What is the mechanism of action (MOA) of temporal arteritis or giant cell arteritis?

Mechanism of Action of Giant Cell Arteritis (Temporal Arteritis)

Giant cell arteritis (GCA) is an immune-mediated disease characterized by granulomatous inflammation of medium and large arteries, with a pathophysiology involving T-cell mediated responses, cytokine production, and macrophage activation leading to vessel wall damage and subsequent tissue ischemia. 1

Immunopathological Components

• GCA involves a two-component immunopathological process:

  • Systemic inflammation with excessive cytokine production (particularly interleukin-1 and interleukin-6) leading to an exuberant acute-phase response 1
  • T-cell mediated local inflammation in the arterial wall with release of interferon-gamma that activates tissue-injurious macrophages 1, 2

• The disease process begins with activation of T lymphocytes that recognize a putative antigen residing in the arterial wall 2

• These activated T cells subsequently trigger macrophage activation, leading to functional differentiation of macrophages that contribute to vessel damage through various pathways 2

Histopathological Features

• Characteristic findings include:
  • Arterial wall thickening with narrowed lumen 3
  • Presence of mononuclear inflammatory cells with invasion of the media layer 3
  • Multinucleated giant cells in the media (though not always present) 3
  • Granulomatous inflammation of the vessel wall 1

Vascular Response and Damage

• In response to immune injury, the artery generates hyperplasia of the intima that leads to luminal occlusion and subsequent tissue ischemia 1

• Vascular response to inflammation amplifies the inflammatory process through:

  • Neovascularization (formation of new blood vessels) 2
  • Increased expression of adhesion molecules 2

• Products released by infiltrating inflammatory cells play an important role in vessel occlusion and resulting ischemic complications 2

Clinical Manifestations Based on Vascular Territory

• Despite the systemic nature of GCA, distinct vascular territories are preferentially affected, leading to different clinical subtypes 1:
  • Cranial GCA with ischemic complications in the eye, face, and central nervous system 1
  • Large-vessel GCA with occlusions in the subclavian or axillary vessels 1
  • Aortic GCA 1
  • GCA presenting as intense systemic inflammatory syndrome with non-stenosing vasculitis 1
  • "Isolated" polymyalgia rheumatica with myalgias, systemic inflammation, and subclinical vasculitis 1

Respiratory Involvement

• Respiratory involvement occurs in <10% of GCA cases and may precede the diagnosis 3
• Chronic cough is the most frequent respiratory symptom, typically harsh and nonproductive 3
• The mechanism of cough in GCA is not fully understood but may be related to:
  • Isolated small airways disease 3
  • Lung nodules and interstitial infiltrates 3
  • Vasculitis of pulmonary arteries 3
  • Ill-defined granulomas within bronchial walls and alveolar interstitium 3

Diagnostic Markers

• Laboratory studies characteristically show marked elevations of acute-phase reactants:
  • Erythrocyte sedimentation rate (ESR) typically exceeds 40 mm/h, with values above 100 mm/h having high specificity (92.2%) 4, 1
  • C-reactive protein (CRP) is also elevated in most cases 4
  • Cytokines like interleukin-6 that induce the acute-phase reaction are being explored as more sensitive markers of disease activity 1

Treatment Response

• Corticosteroids are highly effective in suppressing systemic inflammation but do not completely eliminate the immune responses in the vessel wall 1
• Prednisone therapy dramatically diminishes symptoms of GCA, including resolution of respiratory manifestations like cough 3
• Tocilizumab has demonstrated efficacy in reducing glucocorticoid requirements and flare rates, suggesting its effectiveness in modulating the underlying immune mechanisms 3, 5

Pitfalls and Caveats

• Despite treatment, the underlying immune-mediated process may persist, requiring long-term monitoring even in patients with apparent remission 5
• The disease is heterogeneous in presentation and course, making early diagnosis challenging 6
• Without prompt treatment, GCA can lead to significant vascular and visual morbidity and may even be fatal 6