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Vasculitis & Alveolar Hemorrhage

Ulrich Specks, MD
Professor of Medicine
Division of Pulmonary and Critical Care Medicine,
Thoracic Diseases Research Unit,
Mayo Clinic, Rochester, MN, USA


Pulmonary Board Review 2013
San Antonio, TX
Disclosures
Financial relationship:
Genentech, research grants and consultant fees to
institution.
Off-label use of drugs:
All references to medications discussed in this
presentation except the use of rituximab for ANCA-
associated vasculitis, constitute off-label applications.
Objectives
Review nomenclature definitions.
ANCA associated vasculitis.
Differential diagnostic approach to diffuse alveolar
hemorrhage (DAH).
Highlight disease entities that can cause DAH.
Nomenclature Changes
Primary Small Vessel Vasculitis
ANCA-associated vasculitis (pauci-immune)
MPA - Microscopic polyangiitis
GPA - Granulomatosis with polyangiitis (Wegeners)
EGPA - Eosinophilic granulomatosis with polyangiitis
(Churg-Strauss)
Immune-complex associated vasculitis
Anti-GBM disease
IgA-vasculitis (Henoch-Schoenlein)
Cryoglobulinemic vasculitis
Hypocomplementemic urticarial vasculitis (anti-C1q vasculitis)
Jennette et al. A & R 2013
Chapel Hill Consensus Nomenclature of Vasculitis
Polyarteritis nodosa
Kawasaki disease
Giant cell arteritis
Takayasu arteritis
GPA (Wegeners)
EGPA (Churg-Strauss)
MPA
IgA-Vasculitis (Henoch-Schnlein)
Cryoglobulinemic vasculitis
Cutaneous leukocytoclastic vasculitis
Capillary
Large to
medium
sized artery
Aorta
Arteriole
Small
artery
Venule
Vein
Arthritis Rheum 2013; 65:1-11
Anti-GBM disease
Chapel Hill Consensus Nomenclature of Vasculitis
Polyarteritis nodosa
Kawasaki disease
Giant cell arteritis
Takayasu arteritis
GPA (Wegeners)
EGPA (Churg-Strauss)
MPA
Henoch-Schnlein purpura
Cryoglobulinaemic vasculitis
Cutaneous leukocytoclastic vasculitis
Capillary
Large to
medium
sized artery
Aorta
Arteriole
Small
artery
Venule
Vein
Arthritis Rheum 2013; 65:1-11
ANCA-associated
C-ANCA - PR3
P-ANCA - MPO
Respiratory Manifestations
of Giant Cell Arteritis
Most common vasculitis: 25 cases per 100,000 per year
Disease of the elderly
High ESR, malaise, myalgias, fever, headaches, visual
symptoms
Respiratory manifestations are rare but may be the first
symptom
Cough, sore throat, hoarseness
Lung nodules, interstitial infiltrates, bronchocentric
granulomas (GPA (Wegeners) versus GCA?)
Larson et al. Ann Intern Med 1984, 101:594
Respiratory Manifestations
of Takayasus Arteritis
Large vessels: aorta and branches.
Age usually < 40, female predominance.
Claudication, mesenteric ischemia, renal artery stenoses.
Granulomatous transmural inflammation, similar to GCA.
Ethnic/geographic variability of vascular territory
preferred.
Pulmonary artery involvement, stenoses, pulmonary
hypertension reported as high as 50% of patients.
V/Q scan and MR angiography.
Maksimowicz-McKinnon A&R 2007; 56:1000
Respiratory Manifestations
of Classic Polyarteritis Nodosa
Not everything called polyarteritis nodosa in the literature
before 1995 is classic PAN.
Necrotizing arteritis of medium-sized arteries
Multi-system disorder: frequent skin, nerves, GI and kidney
Really rare.
3 NOs: no ANCA, no glomerulonephritis, no pulmonary
capillaritis (if the lung is involved it is probably not PAN)
Often associated with hepatitis B.
Rare cases of lung hemorrhage from involvement of
bronchial arteries.
Usually not relapsing
Stone JAMA 2002; 288:1632-39
ANCA-Associated Vasculitis (AAV)
Systemic necrotizing small vessel vasculitis
Frequent occurrence of ANCA
pathognomonic
not required for diagnosis
thought to be pathogenic (modulating the
disease phenotype)
Spectrum of disease manifestations with lot of
overlap between GPA and MPA
Pathology
Terminology
Serology
GPA MPA
Necrotizing
Granuloma
Small Vessel
Vasculitis
C-ANCA/PR3-ANCA P-ANCA/MPO-ANCA
The Spectrum of GPA-MPA
Core Knowledge About ANCA Testing
Immunofluorescence and antigen-specific testing.
The right pairing has high specificity and positive
predictive value for AAV.
ANCA testing performed indiscriminately in low
pre-test probablility situations can cause false-
positive results.
Correlation of serial ANCA level determinations
with disease activity is unreliable.
Positive predictive value of ANCA level increases
for relapse is low.
Treatment decisions should not be based on
ANCA levels alone.
C-ANCA - PR3
P-ANCA - MPO
Finkielman. Ann Intern Med 2007; 147:611-9
Limited Disease = Localized to Early Systemic Dz
Necrotizing granulomatous
inflammation
of GPA (Wegeners)
Small vessel vasculitis
& capillaritis
Common to MPA and GPA
Severe Disease
Small vessel
vasculitis
& capillaritis
of MPA & GPA
Palpable purpura
Leukocytoclastic vasculitis
Pauci-immune
Focal segmental
Necrotizing GN
Multiple Mononeuritis
Sensori-neural HL
Scleritis
Severe Disease = Generalized Disease
Therapeutic Concepts for GPA & AAV
Multidisciplinary approach
Individualized therapy
- non-severe (limited) disease (non-life/organ threatening)
- severe disease (generalized - life/organ threatening)
Remission induction therapy
Remission maintenance therapy
Prevention of drug toxicity
Treatment of sequelae
QUESTION 1

