vasculitis a review of pathogenesis, vasculitis a review of pathogenesis,
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8/12/2019 Vasculitis a Review of Pathogenesis, Vasculitis a Review of Pathogenesis,
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Va s c u l i t i s : A R e v i e w o f Pa t h o g e n e s i s ,V a s c u l i t i s : A R e v i e w o f Pa t h o g e n e s i s ,
D i a g n o s i s a n d T r e a t m e n t D i a g n o s i s a n d T r e a t m e n tI SNH J u l y 1 2 , 2 0 1 0 I SNH J u l y 1 2 , 2 0 1 0
Joanne M. Bargman MD FRCPCJoanne M. Bargman MD FRCPC
Staff Nephrologist and Professor of MedicineStaff Nephrologist and Professor of Medicine
University Health Network and University ofUniversity Health Network and University ofTorontoToronto
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M r . P .M r . P .
1999: 53 yo construction worker • dyspnea, cough, purulent nasal discharge,
anorexia, wt. loss and fever X 3 months
• 10 days PTA had nasal polyps removed,complicated by nosebleed +++
• FD: elevated creatinine – to ER
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M r . P .M r . P .
O/E mildly hypoxic, BP 160/100
• elevated JVP, bibasilar crackles
• Urinalysis: blood, protein, pigmented casts
Labs: Hb 9.8 g/dl, WC 36K, plts 522K• K+ 6.1, creatinine 10.4 mg/dl
• pANCA +; cANCA -
• CXR: diffuse bilateral interstitial infiltrates
• failed diuresis – line inserted for urgenthemodialysis
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Mr P: Renal BiopsyMr P: Renal Biopsy
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H ow Wou ld Y o u T r e a t T h i s
P a t i e n t ?
1. High-dose corticosteroid plus monthly pulsed
cyclophosphamide2. High-dose corticosteroid plus daily oral
cyclophosphamide
3. High-dose corticosteroid alone and monitorclosely
4. High-dose corticosteroid plus mycophenolate
mofetil (MMF)5. High-dose corticosteroid, cyclophosphamideand adjunctive plasmapheresis
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Co u r s e i n H o s p i t a l Co u r s e i n H o s p i t a l
pulsed with solumedrol, started on daily oralcyclophosphamide
P ANCA positive, C ANCA negative
able to come off hemodialysis
discharged Jan 2000: creatinine 3.0 mg/dl• Prednisone 25 mg tid, cyclophosphamide 200 mg od
Jan 2001: pred/CTX stopped, creatinine stable at
1.9 mg/dl
May 2010: creatinine 1.9 mg/dl, ANCA neg
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Ou t l i n e Ou t l i n e
ANCA-associated vasculitis
• description
• pathogenesis
• treatment
summary
8/12/2019 Vasculitis a Review of Pathogenesis, Vasculitis a Review of Pathogenesis,
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Th e Sy n d r om e o f Ra p i d l y Pr o g r e s s i v eT h e Sy n d r om e o f Ra p i d l y P r o g r e s s i v e
G l ome r u l o n e p h r i t i s G l ome r u l o n e p h r i t i s (RPGN) (RPGN)
Differential Diagnosis
Immune complex-associated (primary or
secondary)
• Lupus nephritis• Membranoproliferative GN
• Acute post-infectious GN
• IgA nephropathy / Henoch-Schonlein nephritis• “idiopathic” immune complex crescentic nephritis
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Th e Sy n d r om e o f Ra p i d l y Pr o g r e s s i v eT h e Sy n d r om e o f Ra p i d l y P r o g r e s s i v e
G l ome r u l o n e p h r i t i s G l ome r u l o n e p h r i t i s (RPGN) (RPGN)
Differential Diagnosis (cont’d)
pauci-immune
• ANCA-associated glomerulonephritis
crescentic nephritis associated with anti-GBMantibody
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Th e Sy n d r om e o f Ra p i d l y Pr o g r e s s i v eT h e Sy n d r om e o f Ra p i d l y P r o g r e s s i v e
G l ome r u l o n e p h r i t i s G l ome r u l o n e p h r i t i s (RPGN) (RPGN)
Differential Diagnosis – other diseases that have
fooled me
cholesterol embolic disease
thrombotic microangiopathy
acute interstitial nephritis
acute tubular necrosis in a patient with GN
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D is t r i b u t i o n o f D i f f e r e n t T y p e s o fD i s t r i b u t i o n o f D i f f e r e n t T y p e s o f
C r e s c e n t i c C r e s c e n t i c GN b y A g eGN b y A g e ( ( J e n n e t t e J e n n e t t e 2 0 0 3 ) 2 0 0 3 )
0
10
20
30
40
50
60
70
80
1-20 yo 21-60 yo > 60 yo
pauci-im
I.C.
