Nierenbeteiligung bei Systemerkrankungen

Transcription

1 Nierenbeteiligung bei Systemerkrankungen ÖGN 2018 Irmgard Neumann

2 Avacopan (CCX168) Small molecule, orally administered Highly selecgve C5aR inhibitor Prevented MPO- ANCA mediated GlomerulonephriGs in C5aR Knock- In Mouse Model (Xiao et al. J Am Soc Nephrol 2014)

3 CLEAR Avacopan (CCX168), selecgve C5a receptor inhibitor, p.o. à Could Avacopan replace oral GC without compromising efficacy? Randomized, double- blind, placebo- controlled trial in Europe Newly- diagnosed or relapsing ANCA- associated vasculigs Jayne, JASN 2017

4 67 pagents 12- week treatment with avacopan or placebo add on SOC 12- week follow- up CLEAR Three treatment groups: Control: Placebo twice daily + RTX/CYC + Full Dose Prednisone (60 mg/day) 30 mg avacopan twice daily + RTX/CYC + Low Dose Prednisone (20 mg/day) 30 mg avacopan twice daily + RTX/CYC + No Prednisone (Placebo) CYC regimen: 15 mg/kg IV up to 1.2 g on Days 1, 15, 29, 57, and 85 RTX regimen: 375 mg/m 2 IV weekly for 4 weeks Prednisone (in control group): 60 mg/day, tapered to 10 mg/day by week 12 and 0 by week 21 I.N Jayne, JASN 2017

5 CLEAR Primary Endpoint CLEAR Study Response based on BVAS at Week 12 BVAS 50% reduc*on from baseline, no worsening in any body system Avacopan treatment groups were numerically superior and stagsgcally non- inferior to standard of care (SOC) Jayne, JASN 2017

6 CLEAR: Changes in CLEAR Disease acgvity (BVAS) B Urinary abnormaliges C,D Quality of life indices E,F,G Jayne, JASN 2017

7 CLEAR CLEAR Study - Primary Endpoint met Clinical response at week 12: Number of Patients High dose steroid SOC BVAS response: 14 / 20 70% % P-value Avacopan patients BVAS response: 36 / 43 84% P = Avacopan plus low dose steroid: 19 / 22 86% P = Avacopan plus no steroid: 17 / 21 81% P = 0.01 Jayne, JASN 2017

8 CLEAR - Adverse Effects CLEAR Less GC- related AE (psychiatric disorders, diabetes, weight, fractures, cataract, hypertension ) 65 % control vs. 34 % avacopan (p = 0.02) Other adverse events similar across groups 91% control vs 86% avacopan + low dose pred vs 96% avacopan Grade 3 adverse events similar 9% in each group, one serious infecgon in each group, no sepsis à Possibly lower with Treatment with Avacopan Jayne, JASN 2017

9 Mepolizumab ang interleukin- 5 monoclonal angbody prevents interacgon with IL- 5- R on the eosinophil surface reduces blood eosinophils (regulates eosinophil proliferagon, maturagon and differengagon) is increased in EGPA

10 mulgcenter, double- blind, parallel- group, phase 3 trial relapsing or refractory EGPA, severe - on treatment for at least 4 weeks and - on stable prednisolone dose Wechsler et al, NELM 2017

11 Design 300 mg mepolizumab or placebo, s.c. every 4 weeks, + SOC (OGC +/- stable IS) 52 weeks 136 pagents (68 mepolizumab, 68 placebo) Wechsler et al, NELM 2017

12 Two primary end points at 12 mo Total accrued weeks of remission Remission: BVAS 0 and Pred 4,0 mg or less Remission at both week 36 and week 48 Wechsler et al, NELM 2017

13 Mepolizumab or Placebo for EGPA, 1 year Treated pagents showed more weeks of remission and fewer relapses Wechsler et al, NELM 2017

14 Wechsler et al, NELM 2017

15 Wechsler et al, NELM 2017

16 Mepolizumab for EGPA - Conclusion Primary endpoints met With Mepolizumab significantly more weeks in remission higher proporgon of pargcipants in remission reduced glucocorgcoids only approximately half the pargcipants had protocol- defined remission Wechsler et al, NELM 2017

17 252 pagents (CYCLOPS, IMPROVE), ANCA at switch from CYCà maintenance 102 (40%) at least one relapse 111 ANCA- posigve, of whom 55 (50%) relapsed, 141 ANCA- negagve, of whom 47 (33%) relapsed Morgan, ArthriGs Research & Therapy 2017

