunosuppression from higher doses of corticosteroids at that stage of the disease.[52]
The inflammatory process may weaken the aortic wall, leading to localized aneurysm formation, aortic annular dilatation, and aortic regurgitation. Narrowing or occlusion of the branch vessels of the thoracic aorta (clinically referred to as aortic arch syndrome) may be found in 9-14% of cases, producing symptoms similar to those of Takayasu arteritis (decreased upper extremity pulses and blood pressure, arm or leg claudication, Raynaud phenomenon, transient ischemic attacks, coronary ischemia, and abdominal angina).
Evans and colleagues reported aortic aneurysms occurring in 15% of patients at a median of 6 years after the initial diagnosis of GCA. Two thirds were thoracic aortic aneurysms, with the majority located in the ascending aorta. Almost 33% of patients developed symptomatic aortic regurgitation. Approximately 50% of patients with thoracic aortic aneurysms died suddenly from aortic dissection.
In very rare cases, GCA involves the central nervous system (CNS), producing abnormal mental status, seizures, or strokes. This is despite the fact that GCA for the most part affects only vessels with an elastica, which intradural blood vessels do not have. However, involvement of the aortic arch vessels, including the subclavian arteries, can lead to subclavian steal syndrome and brain ischemia.
Peripheral nerve involvement is rare in GCA. For unknown reasons, renal involvement is also rare.
Education is the most important step in helping the patient appreciate the clinical facets of this illness, the potential adverse effects of the therapy, and the need for monitoring. Patients who experienced visual loss prior to the initiation of therapy should be cautioned that despite therapy, the lost vision may not be regained.
Patients must be instructed about the risk of complications and symptomatic relapses. Advise patients to immediately consult a physician if they experience symptoms of transient blurring of vision because of the possibility of impending attacks of GCA or transient ischemic attack.
Patients must understand the importance of strictly adhering to their steroid dose schedule and the possible need for ancillary interventions, such as dietary restrictions, to reduce the incidence of steroid-related adverse effects. To avoid misunderstandings, inform patients and their families about vertebral compression fracture and other potential complications of steroid therapy that can occur even with proper therapy.
Patients should be informed that they carry a lifelong risk for the development of large-vessel disease, particularly aortic aneurysms. The need for long-term followup should be stressed.
For patient education information, see Temporal Arteritis.
The onset of giant cell arteritis (GCA) may be either abrupt or insidious.[53] GCA may begin with constitutional manifestations such as anorexia, fever, malaise, myalgia, night sweat, and weight loss. These prodromal symptoms may occur for a few days and may even stretch out to weeks.
The most commonly reported symptoms in patients with GCA are as follows:
The headache of GCA has no pathognomonic features, but typically—and most importantly—the headache is either new, in a patient without a history of headaches, or of a new type, in a patient with a history of chronic headache. The headache is usually localized to the temporal or occipital area. Less often, the pain may be predominantly occipital or occipitonuchal; occasionally it is diffuse.
The headache is usually throbbing and continuous. Other descriptions of the pain include dull, boring, and burning. Focal tenderness on direct palpation is typically present. The patient may note scalp tenderness with hair combing, or with wearing a hat or eyeglasses.
Patients with mild GCA may complain only of generalized muscle aches and pains and unusual fatigue.[54, 55] These may be mistaken for symptoms of PMR.
Jaw claudication is noted as fatigue or discomfort of the jaw muscles during chewing of firm foods such as meat, chewing gum, or prolonged speaking. Jaw claudication is highlly predictive of temporal arteritis, and it is a result of ischemia of the maxillary artery supplying the masseter muscles. Tongue infarction is almost pathognomonic for GCA.[56]
Nonspecific symptoms of cough and sore throat occur in 17% and 11% of patients, respectively, but are rarely the presenting complaints. Amaurosis fugax occurs in 10% overall (initially in 2%), and some degree of permanent visual loss occurs in 8% (initial symptom in 3%).
Less common symptoms, which are almost never the presenting complaint, include the following:
Around 50% of patients with GCA experience visual symptoms over the course of the disease. Initial visual symptoms may be transient and intermittent, typically consisting of unilateral visual blurring or vision loss, often painless, or occasionally diplopia. Alternatively, a partial field defect may progress to complete blindness over days. Patients may experience visual hallucinations, which may precede permanent loss of vision.[65]
Transient repeated episodes of blurred vision are usually reversible, but sudden irreversible loss of vision may occur, especially if treatment is not started promptly. If GCA remains untreated in patients with unilateral vision loss, the second eye may become affected within 1-2 weeks.
Vertebrobasilar events sometimes present as acute confusional states or coma as opposed to discrete focal syndromes. Presumably, cognitive changes reflect thalamic, mesial temporal, and mesencephalic involvement in most cases. Acute encephalopathy is a rare complication of GCA and is a poor prognostic sign. Many patients with this complication progress to coma and die.
In 2003, Amor-Dorado et al[66] reported a previously unrecognized high incidence of audiovestibular disturbances such as vestibular dysfunction and/or hearing impairment in their GCA patients.
Most patients have poorly localized tenderness over the joints, especially the shoulders and hips. 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).
Involvement of the posterior auricular artery may manifest as pain in the ear canal, pinna, or parotid gland.
Certain clinical characteristics distinguish large-vessel GCA from cranial GCA. 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.
Physical signs parallel symptoms and depend on the organ systems that are damaged by vasculitic ischemia. The clinician should conduct a head and neck, ophthalmologic, and neurologic examination and assess vital signs and blood pressure in both arms to rule out aortic arch involvement.
Approximately half of patients have signs of superficial temporal artery inflammation, including erythema, pain on palpation, nodularity, thickening, or reduced pulsation on the affected side (see the image below). The examiner may be able to roll an affected temporal artery between the fingers and the skull.
