We found that treatment with sirolimus was associated with improvement or stabilization of lung function and decrease in the size of chylous effusions and lymphangioleiomyomas in a selected population of patients with LAM. Of note, adverse events associated with sirolimus therapy were manageable and, as of now, all patients continue to receive this therapy and have sustained improvement or stabilization of lung function and continued resolution of effusions and lymphangioleiomyomas.
Although previous reports have described improvement (31
) or stabilization (32
) of lung function associated with sirolimus therapy, we believe that our study is the first to systematically evaluate the effect of sirolimus in patients with chylous effusions and lymphangioleiomyomas. In this subgroup of patients, sirolimus therapy was associated with reduction or resolution of the effusions and lymphangioleiomyomas, with consequent dramatic improvement in lung function. Patients with uncontrolled pleural effusions that required frequent pleural drainage no longer required repeated drainage after beginning sirolimus therapy. Another strength of our study is the body of both radiologic and physiologic information spanning several years preceding treatment with sirolimus, which provides a valuable basis for comparison with posttherapy data.
In patients without baseline pleural effusions, lung function during sirolimus therapy stabilized and, in contrast to the characteristic progressive nature of LAM (20
), no substantial decline in lung function was observed. This finding suggests that the beneficial effects of sirolimus therapy in patients with LAM may extend to those without involvement of the lymphatic system, although our small sample limits robust conclusions. Overall, however, our data are consistent with those of the recently completed MILES Trial (37
), which showed that 1 year of sirolimus therapy was associated with stabilized lung function and reported changes in FEV1
in the placebo and sirolimus groups that were similar to those in our study ().
Our hypothesis was that suppression of LAM cell proliferation and growth by the sirolimus-mediated inhibition of the mTOR pathway would improve lung function and reduce the size of chylous effusions and lymphangioleiomyomas. This hypothesis was based on previous studies showing that sirolimus reduced the size of neoplastic growths in animal models of TSC (28
). A literature search of the PubMed database for all articles related to sirolimus therapy in human patients with LAM through 2010 revealed individual case reports of reduction in the size of chylous effusions and lymphangioleiomyomas (33
) and improved lung function in a series of patients treated for 1 year (31
). Reductions in the size of angiomyolipomas (31
) and giant cell astrocytomas in patients with LAM or TSC have also been reported (36
). Now, the MILES Trial (37
) and our data show that sirolimus therapy is associated with stabilization of lung function. Our study, however, extends these observations to patients with LAM and lymphatic involvement.
During the observation year of the MILES Trial, when patients did not receive sirolimus therapy, changes in FEV1
and FVC in the sirolimus and placebo groups did not significantly differ, which indicates that the beneficial effects of sirolimus ceased after sirolimus therapy was discontinued (37
). Our study shows that the benefits of sirolimus seem to be sustained for more than 2 years of therapy as long as patients continue to receive the drug. In addition, as in the MILES Trial, the adverse events associated with sirolimus in our study were manageable.
The MILES Trial (37
) also showed that levels of serum vascular endothelial growth factor-D (VEGF-D), a lymphangiogenic growth factor implicated in the pathophysiology of LAM, were reduced in response to sirolimus, and that a decrease in mean VEGF-D levels even after discontinuation of the drug was consistent with a sustained effect on the lymphatic component of the disease. Because VEGF-D levels are reported to be higher in patients with LAM and lymphatic involvement than in those with cystic disease limited to the lung (14
), the data from the MILES Trial (37
) are consistent with our finding that lymphatic involvement in LAM seems to be highly responsive to sirolimus therapy.
Our study has limitations. The selected LAM population in our study consisted of patients with progressive disease, most of whom had lymphatic involvement and chylous effusions. The rates of decline in pulmonary function observed in our patients before sirolimus therapy were higher than those previously reported (20
). In other studies, reported rates of decline in FEV1
have ranged from 75 ± 9 mL per year to 118 ± 21 mL per year (20
) and rates of decline in DLCO
have ranged from 0.69 ± 0.07 mL/min per mm Hg to 0.90 ± 0.26 mL/min per mm Hg per year (20
); each of these values is less than one half of the unadjusted rates of decline in pulmonary function that our patients experienced.
In a large previous study, the rates of decline in percentage of predicted FEV1
were 1.7% ± 0.4% predicted and 2.4% ± 0.4% predicted per year, respectively (20
). In our study, the average unadjusted rates of decline in FEV1
were approximately 9% predicted per year, which reflects rapidly progressing severe disease.
A large difference in the rates of decline in FEV1
between patients who present with dyspnea and those who present with pneumothorax has been reported (41
). This finding suggests that LAM can be a very aggressive disease in some patients and can cause declines in FEV1
ranging from 5% to 10% predicted per year, whereas in other patients, lung disease progresses slowly and interferes little with activities of daily living. Therefore, our findings cannot be generalized to patients with LAM who have milder disease without chylous effusions or lymphangioleiomyomas.
In addition, our study was not controlled, and it is possible that the pleural effusions may have resolved spontaneously. However, we have never observed spontaneous resolution of large chylous effusions in the NHLBI natural history protocol cohort.
Overall, our data suggest that sirolimus should be evaluated as a treatment of chylous effusions and symptomatic lymphangioleiomyomas in patients with LAM. As our study demonstrates, chylous effusions in LAM are difficult to treat and repeated thoracentesis may lead to severe weight loss. Other therapies, such as pleuroperitoneal shunts and octreotide, have been tried, but there is little experience with these therapeutic methods in patients with LAM (43
). Although lymphangioleiomyomas are usually asymptomatic, compression of the bladder, bowel, pelvic veins, nerves, and other organs may cause pain, obstipation, frequent urination, and peripheral edema. Surgery has been performed but can lead to persistent lymphatic leakage, chylothorax, and ascites.
In conclusion, we found that sirolimus therapy was associated with improved or stabilized lung function and reductions in the size of chylous effusions and lymphangioleiomyomas in patients with aggressive LAM. Our findings suggest a potential role for sirolimus in the management of patients with LAM, especially for those with lymphatic involvement. The adverse events associated with sirolimus therapy were manageable in our patients. However, the long-term risks of sirolimus therapy must be weighed against its benefits, as we lack information regarding the optimal duration of therapy and when cessation should be considered. Lifelong therapy may be required, or resistance to sirolimus may eventually develop. Despite these possibilities, sirolimus therapy may be a reasonable consideration for patients with intractable chylous effusions and lymphangioleiomyomas.