pharmacological therapy of lupus nephritis

CLINICIAN’S CORNERGRAND ROUNDSAT THE JOHNS HOPKINS BAYVIEW MEDICAL CENTER

Pharmacological Therapy of Lupus NephritisDerek M. Fine, MD

CASE PRESENTATIONMrs P, a 31-year-old woman, developeda blood pressure of 170/104 mm Hg at38 weeks of pregnancy. Her obstetri-cian performed a laboratory evaluationthat revealed proteinuria (2�), throm-bocytopenia(plateletcount,121�103/µL[normal range: 150-350�103/µL]), aserumcreatinine levelof0.8mg/dL(70.7µmol/L) (normal range: 0.4-1.1 mg/dL[35.3-97.2µmol/L]),uricacid levelof9.0mg/dL (normal range: 2.4-5.7 mg/dL),and aspartate and alanine aminotrans-ferase levels of 170 U/L and 190 U/L,respectively (normal range: 0-35 U/L).Mrs P was diagnosed with the HELLP(hemolysis, elevated liver enzymes, lowplatelets) syndrome1 and underwent anemergent cesarean delivery of a healthymale newborn. Despite this interven-tion, Mrs P continued to have thrombo-cytopenia and hypertension. In addi-tion, she developed temperatures up to102° F. She was treated empirically withantibiotics and received heparin brieflyfor a presumptive diagnosis of pelvicthrombophlebitis. Fevers continued andshe developed weakness and fatigue.

Four months after delivery, she de-veloped progressive dyspnea on exer-tion and orthopnea. Echocardiogra-phy revealed an ejection fraction of30%. Therapy was initiated with an an-giotensin-converting enzyme inhibi-tor and a loop diuretic, with resolu-tion of her symptoms and normalizationof her cardiac function over the subse-

quent 2 months. Her transient conges-tive heart failure was attributed to post-partum cardiomyopathy. Five monthsafter delivery, she presented with fe-ver, fatigue, arthralgias, malar rash, apapular eruption on her forearms, andalopecia. Her platelet count was still low(69�103/µL) and she remained ane-mic (hematocrit, 26% [normal range:38%-47%]). These findings prompteda serological workup that revealed hightiter positive assay for antinuclear an-tibodies (ANAs) and antibodies todouble-stranded DNA (dsDNA). Her se-rum complement levels were low, withthe C3 and C4 complements measur-ing 43 mg/dL (normal range: 79-152mg/dL) and 5 mg/dL (normal range:12-42 mg/dL), respectively. Her eryth-rocyte sedimentation rate was el-evated at 107 mm/h (normal range: 4-25mm/h). The diagnosis of systemic lu-pus erythematosus (SLE) was made.

At the time of Mrs P’s nephrologyevaluation, her medications includedcandesartan (32 mg/d) and metopro-lol succinate (150 mg/d). The familymedical history was noncontributory.She had previously worked as a neo-natal nurse and did not smoke or drink.Her child was now 6 months old; sheand her husband were eager to havemore children.

On physical examination the pa-tient was afebrile with a blood pres-sure of 132/80 mm Hg, a resting pulse

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Author Affiliation: Division of Nephrology, Depart-ment of Medicine, Johns Hopkins University Schoolof Medicine, Baltimore, Md.Corresponding Author: Derek M. Fine, MD, Divisionof Nephrology, Department of Medicine, Johns Hop-kins University School of Medicine, 1830 E Monu-ment St, Suite 416, Baltimore, MD 21205 ([email protected]).Grand Rounds at The Johns Hopkins Bayview Medi-cal Center Section Editors: John H. Stone, MD, MPH,Charles Weiner, MD, Stephen D. Sisson, MD, The JohnsHopkins Hospital, Baltimore, Md; David S. Cooper, MD,Contributing Editor, JAMA.

