Systemic lupus erythematosus (SLE) is a complex and potentially life-threatening disease that
affects about 40 per 10,000 people in the general population (Mills 1994, Brown & Schrieber
1996). SLE is a chronic inflammatory disease characterized by auto-antibody overproduction
and other distinct immunological abnormalities (Boumpas, et al 1995, Mohan & Datta 1995). It
may affect the skin, joints, lungs, heart, serous membranes, nervous system or other organs.
Improvements in treatment over the last decade have increased 10-year survival rates in
Western countries to 90% or more, and 20-year survival rates of nearly 70% have also been
reported (Abu-Shakra, et al 1995).
Newer treatment strategies include the use of novel immunosuppressive agents, such as
mycophenolate mofetil (MMF). MMF has been widely used in solid-organ transplantation
(Sollinger 1995, The Tricontinental Mycophenolate Mofetil Renal Transplantation Study Group
1996). MMF also has been used increasingly in autoimmune diseases (e.g., dermatomyositis,
primary glomerular disease or psoriasis (Epinette, et al 1987, Gelber, et al 2000, Choi, et
al 2002)).
MMF is the morpholinoethylester prodrug of mycophenolic acid (MPA). After oral administration
MMF is well absorbed and rapidly hydrolyzed to MPA. MPA is a noncompetitive inhibitor of
inosine monophosphate (IMP) dehydrogenase (DH). Inhibition of IMPDH leads to the depletion of
deoxyguanosine triphosphate and a consequent decrease in the level of substrate required for
DNA polymerase activity. This results in inhibition of DNA production and cell proliferation.
T and B cells are more dependent on this de novo pathway of purine synthesis because
alternative salvage pathways are unavailable. Thus, MPA is a selective inhibitor of
lymphocyte proliferation, especially in activated lymphocytes (Allison & Eugui 2000).
A limited number of clinical studies have been performed to study the efficacy of MMF in the
treatment of SLE. Most of these studies involved the treatment of nephritis. Chan, et al
(2000) showed that the combination of MMF and prednisolone is as effective as a regimen of
cyclophosphamide and prednisolone followed by azathioprine and prednisolone. Azathioprine and
MMF as maintenance therapy were compared to cyclophosphamide therapy (Contreras, et al 2004)
and appeared to be more efficacious and safer than long-term therapy with i.v.
cyclophosphamide. In this study, it was also noted that patients treated with MMF had
received lower doses of corticosteroids during maintenance therapy as compared to patients
treated with azathioprine.
Recent reports suggest that MMF may also be effective in systemic lupus without severe renal
involvement.(Pisoni, et al 2005) Yet, the superiority over azathioprine in this patient group
has not been established. Own observations show that approximately 50% of patients with SLE
treated with azathioprine have at least some evidence of lupus activity. The aim of this
study will be to show a decreased lupus activity in patients treated with myfortic ® compared
to therapy with azathioprine. Data so gathered may be useful in planning future developments
in this indication
This is a 12 months, multi-center, 2-treatment arm, parallel-group, randomized, open label
study in patients with systemic lupus erythematosus currently on azathioprine. The patients
will be randomized to one of the following two treatment groups:
Maintenance of previous therapy including azathioprine.
Switch to a myfortic ® based regimen: myfortic ® (dose of 1440mg/day) A total of 48
patients (24 patients per arm) fulfilling the inclusion/exclusion criteria will be
enrolled in the study from approximately 5 centers in the Netherlands. Screening
evaluations and assessments will be performed in the period after informed consent has
been signed by the patient and before randomization of the patient (Baseline, Day 1).
Visits are scheduled for Baseline, Weeks 2, 4, 12, Months 6, 9 and 12.
The final analysis will be performed after the last patient has reached the 12 months of the
study.
The following efficacy variables will be obtained and recorded:
Disease activity index measured with SLEDAI
Disease activity index measured with BILAG (numerical score)
(Average) daily dose of prednisone (mg/kg/day). The dose will be measured from the
patient starting the study and for the whole duration of the study.
Damage index measured with SLICC/ACR
Serum creatinine
Creatinine clearance
Urine protein:creatinine ratio