Pharmacological Therapy of Lupus Nephritis
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GRAND ROUNDS CLINICIAN’S CORNER
AT THE JOHNS HOPKINS BAYVIEW MEDICAL CENTER
Pharmacological Therapy of Lupus Nephritis
Derek M. Fine, MD
Kidney involvement is common in systemic lupus erythematosus, occurring
CASE PRESENTATION in up to 60% of affected adults during the course of their disease. Diffuse
Mrs P, a 31-year-old woman, developed proliferative lupus nephritis (World Health Organization class IV), the most
a blood pressure of 170/104 mm Hg at ominous variant, has traditionally been treated with cyclophosphamide and
38 weeks of pregnancy. Her obstetri- glucocorticoids. With cyclophosphamide, women of childbearing potential
cian performed a laboratory evaluation must weigh the risks of sustained amenorrhea, infertility, increased suscep-
that revealed proteinuria (2⫹), throm- tibility to infection, bone marrow suppression, hemorrhagic cystitis, and ma-
bocytopenia (platelet count, 121⫻103/µL
lignancy against the benefits of better disease control compared with glu-
[normal range: 150-350⫻ 103/µL]), a
serum creatinine level of 0.8 mg/dL (70.7 cocorticoids alone. Because of the host of adverse effects associated with
µmol/L) (normal range: 0.4-1.1 mg/dL cyclophosphamide, alternative approaches to the treatment of lupus nephri-
[35.3-97.2 µmol/L]), uric acid level of 9.0 tis are desirable. A 31-year-old woman developed class IV lupus nephritis
mg/dL (normal range: 2.4-5.7 mg/dL), in the postpartum period. Seeking to preserve fertility and avoid other known
and aspartate and alanine aminotrans- toxicities of cyclophosphamide, she chose to undergo therapy with myco-
ferase levels of 170 U/L and 190 U/L, phenolate mofetil. In the treatment of severe lupus nephritis, mycopheno-
respectively (normal range: 0-35 U/L).
late mofetil has emerged as an alternative to cyclophosphamide, offering a
Mrs P was diagnosed with the HELLP
(hemolysis, elevated liver enzymes, low major advance in the therapy of lupus nephritis.
platelets) syndrome1 and underwent an JAMA. 2005;293:3053-3060 www.jama.com
emergent cesarean delivery of a healthy
male newborn. Despite this interven- quent 2 months. Her transient conges- At the time of Mrs P’s nephrology
tion, Mrs P continued to have thrombo- tive heart failure was attributed to post- evaluation, her medications included
cytopenia and hypertension. In addi- partum cardiomyopathy. Five months candesartan (32 mg/d) and metopro-
tion, she developed temperatures up to after delivery, she presented with fe- lol succinate (150 mg/d). The family
102° F. She was treated empirically with ver, fatigue, arthralgias, malar rash, a medical history was noncontributory.
antibiotics and received heparin briefly papular eruption on her forearms, and She had previously worked as a neo-
for a presumptive diagnosis of pelvic alopecia. Her platelet count was still low natal nurse and did not smoke or drink.
thrombophlebitis. Fevers continued and (69 ⫻ 103/µL) and she remained ane- Her child was now 6 months old; she
she developed weakness and fatigue. mic (hematocrit, 26% [normal range: and her husband were eager to have
Four months after delivery, she de- 38%-47%]). These findings prompted more children.
veloped progressive dyspnea on exer- a serological workup that revealed high On physical examination the pa-
tion and orthopnea. Echocardiogra- titer positive assay for antinuclear an- tient was afebrile with a blood pres-
phy revealed an ejection fraction of tibodies (ANAs) and antibodies to sure of 132/80 mm Hg, a resting pulse
30%. Therapy was initiated with an an- double-stranded DNA (dsDNA). Her se-
Author Affiliation: Division of Nephrology, Depart-
giotensin-converting enzyme inhibi- rum complement levels were low, with ment of Medicine, Johns Hopkins University School
tor and a loop diuretic, with resolu- the C3 and C4 complements measur- of Medicine, Baltimore, Md.
ing 43 mg/dL (normal range: 79-152 Corresponding Author: Derek M. Fine, MD, Division
tion of her symptoms and normalization of Nephrology, Department of Medicine, Johns Hop-
of her cardiac function over the subse- mg/dL) and 5 mg/dL (normal range: kins University School of Medicine, 1830 E Monu-
12-42 mg/dL), respectively. Her eryth- ment St, Suite 416, Baltimore, MD 21205 (dfine1
@jhmi.edu).
