Diagnosis and Treatment of Giant Cell Arteritis

Drugs Aging 2008; 25 (4): 281-297 1170-229X/08/0004-0281/$48.00/0 THERAPY IN PRACTICE  2008 Adis Data Information BV. All rights reserved. Diagnosis and Treatment of Giant Cell Arteritis Fabrizio Cantini,1 Laura Niccoli,1 Carlotta Nannini,1 Michele Bertoni1 and Carlo Salvarani2 1 2 2nd Division of Medicine, Rheumatology Unit, Hospital Misericordia e Dolce, Prato, Italy Division of Rheumatology, Hospital S. Maria Nuova, Reggio Emilia, Italy Contents Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 281 1. Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 282 2. Relationship with Polymyalgia Rheumatica (PMR) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 283 3. Aetiology, Pathogenesis and Pathology of Giant Cell Arteritis (GCA) . . . . . . . . . . . . . . . . . . . . . . . . . 284 4. Clinical Manifestations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 284 5. Onset Patterns of GCA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 286 5.1 Typical Cranial GCA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 287 5.2 Typical Cranial GCA with Associated PMR . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 287 5.3 GCA with Normal Erythrocyte Sedimentation Rate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 287 5.4 PMR with Silent GCA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 287 5.5 Fever of Unknown Origin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 288 5.6 Isolated Vision Disturbances and Vision Loss with Occult GCA . . . . . . . . . . . . . . . . . . . . . . . . . . . 288 5.7 Isolated Extra-Cranial Large-Vessel GCA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 288 5.8 Rarer Presentations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 289 6. Laboratory Examinations in GCA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 289 7. Temporal Artery Biopsy Histological Findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 289 8. Diagnostic Steps for GCA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 290 8.1 Temporal Artery Biopsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 290 8.2 Imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 290 9. Differential Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 290 10. Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 291 10.1 Corticosteroids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 291 10.1.1 Initial Dose . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 291 10.1.2 Tapering . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 291 11. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 293 Abstract Giant cell arteritis (GCA) is a chronic granulomatous vasculitis of unknown aetiology occurring in the elderly. It affects the cranial branches of the arteries originating from the aortic arch and is usually associated with markedly elevated acute-phase reactants. In 10–15% of cases the extra-cranial branches of the aortic Cantini et al. 282 arch are involved. GCA is closely related to polymyalgia rheumatica (PMR), although the relationship between the two disorders is still unclear. New-onset headache, scalp tenderness, jaw claudication, temporal artery abnormalities on physical examination, visual symptoms and associated PMR represent the most typical and frequent features of the disease. Systemic manifestations, including fever, anorexia and weight loss, are observed in 50% of cases. Less frequent manifestations are related to the central or peripheral nervous systems, the respiratory tract and extra-cranial large-vessel involvement. As GCA is characterized by a wide spectrum of clinical manifestations, it is important to recognize the different onset patterns of the disease and related diagnostic steps. The diagnosis is relatively straightforward in the presence of typical cranial manifestations, but it may be challenging in the case of a normal erythrocyte sedimentation rate, occult GCA or in patients with isolated extra-cranial features. Temporal artery biopsy still represents the gold standard for diagnosis, while the role of ultrasonography, high-resolution magnetic resonance imaging and positron emission tomography should be better addressed. Corticosteroids remain the therapy of choice. Data supporting the usefulness of antiplatelet agents and anticoagulants combined with corticosteroids to prevent ischaemic complications as well as the corticosteroidsparing effect of methotrexate and anti-tumour necrosis factor-α drugs are limited and non-conclusive. Giant cell arteritis (GCA) is a chronic granulomatous vasculitis of large and medium size vessels that occurs in the elderly. Symptomatic vessel inflammation usually involves the cranial branches of the arteries originating from the aortic arch; in around 10–15% of cases the branches of the aortic arch, particular the subclavian and axillary arteries, become narrowed and result in claudication of the arm.[1] Although the relationship between an inflamed temporal artery and headache with visual symptoms was noted in ancient Egypt,[2] the first complete description of the clinical characteristics of GCA was provided by Hutchinson[3] in 1890. In 1932, Horton et al.[4] described the granulomatous involvement of the temporal artery, and almost a decade later Gilmore[5] pointed out the presence of giant cells as the hallmark of the inflammatory infiltrate. GCA is also known as temporal arteritis, cranial arteritis or Horton’s arteritis. All these designations do not fully highlight the different aspects of  2008 Adis Data Information BV. All rights reserved. the disease. Indeed GCA, which is actually the most frequent designation in the medical literature, denotes the presence of giant cells as the typical pathological finding, although this is detected in only around 50% of cases.[6] The designations ‘temporal arteritis’ or ‘cranial arteritis’ emphasize the prominent involvement of temporal arteries or other cranial arteries, but fail to include the extra-cranial vessel involvement. 