Hereditary angioedema (HAE) is a rare, genetic disorder, attributed in most cases to the SERPING 1 gene mutations, resulting in functional (HAE-C1INH type1) or quantitative (HAE-C1INH type2) deficiency of the C1 esterase inhibitor (C1INH) protein (1, 2).

The disease follows an autosomal dominant inheritance pattern, with de novo mutations accounting for approximately 25% of cases (2, 3).

The prevalence of the disease is estimated at approximately 1 in 50,000 individuals, with no significant differences observed across sex or ethnic groups (2, 4).

Clinical symptoms consist in recurrent painful swellings of the subcutaneous and/or submucosal tissues, mediated by the vasoactive peptide, bradykinin (5). The swelling can affect any body part, with the skin, gastrointestinal tract, and upper airways being the most commonly involved sites (2, 4).

If untreated, the attacks last 2–5 days (2, 3, 6, 7) and in case of upper airway edema it can be life-threatening due to risk of asphyxiation (2, 8).

Similar clinical pictures are found in the HAE forms with normal C1-INH level (HAE-nC1INH), which result from distinct genetic mutations. These includes variants in factor XII (HAE-F12) (9), plasminogen (HAE-PLG), angiopoietin (HAE-ANGPT1), kininogen (HAE-KNG1), myoferlin (HAE-MYOF) (2, 10–15) (HAE-HS3ST6) (16), (HAE-CPN) (17), or (HAE-DAB2IPE) (18) genes. Nevertheless, a substantial number of HAE-nC1INH cases remain genetically unexplained (HAE-UNK) (19).

Although certain trigger factors have been identified, HAE attacks are often unpredictable and can be intensely painful, significantly affecting patients' daily functioning, including work and school productivity (1, 2, 20–27).

In a survey conducted among Romanian HAE-C1INH patients, the mean number of missed work or school days was 9.3 over the 12-month evaluation period (28). As such, treatment primarily aims to enhance the patient's quality of life and prevent the occurrence of attacks, ultimately seeking to achieve complete disease control (19). In most cases, this goal can be attained through the regular administration of specific medications, referred to as long-term prophylaxis (LTP).

At present, three medications are approved as first-line therapy for LTP: the plasma derived C1INH, the kallikrein inhibitor monoclonal antibody—lanadelumab and the small molecule plasma kallikrein inhibitor berotralstat. Attenuated androgens are considered second-line treatment drugs in HAE -LTP and the antifibrinolytics, such as tranexamic acid, are no longer recommended (19).

In accordance with EAACI/WAO guideline recommendations, the initiation of LTP should be guided by an assessment of disease activity, the impact on the patient's quality of life, the availability of healthcare resources, insufficient response to on-demand therapy, and the patient's informed preferences (19).

These parameters can be assessed using patient-reported outcomes (PROs), such as the Angioedema Control Test (AECT), the Angioedema Quality of Life Questionnaire (AE-QoL), and the attack diary. These tools are also valuable for evaluating the safety and efficacy of chronic treatments. In this manner, a personalized and comprehensive treatment plan can be developed for each patient with HAE.

As an angioedema attack can appear during the LTP, the on-demand therapy (pdC1INH, rhC1INH icatibant and ecallantide) should be available (19, 29), or, if these are not accessible, fresh frozen plasma can be administered (19, 29).

Our study aimed to assess the changes of quality of life, disease control and attacks frequency in the Romanian HAE-C1INH patients during the first year of treatment with the kallikrein inhibitor monoclonal antibody—lanadelumab, based on the above-mentioned PRƠ's.

This was a non-interventional study of the HAE-C1INH patients from Romania included in the first year of lanadelumab treatment program, conducted by the Romanian HAE Center of Reference and Excellence. Patients were announced about the availability of this drug via an on-line meeting when the inclusion criteria were also presented: age of ≥12 years, confirmed diagnosis of HAE-C1INH type1 or 2, and for the last 3 months period: 1. the frequency and severity of the attacks (≥2 attacks/last 3 months based on patient diary),and/or 2. an inadequate control of the disease on used treatment (AECT score <10), and/or 3. the impact of the disease on quality of life (based on AE-QoL questionnaire, score ≥39, moderate or severe effect), and/or 4. an important burden of the used treatment and 5. the patients preferences.