View Image | Prominent temporal artery is visible on the temple of a 76-year-old woman with temporal arteritis. Courtesy of ScienceSource (https://www.sciencesourc.... |
Gentle pressure on the scalp may elicit focal or generalized tenderness. This differs from the hypersensitivity or hyperesthesia (unusual discomfort from a very mild stimulus, such as gently stroking the patient's hair) that is commonly found with migraine.[67]
Tenderness to pressure on the carotid artery (carotodynia) occurs in about 15% of patients. Cranial nerve palsies, particularly of the sixth nerve, should also be noted. The carotid, axillary, and brachial arteries should be assessed for bruits. Carotid bruits occur in 10-20% of patients with giant cell arteritis (GCA) and are frequently bilateral.
A complete eye examination should be performed, including the following:
Special attention should be paid to the optic nerve and central retinal artery. The retina should be carefully examined for nerve fiber layer infarcts.
The most common cause of vision loss in GCA is anterior ischemic optic neuropathy (AION), which is caused by vasculitis of the posterior ciliary artery.[68, 69, 70, 71, 72, 73, 74, 75, 30, 76] Vision loss may precede the funduscopic changes of optic nerve infarction by roughly 36 hours.[77]
Ophthalmoscopy in acute AION may show sludging of blood in retinal arterioles, which can be orthostatically sensitive. The optic disc may show chalky white pallor and edema, with or without splinter hemorrhages along the disc margin. See the image below.
View Image | Anterior ischemic optic neuropathy. Image courtesy of Richard Kho, MD, Q.C. Eye Center, Quezon City, Philippines. |
As AION evolves, the absolute amount of disc elevation tends to be modest (< 3 diopters in most cases), with infrequent areas of disc hemorrhage. Edema resolves within 10 days or so; within 2-4 weeks, it is replaced by optic atrophy.
Other important vascular ophthalmic presentations of GCA include the following[78, 79, 80, 81] :
With retrobulbar involvement (posterior ischemic optic neuropathy), optic pallor and atrophy gradually develop without antecedent papillitis. Central retinal artery occlusion causes pallor and diffuse retinal edema with a cherry-red spot because there are no ganglion cells at the foveal center (see the image below). Occlusion of the central retinal artery or its branches occurs in fewer than 10% of GCA cases with eye involvement.[85] Nerve fiber layer infarcts may be a sign of retinal ischemia.
View Image | Central retinal artery occlusion (CRAO). |
Neuro-ophthalmic manifestations[86] of GCA include the following:
The oculomotor apparatus can be involved at any level, including the extraocular muscles (EOM), nerves, and brain stem. However, the most common site is the EOM. A characteristic feature of EOM involvement is daily fluctuation of the ocular motility disorder. Horner syndrome is uncommon, judging from a review of several large series; however, ptosis and miosis may occur together, separately, or in conjunction with other oculomotor disturbances.
Statistical prediction models can guide decisions to perform temporal artery biopsy and initiate glucocorticoids in giant cell arteritis (GCA), but do not supplant clinical judgment.[92, 93]
The laboratory hallmarks of GCA include elevation in the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) level and thrombocytosis. The ESR usually exceeds 50 mm/h and may exceed 100 mm/h, but may be normal in 7-20% of patients with GCA.[94, 95] Therefore, a normal ESR does not rule out GCA, and the level of elevation of ESR does not correlate reliably with the severity of the disease. Because normal values of ESR are known to increase with age and are higher in women, the ESR should be appropriately adjusted.[96]
CRP is of hepatic origin. The level usually rises before ESR in most disease states, and is often elevated in GCA. It has higher sensitivity and specificity than ESR (98.6% and 75.7%, respectively) and is relatively unaffected by age, gender, and other hematologic parameters.[97]
Nonconcordance between ESR and CRP can occur (ie, either an elevated ESR with normal CRP or a normal ESR with an elevated CRP). The use of both tests provides a slightly greater sensitivity for the diagnosis of GCA (99%) than the use of either test alone.[98]
Alpha-2 globulin, fibrinogen, and other acute-phase reactants are elevated mildly but nonspecifically in 72% of patients with GCA. A study of 26 markers related to immune cells identified serum B-cell activating factor (BAFF) and interleukin-6 (IL-6) as having the strongest association with GCA; elevated levels of BAFF and IL-6 accurately distinguished patients with newly diagnosed GCA from healthy controls.[99] However, currently these tests are not readily available in most laboratories.
A complete blood cell count (CBC) should always be obtained. CBC reveals mild normochromic normocytic anemia in most patients, with a mean hemoglobin level of 11.7 ± 1.6 g/dL. Anemia has been shown to have a good negative predictive value for severe ischemic complications in GCA.[100] The leukocyte and differential counts are generally normal.
Platelet counts are mildly elevated in most patients. A platelet count greater than 400,000/µL, although not in itself diagnostic, is more helpful than an elevated ESR for ruling in GCA.[101] Conversely, a normal platelet count is more accurate than a normal ESR for ruling out GCA.[102] Additionally, in the largest population-based GCA study to date in the United States (3001 patients), the combination of elevated platelet counts and CRP levels greater than 2.45 mg/dL was associated with a positive temporal artery biopsy, while ESR results were not as specific a predictor.[101]
Liver function test results (eg, alkaline phosphatase and aspartate aminotransferase), are elevated in 20-30% and 15% of GCA cases, respectively. In addition, the prothrombin time may be prolonged. Muscle enzyme levels (eg, creatine kinase, aldolase) are normal.
In GCA, 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.
Automated visual field testing typically reveals an inferior altitudinal defect, inferior nasal sectorial defect, or central scotoma.
Superficial temporal artery biopsy (TAB) is the criterion standard for diagnosing temporal arteritis. TAB should be obtained almost without exception in patients in whom GCA is suspected clinically. It is important because the treatment course for GCA is long and often complicated, and many of the nonspecific symptoms of GCA (eg, headache, body aches, fatigue) occur in myriad other disorders. A positive TAB has 100% specificity but relatively low sensitivity (15%-87%) for the diagnosis of GCA.
Color duplex ultrasonography of the temporal artery has emerged as a promising alternative or complement to TAB.[103, 104, 105, 106, 107, 108] Its specificity is 80%-100% when a dark halo (classic halo sign) is seen about the vessel.[105] This key diagnostic feature is believed to represent vessel wall edema. Its sensitivity is limited, however; in particular, early inflammatory changes that can be seen on TAB specimens do not produce the characteristic halo effect.