anti-GBM
other cresc
%%
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ANCAANCA - - A s s o c i a t e d Di s e a s e A s s o c i a t e d Di s e a s e
With evidence of systemic vasculitis:
microscopic polyangiitis
Wegener’s granulomatosis
Churg-Strauss vasculitis
Without evidence of systemic vasculitis:
“Renal-limited” vasculitis
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“ “ Y o u Ca n Sm e l lY o u Ca n Sm e l l V a s c u l i t i s V a s c u l i t i s ” ”
Request from FD: “Very pleasant 61 y lady. Flushot in October. Saw me Nov 4 for abd pain:
U/A trace of blood, abdo U/S normal. Seen
again Nov 11 with decreased energy sinceSeptember, with chronic cough. CXR shows
consolidation L base. Nov 27 still c/o
decreased energy. Dec 8 bloodwork showscreatinine 1.9 mg/dl, Hb 8.3, ESR 72.”
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Th e Re n a l L e s i o n T h e Re n a l L e s i o n
focal necrotizing glomerulonephritis
crescents
VERY RARE to see small vessel vasculitis orgranulomatous angiitis on renal biopsy
therefore, usually cannot differentiate betweenmicroscopic polyangiitis and Wegener’s onusual kidney biopsy
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T h eT h e V a s c u l i t i d i e s V a s c u l i t i d i e s : C l i n i c a l Ch a r a c t e r i s t i c s: C l in i c a l C h a r a c t e r i s t i c s
a n d D i s t i n c t i o n s a n d D i s t i n c t i o n s
Microscopic polyangiitis
• constitutional symptoms, anemia,lung,neurologic, skin
Wegener’s granulomatosis• ENT, lung, granulomatous angiitis
Churg-Strauss vasculitis
• eosinophilia, asthma, granulomatousinflammation
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Et i o l o g y o f Pu lm o n a r y E t i o l o g y o f Pu lm o n a r y - - Re n a lR e n a l
S y n d r om eS y n d r om e (N i l e s e t a l 1 9 9 6 ) (N i l e s e t a l 1 9 9 6 )
0
10
20
30
40
50
60
ANCA GBM
etiology
the most commoncause of
“pulmonary- renal
syndrome” is ANCA-associated
vasculitis
• Microscopicpolyangiitis
• Wegener’s
Granulomatosisbothboth
%%
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T y p e s o f AN CAT y p e s o f AN CA
Directed against myeloperoxidase
(MPO)
• “perinuclear” IF: pANCA
Directed against PR3 antigen• “cytoplasmic” IF: cANCA
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I mm u n o f l u o r e s c e n c e I mm u n o f l u o r e s c e n c e :: P e r i n u c l e a r P e r i n u c l e a r A NCAANCA
( ( p ANCApANCA ) )
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I mm u n o f l u o r e s c e n c e I mm u n o f l u o r e s c e n c e :: C y t o p l a sm i c C y t o p l a sm i c ANCAANCA
( ( c A NCAc A NCA ) )
