Extract
Lymphangioleiomyomatosis (LAM) is a multisystem disease associated with progressive pulmonary disease that affects almost exclusively women. LAM is characterised pathologically by proliferation of abnormal smooth muscle-like cells carrying mutations in predominantly the tuberous sclerosis complex (TSC) gene TSC2 and, rarely, in TSC1 [1]. LAM can occur sporadically or in association with TSC. Mutations in the TSC genes lead to activation of the mammalian/mechanistic target of rapamycin complex 1 (mTORC1) [2]. In the landmark randomised controlled MILES (Multicenter International LAM Efficacy of Sirolimus) trial, the mTORC1 inhibitor rapamycin stabilised lung function and improved symptoms in LAM patients with moderate to severe changes in lung function (forced expiratory volume in 1 s (FEV1) <70%) [3]. Recent in vitro and preclinical evidence showed that loss of TSC2 resulted in upregulation of COX-2 and prostacyclin synthase (PGTIS) expression, independent of mTORC1. Treatment of Tsc2+/− mice with celecoxib, a COX-2 specific inhibitor, resulted in a 50% decrease in renal cystadenomas volume, which occur spontaneously in this model [4]. In addition, LAM nodules were found to express higher levels of COX-2 in comparison with control lungs [4].
Abstract
COX2 inhibition is safe in LAM patients with mild disease. In the subset of patients with high VEGF-D (>800 pg per mL) COX2 inhibition appears to cause a decrease in VEGF-D levels and may provide clinical benefit. http://bit.ly/395drXs
Acknowledgement
We are indebted to patients and their families for their participation in this study. We also thank The LAM Foundation and the Tuberous Sclerosis Alliance for patient referral. We thank the Data Safety Monitoring Board Members and Medical Monitor, as well as the clinical trials support staffs at the BWH and the Office of the Clinical Director, National Heart, Lung, and Blood Institute, NIH. We are grateful to Saint George's, University London for permission to use the SGRQ.
Footnotes
This study is registered as clinical trial NCT02484664. Data generated in this study will be made available in de-identified fashion upon reasonable request and with appropriate institutional review board approvals.
Conflict of interest: S. El-Chemaly has nothing to disclose.
Conflict of interest: A. Taveira-DaSilva has nothing to disclose.
Conflict of interest: S. Bagwe has nothing to disclose.
Conflict of interest: K. Katarzyna has nothing to disclose.
Conflict of interest: T. Machado has nothing to disclose.
Conflict of interest: A.M. Lamattina reports personal fees from Wave Life Sciences, outside the submitted work.
Conflict of interest: H.J. Goldberg has nothing to disclose.
Conflict of interest: A.M. Jones has nothing to disclose.
Conflict of interest: P. Julien-Williams has nothing to disclose.
Conflict of interest: R. Maurer has nothing to disclose.
Conflict of interest: I.O. Rosas has nothing to disclose.
Conflict of interest: E.P. Henske has nothing to disclose.
Conflict of interest: J. Moss has nothing to disclose.
Conflict of interest: D.J. Kwiatkowski has nothing to disclose.
Support statement: This study was supported by a Department of Defense Grant W81XWH-15-1-0511, TS140054 to D.J. Kwiatkowski and in part by the Division of Intramural Research NIH/NHLBI and the Lucy Engles Program in TSC and LAM research. Funding information for this article has been deposited with the Crossref Funder Registry.
- Received December 3, 2019.
- Accepted February 2, 2020.
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