ANCA-associated Vasculitides

1. The Clinical Features and Treatment
of ANCA-Associated Vasculitis
Evan Nair-Gill MD, PhD
Internal Medicine Resident, UTSW

3. VASCULITIS: Inflammation of blood vessels
Vessel aneurysm,
hemorrhage
Vessel thrombosis,
ischemia and necrosis
Target tissue damage and systemic disease
(manifestations dependent on the size and distribution of affected vessels)

4. The spectrum of primary vasculitic diseases
Immune Complex Small Vessel Vasculitis
Cryoglobulinemic Vasculitis
IgA Vasculitis (HSP)
Hypocomplementemic Urticarial Vasculitis
(Anti-C1q)
Anti-GBM disease
Medium Vessel Vasculitis
Polyarteritis Nodosa
Kawasaki Disease
ANCA-Associated Small Vessel Vasculitis
Microscopic Polyangiitis
Granulomatosis with Polyangiitis
(Wegener’s)
Eosinophilic Granulomatosis with Polyangiitis
(Churg-Strauss)
Large Vessel Vasculitis
Takayasu Arteritis
Giant Cell Arteritis
Jennette JC, Falk RJ, Bacon PA, et al. 2012 revised International Chapel Hill Consensus
Conference Nomenclature of Vasculitides. Arthritis Rheum 2013; 65:1.

5. Major Features of ANCA-Associated Vasculitis
Granulomatosis with polyangiitis
(GPA, Wegener’s granulomatosis)
Microscopic polyangiitis
(MPA)
Eosinophilic GPA
(EGPA, Churg-Strauss)
(1) Necrotizing vasculitis of small and
medium-sized vessels
(2) Absence of immune deposits on
vessel pathology
(3) ANCA positive
-~30,000 people have GPA and ~10,000 people have MPA in the US.
-~2600 new cases of GPA and 900 new cases of MPA are seen annually in the United States
-EGPA is rarer and estimated to affect about 3 people per million
-68,000 to 140,000 new cases of ANCA-associated vasculitis are diagnosed per year worldwide
-Onset for AAV is typically after the 5th decade but cases have been reported for all ages.
-Majority of patients are of Caucasian ancestry
-Slight male predominance (1.5:1 male:female)
Epidemiology and demographics

6. ANCAs: Antibodies against cytoplasmic antigens in neutrophils
P-ANCA is an antibody typically directed against myeloperoxidase (MPO), associated with MPA and EGPA
http://www.unckidneycenter.org
Perinuclear staining pattern: P-ANCA Cytoplasmic staining pattern: C-ANCA
C-ANCA is an antibody typically directed against proteinase-3 (Pr-3), associated with GPA
The titer of ANCA does not correlate with disease severity
Other diseases can give ANCA positivity: eg. SLE, RA, UC, PSC, Endocarditis, meds (hydralazine, PTU)

7. A possible role for ANCA in the pathogenesis of AAV
Schönermarck U et al. Nephrol. Dial. Transplant. 2014

8. http://www.mayoclinic.org
x
Clinical Features of ANCA-Associated Vasculitis
GPA MPA EGPA
+
Fevers
Fatigue
Arthralgias
Myalgias
Weight loss

9. Upper Airway Disease
GPA MPA EGPA
x
GPA: epistaxis, otitis media and mastoiditis,
destructive sino-nasal disease and saddle nose
deformity, subglottic stenosis
EGPA: allergic rhinitis, recurrent sinusitis--no
destructive disease, serous otitis media, nasal
polyposis
Kelley’s Texbook of Rheumatology 8th edition
Saddle nose
Erosive sinus disease
Subglottic stenosis, s/p stent
Clinical Features of ANCA-Associated Vasculitis

10. Pulmonary Disease
GPA MPA EGPA GPA/MPA: Hemoptysis. Imaging can show fixed nodules
(+/- cavitation), diffuse infiltrates, hilar adenopathy
EGPA: History of asthma poorly responsive to therapy.
Nodules (often non-cavitary), pleural effusions
(eosinophilic), transient infiltrates on CXR
DAH: Due to pulmonary capillaritis. GPA/MPA>>EGPA
Cavitary lesion in a patient with GPA.
Thickett D R et al. Rheumatology 2006;45:261-268
Capillaritis
http://pathhsw5m54.ucsf.edu/
Clinical Features of ANCA-Associated Vasculitis

11. Renal Disease
GPA MPA EGPA
Jennette, J. C. & Falk, R. J. (2014) Nat. Rev. Rheumatol.
Crescent
Fibrinoid
Necrosis
Asymptomatic hematuria, proteinuria (usually sub-
nephrotic range), AKI, casts on UA. Can present
indolently with preserved renal function or as RPGN.
On biopsy “pauci-immune” crescentic glomerular
nephritis is the typical finding.
RBC Casts
Normal Glomerulus
Clinical Features of ANCA-Associated Vasculitis

12. Cutaneous Manifestations
GPA MPA EGPA
http://www.hopkinsvasculitis.org/
Palpable purpura
Rashes for these three diseases similar to other
small vessel vasculitides: Leukocytoclastic vasculitis
with palpable purpura typically in lower
extremities, ulceration, skin necrosis.
Urticaria, livido reticularis, tender nodules can also
occur.
Ulcerated nodule
Clinical Features of ANCA-Associated Vasculitis

