giant cell arteritis: an updated review

Historical perspective

One of the earliest recorded observa-tions of giant cell arteritis (GCA)dates from the 10th century, whenoculist Ali Ibn Isa of Baghdadremarked on the relationship betweeninflamed arteries and muscles andvisual symptoms in his book, TheTadhkirat (Ibn Isa 1936). His pro-posed treatment was excision of thetemporal arteries. ‘By these means onetreats not only migraine and headachein those patients that are subject to

chronic eye disease, but also, acute,sharp catarrhal affections, includingthose showing heat and inflammationof the temporal muscles. These dis-eased conditions may terminate in lossof eye sight…’ The first description inthe English literature is attributed toHutchinson (1890), who was asked toconsult on an 80-year-old man for red‘streaks on his head’ that were so pain-ful as to prevent his wearing a hat(Hutchinson 1890). The red streakswere, in fact, inflamed and swollentemporal arteries. Interestingly, no

mention of any other clinical symp-toms or signs were noted and the natu-ral course of this man’s conditionproved self-limiting and benign. Thefirst histopathological evidence of agranulomatous vasculitis in the tempo-ral arteries was reported by Hortonet al. (1932) in two patients. These twopatients had systemic symptoms offever, weakness and anaemia as well asscalp tenderness and painful temporalarteries. In a later publication, thesame authors expanded the clinicalcharacterization of the then-unknowndisease to include pain with chewingfood, headache, double vision andvisual loss. This disease, now com-monly called GCA, still carries the epo-nym ‘Horton’s disease’. Various otherterms have also been used to refer tothis inflammatory vasculopathy affect-ing large- and medium-sized arteries,including thrombotic arteritis, granu-lomatous arteritis, cranial arteritis andtemporal arteritis. In this article, theterm GCA is favoured.

Polymyalgia rheumatica (PMR) isanother common inflammatory syn-drome in elderly patients. PMR ischaracterized primarily by bilateralshoulder or pelvic girdle aching andmorning stiffness but it has a diverseclinical profile that often overlaps withother rheumatic and inflammatoryconditions, including GCA (systemicmanifestations, elevation of serummarkers and favourable response tosteroids). Over one third of patientswith GCA have PMR at presentation;conversely, about one third of patients

Review Article

Giant cell arteritis: an updatedreview

Aki Kawasaki1 and Valerie Purvin2

1Department of Neuro-ophthalmology, Hopital Ophtalmique Jules Gonin,

Lausanne, Switzerland2Departments of Ophthalmology and Neurology, Midwest Eye Institute and IndianaUniversity, Indiana, USA

ABSTRACT.

Giant cell arteritis (GCA) is the most common primary vasculitis of adults.

The incidence of this disease is practically nil in the population under the age

of 50 years, then rises dramatically with each passing decade. The median age

of onset of the disease is about 75 years. As the ageing population expands, it

is increasingly important for ophthalmologists to be familiar with GCA and its

various manifestations, ophthalmic and non-ophthalmic. A heightened aware-

ness of this condition can avoid delays in diagnosis and treatment. It is well

known that prompt initiation of steroids remains the most effective means for

preventing potentially devastating ischaemic complications. This review sum-

marizes the current concepts regarding the immunopathogenetic pathways that

lead to arteritis and the major phenotypic subtypes of GCA with emphasis on

large vessel vasculitis, novel modalities for disease detection and investigative

trials using alternative, non-steroid therapies.

Key words: anterior ischaemic optic neuropathy – giant cell arteritis – inflammation – temporal

arteritis

Acta Ophthalmol. 2009: 87: 13–32ª 2008 The Authors

Journal compilation ª 2008 Acta Ophthalmol

doi: 10.1111/j.1755-3768.2008.01314.x

Acta Ophthalmologica 2009

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with PMR have systemic manifesta-tions like fever, weight loss and anor-exia (Dasgupta et al. 2007). Somepatients may have both PMR andGCA syndromes simultaneously; oth-ers evolve from one condition to theother. Among patients with pure PMRclinically, the incidence of a positivetemporal artery biopsy is 10–20%(Hunder 2006). While it is clear thatthese two disorders are related, themechanisms by which they are linkedremain uncertain. Because similar his-topathological findings may be foundin both PMR and GCA, the distinctionbetween them is clinical (diagnosticcriteria, laboratory findings, diseaseevolution, imaging studies).

Epidemiology andrisk factors of GCA

GCA is the most common primaryvasculitis of adults in the Westernworld (Weyand & Goronzy 2003); itsgeographical distribution suggests agreater susceptibility with increasinglynorthern latitude. The worldwideannual incidence rate of GCA rangesfrom 1.28 to 29.1 per 100 000 amongpersons aged 50 years or more (Ram-stead & Patel 2007). Highest rates arefound in White individuals of north-ern European descent (e.g. about30 ⁄100 000 in Norway) and lowestrates are found in African, Asian andArab populations (e.g. 1.47 ⁄100 000in Japan) (Hunder 2002; Miller 2007).The actual prevalence of the diseasemay be underestimated based on clini-cal incidence rates: one autopsy seriesfrom Sweden showed evidence ofGCA in 1.2% of temporal arteries(Ostberg 1971). There is a gender pre-dilection favouring women, who areaffected 2–6 times more commonlythan men (Salvarani et al. 2004). Ithas been speculated that some of thisfemale predisposition is reflective ofthe higher proportion of women inthe elderly population. Seasonal clus-tering in the late spring–early summermonths has been reported by severalgroups but is not observed regularly(Salvarani et al. 2004; Smeeth et al.2006).

A genetic predisposition has beensuspected from reports of increasedprevalence among first-degree relativesand occasional familial forms of GCA(Fietta et al. 2002; Raptis et al. 2007).

GCA is a polygenic disorder, and dis-ease susceptibility has been associatedwith selected genes located within thehuman leucocyte antigen (HLA) classI and class II regions, particularlyHLA DRB1*04 (Weyand et al. 1992;Gonzalez-Gay et al. 2007b). Othergenes, particularly those related tocytokine and chemokine expression,can modulate the clinical expressionof GCA. For example, polymorphismsat the tumour necrosis factor-a locusand the interleukin (IL)-10 promoterregion have correlated independentlyto an increased risk of developingGCA and polymorphisms; genesencoding vascular endothelial growthfactor (VEGF), interferon-c and plate-let glycoprotein receptor are associ-ated with increased risk of ischaemiccomplications in GCAC Rueda et al.2007; Salvarani et al. 2007a).

All factors considered, the singlegreatest risk factor for GCA is age(Nordborg et al. 2003). From a popu-lation-based study in the UK, the inci-dence rate of GCA rose markedly to60 ⁄10 000 when only persons aged80 years or older were considered(Smeeth et al. 2006). The median ageof onset is about 75 years. Cases ofGCA reported in persons youngerthan 50 years must be highly excep-tional (Hunder 2002; Langford 2006).

Pathogenesis: anoverview

Two different immunopathogeneticprocesses underlie the clinical manifes-tations of GCA (Weyand & Goronzy2003). One is a systemic inflammatoryreaction that results from over-activa-tion of the innate acute phaseresponse, a non-antigen-driven, non-adaptive defence mechanism to stressand injury. The acute-phase responseinvolves a cascade of chemical signals,driven in large part by IL-6, whichderives from circulating monocytes,neutrophils and macrophages (Gor-onzy & Weyand 2002). The serumlevel of IL-6 generally reflects theintensity of the response and corre-lates with circulating levels of theother acute-phase proteins such asC-reactive protein, serum amyloid A,haptoglobin, fibrinogen and comple-ment. Clinical manifestations relatedto the acute-phase response are non-specific markers of inflammation,

including fever, night sweats, anor-exia, myalgias and weight loss.

The second process in GCA repre-sents a maladaptive, antigen-specificimmune response that directs anattack on arterial walls in GCA andis responsible for the focal ischae-mic complications of GCA. Takentogether, the innate response is thebasis for the systemic inflammatorysyndrome of GCA while the antigen-specific response mediates the arteritis.These two pathogenetic componentsare parallel yet inter-related processes,and one component may dominatethe picture in any given individual.

The vasculitis of GCA

A complete understanding of theimmunological events that lead toarterial wall inflammation anddestruction is not fully established. Itis accepted that the arteritis of GCAis an adaptive antigen-driven, T-cell-mediated process; the inflammatoryinfiltrate is composed primarily ofCD4 T-cells and macrophages (Wey-and et al. 2004). But what triggers theprocess? A microbial pathogen as theinstigating agent has been a popularbut still unsubstantiated hypothesis.Another hypothesis holds forth thatthe triggering antigen may be anendogenous element within the arterialwall. Age-related calcifications in thelamina, elastin and extracellular matrixproteins have been proposed and mayexplain the age-specific expression ofGCA (Ma-Krupa et al. 2005).

GCA displays a peculiar preferencefor certain large- and medium-sizedarteries while rarely affecting othervessels of similar calibre. Commonlyaffected vessels include the ascendingaorta, the extracranial branches of thecarotid artery, the subclavian andaxillary arteries and the vertebralarteries; involvement of the descend-ing aorta, coronary arteries, mesen-teric arteries and femoral arteries isunusual (Weyand & Goronzy 2003).The intracerebral arteries are typicallyspared from the vasculitic attack ofGCA, presumably because of the pau-city of elastic tissue in their walls.Such vascular tropism implicates thearterial wall itself as an importantparticipant in the propagation of animmune attack (Fig. 1) (Weyand et al.2004).


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Activation of T-cells

GCA preferentially affects arterieswith a certain architecture: walls com-posed of three well-developed layers(an outer adventitia, a muscular med-ial layer and an intima) separated byan elastic lamina. It is the arterialadventitia that is the site of the pri-mary immunological injury (Weyandet al. 2004) and there are two struc-tural reasons for this. In medium- andlarge-sized arteries, only the adven-titial layer is vascularized with acapillary network (the vasa vasorum),whereas the medial and intimal layersare avascular. Via the vasa vasorum,T-cells and macrophages gain accessto the arterial wall. Access from theluminal side is not feasible becausethe strong shearing forces generated

by the high velocity of blood flowthrough these large arteries prohibitcell adhesion and entry. In addition,the adventitia harbours an indigenouspopulation of immunological surveil-lance cells, called dendritic cells, whichpatrol the outer layer of the arterialwall for possible intruders (Weyandet al. 2004, 2005; Ma-Krupa et al.2005). Under physiological conditions,these dendritic cells are immature,phagocytic, relatively quiescent cellsthat act to inhibit T-cell activation inthe perivascular space. Once activated,however, dendritic cells transform intopowerful antigen-presenting cells thatrecruit, prime and activate naive CD4T-cells against invading antigen in thetissue. It is this change in the func-tional status of dendritic cells that

marks a critical and early event in thedevelopment of vasculitis (Weyandet al. 2005). Thereafter, dendritic cellscan persist in the inflamed arterialwall and continue their stimulation ofT-cells, thus sustaining the inflamma-tory process chronically. Remarkably,in vitro blocking of the dendritic cellsabolishes T-cell functioning and theinflammatory process aborts (Weyandet al. 2004).

