Giant Cell Arteritis

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Giant Cell Arteritis


Disease Entity

Disease

Giant cell arteritis (GCA) is the most common primary vasculitis in adults. Histopathologically, GCA is marked by generalized granulomatous inflammation of medium- to large-sized vessels that occurs in the elderly. The condition is also known as temporal arteritis. Based on United States census data from 2000, the prevalence of GCA is approximately 160,000. Since patients with GCA often present with vision loss, ophthalmologists are on the front lines of diagnosing the disorder. In addition to vision loss, patients commonly note associated symptoms such as headache, jaw claudication, diplopia, myalgias, and constitutional symptoms. The most commonly feared sequela of GCA is permanent visual loss secondary to arteritic anterior ischemic optic neuropathy (AAION). Since the vision loss from AAION can progress rapidly, and can involve the fellow eye within a matter of days, GCA is considered an ophthalmologic emergency. When GCA is suspected, treatment with corticosteroids is indicated on an urgent basis, as further vision loss and fellow eye involvement are usually preventable. There is much research and discussion regarding the underlying etiology, pathogenesis, and appropriate management of patients with GCA. This review serves to highlight the essential concepts in our current understanding of the management of patients with GCA.

History

References to GCA can be found dating all the way back to 10th century Baghdad. The earliest observation was recorded by an oculgiaist named Ali Ibn Isa. He had discussed a potential relationship between inflamed arteries and visual signs and symptoms. He noted that “these diseased conditions may terminate in loss of sight”[1]. In his observations, he suggested excising the temporal arteries in order to treat these patients and save their vision. The next time GCA is noted was in the English literature in 1890 by Jonathan Hutchinson[2]. Hutchinson was treating an 80-year-old patient who had been experiencing “painful red streaks” on his head that were so uncomfortable he was unable to wear his hat. Hutchinson described these findings as a “thrombotic arteritis of the aged.” At the time, there was no known link between atherosclerosis/arteriolosclerosis and this arteritis.

Then in 1932, Bayard Horton reported two patients presenting with symptoms that would eventually be highly characteristic of giant cell arteritis[3]. Their presentation included systemic symptoms such as fever, weakness and anemia, as well as headache, pain and difficulty chewing, transient diplopia and even vision loss. Horton and his team were the first to perform a temporal artery biopsy and describe the now well-known histopathological findings of granulomatous vasculitis. At the time, the disease was known as “Horton’s disease”. The pathology of the disease was further explained by Gilmoure in 1941 when he described the presence of giant cells as part of the disease. The term “temporal arteritis” began to gain popularity in the 1930s and was further linked to other inflammatory and rheumatological diseases such as polymyalgia rheumatica (PMR) by Jennings in 1938[4]. Current literature estimates that approximately one third of patients with GCA have PMR at presentation. 

Epidemiology and Risk Factors

Giant cell arteritis is the most common primary systemic vasculitis in adults. The incidence is negligible in patients below 50 years old and rises relative to the patient’s age, with a median age of 75 years. Specifically, the average estimates range between 2.3 per 100,000 cases per year in the sixth decade of life to 44.7 per 100,000 cases per year in patients in their ninth decade.[5][6] The average age of presentation is 72.5 years for women, and 70.3 years old for men.[7] Furthermore, women are affected between 2 and 6 times more often than men.[8] This increased incidence in women might be explained by the higher proportion of women in the elderly population. When examining the role of race and epidemiology in GCA, white patients of northern European descent have the highest rates (about 30⁄100,000  in Norway) while African, Asian and Arab populations had the lowest rates (1.47⁄100,000 in Japan).[9] Other risk factors may include smoking, low body mass index, early menopause[10], and relative adrenal hypofunction.[11]

Etiology

The underlying etiology of GCA is complex and has been widely researched, yet is still not well understood. This includes genetic and possibly infectious factors, which go on to trigger an immune response.

A genetic predisposition for GCA has been suspected, due to increased reports of GCA among first degree relatives and rare familial forms of GCA.[12] There have also been reports of monozygotic twin concordance. further increasing this suspicion.[13] [14] Certain genes within the human leukocyte antigen (HLA) class I and class II regions, specifically, HLA DRB1*04, DRW6, and DR3 have been associated with increased susceptibility to GCA as well[15]. These genes encode amino acids in the antigen-binding pocket of the HLA molecule, which suggests that the disease may be antigen-driven and further highlights the role of adaptive immunity in the pathogenesis.[16]

Other linked genes are those related to cytokine and chemokine expression, which can alter the clinical presentation of GCA in different patients. For example, polymorphisms at the tumor necrosis factor-a (TNF-a) locus and the interleukin (IL)-10 promoter region have independently correlated to a greater risk of developing GCA. Similarly so, genes encoding vascular endothelial growth factor (VEGF), interferon-c and platelet glycoprotein receptor (PGR) are linked to an increased risk of ischemic complications in GCA.[17]

In addition to genetic factors, an infectious or environmental factor has been suspected due to successive studies of a stable population in Minnesota, where a cyclic fluctuation in the incidence of GCA was noted. [18] A range of infectious stimuli have been implicated, including Chlamydia pneumoniae, varicella virus, and parvovirus B19. [19][20][21] However, there are conflicting reports that argue against these infectious stimuli in select patients. [22][23] Additionally, some have suggested that an endogenous element in the arterial wall stimulates the initial inflammatory event.[24] Furthermore, the age-specific expression of GCA may be explained by age-related calcifications in the lamina, elastin and extracellular matrix proteins.[25]

