**Author details**

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

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

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

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

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

and has been shown to respond adequately to steroids. [38]

from this Th1-IFN-γ driven process.

104 Updates in the Diagnosis and Treatment of Vasculitis

differentiation, such as tocilizumab. [58]

pharmaceutical means or both.

even if used in high doses.

Panagiota Boura\* , Konstantinos Tselios, Ioannis Gkougkourelas and Alexandros Sarantopoulos

Clinical Immunology Unit, 2nd Department of Internal Medicine, Hippokration General Hos‐ pital, Aristotle University of Thessaloniki, Thessaloniki, Greece

### **References**


[11] Pietro-Gonzalez S, Arguis P, Garcia-Martinez A, Espigol-Frigole G, Tavera-Bahilo I, Butjosa M et al. Large vessel involvement in biopsy-proven giant cell arteritis: pro‐ spective study in 40 newly diagnosed patients using CT angiography. Ann Rheum Dis 2012; 71: 1170-6

[23] Yilmaz A, Arditi M. Giant cell arteritis: DCs take two T's to tango. Circ Res 2009; 104:

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

http://dx.doi.org/10.5772/55222

107

[24] Ma-Krupa W, Dewan M, Jeon MS, Kurtin PJ, Younge BR, Goronzy JJ et al. Trapping of misdirected dendritic cells in the granulomatous lesions of giant cell arteritis. Am J

[25] Ma-Krupa W, Jeon MS, Spoerl S, Tedder TF, Goronzy JJ, Weyand CM. Activation of the arterial wall dendritic cells and breakdown of self-tolerance in giant cell arteritis.

[26] Caux C, Ait-Yahia S, Chemin K, De Bouteiller O, Dieu-Nosjean MC, Homey B et al. Dendritic cell biology and regulation of dendritic cell trafficking by chemokines.

[27] Han JW, Shimada K, Ma-Krupa W, Johnson TL, Nerem RM, Goronzy JJ et al. Vesselwall embedded dendritic cells induce T-cell autoreactivity and initiate vascular in‐

[28] Weyand CM, Ma-Krupa W, Pryschep O, Groschel S, Bernardino R, Goronzy JJ. Vas‐ cular dendritic cells in giant cell arteritis. Ann N Y Acad Sci 2005; 1062: 195-208 [29] Chang K, Rizzo F. Recent advances in the immunopathology of giant cell arteritis. Int

[30] Pryschep O, Ma-Krupa W, Younge BR, Goronzy JJ, Weyand CM. Vessel specific Tolllike receptor profiles in human medium and large arteries. Circulation 2008; 118:

[31] Deng J, Ma-Krupa W, Gewirtz AT, Younge BR, Goronzy JJ, Weyand CM. TLR4 and

[32] Weyand CM, Tetzlaff N, Bjornsson J, Brack A, Younge BR, Goronzy JJ. Disease pat‐ terns and tissue cytokine profiles in giant cell arteritis. Arthritis Rheum 1997; 40:

[33] Brack A, Geisler A, Martinez-Taboada VM, Younge BR, Goronzy JJ, Weyand CM. Giant cell vasculitis is a T cell-dependent disease. Mol Med 1997; 3: 530-43

[34] Grunewald J, Andersson R, Rydberg L, Gigliotti D, Schaufelberger C, Hansson GK et al. CD4+ and CD8+ T cell expansions using selected TCR V and J gene segments at

[35] Schaufelberger C, Andersson R, Nordborg E, Hansson GK, Nordborg C, Wahlstrom J. An uneven expression of T cell receptor V genes in the arterial wall and peripheral

[36] Weyand CM, Schonberger J, Oppitz U, Hunder NN, Hicok KC, Goronzy JJ. Distinct vascular lesions in giant cell arteritis share identical T cell clonotypes. J Exp Med

