1. The Pulmonary Vasculitides
Stephen K. Frankel and Marvin I. Schwarz
Am J Respir Crit Care Med Vol 186, P216–224  
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2. Definitions of Vasculitis
Disorders of inflammation and necrosis of the blood vessel wall
Categorized by the size of vessel involved (small, medium, and large),
the underlying immunologic mechanism (pauci-immune, immune-
complex mediated), and associated systemic disease

3. Definitions of ANCA-associated vasculitis by the Chapel Hill conference consensus, 1994
ANCA-associated vasculitides (AAVs)
Necrotising vasculitis of small & medium sized vessels
Commonly associated with ANCA
Commonly involve the respiratory tract
1. Granulomatosis with polyangiitis (GPA)
(no longer called Wegener’s granulomatosis)
2. Microscopic polyangiitis (MPA)
3. Churg-Strauss Syndrome (CSS)
(Eosinophilic Granulomatosis with Polyangiitis (EGPA))
4. Idiopathic pauci-immune pulmonary capillaritis (IPIPC)
Lancet 2006; 368: 404–18

4. Epidemiology ANCA-associated vasculitis is rare
(overall incidence cases/million/year)
- There is no gender predominance
- The peak incidence is in the fourth through sixth decades
: children or adolescents are rarely affected
Churg-Strauss syndrome is quite rare, even less common than both
GPA & MPA
Survival rates are decreased compared to the general population
(RR 2.6) with 1, 2, and 5 year survival rates of 88, 85, and 78% overall
Poor prognostic factors
- Older age, greater disease activity, alveolar hemorrhage,
cardiac involvement, and proteinase-3 positivity

5. Clinical manifestations

6. Granulomatosis with Polyangiitis (formerly Wegener’s)
Commonly affects the upper respiratory tract (>85%)
(otitis, hearing loss, sinusitis, epistaxis, nasal septal perforation, mastoiditis, and saddle nose deformity)
Lower respiratory tract (>80%)
(cough, dyspnea, chest discomfort, hemoptysis, diffuse alveolar hemorrhage, pulmonary nodules, cavities, and infiltrates)
Tracheobronchial tree (50-60%) (stenosis, ulceration)

7. Microscopic polyangiitis
Less commonly involves the upper respiratory tract (<15%) and lower respiratory tract (diffuse alveolar hemorrhage in up to 30%, but also infiltrates, pulmonary artery aneurysms, fibrosis, and airway disease)
Constitutional symptoms and extrapulmonary involvement (renal, cutaneous, musculoskeletal, ocular, cardiovascular, and peripheral nerves) occur in both granulomatous polyangiitis and microscopic polyangiitis
Glomerulonephritis and constitutional symptoms are particularly common in both, and are nearly the rule in microscopic polyangiitis

8. Idiopathic pauci-immune pulmonary capillaritis
“Lung-limited microscopic polyangiitis” presenting as isolated diffuse alveolar hemorrhage.

9. Churg-Strauss Syndrome
The triad of asthma, eosinophilia, and vasculitis, described to occur in three phases of disease:
- Prodromal, allergic/atopic phase
: manifest as asthma and rhinosinusitis
: asthma generally precedes vasculitis by an average of 7-8 years
and is often severe and steroid-dependent
- Eosinophilic phase
: tissue eosinophilic inflammation including eosinophilic pneumonia
- Vasculitic phase: palpable purpura and mononeuritis multiplex
Upper airway disease (70-90%) is generally non-destructive (in contrast to GPA) manifest as chronic rhinosinusitis
Extrapulmonary manifestations are common, but cardiac involvement (30-50%) is responsible for half the mortality

