Symptoms of HAE Can Occur Without Swelling Attack: Study

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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Many people with hereditary angioedema (HAE) have non-swelling symptoms, such as rash or fatigue, even when they aren’t having an acute swelling attack, a new study highlights.

“HAE symptoms are not limited to only those experienced during HAE swelling attacks. Many different symptoms (including abdominal symptoms, pain, headache, fatigue, depression, and anxiety) may also occur at different times,” its researchers wrote.

The study, “The symptom experience of hereditary angioedema (HAE) patients beyond HAE attacks: literature review and clinician interviews,” was published in the Orphanet Journal of Rare Diseases. The study was funded by CSL Behring, which sells the HAE treatment Haegarda.

HAE is a genetic disorder marked by recurring episodes of acute swelling, commonly referred to as attacks. In recent years, a number of prophylactic (preventive) medicines have been approved for HAE, including Haegarda, Takhzyro (lanadelumab), and Orladeyo (berotralstat).

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Because these medicines can substantially reduce the likelihood of swelling attacks, and their availability is increasing, clinicians have sought to characterize how HAE affects a person’s life outside of these acute episodes.

Scientists at CSL Behring and other institutions conducted a review of the literature to identify non-swelling symptoms associated with HAE. The review included seven full studies, as well as data from 15 presentations at scientific conferences.

The review identified 20 non-swelling HAE symptoms. Among the most common were fatigue, redness or rash, unusual sensations like tingling or stinging, abdominal cramping or stomach ache, nausea, vomiting, pain, flu-like symptoms, pruritus, and rumbling in the body.

Researchers noted that most of these symptoms were reported just before a swelling attack took place, sometimes referred to as the prodromal period.

Scientists conducted interviews with 11 clinicians with expertise in caring for people with HAE.

“While clinicians reported many of the same symptoms appearing in the literature, their interviews added more detail about these symptoms,” the research team wrote.

Clinicians emphasized the emotional impact that living with HAE can take on patients, noting for example that many people experience substantial anxiety about attacks.

Clinicians all broadly acknowledged that HAE symptoms can occur outside of attacks, though there was some disagreement among the experts as to exactly when some symptoms should be counted as pre- or post-attack, as opposed to during or between attacks.

“Most clinicians described patients experiencing symptoms occurring just prior to the swelling, during the actual swelling episode, after an episode as the swelling subsides, or in between episodes. This reflects how HAE symptoms could occur on a continuum,” the researchers wrote.

Clinicians also said many of their patients who are being treated with prophylactic therapies report that they still sometimes experience symptoms that used to signal a swelling attack was imminent, even though they no longer experience the attack.

“One of the most prominent changes clinicians heard from patients being treated prophylactically with C1 INH inhibitors (such as Haegarda and Firazyr) or monoclonal antibodies (such as Takhzyro) was that they still experienced symptoms associated with attack onset — but now that they were on prophylactic treatment, these symptoms were not followed by an attack,” the researchers wrote.

Scientists next assessed several standardized assessments commonly used to evaluate HAE symptoms to see if they adequately covered non-swelling HAE symptoms. The assessments included the AAS, AECT, AE-QoL, HAE-PRO, HAE-AS, HAE-QoL, and HAEA-QoL. Results generally showed the HAE-PRO provided the best coverage for non-swelling symptoms.

“Only the HAE-PRO, AAS, HAE-AS, and HAEA-QoL adequately assessed the symptoms described in the literature review and by clinicians. Of these four instruments, only the 18-item HAE-PRO identified more than three symptom categories,” the researchers wrote.

Scientists noted, nevertheless, that several symptoms described in the literature and by clinicians — including flu-like symptoms, fever, itching, nausea, tingling, and numbness — were not assessed by any of the instruments.

“The current PRO [patient-reported outcome] tools may not fully reflect the symptom experience of HAE patients across this continuum of symptoms in their everyday lives,” they wrote, noting that more research was needed to better “understand and describe the changes occurring in symptom frequency and severity, attack frequency and severity, and duration for patients living with HAE and starting new prophylactic therapies.”