**5. Imaging features of large-vessel giant cell arteritis**

Several imaging techniques have contributed to significant improvements in the assessment and management of LV-GCA, yet no single method is considered preferable (**Table 3**).

#### **5.1 Ultrasonography**

Ultrasonography has become widely used in GCA as it can be comparable to biopsy in the diagnosis of temporal arteritis [48, 73]. The presence of a regular hypoechoic non-compressible area around the lumen (the "halo sign") that reflects an oedematous inflammatory intima-media thickening is considered diagnostic of medium and large vessel vasculitis [74]. It is distinguished from atherosclerotic plaques since atherosclerosis presents as irregular iso- or hyper-echoic extrusions. Ultrasonography identifies aspects compatible with LV-GCA in 29–48% of patients when axillary-subclavian arteries are systematically analysed, and this standard evaluation is particularly important as 13–33% of patients have LV-GCA in the absence of temporal involvement [10, 11, 48, 58, 59]. The identification in the axillary arteries of a smooth hypoechoic increase in the intima-media thickness (IMT)


*CT, Computed tomography; CTA, CT angiography; MRI, magnetic resonance; 18FDG-PET, 8 F-deoxyglucose positron emission tomography;* −*, unavailable data.*

#### **Table 3.**

*Imaging methods in the diagnosis of large vessel inflammation in giant cell arteritis.*

#### **Figure 2.**

*Doppler ultrasonography of a right axillary artery in a patient with Large Vessel Giant Cell Arteritis. White line shows a smoothly increased hypo-echoic intima-media thickness of around 1.5 mm.*

(with a local cut-off for IMT ≥1 mm) correctly identified LV-GCA (**Figure 2**) with a sensitivity and a specificity of close to 100% [75].

Ultrasonography has the advantage of being inexpensive, not using ionising radiation and can be readily accessible to use, as demonstrated in the implementation of fast track clinics [55, 57], though it requires experienced sonographers. Ultrasonography may also be useful in disease monitoring, as most patients show the disappearance of wall thickening over the course of steroid treatment [76]. This is why ultrasonographic signs are accurate for diagnosis purposes only within the first two weeks of corticosteroid treatment, losing sensitivity thereafter [74, 76], whilst thoracic aorta examination is not easily accessible by ultrasound.

#### **5.2 Computed tomography**

Computed tomography (CT) and CT angiography (CTA) are useful for LV imaging: they have a short scanning time yet allowing for a comprehensive vascular assessment, including the thoracic and abdominal aorta. Prospective studies of newly diagnosed

#### **Figure 3.**

*Computed tomography (CT) and CT angiography (CTA) revealing Large Vessel Vasculitis in Giant Cell Arteritis (GCA). Left image shows a CTA image with circumferential wall thickening >2 mm of the thoracic aorta. Central CTA image shows the extent of thoracic aorta wall thickening in the same patient, predominantly involving posterior wall. Right image reveals thoracic wall thickening in CT of another GCA patient. Arrow depicts vasculitic wall thickening, arrowhead depicts atherosclerotic calcified plaque.*

GCA patients assessed by CTA have revealed LV involvement in 45–68% of subjects [12, 77, 78]. Typical findings of LV include circumferential wall thickening and vessel wall contrast enhancement. However, CTA findings may be attenuated by an as short as three-day course of corticosteroid treatment [12]. Nevertheless, up to 43% of patients still present significant arterial wall thickening one year after treatment [79]. The simultaneous assessment of aortic dilation and the adequate distinction between vasculitis and atherosclerosis, which appears as focal calcifications, are other advantages of CTA. Ionising radiation is of concern when repetitive evaluations are performed, but novel low-dose CTA techniques may reduce radiation exposure (**Figure 3**) [80].

#### **5.3 Magnetic resonance**

Magnetic Resonance (MRI) conveys a wide vascular assessment with vasculitis appearing as a mural thickening or wall oedema, enhanced in T2 sequences. Highresolution MRI has been extensively used to assess temporal arteritis, but there is little experience with MRI in LV-GCA [13, 81, 82]. In contrast, and as MRI does not require iodinated contrast or ionising radiation, it has been exhaustively used for periodic assessment in younger patients with TAK [80].

