anca associated pulmonary vasculitis management guidelines

1. ANCA Associated Pulmonary
Vasculitis
Bayyaram Rambhoopal Reddy
1st year DM Resident

2. Introduction
• • The vasculitides are a set of related disorders characterized by
blood vessel inflammation leading to tissue or end‐organ injury
• Differentiated from other vascular disorders by the presence of
inflammation of the vessel wall as compared to bland vasculopathy.
• Small vessel vasculitis, usually associated with antineutrophil
cytoplasmic antibodies (ANCA), is relatively common, and frequently
affects the lung in the form of diffuse alveolar hemorrhage (DAH),
pulmonary nodules, cavities or parenchymal infiltrates. The large and
medium vessel vasculitides are rarer, and the spectrum of their
clinical manifestations are less well-known, yet they may also feature
prominent pulmonary involvement.

3. Differential diagnosis
• Pulmonary nodules and parenchymal infiltrates
• Infection
• Malignancy
• Connective tissue disease
• PA aneurysms
• DAH
• Pulmonary infarction

4. Frankel SK, Jayne D. The
Pulmonary Vasculitides.
Clin Chest Med 31
(2010) 519–536

5. ACR classification criteria
Sensitivity 71∙0% ‐ 95∙3%
Specificity 78∙7% ‐ 99∙7%
Frankel SK, Jayne D. The Pulmonary Vasculitides. Clin Chest Med 31 (2010)
519–536

6. Limitations
1. ANCA  developed afterwards
2. No distinction made between poly arteritis
nodosa and MPA
3. Evolving diagnostic techniques and
pathophysiology has made distinction easier
4. Not intended to be used as diagnostic but as
classification criteria

7. Chapel Hill Consensus Conference (CHCC)
• Held at Chapel Hill, North Carolina
• Goals
– To reach consensus on the names for some of the most
common forms of noninfectious systemic vasculitis
– To construct root definitions for the vasculitides so
named
• Jennette JC, Falk RJ, Andrassy K, et al. Nomenclature of
systemic vasculitides. Proposal of an international
consensus conference. Arthritis Rheum 1994;37:187

8. 2012 revised chapel hill consensus
classification of vasculitis
,

9. • Granulomatosis with polyangitis
– Granulomatous inflammation involving the respiratory tract, and
necrotizing vasculitis affecting small to medium‐sized vessels
(e.g., capillaries, venules, arterioles, and arteries)
– Necrotizing glomerulonephritis is common
• Eosinophilic granulomatous polyangitis
– Eosinophil‐rich and granulomatous inflammation involving the
respiratory tract, and necrotizing vasculitis affecting small to
medium‐sized vessels, and associated with asthma and
eosinophilia.

10. • Microscopic polyangiitis
– Necrotizing vasculitis, with few or no immune deposits,
affecting small vessels (i.e., capillaries, venules, or arterioles)
– Necrotizing arteritis involving small and medium sized arteries
may be present
– Necrotizing glomerulonephritis is very common
– Pulmonary capillaritis often occurs

12. • Sorensen etal tested the CHCC for diagnosis and
found that only 8 of 27 patients were diagnosed with
Wegener’s granulomatosis, and 3 of 12 cases with
microscopic polyangiitis
Surrogate parameters for vasculitis

14. • New diagnostic criteria:
– Wegener’s granulomatosis
1. Biopsy or surrogate parameter for granulomatous
inflammation in the respiratory system
2. Biopsy verified necrotising vasculitis in small to
medium sized vessels or biopsy/surrogate parameter
for glomerulonephritis or positive PR3‐ANCA test
3. Lack of eosinophilia in blood and biopsy samples

15. – Microscopic polyangiitis
1. Biopsy verified necrotising vasculitis in small vessels and/or
glomerulonephritis with few or no immune deposits
2. Involvement of more than one organ system as indicated
by biopsy verified vasculitis in small to medium sized
vessels or surrogate parameter for glomerulonephritis
3. Lack of biopsy and surrogate parameter for granulomatous
inflammation in the respiratory system
• Sorensen SF, Slot O, Tvede N, Petersen J. A prospective study of
vasculitis patients collected in 5‐year period: evaluation of the
Chapel Hill nomenclature. Ann Rheum Dis 2000;59:478–82.

