Background:
In 1908, Mikito Takayasu, a
Japanese ophthalmologist, reported the association
of retinal arteriovenous anastomoses and absent
upper extremity pulses. Takayasu arteritis (TA) is
a chronic inflammatory disease of the aorta and
its major branches. TA is a large vessel
vasculitis of unknown origin that most often
affects young women in the second and third
decades of life. TA has been reported in children
as young as 6 months and in adults of every age.
The initial complaints may be
nonspecific constitutional signs and symptoms (eg,
fever, weight loss, lethargy). Because these
complaints lack specificity, the correct diagnosis
may be delayed for months or years. On histologic
examination, the aorta demonstrates evidence of
inflammation. Mixed areas of stenosis or aneurysm
formation are found on angiogram or magnetic
resonance angiography (MRA). Vascular
insufficiency related to stenosis and thrombosis
of affected vessels may cause renovascular
hypertension, neurologic symptoms, or lower
extremity claudications.
Cardiac involvement may include
aortic regurgitation and congestive heart failure
resulting from myocarditis or increased afterload.
Often the diagnosis of TA is made when a widened
mediastinum is appreciated on chest roentgenogram
and a tumor is suspected. CT scan instead
demonstrates a widened aortic arch.
Despite the term pulseless
disease, which is a synonym for TA, the
predominant finding in individuals with TA is
asymmetric pulse. Absent peripheral pulses occur
late in the course of the disease. While 5-year
survival rates exceed 90%, the disease has a high
incidence of residual morbidity.
Pathophysiology:
TA is characterized by
granulomatous inflammation of the aorta and its
major branches, leading to stenosis, thrombosis,
and aneurysm formation. The lesions of TA are
segmental with a patchy distribution.
Mononuclear infiltration of the
adventitia occurs early in the course of the
disease, with cuffing of the vasa vasorum.
Granulomatous changes may be observed in the
tunica media with Langerhans cells and central
necrosis. Fibrosis of the media and acellular
thickening of the intima compromise the vessel
lumen. Wrinkling of the intima is visible on gross
examination.
Stenoses are found in 90% of
patients with TA disease. Often patients have
poststenotic dilatations and other aneurysmal
areas. Stenotic arterial segments result in varied
ischemic symptoms. These symptoms may range from
abdominal pain after eating secondary to narrowing
of the mesenteric arteries to renovascular
hypertension to claudication of extremities.
Endothelial activation leads to a hypercoagulable
state predisposing the patient to thrombosis.
Congestive heart failure in individuals with TA
may occur as a result of hypertension, aortic root
dilation, or myocarditis. Transient ischemic
attacks, cerebrovascular accidents, mesenteric
ischemia, carotidynia, and claudication may occur.
Symptoms of vascular compromise may be minimized
by the development of collateral circulation with
the slow onset of stenosis.
One hypothesis for granulomatous
vasculitis development is that antigens deposited
in vascular walls activate CD4+ T cells, followed
by release of cytokines chemotactic for monocytes.
These monocytes are transformed into macrophages
that mediate endothelial damage and granuloma
formation in the vessel wall. A mouse model
supports this hypothesis. When syngeneic T cells
sensitized to vascular smooth muscle cells were
injected into mice, a granulomatous vasculitis of
the pulmonary arterioles occurred in 20% of the
mice. Human studies suggesting endothelial cell
activation have demonstrated increased expression
of intercellular adhesion molecule-1 (ICAM-1) and
vascular cell adhesion molecule-1 (VCAM-1) in
patients with TA. Humoral immunity also is
believed to be involved in this disease; antiaorta
antibodies and antiendothelial cell antibodies
have been found in patients with TA.
Immunoglobulin G, immunoglobulin M, and properdin
are found in lesions from pathologic specimens.
Frequency:
- In the US:
In Minnesota's Olmstead
County, incidence of TA was estimated at 2.6 per
million. However, the applicability of this
number to the diverse population of the US as a
whole is uncertain.
