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Vasculitis and
Thrombophlebi |
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Background:
Vasculitis is a descriptive term
associated with a heterogeneous group of diseases
that results in inflammation of blood vessels.
Arteries and veins of any size in any organ may be
affected, leading to ischemic damage to organs.
The pattern of vessel involvement is highly
variable, leading to innumerable clinical
presentations. The most common vasculitides of
childhood are Henoch-Schönlein purpura and
Kawasaki disease. The reader is referred to
special sections on Kawasaki disease, infantile
polyarteritis nodosa, polyarteritis nodosa and
Takayasu's arteritis in this volume.
For the clinician, diagnosing
the cause of vasculitis is a difficult task that
involves distinguishing disease entities whose
clinical presentations may overlap. Classification
criteria have been established for a number of
distinct clinical syndromes, but these are less
useful in making a diagnosis in patients who do
not meet all the criteria of any one disease.
While groups of patients with unifying features
can be identified, a patient with vasculitis often
presents initially with nonspecific constitutional
findings. Diagnosis may not be made until more
specific organ involvement occurs. Making a
diagnosis in a patient with vasculitis is an
evolving process, as later organ system
involvement may suggest revision of the initial
diagnosis. Diagnosis must be flexible, following
the course of the illness over time.
Primary systemic vasculitis is
relatively rare, so the physician must eliminate
other known causes of vasculitis, including
infection, malignancy, collagen vascular disease,
hypocomplementemic urticarial vasculitis, drug
hypersensitivity, inflammatory bowel disease, and
sarcoidosis. A host of other infectious and
inflammatory conditions mimic the signs and
symptoms of vasculitis and must be ruled out.
Consider vasculitis in patients
with constitutional symptoms in conjunction with
multisystem disease, palpable purpura, unexplained
neurological symptoms, decreased pulses, bruits,
or elevated inflammatory indices. Conversely,
physical findings may be scant, without
explanation for the presenting symptoms. A high
index of suspicion may lead to early and
aggressive treatment, with better outcomes for
previously fatal diseases.
Various classification schemes
for vasculitis have been proposed, most recently
by an international consensus conference in Chapel
Hill, North Carolina, in 1994, as follows:
Large-sized vessel vasculitis
- Temporal arteritis:
Granulomatous arteritis of the aorta and major
branches, especially extracranial branches of
the carotid artery; usually in patients older
than 50 years.
- Takayasu’s arteritis:
Granulomatous arteritis of the aorta and major
branches; usually in patients younger than 50
years.
Medium-sized vessel vasculitis
- Polyarteritis nodosa:
Necrotizing vasculitis of medium- or small-sized
arteries, without involvement of large arteries,
veins, or venules; renal involvement without
glomerulonephritis.
- Kawasaki disease: Medium- and
small-sized arteritis of childhood, associated
with mucocutaneous lymph node syndrome; most
commonly affects coronary arteries, although
veins and aorta may be involved. Lesions of the
aorta have been found on autopsy.
Small-sized vessel vasculitis
Pathophysiology:
As the vasculitides
comprise a group of different diseases, there is
no single disease process that explains the common
final pathway of vessel wall inflammation. Immune
complex disease, antibody-dependent cellular
cytotoxicity (ADCC), endothelial activation, and
coagulopathy have been invoked in models of
inflammatory disease of the vasculature.
In immune complex disease, small
(19S) immune complexes reach the vessel wall
through increased vascular permeability and are
deposited in the wall where Fc portions of
immunoglobulin G (IgG) and immunoglobulin M (IgM)
activate complement, and initiate T- and B-cell
responses with cytokine activation and recruitment
of neutrophils. Levels of interferon-alpha and
interleukin-2 (IL-2) are highly elevated in
patients with polyarteritis nodosa (PAN). Tumor
necrosis factor-alpha (TNF-alpha) and
interleukin-1 (IL-1) beta are moderately elevated
in PAN.
In antibody-mediated disease,
endothelial cell cytolysis follows binding of
specific antibodies to granulocytic cells with
subsequent activation of natural killer cells.
Superantigen mediated activation
of B-cell subsets is proposed as a mechanism for
Kawasaki disease but is unproven.
Antineutrophil cytoplasmic
antibodies (ANCA) have been implicated as
pathogenic in Wegener's granulomatosis, MPA, and
polyarteritis nodosa. These antibodies, directed
against proteins in the cytoplasm, were first
described in 1985. In vitro, ANCA activate
neutrophils with up-regulation of adhesion
molecules. The activated neutrophils adhere to
endothelium and stimulate lysis of endothelial
cells in the presence of TNF-alpha. Activated
neutrophils express membrane bound proteinase 3
(PR3; normally a cytosolic protein), the target
antigen of cytoplasmic pattern anti-neutrophil
cytoplasmic antibodies (c-ANCA). p-ANCA antibodies
are directed against myeloperoxidase, as well as
other antigens including elastase and lactoferrin.
Antiendothelial cell antibodies
(AECA) are found in primary vasculitis, as well as
in infection-related vasculitis, so they are not
helpful in differentiating primary vasculitis. In
vitro, these antibodies demonstrate
complement-dependent cytotoxicity against
endothelial cells. The antibodies may play a role
in vascular damage as an end pathway in multiple
vasculitis syndromes. Bound to endothelial cells,
AECA also may potentiate injury by neutrophils via
Fc receptor binding on neutrophils.
