INTRODUCTION
Hereditary angioedema (HAE) (ICD10: D84.1) is an autosomal dominantly inherited disorder caused by deficiency of C1 esterase inhibitor protein. The main symptoms of HAE include episodes of localized oedema involving subcutaneous or submucosal tissue. The attacks occur with variable frequency and can be triggered by stress, trauma, medical procedures, menstruation, oestrogen replacement hormone therapy, medications, among others [1]. In the treatment of HAE, it is recommended to avoid factors that can trigger an attack of the disease, but this is not always possible, so appropriate therapy should be implemented in patients to prevent recurrence. According to current Polish recommendations, the introduction of short-term prophylaxis is recommended before exposure to a risk factor for symptoms such as before a medical procedure. Long-term prophylaxis is used in patients in whom the chances of flare-ups recurrence are higher or short-term therapy has proved insufficient. Ad hoc interruption of attacks involves administration of plasma-derived (Berinert®) or recombinant human analogue (Ruconest®) C1-INH. Second-choice drugs are modulators of the kinin pathway – ecallantide (Kalbitor®) and icatibant (Firazyr®), a B2 receptor blocker for bradykinin. As the last resort in the most severe attacks, fresh frozen plasma can be administered in the absence of access to C1-INH concentrate. Long-term prophylaxis is reserved for patients in whom ad hoc treatment does not have adequate effect. It is introduced when moderate to severe flare-ups occur ≥ 2 times a month despite optimized treatment. The decision to include treatment is made on an individual basis, depending on the patient’s overall clinical picture (frequency of flare-ups, their location, severity, access to emergency medical care) and the patient’s socioeconomic conditions. Possible other causes of oedema such as the use of therapy should be excluded: ACEIs, sartans, oestrogens. It is important that the patient is always supplied with flare-ups-interrupting drugs for immediate use. For long-term treatment, the plasma-derived C1 esterase inhibitor is recommended, as well as the plasma kallikrein inhibitors, berotralstat and lanadelumab. Gene therapies remain under investigation, as well as Garadacimab®, a human monoclonal antibody that inhibits activated factor XII [2]. Second-line drugs for off-label use when standard therapy is ineffective or unavailable are androgens and tranexamic acid [3]. Recently, lanadelumab therapy has appeared to be the most promising preventive treatment. In order to qualify for the B.122 drug program, patients must meet 3 criteria: a diagnosis of hereditary angioedema type 1 or 2, be at least 12 years old, and have a documented history of at least 12 attacks in the past 6 months with flare-ups-interrupting medication. As of April 2024, the number of participants in the program was 60 [4].
CASE REPORT
In September 2014, a 17-year-old female patient presented to the allergy clinic for follow-up care and further treatment of HAE. The main reason for attending the outpatient clinic was frequent laryngitis and complaints of abdominal pain. The diagnosis of HAE was made at the age of 4, when bronchiolitis and cerebellitis occurred simultaneously, following a history of chickenpox. The patient has a family burden of the disease from her father’s side. The C4 component of the complement system and the level of C1q inhibitor was determined: C4 < 0.048 and C1q inhibitor < 0.048. Two weeks after the diagnosis, she developed cerebral oedema, the probable cause of which could be HAE. The patient’s siblings, two brothers and a sister, also suffer from hereditary angioedema, but their symptoms are much milder.
The diagnosis of hereditary angioedema is based on medical history, in which there will be episodes of angioedema that are refractory to standard treatment: systemic inhaled corticosteroids (ICS), antihistamines and epinephrine. The diagnosis is confirmed by laboratory results of complement component levels [5]. The average age of onset of first symptoms is 10 years, but 40% of patients experience their first attack under the age of 5 [6]. To confirm the diagnosis, C1-INH concentration, C1-INH activity, C4 concentration should be determined. If all of the above parameters are decreased and the history of bradykinin oedema is positive, HAE-1 should be diagnosed, while if C1-INH concentration is normal or elevated, and inhibitor activity is decreased, HAE-2 is diagnosed. When laboratory results are normal and the patient develops oedema independently of histamine, we can suspect angioedema of the 3rd type, resulting, for example, from the use of drugs such as oestrogens or ACEIs, or the presence of mutations in the genes encoding kininogen, myoferlin, plasminogen, angiopoietin, factor XII, or, as a last resort, we diagnose idiopathic angioedema [5].
