Highly Unpredictable Rate of Annual Attacks Seen in Certain Patients

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by Patricia Inacio PhD |

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Over a third of hereditary angioedema patients continue to experience an unpredictable rate of annual attacks, including those on long-term preventive therapy, a retrospective analysis shows.

These findings highlight the variability of the disease and support the need for constant vigilance by patients and their doctors.

The study, “Variability of disease activity in patients with hereditary angioedema type 1/2: longitudinal data from the Icatibant Outcome Survey,” was published in the Journal of the European Academy of Dermatology and Venereology.

Hereditary angioedema (HAE), types 1 and 2, is a rare genetic disorder that can be caused by genetic mutations in the SERPING1 gene, which carries the instructions for making a protein called C1-inhibitor. The disease is characterized by sudden and recurrent episodes of swelling in the face, tongue, hands, feet, gastrointestinal tract, genitalia, and upper airways.

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HAE results in varying symptoms across patients and over the course of the disease. Despite this, few studies have assessed its variability over time, even though this would be valuable for treatment management.

Now, a team led by researchers in Germany analyzed data from the Icatibant Outcome Survey (IOS, NCT01034969), an ongoing international, observational registry study monitoring the outcomes of HAE patients being treated with Firazyr (icatibant injection) and/or Cinryze (C1 inhibitor). The team’s goal was to characterize temporal changes in disease activity in these patients. Both Firazyr and Cinryze are commercialized by Takeda Pharmaceuticals.

The researchers analyzed data from 607 patients with HAE type 1 or 2 in 12 countries, specifically the attack rates in the 12 months prior to study’s enrollment and then for every year up to seven years.

Of all the patients, 292 on long-term preventive treatment (prophylaxis; median age 39.5 years at enrollment) and 315 not on such treatment (median age 38.4 years at enrollment) reported attacks during follow-up. The majority of patients in both groups were women diagnosed with HAE type 1 (95.9% of the long-term preventive therapy group and 92.7% of those not on prophylaxis).

Attenuated androgens were the most frequently used preventive treatment (80.8%), followed by tranexamic acid (40.1%), and plasma-derived C1 inhibitor (26.4%).

The analysis of the overall population, regardless of being on long-term preventive therapy or not, showed that the median number and severity of annual attacks did not change significantly over time.

Most patients (52%–80%) experienced less than five attacks in the first year, and continued with a low attack frequency in the following years. Among those who reported a higher attack frequency (10 or more attacks per year), 25%–76% continued to experience this high attack rate in the following years.

The researchers then evaluated the annual attack frequency from year to year and how it varied. For this analysis, they categorized the changes as a difference compared with the previous year for three groups: below five attacks, from 5–10 attacks, or above 10 attacks per year.

The results showed that in patients not on long-term prophylaxis, 35% experienced a moderate (5–10 attacks) or high (10 or more) increase from the first to second year. In subsequent years, this proportion varied between 31% and 51%.

In turn, a slightly higher proportion of patients on long-term prophylaxis reported no such yearly change increase.

Among patients who reported little change in attack frequency between year one and two, 52%–80% on prophylaxis and 43%–70% not on prophylaxis continued to report no notable changes.

However, patients with a notable change after the first year (increase/decrease of five or more attacks) continued to experience fluctuating disease activity.

These changes were particularly inconsistent among patients not on prophylaxis, with 50%–77% of them still experiencing changes (of five or more attacks) for up to five years of follow-up. Also, 17%–50% of patients with a higher rate of attacks (10 or more) between year one and two continued to experience marked changes for up to six years of follow-up.

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Overall, this study shows that certain HAE patients often experience an unpredictable rate of attacks, including those on long-term prophylaxis.

“At the population level, the frequency and severity of attacks per patient per year following IOS [enrollment] were generally consistent over the 7-year analysis period, confirming the chronic nature of the disease,” the researchers wrote. However, “although disease activity may be more or less consistent for many patients, those who report a notable change in annual attack frequency may continue to experience changes of similar magnitude for several years.”

Specifically in this study, up to half of the patients not on preventive treatment and up to one-third of patients on preventive treatment experienced fluctuating disease activity.

“The high variability in attack frequency observed … reflects the need for patients and physicians to continually evaluate disease activity and ensure that acute treatment can be accessed and [preventive treatment], when needed, is optimized,” the team wrote.