The importance of recognizing and managing a rare form of angioedema: hereditary angioedema due to C1-inhibitor deficiency

Figures & data

Table 1. Typical clinical and laboratory characteristics of various types of angioedema disorders.^a

		Laboratory Findings
Angioedema Type	Clinical Features	C4	C1-INH Level	C1-INH Function
Bradykinin-mediated
C1-INH-HAE type 1 (85% of HAE cases)	Onset <20 yr; angioedema typically affects the face, oropharynx (including tongue, palate, and uvula), legs, arms, buttocks, abdomen, and genitalia. Due to mutation(s) in the SERPING1 gene on chromosome 11 which codes for C1-INH resulting in lower than normal levels of functional C1-INH; autosomal dominant disease with 75% having a family history and 25% being de novo mutations.	Low	Low	Low
C1-INH-HAE type 2 (15% of HAE cases)	Onset <20 yr; angioedema affects the face, oropharynx (including tongue, palate, and uvula), legs, arms, buttocks, abdomen, and genitalia. Due to a missense mutation interfering with the ability of mutant C1-INH to inhibit target proteases.	Low	Normal or high	Low
HAE with normal C1-INH^b	Rare; known mutations to date include genes coding for factor XII, angiopoietin-1, plasminogen, kininogen-1, myoferlin, and heparan sulfate glucosamine 3-O-sulfotransferase-6ulfotransferase-6. In most cases, responsible genetic mutation not clear.	Normal	Normal	Normal
Acquired angioedema	Less common; onset >40 yr. Underlying MGUS, B-cell clonal disorders/paraproteinemia, lymphoreticular neoplasia, or autoimmune disorders (such as systemic lupus erythematosus). Can be a primary autoantibody as well. Symptoms same as HAE.	Low	Low	Low
ACEI-induced	Symptoms usually localized to face or upper aerodigestive tract. Characterized by erythema (without itching). More prevalent among Black patients.	Normal	Normal	Normal
Histamine (mast cell)-mediated
Allergic/histamine-mediated angioedema	Can occur at any age but usually younger patients; associated with urticaria; may progress to anaphylaxis; onset minutes to hours after contacting potential allergen.	Normal	Normal	Normal
Idiopathic-mediated
Idiopathic non-histaminergic angioedema	Diagnosis after exclusion of above diagnoses; both histaminergic and nonhistaminergic varieties have been described; absence of allergy, HAE, or medications.	Normal	Normal	Normal

^aTable adapted with permission from Lumry et al., “Advances in Heredity Angioedema: The Prevention of Angioedema Attacks with Subcutaneous C1-Inhibitor Replacement Therapy” [4].

^bFormerly designated as “HAE type 3.”

ACEI, angiotensin-converting enzyme inhibitor; C1-INH, C1-inhibitor; C1-INH-HAE, hereditary angioedema due to C1-inhibitor deficiency; HAE, hereditary angioedema; MGUS, monoclonal gammopathy of uncertain significance.

Figure 1. Pathway of contact system activation and interaction with fibrinolytic system. Contact system activation starts with the activation of factor XII. Activated factor XII converts plasma prekallikrein into plasma kallikrein. Kallikrein cleaves high molecular weight kininogen to produce bradykinin. Bradykinin causes vasodilatation and increased vascular permeability, leading to angioedema. The fibrinolytic system can also lead to bradykinin formation and vascular leakage via factor XII activation by plasmin. Kallikrein regulates the fibrinolytic system by cleaving pro-urokinase plasminogen activator into urokinase-type plasminogen activator, causing activation of plasminogen to plasmin. C1 inhibitor (C1-INH) regulates these pathways via inhibition (bold crosses) [30].

