CUEN 20-22 Juin 2010

Avancées thérapeutiques au cours des vascularites rénales associées aux ANCA

Service Néphrologie – Médecine Interne et Vasculaire Centre Hospitalier de Valenciennes

Philippe Vanhille

Aorta

Large to mediumsized artery

Smallartery

ArterioleCapillary

VenuleVein

Leucocytoclastic vasculitis

Henoch-Schonlein purpuraCryoglobulinaemic vasculitis

Microscopic polyangiitis*

Wegener’s granulomatosis*Churg-Strauss syndrome*

Polyarteritis nodosaKawasaki disease

Giant cell arteritisTakayasu arteritis

Classification of systemic vasculitis: Chapel Hill Nomenclature

* ANCA associated

Anti-GBM

Arthritis Rheum, 1994

ANCA Associated Vasculitis

Cumulative Survival & AASV

Time to death

6050403020100

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lativ

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iva

l

1.1

1.0

.9

.8

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ANCA-Associated Vasculitis

Booth, AJKD 2003

IdentificationInduction therapy Maintenance

therapy

Long-term follow-up17% 25% death

•Remission 81%•Relapses 34%•ESRD 28% / 5y

AASV EUVAS: Disease Subgrouping

NORAM

CYCLOPS

MEPEX

Modified from N Rasmussen, D Jayne et al. Clin Exp Immunol 1995

CYCAZAREM IMPROVE

RAVE RITUXVAS

MAINRITSAN

CURRENT TREATMENT OF AASV

What is the most effective induction therapy?

“CYCLOPS” IV cyclophosphamide regimen. 149 pts

0 2 4 6 8 10 12 14 16 18 20 22 24 26

10 x 15mg/kg2.5 > 60yr2.5 creatinine >300 5 >70yr

weeks

2 weekly 3 weekly

de Groot K, Ann Intern Med 2009

Time to remission

Months from entry

181614121086420

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1.0

.8

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.4

.2

0.0

LIMB

Daily oral

Pulse

Time to relapse

Months from entry

181614121086420

Tim

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o r

ela

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m e

ntr

y

1.0

.9

.8

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LIMB

Daily oral

Pulse

• 76 pulse, 73 oral

• Azathioprine started at remission + 3 months

• Remission at 9 months: -88.1% pulse

-87.7% oral

• Relapses after remission (131 pts) 19 (14.5%)

-13 pulse, 7 major

-6 oral, 3 major

de Groot K, Ann Intern Med 2009

CYCLOPS

• Fewer episodes of leukopenia with pulse (26% vs 45%)

• SAE: 19 pulse, 31 oral

severe infection: 7 pulse, 10 oral

• Death: 14 pts

-5 pulse; 3 active disease

-9 oral; 7 active disease

de Groot K, Ann Intern Med 2009

CYCLOPS

Jayne D, JASN 2007

151 pts

MEPEX

67

70

High mortality in both arms: 25%: infection 19, pulm. hemorrhage 6, CVD 4.

Jayne D, JASN 2007

MEPEX trial

MEPEX trial: Long-Term Follow-up

ESRD or Death

ANCA-associated Vasculitis

CURRENT TREATMENT OF AASV

Maintenance therapy:

How can one prevent relapses?

‘Generalised’ - CYCAZAREM n=155

0 3 12 186 9

CYC

AZA AZA

CYC

Induction Remission

Jayne D, NEJM 2003

Prednisolone 10 mg/d 7,5 mg/d

Severe and life-threatening adverse-effects

Time from remission to relapse (months)

1614121086420

Sur

viva

l

1.0

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Group

Cyclophosphamide

Azathioprine

Relapses

‘Generalised’ - CYCAZAREM n=155

Jayne D, NEJM 2003

1815

12

0

2

4

6

8

10

12

14

16

18

Induction 0-3m Remission 3-18m

CYCAZA

CURRENT TREATMENT OF AASV

• Remission induction• Remission maintenance• Problems :

- Relapses- Refractory disease- ESRD or other damage- Drug toxicity- Mortality

Disease manifestation associated with relapse

de Groot K, ASN 2008

550 pts EUVAS

Disease manifestation associated with relapse

Predictors of relapses

Pagnoux C, Arthritis Rheum 2008de Groot K, ASN 2008

Impact of relapse on outcome

Mortality and Adverse effects: EUVAS cohort

• 524 pts

• 1st year mortality 11%

Active vasculitis 14%

Infections 50%

leukopenia, old age, RF

• Thrombo-embolic disease: 10%

M Little, L. Harper, 2010Courtesy of D. Jayne

AAV: New Therapies

• MMF, Leflunomide, Deoxyspergualine• Plasma exchanges• IVIg• Biologic agents

- anti-TNF

- B-cell depletion

MMF vs Cyclophosphamide

• MMF 2g/d vs monthly CyP 0.75-1g/m2

• iv MP 0.5g x3 and Pred. in all pts

• 35 pts, 28 MPO, 2 PR3 ANCA

• Complete remission:

