Summary Hereditary angio-oedema is caused by a heterozygous deficiency of C1 inhibitor. This inhibitor regulates several inflammatory pathways, and patients with hereditary angio-oedema have ...intermittent cutaneous or mucosal swellings because of a failure to control local production of bradykinin. Swellings typically evolve in several hours and persist for a few days. In addition to orofacial angio-oedema, painless swellings affect peripheries, which causes disfigurement or interference with work and other activities of daily living. Angio-oedema affecting the gastrointestinal tract or abdominal viscera causes severe pain often with vomiting due to oedematous bowel obstruction. About 2% of swellings involve the larynx and can be fatal if untreated. About 50% of patients have laryngeal swellings that are potentially fatal despite prophylaxis. In this Seminar we review the clinical features, diagnosis, and management of hereditary angio-oedema, with specific emphasis on the new treatments available for acute swellings.
Abstract Background Hereditary angioedema (HAE) is a rare genetic disease usually due to mutation within the C1 inhibitor or the coagulation Factor XII gene. However, in a series of patients with HAE ...no causative variants have been described and the pathophysiology of the disease remains unknown (U-HAE). Identification of causative genes in U-HAE is valuable for understanding the cause of the disease. Objective We conducted genetic studies in Italian patients with U-HAE to identify novel causative genes. Methods Among patients belonging to 10 independent families and unrelated index patients with U-HAE disease recruited from the Italian network for C1-INH-HAE (ITACA), we selected a large multiplex family with U-HAE and performed whole-exome sequencing. The angiopoietin-1 gene ( ANGPT1 ) was investigated in all patients with familial or sporadic U-HAE. The effect of ANGPT1 variants was investigated by in silico prediction and using patients and control plasmas and transfected cells. Results We identified a missense mutation ( ANGPT1 , c.807G>T, p.A119S) in a family with U-HAE. The ANGPT1 p.A119S variant was detected in all members of the index family with U-HAE but not in asymptomatic family members, nor in an additional 20 patients with familial U-HAE, 22 patients with sporadic U-HAE, and 200 controls. Protein analysis of the plasma of patients revealed a reduction of multimeric forms and a reduced ability to bind the natural receptor “tunica interna endothelial cell kinase-2” (TIE2) of the ANGPT1 p.A119S variant. The recombinant mutated ANGPT1 p.A119S formed a reduced amount of multimers and showed a reduced binding capability to its receptor. Conclusion ANGPT1 impairment is associated with angioedema and ANGPT1 variants can be the basis of HAE.
Monoclonal antibodies (mAbs) have been shown to be effective and generally safe across a continually expanding list of therapeutic areas. We describe the advantages and limitations of mAbs as a ...therapeutic option compared with small molecules. Specifically, we discuss a novel mAb in the treatment of hereditary angioedema (HAE), a rare and potentially life-threatening condition characterized by recurrent unpredictable swelling attacks. HAE is mediated by dysregulation of plasma kallikrein activity leading to overproduction of bradykinin. Current prophylactic treatment for HAE includes androgens or replacement of the endogenous plasma kallikrein inhibitor, C1 inhibitor. However, there remains an unmet need for an effective, less burdensome treatment option. Lanadelumab is a fully human mAb targeting plasma kallikrein. Results from clinical trials, including a pivotal Phase 3 study and its ensuing open-label extension study, demonstrated that lanadelumab is associated with few treatment-related adverse events and reduced the rate of HAE attacks. This novel treatment option has the potential to significantly improve the lives of patients with HAE.
Background Patients with angioedema experience unpredictable attacks of tissue swelling in which bradykinin is implicated. Several distinct mutations in Factor XII (FXII) are associated with ...hereditary angioedema (HAE) in the presence of normal C1 esterase inhibitor activity (FXII-HAE). The underlying disease mechanisms are unclear, which complicates diagnosis and treatment. Objective We sought to identify the natural trigger for FXII activation, which causes uncontrolled bradykinin production in patients with FXII-HAE. Methods We generated recombinant variants of FXII, representing health and disease, and studied their behavior in functional studies. We investigated bradykinin-forming pathways in blood plasma with newly developed nanobody-based analytic methods. Results We here report that FXII-HAE mutations collectively introduce new sites that are sensitive to enzymatic cleavage by plasmin. These FXII mutants rapidly activate after cleavage by plasmin, escape from inhibition through C1 esterase inhibitor, and elicit excessive bradykinin formation. Furthermore, our findings indicate that plasmin modulates disease activity in patients with FXII-HAE. Finally, we show that soluble lysine analogs attenuate this mechanism, explaining their therapeutic value in patients with HAE. Conclusion Our findings indicate a new pathway for bradykinin formation in patients with HAE, in which FXII is cleaved and activated by plasmin. This should lead to the identification of new markers for diagnosis and targets for treatment.