The endothelium plays an active
role in physiologic function, controlling vascular
permeability and cell-adhesion molecules. In
addition, the endothelium secretes a large range
of proinflammatory cytokines, including
prostaglandins, nitric oxide, adenosine
nucleotides, and platelet activating factor, in
response to cellular injury. Endothelium also can
be stimulated to express major histocompatibility
complex II (MHC II) molecules and can present
antigen to T-cells with subsequent proliferation
of T-cell populations.
In thrombophlebitis, a complex
interaction of endothelial activation,
thrombogenic nidus, and hypercoagulability leads
to thrombosis and vessel inflammation.
Frequency:
- In the US:
Henoch-Schönlein purpura
occurs in 10,000 children per year, with an
estimated incidence of 13.5 per 100,000
children. Kawasaki disease occurs in 1-3 per
10,000 children. Takayasu's arteritis occurs
much less frequently, with a total incidence of
2.6 per million people. Polyarteritis nodosa has
a reported incidence of 0.7 per 100,000 people.
Wegener's granulomatosis is similarly rare, with
an incidence of 1-3 per 100,000 adults.
Mortality/Morbidity:
Morbidity and
mortality of these syndromes is highly variable,
from the self-limited course of uncomplicated
Henoch-Schönlein purpura to fulminant Wegener's
granulomatosis. Overall, morbidity and mortality
are determined by the extent of end-organ renal,
pulmonary, cardiac, or CNS disease and ischemic
disease caused by thrombosis. Children with renal
and pulmonary involvement have a poorer outcome.
Aggressive early treatment is
essential in a number of vasculitis syndromes.
Untreated, Wegener's granulomatosis carries a 100%
mortality rate with a mean survival rate of 5
months. Treatment of Wegener's granulomatosis has
resulted in 87% remission rate, but with 53%
relapse. In a series by Valentini, renal failure
occurred in only one seventh (14%) of pediatric
patients treated with cyclophosphamide and
corticosteroids for ANCA positive
glomerulonephritis. In patients with polyarteritis
nodosa, mortality at 5 years decreased from 85% to
20% with cytotoxic and glucocorticoid therapy.
Most deaths due to uncontrolled vasculitis occur
in the first 6 months. Additional morbidity and
ultimately mortality accumulates due to cytotoxic
and immunosuppressive therapies used to control
the disease.
In contrast, cutaneous
polyarteritis nodosa is a relapsing, often painful
disease limited to skin with nodules or
ulceration, and prognosis is excellent.
Patients with vasculitis
secondary to hepatitis B become chronic viral
carriers, and many progress to hepatic cirrhosis
and esophageal varices.
Venous thrombophlebitis may lead
to chronic vasculopathy, known as post-phlebitic
syndrome, with venous insufficiency, swelling,
pain, and ulceration.
Race:
The vasculitides are seen in all
races and ethnicities, but are not equally
distributed. Children of Japanese descent have a
higher incidence of Kawasaki disease. Young women
of Japanese and Indian descent are affected more
often with Takayasu's arteritis. Non-Hispanic
whites living in Turkey and other areas of the
Middle East have an increased incidence of Behçet
disease.
Sex:
- Henoch-Schönlein purpura:
Male-to-female ratio of 1.5:1
- Kawasaki disease:
Male-to-female ratio of 1.5:1
- Polyarteritis nodosa: up to
2:1 male-to-female ratio, some demonstrate no
preponderance.
- Takayasu arteritis: Primarily
affects adolescent and young adult females;
male-to-female ratio of 1:8
- Wegener granulomatosis:
Male-to-female ratio of 2:1
Age:
- Henoch-Schönlein purpura:
Peak age of onset 5-15 years
- Kawasaki disease: Mean age of
onset 1.5 years. 80% of cases are under 5 years
of age.
- Polyarteritis nodosa: Peak
age of onset 40-60 years
- Takayasu's arteritis: Peak
age of onset 20-30 years; 20% of patients aged
19 years or younger
- Wegener's granulomatosis:
Peak age of onset 40-50 years; only 1-3% of
cases younger than 20 years
History:
Obtain a comprehensive history and full
review of systems in all patients where vasculitis
is suspected. The complete clinical picture often
will suggest the diagnosis. History should address
any medications or herbal remedies, recent or
recurrent upper respiratory illness, rashes, skin
ulcerations, constitutional symptoms, and central
and peripheral neurological symptoms. Also seek
other conditions, such as asthma, anemia,
malignancy, and inflammatory bowel disease. Family
history may help to identify patients with
coagulopathy, antiphospholipid antibody syndrome,
or other autoimmune diseases.
Classification criteria for
vasculitis have been established by the American
College of Rheumatology. These clinical guidelines
were not meant for diagnostic purposes but to
define uniform and distinct patient groups for
definition and analysis of study populations for
clinical research studies and treatment protocols.
Clinical information for several
vasculitides are given below:
- Henoch-Schönlein purpura:
American College of Rheumatology criteria
include the following:
- Palpable purpura
- Age of onset less than 20
years
- Abdominal pain or “bowel
angina”
- Positive wall granulocytes
Up to 50% of patients may
report a history of preceding upper respiratory
tract infection or pharyngitis. The triad of
abdominal pain, palpable purpura, and
periarticular inflammation/swelling may be
incomplete at presentation. Abdominal complaints
include severe, colicky, abdominal pain, nausea,
vomiting, and hematochezia or diarrhea. Initial
presentation of rash may be a bluish
discoloration of the ankles, urticaria, or
maculopapular rash before progressing to the
characteristic palpable purpura. Nephritis is a
late finding, but if present initially, portends
a worse renal outcome.
