Abstract

Lymphangioleiomyomatosis (LAM) is a rare, progressive, estrogen-sensitive cystic lung disease that primarily affects women and is frequently associated with Tuberous Sclerosis Complex. It is characterized by the abnormal proliferation of smooth muscle-like LAM cells, leading to progressive lung destruction, airflow limitation, recurrent pneumothorax, chylous effusions, and renal angiomyolipomas (AMLs). Sirolimus, a mammalian target of rapamycin inhibitor, is the current standard pharmacological therapy for LAM. This research aimed to optimize dosing strategies, evaluate biomarkers such as vascular endothelial growth factor-D (VEGF-D), and improve long-term disease management. This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses 2020 guidelines. A comprehensive search of PubMed, Scopus, and the Cochrane Library was performed up to June 2025. Eligible studies included patients with confirmed LAM who received sirolimus therapy and had stable VEGF-D levels monitored over time. Data extraction was conducted systematically, and methodological quality was assessed using the National Institutes of Health quality assessment tool. Five studies involving 195 female patients with a mean age of 44.5 years met the inclusion criteria. Sirolimus therapy was associated with stabilization of lung function, significant reduction in VEGF-D levels, regression of AMLs, and improvement or maintenance of quality of life. Benefits diminished following treatment discontinuation. Adverse events were mostly mild to moderate, including mucositis, rash, and gastrointestinal symptoms, and were more common early in therapy. Serious adverse events were rare. Overall, sirolimus demonstrates sustained clinical benefit with appropriate long-term monitoring.

Key words: Sirolimus, Lymphangioleiomyomatosis, safety, efficacy, treatment, Saudi Arabia