Transcript Document

Update on classification of
vasculitis and Wegener’s
granulomatosis
Dr.
Overview
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Classification of vasculitis
Wegener’s granulomatosis
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Epidemiology
Clinical features
Pathogenesis
Diagnosis
Treatment
Prognosis
Vasculitis classification– the first
step
Primary Systemic Vasculitis
classification
Classification of systemic vasculitis
Chapel Hill Consensus Conference on the
Nomenclature of Systemic Vasculitis
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Small vessel
vasculitis
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Wegener’s
granulomatosis
Churg-Strauss
syndrome
Microscopic
polyangiitis
Henoch-Schonlein
purpura
Essential
cryoglobulinemic
vasculitis
Cutaneous
leukocytoclastic
angiitis
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Medium-sized
vessel vasculitis
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Polyarteritis nodosa
Kawasaki disease
Large-vessel
vasculitis
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Giant cell (temporal)
arteritis
Takayasu arteritis
Classification of systemic vasculitis
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2 major groups based on clinical and
histopathological features of vasculitis
1. Large vessel vasculitis: aorta and
major branches
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Giant cell arteritis / temporal
arteritis
Takayasu arteritis
2. Medium-sized vasculitis: medium
arteries
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Polyarteritis nodosa (PAN)
Kawasaki disease
Classification of systemic vasculitis
2. medium-sized vasculitis:
arterioles, capillaries and venules
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Wegener’s granulomatosis (WG)
Churg-Strauss syndrome (CSS)
Microscopic polyangiitis (MPA)
3. small vessel vasculitis: venules,
capillaries
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Henoch Schonlein purpura (HSP)
Cryoglobulinaemic vasculitis
Pathogenesis of vasculitis
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Antibody mediated inflammation
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Wegener’s granulomatosis (WG)
Churg-Strass syndrome (CSS)
Microscopic polyangiitis (MPA)
Pathogenesis of vasculitis
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Immune complex-mediated inflammation
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Henoch SchÖlein purpura (HSP)
Cryoglobulinaemic vasculitis
Polyarteritis nodosa (PAN)
Cell-mediated inflammation
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Giant cell arteritis
Takayasu arteritis
Wegener’s granulomatosis (WG)
Churg-Strass syndrome (CSS)
Small vessel pauci-immune vasculitis
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Wegener’s granulomatosis:
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Churg-Strauss syndrome:
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Necrotizing granulomatous inflammation, most often
affecting respiratory tract
Occurs in association with asthma, eosinophilia,
and necrotizing granulomatous inflammation
Microscopic polyangiitis:
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Pauci-immune systemic vasculitis occurring in
the absence of asthma and eosinophilia with no
evidence of granulomatous inflammation
Wegener’s
Granulomatosis
Wegener’s Granulomatosis
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Vasculitis and
Granulomas in
Lung and Upper
Airway and also
Glomerulonephritis
History of Wegener’s
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In 1931
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In 1936
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Two patients died from prolonged
sepsis with inflammation of blood
vessels scattered throughout the body
Wegener first described a distinct
syndrome in three patients found to
have necrotizing granulomas involving
the upper and lower respiratory tract
In 1954
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Seven more patients described,
resulting in definate criteria
Wegener’s granulomatosis
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Epidemiology:
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Prevalence in US estimated at 3 per
100,000
Male : Female = 1 : 1
80-97% are Caucasian
Mean age at diagnosis: 41-56
Definitions
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Wegener’s granulomatosis is a systemic
vasculitis of the medium and small
arteries, as well as venules, arterioles and
occasionally large arteries
“Classic” Wegener’s primarily involves the
upper and lower respiratory tracts and
the kidneys
Definitions (Contd)
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“Limited” form have clinical findings
isolated to the respiratory tract- can occur
in ¼ of cases, although 80% may go on
to develop glomerulonephritis
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Specifically, pts with limited disease are
younger at disease onset, and more likely to
be women
The Controversy
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Wegener’s vs PR3-ANCA vasculitis
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Lancet, 22 April 2006