After the initial trigger, regardless of etiology, a dual immune response begins.[26] One involves a systemic inflammatory reaction and the other is a maladaptive, antigen-specific immune response. The systemic inflammatory reaction results from over-activation of the innate acute phase response: a non-antigen-driven, non-adaptive defense mechanism to overall stress and injury. This response is mediated by IL-6, produced by circulating macrophages, neutrophils and monocytes[27]. IL-6 levels have correlated with the intensity of the immune response and other acute phase reactants such as C-reactive protein, haptoglobin, fibrinogen, and complement. The combination of these reactants under the systemic inflammatory reaction leads to the general signs of inflammation seen in GCA such as fevers, chills, sweats, myalgias, anorexia, and weight loss. In comparison, the antigen-specific immune response damages the arterial walls and results in the focal ischemic complications seen in GCA. The combination of these two processes result in the systemic inflammatory syndrome and arteritis, respectively.

GCA preferentially affects three-layered vessels. These layers include an outer adventitia, a muscular medial layer, and an elastic lamina separating the inner intimal layer. The primary site of injury is in the adventitial layer[28]. This is due to the fact that the adventitial layer is the only vascularized layer – composed of the vasa vasorum. Macrophages and T cells then utilize the vasa vasorum to enter the arterial wall. The luminal side is not usually affected because cell adhesion and entry is prohibited by the high velocity of blood flow through these arteries.

Ativated T-cells in the vasa vasorum of medium and large vessels up-regulate and activate macrophages, which then form a granulomatous immune reaction. Activated T-cells lead to the maturation of dendritic cells  in the adventitia of the arteries, which produce chemokines that trigger the recruitment of CD4+ T cells. These CD4+ T cells then become activated, multiply and polarize to Th1 and Th17 cells, which in turn produce IFN-γ and IL-17 respectively. In response to IFN-γ release endothelial cells and smooth muscle cells produce chemokines which lead to the recruitment of  Th1 cells, CD8+ T cells and monocytes. The monocytes differentiate into macrophages, which form giant cells, the histological trademark of GCA. Result in destruction and remodeling of the arterial wall and progressive occlusion of the lumen responsible for the ischemic symptoms of GCA.[29]

Metalloproteinases and reactive oxygen intermediates expressed by macrophages ultimately cause destruction within the blood vessel wall.[30] After this initial immune response, the vessel undergoes a healing response to injury, which includes intimal thickening, myofibroblast proliferation, and extracellular matrix deposition – all of which contribute to vascular stenosis and occlusion. This vascular stenosis and occlusion ultimately causes variable signs and symptoms, depending on the territory supplied by the affected vessel. For example, short posterior ciliary artery occlusion results in ischemic optic neuropathy. Of note, there has been no evidence demonstrating the role of B cells in the development of GCA. This is an important distinguishing point between large vessel vasculitides and ANCA associated vasculitides.[31]

General Pathology

GCA is characterized by a nodular granulomatous inflammation of medium- and large-sized arteries.[32] Pathological examination of affected vessels usually reveals a fragmented internal elastic lamina, with a cellular infiltrate extending transmurally.[33] Giant cells are not necessary on the pathologic specimen to confirm the diagnosis; however, when they are present, they are most often situated near the fragmented internal elastic membrane.[34] The most common vessels affected are the superficial temporal artery, the ophthalmic artery, the posterior ciliary arteries, and the vertebral arteries.[35] Less commonly, the aorta, coronary arteries, and carotid circulation are affected; intracranial arteries are typically spared.[34] The intracerebral arteries are typically spared from the vasculitic attack of GCA, presumably because of the paucity of elastic tissue in their walls[28]


Pathologic specimen from a patient with biopsy proven giant cell arteritis.  Multi-nucleated giant cells (arrow) are present in the vessel wall.  Photograph courtesy of Ben Glasgow, M.D.


Figure 1. Top panel: Pathologic specimen from a patient with biopsy proven giant cell arteritis. Multi-nucleated giant cells (arrow) are present in the vessel wall. Bottom panel: Higher power view.
Photograph courtesy of Ben Glasgow, M.D.

Pathophysiology

Ocular manifestations are common in GCA and can arise at any point of the disease including during treatment. The most common ocular manifestation of GCA is visual loss, most commonly secondary to AAION.[36]In these cases, the short posterior ciliary arteries are occluded by intimal hyperplasia, secondary to systemic inflammation.[36][37][38][39][40] Once occluded, the short posterior ciliary arteries cannot provide blood flow to the prelaminar and laminar portions of the optic nerve head, this results in an ischemic injury to the anterior portion of the optic nerve (AAION). Pallid optic nerve edema is a common finding.

A similar phenomenon, classically not associated with GCA is non-arteritic ischemic optic neuropathy (NAION), which is due to hypoperfusion of the terminal para-optic branches of the short posterior ciliary artery leading to optic disc ischemia NAION presents with either segmental or diffuse optic nerve head edema with hemorrhage, which can evolve to pallor. However, there have been cases reported of biopsy confirmed AAION secondary to GCA presenting with segmental disk edema without pallor, mimicking NAION. These cases were presumed to be due to GCA involving only a subset of the short posterior ciliary arteries supplying the optic nerve head. Therefore, it is important to have a high index of suspicion for GCA when examining patients with atypical presentation of NAION.