See also Patient Page. rocyte sedimentation rate was el- Grand Rounds at The Johns Hopkins Bayview Medi-
evated at 107 mm/h (normal range: 4-25 cal Center Section Editors: John H. Stone, MD, MPH,
CME available online at mm/h). The diagnosis of systemic lu- Charles Weiner, MD, Stephen D. Sisson, MD, The Johns
www.jama.com Hopkins Hospital, Baltimore, Md; David S. Cooper, MD,
pus erythematosus (SLE) was made. Contributing Editor, JAMA.
©2005 American Medical Association. All rights reserved. (Reprinted) JAMA, June 22/29, 2005—Vol 293, No. 24 3053PHARMACOLOGICAL THERAPY OF LUPUS NEPHRITIS of 80/min, and a respiratory rate of plications. Most of the 22 glomeruli in mofetil in lupus nephritis, Mrs P chose 12/min. She had thinning hair and a ma- the sample showed diffuse mesangial ex- to undergo therapy with mycopheno- lar rash, but her skin was otherwise pansion and proliferative changes, with late mofetil. clear. Her cardiac examination re- mesangial and endocapillary prolifera- vealed a regular rate and rhythm, nor- tion. There were segmental necrotizing DISCUSSION mal S1 and S2, and no murmurs. Her lesions in 4 of the glomeruli and fibro- Mrs P’s presentation is instructive be- lungs were clear to auscultation. There cellular crescents in 2, indicating signifi- cause it highlights the fact that SLE can was no organomegaly, and she had no cant activity (representative glomeruli develop during or after pregnancy and clubbing, cyanosis, edema, or arthritis shown in FIGURE 1). In addition, im- that it can mimic preeclampsia and the in her extremities. The neurological ex- munofluorescence revealed a “full HELLP syndrome. Her case also dem- amination was normal. Additional labo- house” of immunoreactants, with onstrates how to approach difficult ratory results were notable for a se- granular staining for IgG, IgA, C3, C1q, therapeutic issues by involving the pa- rum creatinine level of 1.1 mg/dL (97.2 and and light chains. The biopsy tient in the decision-making process. In µmol/L) with a urine protein to creati- was consistent with diffuse prolifera- Mrs P’s case, the particular concern re- nine ratio of 2.5 mg protein/mg creati- tive (World Health Organization lated to the potential for both short- and nine (proteinuria approximately 2.5 [WHO] class IV) glomerulonephritis. long-term adverse effects of cyclophos- g/d). Microscopic examination of her A meeting including the patient, her phamide, particularly those related to urine showed 10 to 15 red blood cells/ husband, the rheumatologist, and the fertility. The choice was between a stan- high power field, but no red cell casts. nephrologists was convened to dis- dard medication associated with sub- Further serological workup revealed an- cuss treatment options. Although cy- stantial risks of toxicity and a newer tibodies to Ro and Sm. clophosphamide was considered the agent with a limited track record. Her A kidney biopsy was performed to de- standard of care in this setting, the pa- case illustrates emerging data that termine the histological nature and se- tient and her husband were con- strongly support mycophenolate mofetil verity of her renal process. However, cerned about the potential effects of that as an alternative to cyclophosphamide given that her platelet count remained medication on fertility, the risk of ma- in the treatment of lupus nephritis. low, biopsy was delayed until after a lignancy, and the possible infectious The diagnosis of SLE was suspected methylprednisolone pulse, 1 g/d for 3 consequences of severe immunosup- in this patient when she developed a days, followed by 60 mg/d of predni- pression. In light of these concerns, malar rash, alopecia, arthralgias, and sone. The methylprednisolone led to a treatment with mycophenolate mofetil worsening fatigue, accompanied by platelet count increase to greater than was considered. Presented with a bal- thrombocytopenia and hemolytic ane- 100⫻103/µL within 5 days, and the kid- anced discussion of the data now avail- mia. The diagnosis was confirmed by ney biopsy was undertaken without com- able on the use of mycophenolate positive assays for ANAs, antibodies to Figure 1. Light Microscopic Findings of Representative Glomeruli A B 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-eosin stain; original magnification x 400). 3054 JAMA, June 22/29, 2005—Vol 293, No. 24 (Reprinted) ©2005 American Medical Association. All rights reserved.