13. Eye and Neurological Problems
GPA MPA EGPA
EGPA: Mononeuritis multiplex is common, rarely CNS
symptoms due to aneurysm or hemorrhage
GPA: Often initial presenting symptom: uveitis,
scleritis, conjunctivitis, corneal ulceration
Mass effect from invading adjacent sinus disease can
cause proptosis
Clinical Features of ANCA-Associated Vasculitis

14. Diagnostic Approach to Small Vessel Vasculitis
Vasculitis suspected
(pulmonary-renal syndrome, purpura, neuropathy)
ANCA associated Not ANCA associated
Granulomatous
NoYes
Asthma/eosinophilia
NoYes
EGPA GPA
MPA
IgA deposit
Yes
IgA vasculitis
(HSP)
No
Cryoglobulins
Yes No
Cryoglobulinemia Other

15. General principles of treating ANCA-associated vasculitis
Assess vasculitis severity
Remission induction (3-6 months)
Maintenance therapy and monitor for relapse
(at least 12-24 months)

16. Induction therapy: GPA and MPA
Prior to Cyc, survival of GPA was ~20% at 18 months. With Cyc this has increased to >80% after 8 years.
Cyclophosphamide (Cyc) combined with glucocorticoids is the mainstay for remission induction for
generalized and severe disease.
Toxicity of sustained Cyc: bone marrow suppression, infection, sterility, induced malignancy, bladder toxicity.
RAVE trial (2010):Rituximab was non-inferior to Cyc for inducing remission and appeared to be more
effective in treating relapsed disease. Adverse events were the same between each group.
In severe disease (RPGN, pulmonary hemorrhage) PLEX is a useful adjunctive therapy.
CYCLOPS trial (2009): IV pulse dosing Cyc was equal to daily oral dosing for inducing remission. Long-term
follow-up (median 4.3 years) showed relapse rates were higher for IV Cyc but overall morbidity and mortality
were unchanged.
Steroids are used regardless of immunosuppression regimen. Pulse dose IV steroids typically used for first 3
days (esp in setting of renal failure, alveolar hemorrhage) then transition to oral prednisone 1mg/kg/day

17. Maintenance therapy for GPA and MPA
Prednisone should be tapered down to the lowest dose to prevent symptoms then tapered off very slowly
(can argue for continuing steroids indefinitely if patient has history of prior relapses).
Methotrexate or azathioprine are the most used medications. Relapse rate ~30% for both. Azathioprine is
preferred in patients with GFR < 50.
Frequent monitoring for drug toxicity and relapse symptoms (hemoptysis, hematuria, cutaneous symptoms,
etc) is necessary.
MAINRITSAN trial (2014) compared rituximab vs. azathioprine for maintaining remission: 29% relapse rate
for azathioprine group vs 5% rituximab group. (Caveat: azathioprine group underwent a dose reduction
not typically used).
Mild relapses (no threat to organs) can be treated by increased prednisone or maintenance
immunosuppression dose. Severe relapses treated with re-induction.

18. Induction and maintenance therapies for EGPA
Five factor score (FFS) to assess severity: Cardiac involvement, Gastrointestinal disease, AKI,
proteinuria >1g/day, CNS symptoms, severe respiratory disease, age>65 all score 1 point.
Patients are usually monitored every 3 months with CBC (for eosinophilia), spirometry, serum
creatinine, UA.
Maintenance therapy with azathioprine or methotrexate + prednisone taper for 12-18 months.
>90% of patients without severe disease—FFS 0 or 1—can be induced to remission with
glucocorticoids alone, usually prednisone 0.5mg/kg-1.5 mg/kg per day.
FFS 2 or more is indication to add Cyc. Dosing protocols are similar to those for GPA/MPA.

19. Summary
AAV generally: necrotizing vasculitis of small to medium vessels, pauci-immune lesions,
predominantly ANCA positive
GPA: Destructive nasal-sinus disease, lung nodules, glomerulonephritis, granulomatous
inflammation, PR3/C-ANCA positive.
MPA: Similar to GPA but less sinus disease, no granulomatous inflammation, more associated with
MPO/P-ANCA.
EGPA: History of asthma, mononeuritis multiplex, peripheral eosinophilia (>10%), eosinophilic
granulomas, migrating or transient CXR infiltrates, MPO/P-ANCA.
Therapy for GPA/MPA: in multi-organ disease use cyclophosphamide or rituximab + steroids.
Duration usually 3-6 months. Maintenance with methotrexate, azathioprine, or rituximab. Taper
slowly off steroids. Treatment for 12-24 months.
Therapy for EGPA: primarily steroids for disease without organ failure. Otherwise Cyc + steroids.
ANCA: autoantibodies against neutrophil enzymes. Likely play pathogenic role in vasculitis. Several
conditions can lead to positive ANCA. Must consider clinical scenario when interpreting ANCA
positivity. ANCA antibody levels not correlated with disease severity.