Home About us Current issue Back issues Submission Instructions Advertise Contact Login   

Search Article 
  
Advanced search 
 
Saudi Journal of Kidney Diseases and Transplantation
Users online: 454 Home Bookmark this page Print this page Email this page Small font sizeDefault font size Increase font size 
 

Table of Contents   
ORIGINAL ARTICLE  
Year : 2017  |  Volume : 28  |  Issue : 5  |  Page : 1069-1077
Mycophenolate mofetil or cyclophosphamide in indian patients with lupus nephritis: Which is better? A single-center experience


1 Department of Medicine, Armed Forces Medical College and Command Hospital, Pune, Maharashtra, India
2 Department of Pathology and Laboratory Science, Armed Forces Medical College and Command Hospital, Pune, Maharashtra, India
3 Radiodiagnosis and Imaging, Armed Forces Medical College and Command Hospital, Pune, Maharashtra, India

Click here for correspondence address and email

Date of Web Publication21-Sep-2017
 

   Abstract 


Mycophenolate mofetil (MMF) is used extensively for the induction therapy of lupus nephritis (LN) and has even outpaced intravenous (i.v.) cyclophosphamide (CyP) as the initial choice of therapy. There are no studies comparing the response of MMF with standard dose i.v. CyP in Indian patients with LN. We conducted a 24-week prospective, randomized, open-label trial comparing oral MMF with monthly i.v. CyP as induction therapy for active biopsy proven Class III and IV LN. The primary end-point was response to treatment at 24 weeks, and the secondary end-points were complete remission, Systemic Lupus Erythematosus Disease Activity Index scores (SLEDAI) and adverse reactions. Of the 40 patients, 17 were randomized to the MMF group and 23 to the i.v. CyP group. Complete remission was seen in nine (52.94%) patients in the MMF group and 11 (47.82%) in the i.v. CyP group. Partial remission was seen in six (35.30%) in the MMF group and nine (39.13%) in the i.v. CyP group. At six months, the cumulative probability of response was not statistically significant between the two groups (P = 1.000). MMF is comparable to i.v. CyP in the management of LN in Indian patients having an equal safety profile. The dose of MMF required was lower than the conventional doses used in other studies suggesting genetic or environmental factors in the Indian population influencing the metabolism of MMF, which requires further evaluation. The cost of MMF is a limiting factor in its use. The use of i.v. CyP is favorable as the monthly doses ensure compliance and is also cost-effective.

How to cite this article:
Mendonca S, Gupta D, Ali S, Gupta P. Mycophenolate mofetil or cyclophosphamide in indian patients with lupus nephritis: Which is better? A single-center experience. Saudi J Kidney Dis Transpl 2017;28:1069-77

How to cite this URL:
Mendonca S, Gupta D, Ali S, Gupta P. Mycophenolate mofetil or cyclophosphamide in indian patients with lupus nephritis: Which is better? A single-center experience. Saudi J Kidney Dis Transpl [serial online] 2017 [cited 2020 Aug 4];28:1069-77. Available from: http://www.sjkdt.org/text.asp?2017/28/5/1069/215147



   Introduction Top


Mycophenolate mofetil (MMF) has now become the preferred initial choice for the induction therapy of lupus nephritis (LN) and has been shown to be noninferior to intravenous cyclophosphamide (i.v. CyP) in achieving adequate response in LN.[1],[2],[3],[4]

It is being used extensively in Indian patients; however, there is a paucity of data on the response of MMF compared to CyP in the Indian subcontinent.[5] Studies have shown that MMF has a better response compared to i.v. CyP in Afro-Americans, Hispanics, and Chinese patients; however, this has not been demonstrated in the Indian patients.[6],[7],[8]

The response to immunosuppressants is dependent on genetic, ethnic, environmental, and socioeconomic factors[9],[10],[11],[12] and hence, more Indian studies are required to validate the response of MMF. In the present study, MMF was compared to i.v. CyP in the induction therapy of LN and to study the response rate and adverse effect profile.


