Cyclophosphamide for connective tissue disease–associated interstitial lung disease

  • Protocol
  • Intervention

Authors


Abstract

This is the protocol for a review and there is no abstract. The objectives are as follows:

To assess the efficacy and adverse effects of cyclophosphamide in the treatment of CTD-ILD.

Background

Description of the condition

Connective tissue disease (CTD) can affect any component of the respiratory tract, causing a diverse range of disorders. When it is associated with interstitial lung disease (ILD), CTD is classified within the current American Thoracic Society (ATS)/European Respiratory Society (ERS) consensus statement as one of the forms of diffuse parenchymal lung disease of known cause (ATS/ERS Consensus Statement). Approximately 30% of individuals with ILD have associated CTD, which presents subsequent to the development of ILD in about 15% of sufferers (Mittoo 2009). 

Various approaches have been used to define connective tissue disease–related interstitial lung disease (CTD-ILD). The most rigorous approach is to include only people with features that clearly meet published diagnostic criteria for systemic autoimmune disease. However, many sufferers of ILD display one or more features of CTD clinically or serologically, without meeting diagnostic criteria. Amongst the definitions that have so far been applied to this cohort, significant heterogeneity in disease behaviour has been displayed, suggesting that further refinement is required to distinguish persons in this group suffering from CTD-ILD from those with idiopathic interstitial pneumonia (Corte 2012). 

The connective tissue disorders most commonly associated with ILD include scleroderma/systemic sclerosis, rheumatoid arthritis, polymyositis/dermatomyositis and Sjögren's syndrome. Each may be associated with progressive and fatal disease, but survival data in general are better than those seen for idiopathic forms of ILD (Fischer 2008; Park 2007). As an example, five-year survival for people with systemic sclerosis–related ILD has been reported to be approximately 85%, as opposed to 50% for idiopathic disease (Wells 1994). It remains to be elucidated what features are the principal determinants of progression among suffers of CTD-ILD. Histologically, non-specific interstitial pneumonia, usual interstitial pneumonia (UIP), organising pneumonia and lymphocytic interstitial pneumonia all may occur. Although for idiopathic interstitial pneumonia, UIP carries a significantly worse prognosis than other histological forms, with the exception of rheumatoid arthritis, a histological impact on prognosis is not seen in CTD-ILD (Bouros 2002; Kim 2010). 

Despite resulting in better survival than its idiopathic counterparts, ILD is the major cause of death amongst individuals with scleroderma (Ferri 2002). When present, ILD contributes to reduced physical function and quality of life (Baron 2008). Correlation has been demonstrated between extent of ILD and degree of disability, and this correlation serves as a predictor of disease behaviour. Radiological and physiological extent of ILD in cohorts suffering from CTD and scleroderma has been demonstrated to adversely affect prognosis (Goh 2008; Park 2007). A greater rate of decline in physiological values such as forced vital capacity (FVC) is a predictor of mortality in people with scleroderma (Assassi 2010).

Description of the intervention

Cyclophosphamide is a highly potent immunosuppressant that has demonstrated efficacy in inducing and maintaining remission in a range of autoimmune and inflammatory illnesses (Gourley 1996; Hoffman 1992). Its immunosuppressant activity may occur in a number of ways. Through its action as an alkylating agent, cyclophosphamide causes cross-linkage of a variety of macromolecules, including DNA, producing cell death amongst resting and dividing lymphocytes. Additionally, it produces impaired humoral and cellular immune responses (Hall 1992). 

Cyclophosphamide is associated with a range of important toxicities that make its usage problematic, limiting its prescription to a specialist setting. Most patients experience nausea and hair thinning. Haemorrhagic cystitis and bladder cancer are produced by exposure of the bladder to acrolein, a metabolite of cyclophosphamide. The risk of each is related to total cumulative dose, with a total dosage greater than 100 g most strongly associated with bladder cancer. To reduce total dosage, duration of cyclophosphamide usage is often limited to periods shorter than 12 months. 

Cyclophosphamide causes bone marrow suppression with associated risks of bacterial and opportunistic infections, as well as reactivation of dormant infections such as tuberculosis. It is associated with gonadal toxicity with the potential to cause premature ovarian failure and oligospermia or azoospermia. It is teratogenic and should be avoided throughout pregnancy. The risk of haematological malignancy, skin cancer and solid organ malignancy is increased.  

Cyclophosphamide is administered in daily oral and intermittent intravenous protocols, with intravenous regimens having gained a vogue because they allow a reduction by up to two-thirds of total cumulative dose, thereby reducing the risk of malignancy and bladder toxicity (Boumpas 1992). The standard oral dosage in patients with normal renal function is 2 mg/kg/d, and intravenous doses range between 500 and 1000 mg/m2 body surface area administered every four to six weeks. Therapy generally is provided for at least six months and is followed by treatment with a less toxic alternative immunosuppressant.

