Acta Ophthalmologica 2009
Review Article
Giant cell arteritis: an updated
review
Aki Kawasaki1 and Valerie Purvin2
1
Department of Neuro-ophthalmology, Hôpital Ophtalmique Jules Gonin,
Lausanne, Switzerland
2
Departments of Ophthalmology and Neurology, Midwest Eye Institute and Indiana
University, 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 awareness 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 summarizes 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: 13–32
ª 2008 The Authors
Journal compilation ª 2008 Acta Ophthalmol
doi: 10.1111/j.1755-3768.2008.01314.x
Historical perspective
One of the earliest recorded observations of giant cell arteritis (GCA)
dates from the 10th century, when
oculist Ali Ibn Isa of Baghdad
remarked on the relationship between
inflamed arteries and muscles and
visual symptoms in his book, The
Tadhkirat (Ibn Isa 1936). His proposed treatment was excision of the
temporal arteries. ‘By these means one
treats not only migraine and headache
in those patients that are subject to
chronic eye disease, but also, acute,
sharp catarrhal affections, including
those showing heat and inflammation
of the temporal muscles. These diseased conditions may terminate in loss
of eye sight…’ The first description in
the English literature is attributed to
Hutchinson (1890), who was asked to
consult on an 80-year-old man for red
‘streaks on his head’ that were so painful as to prevent his wearing a hat
(Hutchinson 1890). The red streaks
were, in fact, inflamed and swollen
temporal arteries. Interestingly, no
mention of any other clinical symptoms or signs were noted and the natural course of this man’s condition
proved self-limiting and benign. The
first histopathological evidence of a
granulomatous vasculitis in the temporal arteries was reported by Horton
et al. (1932) in two patients. These two
patients had systemic symptoms of
fever, weakness and anaemia as well as
scalp tenderness and painful temporal
arteries. In a later publication, the
same authors expanded the clinical
characterization of the then-unknown
disease to include pain with chewing
food, headache, double vision and
visual loss. This disease, now commonly called GCA, still carries the eponym ‘Horton’s disease’. Various other
terms have also been used to refer to
this inflammatory vasculopathy affecting large- and medium-sized arteries,
including thrombotic arteritis, granulomatous arteritis, cranial arteritis and
temporal arteritis. In this article, the
term GCA is favoured.
Polymyalgia rheumatica (PMR) is
another common inflammatory syndrome in elderly patients. PMR is
characterized primarily by bilateral
shoulder or pelvic girdle aching and
morning stiffness but it has a diverse
clinical profile that often overlaps with
other rheumatic and inflammatory
conditions, including GCA (systemic
manifestations, elevation of serum
markers and favourable response to
steroids). Over one third of patients
with GCA have PMR at presentation;
conversely, about one third of patients
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Acta Ophthalmologica 2009
with PMR have systemic manifestations like fever, weight loss and anorexia (Dasgupta et al. 2007). Some
patients may have both PMR and
GCA syndromes simultaneously; others evolve from one condition to the
other. Among patients with pure PMR
clinically, the incidence of a positive
temporal artery biopsy is 10–20%
(Hunder 2006). While it is clear that
these two disorders are related, the
mechanisms by which they are linked
remain uncertain. Because similar histopathological findings may be found
in both PMR and GCA, the distinction
between them is clinical (diagnostic
criteria, laboratory findings, disease
evolution, imaging studies).
Epidemiology and
risk factors of GCA
GCA is the most common primary
vasculitis of adults in the Western
world (Weyand & Goronzy 2003); its
geographical distribution suggests a
greater susceptibility with increasingly
northern latitude. The worldwide
annual incidence rate of GCA ranges
from 1.28 to 29.1 per 100 000 among
persons aged 50 years or more (Ramstead & Patel 2007). Highest rates are
found in White individuals of northern European descent (e.g. about
30 ⁄ 100 000 in Norway) and lowest
rates are found in African, Asian and
Arab populations (e.g. 1.47 ⁄ 100 000
in Japan) (Hunder 2002; Miller 2007).
The actual prevalence of the disease
may be underestimated based on clinical incidence rates: one autopsy series
from Sweden showed evidence of
GCA in 1.2% of temporal arteries
(Ostberg 1971). There is a gender predilection favouring women, who are
affected 2–6 times more commonly
than men (Salvarani et al. 2004). It
has been speculated that some of this
female predisposition is reflective of
the higher proportion of women in
the elderly population. Seasonal clustering in the late spring–early summer
months has been reported by several
groups but is not observed regularly
(Salvarani et al. 2004; Smeeth et al.
2006).
A genetic predisposition has been
suspected from reports of increased
prevalence among first-degree relatives
and occasional familial forms of GCA
(Fietta et al. 2002; Raptis et al. 2007).
14
GCA is a polygenic disorder, and disease susceptibility has been associated
with selected genes located within the
human leucocyte antigen (HLA) class
I and class II regions, particularly
HLA DRB1*04 (Weyand et al. 1992;
Gonzalez-Gay et al. 2007b). Other
genes, particularly those related to
cytokine and chemokine expression,
can modulate the clinical expression
of GCA. For example, polymorphisms
at the tumour necrosis factor-a locus
and the interleukin (IL)-10 promoter
region have correlated independently
to an increased risk of developing
GCA and polymorphisms; genes
encoding vascular endothelial growth
factor (VEGF), interferon-c and platelet glycoprotein receptor are associated with increased risk of ischaemic
complications in GCAC Rueda et al.
2007; Salvarani et al. 2007a).
All factors considered, the single
greatest risk factor for GCA is age
(Nordborg et al. 2003). From a population-based study in the UK, the incidence rate of GCA rose markedly to
60 ⁄ 10 000 when only persons aged
80 years or older were considered
(Smeeth et al. 2006). The median age
of onset is about 75 years. Cases of
GCA reported in persons younger
than 50 years must be highly exceptional (Hunder 2002; Langford 2006).
Pathogenesis: an
overview
Two different immunopathogenetic
processes underlie the clinical manifestations of GCA (Weyand & Goronzy
2003). One is a systemic inflammatory
reaction that results from over-activation of the innate acute phase
response, a non-antigen-driven, nonadaptive defence mechanism to stress
and injury. The acute-phase response
involves a cascade of chemical signals,
driven in large part by IL-6, which
derives from circulating monocytes,
neutrophils and macrophages (Goronzy & Weyand 2002). The serum
level of IL-6 generally reflects the
intensity of the response and correlates with circulating levels of the
other acute-phase proteins such as
C-reactive protein, serum amyloid A,
haptoglobin, fibrinogen and complement. Clinical manifestations related
to the acute-phase response are nonspecific markers of inflammation,
including fever, night sweats, anorexia, myalgias and weight loss.
The second process in GCA represents a maladaptive, antigen-specific
immune response that directs an
attack on arterial walls in GCA and
is responsible for the focal ischaemic complications of GCA. Taken
together, the innate response is the
basis for the systemic inflammatory
syndrome of GCA while the antigenspecific response mediates the arteritis.
These two pathogenetic components
are parallel yet inter-related processes,
and one component may dominate
the picture in any given individual.
The vasculitis of GCA
A complete understanding of the
immunological events that lead to
arterial
wall
inflammation
and
destruction is not fully established. It
is accepted that the arteritis of GCA
is an adaptive antigen-driven, T-cellmediated process; the inflammatory
infiltrate is composed primarily of
CD4 T-cells and macrophages (Weyand et al. 2004). But what triggers the
process? A microbial pathogen as the
instigating agent has been a popular
but still unsubstantiated hypothesis.
Another hypothesis holds forth that
the triggering antigen may be an
endogenous element within the arterial
wall. Age-related calcifications in the
lamina, elastin and extracellular matrix
proteins have been proposed and may
explain the age-specific expression of
GCA (Ma-Krupa et al. 2005).
GCA displays a peculiar preference
for certain large- and medium-sized
arteries while rarely affecting other
vessels of similar calibre. Commonly
affected vessels include the ascending
aorta, the extracranial branches of the
carotid artery, the subclavian and
axillary arteries and the vertebral
arteries; involvement of the descending aorta, coronary arteries, mesenteric arteries and femoral arteries is
unusual (Weyand & Goronzy 2003).
The intracerebral arteries are typically
spared from the vasculitic attack of
GCA, presumably because of the paucity of elastic tissue in their walls.
Such vascular tropism implicates the
arterial wall itself as an important
participant in the propagation of an
immune attack (Fig. 1) (Weyand et al.
2004).
Acta Ophthalmologica 2009
Activation of T-cells
GCA preferentially affects arteries
with a certain architecture: walls composed of three well-developed layers
(an outer adventitia, a muscular medial layer and an intima) separated by
an elastic lamina. It is the arterial
adventitia that is the site of the primary immunological injury (Weyand
et al. 2004) and there are two structural reasons for this. In medium- and
large-sized arteries, only the adventitial layer is vascularized with a
capillary network (the vasa vasorum),
whereas the medial and intimal layers
are avascular. Via the vasa vasorum,
T-cells and macrophages gain access
to the arterial wall. Access from the
luminal side is not feasible because
the strong shearing forces generated
by the high velocity of blood flow
through these large arteries prohibit
cell adhesion and entry. In addition,
the adventitia harbours an indigenous
population of immunological surveillance cells, called dendritic cells, which
patrol the outer layer of the arterial
wall for possible intruders (Weyand
et al. 2004, 2005; Ma-Krupa et al.
2005). Under physiological conditions,
these dendritic cells are immature,
phagocytic, relatively quiescent cells
that act to inhibit T-cell activation in
the perivascular space. Once activated,
however, dendritic cells transform into
powerful antigen-presenting cells that
recruit, prime and activate naive CD4
T-cells against invading antigen in the
tissue. It is this change in the functional status of dendritic cells that
marks a critical and early event in the
development of vasculitis (Weyand
et al. 2005). Thereafter, dendritic cells
can persist in the inflamed arterial
wall and continue their stimulation of
T-cells, thus sustaining the inflammatory process chronically. Remarkably,
in vitro blocking of the dendritic cells
abolishes T-cell functioning and the
inflammatory process aborts (Weyand
et al. 2004).