16. • Lane etal  evaluated the Sorensen criteria and found
that
– They were not useful for MPA
– The exclusion of eosinophilia limited the usefulness of the
criteria for WG
• Lane SE, Watts RA, Barker THW, Scott DGI. Evaluation of the
Sorensen diagnostic criteria in the classification of systemic
vasculitis. Rheumatology 2002;41:1138–41.

17. • An algorithm to classify ANCA associated vasculitis for
epidemiological studies was developed that included
MPA and incorporated ANCA
• Known as the EMEA (European Medicine Agency)
algorithm
• However, this was too cumbersome to use in individual
patients
• Watts R, Lane S, Hanslik T et al. Development and validation of a
consensus methodology for the classification of the ANCA
associated vasculitides and polyarteritis nodosa for
epidemiological studies. Ann Rheum Dis 2007; 66:222–7

18. Recent revision of the classification scheme based on
1. The traditional approach of classifying vasculitis by size
of predominant vessel involved
2. Diagnostic auto‐antibodies (ANCA)
3. Current understanding of pathogenesis
» Watts RA, Suppiah R,Merkel PA, Luqmani R. Systemic vasculitis
– is it time to reclassify? Rheumatology 2011;50:643‐645

19. Management

20. Mukhtyar C etal. EULAR recommendations for the management of
primary small and medium vessel vasculitis. Ann Rheum Dis 2009;68:310–317.

21. ACR 2021 disease severity classification
• Active disease: new, persistent, or worsening clinical signs and/or symptoms
attributed to GPA, MPA, or EGPA and not related to prior damage
• Severe disease: Vasculitis with life- or organ-threatening manifestations (e.g.,
alveolar haemorrhage, glomerulonephritis, central nervous system vasculitis,
mononeuritis multiplex, cardiac involvement, mesenteric ischemia, limb/digit
ischemia)
• Nonsevere disease: Vasculitis without life- or organ-threatening manifestations
(e.g., rhinosinusitis, asthma, mild systemic symptoms, uncomplicated cutaneous
disease, mild inflammatory arthritis)
• Remission: Absence of clinical signs or symptoms attributed to GPA, MPA, or
EGPA, on or off immunosuppressive therapy
• Refractory disease: Persistent active disease despite an appropriate course of
immunosuppressive therapy
• Relapse: Recurrence of active disease following a period of remission

22. Frankel SK, Jayne D. The Pulmonary Vasculitides. Clin Chest Med 31 (2010) 519–536

23. Recommendations and ungraded position
statements for GPA and MPA
Remission induction for active, severe disease Recommendation:
For patients with active, severe GPA/MPA, we conditionally
recommend treatment with rituximab over cyclophosphamide for
remission induction
In patients with GPA/MPA with active glomerulonephritis, we
conditionally recommend against the routine addition of plasma
exchange to remission induction therapy
In patients with active, severe GPA/MPA with alveolar hemorrhage,
we conditionally recommend against adding plasma exchange to
remission induction therapies

24. For patients with active, severe GPA/MPA, we conditionally
recommend a reduced-dose glucocorticoid regimen over a standard-
dose glucocorticoid regimen for remission induction
Ungraded position statement: For patients with active, severe
GPA/MPA, either IV pulse glucocorticoids or high-dose oral
glucocorticoids may be prescribed as part of initial therapy

25. Remission induction for active, nonsevere disease Recommendation:
 For patients with active, nonsevere GPA, we conditionally recommend initiating
treatment with methotrexate over cyclophosphamide or rituximab
: For patients with active, nonsevere GPA, we conditionally recommend initiating
treatment with methotrexate and glucocorticoids over glucocorticoids alone
For patients with active, nonsevere GPA, we conditionally recommend initiating
treatment with methotrexate and glucocorticoids over azathioprine and
glucocorticoids or mycophenolate mofetil and glucocorticoids
For patients with active, nonsevere GPA, we conditionally recommend initiating
treatment with methotrexate and glucocorticoids over trimethoprim/
sulfamethoxazole and glucocorticoids.

26. Remission maintenance
For patients with severe GPA/MPA whose disease has entered remission
after treatment with cyclophosphamide or rituximab, we conditionally
recommend treatment with rituximab over methotrexate or azathioprine
for remission maintenance.
For patients with GPA/MPA who are receiving rituximab for remission
maintenance, we conditionally recommend scheduled re-dosing over using
ANCA titers or CD19+ B cell counts to guide re-dosing
For patients with severe GPA/MPA whose disease has entered remission
after treatment with cyclophosphamide or rituximab, we conditionally
recommend treatment with methotrexate or azathioprine over
mycophenolate mofetil for remission maintenance.

