0715 - Saturday - Vasculitis and Alveolar Hemorrhage - Specks

Vasculi(s
& Alveolar Hemorrhage

Review 2014
Pulmonary Board

Orlando, FL
Ulrich Specks, MD

Professor of Medicine
Chair, Division of Pulmonary and Cri(cal Care Medicine,
Mayo Clinic, Rochester, MN, USA
© 2014 American College of Chest Physicians

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
After this session, you will be able to:

Ø  State nomenclature definitions.
Ø  Explain ANCA – associated vasculitis.
Ø  Utilize differential diagnostic approach to
diffuse alveolar hemorrhage (DAH).
Ø  Highlight disease entities that can cause DAH.

Vasculitis: Vessel Size
Jennette et al., Arthritis Rheum 2013; 65: 1-11

Nomenclature Changes
Primary Small Vessel Vasculitis
ANCA-associated vasculitis (pauci-immune)
Ø  MPA - Microscopic polyangiitis
Ø  GPA - Granulomatosis with polyangiitis (Wegener’s)
Ø  EGPA - Eosinophilic granulomatosis with polyangiitis
(Churg-Strauss)
Immune-complex associated vasculitis
Ø  Anti-GBM disease
Ø  IgA-vasculitis (Henoch-Schoenlein)
Ø  Cryoglobulinemic vasculitis
Ø  Hypocomplementemic urticarial vasculitis (anti-C1q
vasculitis)
JenneNe et al. A & R 2013
Vasculitis: Vessel Size
ANCA-associated Vasculitis
Typical ANCA-test in Vasculitis

Jennette et al., Arthritis Rheum 2013; 65: 1-11 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 (Wegener’s) versus GCA?)
Larson et al. Ann Intern Med 1984, 101:594
of Takayasu’s 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
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 NO’s: 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
Ø  pathognomonic
Ø  not required for diagnosis
Ø  thought to be pathogenic (modulating the
disease phenotype)
•  Spectrum of disease manifestations with lot
of overlap between GPA and MPA
The Spectrum of GPA-‐MPA
Terminology GPA MPA
Necro(zing Small Vessel

Pathology Granuloma Vasculi(s
Serology C-‐ANCA/PR3-‐ANCA P-‐ANCA/MPO-‐ANCA

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 C-‐ANCA -‐ PR3
results.
•  Correlation of serial ANCA level determinations with
disease activity is unreliable.
•  Positive predictive value of ANCA level increases for
relapse is low.
P-‐ANCA -‐ MPO
•  Treatment decisions should not be based on ANCA
levels alone.
Finkielman. Ann Intern Med 2007; 147:611-‐9
Necro(zing granulomatous
inflamma(on
of GPA (Wegener’s)
Limited Disease = Localized to Early Systemic Dz

Small vessel vasculi(s
& capillari(s
Common to MPA and GPA
Severe Disease

Severe Disease = Generalized Disease
Therapeutic Concepts for GPA & AAV
•  Multidisciplinary approach
•  Individualized therapy
Ø  non-severe (limited) disease (“non-life/organ threatening”)
Ø  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) A&R 2005; 52:2461-9
Ø  MTX replaces CYC for limited disease.
CYCAZAREM (generalized GPA & MPA) NEJM 2003; 349:36-44
Ø  AZA should replace CYC once remission has been induced.
WGET (limited & severe GPA) NEJM 2005; 352:351-61
Ø  No role for etanercept (anti-TNF) in addition to standard Rx.

RAVE (severe GPA & MPA) NEJM 2010; 363:221-32
Ø  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…
C. Prednisone, TMP/SMX
D. Prednisone, cyclophosphamide, etanercept

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
Ø Rituximab is not inferior to cyclophosphamide
Ø Rituximab is superior for patients with severe disease flares
•  Main Conclusions - Rituximab is:
Ø first proven alternative to cyclophosphamide
Ø preferred for severe relapses
Ø preferred for patients who want to preserve fertility
Ø 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…
C. Prednisone, TMP/SMX
D. Prednisone, cyclophosphamide, etanercept

Meeting the Primary Outcome of the RAVE Trial
by Disease Status at Baseline
Rituximab Cyclophosphamide
80 P=0.67 P=0.013
66.7%
70 64.6%
60.4%
60
% 50 42.0%
40
30
20
10
0
Newn=96
disease Severe flare
n=101
NEJM 2010; 363:221-‐32 © 2014 American College of Chest Physicians
Treatment of AAV: Summary I
For remission induction in limited (non-severe) GPA:
Ø  MTX plus GCS
For remission induction in newly diagnosed severe
GPA & MPA:
Ø  CYC plus GCS or RTX plus GCS
Ø  CYC daily oral or intravenous bolus
For remission induction in rapidly progressive GPA
or MPA:
Ø  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:
Ø  Following CYC: MTX or AZA1, better than MMF2
Ø  Following RTX: nothing (?)3
•  For refractory GPA and severe relapses of GPA or
MPA:
Ø  RTX plus GCS for induction4
Ø  RTX alone for maintenance4
1.  Pagnoux. NEJM 2008; 359:2790
2.  Hiemstra. JAMA 2010; 304:2381
3.  Stone. NEJM 2010; 3363:211
4.  Car(n-‐Ceba. 2012; A&R;64:3770 © 2014 American College of Chest Physicians
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
EGPA
Eosinophilia Vasculi(s
blood & (ssue (ssue necrosis
Age of onset 49 ± 16 yrs, Sex 56% male
EGPA (Churg-Strauss)
Clinical Findings in 961 and 912 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 © 2014 American College of Chest Physicians
Radiographic
Presentation
of EGPA (CSS)

