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    A 2-year randomised placebo-controlled trial of doxycycline for lymphangioleiomyomatosis. Chang William Y C,Cane Jennifer L,Kumaran Maruti,Lewis Sarah,Tattersfield Anne E,Johnson Simon R The European respiratory journal 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; p=0.35). 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 (p=0.03). 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. 10.1183/09031936.00167413
    Sustained effects of sirolimus on lung function and cystic lung lesions in lymphangioleiomyomatosis. Yao Jianhua,Taveira-DaSilva Angelo M,Jones Amanda M,Julien-Williams Patricia,Stylianou Mario,Moss Joel American journal of respiratory and critical care medicine RATIONALE:Sirolimus therapy stabilizes lung function and reduces the size of chylous effusions and lymphangioleiomyomas in patients with lymphangioleiomyomatosis. OBJECTIVES:To determine whether sirolimus has beneficial effects on lung function, cystic areas, and adjacent lung parenchyma; whether these effects are sustained; and whether sirolimus is well tolerated by patients. METHODS:Lung function decline over time, lung volume occupied by cysts (cyst score), and lung tissue texture in the vicinity of the cysts were quantified with a computer-aided diagnosis system in 38 patients. Then we compared cyst scores from the last study on sirolimus with studies done on sirolimus therapy. In 12 patients, we evaluated rates of change in lung function and cyst scores off and on sirolimus. MEASUREMENTS AND MAIN RESULTS:Sirolimus reduced yearly declines in FEV1 (-2.3 ± 0.1 vs. 1.0 ± 0.3% predicted; P < 0.001) and diffusing capacity of carbon monoxide (-2.6 ± 0.1 vs. 0.9 ± 0.2% predicted; P < 0.001). Cyst scores 1.2 ± 0.8 years (30.5 ± 11.9%) and 2.5 ± 2 years (29.7 ± 12.1%) after initiating sirolimus were not significantly different from pretreatment values (28.4 ± 12.5%). In 12 patients followed for 5 years, a significant reduction in rates of yearly decline in FEV1 (-1.4 ± 0.2 vs. 0.3 ± 0.4% predicted; P = 0.025) was observed. Analyses of 104 computed tomography scans showed a nonsignificant (P = 0.23) reduction in yearly rates of change of cyst scores (1.8 ± 0.2 vs. 0.3 ± 0.3%; P = 0.23) and lung texture features. Despite adverse events, most patients were able to continue sirolimus therapy. CONCLUSIONS:Sirolimus therapy slowed down lung function decline and increase in cystic lesions. Most patients were able to tolerate sirolimus therapy. 10.1164/rccm.201405-0918OC
    Lymphangioleiomyomatosis: Current understanding and potential treatments. Moir Lyn M Pharmacology & therapeutics Lymphangioleiomyomatosis (LAM) is a rare neoplastic disease affecting predominantly young women. Clinical symptoms of this progressive disease include dyspnoea, cough, recurrent pneumothorax, hemoptysis and chylothorax. LAM is generally aggressive in nature and ultimately results in respiratory failure. Important hallmark features of this metastatic disease include the formation of lesions of abnormal smooth muscle cells, cystic destruction of the lung tissue and lymphangiogenesis affecting the lungs, abdomen and lymphatics. Research over the last 10-15 years has significantly enhanced our understanding of the molecular and cellular processes associated with LAM. These processes include mutational inactivation of the tuberous sclerosis complex genes, TSC1 and TSC2, activation of the mammalian target of rapamycin (mTOR) pathway, enhanced cell proliferation and migration, lymphangiogenesis, metastatic spread through the blood and lymphatic circulations, sex steroid sensitivity and dysregulated autophagy. Despite this increased knowledge there is currently no cure for LAM and treatment options remain limited. Whilst the mTOR inhibitor rapamycin has shown some benefit in patients with LAM, with stabilisation of lung function and improved quality of life, cessation of treatment results in recurrence of the disease progression. This highlights the urgent need to identify novel targets and new treatment regimens. The focus of this review is to summarise our current understanding of the cellular and molecular processes associated with LAM and highlight emerging treatments. 10.1016/j.pharmthera.2015.12.008
