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clinical trial

www.kidney-international.org

Comparison of low-dose intravenous
cyclophosphamide with oral mycophenolate
mofetil in the treatment of lupus nephritis

see commentary on page 25

Manish Rathi1, Ajay Goyal1, Ajay Jaryal1, Aman Sharma2, Pramod K. Gupta3, Raja Ramachandran1,
Vivek Kumar1, Harbir S. Kohli1, Vinay Sakhuja4, Vivekanand Jha1 and Krishan L. Gupta1
1

Department of Nephrology, Post Graduate Institute of Medical Education and Research, Chandigarh, India; 2Department of Internal
Medicine, Rheumatology Wing, Post Graduate Institute of Medical Education and Research, Chandigarh, India; 3Department of
Biostatistics, Post Graduate Institute of Medical Education and Research, Chandigarh, India; and 4Department of Nephrology and Renal
Transplant Surgery, Max Super Speciality Hospital, Mohali, India

No previous study has compared mycophenolate mofetil
(MMF) with low-dose cyclophosphamide (CYC) in the
treatment of lupus nephritis (LN). To do so, we recruited
patients with LN (class III, IV, or V) and randomized them to
receive either low-dose CYC or oral MMF. Those with
crescentic LN, a serum creatinine over 265 mmol/l, and
neurological or pulmonary lupus were excluded. MMF was
prescribed at daily doses of 1.5–3 g for 24 weeks, while CYC
was administered as six fortnightly infusions of 500 mg
each. All patients received three methylprednisolone
injections, followed by oral corticosteroids. Maintenance
therapy with azathioprine and low-dose corticosteroid was
started at end of induction therapy. The primary end point
was treatment response at 24 weeks, while secondary end
points were complete remission, Systemic Lupus
Erythematosus Disease Activity Index and adverse events.
Of the 173 patients recruited, 100 were equally randomized
to receive either CYC or MMF. Baseline characteristics were
similar, except for higher 24 h proteinuria in the CYC group.
At 24 weeks, 37 patients in each group achieved the
primary end point. The complete remission rate was 50% in
CYC and 54% in MMF group. Gastrointestinal symptoms
were significantly more frequent in patients receiving MMF
(52 vs. 4%). However, other adverse events were similar.
Thus, low-dose intravenous CYC is comparable in safety
and efficacy to oral MMF in the induction treatment of less
severe LN.
Kidney International (2016) 89, 235–242; http://dx.doi.org/10.1038/
ki.2015.318
KEYWORDS: cyclophosphamide; lupus nephritis; mycophenolate mofetil
ª 2015 International Society of Nephrology

Correspondence: Manish Rathi, Department of Nephrology, Post Graduate
Institute of Medical Education and Research, Sector-12, Chandigarh 160 012,
India. E-mail: drmanishrathi2000@yahoo.co.in
Received 22 May 2015; revised 4 August 2015; accepted 20 August
2015; published online 21 October 2015
Kidney International (2016) 89, 235–242

L

upus nephritis (LN) is a serious complication of systemic lupus erythematosus (SLE) and needs to be
treated with toxic immunosuppressive therapy.1–3 Attempts have been made to reduce toxicity by altering the
route of administration or dosage of drugs or substituting
them with less toxic alternatives.
Cyclophosphamide (CYC), the traditional standard treatment of LN,4–7 carries significant dose-dependent short- and
long-term toxicity, prompting investigators to explore the
effectiveness of lower doses.8,9 The Euro–lupus nephritis trial
(ELNT) demonstrated a comparable efficacy and safety profile
of low-dose CYC to the high-dose National Institutes of Health
(NIH) regimen.10 Mycophenolate mofetil (MMF), a selective
lymphocyte antiproliferative agent, has also emerged as a
promising drug for treatment of LN. Recent studies have
established MMF as a safe and an effective alternative to fulldose CYC for LN.11–16 Both the ELNT regimen and MMF
have been used successfully in subjects with less severe LN with
the advantage of reduced toxicity. However, it is not clear
whether low-dose ELNT CYC or oral MMF is superior, because
these have not been compared in a head-to-head trial. The
present study was aimed at comparing the efficacy and safety of
these treatment options in subjects with less severe LN.
RESULTS

