History of Giant Cell Arteritis

Giant cell arteritis (GCA), also known as temporal arteritis, is a granulomatous vasculitis that mostly affects large- and medium-sized arteries, particularly the branches of the proximal aorta. In adults, giant cell arteritis is the most frequent kind of vasculitis, especially in Western countries.1 In 1890, Sir Jonathan Hutchinson documented a case of painful, inflamed temporal arteries that made it impossible for a man to wear his hat.2

Later research discovered that GCA is associated with a wide range of symptoms and signs, including tenderness in the temporal area, fever, malaise, headache, vision difficulties, and elevated levels of inflammatory markers.3 In 1932, Bayard T. Horton, MD, and colleagues characterized giant cell arteritis as a unique entity. In 2012, giant cell arteritis was categorized as a large vessel vasculitis by the Revised Chapel Hill Consensus Conference nomenclature,4 encouraging the adoption of the equivalent term, large vessel GCA.2

The American College of Rheumatology developed classification criteria for giant cell arteritis in 1990, which are listed below.5 With a sensitivity of 93.5% and a specificity of 91.2%, the presence of 3 or more of the 5 criteria is regarded as sufficient to make a clinical diagnosis of giant cell arteritis.5

  1. Age at disease onset: development of symptoms or findings beginning at age 50 or older
  2. New headache: new onset of or a new type of localized pain in the head
  3. Temporal artery abnormality: temporal artery tenderness to palpation or decreased pulse, unrelated to arteriosclerosis of cervical arteries
  4. ESR: ESR ≥50 mm/h by the Westergren method
  5. Abnormality on artery biopsy: biopsy specimen with artery showing vasculitis characterized by a predominance of mononuclear cell infiltration or granulomatous inflammation, usually with multinucleated giant cells

Epidemiology

Giant cell arteritis is the most frequent systemic vasculitis involving large and medium vessels, with advanced age being the most significant risk factor. Although the incidence of GCA steadily increases after age 50, it peaks between the ages of 70 and 79,6 and it rarely affects younger people.3 Women are 2.5 times more likely than men to develop giant cell arteritis, with a lifetime risk of 1% for women and 0.5% for men.6,7

The estimated incidence of giant cell arteritis is approximately 20 per 100,000 population per year, and the condition is more prevalent in North American and Western European populations.8 A population-based study in Ontario, Canada, found a reasonably consistent incidence of 25 new cases per 100,000 persons aged 9 to 50 years.9

Another study investigating time trends in the incidence and survival of GCA over a 50-year period in Olmsted County, Minnesota, found the age- and sex-adjusted annual incidence rate of giant cell arteritis was 18.8 (95% CI, 15.9-21.6) per 100,000 persons aged 50 years and older.10 In addition, the overall incidence rate in women was double that in men, and age-specific rates were higher in women of all age groups. 

People of Scandinavian heritage have the highest frequency, specifically in Norway, where the mean annual incidence was 32.8 per 100,000 inhabitants older than age 50 and 29 per 100,000 for biopsy-proven GCA.11 Southern European countries and the Mediterranean region have recorded a substantially lower annual occurrence of giant cell arteritis.6

Etiology and Risk Factors

The main clinical risk factor for GCA is age-related predisposition. This could be linked to concurrent aging of the immune system and the blood vessel wall, where dendritic cells are generally found.12 Other risk factors for giant cell arteritis are smoking history and increased diastolic blood pressure.6

Some unknown triggers cause abnormal maturation of vascular dendritic cells in the adventitia of large vessel walls. Cluster differentiation (CD) 4+ naive T lymphocytes are recruited and activated by these activated dendritic cells. Naive CD4+ cells are activated and differentiate to T helper (Th) 1 cells, Th17 cells, and T regulatory (Treg) cells.13

Macrophages also secrete metalloproteinases within the tunica media, which damages the internal elastic lamina and other connective tissues. Reactive oxygen species and released interleukin (IL)-6 by macrophages cause inflammation and local vascular injury. Intimal hyperplasia and subsequent vascular stenosis and occlusion are caused by vascular injury and macrophage-derived growth factors. Damaged artery cells respond to the injury leading to a defective repair, which in turn leads to media thickening, luminal blockage, ischemia, and ultimately end-organ damage.13