Those who did not attend this meeting were informed at the annual visit (face-to-face visit or phone-call visit).

At pre-treatment visit (T0) the mentioned questionnaires were completed electronically, after a phone-call discussion or during the annual visit at the Center. Patients included in the treatment program were evaluated using the same tools, at every three months (T1, T2, T3 and T4).

Participation in the treatment program was independent of the patients' consent to participate in this survey.

Both the AECT and the AE-QoL are available in Romanian. While not specific to HAE, these tools have been validated and are frequently used in the context of this disorder, both in clinical trials and routine clinical practice, due to their brevity and ease of scoring.

AECT is a four-item patient-related tool used in subjects with recurrent angioedema. The first question refers to the attack's frequency and the second one to their consequences on the patient's daily life. The unpredictability of the attacks is evaluated by the third question and, the last one assesses the used treatment efficiency (30, 31). Two versions for AECT are accessible: for a recall period of four weeks and three months respectively. In our study the last one was used.

AE-QoL contains 17 items grouped in four domains: functioning, fatigue/mood, fears/shame, and nutrition. In this case the questions are referred to the previous four weeks (2, 32).

In both cases answers are predetermined using a five-point verbal rating scale, and for all responses the score ranges from 0 to 4 points (33).

In the case of AECT the total score is 16 points, which reflects a complete control of the disease, the main goal of the treatment in HAE. A result of ≥10 points show a well-controlled disease and if it is <10 points, indicates an inadequately controlled status. The grades used for this questionnaire were the following: very often = 0 points, often = 1 point, sometimes = 2 points, seldom = 3 points, and not at all = 4 points Increasing the score by three points or more at two consecutive visits, can be considered as an important improvement for the patient (34).

The AE-QoL score is obtained by converting the sum of points for every question to a linear 0–100 scale with higher values pointing to a higher QoL impairment. Intervals of total scores of 0–23, 24–38, and 39 or more describe patients with “no effect,” “small effect,” and “moderate to large effect” of swelling episodes on their quality of life, respectively (14). In the case of this questionnaire, the minimal clinically important difference was established to be six points (35).

For this questionnaire the following grades were used: never = 0 point, seldom = 1 point, sometimes = 2 points, often = 3 points and very often = 4 points.

The four individual domain scores were computed by summing the points assigned to the specific questions to each dimension, as follows: functioning—questions 1, 2, 3 and 4, fatigue/mood questions 6, 7, 8, 9 and 10, fears/shame questions 12, 13, 14, 15, 16 and 17 and nutrition questions 5 and 11.

Attacks frequency and severity were established using the attacks diary. For every swelling episode the same data were recorded: date of the attack, location, severity (mild/moderate or severe depending on the capability to perform daily activities) and the used treatment. Patient utilized either the paper-and-pen diary or the electronic one.

Information regarding socio-demographic data (age, sex), HAE type, and used treatment, were collected from the Romanian HAE Registry.

The study was conducted in compliance with the requirements set forth in the Declaration of Helsinki and was approved in December 2022 by the IRB of the George Emil Palade University of Medicine, Pharmacy, Science, and Technology of Targu Mures, Romania (Decision no. UMFST-nr 1914/02.11.2022 -REG-74-F03-Ed.02).

The present study describes real-life clinical data regarding the benefits of the LTP with lanadelumab in Romanian HAE-C1INH patients. Being a relative new drug, with limited data on its long-term effectiveness and safety, our results can serve as additional information to the data published so far.

The evaluated patients were predominantly adults, females, with HAE type 1, and most of them used only OD therapy. Lanadelumab treatment was assessed during one year period using three parameters: AECT, AE-QoL and attacks frequency. These tools were completed every three months assuring a close monitoring of these patients.

Adherence to lanadelumab treatment was excellent, with no missed doses (each dose was recorded and verified) through the evaluation period. Although all participants reported a local, injection site reaction (redness, swelling, pain) as adverse event, with the exception of one patient who experienced moderate pain during the first two administrations, all side effects were mild in intensity. No issues with tolerability were observed throughout the study duration.

