15-Aug-18

Hui-Kim Yap
Shaw-NKF-NUH Children’s Kidney Centre
KTP-National University Children’s Medical Institute
Yong Loo Lin School of Medicine
National University of Singapore

Systemic lupus erythematosus

Prevalence in adults:
30-40 per 100,000
15-20% of SLE
begins in childhood

1
 15-Aug-18

Estimates of incidence of SLE

in children by ethnic group

31 per 100,000 for

Asians
20 per 100,000 for
Blacks
13 per 100,000 for
Hispanics
4 per 100,000 for Whites

Key
Points
What are the issues involved in the treatment
of childhood lupus nephritis?
What are the treatment options for lupus
nephritis?
Do these recommendations apply to children?
What is the role of biologics in the treatment
of lupus nephritis?

2
 15-Aug-18

What are the issues involved in the

treatment of children with lupus nephritis?

SLE in children is more acute and severe at

onset: Higher SLEDAI score at presentation
25

20
P<0.001

15
SLEDAI

10

Adult onset (n=213) Childhood onset (n=50)

(Mok CC et al, Medicine 2005)

3
 15-Aug-18

Higher prevalence of LN within the adolescent cohort

Adult-onset SLE Adolescent- P-
(%) onset SLE (%) value
Rash 65.6 67.5 0.75
Photosensitivity 40.8 38.5 0.68
Alopecia 22.5 22.6 1.00
Oral ulcers 25 29 0.359
Musculoskeletal 92.8 88.7 0.14
Serositis 41.4 28.2 0.007*
Renal 27.1 42.7 0.001*
CNS 20.8 22.6 0.712
SS 9.9 2.4 0.006*
Hemolytic anemia 2.9 7.3 0.035*
Leucopenia 29.7 29.8 1.00
Lymphopenia 75.7 72.7 0.56
Thrombocytopenia 14.8 18.0 0.40
(Amaral B et al; Rheumatology 2014)

Higher rates of organ involvement: >70% of Singapore

children developed lupus nephritis during the course of SLE

30-80%

20-95%

39%

74-90%

44-74%

5-77%

5-26%

Worldwide Singapore children (1976-1985) Singapore adults (Thumboo J et al, 1998)

4
 15-Aug-18

More aggressive clinical course: Cumulative survival

worse in children with lupus nephritis
(including renal survival)
1
Cumulative survival

0.8

0.6

SLE overall Lupus nephritis

0.4
0 1 2 3 4 5 6 7 8 9 10

Years

(Singapore 1976-1985, Lee BW, Yap HK, et al, Austr Pediatr J 1987)

Standardized mortality ratio in adult SLE is increased

(Multisite international cohort study: 23 centres, 9547 patients)

Cause of death Standardized 95% CI

mortality ratio
All deaths 2.4 2.3-2.5
Heart disease 1.7 1.4-2.0
Stroke 1.1 0.7-1.7
Malignancy 0.8 0.6-1.0
Infections 5.0 3.7-6.7
Respiratory 1.3 0.8-1.6
Renal 7.9 5.5-11.0
(Bernatsky S et al; Arthritis Rheum 2006)

5
 15-Aug-18

How do we classify lupus nephritis?

Case

6
 15-Aug-18

A 6-year old girl was referred for asymptomatic

hematuria and proteinuria detected 3 months
previously. The first episode was detected during an
episode of adenovirus infection, and again a month
later following influenza infection. Clinically she had no
evidence of edema. There were no pallor, rash or
arthritis. She was normotensive.
Investigations showed microscopic hematuria (RBC 20-
22/hpf), associated with heavy proteinuria of 1.2
g/day/1.73m2. Her serum albumin and renal function
was normal. Serum complements C3 and C4 were
normal.
Renal biopsy revealed membranous nephropathy.

