IT's a presntation to decide induction treatment for lupus nephritis

1. Journal of American Society of Nephrology
20:1103-1112,2009
SPEAKER MODERATOR
DR. ANKUR NANDAN VARSHNEY PROF. N. K. SINGH

2.  Most serious manifestations of SLE
 It present as microscopic hematuria and
proteinuria (>500 mg /24 hrs)
 Approx half patients develop nephrotic
syndrome
 Hypertension is common
 If left untreated , virtually all patient of DPGN
develops ESRD within 2 years of diagnosis
Al Arfaraj AS et al. Rheumatol Int2009 Jul;29(9):1057-67

3. Class I: Minimal Mesangial Lupus Nephritis
Class II:Mesangial Proliferative Lupus Nephritis
Class III: Focal Lupus Nephritis
Class III (A): Active lesions—focal proliferative lupus nephritis
Class III (A/C): Active and chronic lesions—focal proliferative and sclerosing lupus
nephritis
Class III (C): Chronic inactive lesions with glomerular scars—focal sclerosing lupus
nephritis
Class IV: Diffuse Lupus Nephritis
class IV-S (A): Active lesions-diffuse segmental proliferative lupus nephritis
class IV-G (A): Active lesions-diffuse global proliferative lupus nephritis
class IV-S(A/C): Active and chronic lesions-diffuse segmental proliferative and sclerosing
lupus nephritis
class IV-G(A/C): Active and chronic lesions-diffuse global proliferative and sclerosing
lupus nephritis
class IV-S(C): Chronic inactive lesions with scars-diffuse segmental sclerosing lupus
nephritis
class IV-G(C): diffuse global sclerosing lupus nephritis
ClassV: Membranous Lupus Nephritis
Class VI:Advanced Sclerotic Lupus Nephritis 90% of glomeruli
globally sclerosed without residual activity.
 Weening JJ et al. J. Am. Soc. Nephrol2004. 15 (2): 241–50.

4.  High dose immunosuppression is required
 Cytotoxic agents are given along with high
dose steroids
 Treatment consists of
1. Induction phase
2. Maintenance phase

5. Induction
 CYCLOPHOSPHAMIDE
Dose = 500- 750 mg/m2 iv monthly for 6 months ( NIH)
500 mg iv 2 weekly for 6 cycles (European)
 MYCOPHENOLATE MOFETIL 2 – 3 gm/daily until remission
occur
 High dose steroids are used along
 Therapeutic responses begin after 3-16 weeks of therapy
Maintenance :-
1. MYCOPHENOLATE 1.5- 2 gm /daily
2. AZATHIOPRINE 2mg/kg/DAY
 Impovement in 80% of individuals occur in a span of 1-2
years
(Chan TM. The American Journal of Medicine2012;125:642-648)

6.  A nitrogen mustard alkylating agent from the
oxazophorines group
 Mechanism : a metabolite called phosphoramide
mustard which forms cross links both between and
within DNA strands at guanine N-7 position leading
to cell death
 Side effects- infections ,bone marrow suppression,
ovarian and testicular failure*, alopecia, hemorrhagic
cystitis, bladder carcinoma, teratogenic, malignancy,
nausea, diahorrea
*54% by McDermott et al. Ann Rheum Dis 1996; 55: 224-229
*26% by Mok CC et al. Arthritis and rheumatism 1998;41:831-837

7.  A prodrug of mycophenolic acid
 Mechanism : inhibitor of inosine
monophosphate dehydrogenase which helps
in purine synthesis needed for growth of B
cells and T cells
 Side effects – infections, bone marrow
suppression, lymphoproliferative disorders,
alopecia, GI symptoms, hypokalemia,
hypercholesterolemia, teratogenic

8. Journal of American Society of
Nephrology 20:1103-
1112,2009

9.  Chan TM , Li FK , Tang CSO, et al. Efficacy of mycophenolate
mofetil in diffuse proliferative lupus nephritis. N Engl J
Med.2000;343;1156-1162 showed that prednisolone + MMF and
prednislone + cyclophosphamide are equally effective (n=42)
 Ong LM , Hooi LS , Lim TO, et al .randomized controlled trial of
pulse intravenous cyclophosphamide versus mycophenolate
mofetil in the induction therapy of proliferative lupus nephritis .
Nephrology,2005; 10; 504-510 showed that prednisolone +
MMF and prednisolone + pulse cyclophosphamide are equally
effective (n=44)
 Ginzler EM , Dooley MA , Aranow C , et al. Mycophenolate mofetil
or intravenous cyclophosphamide for lupus nephritis. N Engl J
Med. 2005; 353 ;2219-2228 showed that prednisolone + MMF is
more effective than prednisolone + pulse cyclophosphamide
(n=140 )

