1. No category

Medical Management of Lupus
Nephritis, Current Therapies
and Future Directions
Gabriel Contreras MD, MPH
Associate Professor of Clinical Nephrology
University of Miami, School of Medicine
Estimated 5-year patient survival for
renal manifestations of SLE (1971)
Total series
All renal disease
0
10
20
30
40
50
60
70
80
Survival at 5 years (%)
Estes D, Christian CL. Medicine 1971;50:85-95.
Lupus Nephritis Classification ISN RPS
2004
Class I: Minimal mesangial: normal LM, deposits IF o EM
Class II: Mesangial proliferativa with mesangial deposits
with/without minimal deposits subepithelial or
subendothelial by IF o ME no visible by LM
Class III: Focal (<50 % glomeruli) proliferativa: A, A/C, C
Class IV: Diffuse proliferativa (proliferation intra y/o
extracapilar with subendothelial deposits)
Subdivision: Segmental (IV-S) y global (IV-G)
A, A/C, C
Class V: Membranosa: with/without classes III o IV
Class VI: Advanced sclerotic: > 90% glomeruli
globally sclerotics
Survival of 213 lupus nephritis patients as a function of WHO classification
Free of doubling creatinine, ESRD or death
Cumulative probability
1.00
Class II
P=0.042
0.75
0.50
Classes III, IV and V
0.25
0.00
0
6 12 18 24 30 36 42 48 54 60 66 72
Contreras et al. Lupus 2005, 14: 890-95 t, months
Lupus Nephritis Indices of Activity and Chronicity
Activity *
Chronicity *
• Glomeruli
Glomerulosclerosis
Hypercellularity
segmental
Karyorrhesis or fibrinoid necrosis **
mesangial
Cellular crescents **
global
Hyaline thrombi, wire loops
Fibrous crescent
Leukocyte infiltration
Interstitial fibrosis
• Tubule/Interstitium
Tubule atrophy
Mononuclear cell infiltration
Vascular
Noninflamatory necrotizing arteritis,
True vasculitis
Immune complex deposit
Thrombotic Microangiopathy
*Score 0-3 for each item. **Multiply by 2 Activity Index
WHO classification: modified Pollak et al. J Lab Clin Med 1964; 63 (4)
Cumulative survival curves based on 166 lupusnephritis patients demostrating the probability of not
reaching the renal insufficiency outcome
Probability of not doubling
Serum creatinine, %
100
80
60
P < 0.0001
40
20
0
137
29
0
112
17
80
11
30
60
Others
High risk
Months 90
High risk = histology showed crescents and moderate to severe
interstitial fibrosis. Austin HA, et al. Nephrol Dial Transplant 1995;10:1620
Survival of 213 Lupus Nephritis Patients as a Function of chronicity index
Free of doubling creatinine, ESRD or death
Cumulative probability
1.00
0.75
Chronicity < 2
P=0.009
0.50
Chronicity  2
0.25
0.00
0 6 12 18 24 30 36 42 48 54 60 66 72 78
t, months
Contreras et al. Lupus 2005, 14: 890-95
Other Factors (than histological
parameters) Associated with Increased
Risk of Chronic Renal Failure
• African-American
• Hispanic
• Male gender
• Age < 24 years
• Hypertension
• High creatinine
• Nephrotic range proteinuria
• Anemia
• Anticardiolipins
• Lack of remission
• Relapse
Survival: Free of doubling creatinine, ESRD or deat
1.00
Cumulative probability
Cumulative probability
Outcomes
in African
Americans
and
Hispanics
with lupus
nephritis
0.75
0.50
Caucasians
Hispanic
0.25
African-Americans
0.00
6 12 18 24 30 36 42 48 54 60 66 72 78
Contreras et al. Kidney
t, months
Inter 69: 1846-1851
0
P=0.04 vs. African-Americans
P=0.05 vs. African-Americans
Remission Predicts Long-term
Outcome in Severe Lupus Nephritis
• 86 patients in trial of high dose prednisone and oral CTX +/plasmapheresis
• Clinical remission (serum creatinine  1.4 mg/dL and
proteinuria  0.33 g/day) in 37 patients (43%)
At 5 years
At 10 years
Patient survival
95%
Remission
95%
60%
No remission
69%
Renal survival
94%
94%
Remission
45%
31%
No remission
Korbet, et al. Am J Kid Dis. 2000;35:904.
