ANCA+ VASCULITIDES CYCAZAREM,

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1 ANCA+ VASCULITIDES CYCAZAREM, q Comparison of 3 to 6 mo. oral CYC + CS then azathioprine or oral CYC for 12 mo.+ 10 mg/d CS. After 12 mo all the patients were treated with azathioprine q 150 patients followed for 18 mo.

2 25 20 BVAS 1 (new/worse) N = Months from entry Randomized trial of cyclophosphamide versus azathioprine as remission maintenance therapy for ANCA-associated vasculitis D Jayne for the EUVAS group. New Engl J Med July 2003

3 Time point 50 Entry 40 Remission months N = Azathioprine Cyclophosphamide Trial group Randomized trial of cyclophosphamide versus azathioprine as remission maintenance therapy for ANCA-associated vasculitis D Jayne for the EUVAS group. New Engl J Med July 2003

4 Months Randomized trial of cyclophosphamide versus azathioprine as remission maintenance therapy for ANCA-associated vasculitis D Jayne for the EUVAS group. New Engl J Med July 2003

5 ANCA+ VASCULITIDES NORAM, q Comparison of CYC vs MTX for induction of remission in non-renal ANCA+ vasculitis q 100 patients q At 6 mo the remission rates were 89.8% (MTX) and 93.5% (CYC)

6 Relapse: MTX 69.5% and CYC 45% NORAM. K de Groot for the EUVAS, Arthritis Rheum, 2005

7 ANCA+ VASCULITIDES WEGENT q Pulse CYC for induction of remission (6 to 9 pulses) q MTX or AZA to maintain remission q 120 patients Pagnoux C, et al, NEJM 2008

8 WEGENT Systemic Wegener s granulomatosis: 2 organs involved or kidney involvement or 1 organ involved + general symptoms (fever, weight loss ) Microscopic polyangiitis: with FFS 1 IV CYC 0.6 g/m 2 (d1, d15, d30) 0.7 g/m 2 /3 wk 6-12 mo Azathioprine 2 mg/kg/d or Methotrexate 25 mg/wk 12 mo Cotrimoxazole 1600 mg/d 2 yrs INDUCTION MAINTENANCE Pagnoux C, et al, NEJM 2008

9 WEGENT Cyclophosphamide All patients (n = 121) AZA MTX No. of bolus 10.2 ± ± 2.3 Total dose 10.4 ± ± ± ± 3.6 Months with CYC 6.7 ± ± ± 2.6 Time to reach CS < 20 mg/d, (months) 5.4 ± ± ± 6.1 Pagnoux C, et al, NEJM 2008

10 WEGENT Pagnoux C, et al, NEJM Relapse-free survival curves % Surviving without relapse p = 0.36 AZA n = 55 MTX n = Months from randomization Relapse-free survival at 18 mo: AZA 77.9% [ ]; MTX 82.4% [ ] Relapse-free survival at 24 mo: AZA 67.5% [ ]; MTX 72.6% [ ]

11 WEGENT Pagnoux C, et al, NEJM % Surviving without relapse and without severe adverse event p = 0.73 Event-free survival curves AZA n = 55 MTX n = Months from randomization Event-free survival at 18 mo: AZA 70.6% [ ]; MTX 67.2% [ ] Event-free survival at 24 mo: AZA 61.9% [ ]; MTX 57.9% [ ]

12 WEGENT Pagnoux C, et al, NEJM 2008 MPA Wegener

13 MYCOPHENOLATE MOFETIL FOR MAINTENANCE TREATMENT

14 IMPROVE Induction (3 to 6 months) Maintenance (39 months) CYC (IV or oral) + CS Remission MMF (2 g/d) + CS AZA (2 mg/kg/d) + CS Follow up (6 months)

15 JAMA 2010, Randomised 13 excluded 6 no remission 155 Entered Remission 79 assigned to Azathioprine 76 assigned to Mycophenolate Mofetil 79 analysed 76 analysed

16 JAMA 2010, 2381 Cumulative Incidence of Relapse Time (years) AZA MMF

17 JAMA 2010, 2381 First Major Relapse Time to first major relapse (HR 1.9, 95% CI ) p=0.11

18 Cumulative Incidence of Severe Adverse Events JAMA 2010, Analysis Time (years) AZA MMF

19 IN CHURG STRAUSS, A TREATMENT WITHOUT CYTOTOXIC AGENTS

20 ASSESSMENT IN NECROTIZING VASCULITIS q FFS : a prognostic score q BVAS: assessment score for initial evaluation and follow-up q VDI: measurement of damage q DEI: assessment for initial evaluation and follow up

21 FFS 2011 ü Symptoms which impair the prognosis ü Age > 60 ü Creatininemia > 150 mmol /l ü GI involvement ü Cardiac involvement ü Symptom which improves the prognosis ü ENT involvement Medicine 2011, January issue

22 SURVIVAL CURVE FOR 215 PATIENTS ACCORDING THE DOSE OF CYC NS

23 SURVIVAL CURVE FOR 215 PATIENTS ACCORDING THE DOSE OF CYC AND FFS p = 0.04

24 CHUSPAN PAN and MPA, poor prognosis CS + 6 bolus CYC vs 12 Guillevin, Arthritis Rheum Care Res 2003; 49: CHUSPAN 12 CSS, poor prognosis CS + 6 bolus CYC vs 12 Cohen, Arthritis Rheum Care Res, 2007; 57: 686

25 TREATMENT OF PAN, MPA AND CSS Poor prognosis group, FFS > or = 1 MPS 15 mg/kg CYC 0.6 gr/m 2 Prednisone: 1 mg/kg/d, 1 mo. Cohen et al, Arthritis Rheum

