Mycophenolate mofetil (MMF) for the treatment of connective tissue disease‐associated interstitial lung disease (ILD)

Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

To assess the efficacy of mycophenolate mofetil in the treatment of connective tissue disease‐associated interstitial lung disease.

Background

Description of the condition

Connective tissue diseases (CTDs) are a heterogeneous group of autoimmune conditions characterised by inflammation and occasionally fibrotic destruction of multi‐organ systems. CTDs can directly involve the respiratory tract in a variety of ways including as an interstitial lung disease (ILD) affecting the lung parenchyma. ILD is an important manifestation of many CTDs including rheumatoid arthritis, systemic sclerosis, idiopathic inflammatory myopathies (such as polymyositis and dermatomyositis), mixed connective tissue disease, as well as Sjögren's syndrome (a systemic autoimmune disease characterised by lymphocytic infiltration of the exocrine glands and potential extra‐glandular manifestations). Clinically significant ILD may be encountered in over half of sufferers of systemic sclerosis (Walker 2007) and in up to a third of patients with rheumatoid arthritis (Kim 2009).

Connective tissue disease‐associated interstitial lung disease (CTD‐ILD) is a major cause of morbidity and mortality, and this diagnosis frequently confers a negative prognostic value (Arsura 1988; Bouros 2002; Kim 2009). ILD may present as the initial manifestation of an underlying CTD. Over time, CTD‐ILD produces gradually worsening dyspnoea and decreased functional capability that place significant limitations on an individual's activities of daily living (Crockett 2010). On longitudinal monitoring, an inexorable decline in pulmonary function usually becomes evident, particularly in parameters that indicate ventilatory restriction (forced vital capacity(FVC) and total lung capacity(TLC)) and impaired gas exchange (diffusing capacity of the lung(DL_CO)). When sufficiently severe, CTD‐ILD has a high likelihood of causing complications such as pulmonary hypertension and cor pulmonale.

Like other forms of diffuse parenchymal lung disease, the presence of CTD‐ILD is best demonstrated using high‐resolution computed tomography (HRCT). The combination of symptom severity, extent of radiological abnormalities and the degree to which lung function is impaired provides a structure for 'staging' CTD‐ILD (Goh 2008).

CTDs arise as a result of generalised and organ‐based immune dysregulation and have a particular predilection for targeting the musculoskeletal and respiratory systems. These aspects of their pathobiology underscore the therapeutic utility of systemic corticosteroids and other immunomodulatory agents in the management of such conditions. Owing to incomplete knowledge about the causes and pathological mechanisms by which these conditions arise, many issues relating to their treatment remain unclear. Whilst a cure for CTD‐ILD is not presently achievable, the paucity of placebo‐controlled evaluations of immunosuppressive therapy in CTD‐ILD means that conventional drug management is reliant on limited prospective studies, retrospective reports and anecdotal experience. Although success in retarding the progression of lung disease may be a realistic goal in managing CTD‐ILD, any decision regarding initiation of therapy must be considered by balancing the likely benefit to be gained against the potential adverse effects of such treatment.

Description of the intervention

Mycophenolate mofetil (MMF) is an ester pro‐drug of the active immunosuppressant mycophenolic acid (MPA). It inhibits cell‐mediated immunity by suppressing the proliferation of T and B lymphocytes and also inhibits secondary antibody production induced by a variety of antigens (Allison 2000). Originally used in combination with other immunosuppressive agents to prevent solid‐organ transplant rejection, MMF has become recognised as a useful steroid‐sparing agent in the treatment of autoimmune disorders including systemic lupus erythematosus‐related renal disease (SLE; lupus nephritis) (Appel 2005). The use of MMF in the treatment of CTD‐ILD is becoming more common because of its relatively safe and better tolerated drug profile compared to a number of other immunosuppressive agents (Swigris 2006).

How the intervention might work

MMF is usually administered in combination with corticosteroids as an oral medication with clinical doses that range from 1 to 5 g over a 24‐hour period. A lower initial dose is often used and gradually increased depending on tolerability and efficacy. The use of MMF allows reduction of the dose of systemic corticosteroid; its efficacy on CTD‐ILD can be assessed clinically (symptom profile) and objectively (pulmonary function testing and radiological imaging). MPA, the active metabolite of MMF, undergoes glucuronidation to form a phenolic glucuronide compound called MPAG which is excreted in urine. MPAG is pharmacologically inactive and does not exert clinically significant adverse effects in individuals with renal, hepatic or cardiac insufficiency. This feature is advantageous to its safety profile when used in patients with complex multi‐system disorders. MMF is rapidly absorbed following oral administration and has a plasma half‐life of between 8 to 16 hours. It is also available as an intravenous formulation if required. Like many other immunosuppressant agents, the use of MMF is associated with risk of bone marrow suppression. Patients on MMF treatment should have regular blood testing to monitor for haematological abnormalities. It is also known to cause mild gastrointestinal side effects in some patients.

