Recombinant C1 Esterase Inhibitor Research Articles

Bradykinin-Mediated Angioedema Induced by Commonly Used Cardiovascular Drugs

ACE inhibitors, sartans, and sacubitril are among the most important drugs for the prevention of cardiovascular mortality and morbidity. At the same time, they are known to cause non-allergic bradykinin-mediated angioedema, a potentially fatal swelling of the mucosa and/or submucosa and deeper skin without signs of urticaria or pruritus, occurring mainly in the head and neck region. In contrast with hereditary angioedema, which is also mediated by bradykinin, angioedema triggered by these drugs is by far the most common subtype of non-allergic angioedema. The molecular mechanisms underlying this type of angioedema, which are discussed here, are not yet sufficiently understood. There are a number of approved drugs for the prevention and treatment of acute attacks of hereditary angioedema. These include inhibitors of bradykinin synthesis that act as kallkrein inhibitors, such as the parenterally applied plasma pool, and recombinant C1 esterase inhibitor, ecallantide, lanadelumab, and the orally available berotralstat, as well as the bradykinin receptor type 2 antagonist icatibant. In contrast, no diagnostic tools, guidelines, or treatments have yet been approved for the diagnosis and treatment of acute non-allergic drug-induced angioedema, although it is more common and can take life-threatening courses. Approved specific drugs and a structured diagnostic workflow are needed for this emergency diagnosis.

Management of hereditary angioedema in resource-constrained settings: A consensus statement from Indian subcontinent.

Hereditary angioedema (HAE) is an uncommon disorder characterized clinically by recurrent episodes of nonitchy subcutaneous and/or submucosal swellings. The estimated prevalence of HAE is ~ 1: 10,000 to 1: 50,000. There are no prevalence data from India, however, estimates suggest that there are 27,000 to 135,000 patients with HAE in India at present. The majority of these, however, remain undiagnosed. Replacement of plasma-derived or recombinant C1-esterase inhibitor (C1-INH) protein, administered intravenously, is the treatment of choice during the management of acute episodes of angioedema (i.e., "on-demand treatment") and is also useful for short-term prophylaxis (STP) and long-term prophylaxis (LTP). This has been found to be effective and safe even in young children and during pregnancy. Until recently, none of the first-line treatment options were available for "on-demand treatment," STP or LTP in India. As a result, physicians had to use fresh frozen plasma for both "on-demand treatment" and STP. For LTP, attenuated androgens (danazol or stanozolol) and/or tranexamic acid were commonly used. These drugs have been reported to be useful for LTP but are associated with a significant risk of adverse effects. Intravenous pd-C1-INH, the first-line treatment option, is now available in India. However, because there is no universal health insurance, access to pd-C1-INH is a significant challenge. HAE Society of India has developed these consensus guidelines for India and other resource-constrained settings where plasma-derived C1-INH therapy is the only available first-line treatment option for the management of HAE and diagnostic facilities are limited. These guidelines have been developed because it may not be possible for all patients to access the recommended therapy and at the recommended doses as suggested by the international guidelines. Moreover, it may not be feasible to follow the evaluation algorithm suggested by the international guidelines.

LIMITED CUTANEOUS SYSTEMIC SCLEROSIS MIMICKING HEREDITARY ANGIOEDEMA WITH NORMAL C1 INHIBITOR

<h3>Introduction</h3> Hereditary angioedema with normal C1 inhibitor (HAE-nl-C1INH) is often diagnosed when patients with antihistamine-resistant angioedema respond to bradykinin-targeted therapies. We present a patient with limited cutaneous scleroderma initially diagnosed as HAE-nl-C1INH, with variable response to HAE therapy. <h3>Case Description</h3> 56-year-old woman with hypertension presented with recurrent periorbital swelling while on ACE inhibitor therapy. After discontinuation, she continued to have episodes of angioedema for two months, responsive to recombinant C1 inhibitor therapy. Initial workup included normal C1 esterase inhibitor antigen and function, C4, C1q, SPEP, tryptase, and thyroid studies. After a six-month symptom-free period, angioedema recurred in the setting of stressful life events, viral infection, and antihypertensive medication changes. When on-demand therapy with recombinant C1 esterase inhibitor was observed to provide insufficient control, she started lanadelumab prophylaxis which stabilized her symptoms. She then developed episodic fluid retention with daily joint and subcutaneous swelling involving the hands, abdomen, and lower extremities coincident with additional changes to her antihypertensive regimen. Discontinuation of suspected culprit medications did not resolve the progression of her symptoms. Evaluation by rheumatology for joint symptoms and persistent hand swelling led to the diagnosis of limited cutaneous systemic sclerosis (scleroderma). Angioedema symptoms resolved after starting mycophenolate mofetil and she no longer required HAE therapy. <h3>Discussion</h3> Our case highlights the complicated and nuanced nature of diagnosing HAE-nl-C1INH, particularly in patients with partial response to HAE therapy. Limited cutaneous scleroderma either mimicked or triggered angioedema in our patient. Her partial response to C1 inhibitor infusions and lanadelumab may have represented off-target effects of HAE therapy.

