Key points from the evidence

The content of this evidence summary was up-to-date in November 2014. See summaries of product characteristics (SPCs), British national formulary (BNF), BNF for children (BNFc) or the MHRA or NICE websites for up-to-date information.

Summary

Evidence from a Cochrane review of randomised controlled trials (RCTs) and quasi-RCTs suggests that mycophenolate mofetil is as effective as cyclophosphamide at inducing remission in lupus nephritis, but with a lower risk of ovarian failure. For maintenance therapy in lupus nephritis the Cochrane review found that mycophenolate mofetil was more effective than azathioprine for preventing relapse, with no increase in clinically important adverse events. Data in non-renal systemic lupus erythematosus mainly come from observational studies; further RCTs assessing the efficacy and safety of mycophenolate in people with non-renal systemic lupus erythematosus are needed.

Regulatory status: Off-label. This topic was prioritised because there was a high volume of requests from the NHS. Immunosuppressants such as mycophenolate are widely used in people with systemic lupus erythematosus, but not all are specifically licensed for this indication.

Effectiveness

  • A Cochrane review found that there was no overall difference for mortality or any renal outcome between mycophenolate mofetil and intravenous (up to 7 studies, n=up to 710) or oral (1 study, n=62) cyclophosphamide for induction therapy in lupus nephritis.

  • The Cochrane review found that there was a higher risk of renal relapse in people with lupus nephritis maintained on azathioprine compared with those maintained on mycophenolate mofetil (3 studies, n=371, RR 1.83, 95% CI 1.24 to 2.71), but there was no statistically significant difference between them in mortality.

  • Low quality data in non-renal systemic lupus erythematosus suggest some effectiveness for mycophenolate mofetil.

Safety

  • Immunosuppressants including mycophenolate have been associated with increased risks of lymphomas, other malignancies, opportunistic infections that can be fatal, sepsis and neutropenia.

  • Mycophenolate has also been associated with pure red cell aplasia and serious gastrointestinal adverse events (Cellcept, Roche and Myfortic, Novartis summaries of product characteristics).

Patient factors

  • For induction therapy in lupus nephritis, mycophenolate mofetil was found to be associated with a lower risk of toxic adverse events such as ovarian failure, alopecia and leucopenia, compared with cyclophosphamide.

  • Reduced risk of ovarian failure may be particularly important because systemic lupus erythematosus affects women of child bearing potential.

  • In a systematic review of mycophenolate mofetil for non-renal manifestations of systemic lupus erythematosus, the most common adverse events were infection (32%), nausea and vomiting (24%) and diarrhoea (12%).

Resource implications

  • The annual cost of generic mycophenolate mofetil at a dose of 2000 mg to 3000 mg daily is £519.76 to £779.64 (excluding VAT; Drug Tariff, October 2014).

  • The annual cost of mycophenolate sodium (Myfortic) at a dose of 720 mg twice daily is higher at £2353.40 (excluding VAT; MIMS, October 2014).

Introduction and current guidance

Systemic lupus erythematosus is a chronic autoimmune condition that causes inflammation in the body's tissues. Disease activity varies over time and, at the onset, symptoms are very general and may include unexplained fever, extreme fatigue, muscle and joint pain and skin rash. Active systemic lupus erythematosus involves frequent flares and more severe symptoms compared with inactive disease which is when the disease is in remission. Systemic lupus erythematosus can lead to arthritis, kidney failure, heart and lung inflammation, central nervous system abnormalities and blood disorders.

The aim of current treatments for systemic lupus erythematosus is to control and ease symptoms. Standard therapy includes the use of non-steroidal anti-inflammatory drugs (NSAIDs); corticosteroids such as prednisolone; disease-modifying drugs such as hydroxychloroquine; and immunosuppressants such as azathioprine, cyclophosphamide, methotrexate and mycophenolate mofetil. Rituximab is also considered as a treatment option, particularly in the case of more severe disease, and is covered by an interim clinical commissioning policy statement by NHS England for certain people with the disease. Not all of these drugs are licensed specifically for use in people with systemic lupus erythematosus and use of some of these drugs would be off-label (see the summaries of product characteristics for the individual drugs for specific prescribing information). Belimumab is a newer therapy which is licensed for add-on therapy in adults with active, autoantibody-positive systemic lupus erythematosus with a high degree of disease activity. A NICE technology appraisal, systemic lupus erythematosus (autoantibody-positive) – belimumab is in development (expected date of publication April 2015).

Full text of Introduction and current guidance.

Product overview

Mycophenolic acid is an immunosuppressant agent with antiproliferative activity that acts through inhibition of the purine biosynthetic pathway. Mycophenolic acid is available as the prodrug, mycophenolate mofetil (which is available as a generic product or as branded products, such as Cellcept) or as mycophenolate sodium (Myfortic).