WHO classification ISN/RPS (2003)

(1982, revised 1995)
Class I Normal glomeruli Minimal mesangial lupus
nephritis
Class II Pure mesangial Mesangial proliferative
alterations lupus nephritis
Class III Focal segmental Focal lupus nephritis
glomerulonephritis III (A); III (A/C); III (C)
Class IV Diffuse Diffuse lupus nephritis
glomerulonephritis IV-S (A); IV-G (A); IV-S
(A/C); IV-S (C); IV-G (C)
Class V Diffuse membranous Membranous lupus
glomerulonephritis nephritis
Class VI Advanced sclerosing Advanced sclerosis lupus
glomerulonephritis nephritis

7
 15-Aug-18

Children with class III and IV lupus nephritis

have significant clinical disease
Class Clinical signs

I Normal urinary sediment, BP, renal function

II Mild proteinuria/hematuria

III Hematuria
Proteinuria (typically <nephrotic range)
IV Hematuria
Nephrotic range proteinuria
Hypertension
Declining renal function
V Proteinuria
Hematuria less common
VI End-stage renal disease
Hypertension

What are the treatment options for

proliferative lupus nephritis?

8
 15-Aug-18

Sequential immunosuppressive therapy for

proliferative lupus nephritis (ISN/RPS class III/IV)

ACHIEVE REMISSION
Induction Decrease lupus activity
Restore renal function
Decrease proteinuria

PREVENT PROGRESSION
OF CKD
Maintenance
Decrease proteinuria
Prevent SLE relapses

IV cyclophosphamide monthly
(± pulse methylprednisolone)
followed by intermittent IV
cyclophosphamide or other oral
immunosuppressive agents
widely considered to be the
gold standard of therapy for
aggressive lupus nephritis

9
 15-Aug-18

NIH study (1986): Treatment with IV cyclophosphamide compared

to steroids alone reduced the risk of ESRD in lupus nephritis
100
IVCY

AZCY
80
Probability of renal failure (percent)

POCY

AZA
60
PRED (Group 1A)

40
PRED (Group 1)

Mantel-Haenszel:
20 PRED (Group 1) vs. IVCY p=0.027
PRED (Group 1A) vs. IVCY p=0.07

0
0 20 40 60 80 100 120 140 160
Follow-up (months)
(Austin III HA et al, NEJM 1986)

Meta-analysis of RCTs looking at low-

dose vs high-dose intravenous
cyclophosphamide conducted
between Jan 1990-July 2009:
– 2 RCTs
– 66 patients

10
 15-Aug-18

Low-dose (500 mg) IV cyclophosphamide has lower relapse

rate but with marginal significance compared to high-dose
(0.5 g/m2, max 1.5g/dose) IV cyclophosphamide

Study RR, 95%CI p-value Risk ratio, 95% CI

Relapse rate:
Sabry et al 2009 0.253 0.184 [0.010, 3.364]
Houssiau et al 2002 0.016 0.484 [0.268, 0.873]
0.010 0.465 [0.261, 0.830]

0.1 0.2 0.5 1 2 5 10

Low-dose cyclophosphamide High dose-cyclophosphamide

Lee YH et al Lupus 2010

A significant proportion (30-50%) of

patients with lupus nephritis do not
achieve complete remission despite
treatment with cyclophosphamide

Associated with a significantly increased

risk of end-stage renal failure, relapses
and death

11
 15-Aug-18

Renal survival rates in severe lupus nephritis based on

remission: 94% at 10 years in remission group
compared with 31% in no remission group
Month 0 12 24 36 48 60 72 84 96 108 120 132 144 156 168 180 192
Remission 37 37 37 36 35 33 31 31 30 30 29 27 27 22 18 14 3
No remission 49 34 26 21 19 19 18 18 16 15 13 13 13 12 5 3

100

Remission
80
% Survival

60
p <0.0001

40

20 No-Remission

0
24 48 72 96 120 144 168 192
Months (Korbet SM et al., Am J Kidney Dis 2000)

Bayesian Network Meta-analysis

CYC MMF

Pred Aza

Direct comparison of 2 therapies

Relative effect of 2 therapies (indirect comparison)

12
 15-Aug-18

2017

Unique records identified through updated database

searching of MEDLINE, Embase and Cochrane
databases through July 20, 2016
53 RCTs were included, 45 on induction therapy
(n= 3,623), 8 on maintenance therapy (n=599)
Involving adults, adolescents and children

2017

Outcomes for induction therapy (compared to IV

cyclophosphamide):
Primary: complete remission and all-cause mortality
Others: ESRD, doubling of serum creatinine level,
failure to induce remission, and side effects of
therapy
Outcomes for maintenance therapy (compared to
oral azathioprine):
Primary: Relapse after remission