   Materials and Methods Top


Study design

This was a prospective, randomized, open-label study on patients with biopsy proven LN, on follow-up from November 2014 to November 2015 at the Department of Nephrology, Armed Forces Medical College, Pune, India. A total of 40 patients (both males and females) of all ages were included in this study. The primary end-point was to study the response to therapy in patients of LN treated with i.v. CyP and MMF. The secondary endpoints were complete remission, disease activity index, and adverse events.

The study population were patients diagnosed with systemic lupus erythematosus (SLE) according to the SLICC 2012[13],[14] and the American College of Rheumatology criteria.[15] LN was diagnosed based on biopsy findings as per the International Society of Nephrology/ Renal Pathology Society classification.[16]

All biopsy proven cases of LN were included in our study. Patients of both sexes and varied age-groups were considered. Patients with the following disease conditions: Chronic kidney disease (CKD) stage-3 and above, crescentic LN, pancreatitis, gastrointestinal hemorrhage within six months or active peptic ulcer disease within last three months, ongoing infection, bone marrow insufficiency with cytopenias not attributable to SLE, and prior treatment with CyP or MMF were excluded from our study group.

Complete remission was defined as urinary protein excretion <0.2 g/24 h with normal urinary sediment, serum albumin >3.5 g/dL, and stable renal function (normal serum creatinine or not >15% above the baseline values).

Partial remission was defined as urinary protein excretion in the range of 0.3–2.9 g/24 h and a decrease of at least 50% of baseline level, with serum albumin concentration of at least 3.0 g/dL and stable renal function.

Treatment failure was defined as urinary protein excretion that remained at/or >3.0 g/24 h, serum albumin concentration <3.0 g/dL and an increase in serum creatinine concentration >30% of the baseline value.

Sample size calculation

The sample size was estimated on the basis of a single proportion design. The target population from which we randomly selected our sample was considered 10,000. We assumed that the confidence interval of 16% and confidence level of 95%. The sample size actually obtained for this study was 36 patients. We planned to include 40 patients with 10% (approximately) dropout rate.

Procedure methodology

After written informed consent was obtained, a well-designed questionnaire was used to collect the data of the recruited patients. The questionnaire included demographic, clinical, and histopathological data. All the recruited patients were evaluated by a detailed physical examination with particular reference to features of SLE and LN, past treatment history, and other comorbid diseases. Renal investigations included complete urine analysis, 24-h urine protein excretion, blood urea, and serum creatinine levels. Renal biopsy was performed under ultrasonographic guidance after obtaining consent of the patient and undertaken only in those who did not have any of the aforementioned contraindications. Biopsy specimens were subjected to conventional histopathology as well as immunofluorescence studies. Based on the International Society of Nephrology/ Renal Pathology Society classification, activity, and chronicity scores were calculated.

Study protocol

Patients who received one of the two treatments (MMF or i.v. CyP) were followed-up over a period of one year. Their records were perused and relevant data obtained for comparison.

MMF group: Oral MMF was given twice daily, titrated from 750 mg twice daily in the 1st week, and 1.0 g twice daily in the 2nd week, to a target dosage of 1.5 g twice daily, if required, based on the disease activity and response. Reduction was permitted to 2 g/day in response to any adverse events.

The i.v. CyP group: patients in the CyP group received pulse CyP (750 mg/m2 of body surface area), which was adjusted to 500–1000 mg/m2 of body surface area every four weeks to maintain a nadir leukocyte count of 2.5–4.0 × 109/L for a total of six pulses. A 25% decrease in dosage for age older than 60 years, and serum creatinine level >3.4 mg/dL was followed.

All participants had received unified concomitant corticosteroid therapy according to protocol that consisted of three doses of i.v. pulse methylprednisolone 500 mg followed by oral prednisone (or equivalent) at an initial dose of 0.5 mg/kg/day. Prednisolone dosage was tapered by a decrease of 5 mg/day every two weeks until a dose of 10 mg/day was achieved, and this dosage was maintained till the end of six months.