Differentiation of macrophages
Once activated in situ, adventitial Tcells (typically CD4) undergo rapid
clonal and secrete a potent cytokine,
interferon-c, which in turn recruits
macrophages and stimulates giant cell
formation. This is a critical point in the
immunopathogenesis of GCA-related
tissue infarction because macrophages
are the effector cells that cause arterial
wall destruction. Macrophages have
the capacity to differentiate and generate several distinct lines of effector cells
and thus acquire a broader spectrum
of harmful actions. Macrophages in
the adventita focus on producing
inflammatory cytokines that optimize
T-cell stimulation. Macrophages in the
media specialize in generating reactive
oxygen intermediates that induce lipid
peroxidation of smooth muscle cell
membranes as well as metalloproteinase
enzymes that break down and digest
the internal elastic lamina (Weyand &
Goronzy 2002a; Weyand et al. 2004).
Macrophages at the media–intima
junction, along with multinucleated
giant cells, form granulomas in the
medial layer and release a variety of
growth factors and angiogenic factors,
notably platelet-derived growth factor
(PDGF) and VEGF (Goronzy &
Weyand 2002).
Intimal hyperplasia and vascular
occlusion
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 vasorum 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, especially 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 necessary
to 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.
Matrix metalloproteinases (MMPs),
also derived from macrophages, are
the enzymes that degrade elastin
(Rodriguez-Pla et al. 2005). Once the
internal elastic lamina is fragmented,
the MMPs enhance migration of
smooth muscle cells from the media
to invade the intima where they proliferate exuberantly under influence of
PDGF, causing intimal hyperplasia
and vessel occlusion. The expansion
of the intima is necessarily accompanied by neoangiogenesis, driven by
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Acta Ophthalmologica 2009
VEGF, in order to support this previously avascular layer.
T-cell differentiation is the chief
determinant of the extent and course
of the vascular inflammation. This
event occurs early in the disease process and determines the pattern and
types of cytokines expressed in the
wall tissue. High levels of interferon-c
in biopsed tissue correlate well with
severe intimal hyperplasia, neovascularization, and luminal occlusion and
tissue ischaemia (Weyand & Goronzy
2002a). Low levels of tissue interferon-c and a predominance of IL-2
are found in biopsy samples showing
wall inflammation without development luminal occlusion (Brack et al.
1999). The mechanisms that induce Tcell differentiation are still unclear but
various host factors may play an
important role (e.g. genetic predisposition). Among patients with GCA,
concentrations of tissue cytokines and
growth factors can vary widely but
they do correlate with each other and
the severity of intimal hyperplasia.
Therefore, early evaluation of the pattern of cytokine expression in biopsied
tissue may provide a means to assess
the ischaemic risk or even predict the
clinical course of the disease for any
given individual.
Clinical subtypes
of GCA
As stated earlier, a variety of endogenous and exogenous factors – for
example genetic make-up, arterial
structure, viral exposure, etc. – influence the direction and severity of the
immunopathogenetic responses of
GCA. The vascular tropism, as yet
incompletely understood, defines the
location of the arteritis. Despite the
protean manifestations of this disorder, three predominant clinical subtypes of GCA have emerged and they
can be distinguished by their clinical
profile and cytokine pattern (Table 1).
Systemic inflammatory syndrome
This subtype of patients is characterized by non-specific constitutional
symptoms related to systemic inflammation in the absence of focal ischaemic symptoms. Such patients have
asthenia, arthralgias, myalgias, achiness, anorexia, weight loss and night
sweats. A fever of unknown origin,
which may be low-grade or spiking up
to 40C, is common and often generates concern and investigations for an
underlying systemic infection or
malignancy. This has been referred to
as ‘silent or masked GCA’, which
should not be confused with ‘occult
GCA’, a term coined for patients in
whom local ischaemic symptoms are
present in the absence of systemic
inflammation (Hayreh et al. 1998a;
Liozon et al. 2003). Serologically,
these patients typically have high sedimentation rates, elevated acute-phase
reactants
(including
C-reactive
protein, haptoglobin and fibrinogen),
elevated liver function tests, low albumin levels, thrombocytosis and a
normocytic normochromic anaemia
(Liozon et al. 2003). The serum level
of the inflammatory cytokine IL-6
that derives from circulating monocytes is a sensitive indicator of an exuberant
systemic
inflammatory
response (Goronzy & Weyand 2002;
Weyand & Goronzy 2003). Such
patients have histopathological evidence of arteritis without hyperplasia
of the arterial intima and without
luminal stenosis. High levels of IL-2
are found in the biopsy specimen of
these patients (Brack et al. 1999).
Cranial arteritis
Patients with this clinical subtype of
GCA have predominantly a localized
vasculitis and subsequent tissue
ischaemia. The best-known example
of focal GCA is inflammation limited
to the branches of the carotid arteries,
hence the name ‘cranial arteritis’.
Common symptoms of cranial arteritis
include headaches or facial pain, even
carotidynia, scalp tenderness, jaw
claudication,
painful
dysphagia,
hoarseness and visual loss. Necrosis of
the scalp or tongue necrosis are
dramatic but rare manifestations of
cranial GCA, inaugural in 1% or less
of cases (Becourt-Verlomme et al.
2001; Campbell et al. 2003). Scalp
necrosis occurs only when all four supplying arteries are occluded, indicating
an extensive vasculitis and portending
a grim prognosis (Fig. 2). In patients
with scalp necrosis, the associated
mortality rate related to cerebral or
coronary artery occlusion is 41% and
the incidence of irreversible visual loss
is 67% (Campbell et al. 2003).
In patients with cranial arteritis,
arterial biopsy shows giant cell formation, intense intimal hyperplasia, luminal stenosis or obstruction, elevated
levels of interferon-c and IL-1b and
PDGF (Goronzy & Weyand 2002;
Weyand & Goronzy 2003).
Large-vessel vasculitis
The third clinical subtype of GCA is
limited to or dominated by involvement of the subclavian and axillary
arteries and ⁄ or the aorta, often
termed ‘extracranial large-vessel GCA’
or ‘large-vessel vasculitis’ (Lie 1995;
Bongartz & Matteson 2006). Largevessel GCA is not a more aggressive
form of the disease, nor is it a chronic
phase of the disease; it represents a
localized arteritis in a different vascular bed compared to cranial arteritis.
Local stenosis develops in the superior
branches of the aortic arch, particulary the subclavian artery and axillary
artery. Vasculitic inflammation of the
aorta leads to dilation, not stenosis,
and aneurysm formation. Involvement
of 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).
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Acta Ophthalmologica 2009
(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). Reprinted from Campbell et al. (2003) with permission from Blackwell Publishers.
extremities occurs far less frequently
(Lie 1995; Nuenninghoff & Matteson
2003). The clinical profile of patients
with the large-vessel subtype of GCA
reflects the vascular compromise in
the upper extremities. Arm claudication and an arterial bruit are present
in 80% of patients; this may be the
only symptom at presentation and is
frequently bilateral (Brack et al.
1999). Other symptoms are peripheral
paresthesias, Raynaud phenomenon,
paleness of the hands with use of the
upper extremities and – rarely – tissue
gangrene (Levine & Hellman 2002).
Physical signs include diminished or
absent pulses, asymmetric blood pressure readings and bruits over the carotid, axillary, brachial or subclavian
arteries. On the other hand, aortitis is
clinically silent in the majority
of patients. Occasionally, patients
report non-specific back pain. It is the
subsequent development of aneurysm,
usually in the thoracic aorta, that is
worrisome because in the event of an
acute complication – aortic valve
insufficiency, aortic rupture or aortic
dissection – mortality is tremendously
high (Nuenninghoff et al. 2003; Gonzalez-Gay et al. 2004).
GCA as a cause of large-vessel vasculitis can be overlooked for several
reasons. Firstly, many of these
patients lack the systemic inflammatory symptoms and markers of GCA.
Secondly, this form of the disease
appears to evolve more slowly than
the cranial arteritis form and an
abrupt infarction of the hand or arm
is hardly ever seen. Ischaemic symptoms in the upper extremities develop
gradually and may be so subtle as to
be dismissed by the patient or the
clinician. Thirdly, the distribution and
histopathology of arterial inflammation in large-vessel GCA can be indistinguishable from that found in
Takayasu areteritis, and may create
some initial diagnostic confusion.
However, the clinical setting (demographic characteristics of the patient,
presence of other clinical signs and
associated serum markers) should
readily distinguish GCA. Finally, the
temporal artery biopsy is negative in
at least half of the patients with largevessel vasculitis (Levine & Hellman
2002; Weyand & Goronzy 2003;
Bongartz & Matteson 2006).
Assessment of large-vessel vasculitis
requires vascular imaging. This can be
achieved with invasive or non-invasive
modalities. With conventional catheter
angiography, the characteristic findings are long segments of stenoses of
large arteries alternating with segments of normal arterial calibre and
smoothly tapering occlusions. Bilateral
involvement of the subclavian, axillary
and brachial arterities is common
(Stanson 2000; Bongartz & Matteson
2006). Non-invasive modalities [computerized tomography (CT), magnetic
resonance imaging (MRI) or positron
emission tomography (PET)] are currently favoured for their ease and high
sensitivity. CT scanning can demonstrate aortic involvement (thickening
of the wall) and aortic aneurysm formation (Herve et al. 2006). MRI findings of aortitis are aortic wall
thickening, wall oedema, increased
mural contrast enhancement and vascular stenosis of aortic branch points.