Differentiation of macrophages

Once activated in situ, adventitial T-cells (typically CD4) undergo rapidclonal and secrete a potent cytokine,interferon-c, which in turn recruitsmacrophages and stimulates giant cellformation. This is a critical point in theimmunopathogenesis of GCA-relatedtissue infarction because macrophagesare the effector cells that cause arterialwall destruction. Macrophages havethe capacity to differentiate and gener-ate several distinct lines of effector cellsand thus acquire a broader spectrumof harmful actions. Macrophages inthe adventita focus on producinginflammatory cytokines that optimizeT-cell stimulation. Macrophages in themedia specialize in generating reactiveoxygen intermediates that induce lipidperoxidation of smooth muscle cellmembranes as well as metalloproteinaseenzymes that break down and digestthe internal elastic lamina (Weyand &Goronzy 2002a; Weyand et al. 2004).Macrophages at the media–intimajunction, along with multinucleatedgiant cells, form granulomas in themedial layer and release a variety ofgrowth factors and angiogenic factors,notably platelet-derived growth factor(PDGF) and VEGF (Goronzy &Weyand 2002).

Intimal hyperplasia and vascular

occlusion

Matrix metalloproteinases (MMPs),also derived from macrophages, arethe enzymes that degrade elastin(Rodriguez-Pla et al. 2005). Once theinternal elastic lamina is fragmented,the MMPs enhance migration ofsmooth muscle cells from the mediato invade the intima where they prolif-erate exuberantly under influence ofPDGF, causing intimal hyperplasiaand vessel occlusion. The expansionof the intima is necessarily accompa-nied by neoangiogenesis, driven by

Fig. 1. Schematic diagram of the adaptive immune responses in the arterial wall. The adventitia

is the site of the initial immune stimulation. T-cells (T) enter the artery through the vasa vaso-

rum to interact with indigenous dendritic cells, which, in turn, regulate T-cell and macrophage

(Mu) recruitment. The T-cell-produced cytokine, interferon (IFN)-c, controls differentiation of

infiltrating macrophages. The media is the site of oxidative damage. Medial macrophages, espe-

cially multinucleated giant cells (GC), produce growth factors and regulate the mobilization,

migration and proliferation of myofibroblasts. This results in rapid intimal hyperplasia and

expansion, causing vessel occlusion. Neoangiogenesis, distantly regulated by IFN-c, is necessaryto support the expanding intima. DC, dendritic cell; CCL, ROI-reactive oxygen intermediates;

MMP, matrix metalloproteinase. Reprinted from Weyand et al. (2004) with permission from

Elsevier.


15

VEGF, in order to support this previ-ously avascular layer.

T-cell differentiation is the chiefdeterminant of the extent and courseof the vascular inflammation. Thisevent occurs early in the disease pro-cess and determines the pattern andtypes of cytokines expressed in thewall tissue. High levels of interferon-cin biopsed tissue correlate well withsevere intimal hyperplasia, neovascu-larization, and luminal occlusion andtissue ischaemia (Weyand & Goronzy2002a). Low levels of tissue inter-feron-c and a predominance of IL-2are found in biopsy samples showingwall inflammation without develop-ment luminal occlusion (Brack et al.1999). The mechanisms that induce T-cell differentiation are still unclear butvarious host factors may play animportant role (e.g. genetic predisposi-tion). Among patients with GCA,concentrations of tissue cytokines andgrowth factors can vary widely butthey do correlate with each other andthe severity of intimal hyperplasia.Therefore, early evaluation of the pat-tern of cytokine expression in biopsiedtissue may provide a means to assessthe ischaemic risk or even predict theclinical course of the disease for anygiven individual.

Clinical subtypesof GCA

As stated earlier, a variety of endoge-nous and exogenous factors – forexample genetic make-up, arterialstructure, viral exposure, etc. – influ-ence the direction and severity of theimmunopathogenetic responses ofGCA. The vascular tropism, as yetincompletely understood, defines thelocation of the arteritis. Despite theprotean manifestations of this disor-der, three predominant clinical sub-types of GCA have emerged and they

can be distinguished by their clinicalprofile and cytokine pattern (Table 1).

Systemic inflammatory syndrome

This subtype of patients is character-ized by non-specific constitutionalsymptoms related to systemic inflam-mation in the absence of focal ischae-mic symptoms. Such patients haveasthenia, arthralgias, myalgias, achi-ness, anorexia, weight loss and nightsweats. A fever of unknown origin,which may be low-grade or spiking upto 40�C, is common and often gener-ates concern and investigations for anunderlying systemic infection ormalignancy. This has been referred toas ‘silent or masked GCA’, whichshould not be confused with ‘occultGCA’, a term coined for patients inwhom local ischaemic symptoms arepresent in the absence of systemicinflammation (Hayreh et al. 1998a;Liozon et al. 2003). Serologically,these patients typically have high sedi-mentation rates, elevated acute-phasereactants (including C-reactiveprotein, haptoglobin and fibrinogen),elevated liver function tests, low albu-min levels, thrombocytosis and anormocytic normochromic anaemia(Liozon et al. 2003). The serum levelof the inflammatory cytokine IL-6that derives from circulating mono-cytes is a sensitive indicator of an exu-berant systemic inflammatoryresponse (Goronzy & Weyand 2002;Weyand & Goronzy 2003). Suchpatients have histopathological evi-dence of arteritis without hyperplasiaof the arterial intima and withoutluminal stenosis. High levels of IL-2are found in the biopsy specimen ofthese patients (Brack et al. 1999).

Cranial arteritis

Patients with this clinical subtype ofGCA have predominantly a localizedvasculitis and subsequent tissueischaemia. The best-known example

of focal GCA is inflammation limitedto the branches of the carotid arteries,hence the name ‘cranial arteritis’.Common symptoms of cranial arteritisinclude headaches or facial pain, evencarotidynia, scalp tenderness, jawclaudication, painful dysphagia,hoarseness and visual loss. Necrosis ofthe scalp or tongue necrosis aredramatic but rare manifestations ofcranial GCA, inaugural in 1% or lessof cases (Becourt-Verlomme et al.2001; Campbell et al. 2003). Scalpnecrosis occurs only when all four sup-plying arteries are occluded, indicatingan extensive vasculitis and portendinga grim prognosis (Fig. 2). In patientswith scalp necrosis, the associatedmortality rate related to cerebral orcoronary artery occlusion is 41% andthe incidence of irreversible visual lossis 67% (Campbell et al. 2003).

In patients with cranial arteritis,arterial biopsy shows giant cell forma-tion, intense intimal hyperplasia, lumi-nal stenosis or obstruction, elevatedlevels of interferon-c and IL-1b andPDGF (Goronzy & Weyand 2002;Weyand & Goronzy 2003).

Large-vessel vasculitis

The third clinical subtype of GCA islimited to or dominated by involve-ment of the subclavian and axillaryarteries and ⁄or the aorta, oftentermed ‘extracranial large-vessel GCA’or ‘large-vessel vasculitis’ (Lie 1995;Bongartz & Matteson 2006). Large-vessel GCA is not a more aggressiveform of the disease, nor is it a chronicphase of the disease; it represents alocalized arteritis in a different vascu-lar bed compared to cranial arteritis.Local stenosis develops in the superiorbranches of the aortic arch, particu-lary the subclavian artery and axillaryartery. Vasculitic inflammation of theaorta leads to dilation, not stenosis,and aneurysm formation. Involvementof the large arteries to the lower

Table 1. Temporal artery cytokine patterns and disease heterogeneity.

Disease phenotype Interleukin-2 Interferon-c Interleukin-1b PDGF VEGF

Large vessel vasculitis (aortic arch syndrome, aortitis) ++ + + ?

Systemic inflammatory syndrome (fever, weight loss) ++ + + )Cranial arteritis (jaw claudication, visual loss) + +++ +++ +++

PDGF, platelet-derived growth factor; VEGF, vascular endothelial growth factor.

) indicates that cytokine transcript was not detected by polymerase chain reaction.

+ to +++ indicates that cytokine transcript was present at different levels.

Modified from Goronzy & Weyand (2002).


16

extremities occurs far less frequently(Lie 1995; Nuenninghoff & Matteson2003). The clinical profile of patientswith the large-vessel subtype of GCAreflects the vascular compromise inthe upper extremities. Arm claudica-tion and an arterial bruit are presentin 80% of patients; this may be theonly symptom at presentation and isfrequently bilateral (Brack et al.1999). Other symptoms are peripheralparesthesias, Raynaud phenomenon,paleness of the hands with use of theupper extremities and – rarely – tissuegangrene (Levine & Hellman 2002).Physical signs include diminished orabsent pulses, asymmetric blood pres-sure readings and bruits over the caro-tid, axillary, brachial or subclavianarteries. On the other hand, aortitis isclinically silent in the majorityof patients. Occasionally, patientsreport non-specific back pain. It is thesubsequent development of aneurysm,usually in the thoracic aorta, that isworrisome because in the event of anacute complication – aortic valveinsufficiency, aortic rupture or aorticdissection – mortality is tremendously

high (Nuenninghoff et al. 2003; Gonz-alez-Gay et al. 2004).

GCA as a cause of large-vessel vas-culitis can be overlooked for severalreasons. Firstly, many of thesepatients lack the systemic inflamma-tory symptoms and markers of GCA.Secondly, this form of the diseaseappears to evolve more slowly thanthe cranial arteritis form and anabrupt infarction of the hand or armis hardly ever seen. Ischaemic symp-toms in the upper extremities developgradually and may be so subtle as tobe dismissed by the patient or theclinician. Thirdly, the distribution andhistopathology of arterial inflamma-tion in large-vessel GCA can be indis-tinguishable from that found inTakayasu areteritis, and may createsome initial diagnostic confusion.However, the clinical setting (demo-graphic characteristics of the patient,presence of other clinical signs andassociated serum markers) shouldreadily distinguish GCA. Finally, thetemporal artery biopsy is negative inat least half of the patients with large-vessel vasculitis (Levine & Hellman2002; Weyand & Goronzy 2003;Bongartz & Matteson 2006).

