Vascularites associées aux ANCA Traitement par le RITUXIMAB Philippe Vanhille Néphrologie Médecine Interne Hôpital de Valenciennes Aix- en- Provence 2013
Cyclophosphamide therapy of severe systemic necrotizing vasculitis AS Fauci, P Katz, BF Haynes, and SM Wolff 1979, Volume 301:235-238 80% survival at 8 years F/U
Therapy of AAV 1st generation, 1948-1992 Glucocorticoids, cyclophosphamide 2 nd generation, 1985-2010 Optimisation of cyclophosphamide Other immune suppressives Azathioprine, methotrexate, mycophenolate Immunomodulators Plasma exchange, IVIg
Relapses EUVAS cohort: 535 patients 50% relapses at 7 y M Walsh AR 2012
Survival and ESRD in AAV EUVAS cohort: 535 patients Patient survival Renal survival 1 year 84% 5 years 73% 10 years 63% 5 years 80% O Flossman ARD 2011
Causes of death EUVAS cohort: 535 patients Flossman ARD 2011
Early pronostic factors Infection 1.2 p< 0.001 Leucopenia 1.2 p< 0.001 GFR 0.7 p= 0.002 Cumulative cyc. dose 1.2 p= 0.04 Li/le M, ARD 2010
Other adverse outcomes Cumulative steroid exposure Damage 95%-irreversible disease scars Depressed QOL
Therapy of AAV Ø 1st generation, 1948-1992 Glucocorticoids, cyclophosphamide Ø 2 nd generation, 1985-2010 Optimisation of glucocorticoids and cyclophosphamide Methotrexate, azathioprine, mycophenolate, plasma exchange, IVIg, antibiotics Ø New generation, 2000- Therapeutic antibodies Rituximab
Mechanisms of onset of AAV Furuta & Jayne KI 2013
B cells at sites of GPA inflammation CD20+ Bcells CD138+ plasma cells Zhao et al. Rheumatology 2012
Rituximab: Chimeric anti-cd20 monoclonal antibody V L Cκ V H Cγ1 Murine variable regions Human constant κ region Human constant Fc region Variable regions from murine anti-cd20 antibody IDEC-2B8 Linked to human IgG1 and kappa constant regions Apparent affinity: 5.2 x 10-9 M
Anti-CD20 Ab: mechanism of action CD20
Rituximab for remission induction NEJM 2010 Hypothesis: Rituximab is not inferior to cyclophosphamide for remission induction 197 pts 53 y GFR 61 RAVE vs oral Cyc New or relapsing AAV RITUXVAS 44 pts (33:11) 68 y GFR 17 vs IV Cyc New severe renal AAV
RITUXVAS: protocol overview and patient characteristics Démographics RTX n = 33 CYC n = 11 Age 68(20-85) 67(51-83) WG 18 (55%) 4 (36%) MPA/RLV 15 (45%) 7 (64%) c-anca 20 (63%) 5 (45%) p-anca 13 (37%) 6 (55%) GFR (ml/mn/ 1.73m2) 20 (0-60) 12 (0-38) Dialysis 8/33 (24%) 1/11 (9%) Lung 17/33 (51%) 1/11 (9%) ENT 16/33 (48%) 5/11 (45%) BVAS 2003 18 (12-33) 19 (12-42) PLEX 8/33 (24%) 3/11 (27%) Jones R, NEJM 2010
RITUXVAS: End points Proportion Achieving Remission 0.00 0.25 0.50 0.75 1.00 0 100 200 300 400 Time (days) Cyclophosphamide Rituximab Results Sustained remission at M12 (BVAS 0x2 at 6m) RTX N=33 CYC N=11 76% 82% Remission 82% 91% egfr at M 12 (recovery from dialysis) 51 (5/8) 33 (1/1) ANCA neg by 6 months 89% 81% time to remission R Jones, NEJM 2010
RITUXVAS: Primary Safety End Point RTX CYC Severe Adverse Events 31 (42%) 1.0 /pt/y Infections 21 (39%) 0.66 /pt/y 12 (36%) 1.1 /pt/y 7 (21%) 0.60 /pt/y Death 6 (18%) 2 (18%) 0.00 0.25 0.50 0.75 1.00 0 50 100 150 200 250 300 350 Time (days) CYC RTX R Jones, NEJM 2010
B cell depletion
Change in ANCA and GFR