Kidney involvement is common in systemic lupus erythematosus, occurringin up to 60% of affected adults during the course of their disease. Diffuseproliferative lupus nephritis (World Health Organization class IV), the mostominous variant, has traditionally been treated with cyclophosphamide andglucocorticoids. With cyclophosphamide, women of childbearing potentialmust weigh the risks of sustained amenorrhea, infertility, increased suscep-tibility to infection, bone marrow suppression, hemorrhagic cystitis, and ma-lignancy against the benefits of better disease control compared with glu-cocorticoids alone. Because of the host of adverse effects associated withcyclophosphamide, alternative approaches to the treatment of lupus nephri-tis are desirable. A 31-year-old woman developed class IV lupus nephritisin the postpartum period. Seeking to preserve fertility and avoid other knowntoxicities of cyclophosphamide, she chose to undergo therapy with myco-phenolate mofetil. In the treatment of severe lupus nephritis, mycopheno-late mofetil has emerged as an alternative to cyclophosphamide, offering amajor advance in the therapy of lupus nephritis.JAMA. 2005;293:3053-3060 www.jama.com

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of 80/min, and a respiratory rate of12/min. She had thinning hair and a ma-lar rash, but her skin was otherwiseclear. Her cardiac examination re-vealed a regular rate and rhythm, nor-mal S1 and S2, and no murmurs. Herlungs were clear to auscultation. Therewas no organomegaly, and she had noclubbing, cyanosis, edema, or arthritisin her extremities. The neurological ex-amination was normal. Additional labo-ratory results were notable for a se-rum creatinine level of 1.1 mg/dL (97.2µmol/L) with a urine protein to creati-nine ratio of 2.5 mg protein/mg creati-nine (proteinuria approximately 2.5g/d). Microscopic examination of herurine showed 10 to 15 red blood cells/high power field, but no red cell casts.Further serological workup revealed an-tibodies to Ro and Sm.

A kidney biopsy was performed to de-termine the histological nature and se-verity of her renal process. However,given that her platelet count remainedlow, biopsy was delayed until after amethylprednisolone pulse, 1 g/d for 3days, followed by 60 mg/d of predni-sone. The methylprednisolone led to aplatelet count increase to greater than100�103/µL within 5 days, and the kid-neybiopsywasundertakenwithoutcom-

plications. Most of the 22 glomeruli inthe sample showed diffuse mesangial ex-pansion and proliferative changes, withmesangial and endocapillary prolifera-tion. There were segmental necrotizinglesions in 4 of the glomeruli and fibro-cellular crescents in 2, indicating signifi-cant activity (representative glomerulishown in FIGURE 1). In addition, im-munofluorescence revealed a “fullhouse” of immunoreactants, withgranular staining for IgG, IgA, C3, C1q,and � and � light chains. The biopsywas consistent with diffuse prolifera-tive (World Health Organization[WHO] class IV) glomerulonephritis.

A meeting including the patient, herhusband, the rheumatologist, and thenephrologists was convened to dis-cuss treatment options. Although cy-clophosphamide was considered thestandard of care in this setting, the pa-tient and her husband were con-cerned about the potential effects of thatmedication on fertility, the risk of ma-lignancy, and the possible infectiousconsequences of severe immunosup-pression. In light of these concerns,treatment with mycophenolate mofetilwas considered. Presented with a bal-anced discussion of the data now avail-able on the use of mycophenolate

mofetil in lupus nephritis, Mrs P choseto undergo therapy with mycopheno-late mofetil.

DISCUSSIONMrs P’s presentation is instructive be-cause it highlights the fact that SLE candevelop during or after pregnancy andthat it can mimic preeclampsia and theHELLP syndrome. Her case also dem-onstrates how to approach difficulttherapeutic issues by involving the pa-tient in the decision-making process. InMrs P’s case, the particular concern re-lated to the potential for both short- andlong-term adverse effects of cyclophos-phamide, particularly those related tofertility. The choice was between a stan-dard medication associated with sub-stantial risks of toxicity and a neweragent with a limited track record. Hercase illustrates emerging data thatstrongly support mycophenolate mofetilas an alternative to cyclophosphamidein the treatment of lupus nephritis.

The diagnosis of SLE was suspectedin this patient when she developed amalar rash, alopecia, arthralgias, andworsening fatigue, accompanied bythrombocytopenia and hemolytic ane-mia. The diagnosis was confirmed bypositive assays for ANAs, antibodies to

Figure 1. Light Microscopic Findings of Representative Glomeruli

BA Fibrocellular Crescent

A, Hyperlobulated glomerulus with global involvement with endocapillary and mesangial hypercellularity with matrix expansion (white arrowheads) and wireloop le-sions (black arrowheads). B, Glomerulus with global endocapillary proliferation, leukocyte influx, mesangial expansion, and crescent formation (hematoxylin-eosinstain; original magnification x 400).

