CUEN Juin 2010 Avancées thérapeutiques au cours des vascularites rénales associées aux ANCA Service Néphrologie – Médecine Interne et Vasculaire Centre Hospitalier de Valenciennes Philippe Vanhille
Aorta Large to medium sized artery Small artery Arteriole Capillary Venule Vein Leucocytoclastic vasculitis Henoch-Schonlein purpura Cryoglobulinaemic vasculitis Microscopic polyangiitis* Wegener’s granulomatosis* Churg-Strauss syndrome* Polyarteritis nodosa Kawasaki disease Giant cell arteritis Takayasu arteritis Classification of systemic vasculitis: Chapel Hill Nomenclature * ANCA associated Anti-GBM Arthritis Rheum, 1994 ANCA Associated Vasculitis
ANCA-Associated Vasculitis Booth, AJKD 2003 Identification Induction therapy Maintenance therapy Long-term follow-up 17% 25% death Remission 81% Relapses 34% ESRD 28% / 5y
AASV EUVAS : Disease Subgrouping NORAM CYCLOPS MEPEX Modified from N Rasmussen, D Jayne et al. Clin Exp Immunol 1995 CYCAZAREM IMPROVE RAVE RITUXVAS MAINRITSAN
CURRENT TREATMENT OF AASV What is the most effective induction therapy?
“CYCLOPS” IV cyclophosphamide regimen. 149 pts 10 x 15mg/kg 2.5 > 60yr 2.5 creatinine >300 5 >70yr weeks 2 weekly3 weekly de Groot K, Ann Intern Med 2009
76 pulse, 73 oral Azathioprine started at remission + 3 months Remission at 9 months: -88.1% pulse -87.7% oral Relapses after remission (131 pts) 19 (14.5%) -13 pulse, 7 major -6 oral, 3 major de Groot K, Ann Intern Med 2009 CYCLOPS
Fewer episodes of leukopenia with pulse (26% vs 45%) SAE: 19 pulse, 31 oral severe infection: 7 pulse, 10 oral Death: 14 pts -5 pulse; 3 active disease -9 oral; 7 active disease de Groot K, Ann Intern Med 2009 CYCLOPS
Jayne D, JASN 2007 MEPEX
Jayne D, JASN pts MEPEX 67 70
High mortality in both arms: 25%: infection 19, pulm. hemorrhage 6, CVD 4. Jayne D, JASN 2007 MEPEX trial
MEPEX trial: Long-Term Follow-up ESRD or Death
ANCA-associated Vasculitis
CURRENT TREATMENT OF AASV Maintenance therapy: How can one prevent relapses?
‘Generalised’ - CYCAZAREM n= CYC AZA CYC InductionRemission Jayne D, NEJM 2003 Prednisolone10 mg/d 7,5 mg/d
Severe and life-threatening adverse-effects Relapses ‘Generalised’ - CYCAZAREM n=155 Jayne D, NEJM 2003
CURRENT TREATMENT OF AASV Remission induction Remission maintenance Problems : -Relapses -Refractory disease -ESRD or other damage -Drug toxicity -Mortality
Disease manifestation associated with relapse de Groot K, ASN ptsEUVAS
Disease manifestation associated with relapse Predictors of relapses Pagnoux C, Arthritis Rheum 2008 de Groot K, ASN 2008
Impact of relapse on outcome
Mortality and Adverse effects: EUVAS cohort 524 pts 1st year mortality 11% Active vasculitis 14% Infections 50% leukopenia, old age, RF Thrombo-embolic disease: 10% M Little, L. Harper, 2010 Courtesy of D. Jayne
AAV: New Therapies MMF, Leflunomide, Deoxyspergualine Plasma exchanges IVIg Biologic agents - anti-TNF - B-cell depletion
MMF vs Cyclophosphamide MMF 2g/d vs monthly CyP g/m2 iv MP 0.5g x3 and Pred. in all pts 35 pts, 28 MPO, 2 PR3 ANCA Complete remission: MMF: 77.8% CyP: 61.5% Hu W, NDT 2008
