Goals Of Treatment İn Anca Assocıated Vasculıtıs

• Patient survival

• Induce remission of active state

• Reduce disease relapse• Reduce disease relapse

• Minimize therapeutic toxicity

– Least toxic and most effective therapy

– Prevent and monitor toxicity

EUVAS approach to trials in renal vasculitis

• Subgroup according to severity

• High intensity treatment to induce remission, low intensity to

prevent relapse

• Agree standard regimen by consensus

• Test against best alternative by RCT

AAV Clinical Trials Overview

3 - 6 mo.

NORAM: MTX vs CYC

MEPEX: PE vs MP

CYCLOPS: CYC iv vs oral

WEGET: Etanercept vs placebo

SOLUTION: ATG

MYCYC: MMF Vs CYC

RITUXIVAS

ACTIVE

InductionACTIVE

MaintenanceNORAM: MTX vs CYC

CYCAZAREM: AZA vs CYC

IMPROVE: AZA vs MMF

REMAIN: AZA, 24 mo vs 48 mo

Alternative agentsMAINSTIRANRAVEABAVASRATTRAP

Cyclophosphamide / Steroid

� Mainstay of treatment for both MPA and WG since 1980s

� High rate of remission

� Significant morbidity� Significant morbidity� Hemorragic cystitis

� Bladder cancer

� Myelodysplasia

� Infertility

� infection

Which is better: Oral or IV CYC?

• Guillevin L et al, Arthritis Rheum, 1997

• RCT of patients with WG

Group A (CYC Group A (CYC

IV) n = 27IV) n = 27

Group B (CYC Group B (CYC

PO) n = 23PO) n = 23

Initial Initial remissionremission

89%89% 78%78%

Infectious side Infectious side effecteffect

41%41% 70% 70% (p < 0.05)(p < 0.05)

RelapseRelapse 60%60% 13% 13% (p = 0.02)(p = 0.02)

CYC: oral vs pulse IV, meta analysis

•• MetaMeta--analysis analysis

•• 11 non11 non--randomized studies randomized studies

•• N = 202 patients N = 202 patients

•• Pulse vs. daily oral CycPulse vs. daily oral Cyc•• No difference in death / ESRD / remissionNo difference in death / ESRD / remission

•• More relapsesMore relapses OR 1.79* (CI 0.85OR 1.79* (CI 0.85--3.75)3.75)

•• Less infectionsLess infections RR 0.45RR 0.45

•• Lower dose Lower dose 17 g vs. 35 g17 g vs. 35 g

**not statistically significantnot statistically significant

K de Groot et al. Nephrol Dial Transplant 2001

CYCLOPS – Time to remission

Cyclops – Time to relapse

Lessons from CYCLOPS

• PULSE cyc is as effective as daily oral cyc

• Pulse cyc is a/w 50% reduction in total cumulative dose

• Pulse cyc Probably more safer than oral cyc• Pulse cyc Probably more safer than oral cyc

Iv pulse

cyc

Oral cyc

dose

15 mg/kg

q2-3 wk2 mg/kg

daily

2009

dose q2-3 wk daily

no 76 73

Remission @ 9 mo 67[88%] 64[88]Not significant

Time to remission not different

Relapse 13 6 Not powered

Cyc cumulative dose 8.2 gm 15.9gm P<0.001

• A retrospective review

• 20 patients with lung hemorrhage(MP 17,WG 2, CSS 1)

• All treated with PE and Prdn/Cyc

• Resolution of lung hemorrhage in 20/20(100%) with6.4(average ) treatments6.4(average ) treatments

• Half of pts who presented with azotemia(7/14) were d/s withimproved renal function

• No complications of PE

• Historical review revealed death in 3/11 patients not receivingPE

Klemmer, Am J Kid Dis 2003

Induction for severe disease :MEPEX Trial

Design

MEPEX –significant differences at 3 months

• Surviving patients • dialysis independent on dialysis

• PE 81 % 19% p=0.012

• MeP 61% 39% • MeP 61% 39%

• In the patient group as a whole

• alive and dialysis –independent on dialysis or dead

• PE 69% 31% p=0.023

• MeP 49% 51%

MEPEX - Renal recovery

What are the approaches to Achieve remission without CYC?

