One Giant Step for Giant Cell Arteritis: Updates in Diagnosis and Treatment

Abstract

Purpose of review: Giant cell arteritis (GCA), a medium and large vessel vasculitis occurring in the aged, remains a formidable disease, capable of taking both vision and life, through a multitude of vascular complications. Our understanding of the spectrum of its manifestations has grown over the years, to include limb claudication, aortitis, and cardiac disease, in addition to the more classic visual complications resulting from of ischemia to branches of the external and internal carotid arteries. While a clinical presentation of headache, jaw claudication, scalp tenderness, fever and other systemic symptoms and serum markers are together highly suggestive of the disease, diagnosis can be challenging in those cases in which classic symptoms are lacking. The purpose of this review is to update the reader on advances in the diagnosis and treatment of giant cell arteritis and to review our evolving understanding of the immunological mechanism underlying the disease, which have helped guide our search for novel therapies.

Recent findings: There is increasing evidence supporting the use of Doppler ultrasound, dedicated post-contrast T1-weighted spin echo MRI of the scalp arteries and PET scan, which can together improve our diagnostic accuracy in cases in which temporal artery biopsy is either inconclusive or not feasible. Advances in our understanding of the immunological cascades underlying the disease have helped guide our search for steroid-sparing treatments for the GCA, the most important of which has been the IL-6 receptor antibody inhibitor tocilizumab, which has been shown to reduce cumulative steroid dose in a large multicenter, placebo-controlled prospective study. Other biologic agents, such as abatacept and ustekinumab have shown promise in smaller studies.

Summary: GCA is no longer a disease whose diagnosis is based exclusively on temporal artery biopsy and whose complications are prevented solely with the use of corticosteroids. Modern vascular imaging techniques and targeted immunologic therapies are heralding a new era for the disease, in which practitioners will hopefully be able to diagnosis it with greater accuracy and treat it with less ischemic complications and iatrogenic side effects.

Keywords: Anterior ischemic optic neuropathy; Doppler ultrasound; Giant cell arteritis; Granulomas; IL-6; Posterior ischemic optic neuropathy; Temporal arteritis; Tocilizumab; Vasculitis.

Fig. 1

Pathogenesis of giant cell arteritis. Unknown environmental stimuli, possibly infectious, activate immature dendritic cells within the adventitia of blood vessels through stimulation of receptors such as the toll like receptor (TLR), leading to the release of chemokines (CCL18–21) that recruit naive CD4+ helper T cells. These T cells, under the influence of interleukin-6 (IL-6), differentiate into Th17 cells which produce IL-17, while others, triggered by IL-12, differentiate into Th1 cells which release interferon gamma (INF-γ). Il-6 and IL-17 may at the same time lead to a reduction in regulatory T cells (Treg). INF-γ causes vascular smooth muscle cells (VSM) to release cytokines that recruit monocytes which are transformed into either macrophages or multinucleated giant cells under the influence of INF-γ. Macrophages release reactive oxygen species that peroxides phospholipids in cellular membranes and matrix metalloproteinase-2 (MMP-2) which, along with MMP-9 released by VSM, destroy cellular matrix proteins such as elastin, resulting in the destruction of the media. CXCL10–11 released by VSM cells recruit CD8+ T cells which release cytotoxic perforin. Macrophages, injured VSM, and giant cells all release platelet-derived growth factor (PDGF) which leads to intimal hyperplasia and associated luminal stenosis, which in turn can lead to luminal thrombosis. Vascular endothelial growth factor (VEGF) released by giant cells leads to neoangiogenesis. TLR, troll-like receptor. CD4, undifferentiated CD4+ helper T cell. INF-γ, interferon gamma. VSM, vascular smooth muscle cells. O-, reactive oxygen species. NO, nitric oxide. Treg, regulatory T cell. MMP, matrix metalloproteinase. CD8, CD8+ killer T cells. PDGF, platelet-derived growth factor. VEGF, vascular endothelial growth factor. NEO, neoangiogenesis. IEL, internal elastic lamina.

Fig. 2

Manifestations of giant cell arteritis. Common manifestations include vision loss from anterior ischemic optic neuropathy, posterior ischemic optic neuropathy, central retinal artery occlusion, jaw claudication headache and scalp tenderness and systemic symptoms such as fever, fatigue, arthralgias, and myalgias. Less common symptoms include scalp or tongue necrosis, stroke, hearing loss, limb claudication, myocardial infarction, aortitis, and pulmonary fibrosis.

Fig. 3

A case of giant cell arteritis. A 92-year-old woman complained of headache, jaw claudication, and vision loss. a Humphrey visual fields showed a superior altitudinal visual field loss in her right eye. b Funduscopy revealed a focal swelling inferiorly in the right optic disc that was also pale, i.e., pallid edema. Erythrocyte sedimentation rate (ESR) was 105 mm/h, C-reactive protein (CRP) was 3.6 dG/L. A temporal artery biopsy showed a mixed inflammatory infiltrate including giant cells within the arterial wall, consistent with GCA. c Elastin stain at low power demonstrate disruption of the internal elastic lamina (IEL) as well as a mixed infiltrate (MI) and intimal hyperplasia (IH). d Low power hematoxylin and eosin (H&E) demonstrates intimal hyperplasia (IH) and a mixed infiltrate (MI). e High power H&E demonstrates disruption of the IEL and a mixed infiltrate (MI). f High power H&E shows giant cells. (GC).