Lupus (2010) 19, 703710

http://lup.sagepub.com

PAPER

Induction and maintenance therapy for lupus nephritis: a systematic review and meta-analysis
YH Lee, J-H Woo, SJ Choi, JD Ji and GG Song
Division of Rheumatology, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea

The aim of this study was to assess the efficacies and toxicities of immunosuppressive treatments for lupus nephritis (LN) versus cyclophosphamide (CYC). A meta-analysis was performed to determine treatment efficacy and toxicity outcomes between mycophenolate mofetil (MMF) and CYC induction therapies, between MMF and azathioprine (AZA) as maintenance therapies, and between low-dose intravenous (IV) CYC and high-dose IV CYC therapy. Ten randomized controlled trials (RCTs) were included in the meta-analysis. In terms of induction therapies, MMF did not increase complete remission or partial remission rates as compared with CYC. However, the relative risks (RRs) of amenorrhea and leukopenia tended to be lower in the MMF group than in the CYC group. Meta-analysis of MMF versus AZA as a maintenance therapy showed no difference between the two groups in terms of response rates or the risk of developing end-stage renal disease. Low-dose IV CYC therapy had lower relapse rates than high-dose IV CYC therapy (RR 0.465, 95% confidence interval [CI] 0.2610.830, p-value 0.010), and was associated with a lower infection risk (RR 0.688, 95% CI 0.5230.905, p-value 0.008). In conclusion, MMF was found to be as effective as CYC and tended to have a better safety profile as an induction therapy for LN than CYC. Lupus (2010) 19, 703710. Key words: cyclophosphamide; lupus nephritis; meta-analysis; mycophenolate mofetil

Introduction
Systemic lupus erythematosus (SLE) is a prototypic human autoimmune disease, and a disorder of generalized autoimmunity with an unknown etiology, which is characterized by intense inammation and multiple organ damage.1 Renal involvement occurs in up to 60% of patients with SLE, and lupus nephritis (LN) remains a predominant cause of morbidity and mortality in SLE.2 Twenty percent of patients with LN develop end-stage renal disease (ESRD) at 10-year follow-up.3 Proliferative disease (WHO class III and class IV) is a more fulminant condition and usually requires aggressive treatment to induce remission and prevent signicant renal and overall mortality.4 Cyclophosphamide (CYC) regimens have improved renal outcomes as compared with steroids alone, and have long been
Correspondence to: Young Ho Lee, MD, PhD, Division of Rheumatology, Department of Internal Medicine, Korea University Anam Hospital, Korea University College of Medicine, 126-1 ga, Anam-dong, Seongbuk-gu, Seoul, 136-705, Korea. Email: lyhcgh@korea.ac.kr Received 19 August 2009; accepted 18 November 2009
! The Author(s), 2010. Reprints and permissions: http://www.sagepub.co.uk/journalsPermissions.nav

considered a gold standard for inducing renal remission and preventing renal ares. However their toxicities raise a number of concerns.5 Furthermore, their benets continue to be tempered by signicant drug-related toxicities, such as an increased risk of infection and ovarian toxicity.6 Pulsed intravenous (IV) high-dose CYC therapy followed by quarterly doses in combination with steroids has been the standard treatment for severe LN. However, several recent studies have suggested that low-dose IV CYC followed by azathioprine (AZA) for maintenance could be as eective as the high-dose IV CYC regimen, but with fewer side eects.7,8 Mycophenolate mofetil (MMF) is a selective inhibitor of B-cell and T-cell proliferation, and has been studied in severe LN to limit therapy-related toxicities. Furthermore, randomized controlled trials (RCTs) that have compared MMF and CYC as induction agents in LN have suggested that MMF is more eective than CYC, and has a more favorable safety prole.914 However, these results are controversial, mainly because of the small number of trials conducted and their small sample sizes.
10.1177/0961203309357763

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Therefore, we performed this meta-analysis of RCTs and included the most recently published studies to evaluate the advantages and disadvantages of MMF and low-dose IV CYC as induction or/and maintenance therapies as compared with high-dose IV CYC therapy in LN.