    Pulmonary rehabilitation in lymphangioleiomyomatosis: a controlled clinical trial. Araujo Mariana S,Baldi Bruno G,Freitas Carolina S G,Albuquerque André L P,Marques da Silva Cibele C B,Kairalla Ronaldo A,Carvalho Celso R F,Carvalho Carlos R R The European respiratory journal Lymphangioleiomyomatosis (LAM) is a cystic lung disease frequently associated with reduced exercise capacity. The aim of this study was to assess safety and efficacy of pulmonary rehabilitation in LAM.This controlled clinical trial included 40 patients with LAM and a low physical activity level. The pulmonary rehabilitation programme comprised 24 aerobic and muscle strength training sessions and education. The primary outcome was exercise capacity (endurance time during a constant work rate exercise test). Secondary outcomes included health-related quality of life (St George's Respiratory Questionnaire (SGRQ)), 6-min walking distance (6MWD), dyspnoea, peak oxygen consumption (V'O2 ), daily physical activity (pedometer), symptoms of anxiety and depression, lung function and peripheral muscle strength (one-repetition maximum).The baseline characteristics were well balanced between the groups. The pulmonary rehabilitation group exhibited improvements in the following outcomes versus controls: endurance time (median (interquartile range) 169 (2-303) s versus -33 (-129-39) s; p=0.001), SGRQ (median (interquartile range) -8 (-16-2) versus 2 (-4-5); p=0.002) and 6MWD (median (interquartile range) 59 (13-81) m versus 20 (-12-30) m; p=0.002). Dyspnoea, peak V'O2 , daily physical activity and muscle strength also improved significantly. No serious adverse events were observed.Pulmonary rehabilitation is a safe intervention and improves exercise capacity, dyspnoea, daily physical activity, quality of life and muscle strength in LAM. 10.1183/13993003.01683-2015
    Official American Thoracic Society/Japanese Respiratory Society Clinical Practice Guidelines: Lymphangioleiomyomatosis Diagnosis and Management. McCormack Francis X,Gupta Nishant,Finlay Geraldine R,Young Lisa R,Taveira-DaSilva Angelo M,Glasgow Connie G,Steagall Wendy K,Johnson Simon R,Sahn Steven A,Ryu Jay H,Strange Charlie,Seyama Kuniaki,Sullivan Eugene J,Kotloff Robert M,Downey Gregory P,Chapman Jeffrey T,Han MeiLan K,D'Armiento Jeanine M,Inoue Yoshikazu,Henske Elizabeth P,Bissler John J,Colby Thomas V,Kinder Brent W,Wikenheiser-Brokamp Kathryn A,Brown Kevin K,Cordier Jean F,Meyer Cristopher,Cottin Vincent,Brozek Jan L,Smith Karen,Wilson Kevin C,Moss Joel, American journal of respiratory and critical care medicine BACKGROUND:Lymphangioleiomyomatosis (LAM) is a rare cystic lung disease that primarily affects women. The purpose of these guidelines is to provide recommendations for the diagnosis and treatment of LAM. METHODS:Systematic reviews were performed to summarize evidence pertinent to our questions. The evidence was summarized and discussed by a multidisciplinary panel. Evidence-based recommendations were then formulated, written, and graded using the Grading of Recommendations, Assessment, Development, and Evaluation approach. RESULTS:After considering the panel's confidence in the estimated effects, the balance of desirable (i.e., benefits) and undesirable (i.e., harms and burdens) consequences of treatment, patient values and preferences, cost, and feasibility, recommendations were formulated for or against specific interventions. These included recommendations for sirolimus treatment and vascular endothelial growth factor D testing and recommendations against doxycycline and hormonal therapy. CONCLUSIONS:Evidence-based recommendations for the diagnosis and treatment of patients with LAM are provided. Frequent reassessment and updating will be needed. 10.1164/rccm.201607-1384ST
    Sirolimus and Autophagy Inhibition in Lymphangioleiomyomatosis: Results of a Phase I Clinical Trial. El-Chemaly Souheil,Taveira-Dasilva Angelo,Goldberg Hilary J,Peters Elizabeth,Haughey Mary,Bienfang Don,Jones Amanda M,Julien-Williams Patricia,Cui Ye,Villalba Julian A,Bagwe Shefali,Maurer Rie,Rosas Ivan O,Moss Joel,Henske Elizabeth P Chest BACKGROUND:Animal and cellular studies support the importance of autophagy inhibition in lymphangioleiomyomatosis (LAM). In a cohort of subjects with LAM, we tested the hypothesis that treatment with sirolimus and hydroxychloroquine (an autophagy inhibitor) at two different dose levels is safe and well tolerated. Secondary end points included changes in lung function. METHODS:This 48-week, two-center phase I trial evaluated the safety of escalating oral hydroxychloroquine doses (100-200 mg) given twice a day in combination with sirolimus to eligible patients ≥ 18 years old with LAM. Subjects received combination therapy for 24 weeks followed by an observation phase without taking study drugs for an additional 24 weeks. RESULTS:Fourteen patients provided written informed consent. Thirteen were treated in cohorts of three patients each with escalating hydroxychloroquine doses (200 and 400 mg) and an extension phase at the 400-mg dose. The most common adverse events were mucositis, headache, and