This document provides an overview of renal vasculitis (AAV). It begins with the historical landmarks in recognizing and classifying different types of vasculitis. It then discusses ANCA-associated vasculitis in more detail, including the role of ANCA testing in diagnosis and monitoring disease. The clinical manifestations, pathology, treatment including induction and maintenance therapies, and prognosis of AAV are summarized. It also reviews recent insights into the genetics and environmental factors involved in AAV.

1. RENAL
VASCULITIS(AAV)
Dr Rajesh Jhorawat
Nephrology, SMS

2. Land mark steps..

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
In 1808, Willan- distinguished purpura caused by
infections from non-infectious purpura
Henoch and his teacher, Schönlein, described a
broad spectrum of signs and symptoms that
were associated with purpura, and with small
vessel vasculitis
In 1866, Kussmaul and Maier described
“periarteritis nodosa” later changed to
“polyarteritis nodosa”
In 1936, Friedrich Wegener, a German
pathologist, described three patients with
necrotizing granuloma

3. 
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

In 1954, Goodman and Churg wrote a
detailed description of “Wegener´s
granulomatosis” (WG)
In 1970s, Fauci and Wolff introduced
treatment with cyclophosphamide and
corticosteroids for WG
In 1985, DeRemee published a report on the
benefits of using cotrimoxazole (trimethoprim/
sulfamethoxazole) in WG
In 1985, Van der Woude et al who reported
autoantibodies(ANCA) sensitive and specific
for the WG

4. Vasculitis
INFLAMMATION OF BLOOD
VESSEL

5. •ANCA testing not
included
•PAN and MPA put
togather
CLASSIFICATION OF
VASCULITIS
1990- American College of Rheumatology
(ACR) Classification Criteria
1994- Chapel Hill Consensus Conference (CHCC)
•Size of blood vessel (tissue
Bx)
•PAN and MPA seperated
•ANCA suggested
•AAV- WG, CSS, MPA
European Medicines
Agency developed a stepwise
lgorithm for vasculitis in 2007
•ACR
•Lanham crietria for
CSS
•ANCA
•CHCC defination
CHCC definitions were
revised in 2012

8. Large vessels are the aorta and its major branches
and the
analogous veins.
Medium vessels are the main visceral arteries and
veins and their initial branches
Small vessels are intraparenchymal arteries,
arterioles, capillaries, venules, and veins

10. ANCA-associated Vasculitis
(AAV)

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Antineutrophil cytoplasm antibody (ANCA)–
associated vasculitis (AAV) is a group of
multisystem diseases
Characterized by a pauci-immune small-vessel
vasculitis with presence of circulating
autoantibodies
Annual incidence of 20 per million
Outcomes are often poor with a mortality of 25%
at 5 years.
Renal involvement is frequently seen and is
strongly associated with outcomes

11. ANCA-associated Vasculitis
(AAV)

12. 


But newer insights for classification have
emerged from large cohort and genetic studies
esp. with two recent studies
Mahr et al
Lyons et al.

17. ANCA and other antibodies



Antineutrophil cytoplasmic autoantibodies
(ANCA) are a group of antibodies that react
with cytoplasmic antigens in human
neutrophils
These antibodies originally reported in 1964
and the first report linking these antibodies to
disease was in 1982(Davies et al)
About 90% of patients with small-vessel
vasculitis or pauci-immune NCGN have ANCA

18. 


The major autoantigens of ANCA are MPO
and PR3.
MPO-ANCA is the predominant serotype in
MPA patients, whereas PR3-ANCA is usually
found in GPA.
True dual positivity is rare and raises suspicion
of a drug-induced vasculitis.

