1. Treatment of Vasculitis: immunesuppressives and biologics
BSR Course, Oxford, 2011
Treatment of Vasculitis: immunesuppressives and biologics
David Jayne
Vasculitis and Lupus Clinic
Addenbrooke’s Hospital
Cambridge UK

2. Principles Identify drives Induce and maintain remission
Infection, drugs, malignancy
Induce and maintain remission
Minimise drug toxicity

3. ‘Standard’ therapy: ‘add-on’ therapy
IV methyl prednisolone
Plasma exchange
Intravenous immunoglobulin
TNF blockade
? improve effective
+ reduce toxicity
Prednisolone
CYC
AZA/MTX
months
CYC; cyclophosphamide, AZA; azathioprine, MTX; methotrexate

4. Reduce cyclophosphamide exposure
Switch to alternative on remission
IV pulse instead of daily oral
Alternative induction for non-severe disease

5. Generalised (CYCAZAREM)
Remission Relapse
Induction rates in this trial were high with oral cyclophosphamide and high dose oral glucocorticoids.
Oral CYC + prednisolone Continued CYC vs. AZA
Jayne, N Engl J Med 2003

6. CYCLOPS
de Groot et al, Ann Int Med 2009

7. Early systemic (NORAM): methotrexate (MTX) vs. cyclophosphamide (CYC)
Remission Relapse
Survival to 1st relapse %
91.5
95.5
MTX
The toxicity of cyclophosphamide exemplified by studies from the National Institutes of Health (USA) have inspired strategies to reduce cyclophosphamide exposure.
Methotrexate is an alternative immunosuppressive for early systemic (limited) vasculitis.
CYC
P = 0.02
EUVAS
de Groot et al, Arthritis Rheum 2005

8. Generalised vasculitis – cyclophosphamide (3-6 months)
Time to remission, BVAS = Recovery of renal function
Median creatinine at entry was 200 (GFR 48ml/min). Good recovery of renal function was observed.
De Groot, ASN 2006
Jayne, New Eng J Med 2003

9. 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:
EULAR Recommendations for the management of primary small and medium vessel vasculitis. Ann Rheum Dis. 2008;68:
EULAR Recommendations for the management of large vessel vasculitis. Ann Rheum Dis. 2008;68:
EUVAS
EUVAS

10. Remission maintenance
Azathioprine ≅ methotrexate
How long ?

11. Less cyclophosphamide increases relapse risk

13. IMPROVE: Cumulative Incidence of Relapse
The primary endpoint of time to first relapse was evaluated using a COX proportional hazards regression model.
Kaplan Meyer cumulative incidence curves show an early divergence which is maintained throughout the follow-up period, with more events occurring in the Azathioprine group. There were 187 patient years follow-up in the MMF group and 217 patient years in the AZA group, reflecting the higher relapse rate in the MMF group.
The analysis was left-censored at the start of remission therapy, and right censored at relapse, death, end of follow-up, or withdrawal.
Hiemstra, Am Soc Nephrol 2009
IMPROVE. 14th ANCA Workshop Thomas F Hiemstra, University of Cambridge, UK

14. Newer therapies, Biologic or non-Biologic ?
IVIg
Anti-TNF
Rituximab
ATG
Alemtuzumab
Abatacept
Mycophenolic acid
Mycophenolate mofetil (Cellcept)
Enteric coated MPA (Myfortic)
Leflunomide
Deoxyspergualin

15. Rituximab

16. Rituximab for refractory vasculitis n = 63
We have conducted a retrospective registry review of 63 AAV patients treated with rituximab.
Jones, Arthritis Rheum 2009

17. Rituximab in ENT/eye disease (n=32)
Pre-RTX
Post-RTX
11 patients with eye symptoms
5 patients had retro-orbital disease
4/5 (80%) responded to rituximab
1 patient resolved completely
3 patients had clinical improvement
Non-responder currently on Alemtuzumab
?Were these slower to respond?
Martinez del Pero et al, Clin Otolaryngol 2009

18. 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

19. RITUVAS - Baseline Characteristics
RTX
CYC
Both
Patients 33 11 44
Age 68 67
PR3/MPO-ANCA
20/13
5/6
25/19
GFR (ml/min/1.73m2) 25 15 21
Dialysis
24% 9%
20%
Patient characteristic at trial entry are illustrated in this table. 33 patients received the rituximab based regimen and 11 received the cyclophosphamide based regimen. An upper age for trial inclusion was not specified and consequently elderly patients were included with a median age of 68 years, which was well balanced between groups. Just over half of patients were PR3 ANCA positive in the rituximab group whereas just under half were PR3 positive in the cyclophophosphamide group. Median GFR at entry was slightly higher in rituximab patients compared to cyc patients; 25mls/min vs 15mls/min, although more rituximab patients required dialysis at entry; 24% vs 9%. Overall you can see that this trial included elderly patients with poor renal function with reasonable balancing between groups.
Jones, New Engl J Med 2010

20. RITUXVAS – remission (BVAS = 0 for 6 months)
Time to Remission
RTX
CYC
Sustained remission
25/33
(76%)
9/11
(82%)
No sustained remission
2 incomplete response
6 deaths
1 incomplete response
1 death
Jones, New Engl J Med 2010

21. RITUXVAS – safety Time to first SAE RTX CYC SAEs 31 (42%) 1.0 /pat yr
12 (36%)
1.1 /pat yr
Infections
21 (39%)
0.66/pat yr
7 (21%)
0.60/pat yr
Death
6 (18%)
2 (18%)
Jones, New Engl J Med 2010

22. Relapse RTX N=33 CYC N=11 Relapse 7 (21%) 2 (18%) Major 1 (3%) Minor
6 (18%)
0 (0%)
Jones, ACR/ASN 2010

23. RAVE = US trial

24. RAVE design 197 new (49%) or relapsing WG/MPA Randomised, double-blind
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

25. RAVE – remission rates % patients p=ns p=ns * p=0.01
Stone J et al, N Engl J Med 2010

26. RAVE results Efficacy Safety 18 month data end 2010
Nephritis and alveolar haemorrhage similar response
Safety
Similar AE rates
18 month data end 2010
Stone J et al, N Engl J Med 2010

27. Dosing
Concomitant medication
Biomarkers

28. 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
David- the more partial remissions in the non-protocol group is probably explained by the short follow-up in some of these patients
Jones, ACR/ASN 2010

29. Relapse 24 months End of follow-up Non-protocol 71% Protocol 22%
From this graph it looks like protocolised patients relapse much more in the first 12 months than in the second 12 months. So in answer to your first question- yes I think patients probably need more than one dose to get into proper remission (However this graph does only consider first relapses in individuals –three patients had second relapes) The slope of the curve from months is very similar to that seen from 0-12 months. Which to me suggests that the 2 year course is not allowing prolonged remissions beyond 2 years.
Jones, ACR/ASN 2010

30. 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

31. Thank you