diarrhea. No drug-related serious adverse events were reported. Secondary end points showed improvement in lung function at 24 weeks, with a decrease in lung function at the 48-week time point. When the higher dose of hydroxychloroquine was analyzed separately, FEV and FVC remained stable at 48 weeks, but the 6-min walk distance showed a decrease toward baseline. CONCLUSIONS:The combination of sirolimus and hydroxychloroquine is well tolerated, with no dose-limiting adverse events observed at 200 mg twice a day. Potential effects on lung function should be explored in larger trials. TRIAL REGISTRY:ClinicalTrials.gov; No.: NCT01687179; URL: www.clinicaltrials.gov. 10.1016/j.chest.2017.01.033
    Lung function response and side effects to rapamycin for lymphangioleiomyomatosis: a prospective national cohort study. Bee Janet,Fuller Sharon,Miller Suzanne,Johnson Simon R Thorax RATIONALE:Mechanistic target of rapamycin inhibitors reduce loss of lung function in lymphangioleiomyomatosis (LAM), although their benefit varies between individuals. We examined lung function response and side effects to rapamycin in a national cohort. METHODS:Subjects were receiving rapamycin for progressive lung disease. Clinical evaluation, detailed phenotyping, serial lung function, rapamycin and safety monitoring were performed according to a clinical protocol. Lung function change, measured as FEV slope (ΔFEV), was reported for those treated for 1 year or longer. RESULTS:Rapamycin was associated with improved ΔFEV in 21 individuals where pretreatment data were available (p<0.0001). In 47 treated for a mean duration of 35.8 months, mean ΔFEV was +11 (SD 75) mL/year, although it varied from +254 to -148 mL/year. The quartile with the highest positive ΔFEV had greater pretreatment FEV (p=0.02) and shorter disease durations (p=0.02) than the lowest quartile. Serum rapamycin level was positively associated with side effects (p=0.02) but not ΔFEV over 1 year. Within the first month of therapy, apthous ulcers, nausea and diarrhoea were associated with higher rapamycin levels. Acne, oedema and menstrual irregularities tended to increase over the first year of therapy. At the end of observation, the prevalence of side effects was 5% or less. CONCLUSIONS:Rapamycin reduces lung function loss in LAM, although in some, ΔFEV continues to fall at an accelerated rate. Poor response to rapamycin was associated with lower pretreatment lung function and longer disease duration but not serum level. Early intervention with low-dose rapamycin may preserve lung function and reduce side effects. 10.1136/thoraxjnl-2017-210872
    Lymphangioleiomyomatosis Diagnosis and Management: High-Resolution Chest Computed Tomography, Transbronchial Lung Biopsy, and Pleural Disease Management. An Official American Thoracic Society/Japanese Respiratory Society Clinical Practice Guideline. Gupta Nishant,Finlay Geraldine A,Kotloff Robert M,Strange Charlie,Wilson Kevin C,Young Lisa R,Taveira-DaSilva Angelo M,Johnson Simon R,Cottin Vincent,Sahn Steven A,Ryu Jay H,Seyama Kuniaki,Inoue Yoshikazu,Downey Gregory P,Han MeiLan K,Colby Thomas V,Wikenheiser-Brokamp Kathryn A,Meyer Cristopher A,Smith Karen,Moss Joel,McCormack Francis X, American journal of respiratory and critical care medicine BACKGROUND:Recommendations regarding key aspects related to the diagnosis and pharmacological treatment of lymphangioleiomyomatosis (LAM) were recently published. We now provide additional recommendations regarding four specific questions related to the diagnosis of LAM and management of pneumothoraces in patients with LAM. METHODS:Systematic reviews were performed and then discussed by a multidisciplinary panel. For each intervention, the panel considered its confidence in the estimated effects, the balance of desirable (i.e., benefits) and undesirable (i.e., harms and burdens) consequences, patient values and preferences, cost, and feasibility. Evidence-based recommendations were then formulated, written, and graded using the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) approach. RESULTS:For women who have cystic changes on high-resolution computed tomography of the chest characteristic of LAM, but who have no additional confirmatory features of LAM (i.e., clinical, radiologic, or serologic), the guideline panel made conditional recommendations against making a clinical diagnosis of LAM on the basis of the high-resolution computed tomography findings alone and for considering transbronchial lung biopsy as a diagnostic tool. The guideline panel also made conditional recommendations for offering pleurodesis after an initial pneumothorax rather than postponing the procedure until the first recurrence and against pleurodesis being used as a reason to exclude patients from lung transplantation. CONCLUSIONS:Evidence-based recommendations for the diagnosis and treatment of patients with LAM are provided. Frequent reassessment and updating will be needed. 10.1164/rccm.201709-1965ST
