BIOMARCADORES EN LINFANGIOLEIOMIOMATOSIS

Abstract

Lymphangioleiomyomatosis (LAM) is a rare progressive disease that predominantly affects women and leads to respiratory failure. It is associated with lung cysts, abdominal tumours and chlylous fluid accumulations in thorax and abdomen. Vascular endothelial growth factor-D (VEGF-D) is the most commonly used biomarker for diagnosing LAM, however, low levels of VEGF-D do not rule out the diagnosis and lung biopsy is often necessary as well. Treatment is based on inhibition of mammalian target of rapamycin. The objective of this work is to search for new biomarkers of disease and to review the long-term effect of sirolimus. With this idea we performed 2 studies. Our first study is a retrospective analysis of 48 patients with LAM treated with sirolimus at our reference center. Patients were evaluated after 1 and 5 years of treatment. Among patients treated with sirolimus for five years, 59% patients experienced a positive response, 30% had a partial response and 11% had a negative response (defined as an FEV1 decline greater than -75 ml/year). The mean FEV1 slope (95% IC) over 5 years was 42 (14 to 70) ml/year in the responder group, -54 (-71 to -36) ml/year in the partial responder group, and - 84 (- 113 to - 54) ml/year in the non-responder group. The second study is a cross-sectional study in which 13 biomarkers related to extracellular matrix remodelling, lymphangiogenesis, and angiogenesis are analysed in different cohorts: LAM patients (n=44), LAM lung transplant patients (n=15), patients with other cystic lung diseases (n=18), and healthy women (n=20). MMP-2 was found to be the only biomarker that distinguished between LAM patients, those with other cystic lung diseases and healthy volunteers. MMP-2 and VEGF-D were combined to create a composite score (-6.36 + 0.0059 x VEGF-D + 0.0069 x MMP-2) that improved diagnostic accuracy (area under the curve 0.88 and sensitivity/specificity 79/87%) compared to VEGF-D alone. Prospective and multicenter studies are needed to confirm these results and improve LAM diagnostic and follow-up tools.

Date of Award	9 Nov 2023
Original language	Spanish
Supervisor	Susana Gomez Olles (Director) & Berta Saez Gimenez (Director)