TLR5 induce distinct types of vasculitis. Circ Res 2009; 104(4): 488-95

the onset of giant cell arteritis. Arthritis Rheum 1994; 37: 1221-7

blood in giant cell arteritis. Inflammation 2008; 31: 372-83

425-7

Pathol 2002; 161: 1815-23

J Exp Med 2004; 199: 173-83

Springer Semin Immunopathol 2000; 22: 345-69

flammation. Circ Res 2008; 102: 546-53

Ophthalmol Clin 2009; 49: 99-109

1276-84

19-26

1994; 179: 951-60


[23] Yilmaz A, Arditi M. Giant cell arteritis: DCs take two T's to tango. Circ Res 2009; 104: 425-7

[11] Pietro-Gonzalez S, Arguis P, Garcia-Martinez A, Espigol-Frigole G, Tavera-Bahilo I, Butjosa M et al. Large vessel involvement in biopsy-proven giant cell arteritis: pro‐ spective study in 40 newly diagnosed patients using CT angiography. Ann Rheum

[12] Nuenninghoff DM, Hunder GG, Christianson TJ et al. Mortality of large-artery com‐ plication (aortic aneurysm, aortic dissection and/or large artery stenosis) in patients with giant cell arteritis: a population-based study over 50 years. Arthritis Rheum

[13] Gonzalez-Gay MA, Amoli MM, Garcia-Porrua C, Ollier WE. Genetic markers of dis‐ ease susceptibility and severity in giant cell arteritis and polymyalgia rheumatica.

[14] Alvarez-Rodriguez L, Lopez-Hoyos M, Carrasco-Marin E, Mata C, Calvo-Alen J, Aurrecoechea E et al. Analysis of the rs20541 (R130Q) polymorphism in the IL-13 gene in patients with elderly-associated chronic inflammatory diseases. Rheumatol

[15] Enjuanes A, Benavente Y, Hernandez-Rodriguez J, Queralt C, Yaque J, Jares P et al. Association of NOS2 and potential effect of VEGF, IL-6, CCL2 and IL-1rn polymor‐ phisms and haplotyoes on susceptibility to GCA. A simultaneous study of 130 poten‐

[16] Palomino-Morales R, Torres O, Vazquez-Rodriguez TR, Morado IC, Castaneda S, Callejas-Rubio JL et al. Association between toll-like receptor 4 gene polymorphism

[17] Mohammadi A, Pfeifer JD, Lewis JS Jr. Association between human papilloma virus

[18] Cooper RJ, D'Arcy S, Kirby M, Al-Buhtori M, Rahman MJ, Proctor L et al. Infection and temporal arteritis: a PCR-based study to detect pathogens in temporal artery bi‐

[19] Elling P, Olsson AT, Elling H. Synchronous variations in the incidence of temporal arteritis and polymyalgia rheumatica in Danish countries. Association with epidem‐

[20] Duhaut P, Bosshard S, Ducroix JP. Is giant cell arteritis an infectious disease? Biologi‐

[21] Mohan SV, Liao J, Kim JW, Goronzy JJ, Weyand CM. Giant cell arteritis: immune and

[22] Weyand CM, Younge BR, Goronzy JJ. IFN-γ and IL-17: The two faces of T cell path‐

ics of Mycoplasma pneumoniae infection. Ugeskr Laeger 1997; 159: 4123-8

cal and epidemiological evidence. Presse Med 2004; 33: 1403-8

ology in giant cell arteritis. Curr Opin Rheumatol 2011; 23: 43-9

vascular aging as disease risk factors. Arthritis Res Ther 2011; 13: 231

tially functional SNPs in 14 candidate genes. Rheumatology 2012; 51: 841-51

and biopsy-proven giant cell arteritis. J Rheumatol 2009; 36: 1501-6

DNA and temporal arteritis. BMC Musculoskelet Disord 2012; 13: 132

Dis 2012; 71: 1170-6

106 Updates in the Diagnosis and Treatment of Vasculitis

2003; 48: 3532-7

Semin Arthritis Rheum 2003; 33: 38-48

Clin 2012 Jun 27 (Epub ahead of print)

opsy specimens. J Med Virol 2008; 80: 501-5


[37] Deng J, Younge BR, Olshen RA, Goronzy JJ, Weyand CM. Th17 and Th1 T-cell re‐ sponses in giant cell arteritis. N Engl J Med 2009; 361: 1114-6