10.  A prospective, randomized, open label,
parallel – group, multicentre study
 Hypothesis was stated that more patient with
lupus nephritis would respond to MMF than
to Cyclophosphamide during 24 weeks

11.  Patients aged between 12 yrs and 75 yrs
 Diagnosis of SLE by ACR criteria (Hochberg MC.
Arthritis Rheum 40:1725,1997)
 Lupus nephritis( active, active/chronic) as
confirmed by renal biopsy as ISN class III , IV-S,
IV-G, V, III+V ,IV+V within 6 months before
randomization
 Must have clinically significant level of proteinuria
( atleast 2g/day)

12.  Treatment with either MMF or cyclophosphamide within
the previous year
 Continuous dialysis for > 2 weeks before randomization
or anticipated duration longer than 8 weeks
 Pancreatitis
 Gastrointestinal hemorrhage within 6 months or active
peptic ulcer within 3 months
 Severe viral infection
 Severe cardiovascular disease
 Bone marrow insufficiency with cytopenias not
attributable to SLE
 Current infection requiring iv antibiotics

13.  Stratified by race and biopsy class, patients were
randomly assigned to treatment with MMF and
cyclophosphamide in a ratio of 1:1
 Cyclophosphamide was given in monthly pulses of 0.5-
1 g/m2 as per NIH protocol
 Oral MMF was given twice daily as 0.5 g in first week,
1.0 g in 2nd week, 1.5 g in 3rd week. Dose were
decreased to 2 g /day in response to adverse effect
 Both groups received oral prednisone

14.  Induction period was defined as 24 weeks based on
prior studies to predict outcome and minimizing
adverse effect.(conteras et al;NEJM350:971-980,2004. Houssiau et
al;arthritis rheu 50:3934-3940,2004)
 Patients were assessed at 2nd week , 4th week and then every
4 weekly
 Patients were withdrawn if
1. At week 12 there serum creatinine was >30% above
baseline on two successive measurements separated by at
least 12 weeks
2. When they required other immunosuppressive therapy
3. If MMF dosage fell below 2 g/day for >14 days or was
stopped for >7 days

15. Patient disposition. *Hepatitis/cytomegalovirus infection (n = 16) or other illness (n = 4).
Appel G B et al. JASN 2009;20:1103-1112
©2009 by American Society of Nephrology

16. Characteristic MMF(n=185) Cyclophosphami Total(n=370)
de
Gender (n [%])
male 28 (15.1) 29 (15.7) 57 (15.4)
female 157 (84.9) 156 (84.3) 313 (84.6)
Race (n [%])
white 75 (40.5) 72 (38.9) 147 (39.7)
Asian 62 (33.5) 61 (33.0) 123 (33.2)
other 48 (25.9) 52 (28.1) 100 (27.0)
Ethnicity (n [%])
Hispanic 64 (34.6) 67 (36.2) 131 (35.4)
non- 121 (65.4) 118 (63.8) 239 (64.6)
Hispanic

17. Characteristic MMF Cyclophosphamide Total
Region (n [%])
Asia 57 (30.8) 60 (32.4) 117 (31.6)
Latin America 56 (30.3) 50 (27.0) 106 (28.6)
United 37 (20.0) 38 (20.5) 75 (20.3)
States/Canada
rest of world 35 (18.9) 37 (20.0) 72 (19.5)
Renal biopsy class
(n [%])
III/III + V 32 (17.3) 26 (14.1) 58 (15.7)
IV/IV + V 124 (67.0) 128 (69.2) 252 (68.1)
V only 29 (15.7) 31 (16.8) 60 (16.2)
Scarring on renal 66 (35.7) 56 (30.3) 122 (33.0)
biopsy (n [%])
Serum creatinine 108.6 ± 1.2 92.7 ± 1.0 (56.9 ± 100.6 ± 1.1
(μmol/L [mg/dl]; (97.2 ± 1.1) 0.6) (80.0 ± 0.9)
mean ± SD)
Urine 4.1 ± 4.2 4.1 ± 3.2 4.1 ± 3.7
protein/creatinine
ratio (mean ± SD)

