Systemerkrankungen mit Nierenbeteiligung

Transcription

1 Systemerkrankungen mit Nierenbeteiligung ÖGN Fuschl 2012 Irmgard Neumann Wilhelminenspital Wien

2 Induktions-Therapie Generalisiert CYC i.v. pulse = CYC oral CYCLOPS, de Groot, Ann Int Med 2009 RIT vs CYC RITUXIVAS, Jones, NEJM 2010 RAVE, Stone, NEJM 2010 PLEX? PEXIVAS Long term data 2 years follow-up 18 months follow-up Severe/Dialyse CYC + Plasmaseparation Long term follow-up MEPEX, Jayne, JASN 2007 Refractory RIT Jones et al., A&R 2009 viele unkontrollierte Studien

3 Erhaltungs - Therapie Generalisiert CYC = CYC AZA CYCYZAREM, Jayne et al., N EJM, 2003 Long term data AZA (2mg/kg) = MTX (25mg/w) WEGENT, Pagnoux Ch, NEJM 2008 LEFLUNOMID vs MTX LEM, Metzler, Reumatology 2007 MMF vs AZA IMPROVE,Hiemstra, JAMA 2010 Rituximab

4 CYCLOPS long term follow-up Data of 148 patients Median follow-up 4.3 years ( ) P=0.029 Harper, Ann Rheum Dis 2011

5 CYCLOPS long term follow-up Pulse daily oral (DO) Deaths Relapse rate patient year p<0.001 Patients relapsed 30 (40%) 15 (21%) Relapses 54 (12 renal) 21 (10 renal) ESRD 10 (13%) 8 (11%) mscrea at f-up (mmol/l) Risk of relapse lower in DO PR3 positive more likly to relapse No difference in - renal function - survival - adverse events Harper, Ann Rheum Dis 2011

6 Plasma Exchange for Severe Renal Vasculitis MEPEX long term follow-up 137 Patients, median follow-up 4 years 70 (51%) developed ESRD, 56 (41%) died, 26 (19%) experianced at least 1 relapse No long term benefit of PLEX over IVMeP considering ESRD, death or relapse Casian, Abstract, ANCA Workshop 2011

7 PLEX for Renal Vasculitis - Meta-analysis 9 trials, 387 patients, renal vasculitis or idiopathic RPGN standard therapy versus standard therapy+plex Pooled RR for ESRD or death was 0.8 for +PLEX vs noplex (95%CI, ; P=0.04) Walsh, Am J Kidney Dis 2011

8 PEXIVAS: a RCT of PLEX and GC dosing in the treatment of severe AAV Efficacy of PLEX and reduction of glucocorticoid exposure 500 patients, new or relapsing AAV, including severe disease, randomized 1:1

9 CYCAZAREM Long term renal outcome Data available for EDRD in 130/155 pts Mean follow-up 7.1 ± 3.14 years CYC limb AZA limb ESRD: 6/65 ( 9%) 8/65 (12%) Mean egfr at 5 years: 51±25ml/min 49±30 ml/min The only independent predictor for ESRD: basline egfr (HR=0.88; p<0.001) Also long term: AZA is as effective as CYC for maintenance therapy Berden, EUVAS, Abstact ANCA Workshop 2011

10 Mortality in 535 Patients with AAV Outcome data of 535 patients with newly diagnosed AAV (EUVAS trials) Median follow-up: 5.2 yrs; 133 deaths (25%) Mortality ratio of 2.6 (95%CI 2.2 to 3.1) compared with general population Survival at 1, 5 and 10 years was 85 %, 74 % and 66% Main causes of death < 1 year: Infection 48% active vasculitis 19.0% Main causes of death > 1 year : cardiovascular disease 26% malignancy 22% infection 20% Negativ prognostic factors for patient survival (MVA): egfr <15ml/min disease activity (BVAS) low haemoglobin, higher white cell count age Conclusion: AAV remains associated with a high mortality rate. Flossmann, Ann Rheum Dis 2011

