Hereditary angioedema (HAE) is a serious, potentially fatal disease of recurrent swelling of various subcutaneous and submucosal tissues throughout the body. Swelling is mediated by uncontrolled regulation of bradykinin, making it pathologically distinct from other forms of angioedema. Diagnosis can be challenging, but distinctions in clinical presentation and laboratory studies can confirm clinical suspicion. Though the disease is rare, the socioeconomic burden of living with and treating HAE is significant for patients and healthcare systems. As a result, there has been a dramatic expansion of treatment options specifically designed for HAE in recent years. Novel treatments are effective in treating swelling attacks, preventing recurrence, and improving patient quality of life. However, significant differences in the risks, benefits, and cost of treatments must be weighed in the determination of clinical protocols to determine optimal utilization of healthcare resources.
Am J Manag Care. 2022;28(suppl 1):S3-S9. https://doi.org/10.37765/ajmc.2022.88822
Hereditary angioedema (HAE) is a rare disease characterized by recurrent, protracted swelling that is highly unpredictable and potentially life-threatening. Swelling of cutaneous and mucosal tissues may present in various locations, most commonly including the extremities, face, and gastrointestinal and respiratory tracts.1,2 HAE can be broadly divided into 2 types, contingent on the involvement of the C1 esterase inhibitor (C1-INH); the C1-INH deficient, HAE−C1-INH, and the C1-INH normal, HAE−nl-C1-INH.3,4 The more common type, HAE−C1-INH, has an estimated prevalence of 1 in 50,000 persons and will be the primary focus of this article.1,3
Misdiagnosis and delays in diagnosis of HAE are common due to the rarity of the disease in comparison with the potential differential diagnoses. Confirmation must be made via definitive laboratory testing, though results will differ between subtypes. Swelling from HAE will not respond to the treatments (antihistamines and corticosteroids) typically given for allergic angioedema, making a prompt and proper diagnosis even more critical.3,5
Treatments specific to the pathophysiology of HAE were essentially nonexistent before 2008, but there are now several available options. An increased cost of treatment accompanied this wave of new treatments, but substantial improvements in patient quality of life were gained.6
The purpose of this article is to review the pathophysiology, diagnosis, treatment, and socioeconomic burden of HAE to promote optimization of healthcare resource utilization and improve access to care.
Overview of HAE
Pathophysiology and Symptoms of HAE
HAE−C1-INH arises from mutations in the serpin peptidase inhibitor, clade G, member 1 (SERPING1) gene, which encodes C1-INH and affects the classical complement pathway and the contact activation and coagulation systems. These mutations are passed as an autosomal dominant trait, meaning children have a 50% chance of inheriting it from a parent with the disease.3,7,8 The resulting failures in C1-INH can be divided into 2 subtypes, HAE-I and HAE-II. HAE-I is defined by insufficient levels of C1-INH and make up about 85% of cases, whereas HAE-II is defined by the presence of dysfunctional C1-INH, making up the remainder of cases.3,7
In contrast, HAE−nl-C1-INH is considerably less frequent than HAE−C1-INH and thus less well-understood. Patients with this type of HAE have normal function of C1-INH, lacking mutation in SERPING1. Mutations in the F12 gene, which encodes coagulation factor XII, have been associated with this type of HAE but are not present in every case, indicating the involvement of other genetic mutations that are not yet identified.3,7,9 HAE subtypes are clinically indistinguishable at presentation, but disease course, prognosis, and treatment options vary.3,7
C1-INH is responsible for the regulation of enzymes that causes bradykinin production via plasma kallikrein enzyme activity. The deficiency or dysfunction of C1-INH present in HAE-I and HAE-II leads to excess bradykinin production and signaling. Bradykinin binds to bradykinin B2 receptors throughout the body, causing increased vascular permeability and leakage of fluid into subcutaneous (SC) and submucosal tissues.10,11
A study by Bork and colleagues evaluated the experiences of 221 patients with HAE-I and HAE-II in an attempt to characterize the course of the disease. They found that most patients experienced episodes involving SC edema of the face, extremities, trunk, or genitals and submucosal edema of the larynx and abdomen. Infrequent sites of involvement include the brain, bladder, muscle, joints, and other organs. The average age of onset was 11.2 years, with younger-onset being associated with more severe disease.2 Women with HAE have more frequent and often more severe episodes of edema than men, which has been linked to endogenous and exogenous estrogen levels.2,12,13
Diagnosis, Prognosis, and Burden of Disease
