Introduction
Giant cell arteritis (GCA) is a chronic inflammatory vasculitis that predominantly affects large- and medium-sized arteries in individuals older than 50. This complex disorder commonly involves the cranial branches of the carotid arteries. The granulomatous nature of GCA contributes to the loss of vascular smooth muscle cells and elastic fibers, potentially leading to aneurysm formation and vascular remodeling. Intimal hyperplasia and lumen occlusion contribute to ischemic complications.
The spectrum of manifestations in GCA varies, ranging from cranial engagement evidenced by constitutional symptoms, headache, and jaw claudication and a positive temporal artery biopsy to the involvement of large vessels, characterized by nonspecific systemic symptoms and observable vasculitis on imaging. Vision loss, a severe complication primarily manifesting as transient monocular visual loss, necessitates early recognition and treatment with high-dose systemic glucocorticoids, possibly combined with interleukin-6 (IL-6) receptor antagonists. Notably associated with polymyalgia rheumatica, management involves considering the diverse clinical presentations and potential surgical interventions for vascular complications. The management approach for GCA with large vessel involvement mirrors that without large vessel involvement, with additional considerations such as antiplatelet therapy for selected patients. Considering the diverse clinical presentations and treatment options, a comprehensive approach is essential in addressing the complexities of GCA.
Etiology
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Etiology
Although the exact etiology is unknown, researchers have associated the disease with several genetic and environmental factors. Large-scale genetic analyses reveal a strong association between GCA and specific polymorphisms in the major histocompatibility complex region, such as human leukocyte antigen (HLA)-DRB1*04:04, HLA-DQA1*03:01, and HLA-DQB1*03:02.[1] Additional variants have also been identified in genes involving T helper (Th) 1, Th17, and regulatory T-cell function.
Epidemiology
Among the various predisposing risk factors, advancing age and Northern European ancestry are the most widely known.[2] Epidemiological studies also demonstrate a predominance in females, although the role of gender in the pathogenesis of the disease remains unclear.[3]
In the United States, the lifetime risk of developing GCA is estimated to be approximately 1% for women and 0.5% for men.[4] GCA predominantly affects patients older than 50, with the highest incidence observed in those between 70 and 79.[5] The mean age of onset is 75. Scandinavian countries and individuals of Scandinavian descent exhibit the highest incidence rates, while lower rates are noted in African American, Asian, Arabic, or Japanese populations.[6][7] Approximately 40% to 60% of patients with GCA may also have polymyalgia rheumatica. Conversely, around 16% to 21% of patients with polymyalgia rheumatica have GCA.[3]
Pathophysiology
The defining pathogenic feature of GCA is the inflammation of medium- and large-sized arteries arising from the aortic arch. Dysregulation in both the innate and adaptive immune systems characterizes GCA. GCA's pathophysiology revolves around the body's improper reaction to vascular endothelial injury. Although numerous triggers, including various pathogens, have been suggested, researchers have not definitively established a causal link between these triggers and GCA.[3]
GCA is a granulomatous vasculitis believed to occur as an immune-mediated disease leading to the activation of vascular dendritic cells. Activated dendritic cells produce chemokines, such as granulocyte-macrophage colony-stimulating factor, that attract and retain dendritic cells, lymphocytes, and macrophages. Upon activation, dendritic cells process and present antigens, expressing activation markers, major histocompatibility complex class II, and costimulatory molecules essential for antigen presentation and T-cell activation.
T lymphocytes also play an essential role in disease pathogenesis. GCA is characterized by a predominant Th1-immune–mediated response with significant expression of interferon-γ and interleukin-17 (IL-17).[8] Activated vascular dendritic cells residing in the adventitia of large vessels initiate the disease process by recruiting T-cells in the arterial wall, which differentiate into interferon-γ–producing Th1 and IL-17–producing Th17 cells. Subsequently, these cytokines activate macrophages, leading to the proliferation of vascular smooth muscle cells and the formation of giant cells. The macrophages also release IL-1β and IL-6, triggering a systemic inflammatory response responsible for the constitutional symptoms of the disease.[9]
Although visual complications can result from ischemia anywhere along the optic pathway, they usually occur due to anterior ischemic optic neuropathy caused by vasculitis involving the ophthalmic artery or the posterior ciliary arteries. [10] Jaw claudication occurs due to decreased blood supply to jaw muscles.