Figure 2. Diagnostic workup for patients with unexplained recurrent angioedema [27,42,64]. Each evaluation step is shown as an oval with possible outcomes indicated with arrows. Eventual diagnoses are shown in boxes. C1-INH testing must include C1-INH functional activity if the antigenic level is normal. Response to antihistamines requires regular and sustained dosing (at least long enough for 3 expected attacks) using high dose antihistamines (at least 4 times the standard dose of second-generation non-sedating antihistamines). C1-INH, C1-inhibitor; HAE-C1-INH, hereditary angioedema due to C1-inhibitor deficiency; HAE-ANGPT1, hereditary angioedema with a specific angiopoietin-1 gene mutation (ANGPT1); HAE-FXII, hereditary angioedema with F12 mutation; HAE-HS3OST6, hereditary angioedema with a mutation coding for the heparan sulfate glucosamine 3-O-sulfotransferase-6 (3-OST-6); HAE-KNG1, hereditary angioedema with a specific kininogegn-1 gene mutation (KNG1); HAE-Myoferlin, hereditary angioedema with a specific myoferlin gene mutation (MYOF); HAE-PLG, hereditary angioedema with a specific plasminogen gene mutation (PLG); HAE-U, hereditary angioedema, unknown mutation

Table 2. Clinical features useful for a differential diagnosis of angioedema [modified from 7]

	Mast Cell-mediated Angioedema	Bradykinin-mediated Angioedema
		Acquired	Hereditary
Speed of symptom onset following trigger	Minutes to hours	Hours	Hours
Time to symptom resolution	Minutes to a few hours	Days	Days
Typical age of onset	Any	40+ years for acquired angioedema related to ACEI	<20 years
Predominant location of symptoms	Face (eyelids, lips), neck	Lips, tongue, uvula, upper airways^a	Face, peripheral, upper airways, GI tract
Triggering factors	Known or probable allergens	Drugs, ACEI, spontaneous	Trauma, infection, emotional stress, estrogen, ACEI; often seemingly spontaneous
Family history^b	No	No	Yes
Inducing/exacerbating drugs	NSAIDs	ACEI, ARB, gliptins	ACEI, estrogen

ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; HAE, hereditary angioedema; NSAID, nonsteroidal anti-inflammatory drug.

^aThese features are variable and can present exactly like C1-INH-HAE.

^bNot necessary for diagnosis.

Table 3. Available treatments for hereditary angioedema in the US

Agent	Mechanism of Action	Route of Administration	FDA-approved Dose	US-approved HAE Indications
Acute Therapy
BERINERT® (C1-INH [human]; CSL Behring, LLC) [87]	C1-INH replacement	IV	20 IU/kg	Treatment of acute attacks in pediatric and adult patients
RUCONEST® (conestat alfa; C1-INH [recombinant]; Pharming Healthcare Inc.) [88]	C1-INH replacement	IV	Patients < 84 kg: 50 U/kg^a Patients ≥ 84 kg: 4200 U^a	Treatment of acute attacks in adolescents and adults^b
FIRAZYR® (icatibant; Shire, Oprhan Therapies LLC now part of Takeda) [89]	Antagonism of bradykinin B2 receptor	SC	30 mg; additional 30 mg doses maybe given at intervals of at least 6 hours; maximum of 3 doses per 24 hours	Treatment of acute attacks in patients ≥18 years of age
KALBITOR® (ecallantide; Dyax Corp, now part of Takeda) [90]	Kallikrein inhibition	SC	30 mg (3X10 mg injections) Additional 30 mg dose may be given within a 24-hour period^c	Treatment of acute attacks in patients ≥12 years of age
Prophylactic Therapy
DANOCRINE® (danazol; Sanofi-Aventis US LLC; Bridgewater, NJ) [91]	Increases C1-INH levels	Oral	Individualized; initiate therapy at 200 mg BID-TID^d	Routine prophylaxis; contraindicated in pregnancy and breast-feeding
CINRYZE® (C1-INH [human]; ViroPharma Biologics LLC, a Takeda Company) [92]	C1-INH replacement	IV	Adults and adolescents 12 years and older: 1000 U every 3–4 days^e Children 6–11 years: 500 U every 3 or 4 days	Routine prophylaxis in adolescents and adults
HAEGARDA® (C1-INH [human]; CSL Behring, LLC) [93]	C1-INH replacement	SC	60 IU/kg twice weekly (every 3 or 4 days)	Routine prophylaxis in adolescents and adults
TAKHZYRO^TM (lanadelumab-flyo; Dyax  Corp, now part of Takeda) [94]	Plasma kallikrein inhibitor (monoclonal antibody)	SC	300 mg every 2 weeks Dosing every 4 weeks may be considered in some patients	Routine prophylaxis in patients 12 years and older
ORLADEYO^TM (berotralstat; BioCryst Pharmaceuticals, Inc.) [95]	Plasma kallikrein inhibitor	Oral	150 mg once daily with food; 110 mg once daily with food recommended in certain patient types or clinical situations^f	Routine prophylaxis in patients 12 years and older

BID, twice a day; C1-INH, C1-inhibitor; HAE, hereditary angioedema; IU, international units; IV, intravenous; SC, subcutaneous; U, units; TID, three times a day.