Doses of angiotensin-converting enzyme (ACE) inhibitors and/or angiotensin receptor blockers had been unchanged during the six-month follow-up period. Target blood pressure was kept at 130/80 mm Hg.

Hyperlipidemia was treated using statins and/or fibric acid derivatives as required.

Patients were on follow-up in the hospital weekly for the initial four weeks, then every alternate week for eight weeks and then monthly thereafter. On each follow-up visit, patients were evaluated for clinical manifestations and laboratory investigations of LN and any adverse effects of therapy. Blood pressure and laboratory assessments, including complete blood cell count, urinalysis, 24-h urinary protein, and kidney and liver function were performed at each visit. Serum anti–double-stranded DNA antibodies and serum complement C3 levels were measured monthly.

A fasting lipid profile was measured every two months. Activity and chronicity indices were based on scores on renal pathologic examination. Renal and extrarenal disease activity of SLE was measured using the validated SLEDAI scores.[17],[18] SLEDAI scores were analyzed at the beginning of the study and six months posttreatment.


   Statistical Analysis Top


For description of baseline characteristics, results are given as mean ± standard or number and percentage for the two treatment groups. Values for proteinuria, serum albumin, serum creatinine, estimated glomerular filtration rate (eGFR; calculated using a version of the Modification of diet in based on data from CKD patients, where eGFR = 175 × (serum creatinine)−1234 × age−0179 × (0.79 if patient is female)[19] and serum complement C3 was log-transformed to obtain better approximation of normal distribution. To compare baseline characteristics between the two groups, analysis of variance was used for continuous variables, and Fisher exact tests were used for categorical variables. Odds ratio was calculated to find the strength of relationship between study parameters and the classes of LN patients. Data were analyzed using Statistical Package for the Social Sciences for Windows version 20.0 (SPSS Inc., Chicago, IL, USA). The level P <0.05 was considered as the cutoff value for significance.


   Results Top


This was a prospective comparative, open-label study where a total of forty patients (both males and females) of all ages were taken [Figure 1]. Baseline characteristics of patients are listed in [Table 1]. There was a predominance of females in both the groups with the average age being 26 ± 10.8 years in the MMF group and 25.7 ± 10.3 in the CyP group. Distributions of baseline serum creatinine, eGFR, serum albumin and serum complement C3 values were similar between the MMF and CyP groups. The degree of proteinuria tended to be higher in the MMF group than that in the CyP group (24-h protein excretion, 2.81g ± 3.2 vs. 2.45 ± 1.9 g/24 h, respectively; P = 0.126); there was no significant difference. The baseline pathologic types, active, and chronic indexes, and SLE disease activity index were comparable between the two groups [Figure 2].
Figure 1: Demographic chart depicting patient enrollment and follow-up.

Click here to view
Table 1: Baseline laboratory and clinical parameters in two groups.

Click here to view
Figure 2: Changes in proteinuria (a), serum albumin (b), eGFR (c), serum C3 levels (d) and SLEDAI scores (e) at 0, 3 and 6 months interval which shows improvement in all parameters. There is no statistically significant difference in response to MMF versus i.v. CyP.
SLE-DAI: Systemic lupus erythematosus disease activity index, MMF: Mycophenolate mofetil, i.v CyP: Intravenous cyclophosphamide.


Click here to view


Outcome at three months of induction therapy

The mean values of the various laboratory parameters in the two groups after three months of induction treatment are shown in [Table 2].
Table 2: Mean values for laboratory parameters of the two groups after 3 months of induction therapy.

Click here to view


Outcome at six months of induction therapy

During the six-month induction therapy, the primary outcome in the form of response to therapy was seen in 88.24% patients in the MMF group and 86.95% in the i.v. CyP group.

