Giant Cell Arteritis
(Temporal Arteritis)
Definition
Giant cell arteritis (GCA) also known as
temporal arteritis is an autoimmune disease. Autoimmune diseases are conditions
in which immune cells, that normally help fight infections, are misdirected to
attack own tissues. In the case of GCA,
these immune cells are involved in an inflammatory reaction in large arteries
of the body, mainly branches of the aorta and often, the aorta itself. The
inflammation damages the affected blood vessels. At present the exact cause of this condition
is unknown.
GCA is a form of vasculitis. Vasculitis
is defined as a condition in which blood vessels, particularly arteries, become
inflamed. In GCA, the aorta and its branches are usually affected. The
inflammation in GCA can cause swelling of the blood vessel wall and narrowing
of the blood vessel lumen causing decreased blood supply to the neighboring
tissues. The blood vessel may also become thrombosed causing severe
ischemia or necrosis of tissues ordinarily supplied by the blood vessel.
Etiology
The etiology of temporal arteritis is multifactorial and is
determined by both environmental and genetic factors. Data indicate that the
disease is probably initiated by exposure to an exogenous antigen. Numerous
viruses and bacteria have been proposed as potential precipitants, including
parvovirus, parainfluenza virus, varicella zoster virus, Chlamydia
pneumoniae, and Mycoplasma pneumoniae.
T
cells are recruited to the vessel wall after initial exposure to the antigen.
They release cytokines that act on local macrophages and multinucleated giant
cells.[4]The response of the macrophages
and multinucleated giant cells to the cytokines depends upon their location
within the vessel wall.
Adventitia-based
macrophages produce interleukin-6 (IL-6), which further augments the
inflammatory cascade. Macrophages within the media produce oxygen free radicals
and metalloproteases, which degrade the arterial wall and fragment the elastic
lamina. With the disruption of the internal elastic lamina, the intima becomes
accessible to migrating myofibroblasts, which proliferate and lay down
extracellular matrix.
This
migratory process is driven by intima-based macrophages that produce
platelet-derived growth factor (PDGF) and vascular endothelial growth factor
(VEGF). The net effect of these events is an arteritis with local vascular destruction
and intimal hyperplasia leading to luminal stenosis and occlusion. The
exuberant release of cytokines associated with this process may be responsible
for the constitutional symptoms frequently encountered with the disease
Pathogenesis
Histologically,
the inflammatory reaction is granulomatous with highly activatedmacrophages 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. The possible antigen might be of external origin,
but it may also be autologous. Theadventitia 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. 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. Moreover,
significant media atrophy and calcification of the internal elastic membrane
(IEM) appear to be prerequisites for its occurrence. The hallmarks of GCA are
the systemic inflammation and the inflammatory infiltrate of the vessel wall,
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.
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 ‘formefruste’ with minor vascular involvement.
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.
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 notmerely the temporal arteries, may be affected in both
conditions.
Epidemiology
Incidence
·
0.22
new cases/year/1000 population aged >50 years
·
The
incidence fluctuates in a cyclical pattern
Prevalence
·
2/1000
population.
Age
·
Almost
exclusively affects those >50 years
·
Incidence
increases with 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, which may indicate
that its pathogenesis is related to the ageing of the arterial wall. 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
autoimmuno inflammatory disorders. Furthermore, a decreased antibody (Ab)
production and a shortened duration of protective immunity following
immunization are characteristic features in the elderly. Despite much research
in this field, basic mechanisms of age-related immune dysfunction have notbeen
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. 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
·
Women
are two or three times more likely to be affected as men.
There is a
clear female predominance in GCA, with 2- to 3-fold more women than men.
Thisdifference appears to be more marked in the northernparts of Europe. Only
in one Spanish study were malesreported to be predominant in GCA . Evidence was
recently presented indicating that other types of primaryvasculitides display
an inverse gender preference. Anepidemiological review of Wegener’s
granulomatosis,Churg–Strauss syndrome and polyarteritisnodosa in theUnited
Kingdom, Spain and Norway showed that, in allareas and in all disease
categories, the incidence was higher in men than women, with a peak incidence
at theage of 65–74 yr. These vasculitides affect mediumsized and small vessels,
in contrast to GCA, whichaffects large and medium-sized arteries.
Consequently,although all these disorders display a peak incidence inelderly
people, there appear to be different genderrelatedfactors behind the initial
immune stimulation in the two disease groups.
·
Impact of the 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 studyrevealed that the number of pregnancies was lower among
GCA patients than among controls. It was suggested that the hyperoestrogenic
state during pregnancy protects the
artery
wall. 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
and there is evidence that it influences the immune system. One recent study
showed that mononuclear and giant cells in GCA display the cytoplasmic
accumulation of oestrogenreceptor-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.
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.
Race
·
Almost
exclusively affects Caucasians of northern European origin.
·
Rare
in African-Americans.
