Giant Cell Arteritis

Giant cell arteritis (GCA), also known as temporal arteritis, is a type of large-vessel vasculitis that predominantly affects the aorta and its major branches, with a predilection for the branches of the carotid (including the temporal artery). Giant cell arteritis is defined by inflammatory leukocytes in the vessel walls leading to reactive damage, ischemia, and necrosis. Giant cell arteritis causes headaches, scalp tenderness, jaw pain, vision problems, and potentially blindness. The diagnosis is made with temporal artery biopsy. Prompt treatment with glucocorticoids can relieve symptoms and prevent vision loss.

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Overview

Epidemiology

  • Most common idiopathic systemic vasculitis
  • Age is the greatest risk factor:
    • Generally affects individuals older than 50 years
    • Increased incidence in the 8th and 9th decades of life
  • 3 times more common in women
  • Northern European and Scandinavian ancestry
  • Lower body mass index (BMI) is associated with a higher risk.

Etiology

  • Exact cause is unknown.
  • Genetic factors may increase susceptibility:
    • Genetic variants in the major histocompatibility complex (MHC)
    • Human leukocyte antigen (HLA) subtypes
    • Genes involved in T cells
  • 45%–50% have concurrent polymyalgia rheumatica.

Pathophysiology

Giant cell arteritis (GCA) is caused by a complicated cascade of vascular inflammation, damage, and dysfunctional repair:

  • Triggering event has not been identified.
  • Involves large- and medium-sized arteries:
    • Usually affecting the aorta and its major branches
    • Common involvement of branches off the carotid and vertebral arteries
  • Most notably involves the superficial temporal artery (STA; branch off the external carotid artery)
  • Mechanism:
    1. An antigen is sensed by dendritic cells in the adventitia → recruits more dendritic cells, lymphocytes, and macrophages.
    2. Dendritic cells process and present the antigens → cluster of differentiation 4 (CD4+) T cell activation.
    3. CD4+ T cells proliferate → vascular inflammation via activation of macrophages.
    4. Medial layer is invaded by inflammatory cells → macrophages undergo granulomatous organization (giant cells) → growth factors and metalloproteinases produced → loss of vascular smooth muscle cells and destruction of the internal elastic lamina.
    5. Injured smooth muscle cells respond to this damage → myofibroblasts differentiate, migrate toward the intimal layer, and produce extracellular matrix proteins → intimal hyperplasia and arterial occlusion → ischemic complications of the disease.
Superficial temporal artery

Branches of the STA, which may be involved in GCA

Image by BioDigital, edited by Lecturio.

Clinical Presentation

Clinical manifestations

  • Constitutional:
    • Fever 
    • Fatigue 
    • Malaise 
    • Weight loss 
    • Anorexia
  • Head and neck:
    • Headache:
      • Occurs in ⅔ of patients
      • Varying severity and quality
      • Localized to the temples and can be tender to the touch
      • Associated scalp tenderness
    • Jaw claudication:
      • Occurs in about ½ of patients
      • Mandibular pain or fatigue during mastication that is relieved with rest
  • Ophthalmic:
    • Transient vision loss (amaurosis fugax):
      • Results from loss of blood flow to the eye
      • Typically monocular  
      • Painless, transient, and intermittent
      • Blurring, diplopia, or vision loss
    • Permanent vision loss:
      • Most dreaded complication
      • Due to anterior or posterior ischemic optic neuropathy, central retinal artery occlusion, or cerebral ischemia 
      • Partial or complete vision loss that is painless and sudden
      • May affect 1 or both eyes
      • Rarely reversible
  • Musculoskeletal:
    • Polymyalgia rheumatica: 
      • Aching and morning stiffness in the proximal muscles and joints
      • Shoulders, hip girdles, neck, and torso affected