1. Epidemiology GCA is the most frequent form of systemic vasculitis in adults in Western countries.[1] Epidemiological studies have shown a stable incidence of around 20/100 000 people aged >50 years, with a peak between 70 and 80 years of age.[1,7] Women are affected at least twice as often as men. A cyclical pattern of increased annual incidence rates every 7 years has been demonstrated in Olmsted County, MN, USA.[8] The frequency of GCA is higher at Drugs Aging 2008; 25 (4) GCA Diagnosis and Therapy 283 Table I. Main features of isolated polymyalgia rheumatica (PMR) and giant cell arteritis (GCA) Feature PMR GCA Frequency (in people aged >50 y) 751.9/100 000 17.8/100 000 Age of onset (y) >50 >50 Sex (female/male) 3/1 3–4/1 Site of the inflammatory process Proximal articular and extra-articular synovial structures Medium- and large-size arteries Clinical manifestations Systemic signs/symptoms (fever, anorexia, weight loss) Systemic signs/symptoms (fever, anorexia, weight loss) Pain and stiffness in the neck, shoulder and pelvic girdles New-onset headache, scalp tenderness, eye and CNS ischaemic manifestations Distal articular features in 40% of cases Neuropathies in 14% of cases Absence of internal organ involvement Widespread vasculitis in 15% of cases Possible internal organ involvement (kidney, lung, heart) Laboratory findings Marked elevation of ESR and CRP Marked elevation of ESR and CRP Histological appearance Mild synovitis with predominance of macrophages and CD4+ T cells Granulomatous infiltrate with CD4+ T cells and macrophages in the artery wall, with or without giant cells, associated with disruption of the internal elastic lamina Therapy Rapid response to 20 mg/day of prednisone or equivalent Rapid response to 40–60 mg/day of prednisone or equivalent Prognosis Favourable: corticosteroid-related adverse events Less favourable: blindness, other ischaemic adverse events, late occurrence of thoracic aortic aneurysms, corticosteroid-related adverse events CRP = C-reactive protein; ESR = erythrocyte sedimentation rate. higher latitudes and in people with a strong Scandinavian ethnic background;[8,9] it decreases in southern European countries such as Spain and Italy,[10,11] and is very low in Japan.[12] Previously reported low incidence rates of GCA in Black and Hispanic individuals should probably be revised upward. Indeed, in an 11-year retrospective study, Gonzalez et al.[13] found that in the Texas Gulf Coast polymyalgia rheumatica (PMR) and biopsy-proven GCA were as frequent in Black as in White individuals, and Lam et al.[14] reported a similar frequency of the disease in Hispanic and non-Hispanic Americans. 2. Relationship with Polymyalgia Rheumatica (PMR) The relationship between PMR and GCA has been widely accepted since the early 1960s when the frequent association of the two diseases became increasingly recognized.[15,16]  2008 Adis Data Information BV. All rights reserved. As summarized in table I, when occurring in isolation, PMR and GCA are characterized by different clinical features, and the only clinical characteristics shared by the two conditions are their association with marked elevation of acute-phase reactants, their systemic symptoms and signs (fever, malaise or fatigue, anorexia and weight loss) and their dramatic response to corticosteroids, although at different doses. Thus, as shown in table I, the two disorders appear different from a clinical point of view and PMR, especially when distal manifestations are present, resembles late-onset rheumatoid arthritis more than vasculitis, while GCA, when clinical features of large-vessel involvement are present, is more similar to Takayasu’s disease, from which it differs only with respect to age of onset. Nevertheless, epidemiological data suggest a possible relationship between PMR and GCA and many authorities consider them to be different phases of the same disease.[17,18] However, other Drugs Aging 2008; 25 (4) Cantini et al. 284 investigators consider that GCA and PMR are different but frequently overlapping conditions.[19] In GCA clinical series, PMR has been found in 40–60% of cases.[1] Conversely, in PMR series, GCA has been reported in 16–21% of cases. However, evidence of a possible common genetic background or aetiological viral trigger, or that patients with PMR have a forme fruste of vasculitis, is weak.[20] In this regard, while in most populations GCA is generally associated with HLA-DRB1*04 alleles, this does not seem to be always the case for patients with isolated PMR.[21] These findings lead us to conclude that PMR and GCA frequently occur together for reasons that remain unclear and no definitive conclusions can be drawn with regard to the nature of this association.[20] 3. Aetiology, Pathogenesis and Pathology of Giant Cell Arteritis (GCA) The triggering role of an infectious agent for GCA has been repeatedly suspected but not confirmed. A close concurrence between the observed incidence peaks of GCA and epidemics of Mycoplasma pneumoniae, parvovirus B19 and Chlamydia pneumoniae has been reported,[22,23] together with an increased prevalence of antibodies to adenovirus and respiratory syncytial virus.[24] However, most of these studies were performed on small series of patients, usually not exceeding 20–30 cases, and did not have sufficient statistical power to prove their hypotheses. Furthermore, conflicting results have been reported regarding the aetiological role of C. pneumoniae and parvovirus B19.[25-29] Other investigators have focused on the possible aetiological role of human parainfluenza virus type 1,[30] but the positive findings reported in that study were not confirmed by others.[31] These data show that more studies about the role of infections in GCA are required.  