Histopathology
In the early stages of the disease, histopathological changes reveal collections of lymphocytes confined to the internal or external elastic lamina or adventitia. Intimal thickening is also probable during this stage. As the disease progresses, transmural inflammation with areas of necrosis is visible, with a predominance of granulomas containing multinucleated histiocytic and foreign body giant cells, histiocytes, predominantly Th lymphocytes, some plasma cells, and fibroblasts.[11] Neutrophils and eosinophils are rare. Active sites may also display thrombotic changes. The artery's involvement in GCA can be uneven, leading to skip lesions. These skip lesions result in false-negative biopsy results in patients with GCA.
History and Physical
Clinicians should suspect GCA in any patient older than 50 who presents with a new headache or change in the typical features of their preexisting headache. Other scenarios that warrant suspicion in such patients are jaw claudication, unexplained fever or other constitutional symptoms, abrupt visual disturbance or loss, and signs of vascular abnormalities.[12] Tongue pain is rare but, if present, significantly increases the likelihood of GCA.[9] Vascular abnormalities may manifest as limb claudication, asymmetric blood pressures, abnormal radial pulses, vascular bruits, and temporal artery abnormalities such as tenderness to palpation, decreased pulse amplitude, and the presence of nodules.
A current or previous diagnosis of polymyalgia rheumatica should also raise clinical suspicion for GCA. Any patient with a diagnosis of polymyalgia rheumatica should undergo evaluation for GCA. Clinicians should inquire about headaches, jaw or arm claudication, visual symptoms, and unusual facial, throat, or tongue pain. At a minimum, patients with polymyalgia rheumatica should undergo carotid and subclavian artery auscultation for bruits and bilateral blood pressure measurements.
Cranial Symptoms and Findings
Headache: A new headache is a primary complaint in nearly two-thirds of patients with typical GCA.[9] Classically described as a temporal headache associated with scalp tenderness, the headache can be frontal, occipital, unilateral, or generalized. The headache may wax, wane, worsen, or subside before treatment begins.
Enlargement, nodular swelling, tenderness, and loss of pulse of the temporal artery, either unilateral or bilateral, are classically ascribed to patients with underlying cranial GCA. The absence of any physical temporal artery findings modestly decreases the likelihood of GCA.[13]
Constitutional symptoms: Nearly 50% of patients with cranial GCA present with nonspecific constitutional symptoms such as fever, malaise, depression, anorexia, and weight loss.[9] Fever is typically low-grade and present in up to 40% of patients, although the temperature may exceed 39 °C (102.2 °F) in 15% of patients.[14] GCA accounts for more than 15% of all fevers of unknown origin in patients aged 65 or older.[13]
Jaw claudication: Jaw claudication, occurring in nearly 50% of patients with GCA, manifests as pain or fatigue in the mandible and occasionally the tongue, triggered by chewing, and typically subsides upon cessation of chewing.
Visual involvement: Approximately 20% to 30% of the patients experience visual disturbances. GCA-associated visual loss can be transient or permanent. Transient visual changes typically present as an abrupt partial field defect or as if a curtain covers the field of vision of 1 eye. Permanent vision loss, most often resulting from anterior ischemic optic neuropathy, is painless and sudden, and it can be unilateral, bilateral, partial, or complete.[13] Current studies estimate that the incidence of permanent vision loss is 8.2% in patients with GCA.[15] Fundoscopy initially reveals pallor and edema of the optic disc and, eventually, optic atrophy. In addition, the presence of retinal or choroidal ischemia strongly suggests GCA.
Ischemia affecting almost any portion of the oculomotor system causes an oculomotor nerve palsy and diplopia that typically precedes vision loss. Diplopia is a highly specific indicator of the disease. A rare finding associated with GCA is the Charles Bonnet syndrome, in which psychologically normal individuals experience visual hallucinations and visual loss due to lesions in either peripheral or central visual pathways.
