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

•  2nd generation, 1985-2010 – Optimisation of cyclophosphamide – Other immune suppressives

•  Azathioprine, methotrexate, mycophenolate – Immunomodulators

•  Plasma exchange, IVIg

Relapses EUVAS cohort: 535 patients

M  Walsh  AR  2012  

50%  relapses  at  7  y  

Survival and ESRD in AAV EUVAS cohort: 535 patients

Patient survival Renal survival

5  years  80%  1  year  84%  5  years  73%  10  years  63%  

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

Ø 1st generation, 1948-1992 – Glucocorticoids, cyclophosphamide

Ø 2nd generation, 1985-2010 – Optimisation of glucocorticoids and

cyclophosphamide – Methotrexate, azathioprine, mycophenolate,

plasma exchange, IVIg, antibiotics Ø New generation, 2000-

– Therapeutic antibodies •  Rituximab

Therapy of AAV

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

•  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

Rituximab: Chimeric anti-CD20 monoclonal antibody

VL

Cκ

VH

Cγ1

Human constant Fc region

Human constant κ region

Murine variable regions

Anti-CD20 Ab: mechanism of action

CD20  

Rituximab for remission induction

                                 RAVE •  197 pts •  53 y •  GFR 61 •  vs oral Cyc •  New or relapsing AAV

RITUXVAS •  44 pts (33:11) •  68 y •  GFR 17 •  vs IV Cyc •  New severe renal AAV

Hypothesis: Rituximab is not inferior to cyclophosphamide for remission induction

NEJM 2010

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%)

RITUXVAS: protocol overview and patient characteristics

Jones R, NEJM 2010

RITUXVAS: End points 0.

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Achi

evin

g Re

miss

ion

0 100 200 300 400Time (days)

Cyclophosphamide Rituximab

time to remission

Results RTX N=33

CYC N=11

Sustained remission at M12 (BVAS 0x2 at 6m)

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%

R Jones, NEJM 2010

RITUXVAS: Primary Safety End Point

RTX CYC

Severe Adverse Events

31 (42%) 1.0 /pt/y

12 (36%) 1.1 /pt/y

Infections 21 (39%) 0.66 /pt/y

7 (21%) 0.60 /pt/y

Death 6 (18%) 2 (18%)

0.00

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0.75

1.00

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Fre

e of

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0 50 100 150 200 250 300 350Time (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

Ritux  N=33

Cyc  N=11

1ry  composite  outcome  (relapse,  death,  ESRF)

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

                                 RAVE •  197 pts •  53 y •  GFR 61 •  vs oral Cyc •  New or relapsing AAV

RITUXVAS •  44 pts (33:11) •  68 y •  GFR 17 •  vs IV Cyc •  New severe renal AAV

Hypothesis: Rituximab is not inferior to cyclophosphamide for remission induction

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)

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%

•  Cohort studies – Most will relapse –  Further RTX

effective –  Trend for Ig to fall

•  RITUXVAS –  New –  24 months –  26%

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

•  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

Rituximab in AAV

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