11 Malignancy in 535 Patients with AAV Outcome data of 535 patients with newly diagnosed AAV (EUVAS trials) Calculations by linkage to five national cancer databases 2650 person-years observation perios: 50 cancers in 46 patients Area-standardized incidence ratios (SIR) (95%CI) : 1.58 (1.17 to 2.08) for all cancers 1.30 (0.90 to 1.89) for all cancers excluding non-myeloma skin cancer (NMSC) 3.23 (0.39to 11.65) for leucaemia 1.11 (0.03 to 6.19) for lymphoma 2.78 (1.56 to 4.59) for NMSC Subgroup SIR for all cancers for GPA 1.92 (1.31 to 2.71) for MPA 1.20 (0.71 to 1.89) Heijl, Mahr Ann Rheum Dis 2011

12 RITUXIVAS 2 Year follow-up At 2 years: RTX CYC Relapse, death or ESRD 42% 36% p=1,00 Relapse 21% 18% p=1.00 Death 18% 27% p=0.67 ESRD 6% 0 p=0.57 Median egfr 20 and 44 ml/ 12 and 31 ml/ at 0 an 24 months Jones, Abstract, ANCA Workshop 2011

13 Continuous RIT administration, 39 patients, retrospective study Initiation: 2x1g 1g every 4 (6) months All >1 year of follow-up, 2 years in 20 patients Total: 708 patients-months follow-up, 253 administered doses Results: Only 3 flares during 708 patient-months (after at least 20 mo of follow-up) Cytotoxic IS decreased 87% 41% at 12 months (P < 0.001) 30% at 24 months (P 0.002) Prednisone decreased from 92% 59% at 12 months (P < 0.001) Conclusions: Potential role of RIT as maintenance therapy Delayed adverse effects of rituximab unclear..

14 Generalized Summary Induction-Therapy CYC i.v. pulse vs CYC oral long term CYCLOPS: higher relapse-rate in iv de Groot, Ann Int Med 2009 Harper, Ann Rheum Dis 2011 RIT vs CYC RIT vs CYC Better for relapsing disease RITUXIVAS, Jones, NEJM 2010 RAVE, Stone, NEJM 2010 Severe/dialysis CYC + PLEX RIT + PLEX MEPEX, Jayne, JASN 2007 RITUXIVAS, Jones, NEJM 2010 Refractory and Relapsing disease RIT Jones et al., A&R 2009 RAVE, Stone, NEJM 2010

15 Summary Maintenance Therapy CYC = CYC AZA AZA (2mg/kg) = MTX (25mg/w) Cave renal!! MMF vs AZA RIT vs (CYC)/AZA RAVE extended data RIT protocolized 1g/6mo vs non protocol. less relapses RIT vs AZA less relapses RIT 1g every 4-6mo less cytotoxic IS, less steroids CYCYZAREM, Jayne, NEJM, 2003 WEGENT, Pagnoux, NEJM 2008 IMPROVE, Hiemstra, JAMA 2010 Specks, ANCA Workshop 2011 Jones, Abstr., ANCA workshop 2011 Guillevin, Abstr., ANCA workshop 2011 Rhee, Niles, Clin JASN 2010

16 Lupus nephrits

17 ISN/RPS 2003 Klassifikation Klasse I Minimale mesangiale Lupus-Nephritis Klasse II Mesangial proliferative Lupus-Nephritis Klasse III Fokal proliferative Lupus-Nephrits (<50% der Glomerula) A A/C C Klasse IV Diffus proliferative Lupus-Nephritis (>50% der Glomerula) - segmental (IV-S) - global (IV-G) A A/C C Klasse V Membranöse Lupus-Nephritis Klasse VI Chronisch sklerotische Lupus-Nephritis