Why it is important to do this review

The management of CTD‐ILD poses significant challenges. CTD‐ILD is associated with significant morbidity in terms of but not limited to frequent and chronic symptoms, lowered health‐related quality of life and a substantial economic burden to society. Lung disease, exemplified by ILD, is now the primary cause of death in connective tissue disorders such as systemic sclerosis (Steen 2007). Immunomodulatory agents such as azathioprine and cyclophosphamide have a more established, albeit still limited, evidence base in the treatment of CTD‐ILD (Dheda 2004; Hoyles 2006; Tashkin 2007). The potential role of MMF is much less well understood, supported only by evidence from small case‐control studies and clinical case series (Gerbino 2008; Swigris 2006). Due to the adverse effect profile and logistic factors associated with parenteral administration of cyclophosphamide and other agents, the potential role of MMF in the treatment of CTD‐ILD has been growing. Its use is increasingly supported by observed efficacy and improved tolerability compared to other agents that induce systemic immunosuppression. Without a systematic review of the evidence supporting its therapeutic utility, it is difficult for clinicians to determine the comparative efficacy of MMF against other more established agents and whether it should be used as first‐line therapy for CTD‐ILD or only after other agents have failed.

Objectives

To assess the efficacy of mycophenolate mofetil in the treatment of connective tissue disease‐associated interstitial lung disease.

Methods

Criteria for considering studies for this review

Types of studies

We will include randomised controlled trials (RCTs).

Types of participants

Adult patients (aged 18 to 75) with interstitial lung disease developing in association with an underlying connective tissue disease, including rheumatoid arthritis, scleroderma/systemic sclerosis, idiopathic inflammatory myopathies (including polymyositis and dermatomyositis), mixed connective tissue disease, Sjögren's syndrome and SLE.

Types of interventions

Treatment with oral mycophenolate mofetil (MMF) in isolation or in combination with systemic corticosteroids, with a minimum treatment and follow‐up period of 12 months.

Comparison of MMF with other more traditionally used agents such as cyclophosphamide, azathioprine or corticosteroids, either used in isolation or in combination.

Types of outcome measures

Primary outcomes

1. Survival and mortality (all‐cause)

2. Stability, improvement or deterioration in lung function (particularly in FVC and DL_CO)

3. Reduced baseline corticosteroid requirements

Secondary outcomes

1. Symptoms (dyspnoea, cough, chest discomfort)

2. Health‐related quality of life (HRQOL) measurements including quality‐adjusted life year (QALY)

3. Radiological scoring of fibrotic extent

4. Additional physiological tests, e.g. six‐minute walk distance (6MWD) and six‐minute walk test with maximal desaturation on oximetry

5. Adverse events secondary to drug side effects

Search methods for identification of studies

Electronic searches

We will identify trials by searches of the following databases:

• the Cochrane Airways Group Register of Trials;

• the Cochrane Central Register of Controlled Trials (CENTRAL), in The Cochrane Library;

• MEDLINE (Ovid);

• EMBASE (Ovid);

• ClinicalTrials.gov;

• WHO International Clinical Trials Registry Platform.

The proposed MEDLINE strategy is listed in Appendix 1. This will be adapted for use in the other databases. We will search all databases from their inception to the present, and there will be no restriction on language of publication.

Searching other resources

We will search reference lists of all primary studies and review articles for additional references. We will contact authors of identified trials and ask them to identify other published and unpublished studies. We will also contact manufacturers and experts in the field.

Data collection and analysis

Selection of studies

Two review authors (NES and LEES) will independently assess for inclusion all the potential studies we identify as a result of the search strategy. We will resolve any disagreement through discussion or, if required, we will consult a third person (FC). We will assign each reference to a study identifier and assess them against the inclusion criteria of this protocol.

Data extraction and management

We will extract data using a data collection proforma and will store data in an electronic database. Two people (NES and LEES) will analyse each report independently. If disagreements occur, a third person (FC) will analyse the report to resolve inconsistencies. One of us (NES) will enter data into RevMan 5.1 and this will be checked by a second review author (LEES).