A total of 173 subjects fulfilling the inclusion criteria were
screened during the study period. Of these, 100 were randomized to receive either low-dose intravenous CYC (n ¼ 50)
or oral MMF (n ¼ 50). The reasons for exclusion of 73
subjects are summarized in Figure 1.
The baseline characteristics of the study population are
described in Table 1. There were 8 males and 92 females in the
cohort. All the baseline characteristics were comparable between the two groups, with the exception of urine protein/
creatinine ratio (uPCR), which was significantly higher in the
CYC group (3 vs. 2.2 in the MMF group, P ¼ 0.02). The
clinical presentation, organ involvement, and the distribution
of various biopsy classes were also similar in the two groups
(Table 1).
Of the 50 subjects in CYC group, 40 (80%) received the
target cumulative dose of 3 g, whereas 48 (96%) subjects in
235

the treatment response rate in class IV was 76. 8) and 4 (2. The anti-double–stranded deoxyribonuclease antibody positivity rate declined from 90 to 58% in the CYC group (P < 0. lupus nephritis.0 µmol/l (n = 16) Previously received CYC or MMF (n = 21) Refused consent (n = 5) Pregnant (n = 1) CNS or pulmonary lupus (n = 6) Randomized (n = 100) 50: Low fixed dose intravenous CYC 50: Oral MMF Withdrawn (n = 9) Withdrawn (n = 8) Death (n = 2) Adverse events (n = 3) Lost to follow-up (n = 3) Deviated from protocol (n = 2) Death (n = 5) Adverse events (n = 1) Lost to follow-up (n = 2) Completed 24 weeks of follow-up (n = 41) Completed 24 weeks of follow-up (n = 42) Figure 1 | Flowchart depicting patient enrollment and follow-up. 23.39 g/day. without any significant difference between the two treatment groups (P ¼ 0. The delta estimated glomerular filtration rate improved by 14. LN. cyclophosphamide.74). CNS. The median (interquartile range) SLEDAI score at the end of 24 weeks was 6 (4. the MMF group received the target dose of 1.005) and 16. with no significant intergroup difference (P ¼ 0. respectively 236 (P ¼ 0.0 g/day with a mean dose of 2. CYC.3.0 ml/min (95% confidence interval: 4. as well as the secondary outcome measures were assessed at 12 and 24 weeks according to the original assigned groups (intention-to-treat (ITT) analysis). as well as the completed follow-up groups (as-per-protocol [APP] analysis). 235–242 .: Low-dose intravenous CYC versus oral MMF in lupus nephritis Screened (n = 173) Biopsy diagnosis of lupus nephritis class III/IV/V Reasons for exclusion (n = 73) Crescentic LN (n = 24) Serum creatinine > 265.001) and from 76 to 40% in the MMF group (P < 0.7) in the CYC group (P ¼ 0.9. Study outcomes The primary.001) and 88 to 62% in the MMF group (P ¼ 0. The prevalence of hypocomplementemia (low C3 or C4) declined from 92 to 32% in the CYC group (P < 0. Using ITT analysis.53). central nervous system.4% in the MMF Kidney International (2016) 89. 28.5–3. The serum creatinine.5 ml/min (95% confidence interval: 4. with no significant intergroup difference (P ¼ 0. The rates of treatment response and complete renal remission at these time points as per the two analyses are summarized in Table 2. MMF.84).01) over 24 weeks.17).clinical trial M Rathi et al. 6) in the CYC and the MMF group. and the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score improved significantly in both the groups over the study period. and there were no differences between the treatment groups (Figure 2).7% in the CYC group compared with 70. The response rate for different pathological classes of LN according to the treatment group was also analyzed. serum albumin.006) over 24 weeks. mycophenolate mofetil. uPCR.22  0.0) in the MMF group (P ¼ 0.001).