18. Characteristic MMF Cyclophosphamide Total
Range of GFR (ml/min per
1.73 m2; n [%])
≥90 80 (43.2) 86 (46.7) 166 (45.0)
≥60 to <90 53 (28.6) 52 (28.3) 105 (28.5)
≥30 to <60 32 (17.3) 34 (18.5) 66 (17.9)
<30 20 (10.8) 12 (6.5) 32 (8.7)
Range of anti-dsDNA
antibody titer (IU/ml; n
[%])
<30 (negative) 32 (18.4) 23 (13.5) 55 (15.9)
30 to 60 (low 25 (14.4) 24 (14.0) 49 (14.2)
positive)
>60 to 200 52 (29.9) 40 (23.4) 92 (26.7)
(positive)
>200 (strong 65 (37.4) 84 (49.1) 149 (43.2)
positive)
Range of C3
concentration (g/L; n [%])
>1.8 1 (0.6) 1 (0.6) 2 (0.6)
0.9 to 1.8 50 (28.4) 34 (19.5) 84 (24.0)
(normal)
<0.9 (low) 125 (71.0) 139 (79.9) 264 (75.4)

19. Characteristic MMF(n=185) Cyclophosphami Total
de(n=185) ( n=370)
Range of C4
concentration
(g/L; n [%])
>0.47 2 (1.1) 1 (0.6) 3 (0.9)
0.16 to 70 (39.8) 47 (27.2) 117 (33.5)
0.47 (normal)
<0.16 104 (59.1) 125 (72.3) 229 (65.6)
Age at 32.4 ± 11.2 31.3 ± 10.3 31.9 ± 10.7
enrollment (yr;
mean ± SD)
Age at diagnosis 30.2 ± 11.0 28.8 ± 10.2 29.5 ± 10.6
of lupus
nephritis (yr;
mean ± SD)
Time since 1.0 (1 to 21) 1.0 (1 to 23) 1.0 (1 to 23)
diagnosis of
lupus nephritis
(yr; median
[range])

20.  RESPONSE : defined as
1. Decrease in urine protein/creatinine ratio to < 3 in patients
with baseline range >3
2. By > 50% decrease in patients with subnephrotic baseline
protein/creatinine ratio (<3)
3. Stabilization or improvement in serum creatinine
 NON RESPONDER : defined as
1. Received pulse methylprednisolone for any renal or extra
renal flare
2. Who did not complete 24 week induction therapy

21.  Key secondary end points included
◦ the proportion of patients who achieved complete
remission, defined as return to normal serum creatinine,
urine protein <0.5 g/d, and inactive urinary sediment (<5
white blood cells per high-power field and <5 red blood
cells per high-power field, and a reading of lower than 2 on
dipstick and absence of red cell casts);
◦ proportion of patients who achieved any one of these renal
outcomes; combined renal and extrarenal remission,
defined as absence of A and B scores on the British Isles
Lupus Assessment Group system;
◦ mean change on the Safety of Exogenous Estrogens in
Lupus Erythematosus National Assessment/Systemic Lupus
Erythematosus Disease Activity Index

22. Response rates of study population and by racial group.
Appel G B et al. JASN 2009;20:1103-1112
©2009 by American Society of Nephrology

23. Parameter MMF ( n= 185) Cyclophosphami Odd’s Ratio
de ( n= 185 ) (95% CI)
Responders with 88 (56.4) 83 (53.9) 1.1(0.7 to 1.8)
renal biopsy
class III or IV
Patients with 16 (55.2) 15(48.4)
class V
Renal remission
criteria
Serum creatinine 130 (70.3) 125 (67.6) 2.7(-6.7 to
12.1)
Urine protein 44 (23.8) 50 (27) -3.2(-12.1to
5.6)
Urine sediments 58 (31.4) 44 (23.8) 7.6(-1.5to16.6)
All three 16 (8.6) 15 (8.1) 0.5(-5.1to6.2)

24. parameter MMF Cyclophosphami Total
de
Renal and extra 54(29.7) 45(24.9) 4.8(4.3 to 14)
renal remission
Absence of
BILAG score
SELENA-SLEDAI -6.2 +/- 10.1 -6.6 +/-8
change in score
from baseline to
endpoint
Anti-DsDNA 117(67.2) 124(72.5)
>60 at baseline
Anti-DsDNA>60 72(41.4) 91(53.2)
at end point
Low C3 at 125(71) 139(79.9)
baseline
Low C3 at end 70(39.8) 90(51.7)
point
Low C4 at 104(59.1) 125(72.3)
baseline
Low C4 at end 51(29) 72(41.6)
point