PHARMACOLOGICAL THERAPY OF LUPUS NEPHRITIS
double-stranded DNA (dsDNA), and
Table 1. Classification and Treatment of the Different Forms of Lupus Nephritis
the findings of her renal biopsy. Her
WHO Immunosuppression
presentation was confusing because Class* Description Recommendations†
both preeclampsia and the HELLP syn- I Minimal mesangial lupus nephritis No specific therapy
drome can mimic SLE closely, and her II Mesangial proliferative lupus nephritis No specific therapy
stage of pregnancy corresponded pre- III Focal (proliferative) lupus nephritis Mild: none or glucocorticoids
cisely to the time at which these enti- Severe: see treatment for class IV below
ties occur. The persistence of her clini- IV Diffuse (proliferative) lupus nephritis Induction (6 mo): cyclophosphamide or
cal and laboratory abnormalities for mycophenolate mofetil
months during the postpartum period Maintenance: mycophenolate mofetil or
azathioprine
were consistent with SLE as the sole
V Membranous lupus nephritis Glucocorticoid with or without cyclosporine
cause of her presentation during preg-
VI Advanced sclerosing lupus nephritis No specific therapy
nancy. In the absence of postpartum Abbreviation: WHO, World Health Organization.
complications, for example, the plate- *Subclasses omitted (see Weening et al6 for full classification).
†Recommendations derived from Rose et al.7
let counts in the HELLP syndrome nor-
mally rebound toward normal within
1 week of delivery.1 The confusion in of Nephrology and the Renal Pathol- score is associated with a worse prog-
the postpartum period was com- ogy Society.6 The general structure in- nosis.15,17,18 The absence of chronic
pounded further by her development cludes 6 principal pathological pat- changes is particularly informative as
of cardiomyopathy. Although post- terns (classes I-VI) (TABLE 1). these patients have an excellent prog-
partum cardiomyopathy is certainly a The focal and diffuse proliferative nosis.19 Therefore, when chronicity is
possible explanation, her cardiac forms of lupus nephritis (classes III and limited, therapeutic interventions are
dysfunction may also have been IV, respectively) are distinguished from likely to have maximum benefit.
related to her SLE.2,3 Moreover, SLE- each other only by the percentage of In Mrs P’s case, the presence of an
related cardiomyopathy has also been glomeruli involved. These renal le- elevation of her creatinine level with
reported in the postpartum period.4 sions generally present with micro- hematuria and moderate levels of pro-
Systemic lupus erythematosus cardi- scopic hematuria with or without red teinuria suggested most likely the
omyopathy, like postpartum cardio- blood cell casts, varying degrees of pro- presence of a class III or IV prolifera-
myopathy, may be associated with a teinuria, and progressive renal failure. tive lesion, although without biopsy
waxing and waning course and spon- In contrast, the membranous lesion these could not be distinguished. Par-
taneous resolution. (class V) typically presents with ne- ticularly important was the need to
phrotic-range proteinuria. Several stud- determine the severity of the activity,
Kidney Involvement in SLE ies, however, have illustrated the un- as the clinical presentation associated
The kidney is a major target organ of reliability of diagnoses rendered on the with mild histopathologic activity can
SLE. Up to 60% of patients with SLE basis of clinical features alone.8-10 Be- be very similar to one seen with more
will develop renal manifestations at cause the optimal treatment varies with active histopathology earlier in its
some point in their course, with 25% the type of glomerular disease, kidney development. Indeed, in this case,
to 50% presenting with kidney involve- biopsy should be performed to make a despite relatively mild clinical fea-
ment early.5 The clinical presentation definitive diagnosis.11,12 In addition to tures, significant disease activity was
of kidney involvement is highly vari- histopathologic confirmation of the present.