Probability of not doubling S Cr
“Nephritic relapses” are predictors of bad long-term
outcome in lupus nephritis
Moroni G, et al. KI 1996; 50: 2047-2053
100
No & proteinuric relapses
Nephritic relapses
80
60
P = 0.00001
40
20
49
21
0
0
27
10
5
10
5
4
15
20
Years
25
30
Nephritic relapse: SCr of  30 %, active sediment and  proteinuria.
By multivariate analysis, male gender (p= 0.015) & HTN (p= 0.004)
were independent predictors of nephritic relapses
Evolving Therapeutic Strategies
for Lupus Nephritis
Cyclophosphamide (CY)
Azathioprine (AZA)
Mycophenolate Mofetil (MMF)
Cyclosporine (CyA)
Abnormal processing of
apoptotic cells may cause
systemic lupus
MM
F,
AZ
erythematosus
A,
CTLA4-Ig
Signal 2:
costimulation
B7
CD 2
8
CD 40
CD 40L
MHC
T-cell
proliferation
CY
Activated
T cells
Signal 3:
IL2/R
TCR
Nucleosome
specific Abs
Nucleosome
Signal 1: Nucleosome
MHC/anti-DNA
Recognition by TCR
CyA
Co-estimulación
gp-39/CD40
B-cell
proliferation
B cells
antigen
Nucleosome
MMF, AZA, CY
Anti-CD20
Apoptotic cell
20
CD
Probability of ESRD
0
Long term preservation of renal function in
111 patients with Lupus Nephritis
 IVCY
 AZACY
20
 POCY
40
AZA
60
p < 0.09 pred vs AZA
p < 0.032 pred vs POCY
p < 0.0011 pred vs AZACY
p < 0.0025 pred vs IVCY
80
100
0
20
40
60

Pred
Months
80 100 120 140 160 180 200
Steinberg AD and Steinberg SC. NIH. Arthritis Rheum 1991;34(8):945-950
Therapy of lupus Nephritis
Complication
Treatment Group
% of the patients at risk
Pred AZA POCY AZACY IVCY
Major infection
Herpes zoster *
Hemorrhagic 
Cystitis
Cancer
Premature ovarian 
Mortality
25
7
0
11
11
0
17
33
17
14
32
14
10
25
0
0
8
11
11
18
11
17
71
11
0
53
14
0
45
15
* p<.05 groups 1 and 2 vs 3, 4 and 5
p<.01 groups 1, 2 and 5 vs 3 and 4
p<0.01 groups 1 and 2 vs 3, 4 and 5
NIH. N Engl J Med 1986;314:614-619
Rate of sustained amenorrhea in patients treated
with IVCY according to duration of therapy and age
70
60
50
% 40
30
20
10
0
64
Age = <25
Age > 25
17
17
0
Short-term IVCY
Long-term IVCY
p= 0.04 short-term vs. long-term IVCY.
Boumpas DT. et al. Ann Inter Med 1993; 119: 366-369.
Probability of no relapse
Controlled trial: two regimens of pulse IVCY in patients with
severe lupus nephritis
100
80
p<0.006 Long-term IVCY vs
Short-term IVCY
60
40
20 15
0
17
0
10  Long-term IVCY
Short-term IVCY
6
13
10
12
24
36
48
60
Months
72
Long-IVCY= monthly x 6 then quarterly x 2 ys; Short-IVCY= monthly x 6.
Boumpas DT, et al. NIH. Lancet 1992;340: 741-45
Azathioprine/methylprednisolone, n=37 (MP 1 g IV x 3
days baseline, 2 and 6 weeks with AZA 2 mg/kg/day)
versus cyclophosphamide, n=50 (IVCY 0.75 g/m2 q
mon x 6 then q3mon) in proliferative lupus nephritis. A
randomized controlled trial.
• Patient histological characteristics (N = 87)
– WHO Class III and Vc = 9%
– WHO Class IV and Vd = 91%
Mean Activity Index: 9/24
Mean Chronicity Index: 2-3/12
• Demographics: Mean age 31, 75% Caucasians, 82%
female,
• Mean BP 140/80 mmHg
• 53% nephrotic, mean urine 24 hr protein 3.75 g
• Mean Cr: 1.25 mg/dL
C Grootscholten et al for the Dutch Working Party on Systemic Lupus Erythematosus.
