Pathophysiology and underlying mechanisms in hereditary angioedema.

This review aims to summarize the main pathophysiological events involved in the development of hereditary angioedema (OMIM#106100). Hereditary angioedema is a rare genetic disease inherited in an autosomal dominant manner and caused by a loss of control over the plasma contact system or kallikrein-kinin system, which results in unrestrained bradykinin generation or signaling. In patients with hereditary angioedema, BK binding to endothelial cells leads to recurrent episodes of swelling at subcutaneous or submucosal tissues that can be life threatening when affecting the upper respiratory tract. The disease can either present with hypocomplementemia owing to the presence of pathogenic variants in the gene encoding complement C1 inhibitor (hereditary angioedema with C1-inhibitor deficiency) or present with normocomplementemia and associate with elevated estrogen levels owing to gain-of-function variants in the genes encoding coagulation proteins involved in the kallikrein-kinin system (namely, coagulation FXII [FXII-associated hereditary angioedema], plasminogen [PLG-associated hereditary angioedema], and high-molecular-weight kininogen [KNG1-associated hereditary angioedema]). Moreover, in recent years, novel pathogenic variants have been described in the genes encoding angiopoietin 1 (ANGPT1-associated hereditary angioedema) and myoferlin (MYOF-associated hereditary angioedema), which further expand the pathophysiological picture of hereditary angioedema.

[Hereditary angioedema due to C1-esterase inhibitor deficiency†: novel approaches]. / Angiœdèmes héréditaires sur ­déficit en C1-inhibiteur†: nouveautés ­thérapeutiques.

Hereditary angioedema type 1 and 2 are due to a deficiency in C1--esterase inhibitor. This molecule inhibits the generation of bradykinin, a potent inflammatory mediator that increases vascular permeability. Upon accumulation of bradykinin, patients affected develop painful subcutaneous or submucosal edemas that last for several days. In case the upper airways are affected, there is risk of suffocation. This type of angioedema does not respond to antihistamines, cortico-steroids or epinephrine. Management of angioedema attacks consists in injecting C1-esterase inhibitor concentrate or icatibant, a bradykinin receptor B2 antagonist. Preventive measures aim at reducing the frequency and the severity of angioedema attacks. Inhibition of -plasma kallikrein by lanadelumab, a monoclonal antibody adminis-tered subcutaneously, is effective and well tolerated.

Les angiœdèmes (AE) héréditaires de types I et II sont dus à un déficit en inhibiteur de la C1 estérase ou C1-inhibiteur (C1-INH). Cette molécule régule la formation de bradykinine, un puissant médiateur vasoactif. En cas d'accumulation de bradykinine, les patients développent des œdèmes sous-cutanés ou sous-­muqueux douloureux qui persistent plusieurs jours. L'atteinte des voies aériennes comporte un risque de suffocation. Ce type d'angiœdème ne répond pas aux antihistaminiques, aux corticoïdes ni à l'adrénaline. Le traitement de la crise comprend ­l'injection de concentré de C1-INH ou d'icatibant, un antagoniste du récepteur B2 de la bradykinine. Le traitement préventif vise à diminuer la fréquence et la sévérité des crises. L'inhibition de la kallicréine plasmatique par lanadélumab, un anticorps mono­clonal administré en sous-cutané, constitue une approche efficace et bien tolérée.

Hereditary angioedema: the plasma contact system out of control.

The plasma contact system contributes to thrombosis in experimental models. Even though our standard blood coagulation tests are prolonged when plasma lacks contact factors, this enzyme system appears to have a minor (if any) role in hemostasis. In this review, we explore the clinical phenotype of C1 esterase inhibitor (C1-INH) deficiency. C1-INH is the key plasma inhibitor of the contact system enzymes, and its deficiency causes hereditary angioedema (HAE). This inflammatory disorder is characterized by recurrent aggressive attacks of tissue swelling that occur at unpredictable locations throughout the body. Bradykinin, which is considered to be a byproduct of the plasma contact system during in vitro coagulation, is the main disease mediator in HAE. Surprisingly, there is little evidence for thrombotic events in HAE patients, suggesting mechanistic uncoupling from the intrinsic pathway of coagulation. In addition, it is questionable whether a surface is responsible for contact system activation in HAE. In this review, we discuss the clinical phenotype, disease modifiers and diagnostic challenges of HAE. We subsequently describe the underlying biochemical mechanisms and contributing disease mediators. Furthermore, we review three types of HAE that are not caused by C1-INH inhibitor deficiency. Finally, we propose a central enzymatic axis that we hypothesize to be responsible for bradykinin production in health and disease.