able, ranging from mild asymptomatic WHO class, biopsy provides impor- The differential diagnosis of kidney
proteinuria to rapidly progressive glo- tant prognostic information by permit- involvement in SLE extends beyond the
merulonephritis. Features generally ting the pathologist to assess both ac- WHO classification to include renal
include varying degrees of glomerular tivity and chronicity.13,14 thrombotic microangiopathy, usually
involvement with proteinuria— Histological activity and chronicity related to presence of antiphospho-
nephrotic in 45% to 65% of cases5—as scores have been developed to allow for lipid antibodies, which may be pres-
well as hematuria with red cell casts improved prediction of the progres- ent in 15% to 90% of SLE patients.20
and/or acute renal failure. sion of lupus nephritis.15 Of the fea- Other nonlupus causes of kidney dis-
The histopathologic manifestations tures indicating activity, the presence of ease that may affect a person of simi-
of lupus nephritis are classified into sev- cellular crescents13,15,16 and fibrinoid ne- lar age or sex (eg, IgA nephropathy, thin
eral categories designated by the WHO crosis15 appear to have the highest pre- basement membrane disease) must
classification. These criteria have un- dictive value for poorer outcome. When also be considered. The differentia-
dergone several revisions, the most re- using the chronicity index, which in- tion of these disorders is once again en-
cent of which evolved under the aus- cludes features such as glomerular scle- hanced by performance of a kidney
pices of both the International Society rosis and interstitial fibrosis, a higher biopsy.
©2005 American Medical Association. All rights reserved. (Reprinted) JAMA, June 22/29, 2005—Vol 293, No. 24 3055PHARMACOLOGICAL THERAPY OF LUPUS NEPHRITIS
Current Treatment Options tion with glucocorticoid therapy. also be recognized, however, that ear-
in Lupus Nephritis Following the protocol popularized by lier trials of cyclophosphamide used
The optimal treatment regimen7 in lu- the NIH investigators, intravenous cy- higher doses for longer durations than
pus nephritis varies according to WHO clophosphamide is used as induction the current standard regimens. Among
class5,14 (Table 1). Patients with the therapy, administered monthly at a dose patients treated with cyclophospha-
mildest forms of lupus nephritis (WHO of 0.5 to 1 g/m2 of body surface area for mide in one study, 26% developed infec-
class I or II) generally do well without 6 months. During the maintenance tion compared with 7% in the glucocor-
specific intervention. In the absence phase, cyclophosphamide is adminis- ticoid group.27 However, there was no
of appropriate immunosuppressive tered at the same dose as induction difference in infection rates on long-
therapy, however, the proliferative therapy for 4 to 6 additional cycles. In- term follow-up, although trends con-
forms (class III and IV) of lupus ne- travenous methylprednisolone treat- sistently show higher infection rates with
phritis typically progress to chronic re- ment (1 g/d for 3 days) is frequently ad- cyclophosphamide treatment. This is
nal failure.21 The benefits of early treat- ministered at initiation of therapy, illustrated by the higher incidence of her-
ment are well documented.22 This has followed by tapering oral doses start- pes zoster infection in 15% of patients
led to a propensity to treat all patients ing at 0.5 to 1.0 mg/kg/d. Based on stud- (vs 4% with glucocorticoids) and cer-
with proliferative lesions regardless of ies that have evaluated the efficacy of vical dysplasia in 11% of patients (vs 0%
severity. In patients such as Mrs P, who intermittent glucocorticoid pulses, with glucocorticoids). Other notable
have the most severe forms of lupus ne- many patients also receive monthly complications during treatment include
