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Systematic review and meta-analysis of randomised trials and cohort studies of mycophenolate mofetil in lupus nephritis

RA Moore and S Derry.

Review published: 2006.

CRD summary

The authors concluded that, compared with cyclophosphamide, mycophenolate mofetil produced more responses to treatment and lower rates of most adverse events in the treatment of lupus nephritis. These conclusions are in line with the evidence presented, but should be treated with some caution in view of the short duration of most included studies and the poor reporting of review methods.

Authors' objectives

To review the available evidence concerning the use of mycophenolate mofetil (MMF) in the treatment of lupus nephritis.

Searching

MEDLINE and PubMed (to October 2006) and the Cochrane Library (Issue 3, 2005) were searched; the search terms were reported. No language restrictions were imposed. Selected review articles and reference lists of articles retrieved by the searches were also screened. The company developing MMF as a therapy for lupus nephritis was approached for information about published or unpublished trials.

Study selection

Study designs of evaluations included in the review

Studies of any design were eligible for the review.

Specific interventions included in the review

Studies of MMF were eligible for inclusion. In the included studies, MMF was given at doses ranging from 125 mg to 3 g daily. Corticosteroids were given in addition to MMF in most studies. The comparator interventions included intravenous cyclophosphamide (CCP) and azathioprine. The patients were treated for less than 3 years in most included studies, although one study involved treatment for up to 84 months.

Participants included in the review

Studies of patients with complications of lupus nephritis or systemic lupus erythematosus (SLE) were eligible for inclusion. Only studies with patients with both SLE and lupus nephritis were included in the analysis of efficacy. Any definition of lupus nephritis was accepted. The patients included in the studies were predominantly women, with an average age ranging from early- to mid-30s. Of those patients with lupus nephritis for whom the World Health Organization classification was reported, the majority were in Class IV. The ethnicity of included patients, either stated or inferred, varied widely between the studies; for example, white patients formed 9% of patients in randomised trials, 24% in cohort studies of lupus nephritis and 59% in cohort studies of SLE generally.

Outcomes assessed in the review

No inclusion criteria were specified for the outcomes. Studies reporting only biochemical, pharmacokinetic or immunological information were excluded. The outcomes reported were complete response to treatment, complete or partial response (both as defined by the study authors), subsequent relapse, mortality and adverse events. Only studies in which all patients had lupus nephritis were included in the analysis of efficacy outcomes.

How were decisions on the relevance of primary studies made?

The authors did not state how the papers were selected for the review, or how many reviewers performed the selection.

Assessment of study quality

The validity of randomised controlled trials (RCTs) was assessed using the Jadad scale; studies were awarded a score of between 0 and 5 based on randomisation, blinding, and the handling of withdrawals and drop-outs. The authors did not state how many reviewers performed the validity assessment. The validity of the cohort studies was not assessed.

Data extraction

Two reviewers independently extracted data for the review; any disagreements were resolved by consensus. For studies published more than once, the study with the largest body of data, the most informative, or the more recent was selected, as appropriate, for data extraction.

Data on the numbers of beneficial and adverse events in MMF and comparator groups were extracted from RCTs and used to calculate relative risks (RRs) and numbers-needed-to-treat (NNT); for cohort studies, the percentage of patients with beneficial or harmful events was calculated.

Methods of synthesis

How were the studies combined?

Pooled RRs and NNT, with 95% confidence intervals (CIs), were calculated for RCTs using a fixed-effect model. One RCT contained no useful data and was not included in the pooled analysis. For cohort studies, the overall percentage of patients with adverse events was calculated by adding the number of patients in each cohort reporting the event and dividing by the total number of patients in these cohorts.

How were differences between studies investigated?

The authors stated that homogeneity between the studies was assessed visually; no further details were reported.

Results of the review

Six RCTs (n=370), 10 cohort studies of patients with lupus nephritis (n=212) and 8 cohort studies of patients with SLE with or without nephritis (n=284) were included.

RCTs.