Assessment of large-vessel vasculitisrequires vascular imaging. This can beachieved with invasive or non-invasivemodalities. With conventional catheterangiography, the characteristic find-ings are long segments of stenoses oflarge arteries alternating with seg-ments of normal arterial calibre andsmoothly tapering occlusions. Bilateralinvolvement of the subclavian, axillaryand brachial arterities is common(Stanson 2000; Bongartz & Matteson2006). Non-invasive modalities [com-puterized tomography (CT), magneticresonance imaging (MRI) or positronemission tomography (PET)] are cur-rently favoured for their ease and highsensitivity. CT scanning can demon-strate aortic involvement (thickeningof the wall) and aortic aneurysm for-mation (Herve et al. 2006). MRI find-ings of aortitis are aortic wallthickening, wall oedema, increasedmural contrast enhancement and vas-cular stenosis of aortic branch points.MRI angiography also allows visuali-zation of the aortic branches (cranial,cervical and thoracic) (Fig. 3) (Nar-vaez et al. 2004). MRI combined withMRI arteriogram (MRA) has theadvantage of examining the entire

large vessel tree in a single examina-tion. Introduced in 1999 for use inGCA, PET scanning has emerged asan alternative and highly effectivetechnique for assessing large-vesselvasculitis (Blockmans et al. 1999; Wal-ter et al. 2005). Active lymphocytes,macrophages and inflammation areaccompanied by accelerated anaerobicmetabolism and glucose consumption,which is readily identified in vivo with18F-fluoro-2-deoxy-d-glucose (FDG)PET. This makes FDG PET very sen-sitive in the detection of inflammationas well as for monitoring changes inactivity with treatment (Fig. 4) (DeLeeuw et al. 2004). However, oneunresolved concern with PET isspecifity: it is not clear that increasedvascular uptake is a finding specific tovasculitis or if it is simply a marker ofany type of wall injury (Bongartz &Matteson 2006). At this time, there isno gold-standard test for large-vesselvasculitis and imaging is selected onindividual considerations. A compara-tive multi-centre trial is under consid-eration to determine the most efficientuse of these different modalities inGCA.

Although large-vessel vasculitis maybe the initial presentation or the pre-dominant manifestation of GCA insome patients, in others large-vesselinvolvement develops as a late compli-cation of the disease – particularly aftersteroids have been tapered. It hasbeen estimated that one out of everyfive patients will eventually developan aortic aneurym and ⁄or dissection

(A)

(B)

Fig. 2. Two of the clinical manifestations of

cranial arteritis. (A) Photograph of an

enlarged and nodular left temporal artery

that is tender to palpation and pulseless. (B)

Haemorrhagic necrosis of the scalp in a

patient with giant cell arteritis (GCA). Rep-

rinted from Campbell et al. (2003) with per-

mission from Blackwell Publishers.

Fig. 3. Magnetic resonance imaging arterio-

gram (MRA) of large vessel involvement in

giant cell arteritis (GCA). Abnormal findings

are a proximal high-grade stenosis in the left

subclavian artery, stenosis in the region of

the left subclavian–axillary junction and mild

long segment narrowing of the proximal right

subclavian artery. From Bongartz & Matte-

son (2006) with permission from Lippincott,

Williams and Wilkins.


17

(Nuenninghoff & Matteson 2003). Thetrue incidence of extracranial large-vessel and aortic involvement in GCAis not known, ranging from 9% to27% in clinical series (Klein et al. 1975;Evans et al. 1995; Nuenninghoff &Matteson 2003; Schmidt & Gromnica-Ihle 2005). Studies using PET scan andautopsy series suggest that subclinicalaortitis is present in more than half ofGCA patients, leading to speculationthat aortitis may be the rule rather thanthe exception in GCA (Ostberg 1971;Blockmans et al. 2006). Despite suchhigh estimates of large-vessel involve-ment in GCA, it is an under-appreci-ated complication because most casesof aortitis are subclinical unless a cata-strophic event intervenes (3–11%)(Levine & Hellman 2002; Gonzalez-Gay et al. 2004).

The natural history of GCA-relatedaneursyms remains unknown. Who isat risk for the development of large-vessel complications is also unsettled.One study found that patients consid-ered high-risk for aortic aneurysm havea murmur of aortic insufficiency, PMRplus erythrocyte sedimentation rate(ESR) > 100 mm ⁄hr, or any two ofthe following: hypertension, hyperlip-idaemia, PMR, coronary artery disease(Bongartz & Matteson 2006). Giventhe potential morbidity and mortality

associated with aortic aneurysm,there is increasing consensus thatpatients with GCA need to be screenedfor early changes consistent withaneurysm formation. However, theadvanced age and other comorbidites(often multiple) in patients with GCAmean that not every patient whodevelops an aneurysm will be anacceptable candidate for surgicalrepair. An efficient screening strategyhas yet to be established but at themoment, one approach recommends aminimum of abdominal ultrasound,chest radiograph and transthoracicechocardiogram annually (Bongartz &Matteson 2006). Patients with anyof the risk factors presented here areadditionally recommended to have aCT or MRI angiography at the time oftheir diagnosis of GCA and again1 year later.

Clinical manifestationsof GCA

The spectrum of clinical manifesta-tions associated with GCA encom-passes a wide range of symptoms andsigns, ranging from non-specific com-plaints such as headache and generalachiness to specific organ dysfunctionsuch as visual loss, arm claudication

or stroke. The onset of symptoms,especially ischaemia-related ones, isfrequently explosive and most patientsmay be able to recall the day of onsetof a specific symptom. In otherpatients, symptoms may appear insidi-ously. Sometimes, there is a migratoryand changing nature of symptomsover an extended period of time sothat each symptom seems unrelated tothe next, and recognition that a singledisease entity accounts for the sumcomplex of signs and symptoms maybe overlooked.

Natural history

The natural history of GCA in non-fatal cases is best revealed fromdescriptions of the disease in the med-ical literature dating from the pre-ste-roid era. In 1971, Hamilton et al.noted that GCA ‘may unfold episodi-cally over a period of many years …and has the capabilities of healingspontaneously’(Hamilton et al. 1971).In describing the natural history ofPMR these authors stated that ‘Theactive disease may last from a fewmonths to 3 years or more, with exac-erbations and remissions. Eventualspontaneous recovery is the rule, evenwithout corticosteroid therapy’ (Ham-ilton et al. 1971). The remitting-relaps-ing nature of GCA is largelyunappreciated since the advent of ste-roid treatment, but several recent arti-cles have brought this aspect back tothe clinical consciousness. Patientswith jaw and leg claudication, fever,weight loss, myalgias, headache, scalptenderness, diplopia and even confu-sion experienced spontaneous remis-sion of their symptoms. In somepatients, the appearance of othersymptoms of GCA, including visualloss, within weeks to months of remis-sion eventually led to diagnosis andtreatment. In other patients, theremission lasted for many years (Her-nandez-Rodriguez et al. 2006; Purvin& Kawasaki 2007). However, one ofthe two patients with episodic tran-sient visual loss did suffer permanentischaemic optic nerve damage. Suchpatients serve to remind clinicians totake a careful retrospective history inany elderly patient, rather than justlooking for symptoms evident at thetime of presentation. Spontaneousremission of signs or symptoms doesnot rule out a diagnosis of GCA.

(A) (B)

Fig. 4.18F-fluoro-2-deoxy-d-glucose positron emission tomography-computerized tomography

(FDG PET-CT) scan of a patient with systemic inflammatory symptoms and markers consistent

with giant cell arteritis (GCA). (A) Initial 18FDG PET-CT scan reveals pathological 18FDG

accumulation along the wall of the aorta and its major branches (arrows) is characteristic of

GCA. (B) Scan after 3 months of oral corticosteroids shows near-complete resolution of abnor-

mal 18FDG uptake in the large vessels walls seen on the prior scan. From Szmodis ML, Reba

RC & Earl-Graef D (2007): Positron Emission Tomography in the diagnosis and management

of giant cell arteritis. Headache 47: 1216–1218, with permission from Blackwell Publishers.


18

Systemic manifestations

At least one symptom or sign of sys-temic inflammation such as anorexia,asthenia, malaise, myalgia, arthralgia,weight loss and fever can be found atpresentation in the majority ofpatients. The frequency at which theseconstitutional signs and symptomsmanifest in GCA is variable amongdifferent studies, in part because ofselection bias of patients, accuracy ofhistory-taking and the use of differentcriteria to diagnose GCA. In one largeseries examining the inaugural symp-toms of 260 patients with GCA, 65%reported an alteration in general well-being (asthenia, weight loss) and feverwas present in 50%; however, the esti-mates range from 38% to 90% and19% to 80%, respectively, for thesetwo symptoms in the literature (Hay-reh et al. 1997; Becourt-Verlommeet al. 2001; Levine & Hellman 2002).The myalgia of GCA is typically inthe large proximal muscles. Thus,patients may report an achiness andfatigue when raising their arms toreach upper shelves or difficulty get-ting out of a low chair or car. Somepatients have a paucity of symptomsor just an isolated abnormality such asunexplained weight loss or fever. Theclassic picture of an elderly patientwith new headache, jaw claudication,fever, anorexia, PMR and a tendertemporal artery is only seen in abouthalf to two thirds of patients, so theclinician must be able to recognizethe less typical presentations of thisdisorder (Levine & Hellman 2002).

Headache and craniofacial pain

The most common symptom of GCA,related to both systemic inflammationand local vascular injury in the caro-tid circulation, is headache. Headacheoccurs in up to 90% of patients, maysometimes localize to the temporaland occipital areas and is very fre-quently bilateral. A unilateral headachein GCA is uncommon (Rahman &Rahman 2005; Schmidt & Gromnica-Ihle 2005). Scalp tenderness is a moredistinctive symptom indicative of tis-sue ischaemia. Patients may reportdiscomfort when brushing or washingtheir hair; others develop such exqui-site sensitivity that even putting theirhead on a pillow becomes painful.

Perhaps the symptom most specificto GCA is jaw claudication, but this

is present in less than half (30–48%)of patients at presentation and maybe misdiagnosed as temporomandibu-lar joint syndrome (Hayreh et al.1997; Becourt-Verlomme et al. 2001;Weyand & Goronzy 2003). Unliketemporomandibular joint pain, whichis immediately present with any jawmovement, claudication pain due tomasseter muscle ischaemia developsafter a few minutes of masticationand then disappears with rest. Patientswith jaw claudication often avoid eat-ing chewy foods and meats. Jaw clau-dication stems from vasculitis andocclusive stenosis in the maxillaryartery, a branch of the external caro-tid artery, and (not surprisingly) cor-relates highly with positive findings onbiopsy of the temporal artery, whichis another branch of the external caro-tid artery (Hayreh et al. 1997; Schmidt& Gromnica-Ihle 2005). Accompany-ing jaw claudication may be painfullocalized swelling of the face or neck,particularly of the orbital region,cheeks and tongue. Such swelling hasbeen noted in 6.5% of patients in oneseries and implies widespread involve-ment of the external carotid artery(Liozon et al. 2006b).

Oral manifestations

GCA should be considered in anyelderly patient with unexplained odon-togenic pain. Other oral symptomsreported variably by patients withGCA are trismus, throat pain, dys-phagia, dysarthria, chin numbness,glossitis, lip or tongue necrosis andfacial swelling (Fig. 5) (Rockey &Anand 2002; Paraskevas et al. 2007).