30 y/o female C-ANCA/PR3-ANCA positive patient with
arthralgias, nasal crusting & septal perforation, pulmonary
nodules, normal ESR, CRP, U/A should be treated with
A. Prednisone, methotrexate, TMP/SMX, folic acid
B. Prednisone, cyclophosphamide, TMP/SMX
C. Prednisone, cyclophosphamide, etanercept
D. Prednisone, TMP/SMX
E. Prednisone, rituximab, TMP/SMX
RCT Data for Remission Induction in AAV
NORAM (early systemic GPA & MPA)
Arthritis Rheum 2005; 52:2461-9
MTX replaces CYC for limited disease.
CYCAZAREM (generalized GPA & MPA)
NEJM 2003; 349:36-44
AZA should replace CYC once remission has been induced.
WGET (limited & severe GPA)
NEJM 2005; 352:351-61
No role for etanercept (anti-TNF) in addition to standard Rx.
RAVE (severe GPA & MPA)
NEJM 2010; 363:221-32
RTX can replace CYC for remission induction in severe AAV.
QUESTION 2

25 y/o male C-ANCA/PR3-ANCA positive patient with acute
onset of malaise, arthralgias, pulmonary mass lesion, RBC
casts on urine micro, creatinine of 2.8 mg/dl, ESR of 78 mm/
hr should be treated with
A. Prednisone, methotrexate, TMP/SMX, folic acid
B. Prednisone, cyclophosphamide, TMP/SMX
C. Prednisone, TMP/SMX
D. Prednisone, cyclophosphamide, etanercept
E. Prednisone, rituximab, TMP/SMX
RAVE-Trial Results
NEJM 2010; 363:221-32
Double-blind, double-placebo randomized controlled trial
197 patients with severe GPA or MPA
Remission induction with rituximab versus cyclophosphamide
Main Results
Rituximab is not inferior to cyclophosphamide
Rituximab is superior for patients with severe disease flares
Main Conclusions - Rituximab is:
first proven alternative to cyclophosphamide
preferred for severe relapses
preferred for patients who want to preserve fertility
now the only FDA approved agent for severe AAV

