SlideShare a Scribd company logo

Lupus Nephritis

edwinchowyw, profile picture
edwinchowyw

The document discusses treatment options for lupus nephritis, specifically comparing cyclophosphamide to alternative therapies. It finds that while cyclophosphamide is effective for inducing remission, it has significant toxicity risks. Studies show mycophenolate mofetil and low-dose cyclophosphamide have similar efficacy with fewer side effects. Many patients also experience treatment failure or relapse even with standard therapies, highlighting the need for improved maintenance regimens and new treatment agents.

Health & Medicine
1 of 71
1
2
3
4
5
6
7
Most read
8
Most read
9
10
11
12
Most read
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
66
67
68
69
70
71
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

More Related Content

PPTX
CKD Mineral Bone Disorder (CKD-MBD) - Dr. Gawad
NephroTube - Dr.Gawad
 
PPTX
Approach to pancytopenia
Dr. Murtaza Kamal MRCPCH,MD,DNB,DrNB Ped Cardiology
 
PPTX
Infection Related Glomerulopathy - Introduction – Rapid Overview - Dr. Gawad
NephroTube - Dr.Gawad
 
PPTX
KDIGO Lupus Nephritis
Redzwan Abdullah
 
PPT
Membranous Nephropathy
Nahid Haque
 
PPT
Membranoproliferative GN - Road to Diagnosis & Management - What is the evide...
NephroTube - Dr.Gawad
 
PPTX
Membranous Nephropathy - Dr. Gawad
NephroTube - Dr.Gawad
 
PPTX
Lupus nephritis 2016
drsamianik
 
CKD Mineral Bone Disorder (CKD-MBD) - Dr. Gawad
NephroTube - Dr.Gawad
 
Approach to pancytopenia
Dr. Murtaza Kamal MRCPCH,MD,DNB,DrNB Ped Cardiology
 
Infection Related Glomerulopathy - Introduction – Rapid Overview - Dr. Gawad
NephroTube - Dr.Gawad
 
KDIGO Lupus Nephritis
Redzwan Abdullah
 
Membranous Nephropathy
Nahid Haque
 
Membranoproliferative GN - Road to Diagnosis & Management - What is the evide...
NephroTube - Dr.Gawad
 
Membranous Nephropathy - Dr. Gawad
NephroTube - Dr.Gawad
 
Lupus nephritis 2016
drsamianik
 

What's hot (20)

PPT
ANCA vasculitis
Diana Girnita
 
PPTX
IgA Nephropathy (KDIGO 2021 Guidelines) - Dr. Gawad
NephroTube - Dr.Gawad
 
PPTX
Lupus Nephritis :From Basics To Practice
Yasser Matter
 
PDF
Chronic Kidney Disease-Mineral Bone Disease
Waleed El-Refaey
 
PPT
Lupus nephritis
University of Florida
 
PPTX
Management of lupus nephritis
Arnab Nandy
 
PPTX
IgA NEPHROPATHY (CLOSING THE LOOP) - Dr. Gawad
NephroTube - Dr.Gawad
 
PDF
ANCA vasculitis (KDIGO 2021 Guidelines) - Dr. Gawad
NephroTube - Dr.Gawad
 
PPTX
Membranous nephropathy
Vishal Golay
 
DOCX
Rheumatological Emergencies
Siti Nurul Afiqah Johari
 
PDF
Hyponatremia (Practical Approach) - Dr. Gawad
NephroTube - Dr.Gawad
 
PPTX
CKD MBD - Think Outside The Box - Case Scenarios Snapshots - Dr. Gawad
NephroTube - Dr.Gawad
 
PPTX
lupus nephritis
Kushal Dp
 
PPTX
Ckd mbd
Harsh shaH
 
PPTX
Lupus Nephritis Guideline Review 2022
Sidney Erwin Manahan
 
PPTX
Membranous Nephropathy - Management Algorithm - Dr. Gawad
NephroTube - Dr.Gawad
 
