Giant Cell Arteritis: The Experience of Two Collaborative Referral Centers and an Overview of Disease Pathogenesis and Therapeutic Advancements

Figures & data

Table 1 Summary of the Main Characteristics in 19 Patients with Ocular Manifestations from Giant Cell Arteritis

Pt. No.	Age, Sex	Clinical Presentation	PMR	Workup	Visual Outcome	Diagnosis
1.	68, M	Constitutional symptoms, bilateral shoulder and hip pain, amaurosis fugax followed two days later by blurred vision of the left eye and visual field loss of the right eye	Yes	Bilateral swollen optic nerve head on funduscopy. Altitudinal defects in the visual field of the left eye > right eye. Left TAB positive. No halo sign on CDUS.	Visual loss in both eyes	A-AION
2.	77, F	Malaise, anorexia, jaw claudication, scalp tenderness of the right side, rapid occurrence of visual loss up to NLP in her right eye	No	Pale disc edema and occlusion of the supero-temporal branch of the retinal artery. Choroidal infarcts on fluorescein angiography. TAB not available. Typical halo sign on CDUS	Visual loss in right eye	A-AION
3.	75, F	Two episodes of fever, weight loss, arthralgias of the pelvic girdles, amaurosis fugax of the right eye	Yes	Chalky-white appearance of the optic nerve head. Typical halo sign on CDUS. Right TAB strongly indicative of GCA.	Visual loss in right eye	A-AION
4.	81, F	Persistent bilateral aching and stiffness affecting the torso, shoulders and proximal aspects of the thighs, headache and jaw claudication, binocular blurred vision	Yes	Optic nerve pallor without optic disc edema. TAB not performed. On CDUS, isolated abnormalities in both axillary arteries and left carotid forking, but not in the temporal arteries. PET/CT showed increased FDG uptake in the ascending aorta and mild increased perisynovial uptake at both shoulders, possibly indicative of associated PMR.	Visual acuity reduced to hand motion in both eyes	A-AION
5.	71, M	Tongue numbness and persistent bilateral blurred vision with occasional scotoma	No	Optic nerve head and retinal ischemia. In the absence of abnormalities in both temporal arteries on examination, TAB was not performed. Wall thickening of the internal carotid artery on CDUS. PET/CT revealed FDG accumulation in the ascending aorta, aortic arch, and bilateral subclavian artery	Impairment of visual acuity and subsequent recovery to 20/25	A-AION
6.	66, F	Tongue claudication, swelling and tenderness of the right temporal artery, visual impairment	No	Pale disc edema with delayed choroidal and central retinal artery filling on fluorescent angiography. TAB clearly positive for GCA, but CDUS was non-informative	Visual loss of right eye	A-AION
7.	65, M	Fatigue, anorexia, bilateral shoulder pain, joint morning stiffness, amaurosis fugax in the left eye with transient blurring or obscuration of vision.	Yes	Pale swelling of the optic nerve head. TAB was refused by the patient and CDUS was not performed. High-resolution MRI of the temporal arteries showed a positive pattern of mural thickening and contrast enhancement	Visual loss of left eye	A-AION
8.	85, F	No constitutional symptoms. Amaurosis fugax in the left eye followed by a reduction of visual acuity to hand motion. After 6 days, sudden painless visual loss in the right eye	No	Bilateral swollen pale disc, especially in the left eye. TAB not performed, but CDUS abnormalities of the left temporal artery (non-compressible halo sign) and dilation of the aortic arch were considered unequivocal evidence of GCA	Binocular visual loss	A-AION
9.	73, M	Headache localized to the right temporal region, scalp tenderness, and systemic discomfort. Reduction of visual acuity to 20/200 in the right eye	No	Chalk-white optic disc edema. TAB with unequivocal skip pattern positivity. CDUS not performed	Reduction to light perception of right eye	A-AION
10.	74, M	Fatigue during a 1 month-history of pain involving the neck, shoulders, and pelvic girdle associated with morning stiffness. Transient diplopia from third nerve paresis, eye pain and visual loss in the left eye	Yes	Edematous and swollen optic nerve head. TAB positive. CDUS not performed	Visual loss reduced to counting fingers in left eye	A-AION
11.	59, F	Persistent fever >38°C, bilateral pain and stiffness prevalently affecting the scapula-humeral and coxo-femoral joints, blurred vision	Yes	Pale, scarcely edematous disc of both eyes. Dubious left TAB followed 8 days later by an unequivocally positive right TAB. On CDUS, the temporal and axillary abnormalities were compatible with GCA	Improvement of visual acuity by two Snellen lines, but not of visual field	A-AION
12.	79, F	Early morning stiffness, intermittent diplopia from sixth nerve paresis, visual loss in the left eye, prominence and tenderness of the temporal artery	Yes	Optic nerve pallor, but no swelling of the optic disc. Relative afferent pupillary defect. TAB positive. Temporal artery stenosis but no halo sign on CDUS	Loss of visual acuity and field in left eye	A-PION
13.	73, F	Sudden occurrence of reduced vision in the left eye and, one week later, of the right eye, in the absence of systemic symptoms	No	Multiple cotton wool spots in both eyes. TAB not performed, but vasculitic wall edema of both temporal arteries on CDUS formed a typical halo sign. MRI showed wall thickening and increased contrast enhancement of both temporal arteries	Transient bilateral visual loss	Cotton wool spots
14.	57, M	Bilateral limb girdle discomfort, right eye pain with transient diplopia of undefined origin	Yes	Multiple cotton wool spots in both eyes. The patient refused TAB. CDUS revealed wall thickening and partial stenosis of both temporal arteries and of the right axillary artery. PET/CT showed increased uptake of FDG in the wall of occipital, temporal, and axillary arteries bilaterally	Improvement of visual acuity and central visual field in both eyes	Cotton wool spots
15.	72, F	Temporal headache and reduced vision in the right eye. Jaw claudication, fever > 38°C and night sweats	No	Numerous peripapillary cotton wool spots. TAB focally but strongly positive. CDUS not performed	Permanent visual loss in right eye	Cotton wool spots
16.	76, F	Transient episodes of blurry and distorted vision associated with a dull ache in both eyes	No	Binocular optic disc edema, intraretinal hemorrhages and diffuse pallor. A cherry red spot in the macula of the left eye. TAB not retrieved but non-compressible halo sign bilaterally positive on CDUS	Hand motion in right eye and NLP in left eye	Central retinal artery occlusion
17.	83, M	Fatigue and headache, followed two days later by soreness and by vision loss of sudden onset in the right eye	No	Intraretinal hemorrhages. Almost complete absence of filling of the central retinal artery in the right eye by fluorescein angiography. TAB positive	Visual loss in right eye	Central retinal artery occlusion
18.	58, F	Occipital condyle syndrome with left mastoid pain, tenderness over the mastoid bone, jaw claudication, left periocular pain, blurred vision of the left eye, and tenderness of the left temporal artery	No	Hypotony, with an intraocular pressure of 8 mm Hg, corneal edema, and Descemet’s folds of the left eye. No filling of the iris vessels in the temporal area on fluorescein angiography. TAB positive.	Partial recovery of visual acuity to 20/200 in left eye	Anterior segment ischemia
19.	64, F	Headache with scalp tenderness, low-grade fever, recurrent amaurosis fugax in the right eye	No	Reduced visual acuity but no optic disc swelling. Blockage corresponding to a choroidal hypoperfusion on fluorescein angiography. TAB positive	Improvement of visual acuity to 6/15	Multifocal choroidal ischemia