- Takayasu's arteritis: Three
out of 6 of the American College of Rheumatology
criteria provide 90% sensitivity and 97.8%
specificity. Criteria are as follows:
- Fever
- Weight loss
- Abdominal pain
- Extremity claudications
- Age younger than 40 years
- Decreased brachial artery
pulses
- Blood pressure difference
greater than 30 mmHg in arms
- Abnormal arteriogram
- Polyarteritis nodosa:
American College of Rheumatology criteria
include the following:
- Weight loss of more than 4
kg
- Livedo reticularis
- Testicular tenderness
- Myalgias or arthralgias
- Mono or polyneuropathy
- Diastolic BP greater than
90 mmHg
- Elevated BUN or creatinine
- Hepatitis B infection
- Abnormal arteriogram
- Positive polymorphonuclear
lymphocytes on artery biopsy
There is renal involvement
without glomerulonephritis. A cutaneous form is
limited to skin only and has an excellent
prognosis. In addition, criteria for the
diagnosis of PAN in children have been proposed
by Ozen et al, as follows (these have not been
validated):
- Major criteria -
musculoskeletal or renal involvement
- Minor criteria
- Cutaneous findings
- Gastrointestinal
involvement
- Peripheral neuropathy
- Central nervous system
involvement
- Hypertension
- Cardiac involvemen
- Lung involvement
- Constitutional symptoms
- Presence of acute-phase
reactants
- Presence of hepatitis B
surface antigen
It is proposed that five of
these, including one major criterion, is highly
suggestive of polyarteritis nodosa in children,
and therapy be instituted pending other
diagnostic procedures.
- Wegener's granulomatosis: Two
of 4 of the American College of Rheumatology
criteria yield 88% sensitivity and 92%
specificity. Criteria include the following:
- Nasal or oral inflammation
- Abnormal chest radiograph
with fixed infiltrates
- Pulmonary nodules or
cavities
- Microhematuria
- Granulomatous inflammation
of artery wall biopsy
Patients have fever, weight
loss, recurrent sinusitis, pneumonias, cough,
and hemoptysis. Additional symptoms may include
saddle-nose deformity or other cartilaginous
destruction, proptosis, and painful oral
lesions.
A strong association with c-ANCA (anti-PR3)
exists.
- Churg-Strauss disease: Four
of 6 of the American College of Rheumatology
criteria yield 85% sensitivity and 99.7%
specificity. Criteria include the following:
- Asthma
- Mononeuropathy or
polyneuropathy
- Migratory or transitory
pulmonary infiltrates
- Paranasal sinus pain or
tenderness
- Extravascular eosinophilia
The asthma or atopic diathesis
is always present first. In adults, onset of
asthma is late, occurring at about 30 years, in
contrast to children. Fever, weight loss,
myalgia, and skin lesions are seen. Serum
eosinophilia is above 1500/mm3. When
renal lesions are present, they usually consist
of glomerulonephritis and hypertension.
- Microscopic polyangiitis
presents with fever, rash, weight loss,
glomerulonephritis, and pulmonary capillaritis.
A strong association with p-ANCA (anti-MPO)
exists.
- Essential cryoglobulinemia is
associated with fever, skin abscesses,
arthralgias, myalgias, and Raynaud's and/or
Sjögren's syndrome. Glomerulonephritis and
peripheral neuropathy are frequent. Type I is
associated with such malignancies as Waldenström
macroglobulinemia or multiple myeloma. Type II
is essential, and Type III is polyclonal and
associated with hepatitis C infection.
- Behçet syndrome is associated
with oral ulcerations, genital ulcerations,
uveitis, erythema nodosum, arthritis, and
pulmonary artery aneurysms.
Physical:
A careful, complete
examination is required when a vasculitis is
suspected.
- Fever
- Hypertension
- Blood pressure difference
between arms greater than 30 mmHg
- Head, ears, eyes, nose, and
throat (HEENT)
- Conjunctivitis
- Chemosis
- Proptosis
- Saddle-nose deformity
- Paranasal sinus tenderness
- Painful aphthous ulcers
- Palatal ulcerations
- Cheilosis
- Injected, swollen lips
- Strawberry tongue
- Hearing loss
- Wheezing
- Stridor or decreased breath
sounds
- Bruits over subclavian
vessels or aorta
- Diminished or absent pulses
- Abdominal tenderness
- Hypoactive bowel sounds
- Palpable purpura
- Erythema nodosum
- Tender subcutaneous nodules
- Livedo reticularis
- Digital ulcers or
peripheral gangrene
- Genital ulcerations
- Musculoskeletal: Arthritis or
periarthritis; muscle pain, especially bilateral
calf pain.