KI (2006) 70, 732–742.
Cumulative incidence of
first complete or partial
remission. Cumulative
incidence of first complete
or partial remission in the
first 2 years of follow-up.
PR, partial remission; CR,
complete remission; CY,
group treated with
intravenous
cyclophosphamide; and
oral prednisone, AZA,
group treated with i.v.MP,
azathioprine, and oral
prednisone.
Kaplan–Meier estimates.
Kaplan–Meier curves
showing (a) proportion of
patients reaching the end
point of the study,
unsustained doubling of
serum creatinine, (b)
proportion of patients free of
relapse, and (c) proportion of
patients free of treatment
failure, relapse, or death. RR
and 95% CI are given.
CY=group treated with
intravenous
cyclophosphamide and oral
prednisone, AZA=group
treated with i.v.MP,
azathioprine, and oral
prednisone. KI
Azathioprine/methylprednisolone, n=37 (MP 1 g IV x 3
days baseline, 2 and 6 weeks with AZA 2 mg/kg/day)
versus cyclophosphamide, n=50 (IVCY 0.75 g/m2 q
mon x 6 then q3mon) in proliferative lupus nephritis. A
randomized controlled trial.
Adverse events
AZA
IVCY
All infections per 100 pts-ys*
37
18
Herpes Zoster
12
3
Premature ovarian failure, N
2 **
2
Cancer, N
1
-
Deaths, N
3
2
* P <0.05, ** received also IVCY
Induction Clinical Trials:
1. Houssiau F, et al, Arthritis Rheum 2002; 8: 2121-31.
2. Chan TM et al. New Engl J Med 2000; 343: 1156-62. (Chan
TM, et al, JASN April 2005).
3. Weixin Hu, et al. Chin Med J 2002; 115: 705-9
4. Lin YK, et al: J Clin Derm31: 636 –638, 2002
5. Flores-Suarez LF, Villa AR. JASN 15: PO257, 2004
6. Ong LM, et al. Nephrol 10: 504 –510, 2005.
7. Ginzler EM, et al. NEJM 24, Nov 2005
8. Aspreva lupus management study (ALMS). JASN May 2009
European Lupus Nephritis Trial (ELNT):
Sequential regimens of IVCY (low-dose vs.
high-dose) induction followed by AZA
maintenance with corticosteroids





Patient histological characteristics (N = 90)
 WHO Class III n = 21
Activity Index: 10/24
 WHO Class IV n = 62
Chronicity Index: 1/12
 WHO Class Vc+b n = 7
Demographics: Mean age 31, 84% Caucasians,
9% Africans, 7% Asians, 93% female
47% hypertensive
24-hs urine protein 3.04 g
Cr: 1.15 mg/dL
Houssiau FA, et al. Arthritis Rheum. 2002;46:2121-2131.
Probability of Remission
ELNT: Remission
Low dose
Remission: < 10 RBC/HPF,
High dose 90 pts=WHO III, IV,
100
24-hour proteinuria < 1 g, no DSC
Vc+d
Methylprednisolone IV
80
0.75 g x3
LD = Low-dose IVCY:
60
0.5 g q2 weeks for 6
pulses followed by
40
AZA maintenance +
corticosteroids
20
HD = High-dose IVCY
0.5 g/m2 monthly x 6
0
followed by 2 pulses
0
24
12
36
48
60 q3 months then AZA
Follow-up (months)
maintenance +
corticosteroids
Houssiau FA, et al. Arthritis Rheum. 2002;46:2121-2131.
Patients Free of Failure (%)
European Lupus Nephritis Trial:
Primary Outcome of Treatment Failure
100
Low dose
High dose
90
80
70
60
50
0
0
12
24
36
Follow-up (months)
48
60
Treatment failure:
• Steroid resistant flare
• Doubling S creat.,
• Failed to < Cr 1.3
(base Cr 1.3-2.6)
Failed to  50% Cr
(base Cr > 2.6)
• Persistent nephrotic
(UP 3 g/d &
albumin <3.5 g/dl)
Houssiau FA, et al. Arthritis Rheum. 2002;46:2121-2131.