Color duplex ultrasonography is user dependent. However, experienced sonographers with proper training and equipment have been shown to provide reliable diagnosis of GCA.[109]
The prospective Temporal Arteries in the Diagnosis and Treatment of Giant Cell Arteritis (TABUL) study, which included an ultrasound training program for diagnosing GCA, analyzed 381 patients who underwent both ultrasound and TAB within 10 days of starting treatment for suspected GCA, and found that the sensitivity of TAB was 39% (95% confidence interval (CI) 33% to 46%), which was significantly lower than previously reported and inferior to that of ultrasound (54%; 95% CI 48% to 60%). However, TAB had 100% specificity (95% CI 97% to 100%), versus 81% (95% CI 73% to 88%) for ultrasound.[110]
The TABUL authors noted that performing ultrasound scans in all patients with suspected GCA and performing biopsies only on negative cases would increase the sensitivity of ultrasound to 65% while maintaining specificity at 81%, reducing the need for biopsies by 43%. Furthermore, strategies that combined clinical judgement with testing showed sensitivity and specificity of 91% for TAB and 81% for ultrasound, and specificity of 93% and 77%, respectively. Cost-effectiveness favored ultrasound, with both cost savings and a small health gain.[110]
At the very least, the use of ultrasonography to “map” the path of the artery is a very useful adjunct to the evaluation of a patient with suspected GCA, making considerably more straightforward the choice of incision site and the biopsy target segment.[111]
Rhéaume et al reported that high-resolution magnetic resonance imaging (MRI) of the scalp arteries had a sensitivity of 93.6% and a specificity of 77.9% for the diagnosis of GCA, with a corresponding negative predictive value of 98.2%. These authors suggested that MRI could be used as the initial investigation in GCA, with TAB being reserved for patients with an abnormal MRI.
Bley et al reported that high-resolution MRI and color duplex ultrasonography have comparable diagnostic power in detecting GCA. Decisions regarding which technique to use may depend on the clinical setting.[112]
Because aneurysms of the aorta or other vessels are often asymptomatic, unless they rupture, screening all patients with GCA for large-vessel disease with computed tomography (CT) is prudent. MRI can also be used to evaluate aortic involvement in GCA.[113] Vessel wall thickening and edema may be evident on T2-weighted images, and increased mural enhancement may be visible on postcontrast T1-weighted images, indicative of regional inflammation. Ultrasonography may be helpful for diagnosing and monitoring aortic involvement in GCA, including aortic aneurysms.[114]
In rare cases, serious suspicion for aortic or carotid artery disease may warrant invasive imaging studies. Aortic arch and cerebral angiography may show occlusion or alternating stenotic areas. However, temporal artery arteriography has no diagnostic value in GCA and does not aid in predicting the proper biopsy site for the temporal artery.
CT and MRI of the brain are not first-line diagnostic procedures for GCA. On CT and MRI, the brain is typically unaffected by GCA, but in patients with a multi-infarct state due to cervicocephalic arteritis, CT and MRI demonstrate multiple areas of infarction.[115, 116, 117, 118]
Positron emission tomography (PET) scanning with 18-fluorodeoxyglucose (FDG) uptake has been used to evaluate the vasculitic process within large vessels such as the thoracic aorta.[119] In a retrospective case-control study by Nielsen et al that evaluated 18-FDG PET/CT in 44 patients with GCA and 44 controls, FDG uptake in the temporal and/or maxillary artery had sensitivity of 64% and specificity of 100% for the diagnosis of GCA. Including the vertebral arteries in the assessment increased sensitivity to 82%, with specificity remaining 100%. Because of the high specificity, the authors suggest that TAB can be omitted in patients whose PET/CT shows 18F-FDG uptake in the cranial arteries.[120]
For further discussion, see Giant Cell Arteritis Imaging.
EULAR guidelines
European League Against Rheumatism (EULAR) guidelines in clinical practice, published in 2018, include the following recommendations on imaging in GCA[121] :
The following are classification criteria for GCA issued by the American College of Rheumatology in 1990[53] :
The presence of 3 or more criteria yields a diagnostic sensitivity of 93.5% and specificity of 91.2%. However, in one study, the American College of Rheumatology classication criteria misclassifed up to 25% of ophthalmology patients with GCA.[122]
Superficial temporal artery biopsy (TAB) is the criterion standard for making a diagnosis of temporal arteritis. (See the image below.) TAB should be obtained almost without exception in patients in whom GCA is suspected clinically. It is important because the treatment course for GCA is long and often complicated, and many of the nonspecific symptoms of GCA (eg, headache, body aches, fatigue) occur in myriad other disorders.
View Image | Hematoxylin- and eosin-stained superficial temporal artery biopsy specimen, cross section. The hallmark histologic features of GCA shown here include .... |
A positive TAB is diagnostic of GCA (100% specificity). The reported sensitivity of TAB has ranged widely, from as low as 15% to as high as 87%.[123] The histopathological changes on TAB often correlate with clinical features of severity.[10]
TAB should be performed as soon as possible after clinical suspicion is raised. If the index of suspicion is high, the clinician should not delay starting therapy while awaiting TAB. Failure to treat increases the risk of ischemic ocular and cerebral complications, and TAB results remain positive for characteristic GCA pathology for at least 2 weeks after treatment is started.
The reported chances of obtaining a positive biopsy after initiation of steroid treatment vary widely in the literature, from only 10% after 1 week to 86% after 4 or more weeks of treatment.[124, 125] This wide variation may relate to issues such as patient selection, differences in biopsy or pathology techniques, or differences in the disease itself in different populations.
A systematic review of the TAB literature showed that the median positive yield of TAB was 25%, with interquartile range of 17% to 34%.[126] Because of this high negative rate, and because there may be "skip lesions" with normal intervening segments of artery in GCA, some authors advocate obtaining 2- to 3-centimeter, and occasionally bilateral, TAB specimens. Surgeons should aim for the longest TAB length that is reasonably possible and compensate for possible shrinkage after fixation of the specimen.
