2. Vasculitis
• DEFINITION AND PATHOGENESIS
• A clinicopathologic process characterized by inflammation
of and damage to blood vessels, compromise of vessel
lumen, and resulting ischemia.
• Clinical manifestations depend on size and location of
affected vessel.
• Most vasculitic syndromes appear to be mediated by
immunemechanisms.
• May be primary or sole manifestation of a disease or
secondary to another disease process.
• Unique vasculitic syndromes can differ greatly with regards
to clinical features, disease severity, histology, and
treatment.
3. PRIMARY VASCULITIS SYNDROMES
• Churg-Strauss Syndrome
• Granulomatous vasculitis of multiple organ
systems, particularly the lung; characterized by
asthma, peripheral eosinophilia, eosinophilic
tissue infiltration; glomerulonephritis can occur.
• Polyarteritis Nodosa (PAN)
• Medium-sized muscular arteries involved;
frequently associated with arteriographic
aneurysms; commonly affects renal arteries, liver,
GI tract, peripheral nerves, skin, heart; can be
associated with hepatitis B.
4. PRIMARY VASCULITIS SYNDROMES
• Microscopic Polyangiitis
• Small-vessel vasculitis that can affect the glomerulus
and lungs; mediumsized vessels also may be affected.
• Giant Cell Arteritis
• Inflammation of medium- and large-sized arteries;
primarily involves temporal artery but systemic and
large vessel involvement may occur; symptoms include
headache, jaw/tongue claudication, scalp tenderness,
fever, musculoskeletal symptoms (polymyalgia
rheumatica); sudden blindness from involvement of
optic vessels is a dreaded complication.
5. PRIMARY VASCULITIS SYNDROMES
• Takayasu’s Arteritis
• Vasculitis of the large arteries with strong
predilection for aortic arch and its branches; most
common in young women; presents with
inflammatory or ischemic symptoms in arms and
neck, systemic inflammatory symptoms, aortic
regurgitation.
• Henoch-Schönlein Purpura
• Characterized by involvement of skin, GI tract,
kidneys; more common in children; may recur
after initial remission.
6. PRIMARY VASCULITIS SYNDROMES
• Cryoglobulinemic Vasculitis
• Majority of cases are associated with hepatitis C where
an aberrant immune response leads to formation of
cryoglobulin; characterized by cutaneous vasculitis,
arthritis, peripheral neuropathy, and
glomerulonephritis.
• Idiopathic Cutaneous Vasculitis
• Cutaneous vasculitis is defined broadly as inflammation
of the blood vessels of the dermis; due to underlying
disease in >70% of cases (see “Secondary Vasculitis
Syndromes,” below) with 30% occurring idiopathically.
7. PRIMARY VASCULITIS SYNDROMES
• Miscellaneous Vasculitic Syndromes
• Kawasaki disease (mucocutaneous lymph
node syndrome)
• Isolated vasculitis of the central nervous
system
• Behçet’s syndrome
• Cogan’s syndrome
• Polyangiitis overlap syndrome
9. Vasculitis
• EVALUATION
• Thorough Hx and physical exam—special
reference to ischemic manifestations and
systemic inflammatory signs/symptoms.
• Laboratories—important in assessing organ
involvement: CBC with differential, ESR, renal
function tests, UA.
• Should also be obtained to rule out other
diseases: ANA, rheumatoid factor, anti-GBM,
hepatitis B/C serologies, HIV.
10. Vasculitis
• EVALUATION
• Antineutrophil cytoplasmic autoantibodies (ANCA)—associated
with granulomatosis with polyangiitis (Wegener’s), microscopic
polyangiitis, and some pts with Churg-Strauss syndrome; presence
of ANCA is adjunctive and should not be used in place of biopsy as a
means of diagnosis or to guide treatment decisions.
• Radiographs—CXR should be performed even in the absence of
symptoms.
• Diagnosis—can usually be made only by arteriogram or biopsy of
affected organ(s).
• DIFFERENTIAL DIAGNOSIS
• Guided by organ manifestations. In many instances includes
infections and neoplasms, which must be ruled out prior to
beginning immunosuppressive therapy. Consideration must also be
given for diseases that can mimic vasculitis
14. Vasculitis
• TREATMENT
• Therapy is based on the specific vasculitic
syndrome and the severity of its manifestations.
