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

ABSTRACT

The majority of angioedema cases encountered in clinical practice are histamine-mediated (allergic); however, some cases are bradykinin-related (non-allergic) and do not respond to standard anti-allergy medications. Among bradykinin-related angioedema, hereditary angioedema (HAE) is a rare, but chronic and debilitating condition. The majority of HAE is caused by deficiency (type 1) or abnormal function (type 2) of the naturally occurring protein, C1-inhibitor (C1-INH)—a major inhibitor of proteases in the contact (kallikrein-bradykinin cascade), fibrinolytic pathway, and complement systems. Failure to recognize HAE and initiate appropriate intervention can lead to years of pain, disability, impaired quality of life (QoL) and, in cases of laryngeal involvement, it can be life-threatening. HAE must be considered in the differential diagnosis of non-urticarial angioedema, particularly for patients with a history of recurrent angioedema attacks, family history of HAE, symptom onset in childhood/adolescence, prodromal signs/symptoms before swellings, recurrent/painful abdominal symptoms, and upper airway edema. Management strategies for HAE include on-demand treatment for acute attacks, short-term prophylaxis prior to attack-triggering events/procedures, and long-term or routine prophylaxis for attack prevention. Patients should be evaluated at least annually to assess need for routine prophylaxis. HAE specific medications like plasma-derived and recombinant C1-INH products, kallikrein inhibitors, and bradykinin B2 receptor antagonists, have improved management of HAE. While the introduction of intravenous C1-INH represented a major breakthrough in routine HAE prophylaxis, some patients fail to achieve adequate control and others have psychological barriers or experience complications related to intravenous administration. Subcutaneous (SC) C1-INH, SC monoclonal antibody (mAb)-based therapies, and an oral kallikrein inhibitor offer effective alternatives for HAE attack prevention and may facilitate self-administration. HAE management should be individualized, with QoL improvement being a key goal. This can be achieved with broader availability of existing options for routine prophylaxis, including greater global availability of C1-INH(SC), mAb-based therapy, oral treatments, and multiple on-demand therapies.

KEYWORDS:

• Angioedema
• hereditary angioedema
• bradykinin
• C1-inhibitor; diagnosis
• prevention
• prophylaxis; subcutaneous 

1. Introduction

Angioedema is commonly encountered by general medicine practitioners. Etiologies of angioedema vary and differential diagnosis can be critical for instituting effective treatment. Typically characterized by tissue swelling resulting from increased vascular permeability in deeper layers of skin and mucous membranes [1–3], the majority of angioedema cases are histamine- (mast cell) mediated; however, the etiology can also be bradykinin-related (Table 1). Histamine-mediated, or allergic angioedema, is a response to external allergens, such as food, insect stings, and drugs, or it may be idiopathic [5]. Allergic angioedema may be associated with urticaria, flushing, generalized pruritus, bronchospasm, throat tightness, and hypotension, and respond to treatment with conventional anti-allergy medications (eg, antihistamines, glucocorticoids, and epinephrine) [6]. In patients presenting with acute allergic angioedema, attention should be given to the signs and symptoms of anaphylaxis and prompt administration of epinephrine should be provided if appropriate. Bradykinin-related, or non-allergic angioedema, may be acquired (ie, related to drugs such as angiotensin-converting enzyme [ACE] inhibitors or underlying lymphoreticular dyscrasias) or inherited (hereditary angioedema [HAE]) [7–9].

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.

HAE is a relatively rare form of non-allergic angioedema, and it is associated with major morbidity and potential mortality [10,11]. While HAE may have similar manifestations as other types of angioedema, there is a notable absence of urticaria [12,13]. In addition, HAE requires a different treatment approach than allergic angioedema since antihistamines, glucocorticoids, and epinephrine are not effective for HAE [6]. Unfortunately, misdiagnosis of HAE is prevalent [14]. Historically, misunderstanding of symptoms and low awareness of HAE has contributed to misdiagnosis and delayed diagnoses [12]. Given the unique nature of HAE in relation to other types of angioedema, the potential for adverse consequences with incorrect or delayed diagnosis, and the availability of highly effective treatment options for HAE, it is imperative to consider HAE in the differential diagnosis of angioedema [10,12].

This article presents an illustrative case study of HAE, provides an overview of epidemiology and pathophysiology, reviews guidelines for diagnosis and management, and describes current and emerging treatment options.