In the pathology literature, the recommended minimum length for fixed TAB specimens has varied. Different studies suggested fixed TAB length thresholds of 0.5 cm (n=1,520 biopsies), 0.7 cm (n=966 biopsies), or 1.5 cm (n=538 biopsies) as the optimum for identifying GCA and avoiding false-negative results.[127, 128, 129]
Clinicians who request TAB, but do not perform TAB themselves, may not appreciate the time required to harvest a TAB specimen, and may not appreciate that the length of the skin incision and biopsy specimen may not correspond, as the artery contracts when removed from the wound bed.
Biopsy of the most symptomatic side should be performed first. If frozen section is available, and the initial biopsy is negative, a contralateral specimen may be considered if clinical suspicion of GCA remains high. In cases in which a large TAB section is obtained from the most symptomatic side and multiple thin sections obtained, diagnosis can be made in 86% of cases with a unilateral TAB.
Studies have found that bilateral biopsies do not increase the diagnostic yield in the vast majority of patients (99%).[130, 131, 132, 133] Nevertheless, most physicians with high clinical suspicion despite an initial negative biopsy would still recommend a second contralateral biopsy, given the consequences of a missed diagnosis of GCA.[134]
The clinical significance of giant cells seen on TAB in temporal arteritis is unknown. Armstrong et al found that patients whose TAB contained giant cells had 3 times the rate of blindness and polymyalgia rheumatica compared with the group with no giant cells; although the difference was not statistically significant, it does suggest an association with giant cells and more aggressive disease.[135]
Alberts et al reported that in clinical practice, bilateral temporal artery duplex ultrasonography can serve the same function as biopsy, but without subjecting patients to the potential morbidity of a surgical procedure. TAB could be reserved for cases in which the ultrasonographic result is inconsistent with the clinical picture, in which case the biopsy result, if different, might influence the treatment decision.[104]
Several clinical studies demonstrate that the likelihood of a positive TAB in patients with GCA 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.[136]
TAB is a safe procedure; however, risks include temporary or permanent damage to the temporal branch of the facial nerve, infection, bleeding, hematoma, skin ulceration, dehiscence, and objectionable scar. Ischemic stroke after TAB occurs in the uncommon situation where the external carotid provides critical collateral circulation to the brain.
TAB may be performed by ophthalmologists, general surgeons, head and neck surgeons, plastic or vascular surgeons, or dermatologic surgeons. The frontal branch of the superficial temporal artery is preoperatively identified by visualization, palpation, or Doppler ultrasonography and then marked with a pen or with dye. In approximately 16% of cases, the frontal branch is atrophic or absent, in which case a biopsy should be performed on the main trunk of the superficial temporal artery using a preauricular approach.[137]
To improve the yield and to avoid complications, proper site selection is important. Focal symptoms or signs, such as erythema, tenderness, absent pulsations, arterial nodularity or swelling, inflammation, bruit, or thickening, help guide biopsy site selection and may improve the yield of the biopsy.
Localizing findings are often absent or misleading, however; frequently, the physical examination findings correlate poorly with the biopsy results. In the absence of localized arterial findings, the zone between the tragus of the ear and the lateral canthus is usually not biopsied, to avoid damage to the temporal branch of the facial nerve. Knowledge of the anatomy and careful dissection above and within the superficial temporal fascia help prevent nerve damage during the procedure.
A small area of hair may have to be shaved. It is essential to accurately mark the location of the artery with a marking pen prior to any local anesthetic administration. If there is concern that the vessel markings will be obscured by the prep solution, the vessel location can be scratched with a needle tip prior to the antiseptic scrub.[138]
In patients with a readily visible or palpable artery, epinephrine can be included with the initial local anesthetic injection. If the artery is difficult to visualize or palpate, avoid epinephrine in the local anesthetic until after the vessel is visualized subcutaneously. Local anesthetic is administered approximately 1 cm from either side of the vessel but not into the vessel.
With the site selected and the patient under local anesthesia, a shallow incision just into the underlying fat is made directly over the artery. The artery is bluntly dissected free from within the superficial temporal fascia. To avoid nerve injury, it is important to undermine just below the dermis in the superficial fat and above the superficial fascia.[139]
A segment of artery is ligated proximally and distally, removed, and sent for histopathologic review. Hemostasis is obtained with electrocoagulation, and a layered closure is performed.
Traditionally, excision of 2-3 cm of artery is recommended to provide accurate diagnosis of temporal arteritis because some studies have noted higher positive rates with longer specimens. Temporal arteritis may have a patchy distribution among extracranial arteries and within small segments of these arteries. In general, longer biopsy specimens provide more tissue in which to demonstrate short, noncontiguous foci of giant cell arteritis, the so-called skip areas.
Skip areas are not commonly identified, but patches of arteritis as short as 0.29 mm have been clearly demonstrated on serial sectioning. Serial sectioning, proper tissue handling, and adequate specimen length are critical to ensure maximum yield from the biopsy. Surgeons should be aware that fixation results in shrinkage of the biopsy specimen.[140]
Although superficial temporal artery biopsy remains the standard for diagnosis of giant cell arteritis (GCA), color duplex ultrasonography can be used to diagnose GCA. A hypoechoic halo around the temporal artery lumen on color duplex sonograms has demonstrated high specificity for GCA, but limited sensitivity; in particular, early inflammatory changes that can be seen on TAB specimens do not produce the characteristic halo effect.[141]
Steroid treatment results in disappearance of the halo. Rarely, the halo may disappear before 2 weeks of steroid treatment; often, it persists for up to 2 months.[142]
The halo represents edema in the artery wall. Some centers consider this finding a major decision-maker in their diagnostic equation, while others do not believe that such a halo is definitive for GCA.
The sensitivity of cerebral angiography in GCA affecting the brain is as low as 10–20%. Consequently, angiography is not the procedure of choice in such cases. However, involvement of multiple vessels in multiple vascular beds (a high-probability angiogram) raises the possibility of RCVS (reversible cerebral vasoconstriction). Documentation of reversibility of the angiographic abnormalities, during the course of the disease, will eventually secure the diagnosis of RCVS.[143]
GCA causes granulomatous inflammation in the wall of medium-size and large arteries and preferentially affects extracranial branches of the carotid artery.[144] Occlusion of the posterior ciliary arteries occurs more commonly. Involvement of intracranial arteries is rare, and cerebral infarctions are the hemodynamic consequences of occlusion of cervical arteries.
