treatment of vasculitis: immunesuppressives and biologics david jayne vasculitis and lupus clinic...
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Treatment of Vasculitis: immunesuppressives and biologics
David JayneVasculitis and Lupus ClinicAddenbrooke’s Hospital
Cambridge UK
BSR Course, Oxford, 2011
Principles
• Identify drives– Infection, drugs, malignancy
• Induce and maintain remission• Minimise drug toxicity
‘Standard’ therapy: ‘add-on’ therapy
CYC
? improve effective+ reduce toxicity
IV methyl prednisolonePlasma exchangeIntravenous immunoglobulinTNF blockade
AZA/MTX
0 3 6 9 12 15 18 24 months
Prednisolone
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)
Jayne, N Engl J Med 2003
Time from remission to relapse (months)
1614121086420
Su
rviv
al
1.0
.9
.8
.7
.6
Group
Cyclophosphamide
Azathioprine
Remission Relapse
Oral CYC + prednisolone Continued CYC vs. AZA
CYCLOPS de Groot et al, Ann Int Med 2009
Months from entry
20181614121086420S
urv
iva
l to
fir
st r
ela
pse
1.0
.9
.8
.7
.6
.5
.4
.3
.2
.1
0.0
LIMB
Cyclophosphamide
Methotrexate
Sur
viva
l to
1st
rela
pse
Early systemic (NORAM): methotrexate (MTX) vs. cyclophosphamide (CYC)
MTX
CYC
P = 0.02
EUVAS
% 91.5 95.5
Remission Relapse
de Groot et al, Arthritis Rheum 2005
Generalised vasculitis – cyclophosphamide (3-6 months)
Time (months)
183-60
Glo
me
rula
r fil
tra
tion
ra
te (
ml/m
in)
80
70
60
50
40
De Groot, ASN 2006Jayne, New Eng J Med 2003
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 remission, BVAS =0 Recovery of renal function
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
EUVASEUVAS
Remission maintenance
Azathioprine ≅ methotrexate How long ?
10
Less cyclophosphamide increases relapse risk
IMPROVE: 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
Hiemstra, Am Soc Nephrol 2009
Newer therapies, Biologic or non-Biologic ?
• 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
RTXRTX CYCCYC BothBoth
PatientsPatients 3333 1111 4444
AgeAge 6868 6767 6868
PR3/MPO-ANCAPR3/MPO-ANCA 20/1320/13 5/65/6 25/1925/19
GFR GFR (ml/min/1.73m(ml/min/1.73m22)) 2525 1515 2121
DialysisDialysis 24%24% 9%9% 20%20%
Jones, New Engl J Med 2010
RITUXVAS – remission (BVAS = 0 for 6 months)
0.0
00
.25
0.5
00
.75
1.0
0P
rop
ort
ion
Ach
ievi
ng
Re
mis
sio
n
0 100 200 300 400Time (days)
Cyclophosphamide Rituximab
Jones, New Engl J Med 2010
RTXRTX CYCCYC
Sustained Sustained remissionremission
25/33 25/33
(76%) (76%)
9/11 9/11
(82%)(82%)
No No sustained sustained remissionremission
2 2 incomplete incomplete responseresponse
6 deaths6 deaths
1 1 incomplete incomplete responseresponse
1 death1 death
Time to Remission
RITUXVAS – safety
RTXRTX CYCCYC
SAEsSAEs 31 (42%)31 (42%)
1.0 /pat yr1.0 /pat yr
12 (36%)12 (36%)
1.1 /pat yr1.1 /pat yr
InfectionsInfections 21 (39%)21 (39%)
0.66/pat yr0.66/pat yr
7 (21%) 7 (21%)
0.60/pat yr0.60/pat yr
DeathDeath 6 (18%)6 (18%) 2 (18%)2 (18%)0.
000.
250.
500.
751.
00P
ropo
rtion
Fre
e of
SA
E
0 50 100 150 200 250 300 350Time (days)
CYC RTX
Time to first SAE
Jones, New Engl J Med 2010
Relapse
RTX RTX N=33N=33
CYC CYC N=11N=11
RelapseRelapse 7 (21%)7 (21%) 2 (18%)2 (18%)
MajorMajor 1 (3%)1 (3%) 2 (18%)2 (18%)
MinorMinor 6 (18%)6 (18%) 0 (0%)0 (0%)
Jones, ACR/ASN 2010
RAVE = US trial
RAVE design
• 197 new (49%) or relapsing WG/MPAcreatinine < 4.0mg/dl, no lung haemorrhage
• Randomised, double-blindrituximab 375mg/m2/wk x4 vs. oral CYC
• Primary end-pointremission and steroid withdrawal at 6 months
Stone J et al, N Engl J Med 2010
RAVE – remission rates
* p=0.01
% p
atie
nts
p=ns p=ns
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
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