Although AAION is the most common manifestation, GCA can affect the entire visual pathway from the retina to the occipital lobe. Retinal ischemia can result from co-existent (or isolated) central retinal artery involvement. This may be evident on funduscopic examination or fluorescein angiography. [41]

Less common causes of ischemic visual loss include posterior ischemic optic neuropathy, cilioretinal artery occlusion, choroidal infarction and rarely ischemia to the optic chiasm or post-chiasmal visual pathway. Furthermore, patients with cortical visual loss may experience visual hallucinations arising from the focal areas of ischemia and usually resolve after a few weeks. Ischemia to other ocular structures, such as the extraocular muscles, can result in dysfunction of the affected structure (see “Physical Examination” section).

In addition to the ocular findings described above, patients often complain of headache and scalp tenderness. These symptoms can be attributed to involvement of the temporal artery, and resultant localized ischemia. Jaw claudication, another common symptom of GCA, is due to vascular involvement in the territory of the masticatory muscles. Systemic symptoms such as fevers and malaise are likely secondary to the release of inflammatory cytokines, such as interleukin-6, during the acute inflammatory phase.

Diagnosis

The diagnosis of GCA is complicated by the fact that there is no single lab value, imaging result or biopsy that will always be positive in all patients. Therefore, no test can be used to rule it in or out.  Additionally, patients can present with a broad range of symptoms including both systemic and ocular complaints; none of which are pathognomonic for GCA. The possibly transient nature of many of the characteristic signs and symptoms further complicates diagnosis. There are several features in the history, physical examination, and in ancillary tests that can aid the clinician in making the diagnosis.  Clinicians must maintain a high index of suspicion is crucial in any elderly patient with a new onset headache or visual changes. However, clinicians must consider each patient on a case-by-case basis as symptoms, examination features, and ancillary test results are analyzed.

History

Ocular Manifestations

The most common ocular manifestation in GCA is acute unilateral vision loss, which has been reported in 7-60% of patients with GCA. Typically, the vision loss is secondary to optic nerve ischemia (AAION); it is less commonly due to a central retinal artery occlusion. Other, less common causes of vision loss include posterior ischemic optic neuropathy (PION), resulting from interrupted blood flow to the retrobulbar portion of the optic nerve, and cerebral ischemia, which can lead to homonymous hemianopsia. Even with effective medical therapy, reports of permanent partial or complete vision loss range between 8.2% to 20%.[42] Once permanent visual loss has ensued, it is irreversible. Furthermore, some estimates in untreated patients have shown that vision loss in the unaffected eye can ensue within one week of the primary insult[43]. Fortunately, the rapid initiation of steroid therapy prior to loss of vision significantly reduces chances of subsequent ocular complications. There are currently no effective methods of stratifying risk factors for developing permanent visual loss in GCA. Although numerous risk factors were analyzed, prior transient vision loss is currently the only strong risk factor associated with developing permanent vision loss[44].

In approximately 30% of patients with permanent vision loss, there are antecedent episodes of amaurosis fugax.[36] Patients typically complain of partial field defects or a curtain covering a portion of vision in one eye. These episodes of transient visual loss typically begin about 8.5 days prior to permanent loss, and are secondary to transient retinal, choroidal, and/or optic nerve ischemia.[45] Other than vision loss, patients may complain of diplopia, eye pain, or symptoms from cranial neuropathies (i.e. ptosis, anisocoria, diplopia).

Systemic Manifestations

Systemic symptoms are present in most patients, may be acute or gradual, and often precede the ocular manifestations.[46][47] The most common systemic complaint of GCA patients is a new onset headache (temporal or occipital), which is present in 90% of cases.[48][49] Headaches are often associated with localized or diffuse scalp tenderness[32], and patients may complain of discomfort when combing their hair or placing their head on a pillow. Patients often note a wide range of constitutional symptoms, such as fatigue, fevers, and weight loss. In addition, they may complain of jaw claudication, and pain in other areas including the face, ears, and mouth. Distinct tongue numbness and vertigo have also been reported.[50] Myalgias, especially of the proximal muscles, are also associated with GCA. Less often, neurological symptoms, such as peripheral neuropathies[51][52], strokes[53], scalp necrosis[54] and dementia[55][56] have all been attributed to GCA.

Symptoms of polymyalgia rheumatica (PMR) are present in up to 50% of patients.[48][57] PMR is a more common inflammatory syndrome that seems to share a similar underlying etiology with GCA, as well as a similar demographic of commonly affected patients. Symptoms of PMR include bilateral aching neck, shoulder pain or stiffness and pelvic pain or stiffness. Additionally, many patients with PMR note constitutional symptoms such as fever, weight loss, and anorexia.