A CASE OF DIFFICULT TO DIAGNOSE C1INH NORMAL HAE

<h3>Introduction</h3> Hereditary Angioedema (HAE) is characterized by recurrent swellings of the face, tongue, oropharynx, extremities, and abdomen. Typically beginning in the second decade of life, these swells often require emergent treatment and may result in intubation. Unchecked production of bradykinin, typically due to low levels of C1 esterase inhibitor (C1INH), results in bradykinin mediated vascular leakage and swelling. Type I and II can be diagnosed by checking C1INH levels and function but C1INH Normal continues to be difficult to diagnose. We present a challenging case detailing the diagnosis and management of probable C1INH normal HAE in a 42-year-old female. <h3>Case Description</h3> A 42-year-old woman with a history of hypothyroidism, GERD, migraine, obesity, and borderline personality disorder, presented to our clinic with a 10-year history of three or more weekly episodes of throat and eyelid angioedema, accompanied by intermittent urticaria. Her controller therapy included montelukast, fexofenadine, cetirizine, zyflo, famotidine, and cromolyn. Despite this regimen, she continued her thrice weekly episodes, so cyclosporine was added without improvement in flare frequency or severity. C1INH level and function, along with her physical exam, were unremarkable. A trial of recombinant C1INH resolved an acute swell, so she was started on C1INH replacement, with significant reduction in her swell frequency. <h3>Discussion</h3> C1INH normal HAE continues to be difficult to diagnose with currently available assays. For patients with recurrent swells, not responding to mast cell stabilizers or antihistamines, a trial of recombinant C1INH or a bradykinin receptor antagonist, may aid in the diagnosis of C1INH Normal HAE.

FACIAL SWELLING, RESPIRATORY FAILURE, FLUCTUATING COMPLEMENT 4 LEVELS, AND RELIGIOUS CONSIDERATION IN A PEDIATRIC PATIENT

<h3>Introduction</h3> Hereditary Angioedema is a rare condition defined by acute, recurring episodes of edema, with the upper airway being particularly dangerous. HAE Type 2 is caused by the dysfunction of the C1-esterase inhibitor with low C4 levels. <h3>Case Description</h3> A 10-year-old female presented with facial and airway swelling unresponsive to steroids, antihistamines, and epinephrine that required intubation. C4 complement was low but then was normal prior to treatment. The patient's religion did not allow for plasma products, but a plasma derived C1 esterase inhibitor product was given emergently with improvement in her swelling. C1 Esterase Inhibitor Function was found to be low. A non-formulary recombinant C1 esterase inhibitor product was arranged for hospital and later home use. At 11 years she was admitted in respiratory failure. She decompensated with failed attempts at intubation and required cricothyrotomy. A recombinant C1 esterase inhibitor product was given. She remained with tracheostomy for 7 days then was de-cannulated. She was discharged with an oral plasma Kallikrein inhibitor, emergency recombinant C1 esterase inhibitor product, and a HAE emergency card. In addition to formulary HAE treatment, a recombinant product was placed in restricted use. A best practice advisory was developed in the EMR to advise physicians of the patient's HAE status. <h3>Discussion</h3> Although HAE Type 2 is well characterized, this is a rare report of a Pediatric patient with HAE requiring intubation on initial presentation and later cricothyrotomy. The challenge was her respiratory failure as a presenting sign of HAE, fluctuating C4 levels, religious consideration, and implementation of an EMR advisory.

