Rheumatology 2003;42:413–421
doi:10.1093/rheumatology/keg116, available online at www.rheumatology.oupjournals.org
Review
Giant cell arteritis: epidemiological clues to its
pathogenesis and an update on its treatment
E. Nordborg and C. Nordborg1
Giant cell arteritis (GCA) is a chronic systemic vasculitis with a marked female
predominance and restriction to old age. The disease process distinctly targets
large and medium sized arteries, preferentially the aorta and its extracranial
branches. Morphological observations indicate that the age and sex distribution of
GCA is related to the occurrence of degenerative changes in the arterial wall. GCA
is not a truly infectious vasculitis. However, an infection might be a triggering
factor. Different centres report an increase in GCA incidence, but annual
fluctuations have not been shown to be statistically significant. However, significant
seasonal variations have been observed by several groups. The mortality is not
increased in adequately treated patients. Although, alternative steroid-sparing
agents have been proposed, corticosteroids are still the first treatment choice.
adventitia was proposed to be the centre of the immune
response, with the vasa vasorum being the port of
entrance of the antigen-presenting cells. The adventitial
macrophages and T lymphocytes produce high levels of
cytokines, thereby promoting further inflammatory
reaction, but not tissue destruction. The macrophages of
the media, on the other hand, produce metalloproteinases and oxygen radicals, leading to the disintegration
of elastic laminae and further injury of the vessel wall.
The tissue cytokine patterns of the temporal artery were
correlated with clinical phenotypes of the disease. Thus,
high levels of the cytokine interferon-c (IFN-c) correlated with cranial symptoms, whereas patients with systemic symptoms only, displayed low levels of this cytokine
w9x. Growth factors, such as platelet-derived growth
factor (PDGF) and vascular endothelial growth factor
(VEGF) are both amply expressed in the inflammatory
infiltrate, stimulating intimal hyperplasia. Interestingly,
these factors were also produced by the multinucleated
giant cells, which are, therefore, not only removers of
debris but also secretory.
Thus, the vascular pathology in GCA is the result of
immunological injury to the vessel wall, as well as
stromal response within the arterial wall w10x. Moreover,
significant media atrophy and calcification of the internal
elastic membrane (IEM) appear to be prerequisites
for its occurrence w11x.
The hallmarks of GCA are the systemic inflammation and the inflammatory infiltrate of the vessel wall,
Introduction
Giant cell (temporal) arteritis (GCA) is a chronic, systemic vasculitis, with a distinct tropism for large and
medium-sized arteries with well-developed elastic membranes. The inflammatory process preferentially involves
the aorta and its extracranial branches, of which the
external carotid artery with its superficial temporal division, in particular, is affected. Although major advances
have been made in recent years in genetics, molecular
biology and the description of the vessel wall morphology, the aetiology and pathogenesis of GCA are still
incompletely understood. A single cause or aetiological
agent has not as yet been identified.
The epidemiology of GCA suggests striking differences in disease risk among ethnic groups, with the
highest incidence rates measured in Scandinavia and in
subjects of Northern European descent, irrespective of
their place of residence w1–5x.
Genetic factors appear to be of importance for the
development of this disease, with a predominance of
certain variants of HLA-DR4 allele expression w6, 7x.
Histologically, the inflammatory reaction is granulomatous with highly activated macrophages and T lymphocytes, of which CD4+ T cells are in the majority.
Despite its name, giant cells are not a prerequisite for the
diagnosis. The local activation of CD4+ T cells in the
outer layers (adventitia) of the vessel wall is suggestive of
an antigen-driven disease w8x. The possible antigen might
be of external origin, but it may also be autologous. The
Departments of Rheumatology and 1Pathology, Sahlgrenska University Hospital, SE-413 45, Göteborg, Sweden.
Submitted 20 September 2001; revised version accepted 4 September 2002.