Suggestion that using Wegener’s name
“needs balanced discussion within the
scientific community”
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Reiter's syndrome- reactive arthritis
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The Problem with Changing
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Multiple ANCA+ diseases:
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microscopic polyangiitis (MPA)
"renal-limited" vasculitis (pauci-immune glomerulonephritis
without evidence of extrarenal disease)
Churg-Strauss syndrome (CSS)
Drug-induced vasculitis
Goodpasture’s
Rheumatic disorders
Autoimmune GI disorders
CF
Diagnostic Criteria primarily clinical
Criteria for Classification
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Nasal or oral inflammation
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Abnormal chest radiograph
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Chest radiograph showing the presence of nodules, fixed infiltrates,
or cavities
Abnormal Urinary sediment
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Development of painful or painless oral ulcers or purulent or bloody
nasal discharge
Microhematuria (>5 red blood cells per high power field) or red cell
casts in urine sediment
Granulomatous inflammation on biopsy
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Histologic changes showing granulomatous inflammation within the
wall of an artery or in the perivascular or extravascular area (artery
or arteriole)
* For purposes of classification, a patient shall be said to have Wegener's granulomatosis if at least 2 of these 4 criteria are
present. The presence of any 2 or more criteria yields a sensitivity of 88.2% and a specificity of 92.0%
Classic Symptoms
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Upper respiratory tract
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sinuses
Nose
ears
trachea
Lungs
Kidneys
Eye
 Scleritis
 Uveitis
 Orbital
pseudotumor
/proptosis
Upper Respiratory Tract
Ear
 Ear
infections that are slow to
resolve
 Recurrent otitis media
 Decrease in hearing
Upper Respiratory Tract
Nose
 Nasal
crusting
 Frequent
nosebleeds
 Erosion and
perforation of
the nasal
septum. The bridge
of the nose can collapse
resulting in a “saddle–nose
deformity”.
Upper Respiratory Tract
Sinuses/Trachea
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Sinuses
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Chronic sinus
inflammation
Trachea
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subglottic stenosis
Lungs
 Nodules (which
may cavitate)
 Alveolar
opacities
 Pleural
opacities
 Diffuse hazy
opacities (which
may reflect alveolar
hemorrhage)
Kidney
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Glomerulonephritis w/ associated
hematuria and proteinuria
Can lead to renal failure if not
treated aggressively
Renal masses (rare)
Active urine sediment: red blood
cell casts
RBC casts
Skin
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“palpable purpura”
most common
Raynaud’s
phenomenon—due
to inadequate
blood flow to
fingers and toes
Ulcers
Miscellaneous
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Joints
Arthritis can occur, with joint swelling and
pain
Nerves
Peripheral nerve involvement leads to
numbness, tingling, shooting pains in the
extremities, and sometimes to weakness
in a foot, hand, arm, or leg
Meninges
Prostate gland
Genito–urinary tract
Constitutional symptoms of fatigue, low–
grade fever, and weight loss
Incidence of symptoms
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Symptom
At Onset
ENT
75%
Lung
50
Joints
30
Fever
25
Kidney
20
Cough
20
Eye
15
Skin
15
Weight Loss
10
Nervous System (Central/Peripheral) 0
Total
95%
85
70
50
75
50
50
45
35
10/15
One-third of patients may be without symptoms at onset of
disease
Update on vasculitis: J Allergy Clin Immunol 2009
Update on vasculitis: J Allergy Clin Immunol 2009
Wegener’s continued. . .
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Renal involvement is manifested by acute
renal failure with red cells, red cell and
other casts , and proteinuria
Pts with microscopic polyangitis have a
renal lesion that is essentially
indistinguishable from that of pts with
classic Wegener’s, the principle difference
is the absence of granulomatosis
inflammation, although some experts
consider the presence of any significant
upper respiratory tract involvement to be
indicative of Wegener’s
In addition to pulmonary and renal…
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Upper and lower airways, including
subglottic region or trachea
Joints (myalgias, arthralgias,
arthritis)
Eyes (conjuctivitis, corneal
ulceration, episcleritis/scleritis, optic
neuropathy, nasolacrimal duct
obstruction…)
In addition to pulmonary and renal…
(Contd)
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Skin (hemorrhagic lesions, palpable
purpura)
Nervous system(cranial nerve
abnormalities)
GI tract/Heart, lower GU
Wegener’s Granulomatosis
About 50% have no lung
100%
•
90%
80%
70%
60%
At Initial
Presentation
50%
Throughout
Disease Course
40%
30%
20%
•
•
10%
0%
ENT
Lung
Kidney
involvement at
presentation.