At pre-treatment evaluation (T0), patient showed a high frequency of attacks (mean score: 10.0), significant impairment of quality of life (total score: 66.1), and uncontrolled disease (AECT score: 4.5).

Comparable data were obtained in a survey conducted by our Center using the Hereditary Angioedema Quality of Life Questionnaire (HAE-QoL), completed by 94 patients with HAE-C1INH during the second year of the COVID-19 pandemic. The survey recorded a total HAE-QoL score of 78 (range: 25–135) and a mean attack rate of 13.8, assessed in a subgroup of 30 patients (36). Additional evidence of suboptimal disease control was provided by a separate survey conducted by our Center in March 2022, involving 56 HAE-C1INH patients, which showed mean AECT scores of 6.9 and 7.0 for the 3-month and 1-month recall versions, respectively (30).

These data indicate an important burden of the disease and an insufficient control with the treatments currently used in HAE patients from Romania.

Initiation of LTP with lanadelumab resulted in statistically significant improvements (p < 0.0001) across all three evaluated parameters at the T1 assessment: AECT score (12.0), AE-QoL score (35.1), and attack frequency (3.4). These improvements were sustained at T2, T3, and T4 visits, with no statistically significant differences observed between these time points for AECT and AE-QoL (Figures 2–4).

Regarding attacks frequency, the initial reduction observed between T0 and T1 was both statistically significant (p < 0.0001) and clinically meaningful, representing a substantial decrease of approximately 66%. Although this reduction was notable, it was somewhat lower than those reported in the Hereditary angioEdema Long-term Prophylaxis Study (HELP, NCT02586805) (37) which demonstrated an 87.0% reduction and its open-label extension part (HELP OLE, NCT02741596) (38) which reported reductions of 82.0% in non-rollover patients and 92.4% in rollover patients.

In contrast, subsequent intervals demonstrated smaller reductions. From T1 to T2, the decrease was not statistically significant (p = 0.104) and corresponded to a 17.7% reduction. However, statistically significant decreases were again observed between T2 and T3 (p = 0.0273) and between T3 and T4 (p = 0.0049), with reductions of 24.1% and 36.4%, respectively. This can be explained by the fact that in some patients the number of attacks decreased progressively over time, with several individuals becoming asymptomatic by the T3 or T4 evaluations.

Our findings demonstrate the rapid onset of lanadelumab's effectiveness shortly after treatment initiation, and its sustained efficacy over time. Similar results have been reported by other groups in Germany (39–41) Poland (42), the United States (43), and Canada (44), confirming both early (within the first month) and long-term (6-, 12-, and 48-month) effectiveness.

Based on our findings, routine follow-up every three months appears unnecessary when lanadelumab is initiated as a LTP therapy. We propose a structured follow-up schedule: an initial assessment at 3 months, a second visit at 6 months to evaluate the possibility of dose reduction to 300 mg/month in asymptomatic patients, and subsequent annual follow-up.

In our study, improvement was observed regardless of whether patients were receiving only OD treatment or were on LTP with intravenous pdC1-INH at a dose of 2 × 1,000 IU per week. The degree of amelioration was similar between the two groups; however, a statistically significant difference (p < 0.05) was noted at the T0 assessment in AECT scores (3.7 vs. 5.9), but not in AE-QoL scores (38.9 vs. 61.6) or attack rates (11.1 vs. 8.2) (Table 4). Similar findings were reported in research conducted by Buttgereit et al. (39) who observed AECT score improvement in HAE patients treated with lanadelumab, without statistically significant pre-treatment differences between those receiving only OD therapy and those on LTP with pdC1-INH. Collectively, these results suggest that lanadelumab may be more effective than intravenous pdC1-INH for long-term prophylaxis. This finding is further supported by data from the PATCH study (44), an indirect treatment comparison demonstrating that patients treated with lanadelumab experienced less than half the number of attacks compared to those receiving intravenous pdC1-INH.

