Dr Rusnawati Yahya Consultant Nephrologist Hospital Kuala Lumpur

1. Lupus Nephritis: Current/Future Treatment Option Dr Rosnawati Yahya Consultant Nephrologist Hospital Kuala Lumpur MALAYSIA

4. Lupus Nephritis Pathology The classification of glomerulonephritis in systemic lupus erythematosus revisited Kidney International 2004 (65): 521-530 JAN J WEENING, VIVETTE D D'AGATI, MELVIN M SCHWARTZ, SURYA V SESHAN, CHARLES E ALPERS, GERALD B APPEL, JAMES E BALOW, JAN A BRUIJN, TERENCE COOK, FRANCO FERRARIO, AGNES B FOGO, ELLEN M GINZLER, LEE HEBERT, GARY HILL, PRUE HILL, J CHARLES JENNETTE, NORELLA C KONG, PHILIPPE LESAVRE, MICHAEL LOCKSHIN, LAI-MENG LOOI, HIROFUMI MAKINO, LUIZ A MOURA and MICHIO NAGATA ON BEHALF OF THE INTERNATIONAL SOCIETY OF NEPHROLOGY AND RENAL PATHOLOGY SOCIETY WORKING GROUP ON THE CLASSIFICATION OF LUPUS NEPHRITIS

6. Lupus Nephritis: Pathology ISN/RPS classification : membranous V Advanced sclerotic LN VI Diffuse proliferative GN (involving >50% glom) IV-S (A) :diffuse segmental –active lesion IV-G (A) :diffuse global –active lesion IV-S (A/C):diffuse segmental –active and chronic lesion IV-G (A/C):diffuse global –active and chronic lesion IV-S (C) :diffuse segmental –chronic lesion with scar IV-G (C) :diffuse global –chronic lesion with scar IV Focal proliferative GN (involving < 50% glom) III (A) : active lesions III (A/C) : active and chronic lesion III C : chronic lesion III Mesangial proliferative LN II Minimal mesangial LN I

8. NIH Trial: Probability of developing ESRD Steinberg et al, Arthritis Rheum 1991, 34 (8):945

9. NIH Trial Probability of Renal Remission N=82, proliferative LN IV methylpred 1 g/m2 x3 days Every months x12 IV cyclophos. Monthly x 6 3 monthly x 2 yrs Combination Methylpred & cyclophos 7/24 (29%) 13/21 (62%) RENAL REMISSION 17/20 (85%) P<0.001 P=NS Gourley et al, Ann Intern Med 1996,125(7):549

10. Long Term Follow-up of protocol completers in proliferative LN in NIH Comb CYP MP Illei et al, Ann Intern Med 2001,135:248-257 14/24 patients received CYP after protocol completion % patients

11. Problems with current standard treatment (1) Illei et al, Ann Intern Med 2001,135:248-257 3.7 3.8 22 13 15 25 Herpes zoster: during after 3.7 18 18 Death 8 19 32 0 26 0 Infection: during rx after rx 33 52 60 Ovarian failure 13 21 23 osteoporosis 30 31 36 Avascular necrosis MP (%) CYCLO (%) COMB (%)

12. Proliferative LN :Renal Remitters and non-remitters N=145 Complete NIH protocol 1990-1999 Complete Remission : 73/145 Partial Remission : 19/145 Total remission : 92/145 (63.4%) No Remission :53/145 (36.6%) Illei et al, Arthritis Rheumatism 2002, 46 :995

13. Relapse Rate with current standard care Median: 38 months 39 38 Standard CYC & pulse MP Cortes-Hernandez 2003 Varied treatment Low dose steroid with Azathioprine Pulse CYC, pulse MP or combination Corticosteroid & immunosupressive Treatment Within 18 months 59 91 Mosca 2002 Mean : 40 months to first flare 37 46 El Hachmi 2003 CR: median 36 mths PR: median 18 mths 45 92 Illei 2002 Within 103 months 51 211 Beji 2005 duration % n Publications

16. Shortcomings of cyclophosphamide therapy in LN TOXICITY Do we have treatment with similar efficacy but better tolerability profile ?