The patient was initially treated with C1-INH concentrates (Berinert® and Ruconest®) for HAE attack interruption, and off-label tranexamic acid (Exacyl®) was used for long-term prophylaxis. With such long-term prophylaxis, the patient’s abdominal, life-threatening symptoms continued at a similar level (3-4 times a month), and other symptoms, e.g., swelling of the face, feet, jaws, occurred sporadically.
DISCUSSION
COURSE OF LANADELUMAB THERAPY
Immediately before lanadelumab therapy, the number of severe HAE flare-ups increased significantly. In the patient’s diary, the following numbers of attacks were found: in 2017 – 25, in 2018 – 30, in 2019 – 43, in 2020 – 80, in 2021 – 40, and in 2022 about 40 from January to the end of April 2022 (before the start of therapy). Despite the changes in treatment, the frequency of abdominal pain increased and the following began to appear with increasing frequency: peripheral oedema, swelling of the face and neck. As of 28.04.2022, the patient, after meeting the eligibility criteria for Drug Program B122, receiving a positive opinion from the selection committee, began therapy with lanadelumab (Takhzyro® 300 mg s.c.). There were no side effects after the injection. Subsequently, the drug was administered according to the drug program, every 2 weeks. The therapy continues – currently 21 months, during which 33 doses of lanadelumab were administered (as of 30.01.2024, last administration 4.01.2024). Due to good tolerance of the drug and stable cessation of flare-ups during treatment, on 13.04.2023 it was decided to decrease the frequency of administration of the drug from 2 weeks to every 4 weeks. During the therapy, two HAE flare-ups occurred: on 16.07.2022 in the form of abdominal swelling, nausea, pressure in the throat and difficulty breathing, and the second on 1.04.2023, accompanied by stress and nausea. The symptoms in both cases, resolved after administration of Berinert®. Apart from the two aforementioned episodes, the patient did not require emergency medication. The patient’s comfort and quality of life improved significantly, compared to the period before the administration of lanadelumab. On this basis, we can conclude that lanadelumab is very effective in long-term HAE prophylaxis therapy.
CLASSIFICATION CRITERIA FOR TREATMENT WITH LANADELUMAB
Patients with recurrent attacks of severe hereditary angioedema may be eligible for biological therapy after meeting criteria that include a diagnosis of hereditary angioedema type 1 or type 2, age over 12 years, and at least 12 attacks of the disease with use of rescue medication in the past 6 months [4].
For long-term prophylaxis, the drug is administered every 2 weeks; in patients with good disease control, the drug can be considered to be administered every 4 weeks. During qualification, it is important to determine the concentration of C1 inhibitor, its activity in the blood, as well as the C4 component of the complement, which confirm the diagnosis of the disease. In addition, a urinalysis is required as well as a number of blood tests: blood count, kaolin-cephalin time (APTT), INR index, aspartate aminotransferase (AST) and alanine aminotransferase (ALT), total bilirubin. In women of childbearing age, a pregnancy test must additionally be performed [4].
The criterion for exclusion from lanadelumab treatment is the fulfilment of at least one of the following criteria: pregnancy or breastfeeding; during the 6-month therapy – no reduction in the monthly mean incidence of life-threatening attacks by at least 50% compared to the 6-month period preceding treatment; the occurrence of symptoms of hypersensitivity to lanadelumab or any of the excipients [4].
Treatment monitoring consists of follow-up examinations and evaluation of the patient’s condition every 6 months [4].
CONCLUSIONS
Hereditary angioedema is a rare life-threatening genetic disease characterized by life-threatening asymmetrical swelling of the skin or mucous membranes of the gastrointestinal tract and respiratory tract; in the case of the skin, the swelling most often occurs in the extremities, face and external genitalia. The disease is caused by a mutation in one of the two alleles of the SERPING1 (serpin family G member 1) gene encoding C1-INH, resulting in a deficiency of the C1 inhibitor (HAE-1) or an abnormal function of the C1 inhibitor, leading to reduced activity of the inhibitor [7]. The use of long-term lanadelumab therapy for HAE prevention is extremely effective. After 2 years of observation of our patient, the number of acute flare-ups has decreased almost to zero, the patient can function normally despite the severe form of the disease, which significantly improves her comfort of life. The possible change in the frequency of administration of the drug – injection every 4 weeks – provides effective, safe therapy.
Biological treatment and personalized therapy for HAE significantly improves the quality and safety of life for patients with HAE.
