Preface

Giant cell arteritis (GCA) is a systemic vasculitis that affects medium- to large-sized arteries, in which the inflammatory reaction destroys the artery wall with the fragmentation of the elastic lamina. Such phenomena can result in vision loss if not treated promptly. Other non-ocular symptoms noted include GCA, headache, tenderness in the temporal area of the scalp, myalgias and arthralgias, fever, weight loss, and jaw claudication. Clinical suspicion is an essential pathway to the diagnosis of this disease. Thus, immediate Westergren sedimentation rate and C-reactive protein should be obtained. A temporal artery biopsy, however, remains the most definitive diagnostic tool to support the clinical diagnosis of GCA. The incidence of GCA remarkably increases with each decade of age among those aged 50 years or older.

In Chapter 1, "Epidemiological Aspects of Giant Cell Arteritis", Riaz et al. discuss notable differences among patients of different ethnicities. They report that the epidemiological characteristics of GCA have been primarily researched in populations from the United States as well as several European countries with an emphasis on the Caucasian population. In more recent years, a handful of studies have emerged from non-European countries regarding the epidemiology of GCA. The results of these findings are in parallel with previous observations, which presumed GCA to be more common in European and North American populations. Nordic countries present the highest annual incidence rates of GCA, which moderately affects southern European countries (Italy, Spain, France, etc.). The lowest incidence rates have been reported in East Asian countries. The authors contend that diverse ethnical populations in countries such as the United States lead to variations across regions, such as a higher incidence rate in the Northern states due to Scandinavian ancestry. Different ethnicities present varying susceptibility, which may exhibit different degrees of suspicion with certain races, leading to influence on the number of biopsies performed and diagnoses made. In some regions, race and ethnicity is self-identified, which may reveal limited information on genetic background. The authors detail the varied incidence rate observed in different populations across the globe. The incidence rate increases substantially with age and a greater ratio of patients are women in most regions, except for Asian countries. Whether female susceptibility is genuinely lower in that region or whether this discrepancy is due to different health-seeking behavior is unknown. Although seasonal and cyclic patterns were observed in a few studies and environmental factors were suggested, such influence remains inconclusive. The authors also note that the definition of GCA is inconsistent across the literature, resulting in the inclusion of heterogeneous data during an extensive review. Hence, there may be an over- or underestimation of statistical values. The criteria for the diagnosis of this disease substantially varied, with incidence rates presented based on biopsy-proven cases, ACR criteria-fulfilling cases, or unspecified clinical diagnoses. Therefore, data may vary depending on which inclusion criteria were used. Moreover, the technicality for biopsy-proven cases (length of the segment or threshold for diagnosis) may also alter the rate of incidence. In many reviews, the length of the arterial specimen remains unmentioned. In 2016, an alteration to the list of criteria for a more comprehensive diagnosis of GCA was submitted.

