Transcript N Engl J Med

BSR Course, Oxford, 2011
Treatment of Vasculitis:
immunesuppressives and biologics
David Jayne
Vasculitis and Lupus Clinic
Addenbrooke’s Hospital
Cambridge UK
Principles
• Identify drives
– Infection, drugs, malignancy
• Induce and maintain remission
• Minimise drug toxicity
‘Standard’ therapy:
‘add-on’ therapy
IV methyl prednisolone
Plasma exchange
Intravenous immunoglobulin
TNF blockade
? improve effective
+ reduce toxicity
Prednisolone
CYC
0
AZA/MTX
3
6
9
12
15
18
24 months
CYC; cyclophosphamide, AZA; azathioprine, MTX; methotrexate
Reduce cyclophosphamide exposure
 Switch to alternative on remission
 IV pulse instead of daily oral
 Alternative induction for non-severe disease
4
Generalised (CYCAZAREM)
Remission
Relapse
1.0
.9
.8
Group
Cyclophosphamide
Survival
.7
Azathioprine
.6
0
2
4
6
8
10
12
14
16
Time from remission to relapse (months)
Oral CYC + prednisolone
Continued CYC vs. AZA
Jayne, N Engl J Med 2003
CYCLOPS
de Groot et al, Ann Int Med 2009
Early systemic (NORAM):
methotrexate (MTX) vs. cyclophosphamide (CYC)
Remission
Relapse
91.5
95.5
Survival to first relapse
%
Survival to 1st relapse
1.0
.9
.8
.7
.6
.5
.4
LIMB
.3
MTX
Cyclophospham
.2
.1
Methotrexate
CYC
0.0
0
2
4
6
8
10
12
14
16
18
20
P = 0.02
Months from entry
EUVAS
de Groot et al, Arthritis Rheum
2005
Generalised vasculitis –
cyclophosphamide (3-6 months)
Time toTime
remission,
BVAS =0
to remission
Recovery of renal function
1.0
80
.8
Glomerular filtration rate (ml/min)
70
.6
.4
.2
0.0
0
2
4
6
8
60
LIMB
Daily oral
50
Pulse
40
10
12
14
16
0
18
3-6
18
Time (months)
Months from entry
De Groot, ASN 2006
Jayne, New Eng J Med 2003
Evidence based recommendations
• EULAR recommendations for conducting clinical studies and/or clinical
trials in systemic vasculitis: focus on ANCA-associated vasculitis.
Ann
Rheum Dis. 2007;66:605-617.
• EULAR Recommendations for the management of primary small and
medium vessel vasculitis. Ann Rheum Dis. 2008;68:310-317.
• EULAR Recommendations for the management of large vessel vasculitis.
Ann Rheum Dis. 2008;68:318-323.
• www.vasculitis.org
EUVAS
EUVAS
Remission maintenance
 Azathioprine ≅ methotrexate
 How long ?
10
Less cyclophosphamide increases
relapse risk
0.00
0.25
0.50
0.75
1.00
IMPROVE: Cumulative Incidence of Relapse
0
1
2
3
4
5
Time (years)
AZA
th
MMF
Hiemstra, Am Soc Nephrol 2009
Newer therapies, Biologic or nonBiologic ?
•
•
•
•
•
•
IVIg
Anti-TNF
Rituximab
ATG
Alemtuzumab
Abatacept
• Mycophenolic acid
– Mycophenolate
mofetil (Cellcept)
– Enteric coated MPA
(Myfortic)
• Leflunomide
• Deoxyspergualin
Rituximab
Rituximab for refractory vasculitis n
= 63
Jones, Arthritis Rheum 2009
Rituximab in ENT/eye disease
(n=32)
Pre-RTX
Post-RTX
Martinez del Pero et al, Clin Otolaryngol 2009
Rituximab - Randomised Trials in
AAV
• RITUXVAS (EUVAS)
– New, with renal involvement
– N=44
– 12 month data reported 2008
• RAVE (US)
– New/relapsing renal/non-renal
– N=197
– 6 month data reported 2009
RITUVAS - Baseline Characteristics
Patients
Age
PR3/MPO-ANCA
GFR (ml/min/1.73m2)
RTX
33
68
20/13
25
CYC
11
67
5/6
15
Both
44
68
25/19
21
Dialysis
24%
9%
20%
Jones, New Engl J Med 2010
RITUXVAS – remission (BVAS = 0 for 6
months)
Time to Remission
CYC
Sustained
remission
25/33
(76%)
9/11
(82%)
No
sustained
remission
2
incomplete
response
1
incomplete
response
6 deaths
1 death
0.00
0.25
0.50
0.75
1.00
RTX
0
100
200
Time (days)
Cyclophosphamide
300
400
Rituximab
Jones, New Engl J Med 2010
RITUXVAS – safety
21 (39%)
7 (21%)
0.66/pat yr 0.60/pat yr
6 (18%)
2 (18%)
1.00
0.75
Infections
Death
12 (36%)
1.1 /pat yr
0.50
31 (42%)
1.0 /pat yr
0.25
SAEs
0.00
CYC
Proportion Free of SAE
RTX
Time to first SAE
0
50
100
150
200
Time (days)
CYC
250
300
350
RTX
Jones, New Engl J Med 2010
Relapse
RTX
N=33
CYC
N=11
7 (21%)
2 (18%)
Major
1 (3%)
2 (18%)
Minor
6 (18%)
0 (0%)
Relapse
Jones, ACR/ASN 2010
RAVE = US trial
RAVE design
• 197 new (49%) or relapsing WG/MPA
creatinine < 4.0mg/dl, no lung haemorrhage
• Randomised, double-blind
rituximab 375mg/m2/wk x4 vs. oral CYC
• Primary end-point
remission and steroid withdrawal at 6 months
Stone J et al, N Engl J Med 2010
% patients
RAVE – remission rates
p=ns
p=ns
* p=0.01
Stone J et al, N Engl J Med 2010
RAVE results
• Efficacy
– Nephritis and alveolar haemorrhage similar
response
• Safety
– Similar AE rates
• 18 month data end 2010
Stone J et al, N Engl J Med 2010
• Dosing
• Concomitant medication
• Biomarkers
Cambridge retrospective survey
• Non-protocol (n=34)
– 82% full remission
– 15% partial remission
– 3% treatment failure
• Protocol (n=72)
– 93% full remission
– 4% partial remission
– 3% treatment failure
Jones, ACR/ASN 2010
Relapse
• 24 months
– Non-protocol 71%
– Protocol 22%
 End of follow-up
–
–
Non-protocol 76%
Protocol 29%
Jones, ACR/ASN 2010
Take home messages
Cyclophosphamide induction has been
optimised
Remission maintenance with AZA or MTX,
MMF less effective
Rituximab alternative to CYC and preferred for
relapsing/refractory disease. ? Maintenance of
remission after RTX
Thank you