8. 269) 6. 25 (50%) subjects in the CYC group and 32 (64%) subjects in the MMF group reported at least one adverse event (P ¼ 0.5 17.7.5. dsDNA. summarized in Table 3.0 (22) (54) (24)  9.5.0 0. more patients receiving MMF experienced gastrointestinal (GI) symptoms (P < 0. intention-to-treat. Over a period of 6 months.79) (0.8) 3. there was no difference in the median time to complete remission in the two groups (9 (7. 9. eGFR. MMF.70) (0.715 Kidney biopsy class.0 and 76.32).7% in the MMF group (P ¼ 0. 264.3 22. 4. n (%) III/IIIþV IV/IVþV V Age (years) Body mass index (kg/m2) SLEDAI scorea Anti-dsDNA positive.35–2. estimated glomerular filtration rate. 235–242 237 .84 0. c eGFR calculated using the Modified MDRD (Modification of Diet in Renal Disease) equation.67) (0.4% in the CYC group compared with 66.12 1.5%) (49. n (%) Hemoglobin (g/l) Leukocyte count (x109/l)b Platelet count (x109/l)b Blood urea nitrogen (mmol/l)b Serum creatinine (mmol/l)b Urine protein/creatinine ratiob eGFR (ml/min)c Serum albumin (g/l) 6 (12) 30 (60) 14 (28) 30.6  9.5) 79.79).2 24.91).2 45 (90) 46 (92) 11 27 12 28.65 1. n (%) Hypocomplementemia (Y C3 or C4). 8. 123. However.8  31. n (%) Female Male 45 (90) 5 (10) 47 (94) 3 (6) 0. Both the groups had an equal number of infection episodes.56–3.5 (108. group (P ¼ 0.0 1.9%) (59.88).93 1.7  7. Similarly.1  6.178 0.6%) (80. others as mean  SD.7%) (80.4  24 6.8.47 (0. double-stranded DNA.866 1 0. whereas in class V it was 71.43).311 0. respectively. The median time to response was 10 (4. Economics of the therapy Adverse events During the study period.84 CYC 26/41 13/41 33/41 20/41 (63. one due to lupus enteritis and septic shock.001).9%) (38. as well as remission was also not different between the treatment groups Figure 3).59). respectively. The cause of death in two subjects in the CYC group was unknown. 2200 INR or 100 vs.7% in the CYC group compared with 90. mycophenolate mofetil.25–3.41 1.42–2. b Measure of central tendency values indicated as median (interquartile range).86) 0.5%) Odds ratio (95% CI) P-value 1.414 0. CI.5 22.0 0. Systemic Lupus Erythematosus Disease Activity Index.9 44 38 89  18 6.203 0.3  3. Value in bold is statistically significant.85 1. The probability of response.51–3.0%) MMF 29/44 17/44 34/42 25/42 (65. P ¼ 0. ITT.3 (70. 8) 143.177 0.6 (88) (76) 0. The treatment response rate did not differ significantly in the two treatment groups even after the exclusion of subjects with pure class-V LN (75.8 (4.942 0.082 CYC.54 1.9% in the MMF group (P ¼ 0. The reported adverse events are The cost of monthly therapy with MMF was fourfold higher than the CYC therapy (8500 vs.4) 78. the cumulative cost of MMF therapy was almost seven times that of 3-month CYC Table 2 | Outcome variables in the 2 groups as per the ITT and APP analysis ITT Outcome measures Response-12 weeks Remission-12 weeks Response-24 weeks Remission-24 weeks APP CYC (n [ 50) MMF (n [ 50) Odds ratio (95% CI) P-value 31 16 37 25 (62%) (32%) (74%) (50%) 29 21 37 27 (58%) (42%) (74%) (54%) 0. whereas the cause was not clear in the other two cases.6. two were due to severe neuropsychiatric lupus.90). Three subjects in the CYC group and one subject in the MMF group required discontinuation of treatment because of adverse events. 3. Kidney International (2016) 89.0 (4.85 0.5.52 APP. There were five deaths in the MMF group and two in the CYC group (P ¼ 0.4  8. a Scoring done according to the Safety of Exogenous Estrogens in Lupus Erythematosus National Assessment (SELENA) modification. mycophenolate mofetil. 21) weeks and 12 (8.98) (0.0 (1.37–2.50–2.693 0. Of the five deaths in the MMF group.8) 2.7.9 27. CYC.1) 220 (133. P ¼ 0.4%) (31. 10) 77.: Low-dose intravenous CYC versus oral MMF in lupus nephritis Table 1 | Baseline characteristics of the study population CYC MMF Variable n [ 50 n [ 50 P-value Gender.3% in CYC and MMF groups.7 (5.2 (1. 12) weeks in the MMF group (P ¼ 0. as-per-protocol. in class III it was 66. 20) weeks in the CYC group as compared with 12 (6.3  32.clinical trial M Rathi et al.5  3.8) 6. cyclophosphamide.77) 0. There was no difference in the incidence of infertility or menstrual abnormalities between the two groups.17 (0.03) (0.9.4) 75. 20 Euros).6  5.1 18.6 (70.5 (4. MMF.024 0.22) (0.237 0.63–3. SLEDAI. cyclophosphamide. 123.5.36 0.056 94.0 0.21). 20) weeks in the CYC and MMF group. confidence interval.99 0.