In Chapter 2, "Cellular and Molecular Characteristics of Vascular Damage in Giant Cell Arteritis, the 'Unmet Needs' for Targeted Treatment", Rusu reports that GCA is a primary systemic vasculitis characterized by systemic inflammation and vascular insufficiency of large and medium blood vessels that may lead to end-organ damage in patients aged 50 years or older. Standard corticosteroid treatment of the disease significantly improves the intima-media thickness while having less influence on vascular endothelial dysfunction. The author describes that GCA morbidity may be related to both cardiovascular complications and corticosteroid toxicity. He discusses characteristic aspects of vascular damage and the several mechanisms that cause vascular dysfunction, intima-media "nodular" thickness, progressive narrowing of the arterial lumen, and vascular blockage in the context of systemic inflammation, thrombosis, and of cardiovascular complications in GCA along with new therapeutic glucocorticosteroid-sparing agents preventing life-threatening cardiovascular complications of GCA. Vasculitis is a heterogeneous group of conditions characterized by inflammation of the vessel wall resulting in narrowing or occlusion of the vessel lumen. The author emphasizes that the use of biomarkers in laboratory testing for GCA may become highly valuable once some specific diagnostic or prognostic blood biomarkers become available. Currently, the criteria used to diagnose GCA are the elevated inflammatory markers usually associated with ischemic events such as acute phase reactants frequently having high blood levels: ESR and CRP, elevated platelets and white blood cell numbers, and elevated blood von Willebrand factor. In addition, elevated serum level of the proinflammatory cytokine interleukin 6 (IL6) is critical in GCA pathogenesis and perhaps the most sensitive marker in GCA. The author emphasizes the role of glucocorticosteroid therapy since such treatment improves GCA symptoms immediately, especially in ischemic complications when it is lifesaving or avoids permanent invalidity (partial/total visual loss). Prompt treatment results in the improvement of blood supply to the vital organs, decreasing cerebrovascular events and myocardial infarction and improving vision loss. Because of the risk of acute CVA and visual loss, GCA is considered an ophthalmological emergency for which the treatment is high-dose methylprednisolone pulse therapy. In this review study, the authors discuss several cellular and molecular pathogenetic mechanisms of vascular damage characteristic of GCA that might occur during the progression of the disease, especially during the active phase. The paradigm in terms of GCA physiopathology is that inflammation starts in the adventitial layer with the activation of the vascular dendritic cells (DCs), which shifts the situation to the point where there are multiple types of immune cells recruited, proliferating, and differentiating in the vessel wall, causing together with inflamed vascular cells an erroneous repair of the arterial wall. It is unlikely that DCs are the cells driving these processes, given the multitude of cell functions the arterial wall's endothelial cells (ECs) play in complicated processes of vascular inflammation, hemostasis/ thrombosis, and vascular repair, resulting in a distinct GCA-specific vasculopathy most commonly referred to as GCA-related vascular remodeling. There are three EC populations in the GCA artery: arterial luminal ECs, vasa vasorum ECs, and capillary ECs formed de novo in the intima and media layers (which showed to be avascular in normal arteries) of the diseased artery. These three types of ECs are activated in a sequential manner; their activation is probably subordinated to the invading immune cells, but not to all. For instance, vasa vasorum ECs are activated after vascular DCs are activated, but ECs activation most probably precedes the activation of T cells. The invading cells must get into the vessel wall through the vasa vasorum. Activated ECs provide the means for invasion by mobilizing, performed contents of storage granules WPBs. These secreted ECs mediators are released in a timely manner to fulfill proinflammatory, chemoattractant, and neoangiogenic roles or increased endothelial

permeability functions. GCA 18 biomarkers have the potential to detect the disease that is missed by TAB/imaging. Several large multi-center clinical trials have led to the discovery of new potential biomarkers to monitor disease activity and relapses, which is a new critical development in the field. Some of the recently published data imply that testing several blood acute phase reactants can optimize earlier diagnosis and the ability to predict flares and complications . In addition, our study underlines the importance of the candidate targets for novel therapeutics. In the more severe complications of this disease, such as blindness or stroke, the underlying GCA-related vascular damage does not respond to GS, as previously reported by several independent studies. A multi-step treatment for GCA should be envisioned that involves steroids, especially when people with GCA are particular ill, and efficient medication to control vascular dysfunction (e.g., to lower proinflammatory cytokine levels, to lower the levels of circulating active vWF in parallel). Of the variety of GCA treatments being investigated, a few have the potential to improve outcomes and reduce the need for steroids. The availability of the new drug tocilizumab was received with a lot of enthusiasm, as it is the only FDA-approved drug for GCA treatment. Tocilizumab is effective to control GCA symptoms, allowing rapid GS tapering, and persistent remission with a low dose GS after six months of follow-up; however, after tocilizumab discontinuation the relapse-free survival percentage decreases, at least in some patients. Tocilizumab poses certain challenges for clinicians regarding biomarker follow-up of patients, since the drug represses both CRP and ESR, thus making careful anamnesis, physical examination, and clinical judgment even more important for disease assessment. Twenty adverse events were considered directly related to the drug; danger with tocilizumab administration was reported in the instance of infection in patients receiving tocilizumab, with pneumonia and no CRP and ESR rise, signifying that more careful assessing of disease activity and infections in patients treated with tocilizumab is required. Further studies are needed to determine the optimal duration of treatment and maintaining of dosing and to further reduce the risk of relapse. An important note to make is that molecular pathogenic pathways promoting GCA disease are changing as the disease progresses under treatment. This situation is frequent in clinical practice and requires adequate follow-up and adapted therapeutic strategies. Hopefully, future research will bring us closer to the goal of identifying new therapies for active and/or refractory GCA, which used in substitution or addition to steroids will provide tide control of the disease, addressing not only vascular inflammation but also vascular remodeling, skewed thrombotic propensity, and luminal changes in GCA patients at risk of VL, stroke, or other ischemic events at the initial onset of the arterial disease or in evolution.