Some patients may develop posterior ischemic optic neuropathy, which manifests as decreased visual acuity. During the acute phase, the optic nerve is normal on ophthalmoscopic examination. A relative afferent pupillary defect, where pupils respond differently to light stimuli shone in 1 eye at a time, exists unless both eyes have optic nerve dysfunction. This defect measures the extent of ipsilateral optic nerve dysfunction.
Musculoskeletal involvement: The most common symptoms in patients with extracranial GCA are associated with polymyalgia rheumatica, manifesting as pain, stiffness, and limited range of motion in the muscles around the shoulders, neck, and hips. Patients may report challenges in activities such as standing up from a chair or brushing their hair. Occasionally, patients experience peripheral synovitis and distal extremity swelling with pitting edema. Polymyalgia rheumatica dominates the clinical presentation in 45% to 61% of patients with extracranial GCA.
Large vessel involvement: Large vessel involvement in GCA generally refers to the aorta and its major proximal branches, especially in the upper extremities. Initial symptoms may be upper extremity claudication, back or chest pain due to aortitis, or aortic dissection.[9] Auscultation should be regularly performed. Clinicians may appreciate bruits on auscultation of the carotid or supraclavicular areas, over the axillary, brachial, or femoral arteries, and the abdominal aorta. Additional physical examination findings include a lack of upper extremity pulses, asymmetric pulses and blood pressure readings in the upper extremities, and Raynaud phenomenon with or without digital ischemia. Aortic aneurysms, with thoracic being more common than abdominal ones, may also form.[16] A heart murmur associated with aortic regurgitation may signify an ascending aortic aneurysm.
Central nervous system involvement: Transient ischemic attacks or strokes, especially involving the posterior circulation, may be associated with GCA. The risk of stroke within the first 4 weeks of diagnosis is 1.5% to 7.5%. Characteristically, strokes associated with GCA involve the vertebrobasilar system, while intracranial involvement is rare. Underlying risk factors for cerebrovascular disease, such as hypertension and peripheral vascular disease, increase the risk of cranial ischemia in patients with GCA.[5]
Additional features: Less commonly observed potential features associated with GCA include upper respiratory tract symptoms, macroglossia, dental pain, dysarthria, sensorineural hearing loss, breast mass, female genital tract involvement, mesenteric ischemia, and pericarditis.
Evaluation
The diagnosis of GCA should not rely on clinical symptoms alone. Clinicians must confirm the typical histopathologic or imaging findings. Although the evaluation may begin with laboratory testing, laboratory data are not specific for GCA and do not confirm the diagnosis.
Laboratory Testing
Laboratory tests for evaluating GCA include complete blood count, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), serum transaminases, blood glucose levels, creatinine kinase, and aldolase.
Clinicians may consider additional laboratory tests, including serum electrolytes, urinalysis, serum creatinine, serum protein electrophoresis, serum calcium, serum phosphorus, serum albumin, alkaline phosphatase, 25-hydroxyvitamin D, and total protein, based on the patient's symptoms.
A significant increase in acute phase reactants such as ESR, CRP, and platelet levels characterizes GCA. Typically, patients exhibit an elevated ESR, but exceptions exist, and biopsy-confirmed cases may show a normal ESR. In corticosteroid-naive individuals with confirmed GCA, most show ESR levels >50 mm/h, with a small percentage having lower values.[17] CRP proves to be a more sensitive marker for inflammation in GCA, as ESR levels can increase with age and the presence of comorbidities such as anemia and chronic kidney disease. A normal CRP carries a high negative predictive value. Concurrent elevation in ESR and CRP enhances specificity, as only 4% of the patients with GCA have both ESR and CRP in the normal range.[17][18] Normal values do not definitively exclude the disease. Non-concordance between ESR and CRP levels is possible, further emphasizing the need for a comprehensive diagnostic approach.[18] Additional indicators of systemic inflammation are normochromic normocytic anemia, thrombocytosis, reduced albumin, elevated α-2 fraction on serum protein electrophoresis, and raised fibrinogen.
Evaluation of the Temporal Artery
Patients suspected of having GCA should undergo a biopsy or color Doppler ultrasound (CDUS) of the temporal artery.