- Pedal edema
- Decreased pulses
- Peripheral neuropathy
- Mononeuritis multiplex
common
- Cranial nerve palsies
common
- Localizing neurological
findings suggesting central nervous system
lesions due to thrombosis or hemorrhage
- Irritability typical in
Kawasaki disease
- Cotton-wool exudates (cytoid
bodies)
- Retinal hemorrhages
- Optic atrophy
- Anterior or posterior
uveitis
- Genitals
- Testicular swelling and
pain
- Vaginal ulcers or scars of
old ulcers
Causes:
- Examples of infectious causes
of vasculitis include the following:
- Lemierre syndrome (internal
jugular vein thrombosis complicating
pharyngeal infection)
- Pylephlebitis (mesenteric
vein thrombosis associated with appendicitis
or appendiceal abscess)
- Viral etiologies, such as
hepatitis B and C, HIV, CMV, EBV, and
Parvovirus B19
- Vasculitis also occurs
secondary to the following:
- Polyarticular and systemic
juvenile rheumatoid arthritis
- Systemic lupus
erythematosus
- Inflammatory bowel disease
Other Problems to be
Considered:
Atrial myxoma
Atrial thrombus
Churg-Strauss disease
Cogan syndrome
Erythema nodosum
Henoch-Schönlein purpura
Lemierre syndrome
Mucha-Habermann syndrome
Microscopic polyangiitis
Panniculitis
Rheumatoid vasculitis
Thrombophlebitis
Glomerulonephritis
Lab Studies:
- CBC: Normochromic, normocytic
anemia of chronic disease; leukocytosis and
thrombocytosis are associated with inflammatory
process.
- Westergren sedimentation rate
is elevated.
- Comprehensive metabolic
profile: Depends on organ involvement. BUN,
creatinine, and transaminases may be elevated.
Hypoalbuminemia may be present (as a reverse
acute-phase reactant or through protein loss).
- ANCA: c-ANCA (central or
cytoplasmic) is associated with Wegener's
granulomatosis; confirmatory enzyme-linked
immunosorbent assay (ELISA) for antiproteinase 3
(anti-PR3) is usually positive. ELISA may be
positive in MPA; anti-PR3 is often negative.
- Peripheral antineutrophil
cytoplasmic antibody (p-ANCA) is associated with
MPA, polyarteritis nodosa, and crescentic
glomerulonephritis. ELISA for myeloperoxidase is
positive. p-ANCA are also directed against other
antigens, including elastase and lactoferrin. In
contrast, over 90% of c-ANCA are directed
against PR3.
- The data issued from the UNC-Chapel
Hill lab with their ANCA reports indicate that
for MPA, 40% are c-ANCA (anti-PR3) positive, 50%
are p-ANCA (anti-MPO) positive and 10% are ANCA
negative. This is compared with Wegener's
granulomatosis in which 75% are c-ANCA positive,
20% are p-ANCA positive and 5% ANCA negative. In
Churg-Strauss, 10% are c-ANCA positive, 60% p-ANCA
positive and 30% ANCA negative. Patients with
NCGN (necrotizing and crescentic
glomerulonephritis) are 20% c-ANCA positive, 70%
p-ANCA positive and 10% ANCA negative.
- c-ANCA and p-ANCA are
identified by the difference in fluorescent
pattern on indirect immunofluorescence due to
ethanol fixation; this difference does not occur
with formaldehyde fixation of the slide. The
indirect immunofluorescence method is widely
regarded as the best assay for ANCA.
Confirmatory ELISA may be performed to identify
the antigen to which these antibodies are
directed.
- Antiendothelial cell antibody
(AECA): May be elevated.
- Hepatitis A, B, and C:
Hepatitis is associated with polyarteritis
nodosa; serology may indicate prior or current
infection.
- Antinuclear antibody (ANA):
Rarely positive
- Rheumatoid factor (latex
fixation): Always elevated in mixed
cryoglobulinemia
- Angiotensin-converting
enzyme: May be elevated in sarcoid vasculitis
(or with any pulmonary granulomatous
involvement).
- Factor VIII related antigen
also called von Willebrand factor antigen (VWFAG):
a marker of endothelial cell activation; may be
elevated.
- Antiphospholipid antibody:
ELISA screen for the presence of anticardiolipin
antibody; antiphosphoserine; antiphosphoglycerol;
antiphosphatidic acid; antiphosphoinositol and
antiphosphoethanolamine assays also are
available.
- Activated partial
thromboplastin time: Prolonged in the presence
of lupus anticoagulant/antiphospholipid
antibody.
- Other markers for
hypercoagulability: Protein C, protein S,
antithrombin III, Factor V Leiden mutation,
prothrombin gene mutation G20210A, methylene
tetrahydrofolate reductase mutation (MTHFR), and
homocysteinemia are all cumulative risk factors
for thrombosis.
Imaging Studies:
- Chest radiograph: Screen for
pulmonary infiltrates or consolidations in
Wegener's granulomatosis and MPA. Look for hilar
adenopathy, suggesting pulmonary sarcoidosis.
- Sinus CT scan: Look for
thickening or opacification as evidence of upper
airway disease in Wegener's granulomatosis.
- Angiogram or magnetic
resonance angiography (MRA): May show long areas
of stenosis or aneurysm formation; bruits or
symptoms of ischemia should guide site.
- Ultrasound: May be useful in
identifying subclavian artery disease;
ultrasound duplex Doppler studies can be used to
identify venous thromboses of the extremities.
- Head CT scan or MRI: As
needed for patients with confusion, mental
status changes, and focal neurological findings.
May show hemorrhage, ischemia, and collateral
formation (eg, moyamoya).
- STIR MRI images of tender
muscles can show edema to help guide biopsy.
Procedures:
- Renal biopsy: May show focal
segmental glomerulonephritis. Immunofluorescence
may demonstrate immune deposition, suggestive of
lupus, or a pauci-immune pattern, suggesting MPA.
- Skin biopsy: May identify
vasculitis, yet not be specific beyond
leukocytoclastic vasculitis. Sural nerve biopsy
is usually nondiagnostic in a patient without
peripheral nerve findings.
