Ask the experts

For the most-anticipated session of any HAEi conference, a panel of international experts answered questions about the science of HAE and its management. With one hour to work through a stack of submitted questions, the panel of Professors Bruce Zuraw, Henrietta Farkas, Anete Grumach, Connie Katelaris, and Dr Ankur Jindal had to keep their answers brief. We present a summary of the questions and answers here.

If a patient has diagnoses of both mast cell activation syndrome (MCAS) and HAE with normal C1-inhibitor, how does that impact treatment, particularly where angioedema is prominent?

The panel expressed some concern about the diagnosis of both MCAS and HAE with normal C1 inhibitor, and that it was extremely unusual if this was the case. Both conditions lack clear diagnostic criteria and are often diagnosed incorrectly. Their view was that it is likely one or the other, and that should guide appropriate treatment.

Do oral on-demand medications currently available or in development work as fast as injectable medications? 

Overall, the panel suggested that the clinical trial data showed oral treatments worked about the same.

How do you decide when a patient should transition from on-demand treatment to long term prophylaxis?

The clinicians suggested that the most commonly used measures are the frequency of episodes, combined with their impact on the patient’s life. Understandably, this is not the situation in every country. In the US, it is more about giving patients the best quality of life. In countries with fewer resources or less access to medication choices, it may be more about just how many attacks occur in a given time period.

The panel made it clear that tracking attacks and their impact is extremely valuable and noted that the HAE TrackR app is a good option for doing so.

How does an oral preventative therapy (berotralstat) compare to injectable therapies?

The panel welcomed the availability of a different option, as it allows for more personalized treatment for people with HAE. Mo medicine will work for 100% of patients 100% of the time. One panelist mentioned that around 75% of patients benefit, and when they do, they appreciate it.

Do injectables have an impact on vein health or the risk of thrombosis?

The panel made clear that all doctors treating HAE take side effects very seriously, and balance the benefits of treatment with the potential for them to cause problems. Studies have shown medicines for HAE are generally well tolerated by patients, but that real life can be different. In close monitoring of patients, they haven’t seen thromboembolic (blood clot) events in commonly used injected treatments.

The consensus was that modern medicines have minor side effects but are safe and well-tolerated.

How does CRISPR-Cas9 gene therapy work? Why was it decided to focus on plasma kallikrein instead of C1 inhibitor?

The panel suggested that the SERPING1 gene, responsible for many HAE cases, is extremely large, with many hundreds of potential mutations or pathogenic variants detected. These mutations cause uncontrolled kallikrein activity, so targeting kallikrein seems reasonable. The panel believed that switching off kallikrein production would not be harmful to the body, beyond preventing HAE attacks.

To date, gene therapy has led to some short-lived adverse reactions, but these were not severe. If the clinical trials continue to show effectiveness, the panel likened the treatment to a functional cure. It means that with a one-off treatment, a patient would no longer experience any HAE symptoms. However, their underlying genetics wouldn’t change, and their children could still inherit HAE.

Can you still have attacks after two infusions of the gene therapy?

The panel suggested that in the trials, patients could still have attacks for a few months. This is because it takes time for the gene to be fully incorporated and for the changed cells in the liver to be produced.

Can patients with HAE take weight loss medication such as Ozempic?

The panel suggested that there was nothing known that would prevent patients with HAE from taking these GLP-1 medications.

Patients with HAE can experience worsening of symptoms during the menopause. What are the best treatment options recommended?

The panel suggested that patients experiencing menopause should avoid oestrogen-based medicines as these are likely to exacerbate HAE. Additionally, there are medicines to support women with menopausal symptoms unrelated to HAE, and these are safe for patients to try using.

Overall, the advice was to consult your doctor if you have a worsening of your HAE for any reason.

Is it possible to use saline solution instead of the water supplied in the kits of C1-inhibitor concentrate?

No. You should always use the items supplied in the package and follow the instructions to reconstitute the medicine before use.

Would Botox or fillers trigger an attack?

The panel did not believe that Botox would trigger an attack, but the trauma of an injection could trigger an acute episode. Of more concern is Botox used in or around the lips or throat, as it may lead to a life-threatening attack. The panel expressed some concern about the use of fillers, as this can lead to pressure and tissue expansion, which is more likely to trigger swelling at the site.

When do I stop being an advocate and start being a patient when seeing my doctor?

The panel admitted this was more philosophical than scientific, but stressed the importance of patients having a relationship with their doctor based on trust and confidence. It means that in any two-way communication, you can be sure your doctor understands your needs.

Can people with HAE manage without medication? Can they be spontaneously cured?

According to the panel, there are periods when patients experience fewer attacks. HAE is an unpredictable condition. Even within families, the number of attacks can vary widely. It is estimated that 5% of people with HAE have no symptoms. HAE can therefore appear to be ‘cured,’ but this is likely to be a period of improvement that could change with a trigger such as stress.

Can IVF be used to prevent HAE from being passed on to children?

The panel suggested that only one case has been published, and this was successful, with healthy newborns. There is the potential to test unborn children for HAE, but we cannot predict the severity.

How reliable is a negative test for HAE type one in a child? Could they later develop the disease?

The panel said that the tests are very reliable if done well by a reliable laboratory. If the child has received these results, then it would definitely rule out HAE type one, but two tests are needed to exclude the possibility completely.

What are the treatment options for children under two years old?

The answer here was essentially C1 inhibitor concentrate treatment.

What can be done about marriage in countries where HAE may be stigmatized?

The panel accepted that, once again, this was less a scientific question and more a societal one. However, the panel understood how complicated and challenging this is. Their advice was to be honest, as it would be difficult, if not impossible, to hide HAE completely. Getting effective medication can go a long way to resolving this issue, as HAE becomes a manageable condition.

This question was also raised to RPAs during a session on Friday morning: The RPAs sympathized with the issues raised, and suggested that by speaking about the condition, it is possible to address stigma. As with the experts, the RPAs emphasized that access to effective treatment was most important, demonstrating that HAE is a condition that people can live with and is not something to fear or be ashamed of.

What can I do to manage my anxiety about HAE attacks?

The panel was aware of the impact of stress on HAE and recognized the importance of managing this, and the burden that chronic and rare diseases have on people’s mental health. They recommended techniques such as relaxation and mindfulness as helpful ways to manage anxiety. They also suggested seeking help from a professional psychologist or counsellor, who can provide specialized support.

Do indigenous peoples, such as those in parts of Brazil, have similar rates of HAE to those of other populations?

There was no known data on this. However, the panel believed that the incidence would be the same as in the general population.

Is there any genetic link between HAE and Ehlers-Danlos syndromes?

The panel was clear: No.

How should patients advocate for themselves if their doctor dismisses their symptoms or ignores their existing HAE diagnosis?

The panel suggested reaching out directly to an expert center, such as an accredited ACARE center or an HAE center of excellence. If your doctor is not supporting you, then find one that will.

The panel recommended that patients be as well-informed as possible about their HAE. Knowing about your HAE improves communication and ultimately leads to better treatment.