PHARMACOLOGICAL THERAPY OF LUPUS NEPHRITIS

3054 JAMA, June 22/29, 2005—Vol 293, No. 24 (Reprinted) ©2005 American Medical Association. All rights reserved.


double-stranded DNA (dsDNA), andthe findings of her renal biopsy. Herpresentation was confusing becauseboth preeclampsia and the HELLP syn-drome can mimic SLE closely, and herstage of pregnancy corresponded pre-cisely to the time at which these enti-ties occur. The persistence of her clini-cal and laboratory abnormalities formonths during the postpartum periodwere consistent with SLE as the solecause of her presentation during preg-nancy. In the absence of postpartumcomplications, for example, the plate-let counts in the HELLP syndrome nor-mally rebound toward normal within1 week of delivery.1 The confusion inthe postpartum period was com-pounded further by her developmentof cardiomyopathy. Although post-partum cardiomyopathy is certainly apossible explanation, her cardiacdysfunction may also have beenrelated to her SLE.2,3 Moreover, SLE-related cardiomyopathy has also beenreported in the postpartum period.4

Systemic lupus erythematosus cardi-omyopathy, like postpartum cardio-myopathy, may be associated with awaxing and waning course and spon-taneous resolution.

Kidney Involvement in SLE

The kidney is a major target organ ofSLE. Up to 60% of patients with SLEwill develop renal manifestations atsome point in their course, with 25%to 50% presenting with kidney involve-ment early.5 The clinical presentationof kidney involvement is highly vari-able, ranging from mild asymptomaticproteinuria to rapidly progressive glo-merulonephritis. Features generallyinclude varying degrees of glomerularinvolvement with proteinuria—nephrotic in 45% to 65% of cases5—aswell as hematuria with red cell castsand/or acute renal failure.

The histopathologic manifestationsof lupus nephritis are classified into sev-eral categories designated by the WHOclassification. These criteria have un-dergone several revisions, the most re-cent of which evolved under the aus-pices of both the International Society

of Nephrology and the Renal Pathol-ogy Society.6 The general structure in-cludes 6 principal pathological pat-terns (classes I-VI) (TABLE 1).

The focal and diffuse proliferativeforms of lupus nephritis (classes III andIV, respectively) are distinguished fromeach other only by the percentage ofglomeruli involved. These renal le-sions generally present with micro-scopic hematuria with or without redblood cell casts, varying degrees of pro-teinuria, and progressive renal failure.In contrast, the membranous lesion(class V) typically presents with ne-phrotic-range proteinuria. Several stud-ies, however, have illustrated the un-reliability of diagnoses rendered on thebasis of clinical features alone.8-10 Be-cause the optimal treatment varies withthe type of glomerular disease, kidneybiopsy should be performed to make adefinitive diagnosis.11,12 In addition tohistopathologic confirmation of theWHO class, biopsy provides impor-tant prognostic information by permit-ting the pathologist to assess both ac-tivity and chronicity.13,14

Histological activity and chronicityscores have been developed to allow forimproved prediction of the progres-sion of lupus nephritis.15 Of the fea-tures indicating activity, the presence ofcellular crescents13,15,16 and fibrinoid ne-crosis15 appear to have the highest pre-dictive value for poorer outcome. Whenusing the chronicity index, which in-cludes features such as glomerular scle-rosis and interstitial fibrosis, a higher

score is associated with a worse prog-nosis.15,17,18 The absence of chronicchanges is particularly informative asthese patients have an excellent prog-nosis.19 Therefore, when chronicity islimited, therapeutic interventions arelikely to have maximum benefit.

In Mrs P’s case, the presence of anelevation of her creatinine level withhematuria and moderate levels of pro-teinuria suggested most likely thepresence of a class III or IV prolifera-tive lesion, although without biopsythese could not be distinguished. Par-ticularly important was the need todetermine the severity of the activity,as the clinical presentation associatedwith mild histopathologic activity canbe very similar to one seen with moreactive histopathology earlier in itsdevelopment. Indeed, in this case,despite relatively mild clinical fea-tures, significant disease activity waspresent.