19. Methods of
Detection
IIF
(screening)
ELISA
(specificity)

20. Indirect Fluorescent Assay (IFA)


In the immunofluorescent test for ANCA, several
patterns of cellular staining may be seen
Two major patterns of staining have been
described and well characterized when ethanolfixed neutrophils are used in the
immunofluorescent ANCA test
1.
2.
Cytoplasmic pattern called C-ANCA, are usually
directed against a serine protease, Proteinase 3
(PR3)
Perinuclear pattern called P-ANCA, are usually
due to antibodies directed against myeloperoxidase
(MPO)

21. C-ANCA
P-ANCA

22. FIXATIVE
PR3
MPO
ETHANOL
CYTOPLASMIC
PERINUCLEAR
FORMALIN
CYTOPLAMIC
CYTOPLASMIC

23. •Selected cohorts studied
•Disease extent and activity at the time of
serum sampling
•Criteria used for setting the diagnoses
•Way positive cutoff values for the assays
used have been set

24. ANCA TESTING- CLINICAL USE
DIAGNOSIS, PROGNOSIS, AND FOLLOWUP


Most experts on vasculitis agree that the level
of PR3-ANCA and MPO-ANCA is higher in
active and/or extensive phase of the disease
PR3-ANCA and MPO-ANCA have some
influence on the development of clinical
features.
 Renal
and respiratory involvement in PR3-ANCA
 Renal limited involvement is more often in MPOANCA

Patients positive for PR3-ANCA suffered more
frequent relapses than those positive for MPOANCA.

25. AAV- other Autoantibodies
These different autoantibodies are likely to reflect mechanisms operating in
the inflammatory events and may even be part of an orchestrated attack
on the endothelium and basement membrane

26. Anti–endothelial cell
antibodies (AECA)
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Directed to small vessel
ECs
Idiopathic AAV and in
drug-induced vasculitis
Increase level is
observed in relapse
Induce adhesion
molecule expression
and increased cytokine
secretion
Don‟t cross react and
fluctuate independently
with ANCA
Antibodies to Glomerular
Basement Membrane( AntiGBM)



Autoantibodies to the
a3-domain of type IV
collagen
Observed cooccurrance with
ANCAs (esp. with
anti-MPO)
co-occurrence with
ANCAs influence
outcome

27. Antiphospholipid
Autoantibodies




Rare
Anti–b2-glycoprotein 1,
anticardiolipin, or the
lupus anticoagulant
With ACA more
extensive and more
severe disease
In Drug-induced
vasculitis,
antiphospholipid
antibodies of the IgM
class

30. Pathology

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
Basic leasion- segmental fibrinoid necrosis,
often accompanied by leukocyte infiltration
and leukocytoclasia (leukocyte fragmentation)
Patients with pauci-immune small-vessel
vasculitis also may have renal arteritis, most
often affecting interlobular arteries and
medullary angiitis affecting the vasa recta
The medullary angiitis may be severe enough
to cause papillary necrosis

32. Clinical Manifestations(AAV)

34. Treatment


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Without therapy, ANCA vasculitis with GN is
associated with very poor outcomes
Treatment with corticosteroids and
cyclophosphamide has dramatically improved
the short- and long-term outcomes of ANCA
vasculitis associated with systemic disease.
Treatment with immunosuppressive therapy is
therefore considered indicated in all cases of
ANCA vasculitis and GN

35. Induction trials in AAV

36. Treatment

38. 

Rare possible exception relates to patients
with severe kidney-limited disease, in the
absence of extrarenal manifestations of smallvessel vasculitis
OR
Patients with severe pauci-immune NCGN
requiring dialysis,

39. Treatment
Benefit/Risk
of Tx

40. Evidence- study-1

41. Study 2

42. Maintenance Therapy

49. Transplantation in AAV

51. Future option in AAV

54. THANK YOU

56. 
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An increased prevalence of thromboembolic
disease occurs in AAV, and autoantibodies
have now been described to plasminogen and
tissue plasminogen activator in the sera of one
quarter of PR3-ANCA-positive AAV patients.
The presence of antiplasminogen antibodies
correlated with venous thrombosis and with
the severity of renal vasculitis

57. GENETICS AND THE
ENVIRONMENT
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Evidence for a genetic contribution in AAV has
been increasing with familial associations and
study of candidate genes, especiallyHLA
DPB1*0401in European GPA patients.
Associations with HLA-DP, SERPINA1, and
PRTN3 were identified for GPA. SERPINA1
encodes for a-1 antitrypsin and PRTN3 encodes
for PR3.
An association with HLA-DQ was identified for
MPA.
Interestingly, the genetics were more strongly
associated with ANCA specificity (MPO-/PR3ANCA) than clinical diagnosis (MPA/GPA).