Recent advances in imaging studies and treatment approaches have greatly improved our knowledge of GCA. Previously thought of as a predominantly cranial disease, we now know that GCA is a systemic disease that may involve other medium and large vessel territories. Several imaging studies have shown that between 30% and 70% of patients with GCA present with large-vessel vasculitis. Moreover, a significant proportion of patients present large-vessel disease in the absence of cranial involvement. GCA is commonly defined as Large-Vessel (LV) GCA if the aorta and its branches are involved. The extra-cranial disease also poses management challenges, as these patients may have a more refractory-relapsing disease course and need additional therapies. Aortic dilation and aneurysms are well-described late complications of GCA involving the large artery territories.

In Chapter 3 "Extra-Cranial Involvement in Giant Cell Arteritis", Serodio, Trinadade, Favas, and Alves discuss the clinical picture of extra-cranial involvement in GCA,

focusing on improved diagnostic protocols and suitable treatment strategies. The authors mention that in the past LV-GCA has been mis-regarded and underdiagnosed. They note that in recent years there has been an increased awareness of the systemic larger artery nature of GCA, based on necropsy studies that have shown histologic evidence of systemic large-artery vasculitis in approximately 80% of patients. Recent advances in diagnostic imaging techniques have confirmed these figures, suggesting that imaging will have an increasing impact on the diagnosis and management of GCA. Furthermore, patients with GCA are at increased risk of developing aortic dilation and aneurysms, among other complications. Altogether, these issues highlight the importance of the extra-cranial involvement of GCA, which has been under-recognized and poorly managed. The interaction of immunopathogenic mechanisms with the different functional and anatomic characteristics of the vessel walls in different parts of the body may explain the distinct aspects of LV-GCA pathophysiology. The authors state that there is consistent evidence confirming that arteries are involved in around two-thirds of patients with GCA and one-third of patients with PMR. Classification criteria are inadequate for LV-GCA and thus a revision of the current criteria may be needed soon. The authors believe that LV-GCA presents a more relapsing-disease course and an increased risk of vascular complications, with LV inflammation being responsible for a considerable increase in the morbidity and mortality associated with this condition. This chapter emphasizes the importance of carefully considering the large artery aspects in the management and treatment of patients with GCA.

The use of medical image processing and analysis tools have improved GCA detection and diagnosis using patient-specific medical imaging In Chapter 4, "Medical Image Processing and Analysis Techniques for Detecting Giant Cell Arteritis", Qasrawi, Al-Halawa, Daraghmeh, Hjouj, and Seir propose several image processing and analysis algorithms for detecting and quantifying GCA from patient medical images. They introduce the connected threshold and region growing segmentation approaches to two case studies with temporal arteritis using US and MRI imaging modalities extracted from a Radiopedia dataset. They developed a GCA detection procedure using the 3D Slicer Medical Imaging Interaction software as a fast prototyping, open-source framework. According to the authors, GCA detection passes through two main procedures: the pre-processing phase, in which the quality of an image is improved and enhanced after removing noise (irrelevant and unwanted parts of the scanned image) using filtering techniques and contrast enhancement methods; and the processing phase, which includes all the steps of processing used for identification, segmentation, measurement, and quantification of GCA. The semi-automatic interaction involves the entire segmentation process for finding the segmentation parameters. The results of two case studies in this chapter show that the proposed approach managed to detect and quantify the GCA region of interest. According to the authors, the proposed algorithm is efficient to perform complete and accurate extraction of temporal arteries. The proposed method can be used for studies focusing on 3D visualization and volumetric quantification of GCA. These algorithms depend on various image processing algorithms, including image enhancement, noise reduction, pixel densities histogram analysis, and statistical analysis tools. First, the Gaussian filters and noise reduction algorithms are applied to enhance the temporal artery structures, which effectively enhances the temporal artery contrast. Then, seed points are detected automatically through a threshold pre-processing operation. Based on the set of seed points and threshold analysis, region growing is applied, which grows in the target region. Then, the temporal artery region is extracted by connected threshold and region growing approaches,