HAE types I and II diagnosis can be challenging as the disease is rare and may be mistaken for more common differential diagnoses of allergic angioedema or urticaria.3,14 Patients with HAE do not develop urticaria as part of the disease but may observe a rash similar to urticaria in the prodromal phase of an angioedema episode. This will progress into disseminated swelling rather than discrete urticarial hives.3,15 HAE should be suspected in patients experiencing recurrent abdominal pain or angioedema in the absence of urticaria. Obtaining a family history is also important due to the autosomal-dominant nature of this disease, though about 25% of patients present with de novo mutations.5,14
Diagnostic confirmation of HAE−C1-INH requires laboratory testing.3,5 Low levels of serum complement factor 4 (C4) are a highly sensitive indicator of HAE but should be considered in combination with C1-INH antigenic protein quantitative and functional levels.5,16 HAE-I will present with low levels of both quantitative and functional C1-INH, while HAE-II will only have low functional C1-INH. Conversely, biochemical testing will not aid in diagnosing HAE−nl-C1-INH, but genetic testing may be helpful. Some forms of HAE−nl-C1-INH are of unknown genetic etiology; thus, diagnosis may be made on clinical criteria alone.3
Acute angioedema attacks can be incredibly painful and are potentially fatal if not identified and treated appropriately. Proper diagnosis early in the disease course is critically important, as HAE does not respond to the same treatments as those differential diagnoses for which it is often mistaken.5 The average patient will experience an attack every 10 to 20 days without preventive treatment.14 Symptoms may last for several days, if untreated, and may be severe, resulting in complications such as hypovolemic shock or life-threatening airway obstruction.14
HAE is a considerable burden for patients, presenting numerous socioeconomic challenges. Diagnostic delay is a significant issue, with about one-half of patients experiencing a minimum 10-year delay in diagnosis from the time of their initial symptoms.17 During that time, patients may make numerous trips to physician offices and emergency departments and can lose faith in a system that cannot diagnose or treat them effectively. They are experiencing disruption in their everyday life, missing work, school, and time with their loved ones while managing these unpredictable and debilitating attacks.1
Banerji and colleagues conducted a survey of patients in the United States with HAE in 2017 to evaluate the burden of disease from the patient’s perspective. Of the 445 patients who completed the survey, 78.7% reported experiencing an attack within the past month, and 34.2% reported that their physical or emotional health prevented them from participating normally in social activities in the last week at the time of the survey. Even with 68.5% of patients reporting current or prior use of prophylactic medication, the frequency of attacks and rates of anxiety and depression remained high.18 Despite substantial growth of HAE treatment options in the past decade, the disease burden from HAE remains high, highlighting the need for optimizing access to appropriate care via the education of healthcare professionals.
Clinical Management With Novel Therapies
Prior to 2008, there were no medications approved by the US Food & Drug Administration (FDA) to treat acute HAE episodes. Attempts were made to utilize fresh frozen plasma, aminocaproic acid, and anabolic androgens, but the majority of management for acute attacks was symptomatic control of swelling. Symptomatic management included intravenous (IV) fluid replacement, antiemetics, analgesics, and even intubation when necessary.19 In recent years, several new medications have been developed and approved for the treatment of acute HAE attacks, as well as for long- and short-term prophylaxis.3
On-Demand Treatment for Acute Attacks
On-demand medications for acute HAE attacks must be readily available to minimize the morbidity and mortality associated with each episode. Appropriate diagnosis and understanding of the pathophysiology of HAE are critical to appropriate treatment, as bradykinin-mediated angioedema will not respond to the same antihistamines, glucocorticoids, and epinephrine used for the more common, histamine-mediated angioedema.3,5
Treatments for acute attacks were developed based on an understanding of the pathophysiology of HAE and were confirmed to be safe and effective for HAE−C1-INH in randomized controlled trials. The efficacy of these treatments in HAE−nl-C1-INH has only been confirmed via open-label reports. No direct comparative studies have been completed. Acute treatment pharmacotherapy is based on supplementing the missing protein (C1-INH), blocking production of a component of the kallikrein-kinin system, inhibiting the fibrinolytics system, or inhibiting the function of bradykinin. On-demand treatment options are outlined in Table 1.3 These treatments are fast-acting, which is necessary for treating acute attacks, but limit their usefulness as prophylactic agents. Treatment is most effective when administered as early as possible and may be initiated at home, during the prodromal phase, by patients who can reliably predict an acute attack.3,20,21 Retreatment with certain on-demand medication is usually only necessary if the attack worsens after treatment or there is no response to the first dose. Recombinant C1-INH and ecallantide are approved for a maximum of 2 doses in a 24-hour time period. Icatibant is approved for up to 3 doses in 24 hours, at an interval of at least 6 hours.3
