|
|
Background We conducted a double-blind, randomized, placebo-controlled trial to determine the effects of oral cyclophosphamide on lung function and health-related symptoms in patients with evidence of active alveolitis and scleroderma-related interstitial lung disease.
Methods At 13 clinical centers throughout the United States, we enrolled 158 patients with scleroderma, restrictive lung physiology, dyspnea, and evidence of inflammatory interstitial lung disease on examination of bronchoalveolar-lavage fluid, thoracic high-resolution computed tomography, or both. Patients received oral cyclophosphamide (
Results Of 158 patients, 145 completed at least six months of treatment and were included in the analysis. The mean absolute difference in adjusted 12-month FVC percent predicted between the cyclophosphamide and placebo groups was 2.53 percent (95 percent confidence interval, 0.28 to 4.79 percent), favoring cyclophosphamide (P<0.03). There were also treatment-related differences in physiological and symptom outcomes, and the difference in FVC was maintained at 24 months. There was a greater frequency of adverse events in the cyclophosphamide group, but the difference between the two groups in the number of serious adverse events was not significant.
Conclusions One year of oral cyclophosphamide in patients with symptomatic scleroderma-related interstitial lung disease had a significant but modest beneficial effect on lung function, dyspnea, thickening of the skin, and the health-related quality of life. The effects on lung function were maintained through the 24 months of the study.
2 mg per kilogram of body weight per day) or matching placebo for one year and were followed for an additional year. Pulmonary function was assessed every three months during the first year, and the primary end point was the forced vital capacity (FVC, expressed as a percentage of the predicted value) at 12 months, after adjustment for the baseline FVC.
A number of agents have been evaluated as treatments for scleroderma-related interstitial lung disease, but none have been proven effective.3 Only cyclophosphamide has shown promise in several retrospective studies, which suggested that it may slow the decrease in or even improve the FVC over time.2,3,4,5,6,7,8,9,10,11 Although these results have encouraged many physicians to adopt cyclophosphamide as a standard of care for patients with this disease, the lack of a randomized, prospective study makes it difficult to draw solid conclusions regarding the efficacy, toxicity, and risk–benefit ratio of this drug.
The Scleroderma Lung Study, a 13-center, double-blind, randomized, placebo-controlled trial sponsored by the National Institutes of Health, was designed to evaluate the effectiveness and safety of oral cyclophosphamide for one year in patients with active, symptomatic scleroderma-related interstitial lung disease who were followed for a total of two years. Results from the study indicate that cyclophosphamide has disease-modifying effects on pulmonary function and such measures of response as dyspnea, the health-related quality of life, functional ability, and skin thickness.
Methods
Subjects
Between September 2000 and January 2004, we enrolled patients with limited or diffuse systemic scleroderma12,13 if they had evidence of active alveolitis on examination of bronchoalveolar-lavage (BAL) fluid (defined as neutrophilia of 
3 percent, eosinophilia of 2 percent, or both)2,14 or on thoracic high-resolution computed tomography (CT), any ground-glass opacity, the onset of the first symptom of scleroderma other than Raynaud's phenomenon within the previous seven years, an FVC between 45 and 85 percent of the predicted value,15 and grade 2 exertional dyspnea according to the baseline instrument of the Mahler Dyspnea Index (as measured with the use of the magnitude-of-task component).16 Primary exclusion criteria included a single-breath carbon monoxide diffusing capacity (DLCO) that was less than 30 percent of the predicted value,17 a history of smoking within the preceding six months, other clinically significant pulmonary abnormalities, or clinically significant pulmonary hypertension requiring drug therapy. Patients taking prednisone at a dose of more than 10 mg per day, those who had previously been treated for more than four weeks with oral cyclophosphamide or had received two or more intravenous doses, and those who had recently received other potentially disease-modifying medications were also excluded. The inclusion and exclusion criteria are described in detail in Supplementary Appendix 1 (available with the full text of this article at www.nejm.org). All patients provided written informed consent, and the study was approved by the medical institutional review board at each clinical center.
Screening and Randomization
Patients were screened at each center as outlined in Supplementary Appendix 2, and their eligibility was determined centrally at the data coordinating center at the University of California at Los Angeles. Patients who met all the inclusion criteria were randomly assigned with the use of a permuted-block design and a 1:1 allocation (in blocks of four to six patients per center) to receive either daily oral cyclophosphamide or matching placebo for 12 months, followed by another year of follow-up without study medication. Treatment of any type was allowed during the second year at the discretion of the primary treating physician.