MRI angiography also allows visualization of the aortic branches (cranial,
cervical and thoracic) (Fig. 3) (Narvaez et al. 2004). MRI combined with
MRI arteriogram (MRA) has the
advantage of examining the entire
large vessel tree in a single examination. Introduced in 1999 for use in
GCA, PET scanning has emerged as
an alternative and highly effective
technique for assessing large-vessel
vasculitis (Blockmans et al. 1999; Walter et al. 2005). Active lymphocytes,
macrophages and inflammation are
accompanied by accelerated anaerobic
metabolism and glucose consumption,
which is readily identified in vivo with
18
F-fluoro-2-deoxy-d-glucose (FDG)
PET. This makes FDG PET very sensitive in the detection of inflammation
as well as for monitoring changes in
activity with treatment (Fig. 4) (De
Leeuw et al. 2004). However, one
unresolved concern with PET is
specifity: it is not clear that increased
vascular uptake is a finding specific to
vasculitis or if it is simply a marker of
any type of wall injury (Bongartz &
Matteson 2006). At this time, there is
no gold-standard test for large-vessel
vasculitis and imaging is selected on
individual considerations. A comparative multi-centre trial is under consideration to determine the most efficient
use of these different modalities in
GCA.
Although large-vessel vasculitis may
be the initial presentation or the predominant manifestation of GCA in
some patients, in others large-vessel
involvement develops as a late complication of the disease – particularly after
steroids have been tapered. It has
been estimated that one out of every
five patients will eventually develop
an aortic aneurym and ⁄ or dissection
Fig. 3. Magnetic resonance imaging arteriogram (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 & Matteson (2006) with permission from Lippincott,
Williams and Wilkins.
17
Acta Ophthalmologica 2009
or stroke. The onset of symptoms,
especially ischaemia-related ones, is
frequently explosive and most patients
may be able to recall the day of onset
of a specific symptom. In other
patients, symptoms may appear insidiously. Sometimes, there is a migratory
and changing nature of symptoms
over an extended period of time so
that each symptom seems unrelated to
the next, and recognition that a single
disease entity accounts for the sum
complex of signs and symptoms may
be overlooked.
Natural history
(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 abnormal 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.
(Nuenninghoff & Matteson 2003). The
true incidence of extracranial largevessel and aortic involvement in GCA
is not known, ranging from 9% to
27% in clinical series (Klein et al. 1975;
Evans et al. 1995; Nuenninghoff &
Matteson 2003; Schmidt & GromnicaIhle 2005). Studies using PET scan and
autopsy series suggest that subclinical
aortitis is present in more than half of
GCA patients, leading to speculation
that aortitis may be the rule rather than
the exception in GCA (Ostberg 1971;
Blockmans et al. 2006). Despite such
high estimates of large-vessel involvement in GCA, it is an under-appreciated complication because most cases
of aortitis are subclinical unless a catastrophic event intervenes (3–11%)
(Levine & Hellman 2002; GonzalezGay et al. 2004).
The natural history of GCA-related
aneursyms remains unknown. Who is
at risk for the development of largevessel complications is also unsettled.
One study found that patients considered high-risk for aortic aneurysm have
a murmur of aortic insufficiency, PMR
plus erythrocyte sedimentation rate
(ESR) > 100 mm ⁄ hr, or any two of
the following: hypertension, hyperlipidaemia, PMR, coronary artery disease
(Bongartz & Matteson 2006). Given
the potential morbidity and mortality
18
associated with aortic aneurysm,
there is increasing consensus that
patients with GCA need to be screened
for early changes consistent with
aneurysm formation. However, the
advanced age and other comorbidites
(often multiple) in patients with GCA
mean that not every patient who
develops an aneurysm will be an
acceptable candidate for surgical
repair. An efficient screening strategy
has yet to be established but at the
moment, one approach recommends a
minimum of abdominal ultrasound,
chest radiograph and transthoracic
echocardiogram annually (Bongartz &
Matteson 2006). Patients with any
of the risk factors presented here are
additionally recommended to have a
CT or MRI angiography at the time of
their diagnosis of GCA and again
1 year later.
Clinical manifestations
of GCA
The spectrum of clinical manifestations associated with GCA encompasses a wide range of symptoms and
signs, ranging from non-specific complaints such as headache and general
achiness to specific organ dysfunction
such as visual loss, arm claudication
The natural history of GCA in nonfatal cases is best revealed from
descriptions of the disease in the medical literature dating from the pre-steroid era. In 1971, Hamilton et al.
noted that GCA ‘may unfold episodically over a period of many years …
and has the capabilities of healing
spontaneously’(Hamilton et al. 1971).
In describing the natural history of
PMR these authors stated that ‘The
active disease may last from a few
months to 3 years or more, with exacerbations and remissions. Eventual
spontaneous recovery is the rule, even
without corticosteroid therapy’ (Hamilton et al. 1971). The remitting-relapsing nature of GCA is largely
unappreciated since the advent of steroid treatment, but several recent articles have brought this aspect back to
the clinical consciousness. Patients
with jaw and leg claudication, fever,
weight loss, myalgias, headache, scalp
tenderness, diplopia and even confusion experienced spontaneous remission of their symptoms. In some
patients, the appearance of other
symptoms of GCA, including visual
loss, within weeks to months of remission eventually led to diagnosis and
treatment. In other patients, the
remission lasted for many years (Hernandez-Rodriguez et al. 2006; Purvin
& Kawasaki 2007). However, one of
the two patients with episodic transient visual loss did suffer permanent
ischaemic optic nerve damage. Such
patients serve to remind clinicians to
take a careful retrospective history in
any elderly patient, rather than just
looking for symptoms evident at the
time of presentation. Spontaneous
remission of signs or symptoms does
not rule out a diagnosis of GCA.
Acta Ophthalmologica 2009
Systemic manifestations
At least one symptom or sign of systemic inflammation such as anorexia,
asthenia, malaise, myalgia, arthralgia,
weight loss and fever can be found at
presentation in the majority of
patients. The frequency at which these
constitutional signs and symptoms
manifest in GCA is variable among
different studies, in part because of
selection bias of patients, accuracy of
history-taking and the use of different
criteria to diagnose GCA. In one large
series examining the inaugural symptoms of 260 patients with GCA, 65%
reported an alteration in general wellbeing (asthenia, weight loss) and fever
was present in 50%; however, the estimates range from 38% to 90% and
19% to 80%, respectively, for these
two symptoms in the literature (Hayreh et al. 1997; Becourt-Verlomme
et al. 2001; Levine & Hellman 2002).
The myalgia of GCA is typically in
the large proximal muscles. Thus,
patients may report an achiness and
fatigue when raising their arms to
reach upper shelves or difficulty getting out of a low chair or car. Some
patients have a paucity of symptoms
or just an isolated abnormality such as
unexplained weight loss or fever. The
classic picture of an elderly patient
with new headache, jaw claudication,
fever, anorexia, PMR and a tender
temporal artery is only seen in about
half to two thirds of patients, so the
clinician must be able to recognize
the less typical presentations of this
disorder (Levine & Hellman 2002).
Headache and craniofacial pain
The most common symptom of GCA,
related to both systemic inflammation
and local vascular injury in the carotid circulation, is headache. Headache
occurs in up to 90% of patients, may
sometimes localize to the temporal
and occipital areas and is very frequently bilateral. A unilateral headache
in GCA is uncommon (Rahman &
Rahman 2005; Schmidt & GromnicaIhle 2005). Scalp tenderness is a more
distinctive symptom indicative of tissue ischaemia. Patients may report
discomfort when brushing or washing
their hair; others develop such exquisite sensitivity that even putting their
head on a pillow becomes painful.
Perhaps the symptom most specific
to GCA is jaw claudication, but this
is present in less than half (30–48%)
of patients at presentation and may
be misdiagnosed as temporomandibular joint syndrome (Hayreh et al.
1997; Becourt-Verlomme et al. 2001;
Weyand & Goronzy 2003). Unlike
temporomandibular joint pain, which
is immediately present with any jaw
movement, claudication pain due to
masseter muscle ischaemia develops
after a few minutes of mastication
and then disappears with rest. Patients
with jaw claudication often avoid eating chewy foods and meats. Jaw claudication stems from vasculitis and
occlusive stenosis in the maxillary
artery, a branch of the external carotid artery, and (not surprisingly) correlates highly with positive findings on
biopsy of the temporal artery, which
is another branch of the external carotid artery (Hayreh et al. 1997; Schmidt
& Gromnica-Ihle 2005). Accompanying jaw claudication may be painful
localized swelling of the face or neck,
particularly of the orbital region,
cheeks and tongue. Such swelling has
been noted in 6.5% of patients in one
series and implies widespread involvement of the external carotid artery
(Liozon et al. 2006b).
Oral manifestations
GCA should be considered in any
elderly patient with unexplained odontogenic pain. Other oral symptoms
reported variably by patients with
GCA are trismus, throat pain, dysphagia, dysarthria, chin numbness,
glossitis, lip or tongue necrosis and
facial swelling (Fig. 5) (Rockey &
Anand 2002; Paraskevas et al. 2007).
Audiovestibular manifestations
In one recent study (Amor-Dorado
et al. 2003), symptoms of hearing loss,
tinnitus, vertigo, disequilibrium and
dizziness were found in nearly two
(A)
(B)
thirds of patients. More remarkably,
almost 90% of patients demonstrated
abnormal function on one or more
objective tests of audiovestibular function. Vestibular dysfunction was
improved in most patients after
3 months of steroid treatment. However, improvement of hearing loss was
more modest, being seen in only 27%
of patients.
Neurological manifestations
Cerebrovascular ischaemic events are
found in 3–4% of patients with GCA
(Caselli et al. 1988; Gonzalez-Gay
et al. 1998). Such events are caused by
arteritic occlusion of the extradural
segment of the vertebral or internal
carotid arteries or embolization from
an inflammatory thrombus. In general,
the vertebral arteries are affected more
often than internal carotid arteries.
The sparing of the intracranial segment of these arteries has to do with
the loss or near-loss of the elastic tissue
once the arteries penetrate the dura at
the base of the brain (Wilkinson &
Russell 1972). Nevertheless, on very
rare occasions, GCA has been documented histologically in the wall of
intracranial arteries; such patients
typically have a fulminant course of
neurological decline to a fatal outcome
(Salvarani et al. 2006).
Other neurological complications
attributed to GCA include dementia,
psychosis, coma, spinal cord infarction, seizures and subarachnoid haemorrhage. The more recent literature
suggests that peripheral complications
– namely neuropathies – may actually
be the most common neurological
complication of GCA (up to 14%).