Methods
Identification of eligible studies and data extraction We performed an exhaustive search for randomized trials that examined current treatment options for LN. Literature searches were performed using MEDLINE (from January 1990 to July 2009) and the Cochrane Controlled Trials Register (up to July 2009) to identify relevant articles. The following keywords and subject terms were used in the searches: lupus nephritis, cyclophosphamide, mycophenolate mofetil, and MMF. All references in the studies were reviewed to identify additional works not included in the electronic databases. RCTs were included if they met the following criteria: (1) the study compared MMF or low-dose IV CYC with high-dose IV CYC as an induction or maintenance therapy for LN; or (2) the study compared MMF with CYC or AZA as a maintenance therapy after the same regimen had been used as an induction therapy for LN; and (3) the study was of patients with biopsy-proven LN class III, class IV, or class V. Unpublished studies and studies of maintenance therapies after dierent induction treatment regimens were excluded. Patients for low- or high-dose IV CYC therapy were assigned to receive one of two regimens: low-dose IV CYC for six fortnightly pulses at a xed dose of 500 mg (The Euro-Lupus Nephritis Trial (ELNT) regimen) or high-dose IV CYC 0.5 g/m2 (a maximum of 1.5 g/ dose) monthly for 6 months and two quarterly pulses (the US National Institute of Health (NIH) regimen). Each regimen was followed by AZA 2 mg/kg/day. Ecacy outcomes were as follows: (1) the number of patients that achieved complete remission; (2) the number of partial remissions; (3) the overall number of remissions; (4) the number of patients that relapsed; (5) the number of treatment of failures; (6) the number of patients with ESRD; and (7) the number of patients that died.
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The toxicity outcome was the number of patients that experienced a side eect, including amenorrhea, infection, herpes zoster infection, and leukopenia. The following information was extracted from each study: rst author, year of publication, immunosuppressive drug dose, length of follow-up, and ecacy and toxicity outcomes. We quantied the methodological qualities of studies using Jadad scores.15 These assessments were based on: (1) whether the randomization method was appropriate; (2) whether double blindness was mentioned in the trial and whether the trial was performed appropriately; and (3) whether the number of patients that withdrew or dropped out and the reasons were stated clearly. Jadad scores ranged from 0 to 5, where higher scores denote a better trial quality. Evaluation of publication bias Funnel plots are normally used to detect publication bias. However, because funnel plots require a range of studies with dierent sizes and subjective judgments, we evaluated publication bias using Eggers linear regression test,16 which measures funnel plot asymmetry using a natural logarithm scale of relative risks (RRs). Evaluations of statistical associations A number of dierent denitions for complete or partial remission, overall remission, and relapse or treatment failure were used in the studied RCTs. However, these dierences were slight and, therefore, we pooled these data as dened in the original articles on the basis of the degree of proteinuria, renal function compared with baseline, and urine analysis. The eect sizes of trial outcomes were expressed as RRs and corresponding 95% condence intervals (CIs). We assessed within- and between-study variations and heterogeneities using Cochrans Q-statistics.17 The heterogeneity test was used to assess the null hypothesis that all studies were evaluating the same eect. When the signicant Q-statistic (p < 0.10) indicated heterogeneity across studies, the random eect model was used for the meta-analysis, and if not, the xed eect model was used. The xed eect model assumes that all studies estimate the same underlying eect and considers only within-study variations. We quantied the eect of heterogeneity using18 I2 100% (Q df)/Q, where I2 measures the degree of inconsistency between studies and

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Table 1 Characteristics of individual studies Included in the meta-analysis of induction therapies for lupus nephritis
Number enrolled Study Ong et al. 20059 Appel et al. 200910 Ginzler and Aranow 200511 Chan et al. 200512 Hu et al. 2002
13

Comparison Study type I I I MMF 2 g/day 3 g/day 3 g/day Cyclophosphamide IV CYC 0.751 g/m2 monthly IV CYC 0.51 g/m2 monthly IV CYC 0.51 g/m2 monthly

E 19 185 71

C 25 185 69

Follow-up period (months) 6 6 6

Results ND ND MMF: more effective and more favorable safety profile than IV CYC. ND MMF: more effective than IV CYC. MMF: more effective and more favorable safety profile than IV CYC.