A case of normal C1 esterase inhibitor hereditary angioedema successfully treated with berotralstat

A case of normal C1 esterase inhibitor hereditary angioedema successfully treated with berotralstat

Physicochemical and Biological Characterization of rhC1INH Expressed in CHO Cells.

The disfunction or deficiency of the C1 esterase inhibitor (C1INH) is associated with hereditary or acquired angioedema (HAE/AAE), a rare life-threatening condition characterized by swelling in the skin, respiratory and gastrointestinal tracts. The current treatment options may carry the risks of either viral infection (plasma-derived Berinert®) or immune reaction (human recombinant C1INH from rabbit milk, Ruconest®). This study describes the physicochemical and biological characterization of a novel recombinant human C1 esterase inhibitor (rhC1INH) from Chinese hamster ovary (CHO) cells for the treatment of hereditary angioedema compared to the marketed products Berinert® and Ruconest®. The mass spectrometry results of total deglycosylated rhC1INH revealed a protein with a molecular mass of 52,846 Da. Almost full sequence coverage (98.6%) by nanoLC-MS/MS peptide mapping was achieved. The purity and C1s inhibitory activity of rhC1INH from CHO cells are comparable with Ruconest®, although we found differences in charge isoforms distribution, intact mass values, and N-glycans profile. Comparison of the specific activity (IC50 value) of the rhC1INH with human C1 esterase inhibitor from blood serum showed similar inhibitory properties. These data allow us to conclude that the novel rhC1INH molecule could become a potential therapeutic option for patients with HAE/AAE.

Convalescent plasma does not provide adequate replacement of C1-Inhibitor and complements in COVID-19 patients

Abstract The rationale of Convalescent Plasma (CP) is to provide passive immunity to acutely ill COVID-19 patients. However, there are other pathologies of COVID disease that may be alleviated by CP. COVID-19 coagulopathy has been hypothesized to be a form of disseminated intravascular coagulopathy, a type of thrombotic microangiopathy. Complement activation has also been implicated in COVID-19 coagulopathy. An alternative hypothesis for additional benefits of CP is replacement of inhibitors of complements. C1-esterase inhibitor (C1-INH) is a major regulator of complement activation. We hypothesized that COVID-19 patients have decreased C1-INH and that CP transfusion would restore intravascular C1-INH and complement levels. We studied serial C1-INH and complement levels in COVID-19 patients before and after CP transfusion (200 mL) and their association with overall mortality. Methods: We identified COVID-19 patients (n=91) that received CP within the first 72 hours after admission. We collected serum and/or plasma samples at day prior and post-day 1, 3, and 10. C1 inhibitor, C3 and C4 were tested in these samples as well as in the respective CP unit given to each patient. Results: C1-INH levels day before transfusion were increased in COVID-19 patients (201.5% +/- 53%) in comparison to CP (93.2% +/- 26.2%). C1-INH transiently increased post CP transfusion and remained relatively high through day 10. No statistical difference was observed in C1-INH between survivors (n=53) and non-survivors (n=39) at any time point before or after transfusion. C3 was higher in COVID-19 patients in comparison to CP (161.5 +/-47.0 vs. 89.6 +/-15.3 mg/dL). However, C3 levels were significantly lower in non-survivors compared to survivors the day before transfusion (131.9 +/- 38.0 vs. 180.9 +/- 45.1 mg/dL, p=2.8E-06). Following transfusion, C3 levels decreased and remained steady afterwards; at all subsequent time points C3 levels were significantly lower in non-survivors compared to survivors (post-day 1: 130.6+/- 33.0 vs. 158.5 +/- 51.5 mg/dL, p=0.006; post-day 3: 116.6+/-46.5 vs. 146.2+/-42.8 mg/dL, p=0.01; post-day 10: 120.8+/-40.9 vs. 150.3+/- 45.9 mg/dL, p=0.03). C4 levels trended lower in non-survivors compared to survivors the day before transfusion (30.8+/- 15.3 vs. 37.9 +/- 16.7 mg/dL, p=0.08). The day following CP, there was a significant decrease in C4 across the entire cohort (35.1+/- 16.4 vs. 27.9+/- 18.3 mg/dL, p=0.01); subsequent levels remained steady. In conclusion, a single CP transfusion does not appear to restore C1-INH, C3 and C4 levels in hospitalized COVID-19 patients. CP transfusion is associated with a transient increase in C1-INH and decreasing C3 and C4 levels. Contrary to our hypothesis, C1-INH levels are increased in COVID-19 patients. The relationship between C1-INH and complements in COVID-19 remains to be fully elucidated. Prospective studies are needed to further delineate these relationships especially in the context of ongoing clinical trials of recombinant C1-INH in COVID-19 patients.

