Hereditary angiodema: a current state-of-the-art review, IV: short- and long-term treatment of hereditary angioedema: out with the old and in with the new?

doi:10.1016/S1081-1206(10)60581-9

Annals of Allergy, Asthma & Immunology

Volume 100, Issue 1, Supplement 2, January 2008, Pages S13-S18

https://doi.org/10.1016/S1081-1206(10)60581-9 Get rights and content

Objective

To provide a context to understand the opportunity for novel therapeutic modalities to transform the treatment of hereditary angioedema (HAE).

Data Sources

MEDLINE and PubMed were searched to identify studies involving current treatment of HAE in the United States.

Study Selection

Studies were selected based on their relevance to the treatment of HAE.

Results

The current HAE treatment strategy is far from satisfactory, and its limitations create an unmet clinical need. Current prophylactic treatment exposes patients with HAE to significant risk of adverse effects, and the efficacy of prophylactic treatment, although generally good, is far from perfect.

Conclusions

No specific treatment is currently available in the United States for acute HAE attacks that will reliably work, resulting in a significant unmet clinical need. The emergence of several promising drugs for the treatment of HAE attacks is, thus, an extraordinarily important development in the management of these patients.

Section snippets

INTRODUCTION

Hereditary angioedema (HAE) is an autosomal dominant disease characterized by recurrent episodes of angioedema. The prevalence of HAE is not known, but it has been estimated to range from 1:10,000 to 1:150,000 in the general population,¹ suggesting that there are 2,000 to 30,000 affected patients in the United States. The pathophysiologic basis of HAE as a deficiency of complement 1 (C1) inhibitor was discovered independently by Landerman et al² and Donaldson and Evans.³ The fundamental

CLINICAL HISTORY OF HAE

Attacks of angioedema in HAE are distinct from other forms of angioedema and can often be suspected based on history. A positive family history of angioedema is present in most patients, although a few have negative family histories with de novo C1 inhibitor mutations.⁷ Patients with HAE typically begin to swell in childhood and often experience increased symptoms beginning about the time of puberty.⁸ Patients with HAE then typically continue to experience recurrent attacks of angioedema

LABORATORY DIAGNOSIS OF HAE

A definitive diagnosis of HAE requires a laboratory diagnosis establishing C1 inhibitor deficiency. Two distinct HAE subtypes are distinguished based on plasma levels of C1 inhibitor. Type 1 HAE (approximately 80%-85% of patients with HAE) is characterized by low antigenic and functional C1 inhibitor levels¹³; type 2 HAE (the other 15% of patients with HAE) is characterized by normal or elevated C1 inhibitor concentrations with low C1 inhibitor functional activity due to the secretion of a

CURRENT TREATMENT OF HAE

Because of the significant morbidity and mortality associated with HAE, a strategy involving careful treatment of acute attacks and prevention of HAE attacks is essential for proper management of these patients. This article briefly reviews the current treatment protocols available in the United States. The treatment of HAE is typically divided into 3 areas: long-term prophylaxis, short-term prophylaxis, and treatment of acute episodes of angioedema.

In addition to the pharmacologic treatment of

CURRENT UNMET NEEDS AND FUTURE TREATMENT OF HAE

The current HAE treatment strategy summarized herein is far from satisfactory, and its limitations create an unmet clinical need. Current prophylactic treatment exposes patients with HAE to significant risk of adverse effects, and the efficacy of prophylactic treatment, although generally good, is far from perfect. Treatment of pregnant women and children presents particular difficulties. Androgens may interfere with normal sexual maturation, and their effects on the fetus are unknown.

SUMMARY

The diagnosis of HAE should be considered in any patient with recurrent angioedema without urticaria. Confirmation of the diagnosis requires laboratory testing, with demonstration of low C1 inhibitor levels or functionality and low C4 levels. Treatment of patients with HAE should be individualized based on attack frequency and severity and on access to medical care. Most patients can be managed without long-term prophylaxis or by using low-dose anabolic androgens for long-term prophylaxis. Many

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Cited by (68)

