Correspondence
Cyclophosphamide in Scleroderma Lung Disease
N Engl J Med 2006; 355:1173-1174September 14, 2006
- Article
To the Editor:
In their report showing the modest efficacy of oral cyclophosphamide in the management of scleroderma-related interstitial lung disease, Tashkin et al. (June 22 issue)1 do not describe glucocorticoid use among study participants. Patients taking prednisone at a dose of up to 10 mg per day were eligible for inclusion in the investigation. Accordingly, it is not possible to determine whether low-dose glucocorticoids may have contributed to the disease-modifying effects attributed to cyclophosphamide. Glucocorticoids in low2 and medium-low3 doses administered with cyclophosphamide have been reported to improve lung function in patients with scleroderma-related interstitial lung disease. The authors should describe glucocorticoid use among participants in their investigation and report whether there was a difference in treatment responses between participants who received both cyclophosphamide and glucocorticoids and those who received cyclophosphamide alone.
3 ReferencesWare G. Kuschner, M.D.
Veterans Affairs Palo Alto Health Care System, Palo Alto, CA 94304
ware.kuschnermd@va. gov 1
Tashkin DP ,Elashoff R ,Clements PJ , et al. Cyclophosphamide versus placebo in scleroderma lung disease. N Engl J Med 2006;354:2655-2666
Full Text | Web of Science | Medline2
Silver RM ,Warrick JH ,Kinsella MB ,Staudt LS ,Baumann MH ,Strange C . Cyclophosphamide and low-dose prednisone therapy in patients with systemic sclerosis (scleroderma) interstitial lung disease. J Rheumatol 1993;20:838-844
Web of Science | Medline3
Beretta L, Caronni M, Raimondi M, et al. Oral cyclophosphamide improves pulmonary function in scleroderma patients with fibrosing alveolitis: experience in one centre. Clin Rheumatol (in press).
To the Editor:
With regard to the article by Tashkin and colleagues on the therapeutic role of oral cyclophosphamide in scleroderma-related interstitial lung disease, we wonder whether the beneficial effect on the forced vital capacity (FVC) could be explained by a putative action of cyclophosphamide on the skin. Was there any relationship between the response of the FVC to cyclophosphamide and the presence of scleroderma-related changes in the skin of the chest wall?
José-Luis Andreu, M.D., Ph.D.
Lucía Silva, M.D.
Hospital Universitario Puerta de Hierro, 28035 Madrid, Spain
jlandreu@arrakis.es To the Editor:
Tashkin et al. report a significant but modest beneficial effect of cyclophosphamide in scleroderma-related interstitial lung disease. This provides support for the concept that immunosuppression may be of benefit in severe systemic sclerosis. However, more effective therapy is needed.
The Scleroderma: Cyclophosphamide Or Transplant (SCOT) study, an ongoing multicenter trial sponsored by the National Institutes of Health, is enrolling patients with high-risk features of severe systemic sclerosis, including lung disease. Immunosuppression with 12 monthly courses of intravenous cyclophosphamide (750 mg per square meter of body-surface area) will be compared with immunoablative therapy followed by CD34-selected autologous hematopoietic stem-cell transplantation. The eligibility criteria are available at www.sclerodermatrial.org. Patients who are eligible for the SCOT trial must have received less than 5 months of oral cyclophosphamide.
Keith M. Sullivan, M.D.
Duke University Medical Center, Durham, NC 27710
sulli025@mc.duke. edu Peter A. McSweeney, M.D.
Rocky Mountain Cancer Center, Denver, CO 80218Richard A. Nash, M.D.
Fred Hutchinson Cancer Research Center, Seattle, WA 98109Author/Editor Response
Kuschner raises a common question about the potential effect of low doses of prednisone on scleroderma-related interstitial lung disease. Although prednisone has been a controversial therapy for many forms of interstitial lung disease, there is little hard evidence of its efficacy.1,2 In the Scleroderma Lung Study, 21 of the 79 patients in the cyclophosphamide group (27%) and 22 of the 79 patients in the placebo group (28%) were receiving prednisone concomitantly at study entry, almost always in doses of 10 mg or less per day (mean [±SE] dose, 8.3±0.85 and 9.0±0.82, respectively) and mainly for management of musculoskeletal symptoms. In nearly all patients, these doses remained stable (35 patients) or tended to decline (6 patients) during the course of the study. When prednisone was added as either a dichotomous covariate (present or absent) or a continuous dose variable (in patients who received prednisone) to the multiple linear regression that included the FVC (as a percentage of the predicted value) at 12 months as the dependent variable and treatment group, baseline FVC (as a percentage of the predicted value), and baseline maximal fibrosis score (from high-resolution computed tomography [CT] of the thorax) as covariates, no significant effect of prednisone was noted (P=0.70 and P=0.90, respectively). These findings confirm that prednisone was not a factor in the favorable response to cyclophosphamide that we reported.
Andreu and Silva speculate that a cyclophosphamide-induced reduction in the thickness of the skin over the chest wall affected by scleroderma could contribute to the drug's benefit in slowing the decline in the FVC, presumably through improvement in chest-wall compliance. Scleroderma is a complex disease, and it is possible that alterations in chest-wall compliance, muscle strength, chronic aspiration, or other factors could contribute to respiratory compromise in some patients. Regarding changes in skin thickness, an ongoing analysis of data from the Scleroderma Lung Study demonstrates a beneficial effect of cyclophosphamide on changes in the FVC over a 1-year period in patients with limited scleroderma similar to that observed in patients with diffuse scleroderma, after adjustment for baseline FVC (as a percentage of the predicted value) and for the extent of lung fibrosis on baseline high-resolution CT. Since truncal skin involvement is absent in patients with limited scleroderma, these findings would argue against the hypothesis of Andreu and Silva that a cyclophosphamide-induced decrease in the thickness of the skin over the chest wall plays an important role in the pulmonary-function changes that we reported.
We agree with Sullivan and colleagues that in view of the modest effects of oral cyclophosphamide-induced immunosuppression on pulmonary function and its potential toxicity, a more effective therapy is needed for scleroderma-related interstitial lung disease.
2 ReferencesDonald P. Tashkin, M.D.
Philip J. Clements, M.D., M.P.H.
Michael D. Roth, M.D.
David Geffen School of Medicine at UCLA, Los Angeles, CA 90095-1690
dtashkin@mednet.ucla. edu 1
Bouros D ,Antoniou KM . Current and future therapeutic approaches in idiopathic pulmonary fibrosis. Eur Respir J 2005;26:693-702
CrossRef | Web of Science | Medline2
Vassallo R ,Thomas CF . Advances in the treatment of rheumatic interstitial lung disease. Curr Opin Rheumatol 2004;16:186-191
CrossRef | Web of Science | Medline