13
 15-Aug-18

Induction Complete All cause ESRD Doubling Treatment

strategy remission mortality Screatinine failure
MMF + CNI 2.69 1.00 3.02
(1.74-4.16) (0.02-52.8) (0.12-74.5)
CNI 1.74 0.83 2.08 3.26 0.28
(1.09-2.79) (0.27-2.56) (0.23-18.9) (0.25-42.0) (0.12-0.65)
IV CYC + 1.48 0.92
MMF (0.62-3.53) (0.06-15.3)
MMF 1.44 1.20 2.60 1.51 0.51
(1.00-2.06) (0.59-2.44) (0.36-18.7) (0.12-19.3) (0.29-0.90)
Oral CYC 0.57 2.86 1.34 1.85 1.70
(0.23-1.40) (0.82-10.0) (0.31-5.88) (0.48-7.22) (0.24-12.5)
Prednisone 0.57 2.03 2.40 2.95 4.03
(0.23-1.40) (0.72-5.77) (1.05-5.48) (1.45-6.01) (1.30-12.6)
Mizoribine/ 0.29 1.52 1.79 3.39 4.15
Azathioprine (0.08-1.11) (0.52-4.46) (0.56-5.70) (1.18-9.71) (0.16-105)
Plasma 1.52 2.92
exchange (0.52-4.46) (0.31-27.8)
Studies; 19; 1,862 21; 1,694 12; 819 9; 984 10; 753
Participants

Induction Complete All cause ESRD Doubling Treatment

strategy remission mortality Screatinine failure
MMF + CNI 2.69 1.00 3.02
(1.74-4.16) (0.02-52.8) (0.12-74.5)
CNI 1.74 0.83 2.08 3.26 0.28
(1.09-2.79) (0.27-2.56) (0.23-18.9) (0.25-42.0) (0.12-0.65)
IV CYC + 1.48 0.92
MMF (0.62-3.53) (0.06-15.3)
MMF 1.44 1.20 2.60 1.51 0.51
(1.00-2.06) (0.59-2.44) (0.36-18.7) (0.12-19.3) (0.29-0.90)
Oral CYC 0.57 2.86 1.34 1.85 1.70
The combination of MMF plus calcineurin
(0.23-1.40) (0.82-10.0) (0.31-5.88) (0.48-7.22) (0.24-12.5)
Prednisone 0.57 2.03 2.40 2.95 4.03
inhibitor ranked
(0.23-1.40) as the
(0.72-5.77) best treatment
(1.05-5.48) (1.45-6.01) to
(1.30-12.6)
Mizoribine/ 0.29
Azathioprine (0.08-1.11)
induce1.52
(0.52-4.46)
remission
1.79
(0.56-5.70)
3.39
(1.18-9.71)
4.15
(0.16-105)
Plasma 1.52 2.92
exchange (0.52-4.46) (0.31-27.8)
Studies; 19; 1,862 21; 1,694 12; 819 9; 984 10; 753
Participants

14
 15-Aug-18

Mycophenolate is among the best for preventing

disease relapse during maintenance therapy while IV
cyclophosphamide is among the worst

Drug(s) comparison for Network meta-analysis

relapse estimate vs azathioprine
Mycophenolate mofetil 0.53
(0.31-0.90)
Calcineurin inhibitor 0.64
(0.22-1.88)
Azathioprine 1.00
(reference)
IV cyclophosphamide 1.68
(0.51-5.51)

But what is the price of aggressive

immunosuppressive treatment?

15
 15-Aug-18

Low-dose (500 mg) IV cyclophosphamide had

lower infection risk than high-dose (0.5 g/m2,
maximum 1.5 g/dose)

Study p-value Risk ratio, 95% CI

RR, 95%CI

Infection risk:
Sabry et al 2009 0.419 1.625 [0.500, 5.280]
Houssiau et al 2002 0.003 0.655 [0.494, 0.868]
0.008 0.688 [0.523, 0.905]