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T y p e s o f ANCAT y p e s o f ANCA ( c o n t ( c o n t ’ ’ d ) d )
Anti PR3 most commonly found inWegener’s Granulomatosis
Anti MPO most commonly found in the
rest Anti MPO has also been detected in
other, non-vasculitic diseases
some pauci-immune vasculitic diseasesare ANCA-negative
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T y p e s o f ANCAT y p e s o f ANCA v a s c u l i t i s v a s c u l i t i s
Drug-associated ANCA vasculitis
• propylthiouracil
• pimagedine
• minocycline
• methimazole
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C l i n i c a l Fe a t u r e s C l in i c a l Fe a t u r e s
Anti PR3 ( Anti PR3 (cANCAcANCA))--associatedassociatedvasculitisvasculitis
male predominance
nodular, cavitating lung disease
more frequent eye involvement
more active, aggressive renal disease
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C l i n i c a l Fe a t u r e s C l in i c a l Fe a t u r e s
Anti MPO (PANCA) Anti MPO (PANCA)--associatedassociatedvasculitisvasculitis
female predominance diffuse, patchy lung disease
more chronic renal lesions (“not-so-RPGN”)
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T im e t o Do u b l i n g Se r umT im e t o D o u b l i n g Se r um C r e a t i n i n e C r e a t i n i n e : PR3: PR3 v s v s
M PO AN CAM PO AN CA ( ( F r a n s s e n F r a n s s e n e t a l , 1 9 9 5 ) e t a l , 1 9 9 5 )
0
10
20
30
40
50
60
70
< 2 wks 2 to 12 wks 3-6 months > 6 months
PR3
MPO
%%
doublingdoubling
s.s. creatcreat
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EB
63 year old woman
Previous history of myocarditis
Presents with SOB, rising creatinine,
active urine sediment, anemia, ANCA +
Biopsy: focal necrotizing glomerulitis
Rx prednisone and cyclophosphamide X3 months, then prednisone and MMF
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Ou t l i n e Ou t l i n e
ANCA-associated vasculitis
•• descriptiondescription
• pathogenesis
• treatment
summary
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Pa t h o g e n e s i s o f AN CAPa t h o g e n e s i s o f AN CA - - A s s o c i a t e dA s s o c i a t e d
V a s c u l i t i s V a s c u l i t i s
MPO and PR3 reside in azurophilic
granules and lysosomes of neutrophils
and monocytes
How do antibodies to MPO/PR3• reach their target inside the cell?
• cause disease in the absence of immunecomplex formation?
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Pa t h o g e n e s i s o f AN CAPa t h o g e n e s i s o f AN CA - - A s s o c i a t e dA s s o c i a t e d
V a s c u l i t i s V a s c u l i t i s
MPO or PR3MPO or PR3
NeutrophilNeutrophilprimingpriming
(TNF? Other?)(TNF? Other?)
