CHAPTER 9.

ANTI-NEUTROPHIL CYTOPLASMIC ANTIBODIES (ANCA)-ASSOCIATED VASCULITIS (AAV)

 ANCA - produced with the help of T cells and activate leukocytes and monocytes, which together damage the
walls of small vessels. Endothelial injury attracts more leukocytes and extends the inflammation.
 ANCA-positive and have a pauci-immune glomerulonephritis with few immune complexes in small vessels
and glomerular capillaries includes:
o Granulomatosis with polyangiitis
o Microscopic polyangiitis
o Churg-Strauss syndrome
o Renal-limited vasculitis

 A group of patients with small-vessel vasculitis (arterioles, capillaries, and venules; rarely small arteries) and
glomerulonephritis have serum ANCA
2 types of antibodies
1. anti-proteinase 3 (PR3) - more common in granulomatosis with polyangiitis
2. anti-myeloperoxidase (MPO) - more common in microscopic polyangiitis or Churg-Strauss
***Lamp-2 antibodies - reported experimentally as potentially pathogenic

 Although each of these diseases has some unique clinical features, most features do not predict relapse or
progression, and as a group, they are generally treated in the same way.

 Once diagnosed, targeted determination of ANCA levels may be useful if a relapse is clinically suspected.
 Mortality is high without treatment, thus all patients receive urgent treatment.
 Induction therapy usually includes glucocorticoids and either cyclophosphamide or rituximab.
 Plasmapheresis - recommended in rapidly progressive renal failure or pulmonary hemorrhage.
 Monthly “pulse” IV cyclophosphamide - induce remission of ANCA-associated vasculitis
o as effective as daily oral cyclophosphamide
o may be associated with increased relapses
 Steroids - tapered soon after acute inflammation subsides, and patients are maintained on cyclophosphamide
or less toxic agents such as azathioprine, methotrexate, or rituximab for up to a year to minimize the risk of
relapse.

DISEASE CLINICAL PRESENTATION DIAGNOSIS

Granulomatosi  fever  Chest x-ray: nodules,  more common in
s with  purulent rhinorrhea persistent infiltrates, patients exposed to
Polyangiitis  nasal ulcers cavities silica dust and those
 sinus pain  Tissue Biopsy: small- with α1-antitrypsin
 polyarthralgia/arthritis vessel vasculitis and deficiency, which is an
 cough adjacent noncaseating inhibitor of PR3
 hemoptysis granulomas
 shortness of breath  Renal biopsies:  Limited
 microscopic hematuria segmental necrotizing Granulomatosis with
 proteinuria (0.5–1 g/24hr) glomerulonephritis Polyangiitis - presen-
 cutaneous purpura without immune tation without renal
(occasional) deposits and have involvement; some will
 mononeuritis multiplex been classified as show signs of renal
(occasional) focal, mixed, injury later
crescentic, or sclerotic
 Relapse after achieving
remission is common
necessitating diligent
follow-up care.

Microscopic  patients look somewhat
Polyangiitis similar to those with
granulomatosis with
polyangiitis, except they
rarely have significant lung
disease or destructive
sinusitis
Churg-Strauss  small-vessel vasculitis is
Syndrome associated with peripheral
eosinophilia, cutaneous
purpura, mononeuritis,
asthma, and allergic rhinitis
 Hypergammaglobulinemia,
elevated levels of serum
IgE, or the presence of
rheumatoid factor
sometimes accompanies
the allergic state
 Lung inflammation,
including fleeting cough and
pulmonary infiltrates, often
precedes the systemic
manifestations of disease by
years; lung manifestations
are rarely absent
 1/3 of patients may have
exudative pleural effusions
associated with eosinophils.
Jameson, et. al. (2018).  Harrison’s Principles of Internal Medicine 20th Edition. New York: McGraw-Hill, Medical
Pub. Division. PART 9: Disorders of the Kidney and Urinary Tract, CHAPTER 308: Glomerular Diseases, Page 2140.
 Greatest threat to
patients: adverse
events that are
secondary to
treatment
 Patients should also be
monitored long term
for malignancy after
immunosuppressive
therapy
 The distinction is  Some patients will also
made on biopsy, have injury limited to
where the vasculitis in the capillaries and
microscopic venules.
polyangiitis is without
granulomas.
 Renal biopsy: Small-  The cause is
vessel vasculitis and autoimmune, but the
focal segmental inciting factors are
necrotizing unknown.
glomerulonephritis,
usually absent
eosinophils or
granulomas.
 Diagnosis: Biopsy strategy in suspected kidney vasculitis