• Immunosuppressive therapy should be avoided in
disease that rarely results in irreversible organ
system dysfunction or that usually does not
respond to such agents (e.g., isolated cutaneous
vasculitis).
• Antiviral agents play an important role in treating
vasculitis occurring with hepatitis B or C.
15. Vasculitis
• TREATMENT
• Glucocorticoids alone may control giant cell
arteritis and Takayasu’s arteritis.
• Therapy that combines glucocorticoids with
another immunosuppressive agent is
particularly important in syndromes with life-
threatening organ system involvement,
especially active glomerulonephritis.
16. Vasculitis
• TREATMENT
• Frequently used agents:
• Prednisone
• Cyclophosphamide
• Rituximab
• Methotrexate
• Azathioprine
• Mycophenolate mofetil
• Plasmapheresis may have an adjunctive role in
rapidly progressive glomerulonephritis.
17. Granulomatosis with Polyangiitis (GPA)
(Wegener's Granulomatosis)
• Granulomatosis with polyangiitis is characterized by necrotizing
granulomatous inflammation, small- and medium-sized vessel
vasculitis, and focal necrotizing glomerulonephritis, often with
crescent formation.
• Typically, the upper and lower respiratory tract and the kidneys are
affected, but any organ may be.
• Symptoms vary depending on the organs and systems affected.
Patients may present with upper and lower respiratory tract
symptoms (eg, recurrent nasal discharge or epistaxis, cough),
followed by hypertension and edema, or with symptoms reflecting
multiorgan involvement.
• Diagnosis usually requires biopsy.
• Treatment is with corticosteroids plus an immunosuppressant.
Remission is usually possible, although relapses are common.
18. Granulomatosis with Polyangiitis (GPA)
(Wegener's Granulomatosis)
• Granulomatosis with polyangiitis (GPA) occurs
in about 1/25,000 people; it is most common
among whites but can occur in all ethnic
groups and at any age. Mean age at onset is
40.
• The cause of GPA is unknown, although
immunologic mechanisms play a role. Most
patients with active generalized disease have
antineutrophil cytoplasmic antibodies (ANCA).
19. Pathophysiology
• Characteristically, granulomas form with histiocytic
epithelioid cells and often with giant cells. Plasma cells,
lymphocytes, neutrophils, and eosinophils are present.
• Inflammation affects tissues as well as vessels; vasculitis
may be a small or large component of the disease.
• Micronecrosis, usually with neutrophils (microabscesses),
occurs early. Micronecrosis progresses to macronecrosis.
• A central area of necrosis (called geographic necrosis) is
rimmed by lymphocytes, plasma cells, macrophages, and
giant cells. A zone of fibroblastic proliferation with
palisading histiocytes may surround the area.
20. Pathophysiology
• Nonspecific chronic inflammation and tissue necrosis
occur in the nose.
• The lungs are most likely to display the full spectrum of
histopathologic abnormalities, but diagnostic features
are not typically identified on the small tissue samples
obtained by transbronchial biopsy.
• In the kidneys, the most common finding is a pauci-
immune crescentic focal glomerulonephritis with
necrosis and thrombosis of individual loops or larger
segments of the glomerulus. Vasculitic lesions and
disseminated granulomas occur only occasionally.
21. Histologic pattern
• May not correlate with the
clinical presentation
• Various histological types of
glomerulonephritis
23. Symptoms and Signs
• Onset of granulomatosis with polyangiitis may be insidious or
acute; the full spectrum of the disease may take years to evolve.
• Some patients present initially with upper and lower respiratory
tract symptoms; at some point later, the kidneys are affected.
• In other patients, onset of systemic manifestations is relatively
acute; several organs and systems, such as the upper respiratory
tract, peripheral nervous system (causing multiple
mononeuropathy [mononeuritis multiplex]), kidneys (causing
glomerulonephritis), and lower respiratory tract (causing
hemorrhage,
• lung nodules, cavities, or a combination), are simultaneously
affected.
24. Symptoms and Signs
• Upper respiratory tract:
• Sinus pain, serosanguineous or purulent discharge, and
epistaxis may occur.
• The mucosa appears granular (like cobblestones) and is
friable; ulcers, thick dark crusts, and septal perforation are
common.
