Key points from the evidence

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

Summary

Observational studies suggest mycophenolate improves skin symptoms and may stabilise lung function in people with systemic sclerosis. The most common adverse effects were gastrointestinal tract disturbances and infections. However, observational studies have limitations and randomised controlled trials, particularly comparing mycophenolate with other treatments for scleroderma, are needed to clarify efficacy and safety in this condition.

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 scleroderma, but none are specifically licensed for this indication.

Effectiveness

  • Observational studies in people with diffuse cutaneous systemic sclerosis (n=25 to 147) suggest mycophenolate improves modified Rodnan skin scores by up to 10.0 points on a 51-point scale.

  • Observational studies including people with systemic sclerosis-associated interstitial lung disease (n=20 to 125) suggest mycophenolate may stabilise lung function, based on disease-oriented outcomes, such as forced vital capacity percentage of the predicted normal value (FVC%).

  • Most studies used mycophenolate mofetil, rather than mycophenolate sodium, at a dose of up to 1000 mg or 1500 mg twice daily.

Safety

  • Immunosuppressants including mycophenolate have been associated with increased risks of lymphomas, other malignancies, opportunistic infections that can be fatal, sepsis and neutropenia. (mycophenolate mofetil and Myfortic summaries of product characteristics [SPCs]).

  • Mycophenolate has been associated with pure red cell aplasia and serious gastrointestinal adverse events (mycophenolate mofetil and Myfortic SPCs).

  • The SPCs for mycophenolate mofetil state that there have been isolated reports of interstitial lung disease and pulmonary fibrosis in people treated with mycophenolate in combination with other immunosuppressants, some of which have been fatal.

Patient factors

  • There is little evidence on the effect of mycophenolate on patient-oriented outcomes, such as functional ability or breathlessness.

  • It is not known if mycophenolate has any effect on preventing scleroderma from progressing or on minimising any disability.

  • In an observational study in people with diffuse cutaneous systemic sclerosis (n=109), mycophenolate was discontinued in 8% of people because of adverse effects. The most common adverse effects were gastrointestinal tract disturbances (4.6%) and infections (3.7%).

Resource implications

  • The estimated annual cost of mycophenolate mofetil at a dose of 1000 mg twice daily is £345.14 (Drug Tariff June 2014; excluding VAT).

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

Introduction and current guidance

Scleroderma is an autoimmune condition affecting the skin, internal organs and blood vessels. This causes scarring and thickening of the tissue in these areas. There are 2 main types of scleroderma: localised scleroderma, which affects just the skin; and systemic sclerosis, which may affect blood circulation and internal organs, as well as the skin.

The aim of treatment in scleroderma is to relieve symptoms, prevent the disease getting worse, detect and treat any complications and minimise disability through occupational therapy and physiotherapy. Because scleroderma can affect many different parts of the body, various different medications may be needed (NHS Choices: scleroderma).

Immunosuppressants such as methotrexate, cyclophosphamide and mycophenolate may be taken to suppress the immune system and attempt to slow the disease's progression. None of these drugs is licensed specifically for use in people with scleroderma and use of any of these drugs would be off-label (NHS Choices: scleroderma; Scleroderma Society: Understanding and Managing Scleroderma).

Evidence-based, consensus-derived recommendations for treating systemic sclerosis were published by the European League against Rheumatism (EULAR) Scleroderma Trials and Research group in 2009 (Kowal-Bielecka et al. 2009). No formal recommendation on the use of mycophenolate was given because there was a lack of appropriate evidence. An update of the EULAR recommendations is expected in 2014.

Full text of introduction and current guidance.

Product overview

Mycophenolic acid is an immunosuppressant agent with antiproliferative activity that inhibits of the purine biosynthetic pathway. Mycophenolic acid is available as the prodrug mycophenolate mofetil or as mycophenolate sodium (Myfortic). Both mycophenolate products are licensed for the prophylaxis of acute transplant rejection. Neither is licensed for treating scleroderma, therefore use for this indication is off-label.

Full text of product overview.

Evidence review

There are no randomised controlled trials (RCTs) of mycophenolate for treating scleroderma. This evidence summary is therefore based on the largest, most recent observational studies that provide the best available evidence for using mycophenolate in people with this condition. Most people in the studies had diffuse cutaneous systemic sclerosis or systemic sclerosis‑associated interstitial lung disease. Most studies used mycophenolate mofetil, rather than mycophenolate sodium, at a dose of up to 1000 mg or 1500 mg twice daily.