European Lupus Nephritis Trial:
Low dose
Renal Flares
High dose
Patients Free of
Renal Flares (%)
100
80
60
40
20
0
0
12
24
36
48
Follow-up (months)
Houssiau FA, et al. Arthritis Rheum. 2002;46:2121-2131.
60
90 pts=WHO III, IV,
Vc+d
Methylprednisolone IV
0.75 g x3
LD = Low-dose IVCY:
0.5 g q2 weeks for 6
pulses followed by
AZA maintenance +
corticosteroids
HD = High-dose IVCY
0.5 g/m2 monthly x 6
followed by 2 pulses
q3 months then AZA
maintenance +
corticosteroids
European Lupus Nephritis Trial:
Severe Infections
Low dose
High dose
Patients Free of Severe
Infection (%)
100
90
80
70
60
50
0
0
12
24
36
Follow-up (months)
Houssiau FA, et al. Arthritis Rheum. 2002;46:2121-2131.
48
60
Adverse events in the European Lupus
Nephritis Trial:
Adverse events
Low DoseIVCY-AZA
High dose
IVCY-AZA
5 (11)
5 (11)
-
1
Menopause, N (%)
2 (5)
2 (4)
AZA induced hepatitis, N (%)
3 (7)
-
Leukopenia, N (%) *
Bone marrow aplasia, N (%)
* WBC < 4000 per cubic L occurred in 2 pts in each group during the
induction phase.
Houssiau FA, et al. Arthritis Rheum. 2002;46:2121-2131.
Efficacy of mycophenolate mofetil in patients
with diffuse proliferative lupus nephritis
Study design: randomized clinical trial
Methods: 42 Asian patients with WHO class IV were randomized to:
1) oral MMF + steroids x 12 months, or
2) sequential oral cytoxan (OCY) + steroid x 6 months
then CY was replaced by azathioprine x 6 months
Patient characteristics
Histological: Activity Index: 9/24
Mean age 37.5
93% female,
24-hs urine protein 5.8 to 3.7 g/day
Cr: 1.2 mg/dL
Duration:
12 months
Chronicity Index: 3.2/12
NEJM 2000;343:1156-62
Efficacy of MMF vs sequential POCY-AZA in 42
patients with diffuse proliferative lupus nephritis
Complete
remission
81%
76%
Partial
remission
14%
14%
Relapse
15%
11%
19%
Infection
Death 0%
0
Group 2: POCY
(2.5 mg/kg/d
x 6 mo), then
AZA (1.5-2.0
mg/kg/d) +
prednisone
33%
10%
20
Group 1: MMF
(2 g x 6 mo,
then 1 g x 6 mo)
+ prednisone
(0.8 mg/kg)
Patients (%)
40
60
80
100
Chan TM et al. New Engl J Med 2000; 343:1156-62.
Long-Term Study of Mycophenolate Mofetil as Continuous Induction
and Maintenance (n=32) Treatment for Diffuse Proliferative Lupus
Nephritis compared to Sequential POCY-AZA (n=30)
Chronic renal
failure
13%
10%
34%
30%
Relapse
P=0.013
13%
Infections
P=0.004
4%
Amenorrhea
Mortality
Group 1: MMF
induction
(2 g x 6 mo, 1 g or
1.5 g x 6 mo, then
1 g x 12 mo or
followed by AZA
(1-1.5 mg/kg/d)
0%
0
36%
Patients (%)
7%
10
40%
20
30
40
Group 2: POCY
(2.5 mg/kg/d
x 6 mo), then
AZA (1.5-2
mg/kg/d x 6 mo,
then 1-1.5
mg/kg/d). Both
groups received
corticosteroids
50
Chan TM et al. JASN 2005; April
Six months induction: MMF (n=71) vs.
