Abstract
Introduction
The purpose of the present study was to systematically review the effect of cyclophosphamide treatment on pulmonary function in patients with systemic sclerosis and interstitial lung disease.
Methods
The primary outcomes were the mean change in forced vital capacity and in diffusing capacity for carbon monoxide after 12 months of therapy in patients treated with cyclophosphamide.
Results
Three randomized clinical trials and six prospective observational studies were included for analysis. In the pooled analysis, the forced vital capacity and the diffusing capacity for carbon monoxide predicted values after 12 months of therapy were essentially unchanged, with mean changes of 2.83% (95% confidence interval = 0.35 to 5.31) and 4.56% (95% confidence interval = -0.21 to 9.33), respectively.
Conclusions
Cyclophosphamide treatment in patients with systemic sclerosis-related interstitial lung disease does not result in clinically significant improvement of pulmonary function.
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Introduction
Scleroderma (systemic sclerosis (SSc)) is an autoimmune connective tissue disorder characterized by microvascular injury, excessive fibrosis of the skin and distinctive visceral changes that can involve the lungs, heart, kidneys and gastrointestinal tract [1]. Interstitial lung disease (ILD) occurs in patients who have CREST (Calcinosis, Raynaud, ESophagitis, Telangiectases), limited cutaneous systemic sclerosis-lcSSc and diffuse cutaneous scleroderma (dcSSc), but it is somewhat more common in patients who have diffuse disease [2, 3]. The ILD that occurs in scleroderma patients includes a number of entities, as summarized in Table 1[4]. The prevalence of ILD in scleroderma varies from 25% to 90% depending on the ethnic background of the patients studied and on the method used to detect the ILD [5].
Pulmonary function tests with evaluation of the forced vital capacity (FVC), the total lung capacity and the diffusing lung capacity of carbon monoxide (DLCO), chest radiography and high-resolution computed tomography are common clinical tests used to evaluate lung disease in scleroderma. Imaging reveals fibrotic changes of lung parenchyma. Previous research has found pulmonary function tests to reveal a restrictive pattern in 23% of patients with limited disease, and found 40% of patients with diffuse disease to have pulmonary fibrosis [4, 5]. ILD as assessed by chest radiography has been reported in 33% of patients with limited scleroderma and in 40% of patients with diffuse SSc [5]. High-resolution computed tomography detects ILD changes in 90% to 100% of SSc patients [2, 5].
ILD is associated with increased mortality in patients who have SSc. The greatest loss of lung volume occurs within the first 2 years of the disease, and pulmonary-related deaths occur with greater frequency in the second 5 years from disease onset [5]. Patients with severe lung involvement (defined as FVC < 55% and DLCO < 40% of predicted) have a worse prognosis, with a mortality of 42% within 10 years of the onset of disease [5].
A number of agents have been evaluated for treatment of SSc-related ILD but none have proven effective in altering the disease course. Cyclophosphamide (CYC) is a cytotoxic immunosuppressive agent that suppresses lymphokine production and modulates lymphocyte function by alkylating various cellular constituents and depressing the inflammatory response. Of all the drugs studied for the treatment of SSc-related ILD, only CYC has shown much promise of benefit in slowing down the decrease in, or even improving, lung function and survival [1]. Retrospective studies, pilot studies, and open-label clinical trials support the effectiveness of CYC therapy in preventing a decline in lung function and premature death in patients with SSc and ILD.
Despite these individual study results, previous systematic reviews of retrospective studies of the CYC effect in SSc lung disease have yielded conflicting results, suggesting either some or no benefit of this agent [6, 7]. To determine the possible benefit of CYC as management for SSc-related ILD, we examined the benefit of CYC on lung function as measured by pulmonary function tests by conducting a systematic review and meta-analysis of randomized clinical trials and prospective observational studies in patients with SSc treated with CYC.
Materials and methods
The study selection, assessment of eligibility criteria, data extraction and statistical analysis were performed based on a prespecified protocol according to the Cochrane Collaboration guidelines [8]. The present article has been prepared in accordance with the QUOROM statement [9]. An expert medical librarian searched Ovid EMBASE, Ovid MEDLINE, and the Ovid Cochrane Library from 1986 to 2008 using the terms systemic scleroderma, autoimmune diseases, cyclophosphamide, immunosuppressive therapies, interstitial lung disease, randomized controlled trials, observational studies, multicenter studies, clinical trials phase II, clinical trials phase III, and clinical trials phase IV.
To locate unpublished trials, we searched the electronic abstract databases of the annual scientific meetings of the European League Against Rheumatism, the American College of Rheumatology and the American Thoracic Society, from the approval of CYC as a treatment for autoimmune disease in 1986 to the present. No restriction for language was used.
Assessment of eligibility criteria for inclusion or exclusion and extraction of outcome variables was performed independently by two investigators (CN and ELM) with an intraobserver agreement kappa statistic of 1.
Selection and outcomes
We selected randomized clinical trials [1, 10, 11] and prospective observational studies [12–18] that included patients classified as having limited and/or diffuse SSc according to the American College of Rheumatology criteria [19] and a diagnosis of ILD [20] treated with oral or intravenous CYC. The dose of CYC administered differed across the various cohorts of patients. Some studies expressed the CYC dose in milligrams per kilogram per day and others in milligrams per square meter of body surface. The oral dose of CYC ranged from 1 mg/kg/day to 2.5 mg/kg/day, and the intravenous dose of CYC ranged from 500 mg/m2 to 750 mg/m2 – except for one study in which 900 mg/kg/day intravenous CYC was administered (Tables 2 and 3).