Eosinophilic Granuloma and Vasculi(s
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:
Ø Heart
Ø CNS
Ø mononeuritis multiplex
Ø 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 Car(n-‐Ceba. Nephrol Dial Transplant 2011.
3 Kim. J Allergy Clin Immunol. 2010 125:1336.
Points to Remember about EGPA
•  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)

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 infec(ous e(ology

> 20% Hemosiderin-‐laden Macrophages
•  Confirm alveolar hemorrhage
1 2 3 4 5
Aliquot number
Robbins RAl. Am J Med 1989;87:511 De Lassence A. AJRCCM
© 2014 American
1995;151:157
College of Chest Physicians
Diffuse Alveolar Hemorrhage:
Mechanisms
•  Immune mediated
Ø  Capillaritis
Ø  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 (Wegener’s)
E.  EGPA (Churg Strauss)

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

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 © 2014 American College of Chest Physicians
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.
Histologic Categories
Lung Biopsy
•  Pulmonary capillaritis
•  Bland pulmonary hemorrhage
•  Diffuse alveolar damage
•  AH with 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 Mø
Causes of Pulmonary Capillaritis
Common in …
Ø  MPA
Ø  GPA (Wegener’s)
Rare in …
Ø  EGPA (Churg-Strauss)
Ø  IgA vasculitis (Henoch-Schönlein)
Ø  Anti-GBM disease (capillaritis is not predominant)
Ø  Secondary vasculitis (SLE, RA, APS, HepC-Cryo)
Ø  Behçet’s disease
Ø  Drug-induced vasculitis
Ø  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
Ø  worse mortality (RR 3.78) Hogan 1996

Ø  higher relapse rate Jayne 2003; Booth 2003
Ø  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 © 2014 American College of Chest Physicians
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
Pooer V. Lupus 2011; 20:656 © 2014 American College of Chest Physicians
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 Arthri(s Rheum. 2005; 35:154
Anti-GBM Disease
•  An(bodies against NC-‐1 domain of α3 (IV) collagen.
•  An(bodies are pathogenic: transfer causes disease
in animals; removal improves disease.
•  Disease manifesta(ons are defined by distribu(on of
target an(gen: limited to lungs & kidneys.
•  Environmental factors (smoking, inhala(onal toxins)
may be triggers.
•  Severity of renal disease at diagnosis
determines prognosis.
•  Rx: Steroids, PLEX, CYC or RTX
IgA-associated Vasculitis (Henoch-Schönlein)
•  Affects children and young adults
•  Fever, purpura, arthritis (large joint
arthralgias, abdominal colic, peritonitis,
melena, nephritis
•  Proliferative and necrotizing GN:
Ø  generally mild and self-limited
•  Lung hemorrhage reported,
Ø  but exceedingly rare
•  Characteristic IgA deposits (skin & kidney)
Mills et al. Arthri(s Rheum 1990; 33;1114-‐21
Nadrous et al. Mayo Clin Proc © 22014
004; 79:1151-‐7
American College of Chest Physicians
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,
Ø  get an ECHO
•  Recurrent hemorrhage may lead to
hemosiderosis and fibrosis of the lung.

Therapeutic Approach
•  Supportive care
•  Methyl-prednisolone: yes or no?
•  Plasma-exchange: yes or no?
•  What else: CYC or RTX?

Therapeutic Approach
Ø  Depends on etiology
•  Methyl-prednisolone: yes or no?

•  Plasma-exchange: yes or no?
•  What else: CYC or RTX?

Early Diagnosis of Immunologic Cause
Variable Points
Time since first
respiratory symptoms ≥ +2
11 days
Fatigue and/or weight +2

loss
Arthralgia/arthritis +3
Proteinuria ≥ 1g/L +3
Picard et al. Respiration 2010;80:313-320
Early Diagnosis of Immunologic Cause
de Prost et al. Lung 2013;191:559-563 © 2014 American College of Chest Physicians

PLEX for DAH in AAV
Study, N PLEX DAH resolu6on No DAH resolu6on
year and hospital PLEX and hospital
survival survival
Car6n-‐Ceba, 2014 53 15 11 38 28

Hruskova, 2013 53 40 18 13 4

Ravindran, 2010 9 5 3 4 3
Chen, 2009 5 2 1 3 2
Lin, 2009 (MPA only) 9 5 1 4 2
Klemmer, 2003 20 20 19 0 0
Total 149 87 53 (61%) 62 39 (63%)

