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