Correspondence to: E. Nordborg. E-mail: [email protected]
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ß 2003 British Society for Rheumatology
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E. Nordborg and C. Nordborg
resulting in luminal narrowing and end-organ ischaemia.
The most feared acute complications include blindness
and infarcts of various vascular territories, whereas the
development of mural weakness, resulting in aortic
dissection, has been considered a late manifestation w12x.
Modern history of giant cell arteritis runs along two
paths; that of temporal arteritis (TA) and that of
polymyalgia rheumatica (PMR). There is still a controversy over whether PMR and GCA (TA) are linked
entities, and specifically if PMR is a vasculitis. Several
contributions over the last decade have indicated a similar pathogenetic process in the two conditions. Analyses
of the temporal artery biopsies have shown similar
patterns of T-cell and macrophage-derived cytokines
winterleukin (IL)-1b, IL-6, transforming growth factor-b
(TGF-b), IL-2x in biopsy-negative PMR patients as well
as in patients with biopsy-proven GCA, but not in agematched controls. However, IFN-c was not found in
PMR patients, but only in the TA patients, indicating
that IFN-c might be crucial for the development of an
overt granulomatous process w9x. These data indicate
that PMR patients have a subclinical vasculitis and
therefore PMR has been regarded as a ‘forme fruste’ with
minor vascular involvement w9x. According to a recent
study, using positron emission tomography (PET) with
fluoro-18-deoxyglycose (18F-glycose), there was a significantly increased vascular uptake in the large thoracic
arteries (aorta, subclavian and carotid arteries) also in
PMR patients without clinical or morphological evidence
of inflammation in temporal arteries w13x. This investigation gave further support to the contention that
PMR and TA are two different expressions of the same
underlying disorder and that the large arteries, and not
merely the temporal arteries, may be affected in both
conditions. Therefore, in this review GCA is used to
signify all different clinical manifestations of this disease,
also including biopsy-negative PMR.
This review will focus on potential epidemiological
clues and issues regarding the aetiopathogenesis of GCA.
Risk factors
Age
GCA is markedly age-restricted. Essentially, no cases
younger than 50 yr of age have been identified and the
likelihood of being diagnosed with this disease increases
continuously with age. GCA is about 20 times more
common among people in their 9th decade compared
with people aged between 50 and 60 yr w14x, which may
indicate that its pathogenesis is related to the ageing of
the arterial wall w14x. Immunosenescence, the term used
for changes in the immune system with ageing, implies a
decline in immunocompetence, resulting in an increased
risk of infections and autoimmuneuinflammatory disorders. Furthermore, a decreased antibody (Ab) production and a shortened duration of protective immunity
following immunization are characteristic features in the
elderly w15x. Despite much research in this field, basic
mechanisms of age-related immune dysfunction have not
been clarified. Recently, it was demonstrated that elderly
people who failed to produce specific Abs following
influenza vaccination showed a predominance of CD8+
CD282 T cells. The aetiology of the CD282 T-cell
recruitment is not fully understood in healthy individuals, but there is evidence that these cells might be a
response to continued antigenic stimulation. An increased
number of autoreactive CD8+ CD282 T cells leads to
the production of large amounts of IFN-c, which might
trigger an imbalance in the production of T helper 1
(TH1) and TH2 cytokines, and a polarization towards the
TH1 effector type with higher age. Furthermore, in the
elderly there is a reduced production of adrenal and
gonadal steroids, resulting in less inhibitory effects on
pro-inflammatory cytokine production. Changes have
also been reported in the activity and reactivity of the
hypothalamus–pituitary–adrenal axis w16x. It has been
speculated that an imbalance in the production of
pro- and anti-inflammatory cytokines could reduce the
protection against infections in elderly people and
also increase the risk of developing other age-related
disorders such as Alzheimer’s disease and atherosclerosis.
Exactly how the ageing of the immune system affects
immune reactivity in a patient with GCA has not been
investigated.