Assessment of risk of bias in included studies

Two of us (NES and LEES) will independently assess risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2008). We will resolve any disagreement by discussion or by involving a third assessor (FC). We will assess the risk of bias according to the following domains:

1. allocation sequence generation;

2. concealment of allocation;

3. blinding of participants and investigators;

4. incomplete outcome data;

5. selective outcome reporting.

We will note other sources of bias. We will grade each potential source of bias as low, high or unclear risk of bias.

Measures of treatment effect

Dichotomous data

We will analyse dichotomous data variables (such as mortality and adverse events) using Mantel‐Haenszel odds ratios with a fixed‐effect model and 95% confidence intervals. If events are rare we will employ the Peto odds ratio since this does not require a continuity correction for zero cells. If count data are not available as the number of participants experiencing an event, we will analyse data as continuous, time‐to‐event or rate ratios, depending on how they are reported. This includes the outcomes serious adverse events and symptoms experienced.

Continuous data

We will analyse continuous outcome data (such as lung function values and corticosteroid requirements) as fixed‐effect mean differences with 95% confidence intervals when the same scale is used, and standardised mean differences when different scales are employed in different studies. Where treatment effects are reported as a mean difference with standard deviations or an exact P value, we will calculate the standard error and enter it with the mean difference and combine the results using the fixed‐effect generic inverse variance model in RevMan 5.1. If data are not available for the same time point in all studies, we will use the closest time points. The second alternative will be to use end of study as time of analysis for all studies.

We will use intention‐to‐treat (ITT) analysis of outcomes from all randomised participants where possible for the primary analyses. We will calculate numbers needed to treat from the pooled odds ratio and its confidence interval, and apply to appropriate levels of baseline risk.

Unit of analysis issues

For continuous data, we will prefer the mean difference based on change from baseline over mean difference based on absolute.

Dealing with missing data

We will contact investigators or study sponsors in order to verify key study characteristics and obtain missing numerical outcome data where possible. We will also consider the impact of the unknown status of participants who withdraw from the trials as part of the sensitivity analysis.

Assessment of heterogeneity

We will use the I² statistic to measure heterogeneity among the trials in each analysis. We will regard an I² statistic value of 60% to represent high heterogeneity.

Assessment of reporting biases

Where we suspect reporting bias (see 'Selective reporting bias' above), we will attempt to contact study authors and ask them to provide missing outcome data. Where this is not possible, and the missing data are thought to introduce serious bias, we will explore the impact of including such studies in the overall assessment of results by a sensitivity analysis. If we encounter meta‐analyses of more than 10 studies, we will visually inspect funnel plots.

Data synthesis

We will present the findings of our primary outcomes in a 'Summary of findings' table using the recommendations in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2008) and GRADEPro software.

Subgroup analysis and investigation of heterogeneity

We will subgroup studies, where possible, according to concomitant immunosuppressive medication.

Sensitivity analysis

We will remove all studies felt to be at high risk of bias from the analysis as a sensitivity analysis.

Appendices

Appendix 1. MEDLINE search strategy

1. exp Connective Tissue Diseases/

2. (rheumatoid$ adj3 arthritis).tw.

3. scleroderma.tw.

4. (systemic adj3 sclerosis).tw.

5. polymyositis.tw.

6. dermatomyositis.tw.

7. Systemic lupus erythematosus.tw.

8. SLE.tw.

9. or/1‐8

10. exp Lung Diseases, Interstitial/

11. (interstitial adj3 lung$ adj3 disease$).tw.

12. ILD.tw.

13. (Diffuse$ adj3 parenchymal$ adj3 lung$).tw.

14. DPLD.tw.

15. or/10‐14

16. 9 and 15

17. Mycophenolic Acid/

18. Mycophenolate$.tw.

19. MMF.tw.

20. CellCept.tw.

21. Myfortic.tw.

22. or/17‐21

23. 16 and 22

This search will be combined with the Cochrane recommended filter for identifying RCTs (Lefebvre 2011).

What's new

Date	Event	Description
6 March 2017	Amended	Withdrawn. See Published notes.

Contributions of authors

NES drafted the protocol with assistance from AD, LEES and FC.

Declarations of interest

None known.

Notes

The protocol has been withdrawn as the author team has stepped down die to other commitments.

Withdrawn from publication for reasons stated in the review