Short- and Long-Term Prophylaxis
Prophylaxis of HAE attacks can be divided into short- or long-term schema based on the goal of treatment. Short-term prophylaxis (STP) is intended to decrease the risk of edema developing from a known stressor. Stressors could include invasive medical, dental, or surgical procedures as well as stressful life events. The risk of swelling after most procedures and events is not well-studied, so the decision to use STP must be individualized to each patient. Options for STP include a single 20 IU/kg dose of plasma-derived (pd) C1-INH given by IV 1 to 12 hours before the stressor or a course of anabolic androgens starting 5 to 7 days before and continued for 2 to 5 days after a procedure.3 Limited evidence also supports the use of recombinant human (rh) C1-INH dosed at 50 IU/kg for STP.3,22 Medication selection should be based on patient preference and ability to self-administer, as well as careful consideration of adverse effect (AE) profiles.2
The goal of long-term prophylaxis (LTP) is to decrease the frequency and severity of HAE attacks. There are currently 5 medications FDA approved for long-term prophylaxis of HAE, including 2 pd-C1-INHs (Cinryze and Haegarda), lanadelumab (Takhzyro), danazol (Danocrine), and berotralstat (Orladeyo).23-27
Clinical guidelines recommend first-line prophylaxis with either pd-C1-INH replacement therapies or the monoclonal plasma kallikrein inhibitor lanadelumab, whenever LTP is indicated for patients with HAE−C1-INH. Second-line options should include anabolic androgens or antifibrinolytics when first-line medications are not available, or patients are only willing to accept oral therapies despite the increased likelihood of AEs.3,28 Berotralstat is the first orally administered kallikrein inhibitor, which was approved by the FDA in December 2020.23 It is not yet included in recent clinical guidelines as an approved agent, but it is an effective option with a favorable AE profile that patients may prefer due to the oral route of administration.3,29Table 2 contains summary information for the FDA-approved treatments for the prophylaxis of HAE.23-27
C1-INH Concentrates for LTP
Plasma-derived C1-INH (Cinryze) was the first approved treatment for routine prophylaxis against angioedema attacks. It is used in patients aged 6 years and older with HAE, and initially dosed at 1000 units IV every 3 to 4 days in patients 12 years and older and at 500 units IV in children aged 6 to 11 years. Patients who do not respond to Cinryze at the initial dose may titrate up to 2500 units (maximum of 100 units/kg) in patients 12 years and older or up to 1000 units in children aged 6 to 11 years.3,24,30 In the prophylactic setting, a phase 2 randomized controlled trial found a significant reduction in the frequency of attacks over 12 weeks with Cinryze (6.3 attacks) versus placebo (12.7 attacks, P <.001).31 Safety and efficacy were further studied in an open-label extension trial conducted over 2.6 years. Treatment with Cinryze yielded a 93.7% reduction in attacks compared with historical rates.32 During the first 3 years of marketing, serious thrombotic events were reported with Cinryze and were linked to indwelling catheters and other underlying risk factors for thrombosis.24
Plasma-derived C1-INH (Haegarda) is approved for routine prophylaxis to prevent HAE attacks in patients 6 years and older, dosed at 60 IU/kg SC twice weekly.25 Haegarda was assessed in a randomized, placebo-controlled phase 3 trial evaluating its efficacy administered SC at either 40 IU/kg or 60 IU/kg twice per week versus placebo. Patients in both groups experienced a statistically significant reduction in attack rate of 95% in the 60 UI/kg cohort and 89% in the 40 UI/kg cohort compared with placebo (P <.001).33 Common AEs included injection site reactions, hypersensitivity, nasopharyngitis, upper respiratory tract infection, and dizziness.25,33 The long-term efficacy and safety of Haegarda were assessed in a parallel-arm, extension trial of both doses for a mean of 2.5 years. The median annualized attack rates were 1.3 and 1.0 in the 40 UI/kg and 60 UI/kg cohorts, respectively, with a similar incidence of AEs in both groups.34
Kallikrein Inhibitors for LTP
Lanadelumab is a monoclonal antibody plasma kallikrein inhibitor indicated for prophylaxis against HAE attacks in patients 12 years and older. It is administered SC at 300 mg every 2 weeks or every 4 weeks in select patients.27 In a phase 3, randomized, placebo-controlled trial, patients received lanadelumab dosed at 150 mg every 4 weeks, 300 mg every 4 weeks, or 300 mg every 2 weeks. Compared with placebo, the average rate of monthly HAE attacks was reduced by 87% in patients receiving twice-monthly dosing and 73% in those receiving monthly dosing.35,36 An open-label extension trial was conducted that evaluated efficacy of lanadelumab for up to 2.5 years. Results confirmed a significant and sustained reduction in attack rates with 70% of subjects having an attack-free period greater than 12 months as well as improvement in quality-of-life scores.37 Commonly reported AEs include injection site reactions, upper respiratory tract infections, headache, rash, myalgia, dizziness, and diarrhea. In addition, serious hypersensitivity reactions have occurred during treatment with lanadelumab.27
