Bronchoalveolar lavage and response to cyclophosphamide in scleroderma interstitial lung disease

Abstract

Rationale: The presence of inflammatory cells on bronchoalveolar lavage is often used to predict disease activity and the need for therapy in systemic sclerosis-associated interstitial lung disease.

Objectives: To evaluate whether lavage cellularity identifies distinct subsets of disease and/or predicts cyclophosphamide responsiveness.

Methods: Patients underwent baseline lavage and/or high-resolution computed tomography as part of a randomized placebo-controlled trial of cyclophosphamide versus placebo (Scleroderma Lung Study) to determine the effect of therapy on forced vital capacity. Patients with 3% or greater polymorphonuclear and/or 2% or greater eosinophilic leukocytes on lavage and/or ground-glass opacification on computed tomography were eligible for enrollment.

Measurements and main results: Lavage was performed in 201 individuals, including 141 of the 158 randomized patients. Abnormal cellularity was present in 101 of these cases (71.6%) and defined a population with a higher percentage of men (P = 0.04), more severe lung function, including a worse forced vital capacity (P = 0.003), worse total lung capacity (P = 0.005) and diffusing capacity of the lung for carbon monoxide (P = 0.004), more extensive ground-glass opacity (P = 0.005), and more extensive fibrosis in the right middle lobe (P = 0.005). Despite these relationships, the presence or absence of an abnormal cell differential was not an independent predictor of disease progression or response to cyclophosphamide at 1 year (P = not significant).

Conclusions: The presence of an abnormal lavage in the Scleroderma Lung Study defined patients with more advanced interstitial lung disease but added no additional value to physiologic and computed tomography findings as a predictor of progression or treatment response. Clinical trial registered with www.clinicaltrials.gov (NCT 000004563).

Trial registration: ClinicalTrials.gov NCT00004563.

Figures

Figure 1.

Screening and enrollment diagram for the Scleroderma Lung Study (SLS) and the cohort with evaluable bronchoalveolar lavage (BAL) results. HRCT = high-resolution computed tomography.

Figure 2.

Course of %predicted FVC over 1 year in Scleroderma Lung Study subjects assigned to the placebo arm. (A) The %predicted FVC at each time point after starting therapy was compared with the baseline value to calculate the change from baseline for all subjects who were assigned to the placebo group, had an evaluable baseline bronchoalveolar lavage (BAL), and completed a follow-up measurement of FVC at the 6, 9, and/or 12-month time point (n = 66 subjects). (B) The change from baseline for the %predicted FVC at each time point stratified by the subject's assignment as either BAL positive (BAL+) (44 subjects) or BAL negative (BAL−) (22 subjects). There was a significant decline in FVC at 1 year in patients assigned to placebo (P = 0.0001, linear mixed model), but no significant difference between the course of decline comparing the BAL+ and BAL− groups ( P = 0.74, linear mixed model).

Figure 3.

Frequency distribution of the change in %predicted FVC over 1 year stratified according to treatment group. The change in %predicted FVC, comparing the value at 1 year with the value at baseline, was calculated for each participant in the Scleroderma Lung Study who had an evaluable baseline bronchoalveolar lavage (BAL) and had completed a follow-up measurement of FVC at the 6, 9, and/or 12-month time point (126 subjects). Frequency distribution curves were calculated based on the magnitude of the change in %predicted FVC, stratified by their assignment to either the cyclophosphamide (CYC) or placebo groups, and displayed for all subjects (A), those with a positive BAL (B), and those with a negative BAL (C). There were significantly more subjects who had a stable or improving FVC when treated with CYC than with placebo when all subjects were analyzed (P = 0.015) and for the BAL-positive cohort (P = 0.034), but not for the BAL-negative cohort (P = 0.42, Fisher's exact test). CYC, solid bars; placebo, hatched bars.