- Electromyogram: May be useful
in evaluating patients with peripheral
neurological involvement, such as mononeuritis
multiplex.
- Lung biopsy: Useful in
Wegener's granulomatosis, Churg-Strauss
syndrome, sarcoidosis.
- Conjunctival biopsy, sinus
biopsy: Useful in Wegener's granulomatosis and
sarcoidosis.
- Testicular biopsy can be
helpful in Polyarteritis Nodosa.
- Muscle biopsy can be helpful
in Polyarteritis Nodosa especially if the muscle
is bright on STIR MRI images.
Histologic Findings:
Leukocytoclastic
vasculitis seen in Henoch-Schönlein purpura,
polyarteritis nodosa, and Wegener's granulomatosis
is characterized by focal segmental necrotizing
full-thickness lesions of varying stages in small
vessels. Fibrinoid necrosis is present. The
cellular infiltrate is predominantly
polymorphonuclear neutrophils. Lymphocytes and
eosinophils may be present. Histologically,
leukocytoclastic vasculitis is indistinguishable
from MPA; indirect immunofluorescence may
distinguish MPA.
Henoch-Schönlein purpura
reveals a leukocytoclastic vasculitis with IgA
immune deposits.
In Churg-Strauss disease,
leukocytoclastic vasculitis, eosinophilic tissue
infiltrate, and extravascular granuloma are
present.
Takayasu disease is
characterized by granulomatous destruction of the
aorta and branches.
In Wegener's granulomatosis,
both leukocytoclastic and granulomatous vasculitis
occur.
Medical Care:
- Most patients who are not
acutely ill may be evaluated on an outpatient
basis.
- Admit patients with
hypertension, mental status changes, pulmonary
hemorrhage, or who are acutely ill for
diagnostic workup and stabilization.
- Admit patients with
thrombophlebitis for evaluation and
anticoagulation. Catheter-directed thrombolysis
by an experienced physician may decrease
morbidity due to postphlebitic syndrome.
- Treatment goals are to
decrease acute inflammation of blood vessels and
to maintain adequate perfusion of skin and vital
organs, while limiting the side effects of
potentially toxic therapies.
- Individualize treatment based
on organs affected and overall condition of the
patient. In general, corticosteroids are
administered to bring acute symptoms and
laboratory evidence of systemic inflammation
under control. After control is achieved,
attempts may be made to taper over a month. For
patients with renal or CNS involvement,
immunosuppression with cyclophosphamide,
azathioprine, methotrexate, or tumor necrosis
factor blockade with etanercept is used. It is
important that the care of these patients be
centralized where possible to optimize diagnosis
and treatment.
- Anticoagulation is indicated
for any patient with a thrombotic episode and an
underlying hypercoagulable state. The protocols
set forth by Andrews in Toronto are useful to
achieve therapeutic heparin and warfarin levels.
- Base treatment of systemic
vasculitis on the severity and distribution of
end-organ involvement. Always seek infectious
etiologies; patients with vasculitis secondary
to hepatitis B respond to conventional therapy,
but become chronic viral carriers, and many
progress to hepatic cirrhosis and esophageal
varices.
Surgical Care:
For patients with
thrombophlebitis, removal of any local
intravascular instrumentation is recommended.
Placement of Greenfield filters is not recommended
for patients with hypercoagulability.
- Stenting of stenotic vessels
is increasingly used. Balloon dilatation also
has been used to improve renovascular flow.
- Patients with Wegener's
granulomatosis may develop subglottic stenosis;
these lesions also are amenable to balloon
dilatation.
Consultations:
- Pediatric nephrology, if
renal involvement
- Vascular surgery or
interventional radiology
- Pediatric cardiology, as
indicated.
- Pediatric neurology, as
indicated
Diet:
Low sodium diet if hypertensive
Activity:
Activity as tolerated.
Patients taking anticoagulants should not
participate in contact sports.
Immunosuppression is achieved
using corticosteroids and, for patients with renal
or CNS involvement, with cyclophosphamide,
azathioprine, methotrexate, or tumor necrosis
factor blockade with etanercept.
Drug Category:
Corticosteroids -- Potent immunosuppressive
activity with rapid onset of action.
Drug Name
|
Prednisone (Deltasone,
Sterapred) -- Used to bring acute symptoms and
laboratory evidence of inflammation under
control. May decrease inflammation by
reversing increased capillary permeability and
suppressing PMN activity. Stabilizes lysosomal
membranes and also suppresses lymphocytes and
antibody production. |
| Adult Dose |
5-60 mg/d PO qd-bid to
normalize symptoms and laboratory parameters;
taper possible by 2 wk in some entities, as
symptoms resolve |
| Pediatric
Dose |
1-2 mg/kg/d to bring acute
symptoms and laboratory evidence of
inflammation under control; after achievement
of control, attempts may be made to taper by a
month in some entities (varies) |
|
Contraindications |
Documented hypersensitivity;
viral infection, peptic ulcer disease, hepatic
dysfunction, connective tissue infections, and
fungal or tubercular skin infections; GI
disease |
|
Interactions |
Coadministration with estrogens
may decrease prednisone clearance; concurrent
use with digoxin, may cause digitalis toxicity
secondary to hypokalemia; phenobarbital,
phenytoin, and rifampin may increase
metabolism of glucocorticoids (consider
increasing maintenance dose); monitor for
hypokalemia with coadministration of diuretics
|
| Pregnancy |
C - Safety for use during
pregnancy has not been established.
