Transcript AZA - CUEN

Avancées thérapeutiques au cours des vascularites
rénales associées aux ANCA
Philippe Vanhille
Service Néphrologie – Médecine Interne et Vasculaire
Centre Hospitalier de Valenciennes
CUEN 20-22 Juin 2010
Classification of systemic vasculitis: Chapel Hill Nomenclature
Large to
medium
sized artery
Capillary
Small
artery
Arteriole
Arthritis Rheum, 1994
Venule
Vein
Anti-GBM
Aorta
Leucocytoclastic vasculitis
Henoch-Schonlein purpura
Cryoglobulinaemic vasculitis
Microscopic polyangiitis*
ANCA Associated Vasculitis
Wegener’s granulomatosis*
Churg-Strauss syndrome*
Polyarteritis nodosa
Kawasaki disease
Giant cell arteritis
Takayasu arteritis
* ANCA associated
ANCA-Associated Vasculitis
•Remission 81%
•Relapses 34%
•ESRD 28% / 5y
Cumulative Survival & AASV
Identification
1.1
Induction
therapy
Maintenance
therapy
1.0
Long-term
follow-up
.9
17%
25% death
.8
.7
0
10
20
30
Time to death
40
50
60
Booth, AJKD 2003
AASV EUVAS: Disease Subgrouping
NORAM
MAINRITSAN
CYCLOPS RAVE
RITUXVAS
CYCAZAREM
IMPROVE
MEPEX
Modified from N Rasmussen, D Jayne et al. Clin Exp Immunol 1995
CURRENT TREATMENT OF AASV
What is the most effective induction therapy?
“CYCLOPS” IV cyclophosphamide regimen. 149 pts
10 x 15mg/kg
2.5 > 60yr
2.5 creatinine >300
 5 >70yr
2 weekly
0
2
3 weekly
4
6
8
10
12
14
weeks
16
18
20
22
24
26
de Groot K, Ann Intern Med 2009
CYCLOPS
Time to remission
1.0
.8
.6
LIMB
.4
Daily oral
.2
Pulse
0.0
0
2
4
6
8
10
12
14
16
• 76 pulse, 73 oral
• Azathioprine started at
remission + 3 months
• Remission at 9 months:
-88.1% pulse
-87.7% oral
18
Months from entry
Time to relapse
1.0
.9
.8
.7
.6
.5
LIMB
.4
.3
Daily oral
• Relapses after remission (131 pts)
19 (14.5%)
-13 pulse, 7 major
-6 oral, 3 major
.2
.1
Pulse
.0
0
2
4
6
8
10
12
Months from entry
14
16
18
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
MEPEX
67
70
151 pts
Jayne D, JASN 2007
MEPEX trial
High mortality in both arms: 25%:
infection 19, pulm. hemorrhage 6, CVD 4.
Jayne D, JASN 2007
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
CYC
CYC
AZA
0
3
Induction
6
AZA
9
12
Remission
Prednisolone
10 mg/d
7,5 mg/d
Jayne D, NEJM 2003
18
‘Generalised’ - CYCAZAREM n=155
Relapses
Severe and life-threatening
adverse-effects
1.0
18
18
15
16
.9
14
12
12
10
.8
CYC
AZA
8
Group
Cyclophosphamide
.7
6
4
2
Azathioprine
0
Induction 0-3m
.6
0
2
4
6
8
10
12
14
Remission 3-18m
16
Time from remission to relapse (months)
Jayne D, NEJM 2003
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
de Groot K, ASN 2008
Predictors of relapses
Pagnoux C, Arthritis Rheum 2008
Impact of relapse on outcome
Mortality and Adverse effects: EUVAS cohort
•
•
•
Courtesy of D. Jayne
524 pts
1st year mortality 11%
Active vasculitis 14%
Infections 50%
leukopenia, old age, RF
Thrombo-embolic disease: 10%
M Little, L. Harper, 2010
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 0.751g/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
Control
CYCLOPHOSPHAMIDE
MMF
Aza
MMF 2-3g/day
Aza
Steroid taper
All patients
0
1.5
3
4.5
6
www.vasculitis.org
MMF vs AZA for remission - IMPROVE n=175
Entry
Wegener’s
MPA
174 pts
CYC
PO/IV
3-6/12
AZA 2mg/kg
N=79
Study end
48/12
2008
MMF 2g/d
N=76
• 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%
ANCA Workshop Lund 2009
0.00
0.25
0.50
0.75
1.00
Cumulative Incidence of Relapse
0
1
2
3
4
Time (years)
AZA
MMF
Courtesy D Jayne
IMPROVE. 14th ANCA Workshop 2009. Thomas F Hiemstra, University of Cambridge, UK
5
Time to First Relapse
UNADJUSTED
AZA (79)
MMF (76)
Total (155)
Relapse (%)
30 (38)
42 (55.3)
72 (46.5)
Hazard Ratio 1.7
Shorter in MMF group
(95% CI 1.06 – 2.71)
p=0.03
0.13
0.22
-
Time to first relapse
Incidence Rate (PPY)
Incidence Risk Ratio 1.6
ADJUSTED
Time to first relapse
(95%CI 1 – 2.71)
p=0.04
Age, Sex, Diagnosis, Renal function at entry, CYC Route
Shorter in MMF group
Hazard Ratio 1.7 (95% CI 1.09 – 2.85)
p=0.02
Courtesy D Jayne
IMPROVE. 14th ANCA Workshop 2009. Thomas F Hiemstra, University of Cambridge, UK
0.00
0.25
0.50
0.75
1.00
Cumulative Incidence of Severe Adverse Events
0
1
2
3
Analysis Time (years)
AZA
4
5
MMF
Courtesy D Jayne
IMPROVE. 14th ANCA Workshop 2009. Thomas F Hiemstra, University of Cambridge, UK
Adverse Events
AZA (217py)
MMF (187py)
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
Cardiovascular
Events
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
Serious Adverse Event
(SAE)
*Hazard Ratio; IRR Incidence Risk Ratio
IRR (95%CI)
P-value
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 for
the 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
RITUXVAS: protocol overview and patient characteristics
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%)
Jones R, in press
Proportion Achieving Remission
0.25
0.50
0.75
1.00
RITUXVAS: End points
Results
RTX
N=33
CYC
N=11
Sustained remission at
M12 (BVAS0x2 at 6m)
76%
82%
Deaths
6 (18%)
2 (18%)
82%
91%
eGFR at M 12
(recovery from dialysis)
51
(5/8)
33
(1/1)
ANCA neg by 6 months
89%
81%
0.00
Remission
0
100
200
Time (days)
Cyclophosphamide
time to remission
300
Rituximab
400
Jones R, in press
RITUXVAS: BVAS score, ANCA and GFR at 12 months
CYC
RTX
Jones R, in press
Infections
21 (39%)
0.66 /pt/y
7 (21%)
0.60 /pt/y
Death
6 (18%)
2 (18%)
0.75
12 (36%)
1.1 /pt/y
0.50
31 (42%)
1.0 /pt/y
0.25
Severe
Adverse
Events
0.00
CYC
Proportion Free of SAE
RTX
1.00
RITUXVAS: Primary Safety End Point
0
50
100
150
200
Time (days)
CYC
250
300
RTX
Jones R, in press
350
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
• 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%)
Jones R, Arthritis Rheum 2009
• 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…