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The Clinical Features and Treatment of ANCA-Associated Vasculitis

Evan Nair-Gill MD, PhD

Internal Medicine Resident, UTSW

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)

The spectrum of primary vasculitic diseasesImmune Complex Small Vessel Vasculitis

Cryoglobulinemic VasculitisIgA Vasculitis (HSP)Hypocomplementemic Urticarial Vasculitis(Anti-C1q)

Anti-GBM disease

Medium Vessel VasculitisPolyarteritis Nodosa

Kawasaki Disease

ANCA-Associated Small Vessel VasculitisMicroscopic Polyangiitis

Granulomatosis with Polyangiitis(Wegener’s)

Eosinophilic Granulomatosis with Polyangiitis(Churg-Strauss)

Large Vessel VasculitisTakayasu ArteritisGiant 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.

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

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)

A possible role for ANCA in the pathogenesis of AAV

Schönermarck U et al. Nephrol. Dial. Transplant. 2014

http://www.mayoclinic.org

x

Clinical Features of ANCA-Associated Vasculitis

GPA MPA EGPA

+

FeversFatigueArthralgiasMyalgiasWeight loss

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


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/


Renal Disease

GPA MPA EGPA

Jennette, J. C. & Falk, R. J. (2014) Nat. Rev. Rheumatol.

Crescent

FibrinoidNecrosis

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


Cutaneous Manifestations

GPA MPA EGPA

http://www.hopkinsvasculitis.org/

Palpable purpura

Rashes for these three diseases similar to other small vessel vasculitides: Leukocytoclastic vasculitiswith palpable purpura typically in lower extremities, ulceration, skin necrosis.

Urticaria, livido reticularis, tender nodules can also occur.

Ulcerated nodule


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


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

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)

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

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.

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.

SummaryAAV 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%), eosinophilicgranulomas, 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.

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