phritis, aggressive immunosuppres- methylprednisolone pulses on the the development of avascular necrosis
sive therapy is warranted. same day they receive cyclophospha- in 11% of patients (vs 22% with gluco-
mide.27,29 corticoids alone). However, the only
Cyclophosphamide in the adverse effect to achieve statistical sig-
Treatment of Lupus Nephritis Cyclophosphamide Toxicity nificance between the cyclophospha-
Early treatment regimens for class IV Mrs P’s concerns about the potential mide and glucocorticoid only groups was
lupus nephritis involved predomi- toxicities of cyclophosphamide and her amenorrhea (52% vs 10%; P⬍.001).27
nantly the use of high-dose glucocor- desire to avoid the drug were well
ticoids. Remissions on low doses were founded. Immediate toxicity of pulse Cyclophosphamide
difficult to maintain, and most pa- cyclophosphamide includes nausea, and Ovarian Failure
tients required high doses of glucocor- vomiting, hair loss, and fatigue. Major The devastating complication of go-
ticoids for long periods of time to toxicities include cytopenias, serious in- nadal failure is well described with the
achieve control of the disease. Due to fections, hemorrhagic cystitis, malig- NIH regimen, with rates of ovarian fail-
the significant toxicity and poor long- nancy, and, of great importance to this ure ranging from 26% to 52%.27,32,33 The
term outcome, the search for more patient, gonadal failure.30 Serious in- risk of toxicity increases with both dose
effective and glucocorticoid-sparing fections are common in SLE, and death and duration of cyclophosphamide
regimens began. In early trials, cyclo- from infection correlates with the therapy. Moreover, amenorrhea is more
phosphamide in combination with glu- recent use of glucocorticoids and likely to occur in older women.
cocorticoids demonstrated improved re- cyclophosphamide.30,31 Boumpas et al33 found that 12% of those
nal survival over glucocorticoid therapy Although their renal outcomes were treated with 7 monthly cyclophospha-
alone23 and achieved lower rates of re- significantly improved and they had mide doses developed amenorrhea,
currence.24 Intravenous cyclophospha- reduced glucocorticoid exposure, compared with 39% of those who re-
mide became preferred over the oral patients treated with cyclophospha- ceived more than 14 doses (P = .07).
agent due to perceived lower levels of mide under NIH protocol had more Rates also increased with older age, with
toxicity. Subsequent studies showed adverse effects in both short- and long- only 12% of patients 25 years or
that longer duration of therapy during term follow-up when compared with younger developing sustained amen-
the maintenance phase improved re- glucocorticoids alone.27,29 Mortality was orrhea, compared with 27% of pa-
mission rates.25 7.4%27 with initial cyclophosphamide tients 26 to 30 years old and 62% of pa-
Based on investigations conducted at administration (mean follow-up, 5 years) tients older than 30 years (P = .04).
the National Institutes of Health (NIH) and 19% at a median 11 years of follow- Although young women may not de-
over the past 20 years,23,25-27 intrave- up,29 compared with 0% and 4%, respec- velop ovarian failure at rates as high in
nous cyclophosphamide became the tively, in the glucocorticoid treatment short-term follow-up, they are likely to
standard therapy for class IV lupus ne- arm. These high mortality rates with the experience menopause earlier. In an ex-
phritis.28 Had Mrs P undergone therapy use of cyclophosphamide, insuffi- tended follow-up of up to 11 years of
with this agent, she would have re- ciently acknowledged in some reviews, an earlier NIH cohort,27 60% of those
ceived cyclophosphamide in an intra- must be considered when contemplat- treated with cyclophosphamide devel-
venous form as a bolus in combina- ing the use of cyclophosphamide. It must oped amenorrhea.
