1. Mycophenolate Mofetil or
Intravenous
Cyclophosphamide
for Lupus Nephritis
The new England
journal of medicine Prepared by
established in 1812
November 24 Dr . Nahed Sherbini
,2005
vol. 353 no. 21

2. Background
Since series and small, prospective,
controlled trials suggest that
mycophenolate mofetil may be effective
for treating lupus nephritis, larger trials are
desirable.

3. Background
IV cyclophosphamide has been the
standard of care for treating severe lupus
glomerulonephritis.
**Potentially severe toxic effects :
Bone marrow suppression,
Hemorrhagic cystitis,
Opportunistic infections, malignant
diseases, and premature gonadal failure.

4. Mycophenolate mofetil
An immunosuppressive agent approved
for the prevention of transplant rejection
--used in patients with lupus nephritis
refractory to cyclophosphamide and in
patients who cannot tolerate
cyclophosphamide.

5. Failure to achieve remission
which is associated with an increased rate
of progression to renal failure, is reported
in 18 to 57 % of patients who received
cyclophosphamide.

6. (Methods (Study Design
Multicenter, randomized, open label,
controlled trial from December 1999 >
October 2003 .
Eligibility criteria :
SLE Pt meeting four classification criteria of
the American College of Rheumatology &
Renal biopsy documenting lupus nephritis
according to the classification of the WHO

7. WHO Classification
Proliferative glomerulonephritis class III
(focal(
IV (diffuse(
V (membranous(

8. Clinical activity as defined by one
:or more of the following
*Incident decrease in renal function .
*Proteinuria (defined as more than 500 mg
of protein in a 24-hour urine specimen(.
*Hematuria (defined as >5 red cells/HPF(
presence of cellular casts, increasing
proteinuria with rising levels of serum
creatinine, active urine sediment or
serologic abnormality (anti-DNA
antibodies or hypocomplementemia(.

9. Exclusion criteria
Creatinine clearance of less than 30 ml per
minute.
Serum creatinine on repeated testing > 3.0 mg
per deciliter.
Severe coexisting conditions
Immunosuppressive therapy or conditions
requiring IV antibiotic therapy.
Prior treatment with MMF or IVC in past 12m.
Monoclonal antibody therapy in the past 30
days.
Pregnancy or lactation

10. Treatment protocol
Oral MMF initiated at a dose of 500 mg
twice daily, and the dose was increased to
750 mg twice daily at week 2 and
advanced weekly to a maximum dose of
1000 mg three times daily unless WBC fell
below 3000 .

11. Treatment protocol
IVC was given as monthly pulses
according to a protocol of the National
Institutes of Health (NIH). Dosage was
modified on the basis of WBC of 2500 at
7-10 days after the infusion.
Prednisone at a dose of 1 mg /kg/ day,
with tapering by 10 to 20% at one-week or
two.

12. Study end points
The primary end point was complete
remission at 24 weeks (normalization of
abnormal renal measurements and
maintenance of baseline normal
measurements).
A secondary end point was partial
remission at 24 weeks.

13. ASSIGNMENT AND
THE RESULTS OF THE
STUDY

14. Eligible patients providing
Signed consent enrolled
)N=140(
Underwent randomization
)N=140(
Assigned to MMF(N=71) )Assigned to IVC (N=69
Received MMF(N=71) )Received IVC (N=66
)Declined therapy (N=3
)MMF for 24w (N=56 )Discontinued (N=15
)CR(N=16 Withdrew before )IVC for 24w (N=42 )Discontinued (N=24
)PR(N=21 )w12(N=6 )CR(N=4 Withdrew before
NR(N=1 Did not have )PR(N=17 )w12(N=10
early response )NR(N=21 Did not have
)by w12(N=8 early response
)by w12(N=12
)Included in analysis (N=71 )Included in analysis (N=69
)Excluded (N=0 )Excluded (N=0

15. Laboratory Values for
Primary and Secondary
End Points.

16. Weeks of Treatment 12
MMF IVC 95% CI P value
Creatinie 0.96±0.36 0.98±0.68 0.02 0.84
(-0.17 to
0.21)
Albumin 3.26±0.29 3.17±0.25 0.09 0.07
(-0.01 to
0.19)
Urine 2.50±3.01 2.97±3.06 0.47 0.39
protein (-0.60 to
1.54)
C3 101.41±22 87.80±35. 13.61 0.01
.78 79 (3.06 to
24.15)

17. Weeks of Treatment 24
MMF IVC 95% CI P value
Creatinie 0.91±0.25 0.85±0.28 0.06 (-0.5 0.27
to 0.17)
Albumin 3.42±0.42 3.44±0.25 0.02 (-0.12 0.79
to 0.16)
Urine 2.03±2.79 1.46±1.27 0.57 (-0.35 0.22
protein to 1.49)
C3 69.8±29.9 91.8±29.5 4.97(-7.18 0.42
to 17.12)

18. Immunosuppressive therapy
The mean maximal tolerated dose of MMF
was 2680 mg/d of a total of 83 patients
receiving MMF --52 (63%) tolerated 3000
mg /d.
Of 69 patients in the IVC group 43 (62 %)
received 6 m doses of the drug. The
cumulative dose of IVC/ patient after 3 m
was 3430±355mg, and after 6 months it
was 7302±1695 mg.

