Vasculitis a Review of Pathogenesis, Vasculitis a Review of Pathogenesis,

8/12/2019 Vasculitis a Review of Pathogenesis, Vasculitis a Review of Pathogenesis,

http://slidepdf.com/reader/full/vasculitis-a-review-of-pathogenesis-vasculitis-a-review-of-pathogenesis 1/82

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



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



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



Mr P: Renal BiopsyMr P: Renal Biopsy





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



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



Ou t l i n e Ou t l i n e

ANCA-associated vasculitis

• description

• pathogenesis

• treatment

summary



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





Differential Diagnosis (cont’d)

pauci-immune

• ANCA-associated glomerulonephritis

crescentic nephritis associated with anti-GBMantibody





Differential Diagnosis – other diseases that have

fooled me

cholesterol embolic disease

thrombotic microangiopathy

acute interstitial nephritis

acute tubular necrosis in a patient with GN



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

%%



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



“ “ 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.”

http://upload.wikimedia.org/wikipedia/commons/0/07/Smell.jpg



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



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



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

%%



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



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 ) )



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 ) )



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



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



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



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”)



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



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







•• descriptiondescription

• pathogenesis

• treatment

summary



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?



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


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



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)

http://www.state.sd.us/doh/images/syringe.gif





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 )



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 )






•• pathogenesispathogenesis

• treatment

summary



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


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





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





What we know:What we know:

corticosteroids and cyclophosphamide

have changed the natural history of this

previously-fatal illness





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



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



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



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



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



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



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



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



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



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



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



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?



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



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





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





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





Current status 2010

• markedly overweight

• diabetic

• hypertensive• PR3 ANCA remains strongly positive

• occasional bloody nasal discharge

• continues on methotrexate weekly





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



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




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







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 )



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)



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



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+



CYCLOPS S t u d y – P t

C h a r a c t e r i s t i c s



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



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



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




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





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



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!





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)



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


Anecdotal reports using

• Cyclosporin

• Rabbit anti-thymocyte globulin

• Anti CD4• Anti CD20

• Anti CD52

• TMP/SMX

• Etanercept (TNF antagonist)



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



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



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


: 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)



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 (?)






the syndrome ofthe syndrome of ““rapidly progressiverapidly progressive

glomerulonephritisglomerulonephritis””

ANCA ANCA--associatedassociated vasculitisvasculitis


•• pathogenesispathogenesis

•• treatment (prevention of progression)treatment (prevention of progression)

summary



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



Documents

Vasculitis a Review of Pathogenesis, Vasculitis a Review of Pathogenesis,