·
The highest figures worldwide were
documented from Southern Norway
Genetics
·
There
may be a genetic tendency to giant cell arteritis - familial clusters have been
found.
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.
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 tumor necrosis factor (TNF), intercellular adhesion molecule
(ICAM-1), regulated on activation, normal T-cell expressed and secreted (RANTES)
and interleukin receptor antagonist IL-1Ra were also shown to influence the
susceptibility for GCA and PMR, irrespective of DRB1 type
Geography
·
There
is a tendency toward increased rates of disease in northern countries
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, 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. Only a few cases are reported in Israel and in black populations, while
in Asian countries GCA is distinctly infrequent.
Clinical findings and Diagnosis
Most patients with GCA will have one or more of the
symptoms listed below. However, in a minority of patients these symptoms are
absent or develop late in the course of the disease making the diagnosis of
underlying GCA a challenge.
Common symptoms
·
New headache, usually in the temples
·
Tenderness of the scalp
·
Swelling of the arteries near the temples
·
Vision changes like a curtain in the field of
vision, sudden vision loss (temporary or permanent) or double vision.
·
Pain in the muscles of the jaw while chewing
food
·
Shoulder or hip joint aching and stiffness
·
Weight loss
·
Poor appetite
·
Low grade temperatures
Less common symptoms
·
Cramping or aching in the arms with activity
·
Audible pulsations (bruits) over the axillary
areas
·
Cramping or aching in the legs while walking
which improves with resting
·
Dry cough or sore throat
·
Stroke-type symptoms
Physical
examination.
In addition
to symptoms physical examination should be performed, paying particular
attention to patient’s temporal arteries. Often, one or both of these arteries
are tender with a reduced pulse and a hard, cord-like feel and appearance.
Differential Diagnosis
The
differential diagnosis for a patient who presents with only the systemic
inflammatory symptoms of temporal arteritis is broad. Systemic infections,
connective tissue diseases, and malignancies may have similar clinical
features. Primary systemic amyloidosis can mimic the symptoms of both PMR and
temporal arteritis. Patients with a monoclonal band on immunoelectrophoresis
and a poor response to systemic corticosteroids should have a Congo red stain
performed on a temporal artery biopsy.
The
ophthalmic features of temporal arteritis can be mimicked by nonarteritic
anterior ischemic optic neuropathy (NAION), a disease characterized by visual
disturbances in patients with cardiovascular risk factors and a susceptible
”crowded” optic disc.
Several
features can be used to differentiate NAION from temporal arteritis. NAION
typically occurs in a younger age group (mean age, 60 years). Constitutional
symptoms are absent in NAION, and the ESR and CRP level are within normal
limits. The visual changes in NAION are less severe and typically do not result
in complete vision loss. On ophthalmic examination, the cup-disc ratio is
reduced in NAION (hence the description of the optic disc as ”crowded”),
whereas it is normal in temporal arteritis.
Several
vasculitides and connective tissue disorders can present with similar systemic
and ophthalmic manifestations, including systemic lupus erythematosus (SLE),
rheumatoid arthritis, polyarteritisnodosa, Churg-Strauss syndrome, microscopic
polyangiitis, Takayasu arteritis, and polymyositis. Differences in systemic
organ involvement, microscopic findings, and distribution of lesions can help
distinguish these entities from temporal arteritis.
Compressive
intracranial lesions, both malignant and benign, may also be considered in the
differential; these can be ruled out with neuroimaging studies.
Laboratory Tests
·
Blood tests.
If your doctor suspects giant cell arteritis, you're
likely to have a blood test that checks your erythrocyte sedimentation rate —
commonly referred to as the sed rate. This test measures how quickly red blood
cells fall to the bottom of a tube of blood. Red cells that drop rapidly may
indicate inflammation in your body.
You may also have a test that measures C-reactive protein
(CRP), a substance your liver produces when inflammation is present. The same
tests may be used to follow your progress during treatment.
·
Biopsy.
The best way to confirm a diagnosis of giant cell
arteritis is by taking a small sample (biopsy) of the temporal artery. Because
the inflammation may not occur in all parts of the artery, more than one sample
may be needed. The procedure is performed on an outpatient basis during local
anesthesia, usually with little discomfort or scarring. The sample is examined
under a microscope in a laboratory.
If you have giant cell arteritis, the artery will often
show inflammation that includes abnormally large cells, called giant cells,
which give the disease its name. Unfortunately, a biopsy isn't foolproof. It's
possible to have giant cell arteritis and still have a negative biopsy result.
If the results aren't clear, your doctor may advise another temporal artery
biopsy on the other side of your head.
Although a temporal artery biopsy is the standard test
for diagnosing giant cell arteritis, imaging tests may also be used for
diagnosing giant cell arteritis and for monitoring treatment. Possible tests
include:
The above image is a biopsy of the
temporal artery shows inflammation almost completely closing the opening of the
artery.