10. Diagnosis
The diagnosis is made clinically through the integration of clinical,
laboratory, radiographic, and pathology data.
Clinical scenarios that should prompt the consideration of ANCA-
associated vasculitis
Diffuse alveolar hemorrhage
Tracheal or subglottic stenosis
Pulmonary nodules and cavities
Glomerulonephritis
Destructive or ulcerating upper airway disease
Mononeuritis multiplex
Retroorbital mass
Palpable purpura
For Churg-Strauss
: severe or refractory adult-onset asthma, peripheral eosinophilia,
or eosinophilic pneumonia

11. Anti-Neutrophil Cytoplasmic Antibodies (ANCAs)
Characteristic, but not required for their diagnosis, if histopathology and clinical features are diagnostic.
- markers of disease
- involved in pathogenesis by promoting neutrophil migration and
degranulation in vessel walls
- may correlate (to some degree) with disease activity
c-ANCA = neutrophil cytoplasmic staining
- antibodies specifically directed at proteinase 3 (PR 3)
- found in GPA (85-90% sensitivity and 95% specificity
: Sensitivity is decreased when disease is limited (60%) or in
remission (40%)
p-ANCA = neutrophil perinuclear staining
- antibodies specifically directed against myeloperoxidase (MPO)
- associated with MPA and CSS.

12. 15% of patients are <19 years of age, but only rarely does the disease occur before adolescence; the mean age of onset is 40 years.
Lancet 2006; 368: 404–18

13. Histopathology
Usually required to confirm a pulmonary vasculitis diagnosis, especially considering the likely side effects of heavy immunosuppressive treatments and the need to rule out infection as the leading differential diagnosis
Should be sent for microbiologic studies in addition to histopathology and immunofluorescence staining
The role of bronchoscopy is mainly to evaluate for diffuse alveolar hemorrhage, infection
- Transbronchial biopsies are usually not diagnostic
Skin and sinus biopsy are minimally invasive but lower yield
Renal biopsy and surgical lung biopsy are probably the highest yield
15% of patients are <19 years of age, but only rarely does the disease occur before adolescence; the mean age of onset is 40 years.

14. Scoring systems for disease activity and severity
Birmingham Vasculitis Activity Score (BVAS)
Five Factor Score (FFS)
Vasculitis Damage Index (VDI)
European Vasculitis Study Group Vasculitis Activity
Score (EUVAS)

15. The Birmingham Vasculitis Activity Score (BVAS)
Ann Rheum Dis 68(12):

16. The Five-Factor Score
Medicine (Baltimore) Jan;90(1):19-27

17. Grading Disease Severity - Treatment

18. Oral Cyclophosphamide combined with Prednisone
In 1983, Fauci and Wolff introduced a regimen that significantly improved
outcome
Prednisone 1 mg/kg daily
(Tapered and discontinued after 6 to 9 months)
Oral cyclophosphamide 1-2 mg/kg daily
(continued minimum of 1 year past remission)
→ Favorable responses were noted in 70 to 95% of patients,
with 5 year mortality rates of <15%
: Relapses were noted in 30 to 70% of patients following cessation or tapering
but reinstitution of therapy was usually efficacious
Ann Intern Med 1983;98:76–85

19. Early Generalized Disease
The identification of cyclophosphamide and corticosteroids as
effective therapy for the induction of disease remission
Recent studies suggest that patients with milder disease may be
candidates for treatment with less potent agents
Methotrexate (MTX) demonstrated similar 6 month remission rates compared to cyclophosphamide but slower time to remission and higher relapse rates in the NORAM study
Mycophenolate mofetil (MMF) was evaluated in a small series of mild-moderate renal MPA patients with high remission rates. There is an ongoing RCT comparing MMF to cyclophosphamide
Azathioprine (AZA) has also been used, but with less evidence for the induction phase. 