Magnetic resonance angiography (MRA) and cerebral angiography reveal occlusion of the affected arteries. While MRA can give useful information in GCA, cerebral angiography is the criterion standard to obtain optimum information, but at the cost of potential complications.
In GCA, vertebral arteries are more likely affected than internal carotid arteries, especially in the extradural portion, where there is more elastic tissue.[145] The vertebral and external carotid arteries (including the superficial temporal artery) may show vasculitic changes of alternating stenotic segments or occlusion. The internal carotid arteries may be occluded, but they rarely demonstrate a characteristic vasculitic pattern.
Electromyography (EMG) is rarely needed in patients with a clinical presentation of giant cell arteritis. Elderly patients frequently have mildly abnormal nerve conduction studies and EMG findings that suggest a mild peripheral neuropathy, regardless of whether they have GCA. The relationship of such neuropathies to the systemic inflammatory state in some patients is uncertain. In other patients, antecedent ischemic mononeuropathies may occur and eventually resemble a "diffuse," severe, peripheral neuropathy.
The histopathology of the diagnostic arterial lesion in giant cell arteritis (GCA; see the image below) includes the following:
Involvement of an affected artery is patchy, with skip lesions and normal intervening segments. It is commonly accepted that because of the patchy involvement of the arteries, biopsies may be nondiagnostic in many patients, and nondiagnostic biopsy specimens do not exclude the diagnosis of GCA. Some authors even suggest that biopsy may not be necessary.[124]
Collections of lymphocytes are confined to the region of the internal or external elastic lamina or adventitia in early cases or regions of arteries with minimal involvement. Intimal thickening, with prominent cellular infiltration, is typically present.
All layers are affected in late cases or regions of arteries with marked involvement. There are widespread areas of necrosis of portions of the arterial wall. The elastic laminae usually are involved, and granulomas containing multinucleated histiocytic and foreign body giant cells, histiocytes, predominantly helper T-cell lymphocytes, and some plasma cells and fibroblasts are usually present.{ref7
Weyand and colleagues have extensively described the distribution and function of inflammatory cells in the artery wall.[146] Eosinophils may be seen in the specimen section, but polymorphonuclear leukocytes (PMNs) are rare. Thrombosis may develop at the sites of active inflammation. These areas with thrombosis may recanalize later.
It has been observed that the inflammatory process is usually most marked in the inner portion of the media adjacent to the internal elastic lamina. This has led to the belief that the internal elastic lamina plays a central role in the initiation of the inflammatory process. Fragmentation and disintegration of elastic fibers occur. This is closely associated with an accumulation of giant cells, which 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 if other features are present. Fibrinoid necrosis is seen less commonly in necrotizing arteritis.
The more sections that are examined in the area of arteritis, the more likely it is that giant cells will be found. What is needed is transmural acute and chronic inflammation for acute diagnosis or evidence of previous repair. Healed or subacute phase shows fibrosis, fragmented internal elastic lamina, chronic inflammatory cells in the intima or media, and ideally neovascularization. Long breaks in internal elastic lamina favor healed arteritis over atherosclerosis.
Intimal proliferation is often marked. However, intimal proliferation is a nonspecific feature in the elderly, and does not suggest past or present arteritis if found alone.
The universally accepted treatment of giant cell arteritis (GCA) is high-dose corticosteroid therapy.[54, 21, 7, 23, 147] The major justification for the use of corticosteroids is the impending danger of blindness in untreated patients. Patients who present with visual symptoms have a 22-fold increased chance of visual improvement if therapy is started within the first day. Damage may be irreversible if treatment is delayed beyond 48 hours.
Few studies exist regarding dosing protocols for corticosteroids in GCA. It is generally agreed that most patients with suspected GCA should be started on oral prednisone 40-60 mg/day, with a temporal artery biopsy performed within 1 week.[107] Prednisone doses of 80-100 mg/day have been suggested for patients with visual or neurologic symptoms of GCA.[148] Follow-up care within 72 hours after starting therapy should be arranged.
Alternatively, patients with acute visual changes from GCA can be started on intravenous (IV) methylprednisolone at a dose of 1,000 mg daily for 3 days. Limited data suggest that initial high-dose IV corticosteroid treatment (eg, methylprednisolone, 15 mg/kg of ideal body weight/day) may reduce remission rates.[149, 150] However, further study is warranted before this is routinely practiced.
Retrospective but impressive data from Nesher and colleagues support the use of low-dose aspirin (81 mg) in patients with GCA for prevention of visual loss and stroke.[151] This therapy should be considered for patients diagnosed with GCA who do not have contraindications to its use.
Improvement of systemic symptoms (eg, headache, lethargy) typically occurs within 72 hours of initiation of therapy. The elevation in erythrocyte sedimentation rate (ESR) and ischemic manifestations (eg, temporal headache, jaw claudication) diminish in several days. The ESR often drops even in patients with a normal baseline reading.
Patients with multi-infarct dementia from GCA should not expect immediate cognitive recovery; however, longitudinal follow-up should show no further deterioration and may show modest improvement. Even with prompt treatment, visual loss may be permanent.
High-dose steroid therapy should be maintained only long enough for symptoms to resolve. Steroids should then be tapered slowly to the lowest dose required to suppress symptoms. Both clinical signs and sequential measurements of the ESR (or C-reactive protein level) assist in monitoring the patient's response. Patients with visual involvement usually require slower tapering of corticosteroids.
British guidelines recommend the following schedule for tapering of standard-regimen corticosteroids[54] :
The guidelines recommend that patients on steroid therapy receive prophylactic treatment with the following medications[54] :
Sequential ESR determination may assist in determining the success of corticosteroid therapy. Once the signs of clinical inflammation are suppressed and the ESR is maintained at a low level, corticosteroids may be tapered In almost all patients, the steroid dosage can be significantly decreased; however, the inflammatory process may ebb and flow, and temporary dose increases may be needed to control disease flares. Relapse occurs in 25-60% of cases.