2. Case

A 14-year-old female was admitted to the hospital with severe abdominal pain and nausea. She was evaluated by the surgical service with a suspicion of acute appendicitis. Abdominal ultrasound was nonspecific except for some edematous loops of bowel. D-Dimer was elevated. While being prepped for the operating room, her mother mentions that her father suffered from recurrent severe abdominal pain and had been diagnosed with a rare condition that causes swelling. The astute resident considers HAE in the differential diagnosis and orders a dose of intravenous (IV) plasma-derived C1-inhibitor (C1-INH) at 20 units/kg along with a C4 level, C1-INH functional activity, and C1-INH level. Within 30 minutes her abdominal pain is resolving, and continues to subside over the next several hours. The operation is canceled. Results for the C4, C1-INH level, and C1-INH function all come back low, confirming a diagnosis of type-I HAE.

3. Overview of HAE

3.1. Epidemiology and types of HAE

HAE is a genetic disorder that affects anywhere between 1:100,000 to 1:10,000 individuals [11,15,16]. HAE is characterized by recurrent episodes of localized subcutaneous (SC) or submucosal nonpruritic swelling [15,17]. Endotypic variants of HAE include C1-INH-HAE type 1, which is characterized by a deficiency of the serine protease inhibitor, C1-INH, and accounts for approximately 85% of cases [15,18,19]. Less common, C1-INH-HAE type 2 is characterized by abnormal C1-INH function in the presence of normal or elevated C1-INH levels, and accounts for approximately 15% of cases. Clinically these endotypes are identical in presentation and response to therapy. They are distinguished biochemically by a quantitative C1-INH level. A third, rare, type of HAE is characterized by recurrent angioedema in the absence of urticaria despite normal C1-INH; this variation has been associated with various genetic mutations, including mutations in genes encoding for factor XII [20–22], angiopoetin-1 [23], kininogen-1 [22,24], plasminogen [25], myoferlin [26], and heparan sulfate glucosamine 3-O-sulfotransferase-6 [27]; many cases are considered idiopathic in the absence of relevant genetic mutation findings. It should be noted that other than factor XII, genetic screening for these other known mutations is not widely available to clinicians, and a specific mutation does not have to be identified in order to diagnose a patients with HAE with normal C1-INH. Given the lower prevalence of this latter type of HAE and dearth of clinical information, for the remainder of this review the term ‘HAE’ denotes C1-INH-HAE types 1 and 2.

3.2. Pathophysiology of HAE

C1-inhibitor is a naturally occurring protein that serves as a major inhibitor of proteases in the contact system (ultimately regulating the downstream production of bradykinin) and the complement system. C1-INH also inhibits proteases in the coagulation system and the fibrinolytic system, although to a lesser degree [28,29] (Figure 1).

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].

In patients with HAE, it is believed that angioedema attacks occur when the contact system is activated; active plasma kallikrein cleaves high-molecular weight kininogen, leading to release of the inflammatory mediator bradykinin [28,29]. The reduced levels of functional C1-INH in HAE types 1 and 2 result from mutations in the SERPING1 gene, which codes for the C1-INH protein [29,31]. In patients with type 1 HAE, mutations result in a failure to synthesize or secrete C1-INH, whereas in type 2 HAE, mutations result in the synthesis of dysfunctional C1-INH proteins that are unable to interact with and inhibit targeted proteases. Thus, the contact system in patients with HAE is disinhibited due to the lack of sufficient functional C1-INH. One study has suggested that lower baseline levels of functional C1-INH correlate significantly with disease severity [32], although such a correlation was not found in a later study [33].

3.3 Clinical manifestations and burden of HAE

Areas of the body that are most commonly affected by angioedema include the extremities, the GI tract, face, the trunk, and the genitals [3,17,18]. The majority of patients with HAE experience recurrent abdominal attacks that are often associated with pain, vomiting, and diarrhea, and cause significant disability and distress [3,34]. Severe headaches, visual disturbances, and other neurological manifestations can also occur [3,35,36]. Laryngeal involvement has the potential to result in death [37,38]. While laryngeal attacks may account for a small proportion of overall HAE attacks, in a survey of patients with HAE, approximately half of patients reported having had at least one laryngeal attack [3]. For all types of HAE, attacks are generally unpredictable, may be acutely painful and disfiguring, and are potentially life-threatening [19,39,40]. Attacks are often spontaneous but can be triggered by physical or emotional factors such as trauma, medical or dental procedures, infections, psychological stress, and hormonal variations including estrogen exposure [41]. Many, but not all, HAE attacks are preceded by “prodromal” symptoms, which may include rash (erythema marginatum), nausea, fatigue, tight/pricking sensation in the skin, and irritability [42,43].