17. Euro-Lupus Nephritis Trial Low vs high dose cyclophosphamide Biopsy proven WHO III,IV, Vc and Vd Age >14 Proteinuria >0.5g/day IV methyprednisolone 750 mg x3/7 Oral steroid 0.5-1 mg/kg/day x4/52 Then taper by 2.5 mg every 2/52 and maintain High dose IV CYC 0.5 mg/m2 monthly x6 Then 3 monthly x 2 doses Max 1.5 g per pulse Low dose IV CYC 0.5 gram fortnightly x6 Azathioprine commenced 2/52 after last CYC x30 months Houssiau et al,Arthritis Rheum 2002,46(8):2121

18. Euro-Lupus Nephritis Trial Probability of renal remission P=0.36 Houssiau et al,Arthritis Rheum 2002,46(8):2121

19. Euro-Lupus Nephritis Trial Probability of renal flares P=0.80 Houssiau et al,Arthritis Rheum 2002,46(8):2121

20. Euro-Lupus Nephritis Trial Adverse Event % patients No is small , differences does not achieved statistically significant difference but a tendency to lower rate of severe infection in low dose group Houssiau et al,Arthritis Rheum 2002,46(8):2121

21. Euro-Lupus Nephritis Trial Houssiau et al,Arthritis Rheum 2002,46(8):2121 11 31 2 10 31 5 WHO : III IV V 2.90 + 2.37 3.17 + 2.43 Urine protein (g/d) 3.01 + 0.60 2.96 + 0.62 Serum albumin 1.09 + 054 1.21 + 0.76 Serum Cr (mg/dl) 39 2 3 37 4 5 Race: caucasian asian african 41/3 43/3 Female /male 33 + 12 30 + 11 age Low Dose (n=44) High Dose (n=46)

23. Mycophenolate Mofetil De novo pathway Ribose-5-phosphate PRPP PRPP synthase IMP GMP GTP RNA Glycoprotein dGTP DNA Guanine Mycophenolic acid Salvage pathway - IMDH

25. Proliferative LN Cyclophosphamide versus Mycophenolate Mofetil WHO IV Proteinuria >1 g/d Serum albumin <35 g/dl MMF 1g BD PRED 0.8 mg/kg/d And taper,main 10 mg/d CYC 2.5 mg/kg/d PRED 0.8 mg/kg/d And taper, main 10 mg/d MMF 0.5 g BD Azath 1.5 mg/kg/d Azath 1.5 mg/kg/d Azath 1.5 mg/kg/d 6 mo 12mo 0 mo Study Duration: 12 mo Chan et al, NEJM 2000, 343 (16): 1156

26. Proliferative LN Cyclophosphamide versus Mycophenolate Mofetil MMF CYP Chan et al, NEJM 2000, 343 (16): 1156 MMF CYP

27. Proliferative LN Cyclophosphamide versus Mycophenolate Mofetil Chan et al, NEJM 2000, 343 (16): 1156

28. Proliferative LN :CYP versus MMF Adverse Event : long term follow-up Chan et al, JASN 2005(16):1076-1084 % patients

29. Chan et al, JASN 2005(16):1076-1084 Proliferative LN :CYP versus MMF relapse free survival : long term follow-up P=0.338 P=0.338

30. Proliferative LN : CYP versus MMF Ginzler E, Appel G et al, NEJM 2005(353:21):2219 P=0.005 % patients P=NS P=0.009 ITT analysis

31. Proliferative LN : CYP versus MMF Adverse Events Ginzler E, Appel G et al, NEJM 2005(353:21):2219 % patients

32. Proliferative LN CYP versus MMF WHO III or IV MMF 1g BD and PREDNISOLONE IV CYC 0.75 –1.0 g/m2 and PREDNISOLONE Study Duration: 12 mo LM Ong, LS Hooi, Nephrology 2005(10) :504-510 For 6/12

33. Proliferative LN : CYP versus MMF P=0.22 % patients P=0.7 LM Ong, LS Hooi, Nephrology 2005(10) :504-510

34. Proliferative LN : CYP versus MMF Adverse Events LM Ong, LS Hooi, Nephrology 2005(10) :504-510 NS 0.08 per pt mth 0.07 per pt mth GI adverse event NS 3 patients 3 patients Herpes zoster NS 3 patients 3 patients infection 0.32 36.8% 52% leucopenia p MMF IV Cyp

35. Summary of MMF versus cyclophosphamide

36. ASPREVA LUPUS MANAGEMENT STUDY (ALMS) WHO III, IV and V MMF IV CYC Induction : 6 months RESPONSE ? MMF AZA Maintenance : 3 years

37. Proliferative LN : CYP versus Azathioprine WHO III & IV IV CYC (0.75g/m2) x 13 Oral PRED for 2 yrs ORAL AZATHIOPRINE Initial IV MP (3x3 pulses) Oral PRED for 2 years N=87 Grootscholten, Ligtenberg et al, KI 2006(70):732-742

38. How about Azathioprine ? Is it better ? Is it safer ?

39. NIH Trial: Probability of developing ESRD Steinberg et al, Arthritis Rheum 1991, 34 (8):945

40. Proliferative LN : CYP versus Azathioprine Grootscholten, Ligtenberg et al, KI 2006(70):732-742 Get figure 3

42. Proliferative LN : CYP versus Azathioprine At last follow-up Grootscholten, Ligtenberg et al, KI 2006(70):732-742 Azathioprine N=37 Cyclophosphamide N=50 Follow-up