18 Induction SLE -Trials MMF 2g vs oral CYC LN IV = Chan, NEJM 2000, JASN 2005 MMF 3g vs NIH-CYC LN III-V > Ginzler NEJM 2005 Iow vs high CYC LN III,IV = EuroLupus Houssiau A & R y follow-up = Houssiau AnnRheumDis 2010 MMF 3g vs NIH-CYC LN III-V = ALMS Appel JASN 2009 subgroup analysis Isenberg Rheumatology 2010 MMF 3g +/- RIT LN III,IV = LUNAR Rovin, A&R 2012 Maintenance Induction via Eurolupus ->MMF 2g vs AZA 2 mg/kg =,> renal MAINTAIN Houssiau Ann Rheum Dis 2010 Induction ALMS (MMF or NIH-CYC) MMF 2g vs AZA 2mg/kg Dooley, NEJM 2011

19 LUNAR Efficacy and safety of rituximab in active proliferative lupus nephritis: The lupus nephritis assessment with rituximab (LUNAR) study Rituximab for Induction, LN III, IV double blind, Phase III, placebo controlled trial 144 patients (67% LN IV) Exclusion: >50% glomeruli with sclerosis/interst fibrosis, GFR<25 ml/ Randomized 1:1 standard therapy (MMF 3g +OCS) + RIT (2x1g at 0 und 6mo) versus placebo OCS 0.75 mg/kg/d taper to 10mg by 16 weeks Primary outcome: renal response at 52 week (CR,PR) Rovin, Arthr Rheum 2012

20 LUNAR Results At week 52: depleted peripheral CD19+ B cells in 71/72 patients placebo RIT CR+PR 46 % 57 % (P=0.55) SAE 35 % 30 % Infections 17 % 16 % - significant improvement with RIT in: dsdna, C3, C4 - cyclophosphamide rescue: 8 placebo 0 rituximab Rovin, Arthr Rheum 2012

21 LUNAR CONCLUSIONS: Although RIT led to more responders and greater reductions in anti-dsdna and C3/C4 levels, it did not improve clinical outcomes after 1 year of treatment. The combination of rituximab with MMF and corticosteroids did not result in any new or unexpected safety signals. Points for Discussion: severe disease high corticosteroids + MMF ( mask ) benefit from experimental therapy may be difficult to detect Renal response may be delayed Rovin, Arthr Rheum 2012

22 MAINTAIN randomized trial, MMF vs AZA as maintenance treatment 105 patients, all proliferative LN Induction: 3x 750 mg MP-pulse oral GC + 6x 500 mg CYC iv fortnightly at week 12: AZA (2 mg/kg/day) or MMF (2 g/day) Endpoint: Time to renal flare M follow-up of was 48 months Houssiau, Ann Rheumat Dis 2010

23 MAINTAIN Renal flares: AZA: 13 (25%), MMF 10 (19%) n.s. Conclusion: Fewer renal flares were observed in patients receiving MMF, but n.s. Houssiau, Ann Rheumat Dis 2010

24 MAINTAIN Over a 3-year period no significant difference in: - 24 h proteinuria - serum creatinine - serum albumin - serum C3 - haemoglobin - global disease activity scores - doubling of serum creatinine - Adverse events, except for haematological cytopenias, (more frequent in AZA group (p=0.03) Houssiau, Ann Rheumat Dis 2010

25 ALMS, ASPREVA maintenance data 36-month, randomized, double-blind, double-dummy, phase 3 study MMF (2 g per day) versus oral azathioprine (2 mg perkgbw/d) 227 patients Dooley, NEJM 2011

26 ALMS, ASPREVA maintenance data Dooley, NEJM 2011

27 ALMS, ASPREVA maintenance data Dooley, NEJM 2011

28 Indications for immunosuppressive treatment and therapeutic strategy Initiation of IS should be guided by a diagnostic renal biopsy. Immunosuppressive agents class IIIA or IIIA/C (±V) class IVA or IVA/C (±V) class V nephropathy if proteinuria >1 g/24-hr despite the optimal use of ACEI/ARB blockers +) considered in class II LN with proteinuria >1 g/day, especially in presence of glomerular hematuria Goal of treatment long-term preservation of renal function prevention of disease flares avoidance of treatment-related harms improved quality of life