Complete remission was seen in nine of 17 patients (52.94 %) in the MMF group and 11 of 23 patients (47.82%) in the CyP group. The cumulative probability of complete remission was not statistically significantly different between the two groups (P = 0.861) [Table 3]. Partial remission was achieved in six patients (35.30 %) in the MMF group and nine patients (39.13%) in the i.v. CyP group, respectively. The difference in cumulative probability of response was not statistically significant between the two groups (P = 1.000) [Table 4]. SLEDAI score was 4.1 in the MMF group and 3.8 in the i.v. CyP group (P =0.14).
Table 3: Response after 6 months in both groups.

Click here to view
Table 4: Patients failing to achieve complete remission.

Click here to view


The mean values of the various laboratory parameters after six months of induction therapy are shown in [Table 5].
Table 5: Mean values for laboratory parameters of the two groups after the 6-month induction therapy.

Click here to view


The median time to response was nine weeks in the i.v. CyP group and 10 weeks in the MMF group (P = 0.9). The median time to achieve complete remission was 16 weeks in the i.v. CyP group and 18 weeks in the MMF group (P =0.7).

Adverse events

Adverse effects observed in both treatment groups are listed in [Table 6].
Table 6: Comparison of adverse effects in both groups.

Click here to view



   Discussion Top


This was a prospective, randomized, open-label comparative study of the efficacy of standard dose i.v. CyP compared to oral MMF in the induction therapy of LN in Indian patients. There is paucity of data on the subset of Indian patients on this aspect in spite of MMF being used extensively for the induction therapy of LN. The majority of studies have reported on Caucasians, Hispanics, Afro-Americans, and Chinese. Considering the large population of India with different genetic, ethnic, socioeconomic and cultural makeup vis a vis the other other subset of patients, this study and further large scale multicentric studies are essential. In our study, we found a very high response rate of 88.29% in the MMF group and 86.95% in the i.v. CyP group. Complete remission was achieved in 52% of the MMF group and 47% of the i.v. CyP group. Chan et al compared oral CyP with MMF and found remission rates of 76% in the CyP group and 81% in the MMF group in Chinese patients.[6] This study was carried out over a period of one year and oral CyP was used which has a higher cumulative immunosuppression due to use of higher dosage. These response rates prompted for further studies for the role of MMF in the induction therapy of LN.

Ginzler et al, compared MMF with i.v. CyP and reported that MMF was significantly superior to CyP (22.5% vs 5.8% complete remission).[20] The study was performed on Caucasian and Afro-American patients. Patients with severe disease and chronicity were also included and hence the low rates of response in this study.

These studies formed the basis of the landmark Aspreva Lupus Management Study (ALMS) which was a multicentric prospective randomized trial. The response rate of MMF was comparable with i.v. CyP and there were fewer side effects with the use of MMF. The response rate seen in the ALMS study was 56.2% and 53.0% and complete remission rates were 8.6% and 8.1% in the MMF and i.v. CyP groups, respectively.[2] This study also included patients with severe disease and hence, the low response rates. It also demonstrated a lower efficacy of i.v. CyP in patients with more resistant disease. These findings were extrapolated, and it was suggested that Asians may also respond poorly to i.v. CyP.

In the only Indian study comparing these two drugs, Rathi et al compared low dose i.v. CyP with oral MMF in Indian patients and found a response rate of 74% in both the groups and a complete remission rate of 50% in the i.v. CyP group and 54% in the MMF group.[5] This study demonstrated that the response to i.v. CyP was comparable to MMF in spite of low doses of i.v. CyP used, which are only recommended for European patients as per the EUROLUPUS study. The study also demonstrated that the use of i.v. CyP may be advantageous in Indian patients taking into consideration financial, educational, and socioeconomic factors of India which are very different compared to the areas and populations of the previous studies.

The adverse event profile in both the groups was comparable with vomiting being more common in the i.v. CyP group whereas diarrhea was more frequent in the MMF group. The rate of opportunistic infections was comparable in the two groups. The rates of alopecia were negligible in the two groups.