Activated PMN Activated PMN
--respiratory burstrespiratory burst
--release of Orelease of O22
radicals and lyticradicals and lytic
enzymesenzymes
--adherence toadherence to
endothelial cellsendothelial cells
ANCA ANCA’’ss
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Ex p e r im e n t a l Ev i d e n c e t h a t A NCAEx p e r im e n t a l Ev i d e n c e t h a t AN CA ’ ’ s a r es a r e
Su f f i c i e n t t o Ca u s e D i s e a s eSu f f i c i e n t t o Ca u s e D i s e a s e (X i a o e t a l , 2 0 0 2 ) (X i a o e t a l , 2 0 0 2 )
MPOMPO--knockout miceknockout mice
Mouse MPOMouse MPO
immunizationimmunization
Spleen cells and/or Spleen cells and/or
purified IgG antipurified IgG anti--MPOMPO
RagRag22--//-- micemice(no functioning(no functioning
B or T lymphocytes)B or T lymphocytes)
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Pa t h o g e n e s i s : A c t i v a t i o n Ph a s e(B o s c h J A MA 2 0 0 7 )
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Pa t h o g e n e s i s : E f f e c t o r Ph a s e(B o s c h J A MA 2 0 0 7 )
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Ou t l i n e Ou t l i n e
ANCA-associated vasculitis
•• descriptiondescription
•• pathogenesispathogenesis
• treatment
summary
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T r e a t m e n t o f A NCAT r e a t m e n t o f A NCA - - A s s o c i a t e dA s s o c i a t e d
V a s c u l i t i s V a s c u l i t i s
Principles of TreatmentPrinciples of Treatment
early diagnosis is important• saves the kidneys
• saves the patient think of the diagnosis
• rapidly falling hemoglobin an important clue
• multi-system symptomatology
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T r e a t m e n t o f A NCAT r e a t m e n t o f A NCA - - A s s o c i a t e dA s s o c i a t e d
V a s c u l i t i s V a s c u l i t i s
Principles of TreatmentPrinciples of Treatment (cont(cont’’d)d)
sensitivity and specificity of ANCA depends on
clinical setting (pre-test probability)
don’t wait for the renal biopsy (and you maynot have to do a renal biopsy!)
warn patient about severity of disease and side
effects of therapy
document this warning in the patient record
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T r e a t m e n t o f A NCAT r e a t m e n t o f A NCA - - A s s o c i a t e dA s s o c i a t e d
V a s c u l i t i s V a s c u l i t i s
What we know:What we know:
corticosteroids and cyclophosphamide
have changed the natural history of this
previously-fatal illness
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T r e a t m e n t o f A NCAT r e a t m e n t o f A NCA - - A s s o c i a t e dA s s o c i a t e d
V a s c u l i t i s V a s c u l i t i s
What we donWhat we don’’t knowt know (or aren(or aren’’t too suret too sureabout):about):
incremental benefit of pulse corticosteroid vsdaily oral prednisone at the start of treatment
the role of plasmapheresis
pulse cyclophosphamide vs daily oral
cyclophosphamide
cyclophosphamide-reducing regimens
preventing relapses
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H ow Wou ld Y o u T r e a t T h i s
P a t i e n t ?
1. High-dose corticosteroid plus monthly pulsed
cyclophosphamide2. High-dose corticosteroid plus daily oral
cyclophosphamide
3. High-dose corticosteroid alone and monitorclosely
4. High-dose corticosteroid plus mycophenolatemofetil (MMF)
5. High-dose corticosteroid, cyclophosphamideand adjunctive plasmapheresis
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P l a sm a p h e r e s i s f o r ANCAP la sm a p h e r e s i s f o r AN CA - - A s s o c i a t e dA s s o c i a t e d
V a s c u l i t i s : S t u d i e s t o D a t e V a s c u l i t i s : S t u d i e s t o D a t e
studies in the 1980’s conflicting, anecdotalIn 1990’s, 2 randomized, controlled trials:
Canadian Apheresis group: patients with
idiopathic crescentic GN
Hammersmith Hospital: patients with focalnecrotizing GN
No benefit for plasmapheresis in the groupsNo benefit for plasmapheresis in the groupsas a wholeas a whole
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Ou t c om e o f Pa t i e n t sOu t c om e o f Pa t i e n t s Who We r e D ia l y s i s Who We r e D i a l y s i s - -
D e p e n d e n tD e p e n d e n t i n t h e S t u d i e s i n t h e S t u d i e s
0
1020
30
40
5060
70
80
90
100
Canadian Hammersmith
PLEX
no PLEX
% ableto come
off
dialysis
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Why Do e s n Wh y Do e s n ’ ’ t P l a sm a p h e r e s is H e l p M o r et P l a sm a p h e r e s is H e l p M o r e
D r am a t i c a l l y ? D r am a t i c a l l y ?