Baseline Measurements
Baseline measurements, including tests of pulmonary function, scores for skin thickness, measures of the quality of life and functional activity, and indexes of cough and breathlessness, are presented in detail in Supplementary Appendix 3.18,19,20,21,22,23,24,25,26,27,28 High-resolution CT scans were scored for the extent of pure ground-glass opacity, lung fibrosis, honeycombing, and emphysema, as described in Supplementary Appendix 4.
Treatment
Cyclophosphamide (Cytoxan, Bristol-Myers Squibb) and placebo were formulated into matching gelcaps at a dose of 25 mg, and treatment was initiated with a dose of 1 mg per kilogram of body weight per day (to the nearest 25 mg). The doses were increased monthly by one capsule up to 2 mg per kilogram. Assessments to monitor toxic effects included a complete blood count and urinalysis every two to four weeks and a chemistry panel every three months. To preserve blinding of investigators, an independent medication-control officer assessed adverse events and regulated all doses of study medication, in accordance with the study protocol. The study drug was discontinued temporarily or permanently if there was evidence of drug-related toxic effects. Reasons for withholding or changing the dose of the study drug and predefined rules for the reintroduction of the drug or adjustment of the dose are given in Supplementary Appendix 5. A data safety and monitoring board provided oversight of the study. An independent morbidity and mortality review committee reviewed all serious adverse events and rendered opinions regarding their relation to the study.
Serial Monitoring and Outcome Measures
Measurements were made at baseline and at three-month intervals throughout the study, except those made with the baseline instrument of the Mahler Dyspnea Index, which was replaced by the Mahler transitional dyspnea index (with a scale from –9 to +9, with the plus sign indicating improvement and the minus sign indicating worsening) at subsequent visits.16 Lung-volume measurements were repeated at six-month intervals.
Treatment Failure
Treatment failure was defined as an absolute decrease from baseline in the FVC of at least 15 percent of the predicted value occurring at least three months after treatment was initiated and lasting for at least one month. Patients whose response met this definition were withdrawn from the double-blind phase of the study but were encouraged to continue scheduled visits that included spirometry, the administration of questionnaires, and other study procedures. These patients were informed of their treatment assignment and offered open-label therapy with cyclophosphamide.
Statistical Analysis
We estimated that we would need to enroll 163 patients, given an expected mean (±SD) annual decline in the FVC of 9±16 percent of the predicted value2,4,5,6 and a dropout rate of 15 percent, to achieve a two-sided alpha level of 0.05 and a statistical power of 90 percent. A prespecified analysis of covariance was used to assess treatment effects, adjusted for baseline values and treatment group, with the FVC (expressed as a percentage of the predicted value) at 12 months identified as the primary outcome. A Huber covariance estimation and testing procedure was used, because the data were not normally distributed and included influential extreme values.29 Patients for whom outcome measures at six months or more were not available or whose primary outcome data were technically not interpretable were excluded from analysis. For all remaining patients who withdrew prematurely, a generalized-estimating-equation regression model was fitted, and data missing at 12 months were imputed. At 24 months after randomization, the FVC was the prespecified primary end point; the analysis was based on a longitudinal model that included terms for treatment and time and an interaction between treatment and time with the baseline FVC included in the model.
Other planned analyses of the primary outcome included a nonparametric analysis with a modified Wilcoxon score test,30 in which the FVC at 12 months and the time to death were considered a combined end point, and an extension of the covariance analysis in which the baseline score for fibrosis (the mean reading by two independent radiologists of the worst degree of fibrosis in any region of the baseline high-resolution CT, as described in Supplementary Appendix 4) was used as an additional covariate.
Prespecified secondary outcomes included values at month 12, adjusted for baseline values, for total lung capacity (expressed as a percentage of the predicted value), DLCO, the diffusing capacity adjusted for alveolar volume (DL:VA), the disability index of the Health Assessment Questionnaire (HAQ), and the Medical Outcomes Study 36-item Short-Form General Health Survey (SF-36). No adjustment was made to the P values for these multiple variables. A post hoc analysis of scores for skin thickness was performed in a similar fashion. The three subscales and the summed focal score for the transitional dyspnea index (a secondary outcome) were analyzed with the use of a mixed-model method.16
The data were collected, held, and analyzed in a secure manner at the data coordinating center, with frequent review by the data and safety monitoring board. The statistical analyses were performed with SAS software (version 9.1, SAS), where appropriate. Bristol-Myers Squibb, the manufacturer of the oral cyclophosphamide used in the study, donated the drug but had no role in the design or conduct of the study or the analysis of the data.
