cuen 20-22 juin 2010 avancées thérapeutiques au cours des vascularites rénales associées aux...
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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
Cu
mu
lativ
e S
urv
iva
l
1.1
1.0
.9
.8
.7
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
Pro
po
rtio
n in
re
mis
sio
n
1.0
.8
.6
.4
.2
0.0
LIMB
Daily oral
Pulse
Time to relapse
Months from entry
181614121086420
Tim
e t
o r
ela
pse
fro
m e
ntr
y
1.0
.9
.8
.7
.6
.5
.4
.3
.2
.1
.0
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
.9
.8
.7
.6
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
Cu
mul
ativ
e In
cide
nce
of R
elap
se
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
0.0
00.2
50.5
00.7
51.0
0C
um
ula
tive I
nci
de
nce
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
.00
0.2
50
.50
0.7
51
.00
Pro
port
ion
Ach
ievin
g R
em
issio
n
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
on F
ree
of S
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…