3056 JAMA, June 22/29, 2005—Vol 293, No. 24 (Reprinted) ©2005 American Medical Association. All rights reserved.PHARMACOLOGICAL THERAPY OF LUPUS NEPHRITIS
Preservation of ovarian function by with cyclophosphamide.39 Although al-
Table 2. Selected Adverse Reactions
inducing gonadal quiescence with go- ternatives to cyclophosphamide have Reported in More Than 10% of Patients
nadotropin-releasing hormone antago- been assessed, until the introduction of Treated With Mycophenolate Mofetil*
nists has been recommended.34,35 Al- mycophenolate mofetil, none had Frequency Frequency
though no large studies have been shown the potential to rival cyclophos- Adverse in Treatment in Placebo
Reaction Groups, % Groups, %
performed, several small studies sug- phamide in efficacy while surpassing it
Abdominal pain 12-28 11
gest that these agents have the poten- in safety. Diarrhea 16-36 14
tial to prevent ovarian failure.34,36-38 The Vomiting 13-14 ...
Use of Mycophenolate Mofetil in Infection† 18-21 14
largest study in SLE patients involved Urinary tract 37-46 ...
36 women treated with cyclophospha- the Treatment of Lupus Nephritis infection
Leukopenia 12-35 4
mide. Chronic amenorrhea occurred in Mycophenolate mofetil is metabo- Anemia 25 ...
11% of those treated with concomi- lized to the active immunosuppres- *Ellipses indicates comparative placebo data not reported.
tant leuprolide and 39% of those with- sant mycophenolic acid. Through the †Most common in transplant patients receiving combina-
tion immunosuppression (includes cytomegalovirus, her-
out it (P = .06). The most serious ad- inhibition of the enzyme inosine mono- pes zoster, and mucocutaneous fungal infections).44-47
verse effect of leuprolide is the potential phosphate dehydrogenase by its me-
for bone mineral density loss caused by tabolite, mycophenolate mofetil blocks
relative estrogen deficiency.35 Under de novo synthesis of purines, a path- domized trials began. Two trials that as-
ideal circumstances, leuprolide is ad- way essential for the synthesis of DNA sessed the role of mycophenolate
ministered 3 to 4 weeks before the first in lymphocytes.40 Through this mecha- mofetil in remission induction and one
dose of cyclophosphamide, but in the nism, it inhibits B and T cell prolifera- that evaluated the use of mycopheno-
presence of acute, life-threatening dis- tion, antibody formation, and genera- late mofetil as a remission mainte-
ease, this is usually not an option. In tion of cytotoxic T cells. In addition, nance agent are discussed below. All 3
such instances, leuprolide may be given mycophenolate mofetil inhibits the ex- of these investigations were random-
closer to the first dose.35 Other op- pression of adhesion molecules on en- ized, but not blinded.
tions include oocyte cryopreservation dothelial cells41 and down-regulates me-
or preservation of fertilized eggs. These sangial cell proliferation.41 Mycophenolate Mofetil
alternatives also suffer from the time Due to its history as an immunosup- and Induction Therapy
constraints necessary for the induc- pressant in solid-organ transplanta- for Lupus Nephritis
tion of hyperovulation. tion, mycophenolate mofetil gener- The first randomized trial of induction
ated interest as a possible therapy for therapy with mycophenolate mofetil
Need for Non–Cyclophosphamide- lupus nephritis. The use of mycophe- was conducted in Hong Kong.48 Forty-
Based Regimens nolate mofetil in the treatment of hu- two patients with diffuse proliferative
Although many patients with prolif- man glomerular disease was pio- lupus nephritis (WHO class IV) were
erative lupus nephritis achieve remis- neered by Briggs and colleagues,42 who assigned to receive either mycopheno-
sions with the current cyclophospha- treated 2 patients with proliferative lu- late mofetil (1 g twice a day) or oral
mide regimens, there remain significant pus nephritis effectively with myco- cyclophosphamide (2.5 mg/kg/d).