The differential diagnosis of kidneyinvolvement in SLE extends beyond theWHO classification to include renalthrombotic microangiopathy, usuallyrelated to presence of antiphospho-lipid antibodies, which may be pres-ent in 15% to 90% of SLE patients.20

Other nonlupus causes of kidney dis-ease that may affect a person of simi-lar age or sex (eg, IgA nephropathy, thinbasement membrane disease) mustalso be considered. The differentia-tion of these disorders is once again en-hanced by performance of a kidneybiopsy.

Table 1. Classification and Treatment of the Different Forms of Lupus Nephritis

WHOClass* Description

ImmunosuppressionRecommendations†

I Minimal mesangial lupus nephritis No specific therapy

II Mesangial proliferative lupus nephritis No specific therapy

III Focal (proliferative) lupus nephritis Mild: none or glucocorticoids

Severe: see treatment for class IV below

IV Diffuse (proliferative) lupus nephritis Induction (6 mo): cyclophosphamide ormycophenolate mofetil

Maintenance: mycophenolate mofetil orazathioprine

V Membranous lupus nephritis Glucocorticoid with or without cyclosporine

VI Advanced sclerosing lupus nephritis No specific therapyAbbreviation: WHO, World Health Organization.*Subclasses omitted (see Weening et al6 for full classification).†Recommendations derived from Rose et al.7




Current Treatment Optionsin Lupus NephritisThe optimal treatment regimen7 in lu-pus nephritis varies according to WHOclass5,14 (Table 1). Patients with themildest forms of lupus nephritis (WHOclass I or II) generally do well withoutspecific intervention. In the absenceof appropriate immunosuppressivetherapy, however, the proliferativeforms (class III and IV) of lupus ne-phritis typically progress to chronic re-nal failure.21 The benefits of early treat-ment are well documented.22 This hasled to a propensity to treat all patientswith proliferative lesions regardless ofseverity. In patients such as Mrs P, whohave the most severe forms of lupus ne-phritis, aggressive immunosuppres-sive therapy is warranted.

Cyclophosphamide in theTreatment of Lupus Nephritis

Early treatment regimens for class IVlupus nephritis involved predomi-nantly the use of high-dose glucocor-ticoids. Remissions on low doses weredifficult to maintain, and most pa-tients required high doses of glucocor-ticoids for long periods of time toachieve control of the disease. Due tothe significant toxicity and poor long-term outcome, the search for moreeffective and glucocorticoid-sparingregimens began. In early trials, cyclo-phosphamide in combination with glu-cocorticoids demonstrated improved re-nal survival over glucocorticoid therapyalone23 and achieved lower rates of re-currence.24 Intravenous cyclophospha-mide became preferred over the oralagent due to perceived lower levels oftoxicity. Subsequent studies showedthat longer duration of therapy duringthe maintenance phase improved re-mission rates.25

Based on investigations conducted atthe National Institutes of Health (NIH)over the past 20 years,23,25-27 intrave-nous cyclophosphamide became thestandard therapy for class IV lupus ne-phritis.28 Had Mrs P undergone therapywith this agent, she would have re-ceived cyclophosphamide in an intra-venous form as a bolus in combina-

tion with glucocorticoid therapy.Following the protocol popularized bythe NIH investigators, intravenous cy-clophosphamide is used as inductiontherapy, administered monthly at a doseof 0.5 to 1 g/m2 of body surface area for6 months. During the maintenancephase, cyclophosphamide is adminis-tered at the same dose as inductiontherapy for 4 to 6 additional cycles. In-travenous methylprednisolone treat-ment (1 g/d for 3 days) is frequently ad-ministered at initiation of therapy,followed by tapering oral doses start-ing at 0.5 to 1.0 mg/kg/d. Based on stud-ies that have evaluated the efficacy ofintermittent glucocorticoid pulses,many patients also receive monthlymethylprednisolone pulses on thesame day they receive cyclophospha-mide.27,29

Cyclophosphamide Toxicity

Mrs P’s concerns about the potentialtoxicities of cyclophosphamide and herdesire to avoid the drug were wellfounded. Immediate toxicity of pulsecyclophosphamide includes nausea,vomiting, hair loss, and fatigue. Majortoxicities include cytopenias, serious in-fections, hemorrhagic cystitis, malig-nancy, and, of great importance to thispatient, gonadal failure.30 Serious in-fections are common in SLE, and deathfrom infection correlates with therecent use of glucocorticoids andcyclophosphamide.30,31