which can segment the artery due to the pixel intensity thresholds and the seed point approach. Three regions of interest can be extracted: the temporal artery wall, the blood flow, and the GCA region. Finally, the statistical and measurement tools are used to quantify the diameters, area, and volume of the GCA regions, and to detect and identify the size and location of the GCA region.

In Chapter 5, "Giant Cell Arteritis: From Neurologist's Perspective", Keni et al. discuss a detailed aspect of GCA that include risk factors, clinical symptoms and examination findings, investigations, treatment, and management of relapse. The authors emphasize having a detailed ophthalmological history and examination that includes aspects of transient or permanent visual loss, visual field defect, relative afferent pupillary defect, anterior ischemic optic neuritis, and central retinal artery occlusion. Some of the investigations the authors recommend in the evaluation of suspected GCA include complete blood count, renal function tests, liver function tests, CRP, and ESR. Some of the other investigations recommended are chest X-ray and urinalysis. Temporal artery biopsy remains the gold standard to support the clinical diagnosis of GCA. Negative biopsy results do not rule out the condition. The findings on temporal artery biopsy in GCA are characterized by inflammatory infiltration of the arterial wall by lymphocytes, macrophages, and giant cells in about 50% of cases. Color-coded duplex US can be utilized to examine the temporal, extracranial, occipital, and subclavian arteries, having a sensitivity of 85% and a specificity of more than 90%. The "halo sign" of the inflammatory edema of the vascular wall is visible as hypoechoic wall thickening is characteristic. Positron emission tomography (PET) uses radioactive metabolites to visualize metabolic processes. Spatial resolution is limited with PET, so visualization can only be determined in the aorta and larger vessels, and the ability to visualize the temporal arteries is limited. However, MRI may be useful as the imaging modality for temporal arteries. Detailed imaging of the walls and lumen of the temporal artery is possible by doing a high-resolution MRI (fat suppression, T1 weighted). Diagnosis of GCA is based on clinical and laboratory tests. In cases where there is a clinical suspicion of GCA, corticosteroid treatment should be initiated immediately and not delayed awaiting the results of blood tests or temporal artery biopsy. In cases of complicated GCA, when there is evolving visual loss or amaurosis fugax, intravenous methylprednisolone in a dosage of 500 mg–1 g IV for three days followed by oral prednisone in the dose range of 40–60 mg daily with a tapering regimen is recommended. In cases of relapse, a rise in inflammatory markers (ESR/CRP) is usually seen, however, these markers can remain normal in some cases. The use of secondary agents such as methotrexate or azathioprine should be considered in patients with recurrent relapse or failure. Clinical experience has shown that methotrexate (7.5–15 mg once a week) reduces the relapse rate and overall duration of exposure to corticosteroids. Tocilizumab is an interleukin-6 (IL-6)-receptor inhibitor. The GCA Actemra (GiACTA) trial demonstrated increased rates of sustained remission using a combination of tocilizumab plus corticosteroids compared to treatment with corticosteroids alone. Furthermore, steroid-induced adverse effects have been reduced with the usage of tocilizumab. Tocilizumab is recommended by NICE as an option for treating GCA in adults if they have relapsing or refractory disease and they have not already taken tocilizumab; it is stopped after one year of uninterrupted treatment at most. Tocilizumab is a potent suppressor of IL-6, which is an important producer of CRP. Therefore, patients on tocilizumab may not produce a biochemical inflammatory response in the setting of infection/inflammation. Caution should be taken while taking tocilizumab, particularly in patients with a history of diverticulitis, as it carries a risk for gastrointestinal perforation.