• Nasal chondritis can occur with swelling, pain, and collapse of
the nasal bridge (saddle nose).
• Patients may report recurrent sinusitis that has responded
inadequately to multiple antibiotic regimens and has required
one or more sinus operations before diagnosis.
• Secondary infections (eg, due to Staphylococcus aureus) may
develop. Subglottic stenosis may develop, causing symptoms
such as pain in the larynx, hoarseness, dyspnea, wheezing,
and stridor.
25.
26. Symptoms and Signs
• Ears:
• Otitis, sensorineural hearing loss, vertigo, and chondritis
may occur. The middle ear, inner ear, and mastoids are
often affected.
• Eyes:
• Eyes may appear red and swollen. Nasolacrimal duct
inflammation and obstruction, conjunctivitis, scleritis,
uveitis, or retinal vasculitis may also occur. Inflammatory
infiltrates in the retro-orbital space (orbital pseudotumor)
can cause proptosis, compression of the optic nerve, and
blindness. Extension into the extraocular muscles leads to
diplopia. If serious eye symptoms develop, evaluation and
treatment are required immediately to prevent permanent
vision loss.
27.
28. Symptoms and Signs
• Lower respiratory tract:
• Respiratory manifestations are common. Inflammation of
the major bronchi and branches can cause localized
wheezing, postobstructive pneumonia, and atelectasis.
Single or multiple pulmonary nodules, with or without
cavitation, and parenchymal infiltrates, sometimes cause
symptoms, such as chest pain, shortness of breath, and
productive cough. Dyspnea with bilateral infiltrates, with
or without hemoptysis, may indicate alveolar hemorrhage
and must be evaluated immediately.
• Heart: Coronary artery disease may occur but rarely.
• Musculoskeletal system: Patients frequently present with
myalgias, arthralgias, or nonerosive inflammatory arthritis.
29.
30.
31.
32. Symptoms and Signs
• Skin: Palpable purpura, tender subcutaneous nodules, papules,
livedo reticularis, or ulcers may develop.
• Nervous system: Vasculitis may cause ischemic peripheral
neuropathy, brain lesions, or extension of lesions from contiguous
sites. Lesions that originate in the sinuses or middle ear may extend
directly to the retropharyngeal area and base of the skull, leading to
cranial neuropathy, proptosis, diabetes insipidus, or meningitis.
• Kidneys: Symptoms and signs of glomerulonephritis develop.
Urinary sediment is frequently abnormal, and serum creatinine may
increase rapidly. Edema and hypertension may result. Rapidly
progressive glomerulonephritis, which is life threatening, can
develop.
• Venous system: Deep venous thrombosis can affect the lower
extremities mostly when granulomatosis with polyangiitis is active.
• Other organs: Occasionally, an inflammatory mass occurs in the
breasts, kidneys, prostate, or other organs.
35. Diagnosis
• Routine laboratory tests, including urinalysis
• Tests for antineutrophil cytoplasmic antibodies
• Biopsy for definitive diagnosis
• Granulomatosis with polyangiitis should be
suspected in patients with chronic, unexplained
respiratory symptoms and signs (including otitis
media in adults), particularly if manifestations in
other organ systems, especially the kidneys, also
suggest the disorder. Routine laboratory tests are
done, but ANCA testing and biopsy yield the
most specific findings.
36. Diagnosis
• Routine laboratory tests include:
• ESR,
• C-reactive protein,
• CBC with differential,
• Serum albumin and total protein,
• Serum creatinine,
• Urinalysis,
• 24-hour urine protein,
• Chest x-ray.
• Chest CT without contrast is nearly always necessary because the chest x-
ray may miss nodules, masses, and/or cavitary lesions caused by
granulomatosis with polyangiitis.
• In most patients with active disease, ESR and C-reactive protein are
elevated, and serum albumin and total protein are decreased; anemia,
thrombocytosis, and mild-to-moderate eosinophilia are detected.
• Dysmorphic RBCs and RBC casts, detected during urinalysis, indicate
glomerular involvement. Proteinuria may be detected. Serum creatinine
may be increased.
37. Diagnosis
• Serologic testing to detect antineutrophil
cytoplasmic antibodies (ANCA) is followed by
enzyme-linked immunosorbent assay (ELISA)
to check for specific antibodies.
