tuesday clinical case conference zae kim. therapy of anca-associated small vessel vasculitis
TRANSCRIPT
Tuesday Clinical Case Tuesday Clinical Case ConferenceConference
Zae KimZae Kim
Therapy of ANCA-Associated Therapy of ANCA-Associated Small Vessel VasculitisSmall Vessel Vasculitis
IntroductionIntroduction
• Best known induction therapyBest known induction therapy• Cyclophosphamide / SteroidCyclophosphamide / Steroid
• Search for alternative induction agentSearch for alternative induction agent• NORAMNORAM
• Minimizing the use of CYCMinimizing the use of CYC• Oral vs IV CyA - CYCLOPSOral vs IV CyA - CYCLOPS
• CYCAZAREM (cyclophosphamide vs azathioprine CYCAZAREM (cyclophosphamide vs azathioprine for early remission phase of vasculitis)for early remission phase of vasculitis)
Cyclophosphamide / SteroidCyclophosphamide / Steroid
Mainstay of treatment Mainstay of treatment for both MPA and WG for both MPA and WG since 1980ssince 1980s
High rate of remissionHigh rate of remission Significant morbiditySignificant morbidity
Hemorragic cystitisHemorragic cystitis Bladder cancerBladder cancer MyelodysplasiaMyelodysplasia InfertilityInfertility infectioninfection
What are the approaches to What are the approaches to maintaining remission without CYC?maintaining remission without CYC?
• NORAM NORAM
Randomized Trial of Cya vs Mtx for Induction of Remissioi nin early systemic ANCAAV_de groot_ArthRheu_2005
NORAM – remission at 6 monthsNORAM – remission at 6 months
Randomized Trial of Cya vs Mtx for Induction of Remissioi nin early systemic ANCAAV_de groot_ArthRheu_2005
NORAM - relapsesNORAM - relapses
Randomized Trial of Cya vs Mtx for Induction of Remissioi nin early systemic ANCAAV_de groot_ArthRheu_2005
Minimizing exposure to CYCMinimizing exposure to CYC
• Minimizing the use of CYCMinimizing the use of CYC• InductionInduction
• Oral vs IV CyA - CYCLOPSOral vs IV CyA - CYCLOPS• MaintenanceMaintenance
• CYCAZAREM (cyclophosphamide vs azathioprine CYCAZAREM (cyclophosphamide vs azathioprine for early remission phase of vasculitis)for early remission phase of vasculitis)
• MMF?MMF?
Which is better: Oral or IV CYC?Which is better: Oral or IV CYC?
• Guillevin L et al, Arthritis Rheum, 1997Guillevin L et al, Arthritis Rheum, 1997• RCT of patients with WGRCT of patients with WG
Group A (CYC IV) Group A (CYC IV) n = 27n = 27
Group B (CYC PO) Group B (CYC PO) n = 23n = 23
Initial remissionInitial remission 89%89% 78%78%
Infectious side Infectious side effecteffect
41%41% 70% 70% (p < 0.05)(p < 0.05)
RelapseRelapse 60%60% 13% 13% (p = 0.02)(p = 0.02)
CYC: oral vs pulse IV, meta CYC: oral vs pulse IV, meta analysisanalysis
• Meta-analysis Meta-analysis • 11 non-randomized studies 11 non-randomized studies • N = 202 patients N = 202 patients
• Pulse vs daily oral CyaPulse vs daily oral Cya• No difference in death / ESRD / remissionNo difference in death / ESRD / remission
• More relapsesMore relapses OR 1.79* (CI 0.85-3.75)OR 1.79* (CI 0.85-3.75)
• Less infectionsLess infections RR 0.45RR 0.45
• Lower dose Lower dose 17 g vs. 35 g17 g vs. 35 g
**not statistically significantnot statistically significant
K de Groot et al. Nephrol Dial Transplant 2001; 16:2018-27
CYC: Is IV pulse as effective as PO CYC: Is IV pulse as effective as PO CYC?CYC?
CYCLOPS – Time to remissionCYCLOPS – Time to remission
Cyclops – Time to relapseCyclops – Time to relapse
Minimizing exposure to CYCMinimizing exposure to CYC
• Minimizing the use of CYCMinimizing the use of CYC• InductionInduction
• Oral vs IV CyA - CYCLOPSOral vs IV CyA - CYCLOPS• MaintenanceMaintenance
• CYCAZAREM (cyclophosphamide vs azathioprine CYCAZAREM (cyclophosphamide vs azathioprine for early remission phase of vasculitis)for early remission phase of vasculitis)
• MMF?MMF?
CYCAZAREM trialCYCAZAREM trial
Jayne et al, NEJM, 349;1, 2003
CYCAZAREM - remissionCYCAZAREM - remission
Jayne et al, NEJM, 349;1, 2003
Time to first relapseTime to first relapse
Jayne et al, NEJM, 349;1, 2003
CYCAZAREM – renal recoveryCYCAZAREM – renal recovery
Jayne et al, NEJM, 349;1, 2003
CYCAZAREM - conclusionCYCAZAREM - conclusion
• No difference in relapse rateNo difference in relapse rate• CTX (14%) vs AZA (15%)CTX (14%) vs AZA (15%)
• Only predictor of relapse wasOnly predictor of relapse was• MPA (8%) vs WG (18%)MPA (8%) vs WG (18%)
• No difference in serious adverse eventsNo difference in serious adverse events
Alternative to AZA as maintenance Alternative to AZA as maintenance therapytherapy
• MTx / LeflunomideMTx / Leflunomide• Metzler et al, Rheumatology 2007Metzler et al, Rheumatology 2007
• 55 patients with generalized WG55 patients with generalized WG• Study terminated early 2/2 Study terminated early 2/2
• higher rate of relapse in MTx group higher rate of relapse in MTx group • high rate of adverse event in Leflunomidehigh rate of adverse event in Leflunomide
• IMPROVE by EUVASIMPROVE by EUVAS• MMF vs AZAMMF vs AZA
Ongoing trials at EUVASOngoing trials at EUVAS• Length of long-term immunosuppressive therapy?Length of long-term immunosuppressive therapy?
• REMAIN REMAIN long-term low dose immunosuppression versus treatment long-term low dose immunosuppression versus treatment
withdrawal for renal vasculitiswithdrawal for renal vasculitis
• Alternative induction agent?Alternative induction agent?• MYCYC (Randomized clinical trial of MMF vs CYC for MYCYC (Randomized clinical trial of MMF vs CYC for
remission induction in ANCA-AV)remission induction in ANCA-AV)• RITUXVASRITUXVAS
• MMF as remission agent?MMF as remission agent?• IMPROVEIMPROVE
• Clearance of nasal carriage of Staph Aureus Clearance of nasal carriage of Staph Aureus with mupirocin in WGwith mupirocin in WG
• MUPIBACMUPIBAC