Hereditary Angioedema With Normal C1 Inhibitor: US Survey of Prevalence and Provider Practice Patterns
2023, Journal of Allergy and Clinical Immunology: In Practice
Hereditary angioedema (HAE) with normal C1-INH (HAE-nl-C1INH) is phenotypically similar to HAE resulting from C1-INH deficiency (HAE-C1INH). Confirmatory diagnostic tests for HAE-nl-C1INH are limited and few clinical study data exist regarding management of the condition. Therefore, survey studies may provide initial estimates of prevalence, diagnosis, and management patterns of this condition.
To estimate the prevalence and describe current management patterns for HAE-nl-C1INH in the United States (US).
We conducted an Internet-based survey of US physicians to estimate the prevalence of the HAE-nl-C1INH population in the United States. Potential participating physicians were identified from the US Hereditary Angioedema Association database and IQVIA Xponent prescription database. Eligible physicians were invited to complete an online survey between June and September 2021.
A total of 113 physicians provided data for the estimation of HAE-nl-C1INH prevalence and 81 physicians treating HAE-nl-C1INH patients provided data about treatment patterns. In bias-corrected analysis, we estimated 1,230 to 1,331 HAE-nl-C1INH patients within the United States between May 2019 and April 2020. Mean time to diagnosis for HAE-nl-C1INH was approximately 6 years (range, 2.4-13.5 years). Response to medication was commonly used to inform diagnosis (antihistamine response or nonresponse used by 73% of physician respondents, corticosteroids by 57%, or HAE-specific medications by 74%), and Factor XII genetic testing was used by 43%.
These survey data provide estimates of HAE-nl-C1INH prevalence in the United States as well as current diagnosis and management strategies. Results may be useful for developing studies to assess treatment efficacy and safety, and potentially improve the diagnosis for and management of this patient population.
Efficacy, pharmacokinetics, and safety of subcutaneous C1-esterase inhibitor as prophylaxis in Japanese patients with hereditary angioedema: Results of a Phase 3 study
2023, Allergology International
Hereditary angioedema (HAE) is a rare and potentially life-threatening genetic disorder characterized by recurrent attacks of angioedema. HAE types I and II result from deficient or dysfunctional C1-esterase inhibitor (C1–INH). This Phase 3 study assessed the efficacy, pharmacokinetics (PK), and safety of subcutaneous (SC) C1–INH in Japanese patients with HAE.
The prospective, open-label, multicenter, single-arm Phase 3 study recruited patients with HAE types I or II to an initial run-in period, followed by a 16-week treatment period where patients received 60 IU/kg C1–INH (SC) twice weekly. The two primary endpoints were the time-normalized number of HAE attacks per month and C1–INH functional activity at Week 16.
Nine patients entered the treatment period and completed the study. Treatment with C1–INH (SC) significantly reduced the mean monthly attack rate from 3.7 during the run-in period to 0.3 during treatment (exploratory p value of within-patient comparison = 0.004). After the last dose of C1–INH (SC) at Week 16, the mean trough concentration of C1–INH was 59.8%, and the mean area under the plasma concentration–time curve to the end of the dosing period and to the last sample were 5317.1 and 13,091.5 h•%, respectively. During the study, there were no deaths, serious adverse events, or adverse events leading to study discontinuation.
C1–INH (SC) (60 IU/kg twice weekly) was efficacious and well tolerated as a prophylaxis against HAE attacks in Japanese patients with HAE types I or II, which was supported by the increased and maintained C1–INH functional activity.
EudraCT Number 2019-003921-99; JapicCTI-205273
Thyroid hormones and complement parameters in hereditary angioedema with C1-inhibitor deficiency
2016, Annals of Allergy, Asthma and Immunology
Thyroid hormones control and up-regulate the synthesis of many plasma proteins.
To explore possible associations between thyroid hormone and complement levels in patients with hereditary angioedema resulting from the deficiency of the C1-inhibitor (C1-INH-HAE).
In this case-control study, serum thyrotropin, free triiodothyronine (FT₃), and free thyroxine (FT₄) levels, anti–thyroid peroxidase and antithyroglobulin antibody titers, and C1-INH concentrations were measured in 117 euthyroid patients with C1-INH-HAE and compared with their clinical properties. The control group comprised 150 healthy, age- and sex-matched, euthyroid individuals.
The thyrotropin and antithyroglobulin levels were similar between the patients and the controls. Significantly lower FT₃ (P < .001) and FT₄ (P = .002) levels, as well as higher anti–thyroid peroxidase titers (P < .001), were seen in the patients with C1-INH-HAE. The proportion of patients with reduced C1-INH activity was greater among those with below-median FT₄ levels than among those with above-median values (P = .02). Patients who experienced more edematous attacks per year had lower FT₄ levels (within the normal range) than those afflicted by fewer episodes (P = .01). The FT₃ and FT₄ levels were significantly higher in patients undergoing long-term danazol therapy than in those who did not receive this drug (P = .01 and P = .02, respectively). The proportion of patients with FT₄ levels in the below-median range was higher in the subset with increased d-dimer concentration (P = .009).
Minor variations of the thyroid hormone levels (within the reference range) can influence the function of C1-INH in C1-INH-HAE. Our findings suggest a role for the endocrine system in the pathophysiology of C1-INH-HAE.
The autoimmune side of hereditary angioedema: Insights on the pathogenesis
2015, Autoimmunity Reviews
Hereditary angioedema (HAE) is an autosomal dominant disease resulting from the deficiency of C1 inhibitor (C1-INH), a glycosylated serine protease inhibitor that plays a regulatory role in the complement system (CS), the contact system and the intrinsic coagulation cascade. HAE disease severity is highly variable and may be influenced by genetic polymorphisms as well as by other factors, such as gender hormone-mediated effects. In HAE, the potential inadequate clearance of immune-complexes (IC) in the presence of reduced levels of CS components and in turn an excess of IC in the tissues results in inflammatory damage and release of autoantigens that may trigger an autoimmune response. Occasional reports link HAE with autoimmune conditions and only few studies have been conducted on large patient populations with controversial results. Although several immunoregulatory disorders have been documented, the prevalence of defined autoimmune diseases in patients with HAE remains debated. The occurrence of autoimmune conditions in HAE patients may worsen the disease severity enhancing the complexity of the comprehensive care.
Does angiotensin-converting enzyme inhibitor use exacerbate hereditary angioedema?
2013, Journal of Emergency Medicine
Citation Excerpt :
Laboratory markers used for diagnostic purposes are C4 level, C1 INH antigenic protein level, functional C1 INH level, and C1q antigenic protein and IC level (2). C4 level measurement is the best initial and most cost-effective method to screen for HAE (24,34). C4 level should be repeated for confirmation during acute AE attack.
Approximately 2% of angioedema (AE) patients have a hereditary or an acquired deficiency of the complement 1 (C1) esterase inhibitor (C1 INH) gene. Some case reports indicate an association between angiotensin-converting enzyme inhibitor (ACEI) use and exacerbation of hereditary AE (HAE).
The aim of this retrospective study is to investigate the association between HAE and ACEI use in a larger patient population.
A retrospective chart review of patients who presented with AE and patients with diagnostic serum assays for functional C1 INH, C1 INH antigenic protein, C1q, C1q immune complex (C1q IC), and complement 4 (C4) regardless of medical complaint. Descriptive statistics were used to analyze the data.
A total of 1594 patients had complement levels measured (136 C1 INH, 55 C1q, 10 C1q IC, and 1500 C4), of which 156 (9.7%) patients presented with AE. Angiotensin-converting enzyme inhibitor use was documented in 747 (47%) patients. Low C1 INH was detected in one patient with recurrent AE who was not taking ACEI. Another patient who presented with recurrent AE was found to have systemic lupus erythematosus with abnormal C4, C1q, and C1q IC, but normal C1 INH. A low C4 level was present in 94 patients, 4 of which had AE.
The risk of exacerbating HAE by ACEI might be present, but we did not find any association in this retrospective study. Further studies are needed to determine the existence of this association.
WAO guideline for the management of hereditary angioedema
2012, World Allergy Organization Journal
Citation Excerpt :
The patient should be aware of the risk and have a management plan and on-demand treatment for attacks. Where available, 2 doses of C1-INH concentrate, ecallantide, or icatibant, should be immediately accessible [11, 95–99]. The administration of short-term prophylaxis should be considered before surgeries, especially dental/intraoral surgery, where endotracheal intubation is required, where upper airway or pharynx is manipulated, and before bronchoscopy or endoscopy.
Hereditary Angioedema (HAE) is a rare disease and for this reason proper diagnosis and appropriate therapy are often unknown or not available for physicians and other health care providers. For this reason we convened a group of specialists that focus upon HAE from around the world to develop not only a consensus on diagnosis and management of HAE, but to also provide evidence based grades, strength of evidence and classification for the consensus. Since both consensus and evidence grading were adhered to the document meets criteria as a guideline. The outcome of the guideline is to improve diagnosis and management of patients with HAE throughout the world and to help initiate uniform care and availability of therapies to all with the diagnosis no matter where the residence of the individual with HAE exists.

