Researchers Develop New Tool to Measure Disease Activity Specifically in Hereditary Angioedema Types 1 and 2

Researchers have developed a new tool that measures disease activity specifically in people with hereditary angioedema due to C1-inhibitor deficiency (C1-INH-HAE), which could prove useful in the medical care of patients and for assessing outcomes in clinical trials.

The Hereditary Angioedema Activity Score (HAE-AS) was described in the Journal of Investigational Allergology and Clinical Immunology, in an paper titled “HAE-AS, a specific disease activity scale for hereditary angioedema with C1-inhibitor deficiency.”

C1-INH-HAE refers to hereditary angioedema (HAE) types 1 and 2, which are both caused by mutations in the gene encoding the C1-inhibitor (C1-IHN) protein. In type 1, mutations prevent the production of enough C1-IHN, whereas in type 2, these mutations lead to the production of a less effective protein.

A relatively objective measurement of disease activity would help in the medical care of people with angioedema, a disease that can vary between patients and within the same individual over time. Such measurements are particularly critical for clinical trials to determine whether a therapy under investigation has an effect on disease activity.

Currently, no tool is available to measure disease activity in C1-INH-HAE specifically. The Angioedema Activity Score is a tool that can be applied broadly to anyone with angioedema, but it’s not well-suited for use in people with C1-INH-HAE because of its relatively short timescale (one month) and because it needs to be completed daily, creating a high burden for patients.

In the new study, researchers set out to create a questionnaire that could be used to measure disease activity specifically in C1-INH-HAE, with relative speed and simplicity.

They designed the HAE-AS with 14 items to assess the frequency, severity, and location of attacks, as well as the impact of the disease on daily life (i.e. having to miss work or finding daily activities difficult due to pain). Psychiatric treatment and emergency room visits were also included. Notably, all but two items had a time frame of six months, rather than one.

“These clinical items were chosen based on a literature review, patient interviews, and discussion with physicians who have extensive experience in the management of C1-INH-HAE,” the researchers wrote.

The HAE-AS questionnaire was completed by 290 adults (69% female, average age of 41.5 years) with C1-INH-HAE in 11 countries around the world. Most had HAE type 1 (80.0%) and a family history of C1-INH-HAE (69.7%).

The respondents’ HAE-AS scores were fitted into a Rasch model, which is basically a statistical framework for analyzing relatively subjective measurements. The best model was developed when two items on the original HAE-AS were excluded; therefore, the final tool had 12 items, scores of which were used for the subsequent analyses.

The average HAE-AS score was 10.66. Further statistical analysis suggested that a score of about 12 could be used as a cutoff for severe disease with high sensitivity and specificity (the rate of correctly identified true positives and true negatives, which were 73.2% and 88.3%, respectively).

On average, HAE-AS scores were 1.597-times higher among female respondents and were 1.182 points higher among respondents who had an earlier onset of clinical symptoms; both of these differences were statistically significant and in agreement with other studies.

Additionally, HAE-AS scores were associated with scores on the HAE-QoL — an assessment of quality of life specific to HAE — with higher HAE-AS scores being significantly correlated with lower HAE-QoL scores. In other words, respondents with more disease activity reported lower quality of life.

HAE-AS scores also similarly correlated, albeit to a lesser extent, with SF-36v2 scores, a more general measurement of quality of life. These findings broadly indicate that HAE-AS scores are in alignment with similar tools currently in use.

“In conclusion, we present the first validated scale developed specifically for measuring C1-INH-HAE activity,” the researchers wrote. “We recommend the use of HAE-AS in future studies on C1-INH-HAE.”