|
|
Precautions |
Cushingoid side effects,
including hypertension, hirsutism, moon facies,
striae; adrenal suppression, osteoporosis,
pseudotumor cerebri, increased appetite |
Drug Category:
Immunosuppressants -- Control of inflammatory
signs and symptoms
Drug Name
|
Cyclophosphamide (Cytoxan) --
Used as first line therapy for severe systemic
vasculitides such as Wegener's granulomatosis
and for steroid-refractory disease. Chemically
related to nitrogen mustards. As an alkylating
agent, the mechanism of action of the active
metabolites may involve cross-linking of DNA,
which may interfere with growth of normal and
neoplastic cells. |
| Adult Dose |
Daily oral dosing: 1-2 mg/kg PO
qd
Intravenous pulse dosing: 0.5-1 g/m2
IV monthly
|
| Pediatric
Dose |
Daily oral dosing: 1-2 mg/kg PO
qd
Intravenous pulse dosing: 0.5-1 g/m2
IV monthly. Has also been used at the lower
dosage every 2 - 3 weeks.
|
|
Contraindications |
Documented hypersensitivity;
severely depressed bone marrow function
|
|
Interactions |
Allopurinol, may increase risk
of bleeding or infection and enhance
myelosuppressive effects; may potentiate
doxorubicin-induced cardiotoxicity; may reduce
digoxin serum levels and antimicrobial effects
of quinolones
Chloramphenicol may increase half-life while
decreasing metabolite concentrations; may
increase effect of anticoagulants;
coadministration with high doses of
phenobarbital may increase rate of metabolism
and leukopenic activity; thiazide diuretics
may prolong cyclophosphamide-induced
leukopenia and neuromuscular blockade by
inhibiting cholinesterase activity.
Watch for additive effects with other drugs
inducing leukopenia.
|
| Pregnancy |
X - Contraindicated in
pregnancy |
|
Precautions |
Hemorrhagic cystitis, syndrome
of inappropriate antidiuretic hormone
secretion, and hypertension
Ovarian failure increases
with age (>50% in patients >35 years of age)
as does male sterility
Neutropenia; nadir may occur
between 7-14 days post intravenous dose |
Drug Name
|
Azathioprine (Imuran) --
Antagonizes purine metabolism and inhibits
synthesis of DNA, RNA, and proteins. May
decrease proliferation of immune cells, which
results in lower autoimmune activity.
|
| Adult Dose |
1 mg/kg/d PO for 6-8 wk;
increase by 0.5 mg/kg q4wk until response or
dose reaches 2.5 mg/kg/d; not to exceed
100-150 mg/d PO |
| Pediatric
Dose |
Initial dose: 2-5 mg/kg/d PO/IV
Maintenance dose: 1-2 mg/kg/d PO/IV
Not to exceed 100-150 mg/d PO
|
|
Contraindications |
Documented hypersensitivity;
low levels of serum thiopurine methyl
transferase (TPMT) |
|
Interactions |
Interactions Toxicity increases
with allopurinol; concurrent use with ACE
inhibitors may induce severe leukopenia; may
increase levels of methotrexate metabolites
and decrease effects of anticoagulants,
neuromuscular blockers, and cyclosporine
|
| Pregnancy |
D - Unsafe in pregnancy
|
|
Precautions |
Leukopenia
Increases risk of neoplasia; caution with
liver disease and renal impairment;
hematologic toxicities may occur; check TPMT
level prior to therapy and follow liver,
renal, and hemotologic function; pancreatitis
rarely associated |
Drug Category:
Anticoagulants -- Acute and chronic treatment
of vascular thrombosis
Drug Name
|
Heparin -- Augments activity of
antithrombin III and prevents conversion of
fibrinogen to fibrin. Does not actively lyse
but is able to inhibit further thrombogenesis.
Prevents re-accumulation of clot after
spontaneous fibrinolysis.
Provide as continuous heparin infusion to
maintain aPTT at 1.5 x control.
|
| Adult Dose |
Initial dose: 40-170 U/kg IV
Maintenance infusion: 18 U/kg/h IV
Alternatively, 50 U/kg/h IV initially,
followed by continuous infusion of 15-25
U/kg/h and increase dose by 5 U/kg/h q4h prn
using PTT results
|
| Pediatric
Dose |
Initial dose: 50-100 U/kg IV
Maintenance infusion: 15-25 U/kg/h IV
Increase dose by 2-4 U/kg/h q6-8h prn using
PTT results
|
|
Contraindications |
Documented hypersensitivity;
subacute bacterial endocarditis, active
bleeding, history of heparin-induced
thrombocytopenia, severe thrombocytopenia,
intracranial hemorrhage |
|
Interactions |
Digoxin, nicotine,
tetracycline, and antihistamines may decrease
effects; NSAIDs, ASA, dextran, dipyridamole,
and hydroxychloroquine may increase heparin
toxicity |
| Pregnancy |
C - Safety for use during
pregnancy has not been established.
|
|
Precautions |
Heparin-induced
thrombocytopenia may occur within hours of
starting/restarting heparin therapy
In neonates, preservative-free heparin is
recommended to avoid possible toxicity
(gasping syndrome) by benzyl alcohol, which is
used as preservative; caution in severe
hypotension and shock; monitor for bleeding in
peptic ulcer disease, menstruation, increased
capillary permeability, and when giving IM
injections |
Drug Name
|
Enoxaparin (Lovenox) -- Low
molecular weight heparin. Augments activity of
antithrombin III and prevents conversion of
fibrinogen to fibrin. Does not actively lyse
but is able to inhibit further thrombogenesis.