MMF for induction – MYCYC n=140 Steroid taper Aza Control MMF CYCLOPHOSPHAMIDE All patients MMF 2-3g/day Aza
MMF vs AZA for remission - IMPROVE n=175 Entry Wegener’s MPA 174 pts CYC PO/IV 3-6/12 AZA 2mg/kg N=79 MMF 2g/d N=76 Study end 48/ ANCA Workshop Lund 2009 WG 99, MPA 56 AZA 79, MMF 76 BVAS: 16 (6-25) Creat 178 ( ) Primary hypothesis: MMF reduces the relapse rate by 50%
Cumulative Incidence of Relapse IMPROVE. 14 th ANCA Workshop Thomas F Hiemstra, University of Cambridge, UK Courtesy D Jayne
Time to First Relapse UNADJUSTEDAZA (79)MMF (76)Total (155) Relapse (%)30 (38)42 (55.3)72 (46.5) Time to first relapse Hazard Ratio 1.7 Shorter in MMF group (95% CI 1.06 – 2.71)p=0.03 Incidence Rate (PPY) Incidence Risk Ratio 1.6 (95%CI 1 – 2.71) p=0.04 ADJUSTEDAge, Sex, Diagnosis, Renal function at entry, CYC Route Time to first relapseShorter in MMF group Hazard Ratio 1.7 (95% CI 1.09 – 2.85) p=0.02 IMPROVE. 14 th ANCA Workshop Thomas F Hiemstra, University of Cambridge, UK Courtesy D Jayne
First Major Relapse Time to first major relapse HR 1.9 (95% CI 0.97 – 4.3)p=0.11 IMPROVE. 14 th ANCA Workshop Thomas F Hiemstra, University of Cambridge, UK Courtesy D Jayne
Cumulative Incidence of Severe Adverse Events IMPROVE. 14 th ANCA Workshop Thomas F Hiemstra, University of Cambridge, UK Courtesy D Jayne
Adverse Events AZA (217py)MMF (187py)IRR (95%CI)P-value Serious Adverse Event (SAE) 21 in 12 patients7 in 7 patients 0.53* ( )p=0.17 Any Infections (0.4 – 1.7)p=0.49 Serious Infections ( )p=0.21 Cardiovascular Events ( )p=0.73 Neoplasia ( )p=0.28 Gastro-intestinal881.2 ( )p=0.75 Drug intolerance84p=0.33 Hepatic dysfunction40p=0.08 *Hazard Ratio; IRR Incidence Risk Ratio
IMPROVE: conclusions The primary hypothesis was not met 1.Event free survival was significantly shorter with MMF than AZA 2.Adverse event rate was not different between groups 3.Characteristics of the two groups were similar
AAV:New Therapies MMF, Leflunomide, Deoxyspergualine Plasma exchanges IVIg Biologic agents - anti-TNF - B-cell depletion
WGET Trial: Etanercept is not superior to placebo for the maintenance of disease remission Only 49% of patients remained in remission throughout the trial. High rate of serious or life threatening adverse events (>50% in both groups) related to conventional therapy rather than to etanercept Increased risk of malignancies with combination of cyclophosphamide and etanercept time to sustained remission defined as a BVASW-G =0 for a minimum of 6 m WGET, NEJM 2000
New Therapies: Resistant or Relapsing diseases MMF, Leflunomide, Deoxyspergualine Plasma exchanges IVIg Biologic agents - anti-TNF - B-cell depletion
Role of B-cells Cytokines Ig production Presentation to T-cells Plasma cells
RAVE trial: Rituximab for the Treatment of Wegener's Granulomatosis and Microscopic Polyangiitis N = 197 1: Experimental Drug: 99 pts Rituximab 375 mg/m2 once weekly x 4 + Azathioprine 2 mg/kg/day for months 4-6 2: Active Comparator Drug: 98 pts Cyclophosphamide 2 mg/kg/day for months 1-3 then Azathioprine 2 mg/kg/day for months 4-6 All patients receive Methylprednisolone 1 g/day IV for up to 3 days within 14 days prior to rituximab followed by Prednisone 1 mg/kg/day, with taper 6 months. WG: 75%, MPA 25 % ; initial BVAS-WG: 8.4 ANCA Workshop Lund 2009