These may take various forms including cranial neuropathy, mononeuropathy multiplex, peripheral polyneuro
pathy, cervical radiculopathy, brachial
plexopathy or pure motor neuropathy
(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 necrosis in temporal arteritis. Headache 47: 1213–1215, with permission from Blackwell Publishers.
19
Acta Ophthalmologica 2009
(Caselli et al. 1988; Rahman & Rahman 2005; Pfadenhauer et al. 2007).
The preference for the cervical nerve
roots and brachial plexus is probably
related to the frequent involvement of
the subclavian, axillary and brachial
arteries among patients with GCA.
Most patients with a peripheral neuropathy related to GCA improve with
steroid treatment. The caveat is to
watch for diaphragmatic weakness in
these patients: if the diagnosis is missed
and steroids are withheld or inadequately dosed, the outcome is potentially fatal (Pfadenhauer et al. 2007).
Cardiovascular manifestations
GCA can affect the coronary arteries,
the aortic valve or the myocardium.
Myocardial infarction, cardiomyopathy and aortic valve insufficiency
have been reported. Left ventricular
dysfunction has been reported in up
to 18% of patients with GCA (Eberhardt & Dhadly 2007).
Atherosclerosis, once viewed as an
age-related process of lipid deposition
and degeneration of arteries, is
increasingly viewed as an immunemediated disorder. Inflammation and
endothelial dysfunction lead to progress of atherosclerosis and plaque
destabilization (Weyand & Goronzy
2002). There is, in addition, growing
evidence showing premature atherosclerosis in chronic inflammatory conditions such as systemic lupus
erythematosus, rheumatoid arthritis
and Takayasu’s arteritis (Bacon et al.
2002). Whether atherosclerosis occurs
more frequently among patients with
GCA is as yet unsettled. Smoking and
previous atheromatous disease have
been associated independently with
GCA in women (Duhaut et al. 1998).
A recent large series of 432 patients
found that patients with GCA have a
twofold increase in relative risk for
ischaemic cardiovascular events such
as stroke, angina or myocardial
infarction compared to the general
population (Le Page et al. 2005). In
contrast, another study reported no
significant differences in the intimamedia thickness of the common carotid artery – a marker of generalized
atherosclerosis – and concluded that
the prevalence of atherosclerotic macrovascular disease was not higher in
GCA patients (Gonzalez-Juanatey
et al. 2007).
20
Bowel infarction
Bowel infarction from mesenteric artery
occlusion caused by GCA is decidedly
rare: one review found 11 cases in the
English literature since 1976 (Annamalai et al. 2007). Absence of cranial
symptoms was noted in nearly half of
the cases and bowel infarction was the
initial presention in two patients. It
should be remembered that other vasculitides such as polyarteritis nodosa,
Churg-Strauss, rheumatoid vasculitis,
Takayasu arteritis and Buerger disease
can also cause localized vasculitis of
the gastrointestinal tract; mesenteric
angiography is the gold standard for
differentiating vasculitis of any cause
from other causes of bowel infarction.
Occult GCA
GCA has been called the great masquerader because it can take on many
clinical forms; when systemic manifestations are minimal or absent, these
have been termed the ‘occult manifestations’ of GCA or ‘occult GCA’.
Diagnosis in such cases can be particularly challenging, especially if serum
inflammatory markers are also normal
(Man & Dayan 2007). Occult GCA
may occur in 5–38% of cases (Carroll
et al. 2006). Patients with occult GCA
typically seek medical attention
because of dysfunction with a particular organ system (such as acute visual
loss), respiratory symptoms (such as
chronic cough or sore throat), peripheral neuropathy, dementia, stroke,
coronary ischaemia, pulmonary artery
thrombosis, haematuria, renal failure
and mesenteric infarction (Hayreh
et al. 1998a; Levine & Hellman 2002).
GCA can even present as a tumourlike lesion of the breast, ovary or
uterus (Onuma et al. 2007). Thus, it is
important that non-rheumatological
specialists such as ophthalmologists,
neurologists, cardiologists, nephrologists, oncologists and even gynaecologists maintain a heightened awareness
for these less common manifestations
of GCA because they may be the first
persons to evaluate such patients.
Ophthalmological
manifestations of GCA
Ocular manifestations are a common
occurrence in patients with GCA and
may arise at any point in the natural
course of the disease or even during
active treatment. Different studies have
estimated the frequency of ocular manifestation at between 14% and 70%;
the wide range perhaps reflects in part
whether populations from tertiary centres or non-ophthalmic clinics were
assessed (Rahman & Rahman 2005). In
two large series, visual symptoms or
ocular findings were present at the time
of 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 common
ocular manifestation of GCA – present
in 97.7% of patients – compared to diplopia (6–21%) and other more unusual
ophthalmological presentations (Hayreh
et al. 1998b; Gonzalez-Gay et al. 2000).
One historical point merits mention: the
introduction of corticosteroid treatment
for GCA has reduced dramatically the
percentage of patients with permanent
visual loss. In the pre-steroid era, an
estimated 35–60% of patients suffered
irreversible visual loss from GCA compared to 7–14% in the post-steroid era
(Gonzalez-Gay et al. 2000).
The high frequency of ocular
involvement in GCA underlines the
need for ophthalmologists to have
familiarity with this disorder. The fact
that visual symptoms may be the first
or sole manifestation of GCA emphasizes further the primary role of the
ophthalmologist for recognizing and
diagnosing this disorder without delay.
Transient visual loss
Visual loss in GCA can be transient
or permanent. Among patients with
visual manifestations of GCA, a history of transient visual loss is reported
by 30–54% of patients (Glutz Von
Blotzheim & Borruat 1997; Hayreh
et al. 1998b; Gonzalez-Gay et al.
2000). In some patients, transient
visual loss may be the only complaint.
Transient monocular blindness, or
amaurosis, is not a trivial symptom in
GCA. It results from insufficient perfusion of the optic nerve, retina or
choroid and precedes the development
of acute and permanent visual loss in
more than half (50–64%) of untreated
cases by an average of 8.5 days (Font
et al. 1997; Hayreh et al. 1998b; Gonzalez-Gay et al. 2000; Miller 2001).
Thus, amaurosis in a patient known or
even suspected to have GCA is considered an ophthalmological emergency
and immediate high-dose steroid treatment is recommended in an effort to
Acta Ophthalmologica 2009
prevent the permanent visual loss that
follows in the majority of untreated
cases. Hospitalization and strict bed
rest during initiation of treatment is
advised because small posturally mediated decreases in perfusion through
inflamed, compromised arteries may
precipate infarction of ocular tissue
(Miller 2001). This seemingly trite recommendation has been, in anecdotal
cases, a vision-saving manoeuvre.
The following clinical scenario is
typical yet challenging. An elderly
patient reports one recent episode of
transient monocular blindness and has
little or no systemic symptoms. Is it
GCA-related amaurosis or classical
amaurosis fugax caused by retinal emboli? Clues that favour GCA in this
setting include a relatively short duration of visual loss (1–2 min or less),
multiple recurrences in the same eye
over a short period of time, photopsias or other positive phenomena during the visual loss and provocation of
visual loss with postural change such
as standing up or bending over. A history of amaurosis alternating between
the two eyes is rarely caused by retinal
emboli and should be considered
GCA. On funduscopic examination,
indirect evidence for GCA includes
cotton-wool spots, intraretinal haemorrhages or optic disc oedema. Even
in patients with no visual complaints,
isolated cotton woolspots have been
found (Glutz Von Blotzheim &
Borruat 1997; Miller 2001).
by insufficient perfusion through the
terminal paraoptic branches of the
short posterior ciliary artery, causing
optic disc ischaemia. Thus, NAION is
not accompanied by evidence of choroidal ischaemia.
A diagnosis of AION is clinically
based on acute monocular visual loss
accompanied by optic disc oedema.
The importance in distinguishing
between arteritic AION and NAION
as quickly as possible lies in the immediate prognosis for the other eye.
Among patients with arteritic AION,
25–50% will suffer a similar event in
the other eye, typically within 1–
14 days, if left untreated (Miller
2001). Thus when a diagnosis of acute
AION is made, the clinician must use
clinical indices to determine if it is
likely to be GCA-related. Certain historical features favour a diagnosis of
arteritic AION: age greater than
70 years, preceding amaurosis, very
severe visual loss in range of counting
fingers or worse, new headache and
positive systemic review of systems,
particularly jaw claudication. On
examination of a suspected patient,
any of the following features are considered practically diagnostic for arteritic AION: severe pallid disc oedema
(often described as ‘chalky white’
swelling), disc swelling in combination
with a retinal ischaemic lesion (central
retinal artery occlusion, cilioretinal
artery occlusion or cotton wool spots)
and a normal or large optic cup in the
contralateral eye (Fig. 6) (Hayreh
et al. 1998b; Miller 2001). The significance of finding retinal ischaemic
lesions simultaneously with optic disc
ischaemia (AION) in a non-diabetic
patient is that it indicates involvement
of two different vascular territories of
the eye (the central retinal arterial circulation and the posterior ciliary arterial circulation). In such cases, a
systemic inflammatory vasculopathy
like GCA must be considered.
Other more subtle eye findings can
provide indirect support for GCA.
Patients with AION caused by GCA
have lower central retinal artery pressures compared to eyes with NAION
(Jonas & Harder 2007). Also, the
mean intraocular pressure (IOP)
in eyes with ophthalmic manifestation
of GCA has been noted to be
lower than the IOP in control eyes and
eyes with non-arteritic AION (11.9 ±
4.5 mmHg versus 15.8 ± 1.8 mmHg
and 15.3 ± 2.3 mmHg, respectively)
(Huna-Baron et al. 2006).