Although their renal outcomes weresignificantly improved and they hadreduced glucocorticoid exposure,patients treated with cyclophospha-mide under NIH protocol had moreadverse effects in both short- and long-term follow-up when compared withglucocorticoids alone.27,29 Mortality was7.4%27 with initial cyclophosphamideadministration(meanfollow-up,5years)and 19% at a median 11 years of follow-up,29 compared with 0% and 4%, respec-tively, in the glucocorticoid treatmentarm. These high mortality rates with theuse of cyclophosphamide, insuffi-ciently acknowledged in some reviews,must be considered when contemplat-ing theuseofcyclophosphamide. Itmust

also be recognized, however, that ear-lier trials of cyclophosphamide usedhigher doses for longer durations thanthe current standard regimens. Amongpatients treated with cyclophospha-mide in one study, 26% developed infec-tion compared with 7% in the glucocor-ticoid group.27 However, there was nodifference in infection rates on long-term follow-up, although trends con-sistently showhigher infectionrateswithcyclophosphamide treatment. This isillustratedbythehigher incidenceofher-pes zoster infection in 15% of patients(vs 4% with glucocorticoids) and cer-vical dysplasia in 11% of patients (vs 0%with glucocorticoids). Other notablecomplications during treatment includethe development of avascular necrosisin 11% of patients (vs 22% with gluco-corticoids alone). However, the onlyadverse effect to achieve statistical sig-nificance between the cyclophospha-mideandglucocorticoidonlygroupswasamenorrhea (52% vs 10%; P�.001).27

Cyclophosphamideand Ovarian Failure

The devastating complication of go-nadal failure is well described with theNIH regimen, with rates of ovarian fail-ure ranging from 26% to 52%.27,32,33 Therisk of toxicity increases with both doseand duration of cyclophosphamidetherapy. Moreover, amenorrhea is morelikely to occur in older women.Boumpas et al33 found that 12% of thosetreated with 7 monthly cyclophospha-mide doses developed amenorrhea,compared with 39% of those who re-ceived more than 14 doses (P=.07).Rates also increased with older age, withonly 12% of patients 25 years oryounger developing sustained amen-orrhea, compared with 27% of pa-tients 26 to 30 years old and 62% of pa-tients older than 30 years (P= .04).Although young women may not de-velop ovarian failure at rates as high inshort-term follow-up, they are likely toexperience menopause earlier. In an ex-tended follow-up of up to 11 years ofan earlier NIH cohort,27 60% of thosetreated with cyclophosphamide devel-oped amenorrhea.




Preservation of ovarian function byinducing gonadal quiescence with go-nadotropin-releasing hormone antago-nists has been recommended.34,35 Al-though no large studies have beenperformed, several small studies sug-gest that these agents have the poten-tial to prevent ovarian failure.34,36-38 Thelargest study in SLE patients involved36 women treated with cyclophospha-mide. Chronic amenorrhea occurred in11% of those treated with concomi-tant leuprolide and 39% of those with-out it (P=.06). The most serious ad-verse effect of leuprolide is the potentialfor bone mineral density loss caused byrelative estrogen deficiency.35 Underideal circumstances, leuprolide is ad-ministered 3 to 4 weeks before the firstdose of cyclophosphamide, but in thepresence of acute, life-threatening dis-ease, this is usually not an option. Insuch instances, leuprolide may be givencloser to the first dose.35 Other op-tions include oocyte cryopreservationor preservation of fertilized eggs. Thesealternatives also suffer from the timeconstraints necessary for the induc-tion of hyperovulation.

Need for Non–Cyclophosphamide-Based Regimens

Although many patients with prolif-erative lupus nephritis achieve remis-sions with the current cyclophospha-mide regimens, there remain significantnumbers of treatment failure and re-nal disease relapses. In view of the fail-ure of cyclophosphamide-based regi-mens to induce lasting remissions inmany patients and the substantial tox-icity associated with this medication,the development of alternative ap-proaches to treatment is essential. In arecent study39 in which women wereasked about hypothetical treatmentpreferences, 98% stated that they wouldchoose azathioprine over cyclophos-phamide if the 2 medications were con-sidered equally effective. Even given atheoretical probability of renal sur-vival of 100% at 5 years with cyclo-phosphamide, a substantial minority of31% would still have preferred azathio-prine, given the risk of ovarian failure

with cyclophosphamide.39 Although al-ternatives to cyclophosphamide havebeen assessed, until the introduction ofmycophenolate mofetil, none hadshown the potential to rival cyclophos-phamide in efficacy while surpassing itin safety.