58. 
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Associations with environmental factors, such
as air pollutants, infections, and drugs, have
also been associated.
Silica is a well-known air pollutant contributing
to many autoimmune diseases including AAV.
Peptides from Staphylococcus aureus have
strong homology with peptides from
complementary PR3, and Staphylococcus
aureus infection has been associated with
initiation and relapse of GPA
The anti-hLAMP-2 antibody also has 100%
homology to FimH in Gram-negative bacteria.

59. 
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In 2011, a Japanese group revealed that MPOANCA– activated glomerular endothelial cells
directly in a murine model. They identified a
new target antigen of MPO-ANCA, moesin, on
the glomerular endothelium.
Moesin has partial amino-acid sequence
homology with an epitope of MPO-ANCA
They found a high prevalence of anti-moesin
antibodies in MPA patients

60. 

Cocaine use has caused several vasculitis
syndromes including AAV, recently associated
with contamination of cocaine by levamisole.
Propylthiouracil (PTU) is the most frequent
cause of drug-induced AAV (especially MPA)
The finding of multiple autoantibodies is more
common in drug-induced than primary AAV,
suggesting a dysregulation of self-tolerance.

61. HISTOPATHOLOGY
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AAV often affects the kidneys and is the most
common cause of rapidly progressive
glomerulonephritis.
Renal involvement is an important predictor of
increased mortality risk and morbidity in AAV,
and renal biopsy aids in both diagnosis and
prognosis.
An outcome-based classification of ANCAassociated glomerulonephritis histology has
been developed to formalize the predictive
value of the renal biopsy.

63. 
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A validation study with 100 renal biopsies from AAV
patients revealed that the classification was an
independent predictor for estimated GFR after 1 year
and 5 years.
Although the „Focal‟ class showed good preservation
of renal function and the „Crescentic‟ class a good
chance for renal recovery, the „Mixed‟ and „Sclerotic‟
classes had, respectively, intermediate and high risks
of progression to end-stage renal disease.
T-cell tubulitis was an independent predictor for
estimated GFR after 12 months and tubular atrophy
was an independent predictor for estimated GFR after
12 months and 24 months.

64. 

Another recent topic in histopathology is the
involvement of the complement system,
especially the alternative pathway.
Xinget al.,detected components of the
alternative pathway, factor B, factor P, C3d,
and membrane-attack complex, in glomeruli
and small blood vessels in kidney biopsy
specimens from AAV patients

66. Treatment
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The current treatment for AAV has been
optimized by randomized controlled trials
performed over the last 20 years
It is not curative but aims to control disease
activity in a 3- to 6-month induction phase of
high-dose glucocorticoid and daily oral or
intravenous-pulsed cyclophosphamide that is
effective in 80–90%.
Despite maintenance therapy of low-dose
glucocorticoid and azathioprine or
methotrexate, at least 10% of patients relapse
each year

67. Induction trials

68. 
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A rationale for B cell–targeted therapy in AAV has emerged
from the presence of B cells at sites of inflammation,
correlation of B-cell activation with disease activity in GPA,
the efficacy of cyclophosphamide, which is a relatively B cell–
specific immunosuppressant, and the contribution of ANCA to
the pathogenesis.
Several case series and small prospective studies highlighted
the efficacy of the anti-CD20 B cell–depleting monoclonal
antibody, rituximab in refractory AAV.
Subsequently, two randomized trials evaluated rituximab for
remission induction in new and relapsing patients.
Both the RAVE and RITUXVAS trials found similar remission
rates for newly diagnosed patients between rituximab- and
cyclophosphamide-based regimens when combined with
high-dose glucocorticoid.

69. 

The RAVE trial also demonstrated superiority
of rituximab for the subgroup treated for
relapsing disease. However, no differences in
safety were observed between the treatment
groups, suggesting that glucocorticoid rather
than cyclophosphamide is the major treatmentrelated cause of toxicity in AAV.
Rituximab is now indicated for relapsing AAV
and newly diagnosed AAV when
cyclophosphamide avoidance is desirable.