Gender
There is a clear female predominance in GCA, with 2- to
4-fold more women than men w3–5, 14, 19, 20x. This
difference appears to be more marked in the northern
parts of Europe. Only in one Spanish study were males
reported to be predominant in GCA w21x. Evidence was
recently presented indicating that other types of primary
vasculitides display an inverse gender preference. An
epidemiological review of Wegener’s granulomatosis,
Churg–Strauss syndrome and polyarteritis nodosa in the
United Kingdom, Spain and Norway showed that, in all
areas and in all disease categories, the incidence was
higher in men than women, with a peak incidence at the
age of 65–74 yr w22x. These vasculitides affect mediumsized and small vessels, in contrast to GCA, which
affects large and medium-sized arteries. Consequently,
although all these disorders display a peak incidence in
elderly people, there appear to be different genderrelated factors behind the initial immune stimulation in
the two disease groups.
Genetic factors
The possibility of a genetic influence on GCA susceptibility was initially supported by reports of cases among
first-degree relatives. Several studies have shown an
association of GCA incidence, and risk of visual complications, with the HLA-DRB1*-04 alleles w23–25x.
However, in isolated PMR, without GCA symptoms,
the HLA class II expression varied from one population
to another w26x. Genetic polymorphisms with regard
to the expression of tumour necrosis factor (TNF),
intercellular adhesion molecule (ICAM-1), regulated
on activation, normal T-cell expressed and secreted
(RANTES) and interleukin receptor antagonist
Giant cell arteritis: pathogenesis and treatment
(IL-1Ra) were also shown to influence the susceptibility
for GCA and PMR, irrespective of DRB1 type w26x.
GCA and arterial degeneration
Atherosclerosis affecting large and medium-sized arteries
accounts for at least half of all deaths in the Western
world. There is growing evidence that its pathogenesis is
driven by inflammatory mechanisms similar to those in
rheumatic disorders (RA) w27x. Geographically, the mortality and morbidity of ischaemic heart disease is considerably lower in the Mediterranean areas compared
with countries in Northern Europe. There is a clear male
predominance in ischaemic heart disease in all European
countries w28x and this gender difference persists throughout life. Apart from gender, the size of the affected
vessels, the age of the patients and the geographical
distribution are similar to those of GCA. However,
morphologically, there is no reason to believe that atherosclerosis is a risk factor or is an initiator of GCA.
Atherosclerosis is seldom seen in temporal arteries.
Instead, in the general population, a morphologically
distinct type of arterial degeneration is encountered,
indicating media atrophy and minute calcification of the
internal elastic membrane (IEM) w29x. The age and sex
distribution of these calcifications is similar to that of
GCA, i.e. they are more common in women and they
increase with age w20x. Using light and electron microscopy, the inflammatory process of GCA appears to
start with the formation of foreign-body giant cells,
which attack the IEM calcifications. The presence of
this degenerative lesion in the general population might
thus explain the age and sex distribution of the disorder.
However, it remains to be elucidated why only a minority of the population react against their IEM calcifications. It may be speculated that infections might play a
role by activating the immune system or, more directly,
by inducing the formation of the foreign-body giant cells
w11, 29x.
A few epidemiological studies have addressed the
question of whether there might be an association
between degenerative vascular disease and GCA. In a
population-based case–control study, Machado et al. w30x
reported that smoking was a statistically significant risk
factor for GCA wodds ratio (OR) 2.3, 95% confidence
interval (CI)=1.3–4.1x, but manifestations of atherosclerosis, such as hypertension, angina, myocardial
infarction, peripheral vascular disease or stroke, were
not significantly related to GCA. However, the limited
number of included cases reduced the power of that
study. A French multicentre, prospective, case–control
study confirmed the association between smoking and
GCA w31x.
Female sex hormones
Since GCA is a disorder among elderly females, the
question might be raised of whether sex hormones are
involved in its pathogenesis. Interestingly, a recent
epidemiological study revealed that the number of pregnancies was lower among GCA patients than among
controls. It was suggested that the hyperoestrogenic
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state during pregnancy protects the artery wall w32x.
