Abstract
Giant cell arteritis (GCA) is the most common vasculitis of the elderly. The diagnosis can be challenging at times because of the limitation of the American Rheumatology Association (ARA) classification criteria and the significant proportion of biopsy-negative patients with GCA. We discuss the role of advanced imaging techniques, including positron emission tomography (PET) scanning, in establishing diagnosis and improved histopathology techniques to improve the sensitivity of temporal artery biopsy.
There have been significant advances in the understanding of the pathogenesis of GCA, particularly the role of cytokine pathways such as the interleukins, IL-6-IL-17 axis, and the IL-12-interferon-γ axis and their implication for new therapies. We highlight that glucocorticoids remain the primary treatment for GCA, but recognize the risk of steroid-induced side effects. A number of pharmacotherapies to enable glucocorticoid dose reduction and prevent relapse have been studied.
Early diagnosis and fast-track pathways have improved outcomes by encouraging adherence to evidence-based practice.
Introduction
Giant cell arteritis (GCA) is a systemic vasculitis affecting medium-size and large arteries. The aorta and its branches, especially cranial branches, are typically involved, and it is the most common vasculitis of the elderly. Patients often present with vascular manifestations and a systemic inflammatory syndrome, and key clinical sequelae are cranial ischemic complications, particularly permanent vision loss and stroke.
Epidemiology
GCA primarily affects people aged over 50 years, with incidence rates increasing with age, peaking around the age of 80 . It is more common in females than males, with reported incidence ratios of approximately 2.5 or higher . The incidence of GCA is highest in Northern European populations (∼20 per 100,000 persons older than 50 years) and relatively lower in Southern European populations (∼10 per 100,000 years) , and it is infrequent among people of Africa, Asia, Hispania, and Arabia .
GCA is associated with a significant disease burden resulting from both disease complications and treatment. The major clinical complication of GCA is vision loss, which may affect up to 30% of patients to some extent with permanent vision loss affecting approximately 15% of patients . High-dose glucocorticoids are the first-line treatment for GCA, and may be used for long durations, with the majority of patients experiencing glucocorticoid-related side effects . Severe infections are also more common during the first year of treatment . A recent systematic literature review has identified a substantial projected worldwide disease burden from GCA by 2050 . The number of incident GCA cases will increase secondary to an aging population, and by 2050, in the United States alone, the cost for the treatment of GCA-related vision loss will reach US $76 billion, with a further US $6 billion for management of glucocorticoid-induced factures.
Several studies have yielded conflicting results as to whether GCA is associated with an increase in mortality rate. A recent meta-analysis of 23 studies indicated a small, but significant increase in mortality rates from GCA (combined submucosal resection (SMR) 1.15, 95% CI 1.01–1.30) . This result is consistent with another recent study which reported that severe infections and infection-related mortality are increased during the first year after the diagnosis of GCA .
Epidemiology
GCA primarily affects people aged over 50 years, with incidence rates increasing with age, peaking around the age of 80 . It is more common in females than males, with reported incidence ratios of approximately 2.5 or higher . The incidence of GCA is highest in Northern European populations (∼20 per 100,000 persons older than 50 years) and relatively lower in Southern European populations (∼10 per 100,000 years) , and it is infrequent among people of Africa, Asia, Hispania, and Arabia .
GCA is associated with a significant disease burden resulting from both disease complications and treatment. The major clinical complication of GCA is vision loss, which may affect up to 30% of patients to some extent with permanent vision loss affecting approximately 15% of patients . High-dose glucocorticoids are the first-line treatment for GCA, and may be used for long durations, with the majority of patients experiencing glucocorticoid-related side effects . Severe infections are also more common during the first year of treatment . A recent systematic literature review has identified a substantial projected worldwide disease burden from GCA by 2050 . The number of incident GCA cases will increase secondary to an aging population, and by 2050, in the United States alone, the cost for the treatment of GCA-related vision loss will reach US $76 billion, with a further US $6 billion for management of glucocorticoid-induced factures.
