Therapeutic options for patients with angioedema due to C1-inhibitor deficiencies: from pathophysiology to the clinic

Abstract

Deficiencies in the inhibitor of the first component of human complement (C1-INH) are clinically associated with both hereditary angioedema (HAE) and acquired angioedema (AAE). The reduction in C1-INH function leads to the activation of the classical complement pathway and consequent complement consumption, as well as to the activation of the contact system and the generation of bradykinin, the vasoactive peptide that increases vascular permeability and causes angioedema. The clinical features of C1-INH deficiencies are the same in both forms of angioedema, and include subcutaneous non-pruritic swelling, the involvement of the upper respiratory tract, and abdominal pain due to partial obstruction of the gastrointestinal tract; however, AAE patients have no family history of angioedema and are characterised by the late onset of symptoms. The aim of therapy is to prevent or reverse angioedema. Advances in our understanding of the complex effects of C1-INH deficiency at molecular level have led to new targeted approaches to the treatment of HAE and AAE. Three new treatments have recently become available: a kallikrein inhibitor that prevents bradykinin release, an antagonist of bradykinin receptors that blocks bradykinin action, and a recombinant human C1-INH molecule produced in transgenic rabbits that replaces the deficient protein. These new drugs have expanded the armamentarium of treatments for angioedema due to C1-INH deficiency, which was previously limited to attenuated androgen, antifibrinolytic drugs, and C1-INH plasma concentrate.

Keywords::

• C1-inhibitor deficiencies
• hereditary angioedema (HAE)
• acquired angioedema (AAE)
• complement pathway
• contact system
• bradykinin
• therapeutic approaches
• B cell malignancies