The dose of prednisone should be increased only if clinical manifestations recur, and not simply on the basis of an elevation of the ESR. An elevated ESR without accompanying symptoms or signs of GCA could be related to an infection.
No absolute guidelines exist as to the length of treatment with corticosteroids for GCA.[107] It may be reasonable to maintain the patient on treatment for 2 years to lessen the chances for relapses. Even then, relapses have been reported.[152] 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 corticosteroid therapy has frequent and potentially serious consequences, including diabetes mellitus, vertebral compression fractures, steroid myopathy, steroid psychosis, and immunosuppression-related infections.[153] Indeed, the cumulative morbidity associated with long-term therapy often exceeds that of the underlying disease.
Interleukin-6 (IL-6) plays a role in the inflammation of GCA (see Pathophysiology). In phase 2 studies, treatment of GCA with the IL-6 receptor blocker tocilizumab resulted in faster achievement of remission, with significant reduction in corticosteroid doses, and prolonged maintenance of remission.[154, 155] In May 2017, the US Food and Drug Administration (FDA) expanded the indications for use of tocilizumab for use in GCA. Tocilizumab had previously been approved for use in rheumatoid arthritis.[156]
Alternative immunosuppressant agents (eg, cyclosporine, azathioprine, methotrexate) may be started later in the course of treatment. They can be useful as steroid-sparing agents in patients who require prolonged treatment with high doses of steroids (more than 5-10 mg/d) and those who experience significant steroid-related complications.
Most patients with GCA can be treated on an outpatient basis. Hospital admission may be indicated for patients with particularly severe symptoms or those unable to provide self-care at home. After resolution of acute GCA, patients require regular followup to monitor for disease recurrence, steroid complications during steroid therapy, and long-term complications such as aortic aneurysm.
Tocilizumab (Actemra) was approved by the FDA in May 2017 for giant cell arteritis (GCA).[156] Approval was based on the phase 3 GiACTA trial (n=251), in which subcutaneous tocilizumab or placebo was added to standardized prednisone regimens.[155]
The primary efficacy endpoint was the proportion of patients achieving sustained remission from week 12 through week 52. Sustained remission (resolution of GCA symptoms, normalization of inflammatory laboratory test results, and tapering of prednisone) occurred in a greater proportion of patients receiving tocilizumab compared with those receiving placebo (P ≤0.0002). The cumulative prednisone dose in patients treated with tocilizumab was less than half of that in patients who received placebo.[155]
In a phase 2 trial in 30 patients with GCA (new onset in 23, relapsing in seven) who were randomized to receive steroids plus either tocilizumab or placebo, 85% of patients given tocilizumab reached complete remission by week 12, compared with 40% of patients given placebo. By week 52, 85% of patients in the tocilizumab group achieved relapse-free survival versus 20% in the placebo group. Due to earlier discontinuation of steroids, the cumulative prednisolone dose after 52 weeks was 43 mg/kg in the tocilizumab group versus 110 mg/kg in the placebo group.[154]
In an open-label study, treatment with tocilizumab led to rapid and maintained improvement in 19 of 22 patients whose GCA was refractory to corticosteroid treatment, or who had experienced unacceptable corticosteroid side effects. However, serious infection-related complications--including a fatal stroke associated with infective endocarditis--occurred in three patients.[157] Tocilizumab carries a boxed warning for serious infections.[156]
Tumor necrosis factor (TNF) inhibitors (eg, infliximab, etanercept) are being evaluated in clinical trials for the treatment of GCA. A randomized controlled trial showed that adding infliximab to steroids provided no measurable benefit in the management of newly diagnosed GCA.[158]
A double-blind, placebo-controlled trial of etanercept in steroid-refractory GCA yielded mixed results. The study included 17 patients who required a stable dose of prednisone of 10 mg/d to maintain clinical remission and had at least one steroid-related adverse effect. After 12 months, more of the patients in the etanercept group had successfully discontinued prednisone (50% versus 22.2% of placebo patients), but the difference was not significant. No difference was noted in the number and type of adverse events.[159]
However, patients in the etanercept group did have a significantly lower cumulative dose of accumulated prednisone during the first year of treatment (p = 0.03). The researchers noted that a larger trial with longer follow-up is needed to determine the role of etanercept in GCA therapy.[159]
Trials of other immunosuppressant agents, including cyclophosphamide, azathioprine, methotrexate, and dapsone, have been attempted for their steroid-sparing effects. Steroid dosages have been lowered successfully but inconsistently in some patients on each of these drugs. Toxicity can be a significant problem, particularly with dapsone and cyclophosphamide.[160]
Limited experience suggests that cyclophosphamide may be the most consistently effective immunosuppressant. It may permit more rapid steroid tapering when instituted after a relapse. Cyclophosphamide may be administered in monthly pulses.[137]
Azathioprine, in an average dosage of 1.5-2.7 mg/kg/day, reduced steroid requirements in a double-blind, placebo-controlled study that included 31 patients with GCA, polymyalgia rheumatic, or both. However, the advantage of azathioprine over placebo did not reach statistical significance until 1 year.[161]
Methotrexate has been used as a steroid-sparing agent, in doses of 15-25 mg/wk. However, evidence regarding its efficacy remains inconclusive.[162, 163, 164, 165]
In a formal meta-analysis, adjunctive methotrexate, 7.5-15 mg/wk, reduced the risk of a first relapse by 35% and of a second relapse by 51%. In addition, methotrexate reduced the cumulative exposure to steroids. However, the superiority of the treatment effect of methotrexate over placebo fully appeared only after a latency period of 24-36 weeks, and no between-group difference was noted in the occurrence of adverse events.[163]
A number of clinical trials of GCA treatment are either actively recruiting or are active but not yet recruiting. For a complete list, see these List Results from ClinicalTrials.gov.
Patients with GCA who are on steroid therapy should be monitored carefully for the steroid-related complications of diabetes mellitus, hypertension, peripheral edema, and weight gain. Management of dietary sugar, salt, and caloric intake may help to prevent such complications.