Plasma-derived and recombinant C1 esterase inhibitor: Binding profiles and neuroprotective properties in brain ischemia/reperfusion injury

C1 esterase inhibitor (C1INH) is known to exert its inhibitory effect by binding to several target proteases of the contact and complement systems. One of C1INH’s targets comprise mannose-binding lectin (MBL), a critical player in post-stroke pathophysiology. We therefore explored the effects of recombinant human (rh) and plasma derived (pd) C1INH in C57BL/6J mice subjected to transient occlusion of the middle cerebral artery (tMCAo), receiving 15U/mouse of pd or rhC1INH intravenously, at reperfusion. We analyzed the compounds’ (i)neuroprotective effects, (ii) plasma presence, (iii)effects on circulating and brain MBL, (iv)time course of endothelial deposition, and (v) effects on the formation of active complement products. rhC1INH-treated mice had neuroprotective effects, including reduced behavioral deficits and neuronal loss, associated with decreased MBL brain deposition and decreased formation of complement C4b active fragments. In contrast, pdC1INH did not show these neuroprotective effects despite its longer plasma residence time. We also analyzed the response to tMCAo in C1INH-deficient mice, observing a poorer ischemic outcome compared to the wild type mice, which could be partially prevented by rhC1INH administration.In conclusion, we show that rhC1INH exhibits stronger neuroprotective effects than the corresponding plasma-derived protein after experimental ischemia/reperfusion injury in the brain, placing it as a promising drug for stroke. Differential effects are likely related to more effective MBL inhibition which further confirms it as a useful pharmacological target for stroke.

Age-dependent possible role of contact-activated blood coagulation factor XII as a potential contributor to the “bradykinin storm” in COVID-19 patients

Bradykinin was implicated in a new complex model of pathomechanism leading to the symptoms of COVID-19 created by a computer-assisted association analysis. According to this model, the decrease in angiotensin-converting enzyme expression leads to impaired bradykinin elimination and subsequent enrichment in the lungs. However, there is no mentioning of the importance of blood coagulation factor XII in increased bradykinin production, in spite of its age-dependent activation and the lower level of C1-esterase inhibitor (C1INH). Activated factor XII may be an important contributor to the "bradykinin storm" in elder cardiovascular patients. Literature review. 1) Activation of the coagulation factor XII on the surface of SARS-CoV-2 infected endothelial cells may trigger the prekallikrein/kallikrein/kinin system producing bradykinin. Such process is taking place in hantavirus infections causing severe lung and kidney damages. 2) The endothelial system is dysregulated in elderly patients, resulting in potentially higher factor XII activities on the surface of damaged endothelial cells in the stiffened arteries. This can contribute to the higher mortality rates in the elderly. The targeted inhibition of activated blood coagulation factor XII may represent a new therapeutic target for COVID-19, especially for elder patients. Recently, beneficial results have already been observed by the clinical applications of recombinant C1INH and bradykinin receptor antagonists. Orv Hetil. 2020; 161(50): 2099-2103.

Treatment of COVID-19 With Conestat Alfa, a Regulator of the Complement, Contact Activation and Kallikrein-Kinin System.

A dysregulated immune response with hyperinflammation is observed in patients with severe coronavirus disease 2019 (COVID-19). The aim of the present study was to assess the safety and potential benefits of human recombinant C1 esterase inhibitor (conestat alfa), a complement, contact activation and kallikrein-kinin system regulator, in severe COVID-19. Patients with evidence of progressive disease after 24 h including an oxygen saturation <93% at rest in ambient air were included at the University Hospital Basel, Switzerland in April 2020. Conestat alfa was administered by intravenous injections of 8400 IU followed by 3 additional doses of 4200 IU in 12-h intervals. Five patients (age range, 53–85 years; one woman) with severe COVID-19 pneumonia (11–39% lung involvement on computed tomography scan of the chest) were treated a median of 1 day (range 1–7 days) after admission. Treatment was well-tolerated. Immediate defervescence occurred, and inflammatory markers and oxygen supplementation decreased or stabilized in 4 patients (e.g., median C-reactive protein 203 (range 31–235) mg/L before vs. 32 (12–72) mg/L on day 5). Only one patient required mechanical ventilation. All patients recovered. C1INH concentrations were elevated before conestat alfa treatment. Levels of complement activation products declined after treatment. Viral loads in nasopharyngeal swabs declined in 4 patients. In this uncontrolled case series, targeting multiple inflammatory cascades by conestat alfa was safe and associated with clinical improvements in the majority of severe COVID-19 patients. Controlled clinical trials are needed to assess its safety and efficacy in preventing disease progression.