HAE may negatively impact patients’ quality of life, both during and in between episodes [44–47], and is associated with elevated rates of anxiety and depression [40,48–50]. Attacks have been associated with missed time from work, school, and social activities, and decreased productivity [40,48,51–54].

4. Guidelines for diagnosis and general management of HAE

4.1. Diagnosis of HAE

Prompt diagnosis and appropriate management of HAE are critical to optimize health and psychosocial outcomes; however, diagnosis of HAE is often delayed [55,56]. HAE symptoms may initially develop in childhood with a relatively lower frequency and severity of attacks [57,58]; however, patients may not seek treatment until attacks become more frequent and/or severe, which typically coincides with puberty. Consequences of delayed diagnosis, whether due to patients not seeking care or providers missing the diagnosis, may result in patients undergoing unnecessary medical procedures and spending years suffering without appropriate or effective treatment. Further, in the case of laryngeal involvement, consequences can be fatal [1,59,60]. Young children may be at particular risk due to the smaller diameter of their airways [58]. Families with a history of HAE, as well as providers who are aware of such family history, need to be proactive in surveilling for HAE in family members since a first attack could be a potentially fatal laryngeal attack. HAE guidelines recommend that family members of individuals with HAE-C1-INH type 1 or 2 be screened for C1-INH function, C1-INH protein, and C4 plasma levels [1,61]. Laboratory testing for HAE in young infants typically has not been advised given a high degree of variability in C4 and C1-INH antigenic levels during the first year of life [61], although some evidence suggest that C1-INH functional assays may have diagnostic value in situations where testing is considered necessary in patients younger than one year of age [62]. It should be noted that HAE symptoms typically begin in childhood or adolescence, rather than infancy; median age of onset is 12 years [1].

Differential diagnosis between allergic (histamine-mediated) and non-allergic (bradykinin-mediated) angioedema is critical since the underlying mechanism guides appropriate treatment [1,7]. Bradykinin-induced angioedema can further be classified into inherited (ie, HAE) and acquired angioedema. Although both HAE and acquired angioedema (AAE) may be due to a deficiency or dysfunction of C1-inhibitor, AAE may be due to drugs (ACEI) or a complement consumptive process, which in many cases can be related to a B-cell dyscrasia (eg, monoclonal gammopathy of uncertain significance) or less commonly an autoimmune process [7]. Recurrent, unexplained angioedema can sometimes be the initial presenting symptom of an underlying lymphoproliferative disease [63], thus patients with diagnosed AAE should be carefully evaluated to rule out underlying malignant pathology.

There should be a high index of suspicion of HAE for patients who have a history of recurrent, otherwise unexplained angioedema attacks [1]. Clinical features that may be helpful in differential diagnosis of angioedema are summarized in Table 2, and a differential diagnosis decision tree is provided in Figure 2. The presence of urticaria with angioedema attacks is typically indicative of a histamine-related pathophysiology, rather than HAE. Diagnosis of HAE is also supported by the following: family history, symptom onset in childhood/adolescence, prodromal signs/symptoms before swellings, recurrent/painful abdominal symptoms, upper airway edema, absence of urticaria, and lack of response to conventional anti-allergy treatments [1]. Of note, up to 25% of HAE may develop as the result of a de novo genetic mutation; therefore, a diagnosis of HAE should not be excluded based on lack of family history of angioedema [7]. The onset of symptoms after age 40 should raise suspicion of AAE.

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.