Audiovestibular manifestations

In one recent study (Amor-Doradoet al. 2003), symptoms of hearing loss,tinnitus, vertigo, disequilibrium anddizziness were found in nearly two

thirds of patients. More remarkably,almost 90% of patients demonstratedabnormal function on one or moreobjective tests of audiovestibular func-tion. Vestibular dysfunction wasimproved in most patients after3 months of steroid treatment. How-ever, improvement of hearing loss wasmore modest, being seen in only 27%of patients.

Neurological manifestations

Cerebrovascular ischaemic events arefound in 3–4% of patients with GCA(Caselli et al. 1988; Gonzalez-Gayet al. 1998). Such events are caused byarteritic occlusion of the extraduralsegment of the vertebral or internalcarotid arteries or embolization froman inflammatory thrombus. In general,the vertebral arteries are affected moreoften than internal carotid arteries.The sparing of the intracranial seg-ment of these arteries has to do withthe loss or near-loss of the elastic tissueonce the arteries penetrate the dura atthe base of the brain (Wilkinson &Russell 1972). Nevertheless, on veryrare occasions, GCA has been docu-mented histologically in the wall ofintracranial arteries; such patientstypically have a fulminant course ofneurological decline to a fatal outcome(Salvarani et al. 2006).

Other neurological complicationsattributed to GCA include dementia,psychosis, coma, spinal cord infarc-tion, seizures and subarachnoid haem-orrhage. The more recent literaturesuggests that peripheral complications– namely neuropathies – may actuallybe the most common neurologicalcomplication of GCA (up to 14%).These may take various forms includ-ing cranial neuropathy, mononeuro-pathy multiplex, peripheral polyneuropathy, cervical radiculopathy, brachialplexopathy or pure motor neuropathy

(A) (B) (C)

Fig. 5. Three examples of ischaemic oral lesions caused by giant cell arteritis (GCA). (A)

Patient with tongue and lip infarction. (B) Cyanosis and oedema in the tongue. (C) A necrotic

lesion of the tongue. From Goicochea M, Correale J, Bonamico L et al. (2007): Tongue necro-

sis in temporal arteritis. Headache 47: 1213–1215, with permission from Blackwell Publishers.


19

(Caselli et al. 1988; Rahman & Rah-man 2005; Pfadenhauer et al. 2007).The preference for the cervical nerveroots and brachial plexus is probablyrelated to the frequent involvement ofthe subclavian, axillary and brachialarteries among patients with GCA.Most patients with a peripheral neuro-pathy related to GCA improve withsteroid treatment. The caveat is towatch for diaphragmatic weakness inthese patients: if the diagnosis is missedand steroids are withheld or inade-quately dosed, the outcome is poten-tially fatal (Pfadenhauer et al. 2007).

Cardiovascular manifestations

GCA can affect the coronary arteries,the aortic valve or the myocardium.Myocardial infarction, cardiomyo-pathy and aortic valve insufficiencyhave been reported. Left ventriculardysfunction has been reported in upto 18% of patients with GCA (Eber-hardt & Dhadly 2007).

Atherosclerosis, once viewed as anage-related process of lipid depositionand degeneration of arteries, isincreasingly viewed as an immune-mediated disorder. Inflammation andendothelial dysfunction lead to pro-gress of atherosclerosis and plaquedestabilization (Weyand & Goronzy2002). There is, in addition, growingevidence showing premature athero-sclerosis in chronic inflammatory con-ditions such as systemic lupuserythematosus, rheumatoid arthritisand Takayasu’s arteritis (Bacon et al.2002). Whether atherosclerosis occursmore frequently among patients withGCA is as yet unsettled. Smoking andprevious atheromatous disease havebeen associated independently withGCA in women (Duhaut et al. 1998).A recent large series of 432 patientsfound that patients with GCA have atwofold increase in relative risk forischaemic cardiovascular events suchas stroke, angina or myocardialinfarction compared to the generalpopulation (Le Page et al. 2005). Incontrast, another study reported nosignificant differences in the intima-media thickness of the common caro-tid artery – a marker of generalizedatherosclerosis – and concluded thatthe prevalence of atherosclerotic mac-rovascular disease was not higher inGCA patients (Gonzalez-Juanateyet al. 2007).

Bowel infarction

Bowel infarction frommesenteric arteryocclusion caused by GCA is decidedlyrare: one review found 11 cases in theEnglish literature since 1976 (Anna-malai et al. 2007). Absence of cranialsymptoms was noted in nearly half ofthe cases and bowel infarction was theinitial presention in two patients. Itshould be remembered that other vas-culitides such as polyarteritis nodosa,Churg-Strauss, rheumatoid vasculitis,Takayasu arteritis and Buerger diseasecan also cause localized vasculitis ofthe gastrointestinal tract; mesentericangiography is the gold standard fordifferentiating vasculitis of any causefrom other causes of bowel infarction.

Occult GCA

GCA has been called the great mas-querader because it can take on manyclinical forms; when systemic manifes-tations are minimal or absent, thesehave been termed the ‘occult manifes-tations’ of GCA or ‘occult GCA’.Diagnosis in such cases can be partic-ularly challenging, especially if seruminflammatory markers are also normal(Man & Dayan 2007). Occult GCAmay occur in 5–38% of cases (Carrollet al. 2006). Patients with occult GCAtypically seek medical attentionbecause of dysfunction with a particu-lar organ system (such as acute visualloss), respiratory symptoms (such aschronic cough or sore throat), peri-pheral neuropathy, dementia, stroke,coronary ischaemia, pulmonary arterythrombosis, haematuria, renal failureand mesenteric infarction (Hayrehet al. 1998a; Levine & Hellman 2002).GCA can even present as a tumour-like lesion of the breast, ovary oruterus (Onuma et al. 2007). Thus, it isimportant that non-rheumatologicalspecialists such as ophthalmologists,neurologists, cardiologists, nephrolo-gists, oncologists and even gynaecolo-gists maintain a heightened awarenessfor these less common manifestationsof GCA because they may be the firstpersons to evaluate such patients.

Ophthalmologicalmanifestations of GCA

Ocular manifestations are a commonoccurrence in patients with GCA andmay arise at any point in the naturalcourse of the disease or even during

active treatment. Different studies haveestimated the frequency of ocular man-ifestation at between 14% and 70%;the wide range perhaps reflects in partwhether populations from tertiary cen-tres or non-ophthalmic clinics wereassessed (Rahman & Rahman 2005). Intwo large series, visual symptoms orocular findings were present at the timeof their initial visit in 26% and 50%of patients, respectively (Hayreh et al.1998b; Gonzalez-Gay et al. 2000).Visual loss is by far the most commonocular manifestation of GCA – presentin 97.7% of patients – compared to dip-lopia (6–21%) and other more unusualophthalmological presentations (Hayrehet al. 1998b; Gonzalez-Gay et al. 2000).One historical point merits mention: theintroduction of corticosteroid treatmentfor GCA has reduced dramatically thepercentage of patients with permanentvisual loss. In the pre-steroid era, anestimated 35–60% of patients sufferedirreversible visual loss from GCA com-pared to 7–14% in the post-steroid era(Gonzalez-Gay et al. 2000).

The high frequency of ocularinvolvement in GCA underlines theneed for ophthalmologists to havefamiliarity with this disorder. The factthat visual symptoms may be the firstor sole manifestation of GCA empha-sizes further the primary role of theophthalmologist for recognizing anddiagnosing this disorder without delay.

Transient visual loss

Visual loss in GCA can be transientor permanent. Among patients withvisual manifestations of GCA, a his-tory of transient visual loss is reportedby 30–54% of patients (Glutz VonBlotzheim & Borruat 1997; Hayrehet al. 1998b; Gonzalez-Gay et al.2000). In some patients, transientvisual loss may be the only complaint.Transient monocular blindness, oramaurosis, is not a trivial symptom inGCA. It results from insufficient per-fusion of the optic nerve, retina orchoroid and precedes the developmentof acute and permanent visual loss inmore than half (50–64%) of untreatedcases by an average of 8.5 days (Fontet al. 1997; Hayreh et al. 1998b; Gonz-alez-Gay et al. 2000; Miller 2001).Thus, amaurosis in a patient known oreven suspected to have GCA is consid-ered an ophthalmological emergencyand immediate high-dose steroid treat-ment is recommended in an effort to


20

prevent the permanent visual loss thatfollows in the majority of untreatedcases. Hospitalization and strict bedrest during initiation of treatment isadvised because small posturally medi-ated decreases in perfusion throughinflamed, compromised arteries mayprecipate infarction of ocular tissue(Miller 2001). This seemingly trite rec-ommendation has been, in anecdotalcases, a vision-saving manoeuvre.

The following clinical scenario istypical yet challenging. An elderlypatient reports one recent episode oftransient monocular blindness and haslittle or no systemic symptoms. Is itGCA-related amaurosis or classicalamaurosis fugax caused by retinal em-boli? Clues that favour GCA in thissetting include a relatively short dura-tion of visual loss (1–2 min or less),multiple recurrences in the same eyeover a short period of time, photop-sias or other positive phenomena dur-ing the visual loss and provocation ofvisual loss with postural change suchas standing up or bending over. A his-tory of amaurosis alternating betweenthe two eyes is rarely caused by retinalemboli and should be consideredGCA. On funduscopic examination,indirect evidence for GCA includescotton-wool spots, intraretinal haem-orrhages or optic disc oedema. Evenin patients with no visual complaints,isolated cotton woolspots have beenfound (Glutz Von Blotzheim &Borruat 1997; Miller 2001).

Anterior ischaemic optic neuropathy

The most common cause of perma-nent visual loss because of GCA isanterior ischaemic optic neuropathy(AION). GCA-related AION, alsocalled arteritic AION, is caused byinflammatory occlusion of the shortposterior ciliary arteries, which pro-vide blood flow to the optic disc, thechoroid and (in some persons) a smallpart of the retina supplied by the cili-oretinal artery (Erdogmus & Govsa2006). As such, arteritic AION(infarction of the prelaminar and lam-inar portion of the optic nerve head)is frequently accompanied by choroi-dal ischaemia or ciliary artery occlu-sion, which may be evident onfundusocopic examination or by flou-rescein angiography (Fig. 2) (Hayrehet al. 1998b). In contrast, the morecommon form of AION, called non-arteritic AION (NAION), is caused

by insufficient perfusion through theterminal paraoptic branches of theshort posterior ciliary artery, causingoptic disc ischaemia. Thus, NAION isnot accompanied by evidence of cho-roidal ischaemia.