2008 Adis Data Information BV. All rights reserved. According to the model of pathogenesis of GCA postulated by Weyand and Goronzy,[32] an unknown antigen is recognized in the adventitia by T cells that enter the artery through the vasa vasorum. After activation, CD4+ T cells expand clonally and produce interferon-γ with consequent macrophage differentiation and migration, followed by formation of granuloma and giant cells. The secretion of macrophages seems to be different depending on their location in the arterial wall.[32] The macrophages produce the proinflammatory cytokines interleukin (IL)-1 and IL-6 in the adventitia, metalloproteinases with tissue-digesting capabilities in the media and nitric oxide synthase-2 in the intima. This destructive mechanism within the arterial wall is associated with a repair mechanism related to the secretion of growth and angiogenic factors. The ultimate outcome is degradation of the internal elastic lamina and the occlusive luminal hyperplasia, leading to the typical histological features of GCA. 4. Clinical Manifestations GCA symptoms may be related to the systemic inflammatory process, to the vascular inflammatory injury itself or to ischaemia caused by artery lumen narrowing or occlusion.[33] Systemic symptoms including fever, malaise, anorexia and weight loss are present in about 50% of patients.[34,35] Fever is usually low grade but can reach 39–40°C in about 15% of cases.[36] A new-onset headache is probably the most frequent symptom and occurs in two-thirds of patients.[37] The pain is located over the temporal or occipital areas, but may be less well defined. It is usually continuous throughout the day, often hampers sleep and is poorly responsive to analgesics, but may sometimes spontaneously subside over weeks.[35] On physical examination, the frontal or parietal branches of the superficial temporal arteries may be thickened, nodular, tender or occasionally erythemDrugs Aging 2008; 25 (4) GCA Diagnosis and Therapy atous (figure 1). Absent or decreased pulsation may also be appreciated. The occipital arteries and, less often, the post-auricular or facial arteries may be enlarged or tender.[1] Scalp tenderness occurs in around 50% of cases and is usually localized to the temporal and less commonly the occipital arteries, but may be diffuse.[1] When touching the scalp or combing their hair, patients describe a diffuse tenderness or painful ‘pin-pricking’ sensation; these findings occur most often in patients with a headache. Physical examination may occasionally disclose areas of scalp necrosis related to territorial ischaemia, and ischaemic lesions of the tongue may concomitantly occur.[38] The temporo-parietal regions are most frequently affected, and lesions usually heal within a few months after commencement of treatment.[39] Around 40% of patients experience jaw claudication due to muscle ischaemia,[36] and a reduction in jaw opening mimicking trismus may occasionally 285 be observed.[40] Intermittent claudication may simultaneously affect the muscles of the tongue or those involved in swallowing.[34] Visual symptoms have been reported in 25–50% of patients with GCA.[34,41-43] Permanent partial or complete loss of vision in one or both eyes has been observed in <20% of patients, and earlier recognition and treatment of the disease have reduced the incidence of this severe and often precocious manifestation.[44] Affected patients typically describe the feeling of ‘a shade covering one eye’, which may progress to total blindness. If untreated, the second eye is likely to become affected within 1–2 weeks. Once established, visual impairment is usually permanent. Visual loss is caused by occlusion of the branches of the ophthalmic or posterior ciliary arteries and, less commonly, of the retinal arterioles. When posterior ciliary arteries are occluded the early funduscopic appearance is ischaemic optic neuritis with slight pallor, oedema of the optic disc and scattered cotton-wool patches; in the case of ophthalmic artery occlusion, retinal stroke aspects with small haemorrhages leading to ‘cherry red spots’ are observed.[1,44] Amaurosis fugax is an important visual symptom that precedes permanent visual loss in 44% of patients.[42] Diplopia or visual hallucinations occur less frequently.[41-45] Neurological manifestations occur in approximately 30% of patients.[46] In around 14% of patients these consist of neuropathies, including mononeuropathies and peripheral polyneuropathies of the upper or lower extremities.[47] Less common are transient ischaemic attacks or strokes in the territory of the carotid or vertebro-basilar artery. Respiratory symptoms such as a non-productive cough, sore throat and hoarseness occur in about 10% of patients.[48] Fig. 1. Typical temporal artery involvement in giant cell arteritis. The left superficial temporal artery is thickened and tender.  2008 Adis Data Information BV. All rights reserved. Large extra-cranial artery GCA is seen in approximately 10–15% of cases.[49] The inflammatory process most frequently affects the aortic arch and its branches, particularly the subclavian and axillary Drugs Aging 2008; 25 (4) Cantini et al. 286 arteries, which become narrowed to produce upper extremity claudication.[50] In such cases, typical cranial symptoms of GCA may be absent due to an undetected diagnosis or to a different pathobiology of the disease leading to a distinct subset of patients.[51] Upper or less frequently lower limb claudication, thoracic discomfort and detection of bruits with decreased or absent pulses on examination, in association with elevated acute-phase reactants, should raise the suspicion of GCA in such cases. Population-based studies from Mayo Clinic, Rochester, MN, USA have shown that thoracic aortic aneurysms are 17 times more common in patients with GCA than in non-affected people.[52] A similar incidence was reported in a study conducted in northwestern Spain.