C1 inhibitor (C1-INH, also known as SERPING1) can be deficient in plasma as a result of genetic or acquired conditions, and this causes an episodic, local increase in vascular permeability in the ...subcutaneous and submucosal layers, identified as angioedema (hereditary or acquired). Bradykinin, the mediator of the increase in vascular permeability, is released on inappropriate activation of the contact system, which is controlled by C1 inhibitor. Therapy aims to reverse or prevent angioedema. Advances in understanding the complex effects of C1-INH deficiency at the molecular level have led to new molecular-targeted approaches. Three new treatments, an inhibitor of kallikrein to prevent bradykinin release, an antagonist of the bradykinin receptor to prevent its action and a recombinant human C1-INH produced in transgenic animals, are under clinical evaluation currently. Here, we review the molecular mechanisms underlying angioedema due to C1-inhibitor deficiency and clinical progress using molecular-targeted interventions.
In a randomized trial, 72 patients with hereditary angioedema presenting with acute attacks of angioedema were randomly assigned to receive either ecallantide, a recombinant plasma kallikrein ...inhibitor, or placebo. The median treatment outcome score, a composite patient-reported outcome measure, was significantly better at 4 hours in the ecallantide group than in the placebo group.
Hereditary angioedema is an autosomal dominant disorder with an estimated prevalence ranging from 1 case in 10,000 to 1 case in 50,000 persons.
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Patients with hereditary angioedema have intermittent acute attacks of edema involving the larynx, oropharynx, face, gastrointestinal mucosa, extremities, or genitalia.
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Attacks occur unpredictably and may persist for 2 to 5 days.
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Gastrointestinal attacks can cause incapacitating colic, vomiting, and diarrhea and can result in unnecessary abdominal surgery. Laryngeal attacks may be life-threatening because of the potential for airway obstruction.
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Attacks do not typically respond to antihistamines, corticosteroids, or epinephrine.
Hereditary angioedema is caused by . . .
This is an update to the 2014 Canadian Hereditary Angioedema Guideline with an expanded scope to include the management of hereditary angioedema (HAE) patients worldwide. It is a collaboration of ...Canadian and international HAE experts and patient groups led by the Canadian Hereditary Angioedema Network. The objective of this guideline is to provide evidence-based recommendations, using the GRADE system, for the management of patients with HAE. This includes the treatment of attacks, short-term prophylaxis, long-term prophylaxis, and recommendations for self-administration, individualized therapy, quality of life, and comprehensive care. New to the 2019 version of this guideline are sections covering the diagnosis and recommended therapies for acute treatment in HAE patients with normal C1-INH, as well as sections on pregnant and paediatric patients, patient associations and an HAE registry. Hereditary angioedema results in random and often unpredictable attacks of painful swelling typically affecting the extremities, bowel mucosa, genitals, face and upper airway. Attacks are associated with significant functional impairment, decreased health-related quality of life, and mortality in the case of laryngeal attacks. Caring for patients with HAE can be challenging due to the complexity of this disease. The care of patients with HAE in Canada, as in many countries, continues to be neither optimal nor uniform. It lags behind some other countries where there are more organized models for HAE management, and greater availability of additional licensed therapeutic options. It is anticipated that providing this guideline to caregivers, policy makers, patients, and advocates will not only optimize the management of HAE, but also promote the importance of individualized care. The primary target users of this guideline are healthcare providers who are managing patients with HAE. Other healthcare providers who may use this guideline are emergency and intensive care physicians, primary care physicians, gastroenterologists, dentists, otolaryngologists, paediatricians, and gynaecologists who will encounter patients with HAE and need to be aware of this condition. Hospital administrators, insurers and policy makers may also find this guideline helpful.
Background Hereditary angioedema (HAE) results from a genetic deficiency of C1-inhibitor. Two similar independent, randomized, saline controlled, double-blind studies were conducted to evaluate the ...efficacy and safety of recombinant human C1-inhibitor (rhC1INH) as a treatment of acute angioedema attacks in patients with HAE. Objective Analysis of pooled study results. Methods Patients with an eligible attack were randomized to a single intravenous dose of rhC1INH or saline. Efficacy was assessed by using patient-reported visual analog scale outcomes, and safety was assessed by using adverse events and immunogenicity of rhC1INH. Results rhC1INH at 100 (n = 29) and 50 (n = 12) U/kg body weight resulted in a significant reduction for both the primary endpoint time to the beginning of relief of symptoms compared with saline (n = 29): median, 66 (95% CI, 61-122) minutes, 122 (72-136) minutes, and 495 (245-520) minutes, P < .001 and P = .013, respectively; and for the secondary endpoint time to minimal symptoms, median, 266 (242-490) minutes, 247 (243-484) minutes, and 1210 (970-1500) minutes, P < .001 and P = .001, respectively. Therapeutic failure occurred in 59% (17/29) of the saline group compared with 0% (0/12) of the 50 U/kg group and 10% (3/29) of the 100 U/kg group. Treatment-emergent adverse events were unremarkable and tended to be reported more frequently in the saline group. No postexposure antibody responses against rhC1INH or host-related impurities were observed. Conclusion Administration of rhC1INH at 100 or 50 U/kg was highly effective as a treatment of acute attacks in patients with HAE and appeared to be safe and well tolerated.