According to genome-wide association studies, HLA genes, such as HLA Br1*04 in the White population, are linked to GCA and increased risk of complications, including loss of vision and increased resistance to glucocorticoids. PTPN22, LRRC32, IL17A, and IL33 are examples of non-HLA genes linked to giant cell arteritis. The majority of the genes discovered are related to endothelial function, innate immunity, and cytokines and their receptors.7

Giant Cell Arteritis Prognosis

Since the introduction of corticosteroids for giant cell arteritis, long-term outcomes and survival rates have been comparable to age-matched populations, even those with large vessel complications. The predicted mortality rate associated with GCA prior to the use of corticosteroids was 12.5%.2

The intensity of symptoms at the time of onset, as well as the speed with which steroids are started, contribute to the visual prognosis. The risk of vision loss is increased in cases of advanced age, thrombocytosis, and anemia. The primary aim of treatment is to keep the unaffected eye from losing vision, and administration of steroid injections helps to reduce contralateral involvement.

Overall, giant cell arteritis is thought to be a self-limiting condition, with morbidity linked to both disease-related systemic problems and toxicity due to the use of corticosteroids.12

Giant Cell Arteritis Diagnosis & Presentation

Giant cell arteritis is best described as an inflammatory vascular condition characterized by cranial and/or large vessel vasculitis, systemic inflammation, and polymyalgia rheumatica, all of which commonly overlap.14

Acute headaches; scalp pain; jaw, tongue, or limb claudication; and vision impairments are the most frequent local symptoms.

Anterior ischemic optic neuropathy, oculomotor cranial nerve palsy/palsies, central retinal artery occlusion, branch retinal artery occlusion, and/or choroidal ischemia are all pathologic findings on ophthalmologic examination.15

Diagnosing giant cell arteritis can be challenging. Duplex ultrasonography is a valuable diagnostic tool that can be used in clinics. The gold standard test for the diagnosis of GCA is temporal artery biopsy (TAB) depicting definitive pathologic diagnosis.

Physical Examination Findings

Findings frequently encountered on physical examination of patients with giant cell arteritis include headache, tenderness of the scalp, elevated ESR and/or C-reactive protein (CRP) levels, and anemia. Patients also often present with polymyalgia rheumatica.

Common findings on presentation include ocular symptoms, claudication of the jaw, malaise, weight loss, and anorexia (Figure 1). GCA is less frequently associated with cerebrovascular accident, myocardial infarction, limb claudication, or high fever.7

Diagnostic Workup

Since 1990, the most common method for detecting giant cell arteritis has been to meet 3 or more of 5 criteria developed by the ACR:

  1. Age of onset ≥50 years
  2. New onset of localized headache
  3. Temporal artery tenderness or reduced pulse
  4. Elevated ESR by 50 mm/h
  5. Temporal artery biopsy showing the presence of predominant mononuclear cell infiltrates or granulomatous inflammation with multinucleated giant cells.5

Laboratory Testing

Elevated ESR, plasma viscosity, and/or CRP are signs of the acute-phase response in giant cell arteritis. As plasma viscosity is unaffected by age, gender, time to analyze, or hematocrit, it is regarded as being superior to ESR if it is available. Thrombocytosis, normocytic normochromic anemia, and normal or mildly increased white blood cell count may be predictive of GCA. Liver function tests often show increased transaminase and alkaline phosphatase levels in the setting of GCA.7,13

The diagnostic gold standard for GCA, TAB must be obtained from the most symptomatic site.16 TAB offers the advantage of assisting in the precise differentiation of giant cell arteritis from other disorders such as amyloidosis or anti-neutrophil cytoplasmic antibody

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. Furthermore, different histologic aspects of TAB have been linked to various clinical presentations of giant cell arteritis, implying that this diagnostic approach may have predictive relevance. A transmural inflammatory infiltration with substantial disruption of the internal elastic lamina along with the presence of giant cells is the characteristic histopathologic appearance of GCA.16