QUESTION 3

73 y/o male C-ANCA/PR3-ANCA positive patient with 8 yr history
of relapsing WG, on maintenance therapy with AZA, has history
of bladder cancer, now flaring with sxs of arthralgias, nasal
crusting, new cavitary pulmonary mass lesion, ESR of 52 mm/hr,
WBC of 3.0 K should be treated with
A. Prednisone, methotrexate, TMP/SMX, folic acid
B. Prednisone, cyclophosphamide, TMP/SMX
C. Prednisone, TMP/SMX
D. Prednisone, cyclophosphamide, etanercept
E. Prednisone, rituximab, TMP/SMX
Patients Meeting the Primary Outcome
of RAVE Trial
by Disease Status at Baseline
%
P=0.67 P=0.013
0
10
20
30
40
50
60
70
80
New disease Severe flare
n=96 n=101
Rituximab Cyclophosphamide
60.4%
64.6%
66.7%
42.0%
NEJM 2010; 363:221-32
Treatment of AAV: Summary I
For remission induction in limited (non-severe) GPA:
MTX plus GCS
For remission induction in newly diagnosed severe GPA
& MPA:
CYC plus GCS or RTX plus GCS
CYC daily oral or intravenous bolus
For remission induction in rapidly progressive GPA or
MPA:
Consider addition of PLEX
1. DeGroot. A&R 2005; 52:2790 3. DeGroot. Ann Int Med 2009; 150:670
2. Stone. NEJM 2010; 3363:211 4. Jayne. JASN 2007; 18:2180
Treatment of AAV: Summary II
For remission maintenance in GPA or MPA:
Following CYC: MTX or AZA
1
, better than MMF
2
Following RTX: nothing (?)
3
For refractory GPA and severe relapses of GPA or
MPA:
RTX plus GCS for induction
4
RTX alone for maintenance
4
1. Pagnoux. NEJM 2008; 359:2790
2. Hiemstra. JAMA 2010; 304:2381
3. Stone. NEJM 2010; 3363:211
4. Cartin-Ceba. 2012; A&R;64:3770
QUESTION 4

