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.
25 20 BVAS 1 (new/worse) 15 10 5 0 N = 76 74 72 68 66 67 66 66 66 67 65 66 65 65 65 66 0 1.5 3 6 9 12 15 18 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
90 80 70 60 Time point 50 Entry 40 Remission 30 18 months N = 75 70 61 76 73 67 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
1.0.9.8.7.6 3 6 9 12 15 18 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
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)
Relapse: MTX 69.5% and CYC 45% NORAM. K de Groot for the EUVAS, Arthritis Rheum, 2005
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
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
WEGENT Cyclophosphamide All patients (n = 121) AZA MTX No. of bolus 10.2 ± 2.2 9.9 ± 2.3 Total dose 10.4 ± 3.3 10.1 ± 3.6 10.4 ± 2.1 10.6 ± 3.6 Months with CYC 6.7 ± 2.1 6.5 ± 1.8 6.9 ± 2.6 Time to reach CS < 20 mg/d, (months) 5.4 ± 4.6 5 ± 1.5 5.9 ± 6.1 Pagnoux C, et al, NEJM 2008
WEGENT Pagnoux C, et al, NEJM 2008 100 90 Relapse-free survival curves % Surviving without relapse 80 70 60 50 p = 0.36 AZA n = 55 MTX n = 59 40 0 3 6 9 12 15 18 21 24 27 30 33 36 Months from randomization Relapse-free survival at 18 mo: AZA 77.9% [66.9 89.0]; MTX 82.4% [72.4 92.3] Relapse-free survival at 24 mo: AZA 67.5% [53.9 81.0]; MTX 72.6% [60.0 85.2]
WEGENT Pagnoux C, et al, NEJM 2008 100 % Surviving without relapse and without severe adverse event 90 80 70 60 50 p = 0.73 Event-free survival curves AZA n = 55 MTX n = 59 40 0 3 6 9 12 15 18 21 24 27 30 33 36 Months from randomization Event-free survival at 18 mo: AZA 70.6% [58.5 82.8]; MTX 67.2% [55.1 79.4] Event-free survival at 24 mo: AZA 61.9% [47.7 76.1]; MTX 57.9% [44.3 71.4]
WEGENT Pagnoux C, et al, NEJM 2008 MPA Wegener
MYCOPHENOLATE MOFETIL FOR MAINTENANCE TREATMENT
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)
JAMA 2010, 2381 174 Randomised 13 excluded 6 no remission 155 Entered Remission 79 assigned to Azathioprine 76 assigned to Mycophenolate Mofetil 79 analysed 76 analysed
JAMA 2010, 2381 Cumulative Incidence of Relapse 0.00 0.25 0.50 0.75 1.00 0 1 2 3 4 5 Time (years) AZA MMF
JAMA 2010, 2381 First Major Relapse Time to first major relapse (HR 1.9, 95% CI 0.97 4.3) p=0.11
Cumulative Incidence of Severe Adverse Events JAMA 2010, 2381 0.00 0.25 0.50 0.75 1.00 0 1 2 3 4 5 Analysis Time (years) AZA MMF
IN CHURG STRAUSS, A TREATMENT WITHOUT CYTOTOXIC AGENTS
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
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
SURVIVAL CURVE FOR 215 PATIENTS ACCORDING THE DOSE OF CYC NS
SURVIVAL CURVE FOR 215 PATIENTS ACCORDING THE DOSE OF CYC AND FFS p = 0.04
1994 2003 11 CHUSPAN PAN and MPA, poor prognosis CS + 6 bolus CYC vs 12 Guillevin, Arthritis Rheum Care Res 2003; 49: 93 1994 2004 CHUSPAN 12 CSS, poor prognosis CS + 6 bolus CYC vs 12 Cohen, Arthritis Rheum Care Res, 2007; 57: 686
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
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. 100 90 % Event-free survival 80 70 60 50 40 30 20 10 12 CY pulses (n = 34) 6 CY pulses (n = 31) P = 0.02 Follow-up months 0 4 8 12 16 20 24 28 32 36
IS IT POSSIBLE TO TREAT SOME VASCULITIDES WITHOUT FACTORS OF POOR PROGNOSIS WITH STEROIDS ONLY?
1994 Ribi, Arthritis Rheum 2010, 62: 1186 1994 Ribi, Arthritis Rheum 2008, 58 : 586 13 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
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
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
TREATMENT OF PAN 19% Minor relapse or corticodependance 121 35% 2 Out of protocol Remission, stop CS 12% Out of protocol for relapse 32% Relapse, randomization
NEXT STEP CHUSPAN 2 FVSG trial, evaluating azathioprine as steroidsparing drug in vasculitis without factors of poor prognosis
BIOTHERAPIES
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
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)
TREATMENT OF VASCULITIDES WITH INFLIXIMAB Individual BVAS 16 14 12 10 8 6 4 2 0 1 2 8 9 6 7 3 4 5 1 d 0 d 42 6 mo Fig 1. Individual BVAS on days 0 and 42, and at 6 months
RELAPSES OF SYSTEMIC VASCULITIS q Long term response q 70% responders relapsed q conclusion: suspensive treatment only
2004 SEVERE RELAPSING 21 VASCULITIS INFLIXIMAB vs RITUXIMAB
REMICANCA COMPARISON q INFLIXIMAB (3 or 5 mg/kg) MONTHLY vs q RITUXIMAB (375 mg/m2) EVERY 4 MONTHS FOR 12 MONTHS
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
2000 2004 17 ANCA + VASCULITIS Treatment of relapses of ANCA+ vasculitis with IgIV (IGANCA) Martinez, Arthritis Rheum december 2008
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
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.
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
RAVE Stone, NEJM 2010, 15 July 1 to 3 pulses MPS CS+CYC oral, 3 to 6 months AZA 12-15 months RTX 375 X 4 + CS + placebo CYC Placebo AZA CROSS OVER IF NEEDED
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)
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
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%
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)