Prevents re-accumulation of clot after
spontaneous fibrinolysis.
Advantages include intermittent dosing and
decreased requirement for monitoring. Heparin
anti-factor Xa levels may be obtained if
needed to establish adequate dosing.
|
| Adult Dose |
1 mg/kg SC BID |
| Pediatric
Dose |
0.5-1 mg/kg SC bid |
|
Contraindications |
Documented hypersensitivity;
subacute bacterial endocarditis, active
bleeding, history of heparin-induced
thrombocytopenia, severe thrombocytopenia,
intracranial hemorrhage |
|
Interactions |
Platelet inhibitors or oral
anticoagulants such as dipyridamole,
salicylates, aspirin, NSAIDs, sulfinpyrazone,
and ticlopidine may increase risk of bleeding
|
| Pregnancy |
C - Safety for use during
pregnancy has not been established.
|
|
Precautions |
Possible accelerated
osteoporosis with long-term use; risk of
heparin induced thrombocytopenia |
Drug Name
|
Warfarin (Coumadin, Coumarin)
-- Interferes with hepatic synthesis of
vitamin K-dependent coagulation factors.
|
| Adult Dose |
5-10 mg PO qd; titrate after
2-5 days to maintain INR following a
thrombotic episode @ 2.5-3.5 Usual maintenance
dose is from 2-10 mg/day |
| Pediatric
Dose |
0.05-0.34 mg/kg/day
|
|
Contraindications |
Documented hypersensitivity to
warfarin, severe liver or renal disease,
active bleeding, peptic ulcer disease,
malignant hypertension, pregnancy.
|
|
Interactions |
Drugs that may decrease
anticoagulant effects include griseofulvin,
carbamazepine, glutethimide, estrogens,
nafcillin, phenytoin, rifampin, barbiturates,
cholestyramine, colestipol, vitamin K,
spironolactone, oral contraceptives, and
sucralfate
Medications that may increase anticoagulant
effects of warfarin include oral antibiotics,
phenylbutazone, salicylates, sulfonamides,
chloral hydrate, clofibrate, diazoxide,
anabolic steroids, ketoconazole, ethacrynic
acid, miconazole, nalidixic acid,
sulfonylureas, allopurinol, chloramphenicol,
cimetidine, disulfiram, metronidazole,
phenylbutazone, phenytoin, propoxyphene,
sulfonamides, gemfibrozil, acetaminophen and
sulindac
|
| Pregnancy |
D - Unsafe in pregnancy
|
|
Precautions |
Response to oral anticoagulants
may be markedly decreased in biliary
obstruction due to reduced vitamin K
absorption, and decreased in hepatitis and
cirrhosis due to decreased production of
vitamin K dependent clotting factors
Do not switch brands once
desired therapeutic range achieved
Discontinue use at least 3
days prior to invasive surgical procedure and
check PT/INR |
Drug Category: Blood
products -- Intravenous gamma globulin is
used as first-line therapy for Kawasaki disease;
decreases risk of coronary artery aneurysms
Drug Name
|
Intravenous gamma globulin (Sandoglobulin,
Gamimune, Gammar-P) -- Multiple mechanisms:
May absorb superantigens or toxins in Kawasaki
disease. May saturate available Fc receptors.
May block cytokines and/or cytokine receptors.
May absorb complement activation products. May
down-regulate immunoglobulin synthesis. Blocks
Fc receptors on macrophages; suppresses
inducer T and B cells and augments suppressor
T cells; blocks complement cascade; may
increase CSF IgG (10%). |
| Adult Dose |
2 gm/kg IV over 2-5 d
|
| Pediatric
Dose |
For Kawasaki disease: 2 gm/kg
infusion over 6-10 h |
|
Contraindications |
Documented hypersensitivity;
IgA deficiency; IgE/IgG anti-IgA antibodies
|
|
Interactions |
Increases toxicity of live
virus vaccine (MMR); do not administer within
3 months of vaccine |
| Pregnancy |
C - Safety for use during
pregnancy has not been established.
|
|
Precautions |
Premedication with
acetaminophen and diphenhydramine to be
considered; possible reduction of side effects
of flushing, fever, hypotension, and aseptic
meningitis |
Drug Category: Antibiotics
-- Role for prophylaxis of relapse in Wegener's
granulomatosis (although an infectious etiology
has not been identified).
Drug Name
|
Trimethoprim-sulfamethoxazole (Bactrim,
Septra) -- As Pneumocystis carinii
prophylaxis. This drug may delay flare in
patients with Wegener's granulomatosis.
Dihydrofolate reductase
inhibitor in combination with sulfonamide. |
| Adult Dose |
1 DS tablet (160 mg TMP/800 mg
SMZ) PO 3 times weekly |
| Pediatric
Dose |
>2 months: 10 mg/kg/d, based on
TMP, PO 3 times weekly; not to exceed 320 mg
trimethoprim |
|
Contraindications |
Documented hypersensitivity,
megaloblastic anemia due to folate deficiency,
porphyria |
|
Interactions |
May increase PT when used with
warfarin (perform coagulation tests and adjust
dose accordingly); coadministration with
dapsone may increase blood levels of both
drugs; coadministration of diuretics increases
incidence of thrombocytopenia purpura in
elderly; phenytoin levels may increase with
coadministration; may potentiate effects of
methotrexate in bone marrow depression;
hypoglycemic response to sulfonylureas may
increase with coadministration; may increase
levels of zidovudine |
| Pregnancy |
C - Safety for use during
pregnancy has not been established.
|
|
Precautions |
Use with caution in patients
with G6-PD deficiency, impaired renal or
hepatic function
May cause Stevens-Johnson
syndrome, toxic epidermal necrolysis,
agranulocytosis and aplastic anemia |
Drug Category:
Antiinflammatory -- Used to decrease
inflammation of blood vessels and to maintain
adequate perfusion of skin and vital organs.
