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252 Textbook of Diagnostic and Therapeutic Procedures in Allergy
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Figure 3. (a) Mechanism of IL-1 secretion and signaling. IL-1α and IL-1β are proinflammatory cytokines that activate
cells by binding and signaling through the IL-1 receptor type I. IL-1β must be proteolytically cleaved into its active form
by caspase-1. Mutations in NLRP-3 result in an overactive inflammasome resulting in increased activated IL-1β that drives
inflammation. (b) Mechanism of IL-1 inhibition with the three currently approved treatments. (Reprinted with permission
from Jesus and Goldbach-Mansky. 2014. IL-1 blockade in autoinflammatory syndromes. Annu. Rev. Med. 223–44).
CPPD: calcium pyrophosphate dehydrate crystals, DAMPs: danger-associated molecular patterns, FFA: free fatty acids;
IAPP: islet amyloid polypeptide, LPS: lipopolysaccharide, MDP: muramyl dipeptide, MSU: monosodium urate, oxLDL:
oxidized low-density lipoprotein, PAMPs: pathogen associated molecular patterns, ASC: adaptor molecule apoptosisassociated speck-like protein containing a CARD, NLRP-3: Nucleotide-binding domain, leucine rich family, pyrin domain
Three different therapies are available for IL-1 blockade in the US. Anakinra is an analog of the
IL-1 receptor antagonist that can target IL-1 alpha (α) or IL-1 beta (β) and binds to the IL-1 receptor,
neutralizing its biological effects. Rilonacept is a fusion protein that contains the extracellular
portions of the IL-1 receptor and IL-1 receptor accessory protein and can neutralize IL-1α and
IL-1β in blood circulation. Canakinumab is a monoclonal antibody that directly binds to only
IL-1β. The mechanism of action for these drugs is outlined in Figure 3. Each of these medications is
containing 3, NALP3: NAcht Leucine-rich repeat Protein 3.
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Table 6. Available anti-IL-1 therapies in the US.
Therapy Immunologic Target Warnings and Precautions
Anakinra
Canakinumab
Rilonacept
Binds IL-1 receptor, aecting IL-1α
and IL-1β activity levels
Binds IL-1β Bacterial and viral infections
Binds IL-1β, IL-1α and IL-1
receptor antagonist
Bacterial and viral infections
Use in combination with Tumor Necrosis Factor (TNF)
blocking agents is not recommended
Live vaccines should not be given concurrently
Neutropenia has been reported with therapy
Live vaccines should not be given concurrently
Neutropenia has been reported with therapy
Bacterial and viral infections
Live vaccines should not be given concurrently
self-administered but the frequency of administration varies. Further details about each medication
are outlined in Tables 6 and 7.
Periodic Fever Syndromes
Cryopyrin-associated periodic syndromes (CAPS), TNF receptor-associated periodic syndrome
(TRAPS), mevalonate kinase deficiency (also known as hyperimmunoglobulin D syndrome
[HIDS]) and familial Mediterranean fever (FMF), have overlapping features in terms of the clinical
phenotype. All three of the above medications are approved for CAPS in the US, but canakinumab
is the only anti-IL-1 therapy that has FDA approval for other periodic fever syndromes (Dinarello
et al. 2012).
Disease States
CAPS is a continuum of diseases, from most to least severe: chronic infantile neurological cutaneous
and articular/neonatal onset multisystem inflammatory disease (CINCA/NOMID), Muckle-Wells
syndrome (MWS) and familial cold-induced autoinflammatory syndrome (FCAS). These diseases
are inherited in an autosomal dominant pattern and involve mutations of the NLRP3 (CIAS1) gene
encoding cryopyrin. Each of these can present with fever, urticaria, arthralgias and conjunctivitis
but only CINCA/NOMID is associated with facial dysmorphisms and developmental delay.
Sensorineural, progressive hearing loss can be seen with MWS and CINCA/NOMID but not FCAS.
IL-1 blockade is the recommended first-line therapy for patients with CAPS given that mutations in
NLRP-3 result in an overactive inflammasome and increased IL-1β that perpetuates inflammation
(Goldbach-Mansky 2011; Kuemmerle et al. 2011a). This relationship is depicted in Figure 3.
