Page 340 - The Vasculitides, Volume 1: General Considerations and Systemic Vasculitis

314 Vanessa Quick and John Kirwan

corresponds to TLR specificity such that TLR4 stimulation induces panarteritis and TLR5
stimulates perivasculitis [41].

At least six observations support a T-cell mediated etiopathogenesis of GCA according to
Borchers and colleagues [23]. First, the inflammatory cell infiltrate in GCA is comprised
mainly of T-cells and macrophages with few or no B-cells and polymorphonuclear cells
notably neutrophils are often absent. Second, the formation of granulomas depends upon T-
cells, particularly the CD4+ subset. Third, infiltrating T-cells in GCA lesions demonstrate
main histocompatibility class II and IL-2 receptor expression with selective T-cell clonal
expansion in TAB tissue specimens. Fourth, GCA is associated with specific human
leukocyte antigen (HLA) alleles. Fifth, there is attenuation of vascular inflammation after
depletion of T-cells in experimental models of GCA. Lastly, two types of T-cells that play
important roles in GCA, Th1 and Th17, express high levels of interferon (IFN)-? mRNA
compared in TAB specimens compared to control samples without arteritis [23]. The balance
between Th1 and Th17 may contribute to the clinical presentation of GCA since T-cell
derived IFN? correlates with visual symptoms and jaw claudication in a manner that those
with high levels demonstrate more intense intimal hyperplasia in tissue samples [42]. In
addition, T-cell derived IFN? expression may contribute to glucocorticoid resistance leading
to a more chronic course, as well as the heightened expression of giant cells, ischemic
complications, and neo-angiogenesis [23] and constitutional symptoms of GCA [38, 43]. The
pro-inflammatory cytokine interleukin (IL)-6 may be a good target molecule to induce
remission in GCA as serum levels mirror disease activity and IL-6 is up-regulated in the
inflamed vessels of patients with GCA [44]. Macrophages are thought to be the effector cells
in GCA as they are the major source of many cytokines and other drivers of the inflammatory
process such as IL-1ß, IL-6, TNF, TGFß, IL-32, matrix metallo-proteins and platelet derived
growth factors that are over expressed in TAB, however their precise role remains to be
elucidated [23]. IL-6 concentrations correlate with a strong inflammatory response in GCA
but appear to be inversely related to GCA related ischemic events. IL-6 is also a potent
inducer of angiogenesis leading to the hypothesis that collateral vessel formation in the
presence of high levels of IL-6 may be protective [45].

Clinical Features

The onset of GCA tends to be insidious over weeks to months, and abrupt in up to 20%
of patients [28], with a spectrum of initial disease manifestations attributable to the localized
effects of vascular and systemic inflammation [46, 47] including new-onset headache, scalp
tenderness, jaw claudication, fever, fatigue, malaise, anorexia, weight loss polymyalgia, and
visual loss [48]. The artificial separation of cranial and extracranial features either localized to
the head or owing respectively to large vessel involvement is misleading as postmortem
studies show that the intracranial arteries are largely spared in GCA [49].

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