PPTX
Focal Segmental Glomerulosclerosis (FSGS)
Tauhid Bhuiyan
 
PPTX
Henoch-Schönlein purpura (HSP)
Ahmed Ghany
 
PPTX
Diabetic nephropathy
Prateek Singh
 
PPTX
Approach to Milestone Regression
NeurologyKota
 
ANCA vasculitis
Diana Girnita
 
IgA Nephropathy (KDIGO 2021 Guidelines) - Dr. Gawad
NephroTube - Dr.Gawad
 
Lupus Nephritis :From Basics To Practice
Yasser Matter
 
Chronic Kidney Disease-Mineral Bone Disease
Waleed El-Refaey
 
Lupus nephritis
University of Florida
 
Management of lupus nephritis
Arnab Nandy
 
IgA NEPHROPATHY (CLOSING THE LOOP) - Dr. Gawad
NephroTube - Dr.Gawad
 
ANCA vasculitis (KDIGO 2021 Guidelines) - Dr. Gawad
NephroTube - Dr.Gawad
 
Membranous nephropathy
Vishal Golay
 
Rheumatological Emergencies
Siti Nurul Afiqah Johari
 
Hyponatremia (Practical Approach) - Dr. Gawad
NephroTube - Dr.Gawad
 
CKD MBD - Think Outside The Box - Case Scenarios Snapshots - Dr. Gawad
NephroTube - Dr.Gawad
 
lupus nephritis
Kushal Dp
 
Ckd mbd
Harsh shaH
 
Lupus Nephritis Guideline Review 2022
Sidney Erwin Manahan
 
Membranous Nephropathy - Management Algorithm - Dr. Gawad
NephroTube - Dr.Gawad
 
Focal Segmental Glomerulosclerosis (FSGS)
Tauhid Bhuiyan
 
Henoch-Schönlein purpura (HSP)
Ahmed Ghany
 
Diabetic nephropathy
Prateek Singh
 
Approach to Milestone Regression
NeurologyKota
 
Ad

Viewers also liked (20)

PPTX
Lupus nephritis 2012
Amit Agrawal
 
PPT
Pathophysiology of lupus nephritis
Mohit Mathur
 
PPT
Lupus nephritis post fff
Faculty of Medicine, Ain Shams University
 
PDF
Lupus nephritis peals
Faculty of Medicine, Ain Shams University
 
PPTX
Lupus Nephritis Management (The Soft Evidence) - Dr. Gawad
NephroTube - Dr.Gawad
 