TRAPS is a disorder resulting from mutations in the tumor necrosis factor (TNF) receptor
superfamily member one-A (TNFRSF1A or TNFR1) gene that leads to misfolding of the receptor
(Gattorno et al. 2017). FMF involves mutations in the gene MEFV (Mediterranean fever) encoding
protein pyrin. Both FMF and TRAPS are characterized by episodic attacks of severe inflammation
associated with fever, malaise, serositis, myalgias and skin rashes.
HIDS is caused by a mutation in the mevalonate kinase gene (MVK). Presentation is in infancy
with fevers lasting 3–7 days, painful lymphadenopathy, aphthous ulcers, abdominal pain, arthritis
and skin with erythematous macules or urticaria-like lesions (Lainka et al. 2012).
Table 7. Targeted therapies for periodic fever syndromes with FDA approval.
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254 Textbook of Diagnostic and Therapeutic Procedures in Allergy
Treatment Level of
Evidence
CAPS (mutation: NLRP3 [CIAS1])
Canakinumab¹ 1B
Rilonacept² 1B
Anakinra³ 2A Any age SC Weight-based daily NOMID/CINCA only
TRAPS (mutation: TNFRSF1A)
Canakinumab 1B ≥ 2 years old SC Weight-based every 4 weeks TRAPS
Rilonacept Not FDA approved for this condition
Anakinra 2B Not FDA approved for this condition
HIDS (MKD) (mutation: MVK)
Canakinumab 1B ≥ 2 years old SC Weight-based every 4 weeks HIDS
Rilonacept NA Not FDA approved for this condition
Anakinra 2B Not FDA approved for this condition
FMF (mutation: MEFV)
Canakinumab 1B ≥ 2 years old SC Weight-based every 4 weeks FMF
Rilonacept 1B Not FDA approved for this condition
Anakinra 2B Not FDA approved for this condition
¹ Cankinumab is also FDA approved for SJIA and Still’s disease (AOSD).
² Rilonacept is also FDA approved for DIRA and recurrent pericarditis.
³ Anakinra is also FDA approved for RA and DIRA.
This table compiles data from the respective medication package inserts which can be reviewed for further information.
Centre for Evidence-based Medicine levels and grades of recommendation: 1B individual randomized controlled trial; 2A systematic review of cohort studies; 2B individual cohort study;
3B, individual case-control study; 4 case series.
SC: subcutaneous, CAPS: Cryopyrin-associated periodic syndromes, FCAS: familial cold-induced autoinflammatory syndrome, MWS: Muckle-Wells syndrome, CINCA/NOMID: chronic
infantile neurological cutaneous and articular/neonatal-onset multisystem inflammatory disease, NLRP-3: Nucleotide-binding domain, leucine-rich family, pyrin domain containing 3, CIAS1:
Cold-Induced Auto-inflammatory Syndrome-1, TNF receptor-associated periodic syndrome (TRAPS), TNFRSF1A: receptor superfamily member one-A, HIDS: hyperimmunoglobulin D
syndrome, MKD: mevalonate kinase deciency, MVK: mevalonate kinase gene, FMF: familial Mediterranean fever, MEFV: Mediterranean fever, NA: not applicable, FDA: United States
Food and Drug Administration.
Age Route of
Administration
≥ 4 years old SC Weight-based every 8 weeks FCAS and MWS
≥ 12 years old SC Weight-based for pediatric patients once weekly
Dosing and Frequency Relevant US FDA Approval
FCAS and MWS
Adults: Loading dose: 320 mg, followed by 160 mg once weekly
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Anti-IL-1 Therapies
Canakinumab
Canakinumab has been approved for CAPS, TRAPS, HIDS and FMF. Up to a 97% response to
canakinumab has been shown based on disease-activity scores, analysis of inflammatory markers
and physician assessment in a placebo-controlled trial (Lachmann et al. 2009). In terms of AEs
in this study, canakinumab was significantly different from placebo for an increased rate of
suspected infections, with 67% in canakinumab group experiencing an infection vs. 25% in the
placebo. Sustained remission, improved QoL and an excellent safety profile have been found with
canakinumab use in pediatric and adult populations with open-label studies (Kuemmerle et al.
2011b; Yokota et al. 2017).