19. The mean dose of IVC
complete 909.7±176.0
response mg per square
meter of body-
surface area
per month .
partial response 746.0±174.4
mg
no response 725.5±190.3
mg

20. Adverse events
There were 2 deaths in IVC group during
treatment.
One patient died  cerebral hemorrhage within
a week of receiving the first dose.
The other patient received two doses, the
second of which was delayed by sepsis—death
3w later and was related to active lupus and
recurrent sepsis.
A 3rd patient declined therapy and died from
pulmonary hemorrhage and renal failure at
another hospital.
There were no deaths in MMF group.

21. Adverse events
Infection and gastrointestinal side effects
accounted.
Severe infections (pneumonia and lung
abscess, necrotizing fasciitis, and gram-
negative sepsis) occurred only with IVC.
Pyogenic infections were significantly less
frequent among patients receiving
MMF>IVC.

22. Adverse events
Hospitalizations for vomiting and
dehydration occurred in five patients (a
total of seven episodes) receiving IVC.
Diarrhea occurred more with MMF(15
patients) .

23. Adverse events
Apparent drug-related hematologic toxic
effects were uncommon.
Incident neutropenia alone was
responsible for a reduction in the dose of
IVC at only 8 infusions among 6 patients.
Baseline lymphopenia was present in 22
patients in MMF group and 15 patients in
IVC group.

24. Outcomes during Follow-up after
Induction Therapy
Event No. of Relative Risk P Value
Events (95%CI)
MMF IVC
1st renal 8 8 0.98 (0.37–2.61) 0.96
flare
Renal 4 7 0.53 (0.15–1.81) 0.31
failure
Death 4 8 0.48 (0.15–1.60) 0.24

25. . CONT
Before this trial was completed, two
randomized studies comparing
mycophenolate mofetil with
cyclophosphamide for lupus nephritis were
reported.

26. Chan et al
Reported on a 12-month study involving 42
patients with class IV nephritis in which MMF
was as effective as oral cyclophosphamide in
inducing remission.
The rate of infectious complications was similar in
the 2 treatment groups, but only patients treated
with cyclophosphamide had amenorrhea,
alopecia, leucopenia, or died.

27. .Hu et al
Reported on 46 patients with class IV
nephritis and concluded that 6 m of MMF
was more effective than IVC in reducing
proteinuria, hematuria, and autoantibody
production.

28. Cont. Results
In this short-term study, the toxicity and
tolerability to MMF compared favorably with that
of cyclophosphamide.
Although upper gastrointestinal symptoms were
common in the 2 groups in the MMF group the
symptoms tended to be mild and self limited,
whereas in the IVC group dehydration following
treatment necessitated 7 hospitalizations.
Serious infections were less common with MMF.

29. In this prospective controlled study
relatively large and involved a
heterogeneous cohort, including patients
from 19 academic and private-practice
centers in the United States.
56% of the patients were
blackassociated with poor outcome.

30. A limitation of the study
The treatment assignment was not blinded.
Although this could lead to potential bias in
patient recruitment and in the interpretation of
results.
Marked differences in side-effect profiles of the
two drugs would probably make true blinding
difficult.
Potential bias was minimized by selecting a
primary end point with the use of objective
laboratory measures.

31. In recent reports, the average time to
remission with cyclophosphamide is 10
months.
Low response rate with IVC may reflect an
inability to achieve the recommended
protocol dosing doses were regulated on
the basis of toxic effects, primarily
gastrointestinal symptoms.

32. Another limitation
Short duration of the study.
and the restriction to induction therapy.
Long term experience in clinical trials
using IVC shows a relapse rate of up to
45 % in patients with proliferative lupus
nephritis despite a complete clinical
response to induction therapy.

33. The long-term follow-up (median, 63
months) in the study by Chan et al.
showed a similar rate of renal relapse in
both treatment groups with more gradual
tapering of the maintenance dose of MMF

34. In summary
Induction therapy with MMF was superior to IVC
in inducing complete remission of lupus nephritis
in this study.
MMF appeared to be better tolerated than IVC.
Unresolved issues include determining the flare
rate after induction with MMF as compared with
that for IVC.
Determining the appropriate dose and duration
of MMF maintenance therapy.