The Immunopathology of Giant Cell Arteritis Across Disease Spectra

Abstract

Giant cell arteritis (GCA) is a granulomatous systemic vasculitis of large- and medium-sized arteries that affects the elderly. In recent years, advances in diagnostic imaging have revealed a greater degree of large vessel involvement than previously recognized, distinguishing classical cranial- from large vessel (LV)- GCA. GCA often co-occurs with the poorly understood inflammatory arthritis/bursitis condition polymyalgia rheumatica (PMR) and has overlapping features with other non-infectious granulomatous vasculitides that affect the aorta, namely Takayasu Arteritis (TAK) and the more recently described clinically isolated aortitis (CIA). Here, we review the literature focused on the immunopathology of GCA on the background of the three settings in which comparisons are informative: LV and cranial variants of GCA; PMR and GCA; the three granulomatous vasculitides (GCA, TAK, and CIA). We discuss overlapping and unique features between these conditions across clinical presentation, epidemiology, imaging, and conventional histology. We propose a model of GCA where abnormally activated circulating cells, especially monocytes and CD4⁺ T cells, enter arteries after an unknown stimulus and cooperate to destroy it and review the evidence for how this mechanistically occurs in active disease and improves with treatment.

Keywords: CIA; GCA; LVV; PMR; Takayasu; giant cell arteritis; temporal arteritis; vasculitis.

Figure 1

Vascular topology and schematic cross sections of GCA, TAK, and normal arteries. (A) Depiction of the normal human large vessel vasculature. Vascular involvement with greatest specificity for GCA shown in red and with greatest specificity for TAK in blue. (B) Cartoon representing a cross section though the temporal artery as indicated in (A) with normal vessel on the left and the inflammatory infiltrate and vascular remodeling found in cranial-GCA on the right. (C) Cartoon representing a cross section through the thoracic aorta as indicated in (A) with TAK on the left, normal in the middle, and LV-GCA on the right.

Figure 2

Comparative features between GCA, PMR, and TAK. PMR and GCA are overlapping clinical entities as patients can concurrently have both conditions. However, more patients with GCA have PMR than do patients with PMR have GCA. Meanwhile, GCA and TAK share features of vascular inflammation in large vessels. PMR, GCA, and TAK all share elevated levels of IL-6 and changes to circulating immune cells. However, distinguishing TAK from GCA are some circulating lymphocytes and cytokines, vascular pathology, and patient age. Many features are common to other types of vascular disease, such as AAA (red). There is not currently enough information to determine the extent to which CIA overlaps with other conditions.