20. Recent regimens Sequelae of vasculitis or complications of CYC
-> contributed to late mortality and morbidity
: eg, cerebrovascular accidents, myocardial infarction, renal failure, hypertension
: eg, opportunistic infections, neoplasia
Recognition of treatment-related toxicities and the chronically relapsing nature
of the disease led to a search for less toxic therapeutic options
Recent regimens
Initial “Induction phase"
[to assure complete remission (CR)]
Followed by less intense “Maintenance therapy”
[to minimize long-term toxicities]

21. Remission-Induction Therapy : CYC + CS
CYC and CS
: Preferred induction therapy for severe, generalized WG
Induction regimen is continued for 3 to 6 months until complete remissions
have been achieved
Mild or limited WG and preserved renal function
: MTX, MMF, or leflunamide (LEF) can be utilized in place of CYC
as induction therapy
CYC-refractory or chronic persistent disease
: may require additional treatment options such as rituximab or infliximab
Treatment of Wegener's granulomatosis with intermittent high-dose intravenous cyclophosphamide. Am J Med 1990; 89(4):403–410

22. IV "pulse" CYC achieves remission rates comparable to daily oral CYC,
IV pulse CYC Vs. Oral CYC
IV "pulse" CYC achieves remission rates comparable to daily oral CYC,
but has been associated with higher relapse rates
149 patients with newly diagnosed generalized AAV
=> IV pulse CYC (n = 76) or daily oral CYC (n = 73) (both combined with CS)
Time to remission and percent of CR were similar between groups
(CR: 88.1% in IV pulse CYC / 87.7% in oral CYC)
The cumulative dose of CYC was lower among those receiving pulse versus
oral therapy (8.2 g vs 15.9 g, p < 0.001)
Am J Med 1990; 89(4):403–410
A prospective study (CYCLOPS trial)
159 patients with newly diagnosed AAV (WG, n = 32 or MPA, n = 8)
=> IV CYC plus CS as initial induction therapy
CR were achieved in 126 (79.2%)
Among patients failing induction therapy with IV CYC,
: 20 were switched to oral CYC, with favorable responses in 15 (75%)
Ann Intern Med 2009;150(10):670–680
137
Treatment of Wegener's granulomatosis with intermittent high-dose intravenous cyclophosphamide. Am J Med 1990; 89(4):403–410
138
Pulse versus daily oral cyclophosphamide for induction of remission in antineutrophil cytoplasmic antibody-associated vasculitis: a randomized trial. Ann Intern Med 2009;150(10):670–680

23. Maintenance therapy
Maintenance regimen is continued at least 18 months
: less toxic agents [eg, methotrexate (MTX), azathioprine (AZA),
or mycophenolate mofetil (MMF)] can be substituted for CYC
MTX or AZA (combined with low-dose CS) has been utilized most often
: MMF has been associated with higher relapse rates compared to
azathioprine and thus may be reserved for patients intolerant of AZA
or MTX
Steroids are generally tapered to the lowest tolerated dose or
discontinuation during the maintenance phase
Randomized trial of cyclophosphamide versus methotrexate for induction of remission in early systemic antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum 2005; 52(8):2461–2469

24. CYCAZAREM study
(Cyclophosphamide versus Azathioprine
for Remission in Generalized Vasculitis)
After remission, randomly assigned
: continued cyclophosphamide (n=79, 1.5 mg/kg/day)
or azathioprine (n=76, 2 mg/kg/day)
Both groups continued to receive CS and were followed for 18 months
Relapse was the primary end point.
Of 155 patients studied,
Remission: Azathioprine (n=71) / continued cyclophosphamide (n=73)
Relapse: Azathioprine (n=11, 15.5 %) / cyclophosphamide (n=10, 13.7%, P=0.65)
=> The withdrawal of cyclophosphamide and the substitution of azathioprine after
remission did not increase the rate of relapse
N Engl J Med 2003;349:36-44

25. IMPROVE trial In open, randomized, multicenter European trial
156 patients with AAV who achieved CR with CYC/CS therapy
Randomized: AZA (n=80, 2 mg/kg/day) or MMF (n=76, 1000 mg twice a day)
and followed for a median of 39 months
Relapses: in the MMF cohort (42/76, 55%) in the AZA cohort (30/80, 37.5%)
Side effect profiles were similar
=> AZA is superior to MMF for maintenance of remissions
JAMA 2010 ;304(21):1237–1240