The specificity of TAB for giant cell arteritis diagnosis is up to 100%, but sensitivity can be as low as 39%. This is primarily due to poor sampling on biopsy, limited access to the procedure, the segmented nature of the pathologic findings (“skip lesions”), and the presence of large vessel GCA, which is associated with less temporal arterial involvement of the disease.16

Imaging Studies

Vascular Ultrasound

Vascular ultrasound of superficial temporal and axillary arteries should be performed according to current guidelines. Sensitivity for a diagnosis was found to be higher for ultrasound than biopsy (54% vs 39%), but specificity was lower for ultrasound (81% vs 100%). Despite the fact that ultrasonography is a cost-effective and risk-free technology, its use has been hampered by inconsistent diagnostic performance across studies and a lack of interoperator reliability.17,18

Magnetic resonance imaging/angiography (MRI/MRA)

In cases of giant cell arteritis with noncranial presentation, MRA can be used to check for large vessel vasculitis. Imaging can identify both luminal (aneurysm or stenosis) and wall abnormalities (thickening, contrast enhancement). Cranial arterial wall thickening may also be visualized with the use of contrast-enhanced, high-resolution MRI.1

Computed tomographic angiography (CTA)

Large vessels in patients with GCA are examined using CTA not just to identify any concurrent aortitis but also for diagnosis of patients who do not have the usual cranial giant cell arteritis signs and symptoms. Because of the high prevalence of large vessel involvement, imaging of the thoracic aorta has been incorporated into giant cell arteritis treatment guidelines.3

Positron emission tomography (PET)

Fluorodeoxyglucose (FDG) PET/CT can detect large vessel involvement before or after a diagnosis of giant cell arteritis and is particularly useful when there is the possibility of an isolated extracranial form of the disease.1 PET could be used as a predictive biomarker in giant cell arteritis as recent study findings indicate that a positive PET scan in patients in clinical remission could predict future disease flare; however, some patients with a high atherosclerosis load had false-positive results.17

Fluorescein funduscopic angiography (FFA) and optical coherence tomographic angiography (OCT-A)

When TAB is negative or inconclusive, FFA might be used as a supplementary tool to evaluate individuals with vision loss and a history of giant cell arteritis. The common findings of choroidal filling abnormalities might assist in differentiating between arteritic and nonarteritic ischemic optic neuropathy and determine a vascular etiology for transitory visual impairment. The role of OCT-A in the evaluation of giant cell arteritis has yet to be determined.17

Table 1. Clinical Manifestations of GCA8

General symptoms1. Low-grade fever, fatigue, weight loss, anorexia
2. General symptoms may be the only early manifestation
Headache1. New onset: temporal but can be occipital or frontal
2. Scalp tenderness
3. Usually nonspecific and other causes should be ruled out
Jaw claudication1. Trismus or severe pain and fatigue on increased use of the jaw that occurs immediately on movement
Transient vision loss1.Amaurosis fugax: abrupt, early, partial field defect or monocular loss
2. May foreshadow permanent vision loss
Permanent vision loss1. Most alarming and debilitating GCA consequence
2. Onset is sudden and painless
3. May be unilateral or bilateral in nature
4. Blindness can occur in 15%-20% of patients despite treatment and is usually irreversible
5. If left untreated, the unaffected eye will lose 25%-50% of its vision
6. Earlier transient vision loss is the strongest risk factor followed by age, hypertension, thrombocytosis, diplopia, and visual hallucinations
Causes of vision loss1. Anterior ischemic optic neuropathy is seen in 80% of patients with GCA and loss of vision
2. Central retinal artery occlusion (10%)
3. Posterior ischemic optic neuropathy (<5%)
4. Cerebral ischemia
Musculoskeletal symptoms1. Peripheral synovitis
2. Distal extremity swelling with pitting edema
Upper respiratory symptoms1. Present in approximately 10% of patients with GCA
2. Nonproductive cough

Management of Giant Cell Arteritis

  • Patients with large vessel vasculitis should be given the best therapy possible, which should be based on shared decision-making among the patient and the rheumatologist and considering efficacy, safety, and cost.
  • Acute treatment of complicated giant cell arteritis may necessitate admission to the hospital.3
  • Historically, high-dose glucocorticoids were the sole successful treatment; however, they are associated with large cumulative morbidity.
  • Biologic treatments hold promise for reducing or replacing treatment with glucocorticoids.19
  • Tocilizumab is the first drug to show a higher remission rate in both new and relapsed cases, as well as the need for lower glucocorticoid dosages overall.