0.1 0.2 0.5 1 2 5 10

Low-dose cyclophosphamide High dose-cyclophosphamide

Lee YH et al Lupus 2010

Mycophenolate had less infection risk compared to oral

cyclophosphamide and azathioprine (Loma K, AJKD 2012)
OUTCOME COMPARISON N RR(95%CI)
Infection
Induction MMF vs Oral CYC 62 0.21 [0.05, 0.89]
MMF vs IV CYC 683 1.11 [0.74,1.68]
MMF + Tac vs IV CYC 40 0.50 [0.14,1.73]
MMF vs Tac 130 2.11 [0.92, 4.80]
RTX + IV CYC vs RTX 19 0.90 [0.07,12.38]
RTX + MMF vs MMF 144 1.00 [0.48, 2.08]
Maintenance Aza vs MMF 105 0.87 [0.31, 2.43]
Aza vs CsA 69 2.18 [1.01, 4.73]
HZV Infection
Induction MMF vs Oral CYC 62 0.38 [0.08,1.79]
MMF vs IV CYC 683 1.35 [0.71, 2.58]
MMF + Tac vs IV CYC 40 1.00 [0.07,14.90]
Maintenance Aza vs MMF 105 1.27 [0.36, 4.48]

16
 15-Aug-18

Mycophenolate was associated with less leukopenia and

more diarrhea compared to oral or IV cyclophosphamide

Study Treatment Cyclophosphamide RR (random) Weight% RR (random)

or sub-category Events Total Events Total 95% CI 95%CI
Leukopenia
Li 2009 1 20 1 20 4.2 1.00 [0.07,14.9]
El-Shafey 2010 1 24 3 23 13.1 1.28 [0.32, 5.10]
Ginzler 2005 4 83 14 75 21.1 0.32 [0.12, 0.85]
Ong 2005 7 19 13 25 29.6 0.71 [0.35, 1.43]
Appel 2009 11 184 38 180 31.9 0.28 [0.15, 0.54]
Subtotal (95% CI) 330 255 100.00 0.49 [0.28, 0.88]
Total events: 28 69
Test for heterogeneity:Tau2=0.17,Chi2=6.81,df =4 (P=0.15), I2 =41%
Test for overall effect: Z =2.40 (P=0.02)
Diarrhea
El-Shafey 2010 5 24 2 23 10 2.40 [0.52,11.14]
Ginzler 2005 15 83 2 75 11.3 6.78 [1.60,28.66]
Appel 2009 52 184 23 180 78.7 2.21 [1.42,3.45]
Subtotal (95% CI) 291 278 100.00 2.53 [1.54,4.16]
Total events: 72 27 0.02 0.1 1 10 50
Test for heterogeneity:Tau2=0.03,Chi2=2.19,df=2,(P=0.34), I2 =9%
Test for overall effect: Z =3.65 (P=0.0003) Less common with MMF Less common with CYC
(Loma K, AJKD 2012)

Mycophenolate-treated patients had 85-90% reduced

risk of ovarian failure and 95% less likely to have
alopecia compared with cyclophosphamide
Study Treatment Cyclophosphamide RR (random) Weight% RR (random)
or sub-category Events Total Events Total 95% CI 95%CI
Ovarian failure
Ginzler 2005 0 65 2 69 32 0.21 [0.01, 4.34]
Appel 2009 1 184 8 180 68 0.12 [0.02, 0.97]
Subtotal (95% CI) 249 249 100.00 0.15 [0.03, 0.80]

Total events: 1 10
Test for heterogeneity:Tau2=0.00,Chi2=0.09,df =1 (P=0.77), I2 = 0%
Test for overall effect: Z =2.18 (P=0.03)
Alopecia
Ginzler 2005 0 83 8 75 8.2 0.05 [0.00, 0.91]
Appel 2009 20 184 64 180 81.8 0.31 [0.19, 0.48]
Subtotal (95% CI) 267 255 100.00 0.22 [0.06, 0.86]

Total events: 20 72
Test for heterogeneity:Tau2=0.53,Chi2=1.49,df=1,(P=0.15), I2 =41%
Test for overall effect: Z =2.18 (P=0.03)
0.02 0.1 1 10 50

Less common with MMF Less common with CYC

(Loma K, AJKD 2012)

17
 15-Aug-18

Current evidence-based treatment of severe

proliferative lupus nephritis in adults

Prednisolone REMISSION INDUCTION

NIH: monthly IV or Euro-Lupus: IV or Mycophenolate

cyclophosphamide cyclophosphamide
for 6 months (6 pulses spaced 2
weeks apart)

REMISSION MAINTENANCE

Azathioprine or Mycophenolate mofetil

(American College of Rheumatology Guidelines; Arth Care Res 2012)

(EULAR/ERA-EDA Recommnedations; Ann Rheum Dis 2012)

Indications for plasmapheresis

Thrombotic
microangiopathy

Pulmonary
hemorrhage

18
 15-Aug-18

Do these recommendations apply to

childhood lupus nephritis ?