Which of the following statements about EGPA
(Churg Strauss) is NOT correct
A. Asthma usually precedes eosinophilia and vasculitis.
B. ANCA are common and of the P-ANCA type in EGPA.
C. Alveolar hemorrhage is a frequent (>20%) occurrence in
EGPA.
D. Cyclophosphamide should be added to glucocorticoids
when heart involvement is present.
E. Drugs reported with the onset of EGPA include leukotriene
receptor antagonists, inhaled glucocorticoids, chromolyn-
sodium and omalizumab.
EGPA (Churg-Strauss)
A Disease with 3 Components
Asthma / Allergic disease
Eosinophilia
blood & tissue
Vasculitis
tissue necrosis
EGPA
Age of onset 49 16 yrs, Sex 56% male
EGPA (Churg-Strauss)
Clinical Findings in 96
1
and 91
2
Patients
Asthma 100% 99%
Peripheral nerve 76% 78%
Sinus 61% 74%
Skin 57% 51%
Lung 38% 58%
(Alveolar hemorrhage 3% 0%)
GI tract 33% 31%
Kidney 26% 25%
Heart 14% 13%
Central nerve 8% 11%
1: Guillevin et al. Medicine 1999; 78:26-37
2: Keogh et al. Am J Med 2003; 115:284-290
Radiographic Presentation of EGPA (CSS)
Eosinophilic Granuloma and Vasculitis of
EGPA (CSS)
Therapy of EGPA (1)
Goal: reduce inflammation and eosinophilia
causing organ damage.
Follow principles of therapy for AAV
Glucocorticoids are mainstay of therapy
Steroid sparing agents: MTX, AZA
Keogh. Seminars Respir Crit Care 2006; 27:148
Therapy of EGPA (2)
CYC is required for severe disease (life or organ-
threatening)
1
:
Heart
CNS
mononeuritis multiplex
severe renal involvement.
Rituximab may be alternative for MPO-ANCA
positive patients
2
Anti-IL5 may be steroid sparing
3
1 Keogh. Seminars Respir Crit Care 2006; 27:148
2 Cartin-Ceba. Nephrol Dial Transplant 2011.
3 Kim. J Allergy Clin Immunol. 2010 125:1336.
Points to Remember about EGPA (CSS)
ANCA less common: 40 70% (usually MPO-/P-ANCA)
ANCA correlates with vasculitis activity and portends more
vasculitic disease manifestations
Leukotriene receptor antagonists seem to unmask - not
cause EGPA (CSS).
Other drugs (omalizumab) can have same effect*.
When vasculitis is treated successfully patients are
frequently left with difficult to manage asthma
Keogh. Seminars Respir Crit Care 2006; 27:148
*Wechsler CHEST 2009; 136:507-18
Diffuse Alveolar Hemorrhage
Clinical Presentation
Hemoptysis (may be absent in up to 30%)
Dyspnea and hypoxemia
Diffuse alveolar infiltrates on CXR
Low and/or falling Hgb (iron-deficiency)
Diffuse Alveolar Hemorrhage
Radiographic Presentation
Causes of Alveolar Filling Patterns on CXR
Water - Pulmonary edema, CHF, ARDS
Pus, debris - Infection
Blood - Alveolar hemorrhage, bronchial source
Cells - Alveolar cell CA, lymphoma
Protein - Alveolar proteinosis
Bronchoalveolar Lavage
Rule out infectious etiology
Confirm alveolar hemorrhage
Aliquot number
1 2 3 4 5
Robbins RAl. Am J Med 1989;87:511
> 20% Hemosiderin-laden Macrophages
De Lassence A. AJRCCM 1995;151:157
Diffuse Alveolar Hemorrhage:
Mechanisms
Immune mediated
Capillaritis
No capillaritis
Capillary stress failure
Diffuse alveolar damage
Other
QUESTION 5

Capillaritis is the cause of diffuse alveolar
hemorrhage in all of the following EXCEPT
A. Microscopic polyangiitis
B. Idiopathic pulmonary hemosiderosis
C. Systemic lupus erythematosus
D. GPA (Wegeners)
E. EGPA (Churg Strauss)
Diffuse Alveolar Hemorrhage
Laboratory Testing - Step 1
1. Determine Severity and Rate of Progression!
2. Look for Other Organ Involvement!
CBC and serial Hgb-determinations
Serum creatinine and BUN
Urinalysis and urine microscopy

Diffuse Alveolar Hemorrhage
Laboratory Testing - Step 2
3. Look for Specific Etiology!
ANCA
ANA, anti-ds-DNA
Serum complement levels (CH50, C3,C4)
Anti-GBM
Anti-phospholipid antibodies
Creatine-Kinase
Rheumatoid-factor, anti-citrullinic peptide Ab
Cryoglobulins
Diffuse Alveolar Hemorrhage
Lung Biopsy: Clinical Considerations
TBLBx: too small to allow diagnosis.
TBLBx: relalatively contraindicated in patients on
ventilator.
VATS: patients usually too sick to tolerate
collapse of one lung.
OLBx: high morbidity and mortality.
If you go for OLBx: snap-freeze portion of tissue
for direct immunofluorescence microscopy.
Diffuse Alveolar Hemorrhage:
Histologic Categories
Lung Biopsy
Pulmonary capillaritis
Bland pulmonary hemorrhage
Diffuse alveolar damage
AH in the presence of other defined
histopathology
Definition of Pulmonary Capillaritis
Alveolar wall infiltration with
inflammatory cells.
Centered on capillaries and
venules.
Neutrophils are the
predominant cell type.
Neutrophils are undergoing
apoptosis (leukocytoclasis).
Fibrinoid necrosis.
Alveolar hemorrhage
hemosiderin-laden M
Causes of Pulmonary Capillaritis
Common in
MPA
GPA (Wegeners)
Rare in
EGPA (Churg-Strauss)
IgA vasculitis (Henoch-Schnlein)
Anti-GBM disease (capillaritis is not predominant)
Secondary vasculitis (SLE, RA, APS, HepC-Cryo)
Behets disease
Drug-induced vasculitis
Isolated without other identifiable cause