Results
Enrollment and Baseline Characteristics
The disposition of the 267 patients who underwent screening and of the 158 eligible patients who underwent randomization is shown in Figure 1. Baseline characteristics of those who underwent randomization are listed in Table 1 and summarized in Supplementary Appendix 6. There were no significant differences between the two groups except that the scores for the HAQ disability index were significantly lower (indicating greater health) in the placebo group than in the cyclophosphamide group.
|
|
The frequency of positive findings on baseline examination of BAL fluid and the mean percentages of neutrophils and eosinophils are shown in Supplementary Appendix 7. Of 144 patients whose BAL-fluid results could be evaluated cytologically, 70.8 percent had evidence of alveolitis according to the study criteria. The frequency and severity of findings on examination of BAL fluid were similar in the two groups. The proportions of eligible patients whose condition fulfilled the criteria for evidence of alveolitis on high-resolution CT, examination of BAL fluid, or both are given in Supplementary Appendix 8.
Responses to Treatment
Of a total of 158 patients, 3 assigned to placebo and 1 assigned to cyclophosphamide withdrew before starting the study treatment and were not included in the analysis. A number of patients who received at least one dose of study medication withdrew from the study, had conditions that met the protocol definition of treatment failure, or died (Figure 1). A total of 20 patients in the cyclophosphamide group and 13 in the placebo group withdrew within 12 months after randomization, most of them because of adverse events or serious adverse events. Three patients in the cyclophosphamide group had treatment failure, as compared with five in the placebo group. Five patients died during the first 12 months, two in the cyclophosphamide group and three in the placebo group. A total of 54 patients (68.4 percent) in the cyclophosphamide group and 55 (69.6 percent) in the placebo group completed all 12 months of treatment. However, a number of those who withdrew, had treatment failure, or died had completed at least the six-month visit, allowing their end-point results to be imputed and included in the analysis. One patient in the placebo group was not included because the results of spirometry were technically unsatisfactory. Thus, data on 145 patients (91.8 percent), including 73 in the cyclophosphamide group and 72 in the placebo group, were evaluated for the primary outcome. Baseline values and outcomes at month 12 for these 145 patients, as well as mean (±SE) changes in these values, adjusted with the use of Huber estimation,29 are shown in Table 2.
|
When the baseline FVC was used as the only covariate in the Huber model (primary analysis), the adjusted mean absolute difference in FVC at 12 months between the cyclophosphamide group and the placebo group was 2.53 percent (95 percent confidence interval, 0.28 to 4.79 percent), favoring cyclophosphamide (P<0.03). When both the baseline FVC and the worst score for fibrosis at baseline on high-resolution CT were included in the model (in the secondary analysis of the primary outcomes), the adjusted mean absolute difference in the FVC at 12 months between the two groups increased to 2.97 percent (95 percent confidence interval, 0.75 to 5.19 percent), favoring cyclophosphamide (P=0.009). We used regression analysis to evaluate the effect of the baseline score for fibrosis on the FVC at 12 months (Figure 2A). In the placebo group, the regression slope was significantly negative (–2.01 percent of the predicted FVC per unit score for fibrosis, P=0.006), indicating a greater decline in FVC over time among those who had more severe fibrosis at baseline. By comparison, the difference from 0 in the regression slope in the cyclophosphamide group (0.96 percent of the predicted FVC per unit score for fibrosis) was not significant (P=0.26). The difference between the regression slopes in the two groups was significant (P<0.009), suggesting that cyclophosphamide protected against the decrease in FVC in patients with fibrosis. The combined end point of the time to death plus the FVC at 12 months among the 145 patients evaluated also favored cyclophosphamide (P=0.04 with the use of a modified Wilcoxon procedure).30
|
A significant difference was also found between the cyclophosphamide group and the placebo group in total lung capacity at 12 months (absolute difference in the percent of the predicted value, 4.09 percent favoring cyclophosphamide; 95 percent confidence interval, 0.49 to 7.65 percent; P=0.026). There were no significant differences between the two groups in either the DLCO (absolute difference in the percent of the predicted value, –1.04; P=0.43) at 12 months or in the DL:VA at 12 months (absolute difference in the percent of the predicted value, 0.0002 percent; P=0.92). Breathlessness is the chief symptom related to scleroderma-related interstitial lung disease. The mean focal score according to the transitional dyspnea index showed a clinically meaningful improvement in dyspnea (by >1 unit) in the cyclophosphamide group (+1.4±0.23), in contrast to a clinically meaningful worsening (by >1 unit) in the placebo group (–1.5±0.43) (Table 2). There were significant differences between the two groups in the focal score (P<0.001) and in the scores for the three-component transitional dyspnea index, which were incorporated into a mixed model (P<0.001) (available in Supplementary Appendix 9). After adjustment for baseline HAQ scores, the adjusted mean HAQ disability scores at 12 months were significantly lower (indicating less disability) in the cyclophosphamide group than in the placebo group, with the difference between the two groups favoring cyclophosphamide (–0.16; 95 percent confidence interval, –0.28 to –0.04; P=0.009).