A diagnosis of AION is clinicallybased on acute monocular visual lossaccompanied by optic disc oedema.The importance in distinguishingbetween arteritic AION and NAIONas quickly as possible lies in the imme-diate prognosis for the other eye.Among patients with arteritic AION,25–50% will suffer a similar event inthe other eye, typically within 1–14 days, if left untreated (Miller2001). Thus when a diagnosis of acuteAION is made, the clinician must useclinical indices to determine if it islikely to be GCA-related. Certain his-torical features favour a diagnosis ofarteritic AION: age greater than70 years, preceding amaurosis, verysevere visual loss in range of countingfingers or worse, new headache andpositive systemic review of systems,particularly jaw claudication. Onexamination of a suspected patient,any of the following features are con-sidered practically diagnostic for arte-ritic AION: severe pallid disc oedema(often described as ‘chalky white’

swelling), disc swelling in combinationwith a retinal ischaemic lesion (centralretinal artery occlusion, cilioretinalartery occlusion or cotton wool spots)and a normal or large optic cup in thecontralateral eye (Fig. 6) (Hayrehet al. 1998b; Miller 2001). The signifi-cance of finding retinal ischaemiclesions simultaneously with optic discischaemia (AION) in a non-diabeticpatient is that it indicates involvementof two different vascular territories ofthe eye (the central retinal arterial cir-culation and the posterior ciliary arte-rial circulation). In such cases, asystemic inflammatory vasculopathylike GCA must be considered.

Other more subtle eye findings canprovide indirect support for GCA.Patients with AION caused by GCAhave lower central retinal artery pres-sures compared to eyes with NAION(Jonas & Harder 2007). Also, themean intraocular pressure (IOP)in eyes with ophthalmic manifestationof GCA has been noted to belower than the IOP in control eyes andeyes with non-arteritic AION (11.9 ±4.5 mmHg versus 15.8 ± 1.8 mmHgand 15.3 ± 2.3 mmHg, respectively)(Huna-Baron et al. 2006).

Oncethesystemicsymptoms,sedimen-tation rate and acute-phase reactants

Fig. 6. Fundus photograph demonstrating two signs highly suggestive of giant cell arteritis (GCA)

in this patient with acute anterior ischaemic optic neuropathy (AION). There is a chalky whiteness

to the disc oedema and focal retinal oedema in the distribution of the cilioretinal artery (arrow).


21

have normalized, recurrent episodes ofischaemic optic neuropathy are rare.When recurrences occur, they are usu-ally associated with a relapse of sys-temic symptoms or re-elevation ofacute-phase reactants. In one study, therecurrent episodes were all ipsilateraland occurred 3–36 months (median8 months) after the initial episode(Chan et al. 2005).

Other types of ischaemic visual loss

GCA can affect any aspect of the ante-rior visual pathway from retina tooccipital lobe. AION is by far the mostcommon cause of GCA-related visualloss (78–99%) (Gonzalez-Gay et al.2000; Hayreh et al. 2002; Carroll et al.2006). Central retinal artery occlusionis the second most common cause ofvisual loss, affecting about 10–13% ofpatients. Less common causes includeposterior ischaemic optic neuropathy,cilioretinal artery occlusion, choroidalinfarction and – rarely – ischaemia tothe chiasm or postchiasmal visual path-way (Miller 2001). Occipital lobeinfarction caused by vertebrobasilarartery involvement occurs in < 5% ofpatients with visual loss (Gonzalez-Gay et al. 2000). In patients with corti-cal visual loss, visual hallucinationsmay arise in the area of visual field lossand generally disappear spontaneouslyafter several weeks. They may resolveabruptly with steroid initiation.

Diplopia

Diplopia is the second most commonvisual symptom related to GCA, butthis occurs far less frequently thanvisual loss. Transient or constant dip-lopia was reported in 5.9–21% ofpatients with visual manifestations(Glutz Von Blotzheim & Borruat1997; Hayreh et al. 1998b; Gonzalez-Gay et al. 2000). In some patients, thediplopia may be a harbinger of subse-quent visual loss. In others, the diplo-pia is transient and the sole visualmanifestation of GCA. Ischaemia tothe extraocular muscles, the cranialnerves or brain stem ocular motorpathways have all been implicated asthe mechanism of diplopia in GCA.Thus, weakness of a single extraocularmuscle, an isolated cranial nerve III,IV or VI palsy (partial or complete),combined cranial nerve palsies, skewdeviation, internuclear ophthalmop-laegia, one-and-a-half syndrome and

upgaze palsy have been described withGCA (Miller 2001; Melson et al.2007).

Orbital and other unusual ocular

manifestations

In occasional patients, GCA maycause efferent pupil abnormalities(tonic pupil, Horner pupil), acute hyp-otony, ocular ischaemic syndrome,orbital ischaemia and – rarely – orbi-tal infarction syndrome (Miller 2001).Signs of orbital inflammation such asred eye, chemosis or proptosis accom-panied by pain typically evoke consid-eration of a more common conditionknown as orbital pseudotumour,which is also treated with steroids.However, the steroid requirement fororbital pseudotumour is lower in dos-age and shorter in duration than thatused for GCA, so caution must betaken to exclude GCA in any olderpatient with an orbital inflammatorysyndrome. In a review of 13 cases ofGCA-related orbital manifestations,all patients had proptosis and onlytwo patients had pain (Lee et al.2001). Chemosis, lid oedema, ophthal-moplaegia, visual loss and episcleritiswere other findings. The outcome wasreported as ‘improved’ in eight ofthese 13 patients.

Laboratory investigationsin GCA

ESR

An elevated ESR strongly supports aclinical suspicion of GCA but a nor-mal ESR does not rule out a diagnosisof GCA. According to the AmericanCollege of Rheumatology, an ESR byWestergren method is elevated if it is‡ 50 mm ⁄hr. Approximately 85% ofpatients have an ESR ‡ 50 mm ⁄hrand almost all patients have an ESRgreater than 20 mm ⁄hr (Schmidt2006). Nevertheless, ESRs as low as4 mm ⁄hr have been reported inpatients with symptomatic, biopsy-positive disease (Hayreh et al. 1997).In interpreting the significance of agiven ESR, it is important to considerother factors that raise or lower theESR. Conditions known to elevate theESR are increasing age, female gen-der, pregnancy, anaemia, inflamma-tory disorders, infection, connectivetissue disorders, trauma, hypercho-

lesterolaemia and malignancy (Hayrehet al. 1997). Conversely, a very lowESR occurs in polycythaemia, heredi-tary spherocytosis, impaired hepaticprotein synthesis, hypofibrinogena-emia, congestive heart failure and useof anti-inflammatory drugs (Hayrehet al. 1997). Some patients with GCAconsistently demonstrate a low ornormal ESR despite active disease,and they have no other condition thatmight lower the ESR. Despite therelative lack of sensitivity and specific-ity, the low cost and universal avail-ability of the ESR make it a usefullaboratory test in the diagnosis andmanagement of patients with GCA.Some investigators have noted that thepresence of a strong acute-phaseresponse defined by fever, weight loss,anaemia and high ESR (> 85 mm ⁄hr)confers a low risk of cranial ischaemiccomplications and an excellentresponse to steroids, but others havenot corroborated this relationship (Cidet al. 1997; Liozon et al. 2001; Her-nandez-Rodriguez et al. 2002). Theprognostic value of the ESR for riskof ischaemic events and response totreatment remains under investigation.

C-reactive protein

C-reactive protein (CRP) is an acute-phase marker measured as a singleprotein quantification. Its advantagesover the ESR are faster responsivenessto inflammation (within 4–6 hr), insen-sitivity to age, gender and haemato-logical factors, and notably highersensitivity and specificity for GCA inthe appropriate clinical setting. Severalstudies have found that the sensitivityof CRP alone is about 98% or higherfor active GCA (Hayreh et al. 1997;Gonzalez-Gay et al. 2005b; Parikhet al. 2006). In fact, performing bothan ESR and a CRP has only a slightlyhigher yield for detecting an abnormalresult compared to performing a CRPalone (Parikh et al. 2006). Nonethe-less, it is advantageous to performboth laboratory tests whenever possi-ble because, not infrequently, theCRP is elevated when the ESR is nor-mal and, very occasionally, the ESR iselevated when the CRP is normal(Parikh et al. 2006). The disadvan-tages of CRP include the higher costof testing compared to ESR and per-haps a relative unfamiliarity with thetest amongst clinicians.


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Thrombocytosis

An elevated platelet count is a com-mon laboratory finding in GCA. In arecent review of the laboratory find-ings of 240 patients with biopsy-posi-tive GCA, 48.8% of patients (most ofwhom had constitutional symptoms)had thrombocytosis at presentation,and thromobocytosis was associatedwith a higher ESR and CRP as wellas lower haemoglobin and albumin(Gonzalez-Gay et al. 2005b). In otherstudies thrombocystosis also appearsto correlate well with the ESR(Foroozan et al. 2002; Costello et al.2004). Although only about half ofpatients with GCA demonstrate aplatelet count greater than 400 ·103 ⁄ll, the finding of thrombocytosishas high predictive value in the settingof a suspected patient with an elevatedESR (Foroozan et al. 2002).

IL-6 and other cytokines

Cytokines are the messenger proteinswithin the cellular immune systemand mediate a variety of functions. InGCA, cytokines play an importantrole in regulating the intensity of cel-lular proliferation and the direction ofcellular differentiation, which ulti-mately determines the nature andmagnitude of the inflammatoryresponse. IL-6 is a cytokine foundboth in inflamed arterial walls and inthe blood circulation. IL-6 is a chiefstimulator of the systemic inflamma-tory response and the production ofmost acute-phase proteins (Goronzy& Weyand 2002). Serum levels of IL-6 are highly elevated in active GCAand respond rapidly to steroid treat-ment. Weyand et al. followed theacute-phase markers in 25 patientswith biopsy-positive GCA prospec-tively (Weyand et al. 2000). At thetime of diagnosis (before treatmentinitiation) the ESR was elevated in76% of patients and plasma IL-6 waselevated in 92%. Within 1 month ofsteroid treatment, all patients experi-enced symptomatic resolution andnormalization of the ESR. Theplasma IL-6 did decrease but did notreturn to normal levels. During a clin-ical relapse of disease, the ESR waselevated in 58% of patients whereasthe plasma IL-6 was elevated in 89%.The authors concluded that plasmaIL-6 appears to be a more sensitiveindicator than ESR for diagnosing

and monitoring GCA patients (Wey-and et al. 2000). How does IL-6 com-pare to CRP? Hayreh et al. found alinear relationship between levels ofIL-6 and CRP, suggesting that IL-6 iscomparable but not superior to CRPfor monitoring the systemic inflamma-tory response (Hayreh et al. 1997).

Anaemia

A normocytic, normochromic anaemiaof mild to moderate degree(<12 g ⁄dl) is frequently observed inpatients with GCA as a result ofdecreased haematopoeisis related tothe acute-phase response. Womenwith GCA tend to have anaemia morecommonly than men with GCA (Mel-son et al. 2007). An unexplained anae-mia may even be the presentingmanifestation of GCA. Some recentstudies have reported that the pres-ence of anaemia at presentation isassociated with a reduced incidence ofischaemic events (Cid et al. 1997;Gonzalez-Gay et al. 2005b).