Patients affected by angioedema due to hereditary and acquired C1-inhibitor (C1-INH) deficiency (HAE and AAE, respectively) report trouble accessing dental care, due to the risk of a life-threatening ...oropharyngeal and laryngeal attack triggered by dental procedures. The aim of this study was to assess the identification of hurdles in receiving dental care, and the effectiveness of short-term prophylaxis (STP) in preventing angioedema attacks. In addition, the study evaluated the impact of dental care in angioedema disease. All patients affected by angioedema due to C1-INH deficiency who were treated in the dentistry outpatient department of ASST Fatebenefratelli Sacco hospital (Milan, Italy) between 2009 and 2017 were considered for the analysis. Data were collected from patients' records.
Twenty-nine patients were analyzed (27 with HAE and 2 with AAE). Of these, 63.0% reported that they had previously experienced hurdles in accessing dental care. Among patients with pathological oral status, at the first visit, 59.26% patients had moderate-to-severe oral disease. Seventy-five dental procedures were performed in 20 patients. Sixty procedures were preceded by STP (58 with plasma-derived C1-INH and 2 with danazol) in patients with/without long-term prophylaxis (LTP). Post-procedural attacks occurred in two patients. One HAE patient undergoing a tooth extraction without STP/LTP experienced a laryngeal attack. The other post-procedural attack occurred in an AAE patient with anti-C1-INH antibodies with STP with pdC1-INH. The angioedema disease did not worsen in any patient after dental care, but improved in four of them.
Most C1-INH-HAE patients reported hurdles in receiving dental care. STP protects against attacks after dental procedures. Treating oral diseases results in improvement in the frequency of attacks.
ACE inhibitor-mediated angioedema Montinaro, Vincenzo; Cicardi, Marco
International immunopharmacology,
January 2020, 2020-Jan, 2020-01-00, 20200101, Volume:
78
Journal Article
Peer reviewed
•ACEi-AE pathogenesis depends on a reduced bradykinin catabolism rate.•ACE inhibitor related angioedema (ACEi-AE) occurs in 0.1–0.7% of treated patients.•Risk factors are African-American ethnicity, ...allergies, female gender.•Major clinical localizations include face, tongue, lips and larynx.•Angiotensin receptor blockers are safe in patients that had experienced ACEi-AE.
Angioedema (AE) occurring during ACE inhibitor therapy (ACEi-AE) is a rare complication involving between 0.1 and 0.7% of treated patients. AE can also complicate other therapeutic regimens that block the renin-angiotensin aldosterone system. Other drugs, such as immune suppressors, some type of antidiabetics or calcium antagonists, can increase the likelihood of ACEi-AE when associated to ACEi. There is a clear ethnic predisposition, since African-Americans or Hispanics show a higher prevalence of this condition compared to Caucasians. At least in African-Americans the genetic predisposition accounts for a general higher prevalence of AE, independently from the cause. People that experience ACEi-AE may have some recurrence when they are switched to an angiotensin-receptor blocker (ARB); however, epidemiological studies on large cohorts have shown that angiotensin receptor blockers (ARB) do not increase the likelihood of AE compared to other antihypertensives. Clinical manifestations consist of edema of face, lips, tongue, uvula and upper airways, requiring intubation or tracheotomy in severe cases. Attacks last for 48–72 h and require hospital admission in most cases. Intestinal involvement with sub-occlusive symptoms has also been reported.
The pathogenesis of ACEi-AE depends mainly on a reduced catabolism and accumulation of bradykinin, which is normally metabolized by ACE. Genetic studies have shown that some single nucleotide polymorphisms at genes encoding relevant molecules for bradykinin metabolism and action may be involved in ACEi-AE, giving a basis for the ethnic predisposition. Treatment of ACEi-AE is still a matter of debate. Corticosteroids and antihistamines do not show efficacy. Some therapeutic attempts have shown some efficacy for fresh frozen plasma or C1 inhibitor concentrate infusion. Interventional studies with the specific bradykinin receptor antagonist icatibant have shown conflicting results; there might be a different ethnic predisposition to icatibant efficacy which has been proven in caucasian but not in black patients.
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