Physical exam

  • Cardiovascular:
    • Diminished pulses 
    • Temporal artery tenderness and enlargement
    • Discrepant blood pressure in arms → subclavian artery involvement
    • Bruits 
    • Aortic regurgitation heart murmur → suspect an ascending aortic aneurysm
  • Fundoscopy:
    • Can be entirely normal with transient symptoms
    • Cotton-wool spots in the retina → retinal ischemia
    • Swollen, pale disc and blurred margins of the retina → anterior ischemic optic neuropathy (loss of blood flow to the anterior portion of the optic nerve)
  • Musculoskeletal:
    • Limited shoulder, neck, and hip range of motion
    • Wrist and metacarpophalangeal synovitis
Acute central retinal artery occlusion

Fundoscopy of the right eye, showing cotton-wool spots along the superotemporal and inferotemporal arterioles (arrows). The cotton-wool spots denote obstruction of the retinal arterioles, leading to retinal ischemia.

Image: “Cotton-wool spots” by James Paget University Hospital NHS Foundation Trust, Lowestoft Road, Gorleston, Great Yarmouth NR31 6LA, Norfolk, UK. License: CC BY 2.0.

Diagnosis

Diagnostic algorithm

Temporal arteritis Diagnostic Algorithm

The above is a simple algorithm to help aid in the diagnosis of GCA. This outlines when this disease should be considered, and the basic steps in diagnosis.

Image by Lecturio.

Diagnostic modalities

  • 1st, check laboratory studies:
    • ESR and CRP:
      • Almost always elevated
      • Non-specific
    • Complete blood count:
      • Normochromic anemia
      • Reactive thrombocytosis
      • Normal or minimally elevated leukocytes
    • Liver function panel: 
      • Elevated alkaline phosphatase
      • Decreased albumin
  • Next steps:
    • Temporal artery biopsy (gold standard): 
      • Should be performed in all patients with suspected GCA
      • Lesions are segmental, so diagnosis requires a biopsy of a long vessel segment.
      • Histopathology findings:
        • Panarteritis
        • Giant cells
        • Fragmented internal elastic lamina
      • If negative, a contralateral temporal artery biopsy should be considered.
    • Color Doppler ultrasound:
      • Possible non-invasive alternative for temporal artery biopsy, but is operator dependent
      • Should evaluate the vessels of the head, neck, and upper extremities
      • “Halo sign” (darkened area surrounding the vascular lumen from mural edema) is highly specific.
  • If the above work-up is not diagnostic, consider evaluation for large-vessel involvement:
    • Color Doppler ultrasound of axillary and subclavian arteries
    • Computed tomography with angiography (CTA)
    • Magnetic resonance imaging (MRI) or magnetic resonance angiography (MRA)
    • Positron emission tomography (PET)
Temporal arteritis

Biopsy of temporal artery showing transmural mixed inflammatory cell infiltrates with intimal thickening, fragmentation, and distortion of the internal elastic lamina

Image: “Biopsy of temporal artery” by the Department of Pathology and Laboratory Medicine, University of Florida, College of Medicine, Jacksonville, FL, USA. License: CC BY 2.0.

Management

Treatment options

  • High-dose systemic glucocorticoids:
    • Mainstay of treatment, and should be initiated promptly if there is a strong suspicion of GCA
    • Without vision loss: prednisone
    • With vision loss: methylprednisolone
    • Tapered slowly over 612 months
  • Adjunctive treatment: 
    • May be used when glucocorticoids are not tolerated
    • Tocilizumab
    • Methotrexate

General measures

  • Rheumatology consultation
  • Monthly routine follow-up:
    • Monitor symptoms and perform examination.
    • Can trend ESR and CRP
  • Tuberculosis screening
  • Immunizations for influenza and pneumococcal pneumonia
  • Antiplatelet therapy in patients with atherosclerosis: A proton pump inhibitor should be considered because aspirin use, glucocorticoids, and age will increase the risk for gastrointestinal bleeding.
  • Osteoporosis prevention with calcium and vitamin D
  • Monitor bone density.