Others

Other laboratory tests that may beabnormal in GCA include white bloodcell count, liver enzymes, other acute-phase reactants (fibrinogen, haptoglo-bin), albumin, gamma globulin, anti-cardiolipin antibodies, plasmaviscosity, and amyloid A apolipopro-tein, von Willebrand factor, alpha-1-antitrypsin (Gonzalez-Gay et al.2005b; Rahman & Rahman 2005;Melson et al. 2007). Fibrinogen isavailable in many hospital laborato-ries. It is often elevated in GCA butremains low in other disease statesthat can cause an elevated ESR.

Diagnosis of GCA

There is no single laboratory value,imaging procedure or even biopsysample that is positive in all patientsand there is no one symptom or signthat is pathognomic of GCA. GCA isa syndrome in which characteristicsymptoms accompanied by objectivesigns of inflammation and vasculopa-thy are used to define the clinicaldiagnosis. Histopathological evidenceof inflammation in arterial tissue pro-vides definitive diagnostic evidenceand should be sought wheneverpossible because the commitment to

treatment is not a trivial matter, oftenlong in duration and fraught withmedication side-effects.

Temporal artery biopsy

The temporal artery biopsy is themost common method of histopatho-logical testing for GCA. It is generallyagreed that an adequate biopsy speci-men should have a minimum lengthof 2 cm (Carroll et al. 2006). Longerspecimens (3–5 cm) are preferable andmultiple fine (0.25–0.5 mm) sectionsare necessary because of the presenceof skip lesions and potential effect ofpost-fixation shrinkage (Sharma et al.2007). In some institutions, a unilat-eral temporal artery biopsy is per-formed and the frozen section isexamined immediately. If the initialexamination is negative and the clini-cal suspicion is high, then a sequentialbiopsy is completed during the sameprocedure. Thereafter, a more criticalexamination of a paraffin-embeddedbiopsy specimen should be performedunder light and electron microscopy.Reliance on frozen sectioning alonehas a high rate of false negatives(Nordborg et al. 1992). If the clinicalsuspicion for GCA is high and thefirst biopsy is negative, the chances ofa second biopsy demonstrating posi-tive histopathology is rather low,ranging from 5% to 9% (Hayrehet al. 1997; Pless et al. 2000). If theclinical suspicion is low, a unilateralbiopsy appears to be sufficient to ruleout the diagnosis (Hayreh et al. 1997;Hall et al. 2003). Findings that shouldraise clinical suspicion for the diagno-sis and that tend to predict a positivebiopsy include: presence of jaw claudi-cation, CRP > 2.45 mg ⁄L, elevatedESR > 47 mm ⁄hr, neck pain, whiteor pale disc oedema, systemic symp-toms other than headache, temporalartery abnormalities and elevatedplatelet count (Hayreh et al. 1997;Hall et al. 2003).

The chief pathological finding is apanarteritis consisting mostly of lym-phocytes and macrophages (Fig. 7).Granuloma formation may be present.The intima is thickened and the inter-nal elastic lamina is fragmented. Infil-tration by mononuclear cells andmultinucleated giant cells is concen-trated around the inner half of themedia, characteristically along thedisrupted internal elastic lamina


23

(Nordborg et al. 1992; Weyand &Goronzy 2003). It is important toremember that giant cells are presentin about 50% of biopsy specimentsand thus are not a necessary featurefor histopathological confirmation ofGCA. Active arteritis can be detectedhistopathologically for 4–6 weeks afterinitiation of corticosteroids so there isno justification for discontinuing ste-roids while a patient with suspectedGCA is under evaluation (Carrollet al. 2006; Narvaez et al. 2007).Fibrinoid necrosis is found rarely inGCA and should raise suspicion ofother vasculitides. The healed orchronic phase of GCA is characterizedby foci of lymphocytes, fibrosis andvascularization with continued evi-dence of intimal disruption.

Although the temporal arterybiopsy is considered the gold-standardtest for diagnosis, it is important toremember that a negative biopsyresult may be found in up to 10–15%of all diagnosed cases (Schmidt 2006).Furthermore, when GCA assumes alocalized form such as large-vesselvasculitis and the arterial inflamma-tion occurs in the relative absence ofsystemic inflammation, the temporalartery biopsy is negative in at least50% of patients (Bongartz & Matte-son 2006). In the setting of a patientwith suspected extracranial large-ves-sel GCA and negative temporal arterybiopsy, pursuit of histopathologicalconfirmation (i.e. biopsy of a largeartery or aorta) is not recommendedroutinely and diagnosis becomesdependent on clinical presentation andimaging findings. If such a patientshould undergo an intervention suchas aortic aneurysm repair or vascular,

a surgical biopsy specimen can betaken at the same time for histopatho-logical confirmation of the disease(Lie 1995).

Certainly having a positive tempo-ral artery biopsy on record helps tojustify the chronic use of steroids tothe patient with GCA, especially whensteroid side-effects become significant.Yet it is important to rememberthat positive histopathology is notmandatory for diagnosis. If bilateraltemporal artery biopsies are negative,non-invasive imaging (duplex sonogra-phy, MRI, PET) of other extracranialarteries, particularly the occipitalarteries, is a reasonable next step (Pfa-denhauer & Weber 2003). Suchmodalities can demonstrate abnormal-ities characteristic of active inflamma-tion in arterial walls and documenttheir reversibility with steroid treat-ment, providing sufficient evidence toestablish a diagnosis of GCA in theproper clinical setting. Less com-monly, non-invasive imaging of extra-cranial arteries may guide the surgeonto an alternative biopsy site inpatients whose clinical presentationmay be more ambiguous and positivehistopathology is strongly desired.The point to remember is that a diag-nosis of GCA is a clinical one, basedon the sum total of corroborative evi-dence, and not simply a pathologicalone.

American College of Rheumatology

criteria

In 1990, the American College ofRheumatology (ACR) developed a setof critieria that have been used todiagnose GCA (Hunder et al. 1990).These are listed in Table 2 and, in

brief, consist of advanced age, newheadache, temporal artery abnormali-ties, high ESR and positive biopsy.The presence of any three of these fivecriteria permitted a diagnosis of GCAwith a sensitivity of 93.5% and aspecificity of 91.2% based on a popu-lation of patients (n = 807) withrheumatological disease (Rahman &Rahman 2005). A note of cautionshould be taken when applying theseACR criteria to the general clinicalpopulation because the criteria weredeveloped primarily to distinguishpatients with GCA (n = 214) frompatients with other vasculitides(n = 593) and to classify patients withrheumatological disorders for researchpurposes. It is thus possible thatpatients who lack typical systemicsymptoms and present with an ischae-mic complication (so-called ‘occultGCA’) may not have been representedaccurately in the ACR study becausethey are more likely to seek the careof a non-rheumatological specialist.From the ophthalmic perspective,Hayreh et al. found that among 85patients who presented with ocularsymptoms caused by biopsy-positiveGCA, 21% had no systemic symp-toms or signs of GCA (Hayreh et al.1998a). In these patients, the diagnosiswas suspected on clinical grounds(AION in a patient aged 50 years orolder) and confirmed by histologicalfindings (biopsy); therefore, strictlyspeaking, this would meet only two ofthe five ACR criteria. Likewise, in thesetting of large-vessel arteritis, imag-ing the vascular territories of interestmay prove most fruitful in aiding thediagnosis.

Given the protean manifestations ofGCA, it is more important to viewthe patient’s presentation as a wholeand ask ‘could this be GCA?’ ratherthan to rely on criteria sets to make a

Fig. 7. Histopathologic examination of a temporal artery biopsy in a patient with giant cell

arteritis (GCA). (A) Haematoxylin and eosin stain shows lymphocytic infiltration of the adven-

titia. (B) Elastic tissue stains shows fragmentation of the internal elastic lamina and intimal

hyperplasia.

Table 2. Criteria of the American College of

Rheumatology for the diagnosis of giant cell

arteritis.

Age at onset ‡ 50 years

New headache

Temporal artery abnormalities

(either tenderness or reduced pulsation)

Elevated erythrocyte sedimentation rate

(‡ 50 mm ⁄ hr by Westergren method)

Positive temporal artery biopsy (arteritis

characterized by a predominance of

mononuclear infiltrates or granulomas,

usually with multinucleated giant cells)


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diagnosis of GCA. In this respect,alternative modalities are emerging forimaging the temporal and other cra-nial arteries to help support a diagno-sis of vasculitis. These modalitiesinclude ultrasound, MRI and singlephoton emission tomography(SPECT) and are discussed in the nextsection.

Non-invasive imaging of the cranial

arteries

Modern sonography can delineatevascular structures with a resolutionof 0.1–0.2 mm (Schmidt & Gromnica-Ihle 2005). In 1997, Schmidt et al.used high-resolution colour Dopplerimaging and duplex ultrasonographyto examine the superficial temporalarteries in patients with GCA(Schmidt et al. 1997). They describedthe presence of a hypoechoic (dark)thickening around the lumen of thetemporal artery – termed a ‘halo’ sign– that represents oedema of the vesselwall (Fig. 8). The sensitivity and speci-ficity of the halo sign varies amongdifferent investigators, ranging from40% to 100% sensitivity and 68% to100% specificity when comparedagainst a biopsy-positive diagnosis ofGCA (Schmidt & Gromnica-Ihle2005). The variability in these esti-mates may be in part related to theskill and experience of the individualoperator and the resolution capacityof the scanner. Flow abnormalities

such as stenoses and occlusions in thetemporal arteries are less helpful find-ings because they are also present inpatients with vascular disease associ-ated with diabetes (Karahaliou et al.2006). A bilateral halo sign, althoughuncommon, has been found to be100% specific for GCA (Karahaliouet al. 2006). Despite the generallyaccepted high specificity of the halosign, it is not considered a pathogno-monic sign of GCA and has beenfound in patients with Wegener’sgranulomatosis and tuberculosis(Schmidt & Gromnica-Ihle 2005;Karahaliou et al. 2006). As such,sonography is not intended to be areplacement for a temporal arterybiopsy in the diagnostic evalution ofGCA. It does, however, play animportant role in the evaluation ofpatients with GCA, some of whichincludes: providing non-histologicalevidence of arterial wall inflammationin the extracranial arteries; guidingthe biopsy site or finding alternativesites other than the temporal arteries;evaluating the axillary arteries for thepresence of large-vessel involvement;and assessing disease activity follow-ing treatment (Schmidt 2007).

