**12. Clinical phenotype and response to treatment are dependent on pathophysiology**

Aneurysm formation in GCA is reported in 3% of the patients with 3 months disease duration and 18-27 % of patients with 6 months duration. [49, 50] Cumulatively, the relative risk for aneurysm formation is estimated to be 17.3. [51]

Disease diagnosis is straightforward in typical cases with headache, temporal tenderness, non palpable temporal arteries, jaw claudication and systemic symptoms (fever, malaise, weight loss) in an individual beyond 50 years of age. Unfortunately, a considerable proportion of patients presents with minor or no symptoms from the cranial arteries, which is presumably the hallmark of GCA.

Temporal artery biopsy represents the diagnostic gold standard, as its sensitivity is reported to exceed 85%. It should be mentioned that negative biopsy does not exclude GCA, as the lesions are skipped and long tissue specimens (>20mm) are required. Common causes of false negative results are the incomplete technique (sampling error) and the lack of sensitive pathologic criteria. Thus, in highly suspected cases, a second, contralateral, biopsy is recom‐ mended. Recent studies suggest ultrasonography-guided biopsy to precisely locate the patchy lesions of vessel wall inflammation. [52]

**Figure 1.** The immunopathophysiologic basis of giant cell arteritis. 1. In normal arteries, immature DCs, in the adventi‐ tia-media border, are the immune sentinels of the vessel wall. 2. In GCA, their maturation and activation (by an un‐ known instigator) leads to the recruitment of CD4+ T cells into the vessel wall. 3. CD4+ T cells are able to differentiate into either the Th17 arm of the immune response, which is responsible for the systemic manifestations of the disease, or the Th1 arm. 4. Th1 cells along with IFN-γ are able to drive the activation of macrophages, the formation of granulo‐

ma and the destruction of the structural integrity of the vessel wall via the secretion of MMPs and ROS.

production by macrophages, dendritic cells, endothelial cells and fibroblasts.

to be the result of two separate degenerative processes.

102 Updates in the Diagnosis and Treatment of Vasculitis

**11. Newer concepts in GCA pathogenesis: Immune and vascular aging**

According to the 1990 ACR criteria for the diagnosis of GCA, age above 50 is considered a major criterion for disease diagnosis. [46] Susceptibility of elder persons for GCA is considered

Firstly, immunesenescence is characterized by the shrinkage of the naïve T-cell pool, loss of immune-regulation and impairment of innate immunity. [47] More specifically, alterations in innate immunity functions, such as impairment of DC trafficking and prolonged maintenance of TLR expression raise the possibility of uncontrolled inflammatory reactions in immunopri‐ viliged sites. Furthermore, the immune aging process results in an increase in basal cytokine Another advanced technique to detect vascular inflammatory sites is FDG-PET (fluorodeox‐ yglucose positron emission tomography) imaging, which is currently incorporated in diag‐ nostic algorithms. [53]

Immune system abnormalities play a critical role in GCA pathogenesis and are able to drive, not only clinical phenotype, but, also, response to treatment. DCs have been shown to initiate the immune response, as the number of myeloid DCs significantly increases in the adventitia of affected arteries and they appear to be activated via ligation of their TLR-4 (LPS) or TLR-5 (flagellin). [31] Stimulation of DCs via these TLRs induces the subsequent recruitment of T cells into the vessel wall, where they undergo local proliferation and activation. T cells produce pro-inflammatory cytokines to regulate the functions of macrophages, vascular smooth muscle cells and endothelial cells, while they were proved to belong to either Th1 or Th17 lineage. [22]

Th17 cells secrete IL-17 and provide the early immune response in GCA, where these cells are reported to be 10-fold elevated in initial phases. Furthermore, in untreated patients, circulating monocytes (primed by IFN-γ) produce significant amounts of Th17-polarizing cytokines, such as IL-6 and IL-23. Th17 response is considerably sensitive to steroids and is related to the inflammatory phenotype of GCA, like fever and PMR. [37] The most common clinical mani‐ festations of the disease include constitutional symptoms (anorexia, weight loss), fever (in some cases fever of unknown origin), headache (usually localized in the temporal region), and polymyalgia rheumatica. This cluster of symptoms is attributed to the initial Th17 response and has been shown to respond adequately to steroids. [38]

**Author details**

Panagiota Boura\*

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Immunopathophysiology of Large Vessel Involvement in Giant Cell Arteritis...

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105

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Th1 cells represent the dominant cellular population at the tissue level and the periphery of patients with untreated GCA. These cells produce IFN-γ, target macrophages and provide a substantial pro-inflammatory environment. Additionally, IFN-γ is strongly related to elevated levels of metalloproteases (MMP-2, MMP-9), which lead to vessel wall destruction and aneurysm formation. Th1 response is believed to be steroid resistant (in usual doses), as IFNγ committed T cells and soluble IFN-γ are not affected even after months of steroid therapy. [38] The late clinical manifestations in the disease course, such as jaw claudication, tongue claudication, scalp necrosis and visual impairment, represent ischemic complications resulting from this Th1-IFN-γ driven process.

On the other hand, thoracic and abdominal aortic aneurysms comprise the most dreaded complications of GCA. These manifestations are mediated through an intense Th1 response that leads to IFN-γ secretion, macrophage activation and release of metalloproteases into the aortic wall. This leads eventually to internal elastic lamina rupture, intimal hyperplasia and lumen stenosis or aneurysm formation. [21] This sequela has been shown to be steroid-resistant even if used in high doses.

Glucocorticoids, while the mainstay of therapy in GCA, do not exert the expected efficacy in Th1-driven aneurysmal disease. [38] Based on these data, glucocorticoids should be instituted promptly once the diagnosis of GCA is suspected. The optimal dose for remission induction in GCA remains uncertain. An initial daily dose of 40 to 60 mg of prednisone or its equivalent is reported to be adequate in almost all cases. [54] In severe, life threatening cases or, when the visual loss is considered imminent, intravenous methylprednisolone is recommended, while tapering can begin once the disease has been adequately controlled, with a rate of 3-4 mg/week. Most patients require medium doses of steroids for at least two years, since relapse risk is high.

Adjuvant therapy is usually needed to avoid chronic side effects, but no agent (methotrexate, IVIGs or other cytotoxic agents) has so far proven satisfactory efficacy. [55-57] Recent advances in GCA pathophysiology may lead to alternative treatments, like those which interrupt Th17 differentiation, such as tocilizumab. [58]

In conclusion, large vessel involvement in GCA is characterized by a biphasic pathophysio‐ logic process. Initial Th17 response will lead to the steroid-sensitive systemic inflammatory features of the disease, while, in late phases, Th1 response is responsible for the steroidresistant aneurysmal disease. Given the fact that these complications may be life-threatening, it is reasonable to be thoroughly evaluated and managed promptly, either by surgical or by pharmaceutical means or both.