Among the scores for all the domains and summary components of the SF-36, only those for the vitality domain (7.99; 95 percent confidence interval, 2.18 to 13.8; P=0.007) and the health-transition domain (–0.66; 95 percent confidence interval, –1.02 to –0.30; P=0.003) showed significant between-group differences, both favoring cyclophosphamide. In none of the domains did the scores show a significant improvement with placebo.
Post Hoc Analyses
When pure ground-glass opacity, the presence or degree of neutrophilia, eosinophilia, or both on examination of BAL fluid, or the degree of honeycombing on the baseline high-resolution CT was added as a covariate to the Huber model, it did not significantly affect the FVC at 12 months. Figure 2B shows the distribution of changes in the FVC (in increments or decrements of 5 percent) in the cyclophosphamide group and the placebo group. A significantly greater percentage of patients in the cyclophosphamide group than in the placebo group had any improvement from baseline values in the FVC (P<0.01 by Fisher's exact test). In 85 patients with diffuse disease, scores for skin thickness showed a significant difference between the two groups favoring cyclophosphamide (–3.06; 95 percent confidence interval, –3.54 to –0.52; P=0.008).
Primary Outcome at 24 Months
Measurements of the FVC were available at 24 months for 113 patients and at 15, 18, and 21 months in an additional 3, 5, and 1 patients, respectively (a total of 122 patients were studied beyond 12 months, 62 in the cyclophosphamide group and 60 in the placebo group). In a longitudinal model made with the use of data collected from months 6 to 24, a significant treatment effect was observed, with a mean absolute difference between the two groups of 1.95 percent in the FVC (95 percent confidence interval, 1.2 to 2.6 percent; P<0.01), favoring cyclophosphamide. No interaction between time and treatment was found.
Adverse Events
Details of adverse events that occurred during the one-year double-blind treatment period (year 1) and the subsequent 12 months of follow-up (year 2) are presented in Table 3. Hematuria, leukopenia, neutropenia, anemia, and pneumonia were more common among patients in the cyclophosphamide group than among those in the placebo group during year 1; the difference between the two groups was significant for leukopenia and neutropenia (P<0.05 by Fisher's exact test). Few adverse events were recorded during year 2. The number of patients with serious adverse events and the total number of these events during year 1 were slightly, but not significantly, higher in the cyclophosphamide group than in the placebo group (17 vs. 11 patients had adverse events; 20 vs. 16 had serious adverse events). A similar trend was observed in year 2. During months 13 to 24 after randomization, four patients in the cyclophosphamide group and three in the placebo group died. In total, 12 patients died during the two years of the study, but none of the deaths were considered to be related to the study treatment.
|
This double-blind, randomized, placebo-controlled clinical trial examined the efficacy of oral cyclophosphamide for the treatment of scleroderma-related interstitial lung disease. Our findings indicate a significant, albeit quite modest, treatment effect of cyclophosphamide on changes in the FVC and total lung capacity over a period of one year but no significant effect on measures of gas transfer (DLCO or DLCO:VA). The clinical importance of this small treatment effect on lung physiology is supported by the additional findings that cyclophosphamide improved dyspnea (according to scores for the transitional dyspnea index), skin thickening, and other outcomes, including functional ability (according to the scores for the HAQ disability index) and some health-related measures of the quality of life (vitality and health transition). For example, the transitional dyspnea index focal score improved by 1.4±0.23 in the cyclophosphamide group and worsened by 1.5±0.43 in the placebo group, a difference that is both statistically significant (P<0.001 with the use of a covariance model) and more than twice the minimal clinically significant level of 1.0.31 Analysis of the primary end point at 24 months showed that the treatment effect on the FVC persisted. Although the limitations of this study included a high dropout rate and the potential for inadvertent unblinding, precautions were taken to minimize the effect of these limitations on the outcome of the trial (Supplementary Appendix 10).