27. For patients with severe GPA/MPA whose disease has entered remission
after treatment with cyclophosphamide or rituximab, we conditionally
recommend treatment with methotrexate or azathioprine over
leflunomide for remission maintenance
For patients with GPA whose disease has entered remission, we
conditionally recommend treatment with methotrexate or azathioprine
over trimethoprim/sulfamethoxazole for remission maintenance
In patients with GPA whose disease has entered remission, we
conditionally recommend against adding trimethoprim/sulfamethoxazole
to other therapies (e.g., rituximab, azathioprine, methotrexate, etc.) for the
purpose of remission maintenance

28. For patients with GPA/MPA receiving remission maintenance therapy
with rituximab who have hypogammaglobulinemia (e.g., IgG<3gm/l)
and recurrent severe infection, we conditionally recommend
immunoglobulin supplementation
Ungraded position statement: The duration of nongluco - corticoid
remission maintenance therapy in GPA/MPA should be guided by the
patient’s clinical condition, preferences, and values
Ungraded position statement: The duration of glucocorticoid therapy
for GPA/MPA should be guided by the patient’s clinical condition,
preferences, and values.

29. Treatment of disease relapse
 For patients with GPA/MPA who have experienced relapse with
severe disease manifestations and are not receiving rituximab for
remission maintenance, we conditionally recommend treatment with
rituximab over cyclophosphamide for remission re-induction
For patients with GPA/MPA who experienced relapse with severe
disease manifestations while receiving rituximab for remission
maintenance, we conditionally recommend switching from rituximab
to cyclophosphamide over receiving additional rituximab for
remission re-induction

30. Treatment of refractory disease
For patients with severe GPA/MPA that is refractory to treatment
with rituximab or cyclophosphamide for remission induction, we
conditionally recommend switching treatment to the other therapy
over combining the 2 therapies
For patients with GPA/MPA that is refractory to remission induction
therapy, we conditionally recommend adding IV immunoglobulin
(IVIG) to current therapy

31. • Treatment of sinonasal, airway, and mass lesions
 Ungraded position statement: For patients with sinonasal involvement in GPA, nasal
rinses and topical nasal therapies (antibiotics, lubricants, and glucocorticoids) may be
beneficial
For patients with GPA in remission who have nasal septal defects and/or nasal bridge
collapse, we conditionally recommend reconstructive surgery, if desired by the patient
For patients with GPA and actively inflamed subglottic and/or endobronchial tissue with
stenosis, we conditionally recommend treating with immunosuppressive therapy over
surgical dilation with intralesional glucocorticoid injection alone
For patients with GPA and mass lesions (e.g., orbital pseudotumor or masses of the
parotid glands, brain, or lungs), we conditionally recommend treatment with
immunosuppressive therapy over surgical removal of the mass lesion with
immunosuppressive therapy

32. Other considerations
In patients with GPA/MPA, we conditionally recommend against dosing
immunosuppressive therapy based on ANCA titer results alone.
For patients with GPA/MPA who are receiving rituximab or
cyclophosphamide, we conditionally recommend prophylaxis to prevent P
jirovecii pneumonia
For patients with GPA/MPA in remission and stage 5 chronic kidney
disease, we conditionally recommend evaluation for renal transplant
For patients with active GPA/MPA who are unable to receive other
immunomodulatory therapy, we conditionally recommend administering
IVIG
The optimal duration of anticoagulation is unknown for patients with
GPA/MPA who experience venous thrombotic events

35. Recommendations and ungraded position
statements for EGPA
Remission induction for active, severe disease
Ungraded position statement: For patients with active, severe EGPA,
either IV pulse glucocorticoids or high-dose oral glucocorticoids may
be prescribed as initial therapy
Ungraded position statement: For patients with active, severe EGPA,
either cyclophosphamide or rituximab may be prescribed for
remission induction
For patients with active, severe EGPA, we conditionally recommend
treatment with cyclophosphamide or rituximab over mepolizumab for
remission induction