Once thesystemic symptoms, sedimentation rate and acute-phase reactants
Anterior ischaemic optic neuropathy
The most common cause of permanent visual loss because of GCA is
anterior ischaemic optic neuropathy
(AION). GCA-related AION, also
called arteritic AION, is caused by
inflammatory occlusion of the short
posterior ciliary arteries, which provide blood flow to the optic disc, the
choroid and (in some persons) a small
part of the retina supplied by the cilioretinal artery (Erdogmus & Govsa
2006). As such, arteritic AION
(infarction of the prelaminar and laminar portion of the optic nerve head)
is frequently accompanied by choroidal ischaemia or ciliary artery occlusion, which may be evident on
fundusocopic examination or by flourescein angiography (Fig. 2) (Hayreh
et al. 1998b). In contrast, the more
common form of AION, called nonarteritic AION (NAION), is caused
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
Acta Ophthalmologica 2009
have normalized, recurrent episodes of
ischaemic optic neuropathy are rare.
When recurrences occur, they are usually associated with a relapse of systemic symptoms or re-elevation of
acute-phase reactants. In one study, the
recurrent episodes were all ipsilateral
and occurred 3–36 months (median
8 months) after the initial episode
(Chan et al. 2005).
Other types of ischaemic visual loss
GCA can affect any aspect of the anterior visual pathway from retina to
occipital lobe. AION is by far the most
common cause of GCA-related visual
loss (78–99%) (Gonzalez-Gay et al.
2000; Hayreh et al. 2002; Carroll et al.
2006). Central retinal artery occlusion
is the second most common cause of
visual loss, affecting about 10–13% of
patients. Less common causes include
posterior ischaemic optic neuropathy,
cilioretinal artery occlusion, choroidal
infarction and – rarely – ischaemia to
the chiasm or postchiasmal visual pathway (Miller 2001). Occipital lobe
infarction caused by vertebrobasilar
artery involvement occurs in < 5% of
patients with visual loss (GonzalezGay et al. 2000). In patients with cortical visual loss, visual hallucinations
may arise in the area of visual field loss
and generally disappear spontaneously
after several weeks. They may resolve
abruptly with steroid initiation.
Diplopia
Diplopia is the second most common
visual symptom related to GCA, but
this occurs far less frequently than
visual loss. Transient or constant diplopia was reported in 5.9–21% of
patients with visual manifestations
(Glutz Von Blotzheim & Borruat
1997; Hayreh et al. 1998b; GonzalezGay et al. 2000). In some patients, the
diplopia may be a harbinger of subsequent visual loss. In others, the diplopia is transient and the sole visual
manifestation of GCA. Ischaemia to
the extraocular muscles, the cranial
nerves or brain stem ocular motor
pathways have all been implicated as
the mechanism of diplopia in GCA.
Thus, weakness of a single extraocular
muscle, an isolated cranial nerve III,
IV or VI palsy (partial or complete),
combined cranial nerve palsies, skew
deviation, internuclear ophthalmoplaegia, one-and-a-half syndrome and
22
upgaze palsy have been described with
GCA (Miller 2001; Melson et al.
2007).
Orbital and other unusual ocular
manifestations
In occasional patients, GCA may
cause efferent pupil abnormalities
(tonic pupil, Horner pupil), acute hypotony, ocular ischaemic syndrome,
orbital ischaemia and – rarely – orbital infarction syndrome (Miller 2001).
Signs of orbital inflammation such as
red eye, chemosis or proptosis accompanied by pain typically evoke consideration of a more common condition
known as orbital pseudotumour,
which is also treated with steroids.
However, the steroid requirement for
orbital pseudotumour is lower in dosage and shorter in duration than that
used for GCA, so caution must be
taken to exclude GCA in any older
patient with an orbital inflammatory
syndrome. In a review of 13 cases of
GCA-related orbital manifestations,
all patients had proptosis and only
two patients had pain (Lee et al.
2001). Chemosis, lid oedema, ophthalmoplaegia, visual loss and episcleritis
were other findings. The outcome was
reported as ‘improved’ in eight of
these 13 patients.
Laboratory investigations
in GCA
ESR
An elevated ESR strongly supports a
clinical suspicion of GCA but a normal ESR does not rule out a diagnosis
of GCA. According to the American
College of Rheumatology, an ESR by
Westergren method is elevated if it is
‡ 50 mm ⁄ hr. Approximately 85% of
patients have an ESR ‡ 50 mm ⁄ hr
and almost all patients have an ESR
greater than 20 mm ⁄ hr (Schmidt
2006). Nevertheless, ESRs as low as
4 mm ⁄ hr have been reported in
patients with symptomatic, biopsypositive disease (Hayreh et al. 1997).
In interpreting the significance of a
given ESR, it is important to consider
other factors that raise or lower the
ESR. Conditions known to elevate the
ESR are increasing age, female gender, pregnancy, anaemia, inflammatory disorders, infection, connective
tissue disorders, trauma, hypercho-
lesterolaemia and malignancy (Hayreh
et al. 1997). Conversely, a very low
ESR occurs in polycythaemia, hereditary spherocytosis, impaired hepatic
protein synthesis, hypofibrinogenaemia, congestive heart failure and use
of anti-inflammatory drugs (Hayreh
et al. 1997). Some patients with GCA
consistently demonstrate a low or
normal ESR despite active disease,
and they have no other condition that
might lower the ESR. Despite the
relative lack of sensitivity and specificity, the low cost and universal availability of the ESR make it a useful
laboratory test in the diagnosis and
management of patients with GCA.
Some investigators have noted that the
presence of a strong acute-phase
response defined by fever, weight loss,
anaemia and high ESR (> 85 mm ⁄ hr)
confers a low risk of cranial ischaemic
complications
and
an excellent
response to steroids, but others have
not corroborated this relationship (Cid
et al. 1997; Liozon et al. 2001; Hernandez-Rodriguez et al. 2002). The
prognostic value of the ESR for risk
of ischaemic events and response to
treatment remains under investigation.
C-reactive protein
C-reactive protein (CRP) is an acutephase marker measured as a single
protein quantification. Its advantages
over the ESR are faster responsiveness
to inflammation (within 4–6 hr), insensitivity to age, gender and haematological factors, and notably higher
sensitivity and specificity for GCA in
the appropriate clinical setting. Several
studies have found that the sensitivity
of CRP alone is about 98% or higher
for active GCA (Hayreh et al. 1997;
Gonzalez-Gay et al. 2005b; Parikh
et al. 2006). In fact, performing both
an ESR and a CRP has only a slightly
higher yield for detecting an abnormal
result compared to performing a CRP
alone (Parikh et al. 2006). Nonetheless, it is advantageous to perform
both laboratory tests whenever possible because, not infrequently, the
CRP is elevated when the ESR is normal and, very occasionally, the ESR is
elevated when the CRP is normal
(Parikh et al. 2006). The disadvantages of CRP include the higher cost
of testing compared to ESR and perhaps a relative unfamiliarity with the
test amongst clinicians.
Acta Ophthalmologica 2009
Thrombocytosis
An elevated platelet count is a common laboratory finding in GCA. In a
recent review of the laboratory findings of 240 patients with biopsy-positive GCA, 48.8% of patients (most of
whom had constitutional symptoms)
had thrombocytosis at presentation,
and thromobocytosis was associated
with a higher ESR and CRP as well
as lower haemoglobin and albumin
(Gonzalez-Gay et al. 2005b). In other
studies thrombocystosis also appears
to correlate well with the ESR
(Foroozan et al. 2002; Costello et al.
2004). Although only about half of
patients with GCA demonstrate a
platelet count greater than 400 ·
103 ⁄ ll, the finding of thrombocytosis
has high predictive value in the setting
of a suspected patient with an elevated
ESR (Foroozan et al. 2002).
IL-6 and other cytokines
Cytokines are the messenger proteins
within the cellular immune system
and mediate a variety of functions. In
GCA, cytokines play an important
role in regulating the intensity of cellular proliferation and the direction of
cellular differentiation, which ultimately determines the nature and
magnitude of the inflammatory
response. IL-6 is a cytokine found
both in inflamed arterial walls and in
the blood circulation. IL-6 is a chief
stimulator of the systemic inflammatory response and the production of
most acute-phase proteins (Goronzy
& Weyand 2002). Serum levels of IL6 are highly elevated in active GCA
and respond rapidly to steroid treatment. Weyand et al. followed the
acute-phase markers in 25 patients
with biopsy-positive GCA prospectively (Weyand et al. 2000). At the
time of diagnosis (before treatment
initiation) the ESR was elevated in
76% of patients and plasma IL-6 was
elevated in 92%. Within 1 month of
steroid treatment, all patients experienced symptomatic resolution and
normalization of the ESR. The
plasma IL-6 did decrease but did not
return to normal levels. During a clinical relapse of disease, the ESR was
elevated in 58% of patients whereas
the plasma IL-6 was elevated in 89%.
The authors concluded that plasma
IL-6 appears to be a more sensitive
indicator than ESR for diagnosing
and monitoring GCA patients (Weyand et al. 2000). How does IL-6 compare to CRP? Hayreh et al. found a
linear relationship between levels of
IL-6 and CRP, suggesting that IL-6 is
comparable but not superior to CRP
for monitoring the systemic inflammatory response (Hayreh et al. 1997).
Anaemia
A normocytic, normochromic anaemia
of
mild
to
moderate
degree
(<12 g ⁄ dl) is frequently observed in
patients with GCA as a result of
decreased haematopoeisis related to
the acute-phase response. Women
with GCA tend to have anaemia more
commonly than men with GCA (Melson et al. 2007). An unexplained anaemia may even be the presenting
manifestation of GCA. Some recent
studies have reported that the presence of anaemia at presentation is
associated with a reduced incidence of
ischaemic events (Cid et al. 1997;
Gonzalez-Gay et al. 2005b).
Others
Other laboratory tests that may be
abnormal in GCA include white blood
cell count, liver enzymes, other acutephase reactants (fibrinogen, haptoglobin), albumin, gamma globulin, anticardiolipin
antibodies,
plasma
viscosity, and amyloid A apolipoprotein, von Willebrand factor, alpha-1antitrypsin (Gonzalez-Gay et al.
2005b; Rahman & Rahman 2005;
Melson et al. 2007). Fibrinogen is
available in many hospital laboratories. It is often elevated in GCA but
remains low in other disease states
that can cause an elevated ESR.