238 Kidney International (2016) 89.15 However. the Aspreva Lupus Management Study (ALMS) trial had compared oral MMF with monthly high-dose intravenous CYC and noted equal rates of complete and partial remission in the two treatment groups.0 0 5 10 15 Time 20 CYC MMF 0 5 10 15 Time 20 Figure 3 | Kaplan-Meier analysis of probability of response (P [ 0. uPCR. urine protein/creatinine ratio. Many observational and randomized trials were conducted to identify the most effective and safe therapy for patients with LN. The ELNT trial had compared six fortnightly injections of CYC at a fixed dose of 500 mg with high-dose monthly injections. Survival for response Survival for remission 1. MMF. the biochemical parameters and uPCR all showed significant improvement over time (P < 0.and low-dose intravenous CYC.0 1. mycophenolate mofetil. 7700 INR [90 Euros]).6 0. as well as adverse event rates were comparable in the two groups.5 10 1.17 Similarly. Comparisons of each variable between treatment groups showed no significant differences (P > 0.8 Survival probability Survival probability 0. serum albumin.6 0. CYC.8 0. DISCUSSION In this randomized trial. and 3 months of azathioprine therapy (52. cyclophosphamide. MMF.5 CYC MMF 15 SLEDAI uPCR CYC MMF 2.2 0.4 0. CYC.05).10 Follow-up for up to 10 years showed that there were no differences in the outcomes parameters or the side effects between high.921) in the 2 treatment groups. SLEDAI. We observed that the treatment response and complete remission rates. to date there have been no studies directly comparing the low-dose CYC regimen with oral MMF.000 INR [618 Euros] vs. cyclophosphamide.5 0 12 Time (weeks) 24 0 12 Time (weeks) 24 Figure 2 | Changes in serum creatinine.5 5 0. mycophenolate mofetil. and disease activity (SLEDAI) score over the 24-week induction period. we compared low-dose intravenous CYC with oral MMF in the induction treatment of mild to moderately severe LN.: Low-dose intravenous CYC versus oral MMF in lupus nephritis 40 MMF CYC 95 Serum albumin Serum creatinine 105 90 85 80 75 MMF CYC 35 30 25 0 12 Time 24 0 12 Time 24 3.05).4 0. Studies have shown that both the low-dose intravenous CYC and oral MMF are equally efficacious and safe alternatives compared with the conventional NIH regimen of high-dose intravenous CYC.clinical trial M Rathi et al. Within each treatment group. uPCR.0 0.2 0.833) and probability of remission (P [ 0. Systemic Lupus Erythematosus Disease Activity Index. 235–242 .0 CYC MMF 0.