An interesting finding was the relationship between fibrosis and the response to cyclophosphamide. Patients in the placebo group who had evidence of more severe fibrosis on baseline high-resolution CT had the greatest declines in FVC during the one-year treatment period; however, the baseline degree of fibrosis had no significant influence on the change in FVC in cyclophosphamide-treated patients in the same period. A significant interaction between fibrosis and treatment was found (P=0.009) (Figure 2A). A possible conclusion from this result is that preexisting fibrosis in our cohort identifies a subgroup of patients with relatively early active systemic sclerosis alveolitis who were at greatest risk for progressive interstitial lung disease unless treated. The potential benefits of treatment with cyclophosphamide need to be weighed against its adverse effects. Although the average number of adverse events per patient during the one-year treatment period was only slightly higher in the cyclophosphamide group (4.0±0.49) than in the placebo group (3.0±0.41), this difference was significant on Poisson analysis (P=0.01). The only adverse events that occurred significantly more often among patients treated with cyclophosphamide were those known to be associated with this drug — namely, leukopenia and neutropenia — which often responded to appropriate dose adjustment. Although five serious adverse events that occurred in the cyclophosphamide group and one that occurred in the placebo group during the one-year treatment period were judged to be treatment-related, the overall number of serious adverse events and deaths was not significantly different between groups during the full two-year study period. Two days after the completion of the 12-month treatment period, however, severe hemorrhagic cystitis developed in one patient in the cyclophosphamide group and has required multiple hospitalizations and a urinary diversion procedure, underscoring the potential for cyclophosphamide to cause serious toxic effects. The potential long-term effects of cyclophosphamide, including its association with bladder cancer32 and other malignant diseases,33,34 were not evaluated in this study.
In summary, we found that one year of treatment with oral cyclophosphamide resulted in a small but significant improvement in the FVC and total lung capacity at 12 months but not in measures of gas transfer. The extent of fibrosis on baseline high-resolution CT, but not other high-resolution CT findings or cellularity on examination of BAL fluid, significantly influenced the primary treatment effect. The beneficial effect of cyclophosphamide on pulmonary function was paralleled by a significant improvement in dyspnea, functional ability, the health-related quality of life, and skin thickness. The favorable effect of cyclophosphamide on FVC was sustained for the two years of the study. Although treatment with cyclophosphamide resulted in a greater number of adverse events than did placebo, the risk–benefit ratio appears to be favorable. Caution regarding the use of cyclophosphamide is still warranted, since potential long-term consequences were not evaluated.
Supported by a grant from the Public Health Service (UO1 HL 60587, to the University of California at Los Angeles Clinical Center) and by grants from the National Heart, Lung, and Blood Institute (UO1 HL 60587 and UO1 HL 60606, to the data coordinating center at the University of California at Los Angeles; UO1 HL 50550, to the University of Medicine and Dentistry of New Jersey; UO1 HL 60895, to the University of Illinois; UO1 HL 60682, to Boston University; UO1 HL 60750, to the Medical University of South Carolina; UO1 HL 60597, to Johns Hopkins School of Medicine; UO1 HL 60794, to Georgetown University; UO1 HL 60839, to the University of Texas at Houston; UO1 HL 60587, to the University of California at San Francisco; UO1 HL 60748, to the University of Alabama at Birmingham; UO1 HL 60587, to the University of Connecticut Health Center, Farmington; UO1 HL 60838, to Wayne State University; and UO1 HL 60823, to the Virginia Mason Research Center); by the National Institute of Arthritis and Musculoskeletal and Skin Diseases; and by a grant from the National Center for Research Resources, National Institutes of Health (5MO1 RR 00865, for the analysis of study data).
No potential conflict of interest relevant to this article was reported.
We are indebted to Bristol-Myers Squibb for supplying cyclophosphamide.