Efficacy of Different Medical Therapies for the Treatment of Acute Laryngeal Attacks of Hereditary Angioedema due to C1-esterase Inhibitor Deficiency.

BACKGROUND: Hereditary angioedema (HAE) is a rare disease characterized by C1-esterase inhibitor (C1-INH) deficiency, resulting in periodic attacks of acute edema, which can be life-threatening if they occur in the upper airway. No head-to-head comparisons of different treatment options for acute HAE attacks are available. Because immediate symptom relief is critical for potentially life-threatening laryngeal attacks, it is important to determine the treatment option that provides optimal treatment response. OBJECTIVE: Review and compare data from clinical studies that evaluated the efficacy and safety of treatments for laryngeal HAE attacks. METHODS: We conducted an indirect comparison of clinical outcomes from prospective studies for treatment of 881 acute laryngeal attacks with plasma-derived C1-INH concentrate (pdC1-INH) at fixed doses (500 or 1000 U) or a body weight-adjusted dose (20 U/kg), recombinant C1-INH concentrate at a fixed dose (2100 U), or a body weight-adjusted dose (50 U/kg), icatibant (30 mg), or ecallantide (30 mg). Comparisons included time to onset of symptom relief and need for re-dosing or emergency procedures. RESULTS: The median time to onset of symptom relief ranged between 15 min and approximately 2 h, and was shortest with body weight-adjusted doses of pdC1-INH. The proportion of laryngeal attacks with re-dosing ranged between 0% and 72%. No re-dosing was needed after treatment with a single body weight-adjusted dose of pdC1-INH (48 attacks). CONCLUSIONS: Available data suggest that among different HAE treatments, body weight-adjusted pdC1-INH (20 U/kg) provides the most reliable treatment response for treatment of laryngeal HAE attacks.

Comprehensive study into the activation of the plasma enzyme systems during attacks of hereditary angioedema due to C1-inhibitor deficiency.

BACKGROUND: The activation of plasma enzyme systems contributes to hereditary angioedema attacks. We aimed to study the activation markers of the fibrinolytic, coagulation, and contact systems in a larger number of paired samples obtained from the same C1-INH-HAE patients in symptom-free periods and during attacks. METHODS: Eleven parameters (Factors XI, XII, and C1-inhibitor activity; the concentrations of the D-dimer, prothrombin fragments 1 + 2, plasminogen, plasminogen activator inhibitor-1 [PAI-1], thrombin-anti-thrombin III [TAT] complex, fibrinogen) were measured along with prothrombin time and activated partial thromboplastin time (aPTT), using commercial kits. We compared these markers in samples obtained from the same 39 patients during attack-free periods and during 62 edematous episodes. Forty healthy subjects of matching sex and age served as controls. RESULTS: Compared with the healthy controls, significantly higher FXI and FXII activity (p = 0.0007, p = 0.005), as well as D-dimer (p < 0.0001), prothrombin fragments 1 + 2 (p < 0.0001), and TAT (p = 0.0303) levels were ascertained in the patients during symptom-free periods. The evaluation of samples from symptom-free periods or obtained during attacks revealed the increase of FXII activity, as well as of the concentration of D-dimer, prothrombin fragments 1 + 2, and TAT during edematous episodes. PAI-1 level, prothrombin time, and aPTT decreased significantly during attacks, compared with symptom-free periods. D-dimer level was significantly higher during multiple- vs. single-site attacks. CONCLUSIONS: Comparing a large number of paired samples from symptom-free periods or from edematous episodes allowed accurate appraisal of the changes occurring during attacks. Moreover, our study pointed out that individual episodes may be characterized by different marker patterns.

C1-inhibitor polymers activate the FXII-dependent kallikrein-kinin system: Implication for a role in hereditary angioedema.