MRI holds promise as anothermeans to evaluate non-invasively thesuperficial temporal and occipitalarteries of patients with suspectedGCA. It has the advantages of wideavailability and reproducibility ofoperator-independent images. Multi-slice contrast-enhanced, T1-weightedspin echo sequences with a submilli-metre spatial resolution on a standard1.5 T scanner can detect inflammatoryvessel wall changes (Bley et al. 2005b).These changes appear as circumferen-tial (mural) thickening of the temporalartery and ⁄or increased contrastenhancement (Fig. 9). In a recentstudy of 64 patients who underwentcontrast-enhanced high-resolutionMRI, sensitivity and specificity fordetecting temporal artery inflamma-tion were 80.6% and 97%, respec-tively, compared against a positivediagnosis using ACR clinical criteriaor histopathological findings (Bleyet al. 2007). The authors used a spe-cific imaging protocol and, in somepatients, a higher strength magnet(3 T) as well – neither of which arecurrently in standard use – raising thequestion of whether ‘community’scanners would have such high yields.

Fig. 8. Colour Doppler ultrasonography of

temporal arteries. Longitudinal (top) and

transverse (bottom) view of superficial tempo-

ral artery branch showing the hypoechoic rim

(arrows) around the perfused lumen, repre-

sentative of oedematous wall swelling in

active arteritis. From Schmidt (2006) with

permission from Current Science Publishers.

(A) (C)

(B)

Fig. 9. High-resolution magnetic resonance imaging (MRI) in giant cell arteritis (GCA). (A)

MRI demonstrates the cranial involvement pattern of the superficial cranial arteries in a patient

with proven giant cell arteritis (arrows). (B) Mural thickening and contrast enhancement can be

readily revealed on the enlarged images of the left frontal branch of the superficial temporal

artery (arrow). (C) Similar changes are noted of the left superficial occipital artery (arrow).

From Bley TA (2007): Imaging studies in the diagnosis of large vessel vasculitis. Clin Exp

Rheumatol 25: S60–S61, with permission from Eular Publishers.


25

Is MRI ready to replace temporalartery biopsy? Not yet. But anMRI ⁄MRA examination can providecomplete information of the superfi-cial cranial arteries as well as themajor cranial, cervical and thoracicvascular beds in a single, rapid non-invasive test; in the future, it may beimportant in guiding treatment (Bleyet al. 2005a, 2005b, 2007).

Increased (67) gallium uptake hasbeen noted in the temporal region ofpatients with GCA, and SPECT scin-tigraphy appears to be a promisingtool to investigate and monitorpatients with GCA (Reitblat et al.2003). PET scanning, however, shouldnot be used to evaluate for arteritis inmedium-sized, superficial cranial arter-ies because it cannot evaluate vesselswith diameter < 2–4 mm and there ishigh background activity related tobrain uptake of the radioactive sub-stance (Bley et al. 2007).

Treatment andprognosis of GCA

As noted earlier, the natural historyof GCA is spontaneous remission.However, the disease activity maysmoulder on for months or yearsbefore extinguishing. The need fortreatment stems from the high rate ofmorbidity related to ischaemic compli-cations caused by GCA, particularlyblindness. Treatment of GCA is aimedat controlling and arresting theinflammatory process in order to pre-vent an ischaemic complication suchas visual loss, neurological dysfunc-tion or other organ infarction.

Corticosteroids

Corticosteroids remain the mainstaytreatment of GCA. Within the firstfew days of steroid initiation, systemicsymptoms of malaise, myalgias, anor-exia and fever begin to subside; withinthe first week, the sedimentation ratereturns to normal. Although there isgeneral consensus about the need toinitiate corticosteroids immediatelyupon diagnosis – even suspicion – ofGCA, there remains controversy con-cerning the dosage, the means ofadministration and the duration ofcortiocosteroid treatment. To date,there are no randomized controlledstudies evaluating the various steroid

regimens used by different clinicians,and the results of treatment reportedin the literature are retrospective andanecdotal. To some degree, differencesin treatment regimens reflect whichaspects of the disease are being man-aged. Overall, rheumatologists tend torecommend maintaining a high doseof corticosteroids for a shorter periodof time than ophthalmologists or neu-rologists (Nordborg & Nordborg2004).

Several single case reports havedescribed dramatic recovery ofvision following treatment with high-dose intravenous (IV) corticosteroids(Model 1978; Rosenfeld et al. 1986;Diamond 1991; Matzkin et al. 1992).The significance of these reports is dif-ficult to assess because of their anec-dotal nature, similarity in rates ofvisual recovery following oral steroidsand differences in the mechanism ofvisual loss central retinal artery occlu-sion (CRAO rather than AION) (Dia-mond 1991; Matzkin et al. 1992). Asmall number of studies have exam-ined visual outcome retrospectively inpatients treated with IV steroids ver-sus those treated with oral steroids.Chan & O’Day reported the results of73 biopsy-positive patients: 43 hadreceived IV steroids as the initialtreatment (average daily dose of1000 mg) and 30 had received oralcorticosteroids (median daily dose75 mg) (Chan & O’Day 2003). Over-all, 21 patients (29%) had a meanimprovement of visual acuity by2 lines. Seventeen of these 21 patientshad received IV treatment, and fourhad been treated orally. Unexpectedly,in nine patients (12%) vision wasworse and seven of these patients hadreceived IV treatment. It was notedthat the IV-treated patients had worsemedian visual acuity and more fre-quent bilateral involvement at presen-tation compared to the group whoreceived oral treatment. In a similarstudy, Liu et al. found that seven of23 patients (39%) improved with IVtreatment compared to five of 18(28%) on an oral regimen (Liu et al.1994). Subsequent fellow eye visualloss occurred only in patients treatedwith oral therapy. Though limited,these data have been cited in supportof recommending IV steroids acutelyin patients with arteritic visual loss.

However, other studies have failedto show a difference in outcome.

Hayreh et al. retrospectively studiedthe visual outcome in 84 patients withGCA, 43 of whom were treated intra-venously and 41 received oral steroids(Hayreh et al. 2002). Of the fivepatients who showed some visualimprovement, three were in the IVgroup and two had received only oralsteroids. As in the study by Chanet al., the patients in the IV grouphad more severe visual loss than thosetreated orally. In the literature, pro-gressive visual deterioration while ontreatment has been described inpatients receiving high-dose IV andin patients taking only oral steroids(Hugod & Scheibel 1979; Slavin &Margolis 1988; Faarvang & Pontoppi-dan Thyssen 1989; Matzkin et al.1992; Cornblath & Eggenberger 1997).

In weighing the relative merits ofIV versus oral steroids, it is importantto keep in mind the potential seriouscomplications of high-dose IV steroidtreatment. The low incidence of com-plications found in the Optic NeuritisTreatment Trial (ONTT) cannot nec-essarily be applied to the older agegroup of GCA patients (Chrousoset al. 1993). Serious adverse reactionsinclude unstable angina, acute pulmo-nary oedema, abdominus rectus haem-orrhage, uncontrolled hypertension,cardiac arrhythmia, anaphylaxis, asep-tic osteonecrosis, acute psychosis, sep-sis and sudden death (Chan & O’Day2003; Carroll et al. 2006; Hall & Bal-cer 2004). The advantages of IV treat-ment include rapid drug delivery,higher tissue levels and additionalhydration. It has been suggested thatthe ‘megadose’ levels used in this set-ting may also have antioxidant effectsthat protect the microvasculaturefrom lipid peroxidative damage andmay help to stabilize damaged neuro-nal membranes (Chan & O’Day 2003;Matzkin et al. 1992). Although datafrom randomized controlled compara-tive studies are not available, manyexperts favour IV treatment forpatients with acute or impendingvisual loss.

Regardless of the route of adminis-tration, there is general agreementthat the initial treatment for thepatient with GCA who has new visualsymptoms should be high-dose ste-roids and that treatment should bestarted promptly. The most importantpredictor for the development of per-manent visual loss appears to be the


26

timeliness of initiating treatment(Nordborg & Nordborg 2004). Thiswas clearly demonstrated by Gonz-alez-Gay et al., who found that iftreatment was instituted within 24 hrof onset of symptoms visual improve-ment was experienced in 57% ofpatients, compared to only 6% incases of longer delay (Gonzalez-Gayet al. 1998). Unfortunately, delayeddiagnosis and treatment is common.One study found that 35% of patientshad systemic symptoms for an averageof 10 months before visual loss and65% experienced premonitory visualsymptoms for an average of 8.5 days(Font et al. 1997).

Waiting for home nursing arrange-ments or hospital admission is never areason to delay steroid treatment.Sending an elderly patient with acutevisual impairment out of the officewith a prescription for oral prednisonecarries a risk of treatment delayrelated to inaccessibility of readytransportation to the pharmacy. Wit-holding steroid treatment while tem-poral artery biopsy results are pendingis also a mistake. To expedite andensure treatment initiation, patientscan be given steroids while in theoffice, either as a single injection ofdexamethasone 10 mg IV or as pred-nisone 80 mg by mouth.

Starting steroids

For the purpose of general guidelines,GCA patients can be divided intotwo groups: those with and thosewithout visual or neurological mani-festations. In patients without visualor neurological manifestations whohave only rheumatic and systemicsymptoms, treatment with oral predni-sone is used (generally 40–60 mg dailyor 1 mg ⁄kg ⁄day, but doses rangingfrom 20 mg to 100 mg have beenused). In patients with acute visual orneurological symptoms or signs,higher doses are generally recom-mended (equivalent of prednisone80 mg or more daily or 1–2 mg ⁄kg ⁄day). It is not uncommon tohospitalize such a patient and initiatetreatment with intravenous steroids(methylprednisolone 250 mg every6 hr) for the first 3–5 days, then con-tinue with high-dose oral prednisone(Hayreh & Zimmerman 2003b; Nord-borg et al. 2003; Nordborg & Nord-borg 2004; Carroll et al. 2006;Dasgupta & Hassan 2007).

Maintenance dose

High-dose daily oral prednisone ismaintained for at least 4–6 weeksuntil systemic symptoms have sub-sided and markers of disease activity(ESR and ⁄or CRP) have normalized.A daily schedule is recommended overalternate-day dosing, which has beenassociated with higher rates of diseaserelapse (Bengtsson & Malmvall 1981;Hayreh & Zimmerman 2003b; Spieraet al. 2003). Calcium supplementation,vitamin D and peptic ulcer prophy-laxis should accompany steroid treat-ment. In patients with or at risk ofosteoporosis, bone densitometry andbone-saving measures should be initi-ated.

Tapering regimen

Steroid tapering is a slow process andhighly individualized with constantmonitoring of symptoms and serummarkers. In most patients, the initialreduction in dosage is 5–10 mg ⁄monthto a daily dosage toward 20–30 mg.Then the rate of reduction should pro-ceed more cautiously, usually by 2.5–5 mg ⁄month. When the daily dose is10–15 mg, tapering might continue byonly 1 mg ⁄month. Clinical evaluationand laboratory markers are repeatedbefore each reduction in daily steroiddosage, watching specifically for recur-rent symptoms of active inflammation.Any recurrence of symptoms or rise inESR ⁄CRP should be considered a reac-tivation of disease activity and shouldprompt a thorough re-evaluation of thesteroid dosage needed. It is importantto keep in mind the alternative possibil-ity of a secondary infection in thisimmunocompromised population. TheESR and CRP levels should always beconsidered along with other clinicalindicators of disease activity. It is amistake to ‘chase’ these laboratory val-ues with steroids to normalize them(Koening & Langford 2006).