No activity restrictions are necessary in a patient with GCA who is asymptomatic on adequate therapy. If a patient has ischemic eye or brain symptoms, then bedrest in a supine position may be desirable before or when first beginning steroid therapy. Some patients may have orthostatically sensitive amaurosis fugax, but this is rare.
Immediate consultation with a rheumatologist is suggested when initiating high-dose steroid therapy for presumed GCA prior to performance of a temporal artery biopsy (TAB). Therapy should not be delayed if consultation is not available immediately, however.
Rheumatologic consultation also is indicated to consider the need for steroid therapy when biopsy results are negative, but the clinical presentation strongly suggests GCA. The occasional patient with GCA who does not respond adequately to steroid therapy requires a referral for reconsideration of the diagnosis and for other forms of immunosuppressive therapy.
Surgical consultation is necessary for TAB. Depending on the institution, this procedure can be performed by a neurosurgeon, plastic surgeon, ophthalmologist, or general surgeon.
It is imperative that the treating physician be familiar and confident with the laboratory that is evaluating the TAB specimen, since this is the criterion standard for GCA diagnosis. A myriad of laboratory errors (eg, specimen handling, fixation, sectioning) can, if they occur, result in a misdiagnosis (most often a false-negative result).
An ophthalmologist should be consulted for a complete, dilated ocular examination to rule out other causes of vision loss, particularly when the diagnosis is uncertain. Consultation with a neurologist is helpful for excluding other causes of headache.
Because giant cell arteritis (GCA) is a potentially blinding and lethal disease, regular follow-up care after a successful initial management of the acute process is considered a standard of care. Routine follow-up should include asking about symptoms of upper extremity claudication or ischemia, listening for bruits, and taking blood pressure in both arms. Ongoing monitoring of symptoms and the erythrocyte sedimentation rate (ESR) is mandatory.
The ESR often normalizes within days of instituting steroid therapy. With tapering of steroid doses, ischemic complications may occur at any time but tend to occur a median of 1 month after beginning therapy.
British guidelines recommend that patients with GCA have follow-up visits at weeks 1, 3, and 6 and then months 3, 6, 9, and 12 in the first year after diagnosis, with extra unscheduled visits as necessary if relapse or adverse events occur.[54] The typical patient with GCA remains on steroid therapy for roughly 2 years. Followup is recommended until 1 year after discontinuation of therapy.
During corticosteroid therapy, monitoring for complications of long-term use of these drugs is indicated. Patients should be screened for diabetes, hypertension, and cataracts.
Given the high risk of corticosteroid-induced osteoporosis, patients should have baseline bone densitometry at the start of therapy. All patients on corticosteroids need adequate calcium and vitamin D for protection against osteoporosis (1500 mg of calcium and 800 IU of vitamin D3 daily).
American College of Rheumatology guidelines provide an algorithm for determining whether a patient receiving corticosteroids is at low, medium, or high risk for osteoporosis. The guidelines also offer recommendations for treatment—including, where appropriate, pharmacologic treatment with alendronate, risedronate, zoledronic acid, or teriparatide, with the choice of agent determined partly by risk level.[166]
Vaccination against influenza and pneumococcal disease is of heightened importance, because of relative immunosuppression from steroids. Long-term high-dose steroid therapy increases risk for peptic ulcer disease, particularly in patients older than 65 years, so prophylaxis with histamine-2 blockers, proton pump inhibitors, or antacids is justified, especially in patients who are also taking nonsteroidal anti-inflammatory drugs.[167]
Oral corticosteroids are the mainstay of treatment for GCA. Intravenous (IV) steroids may be administered if visual deficit is established or if the patient requires admission for other reasons.
Despite corticosteroids serving as the mainstay of therapy, no consensus exists regarding a standard initial dose or maintenance dosing schedules. Authorities do agree that the initiation of steroid therapy should not be delayed while awaiting temporal artery biopsy, because biopsy can still confirm the diagnosis, especially during the first week of steroid therapy, and prompt therapy can help the patient avoid serious sequelae.
The US Food and Drug Administration (FDA) approved tocilizumab, the first drug specifically approved for giant cell arteritis (GCA), in May 2017. It is a humanized monoclonal anti–interleukin-6 receptor antibody. Approval was based on the GiACTA trial,in which tocilizumab was added to standardized prednisone regimens.[155]
Other possible therapeutic drug options include cyclophosphamide, cyclosporine, dapsone, rituximab (anti-CD20 monoclonal antibody), and abatacept (a recombinant fusion protein that modulates CD28-mediated T cell co-stimulation).[20] Generally, none of these agents is routinely recommended.
Clinical Context: The drug of choice in GCA, prednisone is an oral corticosteroid that must be metabolized in the liver to its active metabolite, prednisolone. Prednisone decreases inflammation by suppressing migration of polymorphonuclear neutrophils (PMNs) and reversing increased capillary permeability.
Typical patients require prednisone for 1-2 y with daily initial doses of 40-60 mg. In acute neurologic syndrome or rapidly worsening neurologic status—whether visual loss, mononeuritis multiplex, or acute encephalopathy—treatment may begin with IV pulses over several days.
A patient with GCA who has a relapse may require only a modest dose increment to control flare in symptoms. Following initiation of treatment, ESR may be expected to drop within days and become normal in 1-2 wk. All neurologic deficits can improve, but irreversible end-organ infarction may preclude clinically significant gains in some patients.
Neurovascular complications may occur during initial tapering of corticosteroid dosage (often around 1 mo after beginning treatment), underscoring the need for ESR monitoring and the importance of small steroid decrements. The doses described below are suggested for general consideration. Tailor dosing regimens to medical circumstances confronting patient.
Clinical Context: Prednisolone decreases inflammation by suppressing migration of PMNs and reducing capillary permeability.
Clinical Context: Methylprednisolone decreases inflammation by suppressing migration of PMNs and reversing increased capillary permeability. This agent is slightly more potent than prednisone; 4 mg of methylprednisolone is equivalent to 5 mg of prednisone.