[53] This complication usually occurs several years after the diagnosis and often after the patient’s other symptoms have subsided. The aneurysm may rupture and cause the patient’s death.[54] PMR may occur before, concomitantly or after the onset of GCA in around 60% of patients.[55] As shown in table II, two sets of criteria are currently used in clinical practice for the diagnosis of Table II. Diagnostic criteria for polymyalgia rheumatica (PMR) Chuang et al.[56] (1982) Age ≥50 y Bilateral aching and stiffness persisting for ≥1 mo involving two of the following areas: neck or torso, shoulders or proximal regions of the arms and hips or proximal aspects of the thighs Erythrocyte sedimentation rate >40 mm/h Exclusion of other diagnoses except giant cell arteritis The presence of all of the above criteria defines PMR diagnosis Healey[57] (1984) Persistent (≥1 mo) pain involving two of the following areas: neck, shoulders and pelvic girdle Morning stiffness lasting >1 h PMR.[56,57] These two sets of criteria are focused on the typical clinical picture of PMR characterized by discomfort in the musculoskeletal structures of the neck, shoulder and pelvic girdles in association with prolonged morning stiffness and marked elevation of acute-phase reactants. Shoulder pain is the presenting finding in the majority (70–95%) of patients.[55] Hips and neck are less frequently involved (between 50% and 70%).[55] In both shoulder and pelvic girdles the pain usually radiates distally toward the elbows and knees. The discomfort may begin on one side, but soon becomes bilateral. In about 30% of cases, distal musculoskeletal manifestations are observed, including acute carpal tunnel syndrome, joint synovitis and distal extremity swelling with pitting oedema; internal organ involvement is usually absent.[58,59] Systemic signs and symptoms such as low-grade fever, depression, fatigue, anorexia and weight loss occur in up to 40% of patients.[55] The frequent association of PMR and GCA has suggested a common vasculitic process. However, studies performed with positron-emission tomography (PET) appear to exclude this hypothesis. In patients with untreated biopsy-proven large-vessel GCA, this diagnostic procedure reveals increased fluorodeoxyglucose uptake in the thoracic aorta and both the subclavian and axillary arteries, but no evidence of vascular involvement is detectable in isolated PMR, in which increased uptake is evident in the shoulder and pelvic girdles.[60] Moreover, imaging studies have shown that the inflammatory process of PMR generally affects extraarticular synovial structures, mostly joint bursae.[61-64] 5. Onset Patterns of GCA Rapid response to prednisone (≤20 mg/day) Absence of other diseases capable of causing the musculoskeletal symptoms Age >50 y Erythrocyte sedimentation rate >40 mm/h The diagnosis of PMR is made if all of the above criteria are satisfied  2008 Adis Data Information BV. All rights reserved. The diagnosis of GCA should be considered in any patient >50 years of age and is relatively easy to make in patients with typical features. Careful clinical history taking and physical examination with detection of ischaemic symptoms and temporal arDrugs Aging 2008; 25 (4) GCA Diagnosis and Therapy tery abnormalities should suggest the need for blood examinations, which usually show elevated erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), anaemia and raised platelet count. In the presence of these findings, patients should undergo a temporal artery biopsy. However, GCA is characterized by a wide spectrum of clinical manifestations associated with different patterns of disease onset, as illustrated in sections 5.1–5.8. 5.1 Typical Cranial GCA Typical cranial GCA is the most frequent pattern.[34] The onset tends to be gradual but can also be abrupt. The clinical history is that of an aged patient, more frequently a female >70 years of age, who begins to complain of headache located in the fronto-temporal areas, scalp tenderness and jaw claudication, generally associated with a low-grade fever and other systemic symptoms and signs including arthralgia, fatigue, anorexia and weight loss. Temporal artery abnormalities with thickening, nodularity, reduced pulsation and tenderness on physical examination, together with laboratory examinations showing marked elevation of ESR and CRP, make the diagnosis straightforward. 5.2 Typical Cranial GCA with Associated PMR The association of typical cranial features of GCA with those of PMR occurs in around 50% of patients.[34,36] The clinical picture is more severe than in isolated GCA, and patients often overlook the cranial symptoms and consult the family physician about pain and loss of function in the girdles. Therefore, in the presence of a patient with the typical clinical picture of PMR, a careful clinical history to detect cranial and visual symptoms and an accurate physical examination of temporal arteries is recommended.  2008 Adis Data Information BV. All rights reserved. 287 5.3 GCA with Normal Erythrocyte Sedimentation Rate The diagnosis of GCA should not be excluded in patients with one or more manifestations suggestive of the disease but normal ESR.[65] In a recent study of 136 patients with biopsy-proven GCA, we found that absence of systemic manifestations together with an elevated platelet count and lower ESR and CRP values was predictive of development of permanent visual loss.[66] Consistent with other investigators,[41] we found a low risk of blindness after commencement of corticosteroid therapy: this event occurred only in 1 of 136 patients. Therefore, when clinical suspicion is sufficiently high, corticosteroid therapy should be started immediately and a temporal artery biopsy carried out soon after. 5.4 PMR with Silent GCA In around 40% of cases, PMR constitutes the presenting feature of GCA, and only later do patients develop typical cranial manifestations of the disease.