numbers of treatment failure and re- phenolate mofetil. Dooley and col- Patients in both treatment arms received
nal disease relapses. In view of the fail- leagues43 subsequently reported a series prednisolone (starting dose 0.8 mg/kg/d
ure of cyclophosphamide-based regi- of 13 patients with lupus nephritis, 12 tapered to 10 mg/d by 6 months). For
mens to induce lasting remissions in of whom had class IV disease, who did maintenance therapy during the sec-
many patients and the substantial tox- not respond to cyclophosphamide ond 6 months of therapy, the patients
icity associated with this medication, therapy. In that series, only 1 patient treated with mycophenolate mofetil had
the development of alternative ap- experienced an elevation in serum cre- a 50% reduction of their dose and the
proaches to treatment is essential. In a atinine level over the course of the patients treated with cyclophospha-
recent study39 in which women were study; 2 patients had increasing pro- mide were switched to azathioprine (2.5
asked about hypothetical treatment teinuria. Adverse effects reported in- mg/kg/d). Both groups continued tak-
preferences, 98% stated that they would cluded pancreatitis (n=1), herpes sim- ing prednisolone at low to moderate
choose azathioprine over cyclophos- plex stomatitis associated with severe doses. Complete remission, defined as
phamide if the 2 medications were con- leukopenia (n = 1), pneumonia with- a stable serum creatinine level (⬍15%
sidered equally effective. Even given a out leukopenia (n = 1), asymptomatic above baseline), normal urine sedi-
theoretical probability of renal sur- leukopenia (n = 2), and nausea/ ment, and less than 0.3 g/d of protein-
vival of 100% at 5 years with cyclo- diarrhea (n = 2). Based on the appar- uria, was achieved in 81% of those
phosphamide, a substantial minority of ent success in this and other reports in treated with mycophenolate mofetil and
31% would still have preferred azathio- addition to a potentially more limited 76% of those treated with oral cyclo-
prine, given the risk of ovarian failure adverse effect profile (TABLE 2),44-47 ran- phosphamide (P⬎.99)(TABLE 3). The
©2005 American Medical Association. All rights reserved. (Reprinted) JAMA, June 22/29, 2005—Vol 293, No. 24 3057PHARMACOLOGICAL THERAPY OF LUPUS NEPHRITIS
Table 3. Summary of Major Mycophenolate Mofetil Trial Outcomes
No. of Subjects
Source and Follow-up Treatment Regimen Primary Outcome Toxicity
Chan et al,48 42 Induction mycophenolate Mycophenolate mofetil: Mycophenolate mofetil:
2000 21 Mycophenolate mofetil mofetil vs oral Complete remission, 81%* Amenorrhea, 0%
21 Cyclophosphamide cyclophosphamide Partial remission, 14%† Severe infection, 19%
1 y follow-up (see text) Relapse, 15% Leukopenia, 0%
Cyclophosphamide: Death, 0%
Complete remission, 76%* Cyclophosphamide:
Partial remission, 14%† Amenorrhea, 23%
Relapse, 11% Severe infection, 33%
Leukopenia, 10%
Death, 10%
Appel et al,49 140 Induction mycophenolate Mycophenolate mofetil: Mycophenolate mofetil:
2003 71 Mycophenolate mofetil mofetil vs intravenous Complete remission, Amenorrhea, no data yet
69 Cyclophosphamide cyclophosphamide 21%ठreported
24-wk outcome Partial remission, 29%|| Severe infection, 6%
Cyclophosphamide: Cyclophosphamide:
Complete remission, 6%ठAmenorrhea, no data yet
Partial remission, 25%|| reported
Severe infection, 13%
Contreras et al,50 59 Maintenance mycophenolate Mycophenolate mofetil: Mycophenolate mofetil:
2004 20 Mycophenolate mofetil mofetil vs azathioprine Chronic renal failure, 95%¶ Amenorrhea, 6%§
19 Azathioprine vs intravenous Renal relapse, 15%#§ Major infection, 2%§
20 Cyclophosphamide cyclophosphamide Cyclophosphamide: Leukopenia, 2%
1- to 5-y follow-up (after intravenous Chronic renal failure, 74%¶ Death, 5%
(cumulative rates) cyclophosphamide Renal relapse, 40%#§ Cyclophosphamide:
induction in both) 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%.
frequency of severe adverse effects was
Figure 2. Mrs P’s Urine Protein Changes and Glucocorticoid Tapering Over the First greater in the cyclophosphamide group,
9 Months of Treatment With Mycophenolate Mofetil
including death (10%) and amenor-
9 rhea (23%), compared with none of
either in the mycophenolate mofetil
(Random Urine: mg Protein/mg Creatinine)
8
group. It is important to recognize that
7
in this trial, oral cyclophosphamide was
6 used, contrary to the intravenous route
of administration according to the NIH
Proteinuria
5
regimen. Nevertheless, the equal effi-
4
cacy of the less toxic drug, mycophe-
3 nolate mofetil, has been a major advance
2
in defining its role in the treatment of
severe lupus nephritis.