BACKGROUND: The FXII-dependent kallikrein-kinin system (KKS) is tightly regulated by the serine protease inhibitor (serpin) C1-inhibitor (C1-inh). When regulation of the FXII-dependent KKS fails, which is the case in hereditary angioedema (HAE), patients consequently experience invalidating edema attacks. HAE is caused by mutations in the C1-inh encoding gene, and we recently demonstrated that some mutations give rise to the presence of polymerized C1-inh in the plasma of HAE patients. METHODS: C1-inh polymers corresponding to the size of polymers observed in vivo were produced using heat denaturation and gel filtration. The ability of these polymers to facilitate FXII activation was assessed in vitro in an FXII activation bandshift assay. After spiking of plasma with C1-inh polymers, kallikrein generation was analyzed in a global kallikrein generation method. Prekallikrein consumption in the entire Danish HAE cohort was analyzed using an ELISA method. RESULTS: C1-inh polymers mediated FXII activation, and a dose dependent kallikrein generation in plasma spiked with C1-inh polymers. An increased (pre)kallikrein consumption was observed in plasma samples from HAE patients presenting with C1-inh polymers in vivo. CONCLUSION: Polymerization of the C1-inh transforms the major inhibitor of the FXII-dependent KKS, into a potent activator of the very same system. GENERAL SIGNIFICANCE: The C1-inh polymers might play a role in the pathophysiology of HAE, but several diseases are characterized by the presence of serpin polymers. The role of serpin polymers has so far remained elusive, but our results indicate that such polymers can play a role as inflammatory mediators through the FXII-dependent KKS.

A novel assay to diagnose hereditary angioedema utilizing inhibition of bradykinin-forming enzymes.

BACKGROUND: Hereditary angioedema types I and II are caused by a functional deficiency of C1 inhibitor (C1-INH), leading to overproduction of bradykinin. The current functional diagnostic assays employ inhibition of activated C1s; however, an alternative, more physiologic method is desirable. METHODS: ELISAs were developed using biotinylated activated factor XII (factor XIIa) or biotinylated kallikrein bound to avidin-coated plates. Incubation with plasma was followed by detection of bound C1-INH. RESULTS: After standard curves were developed for quantification of C1-INH, serial dilutions of normal plasma were employed to validate the ability to detect known concentration of C1-INH in the plasma as a percent of normal. Hereditary angioedema (HAE) types I and II were then tested. The level of functional C1-INH in all HAE types I and II plasma tested was less than 40% of our normal control. This was evident regardless of whether we measured factor XIIa-C1-INH or kallikrein-C1-INH complexes, and the two assays were in close agreement. By contrast, testing the same samples utilizing the commercial method (complex ELISA, Quidel Corp.) revealed the levels of C1-INH between 0 and 57% of normal (mean, 38%), and 42 samples were considered equivocal (four controls and 38 patients). CONCLUSIONS: Diagnosis of HAE types I and II can be ascertained by inhibition of enzymes of the bradykinin-forming cascade, namely factor XIIa and kallikrein. Either method yields functional C1-INH levels in patients with HAE (types I and II) that are clearly abnormal with less variance or uncertainty than the commercial method.

Escalating doses of C1 esterase inhibitor (CINRYZE) for prophylaxis in patients with hereditary angioedema.

BACKGROUND: Nanofiltered C1 inhibitor (human) is approved in the United States for routine prophylaxis of angioedema attacks in patients with hereditary angioedema, a rare disease caused by a deficiency of functional C1 inhibitor. OBJECTIVE: To assess the safety of escalating doses of nanofiltered C1 inhibitor (human) in patients who were not adequately controlled on the indicated dose (1000 U every 3 or 4 days). METHODS: Eligible patients had >1 attack/month over the 3 months before the trial. Doses were escalated to 1500 U every 3 or 4 days for 12 weeks, at which point, the patients were evaluated. If treatment was successful (≤1 attack/mo) or at the investigator's discretion, the patients entered a 3-month follow-up period. The patients with an average of >1 attack/month were eligible for further escalation to 2000 U and then 2500 U. RESULTS: Twenty patients started at 1500 U; 13 were escalated to 2000 U, and 12 were escalated to 2500 U. Eighteen patients reported adverse events. Two patients reported 4 serious adverse events (cerebral cystic hygroma, laryngeal angioedema attack, anemia, and bile duct stone) that were considered by investigators to be unrelated to treatment. Notably, there were no systemic thrombotic events or discontinuations due to adverse events. Fourteen patients were treated successfully (70%), continued to the follow-up period at the investigator's discretion, or experienced a reduction in attacks of >1.0/month. CONCLUSIONS: Dose escalation of nanofiltered C1 inhibitor (human) up to 2500 U was well tolerated and reduced attack frequency in the majority of patients.

