How to control recurrent angioedema using monoclonal antibody therapies?

KEYWORDS:

• Recurrent angioedema
• bradykinin
• mast cell
• disease control

1. Recurrent angioedema – a group of challenging conditions

Angioedema is defined as transient and localized swelling resulting from vascular reactions of deep dermal/subcutaneous or mucosal/submucosal tissues leading to locally increased permeability of blood vessels. Angioedema greatly affects patients’ quality of life and can lead to death by suffocation. Recurrent angioedema (RA) is commonly classified as mast cell-mediated or bradykinin-mediated, and their treatment is very different (see Table 1) [1]. As the clinical picture at the time of first presentation rarely allows physicians to distinguish these two types, a comprehensive and thorough history, clinical examination and some bloodwork are essential to achieve the correct diagnosis and to take the appropriate therapeutic measures [2].

Table 1. Classification of angioedema.

Bradykinin-induced AE				Mast Cell Mediator-induced AE
C1-INH deficiency/defect		C1-INH normal		Allergic	Non Allergic
Inherited	Acquired	Inherited	Acquired	Acquired	Acquired
HAE-1 HAE-2	AAE-C1-INH	HAE nC1-INH (HAE-FXII, HAE-ANGPT1, HAE-PLG, HAE-KNG1, HAE-UNK)	ACEI-AE	Anaphylaxis, Type I Allergy	Chronic urticaria

HAE-1: Hereditary angioedema due to C1-Inhibitor deficiency

HAE-2: Hereditary angioedema due to C1-Inhibitor dysfunction

AAE-C1-INH: acquired angioedema due to C1-Inhibitor deficiency

HAE nC1-INH: Hereditary angioedema with normal C1-Inhibitor levels, either due to a mutation in FXII, ANGPTI, PLG, KLK or unknown (HAE-FXII, HAE-ANGPT1, HAE-PLG, HAE-KNG1, HAE-UNK)

ACEI-AE: angiotensin converting enzyme inhibitor-induced angioedema.

By far, most cases of RA are mast cell-mediated and caused by chronic spontaneous urticaria (CSU). CSU, i.e. the occurrence of itchy hives, angioedema, or both for at least 6 weeks, has a prevalence of 0.5% to 3.4% [3,4]. Currently, autoimmunity (IgG-autoantibodies) and autoallergy (IgE-autoantibodies) are thought to contribute to the pathogenesis of this disorder [5–7].

Approximately 60% of CSU patients have RA, and in most of these patients, hives also occur. About 10-15% of CSU patients report only RA and do not develop hives [8]. In some publications, this type of CSU is referred to as ‘idiopathic histaminergic acquired angioedema’ (and ‘idiopathic non-histaminergic acquired angioedema’ if antihistamine treatment fails) [9]. The quality of life in patients with CSU is remarkably impacted, especially the aspects of physical symptoms/discomfort, emotional well-being, interference with daily activities, sleep, and work performance. The impairment of quality of life is more pronounced in CSU patients with RA [10]. In patients with RA due to CSU, the family history is usually negative, and swellings are often located in the face, the hands and feet, as well as the genitalia. Angioedema of the upper throat may cause breathing difficulties, however, suffocation does not occur. Some CSU patients with RA have mild or moderate recurrent abdominal discomfort [11], but abdominal swelling attacks do not occur.

The most common reason for the occurrence of bradykinin-induced RA is the intake of drugs that inhibit the degradation of bradykinin. These include angiotensin converting enzyme (ACE) inhibitors, angiotensin 1-blockers, and, rarely, the renin-inhibitor aliskiren or gliptins. As the occurrence of angioedema attacks is usually restricted to the time of treatment with these drugs, the swellings cease to occur after diagnosis and drug discontinuation, and no further treatment is needed [1,12].