 Relapses: persistence of ANCA positivity, an increase in ANCA levels, and a change in ANCA from negative to
positive are only modestly predictive of future disease relapse and should not be used to guide treatment
decisions.

 Induction: KDIGO CPG on Glomerular Diseases recommend that corticosteroids in combination with
cyclophosphamide or rituximab be used as initial treatment of new-onset AAV

 Treatment: Recommended treatment regimen for AAV

Patients presenting with markedly reduced or rapidly declining GFR (SCr >354 μmol/l)
 there are limited data to support rituximab and glucocorticoids
 Cyclophosphamide and glucocorticoids are preferred for induction therapy
 The combination of rituximab and cyclophosphamide can also be considered in this setting
 Factors for consideration when choosing between rituximab and cyclophosphamide for induction therapy of
AAV

 Considerations for the route of administration of cyclophosphamide for AAV

 Discontinue immunosuppressive therapy after three months in patients who remain dialysis-dependent and
who do not have any extrarenal manifestations of disease.

 Prednisolone tapering regimen for AAV

  Immunosuppressive drug dosing for AAV

 Consider plasma exchange for patients requiring dialysis or with rapidly increasing serum creatinine, and in
patients with diffuse alveolar hemorrhage who have hypoxemia.
 Add plasma exchange for patients with an overlap syndrome of ANCA vasculitis and anti-GBM.

 Maintenance therapy: KDIGO CPG on Glomerular Diseases recommend maintenance therapy with either
rituximab or azathioprine and low-dose glucocorticoids after induction of remission
 Following cyclophosphamide induction, either azathioprine plus low-dose glucocorticoids or rituximab
without glucocorticoids should be used to prevent relapse
 Following rituximab induction, maintenance immunosuppressive therapy should be given to most patients
 The optimal duration of azathioprine plus low-dose glucocorticoids is not known but should be between
18 months and four years after induction of remission.
 The optimal duration of rituximab maintenance is not known, but studies to date have evaluated a
duration of 18 months after remission. There is no role for the routine use of an oral corticosteroid or oral
immunosuppressive with rituximab maintenance.

 When considering withdrawal of maintenance therapy, the risk of relapse should be considered, and
patients should be informed of the need for prompt attention if symptoms recur.
 Factors that increase relapse risk for AAV

 Consider methotrexate for maintenance therapy in patients induced with methotrexate or who are
intolerant of azathioprine and MMF, but not if GFR is <60 ml/min/1.73 m2.
  Considerations for using rituximab or azathioprine for AAV maintenance therapy

 Immunosuppressive dosing and duration of AAV maintenance therapy

 Relapsing disease: Patients with relapsing disease (life- or organ-threatening) should be reinduced
preferably with rituximab.

 Special situations
 Refractory disease: can be treated by an increase in glucocorticoids (intravenous or oral), by the
addition of rituximab if cyclophosphamide induction had been used previously, or vice versa. Plasma
exchange can be considered.
 In the setting of diffuse alveolar bleeding with hypoxemia, plasma exchange should be considered in
addition to glucocorticoids with either cyclophosphamide or rituximab.

 Transplantation: Delay transplantation until patients are in complete clinical remission for at least six
months. Persistence of ANCA should not delay transplantation

KDIGO Clinical Practice Guideline on Glomerular Diseases (2020)