Abbreviations: A-AION, arteritic anterior ischemic optic neuropathy; A-PION, arteritic posterior ischemic optic neuropathy; CDUS, color Doppler ultrasonography; FDG, fluorodeoxyglucose; GCA, giant cell arteritis; NLP, no light perception; PET/CT, positron emission tomography/computed tomography; PMR, polymyalgia rheumatica; TAB, temporal artery biopsy.

Figure 1 Frequency of clinical features and abnormalities of laboratory data, temporal artery biopsy findings and color Doppler ultrasound imaging in our cohort of GCA patients.

Figure 2 Giant cell arteritis with subatrophy of the right eyeball as a consequence of the ophthalmic artery occlusion (panels A and B). In addition to constitutional symptoms, the patient complained of persistent headaches and scalp tenderness. Three weeks later, one large and one smaller eschars appeared on the scalp that eventually resulted in cicatricial areas of alopecia (panels C and D).

Figure 3 (A) Color Doppler ultrasonography (CDUS): longitudinal scan reveals a hypoechoic plaque in the proximal internal carotid artery. (B) CDUS of the right temporal artery shows a hypoechoic halo around the lumen in transverse view (arrow). (C) CDUS of the right temporal artery shows a hypoechoic halo around the lumen in transverse view (arrow). The halo sign corresponds to edema of the artery wall. (D) Longitudinal view of the right temporal artery by CDUS shows a hypoechoic halo of the temporal artery and the presence of turbulent and weak flow, suggesting the presence of stenosis. The peak systolic velocity is 1 m/s, that is double compared to the segment without stenosis.

Figure 4 Giant cell arteritis of the left temporal artery. Panel A shows a prominent, tender and beaded artery, that was also hypo-pulsating on palpation. Panels B to F illustrate the various phases of the temporal artery biopsy. A 2 cm-long segment of the frontal branch of the superficial temporal artery was surgically removed.

Figure 5 (A) Histological findings in the wall of a giant cell arteritis. Wall thickening is mainly due to myofibroblastic proliferation of the intima, with a minimal exudate consisting of lymphocytes and plasma cells. The media is distorted by the granulomatous process, which extends into the adventitia. In the latter, a minimal fibrosis is present. (B) The media of the artery shows a layer of giant cells on its inner aspect, the site of the inner elastic membrane, and small fragments of elastic fibers in the cytoplasm of giant cells (arrows). Numerous other inflammatory cells are seen in the intima wall. The muscular fibers are degenerate, as evidenced by the cytoplasmic vacuoles.

Figure 6 Distribution of ocular manifestations in 19 GCA patients of our cohort. The numbers between brackets indicate the relative percentages.

Figure 7 Scanning laser ophthalmoscopy and fluorangiography patterns in a GCA patient with acute ischemia of the papilla. Pale colored edema and light swelling are evident on the optic disc (panels A and B). Four months later the pattern changed to optic nerve atrophy (panel C). 

Figure 8 Possible pathogenetic algorithm of giant cell arteritis (GCA). After activation by danger signals, dendritic cells resident in the arterial adventitia mature, produce chemokines such as CCL19 and CCL21, and express the co-stimulatory molecules CD83 and CD86 required for their interaction with CD4⁺ T cells. Dendritic cells also release cytokines, such as IL-1 β, IL-6, IL-23 and IL-21 or IL-12 and IL-18 that trigger two distinct networks. The first network induces the differentiation of activated T cells into Th17 cells; the second drives Th1 cell formation. Both T cell lineages participate in the evolving granulomatous inflammation. See text for details.