Prognosis of Alveolar Hemorrhage
Caused by ANCA-associated Vasculitis
Age of the patient Hogan 1996; Lauque 2000
Need for ventilator support Lauque 2000
ANCA-type: PR3-ANCA conveys
worse mortality (RR 3.78) Hogan 1996
higher relapse rate Jayne 2003; Booth 2003
more rapid loss of renal function Franssen 1995
Plasma Exchange for DAH in MPA
N=20
Retrospective analysis of all patients 1995 - 2001
All received iv methyl-prednisolone + PLEX
Average of 6.4 treatments
All survived - no complications of PLEX
Half had renal disease and experienced improvement
of renal function
Conclusion: early PLEX may improve outcome of DAH
Klemmer. Am J Kidney Dis 2003; 42:1149-1153
Isolated Pauci-immune Pulmonary Capillaritis
N = 8
8/29 (28%) of patients with DAH and
capillaritis on biopsy.
No clinical, serological, histopatholical
evidence of associated illness.
No exposure to drugs or inhalational toxins.
Response to immunosuppression.
Relapses possible.
Jennings. Am J Respir Crit Care Med. 1997; 155:1101
Diffuse Alveolar Hemorrhage in SLE
Less than 5% of SLE pts affected not first sign of SLE
Kidney involvement increases risk for DAH
Subclinical to massive, hemoptysis may be absent in 50%
Usually fever - may mimic pneumonia
Reported mortality 0-90%
Negative prognostic factors:
infection, CYC,
mechanical ventilation
Survivors may progress to fibrosis
Capillaritis, immune-complex deposits
Zamora. Medicine 1997; 76:192 Koh. Lupus 1997; 6:713
Santos-Ocampo. Chest 2000; 118:1083
Kwok. Lupus 2011; 20:102
Diffuse Alveolar Hemorrhage in SLE
Treatment
No good data
High dose steroids (not very effective)
Cytotoxic agents (CYC) generally viewed as necessary
Only case reports suggest efficacy of PLEX
Synchronized PLEX and intravenous CYC
Few case reports of successful outcomes with rituximab
Euler HH. Ann Intern Med 1994; 145:296
Pagnoux. Transfusion Apheresis Sci 2007; 36:187
Pottier V. Lupus 2011; 20:656
DAH in Primary Antiphospholipid Syndrome
Considered rare; denominator unclear
Rarely (but may be) initial manifestation of APS
Usually life threatening high mortality
Microvascular thrombosis capillaritis
Corticosteroids first line of therapy (effective)
Role of PLEX, cyclophosphamide, rituximab ?
Gertner. J Rheumatol. 1999;26:805
Deane. Semin Arthritis Rheum. 2005; 35:154
Anti-GBM Disease
Antibodies against NC-1 domain of 3 (IV) collagen.
Antibodies are pathogenic: transfer causes disease in
animals; removal improves disease.
Disease manifestations are defined by distribution of
target antigen: limited to lungs & kidneys.
Environmental factors (smoking, inhalational toxins)
may be triggers.
Severity of renal disease at diagnosis
determines prognosis.
Rx: Steroids, PLEX, CYC or RTX

