CUEN 20-22 Juin 2010

1. 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

2. Classification of systemic vasculitis: Chapel Hill Nomenclature Arthritis Rheum, 1994 Capillary Small artery Arteriole Venule Large to medium sized artery Vein Anti-GBM Aorta Leucocytoclastic vasculitis Henoch-Schonlein purpura Cryoglobulinaemic vasculitis ANCA Associated Vasculitis Microscopic polyangiitis* Wegener’s granulomatosis* Churg-Strauss syndrome* * ANCA associated Polyarteritis nodosa Kawasaki disease Giant cell arteritis Takayasu arteritis

3. Remission 81% • Relapses 34% • ESRD 28% / 5y ANCA-Associated Vasculitis Identification Induction therapy Maintenance therapy Long-term follow-up 17% 25% death Booth, AJKD 2003

4. AASV EUVAS: Disease Subgrouping NORAM MAINRITSAN CYCLOPS RAVE RITUXVAS CYCAZAREM IMPROVE MEPEX Modified from N Rasmussen, D Jayne et al. Clin Exp Immunol 1995

5. CURRENT TREATMENT OF AASV What is the most effective induction therapy?

6. “CYCLOPS” IV cyclophosphamide regimen. 149 pts 10 x 15mg/kg 2.5 > 60yr 2.5 creatinine >300  5 >70yr 2 weekly 3 weekly de Groot K, Ann Intern Med 2009 weeks

7. CYCLOPS • 76 pulse, 73 oral • Azathioprine started at remission + 3 months • Remission at 9 months: -88.1% pulse -87.7% oral • Relapses after remission (131 pts) 19 (14.5%) -13 pulse, 7 major -6 oral, 3 major de Groot K, Ann Intern Med 2009

8. 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

9. MEPEX 67 70 151 pts Jayne D, JASN 2007

10. MEPEX trial High mortality in both arms: 25%: infection 19, pulm. hemorrhage 6, CVD 4. Jayne D, JASN 2007

11. MEPEX trial: Long-Term Follow-up ESRD or Death

12. ANCA-associated Vasculitis

13. CURRENT TREATMENT OF AASV Maintenance therapy: How can one prevent relapses?

14. ‘Generalised’ - CYCAZAREM n=155 CYC CYC AZA AZA 0 3 6 9 12 18 Induction Remission Prednisolone 10 mg/d 7,5 mg/d Jayne D, NEJM 2003

15. ‘Generalised’ - CYCAZAREM n=155 Severe and life-threatening adverse-effects Relapses Jayne D, NEJM 2003

16. CURRENT TREATMENT OF AASV • Remission induction • Remission maintenance • Problems : • Relapses • Refractory disease • ESRD or other damage • Drug toxicity • Mortality

17. Disease manifestation associated with relapse 550 pts EUVAS de Groot K, ASN 2008

18. Disease manifestation associated with relapse Predictors of relapses de Groot K, ASN 2008 Pagnoux C, Arthritis Rheum 2008

19. Impact of relapse on outcome

20. Mortality and Adverse effects: EUVAS cohort • 524 pts • 1st year mortality 11% Active vasculitis 14% Infections 50% leukopenia, old age, RF • Thrombo-embolic disease: 10% Courtesy of D. Jayne M Little, L. Harper, 2010

21. AAV: New Therapies • MMF, Leflunomide, Deoxyspergualine • Plasma exchanges • IVIg • Biologic agents - anti-TNF - B-cell depletion

22. MMF vs Cyclophosphamide • MMF 2g/d vs monthly CyP 0.75-1g/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

23. MMF for induction – MYCYC n=140 Steroid taper Control CYCLOPHOSPHAMIDE Aza MMF MMF 2-3g/day Aza All patients 0 1.5 3 4.5 6 www.vasculitis.org

24. AZA 2mg/kg N=79 Entry Wegener’s MPA 174 pts CYC PO/IV 3-6/12 Study end 48/12 2008 MMF vs AZA for remission - IMPROVE n=175 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

25. Cumulative Incidence of Relapse Courtesy D Jayne IMPROVE. 14th ANCA Workshop 2009. Thomas F Hiemstra, University of Cambridge, UK

26. Time to First Relapse Courtesy D Jayne IMPROVE. 14th ANCA Workshop 2009. Thomas F Hiemstra, University of Cambridge, UK

27. Cumulative Incidence of Severe Adverse Events Courtesy D Jayne IMPROVE. 14th ANCA Workshop 2009. Thomas F Hiemstra, University of Cambridge, UK

28. Adverse Events *Hazard Ratio; IRR Incidence Risk Ratio

29. IMPROVE: conclusions The primary hypothesis was not met • Event free survival was significantly shorter with MMF than AZA • Adverse event rate was not different between groups • Characteristics of the two groups were similar

30. AAV:New Therapies • MMF, Leflunomide, Deoxyspergualine • Plasma exchanges • IVIg • Biologic agents - anti-TNF - B-cell depletion

31. WGET Trial: Etanercept is not superior to placebo forthe 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

32. New Therapies: Resistant or Relapsing diseases • MMF, Leflunomide, Deoxyspergualine • Plasma exchanges • IVIg • Biologic agents - anti-TNF - B-cell depletion

33. Cytokines Ig production Presentation to T-cells Plasma cells Role of B-cells

34. 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

35. RAVE trial: Rituximab for the Treatment of Wegener's Granulomatosis and Microscopic PolyangiitisN = 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

36. RITUXVAS: protocol overview and patient characteristics Jones R, in press

37. RITUXVAS: End points time to remission Jones R, in press

38. RITUXVAS: BVAS score, ANCA and GFR at 12 months CYC RTX Jones R, in press

39. RITUXVAS: Primary Safety End Point Jones R, in press

40. 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

41. 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

42. 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

43. 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…