Physical examination

The physical examination of a patient in whom GCA is suspected should include careful evaluation of the following elements:

  1. Detailed examination of the temporal artery to detect prominence (Figure 2), nodularity, or tenderness to palpation of the artery and the surrounding skin. In addition, an evaluation of the strength of the temporal artery pulse is crucial.
  2. Detailed ophthalmologic examination evaluating visual acuity, pupils (looking for a relative afferent defect), intraocular pressures, anterior segment examination, motility examination (looking for ocular misalignment and/or evidence of cranial neuropathies), and a dilated fundus examination (evaluating for signs of optic nerve or retinal ischemia)
  3. Visual fields testing
  4. Auscultation of the carotid artery for bruits
  5. Auscultation of the heart for an aortic regurgitation murmur to evaluate for aortic aneurysm

Preoperative appearance of a patient with a prominent left superficial temporal artery. The vessel was tender and pulseless. Histopathology confirmed a positive result for temporal arteritis in this case. Image courtesy of Marcus M. Marcet, MD FACS.  

Figure 2. Preoperative appearance of a patient with a prominent left superficial temporal artery. The vessel was tender and pulseless. Histopathology confirmed a result positive for temporal arteritis in this case. Image courtesy of Marcus M. Marcet, MD FACS.

AAION is characterized by acute monocular vision loss accompanied by optic disc edema. The optic disc edema in AAION is usually diffusely “chalk white”, and may be accompanied by disc hemorrhage, retinal whitening or cotton wool spots.[58] Adjacent retinal whitening and cotton wool spots are crucial findings that indicate concurrent retinal ischemia, and should raise a clinician’s suspicion for GCA. Visual acuity is often 20/200 or worse, with up to 21% demonstrating no light perception.[59] An obvious afferent pupillary defect is often present. Visual field loss in patients with AAION is typically in a central, arcuate, or altitudinal pattern.

A much less common cause of GCA-associated optic neuropathy is posterior ischemic optic neuropathy. In cases of posterior ischemic optic neuropathy, patients will present with similar symptoms to those with AAION, and will have similarly decreased visual acuity, abnormal visual fields, and a relative afferent pupillary defect. However, in posterior ischemic optic neuropathy, the optic disc will appear perfectly normal; therefore, a high index of suspicion for posterior ischemic optic neuropathy is warranted in elderly patients presenting with acute visual loss and a normal appearing optic nerve.

In addition to the optic nerve circulation, the central retinal artery can also be affected by GCA: approximately 10% of patients with ocular involvement experience a central retinal artery occlusion.[36][60] Central retinal artery occlusions are manifest by retinal whitening with an associated “cherry red spot” in the macula. If the retinal whitening is more diffuse, and there is absence of a “cherry red spot”, then ophthalmic artery occlusion should be suspected. GCA should be considered in any patient with a central retinal artery occlusion over the age of 50.

Localized ischemia to the extra-ocular muscles and/or cranial nerves can result in diplopia and ocular misalignment in 2-15% of patients.[61][62] Additionally, Horner’s syndrome50, anterior segment ischemia[63], and hypotony (likely secondary to decreased aqueous humor production)[64] have all been reported in patients with GCA.

Typical findings in a patient with arteritic ischemic optic neuropathy.  Note the pallid optic disc edema, associated hemorrhages, and adjacent cotton wool spot.  Photograph courtesy of Dr. Nicholas Volpe.

Figure 3. Typical findings of a patient with arteritic ischemic optic neuropathy. Note the pallid disc edema, associated hemorrhages, and adjacent cotton wool spot. Photograph courtesy of Dr. Nicholas Volpe.

Signs

Although ocular involvement is common in GCA, the incidence of ocular findings in all GCA patients is not well-defined. In various studies, ocular findings range from 14-70%[7][36][50][61][65][66][67](this wide range is largely due to differing study populations). The visual loss can initially be transient, and can become bilateral and permanent, with typical involvement of the second eye often within 14 days in untreated cases.[36][68] In addition, GCA can present with any ocular symptoms (vision loss or diplopia) without additional systemic findings; this type of presentation is considered “occult”, and can occur in up to 38% of cases.[59]

Symptoms

Reliability of symptoms

The sensitivity and specificity of many ocular and non-ocular findings have been intensively studied in order to delineate clear indications for further testing. Meta-analyses of several studies have determined that both jaw claudication and diplopia are the most diagnostically powerful indicators of GCA.[69][70] Furthermore, temporal artery abnormalities such as temporal artery pain and an abnormal temporal artery on palpation are good indicators of disease.[69]


In 1990, the American College of Rheumatology set forth criteria for the diagnosis of GCA. The criteria include the presence of at least 3 of the following 5 findings[71]:

  1. Greater than 50 years old
  2. New onset of headache
  3. Temporal artery abnormality on examination
  4. Elevated erythrocyte sedimentation rate (ESR) using the Westergreen method (>50 mm/h)
  5. Abnormal arterial biopsy demonstrating a necrotizing vasculitis with predominance of mononuclear cells and granulomatous inflammation.



These criteria have been shown to have a sensitivity of 93.5% and a specificity of 91.2% in diagnosing GCA in patients with vasculitis.[71] However, the importance of the clinical history and setting cannot be understated when diagnosing GCA. Furthermore, these criteria were determined by rheumatologists, and studies that defined them were likely subject to under-representation of patients with solely ocular manifestations.[69] Several criticisms have been raised regarding these criterion, including the lack of specificity of headache[72][73], the lack of inclusion of several very significant markers such as CRP, jaw claudication, and neck pain, and the possibility of GCA with a normal ESR or temporal artery biopsy.[73] A 2012 retrospective chart review of all patients undergoing biopsy at a single institution showed that 9 out of 35 patients with positive biopsies would not have been diagnosed with GCA using the 1990 guidelines. Furthermore, 11 out of 39 patients with negative biopsies met the criteria and would not have been diagnosed with GCA[74].

