Our study shows that treatment with sirolimus for 1 year has beneficial effects in patients with LAM, including the stabilization of FEV1 and improvement in FVC, quality of life, and some functional performance measures. No effects were observed on the diffusing capacity of the lung for carbon monoxide or on exercise tolerance, and the positive effects on airflow waned after sirolimus was discontinued. Sirolimus was associated with an increased frequency of adverse events, as compared with placebo, though the rates of serious adverse events were similar in the two study groups.
Although the minimum clinically important differences for measures of lung function have not been established in patients with LAM, the minimum clinically important difference in FEV1
in patients with chronic obstructive lung disease has been estimated to be 100 to 140 ml,22
which is a change that patients can perceive, that is a typical response after use of a bronchodilator, and that predicts a relapse after an exacerbation.22
The absolute mean between-group change of 153 ml in the FEV1
over the course of 1 year in our study compares favorably with this estimate. In the placebo group, the observed annual mean decline of 134 ml per year in the FEV1
from the baseline level of 1.38 liters indicates that lung function is lost at the rate of almost 10% per year in patients with moderately severe LAM. Therapies that stabilize lung function could potentially delay the need for lung transplantation, with its associated risks. The importance of the observed changes in lung function is further supported by the positive correlation with the scores on the Functional Performance Inventory and the EuroQOL visual-analogue scale for quality of life, both of which have been validated in patients with other lung diseases.23,24
Sirolimus therapy positively affected lung function only during the treatment period. After discontinuation of sirolimus, the FEV1
in patients in the sirolimus group declined in parallel with the decline in the placebo group, and the mean change from baseline to 24 months did not differ significantly between the two groups. Thus, sirolimus therapy for 1 year did not appear to accelerate the subsequent rate of decline in lung function — a theoretical concern raised by the apparent rebound increase in growth rates of angiomyolipomas after withdrawal of sirolimus.18
These data should be interpreted with caution, given the high withdrawal rate in the observation period and the early termination of the second trial year for some patients. Other study limitations include the possibility that the treatment assignments may have been inadvertently revealed owing to cholesterol elevations and the development of mouth ulcers and rashes in some patients in the sirolimus group.
Sirolimus was associated with an improvement in FVC; the absolute mean change in FVC (230 ml) was similar in magnitude to the minimum clinically important difference of 250 ml proposed for scleroderma-related lung disease.25
The increase in FVC with sirolimus was accompanied by an increase in the slope for functional residual capacity and trends toward increases in the slopes for total lung capacity and residual volume, suggesting that a reduction in restrictive impairment is a potential mechanism for higher airflow. The reduction in residual volume noted in a previous open-label trial, which suggested a reduction in gas trapping, was not seen in our trial.18
Serious adverse respiratory events occurred less frequently in the sirolimus group than in the placebo group during the treatment period, a finding that is consistent with a potential beneficial effect of the drug on other manifestations of the disease. The between-group difference of 8.44 from baseline to 12 months in the quality of life scores on the EuroQOL visual-analogue scale (on which scores range from 0 to 100, with lower scores indicating worse functioning) was greater than half the standard deviation, an accepted threshold for clinical significance.26
The lack of a significant between-group difference in the distance covered on a 6-minute walk test suggests that improvement in lung function may not be accompanied by an increase in exercise capacity, though a treatment effect might have been obscured by the relatively high baseline exercise tolerance of the patients or limitations in the performance characteristics of the test.
Levels of serum VEGF-D, a lymphangiogenic growth factor implicated in the pathophysiology of LAM,11,12
were reduced in response to sirolimus. The persistent depression in mean VEGF-D levels after discontinuation of the drug may be consistent with a durable treatment effect in some patients, but this finding is difficult to interpret, given the attrition that occurred during the observation year. Further study is needed to determine whether it is possible to predict which patients will benefit from sirolimus treatment and whether the VEGF-D level can serve as a biomarker of disease severity, disease progression, or treatment response.
These results indicate that sirolimus may be useful in treating patients with moderately severe LAM-related lung disease. LAM typically progresses slowly, and given the risks of sirolimus therapy, treatment decisions should be made on an individual basis. The mean FEV1
for patients in this trial (48% of the predicted value) was lower than the population-based mean among patients in the LAM Registry of the NIH27
(70% of the predicted value), making it difficult to generalize the results from the patients in this study to patients with milder or more severe lung disease due to LAM. Since the stabilization of lung function appears to require continuous exposure to sirolimus, additional trials are needed to determine which patients will benefit from treatment and the optimal dose and duration of treatment. Given the side-effect profile of the drug during a 1-year period, future studies must carefully evaluate the long-term safety of sirolimus.