Berotralstat is a small-molecule plasma kallikrein inhibitor approved for prophylaxis against HAE attacks in patients 12 years and older. It is administered orally, as a single 150-mg capsule taken once daily with food.23 The oral administration option provides an enticing alternative for patients unwilling to receive IV or SC medications while still avoiding the use of second-line androgen therapies.3,28 Berotralstat was studied in a phase 2 double-blind, parallel-group trial that randomized patients to receive berotralstat dosed at either 110 mg or 150 mg once daily or placebo. Patients receiving berotralstat experienced a significant reduction in monthly HAE attack rates of 1.65 attacks per month at 110 mg (P <.02) and 1.31 attacks per month (P <.001) at 150 mg, compared with 2.35 attacks per month with placebo. Reductions in attack rates were seen in the first month of treatment and were sustained through the 24-week trial.29 The open-label extension trial demonstrated the durability of this response through 48 weeks, with further reduction in the frequency of attack, reaching an average of 0.8 attacks per month for both doses by 1 year.38 The most common AEs reported were abdominal pain, vomiting, diarrhea, back pain, and gastroesophageal reflux disease.23 Recent data indicate that patients have been successfully transitioned from injectable prophylaxis to berotralstat while reporting increased satisfaction.39-41
The novel coronavirus disease 2019 (COVID-19) was hypothesized by researchers to increase disease activity of HAE based on shared pathophysiology. COVID-19 is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which enters host cells via angiotensin-converting enzyme 2 (ACE2). This depletes the ACE2 enzyme, which is necessary for bradykinin metabolism. Accumulation of bradykinin leads to lung injury and inflammation associated with COVID-19 and is the same mechanism that drives swelling in HAE. This pathophysiologic link suggests that progression and outcomes for both HAE and COVID-19 may be worse as each disease potentiates the symptoms of the other.42
It has been suggested that patients with HAE who are at risk of SARS-CoV-2 infection utilize LTP with C1-INH or lanadelumab and avoid using anabolic androgens given the worsened COVID-19 outcomes seen in men compared with women.42 Researchers attempted to answer the question—does HAE make COVID-19 worse?—through observation of patients with known HAE, subsequently diagnosed with COVID-19. Sample sizes were very small, but the data suggested that the symptoms of COVID-19 were not more severe in patients with HAE, and the frequency and severity of HAE attacks were not worsened.43-45 Additionally, a study enrolled 93 patients with HAE−C1-INH types I and II to assess the HAE attack rate following vaccination against COVID-19, though only 63 patients received a vaccine by the time the study was published. Eleven angioedema attacks were reported following the administration of 111 vaccinations, with most patients receiving a 2-dose series. Nine of these attacks occurred following the first vaccine and were of mild or moderate severity, requiring treatment with on-demand medication. Ninety percent of the study population did not experience an attack after vaccination. Larger studies are needed to allow for subgroup analyses of various patient characteristics and vaccine types, but these findings provide reassurance that COVID-19 vaccination is safe to administer in patients with HAE.46
The Cost of Treatment
Before the introduction of disease-specific treatments in 2008, the average annual cost per patient to manage HAE was $44,597. This ranged from $11,587 for patients with mild disease to $104,857 for patients with severe disease. For the average patient, 65% of this expense was due to direct medical costs, including hospital admissions, emergency department visits, outpatient care, and medications. The remainder resulted from indirect costs, including reduced productivity, reduced income, missed work, travel, and childcare.6,47
The FDA has approved several novel on-demand and prophylactic treatments for HAE in recent years, several of which were granted orphan drug status. These new treatments came with a large price tag, with the average wholesale price for on-demand treatments ranging from $5000 to more than $12,000 per attack in 2018.6 Bernstein and colleagues conducted a cost-effectiveness modeling study of the approved on-demand treatments ecallantide, icatibant, pd-C1-INH, and rh-C1-INH, using effectiveness and overall cost to estimate cost per quality-adjusted life-year (QALY) as well as developing a budget impact model for health plans. The study, published in 2020, found that the cost of treating acute attacks ranged from $347,145 to $566,729 per patient per year, assuming an average of 26.9 attacks per year. Extrapolating from this, the overall annual cost to the health plan could range from $6.94 million to $11.3 million, depending on which on-demand treatment is used.48