Oestrogen is involved in a wide variety of different
mechanisms which, theoretically, may be related to
GCA. It is thus known to preserve a normal vessel
wall by stimulating as well as inhibiting the growth of
vascular smooth-muscle cells w33–37x and there is
evidence that it influences the immune system w38x. One
recent study showed that mononuclear and giant cells in
GCA display the cytoplasmic accumulation of oestrogen
receptor-a (ER-a). Cytoplasmic ER-a was also seen in
media smooth muscle in GCA and in non-GCA controls.
The nucleotide sequence analysis of the ER-a gene
revealed no differences between GCA patients and
controls w39, 40x. Whether the reduction in circulating
oestrogen in post-menopausal women plays a role in the
development of the asymmetrical loss of smooth-muscle
cells in the temporal arteries and IEM calcification,
which appear to be a prerequisite for the disorder,
requires further investigation.
Environmental factors
Since fever, high erythrocyte sedimentation rate (ESR)
and general illness are some of its clinical symptoms,
GCA has repeatedly been suggested to be infectious.
Clustering in disease incidence, as well as rhythmic
annual and seasonal fluctuations in incidence, may
indicate the involvement of epidemic infections or other
exogenous aetiological factors. A study from Olmsted
County described a cyclic pattern in the annual incidence
during the period 1950–1991, with peaks every 7th yr,
each period lasting for about 3 yr w19x. Due to the relatively small number of cases (n=125), the statistical
power was low. The cyclic annual fluctuation was not
confirmed in a large series (n=665) of biopsy-positive
GCA in Göteborg in 1976–1995. However, there was a
significant seasonal variation with peaks in late winter
and autumn w41x. Other studies report peaks in clinical
onset during the summer or winteruspringtime w42–45x.
A Danish study reported a clustering of GCA in relation
to two epidemics of Mycoplasma pneumoniae and two
major outbreaks of human parvovirus B19 w46, 47x.
Interestingly, human parvovirus B19, which infects endothelial cells, has been reported in connection with other
vasculitides, such as Wegener’s granulomatosis and
cerebral vasculitis in children w48, 49x.
Serological studies, including influenza A and B,
mumps, adeno-, rota- and enterovirus, Q-fever, leptospirosis, M. pneumoniae and Chlamydia, most of them
performed on small series of patients, revealed no
difference in seroprevalence between GCA cases and
controls w50x.
The seroprevalence was also similar in cases and
controls regarding viruses known to induce giant cells in
humans, i.e. the herpes virus group, Epstein–Barr virus,
measles, respiratory syncytial virus and parainfluenza
types 1, 2 and 3 w50x. One French study suggested that
newly diagnosed cases of GCA were more likely to be
positive for IgM anti-human parainfluenza virus type 1,
compared with randomly selected sex- and age-matched
controls from the general population w51x. Varicella
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E. Nordborg and C. Nordborg
zoster virus (VZV) produces multinucleated giant cells in
acutely infected tissue w52x and is commonly reactivated
in elderly people. A study of biopsy-positive temporal
arteries, using immunohistochemical and polymerase
chain reaction (PCR) techniques, did not reveal VZV
antigen or DNA in any of the subjects w53x.
Several studies associate Chlamydia pneumoniae
(TWAR) organisms with the atheromatous plaque,
although their pathogenetic role is unclear w54–58x. The
role of C. pneumoniae in GCA was recently addressed.
Wagner et al. w59x, detected C. pneumoniae, using
immunocytochemistry and PCR techniques, in the
majority of their GCA patients but in none of the controls. In contrast, Haugeberg et al. w60x, using the same
techniques on a southern Norwegian population, were
not able to detect C. pneumoniae in any of 20 patients
with biopsy-proven GCA.