1 A more recent study49 presented in
0 abstract form compared remission in-
3/1/2004 6/1/2004 9/1/2004 12/1/2004
duction with mycophenolate mofetil to
Date of Assessment
conventional intravenous cyclophos-
Intravenous Methylprednisolone 1 g/d for 3 d phamide (Table 3). In this multi-
Prednisone
center trial based in the United States,
60 55 40 30 25 17.5 15 12.5 10 7.5 5 2.5
140 patients were randomized to re-
mg/d ceive treatment with intravenous cy-
Mycophenolate Mofetil 1g Twice Daily clophosphamide or mycophenolate
mofetil, with a target dose of mycophe-
3058 JAMA, June 22/29, 2005—Vol 293, No. 24 (Reprinted) ©2005 American Medical Association. All rights reserved.PHARMACOLOGICAL THERAPY OF LUPUS NEPHRITIS
nolate mofetil (1500 mg twice daily) mofetil and azathioprine groups. Al- jor issues surrounding the risk of fu-
higher than that used in the Hong Kong though these results support the use of ture pregnancy—the risk of an SLE
study.48 The rationale for the higher my- mycophenolate mofetil (and azathio- flare, preeclampsia, premature deliv-
cophenolate mofetil dose was evi- prine) in maintenance therapy, there are ery, or poor fetal outcome 5 5 - 5 8 —
dence in the transplantation literature several major limitations.54 First, the continue to be discussed with Mrs P on
that African Americans, who com- definition of remission—reduction in a regular basis.
prised 56% of the trial cohort in the US the urine protein:creatinine ratio to less
study, require higher doses of myco- than 3 if nephrotic at enrollment, and CONCLUSION
phenolate mofetil than whites.51 Al- a ratio 50% of baseline if subne- Mycophenolate mofetil has substan-
though mycophenolate mofetil was phrotic—was less stringent in compari- tial appeal as a new approach to the
superior to cyclophosphamide in re- son to other trials. Second, many pa- treatment of lupus nephritis. Addi-
mission induction, the preliminary data tients did not reach a satisfactory tional data related to the use of myco-
showed much lower rates of remis- remission by the end of the induction phenolate mofetil, including long-
sion with induction than in the Hong phase, which made it likely that they term remission and relapse rates, ideal
Kong trial. Only 21% of those receiv- would fare poorly with the same drug length of treatment, optimal glucocor-
ing mycophenolate mofetil and 6% of (cyclophosphamide) continued in the ticoid tapering, and long-term toxici-
those receiving cyclophosphamide maintenance phase. Overall, the poor ties, are the subject of ongoing studies.
achieved complete remissions in the US response to induction seen in this study For now, as Mrs P’s case demon-
study (P=.005). Some of the disparity can in large part be accounted for by strates, mycophenolate mofetil is a rea-
between the 2 studies can be explained the large proportion of Hispanic and sonable option for many patients with
by racial differences between the co- black patients (5% were white).52 lupus nephritis who seek a safer, effec-
horts (black race predicts poorer out- tive alternative to cyclophosphamide.
come in class IV lupus nephritis52,53). CASE RESOLUTION
Financial Disclosures: None reported.
There may also have been differences in Mrs P began receiving mycophenolate Acknowledgment: I thank my patient for sharing her
the histological severity and clinical se- mofetil, 1000 mg twice daily in addi- story and Allan Gelber, MD, MPH, PhD, John Stone,
MD, MPH, and Michael Choi, MD, for reading and
verity of disease in the 2 trials. Other po- tion to the 60 mg daily of prednisone. improving the manuscript.
tential explanations include the route of Within weeks, her serum creatinine
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