Jadad score 3 3 3

21 23 9

21 23 11

I I I

1 g/day 11.5 g/day 1.52 g/day

Oral CYC 2.5 mg/kg/day for 6 mo then AZA IV CYC 0.751 g/m2 monthly IV CYC 0.751 g/m2 monthly

12 6 6

1 1 2

Wang et al. 200714

E, experimental group; C, control group; I, induction therapy; MMF, mycophenolate mofetil; IV, intravenous; CYC, cyclophosphamide; ND, no difference was found between the MMF and IV CYC groups with regard to response rate and adverse events.

determines whether the percentage total variation across studies is due to heterogeneity rather than to chance. The value of I2 ranges between 0% and 100%; I2 values of 25%, 50%, and 75% are referred to as low, moderate, and high estimates. Statistical manipulations were undertaken using a Comprehensive Meta-Analysis computer program (Biosta, Englewood, NJ, USA).

Trial outcomes of MMF versus CYC as LN induction therapies Six RCTs compared MMF and CYC induction therapies (Table 1). MMF did not increase complete remission or partial remission rates compared with CYC (RR 1.613, 95% CI 0.9082.863, p-value 0.103 and RR 1.031, 95% CI 0.6781.567, p-value 0.887, respectively; see Figure 1, Table 3), and the two groups were not dierent in terms of overall response rate. Furthermore, the two groups were not signicantly dierent in terms of the risk of developing ESRD or mortality (Table 3). The RRs of amenorrhea and leukopenia tended to be lower in the MMF group than in the CYC group (RR 0.166, 95% CI 0.0201.343, p-value 0.092 and RR 0.412, 95% CI 0.1491.135, p-value 0.086, respectively). Finally, MMF did not reduce the risk of developing a herpes infection or any other infection as compared with CYC. Trial outcomes of MMF versus AZA maintenance therapies for LN Following induction therapy, a maintenance regimen is essential to reduce the risk of renal ares. We compared immunosuppressive agents used in maintenance treatments after same LN induction regimen therapies (Table 2). The pooled data of two RCTs on MMF versus AZA maintenance therapies showed no dierence between the two groups in terms of response or risk rates of developing ESRD (RR 1.623, 95% CI 0.3697.146, pvalue 0.522 and RR 1.360, 95% CI 0.2367.828, pvalue 0.730, respectively; see Table 3). One RCT compared MMF or AZA with CYC as maintenance therapies in LN.28 Six-year event-free survival rates for death and chronic renal failure
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Results
Studies included in the meta-analysis Sixty-three studies were identied by electronic and manual searches and 19 were selected for a full-text review based on titles and abstracts.713,1923 However, nine of the 19 were excluded; ve of these were review articles,19,20,2426 two were RCTs which did not compare MMF versus CYC or AZA and did not meet the inclusion criteria21,22 and one contained duplicate data.23,27 Thus, 10 studies met the meta-analysis inclusion criteria.28,29 These 10 studies involved a total of 450 patients from in experimental groups and 441 controls. Six studies addressed the LN induction therapy,914 two studies addressed maintenance therapy,27,28 and two studies were meta-analyses of low-dose versus high-dose IV CYC therapy in LN.7,8 Relevant features of the studies included in the meta-analysis are provided in Table 1. Follow-up periods in induction therapy ranged from 6 to 12 months, in maintenance therapy from 39 to 72 months, and in low-dose IV CYC versus high-dose IV CYC therapy from 12 to 60 months. Jadad scores ranged from 1 to 3 (Table 1).

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(A) Study name Risk ratio

Appel et al. 2009 ; Wang et al. 200714; Ong et al. 20059; Ginzler and Aranow 200511; Chan et al. 2005 ;
12 10

Statistics for each study Lower limit 0.543 0.658 0.597 1.368 0.774 0.908 Upper limit 2.093 177.358 8.056 11.046 1.458 2.863 p -Value 0.851 0.096 0.237 0.011 0.707 0.103

Risk ratio and 95% CI

1.067 10.800 2.193 3.887 1.063 1.613

0.1 0.2 0.5

10

Cyclophosphamide (B) Study name Statistics for each study Rrisk Lowre Upper ratio limit limit Z -Value p -Value
Wang et al. 200714;
9 Ong et al. 2005 ;

MMF

Risk ratio and 95% CI

Ginzler and Aranow 11 2005 ;

12 Chan et al. 2005 ;

0.815 0.789 1.200 1.000 1.031

0.172 0.349 0.695 0.227 0.678

3.867 0.258 1.788 0.567 2.074 0.655 4.400 0.000 1.567 0.142

0.797 0.571 0.513 1.000 0.887 0.1 0.2 0.5 1 2 5 10

Cyclophosphamide

MMF

Figure 1 Meta-analysis of complete (A) and partial remission (B) for mycophenolate mofetil (MMF) versus cyclophosphamide (CYC) induction treatments in lupus nephritis.