• Most patients with active disease have
cytoplasmic ANCA (c-ANCA), with antibodies
against proteinase-3 (PR3); these findings plus
characteristic clinical findings suggest GPA.
38. Diagnosis
• Some patients with other disorders (eg, bacterial
endocarditis, cocaine abuse, systemic lupus erythematosus,
amebiasis, tuberculosis) test positive for ANCA.
• Because tests for rare diseases are likely to be falsely
positive when ordered for the general population and the
positive predictive value of a positive ANCA test is around
50%,
• ANCA testing should be reserved for patients in whom the
pretest probability for GPA or another ANCA-associated
vasculitis is at least moderately high (eg, patients with
alveolar hemorrhage, glomerulonephritis, or multiple
mononeuropathy plus other features of microscopic
polyangiitis or GPA).
39. Diagnosis
• A positive ANCA test does not rule out mycobacterial and
fungal infections; thus, patients with positive ANCA results
and cavitary lung lesions still require bronchoscopy and
adequate cultures and other tests for tuberculosis and
fungal infections.
• ANCA testing (titre) should not be used to guide
subsequent treatment.
• During apparent remission, ANCA may increase or ANCA
test results may change from negative to positive.
• In some of these patients, symptoms do not recur; in
others, symptoms recur or worsen soon after the test is
done or during the next few weeks, months, or sometimes
years.
40. Diagnosis
• Biopsy should be done if possible to confirm the diagnosis of GPA.
• Clinically abnormal sites may be biopsied first.
• Biopsy of affected lung tissue is most likely to reveal characteristic
findings; open thoracotomy provides the best access.
• Biopsies of lung or sinus tissue are cultured to exclude infection.
• Renal biopsy that shows pauci-immune necrotizing focal crescentic
or noncrescentic glomerulonephritis strongly supports the
diagnosis.
• Biopsy results of various tissues may also provide histologic
information that can help guide treatment (eg, renal fibrosis).
• Differential diagnosis includes other vasculitic disorders that affect
small- and medium-sized vessels.
• Infections, especially those due to slow-growing fungi or acid-fast
organisms, should be ruled out by staining and culture of the
sampled tissues.
•
41. Treatment
• To induce remission in life- or organ-threatening GPA, high-
dose corticosteroids plus
either cyclophosphamide or rituximab
• To induce remission in less severe GPA, corticosteroids and
either methotrexate or rituximab
• To maintain remission, rituximab alone or another drug
such as methotrexate, azathioprine,
or mycophenolate mofetil (rituximab plus another of these
drugs, sometimes with a low dose of a corticosteroid, if
patients have multiple relapses or GPA is difficult to control)
• Kidney transplantation if necessary.
• Treatment of granulomatosis with polyangiitis depends on
the severity of disease. A multidisciplinary approach is
required for multiorgan disease, often including a
rheumatologist, otorhinolaryngologist, pulmonologist, and
nephrologist.
42. Treatment
• Patients who have severe life-threatening or organ-
threatening manifestations (eg, alveolar hemorrhage,
rapidly progressive glomerulonephritis, multiple
mononeuropathy with motor involvement) require
immediate hospital admission for treatment to induce
remission. These patients require high-dose corticosteroids
and cyclophosphamide or rituximab.
• Efficacies of rituximab and cyclophosphamide appear to be
similar for inducing and maintaining remission.
• Although the evidence supporting use of plasma exchange
is weaker than that for the other interventions, plasma
exchange can be added to the standard treatment regimen
in patients with severe acute renal insufficiency
(particularly if the anti–glomerular basement membrane
antibody test is not known to be negative, so that rapidly
progressive glomerulonephritis has not been excluded) or
alveolar hemorrhage.
43. Treatment
• Rituximab seems to be particularly helpful in patients with
recurrent disease. In one study that included patients with
GPA and other ANCA-associated vasculitides, major
relapses occurred in only 5% of patients treated
with rituximab but occurred in 29% of patients treated
with azathioprine.
• Whether rituximab should be given alone or in combination
with another drug and the dose and frequency
of rituximab are not entirely clear. However, in one
retrospective study, relapse rates were lower
when rituximab was combined
with methotrexate, azathioprine,
or mycophenolate mofetil than when rituximab was used
alone.