Bonus Slides

Exposure and Medical History
Provide the Clues to Etiology of DAH
•  History of mitral valve disease
•  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
Ø Within first 30 days
Ø Risk higher with autologous than allogeneic
Ø Risk factors: intensive conditioning, age > 40.
Ø Hemoptysis often absent - don’t be mislead
Hypocomplementemic Urticarial Vasculitis
(Anti-C1q Vasculitis)
•  Urticaria, arthralgias, abdominal pain, angioedema,
fever, uveitis/episcleritis
•  Association with COPD/emphysema (20-60%)
Ø  Smoking
Ø  “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
Behçet’s 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:
Ø Pleural effusions (from infarcts or infections)
Ø Pulmonary infiltrates
Ø Prominent pulmonary arteries
Ø Pulmonary artery aneurysm
Ø Hemoptysis
Uzun et al. Chest 2005; 127:2243
Alveolar Hemorrhage in Behçet’s
•  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 © 2014 American College of Chest Physicians
Miscellaneous Rare Causes of DAH
•  Malignancies
•  Lymphangioleiomyomatosis
•  Pulmonary veno-occlusive disease
•  Pulmonary capillary hemangiomatosis

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Vasculi(s

& Alveolar Hemorrhage

Ulrich Specks, MD

© 2014 American College of Chest Physicians

© 2014 American College of Chest Physicians

After this session, you will be able to:

© 2014 American College of Chest Physicians

Jennette et al., Arthritis Rheum 2013; 65: 1-11

Typical ANCA-test in Vasculitis

Terminology GPA MPA

Necro(zing Small Vessel

Serology C-­‐ANCA/PR3-­‐ANCA P-­‐ANCA/MPO-­‐ANCA

© 2014 American College of Chest Physicians

© 2014 American College of Chest Physicians

© 2014 American College of Chest Physicians

• Remission induction therapy

30 y/o female C-ANCA/PR3-ANCA positive

B. Prednisone, cyclophosphamide, TMP/SMX

C. Prednisone, cyclophosphamide, etanercept

E. Prednisone, rituximab, TMP/SMX

© 2014 American College of Chest Physicians

Ø No role for etanercept (anti-TNF) in addition to standard Rx.

© 2014 American College of Chest Physicians

25 y/o male C-ANCA/PR3-ANCA positive

A. Prednisone, methotrexate, TMP/SMX, folic acid

B. Prednisone, cyclophosphamide, TMP/SMX

D. Prednisone, cyclophosphamide, etanercept

E. Prednisone, rituximab, TMP/SMX

• Double-blind, double-placebo randomized controlled trial

73 y/o male C-ANCA/PR3-ANCA positive patient

B. Prednisone, cyclophosphamide, TMP/SMX

D. Prednisone, cyclophosphamide, etanercept

E. Prednisone, rituximab, TMP/SMX

Which of the following statements about

A. Asthma usually precedes eosinophilia and vasculitis.

© 2014 American College of Chest Physicians

© 2014 American College of Chest Physicians

• Follow principles of therapy for AAV

• Glucocorticoids are mainstay of therapy

• Steroid sparing agents: MTX, AZA

Keogh. Seminars Respir Crit Care 2006; 27:148

• ANCA correlates with vasculitis activity and portends more

• Leukotriene receptor antagonists seem to unmask - not

• Other drugs (omalizumab) can have same effect*.

• When vasculitis is treated successfully patients are

• Dyspnea and hypoxemia

• Diffuse alveolar infiltrates on CXR

• Low and/or falling Hgb (iron-deficiency)

© 2014 American College of Chest Physicians

© 2014 American College of Chest Physicians

Blood - Alveolar hemorrhage, bronchial source

Cells - Alveolar cell CA, lymphoma

Protein - Alveolar proteinosis

© 2014 American College of Chest Physicians

• Rule out infec(ous e(ology

© 2014 American College of Chest Physicians

Capillaritis is the cause of diffuse alveolar

A. Microscopic polyangiitis

© 2014 American College of Chest Physicians

Serology C-‐ANCA/PR3-‐ANCA P-‐ANCA/MPO-‐ANCA

•  Remission induction therapy

Ø  No role for etanercept (anti-TNF) in addition to standard Rx.

•  Double-blind, double-placebo randomized controlled trial

A.  Asthma usually precedes eosinophilia and vasculitis.

•  Follow principles of therapy for AAV

•  Glucocorticoids are mainstay of therapy

•  Steroid sparing agents: MTX, AZA

•  ANCA correlates with vasculitis activity and portends more

•  Leukotriene receptor antagonists seem to unmask - not

•  Other drugs (omalizumab) can have same effect*.

•  When vasculitis is treated successfully patients are

•  Dyspnea and hypoxemia

•  Diffuse alveolar infiltrates on CXR

•  Low and/or falling Hgb (iron-deficiency)

•  Rule out infec(ous e(ology

A.  Microscopic polyangiitis

Ø  worse mortality (RR 3.78) Hogan 1996

•  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 ?

•  Methyl-prednisolone: yes or no?

•  Majority with renal involvement

•  Portends poor prognosis, high mortality (80%)