Clinical diagnosis

The diagnosis of GCA should be considered in any patient over the age of 50 with new headaches, acute visual changes, symptoms of polymyalgia rheumatica, unexplained constitutional symptoms, or jaw claudication.  Since individual patients with GCA can present with a wide range of symptoms and examination findings, and many of the symptoms may be transient, patients must be questioned directly about symptoms of GCA.  In any patient in whom GCA is suspected based on history, examination findings, or an elevated ESR, a temporal artery biopsy and initiation of corticosteroid treatment should be considered.  In addition, several ancillary tests may help to confirm the diagnosis.

Diagnostic procedures

Temporal artery biopsy

Unfortunately, there is no single test that is positive in all cases of GCA. Temporal artery biopsy is the gold standard (Figure 4); however, a negative biopsy does not confirm a negative diagnosis. The biopsy should be obtained as soon as possible after the patient’s presentation, but should not delay the initiation of treatment with corticosteroids. Most authors feel that the sensitivity of the biopsy is not significantly affected for the first 2 weeks after starting therapy.[75] However, there has been one study that demonstrated a decrease in sensitivity from 82% to 60% after 1 week of steroid therapy.[76]


False negatives are relatively common (5-13%) because of “skip lesions”, or areas without disease within the vessels.24 In order to avoid false negatives, it has been recommended that the biopsy sample have a length of 1 cm to up to 2.5 cm of artery.  In general, longer biopsy specimens have led to increased chances of positive results[77]. But more contemporary studies have challenged this belief, showing that shorter biopsy lengths may be adequate[78]. However, it is also important to note that shrinkage of the specimen will occur with fixation and should be taken into account. Approximately 10 percent shrinkage can be expected on average.[79][80]

Initial negative biopsy results may warrant follow-up with a contralateral biopsy depending on the clinical context. Physicians should evaluate the overall clinical picture including any additional imaging studies available before making this decision. Studies have demonstrated that repeat biopsy may be positive in 1-15% of patients.[72][81][82][83][84][85]

All sections should be stained with hematoxylin and eosin. Furthermore, staining for elastin using an elastic Van Gieson stain has been proposed in order to identify the internal elastic lamina. However, a 2010 retrospective case series studying 105 biopsies showed no increase in diagnostic sensitivity using this method. Van Gieson staining may be helpful in cases of supplementary investigation, such as repeat biopsies.[86]

Most commonly, a panarteritis consisting of lymphocytes and macrophages with or without granuloma formation is seen during inspection. Additionally, intimal thickening and fragmentation of the internal elastic lamina should be sought. The procedure for obtaining a temporal artery biopsy is relatively safe, with rare reports of complications including hematoma, infection[72], nerve damage[87], stroke[88] and scalp necrosis.[89]

Initial intraoperative appearance of a temporal artery biopsy. The ruler along the left side is located posteriorly in this case. The incision is made posterior to the hairline (hair shaved) to avoid damage to the temporalis branch of the facial nerve. The right superficial temporal artery is clearly seen prior to complete dissection and biopsy. Except for grossly visible age-related calcification, the intraoperative appearance of the vessel was otherwise normal. The histopathology confirmed a negative result. Image courtesy of Marcus M. Marcet, MD FACS  

Figure 4. Initial intraoperative appearance of a temporal artery biopsy. The ruler along the left side is located posteriorly in this case. The incision is made posterior to the hairline (hair shaved) to avoid damage to the temporalis branch of the facial nerve. The right superficial temporal artery is clearly seen prior to complete dissection and biopsy. Except for grossly visible age-related calcification, the intraoperative appearance of the vessel was otherwise normal. The histopathology confirmed a negative result. Image courtesy of Marcus M. Marcet, MD FACS.

Ancillary imaging tests

Patients with GCA have abnormalities on several ancillary tests. Fluorescein angiography has been found to show delayed choroidal and central retinal artery filling, with possible choroidal non-perfusion, especially in the peri-papillary area. [37][36][73][90] Angiographic findings are usually seen within the first days of symptom onset.

Color Doppler ultrasound (CDUS) has been gaining popularity as an alternative to temporal artery biopsy. CDUS provides many advantages such as being non-invasive, safe, and providing real time imaging and analysis in addition to visualizing multiple arteries including the facial, occipital and vertebral arteries. [91][92] Ultrasonography may demonstrate arterial edema, which is represented by hypoechoic halos immediately adjacent to the arterial wall;[93][94][95] this finding has been shown to have a sensitivity of 69% and specificity of 82% in a recent meta-analysis.[96] In a single study, the specificity reached 100% when the halos were found bilaterally.[97] Furthermore, CDUS is largely operator-dependent and lack of experience and standardization of image acquisition can hinder its potential assistance in diagnosis.