    Effect of beta-agonists on LAM progression and treatment. Le Kang,Steagall Wendy K,Stylianou Mario,Pacheco-Rodriguez Gustavo,Darling Thomas N,Vaughan Martha,Moss Joel Proceedings of the National Academy of Sciences of the United States of America Lymphangioleiomyomatosis (LAM), a rare disease of women, is associated with cystic lung destruction resulting from the proliferation of abnormal smooth muscle-like LAM cells with mutations in the tuberous sclerosis complex (TSC) genes and/or The mutant genes and encoded proteins are responsible for activation of the mechanistic target of rapamycin (mTOR), which is inhibited by sirolimus (rapamycin), a drug used to treat LAM. Patients who have LAM may also be treated with bronchodilators for asthma-like symptoms due to LAM. We observed stabilization of forced expiratory volume in 1 s over time in patients receiving sirolimus and long-acting beta-agonists with short-acting rescue inhalers compared with patients receiving only sirolimus. Because beta-agonists increase cAMP and PKA activity, we investigated effects of PKA activation on the mTOR pathway. Human skin fibroblasts or LAM lung cells incubated short-term with isoproterenol (beta-agonist) showed a sirolimus-independent increase in phosphorylation of S6, a downstream effector of the mTOR pathway, and increased cell growth. Cells incubated long-term with isoproterenol, which may lead to beta-adrenergic receptor desensitization, did not show increased S6 phosphorylation. Inhibition of PKA blocked the isoproterenol effect on S6 phosphorylation. Thus, activation of PKA by beta-agonists increased phospho-S6 independent of mTOR, an effect abrogated by beta-agonist-driven receptor desensitization. In agreement, retrospective clinical data from patients with LAM suggested that a combination of bronchodilators in conjunction with sirolimus may be preferable to sirolimus alone for stabilization of pulmonary function. 10.1073/pnas.1719960115
    Effects of sirolimus in lymphangioleiomyomatosis patients on lung cysts and pulmonary function: long-term follow-up observational study. Kim Cherry,Do Kyung-Hyun,Cha Jaehyung,Song Jin Woo,Lee Sang Min,Lee Ki Yeol European radiology OBJECTIVES:To determine whether sirolimus has beneficial effects on lymphangioleiomyomatosis (LAM) lung cysts in CT with long-term follow-up (FU) and to investigate whether CT is an appropriate imaging biomarker to monitor and evaluate LAM progression. METHODS:In this retrospective study, 73 female patients diagnosed with definite LAM between May 2001 and June 2018 were included. Among these, 39 (53.4%) were treated with sirolimus. Quantitative and qualitative CT scoring for lung cysts (CS) were performed and compared between time points (baseline vs. FU at starting sirolimus, baseline vs. last FU, and FU at starting sirolimus vs. last FU for patients treated with sirolimus; baseline vs. last FU for patients without sirolimus). The correlation between CS at each time point and pulmonary function tests (PFTs) at each time point in the patients treated with sirolimus was also investigated. The quantitative and qualitative analyses and PFT results were compared between time points. RESULTS:In both quantitative and qualitative analyses, CS significantly increased from baseline to FU after starting sirolimus, and from baseline to last FU (all p < 0.05), whereas there was no significant difference between scores at the start of sirolimus vs. last in the patients treated with sirolimus. After sirolimus treatment, diffusing capacity for carbon monoxide (DL) was significantly increased. There were significant correlations between CS at each time point and PFT (correlation coefficient [r], - 0.383-0.935; all p < 0.001). CONCLUSION:Patients with LAM benefited from sirolimus. CT could be a useful imaging biomarker for evaluating and monitoring lung cysts in LAM. KEY POINTS:• Qualitative analysis showed a total of 15.8% to 21.1% of patients had a reduced lung cyst volume after sirolimus treatment, and in quantitative analysis, there was no significant difference in lung cyst volume between CT at the start of sirolimus therapy and the last CT. • Pulmonary function was also improved or maintained after sirolimus treatment. • Chest CT could be a useful imaging biomarker for evaluating and monitoring lung cysts in patients with lymphangioleiomyomatosis. 10.1007/s00330-019-06412-4