Use of Mycophenolate Mofetil inthe Treatment of Lupus Nephritis

Mycophenolate mofetil is metabo-lized to the active immunosuppres-sant mycophenolic acid. Through theinhibition of the enzyme inosine mono-phosphate dehydrogenase by its me-tabolite, mycophenolate mofetil blocksde novo synthesis of purines, a path-way essential for the synthesis of DNAin lymphocytes.40 Through this mecha-nism, it inhibits B and T cell prolifera-tion, antibody formation, and genera-tion of cytotoxic T cells. In addition,mycophenolate mofetil inhibits the ex-pression of adhesion molecules on en-dothelial cells41 and down-regulates me-sangial cell proliferation.41

Due to its history as an immunosup-pressant in solid-organ transplanta-tion, mycophenolate mofetil gener-ated interest as a possible therapy forlupus nephritis. The use of mycophe-nolate mofetil in the treatment of hu-man glomerular disease was pio-neered by Briggs and colleagues,42 whotreated 2 patients with proliferative lu-pus nephritis effectively with myco-phenolate mofetil. Dooley and col-leagues43 subsequently reported a seriesof 13 patients with lupus nephritis, 12of whom had class IV disease, who didnot respond to cyclophosphamidetherapy. In that series, only 1 patientexperienced an elevation in serum cre-atinine level over the course of thestudy; 2 patients had increasing pro-teinuria. Adverse effects reported in-cluded pancreatitis (n=1), herpes sim-plex stomatitis associated with severeleukopenia (n=1), pneumonia with-out leukopenia (n=1), asymptomaticleukopenia (n = 2), and nausea/diarrhea (n=2). Based on the appar-ent success in this and other reports inaddition to a potentially more limitedadverse effect profile (TABLE 2),44-47 ran-

domized trials began. Two trials that as-sessed the role of mycophenolatemofetil in remission induction and onethat evaluated the use of mycopheno-late mofetil as a remission mainte-nance agent are discussed below. All 3of these investigations were random-ized, but not blinded.

Mycophenolate Mofetiland Induction Therapyfor Lupus Nephritis

The first randomized trial of inductiontherapy with mycophenolate mofetilwas conducted in Hong Kong.48 Forty-two patients with diffuse proliferativelupus nephritis (WHO class IV) wereassigned to receive either mycopheno-late mofetil (1 g twice a day) or oralcyclophosphamide (2.5 mg/kg/d).Patients in both treatment arms receivedprednisolone (starting dose 0.8 mg/kg/dtapered to 10 mg/d by 6 months). Formaintenance therapy during the sec-ond 6 months of therapy, the patientstreated with mycophenolate mofetil hada 50% reduction of their dose and thepatients treated with cyclophospha-mide were switched to azathioprine (2.5mg/kg/d). Both groups continued tak-ing prednisolone at low to moderatedoses. Complete remission, defined asa stable serum creatinine level (�15%above baseline), normal urine sedi-ment, and less than 0.3 g/d of protein-uria, was achieved in 81% of thosetreated with mycophenolate mofetil and76% of those treated with oral cyclo-phosphamide (P�.99)(TABLE 3). The

Table 2. Selected Adverse ReactionsReported in More Than 10% of PatientsTreated With Mycophenolate Mofetil*

AdverseReaction

Frequencyin TreatmentGroups, %

Frequencyin PlaceboGroups, %

Abdominal pain 12-28 11Diarrhea 16-36 14Vomiting 13-14 . . .Infection† 18-21 14Urinary tract

infection37-46 . . .

Leukopenia 12-35 4Anemia 25 . . .*Ellipses indicates comparative placebo data not reported.†Most common in transplant patients receiving combina-

tion immunosuppression (includes cytomegalovirus, her-pes zoster, and mucocutaneous fungal infections).44-47




frequency of severe adverse effects wasgreater in the cyclophosphamide group,including death (10%) and amenor-rhea (23%), compared with none ofeither in the mycophenolate mofetilgroup. It is important to recognize thatin this trial, oral cyclophosphamide wasused, contrary to the intravenous routeof administration according to the NIHregimen. Nevertheless, the equal effi-cacy of the less toxic drug, mycophe-nolate mofetil, has been a major advancein defining its role in the treatment ofsevere lupus nephritis.