In Chapter 6, "Clinical Manifestations of Giant Cell Arteritis", Silva, Silva, Santos, Vassalo, Martins, and Peixoto discuss the clinical manifestations of GCA in detail. They report that GCA is commonly categorized as a large- and medium-sized vessel vasculitis with systemic symptoms being common. Systemic symptoms associated with GCA are frequent and include fever, fatigue, anorexia, and weight loss. These symptoms may occur for a few days and may prolong to several weeks. Fever is usually low grade and occurs in up to one-half of patients. It has been stated as well that 1 out of 6 fevers of unknown origin in older adults may have been due to GCA. About 10% of patients with GCA present with constitutional symptoms and laboratory evidence of inflammation as the only clues to the diagnosis. Headache is a common presentation of GCA, being the initial symptom in 33% of cases and present in about 80% of patients, which is either new in a patient without previous history of headaches or of a new type in a patient with chronic headaches. Headaches due to GCA are typically throbbing and continuous, located over the temples, but can also be frontal, occipital, unilateral, or generalized. Descriptions of the pain range from a dull or burning sensation to focal tenderness on direct palpation. Patients may note scalp tenderness with hair combing or when wearing a hat. Jaw claudication results from ischemia of the maxillary artery supplying the masseter muscles and is highly predictive of temporal arteritis. Nearly 50% of patients experience jaw claudication, a symptom consisting of mandibular pain, discomfort, or fatigue triggered by mastication or prolonged speaking and relieved by stopping. The incidence of permanent loss of vision ranges from 15% to 20% of patients. When untreated, contralateral eye involvement commonly occurs within the first two weeks after initial onset. Extraocular motility disorders occur in approximately 5% of patients and include diplopia, which has a high specificity when accompanied by other symptoms suggestive of GCA. Diplopia, which is usually transient, can result from ischemia of any portion of the oculomotor system, including the brainstem, oculomotor nerves, and the extraocular muscles themselves. Less common manifestations reported include CNS involvement, audiovestibular and upper respiratory symptoms, pericarditis, mesenteric ischemia, and female genital tract involvement. Patients with GCA are at increased risk for pulmonary and cardiovascular events, but cardiac involvement is rare. Stroke is a rare but important complication of GCA and is typically due to stenosis of the carotid and the vertebral or basilar arteries. Even with aggressive steroids and immunosuppressive therapy, it is associated with high morbidity and mortality. More than one-half of strokes attributable to GCA occur in the vertebrobasilar system. Bilateral vertebral artery involvement, which causes rapidly progressive brainstem or cerebellar neurologic deficits with high mortality, is highly suggestive of GCA. Peripheral neuropathy, myelopathy, higher cortical dysfunction or dementia, and pachymeningitis are uncommon complications of GCA. GCA is closely linked to polymyalgia rheumatica (PMR) and this well-known association has therapeutic and prognostic consequences. About 40% to 60% of GCA patients have manifestations of PMR, an inflammatory rheumatic condition clinically characterized by symmetrical proximal polyarthralgia and myalgia, with aching and stiffness on shoulders, hip girdle, neck, torso, and an unfamiliar sense of fatigue. Less commonly, distal findings can occur, involving synovitis of peripheral joints, especially at the wrists and metacarpophalangeal joints, with distal extremity swelling and pitting edema, known as remitting seronegative symmetrical synovitis with pitting edema (RS3PE) syndrome, puffy edematous hand syndrome, or distal extremity swelling with pitting edema. The authors emphasize that GCA should always be considered in the differential diagnosis of a new-onset headache in patients 50 years of age or older with an elevated ESR. The onset of symptoms in GCA tends to be subacute, but abrupt presentations occur in some patients. Although systemic manifestations are characteristic of GCA, vascular involvement can be widespread. Clinical manifestations of