In contrast, hereditary angioedema due to C1-inhibitor deficiency (HAE-C1INH), another bradykinin-mediated form of RA, is a lifelong genetic disease (autosomal dominant, mutation in SERPING Gene) with a prevalence of approximately 1:67,000 [13]. The deficiency of C1-INH results in impaired inhibition of kallikrein, the central player in the generation of bradykinin. Virtually all HAE patients in the western world experience recurrent swellings of the skin, and almost all have recurrent colicky abdominal attacks, which resemble acute abdomen and last up to 4 or 5 days. Laryngeal attacks occur in up to 50% of HAE patients, and they can and do cause death due to suffocation. HAE results in considerable impairment of quality of life (functioning, fatigue/mood, fears/shame and food), and HAE markedly impacts education, career, and work productivity [14–16].

2. What does disease control mean for patients with recurrent angioedema, and how is it measured?

The treatment of RA, in the majority of patients, is symptomatic and aimed at the prevention of swellings. Providing patients with medication that helps them to do this, i.e. to control their disease, is a major goal of RA management. For patients, having control over their disease by preventing attacks is very different than using on demand medication (which can help to control an attack, but not the disease).

Current guidelines recommend the use of patient-reported outcome measures (PROMS) to assess and monitor disease control together with disease activity and impact in patients with RA due to CSU. The current guideline for HAE also recommends to assess patients with the use of PROMS [17]. Tools for measuring disease activity and impact in RA patients such as the Angioedema Activity Score (AAS) and the Angioedema Quality of Life Questionnaire (AE-QoL) are well established in clinical practice and commonly used in clinical trials [15,16,18,19]. Recently, the urticaria control test (UCT) and the Angioedema Control Test (AECT) have been developed [20–22]. The UCT allows to assess disease control in all patients with CSU including those with RA with or without wheals. The AECT is suitable for the use in patients with any type of RA. The UCT and the AECT are short, easy to administer, and fast to complete, as well as easy to evaluate and interpret. These tools help to quantify disease control and aid treatment decisions.

In mast cell-mediated RA, the benefit of any treatment and the response to treatment is evaluated based on the reduction in disease activity and the level of control that patients achieve with it. A beneficial treatment response is one that reduces disease activity to levels of mild disease or less (i.e. UAS7 values or 6 or less) and that increases levels of disease control to well controlled or better (i.e. UCT values of ≥12). To move patients from having poorly controlled RA to well controlled RA is an important first step toward the ultimate goal of complete control, i.e. no more signs and symptoms of RA. In bradykinin-mediated RA, disease control is also what patients want, but on demand treatment rather than prophylaxis is still a quite common management approach.

3. How to control mast cell-mediated recurrent angioedema and the role of monoclonal antibody therapy

Complete control is the guideline-recommended goal of treatment of patients with RA due to CSU. Prophylaxis is the only recommended type of treatment [17]. A step-wise approach is used to achieve this. The first and second line treatment is a standard-dosed and updosed (up to four fold) second generation antihistamine, respectively. Less than 50% of patients with RA due to CSU achieve complete disease control and freedom of attacks with this [23]. Those who do not are recommended to treat with omalizumab, which benefits up 80% of them (see Table 2) [24].

Table 2. Estimated rates of patients with recurrent angioedema who experience complete disease control using monoclonal antibody therapies.

	Drug	Patients with complete control
Bradykinin-mediated RA	Lanadelumab	80%
Mast cell-mediated RA (step-wise treatment algorithm)	nsAH (once daily)	25%
	nsAH (up to 4x daily)	+20% (∑ 45%)
	Omalizumab	+30% (∑ 75%)

nsAH = non-sedating antihistamine

∑ = Total proportion of patients with complete control, including responders to previous treatments of the algorithm.