[34] Population-based studies from different geographical areas have more precisely demonstrated the presence of biopsy-proven GCA in 16–21% of patients with PMR.[67,68] However, patients with PMR who do not have cranial symptoms and signs have a very high probability of having normal findings on temporal artery biopsy. Our experience confirms these data. PMR occurred in 42 of 92 (45.6%) patients with biopsy-proven GCA observed over a 5-year period (1996–2000) at Prato Hospital.[20] PMR occurred before GCA onset in eight patients, simultaneously in 21 patients and after GCA onset in 13 patients. Conversely, we found 12 of 76 (15.7%) consecutive patients satisfying the Healey criteria[57] for the diagnosis of PMR (table II) who also had histological evidence of GCA.[69] However, only 1 (1.3%) of these 12 patients had no clinical manifestations of GCA. In other PMR series, GCA was heralded by the presence of systemic symptoms Drugs Aging 2008; 25 (4) 288 and an ESR >80 mm/h.[70] Usually, we perform a temporal artery biopsy only in the presence of systemic symptoms, cranial signs and/or symptoms and an ESR >80 mm/h. Alternatively, PMR patients without symptoms and signs of GCA might be investigated by duplex ultrasonography,[71] but the sensitivity of this non-invasive diagnostic tool is limited.[69] 5.5 Fever of Unknown Origin Up to 15% of patients with GCA may present with fever of unknown origin (FUO).[35] In a population-based study, the incidence of fever, defined as an axillary temperature of ≥38°C at the time of admission or during follow-up prior to the onset of corticosteroid therapy, in biopsy-proven GCA patients was 10% and 2 of 210 patients presented to the hospital with FUO.[72] The patient’s temperature may reach 39°C, and in the majority of cases presents as shaking associated with sweating, thereby mimicking septic or neoplastic fever. GCA is responsible for only 2% of all FUO, but causes up to 16% of FUO in patients >65 years of age.[35] Therefore, in the presence of a febrile aged patient, the classic diagnostic algorithm to investigate FUO may be simplified by excluding those disorders typical of younger people.[73] Once malignancies and tuberculosis have been excluded, a normal white blood cell count, which is normally elevated in the presence of infection, and elevated levels of alkaline phosphatase should alert physicians to the possible diagnosis of GCA. A temporal artery biopsy should be performed to confirm the diagnosis, and a contralateral biopsy may be required if the first biopsy is negative.[1] 5.6 Isolated Vision Disturbances and Vision Loss with Occult GCA Previously described visual disturbances and sudden vision loss (see section 4) may represent the first isolated manifestations of otherwise clinically  2008 Adis Data Information BV. All rights reserved. Cantini et al. silent GCA.[43] Cranial symptoms may be absent or so mild as to be overlooked by both the patient and physicians. In a prospective, 22-year study, 18 of 85 (21.2%) patients with GCA and ocular involvement had otherwise clinically silent disease, with no cranial or systemic manifestations.[74] All 18 patients presented with visual loss of varying severity, six patients (33.3%) had amaurosis fugax, two patients (11.1%) had diplopia and one patient (5.6%) had eye pain. These data provide an important message for clinicians: people >50 years of age presenting with vision disturbances such as amaurosis fugax and/or permanent partial or complete visual loss caused by ischaemia of the optic nerve or, less commonly, by occlusion of the central retinal artery should be suspected as having GCA and rapidly evaluated for acute-phase reactants. In cases of raised ESR or CRP, or both, corticosteroid therapy should be promptly commenced and a temporal artery biopsy performed as soon as possible. 5.7 Isolated Extra-Cranial Large-Vessel GCA Population-based studies from Mayo Clinic have demonstrated the possibility of a distinct clinical subset of GCA characterized by arteritis of the aortic arch and its main branches.[49-51] Therefore, isolated extra-cranial large-vessel GCA should be suspected in an elderly patient with chest pain, radiating to the interscapular area, or with symptoms related to reduced blood flow in the upper extremities. Lower extremities are less frequently involved. This clinical suspicion is reinforced by the detection on physical examination of arterial bruits and diminished or unpalpable radial or ulnar pulses in association with elevation of acute-phase reactants.[50] The diagnosis may be confirmed by CT and magnetic resonance angiography, and/or by arteriography that demonstrates segments of smoothly tapered stenosis and/or occlusion, almost always bilateral, preferentially located in the subclavian and axillary arteries, or thoracic aorta aneurysms or dissections.[51] In recent Drugs Aging 2008; 25 (4) GCA Diagnosis and Therapy 289 Table III. American College of Rheumatology 1990 criteria for the classification of giant cell arteritis (GCA) [traditional format][82]a Criterion Definition Age at disease onset ≥50 y Development of symptoms or findings beginning at age 50 y or older New headache New onset of or new type of localized pain in the head Temporal artery abnormality Temporal artery tenderness to palpation or decreased pulsation, unrelated to arteriosclerosis of cervical arteries Elevated erythrocyte sedimentation rate Erythrocyte sedimentation rate ≥50 mm/h by the Westergren method Abnormal artery biopsy Biopsy specimen with artery showing vasculitis characterized by a predominance of mononuclear cell infiltration or granulomatous inflammation, usually with multinucleated giant cells a For purposes of classification, a patient with vasculitis is considered to have GCA if at least three of the five criteria above are present. The presence of any three or more criteria yields a sensitivity of 93.5% and a specificity of 91.2%. years, PET has been proposed as a means of evaluating patients with large-vessel GCA.