GCA is a medical emergency and as such should be treated as soon as the diagnosis is suspected because it can lead to blindness. Care for giant cell arteritis focuses on protecting vision, limiting end-organ damage, and reducing toxicity and morbidity due to treatment with glucocorticoids.9

Nonpharmacologic

Dietary or lifestyle adjustments have not been found to reduce the risk of giant cell arteritis complications. Patients on corticosteroids should be encouraged to exercise and limit their salt intake to minimize weight gain and fluid retention associated with the class of medication. Weight-bearing exercise, bone density monitoring, and vitamin D and calcium supplementation may help to prevent osteoporosis and fracture.6

Pharmacologic

Main therapy

  • Glucocorticoids
  • Corticosteroid-sparing immunosuppressants
    Methotrexate
    — Leflunomide
    — Cyclosporine
    — Azathioprine
    — Cyclophosphamide
    — Mycophenolate mofetil
    — Hydroxychloroquine
    — Dapsone

Alternative therapies

  • Tocilizumab: anti-interleukin-6 (anti-IL-6) receptor blocker
  • Abatacept: CTLA-4 inhibitor, anti-T-cell therapy
  • Ustekinumab: IL-12/23 inhibitor
  • Infliximab, adalimumab, and etanercept: anti-tumor necrosis factor (TNF) therapy
  • Anakinra: anti-IL-1 therapy
  • Tofacitinib and baricitinib: Janus kinase (JAK) inhibitors
  • Gevokizumab: anti-IL-1β monoclonal antibody
  • Secukinumab: anti-IL-17A monoclonal antibody
  • Aspirin

Glucocorticoids
Historically, high-dose glucocorticoids have been the cornerstone of giant cell arteritis treatment, with the goal of induction and maintenance of remission, or the absence of disease activity. When a patient has imaging findings highly suggestive of giant cell arteritis and a positive temporal artery biopsy, steroids are often given with greater confidence.8 Glucocorticoids are administered on a daily basis. Alternative treatments are given for patients at high risk for complications associated with daily steroid treatment, such as those with diabetes or chronic infections.

Although the ideal starting dose of glucocorticoids has yet to be determined, the usual approach is to begin with a daily dose comparable to 1 mg/kg of prednisone up to a maximum dosage of 60 mg/d.8 The minimum effective dose of corticosteroids should be maintained, and weaning should be done gradually and adjusted according to the individual patient. Patients who have just started treatment should be closely monitored for the first month and then every 3 months for the first year, with serial tests of blood count, ESR, CRP, electrolytes, and glucose.12

Follow-up for large vessel complications should be performed for at least 2 years using chest radiography, echocardiography, MRI, or PET. A corticosteroid-sparing immunosuppressant such as cyclosporine, azathioprine, or methotrexate may be administered in individuals with steroid-resistant illness, although the efficacy of such treatment is unknown.12

Corticosteroid-sparing immunosuppressants
Methotrexate has been used to treat refractory giant cell arteritis as a steroid-sparing drug. Presently, the European League against Rheumatism (EULAR) advises that every patient with giant cell arteritis be considered for methotrexate treatment.17 In 1 open-label, single-center study, 76 patients were administered leflunomide after 12 weeks of treatment with glucocorticoids.

Relapses were lower (13.3%) in patients receiving leflunomide compared with those who received only glucocorticoids (39.1%) after a 48-week follow-up period.20 Azathioprine, mycophenolate mofetil, cyclophosphamide, hydroxychloroquine, dapsone, and cyclosporine have only low-quality and/or negative evidence, and use of these agents for giant cell arteritis is not recommended.15

Tocilizumab. Tocilizumab is a humanized recombinant anti-IL-6 receptor antibody that inhibits the binding of IL-6 to membrane-bound and soluble IL-6 receptors in a competitive manner. IL-6 supports the shift from acute to chronic inflammation and stimulates the release of CRP from hepatocytes. Its excessive production adds to giant cell arteritis pathogenesis. Drugs that block IL-6 should be able to stop the inflammatory cascade.13