Gene therapy for C1 esterase inhibitor deficiency in a Murine Model of Hereditary angioedema.

Hereditary angioedema (HAE) is a life-threatening, autosomal dominant disorder characterized by unpredictable, episodic swelling of the face, upper airway, oropharynx, extremities, genitalia, and gastrointestinal tract. Almost all cases of HAE are caused by mutations in the SERPING1 gene resulting in a deficiency in functional plasma C1 esterase inhibitor (C1EI), a serine protease inhibitor that normally inhibits proteases in the contact, complement, and fibrinolytic systems. Current treatment of HAE includes long-term prophylaxis with attenuated androgens or human plasma-derived C1EI and management of acute attacks with human plasma-derived or recombinant C1EI, bradykinin, and kallikrein inhibitors, each of which requires repeated administration. As an approach to effectively treat HAE with a single treatment, we hypothesized that a one-time intravenous administration of an adeno-associated virus (AAV) gene transfer vector expressing the genetic sequence of the normal human C1 esterase inhibitor (AAVrh.10hC1EI) would provide sustained circulating C1EI levels sufficient to prevent angioedema episodes. To study the efficacy of AAVrh.10hC1EI, we used CRISPR/Cas9 technology to create a heterozygote C1EI-deficient mouse model (S63±) that shares characteristics associated with HAE in humans including decreased plasma C1EI and C4 levels. Phenotypically, these mice have increased vascular permeability of skin and internal organs. Systemic administration of AAVrh.10hC1EI to the S63± mice resulted in sustained human C1EI activity levels above the predicted therapeutic levels and correction of the vascular leak in skin and internal organs. A single treatment with AAVrh.10hC1EI has the potential to provide long-term protection from angioedema attacks in affected individuals.

RECOMBINANT C1 ESTERASE INHIBITOR FOR SHORT-TERM PROPHYLAXIS IN PATIENTS WITH HEREDITARY ANGIOEDEMA

Introduction Patients with hereditary angioedema (HAE) are at risk for an acute attack after medical procedures. Short-term prophylaxis may minimize this risk. This study evaluated recombinant C1 esterase inhibitor (rhC1-INH) as short-term prophylaxis. Methods Patients with angioedema were treated with rhC1-INH prior to medical procedures/stressful life events; HAE attacks were recorded through 2 days and >2-7 days postprocedure. Results Fifty-one patients (median age, 44 years [range, 17-73 years]; 62.7% female; 92.2% HAE type 1) were included. A median rhC1-INH dose of 3075 IU (range, 2100-4200 IU) was administered as prophylaxis, median of 60 minutes prior, for 70 procedures (52.9% [n=37] dental [median, 60 minutes preprocedure]); 30.0% [n=21] surgical [median, 45 minutes preprocedure]; 15.7% [n=11] endoscopy [median, 30 minutes preprocedure, and 1.4% [n=1] stressful life event). Majority (n=48; 68.6%) of 70 cases had rhC1-INH administered 10-65 minutes preprocedure: 25 of 48 (52.1%) dental, 16 (33.3%) surgical, and 7 (14.6%) endoscopy. Nineteen (27.1%) cases involved long-term prophylaxis (danazol/tranexamic acid). Overall, 97.1% (68/70) of cases did not have an HAE attack within 2 days postprocedure; 91.4% (64/70) during >2-7 days postprocedure. For 2 attacks occurring within 2 days, rhC1-INH was administered 230 minutes and ≥24 hours preprocedure, respectively. No adverse events were reported. As a self-control group, 76.9% of 26 cases with no long-term/short-term prophylaxis preprocedure had an attack within 2 days postprocedure. Conclusions Short-term prophylaxis with rhC1-INH, administered within several hours preprocedure, was efficacious and safe in adolescents/adults and reduced the risk of an HAE attack postprocedure.