Temporal artery biopsy: Traditionally, the gold standard diagnostic test for detecting GCA temporal artery biopsy has some limitations. The diagnostic sensitivity of temporal artery biopsy is approximately 77%.[19] The initial biopsy is unilateral, aiming to obtain a specimen of at least 1 cm. Factors decreasing the sensitivity of the temporal artery biopsy include skip lesions, lack of temporal artery involvement, inadequate specimens, and glucocorticoid therapy.[20] Ideally, the biopsy should be performed before glucocorticoid therapy. However, given the risk of permanent vision loss, clinicians begin glucocorticoid therapy as soon as the diagnosis of GCA is suspected. Temporal artery biopsy should be completed within 2 weeks of initiating glucocorticoid therapy.[20] False-negative results occur in up to 44% of patients with an established diagnosis of GCA.
In patients with headaches, the biopsy should be performed first on the symptomatic side. Clinicians can immediately evaluate the frozen section of the specimen. If this review is positive, no further biopsy is necessary. In cases where a unilateral biopsy on the frozen section is negative, clinicians proceed to perform the biopsy on the contralateral side. The second biopsy can increase the yield by 5% to 14%.[21]
Ultrasonography: CDUS of the head, neck, and upper extremities is a diagnostic alternative for temporal artery biopsy. Clinicians should perform a CDUS upon suspecting GCA or within 1 week of beginning glucocorticoid therapy, as glucocorticoids lower the sensitivity of CDUS. The sonographic hallmark of vasculitis is the halo sign, described as a sonographically hypoechoic ring of inflamed and edematous vessel walls surrounding the Doppler signal in the lumen of an artery.[22] Bilateral halo signs of the temporal arteries are highly specific for GCA. The compression sign manifesting as persisting visibility of the halo during compression of the vessel lumen by the ultrasound probe has a sensitivity and specificity of 79% and 100%, respectively.[5]
European clinical guidelines comparing the halo sign with temporal artery biopsy reported a pooled sensitivity of 74% and a pooled specificity of 81% for this radiographic finding. European guidelines outlined by the British Society for Rheumatology advocate for increased use of ultrasonography in the evaluation of GCA given the noninvasive nature of the test and the ability to assess the temporal artery along its entire length compared to limited portions available on temporal artery biopsies. These guidelines note that decreased sensitivity for ultrasound in detecting GCA is partly explained by the imperfect reference standards of comparison.[5]
A recent study investigating the role of ultrasonography in diagnosing GCA reports a sensitivity of 39% for temporal artery biopsy and 54% for ultrasound. The specificity of biopsy is 100%, which is superior to the 81% specificity of ultrasound. The study proposes ultrasonography as the initial diagnostic modality, followed by biopsies performed only in negative cases. This approach aims to reduce the need for biopsies. Using this proposed approach, the study reports a sensitivity of 65% and a specificity of 81%, decreasing the need for temporal artery biopsies by 43%.[23]
Other Imaging
If the initial temporal artery biopsy or ultrasound is negative, and the clinical suspicion based on symptoms and inflammatory markers remains high, the American College of Rheumatology (ACR) recommends noninvasive vascular imaging of the neck, thoracic, abdominal, or pelvic vessels using high-resolution magnetic resonance imaging (MRI) with magnetic resonance angiography (MRA).[20] Positron emission tomography (PET), computed tomography (CT), CT with angiography (CTA), and conventional MRA do not have adequate spatial resolution to assess the temporal artery adequately.
Patients with newly diagnosed GCA also warrant imaging to assess for large vessel involvement. Imaging for large vessel disease may include CT or CTA, MRI or MRA, and fluorodeoxyglucose (FDG) PET or PET with CT of the aorta and its branches. CDUS is another option. Each imaging option is helpful, and the choice of which one to use must consider its individual benefits, cost, use of contrast, and exposure to ionizing radiation. CDUS can visualize the axillary, subclavian, and carotid arteries but not the intrathoracic aorta. PET has superior sensitivity compared to CDUS for detecting abdominal aorta involvement. At the same time, CT and CTA can demonstrate concentric mural thickening, which is continuous over long segments, and MRI and MRA can detect wall thickening. CTA and MRA have the added benefit of identifying stenoses, dilatation, and aneurysms.
