Determinants of Progression and Mortality in Lymphangioleiomyomatosis

Abstract

BackgroundLymphangioleiomyomatosis is a progressive diffuse cystic lung disease with approximately 85% survival at 10 years. The determinants of disease progression and mortality after the introduction of sirolimus therapy and vascular endothelial growth factor D (VEGF-D) as a biomarker have not been well defined.Research QuestionWhich factors, including VEGF-D and sirolimus therapy, influence disease progression and survival prognosis in patients with lymphangioleiomyomatosis?Study Design and MethodsThe progression dataset and the survival dataset included 282 and 574 patients, respectively, from Peking Union Medical College Hospital, Beijing, China. A mixed-effects model was used to compute the rate of decline in FEV1, and generalized linear models were used to identify variables affecting FEV1 decline. A Cox proportional hazards model was used to explore the association between clinical variables and the outcomes of death or lung transplantation in patients with lymphangioleiomyomatosis.ResultsVEGF-D levels and sirolimus treatment were associated with FEV1 changes and survival prognosis. Compared with patients with VEGF-D of < 800 pg/mL at baseline, patients with VEGF-D of ≥ 800 pg/mL lost FEV1 faster (SE, –38.86 mL/y; 95% CI, –73.90 to –3.82 mL/y; P = .031). The 8-year cumulative survival rates of patients with VEGF-D of ≥ 2,000 pg/mL and < 2,000 pg/mL were 82.9% and 95.1%, respectively (P = .014). The generalized linear regression model also demonstrated the benefit of delaying the decline of FEV1 by 65.56 mL/y (95% CI, 29.06-102.06 mL/y) in patients treated with sirolimus compared with those without sirolimus (P < .001). The 8-year risk of death was reduced by 85.1% (hazard ratio, 0.149; 95% CI, 0.075-0.299) after sirolimus treatment. After inverse treatment probability weighting, the risks of death in the sirolimus group were reduced by 85.6%. CT scan results of grade III severity were associated with worse progression than results of grades I or II severity. Patients with baseline FEV1 of 70% predicted or St. George’s Respiratory Questionnaire Symptoms domain 50 or higher predicted a higher risk of worse survival.InterpretationSerum VEGF-D levels, a biomarker of lymphangioleiomyomatosis, are associated with disease progression and survival. Sirolimus therapy is associated with slower disease progression and better survival in patients with lymphangioleiomyomatosis.Trial RegistryClinicalTrials.gov; No.: NCT03193892; URL: www.clinicaltrials.gov Lymphangioleiomyomatosis is a progressive diffuse cystic lung disease with approximately 85% survival at 10 years. The determinants of disease progression and mortality after the introduction of sirolimus therapy and vascular endothelial growth factor D (VEGF-D) as a biomarker have not been well defined. Which factors, including VEGF-D and sirolimus therapy, influence disease progression and survival prognosis in patients with lymphangioleiomyomatosis? The progression dataset and the survival dataset included 282 and 574 patients, respectively, from Peking Union Medical College Hospital, Beijing, China. A mixed-effects model was used to compute the rate of decline in FEV1, and generalized linear models were used to identify variables affecting FEV1 decline. A Cox proportional hazards model was used to explore the association between clinical variables and the outcomes of death or lung transplantation in patients with lymphangioleiomyomatosis. VEGF-D levels and sirolimus treatment were associated with FEV1 changes and survival prognosis. Compared with patients with VEGF-D of < 800 pg/mL at baseline, patients with VEGF-D of ≥ 800 pg/mL lost FEV1 faster (SE, –38.86 mL/y; 95% CI, –73.90 to –3.82 mL/y; P = .031). The 8-year cumulative survival rates of patients with VEGF-D of ≥ 2,000 pg/mL and < 2,000 pg/mL were 82.9% and 95.1%, respectively (P = .014). The generalized linear regression model also demonstrated the benefit of delaying the decline of FEV1 by 65.56 mL/y (95% CI, 29.06-102.06 mL/y) in patients treated with sirolimus compared with those without sirolimus (P < .001). The 8-year risk of death was reduced by 85.1% (hazard ratio, 0.149; 95% CI, 0.075-0.299) after sirolimus