Lung involvement:
 Infiltrates
 Nodules
 Hemoptysis
 Pleuritis
33% with lung involvement
are asymptomatic.
About 80% have no renal
involvement at
presentation.
Klippel, 1998
Pathogenesis
Risk factors and inciting events
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Exact events obscure
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Infectious—staph?
Genetic
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single nucleotide polymorphism in a gene
encoding a protein tyrosine phosphatase
(PTPN22)
AAT deficiency
Environmental—inhalational?
Silica
 lead
 mercury
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Pathogenesis
ANCA
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ANCAs may be not only markers for
Wegener's granulomatosis and
related disorders, but they may also
be actors in pathogenesis
Neutrophils exposed to cytokines
such as TNF, express PR3 & MPO
(the targets for ANCAs)
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Adding ANCAs to these cytokineprimed neutrophils causes them to
generate oxygen radicals and release
enzymes capable of damaging blood
vessels
Pathogenesis (Contd)
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“Priming” of Neutrophils
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Exposing PR3 and MPO epitopes
ANCA binding
Degranulation/ROS
production/neutrophil-endothelial
cell interaction
Increased ANCA = Increased
degranulation rate
Pathogenesis (Contd)
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Production of ANCA (anti-neutrophil cytoplasmic
antibodies) is one of the hallmarks of WG and
related forms of vasculitis(Churg-strauss, MPA,
pauciimmune glomerulonephritis, drug –induced).
ANCA are directed against antigens present within
the primary granules of neutrophils and
monocytes, and thus produce tissue damage via
interactions with primed neutrophils and
endothelial calls.
~90% of pts with active generalized WG are
ANCA positive, but some do not have ANCA, and
those with limited forms of the dz, up to 40%
may be ANCA negative, thus the absence of ANCA
does not exclude the diagnosis of Wegener’s.
Pathogenesis (Contd)
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Most common targeted antigens in
WG :
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Proteinase 3 (PR3), observed in 7080% of pts
Myeloperoxidase (MPO)-target in
approximately 10%
Dual postivity is rare and , and
generally indicated the presence of
another condition such as SLE
~70% of pts with MPA are ANCA
positive and most have MPO-ANCA,
with only a minority having PR3
Diagnosis
Criteria for Classification
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Nasal or oral inflammation
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Abnormal chest radiograph
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Chest radiograph showing the presence of nodules, fixed
infiltrates, or cavities
Abnormal urinary sediment
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Development of painful or painless oral ulcers or purulent
or bloody nasal discharge
Microhematuria (>5 red blood cells per high power field) or
red cell casts in urine sediment
Granulomatous inflammation on biopsy
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Histologic changes showing granulomatous inflammation
within the wall of an artery or in the perivascular or
extravascular area (artery or arteriole)
Diagnosis (Contd)
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American College of Rheumatology –not
intended to be used in routine clinical
practice and established before ANCA.
Presence of 2 or more yield 88%
sensitivity and 92% specificity
Nasal or oral inflammation
 Abnormal chest radiograph (nodules,
alveolar opacities)
 Abnormal urine sediment
 Granulomatous inflammation on biopsy of
an artery or perivascular area
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Diagnosis (Contd)
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Routine Labs-nonspecific- Leukocytosis,
thrombocytosis (>400,000), marked ESR, and
normocytic,normochromic anemia, mildly
elevated RF
ANCA- as previously described
Tissue Biopsy- dx should be confirmed by tissue
bx at site of active disease
 .Nasopharyngeal bx less invasive, but may not
see full pathogenesis due to small amount of
tissue- acute and chronic inflammation
 Renal bx-segmental necrotizing
glomerulnephritis w or w/o cresents
 Skin-leukocytoclastic vasculitis with little or no
complement and immunoglobulin
 Lung-granulomatous and vasculitis
Diagnosis (Contd)
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Biopsy specimens showing the triad of vasculitis,
granulomata, and large areas of necrosis
 Sinuses
 Nose
 Skin--leukocytoclastic vasculitis with little or no complement
and immunoglobulin on immunofluorescence
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Kidney--segmental necrotizing glomerulonephritis that is
usually pauci-immune on immunofluorescence / EM
Lung--vasculitis and granulomatous inflammation
(Only large sections of lung tissue obtained via
thoracoscopic or open lung biopsy are likely to show all of
the histologic features)
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Seropositivity for C-ANCAs
Antineutrophil cytoplasmic antibodies
Focal or diffuse necrotizing extracapillary glomerulonephritis is the
histological hallmark of ANCA-associated Vasculitis
Massive necrosis is usually associated to diffuse circumferential
extracapillary proliferation. From a clinical point of view, the patient is affected
by rapidly progressive renal failure
.