Of the 5 studies used for the efficacy analysis, one had a quality score of 2 out of 5 and four scored 3 out of 5. MMF was significantly superior to CCP in the pooled analysis for complete response (RR based on 4 studies 1.5, 95% CI: 1.1, 2.1) and complete or partial response (RR based on 5 studies 1.2, 95% CI: 1.03, 1.4), but not for subsequent relapse (RR based on 2 studies 0.8, 95% CI: 0.4, 1.4). Death was significantly less common with MMF than with CCP (RR based on 5 studies 0.2, 95% CI: 0.07, 0.7), as were hospital admission, infections, serious infections, leucopenia, amenorrhoea and hair loss. Diarrhoea was significantly more common with MMF (RR based on 4 studies 4.0, 95% CI: 1.5, 10).

Cohort studies.

Complete or partial response to MMF was reported in 121 out of 151 patients (80%) in 7 cohorts. The most common adverse events reported in cohort studies were gastrointestinal disorders (30%; reported in 14 cohorts), infections (23%; reported in 10 cohorts) and hair loss (12%; reported in 2 cohorts). Forty out of 285 patients (14%) in 9 cohorts withdrew from treatment with MMF because of an adverse event.

Authors' conclusions

Compared with CCP, MMF produced more responses to treatment and the absolute difference was clinically meaningful, although the data were limited by the short-term nature of most of the studies.

CRD commentary

This review addressed a clear research question. The inclusion criteria for the participants and interventions were clear, whereas broad criteria were used for study designs and outcomes. The authors searched two databases without language restrictions and made some attempt to locate unpublished studies. Publication bias was not assessed, so it is difficult to comment on the risk of this bias in the review. The validity of RCTs included in the efficacy analysis was assessed using a standard method. The methods used for the study selection and validity assessment were not reported, making it difficult to assess the risk of errors and bias during these stages of the review. Two independent reviewers extracted the data.

Details of the included studies were presented in the paper; additional files are available on the Arthritis and Research Therapy website (accessed 03/10/2007). See Web Address at end of abstract. RCTs were combined by meta-analysis to give pooled estimates of efficacy and safety of MMF relative to CCP. Although the authors stated that they assessed heterogeneity, lack of detailed reporting makes it difficult to comment on whether the trials were sufficiently homogeneous for pooling to be appropriate. The appropriateness of combining the cohort studies is unclear given the diversity of the study designs and outcomes included. As the authors noted, most studies involved relatively short periods of treatment and follow-up and the results may not be applicable to longer term treatment. Overall, the authors' conclusions are in line with the evidence presented, but should be treated with some caution in view of the limitations of the evidence and lack of reporting of review methods. The review was partly funded by a company working on behalf of the company developing MMF as a treatment for lupus nephritis.

Implications of the review for practice and research

Practice: The authors did not state any implications for practice.

Research: The authors stated that future studies should not only report results for induction and maintenance of treatment response but should also investigate the effects of MMF in patients with different classes of lupus nephritis and different risk factors, for example, ethnicity.

Funding

Oxford Pain Research Trust; Hayward Medical Communications (working on behalf of Aspreva Pharmaceuticals Ltd).

Bibliographic details

Moore R A, Derry S. Systematic review and meta-analysis of randomised trials and cohort studies of mycophenolate mofetil in lupus nephritis. Arthritis Research and Therapy 2006; 8(6): R182. [PMC free article: PMC1794528] [PubMed: 17163990]

Indexing Status

Subject indexing assigned by NLM

MeSH

Cohort Studies; Humans; Immunosuppressive Agents /therapeutic use; Lupus Nephritis /drug therapy; Mycophenolic Acid /analogs & derivatives /therapeutic use; Randomized Controlled Trials as Topic

AccessionNumber

12007005095

Database entry date

31/01/2008

Record Status

This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.

CRD has determined that this article meets the DARE scientific quality criteria for a systematic review.

Copyright © 2014 University of York.

PMID: 17163990

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