[60] In such cases, PET shows an increased F18-fluorodeoxyglucose uptake in the aorta and its primary branches. However, the diagnostic role of PET remains uncertain and needs to be addressed further in controlled studies. 5.8 Rarer Presentations Severe anaemia,[75] scalp necrosis,[39] pericardial[76] and pleural effusions,[77] dry cough and toothache,[78] central or peripheral nervous system symptoms[79,80] and female genital tract involvement[81] as the first symptoms of GCA have been described in sporadic case reports and very small clinical series. All of these cases were observed in elderly patients with occult GCA. In these cases, only histological findings or the occurrence of additional features of GCA may lead the clinician to the correct diagnosis. 6. Laboratory Examinations in GCA Laboratory findings in GCA are nonspecific with no immunological marker associated with the disease. A markedly elevated ESR represents the hallmark of GCA and an ESR of ≥50 mm/h has been included in the GCA classification criteria formulated by the American College of Rheumatology (ACR)[82] [table III]. However, a ‘normal’ ESR (<50 mm/h) does not exclude the diagnosis. A recent  2008 Adis Data Information BV. All rights reserved. population-based study from the Mayo Clinic reported that 5.4% of patients with GCA had an ESR <40 mm/h at diagnosis and 10.8% had an ESR <50 mm/h.[65] In a previous study, 24% of patients with biopsy-proven GCA had a ‘normal’ ESR before starting corticosteroids.[83] Therefore, the occurrence of GCA with a normal ESR is not a rare event. Unlike ESR, CRP is not influenced by the number and shape of erythrocytes, circulating immunoglobulins, hypercholesterolaemia or renal function. Consequently, CRP has been demonstrated as a more sensitive indicator of disease activity than ESR both at diagnosis and during relapse/ recurrence of GCA.[84,85] IL-6 level has been reported as an accurate indicator of inflammatory activity in GCA[83] but the test is not routinely available in most clinical laboratories. A modest anaemia of chronic disease is present in about two-thirds of patients and mildly abnormal liver function tests, particularly alkaline phosphatase, in up to about one-third of patients.[1] 7. Temporal Artery Biopsy Histological Findings The classic histological picture of GCA, observed in 50% of cases, is characterized by granulomatous inflammatory infiltrate with giant cells located usually at the intima-media junction.[6] The other 50% of cases show a mixed-cell inflammatory infilDrugs Aging 2008; 25 (4) Cantini et al. 290 trate predominantly consisting of lympho-mononuclear cells, occasional neutrophils and eosinophils, without giant cells. In rare patients the only histological abnormality may be a small-vessel vasculitis surrounding a spared temporal artery.[86] The inflammation affects the arteries in a segmental or focal fashion, and the inflammatory process is usually more severe in the inner portion of the media adjacent to the disrupted internal elastic lamina.[1] Given these pathological features, at least two key points need to be considered in terms of obtaining the correct diagnosis: first, because of the segmental involvement of the arterial wall, temporal artery biopsy specimens >1.5 cm in length should be obtained; second, the presence of giant cells is not mandatory for the diagnosis of GCA (although histological confirmation, if possible, is advisable). 8. Diagnostic Steps for GCA 8.1 Temporal Artery Biopsy Criteria for the classification of GCA were formulated by the ACR in 1990[82] (table III). These criteria do not necessarily require a biopsy for the classification of GCA. Although the ACR criteria were designed for research, clinicians often apply them in the diagnostic process; however, they have low sensitivity in individual patients.[87] A temporal artery biopsy is recommended for all patients suspected of having GCA.[1,88] If the temporal artery is abnormal at inspection, a specimen of around 1.5 cm in length needs to be removed for histopathological review. When extra-cranial arteries are normal and GCA suspected, it is important to biopsy a longer segment of temporal artery (>1.5 cm) and consider a contralateral biopsy if the first side is normal. Using this approach, only 10% of patients with GCA were biopsy negative.[65] When possible, a temporal artery biopsy should be performed before initiating treatment; however, temporal artery biopsy specimens may show arteritis even  2008 Adis Data Information BV. All rights reserved. after more than 2 weeks of corticosteroid therapy.[89] Therefore, in a patient at risk for visual loss, therapy should not be postponed while waiting for a biopsy. 8.2 Imaging A role for colour duplex ultrasonography in the diagnosis of GCA was proposed by Schmidt et al.,[71] who found that a dark halo around the lumen of temporal arteries was specific for GCA diagnosis. However, we found that ultrasonography does not improve the diagnostic accuracy of a careful physical examination, and we therefore do not routinely employ this technique.[69] Other studies have subsequently confirmed the limited role of ultrasonography for the diagnosis of GCA, although this easy-to-perform method may be useful for allowing a directional, less invasive temporal artery biopsy.[90] When there is clinical suspicion of extra-cranial GCA, the diagnostic modalities required are arteriography, CT scanning and magnetic resonance angiography.[1] High-resolution magnetic resonance imaging can reveal inflammatory changes in the walls of the superficial temporal arteries in GCA.[91,92] However, more studies should be performed to define the diagnostic accuracy of this imaging method for GCA. The diagnostic accuracy of PET is also not clearly defined.[60] Interestingly, this examination might be useful for diagnosing GCA in patients with FUO.