Several studies have yielded conflicting results as to whether GCA is associated with an increase in mortality rate. A recent meta-analysis of 23 studies indicated a small, but significant increase in mortality rates from GCA (combined submucosal resection (SMR) 1.15, 95% CI 1.01–1.30) . This result is consistent with another recent study which reported that severe infections and infection-related mortality are increased during the first year after the diagnosis of GCA .
Pathogenesis
GCA is a systemic vasculitis affecting medium-size and large arteries. GCA lesions tend to be localized in more peripheral, medium-sized arteries, affecting the third to fifth branches of the aorta, in contrast to Takayasu arteritis, which preferentially affects the aorta . The mechanisms underlying the selective targeting of vascular beds are not understood, but molecular and structural characteristics of the arteries must play a role in susceptibility toward intra-wall inflammation .
The immunopathology of GCA derives from dysregulated interaction between the vessel wall and the immune system. Both innate and adaptive immune mechanisms combine to drive local vascular damage, resulting in intimal hyperplasia and occlusion, which may result in blindness and stroke, the most significant clinical consequences of GCA. Other manifestations of GCA, such as an acute phase response, fever, anorexia, malaise, and myalgia, are related to the ensuing systemic inflammation .
It is thought that the disease is triggered by toll-like receptor (TLR) activation of vascular dendritic cells (reviewed in Ref. ), and vascular dendritic cells, endothelial cells, smooth muscle cells, and fibroblasts subsequently interact with T cells and macrophages, resulting in the vascular lesion (reviewed in Ref. ).
The inflammatory process appears to be antigen-driven , although the specific antigen(s), either exogenous or endogenous, has not been identified. While the importance of T cells (predominantly CD4+) is understood, the role of B cells is not clear. B cells are scarce in inflammatory infiltrates, yet a recent report implicates B effector cells in active disease . Several studies have also detected autoantibodies against endogenous antigens derived from proteins involved in cell biology and homeostatsis in GCA (reviewed in Ref. ), and there is a case report of successful treatment of GCA with rituximab .
Infection as a trigger for GCA is an attractive hypothesis, which is consistent with reports of seasonal variations in GCA incidence , the proposed pivotal role of TLR activation in disease initiation , and the antigen-driven nature of the inflammatory process . Several infectious agents have been implicated in the pathogenesis of GCA, including Mycoplasma pneumoniae , Chlamydia pneumonia, and varicella-zoster (reviewed in Ref. ); however, to date, there has been no definitive evidence linking any infectious agent to GCA.
The following two independent inflammatory processes have been identified in GCA, which are likely to play different roles in the vasculitic process (reviewed in Ref. ): (i) The IL-6-IL-17 axis: IL-6 is critically involved in promoting T-cell differentiation toward the T H 17 lineage, resulting in a plethora of cytokines that regulate local and systemic inflammatory effects in GCA. This axis is highly active in early and untreated disease, and is rapidly suppressed by GCs, and presumably tocilizumab (TCZ), which has recently been shown to be glucocorticoid-sparing in GCA . This axis is thought to be responsible for the marked elevation of acute phase reactants and the development of anemia and thrombocytosis in GCA. (ii) The IL-12-IFNγ axis: IL-12 is a major inducer of T H 1 cells resulting in the secretion of the highly potent cytokine IFNγ, which regulates macrophage activation, and endothelial and smooth muscle cells in vasculitis. Evidence suggests that this axis is responsible for a chronic T H 1-driven vasculitis, which may occur even after effective IL-6 blockade, leading to occlusive vascular disease and ischemic complications.
Genetic studies
There is a known familial component to GCA , and genetic susceptibility studies may provide unique insights into disease pathogenesis and subgroups. While there have been a number of candidate gene studies for GCA (reviewed in Ref. ), interpretation of these studies has been hampered by difficulties in achieving the required large sample sizes for derivation and replication data sets. The first large-scale GCA genetic study, using the ImmunoChip platform, was published in 2013, and confirmed HLA-DRB1*04, followed by PTPN22 rs2476601, as the strongest genetic risk factors for GCA . The study also identified other putative risk loci for GCA involved in Th1, Th17, and Treg cell function. Collaborative efforts for larger, genome-wide association studies, involving international consortia from Europe, North America, and Australasia, are currently underway.