The efficacy of canakinumab for the treatment of TRAPS, HIDS and colchicine-resistant
FMF was demonstrated in the CLUSTER RCT where significantly more patients receiving
canakinumab had a complete response than those receiving placebo: 61% vs. 6% of patients with
colchicine-resistant FMF, 35% vs. 6% of those with MVK deficiency and 45% versus 8% of
those with TRAPS (De Benedetti et al. 2018). Increased dosing of canakinumab from 150 mg to
300 mg Q4W resulted in further improvements in disease control, particularly for HIDS. Infections,
especially respiratory, were the most prevalent AEs. Patients should be informed about the increase
in the rate of infections seen with canakinumab but otherwise, this therapy has been well tolerated
and has consistently shown decreases in the frequency of attacks in patients with CAPS, TRAPS
and HIDS (Kuemmerle et al. 2011c; Arostegui et al. 2017). There has also been substantial evidence
to reinforce canakinumab use in FMF from RCT showing a reduction of flares and a decrease
in inflammatory markers along with observational studies showing remission in most patients by
12 months with a high relapse rate upon treatment withdrawal (Gülez et al. 2020; van der Hilst
et al. 2016).
Anakinra
Anakinra is FDA-approved for NOMID/CINCA. There have been observational studies for anakinra
in CAPS showing reduced musculoskeletal symptoms and decreased inflammatory markers in the
majority of patients (Goldbach-Mansky 2011). In a single-arm, open-label study, anakinra was
given to 18 NOMID/CINCA patients with up to 5 years of follow-up showing rapid response with
the disappearance of the rash. There was also improvement in hearing, resolution of headache,
decrease in or disappearance of cochlear and leptomeningeal enhancement and reduced steroid use
(Goldbach-Mansky et al. 2006). Global diary scores and inflammatory markers reduced significantly
compared to the patient’s own baseline. The most common AEs were headaches and arthralgia.
Treatment with anakinra in TRAPS has fewer data but has shown efficacy in an open-label
trial and with on-demand therapy (Gattorno et al. 2008; Grimwood et al. 2015). In a registry-based
study, anakinra induced a complete response in 26 of 33 patients (79%) and a partial response in 5
(ter Haar et al. 2013).
With HIDS, anakinra has been used to attenuate the severity and duration of acute events,
ultimately improving disease control (van der Hilst et al. 2008). A prospective trial with 7 patients
receiving on-demand anakinra showed that the attack duration was shorter and the maximum
C-reactive protein level decreased. Additionally, a registry-based study of HIDS patients revealed
that anakinra was effective in 24 (89%) of 27 patients, inducing complete remission in 6 (22%)
(ter Haar et al. 2013).
A retrospective review of compiled FMF cases found that the use of anakinra resulted in a
77% complete response rate, with a partial response in an additional 19% of patients (van der Hilst
et al. 2016). RCT by Ben-Zvi et al. has supported these positive findings, where 25 patients with
colchicine-resistant FMF were given anakinra or placebo and the mean ± standard deviation (SD)
number of attacks per patient per month was 1.7 ± 1.7 in those receiving anakinra and 3.5 ± 1.9 in
those receiving placebo (Ben-Zvi et al. 2017). QoL was also improved. AEs included gastrointestinal
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and musculoskeletal symptoms as well as injection-site reactions as the most common, but these
were comparable between anakinra and placebo. There were no severe AEs. Retrospective and
registry-based reviews have also supported the reduction of flares, improvement in QoL and
increased school attendance with anakinra use (Kurt et al. 2020; Sag et al. 2020).
More safety data is available for anakinra than canakinumab given its earlier release and
approval. Five-year safety data for anakinra has shown that it is well tolerated in both pediatric and
adult patients with CAPS. In this clinical cohort study, 43 patients with CAPS were monitored with
a yearly rate of 7.7 AEs that decreased over time and were not dose-dependent (Ben-Zvi et al. 2017).
The most frequent AEs were headaches and arthralgia.
A small open-label study in pediatric patients did reveal more noncompliance with anakinra
than canakinumab presumably due to daily administration as opposed to every 4 or 8 weeks (Başaran
et al. 2015). More frequent administration has also led to more injection-site reactions. A Cochrane
review has demonstrated a statistically significant higher risk for serious infections associated with
anakinra therapy in general (Singh et al. 2011). Like with canakinumab, patients should be informed
of increased infection risk when being started on anakinra. Successful transitions from anakinra to
canakinumab and vice versa have been documented (Cetin et al. 2015).