Diagnosis of GCA
There is no single laboratory value,
imaging procedure or even biopsy
sample that is positive in all patients
and there is no one symptom or sign
that is pathognomic of GCA. GCA is
a syndrome in which characteristic
symptoms accompanied by objective
signs of inflammation and vasculopathy are used to define the clinical
diagnosis. Histopathological evidence
of inflammation in arterial tissue provides definitive diagnostic evidence
and should be sought whenever
possible because the commitment to
treatment is not a trivial matter, often
long in duration and fraught with
medication side-effects.
Temporal artery biopsy
The temporal artery biopsy is the
most common method of histopathological testing for GCA. It is generally
agreed that an adequate biopsy specimen should have a minimum length
of 2 cm (Carroll et al. 2006). Longer
specimens (3–5 cm) are preferable and
multiple fine (0.25–0.5 mm) sections
are necessary because of the presence
of skip lesions and potential effect of
post-fixation shrinkage (Sharma et al.
2007). In some institutions, a unilateral temporal artery biopsy is performed and the frozen section is
examined immediately. If the initial
examination is negative and the clinical suspicion is high, then a sequential
biopsy is completed during the same
procedure. Thereafter, a more critical
examination of a paraffin-embedded
biopsy specimen should be performed
under light and electron microscopy.
Reliance on frozen sectioning alone
has a high rate of false negatives
(Nordborg et al. 1992). If the clinical
suspicion for GCA is high and the
first biopsy is negative, the chances of
a second biopsy demonstrating positive histopathology is rather low,
ranging from 5% to 9% (Hayreh
et al. 1997; Pless et al. 2000). If the
clinical suspicion is low, a unilateral
biopsy appears to be sufficient to rule
out the diagnosis (Hayreh et al. 1997;
Hall et al. 2003). Findings that should
raise clinical suspicion for the diagnosis and that tend to predict a positive
biopsy include: presence of jaw claudication, CRP > 2.45 mg ⁄ L, elevated
ESR > 47 mm ⁄ hr, neck pain, white
or pale disc oedema, systemic symptoms other than headache, temporal
artery abnormalities and elevated
platelet count (Hayreh et al. 1997;
Hall et al. 2003).
The chief pathological finding is a
panarteritis consisting mostly of lymphocytes and macrophages (Fig. 7).
Granuloma formation may be present.
The intima is thickened and the internal elastic lamina is fragmented. Infiltration by mononuclear cells and
multinucleated giant cells is concentrated around the inner half of the
media, characteristically along the
disrupted internal elastic lamina
23
Acta Ophthalmologica 2009
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)
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 adventitia. (B) Elastic tissue stains shows fragmentation of the internal elastic lamina and intimal
hyperplasia.
(Nordborg et al. 1992; Weyand &
Goronzy 2003). It is important to
remember that giant cells are present
in about 50% of biopsy speciments
and thus are not a necessary feature
for histopathological confirmation of
GCA. Active arteritis can be detected
histopathologically for 4–6 weeks after
initiation of corticosteroids so there is
no justification for discontinuing steroids while a patient with suspected
GCA is under evaluation (Carroll
et al. 2006; Narvaez et al. 2007).
Fibrinoid necrosis is found rarely in
GCA and should raise suspicion of
other vasculitides. The healed or
chronic phase of GCA is characterized
by foci of lymphocytes, fibrosis and
vascularization with continued evidence of intimal disruption.
Although the temporal artery
biopsy is considered the gold-standard
test for diagnosis, it is important to
remember that a negative biopsy
result may be found in up to 10–15%
of all diagnosed cases (Schmidt 2006).
Furthermore, when GCA assumes a
localized form such as large-vessel
vasculitis and the arterial inflammation occurs in the relative absence of
systemic inflammation, the temporal
artery biopsy is negative in at least
50% of patients (Bongartz & Matteson 2006). In the setting of a patient
with suspected extracranial large-vessel GCA and negative temporal artery
biopsy, pursuit of histopathological
confirmation (i.e. biopsy of a large
artery or aorta) is not recommended
routinely and diagnosis becomes
dependent on clinical presentation and
imaging findings. If such a patient
should undergo an intervention such
as aortic aneurysm repair or vascular,
24
a surgical biopsy specimen can be
taken at the same time for histopathological confirmation of the disease
(Lie 1995).
Certainly having a positive temporal artery biopsy on record helps to
justify the chronic use of steroids to
the patient with GCA, especially when
steroid side-effects become significant.
Yet it is important to remember
that positive histopathology is not
mandatory for diagnosis. If bilateral
temporal artery biopsies are negative,
non-invasive imaging (duplex sonography, MRI, PET) of other extracranial
arteries, particularly the occipital
arteries, is a reasonable next step (Pfadenhauer & Weber 2003). Such
modalities can demonstrate abnormalities characteristic of active inflammation in arterial walls and document
their reversibility with steroid treatment, providing sufficient evidence to
establish a diagnosis of GCA in the
proper clinical setting. Less commonly, non-invasive imaging of extracranial arteries may guide the surgeon
to an alternative biopsy site in
patients whose clinical presentation
may be more ambiguous and positive
histopathology is strongly desired.
The point to remember is that a diagnosis of GCA is a clinical one, based
on the sum total of corroborative evidence, and not simply a pathological
one.
American College of Rheumatology
criteria
In 1990, the American College of
Rheumatology (ACR) developed a set
of critieria that have been used to
diagnose GCA (Hunder et al. 1990).
These are listed in Table 2 and, in
brief, consist of advanced age, new
headache, temporal artery abnormalities, high ESR and positive biopsy.
The presence of any three of these five
criteria permitted a diagnosis of GCA
with a sensitivity of 93.5% and a
specificity of 91.2% based on a population of patients (n = 807) with
rheumatological disease (Rahman &
Rahman 2005). A note of caution
should be taken when applying these
ACR criteria to the general clinical
population because the criteria were
developed primarily to distinguish
patients with GCA (n = 214) from
patients with other vasculitides
(n = 593) and to classify patients with
rheumatological disorders for research
purposes. It is thus possible that
patients who lack typical systemic
symptoms and present with an ischaemic complication (so-called ‘occult
GCA’) may not have been represented
accurately in the ACR study because
they are more likely to seek the care
of a non-rheumatological specialist.
From the ophthalmic perspective,
Hayreh et al. found that among 85
patients who presented with ocular
symptoms caused by biopsy-positive
GCA, 21% had no systemic symptoms or signs of GCA (Hayreh et al.
1998a). In these patients, the diagnosis
was suspected on clinical grounds
(AION in a patient aged 50 years or
older) and confirmed by histological
findings (biopsy); therefore, strictly
speaking, this would meet only two of
the five ACR criteria. Likewise, in the
setting of large-vessel arteritis, imaging the vascular territories of interest
may prove most fruitful in aiding the
diagnosis.
Given the protean manifestations of
GCA, it is more important to view
the patient’s presentation as a whole
and ask ‘could this be GCA?’ rather
than to rely on criteria sets to make a
Acta Ophthalmologica 2009
diagnosis of GCA. In this respect,
alternative modalities are emerging for
imaging the temporal and other cranial arteries to help support a diagnosis of vasculitis. These modalities
include ultrasound, MRI and single
photon
emission
tomography
(SPECT) and are discussed in the next
section.
Non-invasive imaging of the cranial
arteries
Modern sonography can delineate
vascular structures with a resolution
of 0.1–0.2 mm (Schmidt & GromnicaIhle 2005). In 1997, Schmidt et al.
used high-resolution colour Doppler
imaging and duplex ultrasonography
to examine the superficial temporal
arteries in patients with GCA
(Schmidt et al. 1997). They described
the presence of a hypoechoic (dark)
thickening around the lumen of the
temporal artery – termed a ‘halo’ sign
– that represents oedema of the vessel
wall (Fig. 8). The sensitivity and specificity of the halo sign varies among
different investigators, ranging from
40% to 100% sensitivity and 68% to
100% specificity when compared
against a biopsy-positive diagnosis of
GCA (Schmidt & Gromnica-Ihle
2005). The variability in these estimates may be in part related to the
skill and experience of the individual
operator and the resolution capacity
of the scanner. Flow abnormalities
such as stenoses and occlusions in the
temporal arteries are less helpful findings because they are also present in
patients with vascular disease associated with diabetes (Karahaliou et al.
2006). A bilateral halo sign, although
uncommon, has been found to be
100% specific for GCA (Karahaliou
et al. 2006). Despite the generally
accepted high specificity of the halo
sign, it is not considered a pathognomonic sign of GCA and has been
found in patients with Wegener’s
granulomatosis
and
tuberculosis
(Schmidt & Gromnica-Ihle 2005;
Karahaliou et al. 2006). As such,
sonography is not intended to be a
replacement for a temporal artery
biopsy in the diagnostic evalution of
GCA. It does, however, play an
important role in the evaluation of
patients with GCA, some of which
includes: providing non-histological
evidence of arterial wall inflammation
in the extracranial arteries; guiding
the biopsy site or finding alternative
sites other than the temporal arteries;
evaluating the axillary arteries for the
presence of large-vessel involvement;
and assessing disease activity following treatment (Schmidt 2007).
MRI holds promise as another
means to evaluate non-invasively the
superficial temporal and occipital
arteries of patients with suspected
GCA. It has the advantages of wide
availability and reproducibility of
operator-independent images. Multislice contrast-enhanced, T1-weighted
spin echo sequences with a submillimetre spatial resolution on a standard
1.5 T scanner can detect inflammatory
vessel wall changes (Bley et al. 2005b).
These changes appear as circumferential (mural) thickening of the temporal
artery and ⁄ or increased contrast
enhancement (Fig. 9). In a recent
study of 64 patients who underwent
contrast-enhanced
high-resolution
MRI, sensitivity and specificity for
detecting temporal artery inflammation were 80.6% and 97%, respectively, compared against a positive
diagnosis using ACR clinical criteria
or histopathological findings (Bley
et al. 2007). The authors used a specific imaging protocol and, in some
patients, a higher strength magnet
(3 T) as well – neither of which are
currently in standard use – raising the
question of whether ‘community’
scanners would have such high yields.