Intermittent IV cyclophosphamide (3 years) arrests

progression of chronicity index in childhood lupus nephritis
Parameter Pretreatment Post-treatment p
CCT 90±23 107±23 <0.01
(ml/min/1.73m2)
Protein excretion 2.0±2.4 0.5±0.7 <0.05
(g/24h)
Creatinine (mg/dL) 0.8±0.2 0.7±0.2 ns
Hb (g/dL) 11.3±1.7 12.7±1.0 <0.01
C3 71±32 101±30 <0.001
ESR (mm/hr) 48±32 25±14 <0.025
Activity index 9±4 1±1 <0.001
Chronicity index 2±1 2±1 ns
(Lehman TJA et al, J Pediatr 2000)

19
 15-Aug-18

Major concern in children:

cumulative cyclophosphamide
and steroid-related toxicities

Infections
Over-immunosuppression
Side effects of long term therapy
Cosmetic effects
Osteoporosis

Height
? Fertility
? Malignancy

Intermittent IV cyclophopshamide treatment for 36 months in

children with lupus nephritis resulted in a 60% reduction in
dosage of prednisolone to a mean of 14 mg DAILY

Mean ± 1 SEM P<0.05 at 6, 12, 18, and 36 months

(Lehman TJA et al, J Pediatr 2000)

20
 15-Aug-18

Growth retardation is a significiant problem in

childhood-onset SLE due to daily steroid dosing

Long-term steroids decreased spine bone

mineral density in children with SLE
1100

800
BMD (mg/cm2)

500

Normals NS on steroids
NS after steroid withdrawal SLE on steroids
200

Age (yrs)

(Bianchi ML, Calcif Tissue Int 2002)

21
 15-Aug-18

Therapy of juvenile-onset SLE resulted in decrease in activity

over time but could not prevent damage scores from increasing
16 2.2
SLEDAI-2K
14 M-SDI 2
1.8
12
1.6

10 1.4
SLEDAI-2K

M-SDI
1.2
8
1
6 0.8
0.6
4
0.4
2 0.2

0
0
First Observation 1 year 3 year 5 year

(Bandeira M et al, Lupus 2006)

Use of mycophenolate in children with SLE

resulted in remission rates of 38-73%
Study n Renal MMF Complete Adverse
pathology dose remission effect

Buratti SL et 11 III,IV,V,VI 22 6/11 Leukopeni

al, 2001 mg/kg/day (54.5%) a (2),
Infection
(4)
Caropreso M 15 II,III,IV,VI 29±7.7 10/15 None
et al, 2007 mg/kg/day (66.6%)

Falcini F et 13 II,III,IV, no 20-25 5/13 Diarrhea

al, 2009 biopsy mg/kg/day (38%) (2)

Aragon E et 16 III, IV 942 12/16 Infection

al, 2010 mg/m2/day (73%) (4)

22
 15-Aug-18

Pulse IV MP up to 6
doses + MMF Prednisolone
REMISSION
Daily
INDUCTION Proteinuria
(>1g/day/BSA)
Normal creatinine

Add CSA
Taper

Remission
(<0.3g/day/BSA)

REMISSION CsA taken off

Alternate
MAINTENANCE Continue MMF day

Combination of pulse methylprednisolone , mycophenolate and

cyclosporine is an effective therapeutic alternative for induction of
children with severe proliferative lupus nephritis
(mg/day/1.73m2) (95%CI)
Mean SLEDAI score (95%CI)

40 12
Mean 24-hr urine protein

10
30 8

20 6
p<0.001 4
p<0.001 p=0.02
10
2 P=0.01
0 0
Pre-induction 6-months 12-months Pre-induction 6-months 12-months
Mean serum complement C3
Mean urine RBC/hpf (95%CI)

80 125
p<0.001
p<0.001
(95%CI)

60 100

40 75

20 50

0 25
-20
Aragon E et al Lupus 2010

23
 15-Aug-18

16 children with proliferative lupus nephritis (III/IV):