Chlamydia pneumoniae is a common infection worldwide w61x and there is a clear sex distribution showing a
considerably higher seroprevalence in men compared
with women in older age groups w61, 62x. However, low
rates were found in Denmark and Norway w62x.
Therefore, C. pneumoniae infection does not relate statistically to the high prevalence of GCA in Scandinavian
women.
To summarize, there is no convincing evidence today
that GCA is a truly infectious vasculitis, although it may
be speculated that environmental factors such as infections might trigger the immune system in a susceptible
host, as suggested by Russo et al. w63x, who, in a clinical
retrospective study, found a correlation between various
infections and the onset of GCA.
Occurrence
Incidence rates
The incidence of GCA varies greatly in different geographical areas. It has repeatedly been shown that the
disease predominately affects subjects of Northern
European descent, in particular those of Nordic heritage,
irrespective of their place of residence w5–13x, with
estimates of about 20 cases annually per 100 000 persons
older than 50 yr of age. The incidence rates are lower in
Southern Europe w64, 65x. Only a few cases are reported
in Israel and in black populations w66, 67x, while in Asian
countries GCA is distinctly infrequent.
The highest figures worldwide were documented from
Southern Norway w68x using the 1990 American College
of Rheumatology criteria w69x. The annual incidence rate
was 32.8u100 000 in individuals older than 50 yr, and
29.1u100 000 for biopsy-proven GCA, thus confirming
the high incidence data reported by Gran et al. w5x.
Whether such figures reflect a high endemic clustering
of GCA in a distinct region or are instead the result of
a continuous increase in incidence rates with time is
not known.
Clearly, the incidence of GCA has increased in recent
years, indicating time trends in morbidity rates. From
Göteborg, Sweden, three previous studies from the periods
1973–1975, 1977–1986 and 1976–1995 w3, 14, 41x
demonstrated a statistically significant increase with an
average annual incidence of biopsy-positive GCA of
16.8, 18.3 and 22.2u100 000, respectively. The relationship between positive and negative biopsies was constant
during this period w41x. A similar trend was suggested in
Olmsted County, Minnesota w2x. Such observations might
reflect genuine changes in morbidity, but they could also
be related to greater awareness of the disease or better
identification of cases. Other independent causes that
might exert an influence are differences in the catchment
area of the population studied or an increase in the age
of the general population. However, our recent statistical
investigation showed that the increase in GCA incidence
was not significantly influenced by the increasing age
of the Göteborg population (Nordborg et al., in
preparation). Furthermore, the study design might differ
with a shift from retrospective to prospective studies.
The Göteborg studies were all retrospective in design,
involving the same catchment area.
As is indicated by the large number of temporal artery
biopsies performed, physicians are definitely aware of
this disease. On the other hand, taking the data from
Östberg w70x into consideration, GCA may be underdiagnosed during life. She found a prevalence of 1.7% in
her post-mortem study, including more than 20 000
cases, using the following histological criteria: ‘intimal
thickening with narrowing of the arterial lumen, ingrowth
of capillaries in media anduor intima, destruction of the
elastic membrane with accumulation of mononuclear
round cells anduor giant cells’.
Recently, a geographical gradient of frequencies in GCA
was reported with a statistically verified increase in
frequency by latitude north w22, 71x. The geoepidemiology
of other primary systemic vasculitides, such as Wegener’s
granulomatosis, Churg–Strauss syndrome, polyarteritis
nodosa and microscopic polyangitis, was recently compared in different European regions w22x; there are
differences between geographical areas also in the incidence of small vessel vasculitides. Wegener’s granulomatosis was thus found to be more common in the UK
than in Spain, with a trend towards even higher incidence
rates in Tromsö (northern Norway), indicating that environmental and genetic factors might also be important in
the aetiopathogenesis of these types of vasculitis.