International and US guidelines recommend that all patients suspected of having HAE should undergo prompt laboratory evaluation to support diagnosis [1,17,61]. Laboratory evaluation for patients suspected of having HAE include blood levels of complement C4, C1-INH protein, and C1-INH function; these tests should be repeated to confirm diagnosis of HAE 1 or 2 if any of these levels are abnormally low [1]. Table 1 outlines laboratory findings typical of the various types of angioedema. C1q levels are typically normal in most types of bradykinin-mediated angioedema; however, low levels can be indicative of AAE, especially in the patient presenting with symptoms after the age of 40 or those with lymphoproliferative or autoimmune disease [61]. Laboratory analysis of complement levels C1q and C4 can be affected by handling of samples, giving spuriously low levels. C1-inhibitor function can be assayed by a commonly available enzyme-linked immunosorbent assay (ELISA) or by a chromogenic method. The ELISA may tend to overestimate function giving a “gray zone” result, a problem not present with the chromogenic assay. The chromogenic assay is unfortunately not as readily available as the ELISA [65]. Laboratory values may also be altered by recent use of C1-INH or 17-alpha alkylated androgenic steroids. Genetic testing for SERPING1 mutations is not essential for the diagnosis of HAE-C1-INH types 1 and 2 [66].

4.2. General approach to the management of HAE

Broadly, management strategies for patients with C1-INH-HAE include treatment of HAE attacks on an episode-by-episode basis (acute, on-demand treatment), pre-treatment prior to an event or procedure that may trigger an attack (short-term prophylaxis), or administration of ongoing therapy to prevent the development of HAE attacks (long-term or routine prophylaxis) [1,67,68].

Clinical guidelines recommend that all patients with HAE should have access to on-demand treatment. Further, all patients should have sufficient medication for treatment of 2 attacks and should carry on-demand medication at all times [1,69–74]. Short-term prophylaxis is recommended before procedures that may induce an attack [1]. Long-term, routine prophylaxis should be considered for patients who have frequent HAE attacks (≥1/month) or a history of laryngeal attacks, for patients whose condition has resulted in excessive loss of work or school, significant anxiety, impaired quality of life, and/or for patients for whom on-demand therapy is not controlling the disease adequately [1,69,75,76]. It is recommended that patients be evaluated for long-term prophylaxis at least once a year [1]. An increasing trend toward home-based treatment has been associated with increased quality of life and may facilitate timely treatment, increase patients’ self-confidence in managing their HAE, and provide patients with greater flexibility and convenience, thus enabling them to lead more normal lives [1,77–81]. Home-based treatment may enhance adherence to routine HAE prophylaxis, possibly because of the added convenience and reduced requirement to travel to physician’s offices or infusion centers [82].

A growing expert consensus recognizes that management of HAE should focus on individualizing patient care, with a key management goal being the improvement of quality of life [1,69,74,83]. Ideally, patients with this condition should be followed by a clinician with knowledge and experience in treating patients with HAE, one who is familiar with all available treatment options, given the complexity and variability of HAE and its management [73,74].

5. Treatment for HAE

5.1. Changes in HAE treatment paradigm

5.1.1. Historical overview of HAE treatments

In the past decade there has been a great expansion in the availability of new HAE-specific medications in the United States (US) and globally. Historically, available treatments for HAE included on-demand treatment with fresh frozen plasma and prophylaxis with attenuated androgens and antifibrinolytics [18,58,67]. Although attenuated androgens effectively reduce attack frequency in most patients and are well tolerated by some patients, their use is limited by potentially serious side effects and poor efficacy in some patients, and efficacy is diminished when used at lower doses [67,84–86]. Antifibrinolytic agents are no longer recommended for long-term prophylaxis because of insufficient evidence of efficacy [70]. These older treatment modalities have largely been displaced following the introduction of newer HAE-specific medications (Table 3).

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.

5.1.2. On-demand treatments

Intravenous C1-INH concentrate, (BERINERT®; CSL Behring, LLC; Kankakee, IL), was approved by the US FDA in 2009 for acute treatment of HAE attacks [87], although this product had been available in Europe since the early 1970s [96]. Additional HAE-pathway specific treatments for on-demand treatment were subsequently approved by the US FDA including a SC kallikrein inhibitor, ecallantide (KALBITOR®; Dyax Corp, now part of Takeda; Lexington, MA) [90] in 2009; a SC bradykinin B2 receptor antagonist, icatibant (FIRAZYR®; Shire Orphan Therapies LLC, now part of Takeda; Lexington, MA) [89] in 2011; and IV recombinant C1-INH (conestat alfa; RUCONEST®; Pharming Healthcare Inc.; Warren, NJ) in 2014 [88]. The IV C1-INH concentrate (CINRYZE®; ViroPharma Biologics LLC, a Takeda Company; Lexington, MA) is approved for on-demand treatment in the European Union, but not the US.

