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Lupus Nephritis
 

Lupus Nephritis

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Dr Rusnawati Yahya

Dr Rusnawati Yahya
Consultant Nephrologist
Hospital Kuala Lumpur

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  • could you send your PP of Nefritis Lupus to my email teddy_kale@yahoo.com thank u verry much
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  • hi! am Jacqueline Shoo currently a fellow in nephrology in Tanzania,this is a very nice presentation,can i please have permission to use your presentation in my learning process.my email is shoojacqueline@yahoo.com
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  • Hello. i am Dr. Rodrigo Capahi, currently on Fellowship training in Nephrology at the National Kidney and Transplant Institute Philippines. We are currently upgrading our treatment protocol for Lupus nephritis. Can I ask a copy of your slides? the graph and Tables could be of great help. thank you very much
    rodcap22@hotmail.com
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  • Good evening ladies and gentleman. Thank you Prof …. For the introduction. First and foremost I would like to thanks the organizing committee for the invitation to speak in today’s meeting. I have been asked to update you on current and future treatment of lupus nephritis.

Lupus Nephritis Lupus Nephritis Presentation Transcript

  • Lupus Nephritis: Current/Future Treatment Option Dr Rosnawati Yahya Consultant Nephrologist Hospital Kuala Lumpur MALAYSIA
  • Lupus Nephritis Pathology
    • WHO classification :
    • 1974 - Pirani and Pollak
    • 1982 – revised
    • 1995 - revised
  • Lupus Nephritis Pathology
    • WHO classification :
    membranous IV Diffuse proliferative GN IV Focal segmental proliferative GN III Mesangial GN II Normal I class
  • 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
  • Lupus Nephritis: Pathology WHO versus ISN/RPS
    • Proliferative lesion is divided into active and chronic lesion.
      • Active : treatable
      • Chronic : scarring/ irreversible
    • Diffuse Proliferative divided into segmental and global - to see if differences exist
    • Membranous is pure membranous
    • if proliferative superimposed:
    • V + III or V + IV
    • proliferative lesion dictate treatment
  • 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
  • Treatment of proliferative LN
    • Induction therapy
    • Intensive immunosuppressives
    • Objectives : to halt injury,
    • : recover renal function
    • : induce remission by controlling immunologic activity
    • Maintenance therapy
    • Longer period
    • Less intensive to reduce complication
    • Objectives : Consolidate remission
    • : Prevent flares
  • NIH Trial: Probability of developing ESRD Steinberg et al, Arthritis Rheum 1991, 34 (8):945
  • 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
  • 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
  • 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 (%)
  • 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
  • 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
  • Successes of cyclophosphamide therapy in LN
    • Combination cyclophosphamide and steroid is more effective in than cytotoxic or steroid alone in proliferative LN.
    • Treatment with combination of cyclophosphamide & steroid result in about 70% remission rate (NIH)
  • Shortcomings of cyclophosphamide therapy in LN
    • Toxicity
    • Treatment failures/Non remitters
    • Renal relapse/flares
  • Shortcomings of cyclophosphamide therapy in LN TOXICITY Do we have treatment with similar efficacy but better tolerability profile ?
  • 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
  • Euro-Lupus Nephritis Trial Probability of renal remission P=0.36 Houssiau et al,Arthritis Rheum 2002,46(8):2121
  • Euro-Lupus Nephritis Trial Probability of renal flares P=0.80 Houssiau et al,Arthritis Rheum 2002,46(8):2121
  • 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
  • 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)
  • Euro-Lupus Nephritis Trial
    • ? Clinically mild disease
    • 22% renal impairment
    • 28% nephrosis
    • Few Black or African Caribbean-worst prognosis.
    • Careful ! In our setting,
    • milder disease in Caucasian
    • ? Long term use of azathioprine-
    • ? Longer maintenance of remission
    Houssiau et al,Arthritis Rheum 2002,46(8):2121
  • Mycophenolate Mofetil De novo pathway Ribose-5-phosphate PRPP PRPP synthase IMP GMP GTP RNA Glycoprotein dGTP DNA Guanine Mycophenolic acid Salvage pathway - IMDH
  • Mycophenolate Mofetil
    • IMPD (Inosine monophosphate dehydrogenase)
    • - 2 isoform
      • Type I : expressed in most cell
      • Type II: expressed in activated B and T cells
    • MPA have higher affinity to Type II isoform
    • Therefore, preferentially inhibits lymphocyte proliferation
  • 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
  • Proliferative LN Cyclophosphamide versus Mycophenolate Mofetil MMF CYP Chan et al, NEJM 2000, 343 (16): 1156 MMF CYP
  • Proliferative LN Cyclophosphamide versus Mycophenolate Mofetil Chan et al, NEJM 2000, 343 (16): 1156
  • Proliferative LN :CYP versus MMF Adverse Event : long term follow-up Chan et al, JASN 2005(16):1076-1084 % patients
  • 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
  • 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
  • Proliferative LN : CYP versus MMF Adverse Events Ginzler E, Appel G et al, NEJM 2005(353:21):2219 % patients