Clinical presentation
GCA is a clinically heterogeneous disease with a wide spectrum of features at onset. Systemic features are frequent and include low-grade fever (50%), fatigue, anorexia, and weight loss. Fever may exceed 39 °C in up to 15% of patients . GCA may present as fever of unknown origin (FUO), and may account for up to 16% of cases of FUO in the elderly . Up to 50% of patients present with symptoms of polymyalgia rheumatica (PMR), including early morning stiffness and pain in the shoulder and/or hip girdle.
Ischemic manifestations include new-onset headaches, scalp tenderness, jaw and upper limb claudication, stroke (particularly of the posterior circulation), visual disturbance, and/or permanent vision loss. Jaw claudication is present in about 50% of patients and is the clinical feature most highly associated with positive biopsy. One study showed that jaw claudication was present in 54% of those with a positive temporal artery biopsy (TAB), compared with 3% with negative TAB . Headaches are present in >60% of patients, are of new onset, and are typically, but not always, temporal in position as they may also be frontal, occipital, or generalized .
Vision loss, one of the most serious complications of GCA, occurs in up to 15–30% of cases . An initial visual manifestation of GCA is often amaurosis fugax. This may be caused by anterior optic ischemic neuropathy (AOIN), central or branched retinal occlusion, or choroidal infarction, with the first one being the most common cause of blindness in GCA. In GCA patients with monocular blindness, loss of vision in the unaffected eye occurs in 25–50% of untreated patients . Blindness is rarely reversible even with high-dose glucocorticoids .
Involvement of branches of the aortic arch (particularly the subclavian and axillary arteries) can cause arm claudication . In prospective studies, large-artery disease is seen in 29–83% of patients with newly diagnosed GCA (reviewed in Ref. ). Several studies, comparing GCA patients with large-vessel disease (axillary/subclavian involvement showed angiographically) to those with cranial involvement, showed differences in important clinical aspects. GCA patients with large-vessel involvement were likely to be younger, less likely to present with headaches, less likely to have a positive TAB, at a lower risk of vision loss, required higher glucocorticoid dose, and at a higher risk of relapse .
Central nervous system involvement includes transient ischemic attacks, homonymous hemianopia, hearing loss, vertigo, and stroke, predominantly related to vertebral artery or extradural internal carotid artery lesions.
Temporal artery abnormalities such as prominent or enlarged temporal artery, absent temporal artery pulse, or temporal artery tenderness may be revealed by physical examination. Arterial pulses may be absent or asymmetric in the presence of large-vessel involvement. In addition, bruits in carotid or subclavicular areas may be present, as well as asymmetric arm blood pressure readings. Vascular physical examination in GCA has recently been shown to have low sensitivity but high specificity in detecting angiographically shown disease .
Approximately 9.5–18% of GCA patients develop aortic aneurysm or dissection . A prospective study of 54 GCA patients, who underwent screening with clinical examination and chest X-ray, with subsequent computed tomography (CT) scan and ultrasound, if indicated, determined that aortic structural damage (either aneurysm or dilatation) affects up to 33.3% of patients, with maximal incidence within first 5 years. The thoracic aorta was affected in all but one case .
Diagnosis
At present, there is no diagnostic criterion for GCA. The American Rheumatology Association (ARA) classification criteria for GCA , ( Table 1 ) have been erroneously used as de facto diagnostic criteria. However, they were intended to discriminate between patients with GCA and those with other forms of systemic vasculitis. These criteria are not useful for distinguishing GCA from various common diseases, such as meningitis or sinusitis, and were not developed as diagnostic criteria. The classification criteria focus on cranial symptoms and do not recognize the importance of large-vessel involvement. Further research is required to determine the best diagnostic criteria for use in clinical practice, particularly incorporation of modern imaging techniques such as ultrasound and PET imaging.