Differential Diagnosis

  • Stroke: disease in which poor blood flow to the brain results in cell death. There are 2 types: ischemic stroke due to lack of blood flow, and hemorrhagic stroke due to bleeding. Symptoms include focal weakness, numbness, loss of vision, dysarthria, and headache. Computed tomography and MRI of the brain are used for the diagnosis, and will differentiate stroke from GCA.
  • Migraine: characterized by recurrent headaches that are moderate to severe, typically affecting ½ of the head, and pulsating in nature. Associated symptoms include nausea, vomiting, and sensitivity to light, sound, or smell. Diagnosis is clinical, based on the history and physical exam. Laboratory and imaging studies will be unremarkable. The history, physical exam, and low inflammatory markers will help differentiate migraine from GCA.
  • Glaucoma: An increase in intraocular pressure damages the optic nerve and causes blindness. Angle-closure glaucoma symptoms include blurred vision, halos around light, severe eye pain, headache, nausea, and vomiting. Diagnosis is made by an ophthalmology exam and intraocular pressure measurements, which will differentiate glaucoma from GCA.
  • Takayasu’s arteritis: a large-vessel, granulomatous vasculitis that primarily affects the aorta and its primary branches. Patients are often young or middle-aged women. Signs and symptoms include tenderness of the carotid artery, limb claudication, and absent or weak pulses. Elevated inflammatory markers and CTA of the aorta can aid in the diagnosis. Treatment includes glucocorticoids and glucocorticoid-sparing agents. The patient’s demographics, history, and exam findings will differentiate Takayasu’s arteritis from GCA. 
  • Non-arteritic anterior ischemic optic neuropathy: an idiopathic, ischemic injury to the optic nerve. Patients present with sudden, painless, and monocular vision loss. A fundoscopic exam will show optic disc swelling. Giant cell arteritis should be considered in these individuals, and can be ruled out with normal inflammatory markers. There is no known effective treatment, but patients are generally placed on aspirin.

References

  1. Docken, W.P., & Rosenbaum, J.T. (2019). Clinical manifestations of giant cell arteritis. In Ramirez Curtis, M. (Ed.), Uptodate. Retrieved October 25, 2020, from https://www.uptodate.com/contents/clinical-manifestations-of-giant-cell-arteritis
  2. Cid, M.C. (2020). Pathogenesis of giant cell arteritis. In Ramirez Curtis, M. (Ed.), Uptodate. Retrieved October 26, 2020, from https://www.uptodate.com/contents/pathogenesis-of-giant-cell-arteritis
  3. Docken, W.P. (2019). Diagnosis of giant cell arteritis. In Ramirez Curtis, M. (Ed.), Uptodate. Retrieved October 27, 2020, from https://www.uptodate.com/contents/diagnosis-of-giant-cell-arteritis
  4. Docken, W.P. (2020). Treatment of giant cell arteritis. In Ramirez Curtis, M. (Ed.), Uptodate. Retrieved October 27, 2020, from https://www.uptodate.com/contents/treatment-of-giant-cell-arteritis
  5. Seetharaman, M., Albertini, J.G., & Paget, S.A. (2020). Giant cell arteritis (temporal arteritis). In Diamond, H.S. (Ed.), Medscape. Retrieved October 26, 2020, from https://emedicine.medscape.com/article/332483-overview
  6. Kasper, D.L., Fauci, A.S., Longo, D.L., Bruanwald, E., Hauser, S.L., & Jameson, J.L. (2007). Harrison’s principles of internal medicine (16th edition.). New York: McGraw Hill Education.
  7. Al-Mousawi, A.Z., Gurney, S.P., Lorenzi, A.R. et al. (2019). Reviewing the pathophysiology behind the advances in the management of giant cell arteritis. Ophthalmology and Therapy 8, 177-193. Retrieved October 27, 2020 from https://link.springer.com/article/10.1007%2Fs40123-019-0171-0

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