Mortality
GCA may be life-threatening. The aorta and its main
branches (subclavian and carotid arteries) are the main
targets for the arteritic process, but coronary arteries
and cerebral arteries are sometimes involved. However,
only few fatal cases are reported in the literature. The
fact that GCA may cause cerebral and myocardial infarction as well as aortic aneurysms is not general
knowledge. Fewer fatal GCA cases are probably
detected today, due to decreasing autopsy rates and to
the fact that post-mortem histological examination of
the arteries is not routinely performed.
Giant cell arteritis: pathogenesis and treatment
Aortic lesions, which are mainly located in the thoracic segment, are asymptomatic in most patients and
may therefore be overlooked. Furthermore, their manifestations evolve slowly and an aortic dissection may
only be overt years after terminated treatment. In a retrospective study, Evans et al. w12x calculated an increased
risk of thoracic aortic aneurysms of 17.3 (95% CI 7.9–33)
compared with the general population; the corresponding risk of an abdominal aneurysm was 2.4 (95% CI 0.8–
5.5). In Sweden, aortic aneurysms were detected in 6u90
patients after a median follow-up period of 11.3 yr w72x.
The prevalence of myocardial infarction in GCA is
unknown. The available literature is sparse and limited
to case reports. Cerebral infarction has been reported in
about 7% of consecutive patients with biopsy-proven
GCA w73x. The preventive effect of corticosteroid treatment on mortality has been documented in many longterm follow-up studies w72, 74, 75x. Although one study
reported increased mortality early in the disease course,
during the first 4 months after the diagnosis of biopsyproven GCA, the death rates were subsequently normalized w76x. Schaufelberger et al. w77x noticed an increased
mortality during the first 2 yr of treatment in patients
with biopsy-negative PMR, but not thereafter (personal
communication). In the latter two studies the patients
were treated by many different physicians without special
knowledge of GCA in contrast to the long follow-up
study from Göteborg w72x, where only doctors with a
special interest in the disease were involved.
The risk of fatal complications in GCA stresses the
importance of early diagnosis and of follow-up, also
after clinical remission.
Occurrence of malignancies in GCA
Malignancy may be associated with polymyalgia
rheumatica-like symptoms w78x. However, cancer-related
symptoms differ from those of classic PMR; symptoms
may appear before the age of 50 yr, they may be asymmetrical and there may be joint pain. Incomplete or
delayed relief from corticosteroid treatment is also
characteristic. Several papers have addressed the potential association between GCA and the incidence of malignancy. One large study found that malignancies were 2.3
times more common in GCA patients compared with
the general population. Considering the long interval
between the diagnosis of malignancy and GCA, the
relationship appeared weak w79x. So far, there is no proof
of a causal association between GCAuPMR and neoplasm.
Treatment
GCA is a highly corticosteroid-responsive disorder. A
majority of the patients experience an excellent therapeutic effect. Moreover, this treatment has a preventive
effect on vascular complications, as has clearly been
shown in many long-term follow-up studies w72, 75x.
The time before the initiation of corticosteroid treatment was the single most important factor predicting
outcome in patients presenting with symptoms of visual
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impairment. Among those who were treated within 24 h
after loss of sight, an improvement was achieved in more
than 50%. In contrast, only 6% of the patients improved
when treatment was delayed for more than 24 h w80x.
Schmidt et al. w81x emphasized the importance of an
early diagnosis and prompt corticosteroid treatment.
They reported six cases with severe vascular complications (bilateral blindness, cerebral strokes) on which
corticosteroid treatment had no effect. The patient delay
between first symptoms (PMR, jaw claudication, headache, amaurosis fugax) and the vascular complication
was on average 7 weeks. When a vascular catastrophy is
manifest, the corticosteroid therapy, whatever dose chosen,
may prevent another vascular incident but does not
reverse the symptoms of the first accident.