treatment. After inverse treatment probability weighting, the risks of death in the sirolimus group were reduced by 85.6%. CT scan results of grade III severity were associated with worse progression than results of grades I or II severity. Patients with baseline FEV1 of 70% predicted or St. George’s Respiratory Questionnaire Symptoms domain 50 or higher predicted a higher risk of worse survival. Serum VEGF-D levels, a biomarker of lymphangioleiomyomatosis, are associated with disease progression and survival. Sirolimus therapy is associated with slower disease progression and better survival in patients with lymphangioleiomyomatosis. ClinicalTrials.gov; No.: NCT03193892; URL: www.clinicaltrials.gov Take-home PointsStudy Question: Which factors, including vascular endothelial growth factor D (VEGF-D) level and sirolimus therapy, influence disease progression and survival prognosis in patients with lymphangioleiomyomatosis?Results: Based on the progression dataset (n = 282) and survival dataset (n = 574) from a cohort with lymphangioleiomyomatosis, patients with baseline VEGF-D levels of < 800 pg/mL lost FEV1 faster than those with VEGF-D levels of ≥ 800 pg/mL, whereas the beneficial effects of delaying FEV1 reduction were observed in patients treated with sirolimus. The risk of death was increased in patients with VEGF-D levels of ≥ 2,000 pg/mL and was reduced after sirolimus therapy.Interpretation: Serum VEGF-D levels may predict disease progression and survival. Sirolimus therapy likely deters disease progression and prolongs the survival of patients with lymphangioleiomyomatosis. Study Question: Which factors, including vascular endothelial growth factor D (VEGF-D) level and sirolimus therapy, influence disease progression and survival prognosis in patients with lymphangioleiomyomatosis? Results: Based on the progression dataset (n = 282) and survival dataset (n = 574) from a cohort with lymphangioleiomyomatosis, patients with baseline VEGF-D levels of < 800 pg/mL lost FEV1 faster than those with VEGF-D levels of ≥ 800 pg/mL, whereas the beneficial effects of delaying FEV1 reduction were observed in patients treated with sirolimus. The risk of death was increased in patients with VEGF-D levels of ≥ 2,000 pg/mL and was reduced after sirolimus therapy. Interpretation: Serum VEGF-D levels may predict disease progression and survival. Sirolimus therapy likely deters disease progression and prolongs the survival of patients with lymphangioleiomyomatosis. Lymphangioleiomyomatosis is a chronic progressive cystic lung disease that predominantly occurs in women.1Xu K.F. Xu W. Liu S. et al.Lymphangioleiomyomatosis.Semin Respir Crit Care Med. 2020; 41: 256-268Crossref PubMed Scopus (16) Google Scholar Lymphangioleiomyomatosis presents as a sporadic form or a type associated with tuberous sclerosis complex (TSC).1Xu K.F. Xu W. Liu S. et al.Lymphangioleiomyomatosis.Semin Respir Crit Care Med. 2020; 41: 256-268Crossref PubMed Scopus (16) Google Scholar Pulmonary functions decline gradually, with an annual loss of FEV1 of 47 to 134 mL.2McCormack F.X. Inoue Y. Moss J. et al.Efficacy and safety of sirolimus in lymphangioleiomyomatosis.N Engl J Med. 2011; 364: 1595-1606Crossref PubMed Scopus (818) Google Scholar, 3Hayashida M. Yasuo M. Hanaoka M. et al.Reductions in pulmonary function detected in patients with lymphangioleiomyomatosis: an analysis of the Japanese National Research Project on Intractable Diseases database.Respir Invest. 2016; 54: 193-200Crossref PubMed Scopus (18) Google Scholar, 4Johnson S.R. Tattersfield A.E. Decline in lung function in lymphangioleiomyomatosis: relation to menopause and progesterone treatment.Am J Respir Crit Care Med. 1999; 160: 628-633Crossref PubMed Scopus (178) Google Scholar, 5Taveira-DaSilva A.M. Stylianou M.P. Hedin C.J. Hathaway O. Moss J. Decline in lung function in patients with lymphangioleiomyomatosis treated with or without progesterone.Chest. 2004; 126: 1867-1874Abstract Full Text Full Text PDF PubMed Scopus (203) Google Scholar, 6Gupta N. et of the cohort determinants of disease progression and treatment in Respir J. Scopus Google Scholar is to identify the that influence disease progression and survival. 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