Table 2 Characteristics of individual studies included in the meta-analysis of maintenance therapy and cyclophosphamide therapy for lupus nephritis
Number enrolled Study Sahin et al. 200828 E 17 C 15 Study type M Comparison IV CYC 0.75-1 g/m2 monthly for 6 mo, then MMF 1.5-2 g/day or AZA 2 mg/kg/day for maintenance therapy IV CYC 0.5-1 g/m2 monthly for 6 mo, then MMF 0.5-3 g/day, AZA 1-3 mg/kg/day or IV CYC quarterly for maintenance therapy Low-dose IV CYC vs high-dose IV CYC* Low-dose IV CYC vs high-dose IV CYC* Follow-up period (months) MMF: 39 14, AZA: 43 18 Results Both MMF and AZA: effective as a maintenance therapy. Jadad score 1

Conteras et al. 200429

20, 19

20

72

Both MMF and AZA: more efficacious and safer than long-term IV CYC therapy.

Houssiau et al. 20027 Sabry et al. 20098

46

46

I, M

60

20

26

I, M

12

Low-dose IV CYC group: comparable to high-dose IV CYC group with regard to the efficacy and the toxicity. Low-dose IV CYC group: comparable to high-dose IV CYC group with regard to the efficacy and the toxicity.

E, experimental group; C, control group; I, induction therapy; M, maintenance therapy; MMF, mycophenolate mofetil; AZA, azathioprine; IV, intravenous; CYC, cyclophosphamide. *Low-dose IV CYC for six fortnightly pulses at a fixed dose of 500 mg or high-dose IV CYC 0.5 g/m2 (a maximum of 1.5 g/dose) monthly for 6 months and two quarterly pulses. Each regimen was followed by AZA 2 mg/kg/day.
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Table 3 Meta-analysis of randomized controlled trials of immunosuppressive agents in lupus nephritis

Test of association Study type MMF versus CYC for induction Outcome CR PR Response Amenorrhea Leukopenia Infection HZV ESRD Death Response ESRD TF Relapse Infection No. of Studies 5 4 6 2 4 4 4 2 3 2 2 2 2 2 RR 1.613 1.031 1.194 0.166 0.412 0.827 0.902 0.07 0.84 1.623 1.360 0.451 0.465 0.688 95% CI 0.9082.863 0.6781.567 0.9971.429 0.0201.343 0.1491.135 0.5521.204 0.3722.191 0.2342.139 0.4131.889 0.3697.146 02367.828 0.2021.009 0.2610.830 0.5230.905 Test of heterogeneity p-val 0.103 0.887 0.054 0.092 0.086 0.35 0.821 0.539 0.750 0.522 0.730 0.053 0.010 0.008 Q 8.7 0.7 9.7 0.2 0.7 19.0 2.1 1.2 3.6 1.6 0.1 0.6 0.4 2.1 p-val 0.068 0.850 0.084 0.885 0.868 0.001 0.550 0.256 0.159 0.203 0.732 0.423 0.523 0.142 I2 54.1 0 48.5 0 0 79.0 0 22.5 45.5 38.4 0 0 0 53.7

MMF versus AZT for maintenance Low-dose versus high-dose IV CYC

MMF, mycophenolate mofetil; CYC, cyclophosphamide; AZA, azathioprine; IV, intravenous; CYC, cyclophosphamide; CR, complete remission; PR, partial remission; HZV, herpes zoster virus; ESRD, end-stage renal disease; TF, treatment failure; RR, relative risk.

