Treatment of lymphangioleiomyomatosis: building evidence in orphan diseases

Abstract

Lymphangioleiomyomatosis (LAM) is a rare (orphan) lung disease, in which the lung parenchyma is progressively replaced by cysts associated with a proliferation of immature smooth muscle cells and perivascular epithelioid cells (so-called LAM cells) around lymphatic vessels [1, 2]. LAM can be sporadic, almost exclusively affecting females, or can be associated with tuberous sclerosis complex (TSC) where it affects 30–50% of adult females, and less frequently males [3–6]. Patients with LAM most commonly present with relapsing pneumothorax and dyspnoea on exertion, and may have angiomyolipomas (benign tumours) of the kidneys and, occasionally, chylothorax or chylous ascites. Computed tomography of the chest shows characteristic multiple, round thin-walled cysts evenly distributed throughout the lung parenchyma [7], possibly associated with pneumothorax, pleural effusion, lymphadenopathies or lymphangiomas. Over time the disease may progress to chronic obstructive respiratory failure that may require lung transplantation. Pulmonary hypertension is very rare [8]. Diagnostic criteria and management guidelines have been proposed by a task force of the European Respiratory Society. Furthermore, the serum level of vascular endothelial growth factor (VEGF)-D, a major growth factor for lymphatic vessels, may further contribute to the noninvasive diagnosis of LAM if elevated [9]. For many years, treatment of LAM has been mostly supportive, including bronchodilators, supplemental oxygen (if needed), management of complications (especially pneumothorax) and lung transplantation. With a high variability of disease progression [10], many patients with LAM do not need a treatment intervention, whereas a minority of patients do progress to respiratory failure. In 2000, a major breakthrough in the understanding of the pathophysiology of the disease led to a novel treatment approach 10 years later [11]. Based on the observation that pulmonary LAM is present in patients with TSC [4], …