| Criterion | Definition |
|---|---|
| 1. Age at disease onset ≥50 years | Development of symptoms or findings beginning at age 50 or older. |
| 2. New headache | New onset of or new type of localized pain in the head. |
| 3. Temporal artery abnormality | Temporal artery tenderness to palpation or decreased pulsation unrelated to arteriosclerosis of cervical arteries. |
| 4. Elevated erythrocyte sedimentation rate (ESR) | ESR ≥ 50 mm/h by the Westergren method. |
| 5. Abnormal artery biopsy | Biopsy specimen with the artery showing vasculitis characterized by prominence of mononuclear cell infiltration or granulocyte inflammation, usually with multinucleated giant cells. |
Serological markers
There is no specific serologic test to aid in the diagnosis of GCA as specific autoantibodies have not been identified and hypergammaglobulinemia is absent. Serology may be useful, however, to exclude other forms of vasculitis that might mimic GCA (such as ANCA-associated vasculitis). While specific laboratory markers for GCA and PMR are lacking, increased levels of the erythrocyte sedimentation rate and C-reactive protein are observed in almost all patients at disease onset. BAFF and IL-6 are serum cytokines that correlate strongly with GCA disease activity , but these markers are not routinely used in the clinic.
Histology
TAB is the gold standard for the diagnosis of GCA. The temporal artery is the chosen biopsy site because of its easy accessibility and frequent involvement in GCA. A unilateral biopsy is performed on the side with the most prominent symptoms.
Typical histological findings are a mixed-cell, predominantly lymphomononuclear, and inflammatory cell infiltration of the artery wall . The classic feature of granulomatous GCA is seen in approximately 50% of positive TAB samples, but the presence of granulomata is not mandatory for a histological diagnosis of GCA. Additional, but not mandatory, features may include fragmentation of the internal elastic lamina and intimal hyperplasia with partial or complete occlusion of the arterial lumen. Occasionally, a circumferential band of fibrinoid necrosis may also be present in the vessel wall.
Estimates of sensitivity of TAB for GCA range from 70% to 90% , that is, up to 30% of patients with a clinical diagnosis of GCA may have a negative biopsy result. There are multiple contributing factors to a negative TAB in patients with clinical GCA. (i) The inflammatory lesions are focal and segmental in nature. These so-called skip lesions have been reported in up to 28% of TAB ; therefore, adequate sampling of the biopsy site is crucial. TAB-positive rate is influenced by biopsy length, and a postfixation TAB length of at least 0.5 cm is recommended . Routine bilateral biopsies may increase the diagnostic yield by only 3–5% and are therefore not recommended. Similarly, the use of color duplex sonography TAB to guide the biopsy to the site of the largest “halo” sign, which is considered characteristic of vasculitis, does not appear to increase TAB sensitivity for GCA . (ii) Healing of the inflammatory lesion may occur if glucocorticoid treatment is initiated before TAB. However, studies suggest that 2–4 weeks of prior glucocorticoid treatment does not affect the likelihood of a positive result appreciably . (iii) The temporal artery may not always be involved. For example, large-vessel involvement may occur in more than one-fourth of patients with GCA , and up to 42% of these patients may have a negative TAB . Patients with biopsy-negative GCA may have less severe ischemic complications and a lower risk of blindness . (iv) There is a lack of systematic protocols for performance, interpretation, and structured reporting guidelines for TAB. Gray areas exist in biopsy interpretation in terms of slight inflammatory changes, healing lesions, and infiltrates surrounding vasa vasorum or inflammation of periadventitial vessels . Structured reporting is necessary to determine whether TAB pathological features may predict some manifestations of GCA . A structured and validated scoring system has been recently proposed , which has identified four histological patterns, and adoption of this could help in this endeavor.
Histological biomarkers may also assist biopsy interpretation. One promising example is rho kinase activity, which is associated with Th17 differentiation, inflammatory cell recruitment, and vascular remodeling, all of which are implicated in GCA pathogenesis. High-intensity staining of TAB for phosphorylated ezrin/radixin/moesin (pERM), a surrogate of rho kinase activity, showed a 90% sensitivity and negative predictive value of 91% for GCA in biopsy-negative patients , although further research is required.