• The optimal dosage of rituximab for maintenance therapy
has not been established. A corticosteroid, given at a low
dose, is often used to help maintain remission.
44. Treatment
• For less severe disease, corticosteroids
and methotrexate are used to induce remission.
• Rituximab may be used instead of methotrexate.
• For upper respiratory tract
manifestations, rituximab appears to maintain
remission better
than cyclophosphamide, methotrexate,
or azathioprine.
• Corticosteroids are tapered to as low a dose as
possible or discontinued.
• Irrigation of sinuses with saline, with or
without mupirocin 2% nasal ointment, helps minimize
crusting and secondary staphylococcal infections.
45. Treatment
• Treatment of subglottic stenosis is difficult. Systemic
immunosuppressants may not be effective.
Intralesional injection of long-acting corticosteroids,
with gentle progressive dilation, markedly improves
outcome and limits the need for tracheostomy.
• Patients should be taught about the disorder so that
relapses can be detected early. Patients should learn
how to test their urine for blood and protein and be
instructed to notify their physician of any sign of
hematuria.
• Kidney transplantation has been successful; the risk of
relapse after transplantation is reduced compared with
maintenance dialysis treatment (possibly due in part to
use of immunosuppressants to prevent rejection).
46. Goodpasture's Syndrome;
Anti-GBM Antibody Disease
• Goodpasture syndrome, a subtype of pulmonary-renal syndrome,
is an autoimmune syndrome of alveolar
hemorrhage and glomerulonephritis caused by circulating anti-
glomerular basement membrane (anti-GBM) antibodies.
• Goodpasture syndrome most often develops in genetically
susceptible people who smoke cigarettes, but hydrocarbon
exposure and viral respiratory infections are additional possible
triggers.
• Symptoms are dyspnea, cough, fatigue, hemoptysis, and hematuria.
• Goodpasture syndrome is suspected in patients with hemoptysis or
hematuria and is confirmed by the presence of anti-GBM antibodies
in the blood or in a renal biopsy specimen.
• Prognosis is good when treatment is begun before onset of
respiratory or renal failure. Treatment includes plasma exchange,
corticosteroids, and immunosuppressants, such
as cyclophosphamide.
47. Pathophysiology
• Goodpasture syndrome is the combination of
glomerulonephritis with alveolar hemorrhage
and anti-GBM antibodies. Goodpasture syndrome
most often manifests as diffuse alveolar
hemorrhage and glomerulonephritis together
but can occasionally cause glomerulonephritis
(10 to 20%) or pulmonary disease (10%) alone.
• Men are affected more often than women.
• Anti-GBM antibodies are directed against the
noncollagenous (NC-1) domain of the alpha3
chain of type IV collagen, which occurs in highest
concentration in the basement membranes of
renal and pulmonary capillaries.
48.
49.
50.
51. Pathophysiology
• Environmental exposures—cigarette smoking,
viral URI, and hydrocarbon solvent inhalation
most commonly and pneumonia less
commonly—expose alveolar capillary antigens
to circulating antibody in genetically
susceptible people, most notably those with
HLA-DRw15, -DR4, and -DRB1 alleles.
• Circulating anti-GBM antibodies bind to
basement membranes, fix complement, and
trigger a cell-mediated inflammatory
response, causing glomerulonephritis,
pulmonary capillaritis, or both.
52. Symptoms and Signs
• Hemoptysis is the most prominent symptom; however,
hemoptysis may not occur in patients with alveolar
hemorrhage, and patients may present with only chest
x-ray infiltrates or with infiltrates and respiratory
distress, respiratory failure, or both.
• Other common symptoms include:
• Dyspnea
• Cough
• Fatigue
• Fever
• Weight loss
• Hematuria
53. Symptoms and Signs
• Up to 40% of patients have gross hematuria,
although pulmonary hemorrhage may
precede renal manifestations by weeks to
years.
• Signs vary over time and range from clear
lungs on auscultation to crackles and rhonchi.
• Some patients have peripheral edema due to
renal failure and pallor due to anemia.
54. Diagnosis
• Serum anti-GBM antibody tests
• Sometimes renal biopsy
• Patients are tested for serum anti-GBM
antibodies by indirect immunofluorescence
testing or, when available, direct enzyme-linked
immunosorbent assay (ELISA) with recombinant
or human NC-1 alpha3.