MMF: 77.8%

CyP: 61.5%

Hu W, NDT 2008

MMF for induction – MYCYC n=140

Steroid taper

1.5 60 3 4.5

AzaControl

MMF

CYCLOPHOSPHAMIDE

All patients

MMF 2-3g/day

Aza

www.vasculitis.orgwww.vasculitis.org

MMF vs AZA for remission - IMPROVE n=175

EntryWegener’s

MPA174 pts

CYCPO/IV 3-6/12

AZA 2mg/kgN=79

MMF 2g/dN=76

Study end48/122008

ANCA Workshop Lund 2009

• WG 99, MPA 56 •AZA 79, MMF 76•BVAS: 16 (6-25) Creat 178 (103-310)

Primary hypothesis: MMF reduces the relapse rate by 50%

Cumulative Incidence of Relapse

IMPROVE. 14th ANCA Workshop 2009. Thomas F Hiemstra, University of Cambridge, UK

0.00

0.25

0.50

0.75

1.00

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of R

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0 1 2 3 4 5Time (years)

AZA MMF

Courtesy D Jayne

Time to First Relapse

UNADJUSTED AZA (79) MMF (76) Total (155)

Relapse (%) 30 (38) 42 (55.3) 72 (46.5)

Time to first relapseHazard Ratio 1.7

Shorter in MMF group(95% CI 1.06 – 2.71) p=0.03

Incidence Rate (PPY) 0.13 0.22 -

Incidence Risk Ratio 1.6 (95%CI 1 – 2.71) p=0.04

ADJUSTED Age, Sex, Diagnosis, Renal function at entry, CYC Route

Time to first relapse Shorter in MMF groupHazard Ratio 1.7 (95% CI 1.09 – 2.85) p=0.02

IMPROVE. 14th ANCA Workshop 2009. Thomas F Hiemstra, University of Cambridge, UK

Courtesy D Jayne

Cumulative Incidence of Severe Adverse Events

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50.5

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0 1 2 3 4 5Analysis Time (years)

AZA MMF

IMPROVE. 14th ANCA Workshop 2009. Thomas F Hiemstra, University of Cambridge, UK

Courtesy D Jayne

Adverse Events

AZA (217py) MMF (187py) IRR (95%CI) P-value

Serious Adverse Event (SAE)

21 in 12 patients 7 in 7 patients 0.53* (0.2-1.3) p=0.17

Any Infections 19 13 0.78 (0.4 – 1.7) p=0.49

Serious Infections 8 3 0.43 (0.07 - 1.8) p=0.21

CardiovascularEvents

6 4 0.79 (0.16-3.3) p=0.73

Neoplasia 4 1 0.29 (0.006-2.9) p=0.28

Gastro-intestinal 8 8 1.2 (0.4-3.6) p=0.75

Drug intolerance 8 4 p=0.33

Hepatic dysfunction 4 0 p=0.08

*Hazard Ratio; IRR Incidence Risk Ratio

IMPROVE: conclusions

The primary hypothesis was not met

1. Event free survival was significantly shorter with MMF than AZA

2. Adverse event rate was not different between groups

3. Characteristics of the two groups were similar

AAV:New Therapies

• MMF, Leflunomide, Deoxyspergualine• Plasma exchanges• IVIg• Biologic agents

- anti-TNF

- B-cell depletion

WGET Trial: Etanercept is not superior to placebo forthe maintenance of disease remission

• Only 49% of patients remained in remission throughout the trial.

• High rate of serious or life threatening adverse events (>50% in both groups) related to conventional therapy rather than to etanercept

• Increased risk of malignancies with combination of cyclophosphamide and etanercept

time to sustained remission defined as

a BVASW-G =0 for a minimum of 6 m

WGET, NEJM 2000

New Therapies: Resistant or Relapsing diseases

• MMF, Leflunomide, Deoxyspergualine• Plasma exchanges• IVIg• Biologic agents

- anti-TNF

- B-cell depletion

Role of B-cells

• Cytokines

• Ig production

• Presentation to T-cells

• Plasma cells

RAVE trial: Rituximab for the Treatment of Wegener's

Granulomatosis and Microscopic Polyangiitis N = 197

1: Experimental Drug: 99 pts

Rituximab 375 mg/m2 once weekly x 4 + Azathioprine 2 mg/kg/day for months 4-6

2: Active Comparator Drug: 98 pts

Cyclophosphamide 2 mg/kg/day for months 1-3 then Azathioprine 2 mg/kg/day for months 4-6

All patients receive Methylprednisolone 1 g/day IV for up to 3 days within 14 days prior to rituximab followed by Prednisone 1 mg/kg/day, with taper 6 months.

