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.

Streptococcus pyogenes Endopeptidase O Contributes to Evasion from Complement-mediated Bacteriolysis via Binding to Human Complement Factor C1q

“…In other studies, the C1 esterase inhibitor (C1-INH), a complement regulating factor that inactivates the C1 complex, has been utilized as a therapeutic agent for sepsis (11,12). In our previous examination, we focused on the similarity of symptoms between STSS and C1-INH deficiency, and noted that a decrease in C1-INH level caused by S. pyogenes infection is associated with the pathogenesis (13,14). In that study, we also demonstrated that streptococcal pyrogenic exotoxin B (SpeB), a representative cysteine protease from S. pyogenes, cleaves C1-INH and complement factors, including C3 and late complement factors, allowing bacterial evasion from complementmediated killing.…”

Cysteine Proteinase from Streptococcus pyogenes Enables Evasion of Innate Immunity via Degradation of Complement Factors

“…In cases with C1-INH deficiency, the contact system becomes unstable and prone to generate kallikrein, which cleaves high molecular weight kinino-gen. Thus, the released bradykinin may function as a mediator of increased vascular permeability (8). In the present study, we focused on the similarity of these symptoms and investigated whether a S. pyogenes protease induces collapse of the complement system through C1-INH.…”