• Presence of these antibodies confirms the
diagnosis.
• Antineutrophil cytoplasmic antibodies (ANCA)
testing is positive (in a peripheral pattern) in only
25% of patients with Goodpasture syndrome.
55. Diagnosis
• If anti-GBM antibodies are absent and patients have
evidence of glomerulonephritis (hematuria, proteinuria,
red cell casts detected with urinalysis, renal insufficiency, or
a combination of these findings), renal biopsy is indicated
to confirm the diagnosis.
• A rapidly progressive focal segmental necrotizing
glomerulonephritis with crescent formation is found in
biopsy specimens in patients with Goodpasture syndrome
and all other causes of pulmonary-renal syndrome.
• Immunofluorescence staining of renal or lung tissue
classically shows linear IgG deposition along the glomerular
or alveolar capillaries. IgG deposition also occurs in the
kidneys of patients with diabetes or with fibrillary
glomerulonephritis (a rare disorder causing the pulmonary-
renal syndrome), but GBM binding of antibodies in these
disorders is nonspecific and does not occur in linear
patterns.
56. Treatment
• Plasma exchange
• Corticosteroids and cyclophosphamide
• Immediate survival in patients with pulmonary
hemorrhage and respiratory failure is linked to
airway control; endotracheal
intubation and mechanical ventilation are
recommended for patients with borderline
ABGs and impending respiratory failure.
• Patients with significant renal impairment may
require dialysis or kidney transplantation.
57. Treatment
• Treatment is daily or every-other-day plasma
exchange for 2 to 3 wk using 4-L exchanges to remove
anti-GBM antibodies, combined with a corticosteroid
(usually methylprednisolone 1 g IV over 20 min
once/day or every other day for 3 doses followed
by prednisone (1 mg/kg po once/day for 3 wk, then
titrated down to 20 mg po once/day for 6 to 12 mo)
and cyclophosphamide (2 mg/kg po or IV once/day for
6 to 12 mo) to prevent formation of new antibodies.
• Therapy can be tapered when pulmonary and renal
function stop improving.
• Rituximab could be used in some patients who have
severe adverse effects due to cyclophosphamide or
refuse cyclophosphamide as treatment, but it has not
been studied in patients with Goodpasture syndrome.
58. Idiopathic pulmonary hemosiderosis
• Idiopathic pulmonary hemosiderosis is a rare
disease that causes recurrent diffuse alveolar
hemorrhage with no detectable underlying
disorder; it occurs mainly in children < 10 years.
In patients with idiopathic pulmonary
hemosiderosis, repeated alveolar bleeding can
eventually result in pulmonary hemosiderosis and
fibrosis.
• The disease is thought to be due to a defect in
the alveolar capillary endothelium, possibly due
to autoimmune injury. Many affected patients
have celiac disease.
59. Idiopathic pulmonary hemosiderosis
• Symptoms and Signs
• Symptoms and signs of idiopathic pulmonary
hemosiderosis in children include recurrent
episodes of dyspnea and cough, particularly
nonproductive cough initially. Hemoptysis occurs
later.
• Children with idiopathic pulmonary
hemosiderosis may present with only failure to
thrive and iron deficiency anemia.
• The most common symptoms in adults are
exertional dyspnea and fatigue due to pulmonary
hemorrhage and iron deficiency anemia.
60. Idiopathic pulmonary hemosiderosis
• Diagnosis
• Bronchoalveolar lavage
• Diagnosis of idiopathic pulmonary hemosiderosis
involves demonstration of a combination of
characteristic clinical findings, iron deficiency
anemia, and hemosiderin-laden macrophages in
bronchoalveolar lavage (BAL) fluid or lung biopsy
specimens plus no evidence of small-vessel
vasculitis (pulmonary capillaritis) or another
explanatory diagnosis; it is confirmed by lung
biopsy if other findings are inconclusive.
61. Idiopathic pulmonary hemosiderosis
• Treatment
• Corticosteroids
• Corticosteroids may reduce the morbidity and
mortality of acute episodes of alveolar
bleeding and may control the disease
progression of pulmonary fibrosis.
• Some patients may require additional
immunosuppressive drugs.
• Patients with celiac disease should be on a
gluten-free diet.