Advances in imaging
About 70% of TABs performed in referral centers are negative , yet it is an invasive procedure that carries some risk, such as facial nerve injury, which is rare but may be permanent . Therefore, there is considerable interest in the application of various imaging technologies to reduce, or replace, the TAB for diagnosis of GCA.
Imaging in its various modalities, including color duplex ultrasonography (CDUS), computed tomography angiography (CTA), magnetic resonance angiography (MRA), and 18F fluorodeoxyglucose positron emission tomography (18F FDG-PET), are emerging as important for the diagnosis and assessment of disease extent and activity in GCA, particularly in large-vessel involvement ( Table 2 ). Overall, there is a paucity of prospective studies to fully determine the utility of many of these modalities, particularly in determining treatment response.
| Modality | Possible Findings | Utility | Advantages | Disadvantages |
|---|---|---|---|---|
| CDUS | Lumen patency assessment, hypoechoic wall thickening (halo sign), areas of occlusion and stenosis | Evidence of temporal artery and large vessel involvement, evaluation of disease extent (supra-aortic branches and extremity arteries) | Inexpensive, no radiation, no contrast/venipuncture, repeatable, good resolution for small arteries, sensitive to both cranial and extracranial disease | Long assessment time needed for wide vascular assessment, highly operator- and equipment-dependent, unable to easily visualize thoracic aorta, not suitable for structures below air or bone |
| CT/CTA | Lumen patency assessment; mural thickening of aorta and first order branches, mural enhancement in venous phase | Evidence of LVV, evaluation of disease extent (supra-aortic branches and extremity arteries), vascular remodeling | Inexpensive, rapid, wide vascular assessment, intraluminal assessment | Radiation, limited resolution for small vessels, contraindications (iodine allergy, impaired renal function), venipuncture needed |
| MRI/MRA | Mural thickening and high T2 signal, wall edema | Diagnosis (MRI), evidence of scalp artery and LVV and disease extent in aorta, major branches, extremity arteries (MRA), conventional angiography of coronary or intracranial arteries (MRA), vascular remodeling (MRA), response to treatment (MRA) | Wide vascular evaluation, acquired images, minimally invasive, repeatable, no radiation | 3 T scanners for cranial imaging, expensive, limited resolution for medium/small vessels, long acquisition time needed for wide vascular assessment, magnet and contrast contraindicated for some patients, claustrophobia, venipuncture needed |
| PET/PET–CT | Mural FDG uptake in large vessels | Evidence of LVV and disease extent in aorta and major tributaries, response to treatment | Wide vascular evaluation, delineates extent of extracranial involvement, very sensitive, discovery of incidental pathology, acquired images, minimally invasive, repeatable, almost whole body assessment | Radiation, expensive, no standards for positivity, not widely available, no lumen patency assessment, unable to visualize temporal arteries |
Color Duplex ultrasound
High-frequency ultrasound probes capable of studying superficial temporal arteries show abnormalities described as “hypoechoic halos” surrounding the vessel lumen. This is caused by an edematous thickened artery wall, which is different from the focal hyperechoic wall thickening seen in atherosclerosis .
Doppler ultrasound can also identify areas of stenosis and occlusion, indicating damage due to arteritis, although this is not specific for GCA. The presence of these abnormalities in extracranial (axillary, subclavian) arteries improves sensitivity. The axillary arteries are easily accessible, and involvement is found in 53% of patients diagnosed with GCA .
GCA of the extracranial carotid and proximal arm arteries can be diagnosed in the presence of a circumferential, homogeneous, hypoechogenic thickening of the vessel wall with smooth delineation toward the vessel lumen. This sonographic finding is distinct from arteriosclerotic lesions, which are characterized by irregularly delineated, nonhomogeneous, eccentric, and/or calcified wall alterations .