Magnetic resonance imaging (MRI) has recently been utilized in the diagnosis of GCA, but may demonstrate blood vessel wall thickening and/or enhancement (in the same area as the “halo-sign” on ultrasound).[98] Comparing MRI results with clinically diagnosed GCA via meta-analysis demonstrated a pooled sensitivity and specificity of 73% and 83% respectively[99]. Similarly so, when compared to a positive temporal artery biopsy, the sensitivity and specificity were 9% and 81%, respectively. Limitations to this method include cost, radiation exposure, and diminishing sensitivity after initiation of glucocorticoid therapy.

Ultrasound biomicroscopy (UBM) has also been used preliminarily to detect the halo sign.[100] Finally, computerized tomography (CT), MRI and PET scanning of the abdomen and chest may be useful to evaluate the aorta and other great vessels if large vessel vasculitis is suspected.

Patients with a negative initial evaluation via biopsy or ultrasound who continue to raise high clinical suspicion may warrant additional testing. Reasons for negative evaluation may include incorrect biopsy location, non-cranial artery involving GCA, or no GCA. Physicians may opt to evaluate patients for potential large vessel GCA using imaging studies such as CDUS, CT, and MRI of the vascular system.

Comparison of different diagnostic imaging modalities

Modality Typical Findings Advantages Disadvantages
CDUS
  • Hypoechogenic wall thickening
  • Halo Sign
  • Compression Sign
  • Good availability
  • Low cost
  • High resolution
  • No radiation
  • No nephrotoxic agents
  • Dynamic exam measuring blood flow
  • Operator-dependent
  • Limited information of inflammatory activity 
  • No view of thoracic aorta and proximal supra-aortic arteries


CT/CT-A
  • Thickened artery wall 
  • Late contrast uptake
  • Ectasia of the aorta
  • Stenosis of aortic branches 
  • Fast
  • Provides combined assessment of inflammatory and morphological changes
  • Broad differential diagnosis
  • Radiation exposure
  • Nephrotoxic contrast agents 
MRI/MR-A
  • Thickened artery wall 
  • Contrast uptake
  • Ectasia of aorta
  • Stenosis of aortic branches
  • No radiation
  • Provides combined assessment of inflammatory and morphological changes
  • Slow
  • Contraindications (claustrophobia, certain medical implants) 
PET-CT
  • Homogenous 18-FDG uptake in the vessel wall
  • Signs of PMR (interspinous uptake, bursitis)
  • Activated bone marrow
  • Shows metabolic activity
  • Broad detection of differential diagnoses including tumours, infection, PMR
  • Availability
  •  Costs
  •  Slow
  • Radiation

Adapted from Berger et al.[101]

There is a lack of substantial data directly comparing the different imaging modalities. Furthermore, a benchmark for comparison is lacking since histological confirmation is not always available. In one cohort of 24 patients with suspected GCA, PET/CT was shown to be superior to CTA (without contrast-enhanced venous phase) with a specificity of 100% vs 84.7% and comparable sensitivities of 66.7% vs 73.3% respectively. A different study in a temporal artery biopsy-positive cohort, with 15 GCA patients and 9 non-GCA patients, compared PET vs. CT-A. PET was slightly superior to CTA due to false positive findings with CTA, which effectively lowered the positive predictive value in that group. Other studies also found comparable outcomes of PET/CT and CTA, with  a slightly better performance of PET/CT, as it was more sensitive in detecting inflammation in a given segment. In summary, PET/CT slightly outperforms CTA for initial GCA diagnosis, but the two techniques show good concordance.

Laboratory tests

The most commonly utilized laboratory test in the diagnosis of GCA is the ESR, measured by Westergren method.[102] The ESR can occasionally be normal (ie. <30-40 mm/hr) in up to 30% of patients with biopsy proven GCA. [61][70][72][73][103][104][105] A meta-analysis of many studies showed that an ESR >100 mm/hr had a positive likelihood ratio (LR) of 2.466 and a negative LR of 0.775. However, the ESR can be normalized by corticosteroids or immunosuppression, and there is often difficulty in decision making when the ESR ranges between 50 and 100. In addition, the ESR may be elevated in other disease states such as anemia, inflammatory disease, malignancy, or infection.[32]Therefore, the ESR must be interpreted within the clinical context of a given scenario.


The C-reactive protein (CRP) has been utilized as an adjunct test to the ESR. The CRP has certain advantages over the ESR, including a lack of variation with age, sex or hematological factors. The sensitivity and specificity of the CRP for the diagnosis of GCA has been reported as 100% and 97%, respectively.[72] Some authors have asserted that the CRP is more sensitive in the diagnosis of GCA.[72] A retrospective chart review of 119 patients with biopsy-proven GCA demonstrated a 99% sensitivity when ESR and CRP were utilized together.[106]


Other markers of GCA include thrombocytosis[69][73][102][107], anti-cardiolipin antibodies[108], elevated IFN gamma[109], and elevated interleukin-6.[110] However, none of these markers have been proven to have definite correlation in large studies, and are thus subjects for future research.