Both mycophenolate products are licensed for the prophylaxis of acute transplant rejection. Neither is licensed for treating systemic lupus erythematosus, therefore use for this indication is off-label.

NICE has published an evidence summary on another off-label use of mycophenolate: scleroderma: oral mycophenolate (ESUOM 32).

Full text of Product overview.

Evidence review

This summary looks at the evidence for using mycophenolate for treating lupus nephritis, and non-renal manifestations of systemic lupus erythematosus. The evidence for lupus nephritis is based on a Cochrane review of RCTs and quasi-RCTs. The evidence for non‑renal systemic lupus erythematosus is based mainly on observational studies, but includes 1 RCT which assessed non-renal secondary outcomes in a trial designed primarily to assess the efficacy of mycophenolate in lupus nephritis, and 1 other small RCT. Two small observational studies assessing mycophenolate for juvenile-onset systemic lupus erythematosus are discussed briefly in the evidence summary.

Most of the studies included in this evidence summary used mycophenolate mofetil, rather than mycophenolate sodium, and the dose was normally between 2000 mg and 3000 mg daily. Only 1 study (n=81) in the Cochrane review used mycophenolate sodium for induction therapy in lupus nephritis, and 1 small RCT (n=14) compared mycophenolate sodium with other conventional immunosuppressive agents in people with systemic lupus erythematosus without renal involvement.

  • Overall, the Cochrane review (Henderson et al. 2012) found that there was no difference in mortality or any renal outcome between people receiving mycophenolate mofetil and intravenous or oral cyclophosphamide (off‑label use) for induction therapy in lupus nephritis.

    • When mycophenolate mofetil plus corticosteroids was compared with intravenous cyclophosphamide plus corticosteroids there was no statistically significant difference between the groups in mortality (7 studies, n=710, relative risk [RR] 1.02, 95% confidence interval [CI] 0.52 to 1.98; absolute risk of mortality in the intravenous cyclophosphamide groups in the studies ranged between 0% and 12%), or complete renal remission (6 studies, n=686, RR 1.39, 95% CI 0.99 to 1.95; absolute rate of complete renal remission in the intravenous cyclophosphamide groups in the studies ranged between 15% and 20%). There was also no statistically significant difference between the groups in partial renal remission (6 studies, n=686), stabilisation of kidney function (5 studies, n=523), incidence of end-stage kidney disease (3 studies, n=231), risk of renal relapse (1 study, n=140), complete remission of proteinuria (6 studies, n=686), partial remission of proteinuria (4 studies, n=602), or daily proteinuria (4 studies, n=271).

    • When mycophenolate mofetil plus corticosteroids was compared with oral cyclophosphamide plus corticosteroids, there was also no statistically significant difference between the groups in mortality, incidence of end-stage kidney disease, or other renal outcomes, but all the results were from 1 small study (n=62).

    • When mycophenolate mofetil plus corticosteroids was compared with tacrolimus (off‑label use) plus corticosteroids, there was no statistically significant difference between them in risk of mortality, end-stage kidney disease, deterioration in kidney function or other renal outcomes. However, these comparisons were based on 1 or 2 small studies (n=40 to 130).

    • The combination of mycophenolate mofetil, plus tacrolimus, and corticosteroids was statistically significantly better than intravenous cyclophosphamide plus corticosteroids for increasing the number of people with stable kidney function and complete renal remission. However, these comparisons were based on just 1 small study (n=40).

    • Comparing rituximab (off-label use) plus mycophenolate mofetil with mycophenolate mofetil alone found no difference between the groups in risk of mortality, stability of kidney function, or other renal outcomes, but again this was based on 1 small study (n=144).

  • Three studies in the Cochrane review (Henderson et al. 2012) compared azathioprine plus corticosteroids (licensed use) with mycophenolate mofetil plus corticosteroids for maintenance therapy in lupus nephritis (n=371). There was a higher risk of renal relapse in people maintained on azathioprine compared with those on mycophenolate mofetil (RR 1.83, 95% CI 1.24 to 2.71), but there was no statistically significant difference between them in mortality.

  • A systematic review (Pego-Reigosa at al. 2013) assessing the efficacy and safety of non-biologic immunosuppressants in the treatment of non-renal systemic lupus erythematosus in adults included 1 RCT (n=370) and 7 cohort studies (n=584) evaluating mycophenolate mofetil. The primary objective of the included RCT (Ginzler et al. 2010) was to assess efficacy of mycophenolate in lupus nephritis and the non-renal outcomes were secondary end points with only descriptive analysis. Although the RCT suggests that both mycophenolate mofetil and intravenous cyclophosphamide are effective at treating non‑renal manifestations of systemic lupus erythematosus, the results are only applicable to people with lupus nephritis and concurrent non-renal disease activity and may not be generalised to people with systemic lupus erythematosus without renal involvement.