Omalizumab is a humanized anti-IgE monoclonal antibody licensed for the treatment of patients with CSU or asthma. Omalizumab treatment effectively controls RA in CSU patients with hives. In the phase III trials, treatment with 300 mg/4 weeks of omalizumab markedly reduced the number of angioedema-burdened days/week as compared to placebo [25]. In a recent randomized controlled study, omalizumab treatment resulted in a threefold improvement in angioedema-burdened days/week as compared to placebo, and omalizumab significantly decreased RA activity as assessed by the AAS and the frequency and size of swellings. The median time to the first recurrence of angioedema was 57–63 days with omalizumab and <5 days with placebo. Omalizumab also significantly improved angioedema-specific QoL [26].

Omalizumab also improves RA in CSU patients without hives, although randomized controlled trials are missing, i.e. the evidence is limited to case reports and series. In these uncontrolled studies, RA ceased to occur after the start of omalizumab treatment, and corticosteroids were stopped in patients who had received them, in all patients reported as of yet [27,28]. In one of these studies, for example, all of eight omalizumab-treated patients with RA due to CSU without hives had no more attacks (AAS decreased to zero) within two days to two weeks after the start of treatment [29].

Other monoclonal antibodies are currently developed for the treatment of patients with CSU including those with RA [30]. These include dupilumab (target: IL-4R), AK002 (target: Siglec-8), and ligelizumab (target: IgE), of which the latter seems to be very promising. In a recent phase 2b study with 382 patients with antihistamine-resistant chronic spontaneous urticaria, ligelizumab showed a substantial superiority as well to placebo as to omalizumab [30–32]. Interestingly, monoclonal antibodies directed against IL-5(R) (mepolizumab, reslizumab, benralizumab) were also reported to be effective in urticaria [33–35], and first exploratory studies with mepolizumab and benralizumab are on the way.

4. How to control bradykinin-mediated recurrent angioedema and the role of monoclonal antibody therapy

For HAE-C1INH, the current guideline recommends the use of icatibant (a bradykinin 2 receptor antagonist) or ecallantide (a kallikrein inhibitor) as on demand medication and of C1 inhibitor as prophylactic and on demand treatment [36].

Recently, the monoclonal anti-kallikrein antibody lanadelumab was approved for the treatment of HAE. Lanadelumab effectively controls RA in patients with HAE [37]. In a 26-week randomized placebo-controlled trial, lanadelumab reduced the number of attacks by up to 87% [37]. At 300mg every 2 weeks, almost 80% of patients treated with lanadelumab were completely symptom free once pharmacological steady state was achieved (see Table 1). The high efficacy, the favorable safety profile and the low burden of treatment significantly improved quality of life. Kallikrein is also the target of several oral inhibitors that are under development for the prophylactic and on demand treatment of patients with HAE, including BCX7353 [38].

Additional monoclonal antibodies are currently being developed for the treatment of patients with HAE, including one that is directed against FXIIa, a crucial activator of kallikrein [39].

5. Expert opinion

Today, we understand that what patients want from us as their treating physicians is to help them control their disease and to stop their lives from being controlled by their disease. We have the tools to assess and achieve disease control in most patients with RA, once the correct diagnosis has been made. As of now, these tools are still not widely available and/or used. Control tests should be routinely used in the management of patients with RA, treatment decision should be based on their outcome, and treatment responses should be assessed by their use. Prophylactic approaches should be considered in all patients with all types of RA, and medication that prevents attacks should be made available to all patients who need it. Also, we need to continue to develop and use better solutions; solutions that help all patients with all types of RA to achieve complete control of their disease. Finally, we must not stop to develop treatment approaches that aim to cure RA.

Declaration of interest

M Maurer recently was a speaker and advisor for, and has received research funding from, Allakos, Alnylam, Aralez, AstraZeneca, Biocryst, Blueprint, CSL Behring, FAES, Genentech, Kalvista, Menarini, Novartis, Leo Pharma, Moxie, MSD, Pharming, Pharvaris, Roche, Sanofi, Shire/Takeda, UCB, and Uriach.

M Magerl was recently was a Speaker and Advisor for BioCryst, CSL Behring, KalVista, Novartis, Shire, and Pharming.

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer Disclosures

The peer reviewers have nothing to disclose.