A note on versions:The version presented here may differ from the published version or from the version of record. If you wish to cite this item you are advised to consult the publisher's version. Please see the repository url above for details on accessing the published version and note that access may require a subscription.For more information, please contact eprints@nottingham.ac.uk Nottingham.NG7 2UH, U.K. simon.johnson@nottingham.ac.uk What is the key question?How can we best optimise the risk / benefit balance of mTOR inhibition for loss of lung function in individuals with LAM? What is the bottom line?Loss of lung function may continue in some individuals treated with rapamycin and a poor response to the drug is more likely in those with lower lung function and longer disease duration at the start of treatment.Lower levels of rapamycin are associated with fewer side effects but equal benefit compared with higher levels. Why read on?We have used a prospective national cohort study to understand the relationship between rapamycin levels, lung function response and side effects to improve the use of mTOR inhibitors in women with LAM. AbstractRationale mTOR inhibitors reduce loss of lung function in 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 FEV1 slope (ΔFEV1), was reported for those treated for one year or longer.Results Rapamycin was associated with improved ΔFEV1 in 21 individuals where pre-treatment data were available (p<0.0001). In 47 treated for a mean duration 35.8 months, mean ΔFEV1 was +11 (SD 75) ml/yr although varied from +254 to -148 ml/yr. The quartile with the highest positive ΔFEV1 had greater pretreatment FEV1 (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 ΔFEV1 over one 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 ΔFEV1 continues to fall at an accelerated rate. Poor response to rapamycin was associated with lower pre-treatment lung function and longer disease duration but not serum level. Early intervention with low dose rapamycin may preserve lung function and reduce side effects.

Lymphangioleiomyomatosis (LAM) is a rare multisystem disease. Progressive airflow limitation, pneumothorax and angiomyolipoma-related bleeding are major morbidities. As treatments are available for these complications, we prospectively audited loss of FEV1 (ΔFEV1), pneumothorax and angiomyolipoma bleeding against clinical standards over 4 years at the UK Clinical Centre. ΔFEV1 for these patients is lower than previously reported and rates of pneumothorax and angiomyolipoma haemorrhage are low. This suggests that real-time analysis of clinical data with targeted interventions can reduce morbidity in LAM. These measures could be applied as quality standards to compare the emerging LAM clinical networks worldwide.