[50] Ghinoi A, Pipitone N, Nicolini A, Boiardi L, Silingardi M, Germano G et al. Largevessel involvement in recent-onset giant cell arteritis: a case-control colour-Doppler

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

http://dx.doi.org/10.5772/55222

109

[51] Evans JK, Bowles CA, Bjornsson J, Mullany CJ, Hunder GG. Thoracic aortic aneur‐ ysm and rupture in giant cell arteritis. A descriptive study of 41 cases. Arthritis

[52] Noel B. An easy and safe procedure for temporal artery biopsy. J Cutan Med 2006;

[53] Lehmann P, Buchtala S, Achajew N, Haerle P, Ehrenstein B, Lighvani H et al. 18F-FDG PET as a diagnostic procedure in large vessel vasculitis-a controlled, blinded re-

[54] Chan M, Lugmani R. Pharmacotherapy of vasculitis. Expert Opin Pharmacother

[55] Hoffman GS, Cid MC. A multicenter, randomized, double-blind, placebo-controlled trial of adjuvant methotrexate treatment for giant cell arteritis. Arthritis Rheum 2002;

[56] Jover A. Combined treatment of giant-cell arteritis with methotrexate and predni‐ sone. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 2001;

[57] Langford CA. Drug insight: anti-tumor necrosis factor therapies for the vasculitic dis‐

[58] Seitz M, Reichenbach S, Bonel HM, Adler S, Wermelinger F, Villiger PM. Rapid in‐ duction of remission in large vessel vasculitis by IL-6 blockade. A case series. Swiss

examination of routine PET scans. Clin Rheumatol 2011; 30(1): 37-42

sonography study. Rheumatology 2012; 51(4): 730-4

eases. Nat Clin Pract Rheumatol. 2008; 4(7): 364-70

Rheum 1994; 37(10): 1539-47

10(3): 147-50

2009; 10(8): 1273-89

46(5): 1309-18

134(2): 106-14

Med Wkly 2011; 141: w13156


[50] Ghinoi A, Pipitone N, Nicolini A, Boiardi L, Silingardi M, Germano G et al. Largevessel involvement in recent-onset giant cell arteritis: a case-control colour-Doppler sonography study. Rheumatology 2012; 51(4): 730-4

[37] Deng J, Younge BR, Olshen RA, Goronzy JJ, Weyand CM. Th17 and Th1 T-cell re‐

[38] Deng J, Younge BR, Olshen RA, Goronzy JJ, Weyand CM. Th17- and Th1-cell re‐

[39] Basu A, Hoerning A, Datta D, Edelbauer M, Stack MP, Calzadilla K et al. Cutting edge: Vascular endothelial growth factor-mediated signalling in human CD45RO +CD4+ T cells promotes Akt and ERK activation and costimulates IFN-gamma pro‐

[40] Kaiser M, Weyand CM, Bjornsson J, Goronzy JJ. Platelet-derived growth factor, inti‐ mal hyperplasia and ischemic complications in giant cell arteritis. Arthritis Rheum

[41] Mesquita D, Cruvinel WM, Camara NOS, Kallas EG, Andrade LEC. Autoimmune

[42] Eid RE, Rao DA, Zhou J, Lo SF, Ranjbaran H, Gallo A et al. Interleukin-17 and inter‐ feron-gamma are produced concomitantly by human coronary artery-infiltrating T cells and act synergistically on vascular smooth muscle cells. Circulation 2009; 119:

[43] Rodriguez-Pla A, Bosch-Gil JA, Rosello-Urgell J, Huguet-Redecilla P, Stone JH, Vilar‐ dell-Tarres M. Metalloproteinase-2 and -9 in giant cell arteritis: involvement in vas‐