  • 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
  • Proliferative LN : CYP versus MMF P=0.22 % patients P=0.7 LM Ong, LS Hooi, Nephrology 2005(10) :504-510
  • 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
  • Summary of MMF versus cyclophosphamide
  • ASPREVA LUPUS MANAGEMENT STUDY (ALMS) WHO III, IV and V MMF IV CYC Induction : 6 months RESPONSE ? MMF AZA Maintenance : 3 years
  • 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
  • How about Azathioprine ? Is it better ? Is it safer ?
  • NIH Trial: Probability of developing ESRD Steinberg et al, Arthritis Rheum 1991, 34 (8):945
  • Proliferative LN : CYP versus Azathioprine Grootscholten, Ligtenberg et al, KI 2006(70):732-742 Get figure 3
  • Proliferative LN : CYP versus Azathioprine Adverse Event
    • In Azathioprine group :
    • Higher infection rate : RR 1.4 (CI 1.1-1.8)
    • herpes zoster RR 1.7 (CI 1.2-2.5)
    • hospitalization RR 1.1 (CI 0.6-2.0)
    • No osteonecrosis
    • No haemorrhagic cystitis.
    Grootscholten, Ligtenberg et al, KI 2006(70):732-742
  • 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
  • Lupus Nephritis :Current Standard Treatment Very toxic Non-remitters High Relapse rate PROBLEMS !!!!
  • 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
  • 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 !!!!
  • Resistant Lupus Nephritis: Other Therapeutic Approach
    • Chemotherapeutic drugs
    • IV immune globulin
    • Mycophenolate Mofetil
    • Cladribine
    • Cyclosporine
    • Combination Chemotherapy
    • Bone marrow ablative chemotherapy and transplantation with stem cell reconstitution
    • High dose chemotherapy
    • Biological response modifier
    • B and T cell co-stimulation inhibitors
    • complement inhibitors: monoclonal a/body to C5b
    • Others:
    • plasmapharesis
    • DNA toleragen
    • vaccination
    • gene therapy
  • IV Immune globulin
    • N=9 (M=4: F=5) from 11 to 14 years old
    • Did not respond to 2 courses of IV methylpred and cyclophosphamide for 56 days
    • Renal biopsy:
      • 5: class IV
      • 2: class V
      • 2: class IV with V
    • Clinical manifestation:
    • nephrotic syndrome and Azotemia
    Lin et al, Nephron 2989(53): 303-310
  • IV Immune globulin Lin et al, Nephron 2989(53): 303-310
  • IV Immune globulin Lin et al, Nephron 2989(53): 303-310
  • 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)
  • Rituximab
    • Selectively target CD 20+ B cells
    • Sparing the plasma cells and stem cells
    • Substantially reduces level of CD 20+ B cells in peripheral blood within days to weeks and up to 6 months
    Browning, Nature Reviews Drug Discovery 5, 564 – 576 (July 2006)
  • Pilot Study of Rituximab in LN refractory to conventional therapy
    • 22 patients with SLE class III and IV
    • Refractory to conventional therapy
    • Rituximab (0.5 to 1.0 g) at day 1 and 15 added to current therapies
    Vigna-Perez M, Arthritis Res Ther 2006: 8(3)
  • Pilot Study of Rituximab in LN refractory to conventional therapy Disease Activity Proteinuria Vigna-Perez M, Arthritis Res Ther 2006: 8(3)
  • Pilot Study of Rituximab in LN refractory to conventional therapy Erythrocyturia Creatinine Clearance Vigna-Perez M, Arthritis Res Ther 2006: 8(3)
  • Pilot Study of Rituximab in LN refractory to conventional therapy
    • Results :
    • Complete renal remission : 5/22
    • Partial renal response : 7/22
    • Improvement : 6/22
    • Renal failure : 2/22
    Vigna-Perez M, Arthritis Res Ther 2006: 8(3)
  • 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 !!!!
  • 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
  • Maintenance Treatment: MMF vs Aza vs CYC
    • Primary End Point
    • Patient Survival
    • CRF doubling serum Cr (>4/12) over the lowest value reached during induction, chronic dialysis or tx
    • Composite end-point of CRF or death
    • Secondary End-point
    • Renal relapse
    • 1. proteinuric doubling of proteinuria > 1/12
    • 2. Nephritic
    • Increased serum Cr > 50% > 1/12
    • Hospitalization and side-effect
    Contreras, NEJM 2004, 350(10): 971
  • Maintenance Treatment: MMF vs Aza vs CYC Contreras, NEJM 2004, 350(10): 971
  • Maintenance Treatment: MMF vs Aza vs CYC Contreras, NEJM 2004, 350(10): 971
  • Maintenance Treatment: MMF vs Aza vs CYC Contreras, NEJM 2004, 350(10): 971
  • Maintenance Treatment: MMF vs Aza vs CYC Contreras, NEJM 2004, 350(10): 971
  • 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
  • Lupus Nephritis Renal Flares
  • 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
  • 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
  • Renal Flares in proliferative LN Time to response
  • 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
  • Predictors of renal flares : multivariate analysis
    • Entire cohort
    • Persistently low C4
    • Africo-american
    • Partial response
      • Likelihood ratio to have a renal flare : 2.1 (95% CI 1.08 –4.2)
    • Complete Response Group
    • Persistently low C4
    • Africo-american
    • Chronicity index at baseline
    Illei et al, Arthritis Rheumatism 2002, 46 :995
  • Factors ass. with ESRD in patient who had CR/PR : univariate analysis
    • severe nephritic flare
    • serum Cr > 2.0 mg/dl at time of response
    • Partial response
    • chronicity index at baseline
    • activity index at baseline
    • proteinuria > 0.5 g at time of response
    • Hematocrit < 33%
    • Any flares
    Illei et al, Arthritis Rheumatism 2002, 46 :995
  • Thank You