Enzymatic pathways in the pathogenesis of hereditary angioedema: the role of C1 inhibitor therapy.

A functional abnormality of C1 inhibitor (C1INH) is present in types I and II hereditary angioedema (HAE), and normal C1INH may be rendered ineffective in the newly described type III HAE. C1INH inhibits factor XIIa, factor XII fragment (XIIf), kallikrein, and plasmin. Thus, in its absence, there is marked activation of the bradykinin-forming cascade resulting in severe angioedema. Factor XII may autoactivate on binding to endothelial cell surface gC1qR (receptor for the globular heads of C1q) thus initiating the cascade. Alternatively, stimuli that activate endothelial cells may liberate (or express at the cell surface) heat shock protein 90 or the enzyme prolylcarboxypeptidase, either of which can interact with the prekallikrein-high-molecular-weight kininogen complex to convert prekallikrein to kallikrein stoichiometrically. The kallikrein produced can cleave high-molecular-weight kininogen to produce bradykinin and also recruit factor XII by enzymatically activating it. Patients with type I or II HAE have mutant C1INH so that control of C1 activation is lost. Autoactivation of C1r in the absence of C1INH leads to C1s activation followed by C4 cleavage and depletion. An attack of swelling is accompanied by conversion of factor XIIa to factor XIIf and further enzymatic activation of C1r so that C4 levels drop further and C2 is depleted. New therapies for HAE focus on the bradykinin-forming cascade and include a kallikrein inhibitor and a bradykinin B-2 receptor antagonist in addition to administration of purified C1INH.

Ecallantide: a plasma kallikrein inhibitor for the treatment of acute attacks of hereditary angioedema.

Hereditary angioedema (HAE) is a debilitating, potentially fatal disease characterized by variable and unpredictable acute attacks of swelling affecting the subcutaneous tissue and mucosa. It is an autosomal dominant disorder resulting from a genetic deficiency of functional C1-esterase inhibitor. Available treatments include long-term prophylaxis, short-term prophylaxis and treatment of acute attacks. Ecallantide is a novel, specific and potent inhibitor of plasma kallikrein that was recently approved in the United States for the treatment of acute attacks of HAE in patients aged 16 years and older. In two phase III clinical trials, the subcutaneous administration of 30 mg ecallantide resulted in significantly greater symptom improvement than placebo for acute attacks of HAE. Ecallantide was generally well tolerated throughout the clinical development program. The main safety concern following ecallantide treatment is hypersensitivity reactions, including anaphylaxis. A Risk Evaluation and Management Strategy (REMS) has been implemented to minimize this risk and a long-term observational safety study is currently under way to collect more information about hypersensitivity and immunogenicity. Ecallantide represents a novel treatment option for patients with HAE.

Ecallantide: its pharmacology, pharmacokinetics, clinical efficacy and tolerability.

Ecallantide (Kalbitor, Dyax Corporation) is a highly specific recombinant plasma kallikrein inhibitor developed for treatment of hereditary angioedema (HAE). Advantages of this agent over plasma-derived treatments are that it poses no risk of viral contamination, is highly selective, has a quick onset of action and can be administered subcutaneously. In clinical trials, ecallantide appears to be a safe and effective drug useful for the treatment of HAE patients suffering from an acute attack. Ecallantide was found to be superior compared with placebo in relieving symptoms, decreasing the severity of attacks and shortening the duration of attacks. The primary safety concern appears to be related to hypersensitivity reactions. Phase IV postmarketing surveillance studies to monitor the incidence of these reactions will be implemented by the company now that the drug has been US FDA approved.