Lupus Nephritis New (?) Treatments. Aurélie HUMMEL Service de Néphrologie Hôpital Necker Enfants-Malades Paris

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1 Lupus Nephritis New (?) Treatments Aurélie HUMMEL Service de Néphrologie Hôpital Necker Enfants-Malades Paris

2 Introduction Lupus nephritis : 30-50% of patients with lupus = mortality risk factor Mok Series Life expectancy patients with lupus - 53% with lupus nephritis = - 15,1 yrs - classes : I : 1%, II : 6% III : 19%, IV : 47%, III/IV + V : 10% = 76% V pure : 16% - SMR (/general pop) : 4,8 without nephritis 9,8 if proliferative lesions 14 if renal insufficiency 63 if ESRD Mok, Arthritis Rheum 2013

3 Introduction Treatment goals : - obtain remission - prevent new flare - reduce side effects = to limit Lupus nephritis impact BIOPSIE INDUCTION MAINTENANCE

4 Induction What we ve learnt

5 Induction treatment 6 month response = predicts renal survival NEJM 1992 (EP) : CS + CYC PO ± EP 61/86 patients (- CR/ESRD/death) separated by proteinuria reduction at 6 month Maintain 10 years follow up Best predictive factor : 1 st year proteinuria Tamirou, Arthritis Rhumatism 2015

6 Steroids Morbi-mortality risk factor Long term follow up of 230 patients with lupus nephritis - 20 years survival : 90,5% - Mortality causes : -Infections : 50% -Cardiovascular diseases 20,8% - Cancer 12,5% Less is enough 2012 EULAR Recommandations 3 bolus of 500 à 750 mg IV 0,5 mg/kg/day for 1 month (+ in severe forms?) progressive reduction for how long? Historic treatment N=30 modern treatment N=30 Initial steroid dose 49 mg/j 22 mg/j M6 steroids dose 4,5 g 1,7 g M6 CYC dose 5g (0-16,8) 3g (0-4,5) M12 CR + PR 63% 87% Toxicity 67% 7% Yap, NDT 2012 R Irastorza G Autoimmun Rev 2014

7 Steroids Steroid free? -> Rituxilup : 50 consecutives patients Solumedrol 500 mg J1 J15 Rituximab J1 J15 MMF max 3 g/jour By S52 : -CR (52%) -PR (34%) -12 relapses (median W65) But - 44% pure class V - 45 yrs, (40% >50 yrs) Condon Ann Rheum Dis 2013

8 PROBABILITY OF NOT DOUBLING CREATININ Cyclophosphamide Cyclophosphamide is effective -to prevent relapse -to prevent deterioration of renal function But toxic Donadio, NEJM 1978, Austin, NEJM 1986, Boumpas, lancet 1992

9 Cyclophosphamide Less is better 6 g EUROLUPUS Trial Steroids azathioprin 2 mg/kg 3 g 90 patients with lupus nephritis, 2/3 proliferative 85% caucasiens 1st flare fot >80% Creatinin 11,5 mg/l, Albumin 30,3 g/l, protu 3,03 g/d follow up 41 mois Houssiau, Arthritis Rhumatism 2002

10 Cyclophosphamide Efficacy Tolerance Houssiau, Arthritis Rhumatism 2002

11 Mycophenolate mofetil MMF as good as CYC Ginzler : patients, % black or hispanic - classes 3, 4 and 5-6 month follow up -> MMF > CYC IV (CR=22,5% vs 5,8%) No / Pu, Creat, Hu -> less infections in MMF group ALMS 1 st part : patients - 40% white, 33% asiatic, 27% others - class 4 : 68,1% - creat 100μmol/l, prot 4 g/g - 6 month follow up - end point : prot <3g/j ou <50% BL -> MMF = CYC IV (56,2% vs 53%) Ginzler NEJM 2005 Appel, JASN 2009

12 Mycophenolate mofetil MMF better than CYC? Ginzler : patients, % black or hispanic -> MMF > CYC IV ALMS 1 st part : Ginzler NEJM 2005 Appel, JASN 2009

13 Induction : conclusion STEROIDS 3 bolus 500 mg 0,5 mg/kg/d 12 months + CYC Low dose X CYC High Dose =? = < (?) MMF 2-3 g/day caucasiens Blacks/hispaniques

14 Induction Far from perfect (= Normale) (= <0,5 g/j) (= Négative) MMF Endoxan Infections 68,5% 61,7% Digestive troubles 61,4% 66,7% Appel, JASN 2009

15 The other tracks

16 Rovin, Arthritis rhumatism 2012 Rituximab LUNAR RITUXIMAB CS 3x1g Puis 0,75 mg/kg + MMF 3g/day PLACEBO

17 Rituximab Meta-analyse 300 patients Refractory lupus nephritis : III, IV ou V class Previous therapies : - cyclophosphamide 60%, - MMF 47%, - azathioprine 47% Weidenbusch, NDT 2013

