Correlation of cough with disease activity and treatment with cyclophosphamide in scleroderma interstitial lung disease: findings from the Scleroderma Lung Study

Abstract

Background: Cough is a significant symptom in patients with scleroderma interstitial lung disease (SSc-ILD), affecting 73% of the 158 patients enrolled in the Scleroderma Lung Study (SLS), a multicenter randomized trial of oral cyclophosphamide (CYC) vs placebo (PLA) in patients with active interstitial lung disease.

Methods: We examined the correlation of cough frequency and severity and phlegm production at baseline in 156 SLS participants with other baseline variables representing SSc-ILD disease activity and the cough response to 1 year of treatment with CYC vs PLA.

Results: Patients with cough at baseline had significantly lower diffusing capacity of the lung for carbon monoxide, dyspnea, the quality-of-life physical component summary, and the maximal fibrosis score on high-resolution CT imaging compared with those without cough at baseline. Cough severity and frequency correlated with FVC % predicted. After 12 months of treatment, cough frequency decreased in the CYC group compared with the PLA group and was significantly different from the PLA group at 18 months (6 months after discontinuation of CYC). However, the decreases in cough frequency did not correlate with the changes in FVC or diffusing capacity of the lung for carbon monoxide observed in the CYC group. Treatment-related improvements in cough frequency, as well as in FVC, were no longer apparent 12 months after discontinuation of CYC.

Conclusions: Cough is a common symptom in SSc-ILD and correlates with the extent of fibrosis. Cough frequency decreases significantly in response to treatment with CYC but returns to baseline 1 year after withdrawal of treatment. Cough may be a symptom of ongoing fibrosis and an independent variable in assessing therapeutic response to CYC.

Trial registry: ClinicalTrials.gov; No.: NCT000004563; URL: www.clinicaltrials.gov

Trial registration: ClinicalTrials.gov NCT00004563 NCT00004563.

Figures

Figure 1.

Cough was scored by patients choosing from the definitions of severity and frequency and phlegm production and marking a corresponding box that was used for grading.

Figure 2.

Percentage of patients without cough and those with cough who had a clinical/endoscopic diagnosis of GERD and used PPI. GERD = gastroesophageal reflux disease; PPI = proton pump inhibitor.

Figure 3.

Time course of the presence of cough in the CYC and PLA groups determined from the time double-blind treatment was begun (time 0) through completion of treatment (12 months) and study completion (24 months [12 months after discontinuation of study medication]). CYC = cyclophosphamide; PLA = placebo.

Figure 4.

A, Comparison of scores between 6 and 18 months by treatment group (patients treated with CYC compared with those treated with PLA) indicates no significant difference in cough severity (0.87 ± 0.66 vs 1.04 ± 0.67, P = .15, Wilcoxon rank sum test); a nearly significant decrease in cough frequency (0.83 ± 0.67 vs 1.04 ± 0.69, P = .056, Wilcoxon rank sum test); and no significant treatment effect on phlegm production (1.10 ± 0.80 vs 1.32 ± 0.86, P = .12, Wilcoxon rank sum test). A, Average cough severity. B, Average cough frequency. C, Average phlegm production. See Figure 3 legend for expansion of abbreviations.