were higher in the MMF and AZA groups than in the CYC group (p 0.05 and p 0.009, respectively), and the rate of relapse-free survival was higher in the MMF group than in the CYC group (p 0.002). The incidences of hospitalization, amenorrhea, and infections were signicantly lower in the MMF and AZA groups than in the CYC group. Trial outcomes for low-dose IV CYC versus high-dose IV CYC therapy The CYC dosing regimen based on the NIH protocol involves a higher cumulative CYC dose than that used in the ELNT.7 The ELNT demonstrated that patients on a lower CYC dose experienced only 50% of the severe infection rate of that experienced by those on a higher CYC dose, at comparable ecacy in terms of renal response. Another study also compared the ecacies and toxicities of low- and high-dose IV CYC for severe LN8 and, therefore, we combined data from the two in this meta-analysis. As compared with the high-dose IV CYC therapy, low-dose IV CYC therapy decreased relapse rate (RR 0.465, 95% CI 0.2610.830, p-value 0.010; see Figure 1A and Table 3), and the rate of treatment failure, but with marginal signicance (RR 0.451, 95% CI 0.2021.09, p-value 0.053). Interestingly, low-dose IV CYC was found to be associated with a reduced infection risk (RR 0.688, 95% CI 0.523 0.905, p-value 0.008; Figure 2B and Table 3). Oral cyclophosphamide versus intravenous cyclophosphamide The optimal route of CYC administration for the treatment of severe LN remains uncertain.

One RCT compared oral CYC and IV CYC in 32 LN patients.30 Intermittent pulse CYC therapy was administered at 10 mg/kg three times weekly for 4 weeks, followed by 10 mg/kg orally over 2 days/ 4 weeks for 9 months, and nally by 10 mg/kg over 2 days/6 weeks for 12 months. The total duration of treatment was 2 years. Daily oral CYC was administered at 2 mg/kg/day for 3 months, and then changed to daily oral AZA at 1.5 mg/kg/day. No signicant dierence was observed between the two regimens in terms of ecacy or side eects. Another prospective study compared the outcomes of 12 intravenous pulses of CYC (n 22) or sequential oral CYC (12 mg/kg/day) followed by AZA (2 mg/kg/day) (n 21) in diuse proliferative LN.31 At 24 months post-treatment commencement, oral CYC followed by AZA showed more complete and partial remission (90% versus 73%) and less treatment failure (5% versus 14%), but dierences were not statistical signicant. Patients treated with oral CYC showed an insignicant increase in infection rate and menstrual disturbance. These ndings suggest that shorter-duration and lower-dose oral CYC induction followed by AZA maintenance is a viable strategy for reducing toxicity without compromising treatment ecacy in LN. Heterogeneity, publication bias, and sensitivity analysis Between-study heterogeneity was found during analyses of complete remission, response rate, and amenorrhea associated with induction therapy. It was dicult to correlate the funnel plot, which
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(A) Study name Statistics for each study Risk ratio Sabry et al. 20098 0.184 0.484 0.465 Lower limit 0.010 0.268 0.261 Upper limit 3.364 0.873 0.830 p -Value 0.253 0.016 0.010 0.1 0.2 0.5 1 2 5 10 Risk ratio and 95% CI

Houssiau et al. 20027

Low-dose IVC high-dose IVC (B) Study name Statistics for each study Rrisk Lowre ratio limit Sabry et al. 20098 1.625 0.655 0.688 0.500 0.494 0.523 Upper limit 5.280 0.868 0.905 p -Value 0.419 0.003 0.008 0.1 0.2 0.5 1 2 5 10 Risk ratio and 95% CI

Houssiau et al. 20027

Low-dose IVC high-dose IVC

Figure 2 Meta-analysis of relapse rate (A) and infection risk (B) for low-dose intravenous cyclophosphamide (IVC) versus high-dose IVC in patients with lupus nephritis.

is usually used to detect publication bias, because of the small number of studies included. Eggers test showed evidence of publication bias in the analysis of response to induction therapy (Eggers regression test p-values 0.04). The trim and ll method estimates the outcome and number of missing studies that would be necessary to correct for publication bias. This method provides three adjusted estimations of eect size based on incorporating these theoretical missing studies into meta-analyses. However, adjusting for publication bias did not change the nding based on the meta-analyses of response rates to induction therapy. In induction therapy studies, only patients in Chans study received daily oral CYC, but when we performed sensitivity analysis excluding this study, trial results were not materially aected.