the disease most frequently result from the involvement of the cranial branches of arteries originating from the aortic arch. A complete diagnosis of GCA requires the presence of American College of Rheumatology (ACR) classification modified criteria: a. age over 50 years at the onset of the disease; b. moderate, bitemporal, recently installed headache; c. scalp tenderness, abnormal temporal arteries on inspection and palpation, reduced pulse, jaw claudication; d. blurred vision or permanent visual loss in one or both; e. systemic symptoms (fatigue, weight loss, fever, pain in the shoulders and hips: polymyalgia rheumatica); f. increased inflammatory markers (ESR > 50 mm/h, CRP > 1.5 mg/dl); g. representative histologic findings on TAB: mononuclear cell infiltration or granulomatous inflammation of the vessel wall, usually accompanied with multinucleated giant cells. Several imaging techniques may be suitable for the diagnosis of GCA. Compared to other imaging techniques, the US is the most suitable for the evaluation of GCA patients. The test can easily be performed by the clinician usually immediately after the general examination of the patient, and it significantly shortens the waiting period until another investigation is performed. Ultrasonography is a safe, non-invasive, accessible, fast, and low-cost bedside screening technique that has the unique capacity of studying real-time hemodynamics. It presents the ability to evaluate the anatomy of a vessel's wall, identifying equally parietal abnormalities (wall thickening, hypoechoic plaques, clotting, parietal hematoma, dissections) and the external diameter of the artery; it can rule out both stenosis and occlusion. The use of US is widespread in neurological clinical practice, mainly in the evaluation of arterial atherosclerotic process but also for monitoring other diseases such as medium-/large-vessel vasculitis. The advantages of US over other imaging techniques in GCA are represented by its safety, accessibility, tolerability, speed, and high resolution (a high-frequency probe offers both an axial and a lateral resolution of 0.1 mm. The smaller the vessel diameter, the more difficult is to appreciate the vessel wall damages, so that, in this case, the most informative US data are based on Doppler spectral evaluation. This is also valid for the assessment of medium- to small-vessel inflammation such as intracranial vasculitis. Using the US, one can reveal pathological characteristics in GCA: noncompressible arteries (compression sign), wall thickening ("halo" sign), stenosis, and vessel occlusion. There are three important items in the US diagnosis of temporal arteritis: "dark halo" sign, a typically homogeneous, hypoechoic, circumferential wall thickening around the lumen of an inflamed TA, which represents vessel wall edema, and a characteristic finding in temporal arteritis/GCA.

In Chapter 7, "An Integrated Approach to the Role of Neurosonology in the Diagnosis of Giant Cell Arteritis", Jianu, Jianu, Munteanu, Dan, Gogu, and Petrica discuss the importance of US in the diagnosis of TA. The authors emphasize that the US should be used as a first-line diagnostic investigation for patients presenting with clinical and biological features suggestive for GCA, taking into consideration that it has a high sensitivity to detect vessel wall thickening (dark halo sign) in the case of large/medium vessels. In their practice, CCDS has emerged as a safe and reliable alternative to TAB as a point-of-care diagnostic tool in the management of temporal arteritis. Because findings of TAs in the US do not correlate with eye complications in GCA, CDI of the orbital vessels is of critical importance to quickly differentiate the mechanism of eye involvement. The authors believe that the US may be helpful to detect the blood flow in the orbital vessels, especially in cases of the opacity of the medium or when the clinical appearance of ophthalmologic complications in temporal arteritis is atypical. The spectral Doppler analysis of the orbital vessels in GCA with eye involvement reveals low blood velocities, especially EDV, and high RI in all orbital vessels, in both orbits, for all patients (especially on the affected side). An added advantage of CDI of orbital vessels is that it provides

immediate information that can be used to make treatment decisions, including a potential reduction in loss of sight and avoidance of unnecessary long-term steroid treatment by early exclusion of mimics. US has a high sensitivity to detect vessel wall thickening in the case of large vessel GCA. The eye involvement in GCA is frequent and consists of A-AION or CRAO, with abrupt, painless, and severe loss of vision of the involved eye. Because findings of TA's and the US do not correlate with eye complications in GCA, color Doppler imaging of the orbital vessels is of critical importance. Doppler US reveals low-end diastolic velocities and high resistance index to quickly differentiate the mechanism of eye involvement (A-AION versus N-AION). A-AION should be treated promptly with systemic corticosteroids to prevent further visual loss of the fellow eye.

> **Imtiaz A. Chaudhry, MD Ph.D. FACS** Medical Director, Houston Oculoplastics, Adjunct Professor, Ruiz Department of Ophthalmology and Visual Sciences, The University of Texas- McGovern Medical School, Houston, Texas, USA
