Decoding Hereditary Angioedema: Expert Insights with Dr. Stephen Betschel

“HAE is a different disease than it was because of the advancement of treatments…make sure that you're offering the best form of therapy available to patients and their families.”  -- Dr. Stephen Betschel

Join Dr. Mariam Hanna in an enlightening conversation with Dr. Stephen Betschel, an associate professor in the Department of Medicine and Clinical Immunologist and Allergist at St. Michael's Hospital, University Health Network. Dr. Betschel, a global authority on hereditary angioedema (HAE), shares his extensive knowledge on this rare and potentially life-threatening condition.

On this episode:

Understanding Hereditary Angioedema:

Dr. Betschel provides a detailed explanation of HAE, an autosomal dominant condition characterized by C1 inhibitor deficiency. He discusses how this deficiency leads to the overproduction of bradykinin, causing swelling in various parts of the body, including the hands, feet, face, abdomen, and throat.

Types and Diagnosis:

Explore the different types of HAE (type 1, type 2, and hereditary angioedema normal) and the importance of accurate diagnosis. Dr. Betschel explains the diagnostic process, which includes measuring C4 and C1 inhibitor levels and function, and emphasizes the role of clinical and family history in identifying potential cases. Genetic testing can also be useful in certain cases.

Clinical Manifestations and Triggers:

Learn about the varying clinical manifestations of HAE, which can differ significantly even among patients in the same family. Dr. Betschel highlights common triggers for HAE attacks, such as infections, trauma, and spontaneous episodes, emphasizing the importance of understanding these triggers for effective management.

Management and Treatment:

Discover the latest advancements in HAE treatment, including on-demand therapies for acute attacks and long-term prophylaxis options. Dr. Betschel discusses medications such as Icatibant, intravenous and subcutaneous C1 inhibitors, and the promising future of oral treatments and gene therapy.

Patient Care and Support:

Dr. Betschel underscores the importance of providing comprehensive care and support for HAE patients. He advises healthcare providers to engage with patients actively, optimize attack control, and improve quality of life through personalized treatment plans.

Tune in to this episode for an in-depth exploration of hereditary angioedema, offering valuable insights and practical advice for healthcare providers.

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Transcript

Dr. Mariam Hanna:

Hello, I'm Dr. Mariam Hanna, and this is The Allergist, a show that separates myth from medicine, deciphering allergies and understanding the immune system.

As a resident, we had a patient who presented numerous times to the hospital with recurrent abdominal pain, even needing exploratory laparoscopy. During their long and frustrating journey, they had many blood tests, too many to actually tell you about. Imaging was also done, numerous specialty consultations, and finally, immunology was consulted. I was surprised as a trainee that on differential was hereditary angioedema. Intrigued, I was thinking perhaps this condition was my first glimpse into how allergists and immunologists earn their coveted zebra stripes for atypical presentations and rare disorders. On the patient side, it served as a reminder of the difficult and sometimes long medical journey patients go on to get to the right diagnosis.

In today's episode, we're going to go and explore the world of hereditary angioedema, and today we have a global leader on this very condition. Joining us to share his knowledge and insights, allow me to introduce Dr. Stephen Betschel. He's an associate professor in the Department of Medicine and Clinical Immunologist and Allergist in the Division of Allergy and Clinical Immunology at St. Michael's Hospital at the University Health Network. He currently serves as chair for the Canadian Hereditary Angioedema Network and as medical advisor for HAE Canada. He's the lead author on Canadian and international guidelines for HAE and serves on the steering committee for the World Allergy Organization for hereditary angioedema guidelines. Dr. Betschel is an invited speaker and presenter at numerous local, regional, national, and international medical conferences, which is why I was especially delighted that he said yes when we invited him to come on this podcast. Dr. Betschel, thank you so much for taking time out of your busy schedule to join us and welcome to the podcast.

Dr. Stephen Betschel:

Mariam, thank you so much for that very kind introduction, and let me thank you also for the invitation. It was very easy for me to say yes when I get to talk about hereditary angioedema. I think you gave that great segue into your perhaps first experience with an HAE patient where it seems like a mystery, but when you know what's going on, it's pretty easy to diagnose. So I'm looking forward to having this conversation and hopefully others who listen in will also gain some insights on this very unique and fascinating condition.

Dr. Mariam Hanna:

Fascinating it is. Okay, so let's start first with the basics. Can you give us all just a brief overview of what hereditary angioedema is?

