Hereditary angioedema (HAE) is a rare genetic disease in which vascular permeability is increased in the deep skin, mucous membranes, or both, with recurrent episodes of localized edema. The incidence of HAE is approximately 1 in 50,000 people [1], but differences between races are unclear. One study reported HAE in 133 cases in 40 families from China [2], but another study reported HAE in only a dozen families [3]. No reports describe the incidence of HAE in Japan. Fewer HAE patients may be diagnosed at medical institutions in Asia compared with the number of cases reported in Europe and the United States, but whether differences in reported cases are due to racial differences or low awareness of the disease is unclear. HAE is classified into three types: type 1 is due to lack of the C1-inhibitor (C1-INH), type 2 is due to dysfunction of C1-INH, and the C1-inhibitor functions normally in the third type (HAE-nC1INH). The edema may be intestinal, which causes abdominal pain, and it may occur in the airway, causing asphyxia. Once formed, the edema lasts for several days, which significantly hampers patients’ social and daily life, and the disease burden is high. However, because episodes occur suddenly in daily life, it is difficult to assess disease activity and impairment of quality of life (QoL) accurately. Questionnaire surveys are typically used to record information retrospectively; therefore, accuracy is dependent on patients’ recall. To reduce potential recall bias and to more accurately describe the timing of episodes, symptom development, and time to recovery, we used an established online platform codeveloped by researchers, medical practitioners, and patients to study HAE.

Thirteen patients (four men, nine women) were recruited between January 2019 and March 2021. The participants’ average age was 47.4 ± 13.8 years. Nine patients (69.2%) had type 1 or type 2 HAE, three patients (23.1%) had HAE-nC1INH, and in one patient (7.7%), the type was unknown (Table 1). A total of 58 episode records and 24 AE-QoL questionnaires were collected. HAE episodes occurred across all time periods, with peaks between approximately 06:00 and 07:00 h and between approximately 16:00 and 20:00 h (Figure 1A). Facial edema occurred in 14 episodes (24.1%); edema occurred in the trunk in 42 episodes (72.4%) and in the extremities in 18 episodes (31.0%); and laryngeal edema occurred in five episodes (8.6%; Figure 1B). Gastrointestinal symptoms were present in 35 episodes (60.3%), and all those episodes were accompanied by abdominal edema. No association between the time period and site of attacks was observed.

Of the 58 recorded episodes, 38 (65.5%) were treated. Of the 20 untreated episodes, 1 (5%) included throat symptoms. However, the attack that caused swelling in the throat was minor. The most common reason for not treating symptoms was that they were mild (14 episodes [70%]); other reasons were that the episodes occurred nocturnally, during holidays, or outside hospital opening hours (5 episodes [25%]) and to avoid missing school or employment (1 episode [5%]). Of the 38 episodes that were treated, 20 (52.6%) had some prodromal symptoms or triggers. Reported triggers for episodes included changes in temperature, mental tension and stress, lack of sleep, and menstruation. We could not identify factors specific to the time of day when most episodes occurred. In all, 24 episodes (63.2%) were treated at home; of these, two were also treated in a healthcare setting. The plasma-derived C1-INH preparation (pdC1-INH) was used alone in 12 episodes (31.6%), and icatibant was used alone in 24 (63.1%) and both were used in 2 (5.3%). For 22 episodes (57.9%), treatment was completed at home with icatibant self-injection alone.

Whereas icatibant can be self-administered at home, pdC1-INH must be administered at a healthcare facility in Japan. Therefore, the time between the onset of symptoms and the start of treatment tended to be shorter with icatibant than with pdC1-INH (Figure 2A). The time from the onset of an episode to the start of recovery was less than 30 min for half the episodes treated with icatibant; in contrast, for most episodes treated with pdC1-INH, this interval was >30 min (Figure 2B). The time from episode onset to full recovery was also longer with pdC1-INH than with icatibant (Figure 2C).

With regard to QoL impairment, analysis of AE-QoL data collected between January 2019 and March 2021 revealed a total score of 37.1 ± 22.9, with scores of 25.5 ± 29.4, 43.1 ± 22.8, 46.0 ± 28.4, and 18.8 ± 19.8 for the function, fatigue/mood, fears/shame, and food domains (Figure 2D).

A previous study of 121 Japanese HAE patients from 2016 to 2017 demonstrated that patients experienced an average of 15.7 attacks per year [8]. At that time, only pdC1-INH preparations were available among first line modern medications recommended by the guideline [9] for acute attacks in Japan. Of the 82% of patients who received pdC1-INH, 69% experienced a therapeutic response. However, only 53.1% of attacks were treated. In our survey, 65.5% of registered attacks were treated. During patient recruitment, written confirmation of their diagnosis (i.e., HAE subtype) and attendance at the hospital was obtained from the attending doctors. The current study included a relatively large proportion of patients with HAE-nC1INH and HAE-unknown, preventing direct comparison with previous evidence. However, the availability of self-injectable icatibant in addition to hospital-administered pdC1-INH may have contributed to the increase in opportunities for therapeutic intervention for attacks.

The advantages of patient-participatory registries are two-way communication and data accumulation. As a result, the design of the study was more suitable for collecting data that reflected patients’ needs. The time of day when HAE episodes are most prevalent had not been reported previously; this study revealed that most episodes coincided with times of day when people are most active, such as commuting to and from work (05:00–09:00 h and 16:00–20:00 h), and of the 38 episodes that were treated, 20 (52.6%) had some prodromal symptoms or triggers. However, attacks frequently reported between 6:00–7:00 may have occurred during sleep and were noticed upon awakening.

Laryngeal edema occurred for few episodes, but gastrointestinal symptoms occurred in the majority. Almost one-third of episodes were not treated, mostly because patients felt symptoms were mild and were reluctant to go to the hospital. However, early intervention is recommended by the guideline for managing attacks of HAE [9]. The widespread use of self-treatment will obviate such reluctance to seek treatment. In a clinical trial with icatibant, symptoms begin to abate in 1.75 h and resolve completely in 5.0 h [10], whereas that with pdC1-INH reported to take 0.5 h before symptoms began to abate after pdC1-INH injection [11]. Our findings, however, show that with icatibant, symptoms started to improve earlier and completely resolved faster than with C1-INH. This result may reflect that icatibant was administered earlier than pdC1-INH.

The total AE-QoL score was 37.1 ± 22.9, close to 39, the threshold of moderate-to-severe impairment of QoL of patients with HAE [6]. Scores in the fatigue/mood and fears/shame domains were particularly high, suggesting that patients with HAE had not only daily physical functions, but also substantial anxiety and fear even without apparent symptoms. Figure 2D shows data from the 24 completed AE-QoL questionnaires. Although ascertainment of whether treatment significantly changed during the study period was not possible, modern and sufficiently effective medications for long-term prophylaxis (e.g., berotralstat and lanadelumab) were unavailable in Japan during this time, suggesting that any changes in HAE treatment protocols were unlikely to substantially affect the AE-QoL scores. This study has some limitations. The sample size of this study is small. We did not collect background information on each patient beyond the information shown in Table 1. Moreover, we did not link each patient to each record or associate attack records or QoL disturbance records.

This study in a patient-participatory registry revealed the basis of QoL in patients with HAE attack episodes, diurnal peaks, and the effectiveness of drugs in treating episodes. The expansion of participants and their time course of clinical observation is warranted for better understanding and management of HAE.