PPT
Lupus nephritis by dr saddique 2
West Medicine Ward
 
PPTX
Management of Lupus Nephritis
mukkukiran
 
PPTX
SLE: present guidelines and consensus
Vishal Golay
 
PPT
Systemic Lupus Erythematosus
Discover Clinical Trials
 
PDF
Systemic lupus erythematosus
Furqan Khan
 
PPTX
Glomerulonephritis =)
kskb
 
PPT
Nefritis lupus
fauzil
 
PDF
17 february lupus nephritis prof ashraf fouda
FarragBahbah
 
PPT
Dialysis and Transplant for Lupus Nephritis
LupusNY
 
PPT
psoriatic arthritis
MOHAMMAD NOUR AL SAEED
 
PPTX
Psoriatic arthritis
hamidreza227
 
KEY
Glomerulonephritis
Simon Prince
 
PPTX
Acute Poststreptococcal Glomerulonephritis
Hakimah Suhaimi
 
PPTX
Glomerulonephritis
mpatjawee
 
PPT
SLE
Omar Moatamed
 
Lupus nephritis 2012
Amit Agrawal
 
Pathophysiology of lupus nephritis
Mohit Mathur
 
Lupus nephritis post fff
Faculty of Medicine, Ain Shams University
 
Lupus nephritis peals
Faculty of Medicine, Ain Shams University
 
Lupus Nephritis Management (The Soft Evidence) - Dr. Gawad
NephroTube - Dr.Gawad
 
Lupus nephritis by dr saddique 2
West Medicine Ward
 
Management of Lupus Nephritis
mukkukiran
 
SLE: present guidelines and consensus
Vishal Golay
 
Systemic Lupus Erythematosus
Discover Clinical Trials
 
Systemic lupus erythematosus
Furqan Khan
 
Glomerulonephritis =)
kskb
 
Nefritis lupus
fauzil
 
17 february lupus nephritis prof ashraf fouda
FarragBahbah
 
Dialysis and Transplant for Lupus Nephritis
LupusNY
 
psoriatic arthritis
MOHAMMAD NOUR AL SAEED
 
Psoriatic arthritis
hamidreza227
 
Glomerulonephritis
Simon Prince
 
Acute Poststreptococcal Glomerulonephritis
Hakimah Suhaimi
 
Glomerulonephritis
mpatjawee
 
SLE
Omar Moatamed
 
Ad

Similar to Lupus Nephritis (20)

PPTX
Landmark trial in lupus.pptx
Ritasman Baisya
 
PPTX
Journal club
muhammad azhar, MD
 
PPTX
LUPUS NEPHRITIS MANAGEMENT.pptx
SuperwomanK
 
PPTX
Therapy of focal or diffuse proliferative lupus nephritis, Moh'd sharshir
Moh'd sharshir
 
PDF
LN management in ASIA Chan TM.pdf
justlim
 
PDF
Lupus landmark trials
Sourabh Gupta
 
PPT
Treatment of Systemic Lupus
Ahmed Elshebiny
 
PPTX
Lupus Nephritis Dilemma - Prof. Mohsen El Kosi
MNDU net
 
PPTX
GN TX.pptx
TinaAldaba2
 
PPT
lupus-nephritis.ppt
ShinilLenin
 
PPT
lupus-nephritis.ppt
YuyunRasulong1
 
PDF
nephro newsletter final ...pdf
amiraibrahim88
 
PPTX
LN KDIGO 2xcccssdtrffgghgggbbbbh024.pptx
Kiran602181
 
PPTX
LN KDIGO 202alalakakakakkakakaklaa4.pptx
Kiran602181
 
PPTX
Calcineurin inhibitors in lupus nephritis
MohammadhassanJokar
 
PDF
Calcineurin inhibitors in lupus nephritis.
MohammadhassanJokar
 
PPTX
Voclosporin journal club
Dr. Prem Mohan Jha
 
PDF
A young woman with lupus
Enida Xhaferi
 
PPT
Mycophenolate Mofetil In Relapsing Lupus Nephritis
edwinchowyw
 
PPT
S Lecture
drmomusa
 
Landmark trial in lupus.pptx
Ritasman Baisya
 
Journal club
muhammad azhar, MD
 
LUPUS NEPHRITIS MANAGEMENT.pptx
SuperwomanK
 
Therapy of focal or diffuse proliferative lupus nephritis, Moh'd sharshir
Moh'd sharshir
 
LN management in ASIA Chan TM.pdf
justlim
 
Lupus landmark trials
Sourabh Gupta
 
Treatment of Systemic Lupus
Ahmed Elshebiny
 
Lupus Nephritis Dilemma - Prof. Mohsen El Kosi
MNDU net
 
GN TX.pptx
TinaAldaba2
 
lupus-nephritis.ppt
ShinilLenin
 
lupus-nephritis.ppt
YuyunRasulong1
 
nephro newsletter final ...pdf
amiraibrahim88
 
LN KDIGO 2xcccssdtrffgghgggbbbbh024.pptx
Kiran602181
 
LN KDIGO 202alalakakakakkakakaklaa4.pptx
Kiran602181
 
Calcineurin inhibitors in lupus nephritis
MohammadhassanJokar
 
Calcineurin inhibitors in lupus nephritis.
MohammadhassanJokar
 
Voclosporin journal club
Dr. Prem Mohan Jha
 
A young woman with lupus
Enida Xhaferi
 
Mycophenolate Mofetil In Relapsing Lupus Nephritis
edwinchowyw
 
S Lecture
drmomusa
 

More from edwinchowyw (20)