Rilonacept
Rilonacept is FDA-approved for CAPS, specifically FCAS and MWS. There is a single RCT that
demonstrates the efficacy of rilonacept in CAPS. Hoffman et al. treated FCAS and MWS patients
with rilonacept and reported a reduction in mean composite symptom score of 84% vs. 13% with
placebo (Hoffman et al. 2008). Besides improvement in clinical findings, laboratory markers also
improved. Rilonacept was generally well tolerated with the most common AEs being injection-site
reactions, followed by URTIs. In an extended treatment duration of 72 weeks, rilonacept showed
a favorable safety and tolerability profile in adult and pediatric patients with CAPS (Hoffman
et al. 2012).
For FMF, RCT found that rilonacept reduced the number of attacks by greater than 50% of the
baseline rate when compared to placebo, 75% vs. 35% respectively (Hashkes et al. 2012). There
were no significant differences found between responders and non-responders in terms of baseline
characteristics Most common AEs were injection-site reactions which were more often reported
in patients receiving rilonacept than placebo (53 events vs. 13 events, respectively). At the present
time, there is no published literature on rilonacept use in TRAPS and HIDS.
Each of the discussed periodic fever syndromes has distinct algorithms for management, including
therapies separate from the anti-IL-1 blockade. These should be reviewed when caring for patients.
Canakinumab, anakinra, and rilonacept have noticeable therapeutic effects in periodic fever
syndromes with good tolerance but there are no controlled head-to-head trials between them.
There are new treatment approaches under development for periodic fever syndromes including
small-molecule inhibitors of the NLRP3 inflammasome, such as MCC950 and therapies that lead
to IL-1 inhibition through a different mechanism of action than previously discussed. Tranilast and
dapansutrile are NLRP3 inhibitors that block the formation of inflammasomes, which are crucial
for caspase 1 activation and thus IL-1β production (Huang et al. 2018; Klück et al. 2020). With
ongoing research, we will obtain more data for existing therapies and potentially add new ones to
our toolbox.
Additional Considerations
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Anti-IL-1 Therapy Key Points
• Anakinra, canakinumab, and rilonacept are all approved for CAPS, but canakinumab is the only
anti-IL-1 therapy that also has FDA approval for other periodic fever syndromes. Further details
about each medication are outlined in Tables 6 and 7.
• In terms of AEs, anakinra and canakinumab have more frequently been associated with
increased infection risk although they have also shown sustained remission of disease and an
otherwise appreciable safety profile.
• The shared decision is of utmost importance when using these medications in an off-label manner
to treat periodic fever syndromes. Patients should be informed that there are no controlled
head-to-head trials between these drugs.
Hereditary Angioedema
Hereditary angioedema (HAE) is a rare, autosomal dominant disorder in which patients develop
episodic swelling episodes of submucosal or subcutaneous tissues, without urticaria or pruritis.
Different genetic mutations have been identified based on the subtype of HAE such as SERPING1
(Serpin Family G Member 1) in patients with deficient C1 esterase inhibitor (C1‐INH) and Factor
XII (FXII) gene mutations in HAE patients with normal C1‐INH (Wilkerson and Moellman 2022).
In most forms of HAE, enhanced generation of bradykinin, a potent mediator of vasodilation, leads
to angioedema. C1 inhibitor replacement and drugs that act on the bradykinin pathway serve as an
effective therapy. Existing HAE treatments target three areas in the pathway of bradykinin formation:
replacement of C1-INH, inhibition of bradykinin formation through inhibition of kallikrein and
antagonism of the bradykinin B2 receptor.
Management of acute attacks involves ensuring airway patency due to the life-threatening
nature of laryngeal edema. Associated deaths from laryngeal edema range from 32.7–56% in a
literature review of 23 HAE articles from September 2020 to April 2021 (Minafra et al. 2022).
The United States Hereditary Angioedema Association Medical Advisory Board (US HAEA MAB)
guidelines, updated in 2020, strongly recommend ecallantide, icatibant, plasma-derived C1-INH
(pdC1-INH) or recombinant C1INH as first-line options for acute attacks (Busse et al. 2021). These
therapies should be initiated as early as possible after the onset of swelling to shorten the duration
and time to resolution (Craig et al. 2013).
Decisions about therapy should consider the burden of disease on an individual patient.