The US Food and Drug Administration (FDA) approved tocilizumab in May 2017 for the treatment of individuals with giant cell arteritis, and the European Commission approved it in September 2017, making it the first drug specifically approved for the treatment of giant cell arteritis.8

Abatacept. Abatacept is a CTLA-4 immunoglobulin that works as a negative regulator of T-cell costimulation. In a study conducted by Langford et al, patients with newly diagnosed or relapsed giant cell arteritis who were administered abatacept had a relapse-free survival rate of 48% vs 31% in those receiving placebo (P =.049). The treatment group also had a longer median duration of remission (9.9 months vs 3.9 months; P =.023). No difference in side effect frequency or severity was reported between the treatment and placebo groups.21,22

Ustekinumab. Ustekinumab is a human IL12-23 inhibitor that is approved for the treatment of plaque and psoriatic arthritis, as well as ulcerative colitis. Although ustekinumab has been examined as a potential glucocorticoid-sparing drug in giant cell arteritis, study findings have been inconsistent. A small, prospective, open-label study of ustekinumab in patients with new-onset or relapsing giant cell arteritis was discontinued prematurely due to a high rate of treatment failure.22,23

Infliximab, adalimumab, and etanercept. TNF-α was discovered in temporal artery biopsies of patients with GCA, and treatment with TNF inhibitors has been found to be beneficial for inflammatory conditions.22,24 However, anti-TNF agents were not shown to be useful in achieving remission in patients with giant cell arteritis.1 Infliximab, adalimumab, and etanercept failed to show efficacy in terms of glucocorticoid-sparing effect, disease activity, glucocorticoid withdrawal or lowering of cumulative glucocorticoid dosages, or side effects for patients with GCA.20

Anakinra. Anakinra, an anti-IL-1 agent, was shown to be more effective than standard therapies in a study that assessed 3 patients with refractory GCA.25 A recent study that included 6 patients with GCA reported clinical remission of disease and corticosteroid sparing with anakinra.26 The GiAnT trial is an ongoing phase 3 trial that will compare the effects of subcutaneous prednisolone plus anakinra 100 mg/d with prednisolone plus placebo in 70 patients with GCA; results are expected in early 2022.13

Tofacitinib and baracitinib. In a model of vascular inflammation in immunodeficient mice reconstituted with T cells and monocytes from patients with GCA, the JAK/STAT inhibitor tofacitinib, a kinase inhibitor of JAK1 and JAK3, inhibited T-cell accumulation in vessel walls and decreased interferon-γ (IFN-γ) production and signaling.27

Baricitinib is an orally bioavailable JAK1 and JAK2 inhibitor that suppresses both the Th17 (IL-6, IL23) and Th1 (IL-12, IFN-γ) pathways.1 According to research presented at EULAR 2021, baricitinib was found to decrease disease activity and exert a steroid-sparing effect in patients with GCA.28

Gevokizumab. Gevokizumab is a recombinant humanized anti-IL-1β antibody that was investigated as a potential treatment for GCA. A randomized controlled trial was initiated but subsequently terminated by the study sponsor.29

Secukinumab. Secukinumab, an IL-17A monoclonal antibody, has been associated with symptom improvement in patients with plaque psoriasis, psoriatic arthritis, and axial spondyloarthritis. According to the results of a phase 2 study presented at ACR. Convergence 2021, treatment with secukinumab resulted in a higher sustained remission rate vs placebo in patients with GCA.30

Aspirin. Although low-dose aspirin has been linked to a lower rate of loss of vision and strokes in patients with GCA and has been used as adjuvant therapy, benefits of treatment should be weighed against bleeding risk, particularly when administered in conjunction with corticosteroids.31,32

Monitoring for Giant Cell Arteritis Side Effects

Approximately 6% of patients who undergo treatment with steroid medication experience significant neuropsychiatric side effects such as mania, depression, mood lability, agitation, anxiety, insomnia, catatonia, delirium, depersonalization, psychosis, and dementia.33 These effects occur in a dose-dependent manner, with a rapidly increasing incidence once the steroid dosage reaches 40 mg/d.