The advantages of CDUS, compared with TAB, are the potential for assessing longer artery segments and additional vascular beds. Disadvantages include the failure to detect incomplete histopathological patterns , and the equipment and operator dependency of results. High sensitivity and specificity can be obtained by an experienced operator, but heterogeneous results have been reported in various studies of this technique, with sensitivities ranging from 35% to 86% . Further, the optimal timing of CDUS for GCA diagnosis is unclear, with conflicting reports on the disappearance of the halo sign after commencement of therapy ranging from 2 days to 2 months . Nevertheless, many studies and three meta-analyses support a role for detection of the halo sign by CDUS in the diagnosis of GCA, and diagnostic utility may be improved by the inclusion of other abnormalities such as stenosis and occlusion . A recently completed, prospective, multicenter cohort study of 381 patients, comparing TAB to ultrasound of temporal and axillary arteries for diagnosis of newly suspected GCA (TABUL study), reported that ultrasound had a higher sensitivity for the diagnosis of GCA (54% vs. 39%) than TAB, but a lower specificity (81% vs. 100%) .
Newer techniques include the use of microbubble contrast-enhanced ultrasound, which is being increasingly used in vascular imaging. A recent prospective study of seven patients with GCA or Takayasu’s arteritis showed improved image quality and definition of the vessel and the ability to assess neovascularization dynamically using contrast-enhanced ultrasound .
Computed tomography angiography
CTA has been used in the diagnosis of extracranial large-vessel involvement and may be more sensitive than FDG-PET for detecting signs suggestive of aortitis . Mural thickening and wall enhancement in the venous phase are considered signs of active large-vessel disease. CTA is more traditionally used to assess the lumen, and can therefore detect stenotic and aneurysmal lesions, which can complicate GCA. CTA is also able to detect atheroma plaques, which are frequent in the aorta and iliac and femoral arteries of the elderly .
CTA has detected a higher than previously suspected prevalence of large-vessel involvement in GCA. A study of 40 consecutive newly diagnosed GCA patients (before or within 3 days of initiation of glucocorticoid) who underwent CTA showed large-vessel vasculitis in 67.5%. The arteries most frequently involved were the aorta (65%), brachiocephalic trunk (47.5%), subclavian (42.5%), carotid (35%), and femoral arteries (30%). The findings on CTA are those of tapered stenoses of large vessel vasculitis. The sensitivity of CTA was significantly reduced in patients who had already received glucocorticoids (29% vs. 79%). A prospective follow-up study determined that signs of LVV improve with treatment, suggesting that CTA may have some utility in monitoring response to treatment .
Magnetic resonance imaging/Magnetic resonance angiography
Magnetic resonance imaging (MRI)/MRA is useful in diagnosing large-vessel GCA, particularly in cases of suspected GCA nonassociated with cranial arteritis. With the use of gadolinium-based intravenous contrast agents, MRI can be used to show vascular luminal anatomy, stenosis, dilation, and measure mural thickening and enhancement. MRI/MRA are highly reproducible, and are potentially useful in monitoring disease activity and response to treatment.
MRA has identified vascular alterations in keeping with extracranial GCA in 19 of 28 patients (67%) with good interobserver agreement ( k = 0.73) , again indicating that there is a greater than previously appreciated tendency for the aorta and its proximal branches to be involved in GCA.
High-resolution MRI/MRA can also identify regions of temporal artery involvement in GCA , thereby either serving as part of a diagnostic algorithm or helping to guide TAB. A recent prospective, multicenter study of MRI of superficial cranial arteries showed a sensitivity of 78.4% and specificity of 90.4% for GCA diagnosis , comparable to a previous study .
18F fluorodeoxy glucose positron emission tomography (PET/PET–CT)
PET scan is emerging as a powerful, noninvasive tool to assist in the diagnosis of large-vessel involvement in GCA. While the spatial resolution of PET is limited, PET–CT improves anatomical precision.
PET takes advantage of increased metabolism in inflamed tissues and permits the noninvasive assessment of inflammation of the aorta and its tributaries via uptake of the glucose analog 18F FDG. FDG-PET can visualize glucose-consuming inflamed vessels, provided their diameter is >4 mm. This limitation – together with their superficial position and proximity to the brain (which has a high FDG uptake) – explains why the temporal arteries themselves cannot be visualized with this technique .