Long-term prophylaxis is indicated for patients with frequent or severe attacks but is not limited
to this population. Lanadelumab and pdC1-INH (specifically Cinryze and Haegarda) are listed
as first-line prophylactic treatments per US HAEA MAB guidelines (Busse et al. 2021). We will
review the eight most efficacious FDA-approved medications by their mechanism of action. The
medications are also summarized in Table 8 with the distinction made between those used for acute
versus prophylactic treatment. The treatment options below were studied in patients with absolute
or functional deficiency of C1-INH. For HAE with normal C1-INH, treatments used are overall like
those for HAE-C1-INH (Bork et al. 2020). However, there are no placebo-controlled clinical trials
for the HAE with a normal C1-INH population and treatment experience is limited.
C1 Esterase Inhibitors
C1-INH therapies function to replace the missing or nonfunctional C1-INH in HAE patients. Brand
names will be used to differentiate between the products. Berinert is a pdC1-INH indicated for
acute attacks and was approved based on results from IMPACT-1. In this RCT, the 20-U/kg dose
shortened duration of symptoms to 0.5 hours from 1.5 hours (Craig et al. 2009). With an OLE of this
study, the median time for onset of symptom relief was 0.46 hours (Craig et al. 2011). There were
Table 8. Select FDA-approved treatments for hereditary angioedema.
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258 Textbook of Diagnostic and Therapeutic Procedures in Allergy
Therapy Indications Route of Administration
and Frequency
Plasma-derived C1
Inhibitor (Berinert)
Recombinant
human C1 inhibitor
(Ruconest)
Ecallantide (Kalbitor)
Icatibant (Firazyr)
Plasma derived C1
inhibitor (Cinryze)
Acute attacks
All ages
Acute attacks
≥ 12 years old
Acute attacks
≥ 12 years old
Acute attacks
≥ 18 years old
Prophylaxis
≥ 6 years old
IV on-demand can be
self-administered
IV on-demand can be
self-administered
SC administered by HCP
(to manage the risk of
anaphylaxis)
SC on demand but with
intervals of at least 6
hours, can be selfadministered
IV, every 3–4 days, can
be self-administered
Mechanism of Action Special Considerations
Inhibits plasma kallikrein
and several coagulation
factors
Inhibits plasma kallikrein
and several coagulation
factors
Inhibits plasma kallikrein Anaphylaxis has occurred in 3.5% of treated patients (Lunn and Banta 2011)
Bradykinin B2 receptor
antagonist
Inhibits plasma kallikrein
and several coagulation
factors
Risk of arterial and venous thromboembolic events, particularly at higher doses
Derived from human plasma with a theoretical risk of infection transmission
The most common adverse reaction is dysgeusia
No more than 2 doses in 24 hours
Rabbit-derived contraindicated in those with known or suspected allergy to rabbits
Risk of arterial and venous thromboembolic events, particularly at higher doses
Derived from human blood with a theoretical risk of infection transmission
The common adverse reactions (≥ 2%) reported in clinical trials were headache, nausea,
and diarrhea
Prolonged PTT
The most common adverse reactions (≥ 3%) in treated patients are headache, nausea,
diarrhea, pyrexia, injection site reactions, and nasopharyngitis
The most commonly reported adverse reactions are injection site reactions
Other common adverse reactions (≥ 1%) include pyrexia, transaminase increase,
dizziness, and rash
Risk of arterial and venous thromboembolic events, particularly at higher doses
Derived from human plasma with a theoretical risk of infection transmission
The most common adverse reactions (≥ 5%) are headache, nausea, rash, vomiting, and
fever
Plasma derived C1
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inhibitor (Haegarda)
Lanadelumab
(Takhzyro)
Berotralstat
(Orladeyo)
Abbreviations: IV: intravenous; SC: subcutaneous; PTT: Partial thromboplastin time; P-gp: P-glycoprotein; BCRP: breast cancer resistance protein
This table compiles data from the respective medication package inserts which can be reviewed for further information.
Prophylaxis
≥ 6 years old
Prophylaxis
≥ 12 years old
Prophylaxis
≥ 12 years old
SC, every 3–4 days, can
be self-administered
SC every 2 or 4 weeks
can be self-administered
Oral capsule daily with
food
Inhibits plasma kallikrein
and several coagulation
factors
A monoclonal antibody
that inhibits plasma
kallikrein
Plasma kallikrein
inhibitor
Risk of arterial and venous thromboembolic events, particularly at higher doses
Derived from human plasma leading to the theoretical risk of infection transmission
The most common adverse reactions are injection site reactions, nasopharyngitis, and
dizziness
The most common adverse reactions are injection site reactions, headache, rash,
myalgia, dizziness, and diarrhea
Prolonged PTT
The most common adverse reactions (≥ 10%) are abdominal pain, vomiting, diarrhea,
back pain, and gastroesophageal reflux disease
An increase in QT prolongation can occur at dosages higher than the recommended 150
mg once-daily dosage
Note for drug-drug interaction with CYP2D6 and CYP3A4, P-gp and BCRP
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no treatment-related safety concerns; however, 43.9% of patients experienced at least one mild or
moderate AE. The most frequently reported AEs are listed in Table 8. Only dysgeusia was reported
at a frequency higher than placebo (4.7% vs. 0%, respectively).