IgA-associated Vasculitis
(Henoch-Schnlein)
Affects children and young adults
Fever, purpura, arthritis (large joint arthralgias,
abdominal colic, peritonitis, melena, nephritis
Proliferative and necrotizing GN:
generally mild and self-limited
Lung hemorrhage reported,
but exceedingly rare
Characteristic IgA deposits (skin & kidney)
Mills et al. Arthritis Rheum 1990; 33;1114-21
Nadrous et al. Mayo Clin Proc 2004; 79:1151-7
Idiopathic Pulmonary Hemosiderosis
Diagnosis of exclusion (many cases reported before 1990
probably represent AAV)
Limited to the lung
Recurrent hemoptysis and ground-glass infiltrates
Anemia, iron-deficiency (!)
Bland histopathology, fibrosis in chronic recurrent cases
Predominantly children, 20% adults (age 20-40)
Rx: (Immunosuppression, PLEX), gluten-free diet
(Idiopathic) Pulmonary Hemosiderosis
Association with gluten-sensitive sprue
Lane-Hamilton syndrome
18 cases described in the literature
All IPH patients should be screened for sprue with
serologies (anti-gliadin and anti-endomysial
antibodies)
Gluten-free diet seems key to therapy and
prevention of relapses.
Agarwal et al. Intern Med J 2007; 37:65-7
Important Non-Vasculitic Cause of DAH:
Mitral Valve Disease
Mitral stenosis (rarely severe mitral insufficiency)
Capillary stress failure
Rupture of dilated and varicose bronchial veins
If auscultation reveals a murmur or if in doubt,
get an ECHO
Recurrent hemorrhage may lead to hemosiderosis
and fibrosis of the lung.
When Exposure History and Medical History
Provide the Clues to Etiology of DAH
History of mitral valve diseae
Medications (anticoagulation, abciximab, sirolimus, all-
trans-retinoic acid, D-penicllamine, Mitomycin C,
epoprostenol)
Renal insufficiency
Inhalational toxins (trimellitic anhydride, isocyanates,
crack-cocaine)
Bone marrow transplantation
Within first 30 days
Risk higher with autologous than allogeneic
Risk factors: intensive conditioning, age > 40.
Hemoptysis often absent - dont be mislead


Miscellaneous Rare Causes of DAH
Malignancies
Lymphangioleiomyomatosis
Pulmonary veno-occlusive disease
Pulmonary capillary hemangiomatosis
Bonus Slides
(Hypocomplementemic)
Urticarial Vasculitis
Urticaria, arthralgias, abdominal pain,
angioedema, fever, uveitis/episcleritis
Association with COPD/emphysema (20-60%)
Smoking
Immunologic processes
Basilar emphysema in rare cases
No pulmonary vasculitis
Schwartz HR et al. Mayo Clin Proc 1982; 57:231-8
Wisnieski et al. Medicine 1995; 74:24-41
Ghamra et al. Respir Care 2003: 48:697-9
Behets Disease
Chronically relapsing, multi-system disorder
Uveitis, aphtous oral/urogenitial ulcers, skin nodules/
pustules, synovitis, meningoencephalitis
Venous thromboses (superficial, deep, upper and lower
extremities, vena cava) are common.
Pulmonary complications in up to a third of patients:
Pleural effusions (from infarcts or infections)
Pulmonary infiltrates
Prominent pulmonary arteries
Pulmonary artery aneurysm
Hemoptysis
Uzun et al. Chest 2005; 127:2243
Alveolar Hemorrhage in Behets
Cough, hemoptysis, fever, dyspnea, chest pain.
Hemoptysis may be massive and fatal in up to 39%.
Immune-complex mediated vasculitis.
May affect vessels of all sizes.
Destruction of elastic lamina of pulmonary artery >
aneurysms > secondary erosion of bronchi > massive
hemotpysis.
Dx: CT-angio or MRI.
Rx: Immunosuppression, coil-embolization therapy
Anticoagulation in this setting may be ineffective and fatal
Cantasdemir. Cardiovasc Intervent Radiol 2002; 25:4
Alveolitis/Alveolar Hemorrhage
of Cryoglobulinemic Vasculitis
Rare: occurs in 3% of patients hospitalized with
cryoglobulinemia
Fatigue, fever, pulmonary infiltrates
Majority with renal involvement
50% with documented HCV infection
50% type II, 50% type III cryoglobulinemia
Portends poor prognosis, high mortality (80%)
Rx: (antivirals), immunosuppression, PLEX, rituximab
Amital. Clin Exp Rheum 2005; 23:616 Ahmed. J Nephrol 2007; 20:350
Ferri. Autoimmunity Reviews 2011; 11:48-55

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