Discussion
In the present meta-analysis, we combined the clinical data of six RCTs that compared MMF with CYC as LN induction therapies.614 It was found
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that MMF and CYC have similar ecacies in terms of the induction of renal remission. Furthermore, although MMF did not reduce infection risk it showed a tendency to reduce amenorrhea and leukopenia (RR 0.166, 95% CI 0.0201.343, p-value 0.092 and RR 0.412, 95% CI 0.1491.135, p-value 0.086, respectively). In terms of maintenance therapy,27,28 MMF and AZA were found to be comparable with respect to response rate and ESRD. Five meta-analyses have been performed to examine whether MMF is superior to CYC in terms of its ecacy and toxicity. However, the results of these meta-analyses were inconsistent. Mak et al.24 concluded MMF and CYC are similar ecacy in terms of renal remission and survival, but that MMF appears to be safer than CYC. Navaneethan et al.25 found that MMF had a lower all-cause mortality rate, but that MMF and CYC were no dierent in terms of progression to ESRD and complete remission, and that MMF had a better safety prole than CYC with lower rates of infections and amenorrhea. Walsh et al.19 has reported that MMF reduced the risk of failure to induce remission during induction therapy and

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that leukopenia occurred more frequently in CYC-treated patients, although all of their ndings lacked signicance. Zhu et al.26 concluded that MMF induces remission in severe LN better than CYC, and that MMF induction therapy has a lower infection rate than CYC induction therapy. In addition, the incidences of amenorrhea and leukopenia were lower for MMF, but no signicantly so. Moore and Derry20 showed that complete remission or partial remission was signicantly more frequent with MMF than with CYC and serious infections, leukopenia, amenorrhea, and hair loss were all signicantly less frequent with MMF than with CYC. Our meta-analysis of RCTs produced the same result as the meta-analysis performed by Mak et al.24 on treatment ecacies, which included the largest number of studies analyzed to date. Furthermore, our analysis also shows that MMF induction therapy tends to have a lower side eect rate than CYC induction therapy in LN, which concurs with all previous meta-analyses. Interestingly, low-dose IV CYC therapy was found to reduce relapse and infection rates as compared with high-dose therapy, which indicates that low-dose IV CYC may be superior to high-dose IV CYC in terms of ecacy and toxicity. However, this nding should be interpreted with caution because our meta-analysis was based on only two controlled trials. The present meta-analysis has several shortcomings that require consideration. First, the possibility of publication bias is always of concern, and it should be recognized that publication bias is dicult to exclude with certainty, particularly when, as in the present study, the number of incorporated studies is small. Second, heterogeneities in clinical features, such as race, sex, age, severity of renal impairment, proportion of patients with class IV LN, and denition of remission or study quality, tend to confuse meta-analysis ndings, and may have biased our analysis. Most studies included LN with class III, class IV, or class IV,7,911,28,29 whereas small numbers of trials included only LN with class IV.8,1214 Owing to limited data on trials including small numbers of class IV LN patients, we could not perform the subgroup analysis. However, the small numbers of patient with LN class III or IV and the similar distribution of the patients with dierent types of LN between the experimental and the control groups may limit this bias. It is known that there are signicant differences in the response of dierent ethnic groups to treatment of LN. The low-dose IV CYC regimen was used initially in European centers (the ELNT

regimen) and high-dose IV CYC therapy came from NIH trials (the NIH regimen). The major difference between the two trials was the type of patient population enrolled. The ELNY included mostly White patients, in contrast to the NIH trials, which enrolled predominantly African American patients, who have a poor renal prognosis. Hispanics and Asians also have a greater severity of LN compared with Europeans. In this meta-analysis, we could not perform meta-analysis based on the ethnic group due to small number of studies in each ethnic group. Third, although our ndings regarding the low-dose IV CYC versus high-dose IV CYC therapy comparison are statistically signicant, they are based on small number of events, and thus, may be aected by random errors. Furthermore, only two RCTs were included in our analysis of maintenance therapies, and thus ndings should be regarded with caution. In conclusion, our meta-analysis based on RCTs, including the most recently published RCTs, suggests that MMF and CYC are comparable in terms of ecacy, that MMF induction therapy tends to have a more favorable safety prole, and that MMF and AZA are comparable maintenance therapies in terms of ecacy and toxicity. Furthermore, our ndings suggest that low-dose IV CYC is more ecacious and safer than high-dose IV CYC for the treatment of severe LN.

Acknowledgment
This study was supported by a grant of the Korea Healthcare technology R&D Project, Ministry for Health, Welfare and Family Aairs, Republic of Korea. (A080588).

References
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Induction and maintenance therapy for lupus nephritis YH Lee et al.

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