Ruconest, is a recombinant human C1-INH that has a mean plasma half-life of 3 hours,
compared to the 33 hours of pdC1-INH (van Doorn et al. 2005). Ruconest nonetheless is effective
in treating acute attacks of HAE. A sustained effect, despite the relatively short half-life, was shown
in a posthoc analysis where relapse of symptoms did not occur in any patients at 24 hours and in
7.1% at 72 hours (Bernstein et al. 2017). Riedl et al. conducted a pooled analysis of three early trials,
including 45 attacks with upper airway involvement, revealing a median time to onset of symptom
relief of 67 minutes, with 91.1% of individuals with upper airway symptoms having relief onset by
4 hours (Riedl et al. 2017). All attacks resolved without the need for any additional medication, and
no patients required intubation or tracheostomy. In these studies, Ruconest was deemed safe and well
tolerated, with no thromboembolic events, anaphylaxis, or neutralizing antibodies observed. More
specifically, in a North American phase 3 trial for Ruconest, no deaths and no discontinuations from
treatment-related AEs were reported. Each treatment-related AE, such as headache or back pain was
not reported in more than one patient (Riedl et al. 2014). The serious adverse reaction reported in
clinical trials was the anaphylactic reaction in an otherwise healthy subject who had an undisclosed
rabbit allergy. Ruconest is generated from the milk of transgenic rabbits so is contraindicated in
patients with rabbit sensitization of clinical significance.
Cinryze is a pdC1-INH that can be used for prophylaxis against HAE attacks, as supported
by randomized and open-label trials (Zuraw et al. 2010; Riedl et al. 2012). When treated with
Cinryze, a 66% decrease in the number of attacks per study period has been noticed (6.26 attacks vs.
12.73 attacks) and there was also a decrease in the average severity and duration of attacks (Zuraw
et al. 2010). Cinryze has been proven to be well tolerated and safe, with an AE profile no different
from that of a placebo on a review of clinical trials performed so far (Farkas and Varga 2012).
Another pdC1-INH, Haegarda is also used for long-term prophylaxis. The COMPACT study
was a phase 3, randomized, placebo-controlled study with patients who received Haegarda every
3 to 4 days versus placebo. For the group treated with 60 IU/kg, which is the currently approved
dose, the attack rate was 0.52 per month versus 4.03 per month in the placebo group (Longhurst
et al. 2017). Also, 83% of this population was attack-free during months 25 to 30 of treatment,
showing sustained efficacy (Craig et al. 2019). A posthoc analysis of the data from the COMPACT
study found greater improvement for multiple HAE-related QoL impairments, including a 42.9%
improvement in anxiety and considerable improvement in work productivity compared with placebo
who were using on-demand treatment alone (Lumry et al. 2018). Safety data has been positive and
consistent among the different trials, with injection-site reactions being the most frequently reported.
Plasma Kallikrein Inhibitors
These medications inhibit the conversion of high molecular weight kininogen to bradykinin by
selectively and reversibly inhibiting plasma kallikrein (Hofman et al. 2017). Reducing bradykinin
helps to control the increased vascular permeability and resultant angioedema in HAE patients.
Ecallantide is a kallikrein inhibitor used for acute attacks that were evaluated in the EDEMA
study series (Cicardi, Levy, et al. 2010). Patients reported treatment outcomes using a score of +100
to –100, with +100 being the most improvement that could be achieved. The median treatment
outcome score at 4 hours was 50.0 in the ecallantide group and 0.0 in the placebo group. The primary
safety concern is related to hypersensitivity reactions, with an anaphylaxis rate of 3.5% (‘FDA
Center for Drug Evaluation and Research 2022’). Therefore, patients must receive ecallantide with
a health-care provider present.
