Study On The Protective Effect Of Sirolimus On Lung Function And The Risk Of Pneumothorax Recurrence In The Treatment Of Lymphangioleiomyomatosi

Part 1.Trajectories of FEV1 Change in Lymphangioleiomyomatosis Patients under Sirolimus TreatmentBackground:In the natural course of lymphangioleiomyomatosis(LAM),patients experience progressive loss of lung function.After treatment with sirolimus,there is significant heterogeneity in lung function response among individuals.Differentiation of lung function response trajectories under sirolimus treatment is valuable for accurately identifying response phenotypes and providing information for the clinical trials of new therapies.Methods:Based on the LAM cohort of Peking Union Medical College Hospital,a groupbased trajectory modeling(GBTM)cohort dataset was derived.LAM patients with sirolimus treatment records and at least two pulmonary function tests at and after the treatment were included,while patients who discontinued medication for more than 6 months or had never undergone monitoring of sirolimus blood concentration were excluded from the analysis.GBTM was used to model the change from baseline in forced expiratory volume in one second(FEV1)at different follow-up time points,and to identify different FEV1 change trajectories after sirolimus treatment.Multiple logistic regression analysis was used to explore the influencing factors of different trajectory groups.Results:The GBTM analysis included 183 LAM patients.The FEV1 change trajectories after sirolimus treatment in LAM patients were classified into three categories:significantly improved,stable,and continuously declined,with the stable group accounting for an estimated proportion of 68%,the continuously declined group 20.7%,and the significantly improved group 11.3%.Using the continuously declined group as a reference,we found that baseline FVC%of predicted value were significantly associated with the improved group(compare with FVC>100%of predicted value,80%-100%of predicted value,OR=13.0,95%CI 1.5-115.1,P=0.022;<80%of predicted value,OR=31.6,95%CI 2.93-341.6,P=0.005)and stable group(compare with FVC>100%of predicted value,<80%of predicted value,OR=4.9,95%CI 1.5-16.3,P=0.010).Conclusion:The trajectories of FEV1 change from baseline after sirolimus treatment in LAM patients can be classified into three categories:significantly improved(11.3%),stable(68%),and continuously declined(20.7%).Compared with the continuously declined group,patients in the stable and significantly improved groups were associated with lower baseline FVC%of predicted value.Part 2.Study on the FEV1 Protection of Low-Dose Sirolimus in Lymphangioleiomyomatosis.Background:It is currently unclear whether a lower sirolimus trough concentration than the traditional target concentration(5 ng/mL)can provide the same pulmonary function protection.Methods:Based on the GBTM cohort in Part 1,we divided time-weighted sirolimus average trough concentrations in lymphangioleiomyomatosis(LAM)patients into two groups:traditional concentration group(≥5 ng/mL)and low concentration group(<5 ng/mL).We used a curvilinear mixed-effect model to estimate the marginal mean change from baseline in FEV1 at different time points after sirolimus treatment.The primary outcome was the change in FEV1 from baseline in the first year of sirolimus treatment.If there was no significant statistical difference in FEV1 change between traditional concentration group and low concentration group,we would then compare the change in FEV1 in the third year of sirolimus treatment.Results:The analysis included 183 LAM patients.The estimated marginal mean change in FEV1 from baseline in the first year of sirolimus treatment in the low concentration group was 45.2(95%CI 13.9 to 76.5)mL,which was not significantly different from that in the traditional concentration group(estimated marginal mean change 33.7 mL,95%CI 6.6 to 60.8 mL;P=0.585).Similarly,there was no significant difference in FEV1 change from baseline at the third year between the two concentration groups(estimated marginal mean change-24.9 mL,95%CI-115.7 to 65.9 mL in the low concentration group;estimated marginal mean change-4.1 mL,95%CI-78.9 to 70.8 mL in the traditional concentration group;P=0.728).Subgroup analyses based on different trajectories also showed no significant difference in FEV1 change between the low and traditional concentration groups in either the first nor the third year.Conclusion:Sirolimus treatment with low concentration(median concentration 4.1 ng/mL,interquartile range 3.5 to 4.5 ng/mL)has a similar protective effect on FEV1 in LAM patients traditional concentration.Therefore,the target concentration of sirolimus treatment for LAM patients may need to be further lowered.Part 3.The Role of Sirolimus in the Recurrence of Pneumothorax in Patients with LymphangioleiomyomatosisBackground:Patients with lymphangioleiomyomatosis(LAM)have a high risk of spontaneous pneumothorax and recurrence,but it is not clear what factors are associated with the occurrence of pneumothorax,and whether treatment with sirolimus can reduce the risk of pneumothorax recurrence in LAM patients is also unclear.Methods:This study included patients registered in the LAM-CHINA study at Peking Union Medical College Hospital from May 10,2017 to August 31,2020,who met the diagnostic criteria for LAM and did not have a history of iatrogenic pneumothorax.Patients were followed up until August 26,2021.Pneumothorax-related data from the onset of LAM to the last follow-up were collected through medical records and telephone inquiries.A cross-sectional analysis at registration was used to explore the factors associated with pneumothorax in LAM patients using multiple logistic regression.A self-control study was performed,and analyzed by Kaplan-Meier analysis to investigate whether sirolimus could reduce the risk of pneumothorax recurrence in LAM patients.Results:A total of 399 LAM patients were analyzed.141(35.3%)patients had a history of pneumothorax at the time of registration.The median number of pneumothorax occurrences in these patients was 2 times,with 63.1%experiencing at least 1 episode of pneumothorax recurrence.Among those whose initial symptom were not pneumothorax,the risks of pneumothorax occurrence were 12.5%,22.5%,and 42.7%at 5,10,and 20 years,respectively.LAM patients with an onset age of≤35 years(OR 2.6,95%CI 1.634.15,P<0.001)and CT stage Ⅲ(vs CT stage Ⅰ,OR 2.8,95%CI 1.50-5.23,P=0.001)had a higher risk of pneumothorax.The risk of pneumothorax in postmenopausal patients was significantly reduced(OR 0.21,95%CI 0.07-0.61,P=0.004).Compared with the control group,treatment with sirolimus reduced the 5-year risk of pneumothorax recurrence in LAM patients by 80%(pneumothorax recurrence hazard ratio 0.2;95%CI 0.14-0.30,P<0.001).Even after excluding patients who had undergone pleurodesis,the 5-year risk of pneumothorax recurrence in the sirolimus group remained significantly lower(pneumothorax recurrence hazard ratio 0.12;95%CI 0.07-0.18,P<0.001).Conclusion:The CT grade of cystic changes in the lungs and an onset age of ≤35 years are associated with an increased risk of pneumothorax in LAM patients,while postmenopausal patients have a reduced risk of pneumothorax.Sirolimus significantly reduces the risk of pneumothorax recurrence in LAM patients.