ANCA-associated vasculitis responds well to
conventional immunosuppression (75-100% remissionrate) so it is hard to show additional benefit of
plasmapheresis
only in subgroup of severe renal impairment hasadjunctive therapy with plasmapheresis been
suggested to be helpful
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Th e Ro l e o f P la sm a p h e r e s i s /P l a sm aTh e Ro l e o f P l a sm a p h e r e s i s /P l a sm a
E x c h a n g e E x c h a n g e
theoretical benefit to removal of ANCA’s if they
are pathogenic to the disease
most studies of PLEX/PE in non-renalvasculitis have not demonstrated benefit
Pusey et al (1991) demonstrated greaterchance of recovery of dialysis-dependent renalfailure with addition of PE
• incremental benefit similar to using pulse compared tooral prednisone
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T h e M EPEX T r i a l T h e M EPEX T r i a lJ a y ne J Am So c N e p h 2 00 7 J a y ne J Am So c N e p h 2 00 7
137 patients
biopsy-proven renal vasculitis
ANCA positive
• 43% PR3 (cANCA)
• 52% MPO (pANCA)
• 5% ANCA negative serum creatinine > 6.0 mg/dl
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MEPEX : T r e a t m e n t Pr o t o c o l M EPEX : T r e a t m e n t P r o t o c o l
Both groupsBoth groups
• oral prednisone 1 mg/kg, tapered to .25 mg/kgby week 10, 15 mg/day by 3 months and 10mg/day from 5 to 12 months
• oral CTX 2.5 mg/kg (2.0 mg/kg if > 60) for 3months
• oral CTX 1.5 mg/kg for the next 3 months
then changed at 6 months to AZA 2 mg/kgthereafter
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MEPEX : T r e a t m e n t Pr o t o c o l M EPEX : T r e a t m e n t P r o t o c o l
Study TreatmentStudy Treatment
• IV methyprednisolone 1000 mg daily X 3;
Or
• plasma exchange• 60 ml/kg BW
• replacement with 5% albumin
• 7 sessions in the first 14 days
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T h e M EPEX T r i a l T h e M EPEX T r i a l
J a y ne J Am So c N e p h 2 00 7 J a y ne J Am So c N e p h 2 00 7
At 3 months:
renal recovery in49% of MP group
and 69% of PLEXgroup (p=0.02)
difference in renalrecoveryestablished by 2months
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T h e M EPEX T r i a l T h e M EPEX T r i a lJ a yn e J Am So c N e p h 2 0 07 J a y n e J Am So c N e p h 20 0 7
no difference in overall
survival in either groupby 12 months
risk reduction of ESRD
was 24% at 12 m inPLEX group
the development ofESRD was a strong
predictor of death
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MEPEX T r i a l : F i n a l T h o u g h t s M EPEX T r i a l : F i n a l T h o u g h t s
took years to be published
benefit of PLEX established by 2
months, no further improvement
why not give PLEX and IVmethylprednisolone?
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On e o f t h e M a n y Pr ob l em s w i t h T r e a t m e n tOn e o f t h e M a n y Pr o b l em s w i t h T r e a t m e n t
o f AN CAo f AN CA - - A s s o c i a t e d V a s c u l i t i s : M r . R .A s s o c i a t e d V a s c u l i t i s : M r . R .