The present study highlights that Indian patients have a very good response to MMF or i.v. CyP during the induction therapy of LN with comparable results. However, India being a developing country with the majority of the population in the lower socioeconomic strata, the cost of MMF is a limiting factor in its use in routine clinical settings. Our center is government funded with free availability of MMF, in spite of which there were several episodes of poor compliance among the patients. Educational factors also play a major part in outcome of the disease. LN is a long-term disease, with prolonged treatment period and gradual response to therapy. This factor also accounts for the compliance fatigue in these patients compounded with the high cost of therapy with MMF. In the case of i.v. CyP, it is a monthly dose and is cost-effective and hence compliance rates may be better. This aspect requires further study and was not within the scope of this study.

The target dose of MMF required to achieve response is lower than that used in other studies suggesting that there may be genetic or environmental factors involved in the metabolism of MMF in Indian patients. This is an important factor brought out in this study which was also observed by Rathi et al and definitely requires further evaluation. It may also throw light on newer factors involved in MMF metabolism and action, suggesting genetic and metabolic investigations in Indian patients on MMF.

The limitation of our study was that it is a single-center study with a small population from Western India. The majority of the patient population had mild-to-moderate disease and the duration of the study was short. India is a country with diverse ethnicity and cultural practices and hence extrapolating these findings as universal can be confounding.

To summarize, MMF is comparable to i.v. CyP in the induction therapy of LN. The safety profile was similar in the two groups. The dose of MMF required in Indian patient to achieve a response is lesser than the conventional studies performed on other population cohorts suggesting further evaluation. i.v. CyP may be preferred in India taking into account cost, compliance, educational and socioeconomic factors in a developing country like India. The study prompts an urgent and essential need of a multicentric large population study comparing the response of these two drugs in the management of LN.


   Conclusion Top


The present study concludes that MMF is as good as i.v. CyP in the induction therapy of mild-to-moderate LN in Indian patients. The study also demonstrated that the dose of MMF required is lower than the dose used in conventional studies suggesting further investigation. It also suggests that i.v. CyP may be a better alternative taking into account the cost-effectiveness, educational, socioeconomic factors, and the prolonged period required to get a favorable outcome in this disease.

It also stimulates the idea of a larger multi-centric study to evaluate the effect of the two drugs, as India is a large country with very diverse racial, ethnic socioeconomic and cultural practices and hence, extrapolating single-center studies can be misleading.

Conflict of interest: None declared.



 
   References Top

1.
Kidney Disease: Improving Global Outcomes (KDIGO) Glomerulonephritis Work Group. KDIGO clinical practice guideline for glomerulonephritis. Kidney Int 2012;2 Suppl 2:S139-274.  Back to cited text no. 1
    