intravenous cyclophosphamide (IVCY) (n=69)
in severe lupus nephritis, FDA sponsored trial:
Demographics: Mean age 32,
79 (56 %) African Americans
90 % female
Patient WHO histological characteristics
Class IV, n = 76
Class III, n = 22
Class V, n = 27
Class V + III or IV, n = 15
• Mean 24-hs urine protein 4.1 – 4.4 g per day
• Mean serum creatinine: 1.1 mg/dL
•
•
•
•
Ginzler E, et al. NEJM 2005; 353: 2219-2228
Complete remission: at 24 weeks, return of serum creatinine,
proteinuria, and urine sediment to normal
Partial remission: ≥50% improvement in all abnormal renal
parameters without worsening of any
p = 0.009
37/71
Responding (%)
60
50
40
p = 0.005
30
16/71
p = NS
21/71
21/69
17/69
20
10
4/69
0
Complete Remission
Ginzler E, et al. NEJM 2005;
353: 2219-2228
Partial Remission
MMF
IVC
Complete + Partial
Remission
MMF vs IVCY Complete + Partial Remission:
African-Americans vs. Others
Intent-to-Treat analysis
P = 0.554
Responding (%)
70
60
P = 0.002
MMF
50
IVCY
40
30
20
10
0
African-Americans
Others
Six months induction: MMF vs. intravenous cyclophosphamide
(IVCY) in severe lupus nephritis, FDA sponsored trial:
Adverse events
MMF (n = 83)
Severe infections
Necrotizing fascitis
Gram-negative sepsis
Pneumonia, lung abscess
Lymphopenia (< 800/mL3)
Neutropenia (< 1000/mL3)
UGI (nausea, vomiting, etc)
Diarrhea
Amenorrhea
Severe rash
Alopecia
Deaths during treatment
1
0
0
1
18
1
23
15
0
1
0
0
* 1 patient died after declining therapy.
IVCY (n = 75)
6
1
1
4
28
1
25
2
2
0
8
3*
Ginzler E, et al.
NEJM 2005; 353:
2219-2228
Aspreva Lupus Management Study (ALMS):
Induction-Phase Results
• Between 27 July 2005 and 6 October 2006, 370 patients with SLE and active
nephritis were enrolled at 88 centers in 20 countries in North America, Latin
America, Asia, Australia, and Europe.
• Mycophenolate Mofetil (n = 185) Compared with Intravenous Cyclophosphamide
(n =185)
• Demographics: Mean age 30 (range 12 to 75)
• Race: 147 Caucasian, 123 Asian, 100 Non-Caucasian/Non-Asian (from whom 46
were of African Ancestry and 54 of others mixed race)
• Ethnicity: 239 Non Hispanics, 131 Hispanics
• Female = 313
• Patient histological characteristics (N = 370)
ISP Class IV = 225
Class V = 60
Class III = 35
Class V + IV =27
Class V + III = 23
Active = 258
Active and Chronic = 122
JASN 2009; 20: 1103-1112
• 24-hs urine protein 4.1 g and Serum Cr: 1.1 mg/dL
Treatment Compliance
Oral corticosteroids twice daily
Mean (SD):
2.5 (0.58) (g/day)
IVCY in monthly pulses
Mean dose per infusion:
0.78 g/m2
Mean (SD) number
infusions: 5.6 (1.1)
Prednisone mg/day (SD)
Oral MMF twice daily
70
MMF
60
IVCY
50
40
30
20
10
0
2
4
6
8
10 12 14 16 18 20 22 24
Week ending dosing period
JASN 2009; 20: 1103-1112
Primary Endpoint:
Responders at 6 Months
100
Proportion of patients
reponding (%)
Response was judged by
a blinded Clinical
Endpoint Committee, by
the criteria:
Decrease in Uprot/Ucreat
to <3 in patients with
baseline nephrotic (≥3) ,
or by ≥50% in patients
subnephrotic (<3)
proteinuria and
stabilization of serum
creatinine level (24-week
level ± 25% of baseline) or
improvement
80
60
OR (95% CI):
1.1 (0.7 to 1.8)
56.2%
53.0%
40
20
0
MMF
IVCY
MMF was not superior to IVCP