Source Information
From the University of California at Los Angeles, Los Angeles (D.P.T., R.E., P.J.C., J.G., M.D.R., D.E.F., E.A.); Medical University of South Carolina, Charleston (R.S., C.S., M.B.); University of Medicine and Dentistry of New Jersey–Robert Wood Johnson Medical School, New Brunswick (J.R.S., D.J.R., V.M.H.); University of Illinois, Chicago (J.V., D.E.S.); Boston University, Boston (A.T., R.S.); Johns Hopkins School of Medicine, Baltimore (R.W., F.W., B.W.); Georgetown University, Washington, D.C. (V.S., C.R.); University of Texas at Houston Medical School, Houston (M. Mayes, E.P.); Wayne State University, Detroit (K.M.); University of California San Francisco, San Francisco (M.K.C., J.G.); University of Alabama, Birmingham (M.O., B.F.); and University of Connecticut Health Center, Farmington (N.R., M. Metersky).
Address reprint requests to Dr. Tashkin at the Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine, 10833 Le Conte Ave., Los Angeles, CA 90095-1690, or at dtashkin{at}mednet.ucla.edu.
References
The following persons and institutions participated in the Scleroderma Lung Study: University of California at Los Angeles (UCLA), Los Angeles: P.J. Clements, D.P. Tashkin, R. Elashoff, J. Goldin, M. Roth, D. Furst, K. Bulpitt, D. Khanna, W.-L.J. Chung, S. Viasco, M. Sterz, L. Woolcock, X. Yan, J. Ho, S. Vasunilashorn, I. da Costa; University of Medicine and Dentistry of New Jersey, New Brunswick: J.R. Seibold, D.J. Riley, J.K. Amorosa, V.M. Hsu, D.A. McCloskey, J.E. Wilson; University of Illinois Chicago, Chicago: J. Varga, D. Schraufnagel, A. Wilbur, D. Lapota, S. Arami, P. Cole-Saffold; Boston University, Boston: R. Simms, A. Theodore, P. Clarke, J. Korn, K. Tobin, M. Nuite; Medical University of South Carolina, Charleston: R. Silver, M. Bolster, C. Strange, S. Schabel, E. Smith, J. Arnold, K. Caldwell, M. Bonner; Johns Hopkins School of Medicine, Baltimore: R. Wise, F. Wigley, B. White, L. Hummers, M. Bohlman, A. Polito, G. Leatherman, E. Forbes, M. Daniel; Georgetown University, Washington, D.C.: V. Steen, C. Read, C. Cooper, S. Wheaton, A. Carey, A. Ortiz; University of Texas at Houston, Houston: M. Mayes, E. Parsley, S. Oldham, T. Filemon, S. Jordan, M. Perry; University of California at San Francisco, San Francisco: K. Connolly, J. Golden, P. Wolters, R. Webb, J. Davis, C. Antolos, C. Maynetto; University of Alabama at Birmingham, Birmingham: B. Fessler, M. Olman, C. Sanders, L. Heck, T. Parkhill; University of Connecticut Health Center, Farmington: N. Rothfield, M. Metersky, R. Cobb, M. Aberles, F. Ingenito, E. Breen; Wayne State University, Detroit: M. Mayes, K. Mubarak, J.L. Granda, J. Silva, Z. Injic, R. Alexander; Virginia Mason Research Center, Seattle: D. Furst, S. Springmeyer, S. Kirkland, J. Molitor, R. Hinke, A. Mondt; Data Safety and Monitoring Board: Harvard Medical School, Boston — T. Thompson; Veterans Affairs Medical Center, Brown University, Providence, R.I. — S. Rounds; Cedars Sinai–UCLA, Los Angeles — M. Weinstein; Clinical Trials Surveys, Baltimore — B. Thompson; Mortality and Morbidity Review Committee: UCLA, Los Angeles — H. Paulus, S. Levy; Johns Hopkins University, Baltimore — D. Martin.
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||
Related Letters:
Cyclophosphamide in Scleroderma Lung Disease
Kuschner W. G., Andreu J.-L., Silva L., Sullivan K. M., McSweeney P. A., Nash R. A., Tashkin D. P., Clements P. J., Roth M. D.
Extract |
Full Text |
PDF
N Engl J Med 2006;
355:1173-1174, Sep 14, 2006.
Correspondence
This article has been cited by other articles:
HOME | SUBSCRIBE | SEARCH | CURRENT ISSUE | PAST ISSUES | COLLECTIONS | PRIVACY | TERMS OF USE | HELP | beta.nejm.org Comments and questions? Please contact us. The New England Journal of Medicine is owned, published, and copyrighted © 2009 Massachusetts Medical Society. All rights reserved. |
Previous