5.1.3. Long-term prophylaxis

5.1.3.1. Prophylaxis with plasma-derived IV C1-INH and unmet needs

Plasma-derived IV C1-INH concentrate (CINRYZE®; ViroPharma Biologics LLC, a Takeda Company; Lexington, MA) was approved for routine prophylaxis in patients with HAE in October 2008 [92]. HAE guidelines are placing greater emphasis on expanding eligibility for prophylaxis and striving to improve quality of life. Until recently, C1-INH replacement therapy for prophylaxis was available only as an IV administered formulation, C1-INH(IV), (CINRYZE®; ViroPharma Biologics LLC, a Takeda Company; Lexington, MA). A limitation of C1-INH(IV) prophylaxis is frequent breakthrough attacks in some patients, especially at the original approved dose of 1000 IU twice weekly [44,97–99]. Doses up to 2500 IU are now allowed [92]. In addition to concerns regarding breakthrough attacks, routine prophylaxis with this IV formulation presents challenges related to IV access, safety risks of thrombosis and infection from indwelling port use, and issues related to patient convenience [73,98,100].

An online survey of 50 adults with HAE, 47 of whom were using C1-INH(IV) for prophylaxis, found that 30% of patients who administered via a peripheral vein were somewhat dissatisfied or not at all satisfied with their treatment, with 62% of patients reporting difficulty in finding usable veins or administering the infusion [98]. Further, complications such as blockage, thrombosis, and infection were experienced by almost half of patients who administered their C1-INH(IV) through a central port catheter. The concerns associated with C1-INH(IV) underscore that additional options for routine prophylaxis of HAE are needed.

5.1.3.2. C1-INH(SC)

In June 2017, the US FDA approved the first SC formulation of C1-INH (C1-INH[SC]; HAEGARDA®; CSL Behring, LLC; Marburg, Germany). C1-INH(SC) is indicated for the routine prevention of HAE attacks in adolescents and adults [93,101]. This relatively new C1-INH treatment option may provide greater convenience, facilitate self-administration, and potentially enhance adherence. The prospective, multicenter, open-label, crossover Clinical Study for Optimal Management of Preventing Angioedema with Low-Volume Subcutaneous C1-INH Replacement Therapy (COMPACT phase 2 study) showed that administration of C1-INH(SC) achieved constant trough C1-INH functional activity levels above 40% at 3000 and 6000 IU, a threshold expected to provide clinical protection against HAE attacks [102]. A post hoc analysis found that, compared with standard C1-INH(IV) prophylaxis, simulated C1-INH functional activity time profiles were associated with a lower peak-to-trough ratio and more consistent exposures. Patients with a low body weight who are administered C1-INH at a fixed dose are predicted to achieve a relatively high C1-INH level compared with higher body weight patients. Therefore, body weight-adjusted dosing is predicted to achieve the same level of activity across the range of body weights.

Clinical efficacy of C1-INH(SC) was evaluated in a prospective, international, multicenter, randomized, double-blind, placebo-controlled, dose-ranging phase 3 trial (COMPACT) [103]. Patients ≥12 years of age with C1-INH-HAE type 1 or 2 who experienced at least 2 attacks per month were randomly assigned to 1 of 4 treatment sequences: C1-INH(SC) 40 IU/kg (n = 45) or 60 IU/kg (n = 45) followed or preceded by a placebo phase in crossover fashion; each treatment was self-administered subcutaneously twice-weekly over a 16-week period. The mean (95% CI) rate of time-normalized attacks per month was significantly lower for patients randomized to C1-INH(SC) versus placebo; for the FDA approved dose of 60 IU/kg, there were 0.52 (0.00 to 1.04) attacks per month versus 4.03 (3.51 to 4.55) for placebo (within-patient difference, −3.51 [−4.21 to −2.81]; P < 0.001). The majority of patients receiving C1-INH(SC) 60 IU/kg had a response, with 90% (95% CI, 77% to 96%), 83% (68–91%), and 58% (42–72%) of patients having a ≥ 50%, ≥ 70%, and ≥ 90% reduction in HAE attacks, respectively. Notably, fewer patients had laryngeal attacks during treatment with C1-INH(SC) 60 IU/kg (0 patients) than while receiving placebo (25 patients). In a long-term, open-label extension of the COMPACT study, C1-INH(SC) demonstrated substantial and sustained efficacy over a median treatment duration of 53 weeks. Nineteen of 23 patients (83%) treated with C1-INH(SC) 60 IU/kg for more than 2 years were attack-free during the final six weeks of the study [104].

