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MIAMI, Fla., March 3 /PRNewswire/ -- Drugs used to
prevent rejection in
transplant patients are proving equally valuable in the fight against
lupus
nephritis (lupus kidney disease), according to researchers at the
University
of Miami in a study published this week in the New England Journal
of Medicine
(NEJM).
Lupus nephritis is the most common severe complication of the autoimmune
disease systemic lupus erythematosus (SLE). Approximately 1.5 million
Americans have SLE and half of those will develop lupus kidney disease.
Lupus
nephritis increases the risk for premature death and chronic kidney
failure, a
condition that may require chronic dialysis or transplantation.
In the study, "Sequential Therapies for Proliferative Lupus
Nephritis,"
researchers showed that maintenance with daily oral treatment with
one of the
most widely prescribed transplant medications, mycophenolate mofetil
(MMF,
also known as CellCept(R)) or the older anti-rejection drug azathioprine
(AZA)
was more effective and safer than the current "gold standard"
therapy,
intravenous quarterly pulses of the chemotherapy drug cyclophosphamide
(IVCY,
also known as Cytoxan(R)) in the long term treatment of lupus nephritis.
"We're very excited about our study results that demonstrate
that new
maintenance treatment regimens with MMF or AZA are more effective
and offer a
much lower incidence of significant adverse events than long-term
IVCY," said
Gabriel Contreras, M.D., MPH, lead author of the NEJM study, Associate
Professor of Medicine at the University of Miami School of Medicine
and
Director of the Dialysis Unit at the Veterans Affairs Medical Center
in Miami.
The most important highlights of the study include the findings
that:
* Long-term IVCY was associated with a greater risk of death or
chronic
renal failure than maintenance therapy with MMF or AZA
* Maintenance therapy with MMF or AZA was safer than long-term
IVCY, with
fewer hospitalizations, severe infections, amenorrhea and
gastrointestinal side effects
Lupus patients with kidney involvement undergo periods of intense
disease
activity known as flaring. Induction therapy is used to try to induce
periods
of remission. "During flares, patients usually require higher
doses of
corticosteroids and additional pulses of IVCY, which increase the
risk for
more adverse events," added Dr. Contreras. "Avoidance
of renal flares is
important as flaring is known to cause damage to the kidneys, which
can lead
to kidney failure. Once a patient is in remission the aim of maintenance
treatment is to keep patients relapse-free."
Lower Relapse Rates Seen
Another highlight of the study included lower relapse rates. In
the
study, the rate of relapse was statistically significantly lower
in the MMF
group versus IVCY. Relapse rates in the AZA group were not significantly
better than in the IVCY group. During maintenance therapy 40 percent
relapsed
in the IVCY group, 32 percent in the AZA group and 15 percent in
the MMF
group.
"These study results are likely to shift the treatment paradigm
away from
long-term chemotherapy drugs," said Dr. Contreras.
This study was funded by a research grant from Roche, manufacturers
of MMF
under the brand name CellCept(R).
Study Design
The open-label, randomized clinical trial of 59 patients with lupus
nephritis included 27 African-Americans, 29 Hispanic-Americans and
3
Caucasians. African-Americans and Hispanic-Americans are populations
known to
be at high risk for lupus nephritis. All patients received the same
induction
therapy with monthly short-term IVCY and corticosteroids. The patients
were
then randomized to one of three maintenance therapies: quarterly
boluses of
IVCY, oral AZA (1-3 mg/kg/day); or MMF (500-3000 mg/day) for one
to three
years. Each group also received oral corticosteroids.
The 72-months event-free cumulative probability of the composite
end-point
(death or chronic renal failure) was higher in the MMF (P=0.05)
and AZA
(P=0.009) groups compared to the IVCY group. Five patients died
(4-IVCY,
1-MMF) and five patients developed chronic renal failure (3-IVCY,
1-AZA, 1
MMF).
Thirty-one percent of the patients who achieved remission had a
relapse
(IVCY=8, AZA=6, MMF=3). The relapse-free cumulative probability
was higher in
the MMF group compared to the IVCY group (P=0.024). Hospitalizations,
amenorrhea, infections, and gastrointestinal side effects were significantly
lower in the MMF and the AZA groups compared to the IVCY group.
"I am really encouraged by these study results, which add to
the growing
body of evidence that CellCept(R) may be an effective treatment
for lupus
nephritis," said Sandra Raymond, President and CEO of the Lupus
Foundation of
America. "Last October, in a study presented at the American
College of
Rheumatology's Annual Meeting, we saw that CellCept(R) as induction
therapy
was at least equivalent and better tolerated than IVCY. Now we're
seeing that
CellCept(R) may prove equally valuable as long-term maintenance
therapy. I'm
very excited that there are now less toxic and more effective treatment
options emerging for the millions of people worldwide with lupus
kidney
disease."
About CellCept(R) (mycophenolate mofetil)
CellCept(R) (mycophenolate mofetil) is an immunosuppressant or
"anti-rejection" drug to be used in combination with other
immunosuppressive
drugs (cyclosporine and corticosteroids) for the prevention of rejection
in
patients receiving heart, kidney and liver transplants. CellCept(R)
received
FDA approval for the prevention of organ rejection in kidney (May
1995), heart
(February 1998), and liver (July 2000). The recommended dosages
for
CellCept(R) follow: for adult kidney transplants, 2 g daily; for
pediatric
kidney transplants, oral suspension 600 mg/m2; for adult heart and
liver, 3 g
daily.
The principal adverse events associated with the administration
of
CellCept(R) (in combination with cyclosporine and corticosteroids
in
transplant patients) include diarrhea, leukopenia, sepsis and vomiting,
and
there is evidence of a higher frequency of certain types of infections.
A
higher proportion of renal transplant patients in the active treatment
groups
experienced one or more opportunistic infections compared with patients
receiving placebo. Cytomegalovirus tissue invasive disease was more
common
in patients receiving 3 g/day.
Increased susceptibility to infection and the possible development
of
lymphoma may result from immunosuppression. Only physicians experienced
in
immunosuppressive therapy and management of renal, cardiac or hepatic
transplant patients should use CellCept(R). Patients receiving the
drug
should be managed in facilities equipped and staffed with adequate
laboratory
and supportive medical resources. The physician responsible for
maintenance
therapy should have complete information requisite for the follow-up
of the
patient.
There are no adequate and well-controlled studies in pregnant women.
However, CellCept(R) has been shown to have teratogenic effects
in animals; it
may cause fetal harm when administered to a pregnant woman. Therefore,
CellCept(R) should not be used in pregnant women unless the potential
benefit
justifies the potential risk to the fetus. For full prescribing
information,
visit http://www.rocheusa.com/products/cellcept/pi.html.
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