RAVE trial: Rituximab for the Treatment of Wegener's Granulomatosis and Microscopic Polyangiitis N = 197 Primary outcome is remission at 6 months: BVAS-WG=0 and w/o Pred. at M 6 - RTX: 64% - CyP: 55% RTX superior in achieving remission in pts (n=101) with severe flares at baseline (66.7% vs 42%) Similar rate of AE: RTX 6%, CyP 8%, with no difference in rate of infection ANCA Workshop Lund 2009
DémographicsRTX n = 33 CYC n = 11 Age68(20-85)67(51-83) WG18 (55%)4 (36%) MPA/RLV15 (45%)7 (64%) c-ANCA20 (63%)5 (45%) p-ANCA13 (37%)6 (55%) GFR (ml/mn/1.73m2) 20 (0-60)12 (0-38) Dialysis8/33 (24%)1/11 (9%) Lung17/33 (51%)1/11 (9%) ENT16/33 (48%)5/11 (45%) BVAS (12-33)19 (12-42) PLEX8/33 (24%)3/11 (27%) RITUXVAS: protocol overview and patient characteristics Jones R, in press
RITUXVAS: End points time to remission Results RTX N=33 CYC N=11 Sustained remission at M12 (BVAS0x2 at 6m) 76%82% Deaths 6 (18%) 2 (18%) Remission82%91% eGFR at M 12 (recovery from dialysis) 51 (5/8) 33 (1/1) ANCA neg by 6 months89%81% Jones R, in press
RITUXVAS: BVAS score, ANCA and GFR at 12 months CYC RTX Jones R, in press
RITUXVAS: Primary Safety End Point RTXCYC Severe Adverse Events 31 (42%) 1.0 /pt/y 12 (36%) 1.1 /pt/y Infections21 (39%) 0.66 /pt/y 7 (21%) 0.60 /pt/y Death6 (18%)2 (18%) Jones R, in press
RITUXVAS Randomised controlled trial of rituximab versus cyclophosphamide for ANCA-associated vasculitis with renal involvement –Elderly patients with severe renal dysfunction –Groups well balanced Efficacy –RTX was not inferior to cyclophosphamide regimen –RTX spares the use of cyclophosphamide Safety equivalent –Similar Severe Adverse Event rates with both regimens typical for this disease subgroup
Jones R, Arthritis Rheum 2009 Retrospective, standardized data collection from 65 sequential pts B cell depletion: 100% Complete remission: 49 (75%) Partial remission: 15 (23%) Median time to remission: 2 m (1-5) Relapse: 57% (28 pts) after CR median time to relapse: 11.5 m > 2 courses of Rtx in 38 pts CR in 32 pts (84%)
Timing of relapse not influenced by: - RTX regimen - withdrawal of immunosuppressive therapy 13/27 pts (48%) relapsed before B cell repopulation 8/25 pts (32%) with B cell return did not have a relapse Jones R, Arthritis Rheum 2009
ANCA Disease Current therapies based on randomised trials for remission induction and maintenance have improved outcome Major issues: diagnostic delay, toxicity of treatment and its contribution to morbidity and mortality, propensity of AAV to relapse Conventional therapies need to be optimized, especially in specific subgroups Targeting B-cells is a new and attractive therapeutic option but long term benefits and safety are unknown Other biologic therapies are under investigation New biomarkers are required to facilitate clinical trials Aknowledgements: EUVAS David Jayne, GFEV Loic Guillevin, and many colleagues…
Steroid withdrawal in vasculitis - STAVE