26 Kaplan Meier curves showing the probabilities of event (relapse and/or death)-free survival for patients with severe PAN or MPA treated with CS and either 6 or 12 CY pulses % Event-free survival CY pulses (n = 34) 6 CY pulses (n = 31) P = 0.02 Follow-up months

27 IS IT POSSIBLE TO TREAT SOME VASCULITIDES WITHOUT FACTORS OF POOR PROGNOSIS WITH STEROIDS ONLY?

28 1994 Ribi, Arthritis Rheum 2010, 62: Ribi, Arthritis Rheum 2008, 58 : CHUSPAN PAN and MPA without poor prognostic factors CS alone then 6 pulses CYC vs AZA 14 CHUSPAN CSS without poor prognostic factors CS alone then 6 bolus CYC vs AZA

29 TREATMENT: PAN, MPA & CSS Good prognosis group, FFS = 0 MPS 15 mg/kg Prednisone: 1 mg/kg/d, 1 m. CYC 0.6 gr/m2 In case of relapse or failure Or azathioprine, 2 mg/kg/d - 6 mo Ribi C et al, Arthritis Rheum 2009, revision

30 TREATMENT OF CSS. FFS = 0 19% Remission. Steroids were stopped 70 43% Minor relapse or corticodependance <20mg 4% Treatment out of the protocol 7% Relapse, treatment out of protocol 24% Relapse or failure: randomization 3% Death during induction treatment Ribi C et al, Arthritis Rheum 2008

31 TREATMENT OF PAN 19% Minor relapse or corticodependance % 2 Out of protocol Remission, stop CS 12% Out of protocol for relapse 32% Relapse, randomization

32 NEXT STEP CHUSPAN 2 FVSG trial, evaluating azathioprine as steroidsparing drug in vasculitis without factors of poor prognosis

33 BIOTHERAPIES

34 TREATMENT OF VASCULITIDES WITH ETANERCEPT. THE WGET STUDY q Objective: to maintain remission q Obtained in 72.4 % patients, but 49% relapses q No significant difference q High rate of malignancies in the etanercept group

35 WEGENER S GRANULOMATOSIS Infliximab in necrotizing vasculitides q 10 patients (7 GW, 2 RA vasculitis, 1 cryo) q 10 responded, 5 CR, 5 PR q 1 pt stopped the treatment (allergy)

36 TREATMENT OF VASCULITIDES WITH INFLIXIMAB Individual BVAS d 0 d 42 6 mo Fig 1. Individual BVAS on days 0 and 42, and at 6 months

37 RELAPSES OF SYSTEMIC VASCULITIS q Long term response q 70% responders relapsed q conclusion: suspensive treatment only

38 2004 SEVERE RELAPSING 21 VASCULITIS INFLIXIMAB vs RITUXIMAB

39 REMICANCA COMPARISON q INFLIXIMAB (3 or 5 mg/kg) MONTHLY vs q RITUXIMAB (375 mg/m2) EVERY 4 MONTHS FOR 12 MONTHS

40 22 pts screened 17 pts included 9 Infliximab 8 rituximab 2 CR + 3 PR 3 failures 2 switched to IgIV,CY 2 «grumbling» 1 death at D22 1 CR + 2 PR 2 deaths + 5 failures (4-6 Long term months 1 persistent PR and 2 relapses 2 CR (Cs+aza) in one, rituxi in one 4 switched to rituximab 4 CR

41 ANCA + VASCULITIS Treatment of relapses of ANCA+ vasculitis with IgIV (IGANCA) Martinez, Arthritis Rheum december 2008

42 ANCA+ VASCULITIDES q Randomized study q Single dose infusion of Ig q Add on therapy, progression of disease q 17 IgIV, 17 placebo q 14 responses with IgIV, 7 with placebo q Clinical effect, no effect on ANCA, + on CRP q Positive effect: 3 months only Jayne, QJM 2000, 93: 933

43 ANCA+ VASCULITIDES IGANCA q Open, prospective, non randomized study in patients with relapses of ANCA+ vasculitides q Monthly infusions of IV Ig for 6 months then «free treatment» q Objective: 20% CR or 50% PR q 21 patients included.

44 ANCA+ VASCULITIDES q RESULTS q 21 patients have been included q 20/21 initial responses q at 9 months q 13 CR, 1 PR, 7 relapses q at 24 months: 7 complete remissions

45

46 RAVE Stone, NEJM 2010, 15 July 1 to 3 pulses MPS CS+CYC oral, 3 to 6 months AZA months RTX 375 X 4 + CS + placebo CYC Placebo AZA CROSS OVER IF NEEDED

47 RAVE: Results Ø Primary endpoint (BVAS=0, stop CS at 6 months) reached by: Ø 63 of the 99 patients in the rituximab group 64% Ø 52 of 98 in the control group 53% Ø The treatment difference of 11% between the groups met the criterion for non inferiority (P<0.001)

48 RAVE: Results Ø Secondary endpoint (BVAS 0, < 10 mg CS, at 6 months) reached by: Ø 70 patients treated with rituximab 71% Ø 61 patients in the control group 62%, P = 0.10

49 RAVE: Results Ø Adverse events: Ø No significant differences between the treatment groups Ø Events leading to discontinuation of treatment: Ø 14 patients in the rituximab group 14% Ø 17 in the control group 17%

50 RITUXVAS: Results Ø Sustained remission Ø 25 of 33 patients in the rituximab group 76% Ø 9 of 11 patients in the control group 82% Ø Absolute difference (rituximab vs. cyclophosphamide) was 6% (95% CI, 33 to 21; P = 0.68)