Median duration of follow-up: 9.2 years (range 5.8-
14.2 years)
All children achieved complete remission within 24
months (median 8.7 months, range 4-24 months)

Cumulative relapse free (proteinuria free) survival at 10

years was 73.3%
Cumulative probability of proteinuria-free survival

1.0

0.8

Urine protein <1 g/day/1.73m2

0.6

0.4

0.2

0.0

0 2 4 6 8 10
Time from complete remission (years)

24
 15-Aug-18

Cumulative hospitalization-free survival at 10 years was

71.4%

1.0
hospitalization-free survival
Cumulative probability of

0.8

0.6

0.4

0.2

0.0

0 2 4 6 8 10
Time from start of induction(years)

Patients treated with MMF/CsA fared better in terms of

growth as shown by the height SDS compared to
CP/AZA group
4

3
p=0.025 p=0.075
2

1
Height SDS

0
Onset Final Adult SD diff

-1

-2

-3

-4
Initial Ffup Initial Ffup Ht SDS
-5
CP/AZA MMF/CsA

(Singapore 1985-2006)

25
 15-Aug-18

Addition of MMF in Era 3 resulted in an increase in the

5-year absolute renal survival from 52% to 91%

(31)
1.0 (23)
(12)
(11)
(17)

0.8
(24) (5) (1) Era 4:
Rituximab ± MMF ± IV CYC
Renal survival (%)

(5)

0.6 (11)
(5)
(4)
Era 3:
MMF ± IV CYC
(1)
0.4 Era 1: PNL + CYC + AZA
(5)

(1)

0.2

Era 2: IV CYC

0.0

0 5 10 15
Years
(Pereira T et al, CJASN 2011)

What is the role of biologics in the

treatment of lupus nephritis?

26
 15-Aug-18

B cells play a central role in the

pathogenesis of SLE

Autoantibodies
Autoreactive
T cell Autoreactive
B cell

Self-reactive T-
cell receptor
Self-peptide MHC
complex
CD4+Foxp3+
Treg
Self-antigens

?
IL-10 T2 B cell

ADCC CDC Signaling-induced

(NK cells,macrophages) apoptosis

Anti-CD20 antibodies

CD20

Autoantibodies
Autoreactive
B cell
Autoreactive
T cell

Self-reactive T-cell
receptor
Self-peptide MHC
complex
CD4+Foxp3+
Treg
Self-antigens

? Induction of T and B
IL-10 T2 B cell regulatory cells

27
 15-Aug-18

OUTCOME COMPARISON N RR(95%CI)

Partial renal RTX+IV CYC vs RTX 19 0.75 [0.35, 1.62]
remission RTX+MMF vs MMF 144 2.00 [1.05, 3.82]

Addition of rituximab to MMF and steroids was

more effective in inducing partial remission than
MMF and steroids alone

3 uncontrolled studies (37 children)

30 patients with class III/IV LN

28
 15-Aug-18

Lupus nephritis and Rituximab in children

No of patients/ Rituximab Ff-up period Outcome
LN WHO class dose
Willems et al, 2006 8 Class IV: 6 350-450 Mean 13.2 CR: 2
V: 2 mg/m2 x 2- mos (6-12 PR: 4
12 infusions mos) NI: 2
Nwobi et al, 2008 15 Class III: 2 375 mg/m2 Mean 36 mos CR: 7
IV: 11 weekly x 2-4 (6-57.6 mos) PR: 7
doses Death: 1
V: 1
NA:1
Podolskaya et al, 15 Class II: 4 750 mg/m2 x Median 20 mos CR: 8
2008 III: 2 2 doses ± (6-38 mos) PR: 7
IV: 9 CYC 250-750
mg/m2
V: 2
TOTAL 38
CR-complete remission, PR-partial remission, NI-no improvement, CYC-cyclophosphamide

Complete remission: 45.9%

Partial remission: 48.6%
No improvement: 5.4%

Reduction in albuminuria following Rituximab

treatment in children with lupus nephritis
(UK JSLE cohort study n=31)
700
(p=0.057)
Median urine albumin:creatinine ratio

600

500
(mg/mmol)

