ANCA Vasculitis Part 1

Question 1

What Is ANCA?

ANCA are antineutrophil cytoplasmic autoantibodies directed against various antigens:

Answer 1

ANCA directed against proteinase 3 (anti-PR3) → cytoplasmic pattern (c-ANCA)

ANCA directed against myeloperoxidase (anti-MPO) → nuclear pattern (p-ANCA)

Question 2

What Is ANCA?

ANCA are antineutrophil cytoplasmic autoantibodies directed against various antigens:

Answer 2

Cystic fibrosis: ANCA directed against bactericidal/permeability-increasing protein

Question 3

What Is ANCA?

ANCA are antineutrophil cytoplasmic autoantibodies directed against various antigens:

Answer 3

Cocaine adulterated with levamisole: all with MPO-ANCA and 50% with positive PR3-ANCA in a series reported from Massachussetts General Hospital involving 30 patients.

Question 4

What Is ANCA?

ANCA are antineutrophil cytoplasmic autoantibodies directed against various antigens:

Answer 4

Others suggest ANCA directed against HNE. Affected patients may present with purpuric to necrotic skin lesions that may involve earlobes and nose. Renal manifestations may include ANCA-associated GN or renal infarction.

Question 5

What Is ANCA?

Answer 5

Cytoplasmic (c-ANCA) or perinuclear (p-ANCA) pattern reflects an artifact that occurs with alcohol fixation of neutrophils. All antigens above (including MPO) are cytoplasmic in vivo.

Question 6

What Is ANCA?

Answer 6

While c-ANCA is anti-PR3, and p-ANCA is typically anti-MPO, c-ANCA and p-ANCA can bind to other proteinases (other than the respective PR3 and MPO) that are not necessarily pathogenic.

Question 7

What Is ANCA?

Answer 7

Testing for ANCA should therefore include both indirect immunofluorescent microscopic assay (IFA) and enzyme immunoassay (EIA). The former is to check for c- or p-ANCA pattern, and the latter is to check for the specificity of ANCA against specific enzymes, that is proteinase 3, myeloperoxidase, or other enzymes.

Question 8

What Is ANCA?

Answer 8

Classic PAN does not have ANCA; hence, ANCA testing may be used to differentiate between ANCA vasculitides and PAN.

Question 9

What Is ANCA?

Answer 9

30% of patients with antiglomerular basement membrane (anti-GBM) positive sera and 25% of patients with idiopathic immune-complex crescentic GN have concurrent ANCA.

Question 10

What Is ANCA?

Answer 10

5% of patients with ANCA-positive sera also have anti-GBM positive sera.

Question 11

Patients with concurrent anti-GBM and ANCA antibodies:

Answer 11

Thought to be either fortuitous coexistence of both anti-GBM and ANCA or anti-GBM develops following glomerular basement membrane (GBM) injury from ANCA-associated GN.

Question 12

Patients with concurrent anti-GBM and ANCA antibodies:

Answer 12

Disease course is similar to anti-GBM GN in early disease, but relapse pattern is similar to ANCA disease. Lone anti-GBM GN typically does not relapse.

Question 13

Evidence for ANCA involvement in pathogenesis of small-vessel vasculitis:

Answer 13

ANCA titers correlate with disease activity within the same individual.

Question 14

Evidence for ANCA involvement in pathogenesis of small-vessel vasculitis:

Answer 14

Drug-induced ANCA production (propylthiouracil, methimazole, hydralazine, pencillamine) is associated with pauciimmune crescentic GN and small-vessel vasculitis.

Question 15

Evidence for ANCA involvement in pathogenesis of small-vessel vasculitis:

Answer 15

Report of neonate with GN and pulmonary hemorrhage from transplacental passage of MPO-ANCA IgG.

Question 16

Proposed chain of events involved in ANCA-induced vasculitis:

Priming of neutrophils by cytokines (e.g., from a viral infection) leads to:

Answer 16

Increased neutrophil expression/trafficking of cytoplasmic ANCA antigens (e.g., PR3 or MPO) onto cell surfaces, where they are accessible to ANCA.