RITUXVAS: conclusions Patients: Elderly, with severe renal failure Efficacy RTX was not inferior to cyclophosphamide regimen RTX spares the use of cyclophosphamide Safety Similar Severe Adverse Event rates with both regimens typical for this disease subgroup
RITUXVAS: 2 year follow-up results 1ry composite outcome (relapse, death, ESRF) Ritux N=33 Cyc N=11 14 (42%) 4 (36%) Relapse 7/27 (26%) 2/10 (20%) Death 6 (18%) 3 (27%) ESRF 2 (6%) 0 p 0.57 Rise in GFR 20 16 SAE 61%* 36% p 0.64 * 3 cancers : breast, melanoma, basal cell carcinoma Jones R, Chapel Hill 2011
Rituximab for remission induction NEJM 2010 Hypothesis: Rituximab is not inferior to cyclophosphamide for remission induction 197 pts 53 y GFR 61 RAVE vs oral Cyc New or relapsing AAV RITUXVAS 44 pts (33:11) 68 y GFR 17 vs IV Cyc New severe renal AAV
RAVE trial Primary outcome is remission at 6 months: BVAS-WG=0 and w/o Pred. at M 6 - RTX: 64% - CyP: 53% RTX superior in achieving remission in pts (n=101) with severe flares at baseline (67% vs 42%, p=0.013) JH Stone NEJM 2010
RAVE trial Primary outcome is remission at 6 months: BVAS-WG=0 and w/o Pred. at M 6 - RTX: 64% - CyP: 53% RTX superior in achieving remission in pts (n=101) with severe flares at baseline (67% vs 42%, p=0.013) Similar number of selected AE: RTX 31%, CyP 33%, with no difference in rate of infection (severe inf.7%) JH Stone NEJM 2010
RAVE trial: time to flare by limb U Specks Chapel Hill 2011
RAVE trial: time to flare ANCA type Disease type U Specks Chapel Hill 2011
RAVE: 18 months FU RTX(99) Cyc-Aza(98) Severe flares (n) 22 23 Still in remission (%pts) 39 33 No difference between 2 arms: - rate of CR - time to CR and 1st flare - rate of flares - rate or severity of AE Severe flares are rare in the absence of B lymphocytes U Specks Chapel Hill 2011
Relapse after RTX induction RAVE New & relapsing 18 months 40% RITUXVAS New 24 months 26% Cohort studies Most will relapse Further RTX effective Trend for Ig to fall
Maintenance strategy after RTX induction Conventional AZA/MTX, ± steroid Further rituximab at time of relapse guided by B cell return or ANCA Routine, fixed interval
Time based routine RTX re-treatment 50% 13 months R Smith AR 2012
MAINRITSAN: protocol
MAINRITSAN: Organ involvement
MAINRITSAN: results Azathiorine (%) Rituximab (%) Major relapses 15 (25.4) 3 (5.2) SAE 4 (6.7) 1 Other drop outs 7 (11.8) 3 (5.2) Total 21/59 (35.6)* 6/58 (10.3)* *sevral causes for the same paqent
MAINRITSAN: SAE and Mortality Azathioprine 37 in 30 pts (50.8%) infections: 9 3 deaths Rituximab 32 in 27 pts (50.%) infections: 9 0 death
MAINRITSAN: Event-free survival
RITUXIMAB in refractory GPA: granulomatous vs vaculitis disease J Holle ARD 2012
Hypogammaglobulinemia post rituximab LON
Rituximab in AAV As effective as CYC for remission induction Same rate of adverse events as conventional immunosuppressive therapy Effective treatment of relapsing/refractory AAV Effective treatment for remission maintenance Allow reduction of steroids and discontinuation of immunosuppressants in maintenance phase
Rituximab in AAV Relapses still common monitoring of patients Long term efficacy and safety remain to be determined (Bio)markers: for detection of relapse? ANCA/B cells MMP-3 BCA-1 (CXCL 13) Breg. (B5+cells) Therapy based on disease and patient specificities
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