36. Remission induction for active, nonsevere disease
For patients with active, nonsevere EGPA, we conditionally recommend
initiating treatment with mepolizumab and glucocorticoids over
methotrexate, azathioprine, or mycophenolate mofetil and glucocorticoids
For patients with active, nonsevere EGPA, we conditionally recommend
initiating treatment with methotrexate, azathioprine, or mycophenolate
mofetil and glucocorticoids over glucocorticoids alone
For patients with active, nonsevere EGPA, we conditionally recommend
initiating treatment with methotrexate, azathioprine, or mycophenolate
mofetil and glucocorticoids over cyclophosphamide or rituximab and
glucocorticoids

37. Remission maintenance
For patients with severe EGPA whose disease has entered remission with
cyclophosphamide therapy, we conditionally recommend treatment with
methotrexate, azathioprine, or mycophenolate mofetil over rituximab for
remission maintenance
For patients with severe EGPA whose disease has entered remission, we
conditionally recommend treatment with methotrexate, azathioprine, or
mycophenolate mofetil over mepolizumab for remission maintenance
Ungraded position statement: The duration of glucocorticoid therapy in
EGPA should be guided by the patient’s clinical condition, values, and
preferences.

38. Treatment of disease relapse
For patients with EGPA who have experienced relapse with severe disease
manifestations after prior successful remission induction with
cyclophosphamide, we conditionally recommend treatment with rituximab
over cyclophosphamide for remission re-induction
For patients with EGPA who have experienced relapse with severe disease
manifestations after prior successful remission induction with rituximab,
we conditionally recommend treatment with rituximab over switching to
cyclophosphamide for remission re-induction
For patients with EGPA who have experienced relapse with nonsevere
disease manifestations (asthma and/or sinonasal disease) while receiving
methotrexate, azathioprine, or mycophenolate mofetil, we conditionally
recommend adding mepolizumab over switching to another agent

39. For patients with EGPA who have experienced relapse with nonsevere
disease manifestations (asthma and/or sinonasal disease) while
receiving low-dose glucocorticoids and no other therapy, we
conditionally recommend adding mepolizumab over adding
methotrexate, azathioprine, or mycophenolate mofetil
For patients with EGPA and high serum IgE levels who have
experienced relapse with nonsevere disease manifestations (asthma
and/or sinonasal disease) while receiving methotrexate, azathioprine,
or mycophenolate mofetil, we conditionally recommend adding
mepolizumab over adding omalizumab

40. Other considerations
For patients with newly diagnosed EGPA receiving leukotriene inhibitors, we conditionally
recommend continuing leukotriene inhibitors over discontinuing them
Ungraded position statement: Use of leukotriene inhibitors is not contraindicated for patients
with EGPA with active asthma and/or sinonasal disease
For patients with EGPA, we conditionally recommend obtaining an echocardiogram at the time of
diagnosis
For patients with EGPA, we conditionally recommend using the Five-Factor Score to guide therapy
Ungraded position statement: In patients with sinonasal involvement in EGPA, treatment with
nasal rinses and topical therapies (e.g., antibiotics, lubricants, and glucocorticoids) may be
considered
For patients with EGPA who are receiving cyclophosphamide or rituximab, we conditionally
recommend prescribing medications for prophylaxis to prevent P jirovecii pneumonia.

50. Take home message
Induction of Remission
First-line agents for induction of remission in severe GPA and MPA include
cyclophosphamide or rituximab, along with glucocorticoids
Rapid reduction of glucocorticoids is safe and should be considered for
induction of remission in severe GPA and MPA
Avacopan, if confirmed safe and cost-effective, may become an alternative
to GC and lead to a GC-free regimen of AAV
Plasma exchange is no longer routinely recommended in most patients
with severe GPA and MPA; it has not been proven effective in terms of
survival and reduction of ESRD risk in patients with severe disease. PLEX
can still be considered in carefully selected patients in conjunction with
vasculitis expert opinions

51. Maintenance of Remission
Rituximab should be considered as the first-choice agent for maintenance
of remission; azathioprine and methotrexate are appropriate alternatives if
rituximab is unavailable or contraindicated
Longer treatment duration with rituximab for maintenance of remission
reduces relapses in severe GPA and MPA, but it is unclear to date whether
all patients, or only some subsets, would benefit of 4- year duration of
repeated, systematic RTX infusions
Leflunomide and mycophenolate mofetil can be used when RTX, MTX, and
AZA are contraindicated or not tolerated
The role of low-dose prednisone in maintenance of remission is not
definitely demonstrated or established (ongoing studies)

52. Thank you