- Internationally:
TA is a common
affliction in third world countries, where the
disease is associated closely with tuberculosis.
The nature of this association is unclear
because most patients with TA in the US do not
have tuberculosis. In contrast, many third world
physicians assume tuberculosis in every patient
with TA.
Mortality/Morbidity:
- Because the disease is rare
in the US, accurate survival data are uncertain.
One study has quoted a survival rate of 85-95%
at 15 years. In a 1994 study, only 2% of deaths
were attributed directly to TA.
- In contrast, in a 1991 series
involving 26 Mexican children aged 3-15 years,
the 5-year survival rate was only 35%. Deaths
resulted from rupture of aorta or aneurysms (2),
stroke (2), cardiac failure (2), and peritonitis
and ventricular fibrillation.
- Morbidities in persons with
TA are related to ischemia and hypertension and
include congestive heart failure, transient
ischemic attacks, stroke, and visual
disturbances. Chronic low-grade dissection of
the aorta may cause recurrent chest pain for
years. At autopsy, children with TA who have
died from acute rupture of the aorta often are
found to have evidence of multiple prior small
dissections that did not progress.
Race:
TA more frequently is found in
Asian populations but has been described in
patients of all races.
- Japanese patients with TA
have a higher incidence of aortic arch
involvement. In contrast, series from India
report higher incidences of thoracic and
abdominal involvement.
- In US patients with TA, the
most commonly involved vessels are the left
subclavian, superior mesenteric, and abdominal
aorta. In US children with TA, lesions of the
thoracic and abdominal aorta, rather than
lesions of the aortic arch, are found most
commonly. However, all patterns of vascular
involvement have been observed in every country.
Sex:
- Females comprise 80-90% of
patients with TA.
- Pediatric studies are more
varied. Sex distribution usually mirrors the
80-90% female preponderance observed in adults.
Series of studies of TA in childhood from India
and South Africa report a 2:1 female-to-male
ratio. However, these are countries in which TA
is associated strongly with tuberculosis, and
additional etiologic and pathophysiologic
factors may be present.
Age:
- TA is the most common large
vessel vasculitis of adolescence.
- TA is an uncommon vasculitis
in children. The most common are postinfectious
vasculitides, Henoch-Schönlein purpura,
polyarteritis nodosa, and Kawasaki disease.
- Most incidents of TA present
in persons aged 10-30 years. In a series of
patients with TA, 20-35% were younger than 20
years at diagnosis. The youngest patient
reported was aged 6 months.
Medical Care:
Medical evaluation and
treatment can be performed on an outpatient basis
unless the patient is acutely ill. Goals of
medical therapy are to control active inflammation
and to normalize clinical and laboratory
parameters while preventing further vascular
damage.
- Daily high-dose
corticosteroid administration is the mainstay of
initial therapy. The authors have used
prednisone at 1-2 mg/kg/d for 4-6 weeks.
- Maintain high-dose
treatment until all evidence of active disease
has resolved.
- Then taper prednisone
dosage over a month to decrease morbidity from
corticosteroid treatment; although 60% of
patients respond to this treatment, 40%
relapse on steroid taper.
- Patients not responding to
corticosteroids or who relapse during
corticosteroid taper require an additional
agent.
- Symptoms of patients who
relapse on corticosteroid taper may be
controlled with weekly infusions of
methylprednisolone (30 mg/kg, not to exceed 1
g/wk).
- However, extensive use of
these infusions is associated with significant
steroid-induced toxicity if continued for any
significant period.
- Regimens including weekly
methotrexate or daily or monthly intravenous
cyclophosphamide have been used in individuals
with glucocorticoid-resistant TA. Low-dose
weekly methotrexate also has been used as a
steroid-sparing agent for patients not
tolerating corticosteroid taper.
- Cyclosporine may be an
alternative therapy offering lower ovarian
toxicity than cyclophosphamide. However,
cyclosporine often is associated with decreased
renal function and increased blood pressure,
which may aggravate the damage to the heart and
great vessels.