13. 5. The ALMS trial included subjects with Kidney International (2016) 89.0) 1 0 5 3 1 2 26 (52)* 0 1 7 0 2 1 0 3 0 1 1 1 1 1 0 1 1 1 0 1 0 2 0 1 Neurological Headache Seizures Stroke Psychosis Worsened GFR Menorrhagia Amenorrhea Alopecia Diffuse alveolar hemorrhage AE. the response and remission rates achieved in our study are better than those seen in the ALMS trial.15 This difference may be due to various reasons. gastrointestinal.5% were Black.0) 25 (50) 5 (10) 32 (64) Infections (total) Pneumonia Urinary tract infection Esophageal candidiasis Breast abscess Gluteal abscess Herpes zoster Pulmonary tuberculosis Acute parotitis Shock 13 4 3 0 0 1 5 0 0 1 10 4 1 1 1 0 3 1 1 1 GI symptoms Gastric ulcer Transaminitis Cytopenia Leg ulcers Steroid induced diabetes Deep vein thrombosis 2 (4. the present study excluded subjects with estimated glomerular filtration rate of <30 ml/min.58 g/day. These remission rates were higher as compared with those seen in our study.0% and complete remission rates of 8. the racial background of subjects in the two studies is different.: Low-dose intravenous CYC versus oral MMF in lupus nephritis Table 3 | Adverse events during 24-week induction phase Adverse events CYC n [ 50 MMF n [ 50 Death Patients with at least one AE 2 (4.0 g dose.11–13. CYC. Another possible reason could be a direct increase in the dose of MMF from 1000 mg bid to 1500 mg bid without a stepwise increase (e.47  0.10 the dose of steroid used in our treatment protocol was high. GFR. 235–242 clinical trial different racial backgrounds. This is less than that achieved by Ginzler et al.19. and majority of GI symptoms like nausea and vomiting with CYC are dose related. The commonest adverse event was GI intolerance and infections. (63%).. however. P ¼ 0.8%.6% and 8. MMF. we did not notice any particular trend of increased GI upset during the hike to this dose at 4-week duration. the dose of CYC was less as compared with previous studies.1% in the MMF and high-dose intravenous CYC groups. Earlier studies that have compared MMF with either oral or high-dose intravenous CYC have also found similar rates of infections. At the end of 24 weeks. which showed response rates of 56.13. Finally. the steroid dose used in our study was close to the one used in the ALMS trial. whereas complete renal remission was achieved in 50% in the CYC group and 54% in the MMF group.8%.005).15 The mean dosage of MMF in our study population (2.15 Although the exact reasons for this difference are unclear. The high response rate with MMF in our study occurred despite a lower received MMF dose. *P < 0. whereas in our study all subjects were Asians.13 or the ALMS trial (91. As compared with low-dose CYC. there were more adverse events in the MMF group.11–15 The rate and severity of infections were similar in the two groups on CYC in the ELNT trial.68 and 2. GI.11 compared MMF with oral CYC for LN induction in Chinese subjects and noted a comparable complete remission in each treatment arm (81% in the MMF group vs. however.2% and 53. The mortality rate in our study was 10% in the MMF group and 4% in the CYC group.g. Genetic differences in the drug metabolism and cultural differences in the concern about body image when faced with a potentially serious illness may also be responsible for this difference. and it is possible that steroids may have driven a significant part of the beneficial effects of the induction therapy at week 24. glomerular filtration rate.18 On the other hand. This may be in part due to the fact that the results in the Chinese study were analyzed at the end of 12 months in contrast to 6 months in our study. we noted similar treatment response of 74% in both the groups. The side effect rate of alopecia in our study was lower in both the treatment groups as compared with the ALMS trial (11% in MMF and 36% in CYC).15 Compared with the ELNT trial.15 Close follow-up. the differences were not significant.15 In our study. Chan et al. respectively. adverse event.39 g/day) was also less than that in the other two trials (2. 2500 mg in divided doses). with more subjects with pure class-V LN in our study.3%). in the ALMS study. However. Achievement of remission is cumulative over a period of time after completion of the induction phase.10 The menstrual abnormalities were also not different in the two groups in our study. regular dose 239 . In contrast to the ALMS trial.5 vs. 76% in the CYC group). The bold and asterisk mark indicate significant difference in the 2 groups.10 but no one withdrew from the study for GI toxicity. Only 40% subjects were able to achieve to receive the target 2. The number of infection episodes was similar in both groups in this investigation. the percentage of subjects with different biopsy classes in the two studies is different.001. respectively. Second. The rate of remission in the CYC arm of our study is also better than that reported in the multicenter study by Ginzler et al.M Rathi et al. it may be due to lower doses of the drugs used in our study as compared with ALMS.75–1 mg/kg per day was used for an unspecified period followed by taper to 10 mg/day. respectively).5–3.22  0.20 no previous studies have reported any difference in GI symptoms between MMF and CYC groups. Although the GI manifestations are known complications of MMF therapy. mycophenolate mofetil. The ELNT trial did not provide details regarding GI side effects in the low-dose CYC group.15 where a dose of 0. which showed significantly higher rates of complete remission with MMF compared with high-dose intravenous CYC (22. cyclophosphamide. and 12. compared with 4.9 and 2. GI symptoms were more frequent in the MMF group.