Routine vascular imaging to assess for large vessel vasculitis outside the head and neck region in patients with GCA demonstrates some degree of aortitis in up to 83% of cases.[5] Patients with GCA rarely have involvement of the visceral arteries and rarely have stenosis or occlusion of the aorta.[9]
Unlike ultrasonography, MRI with MRA should not be considered initial testing for GCA. Cranial artery MRI revealing edematous vascular walls with contrast enhancement demonstrates a sensitivity of 75% and a specificity of 89% for detecting GCA. However, sensitivity decreases after 5 days of glucocorticoid therapy.
Treatment / Management
Guidelines state that all patients with GCA warrant high-dose glucocorticoids as the initial treatment. The dosage and route of administration depend on the presence or absence of threatened or established vision loss.
No Visual Loss at Diagnosis
Corticosteroids: The ACR recommends initiating treatment with high-dose oral glucocorticoids in patients with GCA who do not have any evidence of cranial ischemia, such as amaurosis fugax, vision loss, or stroke.[20] Patients receive early treatment with a once-daily dose of 40 to 60 mg/d of prednisone or an equivalent corticosteroid.[5] This dosage should be continued for approximately 2 to 4 weeks until all symptoms resolve and acute phase reactants normalize.[5] Alternate-day dosing and doses lower than 40 mg are not indicated.[20]
Upon clinical remission, clinicians decrease the corticosteroid dose by 10 mg every 2 weeks to reach 20 mg/d of prednisone after the patient has been in remission for 4 to 8 weeks. At this point, the daily prednisone dose decreases by 2.5 mg every 2 to 4 weeks until the patient achieves 10 mg/d. Clinicians can continue to taper the prednisone 1 mg every 1 to 2 months if clinical remission continues.[5] The ultimate goal is to taper glucocorticoid therapy to zero over a period of 12 to 18 months while maintaining clinical remission and normal inflammatory markers. Patients at risk of glucocorticoid toxicity may warrant a more rapid glucocorticoid taper.[5]
Corticosteroid-sparing agents: Patients at increased risk of developing complications from glucocorticoids or those experiencing their first relapse should also begin a corticosteroid-sparing agent. The ACR recommends tocilizumab, an IL-6 inhibitor antagonist, and high-dose glucocorticoids for patients requiring a corticosteroid-sparing agent.
In a recent phase 2 randomized, double-blind, placebo-controlled trial, tocilizumab demonstrated relapse-free survival in 85% of patients receiving tocilizumab plus corticosteroids compared to 20% in those receiving placebo plus corticosteroids by week 52 of treatment.[24] Another randomized, double-blind, placebo-controlled trial showed sustained corticosteroid-free remission in more than 50% of patients treated with tocilizumab plus corticosteroids for 26 weeks compared to 14% in those treated with corticosteroid monotherapy for 26 weeks and 18% in those treated with corticosteroid monotherapy for 52 weeks. Relapses occurred in 23% of the patients treated with tocilizumab compared to 68% in those treated with corticosteroid monotherapy.[25] Other options include methotrexate plus glucocorticoids and glucocorticoid monotherapy. Currently, the lack of long-term follow-up data and the cost limit the use of tocilizumab.[20] (A1)
Patients receive tocilizumab as a 162 mg subcutaneous weekly injection or as a monthly intravenous (IV) infusion in combination with glucocorticoids. The IV dose is 8 mg/kg once every 4 weeks, with a maximum of 800 mg/infusion. Similar to glucocorticoids, tocilizumab therapy continues for 12 to 18 months. Tapering of tocilizumab occurs when the patient maintains clinical remission and completes the course of corticosteroids.
As tocilizumab completely inhibits IL-6, the normalization of CRP and ESR levels can make disease monitoring challenging. Clinicians must rely on clinical symptoms and imaging for large vessel involvement.