Clinical Context: Dexamethasone is a glucocorticoid that acts as an immunosuppressant by stimulating the synthesis of enzymes needed to decrease the inflammatory response. It also acts as an anti-inflammatory agent by inhibiting the recruitment of leukocytes and monocyte-macrophages into affected areas via inhibition of chemotactic factors and factors that increase capillary permeability.
Dexamethasone is readily absorbed via the GI tract and metabolized in the liver. Inactive metabolites are excreted via the kidneys. Most of the adverse effects of corticosteroids are dose-dependent or duration-dependent.
These agents have anti-inflammatory properties and cause profound and varied metabolic effects. They modify the body's immune response to diverse stimuli and inhibit the synthesis of tumor necrosis factor (TNF)-alpha, interleukin-2 (IL-2), IL-6, and interferon (IFN)-gamma. In addition, glucocorticoids modulate serum and leukocyte-bound levels of cell adhesion molecules.
Corticosteroid therapy for GCA is started at high doses with gradual tapering, using clinical manifestations and the erythrocyte sedimentation rate (ESR) to gauge disease activity. An initial dose of 40-60 mg/d of prednisone (or equivalent) in a single or divided dose is adequate in the vast majority of cases. This dose is usually given for 2-4 weeks until all reversible signs and symptoms have resolved and levels of acute-phase reactants are back to normal. The dose is then gradually reduced every 1-2 weeks by a maximum of 10% of the total daily dose.
Most patients are treated for 1-2 years, but some with a prolonged or relapsing course may require low doses of steroids for several years. Clinical flares usually occur when the prednisone is reduced to 5-10 mg/d.
Clinical Context: Interleukin-6 receptor antagonist. Inhibits IL-6-mediated signaling that results in proinflammatory cytokines. It is indicated for treatment of GCA in adults.
Adventitial macrophages produce interleukin-6 (IL-6), augmenting the inflammatory response. This results in inflammation with local vascular damage and intimal hyperplasia, leading to stenosis and occlusion. IL-6 antagonists may decrease inflammation from this pathway.
Clinical Context: Azathioprine is an imidazolyl derivative of 6-mercaptopurine, and many of its biological effects are similar to those of the 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 the agent is taken.
Azathioprine inhibits mitosis and cellular metabolism by antagonizing purine metabolism and inhibiting the synthesis of DNA, RNA, and proteins. The mechanism by which azathioprine affects autoimmune diseases is unknown. Azathioprine works primarily on T cells; it suppresses hypersensitivities of the cell-mediated type and causes variable alterations in antibody production. Immunosuppressive, delayed hypersensitivity, and cellular cytotoxicity test results are suppressed to a greater degree than antibody responses.
This agent is reserved for patients experiencing steroid failure or unacceptable adverse effects from prolonged steroid use; it can be used for its steroid-sparing effects to allow lowering of the steroid dose. It is available in tablet form for oral administration and in 100-mg vials for intravenous injection.
Clinical Context: Cyclosporine is a cyclic polypeptide that suppresses some humoral immunity and, to a greater extent, cell-mediated immune reactions such as delayed hypersensitivity, allograft rejection, experimental allergic encephalomyelitis, and graft-vs-host disease for a variety of organs. For children and adults, base dosing on ideal body weight. Available dosage strengths include 25 mg, 50 mg, and 100 mg/mL.
Clinical Context: Methotrexate ameliorates symptoms of inflammation (eg, pain, swelling, stiffness). Its
mechanism of action in treatment of inflammatory reactions is unknown; this agent may affect immune function. Adjust dose gradually to attain satisfactory response.
These agents inhibit key factors of the immune system. They may have anti-inflammatory properties in GCA and result in steroid sparing in relatively resistant cases.
Clinical Context: Aspirin is an odorless white powdery substance available in 81 mg, 325 mg, and 500 mg strengths for oral use. When exposed to moisture, aspirin hydrolyzes into salicylic acid and acetic acids. Aspirin is a 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.
Aspirin irreversibly inhibits platelet aggregation by inhibiting platelet cyclooxygenase. This, in turn, inhibits conversion of arachidonic acid to prostaglandin I2 (PGI2, is a potent vasodilator and inhibitor of platelet activation), and thromboxane A2 (a potent vasoconstrictor and platelet aggregator). Platelet inhibition lasts for the life of the cell (approximately 10 d).
Aspirin may be used in a low dose to inhibit platelet aggregation and improve the complications of venous stasis and thrombosis. It reduces the likelihood of myocardial infarction and the risk of stroke.
Low-dose aspirin decreases the rates of visual loss and strokes in patients with giant cell arteritis.[151]
Hematoxylin- and eosin-stained superficial temporal artery biopsy specimen, cross section. The hallmark histologic features of GCA shown here include intimal thickening with luminal stenosis, mononuclear inflammatory cell infiltrate with media invasion and necrosis, and giant cell formation in the media.
Hematoxylin- and eosin-stained superficial temporal artery biopsy specimen, cross section. The hallmark histologic features of GCA shown here include intimal thickening with luminal stenosis, mononuclear inflammatory cell infiltrate with media invasion and necrosis, and giant cell formation in the media.
Hematoxylin- and eosin-stained femoral artery branch, cross section, taken from a lower limb amputation specimen. Mononuclear cell invasion and necrosis in the media of this large artery can be observed. Extensive lower limb vasculitis from GCA resulted in ischemic necrosis of the lower limb, necessitating amputation.
Hematoxylin- and eosin-stained superficial temporal artery biopsy specimen, cross section. The hallmark histologic features of GCA shown here include intimal thickening with luminal stenosis, mononuclear inflammatory cell infiltrate with media invasion and necrosis, and giant cell formation in the media.
Hematoxylin- and eosin-stained femoral artery branch, cross section, taken from a lower limb amputation specimen. Mononuclear cell invasion and necrosis in the media of this large artery can be observed. Extensive lower limb vasculitis from GCA resulted in ischemic necrosis of the lower limb, necessitating amputation.
Hematoxylin and eosin stain, low power. Temporal artery. Note the thrombosis in the lumen, intimal hyperplasia, and infiltration of the arterial wall muscular layers with inflammatory cells. A multinucleated giant cell is seen internal to the muscularis at the area of the internal elastic lamina (upper right).