Another important limitation is that the dose of MMF was not concentration controlled. and uPCR were performed. whereas complement levels and anti-double–stranded deoxyribonuclease antibody were checked at the end of 12 and 24 weeks. IIIþV. with fewer GI side effects. These include a better GI tolerability and shorter course of induction treatment. and the cost advantage of CYC therapy may be lost if payment is needed for extra visits. Larger multicenter studies with a longer follow-up are required to extrapolate these results to lupus populations in other parts of the world. There may be some differences in the metabolism of this drug by race leading to higher exposure and toxicity in our subjects despite receiving a relatively low dose. The study was approved by the Institute Ethics Committee and was registered with Clinical Trial Registry–India (CTRI/2013/12/004179). or IVþV LN based on the International Society of Nephrology/Renal Pathology Society classification were included. 25% patients in our study had pure class-V lesion. The treatment protocol remained the same with no change during the trial period. In case of GI intolerance. all subjects were shifted to maintenance treatment with azathioprine (2 mg/kg) and steroids (5–7. randomized.: Low-dose intravenous CYC versus oral MMF in lupus nephritis adjustments. week 4. complete blood counts. renal function tests. depending on the leukocyte count and tolerability. thus. The cost of therapy is a major factor driving treatment decisions in economically deprived countries. V. between June 2011 and March 2014. and this cost difference was despite using generic MMF. and results may have been different had we included only proliferative LN. The total treatment cost over a 6-month period was almost sevenfold lower in the CYC group as compared with the MMF group. and 24 weeks. single daily dose) as well as either angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. IV. patients with severe LN and crescentic LN were excluded by design. Similarly. non-inferiority. avoiding hospitalization and ensuring that the drug was received.5–3. Considering these advantages.23. Finally. The CYC was given in the day care setting. anti-double–stranded deoxyribonuclease antibody.0 mmol/l.24 The estimated glomerular filtration rate Kidney International (2016) 89. Our study also had a short follow-up. which is considered to be a more benign disease. MATERIALS AND METHODS Study design and subjects This was an open-label. An informed consent was obtained from all study participants or their parents/legal guardians. whereas it was increased to a maximum dose of 1500 mg twice a day at 4 weeks. it is reasonable to choose low-dose CYC over MMF for the treatment of less severe LN. This was a single-center study with subjects belonging to a single ethnicity. the results need validation in a large multicenter study involving different races and ethnicities. it is worth pointing out that the cost difference is related to the way the health-care system is structured. the dose was increased to 1000 mg twice a day. The study was not blinded. and complement levels. Ours is a public sector hospital that does not charge patients for infusion. At 2 weeks. renal function tests. Moreover. the frequency of drug was changed to thrice daily. Those in the MMF group were followed-up at week 2.22 Those with crescentic LN (>50% crescents in biopsy). uPCR in a 24 h urine sample. However. CYC was administered as six fortnightly intravenous infusions at a fixed dose of 500 mg each.5 mg/day). Subjects were enrolled from the Nephrology and Rheumatology departments of the Post Graduate Institute of Medical Education and Research. Patients of either sex between the ages of 12 and 65. followed by a change to mycophenolate sodium formulation if required. serum albumin. Although we observed no difference in the treatment outcomes in the MMF and CYC groups. prospective. infusion. particularly when the cost of therapy is met by out-of-pocket expenditure. and thus is a good induction treatment option for patients with moderately severe LN in the Indian population. anti-nuclear antibodies. At the end of induction treatment. Follow-up visits Subjects in the CYC group were followed-up every 2 weeks for 12 weeks and then every 4 weeks through week 24. 6 months in the MMF group and 3 months in the CYC group.0 g/day. serum creatinine of >265. or day care treatment. as revised in 2000. pregnancy. low-dose intravenous CYC appeared to have some advantages over MMF. we cannot predict the durability of response over the long term. urine examination. that is. In addition. and this might have led to biases in recruitment of subjects or analysis of results. 235–242 . Baseline investigations included complete blood counts. or nursing care. and subsequently every 4 weeks through week 24. and a timely switch to monthly CYC regimen in cases of non-responsive patients may help in reducing the mortality rate. Thus. and thus it remains to be seen how each of these treatment regimens performs in that situation.clinical trial M Rathi et al. and prior treatment with CYC or MMF were excluded. nursing. 12 weeks. These results should be interpreted in the light of several limitations of our study. All subjects were given hydroxychloroquine (6 mg/kg. and the procedures followed were in accordance with the ethical standards of the responsible committees on human experimentation (institutional and national) and with the Declaration of Helsinki Principles 1975. ongoing infection. all subjects received three daily intravenous injections of methylprednisolone (750 mg each) at the beginning of treatment followed by oral prednisolone (1 mg/kg per day) for 8 weeks and subsequent tapering. Study treatment and drug dosing MMF was initiated at a dose of 500 mg twice a day and increased every 2 weeks to achieve a target dose of 1. understanding how MMF blood levels correlate with response and toxicity may also permit more careful monitoring of the drug and decrease adverse outcomes. neurological or pulmonary lupus. diagnosed to have SLE as per American College of Rheumatology (ACR) criteria. Chandigarh. A monthly telephonic contact was made throughout the study period to collect safety and concomitant medication information. In conclusion. our study demonstrates low-dose intravenous CYC to be as effective as oral MMF. The disease activity was assessed by SLEDAI scoring according to Safety of Exogenous Estrogens in Lupus Erythematosus National Assessment modification (SELENA–SLEDAI) at baseline. parallel group study conducted at a single center with the 240 hypothesis that the low-dose intravenous CYC is similar to oral MMF in terms of efficacy and safety in subjects with less severe LN. At each follow-up.21 and biopsy-proven class III. In case of persistence of symptoms. the dose of MMF was reduced stepwise by 25%.