In the randomized clinical trials, patients were randomly allocated to receive treatment with CYC versus placebo [1, 10] or versus azathioprine [11] for at least 12 months. In the observational prospective studies, scleroderma patients were treated with CYC for at least 12 months, and were evaluated at baseline and after 12 months of therapy. Corticosteroid treatment was permitted in both the randomized clinical trials and observational studies.
A clinically important change between two groups of treatment (CYC versus non-CYC) has been previously reported as an improvement ≥ 10% of the predicted value at 12 months or from the baseline value of FVC or DLCO [12, 11]. Previous studies have reported no or very mild adverse events in patients with SSc-related ILD who were treated with CYC [26, 27]. Other studies have reported bladder complications secondary to the drug in patients with SSc [28, 29]. The adverse events counted in our nine studies included two cases of hemorrhagic cystitis [17] and several cases of hematuria – one case in Valentini and colleagues [18], two cases in Hoyles and colleagues [10] and nine cases in Tashkin and colleagues [1]; bladder cancer was not reported. A doubling of bladder cancer risk in Wegener's granulomatosis patients for every 10 g increase in the cumulative dose of CYC and an eightfold increased risk for treatment duration longer than 1 year has been reported [30]. Since the results of our meta-analysis are based on 12 months of follow-up they may not reflect adverse events develo** over longer durations of treatment or follow-up.
Our study has additional limitations. The number of patients enrolled, the dose of CYC, concomitant corticosteroid use, the SSc-related ILD disease extent and SSc disease duration, and the comparator treatments varied across studies. For example, some evidence suggests that glucocorticoids may be effective in SSc-related ILD in certain situations [5, 25, 31–33]. There may be other factors contributing to heterogeneity unidentified by our review. The shortage of randomized controlled trials on this topic is a limitation, and larger randomized controlled trials are needed to better understand the role of CYC in the care of these patients. In our meta-analysis, two of the three greatest mean differences of the FVC after 12 months of therapy were achieved in observational studies using higher doses of corticosteroids [15, 16], limiting our ability to draw a clear conclusion of beneficial effect of CYC alone. It is also possible that azathioprine has a beneficial treatment effect, which would reduce the magnitude of difference in benefit seen in comparison with CYC. A further limitation is that several studies, particularly the observational studies, had small numbers of patients.
Conclusions
Based on available data, CYC treatment in patients with SSc-related ILD does not appear to result in clinically significant improvement of pulmonary function. Since none of the patients included in these studies were selected on the basis of progression of ILD or the time from the SSc-related ILD diagnosis, further randomized clinical studies are needed to evaluate whether CYC (or any) therapy might exert a beneficial effect in patients with worsening ILD. It is possible, for example, that patients treated sooner after diagnosis or at earlier stages of SSc-related ILD might have a better response to CYC treatment. Based on current understanding, however, SSc-related ILD will be only effectively addressed when better understanding of the immunopathophysiology of the disease is understood and when treatment options more effective than CYC become available.
Abbreviations
- ACR:
-
American College of Rheumatology
- AZA:
-
azathioprine
- BAL:
-
bronchoalveolar lavage
- CI:
-
confidence interval
- CREST:
-
Calcinosis, Raynaud, ESophagitis, Sclerodactylia, Telangiectases
- CT:
-
computed tomography
- CXR:
-
chest radiography
- CYC:
-
cyclophosphamide
- dcSSC:
-
diffuse cutaneous systemic sclerosis
- DLCO:
-
diffusing lung capacity of carbon monoxide
- EULAR:
-
European League Against Rheumatism
- FVC:
-
forced vital capacity
- HRTC:
-
high resolution computed tomography
- ILD:
-
Interstitial Lung Disease
- IV:
-
intravenous
- lcSSc:
-
limited cutaneous systemic sclerosis
- PFT:
-
pulmonary function test
- RR:
-
relative risk
- SE:
-
standard error
- SSC:
-
systemic sclerosis
- SSc-ILD:
-
systemic sclerosis related interstitial lung disease
- TLC:
-
total lung capacity.
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Acknowledgements
The authors would like to thank Dr Victor Montori and Dr Hassan Murad for their expertise and advice in the conduct of this study. There was no funding support for the present study.
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CN conceived the study and participated in its design, coordination, data acquisition and analysis, and in manuscript preparation. CPW and ELM participated in the study design, data acquisition and analysis, and in manuscript preparation. PJE participated in data acquisition and in manuscript preparation. All authors read and approved the final manuscript.
An erratum to this article is available at http://dx.doi.org/10.1186/ar2679.
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Nannini, C., West, C.P., Erwin, P.J. et al. Effects of cyclophosphamide on pulmonary function in patients with scleroderma and interstitial lung disease: a systematic review and meta-analysis of randomized controlled trials and observational prospective cohort studies. Arthritis Res Ther 10, R124 (2008). https://doi.org/10.1186/ar2534
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DOI: https://doi.org/10.1186/ar2534