The biopsy specimen of a lung from a patient with Wegener
granulomatosis showing evidence of vasculitis and inflammation
C-ANCA staining pattern of ethanol-fixed normal human
neutrophil
ANCA
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~90% of Wegener's cases are
ANCA+
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In limited dz, up to 40% may be ANCA
neg
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80 - 90 % PR3-ANCA
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Remaining MPO-ANCA
Is ANCA sufficient?
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Concensus is that tissue dx is
necessary
Rarely may initiate tx w/o biopsy
Should attempt to confirm w/
biopsy when able
Differential Dx of Vasculitis
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Fibromuscular dysplasia
Cholesterol emboli
Atrial myxoma with emboli
Infective endocarditis
Malignancies,ie lymphamatoid
granulomatosis
Bacteremia
Rickettsial dz
Amyloid
SLE
Differential of Pulmonary Renal Syndrome
Goodpasture’s Disease
Systemic Vasculitis
Wegener’s Granulomatosis
Microscopic Polyangiitis
Churg-Strauss Syndrome
Cryoglobulinemia
Henoch-Schonlein Purpura
Connective Tissue Disease
Polymyositis/Dermatomyositis
Progressive Systemic Sclerosis
SLE
Primary Glomerular Disease
IgA Nephropathy
Post-Infectious GN
Membranoproliferative GN
Treatment
Traditional
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Prednisone (initiated at 1 mg/kg daily
for 1 to 2 months. then tapered)
Cyclophosphamide (2mg/kg daily for
at least 12 months)
>90% improve and 75% remit
Treatment (Contd)
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Many physicians favor use of daily
oral cyclophosphamide/corticosteroid
combination therapy in the initial
treatment of all pts dx with
Wegener’s, and
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Once remission is induced (which
requires a minimum of 3-6 months for
most pts), other less toxic
immunosuppressives can be employed
Treatment (Contd)
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Use of aggressive immunotherapy is
justified b/c survival in untreated
generalized Wegener’s is extremely poor,
with up to 90% of pt’s dying with in 2 yrs
from respiratory or renal failure, but
mortality is markedly diminished with
introduction of
cyclophosphamide/corticosteroid therapy
Treatment (Contd)
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Response to therapy-partial or complete
resolution of inflammatory
manifestations, such as inactive urine
sediment, although renal failure can
persist
Treatment (Contd)
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IV Cyclophosphamide monthly- lowers the
overall cumulative dose-role is
incompletely defined, and both equal and
decreased efficacy has been described in
Wegener’s, which may be due to different
pt populations in the studies,
nonresponders had more severe disease,
and those with incomplete responseswitching to oral daily regimen may
induce remission
Treatment (Contd)
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Methotrexate-mild dz, higher relapse
rate, can’t use in Cr >2.0
Plasmapharesis-pts with renal dz needing
dialysis, pulmonary hemorrhage, or also
with anti-GBM
Treatment (Contd)
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In one of largest nonrandomized prospective
single center studies, outcomes of 158 pts with
Wegener’s treated with varying regimens at NIH
were reported
Standard low dose cyclophosphamide plus
prednisone(133), cyclophos alone (8),
glucocorticoids alone(10), or other cytotoxic
agents plus steroids(6).
Cyclophos administered for a mean of 2 yrs.