Drug Name
|
Methotrexate (Rheumatrex, Folex)
-- Antimetabolite that inhibits dihydrofolate
reductase, thereby hindering DNA synthesis and
cell reproduction. Effects may also be
mediated by adenosine via the inhibition of
aminoimidazole carboxamide ribonucleotide (AICAR)
transformylase, leading to increased release
of adenosine.
Adjust dose gradually to
attain satisfactory response. |
| Adult Dose |
0.3 mg/kg/wk PO/IM; not to
exceed 20 mg |
| Pediatric
Dose |
0.3 mg/kg PO/SQ weekly, titrate
upwards to 1 mg/kg/weekly, maximum dose 30 mg;
although higher doses (50 mg) have been used
over shorter treatment periods
Alternatively, standard
range 10-20 mg/m2 |
|
Contraindications |
Documented hypersensitivity;
alcoholism; hepatic insufficiency; documented
immunodeficiency syndromes; preexisting blood
dyscrasias (eg, bone marrow hypoplasia,
leukopenia, thrombocytopenia, significant
anemia); renal insufficiency |
|
Interactions |
Oral aminoglycosides may
decrease absorption and blood levels of
concurrent oral methotrexate (MTX); charcoal
lowers MTX levels; coadministration with
etretinate may increase hepatotoxicity of MTX;
folic acid or its derivatives contained in
some vitamins may decrease response to MTX
Indomethacin and phenylbutazone can increase
MTX plasma levels; may decrease phenytoin
serum levels
Probenecid, salicylates, procarbazine, and
sulfonamides, including TMP-SMZ, may increase
effects and toxicity of MTX; may increase
plasma levels of thiopurines
|
| Pregnancy |
D - Unsafe in pregnancy
|
| Precautions |
Monitor CBCs monthly, and liver
and renal function q1-3mo during therapy
(monitor more frequently during initial
dosing, dose adjustments, or when risk of
elevated MTX levels, eg, dehydration); MTX has
toxic effects on hematologic, renal, GI,
pulmonary, and neurologic systems
Discontinue if significant drop in blood
counts; aspirin, NSAIDs, or low dose steroids
may be administered concomitantly with MTX
(possibility of increased toxicity with NSAIDs
including salicylates has not been tested) |
Further Outpatient Care:
- A pediatric rheumatologist
should provide follow-up care for patients with
vasculitis to monitor for appearance of new
manifestations that may indicate a different
diagnosis.
- Patients with
Henoch-Schönlein purpura should have urinalysis
performed monthly for 6-12 months as a screen
for late-onset nephritis.
- CBC and erythrocyte
sedimentation rate (ESR) at a minimum may be
used as markers of disease activity. For
patients with elevated c-ANCA, titers may
normalize during periods of disease control and
increase with disease activity. Serial ANCA has
been used to measure disease activity, with
limited success.
In/Out Patient Meds:
- Nonsteroidal antiinflammatory
for myalgias
- Corticosteroid in tapering
doses as tolerated, once adequate control of
disease achieved
- Maintenance daily oral or
monthly intravenous Cytoxan for renal or CNS
vasculitis
- Antihypertensive therapy as
needed
- Oral anticoagulant therapy as
maintenance with documented thrombus and
evidence for underlying hypercoagulable state
Transfer:
- Transfer patients to a
tertiary care center for undiagnosed systemic
vasculitis with life-threatening complications.
- Transfer patients with a
clinical picture consistent with pulmonary,
renal, or central nervous system involvement.
Deterrence/Prevention:
- Prevention of complications
of vasculitis is achieved by early diagnosis and
aggressive treatment, where indicated, of both
systemic/idiopathic and secondary vasculitis. A
high index of suspicion is essential for the
diagnosis of this group of diseases.
- Immunization against
hepatitis B is the current standard of care in
the US and may decrease the prevalence of
hepatitis B-associated vasculitis over time.
- Minimize catheter
instrumentation.
- Treat hypercoagulable
patients with a history of arterial or venous
thrombosis with lifelong anticoagulation.
Complications:
- Central nervous system
infarction
- Arterial or venous thrombosis
Prognosis:
- Directly related to the
degree of end-organ involvement.
Patient Education:
- Advise patients requiring
corticosteroids of Cushingoid symptoms,
including, but not limited to, hypertension,
glucose intolerance, weight gain, hirsutism,
mood swings, osteonecrosis, and growth
disturbance.
- Advise patients requiring
immunosuppression of increased risk of
infections, myelosuppression, teratogenic, and
oncogenic potential, as well as any hepatic,
pulmonary, cardiac, or renal toxicities.
- Discuss use of adequate low
estrogen birth control with patients of
childbearing age if warfarin is used; enoxaparin
may be considered, but increased risk of
osteoporosis is associated with long-term use.
- Patients taking
anticoagulants should not participate in contact
sports.
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