Mycophenolate mofetil or intravenous cyclophosphamidePresentation Transcript
Mycophenolate Mofetil or Intravenous Cyclophosphamide for Lupus NephritisThe new Englandjournal of medicine Prepared byestablished in 1812November 24 Dr . Nahid Sherbini,2005vol. 353 no. 21
BackgroundSince series and small, prospective,controlled trials suggest thatmycophenolate mofetil may be effectivefor treating lupus nephritis, larger trials aredesirable.
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.
Mycophenolate mofetilAn immunosuppressive agent approvedfor the prevention of transplant rejection--used in patients with lupus nephritisrefractory to cyclophosphamide and inpatients who cannot toleratecyclophosphamide.
Failure to achieve remissionwhich is associated with an increased rate of progression to renal failure, is reported in 18 to 57 % of patients who received cyclophosphamide.
(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
WHO ClassificationProliferative glomerulonephritis class III (focal(IV (diffuse(V (membranous(
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(.
Exclusion criteriaCreatinine clearance of less than 30 ml perminute.Serum creatinine on repeated testing > 3.0 mgper deciliter.Severe coexisting conditionsImmunosuppressive therapy or conditionsrequiring IV antibiotic therapy.Prior treatment with MMF or IVC in past 12m.Monoclonal antibody therapy in the past 30days.Pregnancy or lactation
Treatment protocolOral MMF initiated at a dose of 500 mgtwice daily, and the dose was increased to750 mg twice daily at week 2 andadvanced weekly to a maximum dose of1000 mg three times daily unless WBC fellbelow 3000 .
Treatment protocol IVC was given as monthly pulsesaccording to a protocol of the NationalInstitutes of Health (NIH). Dosage wasmodified on the basis of WBC of 2500 at7-10 days after the infusion.Prednisone at a dose of 1 mg /kg/ day,with tapering by 10 to 20% at one-week ortwo.
Study end pointsThe primary end point was completeremission at 24 weeks (normalization ofabnormal renal measurements andmaintenance of baseline normalmeasurements).A secondary end point was partialremission at 24 weeks.
ASSIGNMENT ANDTHE RESULTS OF THE STUDY
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
Laboratory Values forPrimary and Secondary End Points.
Weeks of Treatment 12 MMF IVC 95% CI P valueCreatinie 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 0.39protein (-0.60 to 1.54)C3 101.41±22 87.80±35. 13.61 0.01 .78 79 (3.06 to 24.15)
Weeks of Treatment 24 MMF IVC 95% CI P valueCreatinie 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 0.22protein to 1.49)C3 69.8±29.9 91.8±29.5 4.97(-7.18 0.42 to 17.12)
Immunosuppressive therapyThe mean maximal tolerated dose of MMFwas 2680 mg/d of a total of 83 patientsreceiving MMF --52 (63%) tolerated 3000mg /d.Of 69 patients in the IVC group 43 (62 %)received 6 m doses of the drug. Thecumulative dose of IVC/ patient after 3 mwas 3430±355mg, and after 6 months itwas 7302±1695 mg.
The mean dose of IVCcomplete 909.7±176.0response mg per square meter of body- surface area per month .partial response 746.0±174.4 mgno response 725.5±190.3 mg
Adverse eventsThere were 2 deaths in IVC group duringtreatment.One patient died cerebral hemorrhage withina week of receiving the first dose.The other patient received two doses, thesecond of which was delayed by sepsis—death3w later and was related to active lupus andrecurrent sepsis.A 3rd patient declined therapy and died frompulmonary hemorrhage and renal failure atanother hospital.There were no deaths in MMF group.
Adverse eventsInfection and gastrointestinal side effectsaccounted.Severe infections (pneumonia and lungabscess, necrotizing fasciitis, and gram-negative sepsis) occurred only with IVC.Pyogenic infections were significantly lessfrequent among patients receivingMMF>IVC.
Adverse eventsHospitalizations for vomiting anddehydration occurred in five patients (atotal of seven episodes) receiving IVC.Diarrhea occurred more with MMF(15patients) .
Adverse eventsApparent drug-related hematologic toxiceffects were uncommon.Incident neutropenia alone wasresponsible for a reduction in the dose ofIVC at only 8 infusions among 6 patients.Baseline lymphopenia was present in 22patients in MMF group and 15 patients inIVC group.
Outcomes during Follow-up after Induction TherapyEvent No. of Relative Risk P Value Events (95%CI) MMF IVC1st renal 8 8 0.98 (0.37–2.61) 0.96flareRenal 4 7 0.53 (0.15–1.81) 0.31failureDeath 4 8 0.48 (0.15–1.60) 0.24
. CONTBefore this trial was completed, tworandomized studies comparingmycophenolate mofetil withcyclophosphamide for lupus nephritis werereported.
Chan et alReported 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.
.Hu et alReported on 46 patients with class IVnephritis and concluded that 6 m of MMFwas more effective than IVC in reducingproteinuria, hematuria, and autoantibodyproduction.
Cont. ResultsIn this short-term study, the toxicity andtolerability to MMF compared favorably with thatof cyclophosphamide.Although upper gastrointestinal symptoms werecommon in the 2 groups in the MMF group thesymptoms tended to be mild and self limited,whereas in the IVC group dehydration followingtreatment necessitated 7 hospitalizations.Serious infections were less common with MMF.
In this prospective controlled studyrelatively large and involved aheterogeneous cohort, including patientsfrom 19 academic and private-practicecenters in the United States.56% of the patients wereblackassociated with poor outcome.
A limitation of the studyThe treatment assignment was not blinded.Although this could lead to potential bias inpatient recruitment and in the interpretation ofresults.Marked differences in side-effect profiles of thetwo drugs would probably make true blindingdifficult.Potential bias was minimized by selecting aprimary end point with the use of objectivelaboratory measures.
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.
Another limitationShort duration of the study.and the restriction to induction therapy.Long term experience in clinical trialsusing IVC shows a relapse rate of up to45 % in patients with proliferative lupusnephritis despite a complete clinicalresponse to induction therapy.
The long-term follow-up (median, 63months) in the study by Chan et al.showed a similar rate of renal relapse inboth treatment groups with more gradualtapering of the maintenance dose of MMF
In summaryInduction therapy with MMF was superior to IVCin inducing complete remission of lupus nephritisin this study.MMF appeared to be better tolerated than IVC.Unresolved issues include determining the flarerate after induction with MMF as compared withthat for IVC.Determining the appropriate dose and durationof MMF maintenance therapy.