Cushingoid appearance, weight gain, and skin atrophy are other adverse effects. Diabetes, glaucoma, and osteoporosis are some of the comorbidities that steroid therapy can aggravate.13 Gastrointestinal upset, mouth ulcers, temporary hair loss, increased liver enzymes, leukopenia, and teratogenicity are the most prevalent adverse effects of methotrexate. The most common adverse effects of leflunomide are hypertension, diarrhea, elevated liver enzymes, and leukopenia.13

Gastrointestinal side effects and the risk of cerebral hemorrhage with concomitant aspirin use may be exacerbated if prescribed with glucocorticoids.32 Tocilizumab has been associated with increased risk of perforation in patients with GCA and diverticulitis, particularly if coadministered with nonsteroidal anti-inflammatory drugs (NSAIDs), glucocorticoids, or methotrexate.13

Giant Cell Arteritis Comorbidities

Patients with GCA are at increased risk of myocardial infarction, with a 4-fold higher risk than age-matched controls.7,34 Cerebrovascular accidents are usually a later occurrence, and patients with GCA have a 2.5-fold increased risk of stroke vs those without GCA.7,34 Other vascular disorders, such as aneurysms and dissections, are also 2.5-times more likely to occur in patients with GCA vs those without.7

Giant Cell Arteritis Complications

Irreversible loss of vision is a potential complication for patients with GCA.8 Almost one-half of patients undergoing long-term use of corticosteroids experience negative side effects. Aortic dissection, aortic aneurysm, and large artery stenosis are all possible sequelae of large vessel involvement.7 Complications of GCA that might be fatal — including acute dissection, aortic rupture, and congestive heart failure — may present years after initial diagnosis.12

Patient Education

GCA is a systemic chronic disease. Close coordination among the patient’s primary care provider, rheumatologist, ophthalmologist, and neurologist is required for optimal management of the disease. Numerous side effects of the disease are linked with long-term use of corticosteroids and must be treated as soon as possible.

Careful observation with laboratory and clinical examinations can help manage GCA and its relapses, as well as prevent treatment-related complications. Information, networking opportunities, and support for patients with GCA and their caregivers are available from the following organizations:

  • Vasculitis Foundation
  • Arthritis Foundation
  • American College of Rheumatoloty
  • John Hopkins Vasculitis Center
  • National Organization of Rare Diseases

FAQs

What is giant cell arteritis?

Giant cell arteritis (GCA), also known as temporal arteritis, is a granulomatous vasculitis that mostly affects large- and medium-sized arteries, particularly the branches of the proximal aorta. In adults, GCA is the most frequent kind of vasculitis, especially in Western countries.

What are the symptoms of giant cell arteritis?

The most typical symptom of GCA is a new headache, which commonly occurs around the temples but can occur anywhere in the skull. Other common symptoms include unexplained fever, weight loss, fatigue, jaw pain, or flu-like symptoms. Eyesight can be compromised if GCA extends to the blood supply of the eye. Temporary blurring of vision, double vision, or blindness are all symptoms of vision problems experienced with GCA. Permanent visual loss in GCA can develop quickly; however, with proper diagnosis and treatment, this outcome can be avoided.

How is giant cell arteritis diagnosed?

The most common way to detect GCA has been to meet 3 or more of the 5 criteria developed by the American College of Rheumatology (ACR). These criteria are: (1) age of onset ≥50 years; (2) new onset of localized headache; (3) temporal artery tenderness or reduced pulse; (4) elevated erythrocyte sedimentation rate (ESR) by 50 mm/h, and (5) temporal artery biopsy showing the presence of predominant mononuclear cell infiltrates or granulomatous inflammation with multinucleated giant cells.

How is giant cell arteritis treated?

High-dose glucocorticoids historically have been the sole successful treatment; however, they are associated with large cumulative morbidity. Biologic treatments hold promise for reducing or replacing glucocorticoids. Tocilizumab is the first drug to show a higher remission rate in both new and relapsed cases, as well as the need for lower dosages of glucocorticoids overall.

References

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