[93] 9. Differential Diagnosis Primary systemic amyloidosis may present with features of PMR and/or GCA.[94] Therefore, in patients with a monoclonal band on immunoelectrophoresis who do not respond to corticosteroids, an appropriate staining of temporal artery specimens for amyloid should be performed. Generally, there is little difficulty in distinguishing GCA from other vasculitis because of the different distribution of lesions, histopathology and organ Drugs Aging 2008; 25 (4) GCA Diagnosis and Therapy involvement. However, the histopathological and radiographic findings of GCA may sometimes be indistinguishable from those observed in Takayasu’s arteritis or isolated angiitis of the CNS. Consideration of the age of the patient and the distribution of lesions allows the proper diagnosis.[1] 10. Treatment Treatment of GCA involves several challenges because of the fragility of the individuals requiring therapy. Patients with GCA are aged and frequently have important co-morbidities, including osteoporosis, atherosclerosis, hypertension, cardiac failure and diabetes mellitus. In this setting, a wide selection of therapies that could be tailored to individual patients to suppress inflammation and avoid major complications relating both to the disease itself and to the patient’s underlying health status would be the preferred option. Unfortunately, although many efforts have been and are currently being made, clinicians are far from this imaginary state, and high-dose corticosteroids remain the mainstay of treatment.[1] However, in this article we suggest a treatment strategy that takes into account the patient’s co-morbidities. 10.1 Corticosteroids 10.1.1 Initial Dose A starting corticosteroid dose of at least 40–60 mg of prednisone in single or divided doses is required to achieve rapid symptom relief after a few days and a significant reduction in the incidence of ocular manifestations and blindness.[1] Data from the Mayo Clinic confirm that after the introduction of corticosteroid therapy, permanent visual loss in patients with GCA decreased from 19% to 6% when the period 1950–69 was compared with that of 1980–5.[95] In addition to the efficacy of corticosteroid therapy, this reduction is probably also related to increased awareness of the disease by physicians,  2008 Adis Data Information BV. All rights reserved. 291 which in turn facilitates earlier diagnosis. Alternateday scheduling of corticosteroid therapy does not appear to offer any advantage compared with daily treatment.[96] Initial intravenous pulse methylprednisolone (1000 mg every day for 3 days) can be tried in patients with recent or impending visual loss.[1] Corticosteroids may prevent but usually do not reverse fixed visual loss and, once this complication has been established, visual recovery has been reported in only a minority of patients. In a recent randomized, double-blind, controlled, single-centre trial of 27 patients with biopsy-proven GCA, induction therapy with high-dose, pulse intravenous methylprednisolone resulted in a more rapid tapering of oral corticosteroids and a higher frequency of sustained remissions with a significant reduction in the corticosteroid cumulative dose.[97] However, these results need to be confirmed by studies involving a larger number of patients. 10.1.2 Tapering The decision to reduce corticosteroid dosage should be supported by clinical remission of symptoms and signs and normalization of markers of inflammation. With this in mind, regular monitoring of clinical manifestations and ESR or CRP values is the most useful way of following patients.[1] In the absence of controlled studies of the rate of reduction of corticosteroids and the optimal maintenance dose and duration of corticosteroid therapy, management of GCA is based largely on the individual clinician’s judgement. However, the following treatment schedule is suggested by the majority of experts in this field. The initial dose should usually be maintained for 2–4 weeks, after which it can be gradually reduced by a maximum of 10% of the total daily dose every 2 weeks until a dose of 10 mg/day is reached. Subsequently, corticosteroid dosage can be reduced by 1–2.5 mg/day every 4 weeks until the suspension of therapy.[1] Drugs Aging 2008; 25 (4) Cantini et al. 292 If corticosteroid doses are reduced or withdrawn too quickly, relapse or recurrence of symptoms usually occurs. However, in about 30–50% of patients, spontaneous exacerbations of disease occur, more frequently in the first 2 years, regardless of the corticosteroid reduction schedule.[98] Flare-ups and relapses require escalation of the corticosteroid dose to the level at which symptoms were previously controlled. A treatment course of 1–2 years is often required. However, some patients may have a more chronic, relapsing course and require low doses of corticosteroids for several years.[36] No consistently reliable predictors of duration of corticosteroid therapy have been identified. One investigation suggested that measuring IL-6 levels after 4 weeks of therapy was helpful for identifying patients with different disease severities.[83] Corticosteroid-related adverse events are frequently observed during the course of treatment. Age at diagnosis, cumulative dose of prednisone of approximately 2 g or more and female gender have been shown to independently increase the risk of adverse events, especially bone fractures.[99,100] Therefore, baseline measurement of bone mineral density is recommended. If normal, calcium and vitamin D supplementation should be added in all patients. If a reduced bone mineral density is detected, bisphosphonates are indicated.[101] As recently reported, low-dose aspirin (acetylsalicylic acid) or warfarin appear to be useful for significantly reducing the rate of ischaemic events with no increased risk of bleeding complications for both drugs.