FDG-PET is the diagnostic technique of choice over TAB in untreated patients with atypical presentations of GCA, such as weight loss, fever, malaise, and arm claudication, in whom the vasculitis probably does not involve the temporal arteries , and it can also be used to detect malignancy.
In general, FDG uptake is considered indicative of vasculitis when the vascular signal is more intense than that of the liver. However, as increased FDG uptake can be seen in atheroma plaques and vascular aging, and systemic inflammation may involve the liver, the threshold above which FDG uptake must be considered indicative of vascular inflammation is unclear. A number of qualitative and semiquantitative methods have been used for the detection of vasculitis, but there is still no clear consensus on the scoring method. A recent systematic review of scoring methods for 18F-FDG PET image analysis of GCA-related vascular inflammation concluded that qualitative methods are less sensitive, but more specific than semiquantitative methods, and that among the semiquantitative methods, the aortic-to-blood pool uptake ratio of the aortic arch seems to be the most accurate one . A recent meta-analysis of performance of FDG-PET for the diagnosis of large-vessel inflammation in GCA (four studies, 57 patients), which included studies utilizing either qualitative (visual) or semiquantitative methods, showed a sensitivity of 89.5% (95% CI 78.5–96) and specificity of 97.7% (95% CI 94–99) for the diagnosis of large-vessel vasculitis in GCA patients compared to controls . Interestingly, FDG-PET was more accurate in GCA patients than Takayasu’s arteritis patients, and vascular FDG uptake, equal or higher than the liver uptake, appeared to be best criterion for the detection of vascular inflammation compared with controls in GCA patients. These results are comparable to an earlier meta-analysis .
There is no consensus on whether FDG-PET can be used reliably to monitor treatment response and disease activity. FDG-PET cannot predict which patients are likely to relapse , and once GCs are started, interpretation is unreliable, which makes its role in follow-up uncertain.
Advances in therapy
Glucocorticoids remain the mainstay of treatment in GCA because of their rapid onset of action and ability to suppress inflammatory symptoms and prevent GCA-related ischemic events. However, because of the highly prevalent and predictable adverse events of glucocorticoids, studies have primarily been aimed at reducing glucocorticoid dependence in GCA ( Table 3 ). Overall, there is a paucity of randomized controlled trials (RCTs), and results have been somewhat disappointing. The lack of a validated outcome measure for clinical investigation in GCA has at least partially contributed to the difficulty conducting these studies. An OMERACT-endorsed core set of outcome measures for use in clinical trials of LVV is currently under development and should improve the ability to adequately assess treatment benefits . Two independent axes of inflammation have been identified in GCA (reviewed in Ref. ), and the IL-6-IL-17 axis is targeted by glucocorticoid treatment and newer biologic agents, such as TCZ and abatacept. However, the IL-12-IFNγ axis has been linked to persistent vasculitis and is resistant to standard therapy in the clinical setting . Agents such as aspirin, statins, and angiotensin II receptor blockers may target this axis, and further research in this area is required.