(p = 0.575)
JASN 2009; 20: 1103-1112
53.2
100
75
50
25
0
56.0 60.4
63.9
MMF
54.2
C
au
N
on
ca
/A - C
si
s i au
an
an c
, P as
= 0 ia n
.0
33
A
si
an
Response %
Response to induction of patients with lupus nephritis:
Mycophenolate mofetil (MMF) versus cyclophosphamide
(IVCY) according to race (P= 0.047 for interaction)
38.5
IVCY
JASN 2009; 20: 1103-1112
Response to induction of patients with lupus nephritis:
Mycophenolate mofetil (MMF) versus cyclophosphamide
(IVCY) according to Hispanic Ethnicity
53.7 60.9
61.0
Response %
No
nH
is
pa
ni
cs
H
is
P pa
= n ic
0. s
01
1
100
75
50
25
0
MMF
38.8
IVCY
JASN 2009; 20: 1103-1112
Response %
Response to induction of patients with lupus nephritis:
Mycophenolate mofetil (MMF) versus cyclophosphamide
(IVCY) according to Geographic area (P=0.069 for
interaction)
100
75
50
25
67.6 54.3 52.6 56.8 60.7
65.0
47.4
32.0 IVCY
A
US
si
/
a
C
La
an
ti n
ad
A
a
m
P
= e ri
0. ca
00
3
w
or
ld
0
R
es
to
ft
he
MMF
JASN 2009; 20: 1103-1112
MMF
120
IVC
MMF
100
IVC
50
Serum albumin (g/L, SD)
Mean plasma concentration (SD)
Key Non-Renal Variables
80
60
40
20
0
40
30
20
10
0
Baseline Endpoint Baseline Endpoint Baseline Endpoint
Anti-dsDNA
Complement C3
Complement C4
Baseline Endpoint
Albumin
JASN 2009; 20: 1103-1112
Percentage of patients reporting adverse events by
treatment group
Any AE
Upper resp. infection
UTI
95
%
100
90
80
70
60
50
40
30
20
10
0
96.2
Any infection
Lower resp. infection
Zoster
JASN 2009;
20: 1103-1112
68.5
61.7
35.6
29.3
9.8 10.9
MMF
8
8.3
IVCY
11.7 6.7
Number of deaths during induction of lupus nephritis by
race and treatment group
12
9
9
MMF
7
N
6
JASN 2009;
20: 1103-1112
IVCY
5
3
2
2
2
0
0
Overall
Asia
Latin
America
0
North
America
0
1
Rest of
the World
The role of MMF Maintenance in Clinical
Trials:
1. Contreras G, et al. NEJM March 2004.
2. ALMS (Aspreva Lupus Management Study)
3. MAINTAIN from Euro-Lupus group
Maintenance Therapy for severe LN: quarterly
IVCY vs. AZA vs. MMF after short-term IVCY
induction in sequential regimens
• Patient histological characteristics (N = 59)
–
–
–
WHO Class III n = 12
WHO Class IV n = 46
WHO Class Vb n = 1
Activity Index: 8/24
Chronicity Index: 1.9-3.6/12
• Demographics: Mean age 33, 46% African-American,
49% Hispanics, 5% Caucasians, 93% female,
• 95% hypertensive
• 64% nephrotic, urine protein/Cr: > 5.0, Alb: 2.7
• Cr: 1.6 mg/dL,
Contreras G, et al. NEJM. March 2004
Results (V): Free of relapse
y
ti
li
b
a
b
o
r
p
e
vi
t
al
u
m
u
C
P = 0.021, MMF vs. IVCY
P = 0.124, AZA vs. IVCY
P = 0.222, MMF vs. AZA
1.00
0.75
0.50
0.25
19
17
19
0.00
0
15
10
17
12
10
4
12
6
2
8
4
2
3
24
36
48
t, months
3
1
2
60
1 AZA
1 IVCY
1 MMF
72
Results (IV): Free of clinical event (death or CRF)
y
ti
li
b
a
b
o
r
p
e
vi
t
al
u
m
u
C
1.00
0.75
0.50
P = 0.049, MMF vs. IVCY
P = 0.009, AZA vs. IVCY
0.25 P = 0.503, MMF vs. AZA
19
20
20
0.00
0
19
19
20
15
12
14
10
6
11
9
3
6
12
24
36
48
t, months
4
2
2
60
2 AZA
1 IVCY
2 MMF
72
Maintenance therapies: IVCY vs AZA vs MMF
Hospitalizations and Side Effects of Therapy
IVCY
AZA
MMF
Hospital days
per pt-yr *
Amenorrhea *
%
Infections 100 pt-ys
Total 
Major 
10
1
1
32
8
6
77
29
32
AZA or MMF vs. IVCY: * p  0.03;  p < 0.01;  p  0.02.