Duration of treatment

On the whole, a maintenance dose of7.5–10 mg daily is generally achievedin 6–12 months (Carroll et al. 2006).Hayreh & Zimmerman treated andfollowed 145 patients with biopsy-positive GCA (Hayreh & Zimmerman2003b). Their average time to 40 mgdaily was 2 months from steroid initi-ation, and the time to reach a mainte-nance dosage (median 7 mg daily) was2 years. After 2 years, more than 92%

of patients (with and without visualloss at presentation) were still on ste-roids, emphasizing the long durationof treatment.

Adjuvant therapies

Because the duration of treatment ofGCA is long, often requiring 1–5 years of steroids, it is not surprisingthat steroid-related complications poseanother source of potential morbidityfor this older patient population.Common side-effects include diabetes,hypertension, secondary infections,osteoporosis and bone fracture, myop-athy and psychiatric changes such asanxiety, depression, confusion and –occasionally – psychosis. Such compli-cations have been reported in up to50% of patients on long-term steroidtherapy for GCA (Proven et al. 2003),underscoring the need for a steroid-sparing agent with equal or superiorefficacy in controlling disease activityand relapse. A number of differentagents have been tried with disap-pointing or, at best, mixed results(Nuenninghoff et al. 2003).

Studies investigating the role ofmethotrexate (MTX) for the treatmentof GCA have yielded conflictingresults. Jover et al. conducted adouble-blind, placebo-controlled trialin which 42 patients with GCA wererandomized to weekly MTX for24 months or MTX plus prednisone(Jover et al. 2001). Treatment withMTX significantly reduced the pro-portion of patients who experiencedrelapse, reduced the duration of pred-nisone treatment and reduced thecumulative dose of prednisone.Despite these benefits, the addition ofMTX did not decrease the rate ofadverse events secondary to cortico-steroid use. In contrast to the resultsof this study, two comparable pla-cebo-controlled trials involving a lar-ger patient group found no suchbenefit (Spiera et al. 2001; Hoffmanet al. 2002). The basis for the differentoutcomes in these studies is unclear(Eberhardt & Dhadly 2007). The doseof MTX used in these and previoustrials has been 10–15 mg ⁄week.Higher doses, needed for adequatedisease control in some patients withother rheumatological disorders, havenot been studied (Nordborg & Nord-borg 2004). At present, there is noestablished role for MTX in the stan-dard treatment regimen of patients


27

with GCA. In patients with severeadverse reactions to steroids or ste-roid-refractive disease, MTX is con-sidered a viable second-line alternative(Hall & Balcer 2004).

More recently, inhibitors of tumournecrosis factor (TNF)-a have beenstudied both as an adjunct to steroidsand as monotherapy (Andonopouloset al. 2003; Uthman et al. 2006). Inf-liximab (a chimeric monoclonal anti-body directed against TNF-a) hasbeen found to be beneficial for thetreatment of GCA in a few anecdotalreports (Cantini et al. 2001; Airo et al.2002; Uthman et al. 2006). Cantiniet al. reported remission after treat-ment with infliximab in three of fourpatients with previously steroid-depen-dent GCA (Cantini et al. 2001).Andonopoulos et al. documented ini-tial improvement in two patients withGCA using infliximab alone (withoutcorticosteroids), although both pati-ents experienced relapse within 12weeks of treatment (Andonopouloset al. 2003). A recent randomized,prospective placebo-controlled multi-centre trial of infliximab as adjunctivetreatment in 44 patients with GCAshowed no significant benefit (Hoff-man et al. 2007). Specifically, theaddition of infliximab failed todecrease the relapse rate or the cumu-lative corticosteroid requirements inthese patients. Similar results werereported in a study of infliximab inpatients with PMR (Salvarini et al.2007b). Rituximab (another anti-TNF-a monoclonal antibody) and eta-nercept (a fusion protein) have eachbeen reported to be beneficial in indi-vidual patients with GCA but havenot been studied in larger groups ofpatients (Tan et al. 2003; Bhatia et al.2005).

Aspirin is commonly used byelderly individuals for the preventionof other ischaemic events and mayhave a protective effect against ischae-mia caused by GCA as well. In addi-tion to its well-established anti-plateleteffect, aspirin may also be beneficialin GCA by virtue of its inhibitoryeffect on interferon-c mRNA produc-tion, which is essential for the devel-opment of the inflammatory infiltrateof the vessel wall. Because corticoster-oids have relatively poor anti-inter-feron-c activity, the combination ofaspirin plus steroids is of particularinterest. In a mouse model of large

vessel vasculitis, Weyand et al. dem-onstrated a synergistic effect of aspirinplus dexamethasone on the produc-tion of inflammatory cytokines (Wey-and et al. 2002b). In two clinicalstudies, patients with GCA who wereon aspirin and steroids since diagnosiswere less likely to present with a cra-nial ischaemic complication such asvisual loss or stroke (Liozon et al.2001; Nesher et al. 2004). A retrospec-tive review of 143 patients with GCAwho received either anti-platelet oranticoagulant therapy found a lowerincidence of ischaemic events withsuch treatment (Lee et al. 2006). Anypotential benefit of combination ther-apy may be offset by an increased riskof gastrointestinal haemorrhage. Ran-domized studies are clearly needed todetermine the benefit of the combina-tion of aspirin and steroids in patientswith GCA.

Other steroid-sparing agents in thetreatment of GCA have been investi-gated. Azathioprine was shown toreduce the maintenance dose ofprednisone in one randomized, dou-ble-blind, placebo-controlled trial;however, the number of patients stud-ied was small (De Silva & Hazleman1986). Two studies of cyclosporine Aas adjuvant treatment in patients withGCA found a high rate of adverseevents and no significant steroid-spar-ing potency in patients (Schaufelber-ger et al. 1998, 2005). Other smallreports have suggested a possible ben-efit of cyclophosphamide and dapsoneas adjuvant therapies (Doury et al.1983; DeVita et al. 1991; Nesher &Sonnenblick 1994). Although dapsonehas allowed a reduction in steroiddose in some patients, significant tox-icity has been reported, thus limitingits use. More recently, a possible anti-inflammatory effect of statins in GCAand other rheumatological diseases isalso under investigation (Abud-Men-doza et al. 2003).

Treatment of large-vessel involvement

It is unknown whether current steroidregimens are adequate for treatinglarge-vessel vasculitis – i.e. alleviatingsymptomatic claudication, restoringflow through occluded arteries oraborting aortitis and preventinganeurysm formation. Although GCA-related aneurysms are generallyassociated with elevated acute-phasereactants (ESR, CRP), it is also

unclear if active aortic inflammation isreflected by these markers, whichare universally used to guide steroiddosing.

If symptoms of large-vessel stenosispersist while the patient is on steroidtherapy, endovascular interventionhas been proposed (Bongartz &Matteson 2006). Anecdotal resultsusing balloon angioplasty for thetreatment of symptomatic arteriticocclusion of the subclavian, axillaryand brachial arteries have beenfavourable. If asymptomatic aorticaneurysm is detected, the choicebetween surveillance and surgerydepends on patient factors and thesize of the aneurysm. Current datasuggest no difference in long-termsurvival between patients withoutlarge artery involvement and patientswith aortic aneurysm except for thesubgroup with aortic dissection, whohave a markedly high mortality rate.

Prognosis

Visual loss from GCA is typically pro-found and permanent. However, theliterature cites favourable rates ofvisual recovery in GCA, ranging from15% to 34% (Danesh-Meyer et al.2005). This discrepancy between whatis observed in clinical practice(patients are still blind) and what isreported in studies (vision canrecover) is likely related to the meansby which vision is assessed. Whenvisual recovery is defined solely as animprovement in visual acuity, it leavesopen the possibility that acquiredeccentric viewing may be reflected inthe reported recovery rate. Studiesthat have assessed changes in visualfield as well as visual acuity followingsteroid treatment report dismallylow rates of recovery, of the order of4–5% of improved central visual field– confirming the generally grim prog-nosis once vision is lost (Hayreh &Zimmerman 2003b; Danesh-Meyeret al. 2005).

During the first few days after initi-ating high-dose steroid treatment,patients are still at some risk for fur-ther visual loss. Two recent studiesreported widely different rates ofvisual deterioration (4% versus 27%),but both studies agree that if furtherdeterioration of vision occurs it hap-pens in the first 5–6 days of steroidinitiation (Hayreh & Zimmerman2003a; Danesh-Meyer et al. 2005).


28

Once vision has stabilized and diseaseactivity is controlled with steroids, itis said that recurrent visual loss israre. In a 5-year retrospective study,Aiello et al. found visual loss follow-ing 1 month of steroid therapy in onlyone of 245 patients (Aiello et al.1993). Yet a recent study found a sur-prisingly higher rate of recurrentischaemic optic neuropathy (seven of67 patients, 10%), all of whichoccurred between 3 and 36 monthsafter the initial visual loss (Chan et al.2005). The basis for this difference isunclear.

The other aspect of prognosis inGCA concerns the large vessels.Development of an aortic aneurysm isassociated with reduced survival rate;effective screening strategies for thisimportant complication are currentlyunder investigation (Bongartz &Matteson 2006). In addition to vascu-litis-related cardiovascular and cere-brovascular ischaemic events,generalized atherosclerosis may con-tribute to stroke and myocardialinfarction in this elderly population.Whether the prevalence of atheroscle-rosis in GCA is truly increased or notis as yet unknown (Duhaut et al.1998; Le Page et al. 2005; Gonzalez-Juanatey et al. 2007).

In one series of 255 patients withGCA followed for 24 years, malig-nancy later developed in 15% (meantime interval 5.2 years) but did notcontribute to an increased mortality(Gonzalez-Gay et al. 2007a). Rarepatients develop GCA concurrent witha malignancy. In such cases, the GCAis thought to be a paraneoplastic vas-culitis induced by the malignancy thatremits when the malignancy is treated(Liozon et al. 2006a). Considering theadvanced age of the patient popula-tion, the potential for significant is-chaemic events secondary tovasculitis, secondary complications oflong-term steroid treatment and asso-ciated comorbidities, the overall prog-nosis of GCA is good. In fact, the lifeexpectancy is normal in treatedpatients without aortic aneurysm(Matteson et al. 1996).

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Received on November 18th, 2007.

Accepted on March 29th, 2008.

Correspondence:

Aki Kawasaki

Hopital Ophtalmique Jules Gonin

Avenue de France 15

Lausanne 1004

Switzerland

Tel: + 41 21 626 8660

Fax: + 41 21 626 8666

Email: [email protected]


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giant cell arteritis: an updated review

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