A 2-year randomised placebo-controlled trial of doxycycline for lymphangioleiomyomatosis

Abstract

Lymphangioleiomyomatosis (LAM) is characterised by lung cysts and airflow obstruction. Matrix metalloproteinases have been implicated in lung destruction in LAM. We performed a randomised, double-blind trial, comparing the matrix metalloproteinases inhibitor doxycycline with placebo on the progression of LAM.23 females with LAM were randomised to doxycycline 100 mg daily for 3 months followed by 200 mg daily for 21 months, or matched placebo. Lung function, exercise capacity, quality of life and matrix metalloproteinases levels were measured. 21 patients completed 6 months of treatment, 17 completed 1 year of treatment and 15 completed 2 years of treatment. Eight withdrew from the trial due, four due to a pneumothorax and four because of other reasons. The mean¡SD decline in FEV1, the primary endpoint, did not differ between the groups being -90¡154 mL?year -1 in the placebo group and -123¡246 mL?year -1 in the doxycycline group (difference -32.5, 95% CI -213-148; p50.35). Doxycycline had no effect upon vital capacity, gas transfer, shuttle walk distance or quality of life. Urine matrix metalloproteinases-9 measurements were lower with doxycycline treatment (p50.03).Although with limited numbers we cannot completely exclude an effect of doxycycline, the lack of effect on any outcome makes it unlikely that doxycycline has a useful effect in LAM. @ERSpublications Doxycycline does not prevent progression of lung disease in LAM http://ow.ly/tiMqo

Doxycycline in lymphangioleiomyomatosis: not all questions are answered

“…We agree that based upon our own, as well as the author's, data that doxycycline cannot currently be recommended as a therapy to reduce a decline in lung function in patients with lymphangioleiomyomatosis (LAM). As the authors pointed out, in our randomised placebo-controlled study, the two groups had slightly differing baseline lung-function values, which may have led to the differences in the rate of progression of LAM and possibly the response to doxycycline [1]. However, the lack of effect on any study endpoint suggests that doxycycline is unlikely to be helpful for the majority of patients.…”

“…Baldi and colleagues for their interest in our paper [1]. We agree that based upon our own, as well as the author's, data that doxycycline cannot currently be recommended as a therapy to reduce a decline in lung function in patients with lymphangioleiomyomatosis (LAM).…”

“…This idea would require testing in a randomised placebo-controlled trial of patients with early or mild disease, as it is also possible that doxycycline does not affect lung function decline in LAM and these observations are due to the variable rate of disease progression in LAM patients. Interest in the efficacy of doxycycline as a metalloproteinase inhibitor in LAM must also be tempered by the modest effect on matrix metalloproteinase (MMP) levels in LAM-derived cell supernatants [4] and serum levels of MMP-2 and MMP-9 in LAM [1,3]. Similarly, the suggestion that doxycycline may work in synergy with other therapies will further need formal testing.…”

The changing face of a rare disease: lymphangioleiomyomatosis

“…31 patients completed 12 months of treatment showing a significant mean decrease in FEV1 (70 mL), but no significant variation in DLCO and 6MWD, and a significant reduction in urinary MMP-9 levels and serum MMP-2 levels but no significant differences between pre-and post-treatment serum MMP-9 levels, suggesting a mechanism of action different from MMP blockade [116]. In a double-blind, placebo-controlled clinical trial of doxycycline, the mean decline in FEV1 per year did not differ between the placebo and the treatment group, although the effect of doxycycline on urinary levels of MMP-9 was confirmed [100]. The results of this study may have been limited by the small number of patients (n=15) who completed the 24 months of treatment, due to a high percentage of withdrawals.…”

“…Mean annual decline in FEV1 has been reported as 60-120 mL per year in different retrospective studies of referral centres or national cohorts [1,97,98]. Two recent clinical trials about use of sirolimus and doxycycline showed a mean ΔFEV1 post-bronchodilator in the placebo group of −134 mL (in the 12 month study period) and −90.3 mL per year, respectively [99,100].…”