Clinical evidence supporting the use of tocilizumab is stronger compared to that of methotrexate. However, methotrexate is an alternative for patients who are unable to receive tocilizumab therapy due to the risk of infections, history of gastrointestinal perforations, or cost.[20][26][27] Methotrexate begins at 10 to 15 mg/wk, with a 5 mg/wk increase in dose every 2 to 8 weeks up to 25 mg/wk.(A1)
Threatened or Established Visual Loss at Diagnosis
Due to the crucial importance of preventing vision loss, the ACR recommends administering 500 to 1000 mg of IV methylprednisolone for 3 days. Alternatively, if methylprednisolone is unavailable, 1 mg/kg/d of oral prednisone should be given to patients with GCA and evidence of cranial ischemia or established or threatened vision loss. Patients with diplopia should also receive IV steroids. IV pulse corticosteroids should be given for 3 consecutive days, followed by high-dose oral corticosteroid therapy as outlined above.[5] The role of IV pulse corticosteroids has been associated with successful and rapid glucocorticoid tapers, with more patients being corticosteroid-free long-term.[28] Sight loss can progress despite glucocorticoid therapy in nearly 10% of patients. (A1)
Large Vessel Involvement
Patients with GCA demonstrating active extracranial large vessel involvement may require more prolonged and intense treatment. The ACR recommends a combination of glucocorticoids and steroid-sparing immunosuppressive therapy in these cases. The ACR discourages corticosteroid monotherapy for patients with large vessel involvement.[20]
Additional Recommendations
Although robust clinical data supporting this recommendation are lacking, the current ACR guidelines recommend adding methotrexate or tocilizumab to glucocorticoid therapy in patients with GCA who develop new, persistent, or worsening extracranial signs and symptoms. Current clinical guidelines report insufficient evidence to recommend other oral immunosuppressive agents such as azathioprine, leflunomide, or mycophenolate mofetil for managing GCA.[5]
Patients with GCA and evidence of critical or flow-limiting involvement of the vertebral or carotid arteries should also receive low-dose aspirin.[20] Low-dose aspirin reduces the incidence of vision loss and stroke associated with GCA and is an adjuvant therapy if no contraindications exist.[29] The efficacy of aspirin in patients without vertebral or carotid narrowing remains unclear and is not endorsed by the ACR.[20]
Management of Relapses
Relapses occur in nearly 50% of patients affected by GCA. Patients who experience disease relapse while receiving glucocorticoids of moderate to high dosage should receive additional therapy with tocilizumab or methotrexate instead of increasing the dose of glucocorticoids. Tocilizumab is the agent of choice, with methotrexate reserved for those who cannot receive tocilizumab due to prohibitive factors.[20]
For patients who experience disease relapse with evidence of cranial ischemia while on glucocorticoid therapy, the ACR recommends adding a steroid-sparing immunosuppressive agent and increasing the dose of glucocorticoid therapy. In contrast, patients experiencing relapses with symptoms of polymyalgia rheumatica are treated by increasing the dose of glucocorticoids alone.[20]
Other Recommendations and Considerations
Hydroxymethylglutaryl-coenzyme A reductase inhibitor or statin therapy in patients with GCA has not been associated with corticosteroid dose reduction or change in the disease course.[30] Therefore, the ACR recommends against the use of statins for the treatment of GCA.[20] However, Statins may be used in conjunction with GCA treatment if patients have other indications for their use. (B2)
Other agents, including tumor necrosis factor inhibitors, antimalarial medications, and cytotoxic agents, have not shown efficacy in treating GCA.[20]
Symptoms consistent with polymyalgia rheumatica are the most frequent presentation associated with a relapse of GCA. Headache and other cranial manifestations are observed less frequently during relapse. Recognizing the frequent overlap of GCA and polymyalgia rheumatica, the 2015 guidelines for managing polymyalgia rheumatica recommend re-evaluating the diagnosis, including vascular imaging of large arteries, to exclude GCA in patients with an inadequate response to standard polymyalgia rheumatica treatment.[9]
GCA Classification Criteria
The ACR developed the first diagnostic criteria for temporal arteritis in 1990.[31] According to these criteria, the diagnosis of GCA is supported by the presence of 3 or more of the following parameters:
- Being 50 or older during the onset of symptoms.
- New headache.
- Tenderness or decreased pulsation of the temporal artery.