26. Treatment of refractory disease
Disease unresponsive to conventional therapy
: can be treated with cytolytic agents, monoclonal antibodies,
or other immunosuppressive agents,
: but data are limited
Tumor necrosis factor-α
Rituximab : an anti-CD20 monoclonal antibody
High-dose IV immunoglobulin (IV IgG)
Alemtuzumab (CAMPATH-1H) : an anti-CD 52 monoclonal antibody
Monoclonal antibodies targeted against T cells
Humanized anti-CD4 antibodies
Anti-thymocyte globulin (ATG)
15-deoxyspergualin
Etoposide
Cyclosporin A
Rapamycin
Autologous hematopoietic stem cell transplants

27. RAVE trial
Rituximab therapy was not inferior to daily cyclophosphamide treatment for
induction of remission in severe AAV
may be superior in relapsing disease
A multicenter, randomized, double-blind, noninferiority trial
197 ANCA-positive patients with either WG or MPA
Rituximab(375 mg/m2 weekly for 4 weeks) Vs Cyclophosphamide(2 mg/kg/day)
for remission induction
The primary end point
: Remission of disease without the use of prednisone at 6 months
Remission rate
: 63 in the rituximab group (64%) / 52 in the control group (53%)
=> Results met the criterion for noninferiority (P<0.001)
Remission of relapsing disease
: 34 /51(67%) in the rituximab group Vs. 21/50 (42%) in the control group
(P = 0.01)
Rate of adverse events
: No significant differences between the treatment groups
N Engl J Med 2010;363:221-32

28. RITUXVAS trial
RITUX group
(n=33)
Control group
(n=11)
Remission rate
25 of 33 (76%)
9 of 11 (82%)
p = 0.68
Median time
To remission
90 days
94 days
p = 0.87
Serious adverse events
14 (42%)
4 (36%)
p = 0.77
An open-label randomized trial by the European Vasculitis Study Group
(RITUXIVAS trial)
Compared RITUX versus IV pulse CYC as induction therapy for AAV
44 patients with newly diagnosed AAV and renal involvement
Randomized in a 3:1 ratio to RITUX (n = 33) or CYC (n = 11)
Rituximab (375 mg/m2 weekly for 4 weeks)
In the RITUX group, patients received CS and two pulses of IV CYC
: did not receive AZA to maintain remission
The control group received conventional IV CYC for 3 to 6 months
: followed by AZA
N Engl J Med 2010;363:211-20

29. Monitoring of immunosuppressive therapy
Don’t forget vaccinations and other considerations for patients on chronic steroids including bone health and PCP prophylaxis
Trimethoprim-sulfamethoxazole
: Stegeman et al.
- Randomized 81 patients who were in remission
- Trimethoprim-sulfamethoxazole or placebo
82% maintain remission (study) Vs 60% maintain remission
(placebo)
Recurrence rate of nasal and upper airway lesions was
lower by reducing nasal carriage of staphylococcus aureus
=> PCP prophylaxis for all patients who are not allergic to sulfa drugs and who are receiving glucocorticoids plus a cytotoxic agent

30. Longitudinal monitoring
Vasculitis is a chronic, systemic disease characterized by periods
of waxing and waning disease activity
In any patient with vasculitis with new signs or symptoms the
differential diagnosis must always consider
(1) vasculitis flare/disease activity, (2) infection
(3) thromboembolic disease (4) drug toxicity
(5) disease states unrelated to the vasculitis or its therapy
Causes of death in patients with vasculitis
- Infection, pneumonia, and sepsis in particular, active vasculitis,
cardiovascular disease (myocardial infarction, cerebrovascular
accident, pulmonary embolus), and malignancy