Veeraraghavan, Srihari

Abstract Rationale Lymphangioleiomyomatosis (LAM) is a progressive cystic lung disease that predominantly affects women and can worsen with pregnancy, estrogen treatment, and the menstrual cycle, suggesting an important role for estrogen in disease pathogenesis. Objectives To assess the efficacy and safety of the aromatase inhibitor letrozole in the treatment of LAM. Methods Seventeen postmenopausal women with LAM were enrolled in this phase II trial and randomized to receive letrozole 2.5 mg daily (n = 9) or placebo (n = 8) for a period of 12 months. Five patients in each group were also taking sirolimus at baseline and remained on the drug throughout the treatment period. Lung function, exercise capacity, quality of life, and serum vascular endothelial growth factor D (VEGF-D) were measured at baseline and at 3-month intervals. Results Fifteen patients completed the study. Two patients withdrew. There were no differences in adverse events in the letrozole and placebo groups. The target enrollment of 25 patients per arm was not met, so the efficacy of letrozole could not be assessed as planned. After adjusting for sirolimus use, we found that the rate of change in FEV1 for all subjects was −3 ± 3 ml/mo (P = 0.4), and for serum VEGF-D, the rate of change was −0.024 ± 0.009 pg/ml/mo (P = 0.015), showing a steeper decline in the letrozole group (−0.029 ± 0.013; P = 0.025). All patients who were taking sirolimus had a reduction in VEGF-D levels from baseline to the last visit, compared with only half of the patients who were not taking sirolimus. In a post hoc analysis, eight matched letrozole-treated–placebo-treated pairs were constructed, six of which demonstrated better FEV1 improvement for the letrozole-treated patients. Conclusions Letrozole treatment appears to be safe and well tolerated in postmenopausal patients with LAM, including those taking sirolimus. Enrollment in this trial was compromised by the publication of an effective treatment (sirolimus) in the same month as the study opened, resulting in limited power to detect treatment effects. Post hoc matched pairs exploration studies provide tentative support for additional studies of letrozole in LAM. Considering the reduced rate of lung function decline in postmenopausal patients, future studies will likely require enhanced study designs, such as selective enrollment of those with prognostic biomarkers predictive of decline. Clinical trial registered with www.clinicaltrials.gov (NCT01353209).

Abstract Survival is linked to the histopathologic distinction between usual interstitial pneumonia (UIP) and nonspecific interstitial pneumonia (NSIP), the most commonly encountered fibrotic idiopathic interstitial pneumonia. We retrospectively compared the prognostic significance of histopathologic diagnoses, baseline pulmonary function indices, and serial trends in pulmonary function indices (diffusing capacity, FVC, FEV1, the recently defined composite physiologic index) at 6 and 12 months in 104 patients (UIP, n = 63; fibrotic NSIP, n = 41). Survival was lower in UIP than in fibrotic NSIP (p = 0.001) but not in patients with severe functional impairment; mortality during the first 2 years was linked solely to the severity of functional impairment at presentation. The composite physiologic index was the strongest determinant of outcome (p < 0.001). At 6 months, serial diffusing capacity levels (p = 0.003) and histopathologic diagnosis (p = 0.002) were prognostically equivalent. At 12 months, serial pulmonary function trends were the only major prognostic determinant (p < 0.0005 for all variables), with no independent significance associated with the distinction between UIP and fibrotic NSIP. We conclude that at 12 months, serial pulmonary function trends have considerable prognostic value in UIP and NSIP. Their histologic distinction provides no additional prognostic information when pulmonary function trends are clear cut or when functional impairment is severe.