A reduction in attack frequency was also reported by Sánchez-Machín et al., who observed a similar trend in four patients with HAE-C1-INH. In their study, patients previously receiving long-term prophylaxis with pdC1-INH (three patients) or Berotralstat combined with danazol (one patient) experienced a decrease in attack frequency after switching to lanadelumab treatment (45).

Complete disease control, defined as an AECT score of 16, was achieved in five patients at the T1 assessment; by the T4 visit, one additional patient had reached this level, bringing the total to six, one from the prior LTP group and five from the OD treatment group. All six patients became symptom-free starting at T1. At the T4 visit, an additional 15 patients had AECT scores between 10 and 15, indicating controlled disease. In two cases, an AECT score of 10 was observed only at the T2 visit, with values below 10 at T1, T3, and T4. One patient consistently presented with an AECT score below 10 at all visits and did not achieve the minimal clinically important difference (MCID) of three points between assessments. Interestingly, this patient's subjective report contradicted the AECT findings; she reported feeling significantly better with lanadelumab treatment, citing reduced attack frequency (from 15 at T0 to 9 at T4), decreased severity, and, most notably a change in attack location, with monthly episodes of upper airway edema decreasing to one episode every three months. In this same patient, a single episode of respiratory tract swelling occurred after a dental extraction performed without pre-procedural prophylaxis.

Upper airway edema occurred in two additional patients during lanadelumab treatment and was successfully managed with self-administered icatibant. Prior to initiating LTP with lanadelumab, 19 patients (79.2%) had a history of upper airway edema. These findings align with those reported by Magerl et al. (44), who demonstrated that lanadelumab reduced the incidence of potentially life-threatening laryngeal attacks fivefold compared to LTP with pdC1-INH.

In our cohort, lanadelumab achieved a symptom-free status in seven patients (29.2%) after the first dose, and in an additional four patients within the first three months of treatment (without swelling episodes after the first dose of lanadelumab and subsequent injections within the first three months of treatment respectively). By the T4 assessment, 14 patients (58.3%), equally distributed between males and females remained attack-free, suggesting comparable efficacy across sexes. Although HAE is generally more severe in females, as also reflected in our baseline data (T0), statistically significant differences (p < 0.05) were observed in total AE-QoL scores (73.79 vs. 55.40 in females vs. males), as well as in the functional domain (76.57 vs. 58.20) and the fear/shame domain (83.07 vs. 62.60). Notably, these sex-related disparities were no longer present starting at the T1 assessment and remained absent at T4 (Table 3).

Quality of life improved significantly in patients treated with lanadelumab, as demonstrated by a statistically significant decrease in AE-QoL total scores between T0 and T1 (p < 0.0001). Although improvement continued at subsequent time points, it was modest, and remained within this range throughout the study period (Figure 4).

A similar pattern was observed across domain-specific AE-QoL scores: significant improvements were recorded at T1 for all domains (p < 0.0001), but no statistically significant changes were observed at T2, T3, or T4 (Table 2).

Notably, some domains showed slight deterioration at specific intervals. A minor decline in functioning was observed between T3 and T4, while both the fatigue/mood domain and the total score decreased slightly from T1 to T2. The most pronounced reduction occurred in the nutrition domain between T1 and T2. In contrast, the fear/shame domain showed continuous improvement across all visits, with no decline observed These findings suggest that each domain contributed relatively equally to the persistence of moderate impairment.

Further investigation is warranted to identify the underlying factors responsible for the sustained moderate level of quality-of-life impairment despite clinical improvements.

Regarding treatment effect classification, a “no effect” AE-QoL category (score 0–23) was observed in eight patients (33.4%) at T1 and nine (37.5%) at T4. A “small effect” category (score 24–38) was recorded in seven patients (29.2%) at T1 and six (25%) at T4.

Our study demonstrated that lanadelumab is an effective and well-tolerated treatment for patients with hereditary angioedema (HAE) in Romania. This therapy provided adequate disease control and significantly improved the patients “quality of life within a relatively short time after initiation, with sustained benefits observed over the one-year treatment period. Regular evaluations at relatively short intervals by the availability and ease of administration of validated questionnaires serve as a useful tool for clinicians in the comprehensive assessment of HAE patients and offer a valuable means of monitoring treatment effectiveness.”