43. Lupus Nephritis :Current Standard Treatment Very toxic Non-remitters High Relapse rate PROBLEMS !!!!

44. Proliferative LN Renal Remitters and non-remitters N=145 Complete/Partial Remission N=92/145 (63.4%) No Remission N=53/145 (36.6%) 17 Cont active - No ESRD 26 cont active – ESRD 5 deaths during follow-up 5 lost to follow-up PR 19 CR 73 Illei et al, Arthritis Rheumatism 2002, 46 :995

45. Lupus Nephritis :Current Standard Treatment Very toxic Non-remitters High Relapse rate Need alternative agent/regime Similar/superior efficacy Less toxic ? other therapeutic agent Mycophenolate mofetil Monoclonal antibodies IVIG Rituximab ? better maintenance agent PROBLEMS !!!!

48. IV Immune globulin Lin et al, Nephron 2989(53): 303-310

49. IV Immune globulin Lin et al, Nephron 2989(53): 303-310

50. Resistant Lupus Nephritis MMF Dooley et al, JASN 1999(10):833-839 30 18 10 48 26 6 10 6 2 3 8 12 Cyclophosphamide (duration/gram) 0 0 21.2 12 11 10 9 8 7 6 5 4 3 2 1 4 0 6.7 0 12 9 0 0 19.4 0 6 16.8 0 0 8.2 3 0 16 12 60 15 72 48 9 0 0 9 0 19 18 0 18 26 Methotrexate (Month) Azathioprine (month)

53. Pilot Study of Rituximab in LN refractory to conventional therapy Disease Activity Proteinuria Vigna-Perez M, Arthritis Res Ther 2006: 8(3)

54. Pilot Study of Rituximab in LN refractory to conventional therapy Erythrocyturia Creatinine Clearance Vigna-Perez M, Arthritis Res Ther 2006: 8(3)

56. Lupus Nephritis :Current Standard Treatment Very toxic Non-remitters High Relapse rate Need alternative agent/regime Similar/superior efficacy Less toxic ? other therapeutic agent Mycophenolate mofetil Monoclonal antibodies IVIG Rituximab ? better maintenance agent PROBLEMS !!!!

57. Maintenance: MMF vs Aza vs CYC WHO III,IV, V INDUCTION: IV CYC 0.5 -1.0 g/m2 for 4-7 doses with PREDNISOLONE 0.5-1.0 mg/kg/d Randomization: closed envelope method Stratified by African American ethnicity IV CYC 3/12 0.5-1.0 g/m2 AZATHIOPRINE 0.5-3.0 mg/kg/d MMF 0.5-3.0g/d + Pred < 0.5mg/kg/d Maintenance 1-3 years Contreras, NEJM 2004, 350(10): 971

59. Maintenance Treatment: MMF vs Aza vs CYC Contreras, NEJM 2004, 350(10): 971

60. Maintenance Treatment: MMF vs Aza vs CYC Contreras, NEJM 2004, 350(10): 971

61. Maintenance Treatment: MMF vs Aza vs CYC Contreras, NEJM 2004, 350(10): 971

62. Maintenance Treatment: MMF vs Aza vs CYC Contreras, NEJM 2004, 350(10): 971

63. Maintenance Treatment: MMF vs Aza vs CYC Contreras, NEJM 2004, 350(10): 971 30.4 (p=0.11) 27.6 (p=0.058) 52.2 Minor Infections 2.0 (p<0.02) 1.8 (p<0.02) 24.9 Major Infections 32.4 (p<0.01) 29.4 (p<0.01) 77.1 Total Infection 6.1 (p<0.035) 7.5 (p<0.035) 32 Amenorrhoea (%) 1 1 10 Hospitalization during maintenance phase MMF AZA IV CYC ADVERSE EVENTS

64. Lupus Nephritis Renal Flares

65. Response to immunosupressive therapy in NIH cohort in 1981-1990 N=145 Active ESRD 26 CR/PR N=92 NO CR/PR N=53 Death during rx 5 Lost to Follow-up N=5 Cont active dis No ESRD 17 PR 19 CR 73 Illei et al, Arthritis Rheumatism 2002, 46 :995

66. Renal Flares in proliferative LN N=145 , WHO III and IV treated with pulsed CYC , pulsed MP or both Proteinuric nephritic Illei et al, Arthritis Rheumatism 2002, 46 :995 CR= 73 PR = 19 Off immunosupression for 6 months Renal Flare

67. Renal Flares in proliferative LN Time to response

68. Renal Flares in proliferative LN Time to relapse after CR or PR Most flares occur within first 4 years (40%) Some will flare even after 10 years of renal remission

71. Thank You