[44] Johnson C, Galis ZS. Matrix metalloproteinase -2 and -9 differentially regulate smooth muscle cell migration and cell-mediated collagen organization. Arterioscler

[45] Kaiser M, Younge BR, Bjornsson J, Goronzy JJ, Weyand CM. Formation of new vasa vasorum in vasculitis. Production of angiogenic cytokines by multinucleated giant

[46] Hunder GG, Bloch DA, Michel BA, Stevens MB, Arend WB, Calabrese LH et al. The American College of Rheumatology 1990 criteria fort he classification of giant cell ar‐

[47] Campisi J, d'Adda di Fagagna F. Cellular senescence: when bad things happen to

[48] Wang M, Monticone RE, Lakatta EG. Arterial aging: a journey into subclinical arteri‐

[49] Bossert M, Prati C, Balblanc JC, Lohse A, Wendling D. Aortic involvement in giant

sponses in giant cell arteritis. N Engl J Med 2009; 361: 1114-6

sponses in giant cell arteritis. Circulation 2010; 121: 906-15

diseases in the Th17 era. Braz J Med Biol Res 2009; 42: 47-86

cular remodelling. Circulation 2005; 112: 264-9

Thromb Vasc Biol 2004; 24: 54-60

cells. Am J Pathol 1999; 155: 765-74

teritis. Arthritis Rheum 1990; 33: 1122-8

good cells. Nat Rev Mol Cell Biol 2007; 8: 729-40

al disease. Curr Opin Nephrol Hypertens 2010; 19: 201-7

cell arteritis: Current data. Joint Bone Spine 2011; 78(3): 246-51

duction. J Immunol 2010; 184: 545-9

1998; 41: 623-33

108 Updates in the Diagnosis and Treatment of Vasculitis

1424-32


**Chapter 5**

**Giant Cell Arteritis and Arteritic Anterior Ischemic Optic**

Ischemic optic neuropathies (IONs) are a major cause of blindness or seriously impaired vision in the middle-aged and elderly population, although they can occur at any age. ION is of two types: anterior (AION) and posterior (PION), the first involving the anterior part of the optic nerve (also called the optic nerve head, ONH) and the second, the rest of the optic nerve. Pathogenetically AION and PION are very different diseases. AION represents an acute ischemic disorder (a segmental infarction) of the ONH supplied by the posterior ciliary arteries (PCAs), while PION has no specific location in the posterior part of the optic nerve and does

Blood supply blockage can occur with or without arterial inflammation. For this reason, AION is of two types: non-arteritic AION (NA-AION) and arteritic AION (A-AION). The former is far more common than the latter, and they are distinct entities etiologically, pathogenetically,

A-AION is an ocular emergency and requires immediate treatment with systemic corticoste‐ roids to prevent further visual loss. This is almost invariably due to giant cell arteritis (GCA), which is a primary vasculitis that affects extracranial medium (especially external carotid artery-ECA-branches) and sometimes large arteries (aorta and its major branches)-large-vessel GCA [3, 4]. The diagnosis of GCA requires age more than 50 years at disease onset, new headache in the temporal area, temporal artery tenderness, and/or reduced pulse, jaw claudication, systemic symptoms, erythrocyte sedimentation rate (ESR) exceeding 50 mm/hr, and typical histologic findings (granulomatous involvement) in temporal artery biopsy (TAB) [5]. Approximately 40-50% of patients with GCA have ophthalmologic complications, including visual loss secondary to A-AION, central retinal artery occlusion, homonymous

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hemianopsia or cortical blindness (uni- or bilateral occipital infarction) [6].

**Neuropathies**

http://dx.doi.org/10.5772/55345

**1. Introduction**

Dragos Catalin Jianu and Silviana Nina Jianu

Additional information is available at the end of the chapter

not represent ischemia in a specific artery [1].

clinically and from the management point of view [1, 2].
