What is the pathophysiology of giant cell arteritis?

Pathophysiology of Giant Cell Arteritis

Giant cell arteritis (GCA) is a granulomatous vasculitis characterized by inflammation of medium and large arteries, involving a complex pathophysiological cascade that begins with dendritic cell activation in the vessel wall, followed by T-cell recruitment and macrophage activation, ultimately leading to vascular remodeling and potential ischemic complications. 1

Initiating Factors

• GCA affects individuals over 50 years of age with a genetic predisposition, though environmental triggers are often critical for disease onset 2
• The pathophysiological process begins with the activation of dendritic cells in the vessel wall, which serve as the initial immune sentinels 1, 3
• These activated dendritic cells produce chemokines that recruit CD4+ T lymphocytes to the arterial wall 1

Immune Cell Activation and Proliferation

• Recruited CD4+ T cells become activated, proliferate, and polarize primarily into:
  • Th1 cells that produce interferon-gamma (IFN-γ) 1, 3
  • Th17 cells that produce interleukin-17 (IL-17) 1, 3
• IFN-γ activates vascular smooth muscle cells, which produce additional chemokines that recruit more immune cells (CD4+ T cells, CD8+ T cells, and monocytes) 1
• Monocytes differentiate into macrophages in the vessel wall and, when persistently exposed to IFN-γ, can fuse to form multinucleated giant cells - the histological hallmark of GCA 3

Vascular Inflammation and Remodeling

• Histopathological hallmarks include:
  • Arterial wall thickening with narrowed lumen 4
  • Presence of mononuclear inflammatory cells with invasion of the media layer 4, 5
  • Multinucleated giant cells in the media (though not always present) 4, 5
  • Fragmentation of the internal elastic lamina 6
• Macrophages in the adventitia produce pro-inflammatory cytokines including IL-1, IL-6, and tumor necrosis factor alpha (TNF-α), which promote both local arterial and systemic inflammation 6
• This inflammatory process leads to destruction and remodeling of the arterial wall, resulting in intimal hyperplasia and progressive occlusion of the arterial lumen 3

Vascular Consequences

• The vascular remodeling causes stenosis or occlusion of affected vessels, leading to the ischemic manifestations of GCA 1
• These manifestations include headache, scalp tenderness, jaw claudication, and potentially vision loss in 14-18% of patients 4, 7
• Less common ischemic complications include stroke, cranial nerve palsy, and scalp necrosis 4
• GCA may also be complicated by large-vessel aneurysms and vascular stenoses 4

Perpetuating Mechanisms

• Recent research has identified mechanisms that allow for the perpetuation of inflammation and vascular remodeling, explaining the chronic evolution of GCA 1
• Formation of tertiary lymphoid organs in the arterial wall may contribute to persistent local inflammation 2
• Vascular smooth muscle cells and endothelial cells actively participate in the inflammatory process and contribute to vascular remodeling 2, 6

Laboratory Markers

• Inflammatory markers are elevated in >95% of GCA cases at diagnosis 4
• Erythrocyte sedimentation rate (ESR) typically exceeds 40 mm/h, with values above 100 mm/h having high specificity 5
• C-reactive protein (CRP) is also elevated in most cases 5, 7
• Platelet count >400 × 10³/μL is common and has diagnostic value 7

Respiratory Involvement

• Respiratory involvement occurs in <10% of GCA cases 4
• Chronic cough is the most frequent respiratory symptom, typically harsh and nonproductive 4
• Respiratory manifestations may be related to isolated small airways disease, lung nodules, interstitial infiltrates, vasculitis of pulmonary arteries, or granulomas within bronchial walls and alveolar interstitium 4

Understanding this complex pathophysiology has led to targeted therapies such as tocilizumab, which has demonstrated efficacy in reducing glucocorticoid requirements and flare rates by modulating the underlying immune mechanisms 5, 8.