The cost-effectiveness model by Bernstein and colleagues assumed an average attack rate of 26.9 attacks per year for patients.48 It is reasonable to assume that decreasing the number of attacks per year through the use of prophylactic treatments could decrease the average attack rate, thus lowering the cost to treat HAE. The Institute for Clinical and Economic Review (ICER) published a report in 2018 evaluating the effectiveness and value of using prophylactic agents for HAE, including the C1 esterase inhibitors and lanadelumab. The study found that all of these medications were exceptionally expensive, with the cost per QALY significantly higher than the $150,000 willingness-to-pay threshold commonly accepted by healthcare systems.49 Furthermore, in 2021, ICER announced that this initial study had overestimated the frequency of baseline attack rates compared with real-world data, and each of these treatments would need a 53% to 75% discount in listing price to reach common thresholds of cost-effectiveness.50
The cost of treating HAE has risen since introducing these disease-specific therapies, highlighting the need for payers to negotiate better pricing of novel therapies.6,49 However, economic considerations should not outweigh clinical considerations in coverage criteria. Managed care companies should include approved products recommended as first-line treatments by evidence-based clinical guidelines in reimbursement schemas.3,48
Importance of Individualized Treatment Plans and Formulary Development
Clinical treatment guidelines acknowledge that patients may present with a wide range of disease severity, variability in symptoms, personal preferences, and life circumstances. There is no one-size-fits-all treatment algorithm that can be applied to treat HAE. Instead, individualized treatment plans must be developed based on patient needs and accessibility of care via shared decision making.3,51
The goals of treatment are to reduce morbidity, prevent mortality, and improve quality of life (QOL). Castaldo and colleagues assessed the QOL impact of using novel SC prophylactic therapies compared with on-demand treatment alone, finding an improvement of median impairment scores of 59.5% (P <.01). Patients using the SC prophylactic therapies also saw a 77% decrease in annual attack rate compared with patients utilizing on-demand treatment alone.52
Patients and physicians must work together to determine the appropriateness of including a prophylactic therapy in the individualized treatment plans, as administration routes and the need for healthcare services may limit the attractiveness of utilizing certain agents. The newly approved oral kallikrein inhibitor berotralstat is an attractive option for patients with limited access to healthcare facilities, intolerance to injectable therapies, or inability to self-administer via SC or IV routes. AE profiles also vary between agents and must be considered in the treatment selection process.
Individualized treatment plans should also consider when and how a patient will access on-demand therapy in the event of an attack. Patients who can identify the onset of an attack and self-administer or quickly access healthcare services will benefit the most, as on-demand treatments are more effective in preventing symptoms when given early on during the episode.3,20 Self-administration of on-demand therapies has been shown to decrease time to treatment, promote earlier resolution of symptoms, reduce emergency department and hospital visits, improve QOL, and reduce the overall cost of the attack.6
Patients must be able to access prophylactic and on-demand treatments for HAE to meet therapy goals, reducing morbidities and preventing mortality.3 Numerous patient- and treatment-specific factors influence the treatment selection process, which should be accounted for by payers developing coverage criteria.49 Patients requiring additional financial support may be eligible for patient assistance programs sponsored by pharmaceutical companies.
Hereditary angioedema is a rare disease of bradykinin dysregulation, characterized by sudden, painful swelling of various tissues throughout the body. The frequency and unpredictability of HAE attacks, coupled with diagnostic challenges, make it incredibly burdensome for patients, severely impacting their quality of life. Numerous novel therapies have been developed in recent years to treat attacks on-demand and prevent future attacks. The risks and benefits of each therapy should be weighed in a shared decision-making process between patients and providers to develop the optimal plan of care for each individual. The financial burden of these treatments can be significant for patients and healthcare systems, so evidence-based clinical protocols should be used to optimize healthcare resource utilization.
Author affiliation: Mark Malesker, PharmD, FCCP, FCCM, FASHP, BCPS, is Professor of Pharmacy Practice and Medicine, Creighton University, Omaha, NE.
Funding source: This activity is supported by an educational grant from BioCryst.
Author disclosure: Dr Malesker has no relevant financial relationships with commercial interests to disclose.
Author information: Substantial contributions to concept and design, drafting of the manuscript, and critical revision of the manuscript for important intellectual content.
Address correspondence to: firstname.lastname@example.org
Medical writing and editorial support provided by: Brittany Hoffmann-Eubanks, PharmD, MBA