·
Magnetic resonance angiography (MRA).
This test combines the use of magnetic resonance imaging
(MRI) with the use of a contrast material that produces detailed images of your
blood vessels. Let your doctor know ahead of time if you're uncomfortable being
confined in a small space because the test is conducted in a tube-shaped machine.
·
Doppler ultrasound.
This test uses sound waves to produce images of blood
flowing through your blood vessels.
·
Positron emission tomography (PET).
Using an intravenous tracer solution that contains a tiny
amount of radioactive material, a PET scan can produce detailed images of blood vessels and highlight areas of
inflammation.
Treatments
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.
The time
before the initiation of corticosteroid treatment was the single most important
factor predicting outcome in patients presenting with symptoms of visual 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. Schmidtemphasized 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, amaurosisfugax) 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 GCAand this treatment does not reduce the
development of steroid-induced osteoporosis.Treatmentwith intramuscular
methylprednisolone was reported to result in a more beneficial side-effect
Major Side effects of corticosteroid therapy
·
Osteoporosis
·
High blood pressure
·
Muscle weakness
·
Glaucoma
·
Cataracts
Other possible minor side effects of corticosteroid therapy
include:
·
Weight gain
·
Increased blood sugar levels, sometimes
leading to diabetes
·
Thinning skin and increased bruising
·
Weakened immune system, leading to
susceptibility to infection and delayed healing
New drugs
such as TNF blockers have rapidly emerged as efficient treatments in GCA.
Regarding their use in GCA, the experience is limited to case reports, albeit
with some encouraging results. Cantini et al. 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 yrafter 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 .
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. 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 thepromptness of the therapeutic effect
seen in glucocorticosteroidtreatment, 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.
Complications
and Outcomes
Complications
Giant cell arteritis can cause the following
complications:
·
Blindness.
This is the most serious complication of giant cell
arteritis. The swelling that occurs with giant cell arteritis narrows your
blood vessels, reducing the amount of blood — and, therefore, oxygen and vital
nutrients — that reaches your body's tissues. Diminished blood flow to your
eyes can cause sudden, painless vision loss in one or, in rare cases, both
eyes. Unfortunately, blindness is usually permanent.
·
Aortic aneurysm.
Having giant cell arteritis increases your risk of
aneurysm. An aneurysm is a bulge that forms in a weakened blood vessel, usually
in the aorta, the large artery that runs down the center of your chest and
abdomen. An aortic aneurysm is a serious condition because it may burst,
causing life-threatening internal bleeding. Because it may occur even years
after the initial diagnosis of giant cell arteritis, your doctor may monitor
the health of your aorta with annual chest X-rays or other imaging tests, such
as ultrasound, CT scan or MRI.
·
Stroke.
In some cases, a blood clot may form in an affected
artery, obstructing blood flow completely, depriving part of your brain of
necessary oxygen and nutrients, and causing stroke. This serious condition is
an uncommon complication of giant cell arteritis.
Outcomes
Giant cell
arteritis is usually a self-limiting disease with a variable duration of months
to years. However, in a subset of patients the disease may follow a protracted
course, requiring long-term treatment with glucocorticoids. To date, glucocorticoids
are the only agents whose efficacy has been unquestionably proven. More
specifically, they can both improve the clinical symptoms of giant cell
arteritis and also prevent its complications, including visual loss.
Glucocorticoids therapy is notoriously fraught with numerous side effects,
therefore it is sensible to taper glucocorticoids as quickly as possible.
Flares are not uncommon and tend often to occur upon tapering of
glucocorticoids dosage or on withdrawal of glucocorticoids therapy.
However, in most
cases flares are mild and appear to respond favorably to an increase in
glucocorticoids dosage or reintroduction of glucocorticoids therapy,
respectively. Mortality rates of giant cell arteritis patients are comparable
to those of the general population, but there is evidence for an increased
frequency of potentially life-threatening ischemic events, such as myocardial
infarction and cerebro-vascular accidents, especially early on in the disease
course. The risk conferred by the disease appears to decrease with time,
presumably as a consequence of glucocorticoids treatment, whereas it can remain
significantly elevated in patients whose disease activity is not sufficiently
controlled by the treatment. By contrast, there is no evidence that giant cell
arteritis is associated with an increased prevalence of malignancies or that it
may represent a paraneoplastic syndrome.
References
·
Robbins and Cotran Pathologic Basis of
Disease -8th edition
·
Davidson’s Principals & Practices
in Medicine – 21st edition
·
American journal of Rheumatology -
2010 release
·
SLMC- Vascular diseases – 2008 release
·
http://www.ncbi.nlm.nih.gov
·
http://www.mayoclinic.com/health/giant-cell-arteritis/DS00440/DSECTION=lifestyle-and-home-remedies
·
http://www.vasculitisfoundation.org
·
http://emedicine.medscape.com
·
http://www.mayoclinic.com/health/giant-cell-arteritis/
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