WG: 75% , MPA 25 % ; initial BVAS-WG: 8.4

ANCA Workshop Lund 2009

RAVE trial: Rituximab for the Treatment of Wegener's

Granulomatosis and Microscopic Polyangiitis N = 197

• Primary outcome is remission at 6 months: BVAS-WG=0 and w/o Pred. at M 6

- RTX: 64%

- CyP: 55%

• RTX superior in achieving remission in pts (n=101) with severe flares at baseline (66.7% vs 42%)

• Similar rate of AE: RTX 6%, CyP 8%, with no difference in rate of infection

ANCA Workshop Lund 2009

Démographics RTX

n = 33

CYC

n = 11

Age 68(20-85) 67(51-83)

WG 18 (55%) 4 (36%)

MPA/RLV 15 (45%) 7 (64%)

c-ANCA 20 (63%) 5 (45%)

p-ANCA 13 (37%) 6 (55%)

GFR (ml/mn/1.73m2)

20 (0-60) 12 (0-38)

Dialysis 8/33 (24%) 1/11 (9%)

Lung 17/33 (51%) 1/11 (9%)

ENT 16/33 (48%) 5/11 (45%)

BVAS 2003 18 (12-33) 19 (12-42)

PLEX 8/33 (24%) 3/11 (27%)

RITUXVAS: protocol overview and patient characteristics

Jones R, in press

RITUXVAS: End points0

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0 100 200 300 400Time (days)

Cyclophosphamide Rituximab

time to remission

Results RTX

N=33

CYC

N=11

Sustained remission at

M12 (BVAS0x2 at 6m)

76% 82%

Deaths 6 (18%) 2 (18%)

Remission 82% 91%

eGFR at M 12

(recovery from dialysis)

51

(5/8)

33

(1/1)

ANCA neg by 6 months 89% 81%

Jones R, in press

RITUXVAS: BVAS score, ANCA and GFR at 12 months

CYC RTX

Jones R, in press

RITUXVAS: Primary Safety End Point

RTX CYC

Severe Adverse Events

31 (42%)

1.0 /pt/y

12 (36%)

1.1 /pt/y

Infections 21 (39%)

0.66 /pt/y

7 (21%)

0.60 /pt/y

Death 6 (18%) 2 (18%)

0.00

0.25

0.50

0.75

1.00

Pro

porti

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ree

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AE

0 50 100 150 200 250 300 350Time (days)

CYC RTX

Jones R, in press

RITUXVAS

• Randomised controlled trial of rituximab versus cyclophosphamide for ANCA-associated vasculitis with renal involvement– Elderly patients with severe renal dysfunction– Groups well balanced

• Efficacy – RTX was not inferior to cyclophosphamide regimen – RTX spares the use of cyclophosphamide

• Safety equivalent– Similar Severe Adverse Event rates with both regimens

typical for this disease subgroup

Jones R, Arthritis Rheum 2009

• Retrospective, standardized data collection from 65 sequential pts

• B cell depletion: 100%

• Complete remission: 49 (75%)

Partial remission: 15 (23%)

• Median time to remission: 2 m (1-5)

• Relapse: 57% (28 pts) after CR

median time to relapse: 11.5 m

• > 2 courses of Rtx in 38 pts

CR in 32 pts (84%)

• Timing of relapse not influenced by:

- RTX regimen

- withdrawal of immunosuppressive therapy

• 13/27 pts (48%) relapsed before B cell

repopulation

• 8/25 pts (32%) with B cell return did not have a relapse

Jones R, Arthritis Rheum 2009

ANCA Disease

• Current therapies based on randomised trials for remission induction and maintenance have improved outcome

• Major issues: diagnostic delay, toxicity of treatment and its contribution to morbidity and mortality, propensity of AAV to relapse

• Conventional therapies need to be optimized, especially in specific subgroups

• Targeting B-cells is a new and attractive therapeutic option but long term benefits and safety are unknown

• Other biologic therapies are under investigation

• New biomarkers are required to facilitate clinical trials

Aknowledgements:EUVAS David Jayne, GFEV Loic Guillevin, and many colleagues…