#### **5.4 Positron emission tomography**

18FDG-PET has become widely used in LV-GCA as it allows broad vascular assessment of inflamed vascular territories that have an increased glucose metabolism. Accordingly, 58–83% of patients with GCA show LV involvement in 18FDG-PET studies [14, 49, 83]. 18FDG-PET also has the advantage of suggesting possible differential diagnoses such as infectious or neoplastic disease. However, it is not as accurate in assessing vascular stenosis or occlusions and distinction with atherosclerotic plaques that also show increased vascular uptake may be troublesome in older patients. Furthermore, a consensus agreement regarding 18FDG-PET criteria of LV vasculitis is lacking. 18FDG uptake equal to or greater than liver uptake on PET has been proposed as the best criterion of LV inflammation in GCA [84]. The vascular uptake in LV is also attenuated after three-day corticosteroid treatment but nevertheless, maintains an adequate sensitivity for diagnostic purposes. Notwithstanding, after ten days of treatment, sensitivity may diminish considerably (**Figure 4**) [85].

#### **Figure 4.**

*18FDG-PET scans of Large vessel GCA. Left panel shows aortitis with involvement of the thoracic and abdominal aorta. Central panel shouws inflammatory uptake of the ascendeing aorta and subclavian arteries. Reight panel reveals inflammatory uptake of the aorta and common carotid arteries. Arrows reveal areas of increased vascular 8 FDG uptake.*

#### **6. Treatment particularities**

There are no studies specifically addressing the treatment of LV-GCA. As such, LV-GCA is currently managed in the same fashion of GCA. Corticosteroids remain the mainstay of treatment. Induction of remission should be started with 40-60 mg/day of prednisone equivalent to suppress systemic and vascular inflammation and prevent ischaemic complications such as blindness, and then followed by progressive tapering [2, 56, 86]. However, GCA relapses are frequent and corticosteroids account for significant complications. Therefore, adjunctive therapy should be considered in selected patients. Methotrexate (MTX) has been used as an adjunctive treatment with modest efficacy [87, 88]. TNF inhibitors have proven to be ineffective in GCA [89–91]. By contrast, the IL6-receptor blocker tocilizumab (TCZ) proved to be an effective and safe adjunctive therapy in GCA. Treatment with TCZ induced remission in over 50% of patients at 52 weeks, compared to less than 20% with placebo, and markedly reduced cumulative corticosteroid doses [92]. Recent results from real-life data corroborate the efficacy of TCZ shown in clinical trials [93].

There is some indirect evidence that LV vasculitis responds equally to standard treatment. This is corroborated by prospective imaging studies that show a decrease in LV inflammation over the course of treatment [76, 79, 85]. In a small study MTX was effective in corticosteroid-resistant LV-GCA [94]. However, it is widely accepted that patients with LV-GCA have a more relapsing disease course and receive higher doses of corticosteroids and more concomitant immunosuppressive therapy [7, 95].

In the GIACTA trial, 119 out of 251 patients included had evidence of LV vasculitis [96]. The outcomes measured did not include vascular imaging, and there is no sub-analysis directly aimed at patients with LV involvement. However, weekly TCZ was superior to biweekly TCZ or placebo in relapsing disease [92]. Being LV-GCA a more relapsing disease, it is possible that TCZ might be a preferred treatment option in this subgroup of patients [97].

Two other drugs have been studied in small GCA trials with data regarding LV-GCA. Ustekinumab, an IL-12/IL-23-blocking monoclonal antibody, was *Extra-Cranial Involvement in Giant Cell Arteritis DOI: http://dx.doi.org/10.5772/intechopen.97715*

prospectively studied in 25 patients with refractory GCA, 10 of them with LV-GCA shown on CTA. Eight of these ten patients had multiple image assessments, and all of them showed improvement of wall thickening including four that had a complete resolution of the lesions [98]. However, in another prospective openlabel trial with 13 patients with newly diagnosed or relapsing GCA, enrolment was prematurely closed due to lack of efficacy and high relapse rates [99]. Abatacept, an IgG1-CTLA4 fusion protein, was evaluated in a trial with 41 patients, (22% had LV vasculitis) and showed an improvement in relapse-free rate and duration of remission as compared to placebo [100]. Both these drugs need to be further evaluated in prospective and more extensive trials to further assess their efficacy.

Encouraging preliminary results were reported from a randomised controlled trial with mavrilumab, an anti-GM-CSF receptor α monoclonal antibody, which has shown sustained remission at week 26 in 83% of the patients, compared to 50% in the placebo group. These results were consistent across the different disease subgroups (final report is still pending) [101].

Another open question is whether current treatment significantly improves vascular remodelling and long-term LV-GCA complications such as aneurysms. The inhibition of both Jak1 and Jak2 may be a reasonable target to reduce the activation of the Th1 and Th17 pathways present in LV-GCA. Two Jak1 and Jak2 inhibitors are currently under investigation in clinical trials: baricitinib and upadacitinib [102, 103].