1989• 20 year old man presented with progressivehemoptysis and severe hypoxia unresponsive toantibiotics
• open lung biopsy: granulomatous angiitis c/wWegener’s Granulomatosis
• renal function normal, trace blood and protein
• Rx cyclophosphamide 2 mg/kg BW daily andprednisone
• treated for 18 months and D/C’ed
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On e o f t h e M a n y P r ob l em s w i t h ANCAOn e o f t h e M a n y Pr ob l em s w i t h A NCA - -
A s s o c i a t e d V a s c u l i t i sA s s o c i a t e d V a s c u l i t i s ( c o n t ( c o n t ’ ’ d ) d )
1991-1995
• continued ANCA PR3 positivity• cough with streaky hemoptysis
• bloody nasal discharge
• intolerant of Septra• red eye: membranous conjuctivitis
1996
• Worsening of red eye: scleritis• no response to topical corticosteroids
• eye doctor recommended re-starting systemic rx
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On e o f t h e M a n y P r ob l em s w i t h ANCAOn e o f t h e M a n y Pr ob l em s w i t h A NCA - -
A s s o c i a t e d V a s c u l i t i sA s s o c i a t e d V a s c u l i t i s ( c o n t ( c o n t ’ ’ d ) d )
May 1996
• pt refused prednisone• restarted cyclophosphamide 100mg/od
• bronchoscopy: inflammatory tracheobronchitis c/w
Wegener’s
June 1997• gross hematuria
• cytoscopy: transitional cell CA• resection and intravesical BCG
• cyclophosphamide discontinued
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On e o f t h e M a n y P r ob l em s w i t h ANCAOn e o f t h e M a n y Pr ob l em s w i t h A NCA - -
A s s o c i a t e d V a s c u l i t i sA s s o c i a t e d V a s c u l i t i s ( c o n t ( c o n t ’ ’ d ) d )
1998
• subglottic stenosis with marked inflammation
c/w Wegener’s, worsening stridor (airway 5
mm)
• restarted high dose prednisone
January 1999
• methotrexate 15 mg weekly
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On e o f t h e M a n y P r ob l em s w i t h ANCAOn e o f t h e M a n y Pr ob l em s w i t h A NCA - -
A s s o c i a t e d V a s c u l i t i sA s s o c i a t e d V a s c u l i t i s ( c o n t ( c o n t ’ ’ d ) d )
Current status 2010
• markedly overweight
• diabetic
• hypertensive• PR3 ANCA remains strongly positive
• occasional bloody nasal discharge
• continues on methotrexate weekly
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On e o f t h e M a n y P r ob l em s w i t h ANCAOn e o f t h e M a n y Pr ob l em s w i t h A NCA - -
A s s o c i a t e d V a s c u l i t i sA s s o c i a t e d V a s c u l i t i s ( c o n t ( c o n t ’ ’ d ) d )
signicant relapse raterelapse rate, especially with
Wegener’s (>50% over 8 yrs)
chronic cyclophosphamide therapy is
associated with• urothelial cancer
• myelodysplastic syndromes up to and including
leukemia
• 10-fold risk of lymphoma
• gonadal toxicity
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Re g im e n s t o Re d u c e Ex p o s u r e t oRe g im e n s t o Re d u c e Ex p o s u re t o
Cy c l o p h o s p h am id e (CTX ) Cy c l o p h o s p h am id e (CTX )
treatment with prednisone and methotrexate in
Wegener’s
pulse CTX instead of daily oral CTX
treatment with prednisone and CTX for 3 to 6months, then conversion to a different drug
• azathioprine
• methotrexate• mycophenolate mofetil
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Re g im e n s t o Re d u c e Ex p o s u r e t oRe g im e n s t o Re d u c e Ex p o s u re t o
Cy c l o p h o s p h am id e (CTX ) Cy c l o p h o s p h am id e (CTX )