Treatment (Contd)
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Mean follow up 8 yrs-In cyclophos and steroids:
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Survival 80%, with deaths due to Wegners, side
effects or both
Significant clinical improvement was observed in
more than 90% of pts, with 75% achieving
complete remission
Among the 98 pts followed for more than 5 yrs,
more than half experienced remission of greater
than 5 yrs
Treament (Contd)
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So, based on studies, first line is daily
oral cyclophosphamide/corticosteroid.
Cyclophos at 1.5-2 mg/kg/day, steroid
(1mg/kg/day).
IV Cyclophosphamide can be used, not
well studied, but associated with higher
relapse and longer to remission
Methotrexate-maybe used in mild
disease, or in maintenance, but either
way, higher relapse rate
Azathioprine-maintence, esp in pts with
renal insuffiency
Steroids- no significant benefit in
maintenance
Treatment (Contd)
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Duration of maintenance therapy12-18 months after stable remission
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May need more long term maintenance
esp if ANCA continues to be positive
Treatment (Contd)
50% in remission relapse
AND daily cyclophos is very toxic
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pancytopenia,
infection,
hemorrhagic cystitis
bladder cancer (increased 33-fold)
lymphoma (increased 11-fold)
Treatment (Contd)
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Monthly IV cyclophosphamide --
less
toxic but less effective
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Weekly methotrexate -- maintains remission
Trimethoprim-sulfamethoxazole -controversial (?effective for disease limited to the respiratory
tract), reduces the relapse rate
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Steroids —prednisone vs solumedrol
Plasmapheresis -unproven, awaiting MEPEX trial
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Recommended for anti-GBM+, pulm hemmorhage, renal
failure
IVIG— recommended in the setting of infection during PLEX
Prognosis
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Overall, the morbidity and mortality
associated with Wegener’s granulomatosis
and microscopic polyangiitis, results from
the combined effects of irreversible organ
dysfunction b/c of inflammatory injury
occurring before and the early phase of
effective therapy, consequences of
immunsuppressive therapy, and natural
hx of disease
Prognosis (Contd)
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Morbidity-consequences of therapy
(glucocorticoid toxicity, increased risk of
malignancy ie bladder cancer, skin ca,
sterility, organ failure); disease related
damage (partial hearing loss and
persistent proteinuria);increased risk of
DVT/PE in ANCA
Prognosis (Contd)
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Renal –ESRD eventually occurs in 20-25%
of pts. Poor renal outcome associated
with more severe renal dysfunction at
presentation, lack of response to initial
treatment,and enhanced amount of
fibrotic changes on renal bx
Mortality- Major causes of death are
complications of underlying disease and
therapy. 90% mortality rate in 2 yrs in
untreated. Higher mortality in elderly,
those with florid organ failure at
presentation.
Prognosis (Contd)
 Poorer
outcomes with advanced age, severe
renal impairment, DAH.
 Mortality >75% if untreated with median
survival of 5 months. Drastic improvement
since 1970s in mortality.
 Permanent morbidity:
•
•
•
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CKD 42%
Hearing Loss 35%
Nasal Deformity 28%
Tracheal Stenosis 13%
Severe Infection 50% (Treatment)
Conclusions
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One of the most frequent pulmonary-renal
syndromes
Granuloma’s in upper respiratory tract:
rhinitis, sinusitis, pharyngits, stomatitis,
pulmonary infiltrates (nodules with
cavitations) with hemoptoe, respiratory
insufficiency, diffusion disturbances
Most frequently RPGN-crescentic GN with
pauci –immune GN
ANCA positive (large majority C-ANCA)
Conclusion
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(Contd)
Oral cyclophosphamide 1 - 2 mg/kg BW + corticosteroids
0.6 -1 mg/kg BW.
I.V. pulse of cyclophosphamide 500 mg/m² every month
for 3 months + corticosteroids- results are not better?
Follow ANCA titers
In case of dialysis need, plasmapheresis is to be
considered, together with pulses of cyclophophamide.
Maintenance therapy: low dose of
cyclophophamide,methotrexate
for pulmonary or upper respiratory tract manifestations:
trimetoprim-sulfamethoxazole