2.
Appel GB, Contreras G, Dooley MA, et al. Mycophenolate mofetil versus cyclophos-phamide for induction treatment of lupus nephritis. J Am Soc Nephrol 2009;20:1103-12.  Back to cited text no. 2
[PUBMED]    
3.
Singh JA, Hossain A, Kotb A, et al. Treatments for lupus nephritis: A systematic review and network metaanalysis. J Rheumatol 2016;43:1801-15.  Back to cited text no. 3
[PUBMED]    
4.
Tian SY, Feldman BM, Beyene J, et al. Immunosuppressive therapies for the induction treatment of proliferative lupus nephritis: A systematic review and network metaanalysis. J Rheumatol 2014;41:1998-2007.  Back to cited text no. 4
[PUBMED]    
5.
Rathi M, Goyal A, Jaryal A, et al. Comparison of low-dose intravenous cyclophosphamide with oral mycophenolate mofetil in the treatment of lupus nephritis. Kidney Int 2016;89: 235-42.  Back to cited text no. 5
[PUBMED]    
6.
Chan TM, Tse KC, Tang CS, et al. Long-term study of mycophenolate mofetil as continuous induction and maintenance treatment for diffuse proliferative lupus nephritis. J Am Soc Nephrol 2005;16:1076-84.  Back to cited text no. 6
[PUBMED]    
7.
Appel AS, Appel GB. An update on the use of mycophenolate mofetil in lupus nephritis and other primary glomerular diseases. Nat Clin Pract Nephrol 2009;5:132-42.  Back to cited text no. 7
[PUBMED]    
8.
Houssiau FA. Therapy of lupus nephritis: Lessons learned from clinical research and daily care of patients. Arthritis Res Ther 2012; 14:202.  Back to cited text no. 8
[PUBMED]    
9.
Deng XY, Wang CX, Wang XD, et al. Genetic polymorphisms of UGT1A8, UGT1A9, UGT2B7 and ABCC2 in Chinese renal transplant recipients and a comparison with other ethnic populations. Pharmazie 2013;68:240-4.  Back to cited text no. 9
[PUBMED]    
10.
Vieira SM, Pagovich OE, Kriegel MA. Diet, microbiota and autoimmune diseases. Lupus 2014;23:518-26.  Back to cited text no. 10
[PUBMED]    
11.
Yang Y, Tang Q, Zhao M, et al. The effect of mycophenolic acid on epigenetic modifications in lupus CD4+T cells. Clin Immunol 2015; 158:67-76.  Back to cited text no. 11
[PUBMED]    
12.
Oglesby A, Shaul AJ, Pokora T, et al. Adverse event burden, resource use, and costs associated with immunosuppressant medications for the treatment of systemic lupus erythe-matosus: A systematic literature review. Int J Rheumatol 2013;2013:347520.  Back to cited text no. 12
[PUBMED]    
13.
Petri M, Orbai AM, Alarcón GS, et al. Derivation and validation of the systemic lupus international collaborating clinics classification criteria for systemic lupus erythe-matosus. Arthritis Rheum 2012;64:2677-86.  Back to cited text no. 13
    
14.
Yu C, Gershwin ME, Chang C. Diagnostic criteria for systemic lupus erythematosus: A critical review. J Autoimmun 2014;48-49:10-3.  Back to cited text no. 14
[PUBMED]    
15.
Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythe-matosus. Arthritis Rheum 1997;40:1725.  Back to cited text no. 15
    
16.
Weening JJ, D’Agati VD, Schwartz MM, et al. The classification of glomerulonephritis in systemic lupus erythematosus revisited. J Am Soc Nephrol 2004;15:241-50.  Back to cited text no. 16
    
17.
Bombardier C, Gladman DD, Urowitz MB, Caron D, Chang CH. Derivation of the SLEDAI. A disease activity index for lupus patients. The committee on prognosis studies in SLE. Arthritis Rheum 1992;35:630-40.  Back to cited text no. 17
    
18.
Isenberg D, Ramsey-Goldman R. Assessing patients with lupus: Towards a drug responder index. Rheumatology (Oxford) 1999;38:1045-9.  Back to cited text no. 18
[PUBMED]    
19.
Levey AS, Bosch JP, Lewis JB, et al. A more accurate method to estimate glomerular filtration rate from serum creatinine: A new prediction equation. Modification of diet in renal disease study group. Ann Intern Med 1999;130:461-70.  Back to cited text no. 19
[PUBMED]    
20.
Ginzler EM, Dooley MA, Aranow C, et al. Mycophenolate mofetil or intravenous cyclo-phosphamide for lupus nephritis. N Engl J Med 2005;353:2219-28.  Back to cited text no. 20
[PUBMED]    

Top
Correspondence Address:
Satish Mendonca
Department of Medicine, Armed Forces Medical College and Command Hospital, Pune - 411 040, Maharashtra
India
Login to access the Email id


PMID: 28937065

Rights and Permissions


    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]



 

Top
   
 
 
    Similar in PUBMED
    Search Pubmed for
    Search in Google Scholar for
    Email Alert *
    Add to My List *
* Registration required (free)  
 


 
    Abstract
   Introduction
    Materials and Me...
   Statistical Analysis
   Results
   Discussion
   Conclusion
    References
    Article Figures
    Article Tables
 

 Article Access Statistics
    Viewed2299    
    Printed16    
    Emailed0    
    PDF Downloaded412    
    Comments [Add]    

Recommend this journal