or interpretation of data for the work. 1997. They have made substantial contributions to the conception or design of the work or the acquisition. analysis. D’Cruz D. Bomback AS. edited the manuscript. 1993.57:95–107.5 g/day and inactive urine sediment. 15. ACKNOWLEDGMENTS We thank Dr Brad H Rovin (Professor and Director. DISCLOSURE All the authors declared no competing interests. Roth D. data analysis. The sample size was determined using the Sealed Envelope sample size calculator to determine the sample size for a 2 arm. Change in the SLEDAI score was assessed by the Wilcoxon signed-rank test. 2006.19:263–270.353:2219–2228. accounting for a withdrawal rate of 10%. J Am Soc Nephrol. Vasconcelos C. J Am Soc Nephrol. Dooley MA. Combination therapy with pulse cyclophosphamide plus pulse methylprednisolone improves long-term renal outcome without adding toxicity in patients with lupus nephritis.and post-treatment values. 2000. Jayne D. along with stabilization or improvement in serum creatinine (a 24-week serum creatinine level within 25% of baseline). Gourley MF. All calculations were performed using SPSS version 21 (Statistical Packages for the Social Sciences. Is “aggressive” therapy necessary for systemic lupus erythematosus? Rheum Dis Clin North Am. MR. et al. Further. and AJ have drafted the manuscript.15 and 71% with low-dose CYC (as per the ELNT study)10 and the noninferiority criteria of 10%. Appel GB. Balow JE. 12. 2002. Controlled trial of pulse methylprednisolone versus two regimens of pulse cyclophosphamide in severe lupus nephritis. Walsh M. Nephrol Dial Transplant. Klippel JH. AS. et al. 16. 50 subjects per group needed to be recruited.M Rathi et al. Efficacy of mycophenolate mofetil in patients with diffuse proliferative lupus nephritis. 235–242 clinical trial AUTHOR CONTRIBUTIONS All the authors meet the four criteria defined by ICMJE. 1986. Ann Intern Med. defined as return to normal serum creatinine along with proteinuria #0. Lancet. N Engl J Med.125: 549–557. 2005. Waldman M. Pardo V. Department of Internal Medicine. Chan TM.19: 703–710. xHong KongGuangzhou Nephrology study group. Austin HA 3rd. 14. The McNemar test was applied to compare between pre. in patients with lupus nephritis. Urowitz MB. IL) on a Windows platform. and provided intellectual support. Appel GB. Boumpas DT. whereas non-normal data were tested by the MannWhitney’s U-test.25 Study end points The primary outcome measure was ‘treatment response’. The randomization was performed with an in-center computergenerated random number table by an authorized study coordinator. A two-sided P-value of <0. leading to a total sample size of 100 subjects. et al. alone or in combination. Kidney International (2016) 89.314:614–619. REFERENCES 1. and the subjects were randomized in a 1:1 ratio to receive either intravenous low-dose CYC or oral MMF. 6. 9. Proportions were compared using c2 or Fisher exact test as applicable. Li FK. depending on the missing observations therein. 45 subjects per group would be required. and (iii) adverse events. VJ and HSK have supervised the patient management. Methylprednisolone and cyclophosphamide. N Engl J Med. Clin Nephrol. et al. Mycophenolate mofetil or intravenous cyclophosphamide for lupus nephritis. provided intellectual support. Statistical analysis Analyses were performed by considering all observations pertaining to each variable. Tse KC. 2010.135:248–257. Division of Nephrology. Austin HA 3rd. The Ohio State University. Induction and maintenance therapy for lupus nephritis: a systematic review and meta-analysis. Lupus. For normally distributed data. MR.12:2057–2059. Lupus nephritis: a clinical review for practicing nephrologists. et al. critically reviewed. Long-term study of mycophenolate mofetil as continuous induction and maintenance treatment for diffuse proliferative lupus nephritis. N Engl J Med. (ii) SELENA– SLEDAI score. a randomized trial of low-dose versus high-dose intravenous cyclophosphamide. 