Lanadelumab is a monoclonal antibody used for long-term prophylaxis that inhibits plasma
kallikrein, with a half-life of around 2 weeks. The HELP trial supported the efficacy of lanadelumab
by finding that both 300 mg Q2W and Q4W significantly decreased the number of HAE attacks
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(Banerji et al. 2018). The 125 patients included in the trial had a baseline mean attack rate ranging
from 3.2 to 4.0 attacks per month. During the treatment period with lanadelumab for 26 weeks, the
mean number of attacks per month for the placebo group was 1.97; 0.53 for the Q4W group; and
0.26 for the Q2W group. Patients also experienced a 63.0% QOL improvement in the Q4W group,
80.8% in the Q2W group and 36.8% in the placebo group. The most commonly occurring AEs
with greater frequency in the lanadelumab treatment groups were injection-site reactions (52.4%
lanadelumab; 34.1% placebo) and dizziness (6.0% lanadelumab; 0% placebo). A 2021 real-life study
reported these side effects with less frequency and no safety concerns or treatment discontinuation
in 34 patients (Buttgereit et al. 2021).
Berotralstat is the most recent addition to medications available for HAE treatment, approved
in 2020. It is an oral medication used to prevent attacks of HAE. APeX‐2, a 3-part phase 3 trial,
includes patients with HAE who experienced ≥ 2 investigator‐confirmed attacks requiring treatment.
In part 1, berotralstat was found to significantly reduce attacks relative to the placebo with
1.31 attacks in the treatment group per month versus 2.35 attacks in the placebo per month over
24 weeks (Zuraw et al. 2021). When studied over 48 weeks of treatment in part 2, mean attack
rates among patients receiving berotralstat 150 mg/day declined by 67% from baseline; reductions
in attack rates either continued or declined further from Part 1 to Part 2 of the study (Wedner
et al. 2021). The durability of the treatment was supported by these findings. Drug-related AEs
were reported in 13 of 39 (33%) and 11 of 34 (32%) participants in treatment and placebo groups,
respectively. AEs were mild or moderate, with no serious drug-related events. Most commonly,
gastrointestinal symptoms were reported including abdominal pain, diarrhea and vomiting but these
were self-limited (Hwang et al. 2019). QoL analysis revealed improved daily functions of life,
mood, emotional health and food intake (Aygören-Pürsün et al. 2018).
Inhibition of Bradykinin B2 Receptor
Icatibant blocks the effects of bradykinin by selectively inhibiting the bradykinin B2 receptor. The
placebo-controlled FAST-3 study assessed a median time to 50% reduction in symptom severity. For
the group of patients with cutaneous and abdominal attacks, the primary outcome was significantly
shorter in the icatibant group (n = 43) compared with the placebo (2.0 hours vs. 19.8 hours) (Lumry
et al. 2011). Similarly, in a posthoc analysis of laryngeal involvement (n = 21) median time to 50%
reduction in symptom severity was 2.0 hours. The incidence of AEs was similar in icatibant- and
placebo-treated subjects (41% and 52%, respectively). No drug-related serious AEs or deaths were
reported.
Second-Line Therapies
Attenuated androgens, antifibrinolytics, and fresh frozen plasma (FFP) are considered
second-line therapies in light of the newer medications outlined above. Orally administered
17α-alkylated androgens including danazol and stanozolol have an FDA indication for short- and
long-term prophylaxis but not acute attacks (Busse et al. 2021). One way these medications improve
HAE is by increasing the amount of C1-INH produced by the liver. If androgens are used, the dosage
must be titrated to the lowest dose that provides effective control of attacks. Common side effects
from the 17α-alkylated androgens include virilization in women along with menstrual irregularities,
acne, changes in libido, increased aggression, weight gain, and increased blood pressure (Zuraw
et al. 2016). These drugs can also cause hepatotoxicity, including the development of hepatic
adenomas and hepatic carcinoma. The 17α-alkylated androgens cannot be used in certain groups
because of these risks, including children and pregnant women (Busse et al. 2021).
Treatment with an antifibrinolytic agent, TXA, has been used for long-term HAE prophylaxis
but is generally less effective than androgen regimens and is now rarely used (Banerji et al. 2020).
The proposed mechanism of action is the inhibition of plasminogen conversion to plasmin leading
to decreased activation of FXII (Wahn et al. 2020). There is no FDA indication for TXA use in HAE.
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