Pharmacokinetics of human recombinant C1-esterase inhibitor and development of anti-drug antibodies in healthy dogs

Complement-mediated intravascular hemolysis occurs in canine immune-mediated hemolytic anemia (IMHA). Complement inhibitors such as recombinant C1 esterase inhibitor (rC1-INH) might prevent this process and alter the disease course. This study aimed to characterize the pharmacokinetics of a single 500 IU IV dose of rC1-INH in 8 healthy beagle dogs, evaluate the dogs for any adverse effects of drug administration, and determine whether rC1-INH administration induces anti-drug antibody formation. Serum rC1-INH concentrations were measured using a commercial functional ELISA at baseline and at 10, 20, 40, 60, 80, 100, 120, 240, 360, 480, 600, 720, 960, and 1440 min post drug administration. Complete blood counts were conducted at baseline, 720 and 1440 min. Western blot analysis, using rC1-INH as the target antigen was used to detect anti-drug antibodies in 14-day serum samples. No adverse clinical reactions were noted following rC1-INH administration. Pharmacokinetic modelling suggested that the peak C1-INH concentration achieved is 0.21 IU/mL and that C1-INH concentration is significantly greater than baseline for 100 min following injection. A robust antibody response was detected which suggests that rC1-INH should not be re-administered after an initial course. Clinical trials of rC1-INH in dogs with intravascular IMHA are now warranted.

Recombinant C1 Esterase Inhibitor Reduces Cytokine Storm in an Ex Vivo Whole Blood Model.

C1 esterase inhibitor (C1INH) is an abundant component of blood plasma (the average concentration is 250 mg/L); it is known to be involved in several biological processes, for instance, in the regulation of the coagulation system, adhesion of leukocytes on endothelial cells, and in the regulation of complement and kallikrein cascades. Lately, the role of C1INH in immunomodulation has gained considerable attention. We used an ex vivo whole blood model to examine the influence of C1INH and its mutated variants on the inflammatory cytokines interleukin (IL)-6, tumor necrosis factor-α (TNFα), and IL-1β. The present study demonstrated for the first time that recombinant C1INH or its Seprin domain can downregulate bacterial endotoxin induced IL-6 release. We also observed that unstructured N-terminal domain of C1INH downregulates the release of IL-1β and TNFα, but not IL-6. Our results suggest that C1INH may have therapeutic potential for treatment of inflammatory conditions.

A Decade of Change: Recent Developments in Pharmacotherapy of Hereditary Angioedema (HAE).

Hereditary angioedema (HAE) due to C1 esterase inhibitor (C1-INH) deficiency (HAE-C1-INH) is a rare but medically significant disease that can be associated with considerable morbidity and mortality. Research into the pathogenesis of HAE-C1-INH has expanded greatly in the last six decades and has led to new clinical trials with novel therapeutic agents and treatment strategies. Mechanisms of pharmacotherapy include (a) supplementing C1-INH, the missing serine-protease inhibitor in HAE; (b) inhibiting the activation of the contact system and the uncontrolled release of proteases in the kallikrein-kinin system, by blocking the production/function of its components; (c) inhibiting the fibrinolytic system by blocking the production/function of its components; and (d) inhibiting the function of bradykinin at the endothelial level. Strategies for managing HAE-C1-INH are aimed at treating acute attacks, or preventing attacks, through the use of prophylactic treatment. Available agents for treating acute attacks include plasma-derived C1-INH concentrates, a recombinant C1-INH, a bradykinin B2 receptor antagonist, and a plasma kallikrein inhibitor. Long-term prophylactic treatments include attenuated androgens, plasma-derived C1-INH concentrates, and anti-fibrinolytics. Plasma-derived C1-INH and a bradykinin B2 receptor antagonist are already approved for self-administration at home. The number of management options for HAE-C1-INH has increased considerably within the past decade, thus helping to alleviate the burden of this rare disease.

Hereditary and acquired angioedema.