pulse vs daily oral CTX in new Wegener’s
(Guillevin 1997)
27 pts IV CTX 0.7 g/m2 q3wk until remission,
then at increasing intervals for 2 yrs
23 pts oral CTX 2 mg/kg/d X 1y, then tapered
by 25% q4months
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Pu l s e v s d a i l y o r a l CTX i n A NCAPu l s e v s d a i l y o r a l CTX i n AN CA - - a s s o c i a t e da s s o c i a t e d
v a s c u l i t i s (H a u b i t z 1 9 9 8 ) v a s c u l i t i s (H a u b i t z 1 9 9 8 )
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CTX : Da i l y O r a lCTX : Da i l y O r a l v s v s Pu l s e T h e r a p y Pu l s e T h e r a p y
“bottom line” appears to be that daily
oral CTX, compared to pulse CTX, is
associated with
• higher remission rate• lower relapse rate (Wegener’s)
• more infectious complications
• more gonadal toxicity (by FSH levels)
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CYCLOPS S t u d y : Pu l s e v e r s u s Da i l y O r a l
C y c l o p h o s p h am i d e (d e G r o o t 2 0 0 9 )
ANCA positive vasculitis with renal
involvement
Serum creatinine > 150 but less than 500 umolper l
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CYCLOPS S t u d y : Pu l s e v e r s u s Da i l y O r a l
C y c l o p h o s p h am i d e (d e G r o o t 2 0 0 9 )
Regimen:
Prednisone 1 mg per kg tapering to 12.5 mg bymonth 3 and 5 mg at month18, AND• IV CTX 15 mg per kg q2weeks X3, q3weeks after
OR
• daily oral CTX
CTX doses reduced in elderly and creat 300+
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CYCLOPS S t u d y – P t
C h a r a c t e r i s t i c s
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CYCLOPS c o n t i n u e d CYCLOPS c o n t i n u e d
Treated until remission + 3 more months
CTX then switched to azathioprine
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CYCLOPS: T im e t o R em i s s i o nCYCLOPS: T im e t o R em i s s i o n
a n da n d eGFR eGFR
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CYCLOPS: Cum u l a t i v e Do s e o fCYCLOPS: Cum u l a t i v e Do s e o f
CT X CT X
daily oral CTX groupreceived 15.9 g (11-22.5)versus pulse groupreceived 8.2 g (5.95-
10.55)
no difference in totalprednisone dose
twice as many relapses
in pulse group comparedto daily oral, but notstatistically significant
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Re g im e n s t o Re d u c e Ex p o s u r e t oRe g im e n s t o Re d u c e Ex p o s u re t o
C y c l o p h o s p h am i d e C y c l o p h o s p h am i d e (CTX ) (CTX )
CTXCTX vsvs AZA as remission maintenance AZA as remission maintenance
therapy in ANCAtherapy in ANCA--associatedassociated vasculitisvasculitis(Jayne et al, 2003)(Jayne et al, 2003)
155 pts ANCA+ vasculitis (most Wegener’s)with mean GFR ~ 50 ml/min
After induction of remission, randomized to• continued CTX (1.5 mg/kg) for 12 mos total, or
• change to azathioprine (2 mg/kg)
18 month total followup
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A ZA v s M TX f o r M a in t e n a n c e
T h e r a p yPa g n o u x e t a l 2 0 0 8
patients with ANCA vasculitis
after remission (prednisone and pulse
CTX)
• azathioprine 2 mg/kgOR
•methotrexate 0.3 mg/kg up to 25 mg/week
X 12 months, then withdrawal over 3 months
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A Z AA Z A v s v s M TX M a in t e n a n c e T h e r a p yM TX M a in t e n a n c e T h e r a p y( c o n t i n u e d )
no difference
between AZA or MTXbut...
by 20 months:
35% relapse
most after
withdrawing the
drugs!