Differential diagnosis

The most common disease in the differential diagnosis of GCA with decreased vision is non-arteritic ischemic optic neuropathy (NAION). There are several differences in the patient population, clinical signs and symptoms that are important to elicit. NAION is associated with small-crowded optic nerves, hypertension, diabetes, and hyperlipidemia[32], whereas AAION patients do not necessarily have the same vascular risk factors. In addition, patients with GCA are typically older than those with NAION (i.e. 8th-9th decade vs. 6th-7th decade). In NAION, patients will usually not note any associated systemic symptoms such as headache, jaw claudication, scalp tenderness, weight loss, anorexia, fever, or myalgias/arthralgias. In general, the vision loss from GCA is more severe than NAION, with one third of the AAION patients demonstrating a visual acuity worse than 20/200[111], and most NAION patients retaining a visual acuity near 20/80. In addition, AAION patients may complain of preceding amaurosis fugax, as well as other ocular symptoms such as diplopia, fellow eye involvement, or ophthalmoplegia.

The physical examination also differs between these two diseases. Unlike NAION, AAION patients demonstrate a diffuse “chalky” white edema[37][59], eventual cupping of the disc, and possible coexistent retinal ischemia. NAION often demonstrates segmental optic nerve edema with eventual sectoral or total flattening and pallor. In addition, laboratory evaluations such as the ESR and CRP are usually normal in patients with NAION.

Aside from NAION, one must consider other systemic causes of vasculitis which may present with similar systemic and possibly ophthalmic manifestations. These conditions include rheumatoid arthritis, systemic lupus erythematosis, polyarteritis nodosa, polymyositis, and Takasayu arteritis.[32] In addition, one should consider malignancy, systemic infections, dental disease, trigeminal neuralgia, and amyloidosis in the appropriate clinical setting.

Table 1. Important features that may help to differentiate arteritic ischemic optic neuropathy (AAION) from non-arteritic ischemic optic neuropathy (NAION).
Important features that may help to differentiate arteritic ischemic optic neuropathy (AAION) from non-arteritic ischemic optic neuropathy (NAION).

Management

Medical therapy

The standard of care for the initial treatment of GCA is corticosteroids. Corticosteroids should be started immediately after patients are suspected of having GCA, and should not be held until a biopsy can be undertaken. There is no standardized regimen for the optimal dose of corticosteroids for either induction or maintenance therapy. It has been shown, however, that higher doses of corticosteroids should be utilized in higher risk patients, ie. those who have had severe vision loss, or those with the potential for severe vision loss or cerebrovascular disease.[73][89] Suggested dosages of prednisone for initiation of treatment range from 40 mg to 100 mg per day, with a common starting point of 1 mg/kg/day.[108] If the diagnosis of GCA is confirmed with a biopsy, prednisone dosage should be increased to 80-100 mg/day, or intravenous corticosteroids (ie. 1 gram of methylprednisone for 3 days followed by 1-2 mg/kg/day of oral prednisone) should be utilized.[48][73]

Some have suggested that IV steroids be utilized in patients with amaurosis fugax, marked loss of vision in one eye, or signs of fellow eye involvement.[48][73] The suggested method is administering “pulses” of 500-1000mg methylprednisolone intravenously each day due to the importance of protecting the patient’s vision. However, there is no consensus regarding the use of IV steroids, since there has not been any significant benefit demonstrated in several studies[112][113][114] and the elderly population is at high risk of serious adverse reactions to high dose IV steroid pulses. However, IV methylprednisone has been shown to demonstrate higher serum concentrations more rapidly than oral dosing, and is probabloy useful in certain clinical scenarios.[115]

In select situations, steroid-sparing agents may be utilized. Situations in which the need for these agents may arise include those patients who do not respond to corticosteroids or for those who require less exposure to steroids because of side effects. Methotrexate has been shown to suppress disease activity when used with lower dosages of corticosteroids over a shorter course.[116][117] Other drugs under investigation include anti-tumor necrosis factor alpha antibody[118], azathioprine[119], cyclophosphamide[120], and anti-platelet agents, such as aspirin.[121]

New treatment strategies

In GCA IL-6 is up regulated within the inflamed arteriesand peripheral circulation. It has been proposed that the pharmacologic inhibition of the IL-6 can ameliorate vascular inflammation in this setting. GiACTA is a Phase III, global, randomized, double-blind, placebo-controlled trial investigating the efficacy and safety of Actemra/RoActemra® (tocilizumab) a humanized anti-interleukin-6 as a novel treatment for GCA. In published reports, tocilizumab therapy leads to rapid and maintained improvement in patients with refractory GCA and/or with unacceptable side effects related to corticosteroids. However, the risk of infection should be kept in mind when using this drug in patients with GCA.led to clinical and serologic improvement in patients with refractory/relapsing GCA.[122] [123] [124]


Patients who were eligible to enroll in the study presented with either new-onset or relapsing GCA, and were diagnosed using either a positive temporal artery biopsy or proof of large vessel disease using imaging (angiography, MRA, CTA or PET-CT) with associated elevations in acute-phase reactants. Tocilizumab was found to be effective either when used in conjunction with corticosteroid therapy or after steroid taper. It was not found to be effective in flares.[125]

As tocilizumab is associated with infection, gastric perforation, and abnormal lab values including thrombocytopenia, neutropenia, transaminitis, and elevated lipids, patients should have routine lab screenings. These include neutrophil count, platelet count and liver function tests starting four to eight weeks after initiating therapy and every three months afterwards. Similarly, lipids should be initially monitored between four and 8 weeks of therapy and every few months afterwards. Other biologics that are currently being tested include TNF-a blockers, IL-12/IL-23 blockers, IL-1b blockers, and T-cell mediated CD28 blockers.