- Recent reports indicate
mycophenolate mofetil may be useful to treat
individuals with glucocorticoid-resistant
disease.
Surgical Care:
Following the acute phase,
patients with fibrotic changes require surgical
treatment of symptomatic stenotic or occlusive
disease. This can be achieved by percutaneous
angioplasty or stenting or, in severe cases, by
resection and placement of a manmade graft.
Children with TA rarely require bypass surgery of
carotid stenting.
- Percutaneous balloon
angioplasty of the aorta
- Percutaneous balloon
angioplasty of the aorta is reported to
normalize systolic and diastolic blood
pressures within 24 hours, with improvement of
exercise tolerance and restoration of
peripheral pulses.
- Both renovascular
hypertension and congestive failure due to
increased afterload are improved.
- Improvement has been
sustained for as long as 3-5 years.
- Endovascular stenting is
used in patients with severe stenoses,
hypertension, or ischemia during the fibrotic
phase of the disease.
- Multiple stents have been
used in children to relieve long-segment renal
artery stenosis and attendant renovascular
hypertension.
- Children with TA who have
received stents have lowered arterial blood
pressures and decreased requirement for
antihypertensives.
Consultations:
Activity:
Patient activity is
generally self-limiting, based on cardiac status.
Drug Name
|
Prednisone (Deltasone,
Meticorten, Orasone, Sterapred) --
Immunosuppressant for treatment of autoimmune
disorders; may decrease inflammation by
reversing increased capillary permeability and
suppressing PMN activity. Stabilizes lysosomal
membranes and also suppresses lymphocytes and
antibody production. |
| Adult Dose |
1-2 mg/kg/d PO qd or divided
bid |
| Pediatric
Dose |
Not to exceed 1-2 mg/kg/d PO qd
or divided bid |
|
Contraindications |
Documented hypersensitivity;
serious infections; systemic fungal
infections; varicella |
|
Interactions |
Induction of cytochrome P450
enzymes decreases vaccine effectiveness;
phenytoin and rifampin decrease corticosteroid
effectiveness |
| Pregnancy |
B - Usually safe but benefits
must outweigh the risks. |
|
Precautions |
Caution in patients with
hypertension, congestive heart failure, or
diabetes |
Drug Name
|
Cyclosporine (Sandimmune,
Neoral) -- Cyclic polypeptide that suppresses
some humoral immunity and, to a greater
extent, cell-mediated immune reactions such as
delayed hypersensitivity, allograft rejection,
experimental allergic encephalomyelitis, and
graft vs host disease for a variety of organs.
Doses used in autoimmune diseases are
generally lower than those used in transplant
patients. Initiate at lowest dose possible,
then taper to lowest effective dose as soon as
possible. Attempt discontinuing cyclosporine
to determine if therapy can stop. |
| Adult Dose |
1-3 mg/kg/d PO initially; may
increase gradually to 5 mg/kg/d PO as needed
to control symptoms; maintain at lowest
effective dose |
| Pediatric
Dose |
Administer as in adults
|
|
Contraindications |
Documented hypersensitivity;
uncontrolled hypertension or malignancies; do
not administer concomitantly with PUVA or UVB
radiation in psoriasis since it may increase
risk of cancer |
|
Interactions |
Carbamazepine, phenytoin,
isoniazid, rifampin, and phenobarbital may
decrease cyclosporine concentrations;
azithromycin, itraconazole, nicardipine,
ketoconazole, fluconazole, erythromycin,
verapamil, grapefruit juice, diltiazem,
aminoglycosides, acyclovir, amphotericin B,
and clarithromycin may increase cyclosporine
toxicity; acute renal failure, rhabdomyolysis,
myositis, and myalgias increase when taken
concurrently with lovastatin |
| Pregnancy |
C - Safety for use during
pregnancy has not been established.
|
|
Precautions |
Evaluate renal and liver
functions often by measuring BUN, serum
creatinine, serum bilirubin and liver enzymes;
may increase risk of infection and lymphoma;
reserve IV use only for those who cannot take
PO |