| Treatment | Highest Evidence Level | Year | Treatment Regimen | N | Result | Reference |
|---|---|---|---|---|---|---|
| GC starting dose | RCT (blinding not clear) | 1989 | High-dose GC (40 mg) vs. low-dose (20 mg) | 35 (20 High dose) | No difference in relapse at 2 months (4/20 vs. 6/15) | |
| GC dosing interval | RCT (blinding not clear) | 1975 | (A) 15 mg GC 8 hourly (B) 45 mg/day (C) 90 mg alternate days | 60 | Poor resolution of symptoms at 4 weeks in group C (6/20) | |
| IV methylprednisolone (MP) pulse | Multicenter RCT (unblinded) | 2000 | Induction IV MP (240 mg)/No pulse + oral GC (0.7/0.5 mg/kg starting dose) | 164 (3 treatment arms) | No GC sparing effect of IV MP pulse at 1 year | |
| RCT | 2006 | Induction IV MP (15 mg/kg/day)/saline for 3 days + oral GC (40 mg/day starting dose) | 27 (14 + IV GC) | More rapid tapering of oral GC, more sustained remission at 78 weeks | ||
| Low-dose aspirin (LDA) | Meta-analysis of 3 cohort studies | 2014 | High-dose GC ± LDA or anticoagulant therapy | 439 (159 LDA) | Reduced risk of severe ischemic complications post diagnosis, no increased risk of bleeding | |
| Cohort study | 2013 | Oral GC ± IV GC ± LDA | 45 (6 + LDA) | Reduced risk of relapse | ||
| Statins | Incident GCA cohort | 2013 | GC ± statins | 279 (49 statin) | Increased risk of GCA, no effect on relapse, prednisone tapering, overall survival | |
| Incident GCA cohort | 2015 | GC ± statins | 103 (28 statin) | Similar risk of GCA, better maintenance on low GC dose, no difference in cumulative GC dose | ||
| Angiotensin II receptor blockers (ARB)/angiotensin-converting enzyme inhibitors (ACEI) | Cohort study | 2014 | GC ± ARB ± ACEI | 106 (14 ARB, 36 ACEI) | Lower relapse risk, faster GC tapering with ARB; no benefit of ACEI | |
| Methotrexate (MTX) | IPD meta-analysis of 3 RCTs | 2007 | GC + MTX/placebo | 161 (84 MTX) | Lower relapse risk, reduced GC exposure | |
| Azathioprine (AZA) | RCT | 1986 | GC + AZA/placebo | 31 (16 AZA) | Lower GC dose at 52 weeks | |
| Hydroxychloroquine (HCQ) | RCT | 2009 | GC + HCQ/placebo | 64 (32 HCQ) | No difference in remission, relapse rate or cumulative GC dose at 96 weeks | |
| Cyclosporine A (CsA) | multicenter open label RCT | 2009 | GC ± CsA | 59 (29 CsA) | No GC sparing effects of CsA | |
| Cyclophosphamide (CYC) | Case series literature review | 2013 | GC + CYC (oral or pulse IV) | 103 | 86% “responsive” to CYC | |
| Leflunomide | Open label case series | 2012 | GC + leflunomide | 9 (refractory GCA) | 9/9 complete or partial response (at a median of 2 months) | |
| Case series | 2013 | GC + leflunomide | 11 (refractory GCA) | 63% reduction in GC use | ||
| Mycophenolate mofetil (MMF) | Case series | 2012 | GC + MMF | 3 (newly diagnosed) | Resolution of systemic symptoms with GC-sparing effects | |
| Dapsone | RCT | 1993 | GC + dapsone/placebo | 47 (24 Dapsone) | Lower relapse risk | |
| Infliximab (anti-TNF) | Multicenter RCT | 2007 | GC + infliximab/placebo | 44 (28 + infliximab) | Study terminated at 22 weeks due to lack of efficacy | |
| Adalimumab (anti-TNF) | Multicenter RCT | 2014 | GC + adalimumab/placebo | 70 (34 adalimumab) | No difference in remission, remission duration or cumulative GC dose at 26 weeks | |
| Etanercept (TNF receptor fusion protein) | Multicenter RCT | 2008 | GC + etanercept/placebo | 17 (8 etanercept) | 50% (vs. 22%) GC free at 12 months ( p > 0.05); lower cumulative GC dose ( p = 0.03) | |
| Tocilizumab (anti-IL6R) | RCT | 2016 | GC + tocilizumab/placebo | 30 (20 Tocilizumab) | Lower relapse risk, shorter GC duration, lower cumulative GC dose at 52 weeks | |
| Abatacept (CTLA-4 fusion protein) | Multicenter RCT | 2015 | GC + abatacept/placebo | 41 (20 abatacept) | Lower relapse risk at 12 months | |
| Ustekinumab (anti-IL12, IL23) | Prospective uncontrolled study | 2015 | GC + ustekinumab | 12 (refractory GCA) | Significant tapering of GC dose, no relapse | |
| Rituximab (anti-CD20) | Case report | 2005 | GC + rituximab | 1 (refractory GCA) | Resolution of symptoms sustained for at least 6 months |
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