70. 
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The pathogenicity of ANCA has contributed to
a therapeutic rationale for plasma exchange in
AAV
A metaanalysis of plasma exchange trials
suggests a beneficial effect on the risk for endstage renal disease but no effect on mortality

74. 
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Current practice recommends plasma
exchangefor those with severe renal disease
or alveolar hemorrhage, although the evidence
base in the latter indication is weak.
The PEXIVAS trial is examining the effect of
plasma exchange on patients with a GFR
below 50 ml/min or with severe alveolar
hemorrhage

75. Maintenance therapy
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Following control of features of vasculitis activity,
the maintenance therapy aims to prevent
vasculitis returning.
The WEGENT trial aimed to demonstrate the
superiority of methotrexate over azathioprine, but
adverse event rates were similar and relapse
rates at 36 months were 50 and 47%,
respectively.
The IMPROVE trial found mycophenolate mofetil
was less effective compared with azathioprine for
prevention of relapse, 55% vs. 38% after 39
months, with similar adverse event rates.

76. Maintenance Trials

77. 
Consequently, azathioprine or methotrexate,
with or without low-dose glucocorticoid, is the
preferred maintenance agents.

78. 
Recently, Smith et al. published a retrospective
study, which revealed that a 2-year fixed
interval routine rituximab therapy reduced
relapse rate in relapsing AAV patients treated
with rituximab.

80. 
This subject will be further studied in the
ongoing RITAZAREM trial

81. EGPA

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EGPA has been excluded from most AAV trials.
Recently, a French group examined the response
to glucocorticoids in nonsevere EGPA and
glucocorticoids, as well as cyclophosphamide in
severe EGPA.
Relapse rates in nonsevere EGPA are high if
treated with glucocorticoids alone and studies of
combinations with other immunosuppressants are
needed.
Similarly, only anecdotal data exist for the role of
rituximab in EGPA.
Two, small, open-label studies of an
antiinterleukin-5 antibody, mepolizumab, have
reported goodeffects in EGPA

82. OUTCOME

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Long-term outcome studies by the European
Vasculitis Society cohort with 535 AAV patients
with a median of 5.2-year follow-up reported
cumulative survival rates at 1 and 5 years of 88
and 78%, respectively.
Frequent causes of death within the first year
were infection (48%) and active vasculitis (19%),
and those after 1 year were cardiovascular
disease (26%), malignancy (22%), and infection
(20%).
In the same cohort, 38% of 535 patients
experienced a relapse, and the relapse was more

83. 
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
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As to malignancy, only the risk of nonmelanoma
skin cancer was increased in this cohort
The low increases in cancer risk compared with
previous studies might reflect short follow-up or
lower exposure to cyclophosphamide in current
protocols.
The French Vasculitis Study Group also showed
similar results in their study for urotoxic adverse
events .The risk of bladder cancer in AAV was low
in an intravenous-pulsed cyclophosphamide group
and a group diagnosed after 1998.
Longer follow-up is necessary because of the late
development of malignancy.

84. Newer Therapeutic Agents


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The proteasome inhibitor Bortezomib has
demonstrated a stronger effect on autoantibody
production than cyclophosphamide in
experimental models.
The immunosuppressive agent gusperimus
proved efficacy in controlling disease activity in
two nonrandomized trials of refractory or relapsing
GPA.
The anti-CD52 pan lymphocyte–depleting
antibody, alemtuzumab, has led to sustained
treatment-free remissions in AAV, but it is strongly
immunosuppressive and is associated with severe
adverse events in the elderly and those with renal

86. CONCLUSIONS


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The classification of vasculitis has been further
revised and new genetic associations are likely to
drive more changes in how vasculitis is subgrouped.
The discovery of newer autoantibodies raises the
potential for newer biomarkers of clinical utility, as well
as inspiring pathogenetic studies.
Rituximab is now firmly established in the treatment of
ANCA vasculitis, and further innovations permitting
reduced immunosuppressive and glucocorticoid
exposure are in development.
Much of the recent progress has developed from the
creation of international collaborative networks
permitting consensus approaches and large-scale
clinical studies.