PPT
Focal Glomerulosclerosis
edwinchowyw
 
PPT
MPGN/MCGN
edwinchowyw
 
PPT
Membranous GN
edwinchowyw
 
PPT
Nodular GN
edwinchowyw
 
PPT
Tubulointerstitial diseases
edwinchowyw
 
PPT
Minimal Light Microscopic Changes
edwinchowyw
 
PPT
Crescentic GN
edwinchowyw
 
PPT
Diffuse Proliferative GN
edwinchowyw
 
PPT
Mesangial proliferative GN
edwinchowyw
 
PPT
Focalproliferative Glomerulonephritis
edwinchowyw
 
PPT
Basement Membrane Abnormalities
edwinchowyw
 
PPT
Humoral Immunity
edwinchowyw
 
PPT
Introduction to Renal Pathology
edwinchowyw
 
PPT
Intro Immune
edwinchowyw
 
PPT
Nephrotic Syndrome
edwinchowyw
 
PPT
Screening
edwinchowyw
 
PPT
Dry Weight Dr Rosna
edwinchowyw
 
PPT
Bartter’S And Gittleman’S Syndromes
edwinchowyw
 
PPT
Mycophenolate Mofetil in Primary Glomerulonephritis
edwinchowyw
 
PDF
Globalwarmingshow
edwinchowyw
 
Focal Glomerulosclerosis
edwinchowyw
 
MPGN/MCGN
edwinchowyw
 
Membranous GN
edwinchowyw
 
Nodular GN
edwinchowyw
 
Tubulointerstitial diseases
edwinchowyw
 
Minimal Light Microscopic Changes
edwinchowyw
 
Crescentic GN
edwinchowyw
 
Diffuse Proliferative GN
edwinchowyw
 
Mesangial proliferative GN
edwinchowyw
 
Focalproliferative Glomerulonephritis
edwinchowyw
 
Basement Membrane Abnormalities
edwinchowyw
 
Humoral Immunity
edwinchowyw
 
Introduction to Renal Pathology
edwinchowyw
 
Intro Immune
edwinchowyw
 
Nephrotic Syndrome
edwinchowyw
 
Screening
edwinchowyw
 
Dry Weight Dr Rosna
edwinchowyw
 
Bartter’S And Gittleman’S Syndromes
edwinchowyw
 
Mycophenolate Mofetil in Primary Glomerulonephritis
edwinchowyw
 
Globalwarmingshow
edwinchowyw
 

Recently uploaded (20)

PDF
Human Health And Disease hggyutgghg .pdf
vaishnavikumarimugha
 
PPT
Obstructive sleep apnea in orthodontics treatment
IOPARGER
 
PPTX
History and examination of abdomen, & pelvis .pptx
drmariaalrafi
 
PPT
1b - INTRODUCTION TO EPIDEMIOLOGY (comm med).ppt
YusuffDamilareAdewol
 
PPTX
Pathophysiology And Clinical Features Of Peripheral Nervous System .pptx
neuroptnagarajssmaka
 
PDF
Khadir.pdf Acacia catechu drug Ayurvedic medicine
BansariPatel112358
 
PPTX
15.MENINGITIS AND ENCEPHALITIS-elias.pptx
wesigeGerald
 
PPTX
Chapter-1-The-Human-Body-Orientation-Edited-55-slides.pptx
JANDIESAGAYNO2
 
PDF
CT Anatomy for Radiotherapy.pdf eryuioooop
DrHabtamu1
 
PDF
Deadly Stampede at Yaounde’s Olembe Stadium Forensic.pdf
academicstrivee
 
PPTX
Uterus anatomy embryology, and clinical aspects
Mandeep Sharma
 
PPTX
JUVENILE NASOPHARYNGEAL ANGIOFIBROMA.pptx
rounakuser
 
PPTX
CEREBROVASCULAR DISORDER.POWERPOINT PRESENTATIONx
jesselejadefernandez
 
PPTX
Gastroschisis- Clinical Overview 18112311
Nathan Lupiya
 
PPTX
Electromyography (EMG) in Physiotherapy: Principles, Procedure & Clinical App...
BALAJI SOMA
 