400

300
284
200
145
100

0
Before rituximab After rituximab
(Watson L, et al Lupus 2014)

29
 15-Aug-18

Adverse effects of Rituximab

n Infections Hematologic Cerebral Febrile Death
(%) toxicity vasculitis rash (%)
(%) (%) (%)
Willems et al, 11 5 4 - 1 -
2006 (45.4%) (36.4%) (9.0%)
Nwobi et al, 2008 15 1 - 1 - 1
(6.7%) (6.7%) (6.7%)
Podolskaya et al, 19 5 0 - - -
2008 (26.3%)
Total 45 11/45 4/45 1/45 1/45 1/45
(24.4%) (8.8%) (2.2%) (2.2%) (2.2%)

Adverse events
Infection:
Septicemia, oral herpes, candidiasis, enteritis, impetigo, herpes zoster,
Staphylococcus endocarditis

Severe hematologic toxicity:

Severe lymphopenia, neutropenia, thrombocytopenia

Retrospective study in 63 children with SLE

receiving 104 courses of rituximab
Adverse events:
18% delayed second course
6% allergy
2% reduced Ig level
2% infection including CMV and herpes
zoster

30
 15-Aug-18

FDA Alert: Rituximab and

progressive multifocal
Pulmonary
leukoencephalopathy Fibrosis

B-cell directed therapies

BLyS

Anti-BLyS
(Belimumab)
TACI
BAFF-R B7.2 CTLA-4
B7.1 CD28
Cytokine
receptor Ag
BCR TCR
T cell
B cell
CD40
CD40L

31
 15-Aug-18

Pooled post-hoc analysis of the phase 3

randomized placebo-controlled BLISS trials
(n=1684):
267 subjects with renal involvement at baseline
Patients with severe lupus excluded from BLISS
trials

Improvement in renal remission rates and median time

to remission in patients with baseline proteinuria
>1g/day following Belimumab treatment

180 167
Median time to first remission

80
160
Patients with renal remission (%)

70.5
70 65.7 139 140
140
58.7
60
120
(days)

50
100
40 80
30 60
20 40
10 20
0 0
Placebo Belimumab Belimumab Placebo Belimumab Belimumab
(n=75) 1 mg/kg (n=67) 10mg/kg (n=78) (n=75) 1 mg/kg (n=67) 10mg/kg (n=78)

32
 15-Aug-18

Reduction in proteinuria in patients with baseline

proteinuria>0.2 g/day following Belimumab
treatment

*p<0.05; +p<0.01; #p<0.001

Median % change in proteinuria

-10

-20
*

-30
+ *
* *
+ *
-40
* + +
# * *
-50
0 4 8 12 16 20 24 28 32 36 40 44 48 52

Placebo, n=215 Belimumab 1mg/kg, n=202 Belimumab 10mg/kg, n=228

Improvement in SELENA-SLEDAI renal involvement in

patients on mycophenolate at baseline following
Belimumab treatment
70
(p=0.03) 63.2
Patients with SELENA-SLEDAI

60
52.6
renal improvement (%)

50

40

30 27.8

20

10

0
Placebo Belimumab 1 mg/kg Belimumab 10mg/kg
(n=18) (n=19) (n=19)

33
 15-Aug-18

B-cell directed therapies

(Gatto M et al, J Autoimmunity 2016)

SLE in children tends to be more acute and severe at

onset, and to have a higher rate of major organ
involvement especially lupus nephritis
Patients with proliferative lupus nephritis have poorer
long-term outcomes in terms of renal survival if they
do not achieve complete renal remission
Treatment of lupus nephritis can be divided into an
induction phase with the goal of achieving renal
remission, and maintenance phase with the goal of
prevention of lupus relapses and reduction of
proteinuria

34
 15-Aug-18

Network meta-analysis showed that the combination

of mycophenolate plus calcineurin inhibitor ranked as
the best treatment to induce remission
Mycophenolate was among the best for preventing
disease relapse during maintenance therapy while IV
cyclophosphamide was among the worst
Meta-analysis showed that plasmapheresis conferred
no additional benefit to pulse IV cyclophosphamide
Mycophenolate had less infectious risk than
azathioprine or cyclophosphamide and less ovarian
failure or alopecia than cyclophosphamide

Addition of rituximab, an anti-CD20 antibody, to

mycophenolate and steroids was more effective in
inducing partial remission than mycophenolate and
steroids alone
Available published data support the continued
investigation of belimumab for the treatment of lupus
nephritis

35
 15-Aug-18

Individualize
therapy: Not
“one size fits
all”

36