13. Mycophenolate mofetil for induction therapy of lupus nephritis: a systematic review and meta-analysis. AG and AJ have recruited the patients and randomized them. Chan TM. 2009. MR and AS have supervised the randomization and patient recruitment and contributed to patient management and end point assessment. Qualitative or categorical variables were described as frequencies and proportions. controlled trial. J Am Soc Nephrol. The authors have contributed to the draft preparation and revising it critically for important intellectual content. Normality of the quantitative data was checked by the Kolmogorov-Smirnov test. Immunosuppressive therapy in lupus nephritis: the Euro-Lupus Nephritis Trial. AG. and 24 weeks. Scott D. USA) for reviewing the manuscript. thus giving a sample size of 90. 3. AG. et al. 2005. randomized. where other variables were taken as predictors for imputing missing observations of the individual variables for ITT analysis. et al. Clin J Am Soc Nephrol. Contreras G. Crane M. and literature search. Austin HA. Aranow C. 2002. With in-patient–related variables were compared using a paired t-test or analysis of variance. Illei GG. Therapy of lupus nephritis: controlled trial of prednisone and cytotoxic drugs. Ginzler EM. Houssiau FA. et al. Tang CS. 2007.16:1076– 1084.343: 1156–1162. Appel GB. 12 weeks.46:2121–2131.340:741–745. Austin HA 3rd. and VK have helped in data acquisition. means for the two groups were compared using Student’s t-test. 241 . The secondary outcome measures were as follows: (i) ‘complete renal remission’. 7. RR. Woo JH. et al. 2010.20:1103–1112. et al. Dooley MA. He has performed language editing and provided valuable feedback to improve the quality of paper. Vaughan EM. et al. and KLG and VS have supervised the study. 5. Contreras G. 1996.21:2028–2035. 1992. Mycophenolate mofetil versus cyclophosphamide for induction treatment of lupus nephritis. Arthritis Rheum. 2001. Chicago. 8. defined as a decrease in the uPCR to <3 in subjects with a baseline ratio $3 or a decrease in uPCR by $50% in those with a baseline ratio <3. Hence. Choi S. 4. Update on the treatment of lupus nephritis.05 was considered significant. Tang CS. Continuous data are presented as mean  SD or median and interquartile range.70:1403–1412. The results under APP analysis thus have different sample sizes (n). and PKG have performed the data acquisition and statistical analysis.: Low-dose intravenous CYC versus oral MMF in lupus nephritis was calculated using modified ‘Modification of Diet in Renal Disease (MDRD)’ equation at baseline. it was estimated that to achieve 80% power with one-sided confidence interval of 95%. the data set was not adjusted by omitting all missing variables globally. Kidney Int. Treatment of lupus nephritis: the advantages of a flexible approach. 2. Missing observations were imputed under a multivariate setting. A randomized. and edited the manuscript. Ann Intern Med. MR has conceptualized and designed the study. OH. James M. as appropriate. Assuming a response rate of 56% with MMF (as per the ALMS trial). Lee Y.2:968–975. All the authors have approved the final version of the draft and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. In addition. et al. parallel group trial with the outcome variable being binary and the objective of showing non-inferiority. Update on the treatment of lupus nephritis. 11. Ponticelli C. 10.

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