- ESR ≥50 mm/h.
- A temporal artery biopsy reveals vasculitis, characterized by a predominance of mononuclear cell infiltration, granulomatous inflammation, or multinucleated giant cells.
Relying solely on these criteria results in the misdiagnosis of patients with isolated large vessel involvement or those presenting with primarily constitutional symptoms and a negative temporal artery biopsy or examination. To improve the sensitivity and specificity of the diagnostic criteria, the ACR and the European Alliance of Associations for Rheumatology (EULAR) published revised classification criteria to aid in diagnosing GCA. The updated diagnostic criteria provide weighted significance to symptoms, laboratory test results, and radiographic findings. Being older than 50 at the time of diagnosis is an absolute requirement.[32][33]
See Table 1 for additional information regarding the ACR/EULAR weighted classification criteria for GCA.
The ACR/EULAR criteria do not outline specific histopathologic criteria for vasculitis. The presence of giant cells, mononuclear lymphocyte infiltration, and fragmentation of the internal elastic lamina are strongly associated with a histopathologic interpretation of definitive vasculitis. A score of 6 or higher establishes the diagnosis of GCA.[32][33]
Table1. American College of Rheumatology/European Alliance of Associations for Rheumatology Classification Criteria for Giant Cell Arteritis
Symptoms, Laboratory Test Results, or Radiographic Findings | Points Awarded | Patient Points |
Morning stiffness in the shoulders and neck | 2 | |
Jaw or tongue claudication | 2 | |
New temporal headache | 2 | |
Scalp tenderness | 2 | |
Absent or diminished pulse, tenderness, or cord-like appearance of the temporal artery | 2 | |
Bilateral axillary involvement, defined as angiographic imaging or ultrasonography showing a halo sign or luminal damage such as occlusion, stenosis, or aneurysm, or increased uptake on PET in the axillary region | 2 | |
Positive FDG-PET activity throughout the aorta, defined as increased uptake in the arterial wall greater than the uptake in the liver | 2 | |
ESR ≥50 mm/h or CRP ≥10 mg/L prior to the initiation of treatment | 3 | |
Sudden vision loss | 3 | |
A positive temporal artery biopsy or halo sign on temporal artery ultrasound | 5 | |
Total |
Differential Diagnosis
The following list includes the differential diagnoses for GCA:
- Takayasu arteritis
- Microscopic polyangiitis
- Granulomatosis with polyangiitis
- Polyarteritis nodosa
- Primary angiitis of the central nervous system
- Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome
- Idiopathic aortitis
- Nonarteritic ischemic anterior optic neuropathy
- Infections such as endocarditis
Prognosis
GCA is a systemic disease of variable duration. Most patients taper and discontinue corticosteroids after a few years of treatment. Some may require long-term use of low-dose corticosteroids. GCA does not affect the overall survival rate of an individual except in patients with aortitis due to the risk of aortic dissection.[34]
The prognosis is poor for untreated individuals. Major mortality stems from myocardial infarction and stroke. The mortality rate secondary to these complications in patients with GCA is approximately 1% to 3%.[35]
The presence of a strong inflammatory response at the time of presentation is a risk factor for a protracted treatment course and a high relapse rate. Symptoms such as fever, weight loss, ESR ≥85 mm/h, and hemoglobin ≤11 g/dL indicate a strong inflammatory response.[5]
Patients with extracranial large vessel involvement may require prolonged glucocorticoid treatment and experience increased mortality and risk of relapse.[5] Large vessel involvement also increases the risk of aortic aneurysms, with a risk of 14% within 4 years compared to 5% in patients with symptoms localized to cranial arteries. In general, the risk of aortic aneurysm in patients with GCA is 2 times higher compared to that in age-matched controls.[36]
Complications
The following is a list of potential complications related to GCA.