25. Parameter MMF (n= 185) Cyclophosphamide ( n= 185)
Completed 24 week open label induction 150 (81.1) 156 (84.3)
phase
Withdrawn prematurely 35 (18.9) 29 (15.7)
Reasons for withdrawl
Adverse event 21 (60) 12(41.4)
Deteoriation with respect to serum 0 2 (6.9)
creatinine after 12 and 16 week
Dosage reduction of MMF <2g/d for >14 1(2.9) 0
day
Lost to follow up 1(2.9) 2(6.9)
Patient died 3 (8.6) 1(3.4)
Withdrew consent 6 (17.1) 5 (17.2)
Physician decision 1 (2.9) 3 (10.3)
Sponsor decision 2 (5.7) 1 (3.4)
Non compliance 0 1 (3.4)
Reason not noted 0 2 (6.9)

26. Parameter MMF (n=184) Cyclophosphamide
(n=180)
Deaths 9 (4.9) 5 (2.8)
Withdrawals as a result 24 (13.0) 13 (7.2)
of AEs
All AEs 177 (96.2) 171 (95.0)
diarrhea 52 (28.3) 23 (12.8)
headache 38 (20.7) 47 (26.1)
peripheral edema 35 (19.0) 30 (16.7)
arthralgia 29 (15.8) 43 (23.9)
nausea 27 (14.7) 82 (45.6)
hypertension 26 (14.1) 25 (13.9)

27. Parameter MMF Cyclophosphamide
25 (13.6) 29 (16.1)
nasopharyngitis
vomiting 25 (13.6) 68 (37.8)
cough 24 (13.0) 16 (8.9)
anemia 23 (12.5) 12 (6.7)
alopecia 20 (10.9) 64 (35.6)
abdominal pain 19 (10.3) 13 (7.2)
back pain 19 (10.3) 16 (8.9)
muscle spasms 19 (10.3) 17 (9.4)
rash 19 (10.3) 21 (11.7)
urinary tract infection 19 (10.3) 17 (9.4)

28.  MMF did not show any superiority over
cyclophosphamide for induction therapy for lupus
nephritis
 However, there were important racial differences as
the Blacks and Hispanics who are at increased risk
of aggressive disease, responded more to MMF
than cyclophosphamide
 Though the most common side effects were
infections and GI side effects that occur
comparatively in both groups, alopecia an
undesirable side effect occur mainly in
cyclophosphamide group

29.  Convenience of twice daily oral medication versus
hospitalization for monthly infusion for
cyclophosphamide was not addressed
 Impact of cyclophosphamide to cause ovarian
dysfunction on women of child bearing age was
not discussed
 24 weeks may be too short to differentiate
between treatments as disease may continue to
improve and side effects may continue to emerge
later with cyclophosphamide (Ioannidis et al. Kidney Int
57:258-264,2000)

30.  Conteras et al. N Engl J Med.2004;350:971-980
Showed in a randomized trial (n=59) that 72 month
survival rate free of renal failure higher in MMF and
AZA group than quarterly cyclophosphamide group
 Houssiau et al. Ann Rheum Dis.2010;69:2083-
2089 showed in a randomized trial (n=105) that
MMF not more effective than AZA in prolonging
time to renal flare

31. Dooley et al.N Eng J med
2011;365:1886-95

32.  Mycophenolate was superior to azathioprine
in maintaining a renal response to treatment
and preventing relapse in patients with lupus
nephritis who had a response to induction
therapy

33.  LUNAR study: a trial on stage III and IV lupus
nephritis showed that add on rituximab had no
clinical impact in patients treated with
corticosteroid and MMF.(Furie et al.Ann Rheum
Dis.2010;69(suppl 3):549a
 EXPLORER study : Rituximab(anti CD20
monoclonal antibody) showed an impact on
serological parameters but not on clinical efficacy
in patients with active nonrenal lupus.(Merrill et
al.Lupus.2011;20:709-716)

34.  A phase III trial with Belimumab (a monoclonal
antibody against the ligand of BlyS/BAFF receptor
on B cells that promotes B cell survival and
differentiation to plasmablasts) showed efficacy
with extrarenal lupus but there is insufficient data
in lupus nephritis.(Navarra et al.Lancet.2011;377:721-
731)

35.  On the basis of above studies, physicians may
consider MMF as an alternative to
Cyclophosphamide in induction treatment of
lupus nephritis depending upon:
1. Adverse effects
2. Socioeconomic factors
3. Racial factors
(Chan TM. The American Journal of Medicine2012;125:642-
648)