Question 17

The ANCA: antigen interaction in cytokine-primed neutrophils leads to the following:

Answer 17

Neutrophil release of IgG from granules, toxic oxygen metabolites, inflammatory mediators into surroundings and

Question 18

The ANCA: antigen interaction in cytokine-primed neutrophils leads to the following:

Answer 18

Adherence of activated neutrophils to endothelial cells, both leading to endothelial cell injury and/or death, hence vasculitis

Question 19

ANCA Vasculitis

Answer 19

Of note, the onset of ANCA small-vessel vasculitis is frequently associated with an influenza-like syndrome, an indicator of high levels of circulating cytokines, thought to serve as priming factors for neutrophils.

Question 20

ANCA Vasculitis

Clinical Manifestations:

Answer 20

In general ANCA-associated GN may present with relatively low degree of proteinuria and hematuria, acute nephritis with necrosis and new crescents, rapidly progressive nephritis with crescentic GN, or slowly progressive nephritis.

Question 21

ANCA Vasculitis

Clinical Manifestations:

Answer 21

Nonspecific signs and symptoms of necrotizing vasculitis: cutaneous purpura, papular/ulcerated lesions, peripheral neuropathy (mononeuritis multiplex), nonspecific muscular/joint pain, evidence of gastrointestinal bleed, tendency for venous thrombosis

Question 22

ANCA Vasculitis

Clinical Manifestations:

Answer 22

Histopathology: ANCA-associated (pauciimmune) crescentic glomerulonephritis often has crescents in different stages simultaneously (acute, subacute, and chronic) due to the relapsing nature of the disease

Question 23

ANCA Vasculitis

Natural History/Prognosis

Answer 23

Five-year renal and patient survival are approximately 65% to 75%.

Question 24

ANCA Vasculitis

Natural History/Prognosis

Answer 24

Poor prognostic risks: older age, higher presenting SCr/dialysis need, pulmonary hemorrhage

NOTE: Risks for higher relapse rates include respiratory tract involvement and PR3-ANCA serology.

Question 25

ANCA Vasculitis

Natural History/Prognosis

Others:

Answer 25

MPO-ANCA patients tend to present with worse renal impairment and more chronic changes. However, if MPO-ANCA is diagnosed early, it may be associated with better renal outcome compare with PR3-ANCA.

Question 26

ANCA Vasculitis

Natural History/Prognosis

Others:

Answer 26

Patients with eosinophilic granulomatous polyangiitis (Churg–Strauss) typically present with less-severe kidney involvement.

Question 27

ANCA Vasculitis

Management:

Initial treatment:

Answer 27

CYC (0.75 g/m2 IV q 3 to 4 weeks or 1.5 to 2.0 mg/kg/d orally; reduce dose if age > 60 years or GFR < 20 mL/min/1.73 m2) and corticosteroids (methylprednisolone 500 mg IV pulse daily × 3 days, followed by 1 mg/kg/d × 4 weeks, not exceeding 60 mg daily, taper over 3 to 4 months)

Question 28

ANCA Vasculitis

Management:

Initial treatment:

Answer 28

Rituximab (375 mg/m2 weekly × 4) and corticosteroids may be used as alternative initial treatment in patients without severe disease or in whom CYC is contraindicated.

Question 29

ANCA Vasculitis

Management:

Initial treatment:

Answer 29

There is no evidence that either agent above is superior to the other: Remission–induction Regimens for ANCA-Associated Vasculitis “RAVE” trial. Rituximab therapy was not inferior to daily CYC treatment for induction of remission in severe ANCA-associated vasculitis. Note however, RAVE trial excluded patients with severe pulmonary hemorrhage requiring mechanical ventilation or severe renal impairment with SCr > 4.0 mg/dL due to current episode of renal disease activity.