18 Other Biotherapies ABATACEPT 300 lupus patients placebo CS + MMF + ABT dose 1 ABT dose lupus patients No significative difference CR/RP CS + CYC + ABT or placebo Furie, Arthritis Rheumatol 2014 BELIMUMAB BLISS 52 et BLISS 76 (>1500 non renal lupus) -Remission 70,5% versus 58,5% -Renal flares 1,4% versus 3% BLISS NL Results in 2018 Dooley, lupus, 2013

19 Calcineurin inhibitors Frank Bao 2008 Martinez pts CS Classes III/IV Alb 24 g/l, prot 4 g/j,creat 9 mg/l MMF 1 g/d CYC HD + Tacro 4 mg/day Bao, JASN 2008

20 Calcineurin inhibitors LIU pts CS Characteristics : 32 yrs, 1 st flare of LN 52% Alb 25,6 g/l, prot 3,6 g/j Creat 70 μmol/l MMF 1 g/d CYC HD + Tacro 4 mg/d Treatments : Tacro : 3,6 mg/day T0 : 5,5 ng/ml MMF : CYC : 0,95 g/day AUC : 29,6->33 mg/h/l 1,10 g/4 weeks Histology : * IV : 66% * III : 16% * V : 18% CS : M1 : 33 mg/d M3 : 21,3 mg/d M6 : 12,6 mg/d Liu, annals of int med 2014

21 Calcineurin inhibitors CR : 45,9% vs 25,6% P + CR : 83,5% vs 63% SLEDAI : -11 vs - 8,5 C3 : 0,38 vs 0,31 Side effects 50,3% vs 52,5% with infections 28,2% vs 25,4% stop : 5,5% vs 1,7% - Digestive symptomes, leucopenia + tremor = diabetes (<3%) Liu, annals of int med 2014

22 Calcineurin inhibitors Wang pts CS Tacro 0,04-0,08 mg/kg/d T0 : 6-8 puis 4-6 ng/ml CYC HD M12 CR : 75% vs 40% GFR : 59->94 ml/min Classes III/IV/V Prot >3,5 g/j : 68% GFR<60 : 50% Wang, lupus, 2012 Mok pts CS Classes III/IV/V Prot : 3,58 g/d Creat 82 μmol/l 68% 1 st RB Tacro 0,1 mg/kg/d T0 : 7,8 ± 3,9 ng/ml MMF 2-3 g/d 6 months M6 CR : 62% vs 59% (Pu<1g/j) PR : 27% vs 21% GFR : 79 vs 91 ml/min SE : 93% vs 78% (p=0,007) - Zona + alopecia, tremor, creat (12%) Mok, Ann of rheum dis, 2014

23 Calcineurin inhibitors Limits? Asiatic essays ++ Isenberg, Rheumatology, 2010

24 Calcineurin inhibitors Limits? short follow up -> Flare when stopping? 1yr 3yrs 5yrs MMF 8% 28% 38% Tacro 9% 33% 54% IMUREL Mok, Ann of rheum dis, 2014 Austin, JASN, 2009

25 Calcineurin inhibitors Limits? Nephrotoxicity? Repeated biopsies : - improvement of lesions on the short course - few long term follow up, no systematic biopsies # Tanaka : 42 months # Yap : 47 months Other toxicities diabetes Tanaka, nephron clinical practice 2012, Yap, Rheumatology, 2014

26 Maintenance Certainties and uncertainties

27 Maintenance Maintenance is mandatory CYC 0,5-1 g/m2 1/ month, 6 months + 1/ trimester stop Boumpas Lancet 1992

28 Maintenance Cyclophosphamide is not an option Contreras -59 patients : 27 afro, 29 hispanics, 3 white - classe IV : 80% - creatinin : 142 μmol/l, prot : 5.1 g/g Contreras NEJM 2004

29 Houssiau Ann Rheum dis 2010 Contreras NEJM 2004 Maintenance MMF or AZA? MAINTAIN Trial 105 patients 80% caucasiens N=3 N=6 = 19% = 25%

30 Maintenance After 10 years 41% additionnal I- 19% bolus CS IV 56% still under I- Tamirou Ann Rheum dis 2015

31 Maintenance ALMS 2 nd part 227 patients (61% from the start) 41% white, 33% asiatic, 25% others End point treatment failure Death/ESRD/doubling of creatinin/renal flare 37,1% (25,2%) 16,4% 32,4% 11% (CYC) 21% (MMF) 28% (CYC) 36% (MMF) 51,4% (39,6%) Dooley, NEJM 2011

32 Conclusions Classe IV CYC 3g MMF 3g/d Remission no yes MMF 2g/d IMUREL MMF / CYC RITUX TACRO

33 And all the rest anti-infectious prophylaxis Optimal treatment of blood pressure (<130/80) Antiproteinuric treatment statins/stop smoking/sport osteoporose prevention Gynecologic follow up And PLAQUENIL 38%

34 Conclusions ESRD 10-30% of LN within 15 years Dialysis Intermediate mortality risk Transplantation Limited access (REIN) risk of lupus flare 2,4% > 1200 paires matchées Contreras, JASN 2010 Contreras, cjasn 2014