Hereditary angioedema (HAE) is an autosomal dominant disorder defined by a deficiency of functional C1 esterase inhibitor (C1-INH). Acquired angioedema is due to either consumption (type 1) or inactivation (type 2) of CI-INH. Both HAE and acquired angioedema can be life-threatening. Of the three types of HAE, type 1 is most common, occurring in approximately 85% of patients and characterized by decreased production of C1-INH, which results in reduced functional activity to 5-40% of normal. Type 2 occurs in 15% of cases; C1-INH is detectable in normal or elevated quantities but is dysfunctional. Also, HAE with normal CI-INH (previously called type 3 HAE) is rare and characterized by normal complement studies. Specific genetic mutations have been linked to factor XII, angiopoietin-1, and plasminogen gene. Patients with unknown mutations are classified as unknown. The screening test for types 1 and 2 is complement component C4, which is low to absent at times of angioedema and during quiescent periods. A useful test to differentiate HAE from acquired angioedema is C1q protein, which is normal in HAE and low in acquired angioedema. The management of HAE has been transformed with the advent of disease-specific therapies. On-demand therapy options include plasma and recombinant C1-INH for intravenous infusion; ecallantide, an inhibitor of kallikrein; and icatibant, a bradykinin β₂ receptor antagonist, both administered subcutaneously. For long-term prophylaxis, intravenous or subcutaneous C1-INH enzyme replacement and lanadelumab, a monoclonal antibody against kallikrein that is administered subcutaneously, are effective agents.

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

BackgroundHereditary 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. ObjectiveReview and compare data from clinical studies that evaluated the efficacy and safety of treatments for laryngeal HAE attacks. MethodsWe 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. ResultsThe 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). ConclusionsAvailable 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.

Hereditary angioedema: what the gastroenterologist needs to know.

Up to 93% of patients with hereditary angioedema (HAE) experience recurrent abdominal pain. Many of these patients, who often present to emergency departments, primary care physicians, general surgeons, or gastroenterologists, are misdiagnosed for years and undergo unnecessary testing and surgical procedures. Making the diagnosis of HAE can be challenging because symptoms and attack locations are often inconsistent from one episode to the next. Abdominal attacks are common and can occur without other attack locations. An early, accurate diagnosis is central to managing HAE. Unexplained abdominal pain, particularly when accompanied by swelling of the face and extremities, suggests the diagnosis of HAE. A family history and radiologic imaging demonstrating edematous bowel also support an HAE diagnosis. Once HAE is suspected, C4 and C1 esterase inhibitor (C1-INH) laboratory studies are usually diagnostic. Patients with HAE may benefit from recently approved specific treatments, including plasma-derived C1-INH or recombinant C1-INH, a bradykinin B2-receptor antagonist, or a kallikrein inhibitor as first-line therapy and solvent/detergent-treated or fresh frozen plasma as second-line therapy for acute episodes. Short-term or long-term prophylaxis with nanofiltered C1-INH or attenuated androgens will prevent or reduce the frequency and severity of episodes. Gastroenterologists can play a critical role in identifying and treating patients with HAE, and should have a high index of suspicion when encountering patients with recurrent, unexplained bouts of abdominal pain. Given the high rate of abdominal attacks in HAE, it is important for gastroenterologists to appropriately diagnose and promptly recognize and treat HAE, or refer patients with HAE to an allergist.

Treatment of hereditary angioedema: a review (CME).

Hereditary angioedema (HAE) is a rare autosomal dominant disorder characterized by recurrent attacks of self-limiting tissue swelling. The management of HAE has transformed dramatically with recently approved therapies in the United States. However, there is lack of awareness among physicians about these new modalities. The aim of this review is to update the practicing physician about various therapeutic options available for HAE patients. An exhaustive literature search of PubMed and OVID was performed to develop this article. Management of HAE is traditionally classified into treatment of acute attacks or on-demand therapy, short-term (preprocedural) prophylaxis, and long-term prophylaxis. Newer therapies include C1 esterase inhibitor (C1-INH) and contact system modulators, namely, ecallantide and icatibant. Recombinant C1-INH, which is available in Europe, is awaiting approval in the United States. C1-INH concentrate is approved for prophylaxis as well as on-demand therapy while ecallantide and icatibant are approved for acute treatment only. Effective HAE management further includes patient education, reliable access to specific medications, and regular follow-up to monitor therapeutic response and safety.