Major infections: pneumonia, sepsis, meningitis.
Contreras G, et al. NEJM. March 2004
25
2
2
Doses of immunosuppressant received
during maintenance therapy
Visit
range
0- 6
AZA
mg/kg/d
1.2  0.4
IVCY
mg/m2
542  70
MMF mg/d,
median (95%CI)
1500 (1500-2000)
6-12
1.0  0.5
565  62
1500 (1500-2000)
12-18
1.1  0.6
562  106
1250 (1000-1500)
18-24
0.8  0.6
530  119
1000 (500-1500)
24-30
1.1  0.5
644  4
1000 (500-1250)
30-36
1.1  0.6
541  36
500 (250-500)
MMF dose = median and 95% CI. Data reported as mean  SD.
A randomized pilot trial comparing cyclosporine
(CyA) vs. azathioprine (AZA) for maintenance
therapy in diffuse lupus nephritis over four years
• Patient Histological characteristics (N = 69)
–
–
–
–
WHO class IV: 60
WHO class Vc or Vd: 9
Activity Index: 7/24
Chronicity Index: 2.5-2.8
• Demographics: Mean age 32, predominantly
Caucasians, 90% female
• Mean Creatinine 0.9 mg/dL, Urine protein: 2.4 g/24 hr
Moroni G, et al. CJASN Oct 2006
Treatment protocol
• Induction phase
– Methylprednisolone 0.5-1.0 g IV daily x 3 followed by
prednisone 0.5–1.0 mg/kg/day x 2 months
– Oral cyclophosphamide 1-2 mg/kg/day x 3 months
• Central Randomization stratified only by center
• Maintenance phase ( 2 years)
– CyA (neoral®) 4 mg/kg/day titrated to keep trough
blood level 75 – 200 ng/mL, creatinine < 30%+ of
baseline, and aiming for proteinuria < 1 g/day
– AZA 1.5 - 2 mg/kg/d titrated to keep WBC > 4000/mm3
– During maintenance, patients received < 0.5 mg/kg/d
prednisone
Moroni G, et al. CJASN Oct 2006
Primary outcome: overall incidence of
SLE relapse over 2 years
Nephritic relapse, N
CyA, N=36 AZA, N=33
1
1
Proteinuric relapse, N
Extra-renal relapse, N
Overall, N
4
2
7
6
1
8
Overall SLE relapses per 100 pts-ys
10.6
13.4
Overall exposure pts-ys
65.9
59.8
Nephritis relapse: creatinine ≥ 30% of baseline accompanied  proteinuria
and/or active urine sediment (≥ 5 RBC x HPF).
Proteinuric relapse:  proteinuria of at least 2g/day (if prior level ≤3.5) or
Moroni G, et al. CJASN. In press
doubling proteinuria.
A randomized pilot trial comparing cyclosporine (CyA) vs.
azathioprine (AZA) for maintenance therapy in diffuse lupus
nephritis over four years
CrCl
mL/min
CyA, incidence
events per 100 pts-ys
Leukopenia
6.1
Infections
10.6
Anemia
7.6
Hypertension
10.6
HTN crisis
1.5
3
 Cholesterol
Diabetes
0
Hyperkalemia
1.5
Gum hyperplasia
3
Hypertrichosis
3
Arhtralgias
21.2
GI disorders
16.7
Adverse events
AZA, incidence
events per 100 pts-ys
16.7
23.4
8.4
8.4
0
6.7
1.7
0
0
0
5
5
Questions:
Induction:
What do we start with? CY or MMF?
Is MMF efficacious as prolong inductionmaintenance therapy in Caucasian, AfricanAmerican and Hispanic populations?
Should we switch to maintenance therapy when
achieving complete or partial remission?
Are there adjuvant therapies that consolidate
complete remission?
Questions:
Maintenance:
Is Mycophenolate Mofetil superior to Azathioprine
or Calcineurin Inhibitors?
Should we continue exposing patients to longterm Cyclophosphamide?
Can be stop maintenance therapy after 3 years?