  • A prospective, multicentre observational study in 147 people with early diffuse cutaneous systemic sclerosis assessed 5 different treatment protocols, 3 of which included mycophenolate mofetil (Herrick et al. 2010). In all patients, the modified Rodnan skin score decreased over time by a median of 8.5 points at 3 years (from a median of 24 [interquartile range 19 to 32] at baseline to 15.5 [interquartile range 9 to 24.5] on a 51-point scale). There were no statistically significant differences in the rate of change of skin scores over time between the different treatment protocols (p=0.43, or p=0.28 when adjusted for possible confounding factors).

  • A prospective, single-centre observational study assessed mycophenolate mofetil in 25 people with previously untreated recent-onset diffuse progressive cutaneous systemic sclerosis (Mendoza et al. 2012). The mean modified Rodnan skin score was reduced by 10 points, from 24.56±8.62 at baseline to 14.52±10.9 at an average of 18 months' follow-up (p=0.004). Lung function was assessed in 15 people using total lung capacity percentage of the predicted normal value (TLC%) and carbon monoxide diffusion capacity percentage of the predicted normal value (DLCO%). There was no change in either of these from baseline.

  • A retrospective, single-centre cohort study assessed mycophenolate mofetil in 98 people with diffuse cutaneous systemic sclerosis (Le et al. 2011). At 12-months' follow-up, there was a statistically significant reduction in the mean modified Rodnan skin score of 6.9 points; from a baseline of 24.4±9.5 to 17.5±10.4 (p<0.001). There was also a statistically significant improvement in physical disability assessed using the Health Assessment Questionnaire Disability Index (from a mean of 1.1±0.6 at baseline to 0.94±0.7 at 12 months; p<0.001), and no change in lung function (forced vital capacity percentage of the predicted normal value [FVC%] and DLCO%).

  • A systematic review and meta-analysis of observational studies assessed mycophenolate mofetil or mycophenolate sodium for the treatment of systemic sclerosis-associated interstitial lung disease (Tzouvelekis et al. 2012). This included a total of 69 people in 6 studies. The main efficacy outcome was lung function (FVC% and DLCO%), assessed before and at least 6 months after mycophenolate treatment. No statistically significant difference was seen for either outcome. For FVC%, the weighted mean difference was 1.48% (95% CI −2.77 to 5.72%, p=0.49), and for DLCO% it was −0.83% (95%CI −4.75 to 3.09%, p=0.93).

  • A retrospective, single-centre, case-control study compared mycophenolate mofetil or mycophenolate sodium (n=10) with oral or intravenous cyclophosphamide (n=10) in people with systemic sclerosis-associated interstitial lung disease (Panopoulos et al. 2013). There was no statistically significant change in lung function (as assessed by FVC%, DLCO% and TLC%) from baseline in either group. After 2 years of treatment, the difference from baseline in mean FVC% was 2.2±11.4% with mycophenolate (p=0.444) and 5.2±12.4% with cyclophosphamide (p=0.326).

  • A retrospective, single-centre, cohort study assessed mycophenolate mofetil in a wider population of 125 people with connective tissue disease-associated interstitial lung disease; 44 of whom had systemic sclerosis-associated interstitial lung disease (Fischer et al. 2013). For the entire cohort, mycophenolate mofetil was associated with statistically significant improvements in FVC% (7.3±2.6% at 156 weeks, p=0.004) and in DLCO% (7.1±2.8% at 104 weeks, p=0.01). The data presented in the paper for the subgroup of people with systemic sclerosis-associated interstitial lung disease were incomplete and difficult to analyse.

  • A retrospective, single-centre, cohort study (Nihtyanova et al. 2007) assessed the tolerability of mycophenolate mofetil in 109 people with diffuse cutaneous systemic sclerosis. Most people (79%) had received the drug for at least 1 year, most commonly at a dose of 2000 mg daily. Mycophenolate mofetil was discontinued in 34% of people; in 8% because of adverse effects. Adverse reactions were reported in 12% of people, most commonly gastrointestinal tract disturbances (4.6%) and infections (3.7%).

  • All the studies of mycophenolate for treating scleroderma are observational and, therefore, have limitations inherent in their non-randomised design. Most studies were single-arm, open-label studies, with no control group, in small numbers of people. This reduces the quality of the evidence on efficacy and safety that they can provide. The studies mainly reported disease-oriented outcomes such as skin score and lung function (FVC%, TLC% or DLCO%); defining what a clinically important difference is in these outcomes for people with scleroderma is difficult.

Full text of evidence review.

Context and estimated impact for the NHS

The estimated annual cost of mycophenolate mofetil at a dose of 1000 mg twice daily is £345.14 (Drug Tariff June 2014; excluding VAT). Mycophenolate sodium (Myfortic) is more expensive, at an estimated annual cost of £2353.40 for 720 mg twice daily (MIMS June 2014; excluding VAT).

No estimate of the current use of off-label mycophenolate for treating scleroderma 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 scleroderma 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.