1. Tuesday Clinical Case Conference Zae Kim

2. Therapy of ANCA-Associated Small Vessel Vasculitis

3. Introduction Best known induction therapy Best known induction therapy Cyclophosphamide / SteroidCyclophosphamide / Steroid Search for alternative induction agent Search for alternative induction agent NORAMNORAM Minimizing the use of CYC Minimizing the use of CYC Oral vs IV CyA - CYCLOPSOral vs IV CyA - CYCLOPS CYCAZAREM (cyclophosphamide vs azathioprine for early remission phase of vasculitis)CYCAZAREM (cyclophosphamide vs azathioprine for early remission phase of vasculitis)

4. Cyclophosphamide / Steroid  Mainstay of treatment for both MPA and WG since 1980s  High rate of remission  Significant morbidity  Hemorragic cystitis  Bladder cancer  Myelodysplasia  Infertility  infection

5. What are the approaches to maintaining remission without CYC? NORAM NORAM Randomized Trial of Cya vs Mtx for Induction of Remissioi nin early systemic ANCAAV_de groot_ArthRheu_2005

6. NORAM – remission at 6 months Randomized Trial of Cya vs Mtx for Induction of Remissioi nin early systemic ANCAAV_de groot_ArthRheu_2005

7. NORAM - relapses Randomized Trial of Cya vs Mtx for Induction of Remissioi nin early systemic ANCAAV_de groot_ArthRheu_2005

8. Minimizing exposure to CYC Minimizing the use of CYC Minimizing the use of CYC Induction Induction Oral vs IV CyA - CYCLOPSOral vs IV CyA - CYCLOPS Maintenance Maintenance CYCAZAREM (cyclophosphamide vs azathioprine for early remission phase of vasculitis)CYCAZAREM (cyclophosphamide vs azathioprine for early remission phase of vasculitis) MMF?MMF?

9. Which is better: Oral or IV CYC? Guillevin L et al, Arthritis Rheum, 1997 Guillevin L et al, Arthritis Rheum, 1997 RCT of patients with WG RCT of patients with WG Group A (CYC IV) n = 27 Group B (CYC PO) n = 23 Initial remission 89%78% Infectious side effect 41%70% (p < 0.05) Relapse60%13% (p = 0.02)

10. CYC: oral vs pulse IV, meta analysis Meta-analysis Meta-analysis 11 non-randomized studies 11 non-randomized studies N = 202 patients N = 202 patients Pulse vs daily oral Cya Pulse vs daily oral Cya No difference in death / ESRD / remissionNo difference in death / ESRD / remission More relapsesOR 1.79* (CI 0.85-3.75)More relapsesOR 1.79* (CI 0.85-3.75) Less infectionsRR 0.45Less infectionsRR 0.45 Lower dose 17 g vs. 35 gLower dose 17 g vs. 35 g * not statistically significant K de Groot et al. Nephrol Dial Transplant 2001; 16:2018-27

11. CYC: Is IV pulse as effective as PO CYC?

12. CYCLOPS – Time to remission

13. Cyclops – Time to relapse

14. Minimizing exposure to CYC Minimizing the use of CYC Minimizing the use of CYC Induction Induction Oral vs IV CyA - CYCLOPSOral vs IV CyA - CYCLOPS Maintenance Maintenance CYCAZAREM (cyclophosphamide vs azathioprine for early remission phase of vasculitis)CYCAZAREM (cyclophosphamide vs azathioprine for early remission phase of vasculitis) MMF?MMF?

15. CYCAZAREM trial Jayne et al, NEJM, 349;1, 2003

16. CYCAZAREM - remission Jayne et al, NEJM, 349;1, 2003

17. Time to first relapse Jayne et al, NEJM, 349;1, 2003

18. CYCAZAREM – renal recovery Jayne et al, NEJM, 349;1, 2003

19. CYCAZAREM - conclusion No difference in relapse rate No difference in relapse rate CTX (14%) vs AZA (15%) CTX (14%) vs AZA (15%) Only predictor of relapse was Only predictor of relapse was MPA (8%) vs WG (18%) MPA (8%) vs WG (18%) No difference in serious adverse events No difference in serious adverse events

20. Alternative to AZA as maintenance therapy MTx / Leflunomide MTx / Leflunomide Metzler et al, Rheumatology 2007 Metzler et al, Rheumatology 2007 55 patients with generalized WG55 patients with generalized WG Study terminated early 2/2Study terminated early 2/2 higher rate of relapse in MTx group higher rate of relapse in MTx group high rate of adverse event in Leflunomide high rate of adverse event in Leflunomide IMPROVE by EUVAS IMPROVE by EUVAS MMF vs AZA MMF vs AZA

21. Ongoing trials at EUVAS Length of long-term immunosuppressive therapy? Length of long-term immunosuppressive therapy? REMAINREMAIN long-term low dose immunosuppression versus treatment withdrawal for renal vasculitis long-term low dose immunosuppression versus treatment withdrawal for renal vasculitis Alternative induction agent? Alternative induction agent? MYCYC (Randomized clinical trial of MMF vs CYC for remission induction in ANCA-AV)MYCYC (Randomized clinical trial of MMF vs CYC for remission induction in ANCA-AV) RITUXVASRITUXVAS MMF as remission agent? MMF as remission agent? IMPROVEIMPROVE Clearance of nasal carriage of Staph Aureus with mupirocin in WG Clearance of nasal carriage of Staph Aureus with mupirocin in WG MUPIBACMUPIBAC