The optimal initial dose regimen of oral prednisolone,
which is the drug most frequently used, has been discussed. According to prospective large series applying
acceptable diagnostic criteria, and using predefined
treatment protocols, 20–60 mg of prednisolone (mostly
40–60 mg) was shown to be an appropriate starting
dosage in about 90% of cases. Alternate-day administration regimens of corticosteroids have not proved
effective in GCA w82–84x and this treatment does not
reduce the development of steroid-induced osteoporosis
w85x. Treatment with intramuscular methylprednisolone
was reported to result in a more beneficial side-effect
profile in patients with pure PMR in one study w86x,
although these data were not confirmed in a recent,
multicentre, prospective study of biopsy-proven GCA
followed up for 1 yr w87x. However, in the latter study,
steroids were administered as intravenous pulses, with
different kinetics, which might have influenced the result.
Due to the well-known comorbidities related to longterm corticosteroid treatment w88x and the fact that
GCA has a remarkably high tendency to relapse during
tapering, alternative corticosteroid-sparing therapy has
been requested. Several approaches, including combined
therapy with cytotoxic (azathioprine, methotrexate and
cyclosporin) agents, have been suggested. To date, the
vast majority of studies in this field have not led to any
firm conclusions, since they are too restricted in number
w89, 90x, short term w91–93x and biased by high drop-out
rates anduor they were uncontrolled w89–91x. So far,
methotrexate is the drug that holds the best promise. The
results of a randomized, double-blind, 24-month, placebocontrolled trial from Spain, published last year, revealed
a significant reduction in the rate of relapses and the
cumulative mean dose of corticosteroids was lower in the
methotrexate arm compared with the placebo group w94x.
Surprisingly, neither the rate nor the severity of adverse
events differed between the two groups. The effect on
bone mineral density or fracture rate was not evaluated
and no information was provided about whether
patients with more aggressive disease did better on this
treatment. A recent, multicentre, placebo-controlled trial
w95x showed no benefit of methotrexate treatment in
terms of the number of relapses, treatment failures,
cumulative steroid doses or treatment toxicities. However,
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E. Nordborg and C. Nordborg
the number of patients included was small, which reduced
the power of this study.
New drugs such as TNF blockers have rapidly
emerged as efficient treatments in rheumatoid arthritis
w96x. Regarding their use in GCA, the experience is
limited to case reports, albeit with some encouraging
results. Cantini et al. w97x reported a complete response
in three of four patients with long-standing active giant
cell arteritis, still requiring high doses of prednisolone
after more than 42 months. All patients had developed
serious corticosteroid-related side-effects. After two infusions with infliximab (3 mgukg), three of the patients
displayed a clinical and humoral remission. The remission sustained after a third infusion and during a
follow-up time of 6 months, despite withdrawal of the
corticosteroids. One patient, who did not respond to
therapy, was withdrawn after the second infusion, in
accordance with the protocol. The therapy was well
tolerated by all patients. No side-effects were reported.
Interestingly, the same group recently reported a similar good response with normalization of clinical and
serological activity after three infusions with infliximab
in three of four patients with persistent PMR, without
cranial symptoms w98x, whereas one patient had a partial
effect. In the good responders corticosteroid therapy was
terminated and in the partial responder it was reduced
by 50%. The remission was sustained at the control 1 yr
after the first infusion. Infliximab was well tolerated; there
were no side-effects. These open pilot studies suggest
that TNF-a blockade may have a steroid-sparing effect
in patients with corticosteroid-resistant GCA.
In a critical review of treatment studies, it was
suggested that only about 10–15% of patients have
a ‘corticosteroid-resistant’ disease, defined as a daily
requirement of >15–20 mg of prednisolone more than
2 months after the start of therapy w99x. These patients
require a safe and effective additional agent. Future
trials should focus on appropriately defined large
cohorts of patients, ideally biopsy-proven patients, who
need >15 mg of prednisolone as chronic maintenance
treatment. The rate of remission in the long run is
another important issue which must be focused on
increasingly in new treatment modalities.