Question 30

ANCA Vasculitis

Management:

Answer 30

All trials report similar adverse effect profiles for rituximab and other immunosuppressive therapies used in the treatment of ANCA vasculitis.

Question 31

ANCA Vasculitis

Management:

Initial treatment:

Plasmapheresis:

Answer 31

Recommended if:

Patients require dialysis at presentation or present with rapidly increasing SCr.

Concurrent diffuse pulmonary hemorrhage

Suggested if concurrent ANCA vasculitis and anti-GBM GN.

Question 32

ANCA Vasculitis

Management:

Initial treatment:

Plasmapheresis:

Answer 32

Plasmapheresis regimen:

60 mL/kg body weight; replacement fluid is 5% albumin. Fresh-frozen plasma may be used at end of apheresis session to replace coagulant factors.

Question 33

ANCA Vasculitis

Management:

Plasmapheresis:

Answer 33

Vasculitis: seven treatments over 14 days if diffuse pulmonary hemorrhage, daily until bleeding stops, then every other day, up to total of 7 to 10 treatments.

Question 34

ANCA Vasculitis

Management:

Plasmapheresis:

Answer 34

Vasculitis in association with anti-GBM antibodies: daily for 14 days or until anti-GBM antibodies are undetectable

Question 35

ANCA Vasculitis

Management:

Plasmapheresis:

Answer 35

Must monitor daily prothrombin time and fibrinogen and replace with fresh frozen plasma (FFP) and cryoprecipitates respectively as needed to correct any coagulopathy associated with removal of coagulant factors with apheresis.

Question 36

ANCA Vasculitis

Management:

Maintenance therapy:

Answer 36

Discontinue CYC/further immunosuppressive therapy if patients remain dialysis-dependent and free of extrarenal manifestations after 3 months.

Otherwise, maintenance therapy is recommended.

Maintenance therapy for at least 18 months is suggested.

Question 37

ANCA Vasculitis

Management:

Choice of maintenance therapy:

Answer 37

Azathioprine (AZA) 1 to 2 mg/kg/d orally is recommended.

MMF may be suggested, up to 1 g twice daily, if intolerant of AZA.

Question 38

ANCA Vasculitis

Management:

Choice of maintenance therapy:

Answer 38

Methotrexate (initially 0.3 mg/kg/wk, maximum of 25 mg/wk) for maintenance therapy in patients intolerant of both AZA and MMF, but not if GFR < 60 mL/min/1.73 m2.

Trimethoprim–sulfamethoxazole as adjunct to maintenance therapy in patients with upper respiratory tract disease is suggested. (Prevents “priming” of neutrophils.)

Question 39

ANCA Vasculitis

Management:

Relapse:

Answer 39

Same therapy as initial therapy is recommended if patients present with severe relapse (e.g., life- or organ-threatening).

Question 40

ANCA Vasculitis

Management:

Relapse:

Answer 40

Otherwise, reinstitution of immunosuppressive therapy or increasing intensity with agents other than CYC, including reinstitution or increasing dose of glucocorticoids, with or without AZA or MMF is suggested.

Question 41

ANCA Vasculitis

Management:

Resistant disease:

Answer 41

Addition of rituximab is recommended.

Suggested alternatives: IV immunoglobulin or plasmapheresis

Question 42

ANCA Vasculitis

Management:

Answer 42

Disease monitoring: changing immunosuppression (i.e., intensifying or reinitiation therapy) with changing (i.e., increasing) ANCA titer alone is not recommended.

Question 43

ANCA Vasculitis

Management:

Answer 43

Avoid over-immunosuppression, provide Pneumocystis jiroveci (Pneumocystis carinii) prophylaxis and be vigilant with infectious complications in ALL patients receiving immunosuppressive therapy.

Question 44

Kidney Transplantation

Answer 44

Delaying transplantation until complete remission for 6 to 12 months is recommended. (opinion-based)

Delaying transplantation in patients in complete remission but with positive ANCA is not recommended.