• Methotrexate –NORAM• Rituximab – RITUXIVAS• MMF• Lefno• TNF alpha inhibitors – WGET • TNF alpha inhibitors – WGET • ATG• IVIG• Cyclosporin• Deoxyspergaulin

INDUCTION THERAPY

3 - 6 mo.

NORAM: MTX vs CYC

MEPEX: PE vs MP

CYCLOPS: CYC iv vs oral

WEGET: Etanercept vs placebo

SOLUTION: ATG

MYCYC: MMF Vs CYC

RITUXIVAS

Induction

RITUXIVAS

MaintenanceNORAM: MTX vs CYC

CYCAZAREM: AZA vs CYC

IMPROVE: AZA vs MMF

REMAIN: AZA, 24 mo vs 48 mo

Alternative agentsMAINSTIRANRAVE

NORAM- NonRenal Wegener’s Alternatively

treated with Methotrexate• A non-inferiority trial, MTx vs cyc in early systemic disease

• Exclusion: abnormal creatinine, > 1g proteinuria, myocarditis ,CHF

• randomized 100 patients to receive either standard oral CYC, 2mg/kg/day or oral MTX, 20–25 mg/week for 12 months andthen withdrew therapy.then withdrew therapy.

• both groups received same dose of steroid- 7.5 mg/d by 6months and stop by 12 months

• FU for 18 months

• A third of these patients did have hematuria,may be ?an earlyrenal trial in some of the patients, although none of them hadbiopsy-proven renal vasculitis

de Groot,Rheumatology,2005

NORAM- Study Design

Stop PRDN by

12 months

Mtx Cyc Remarks

Remission @ 6 months 90 93 P=0.78 No difference

Months to remission 3 2

Relapse @ 18 months 70 46.5 P=0.02 significant

Median cumulative Prdn dose 8.8 gm 6.2 gm P=0.001 significant

NORAM results

Lessons from NORAM

• WITH Mtx there is delayed onset of remission in pts with pulmonary involvement or relatively extensive disease

• With Mtx,there is significantly higher rate of • With Mtx,there is significantly higher rate of relapse than cyc

How to Maintain remission?

• CYCAZAREM- early remission phase of generalized vasculitis- CYC vs AZA

• WEGENT –AZA vs Mtx

• WGET-role of Ethanercept • WGET-role of Ethanercept

• Prospective RCT-open label trial by EUVAS

• New pts with WG or MPA

- First EUVAS trial to be published

CYCAZAREM Trial

- First EUVAS trial to be published

- Can exposure to CYC in pts with generalized vasculitis could be reduced by substitution of AZA at remission

• 3-6 months of oral Cyc + PRDN, then either oral CYC or AZA for 12 mo. After 12 months all pts on AZA up to 18 months

CYCAZAREM trial design

n =144 AZA-73 , CYC-71

Mostly WG, creatinine- < 5.7 mg%

Jayne et al, NEJM, 349;1, 2003

CYCAZAREM - Results

p=0.65

Lessons from CYCAZAREM

• Lower dose of Cyc with early conversion to Aza is justified and probably safer long-term

• The relapse rate among MPA was lower than WG (p=0.03)WG (p=0.03)

• To test that mtx is a/w less serious adverse events than aza

• Primary outcome measure is not relapse rate

WEGENT trial

• Primary outcome measure is not relapse rate but adverse event that causes drug discontinuation or death

WEGENT Trial design

AZA MTX

55 pts 59 pts

RELAPSE @18 17.8 13.7

RELAPSE @ 36 50.1 46.7RELAPSE @ 36 50.1 46.7

RELAPSE FREESURVIVAL @ 18 88.9 90.5

RELAPSE FREESURVIVAL @ 36

64.1 69

TOXICITY GRADE ¾@ 18 7.9 17.4

DRUG WITHDRAWL@36 11.1 17.4

Lessons from WEGENT

• MTX IS not safer than aza

• Both are similar in remission maintenance in mpA AND WG- so choice of drug is best decided on basis of each patients individual decided on basis of each patients individual situation

• A SETBACK TRIAL FOR MTX

• RCT –ethanercept ys placebo in remission maintemance-180

• Both groups received cyc/ mtx

• Only 49 percent of patients remained in remission

throughout the trial, and etanercept did not result in a

higher rate of sustained remission than placebo

2005

higher rate of sustained remission than placebo

• No difference in remission rates and disease flares

• Why no benefit of ethanercept?