The characteristic prompt relief of symptoms and
preventive effect on vascular complications after the initiation of corticosteroid therapy in the vast majority of
patients indicates the unique role of steroid-mediated
immunosuppression in GCA. Corticosteroids have been
regarded as the cornerstone in the therapy of GCA and
today there is little evidence, if any, that they can or
should be replaced. On the other hand, despite good
clinical improvement in the systemic signs of the disease,
the inflammatory infiltrate persists for a long time in
the vessel wall, which further emphasizes the need for
optimized therapy in GCA.
Recently, the biological action of corticosteroids was
elucidated, using temporal arteries with biopsy-proven
GCA explanted into immunodeficient SCID mice w100x.
NFkB-dependent cytokines (IL-2, IL-1b, IL-6) were
suppressed, whereas TGF-b and IFN-c did not appear to
be influenced, despite high doses of corticosteroid treatment. These observations provide an explanation for the
promptness of the therapeutic effect seen in glucocorticosteroid treatment, but they also indicate why patients
have to be treated for a long time. Persistent disease is
evidenced by active histological lesions, as well as by the
fact that patients develop aortic aneurysms even years
after they were considered to be in remission w12x.
Osteoporosis
The age of the GCA population puts them at great risk
for corticosteroid side-effects, of which osteoporosis
leads to the most severe sequelae. In contrast to increased
resorption, resulting from the disease process, the
steroid-induced loss of bone is due to decreased formation of bone. However, studies of corticosteroidrelated osteoporosis morbidity in GCA have produced
contradictory results. Pearce et al. w101x reported that
even small daily doses of 6 mg of prednisolone might
result in bone loss, initially in trabecular bone, such as
the spine, followed by cortical bone. On the other hand,
in a recent Norwegian study the authors focused on bone
mineral density of the radius, spine and hip, measured by
dual-energy X-ray absorptiometry (DEXA) in GCA
(PMR and TA). Patients currently or previously treated
with prednisolone were compared with 30 newly
diagnosed cases of GCA (PMR or TA), examined
prior to the start of corticosteroid therapy, and with
70 healthy controls. For current users the mean daily
dose was 6.5 mg of prednisolone, the mean cumulative
dose 7.7 g, and for previous users 5.6 mg and 6.6 g,
respectively. No statistically significant difference was
found between any of the four groups w102x. A British
prospective study over 2 yr in patients with PMR w103x
showed increased levels of cross-links (resorption markers) before the start of corticosteroids, and a significant
decrease at 6 months. Bone mineral density (BMD)
at 1 yr correlated with ESR at baseline, but not with
the cumulative dose of corticosteroids. The last study
stresses the impact of the systemic inflammation per se
on bone mass. Thus, the morbidity of bone loss in GCA
is multifactorial. If BMD is within the normal range, the
bone-sparing agents calcium and vitamin D should be
given generously to patients at the start of treatment
with corticosteroids. Bisphosphonates could be instituted if BMD shows decreased bone density on the
DEXA scan. In patients for whom corticosteroids are an
unavoidable necessity, always try to use the lowest
possible dose to suppress the inflammation, at initiation
and during maintenance therapy.
Conclusions
GCA is suggested to be an antigen-driven disease, where
the antigen might be exogenous or endogenous. A single
cause or aetiological antigen has not as yet been found.
There is no proof that GCA is a truly infectious disease
and, on morphological and epidemiological grounds,
there is no reason to believe that atherosclerosis initiates
or is a risk factor for GCA. For the future, efforts should
Giant cell arteritis: pathogenesis and treatment
be made to identify further relevant environmental, agerelated, genetic and, in particular, gender-specific risk
factors.
Corticosteroids remain the cornerstone of drug treatment of GCA. Future large trials, divided into clinically
important subgroups, may provide information about
the optimal therapy for each patient with GCA.
Other approaches with new drugs, such as TNF-a
blockades, might hold promise but have not as yet been
tested in controlled trials in GCA.
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