A more recent study49 presented inabstract form compared remission in-duction with mycophenolate mofetil toconventional intravenous cyclophos-phamide (Table 3). In this multi-center trial based in the United States,140 patients were randomized to re-ceive treatment with intravenous cy-clophosphamide or mycophenolatemofetil, with a target dose of mycophe-

Table 3. Summary of Major Mycophenolate Mofetil Trial Outcomes

SourceNo. of Subjectsand Follow-up Treatment Regimen Primary Outcome Toxicity

Chan et al,48

200042

21 Mycophenolate mofetil21 Cyclophosphamide

1 y follow-up

Induction mycophenolatemofetil vs oralcyclophosphamide(see text)

Mycophenolate mofetil:Complete remission, 81%*Partial remission, 14%†Relapse, 15%

Cyclophosphamide:Complete remission, 76%*Partial remission, 14%†Relapse, 11%

Mycophenolate mofetil:Amenorrhea, 0%Severe infection, 19%Leukopenia, 0%Death, 0%

Cyclophosphamide:Amenorrhea, 23%Severe infection, 33%Leukopenia, 10%Death, 10%

Appel et al,49

2003140

71 Mycophenolate mofetil69 Cyclophosphamide

24-wk outcome

Induction mycophenolatemofetil vs intravenouscyclophosphamide

Mycophenolate mofetil:Complete remission,

21%‡§Partial remission, 29%||

Cyclophosphamide:Complete remission, 6%‡§Partial remission, 25%||

Mycophenolate mofetil:Amenorrhea, no data yet

reportedSevere infection, 6%

Cyclophosphamide:Amenorrhea, no data yet

reportedSevere infection, 13%

Contreras et al,50

200459

20 Mycophenolate mofetil19 Azathioprine20 Cyclophosphamide

1- to 5-y follow-up(cumulative rates)

Maintenance mycophenolatemofetil vs azathioprinevs intravenouscyclophosphamide(after intravenouscyclophosphamideinduction in both)

Mycophenolate mofetil:Chronic renal failure, 95%¶Renal relapse, 15%#§

Cyclophosphamide:Chronic renal failure, 74%¶Renal relapse, 40%#§

Mycophenolate mofetil:Amenorrhea, 6%§Major infection, 2%§Leukopenia, 2%Death, 5%

Cyclophosphamide:Amenorrhea, 32%§Major infection, 25%§Leukopenia, 10%Death, 20%

*Complete remission: less than 0.3 g/d protein, normal serum albumin, normal urine sediment, creatinine no more than 15% above baseline.†Partial remission: 0.3-2.9 g/d protein, albumin level greater than 3.0 g/dL.‡Complete remission: urine protein less than 0.5 g/d and normal sediment, serum creatinine level normal.§P�.05.||Partial remission: more than 50% improvement.¶Doubling of the nadir serum creatinine level or the development of end-stage renal disease.#Doubling of urine protein:creatinine ratio or increase in serum creatinine level of at least 50%.

Figure 2. Mrs P’s Urine Protein Changes and Glucocorticoid Tapering Over the First9 Months of Treatment With Mycophenolate Mofetil

Pro

tein

uria

(Ran

dom

Urin

e: m

g P

rote

in/m

g C

reat

inin

e)

1

2

3

4

5

6

7

8

9

03/1/2004 6/1/2004 12/1/20049/1/2004

Date of Assessment

Intravenous Methylprednisolone 1 g/d for 3 d

Mycophenolate Mofetil 1g Twice Daily

60 55 40 30 25 17.5 15 12.5 10 7.5 5 2.5

Prednisone

mg/d




nolate mofetil (1500 mg twice daily)higher than that used in the Hong Kongstudy.48 The rationale for the higher my-cophenolate mofetil dose was evi-dence in the transplantation literaturethat African Americans, who com-prised 56% of the trial cohort in the USstudy, require higher doses of myco-phenolate mofetil than whites.51 Al-though mycophenolate mofetil wassuperior to cyclophosphamide in re-mission induction, the preliminary datashowed much lower rates of remis-sion with induction than in the HongKong trial. Only 21% of those receiv-ing mycophenolate mofetil and 6% ofthose receiving cyclophosphamideachieved complete remissions in the USstudy (P=.005). Some of the disparitybetween the 2 studies can be explainedby racial differences between the co-horts (black race predicts poorer out-come in class IV lupus nephritis52,53).There may also have been differences inthe histological severity and clinical se-verity of disease in the 2 trials. Other po-tential explanations include the route oftherapy (intravenous vs oral) and thedoses of glucocorticoids used. The defi-nitions of remission were similar andprobably cannot explain the differ-ences seen. Because detailed data fromthe latter trial are not available, these ex-planations remain speculative.