How the intervention might work

On radiological grounds, fibrotic lung disease associated with CTD is similar to that seen in idiopathic interstitial pneumonia (Hwang 2009). Similar pathways have been suggested in their causation with elevated levels of a range of similar pro-inflammatory and pro-fibrotic cytokines such as transforming growth factor (TGF)-beta signalling pathways, along with growth factors and chemokines involved in connective tissue deposition (Mathai 2010; Murray 2011; Peng 2011).

Despite these similarities, recent research has highlighted genetic differences in the MUC5-B promoter region between sufferers of idiopathic pulmonary fibrosis (IPF) and scleroderma-related ILD (Stock 2013). Histological differences are apparent, with CTD-ILD demonstrating an increase in germinal centre density and inflammation and reduced numbers of fibroblastic foci (Song 2009). These differences suggest an alternative "inflammatory" pathogenesis that is likely crucial in providing the basis for CTD-ILD’s improved natural history and responsiveness to immunosuppressant therapy. A number of immunosuppressant approaches have been used for the treatment of IPF, and each has demonstrated a disappointing lack of efficacy (Raghu 2012). Only limited data can be found for most of the immunosuppressant therapies used in CTD-ILD, but supportive case series data are available for a number of them, including prednisolone, methotrexate, azathioprine, cyclosporine and mycophenolate mofetil (Fischer 2013). Cyclophosphamide has a significantly greater literature exploring its use, including several placebo-controlled trials in CTD-ILD (Hoyles 2006; Tashkin 2006).

Why it is important to do this review

Decision making in the treatment of CTD-ILD is difficult, with the clinician having to balance a high level of need for therapy in a severely unwell patient population against the potential for adverse effects from highly toxic therapy for which only relatively limited data on efficacy can be found. Research in this field has been limited, with publications frequently representing case reports or case series. It is not clear whether evidence of efficacy in one CTD subtype can be extrapolated to all forms. Similarly, it is not clear whether histological subtype, disease duration or disease extent can be used to predict responsiveness. Although these issues cannot currently be answered in the absence of sufficient clinical studies, improved understanding of the strength of the treatment effect of cyclophosphamide in CTD-ILD, as well as the extent to which adverse effects can be expected, would be of great assistance in clinical decision making.

Objectives

To assess the efficacy and adverse effects of cyclophosphamide in the treatment of CTD-ILD.

Methods

Criteria for considering studies for this review

Types of studies

We will include randomised controlled parallel-group trials.

Types of participants

Adults (18 to 80 years of age) suffering from CTD-ILD. Only individuals with definitive connective tissue disease as defined by accepted diagnostic criteria at the time studies are identified will be included. We will include the connective tissue diseases commonly associated with interstitial lung disease: scleroderma, rheumatoid arthritis, polymyositis/dermatomyositis, Sjögren’s syndrome, SLE and mixed connective tissue disorders. People with clinically unstable disease, respiratory sepsis or coexistent obstructive lung disease will be excluded from the analysis.

Types of interventions

Cyclophosphamide, intravenous or oral, used individually or concomitantly with other immunomodulating or immunosuppressant therapies for periods of at least six months and for follow-up periods of at least 12 months. Comparator groups will include non–cyclophosphamide-containing therapies. Comparisons of interest include cyclophosphamide versus placebo, cyclophosphamide versus prednisolone alone and cyclophosphamide versus prednisolone plus a non-cyclophosphamide immunosuppressant/immunomodulator.

Types of outcome measures

Primary outcomes
  1. Change in lung function (FVC % predicted and diffusing capacity of the lung for carbon monoxide (DLCO) % predicted).

  2. Adverse events.

  3. Health-related quality of life, as measured by validated questionnaires.

Secondary outcomes
  1. Survival and mortality (all-cause).

  2. Dyspnoea.

  3. Cough.

  4. Functional exercise tolerance (e.g. six-minute walk test).

Search methods for identification of studies

Electronic searches

We will identify trials by conducting searches of the following databases.

  • The Cochrane Airways Group Register of Trials.

  • The Cochrane Central Register of Controlled Trials (CENTRAL), on T he Cochrane Library.

  • MEDLINE (Ovid).

  • EMBASE (Ovid).

  • ClinicalTrials.gov and the World Health Organization (WHO) trials portal

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

Searching other resources

We will check reference lists of all primary studies and review articles for additional references.  We will contact authors of identified trials and will 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

ING and GPW will independently assess for inclusion all potential studies identified as a result of the search strategy applied in an unblinded fashion. Duplicate records will be identified and titles and abstracts examined with the goal of removing obviously irrelevant reports. Multiple reports of the same study will be identified and linked. Full-text reports from potentially relevant studies will be examined for compliance with eligibility criteria, and, when appropriate, we will correspond with investigators to clarify study eligibility. We will resolve any disagreement through discussion, or, if required, we will consult AEH.

Data extraction and management

We will extract data using a data collection proforma and will store data in an electronic database. ING and GPW will analyse each report independently. If disagreements occur, AEH will analyse the report to resolve inconsistencies. ING will enter data into Review Manager, and this information will be checked by GPW.

Assessment of risk of bias in included studies

ING and GPW will independently assess risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2008). Any disagreement will be resolved by discussion or by involving AEH. We will assess the risk of bias according to the following domains.