^aIf the attack symptoms persist, an additional (second) dose can be administered at the recommended dose level, not to exceed 4200 U per dose. No more than two doses should be administered within a 24-hour period.

^bEfficacy not established in patients with laryngeal attacks.

^cDue to risk of anaphylaxis, must be administered by a healthcare professional with appropriate medical support to manage anaphylaxis and hereditary angioedema.

^dAfter a favorable initial response is obtained in terms of prevention of episodes of edematous attacks, the proper continuing dosage should be determined by decreasing the dosage by 50% or less at intervals of one to three months or longer if frequency of attacks prior to treatment dictates. If an attack occurs, the daily dosage may be increased by up to 200 mg. During the dose adjusting phase, close monitoring of the patient’s response is indicated, particularly if the patient has a history of airway involvement.

^eDoses up to 2500 U (not exceeding 100 U/kg) every 3 or 4 days may be considered based on individual patient response.

^fPatients with moderate or severe hepatic impairment; patients with chronic administration of P-gp or BCRP inhibitors (eg, cyclosporine); patients with persistent gastrointestinal reactions to ORLADEYO.

Table 4. Products in clinical development for HAE prophylaxis

Investigational Product	Mechanism of Action	Route of Administration	Development Status As of March 2021
Garadacimab (CSL312; CSL Behring)	Factor XIIa-inhibitory monoclonal antibody	SC	Phase 3 trial (prophylaxis) [119]
IONIS-PKK-LRx (Ionis Pharmaceuticals, Inc)	Reduces production of prekallikrein	SC	Phase 2 trial (prophylaxis) [120] and open-label extension] [121]
PHA-022121 (Pharvaris Netherlands B.V.)	Bradykinin B2 receptor antagonist	Oral	Phase 2 trial (acute attack treatment) [122]
KVD900 (KalVista Pharmaceuticals)	Plasma kallikrein inhibitor	Oral	Phase 2 trial (acute attack treatment) completed [123]
KVD824	Plasma kallikrein inhibitor	Oral	Phase 2 trial (prophylaxis) being initiated [124]

SC, subcutaneous

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BERINERT® [package insert]. Kankakee, IL: CSL Behring, LLC; 2019.

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RUCONEST® [package insert]. Warren, NJ: Pharming Healthcare Inc.; 2020.

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FIRAZYR® [package insert]. Lexington, MA: Shire Orphan Therapies LLC, now part of Takeda; 2015.

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KALBITOR® [package insert]. Burlington, MA: Dyax Corp, now part of Takeda; 2015.

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DANOCRINE® prescribing information. Bridgewater, NJ: Sanofi-Aventis US LLC. December 2011.

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CINRYZE® [package insert]. Lexington, MA: ViroPharma Biologics LLC, a Takeda Company; 2021.

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HAEGARDA® [package insert]. Kankakee, IL: CSL Behring, LLC; 2017.

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TAKHZYRO^TM [package insert]. Lexington, MA: Dyax Corp, now part of Takeda; 2018.

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ORLADEYO^TM [package insert]. Durham, NC: BioCryst Pharmaceuticals, Inc.; 2020.

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CSL Behring. CSL312 (Garadacimab) in the prevention of hereditary angioedema attacks. [ cited 2021 Mar 3]. Available from: https://clinicaltrials.gov/ct2/show/NCT04656418?term=Garadacimab&draw=2&rank=1.

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KalVista Pharmaceuticals. A phase II, cross-over clinical trial evaluating the efficacy and safety of KVD900 in the on-demand treatment of angioedema attacks in adult subjects with hereditary angioedema Type I or II. [ cited 2021 Mar 3]. Available from: https://clinicaltrials.gov/ct2/show/NCT04208412?term=KVD900&draw=2&rank=1.

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KalVista Pharmaceuticals. KVD824 for HAE. [ cited 2021 Mar 9]. Available from: https://www.kalvista.com/products-pipeline/kvd824-hae.

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