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: Disclosure: The author is an investigator for LEV, Pharming, and Dyax studies and a consultant to LEV, Pharming, Dyax, Jerini, and Behring.

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ArticlesHereditary angiodema: a current state-of-the-art review, IV: short- and long-term treatment of hereditary angioedema: out with the old and in with the new?

Objective

Data Sources

Study Selection

Results

Conclusions

Section snippets

INTRODUCTION

CLINICAL HISTORY OF HAE

LABORATORY DIAGNOSIS OF HAE

CURRENT TREATMENT OF HAE

CURRENT UNMET NEEDS AND FUTURE TREATMENT OF HAE

SUMMARY

J Allergy

Am J Med

J Allergy Clin Immunol

Immunol Allergy Clin North Am

J Allergy Clin Immunol

Am J Med

J Am Dent Assoc

Mayo Clin Proc

Immunol Allergy Clin North Am

Immunol Allergy Clin North Am

J Allergy Clin Immunol

J Allergy Clin Immunol

Lancet

Immunol Allergy Clin North Am

Biochem Biophys Res Commun

Am J Hum Genet

Immunol Allergy Clin North Am

Am J Med

Immunol Allergy Clin North Am

Ann Allergy Asthma Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

Articles
Hereditary angiodema: a current state-of-the-art review, IV: short- and long-term treatment of hereditary angioedema: out with the old and in with the new?