o Insufficient dose

o Inefficacy in granulomatous disorders

• Increased malignancy rate in ethanercept group

• Conclusion- no role of ethanercept in WG

MMF

• No RCTs till nowStassen et al Langford et al Koukoulaki et al

Ann RD 2007 A&R 2004Nephron clin prac

2007

Refractory aav-induction trial maintenance

Ind -3

Rem.main -29

High response rates but a

high relapse rate ,upto 50% induction trial maintenance 3 29

32 pts 14 wg pts 19-active disease rx

Cr 25(78%) 100%

Pr 19

relapse 61% 6 (43%) 10 pt 14

Median Relapse free 16 mo

17.5 mo 14mo

high relapse rate ,upto 50%

@ 2yrs as well as adverse

effects upto 70 %

MYCYC trial • RCT of MYC Vs. IV CYC in remission induction in AAV

• Primary endpoint- remission induction by 6 months

• MMF Dose- 2 gram/ day for 3-6 mo ,until remission, thenswitch to AZA

IMPROVE trial International Mycophenolate mofetil Protocol to Reduce Outbreaks of Vasculitis

•Randomised ,open label ,phase 3 ,interventional trial

•Compares MMF with AZA in remission maintenance

Anti-CD 52 therapy• Alemtuzumab (Campath-1H)

• Walsh et al:

� 71 pts –remission in 60 pts (85%)

� CR in 46 pts

� Severe infections in 27%

� Total deaths – 31(infection in 6)

� Conclusion- grave adverse affect profile- so only

experimental in AAV

Walsh et al,ARD,2007

15- DeoxySperGualin

• 15 –DSG is a synthetic derivative of SPERGUALIN, a protein from

Bacillus laterosporus that is capable of preventing B and T cell

maturation

• Inhibits NF-κβ translocation into nucleus• Inhibits NF-κβ translocation into nucleus

• Reversibly inhibits T-cell proliferation and monocyte activation

• Marked neutropenia but no neutrophil dysfunction

• SC Injection in 6 cycles of 21 days with a 7 day washout b/w cycles-

dose: 0.5 mg/kg/day

• Cycles stopped if WBC < 4000

Birck et al Flossmann et al 15-DSG may be a safer

alternative to CYC in

remission

JASN,2003 ARD ,2009

Refractory AAV

Relapsing or refractory AAV

Induction study

Induction Trial

20 pts 44 pts remission induction ,but

not yet approved for

routine clinical use

CR 6 20(45%)

PR 8 22(50%)

Relapses 18(43%)

Median time to relapse

170(44-316days)

Severe adverseeffects

none 24(53%)Leucopenia related

IVIg

• RCT – IVIG vs. placebo

• 34 pts -24 WG and 10 MPA –refractory AAV

• All pts had received 2 mo of PRDN + CYC or AZA and continued on

these for at least 3 mo after IVIGthese for at least 3 mo after IVIG

• IVIG dose-0.4g/kg/d for 5 days

• @ 3 mo- remission in ivig-14/17(82%) and 6/17(35%)– p=0.015

• Limitation- benefit of IVIG did not last beyond 3 months as

subsequent vasculitic activity ,relapse frequency and IS need were

similar in both groups

Jayne et al,2000, Quarterly Journal Of Medicine

Anti Thymocyte Globulin(ATG)

• SOLUTION- Anti Thymocyte Globulin for refractory vasculitis trial

• A single arm pilot study by EUVAS

• 15 wg pts • 15 wg pts

• CR- 4 ,PR-9 ,no remission- 2

• Relapse -7 after a mean of 8.4 months

• 2 deaths soon after ATG-pul.infection & pul.hemorrhage

• Conclusion- not supported clinically

Schmitt et al,Kidney International ,2004

Leflunomide – remission maintenance • An RCT –planned 154 pts ,but stopped after 54 pts

..prematurely

• Reason- very high relapse rate in Mtx arm

• 26 pts -LEf oral daily for 24 mo vs 28 pts - weekly MTX

• Mtx -13/28 –relapse within 6 months;7 relapses were severesevere

• Lef- 6/26 –relapse;1-severe relapse

• Total follow up- 21 months

• High adverse rate of lef leading to stoppage in 4 pts

Q.Why mtx did not work here unlike in wegent trial?