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Re g im e n s t o Re d u c e Ex p o s u r e t oRe g im e n s t o Re d u c e Ex p o s u re t o
C y c l o p h o s p h am i d e C y c l o p h o s p h am i d e (CTX ) (CTX )
Remission therapy with MMF in ANCARemission therapy with MMF in ANCA--
associatedassociated vasculitisvasculitis ((NowackNowack 1999)1999)
9 WG and 2 PA pts remission induction with
corticosteroids and CTX (3 IV)
CTX changed to MMF 2 g/day
followed for 15 months
only 1 relapse (WG)
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Ot h e r Re g im e n s t o R e d u c e E x p o s u r e t oO t h e r Re g im e n s t o Re d u c e Ex p o s u r e t o
C y c l o p h o s p h am i d e C y c l o p h o s p h am i d e (CTX ) (CTX )
Anecdotal reports using
• Cyclosporin
• Rabbit anti-thymocyte globulin
• Anti CD4• Anti CD20
• Anti CD52
• TMP/SMX
• Etanercept (TNF antagonist)
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T r e a t m e n t o fT r e a t m e n t o f A n t i n e u t r o p h i l A n t i n e u t r o p h i l C y t o p l a sm i c C y t o p l a sm i c A n t i b o d y A n t i b o d y - -
A s s o c i a t e dA s s o c i a t e d V a s c u l i t i s V a s c u l i t i s : A Sy s t em a t i c R e v i e w: A Sy s t em a t i c R e v i e w
(B o s c h J AM A 2 0 0 7 ) (B o s c h J AM A 2 0 0 7 )
2 meta-analyses, 20 RCTs, 62uncontrolled trials with > 10 patients
EUVAS definitions of disease
T r e a t m e n t o fT r e a t m e n t o f A n t i n e u t r o p h i lA n t i n e u t r o p h i l C y t o p l a sm i cC y t o p l a sm i c
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T r e a t m e n t o fT r e a t m e n t o f A n t i n e u t r o p h i l A n t i n e u t r o p h i l C y t o p l a sm i c C y t o p l a sm i c
A n t i b o d y A n t i b o d y - - A s s o c i a t e dA s s o c i a t e d V a s c u l i t i s V a s c u l i t i s : A S ys t em a t i c: A Sy s t em a t i c
Re v ie wRe v ie w (B o s c h J A MA 2 0 0 7 ) (B o s c h J A MA 2 0 0 7 )
Generalized Organ-Threatening Disease,including serum creatinine < 5.7 mg/dl
Induction: daily oral CTX + prednisone remains
“gold standard”
intravenous CTX less toxic but may (or maynot) have more relapses
Maintenance: continue CTX pulse or switch to AZA, MMF or leflunomide
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T r e a t m e n t o fT r e a t m e n t o f A n t i n e u t r o p h i l A n t i n e u t r o p h i l C y t o p l a sm i c C y t o p l a sm i c
A n t i b o d y A n t i b o d y
- - A s s o c i a t e dA s s o c i a t e d
V a s c u l i t i s V a s c u l i t i s
: A S ys t em a t i c: A Sy s t em a t i c
Re v ie wRe v ie w (B o s c h J A MA 2 0 0 7 ) (B o s c h J A MA 2 0 0 7 )
Severe Renal Vasculitis and Immediately Life-Threatening Disease
pulse cyclophosphamide (no trials)
intravenous methylprednisolone (no trials)
plasma exchange (MEPEX)
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A N ew Fr on t i e r : I n d u c t i o n w i t h M MF? A N ew Fr on t i e r : I n d u c t i o n w i t h M M F?
HuHu NephNeph Dial Transplant 2008Dial Transplant 2008
• MMF vs pulse CTX for induction
• 35 patients, mostly pANCA
•MMF: 2 g/day
•CTX: 0.75-1.0 g/m2 monthly X 6
• 4 pts in CTX group lost to F/U (?)
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Ou t l i n e Ou t l i n e
the syndrome ofthe syndrome of ““rapidly progressiverapidly progressive
glomerulonephritisglomerulonephritis””
ANCA ANCA--associatedassociated vasculitisvasculitis
•• descriptiondescription
•• pathogenesispathogenesis
•• treatment (prevention of progression)treatment (prevention of progression)
summary
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Sum m a r y (I ) Sum m a r y (I )
in adulthood, the syndrome of rapidly
progressive glomerulonephritis is most oftenthe result of a pauci-immune crescentic
nephritis
the commonest correlate of this lesion is with
ANCA positivity and vasculitis
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