(B)
(A)
Fig. 8. Colour Doppler ultrasonography of
temporal arteries. Longitudinal (top) and
transverse (bottom) view of superficial temporal artery branch showing the hypoechoic rim
(arrows) around the perfused lumen, representative of oedematous wall swelling in
active arteritis. From Schmidt (2006) with
permission from Current Science Publishers.
(C)
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
Acta Ophthalmologica 2009
Is MRI ready to replace temporal
artery biopsy? Not yet. But an
MRI ⁄ MRA examination can provide
complete information of the superficial cranial arteries as well as the
major cranial, cervical and thoracic
vascular beds in a single, rapid noninvasive test; in the future, it may be
important in guiding treatment (Bley
et al. 2005a, 2005b, 2007).
Increased (67) gallium uptake has
been noted in the temporal region of
patients with GCA, and SPECT scintigraphy appears to be a promising
tool to investigate and monitor
patients with GCA (Reitblat et al.
2003). PET scanning, however, should
not be used to evaluate for arteritis in
medium-sized, superficial cranial arteries because it cannot evaluate vessels
with diameter < 2–4 mm and there is
high background activity related to
brain uptake of the radioactive substance (Bley et al. 2007).
Treatment and
prognosis of GCA
As noted earlier, the natural history
of GCA is spontaneous remission.
However, the disease activity may
smoulder on for months or years
before extinguishing. The need for
treatment stems from the high rate of
morbidity related to ischaemic complications caused by GCA, particularly
blindness. Treatment of GCA is aimed
at controlling and arresting the
inflammatory process in order to prevent an ischaemic complication such
as visual loss, neurological dysfunction or other organ infarction.
Corticosteroids
Corticosteroids remain the mainstay
treatment of GCA. Within the first
few days of steroid initiation, systemic
symptoms of malaise, myalgias, anorexia and fever begin to subside; within
the first week, the sedimentation rate
returns to normal. Although there is
general consensus about the need to
initiate corticosteroids immediately
upon diagnosis – even suspicion – of
GCA, there remains controversy concerning the dosage, the means of
administration and the duration of
cortiocosteroid treatment. To date,
there are no randomized controlled
studies evaluating the various steroid
26
regimens used by different clinicians,
and the results of treatment reported
in the literature are retrospective and
anecdotal. To some degree, differences
in treatment regimens reflect which
aspects of the disease are being managed. Overall, rheumatologists tend to
recommend maintaining a high dose
of corticosteroids for a shorter period
of time than ophthalmologists or neurologists (Nordborg & Nordborg
2004).
Several single case reports have
described dramatic recovery of
vision following treatment with highdose intravenous (IV) corticosteroids
(Model 1978; Rosenfeld et al. 1986;
Diamond 1991; Matzkin et al. 1992).
The significance of these reports is difficult to assess because of their anecdotal nature, similarity in rates of
visual recovery following oral steroids
and differences in the mechanism of
visual loss central retinal artery occlusion (CRAO rather than AION) (Diamond 1991; Matzkin et al. 1992). A
small number of studies have examined visual outcome retrospectively in
patients treated with IV steroids versus those treated with oral steroids.
Chan & O’Day reported the results of
73 biopsy-positive patients: 43 had
received IV steroids as the initial
treatment (average daily dose of
1000 mg) and 30 had received oral
corticosteroids (median daily dose
75 mg) (Chan & O’Day 2003). Overall, 21 patients (29%) had a mean
improvement of visual acuity by
2 lines. Seventeen of these 21 patients
had received IV treatment, and four
had been treated orally. Unexpectedly,
in nine patients (12%) vision was
worse and seven of these patients had
received IV treatment. It was noted
that the IV-treated patients had worse
median visual acuity and more frequent bilateral involvement at presentation compared to the group who
received oral treatment. In a similar
study, Liu et al. found that seven of
23 patients (39%) improved with IV
treatment compared to five of 18
(28%) on an oral regimen (Liu et al.
1994). Subsequent fellow eye visual
loss occurred only in patients treated
with oral therapy. Though limited,
these data have been cited in support
of recommending IV steroids acutely
in patients with arteritic visual loss.
However, other studies have failed
to show a difference in outcome.
Hayreh et al. retrospectively studied
the visual outcome in 84 patients with
GCA, 43 of whom were treated intravenously and 41 received oral steroids
(Hayreh et al. 2002). Of the five
patients who showed some visual
improvement, three were in the IV
group and two had received only oral
steroids. As in the study by Chan
et al., the patients in the IV group
had more severe visual loss than those
treated orally. In the literature, progressive visual deterioration while on
treatment has been described in
patients receiving high-dose IV and
in patients taking only oral steroids
(Hugod & Scheibel 1979; Slavin &
Margolis 1988; Faarvang & Pontoppidan Thyssen 1989; Matzkin et al.
1992; Cornblath & Eggenberger 1997).
In weighing the relative merits of
IV versus oral steroids, it is important
to keep in mind the potential serious
complications of high-dose IV steroid
treatment. The low incidence of complications found in the Optic Neuritis
Treatment Trial (ONTT) cannot necessarily be applied to the older age
group of GCA patients (Chrousos
et al. 1993). Serious adverse reactions
include unstable angina, acute pulmonary oedema, abdominus rectus haemorrhage, uncontrolled hypertension,
cardiac arrhythmia, anaphylaxis, aseptic osteonecrosis, acute psychosis, sepsis and sudden death (Chan & O’Day
2003; Carroll et al. 2006; Hall & Balcer 2004). The advantages of IV treatment include rapid drug delivery,
higher tissue levels and additional
hydration. It has been suggested that
the ‘megadose’ levels used in this setting may also have antioxidant effects
that protect the microvasculature
from lipid peroxidative damage and
may help to stabilize damaged neuronal membranes (Chan & O’Day 2003;
Matzkin et al. 1992). Although data
from randomized controlled comparative studies are not available, many
experts favour IV treatment for
patients with acute or impending
visual loss.
Regardless of the route of administration, there is general agreement
that the initial treatment for the
patient with GCA who has new visual
symptoms should be high-dose steroids and that treatment should be
started promptly. The most important
predictor for the development of permanent visual loss appears to be the
Acta Ophthalmologica 2009
timeliness of initiating treatment
(Nordborg & Nordborg 2004). This
was clearly demonstrated by Gonzalez-Gay et al., who found that if
treatment was instituted within 24 hr
of onset of symptoms visual improvement was experienced in 57% of
patients, compared to only 6% in
cases of longer delay (Gonzalez-Gay
et al. 1998). Unfortunately, delayed
diagnosis and treatment is common.
One study found that 35% of patients
had systemic symptoms for an average
of 10 months before visual loss and
65% experienced premonitory visual
symptoms for an average of 8.5 days
(Font et al. 1997).
Waiting for home nursing arrangements or hospital admission is never a
reason to delay steroid treatment.
Sending an elderly patient with acute
visual impairment out of the office
with a prescription for oral prednisone
carries a risk of treatment delay
related to inaccessibility of ready
transportation to the pharmacy. Witholding steroid treatment while temporal artery biopsy results are pending
is also a mistake. To expedite and
ensure treatment initiation, patients
can be given steroids while in the
office, either as a single injection of
dexamethasone 10 mg IV or as prednisone 80 mg by mouth.
Starting steroids
For the purpose of general guidelines,
GCA patients can be divided into
two groups: those with and those
without visual or neurological manifestations. In patients without visual
or neurological manifestations who
have only rheumatic and systemic
symptoms, treatment with oral prednisone is used (generally 40–60 mg daily
or 1 mg ⁄ kg ⁄ day, but doses ranging
from 20 mg to 100 mg have been
used). In patients with acute visual or
neurological symptoms or signs,
higher doses are generally recommended (equivalent of prednisone
80 mg or more daily or 1–
2 mg ⁄ kg ⁄ day). It is not uncommon to
hospitalize such a patient and initiate
treatment with intravenous steroids
(methylprednisolone 250 mg every
6 hr) for the first 3–5 days, then continue with high-dose oral prednisone
(Hayreh & Zimmerman 2003b; Nordborg et al. 2003; Nordborg & Nordborg 2004; Carroll et al. 2006;
Dasgupta & Hassan 2007).
Maintenance dose
High-dose daily oral prednisone is
maintained for at least 4–6 weeks
until systemic symptoms have subsided and markers of disease activity
(ESR and ⁄ or CRP) have normalized.
A daily schedule is recommended over
alternate-day dosing, which has been
associated with higher rates of disease
relapse (Bengtsson & Malmvall 1981;
Hayreh & Zimmerman 2003b; Spiera
et al. 2003). Calcium supplementation,
vitamin D and peptic ulcer prophylaxis should accompany steroid treatment. In patients with or at risk of
osteoporosis, bone densitometry and
bone-saving measures should be initiated.
Tapering regimen
Steroid tapering is a slow process and
highly individualized with constant
monitoring of symptoms and serum
markers. In most patients, the initial
reduction in dosage is 5–10 mg ⁄ month
to a daily dosage toward 20–30 mg.
Then the rate of reduction should proceed more cautiously, usually by 2.5–
5 mg ⁄ month. When the daily dose is
10–15 mg, tapering might continue by
only 1 mg ⁄ month. Clinical evaluation
and laboratory markers are repeated
before each reduction in daily steroid
dosage, watching specifically for recurrent symptoms of active inflammation.
Any recurrence of symptoms or rise in
ESR ⁄ CRP should be considered a reactivation of disease activity and should
prompt a thorough re-evaluation of the
steroid dosage needed. It is important
to keep in mind the alternative possibility of a secondary infection in this
immunocompromised population. The
ESR and CRP levels should always be
considered along with other clinical
indicators of disease activity. It is a
mistake to ‘chase’ these laboratory values with steroids to normalize them
(Koening & Langford 2006).
Duration of treatment
On the whole, a maintenance dose of
7.5–10 mg daily is generally achieved
in 6–12 months (Carroll et al. 2006).
Hayreh & Zimmerman treated and
followed 145 patients with biopsypositive GCA (Hayreh & Zimmerman
2003b). Their average time to 40 mg
daily was 2 months from steroid initiation, and the time to reach a maintenance dosage (median 7 mg daily) was
2 years. After 2 years, more than 92%
of patients (with and without visual
loss at presentation) were still on steroids, emphasizing the long duration
of treatment.