Results from a post hoc analysis of data from the COMPACT study suggest that, compared with placebo, C1-INH(SC) may have important benefits with regard to anxiety and work productivity [54]. Another post hoc analysis of COMPACT data indicated that patients using C1-INH(IV) as routine prophylaxis prior to the COMPACT study experienced an approximately 50% further mean reduction (>70% median reduction) in HAE attack rate while using C1-INH(SC) (40 or 60 IU/kg) for prophylaxis during the study [105].

In the double-blind COMPACT study, adverse events were reported by similar percentages of patients while using C1-INH(SC) or placebo injections. The most common events in the placebo-controlled and open-label studies were injection site reactions, the great majority of which were mild and transient. There were no anaphylactic reactions or evidence of inhibitory anti-C1-INH antibodies during these studies [103,104].

5.1.3.3. Lanadelumab-flyo

A recombinant, human monoclonal antibody long-acting inhibitor of kallikrein formulated for SC administration, lanadelumab-flyo (TAKHZYRO^TM; DX-2930; Shire, now part of Takeda; Lexington, MA) [106] was approved by the FDA in August 2018 for prophylaxis to prevent HAE attacks [94]. The recommended dose of lanadelumab is 300 mg every 2 weeks; dosing every 4 weeks can be considered in patients who are well-controlled (eg, attack free) for more than six months [94]. In a 26-week, phase 3, multicenter, randomized, double-blind, placebo-controlled trial in patients 12 years of age or older with HAE (HELP study; NCT02586805), all lanadelumab treatment regimens were more effective than placebo in reducing the number of HAE attacks during the 26-week treatment period. When given at the FDA approved dose (300 mg SC given every 2 weeks), lanadelumab reduced the monthly HAE attack rate by 87% versus placebo (mean rate ratio 0.13 [95% CI, 0.07–0.24]; P < 0.001) [107]. Post hoc analyses of the HELP study found that attack prevention was evident within the initial 2 weeks of treatment, and sustained, even among patients who had a high baseline attack frequency [108]. A phase 3 long-term/extension study was conducted (NCT02741596; N = 212; median [range] 33 [1.4, 34.2] months of therapy), and reported that efficacy was sustained without emergence of any new safety concerns [109,110].

Injection site reactions (pain, erythema, bruising at injection site) were the most common adverse reactions in the pivotal clinical trial, reported in 52% of lanadelumab-treated patients and 34% of placebo-treated patients. Headache was reported by 33%, 21%, and 11% of patients receiving lanadelumab 300 mg every 2 weeks, 300 mg every 4 weeks, and 150 mg every 4 weeks, respectively, and reported by 22% of patients receiving placebo [94]. Low-titer neutralizing anti-drug antibodies were identified in two lanadelumab patients in the phase 3 double-blind trial and six (2.8%) patients in the extension study; the presence of the antibodies had no noticeable clinical impact [107,110].

5.1.3.4. Berotralstat

Berotralstat (ORLADEYO^TM; BioCryst Pharmaceuticals, Inc.; Durham, NC), approved by the FDA in December 2020, is a small molecule plasma kallikrein inhibitor and the first oral drug developed specifically for HAE prophylaxis. The recommended dose is one 150 mg capsule daily [95]. The safety and efficacy of berotralstat were established in the phase 3 Angioedema Prophylaxis-2 (APeX-2; NCT03485911) trial, a double-blind, parallel-group study in patients with HAE-C1-INH aged 12 years or older [111]. At the FDA-approved dose of 150 mg once daily, the rate of HAE attacks was reduced significantly relative to placebo (1.31 vs 2.35 attacks per month; P < 0.001) during a 24-week treatment period. Gastrointestinal adverse events including abdominal pain, vomiting, and diarrhea occurred primarily during the first month of treatment were more common among patients taking berotralstat 150 mg as compared to those taking placebo (50% vs 36%); the median duration of these events in the berotralstat group was 2 days, as compared to 1 day in the placebo group. Back pain was also reported more frequently in the berotralstat group.