  • Random sequence generation.

  • Allocation concealment.

  • Blinding of participants and personnel.

  • Blinding of outcome assessment.

  • Incomplete outcome data.

  • Selective outcome reporting.

  • Other bias.

We will grade each potential source of bias as high, low or unclear.

Measures of treatment effect

Dichotomous data

For a dichotomous (‘yes’ or ‘no’) outcome, the number of participants and the number who experienced the outcome will be sought for each group. Effect will be reported as Peto odds ratio data. We will convert the pooled relative measure and its confidence interval to a risk difference using the control event rate(s) from the included trials.

Continuous data

For continuous variables, we will record either the mean change from baseline or the mean postintervention value and standard deviation (SD) for each group. The mean difference (MD) for outcomes measured with the same metrics or the standardised mean difference (SMD) for outcomes measured with different metrics, along with 95% confidence intervals, will be calculated.

Unit of analysis issues

For change in FVC % predicted, we will use both relative and absolute changes (Richeldi 2012). We will analyse treatment effect measured 12 months post initiation of therapy and other shared time points, if data are available.

Dealing with missing data

We will contact investigators or study sponsors to verify key study characteristics and to obtain missing numerical outcome data when possible.

Assessment of heterogeneity

We will use the I² statistic to measure heterogeneity among the trials in each analysis. If we identify substantial heterogeneity, we will explore it by prespecified subgroup analysis. We will consider an I2 statistic greater than 50% as evidence of substantial heterogeneity.

Assessment of reporting biases

We will attempt to contact study authors to ask them to provide missing outcome data. When this is not possible, and the missing data are thought to introduce serious bias, the impact of including such studies in the overall assessment of results will be explored by a sensitivity analysis. Provided that more than 10 studies are available for meta-analysis, we will visually inspect funnel plots.

Data synthesis

We will perform a pooled quantitative analysis when trials are clinically homogeneous. When trials are clinically heterogeneous, we will perform a narrative synthesis. We plan to create a summary of findings for change in FVC % predicted and DLCO % predicted, adverse events and health-related quality of life in a table using the methods and recommendations described in Section 8.5 and Chapter 12 of the Cochrane Handbook for Systematic Reviews of Interventions along with GRADE Pro software.

Subgroup analysis and investigation of heterogeneity

We plan to carry out the following subgroup analyses.

  1. FVC < 70% predicted.

  2. Analysis by connective tissue disease diagnosis: scleroderma, rheumatoid arthritis, polymysositis/dermatomyositis.

  3. Analysis by radiological pattern: UIP, non-UIP.

  4. CTD symptom onset date < two years.

The following outcomes will be used in subgroup analysis. 

  1. Change in lung function (FVC and DLCO).

  2. Adverse events.

  3. Health-related quality of life.

Homogeneity of effect sizes between pooled studies will be examined with the I2 statistic. In the absence of heterogeneity, the fixed-effect model will be used; otherwise a random effects model will be used.

Sensitivity analysis

Sensitivity analyses will be performed when data are sufficient, to analyse the effects of studies at risk of bias by excluding those studies that do not report an intention-to-treat analysis, or that demonstrate other potential forms of bias identified during the review process.

Acknowledgements

Christopher Cates was the Editor for this protocol and commented critically on the protocol.

Appendices

Appendix 1. MEDLINE search strategy

1. exp Lung Diseases, Interstitial/

2. (interstitial$ adj3 (lung$ or pulmonary$ or pneumon$)).tw.

3. ILD.ti,ab.

4. ((pulmonary$ or lung$) adj3 (fibros$ or fibrot$)).tw.

5. sarcoidosis$.tw.

6. alveolitis$.tw.

7. or/1-6

8. exp Connective Tissue Diseases/

9. (connective adj3 tissue adj3 (disorder$ or disease$)).tw.

10. scleroderma.tw.

11. sclerosis.tw.

12. systemic lupus erythematosus.tw.

13. Libman-Sacks.tw.

14. rheumatoid arthritis.tw.

15. polymyositis.tw.

16. dermatomyositis.tw.

17. myositis.tw.

18. Sjogren's syndrome.tw.

19. or/8-18

20. 7 and 19

21. exp Cyclophosphamide/

22. cyclophosphamide.tw.

23. Endoxan.tw.

24. Cytoxan.tw.

25. Neosar.tw.

26. Procytox.tw.

27. Sendoxan.tw.

28. Clafen.tw.

29. or/21-28

30. 20 and 29

31. (clinical trial or controlled clinical trial or randomised controlled trial).pt.

32. (randomised or randomised).ab,ti.

33. placebo.ab,ti.

34. dt.fs.

35. randomly.ab,ti.

36. trial.ab,ti.

37. groups.ab,ti.

38. or/31-37

39. Animals/

40. Humans/

41. 39 not (39 and 40)

42. 38 not 41

43. 30 and 42

Contributions of authors

ING drafted the protocol with assistance from GPW, NSLG and AEH.

Declarations of interest

None known.

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