  • Another systematic review (Mok 2007) assessed using mycophenolate mofetil for non‑renal manifestations of systemic lupus erythematosus. The review included 20 studies, which were all case series and open-label studies. Favourable results with mycophenolate mofetil were reported in people with haematological disease, while conflicting evidence regarding the efficacy of mycophenolate on lupus skin lesions was reported.

  • Lourdudoss and van Vollenhoven (2014) report the results of a single centre retrospective cohort study using mycophenolate mofetil for treating systemic lupus erythematosus and vasculitis. Separate results for those with a diagnosis of systemic lupus erythematosus, and those with vasculitis were not presented and so it is difficult to draw any firm conclusions from this study.

  • Two small observational studies (Falcini et al. (2009); n=26, and Buratti et al (2001); n=11) assessed using mycophenolate mofetil for treating juvenile-onset systemic lupus erythematosus. For more information about these studies see the evidence review section.

  • The Cochrane review (Henderson et al. 2012) found that, when used as induction therapy, mycophenolate mofetil was associated with an 85-90% lower risk of ovarian failure, compared with either oral or intravenous cyclophosphamide. The actual risk of ovarian failure ranged from 3% to 4.4% in the intravenous cyclophosphamide groups compared with an estimated risk in the mycophenolate mofetil groups of 0.5% to 0.7%.

    • The incidence of alopecia and leucopenia was also statistically significantly lower with mycophenolate mofetil compared with either oral or intravenous cyclophosphamide. The rate of major infections was statistically significantly lower with mycophenolate mofetil compared with oral cyclophosphamide, but there was no difference compared with intravenous cyclophosphamide.

    • Diarrhoea was statistically significantly more common with mycophenolate mofetil compared with cyclophosphamide, but there was no statistically significant difference in the incidence of vomiting, nausea, or general gastrointestinal upset between groups.

    • There was no difference between mycophenolate mofetil plus corticosteroids and tacrolimus plus corticosteroids in risk of major infection or leucopenia. There was also no difference between rituximab plus mycophenolate mofetil and mycophenolate mofetil alone in risk of major infection or leucopenia.

  • The Cochrane review (Henderson et al. 2012) also reported safety data from studies in maintenance therapy in lupus nephritis. Compared with azathioprine plus corticosteroids, mycophenolate mofetil plus corticosteroids was associated with a statistically significantly lower incidence of leucopenia.

  • In the studies assessing mycophenolate for non-renal systemic lupus erythematosus that reported safety, gastrointestinal upset (for example diarrhoea, nausea and vomiting) and infections were the most commonly reported adverse events.

  • The evidence base for lupus nephritis comes from a Cochrane review. However the review had some important limitations such as heterogeneity in interventions, definitions of remission and outcome reporting. In addition some of the studies included in the review had follow-up durations that were too short to pick up important outcomes such as remission with cyclophosphamide, ovarian failure and end-stage kidney disease. The evidence base for non-renal manifestations of systemic lupus erythematosus is mainly based on observational studies, which have limitations inherent in their non-randomised design. Of the 2 RCTs included, 1 assessed non-renal secondary outcomes in a trial primarily designed to assess efficacy in lupus nephritis; therefore limiting the applicability of the results to people with systemic lupus erythematosus without renal involvement. The other RCT was very small (n=14) and underpowered.

Context and estimated impact for the NHS

The estimated annual cost of generic mycophenolate mofetil at a dose of 2000 mg to 3000 mg daily is £519.76 to £779.64 (Drug Tariff October 2014; excluding VAT). Mycophenolate sodium (Myfortic) is more expensive, at an estimated annual cost of £2353.40 for 720 mg twice daily (MIMS October 2014; excluding VAT).

No estimate of the current use of off-label mycophenolate for treating systemic lupus erythematosus in UK clinical practice was identified.

Full text of Context and estimated impact for the NHS.

Information for the public

A plain English summary is available on the NICE website. This sets out the main points from the evidence summary in non-technical language and may be especially helpful for people with systemic lupus erythematosus who are thinking about trying mycophenolate.

About this evidence summary

'Evidence summaries: unlicensed or off-label medicines' summarise the published evidence for selected unlicensed or off-label medicines that are considered to be of significance to the NHS, where there are no clinically appropriate licensed alternatives. The summaries provide information for clinicians and patients to inform their decision-making and support the construction and updating of local formularies.

The summaries support decision‑making on the use of an unlicensed or off-label medicine for an individual patient, where there are good clinical reasons for its use, usually when there is no licensed medicine for the condition requiring treatment, or the licensed medicine is not appropriate for that individual.

The strengths and weaknesses of the relevant evidence are critically reviewed within this summary, but this summary is not NICE guidance.