Systemic therapies in hereditary hemorrhagic telangiectasia: Current evidence and emerging targets

Hereditary hemorrhagic telangiectasia (HHT) is a rare autosomal dominant vascular disorder characterized by mucocutaneous telangiectases and visceral vascular malformations, leading to recurrent bleeding, iron-deficiency anemia, and organ complications. Pulmonary, cerebral, and hepatic involvement are major determinants of morbidity and mortality. Management has traditionally relied on local and interventional approaches, which are largely palliative and do not address underlying disease mechanisms. New insights in HHT pathophysiology, particularly in the dysregulated BMP9-BMP10/ENG/ALK1 pathway, which is fundamental to the angiogenesis process, have enabled the development of targeted systemic therapies. Although no systemic drug is specifically approved for HHT, antifibrinolytics, anti-angiogenic agents, mTOR and AKT inhibitors, and immunomodulatory drugs have shown variable efficacy in selected patients. This review summarizes current evidence on systemic therapies and ongoing clinical trials, highlighting their potential to complement existing strategies and move toward disease-modifying approaches.