Adjuvant therapies
Because the duration of treatment of
GCA is long, often requiring 1–
5 years of steroids, it is not surprising
that steroid-related complications pose
another source of potential morbidity
for this older patient population.
Common side-effects include diabetes,
hypertension, secondary infections,
osteoporosis and bone fracture, myopathy and psychiatric changes such as
anxiety, depression, confusion and –
occasionally – psychosis. Such complications have been reported in up to
50% of patients on long-term steroid
therapy for GCA (Proven et al. 2003),
underscoring the need for a steroidsparing agent with equal or superior
efficacy in controlling disease activity
and relapse. A number of different
agents have been tried with disappointing or, at best, mixed results
(Nuenninghoff et al. 2003).
Studies investigating the role of
methotrexate (MTX) for the treatment
of GCA have yielded conflicting
results. Jover et al. conducted a
double-blind, placebo-controlled trial
in which 42 patients with GCA were
randomized to weekly MTX for
24 months or MTX plus prednisone
(Jover et al. 2001). Treatment with
MTX significantly reduced the proportion of patients who experienced
relapse, reduced the duration of prednisone treatment and reduced the
cumulative dose of prednisone.
Despite these benefits, the addition of
MTX did not decrease the rate of
adverse events secondary to corticosteroid use. In contrast to the results
of this study, two comparable placebo-controlled trials involving a larger patient group found no such
benefit (Spiera et al. 2001; Hoffman
et al. 2002). The basis for the different
outcomes in these studies is unclear
(Eberhardt & Dhadly 2007). The dose
of MTX used in these and previous
trials has been 10–15 mg ⁄ week.
Higher doses, needed for adequate
disease control in some patients with
other rheumatological disorders, have
not been studied (Nordborg & Nordborg 2004). At present, there is no
established role for MTX in the standard treatment regimen of patients
27
Acta Ophthalmologica 2009
with GCA. In patients with severe
adverse reactions to steroids or steroid-refractive disease, MTX is considered a viable second-line alternative
(Hall & Balcer 2004).
More recently, inhibitors of tumour
necrosis factor (TNF)-a have been
studied both as an adjunct to steroids
and as monotherapy (Andonopoulos
et al. 2003; Uthman et al. 2006). Infliximab (a chimeric monoclonal antibody directed against TNF-a) has
been found to be beneficial for the
treatment of GCA in a few anecdotal
reports (Cantini et al. 2001; Airo et al.
2002; Uthman et al. 2006). Cantini
et al. reported remission after treatment with infliximab in three of four
patients with previously steroid-dependent GCA (Cantini et al. 2001).
Andonopoulos et al. documented initial improvement in two patients with
GCA using infliximab alone (without
corticosteroids), although both patients experienced relapse within 12
weeks of treatment (Andonopoulos
et al. 2003). A recent randomized,
prospective placebo-controlled multicentre trial of infliximab as adjunctive
treatment in 44 patients with GCA
showed no significant benefit (Hoffman et al. 2007). Specifically, the
addition of infliximab failed to
decrease the relapse rate or the cumulative corticosteroid requirements in
these patients. Similar results were
reported in a study of infliximab in
patients with PMR (Salvarini et al.
2007b). Rituximab (another antiTNF-a monoclonal antibody) and etanercept (a fusion protein) have each
been reported to be beneficial in individual patients with GCA but have
not been studied in larger groups of
patients (Tan et al. 2003; Bhatia et al.
2005).
Aspirin is commonly used by
elderly individuals for the prevention
of other ischaemic events and may
have a protective effect against ischaemia caused by GCA as well. In addition to its well-established anti-platelet
effect, aspirin may also be beneficial
in GCA by virtue of its inhibitory
effect on interferon-c mRNA production, which is essential for the development of the inflammatory infiltrate
of the vessel wall. Because corticosteroids have relatively poor anti-interferon-c activity, the combination of
aspirin plus steroids is of particular
interest. In a mouse model of large
28
vessel vasculitis, Weyand et al. demonstrated a synergistic effect of aspirin
plus dexamethasone on the production of inflammatory cytokines (Weyand et al. 2002b). In two clinical
studies, patients with GCA who were
on aspirin and steroids since diagnosis
were less likely to present with a cranial ischaemic complication such as
visual loss or stroke (Liozon et al.
2001; Nesher et al. 2004). A retrospective review of 143 patients with GCA
who received either anti-platelet or
anticoagulant therapy found a lower
incidence of ischaemic events with
such treatment (Lee et al. 2006). Any
potential benefit of combination therapy may be offset by an increased risk
of gastrointestinal haemorrhage. Randomized studies are clearly needed to
determine the benefit of the combination of aspirin and steroids in patients
with GCA.
Other steroid-sparing agents in the
treatment of GCA have been investigated. Azathioprine was shown to
reduce the maintenance dose of
prednisone in one randomized, double-blind, placebo-controlled trial;
however, the number of patients studied was small (De Silva & Hazleman
1986). Two studies of cyclosporine A
as adjuvant treatment in patients with
GCA found a high rate of adverse
events and no significant steroid-sparing potency in patients (Schaufelberger et al. 1998, 2005). Other small
reports have suggested a possible benefit of cyclophosphamide and dapsone
as adjuvant therapies (Doury et al.
1983; DeVita et al. 1991; Nesher &
Sonnenblick 1994). Although dapsone
has allowed a reduction in steroid
dose in some patients, significant toxicity has been reported, thus limiting
its use. More recently, a possible antiinflammatory effect of statins in GCA
and other rheumatological diseases is
also under investigation (Abud-Mendoza et al. 2003).
Treatment of large-vessel involvement
It is unknown whether current steroid
regimens are adequate for treating
large-vessel vasculitis – i.e. alleviating
symptomatic claudication, restoring
flow through occluded arteries or
aborting aortitis and preventing
aneurysm formation. Although GCArelated aneurysms are generally
associated with elevated acute-phase
reactants (ESR, CRP), it is also
unclear if active aortic inflammation is
reflected by these markers, which
are universally used to guide steroid
dosing.
If symptoms of large-vessel stenosis
persist while the patient is on steroid
therapy, endovascular intervention
has been proposed (Bongartz &
Matteson 2006). Anecdotal results
using balloon angioplasty for the
treatment of symptomatic arteritic
occlusion of the subclavian, axillary
and brachial arteries have been
favourable. If asymptomatic aortic
aneurysm is detected, the choice
between surveillance and surgery
depends on patient factors and the
size of the aneurysm. Current data
suggest no difference in long-term
survival between patients without
large artery involvement and patients
with aortic aneurysm except for the
subgroup with aortic dissection, who
have a markedly high mortality rate.
Prognosis
Visual loss from GCA is typically profound and permanent. However, the
literature cites favourable rates of
visual recovery in GCA, ranging from
15% to 34% (Danesh-Meyer et al.
2005). This discrepancy between what
is observed in clinical practice
(patients are still blind) and what is
reported in studies (vision can
recover) is likely related to the means
by which vision is assessed. When
visual recovery is defined solely as an
improvement in visual acuity, it leaves
open the possibility that acquired
eccentric viewing may be reflected in
the reported recovery rate. Studies
that have assessed changes in visual
field as well as visual acuity following
steroid treatment report dismally
low rates of recovery, of the order of
4–5% of improved central visual field
– confirming the generally grim prognosis once vision is lost (Hayreh &
Zimmerman 2003b; Danesh-Meyer
et al. 2005).
During the first few days after initiating high-dose steroid treatment,
patients are still at some risk for further visual loss. Two recent studies
reported widely different rates of
visual deterioration (4% versus 27%),
but both studies agree that if further
deterioration of vision occurs it happens in the first 5–6 days of steroid
initiation (Hayreh & Zimmerman
2003a; Danesh-Meyer et al. 2005).
Acta Ophthalmologica 2009
Once vision has stabilized and disease
activity is controlled with steroids, it
is said that recurrent visual loss is
rare. In a 5-year retrospective study,
Aiello et al. found visual loss following 1 month of steroid therapy in only
one of 245 patients (Aiello et al.
1993). Yet a recent study found a surprisingly higher rate of recurrent
ischaemic optic neuropathy (seven of
67 patients, 10%), all of which
occurred between 3 and 36 months
after the initial visual loss (Chan et al.
2005). The basis for this difference is
unclear.
The other aspect of prognosis in
GCA concerns the large vessels.
Development of an aortic aneurysm is
associated with reduced survival rate;
effective screening strategies for this
important complication are currently
under investigation (Bongartz &
Matteson 2006). In addition to vasculitis-related cardiovascular and cerebrovascular
ischaemic
events,
generalized atherosclerosis may contribute to stroke and myocardial
infarction in this elderly population.
Whether the prevalence of atherosclerosis in GCA is truly increased or not
is as yet unknown (Duhaut et al.
1998; Le Page et al. 2005; GonzalezJuanatey et al. 2007).
In one series of 255 patients with
GCA followed for 24 years, malignancy later developed in 15% (mean
time interval 5.2 years) but did not
contribute to an increased mortality
(Gonzalez-Gay et al. 2007a). Rare
patients develop GCA concurrent with
a malignancy. In such cases, the GCA
is thought to be a paraneoplastic vasculitis induced by the malignancy that
remits when the malignancy is treated
(Liozon et al. 2006a). Considering the
advanced age of the patient population, the potential for significant ischaemic
events
secondary
to
vasculitis, secondary complications of
long-term steroid treatment and associated comorbidities, the overall prognosis of GCA is good. In fact, the life
expectancy is normal in treated
patients without aortic aneurysm
(Matteson et al. 1996).
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Received on November 18th, 2007.
Accepted on March 29th, 2008.
Correspondence:
Aki Kawasaki
Hôpital Ophtalmique Jules Gonin
Avenue de France 15
Lausanne 1004
Switzerland
Tel: + 41 21 626 8660
Fax: + 41 21 626 8666
Email: aki.kawasaki@ophtal.vd.ch