18 two clinical trials (200 newly diagnosed GPA) early systemic (n = 83) and generalized (n = 117) Salmela A, Rheumatologiy 2017

19 GPA - Time to first relapse early systemic (A) and generalized disease (B) Salmela A, Rheumatologiy 2017

20 REMAIN Maintenance therapy AZA/Predn 24 vs 48 months, n=117 (CYC/Pred for inducgon) Long congnuagon of AZA - less relapses (63% vs 22%, p<0.0001) - beqer renal outcome (0 vs 4 ESRD) - more adverse events ANCA posigve at randomisagon associated with higher relapse risk (51% vs 29%, p=0.017) Karras Ann Rheum Dis 2017

21 380 newly diagnosed AAV (236 GPA, 132 MPA, 12 renal limited) Post hoc analysis from 6 European mulgcentre studies all AZA maintenance Primary Outcome: Relapse- free survival at 60 months à 65 % for AZA >18 mo vs 55% AZA stopp at 18 mo (P= 0.11) de Joode, Rheumatology 2017

22 à ANCA specificity more effect on relapse- free survival than duragon of maintenance should be used to tailor therapy individually de Joode, Rheumatology 2017

23 Goodpasture SOC IndukGon: OCS, Cyclophosphamid, PLEX (ang- GBM- AK- monitoring) Stop CYC nach 3 Monaten, OCS nach 6 Monaten Keine Erhaltungstherapie!

24 ANCA + an*- GBM 568 AAV pagents 41 ang- GBM disease 37 double- posigve (ANCA and ang- GBM) McAdoo st al, KI 2017

25 Demographics at presentagon AAV ang- GBM double +ive DuraGon of symptoms (mo) 12 (0-56) 2 (0-20) 10 (1-26) Lung hemorrhage 23 % 40 % 38 % RRT 23 % 63 % 57 % Serology ang- MPO 48 % 70 % ang- PR3 51 % 27 % McAdoo st al, KI 2017

26 PaGent survival double posigv similar to ang- GBM Trend for more double posigve to come off dialysis Relapses in double posigve pagents similar to AAV McAdoo st al, KI 2017

27 Conclusion double posigve Double posigve pagents 47% of ang- GBM cases (in all 3 centers) 3%, 11%, 6 % of AAV pagents have a truly hybrid disease phenotype requiring aggressive early treatment for ang- GBM disease careful long- term follow- up consider maintenance therapy as for AAV McAdoo st al, KI 2017

28 IniGale Therapie Class III, IV Predn (+ MP) + MMF (2-3 g/day) oder Low- dose i.v. CYC (Euro Lupus) Class V SubnephroGc (<3g/24h) RAAS NephroGsch Predn + MMF 2g (or AZA or CNI or CYC) Erhaltungs Therapie (III, IV, V) mindestens 3 Jahre ab Remission! Low dose Predn + MMF (od AZA od CNI) Generell: Ausschleichen der Substanzen, GC zuerst! Alle: Hydroxychloroquin Lupus nephrigs - SOC Rituximab: negagve Trial- viele posigve klinische Erfahrungen

29 15 pure class V lupus nephrigs median PCR 4.9 g/g, 80% nephrogc, median Screa 0.9 à Rituximab + low dose predn (<20mg/d) Remission 13/15 Relapse 3/13 CR... <0.5 g/g PR...>50% reducgon proteinuria No SEA Chavarot, Medicine 2017

30 Classes III, IV or V lupus nephrigs on HCQ for at least 3months ( mg daily) 171 pagents, 1282 samples Average HCQ blood level by follow- up status % of LN flare per average HCQ blood level quingles Remission Flare Q1:<0.31mg/L, Q2: mg/L, Q3: mg/L, Q4: mg/L, Q5:>1.12mg/L Cunha, NDT 2017

31 ANCA in LN LN- Biopsies: 32 (14%) ANCA posigve (82% MPO, 7% PR3, 11% both) 222 ANCA negagve Necrosis 35% vs. 15%, P = Crescents 62% vs. 45% P = 0.141, n.s. Turner- Stokes, Lightstone KI 2017

32 ANCA +ve pa*ents higher dsdna Gters (335u/ml vs. 52u/ml) lower serum C4 (0.125g/L vs. 0.15g/L) Higher SCreaGnine at the Gme of bx (130μmol/L vs. 84μmol/L) Trend to worse outcome Turner- Stokes KI 2017