A Low initial dose of 7.5 mg/week used .wegent-20 mg/wk

• Lesson- higher Mtx dose needed in AAV than in RA

• Positive finding in this study-• Positive finding in this study-• Remission maintenance in lef group similar to aza in

cycazarem,although no.are small

• Conclusion - trial inconclusive, but suggests a possible role for LEF@ 30 mg/day in maintenance therapy for wg,albeit with increased adverse events

Role of biologics in AAV

• Ethanercept –WGET trial

• Infliximab – ACTIVE trial

• Rituximab

ACTIVE –INFLIXIMAB in systemic vasculitis

• A pilot study

• 32 pts with 19 WG/ 13 MPA

• 16-acute disease & 16-persistent disease

• Treated with infliximab 5 mg/kg @0,2,6 and 10 weeks

• 88% remission(both groups)• 88% remission(both groups)

• 20% relapse(mainly group 2)

• 21% infection –high incidence

• 6% mortality(pulmonary hemorrhage ,pneumonia)

• Steroid sparing

• Conclusion- no control arms in this study ;may provide a support for larger clinical trial acc.to authors

Booth ,J A S N ,2004

RATTRAP

• Infliximab Versus Rituximab In Systemic Necrotizing Vasculitis

Compares both in 200 pts with resistant AAV• Compares both in 200 pts with resistant AAV

ABAVAS

• Abatacept in AAV

• a pilot study by EUVAS

54 pts 35 wg+ 16 mpa,2 rv,1 mc

37 are refractory vasculitis(69%)

43 (81%)Remission 10 no Remission

6-bvas improved1 year

28(85%) sustained

remission

6-bvas improved

1 -died

3 –remission induced

with other agents

1 year

f/u

5(12%) relapses

C mukt\htyar,r luqmani ,ARD 2005;64

Rituximab

• What is the place of Rituximab in AAV ?

• Induction

• Maintenance

• Relapses• Relapses

• Refractory AAV

• Aim- efficacy & safety of rituximab

• Retrospectively - 65 pts with refractory AAV

• All pts achieved B cell depletion

• 2 REGIMENS• 2 REGIMENS

• LYMPHOMA regimen-375 mg/m2 weeklyx4

• RA regimen-2 one gram iv 2 weeks apart

65 Refractory AAV pts

CR -49 (75%)NO RESPONSE-1 (2%)PR -15 (23%)

MEDIAN-11.5 mo

RELAPSE-

28(57%)

MEDIAN-11.5 mo

•B cell return preceded relapse only in 14/27 pts(52%)•Relapse not a/w anca titer rise or positivity•Immunosupressive rx withdrawn in 37/60 (62%)•Type of rx or IS withdrawl dinot effect relapse timing

Ra-30

Lym-26

Open label trial-rituximab

• 11 pts with pr3-anca(10 wg,1 mp)

• 10 CR ,1 PR at 6 mo

• B cell depletion in all patients

• Fall in ANCA titer in all pts• Fall in ANCA titer in all pts

• Relapse in 5/11 as B cells returned(5-12 mo)

• However, all responded to retreatment Keogh ,A&R 2005

Rituximab In AAV remission induction

• RITUXIVAS- Randomized open label trial comparing rituximab vs.cyc/aza in induction in refractory vasculitisvasculitis

• RAVE- RCT, double blind, placebo controlled-Oral cyc vs rituximab in remission induction in severe WG

Maintenance of remission using Rituximab in

Systemic ANCA associated vasculitis

• Inclusion-remission (first or after a second remission)remission)

• In the first 3 months after starting aza

• Objectives-

• Decrease the relapse rate by 50%

• Increase the tolerance of maintenance treatment

MAINRITSAN study design

Ongoing trials at EUVAS• Length of long-term immunosuppressive therapy?

• REMAIN -long-term low dose immunosuppression

versus treatment withdrawal for renal vasculitis

• Clearance of nasal carriage of Staph Aureus with mupirocin in

WG

• MUPIBAC

Take home messages

• Pulse iv cyc –best induction strategy• Add plasma exchange if severe disease especially renal and

pulmonary • The optimal choice of medication for relapse prevention is not well

established• Azathioprine is the best –validated maintenance therapy to date• Azathioprine is the best –validated maintenance therapy to date• Overall data do not support routine use of Mtx in prevention of

relapse in AAV • Lefno and MMF- good remission induction but a/w high adverse

rates• Tnf alpha inhibitors- so far useless• Rituximab -results are encouraging.. But Needs to wait a liitle more• Ivig –effects not longl asting

Thank you