Medical follow up

Once corticosteroid treatment is initiated, it is important to follow the patient closely to determine the response to therapy. Some have recommended following the ESR and CRP from every 3 days to weekly, depending on the severity and route of administration of the corticosteroids.98 Although symptomatic improvement may be reached within days of therapy initiation, the ESR can take several weeks to decrease. Once an effective dose of corticosteroid is reached (based upon improvement in symptoms), the treatment at this dose should be continued for a minimum of 4-6 weeks.[126] However, treatment courses typically last for 1 to 2 years, given the importance of a very slow steroid taper to avoid a relapse of the GCA.[127]

There is no consensus on how frequently patients should be seen after starting treatment. A 2019 article in the British Medical Journal recommended follow-ups in weeks 0, 1, 3, and 6, and then monthly follow up afterwards for the first year.[125]Physicians may choose to design their own follow-up schedules and should individualize management focusing on patient disease progression, symptoms, and complications. Each visit should screen for progressing GCA and PMR including cranial symptoms and ischemic symptoms. Adverse effects to steroids should also be monitored closely. Proper patient education and access to support should not be overlooked as GCA is a chronic condition.

Once the decision is made to taper the corticosteroids, it is usually decreased at a rate of 5-10 mg per month until a dose of 10-15 mg per day is reached, and then the taper is decreased by 1-5 mg per month.[128] The patient should be followed closely for any relapse of symptoms, or increase in ESR or CRP. Relapses typically occur within the first 1.5 years, with a median time of approximately 7 months;106 however, active disease has been reported up to 9 years after initiating therapy.[129]

Complications

Patients with known GCA can rarely develop sequelae of large vessel vasculitis, including aortic aneurysms or dissection, after steroid treatment has been tapered. Studies using positron emission tomography (PET) and autopsy suggest that more than 50% of patients with GCA may have subclinical aortitis.[130][131]Fortunately, the rate of catastrophic events from aortic aneurysms in this population is probably less than 10%.[132][133] In addition, GCA can affect the coronary arteries, and patients with GCA have an increased relative risk of ischemic cardiovascular events, such as angina or myocardial infarction.[134]

There are several side effects and complications related to the use of long-term corticosteroids. Most commonly, patients are at increased risk for osteoporosis and gastrointestinal disturbances. For this reason, it is recommended that patients on long term corticosteroids should be given calcium, vitamin D supplementation, and an H2 blocker or proton pump inhibitor. Furthermore, one should consider the use of bisphosponates in selected patients. Other complications for which patients must be monitored include diabetes mellitus, hypertension, immunosuppression, glaucoma, and cataracts.

Population-based studies have estimated approximately 43% of patients suffer one or more relapses of GCA either during or after initial treatment.[135][136][137][138][139] However, differing studies have reported values ranging from 34 percent to 74 percent. The reason for variation is multifactorial. Signs and symptoms of relapse can vary from patient to patient and inflammatory markers may be normal during the flare. Physicians should ask about new-onset ischemic complications, symptoms similar to original presentation, or classic manifestations of GCA or PMR. Due to the lack of consensus in defining a relapse, accurate diagnosis is not possible and therefore physicians must have a high index of suspicion. In the event of diagnosed relapse, patients should be re-started on glucocorticoid therapy. In general, most cases of GCA relapse have been shown to occur at prednisone doses below 20mg/day especially during the first year of treatment.

Prognosis

The visual prognosis is highly dependent on the rapidity with which steroids are started, and the status of the patient’s vision upon presentation. If the patient has already had an ischemic event resulting in AAION or a CRAO, it is rare that vision will improve appreciably.[60][140] However, up to one-third of treated cases may demonstrate some small degree of improvement in acuity after treatment has been initiated.[59][60][113][141][142]

In general, vision often stabilizes once steroids are started; however, if it deteriorates on steroid therapy, it tends to be within 5 days[60][114] and is rare after 1 month.[143] It has been suggested that 9-17% of patients may have a deterioration of their vision while on corticosteroids.[143][144] Additionally, one small study suggested that approximately 9% of patients can progress to fellow eye involvement after therapy is initiated;[60] in contrast, 20-62% of untreated patients may progress to this stage.[143] If there is visual deterioration after treatment is initiated, the prognosis is grim, with 80% of patients progressing to light perception or no light perception in one small study.[60] Features that are associated with a worse visual prognosis include visual symptoms before the steroids are initiated, older age, fever, weight loss, antecedent transient visual loss, diplopia, and jaw claudication.[59][68][73][143] In addition, studies have demonstrated a worse ocular prognosis in patients with a high concentration of hemoglobin and a lower ESR.[46]

Patients with GCA may also be at increased risk for cardiovascular disease within the first year of diagnosis[145], including myocardial infarction from coronary artery vasculitis[146], aortic disease[147], and stroke.[58] These patients also may experience complications from long-term steroid use.[148] Finally, it has been suggested that GCA patients are at increased risk for malignancy, which has been observed in 7% of patients.[149] Fortunately, despite all of these potential complications, the life expectancy of this population is not significantly different than that of the general population.[66][150][151]


Additional Resources

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