5.1.3.5. Recombinant C1-INH (conestat alfa)

RUCONEST® (conestat alfa; recombinant C1-INH; Pharming Healthcare Inc.) is currently FDA-approved only as on-demand treatment in HAE [88]. However, some published clinical study data suggest efficacy with this product when used as short-term or long-term prophylaxis [97,112].

5.2. HAE management in special populations

5.2.1. Pregnant and lactating patients

Increased estrogen exposure during pregnancy (as well as menstruation and use of combination oral contraceptives), can increase the severity of HAE symptoms in some, but not all, women adding to the challenge of disease management [113,114]. HAE management guidelines recommend C1-INH products during pregnancy for prophylaxis and as on-demand treatment when necessary [1,61]. Available data gathered from women exposed to C1-INH during pregnancy suggest that C1-INH use appears to be generally safe for both mother and baby [113,115,116]. Androgens cross the placental barrier and can lead to virilization of a female fetus, thus are absolutely contraindicated during pregnancy [1,61,117]. Surprisingly, the labor and delivery process does not generally trigger HAE attacks [1].

Breastfeeding can trigger HAE attacks but is still encouraged because of the benefits to the baby [1]. C1-INH is the preferred therapy choice in breastfeeding women. It is unknown whether androgens are excreted in breast milk, but their use during breastfeeding is not advised [117].

5.2.2. Pediatric patients

Due to the rarity of HAE and the tendency of clinical trials to focus largely on adult patients, there is a relative lack of data overall in this age group. Yet, several HAE medications have been granted FDA approval for use in pediatric patients of any age (BERINERT®/C1-INH[IV]) or in age groups defined as either ‘adolescents’ or ‘12 years and older’ (RUCONEST®/recombinant C1-INH; CINRYZE®/C1-INH[IV], HAEGARDA®/C1-INH[SC]; TAKHZYRO^TM/lanadelumab-flyo; ORLADEYO^TM/berotralstat) (Table 3). Guidelines currently recommend C1-INH as first-line therapy in pediatric patients as both on-demand and prophylactic therapy [1,61]. Guidelines stress that androgens should not be used for prophylaxis in patients younger than 16 [61]. The smaller airway diameter in children may contribute to a particularly rapid progression to asphyxiation in laryngeal attacks, so rapid and effective intervention is critical [1,118].

5.3. Emerging and future therapies for HAE prophylaxis

In light of recent and ongoing advancements in medical therapies for HAE, more individualized management goals are being developed. Early recognition of HAE and early introduction of appropriate therapy, including prophylaxis, are management goals that aim to improve patients’ quality of life to the greatest extent possible.

Novel treatments and treatment approaches for HAE continue to be actively investigated. Molecules under clinical development at the time of manuscript writing are summarized in Table 4 and include a SC factor XIIa-inhibitory monoclonal antibody, a SC compound that reduces production of prekallikrein, an oral bradykinin B2 receptor antagonist, and an oral plasma kallikrein inhibitor.

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

6. Summary and conclusions

HAE is a lifelong, disabling, and potentially life-threatening condition. The root cause of HAE is related to an absence of functional C1-INH. HAE should be included in the differential diagnosis of patients presenting with angioedema given that misdiagnosis could lead to unnecessary interventions or even potentially life-threatening outcomes. Once HAE is identified, therapy (both acute treatment and prophylaxis) should be individualized considering unique patient factors such as attack history, proximity to a medical/infusion center, occupation/student status, impact of HAE on patients’ quality of life, and other patient circumstances and preferences/expectations [84].

Guidelines recommend that the need for long-term prophylaxis be evaluated at least annually in each patient with HAE [1,84]. Ideally, patients with HAE should follow-up with a clinician who has expertise/experience with the management of HAE [73,74].

Acknowledgments

Medical writing and editorial assistance were provided by Katie Singh, of Churchill Communications, Maplewood, New Jersey.

Disclosure statement

JJ has received funds for sponsored research from CSL Behring, Takeda, and BioCryst Pharmaceuticals, Inc. and consulting fees and speaker honoraria from CSL Behring and Takeda.

TN has no conflicting interests to disclose.

A reviewer on this manuscript has disclosed that they have received fees for consultation from Takeda. The other peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

Medical writing support funding was provided by CSL Behring.