Mycophenolate Mofetiland Maintenance Therapy

Another major trial recently evaluatedthe use of mycophenolate mofetil in re-mission maintenance.50 After induc-tion with 4 to 7 months of 0.5 to 1 g/m2

of intravenous cyclophosphamide, pa-tients were randomized to 1 of 3 treat-ment groups (Table 3): quarterly in-travenous cyclophosphamide, daily oralmycophenolate mofetil, or daily oralazathioprine. Although the cumula-tive rate of renal survival did not differsignificantly between the groups, thosein the cyclophosphamide group had anincreased relapse rate compared withmycophenolate mofetil, increased mor-tality compared with azathioprine, andincreased drug-related morbidity com-pared with both the mycophenolate

mofetil and azathioprine groups. Al-though these results support the use ofmycophenolate mofetil (and azathio-prine) in maintenance therapy, there areseveral major limitations.54 First, thedefinition of remission—reduction inthe urine protein:creatinine ratio to lessthan 3 if nephrotic at enrollment, anda ratio 50% of baseline if subne-phrotic—was less stringent in compari-son to other trials. Second, many pa-tients did not reach a satisfactoryremission by the end of the inductionphase, which made it likely that theywould fare poorly with the same drug(cyclophosphamide) continued in themaintenance phase. Overall, the poorresponse to induction seen in this studycan in large part be accounted for bythe large proportion of Hispanic andblack patients (5% were white).52

CASE RESOLUTIONMrs P began receiving mycophenolatemofetil, 1000 mg twice daily in addi-tion to the 60 mg daily of prednisone.Within weeks, her serum creatininelevel had improved from 1.1 mg/dL(97.2 µmol/L) to 0.8 mg/dL (70.7µmol/L) and her thrombocytopenia hadresolved. Her hematocrit increased to35% and her complement levels nor-malized. After an initially sharp in-crease in proteinuria, within 3 months,her proteinuria had decreased to lessthan 1 g/mg creatinine (FIGURE 2).Prednisone was tapered and discontin-ued 5 months after the initiation of my-cophenolate mofetil. No longer takingprednisone for over 4 months, Mrs Phas maintained improved renal func-tion (serum creatinine level, 0.8 mg/dL[70.7 µmol/L]) and proteinuria (0.4g/mg creatinine), a stable hematocritand platelet count, and normocomple-mentemia. Mild fatigue and a minimalmalar rash remain her only currentsymptoms. We plan to complete 18months of maintenance therapy, basedon the experience when using cyclo-phosphamide. Because mycopheno-late mofetil is contraindicated in preg-nancy, future pregnancy could beconsidered after the maintenance courseif she remains in remission. Other ma-

jor issues surrounding the risk of fu-ture pregnancy—the risk of an SLEflare, preeclampsia, premature deliv-ery, or poor fetal outcome55-58—continue to be discussed with Mrs P ona regular basis.

CONCLUSIONMycophenolate mofetil has substan-tial appeal as a new approach to thetreatment of lupus nephritis. Addi-tional data related to the use of myco-phenolate mofetil, including long-term remission and relapse rates, ideallength of treatment, optimal glucocor-ticoid tapering, and long-term toxici-ties, are the subject of ongoing studies.For now, as Mrs P’s case demon-strates, mycophenolate mofetil is a rea-sonable option for many patients withlupus nephritis who seek a safer, effec-tive alternative to cyclophosphamide.

Financial Disclosures: None reported.Acknowledgment: I thank my patient for sharing herstory and Allan Gelber, MD, MPH, PhD, John Stone,MD, MPH, and Michael Choi, MD, for reading andimproving the manuscript.

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pharmacological therapy of lupus nephritis

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