29 Goals and definitions: Complete renal response: proteinuria less than 0.5 g/24-hr and normal or stable GFR Response to treatment: as at least 50% reduction in proteinuria and stability or improvement in GFR should be achieved by 6 to 12 months following initiation of treatment. Nephritic flare: in renal function ( of SCr 30% over the basal value) and active urine sediment with in glomerular RBC ( 10/hpf) irrespective of changes in proteinuria; Proteinuric flares: reproducible doubling of proteinuria to Uprot/Ucreat ratio 2; *) active urine sediment alone is not an indication for pre-emptive treatment [consider close follow-up and/or re-biopsy

30 Treatment of adult lupus nephritis Initial treatment Class IIIA or IIIA/C (±V) and Class IVA or IVA/C (±V) LN MMF (3 g/day) or low-dose i.v. CYC (total dose 3g, Euro Lupus) Adverse prognostic factors (acute deterioration in renal function, cellular crescents and/or fibrinoid necrosis) CY also monthly at higher doses (0.75-1g/m2) for 6 months + Glucocorticoids: Initially: 3 x of IV methylprednisolone mg oral prednisolone 0.5 mg/kg/day for 4 weeks, reducing to 10 mg/day by 4 to 6 months Non-responders with MPA or CY - switched from MPA to CY, or CY to MPA - rituximab Class V nephritis with nephrotic-range proteinuria MMF (3 g/day9 + oral prednisolone (0.5 mg/kg/day) Non-responders: CY or calcineurin inhibitors (cyclosporin, tacrolimus) or rituximab

31 Maintenance Therapy MMF (2 g/day) or AZA (2 mg/kg/day) for at least 3 years, + low dose prednisone (5-7.5 mg/day) Calcineurin inhibitors can be considered for V nephritis. - Gradual drug withdrawal, glucocorticoids first - Pregnancy contempted: switch to AZA prior to conception.

32 Adjunct treatment ACE-I or ARBs for patients with proteinuria (>0.5 g/24-hr) or hypertension Statins for persistent dyslipidaemia (target LDL-C 2.58 mmol/l [100 mg/dl]) Hydroxychloroquine to improve outcomes - by reducing renal flares - limiting renal and cardiovascular damage Acetyl-salicylic acid in patients with antiphospholipid antibodies Calcium and vitamin D supplementation Immunizations with non-live vaccines Anticoagulant treatment in nephrotic syndrome with serum albumin <20g/L, (especially if persistent or in the presence of antiphospholipid antibodies)

33 Lupus nephritis and pregnancy Pregnancy may be planned in stable lupus patients with inactive lupus and proteinuria <0.5 g/24-hr, for the preceding 6 months GFR preferably > 50ml/min Acceptable medications: hydroxychloroquine low dose prednisolone, azathioprine and/or calcineurin inhibitors The intensity of treatment should not be reduced in anticipation of pregnancy. Acetylsalicylic acid should be considered to reduce the risk of pre-eclampsia. Assessment: at least every 4 weeks

34 Pregnancy MMF or IV-CY should not be used in last 3 months, biological agent not in last 6-12 months Good blood pressure control (without ACEi/ARB), use nifedipine, labetalol or methyldopa data on ASS for prevention of pre-eclampsia from non-sle specific literature Cave APS: increased risk of hypertension, pre-eclampsia, IUGR, fetal loss and premature delivery, anti-coagulation with LMWH before diagnosing LN flare, assessment for pre-eclampsia should be undertaken Cave: risk for flare during post-partum (vigilant monitoring) anti-ro/la antibodies: risk of cardiac block and neonatal SLE