- Vision loss
- Aortic aneurysm and dissection
- Stroke
- Tongue necrosis
- Adverse effects of glucocorticoids
- Cataract formation
- Fragility fractures
- Infection
- Hypertension
- Adrenal insufficiency
- Diabetes
- Osteoporosis
- Osteonecrosis
- Weight gain [7]
- Adverse effects associated with tocilizumab
- Opportunistic infection
- Neutropenia
- Elevated transaminase levels
- Hyperlipidemia
- Diverticulitis
- Gastrointestinal perforation
Patients with GCA have a higher risk for comorbid coronary artery disease, myocardial infarction, and cerebrovascular disease with cranial ischemia. Patients with GCA are 4 times more likely to have a myocardial infarction and 2.5 times more likely to experience a cerebrovascular accident compared to age-matched controls.[37]
Deterrence and Patient Education
Patient education is crucial in the comprehensive treatment approach for individuals with GCA. Focusing on strategies that help mitigate complications associated with high-dose glucocorticoid therapy is imperative. The average duration of glucocorticoid therapy in patients with GCA spans approximately 2 to 3 years, during which adverse effects may affect nearly 90% of individuals. Weight gain, cataract formation, osteopenia, osteoporosis, fragility fractures, glucose intolerance or diabetes, and adrenal insufficiency are among the commonly observed complications. Clinicians must evaluate the risk of these complications and implement measures to reduce their occurrence.
For individuals at the highest risk of complications, a combination of glucocorticoid and glucocorticoid-sparing therapy is essential to reduce cumulative glucocorticoid exposure. Tools such as the Fracture Risk Assessment Tool aid in evaluating osteoporosis risk in patients on high-dose glucocorticoid therapy. Lifestyle interventions, including weight-bearing exercise, strength training, smoking cessation, and sufficient dietary calcium intake, are necessary. Calcium and vitamin D supplementation should be provided when appropriate, with regular monitoring of bone mineral density and initiation of bisphosphonate therapy when indicated.
Monitoring for glucose intolerance through blood glucose checks before initiating therapy and every 3 months is crucial. Clinicians should universally advise lifestyle adjustments, encompassing a balanced diet, regular exercise, and weight loss strategies. Slow tapering of corticosteroids is necessary to mitigate the risk of adrenal insufficiency.
Moreover, transient visual loss can serve as an early warning sign of permanent visual impairment, necessitating urgent attention in individuals suspected of having polymyalgia rheumatica or GCA. Raising awareness regarding these aspects empowers patients to participate in their care actively and promotes optimal outcomes.
Enhancing Healthcare Team Outcomes
GCA is a chronic inflammatory vasculitis affecting large- and medium-sized arteries, primarily encountered in individuals older than 50. The disease commonly involves the cranial branches of the carotid arteries, leading to the frequent use of a superficial temporal artery biopsy for confirmation. Characterized by granulomatous vasculitis, GCA presents a spectrum of manifestations, ranging from cranial vessel involvement and ischemia to large vessel involvement with nonspecific symptoms, necessitating large vessel imaging for diagnosis.
Vision loss, a severe complication, underscores the importance of recognizing GCA and initiating high-dose systemic glucocorticoids in a timely manner. In addition, healthcare professionals must recognize the potential adverse effects of glucocorticoids and provide combination therapy with an IL-6 receptor antagonist or methotrexate to create a steroid-sparing effect for those at highest risk of adverse effects. Considerations in large vessel involvement include antiplatelet therapy and potential surgical interventions. Management considerations extend to patients with threatened or established visual loss, large vessel involvement, and relapses.
Diagnostic evaluation involves laboratory testing and imaging, with marked elevation in acute phase reactants. Traditional approaches such as temporal artery biopsy and CDUS are used, with ultrasonography providing a noninvasive alternative. Large vessel involvement may require FDG-PET, MRI, MRA, CT, or CTA imaging. The ACR recommends a comprehensive approach, considering individual patient characteristics and tailoring treatment strategies. Healthcare professionals, including physicians, advanced care practitioners, pharmacists, nurses, physical therapists, and ophthalmologists, should establish a system that promotes interprofessional communication, fostering collaborative decision-making. Care coordination is crucial for ensuring prompt and effective management, reducing errors, and enhancing patient safety. Incorporating these principles of expertise, strategic planning, clearly defined responsibilities, interprofessional communication, and care coordination enables healthcare professionals to provide patient-centered care, leading to improved patient outcomes and enhanced team performance in the management of giant cell arteritis.
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