[102,103] However, the retrospective nature of these studies does not allow definitive conclusions to be drawn. Moreover, in another populationbased study, a reduction in the incidence of severe ischaemic complications in GCA patients receiving antiplatelet therapy prior to the onset of GCA symptoms was not found.[104]  2008 Adis Data Information BV. All rights reserved. HMG-CoA reductase inhibitors (statins) interfere with inflammatory immune mechanisms shared by atherosclerosis and GCA and have therefore been employed as adjunctive therapy to reduce corticosteroid requirements in patients with GCA. However, the results of a retrospective study of this approach were disappointing.[105] The treatment indications described above are usually adopted for patients with extra-cranial largevessel GCA. However, it is unclear if the ESR and CRP closely reflect the degree of inflammation of the aorta and its branches. Therefore, the response to therapy in terms of controlling wall inflammation and preventing arterial stenosis, and the best times to taper and discontinue corticosteroid therapy, are often difficult to assess in these patients.[51] When arterial stenoses occur, balloon angioplasty restores vessel patency in almost all patients (figure 2), and while long-term results show that there is a high rate a b c d Fig. 2. Large-vessel giant cell arteritis. (a) Occlusion of the left axillary artery with absence of distal arterial circulation; (b) appearance immediately after balloon angioplasty with stenting implantation; (c) double critical stenosis of the right axillary artery; (d) appearance immediately after balloon angioplasty and stenting implantation. Drugs Aging 2008; 25 (4) GCA Diagnosis and Therapy of restenosis, this can be successfully re-treated using the same procedure.[106] To date, there is no definitive evidence for the efficacy of immunosuppressive or cytotoxic drugs as corticosteroid-sparing agents in GCA. Methotrexate has been used as a corticosteroid-sparing drug with conflicting results. In a randomized, placebo-controlled, single-centre study of 42 patients with GCA, Spanish investigators reported a significant efficacy for methotrexate in terms of reducing the number of relapses and the cumulative corticosteroid dose.[107] However, these results were not confirmed in a subsequent multicentre study of 96 patients.[108] Nevertheless, methotrexate may be given to patients who need high doses of corticosteroids to control active disease but have serious adverse effects from these drugs.[1] The vasculitis of GCA is characterized by infiltration of the vessel wall by macrophages, giant cells and T lymphocytes with production of many cytokines that are responsible for the acute-phase response.[109] Tumour necrosis factor-α (TNFα), which is released by macrophages and activated T lymphocytes, plays a major role in the inflammatory response. Immunohistochemical techniques have shown that TNFα is present in up to 60% of cells in all areas of inflamed arteries, a finding that suggests that TNFα could play a primary role in the GCA inflammatory process.[110] These data provide the rationale for the employment of anti-TNFα drugs in patients with GCA. Case reports and small clinical series have documented the efficacy of infliximab, etanercept and adalimumab in controlling the inflammatory process of GCA and sparing corticosteroids in patients with either early or long-standing disease.[111-115] However, these promising results were not confirmed by a double-blind, placebocontrolled, multicentre study that failed to show a corticosteroid-sparing effect of infliximab in patients with newly diagnosed GCA at the 6-month interim analysis.[116] Notwithstanding this finding, a  2008 Adis Data Information BV. All rights reserved. 293 corticosteroid-sparing effect of infliximab might be seen over a longer follow-up period, or in patients with relapsing disease. In our opinion, further studies are required to investigate the efficacy of antiTNF drugs with respect to disease control in longstanding GCA and in selected clinical series of patients with co-morbidities that contraindicate long-term, high-dose corticosteroid administration. In our current clinical practice we successfully use anti-TNFα drugs to treat selected patients with relapsing disease and contraindications to corticosteroid use, such as patients with poorly controlled diabetes, hypertension and bone fractures. 11. Conclusion GCA is characterized by a wide spectrum of onset patterns and clinical manifestations that may make the diagnosis difficult with a consequent delay in instigation of the proper therapeutic approach. Typical cranial GCA, with or without associated PMR, is usually easy to diagnose, but other presentations including GCA with normal ESR, PMR with silent GCA, FUO, isolated vision disturbances with occult GCA and isolated extra-cranial GCA often represent a challenge for clinicians. Temporal artery biopsy still represents the gold standard for the diagnosis of GCA. Although corticosteroids remain the mainstay of treatment, the therapeutic approach should take into account the patient’s co-morbidities and drugs such as methotrexate or anti-TNF agents may be tried in selected cases. Acknowledgements No sources of funding were used to assist in the preparation of this article. The authors have no conflicts of interest that are directly relevant to the content of this article. References 1. Salvarani C, Cantini F, Boiardi L, et al. Polymyalgia rheumatica and giant cell arteritis. N Engl J Med 2002 Jul 25; 347 (4): 261-71 Drugs Aging 2008; 25 (4) 294 2. Portioli I. 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Ann Intern Med 2007 May 1; 146 (9): 621-30 Correspondence: Dr Fabrizio Cantini, 2nd Division of Medicine, Rheumatology Unit, Hospital Misericordia e Dolce, Piazza Ospedale, 1, 59100, Prato, Italy. E-mail: [email protected] Drugs Aging 2008; 25 (4) View publication stats