PPTX
Slider: TOC sampling methods for cleaning validation
Markus Janssen
 
PPTX
Acid Base Disorders educational power point.pptx
YordanosAyele3
 
PPTX
CME 2 Acute Chest Pain preentation for education
KhausalyaAndy
 
PPTX
Note on Abortion.pptx for the student note
MikeMalou
 
PPT
Management of Acute Kidney Injury at LAUTECH
popooladamilare28
 
Human Health And Disease hggyutgghg .pdf
vaishnavikumarimugha
 
Obstructive sleep apnea in orthodontics treatment
IOPARGER
 
History and examination of abdomen, & pelvis .pptx
drmariaalrafi
 
1b - INTRODUCTION TO EPIDEMIOLOGY (comm med).ppt
YusuffDamilareAdewol
 
Pathophysiology And Clinical Features Of Peripheral Nervous System .pptx
neuroptnagarajssmaka
 
Khadir.pdf Acacia catechu drug Ayurvedic medicine
BansariPatel112358
 
15.MENINGITIS AND ENCEPHALITIS-elias.pptx
wesigeGerald
 
Chapter-1-The-Human-Body-Orientation-Edited-55-slides.pptx
JANDIESAGAYNO2
 
CT Anatomy for Radiotherapy.pdf eryuioooop
DrHabtamu1
 
Deadly Stampede at Yaounde’s Olembe Stadium Forensic.pdf
academicstrivee
 
Uterus anatomy embryology, and clinical aspects
Mandeep Sharma
 
JUVENILE NASOPHARYNGEAL ANGIOFIBROMA.pptx
rounakuser
 
CEREBROVASCULAR DISORDER.POWERPOINT PRESENTATIONx
jesselejadefernandez
 
Gastroschisis- Clinical Overview 18112311
Nathan Lupiya
 
Electromyography (EMG) in Physiotherapy: Principles, Procedure & Clinical App...
BALAJI SOMA
 
Slider: TOC sampling methods for cleaning validation
Markus Janssen
 
Acid Base Disorders educational power point.pptx
YordanosAyele3
 
CME 2 Acute Chest Pain preentation for education
KhausalyaAndy
 
Note on Abortion.pptx for the student note
MikeMalou
 
Management of Acute Kidney Injury at LAUTECH
popooladamilare28
 

Lupus Nephritis

  • 1. Lupus Nephritis: Current/Future Treatment Option Dr Rosnawati Yahya Consultant Nephrologist Hospital Kuala Lumpur MALAYSIA
  • 2. Lupus Nephritis Pathology WHO classification : 1974 - Pirani and Pollak 1982 – revised 1995 - revised
  • 3. Lupus Nephritis Pathology WHO classification : membranous IV Diffuse proliferative GN IV Focal segmental proliferative GN III Mesangial GN II Normal I class
  • 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
  • 5. 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
  • 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
  • 7. 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
  • 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
  • 14. 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)
  • 15. Shortcomings of cyclophosphamide therapy in LN Toxicity Treatment failures/Non remitters Renal relapse/flares
  • 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)
  • 22. 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
  • 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
  • 24. 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
  • 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
  • 41. 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
  • 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 !!!!
  • 46. 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
  • 47. 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
  • 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)
  • 51. 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)
  • 52. 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)
  • 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)
  • 55. 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)
  • 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
  • 58. 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
  • 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
  • 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
  • 69. 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
  • 70. 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

Editor's Notes

  • #2: 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.