Dr. Stephen Betschel:

Sure. So hereditary angioedema, as you point out, is hereditary. It’s an autosomal dominant condition where 50% of offspring can inherit the disease. It is a disease of C1 inhibitor, so C1 inhibitor dysfunction through either lack of production or through the inability of C1 inhibitor to get out of the cells leads to C1 inhibitor deficiency. C1 inhibitor is a key mediator in regulating the production of bradykinin. Bradykinin is that molecule that interacts with the bradykinin 2 receptor on the surface of endothelial cells. When there is overproduction of bradykinin, it leads to swelling, typically involving the periphery, such as the hands and feet. It can involve the face where lips and tongue can swell. You can get swelling in the abdomen, much like you discussed in your patient that you saw when you were a resident with very significant, excruciating abdominal pain. Genitalia can swell. Most concerning though is swelling of the retropharyngeal laryngeal swelling, which is life-threatening. It is concerning because swelling in patients with C1 inhibitor deficiency or hereditary angioedema can be triggered by infections, trauma, or can occur spontaneously. Spontaneous swelling of the retropharynx or the larynx can lead to asphyxiation. If patients aren't diagnosed, they can actually die from lack of oxygen getting to the brain.

Dr. Mariam Hanna:

Wow. And this is one of the screening questions that I recall even from fellowship: has anyone passed away from asphyxiation? Do we still see misdiagnosis in patients presenting with asphyxiation?

Dr. Stephen Betschel:

Yeah, unfortunately, it still is an issue. Today we estimate that about 60-70% of patients in Canada are diagnosed, but that leaves about 35% of patients undiagnosed. If you're undiagnosed, your risk of asphyxiation is about 35% going forward. So yes, it's very important to make this diagnosis early to prevent that life-threatening complication. Because it’s an autosomal dominant condition, once you've made the diagnosis, you should be able to track other family members. Unfortunately, because there are so many that are still undiagnosed, that is a realistic potential situation.

Dr. Mariam Hanna:

What are the different types of hereditary angioedema?

Dr. Stephen Betschel:

Sure, and I think you can probably envision it best as thinking of them as three different types. The first one, HAE type 1, affects about 85% of patients and it is a deficiency of C1 inhibitor where the level and the function are low. The C4 is almost always low except between attacks. Sometimes, about 10% of patients can have normal levels of C4. Hereditary angioedema type 2, which is about 15% of patients, involves normal C1 inhibitor antigenic levels but low function. These patients also have low C4 between attacks and about 10% can have normal C4. There is also another type called hereditary angioedema normal, formerly hereditary angio type 3, which is characterized by normal biochemical markers (C4, C1 inhibitor level, and function). These patients typically have a family history and present with the same type of swelling that patients with HAE type 1 and type 2 have. I want to highlight a Canadian contribution here: the first case of hereditary angioedema type 3 was published in Canada at the same time as in Germany. Dr. Binkley, a Canadian, was the first to describe this condition, identifying a problem with factor 12. A gain of function mutation leads to the swelling. We now know of six known mutations, and that list is growing.

Dr. Mariam Hanna:

We've talked a little bit already about the different clinical manifestations that patients can have with angioedema. Do they tend to vary within the same patient and do they vary from one patient to the next?

Dr. Stephen Betschel:

Yeah, that's a great question. The pattern of swelling can vary not only within the same patient over time but also between patients. A patient can be asymptomatic and have their first swelling at age 30, or even in their seventh decade of life. The frequency and types of swelling can vary. Patients may experience periods where they only have swelling of their hands, abdominal swelling, or laryngeal swelling. It's difficult to predict the type of swelling, and the type of swelling one has on one occasion doesn't predict the location of swelling at other times. What is more consistent are triggers. Patients often know what triggers their swelling, and these tend to be uniform over a lifetime. Variation within a patient is also seen between patients in the same family. Patients in the same family can have completely different patterns of swelling, frequencies, locations, and severity. It's quite heterogeneous in terms of clinical presentations.

Dr. Mariam Hanna:

Which is part of the challenge when we think about the differential diagnosis. When should we be thinking about HAE because of these varying presentations, even among the same family members? What should be considered in our differential diagnosis when we see a patient for suspected HAE? We're kind of all biased being in allergy and immunology to think of HAE, but what else is part of that differential from our side?

Dr. Stephen Betschel:

Unfortunately, many of these patients collect a list of allergies they've been told they have because they present somewhat similarly. The key difference in the types of swelling we see, so the histaminergic or histamine-mediated types of swelling, tends to be very rapid in onset and respond well to antihistamines, corticosteroids, and sometimes epinephrine, depending on the cause of the underlying histamine-mediated swelling. The difference you see with hereditary angioedema is the swelling tends to be more insidious, coming on more slowly. Additionally, it doesn't respond to typical histamine-directed therapies. Antihistamines, corticosteroids, and epinephrine are not effective for this type of swelling. These should be some of the clues that help separate out the common types of swelling we see in histaminergic angioedema. Even the spontaneous types, what used to be called idiopathic types, are much more common than hereditary angioedema. Those key clinical features are important. The other thing, as you mentioned in your patient, is that they can present with abdominal pain. When you link episodes of swelling that don't respond to typical histamine-mediated treatments with a history of abdominal pain and especially a family history, that combination has a specificity of nearly 95%.

Dr. Mariam Hanna:

I didn't realize it was 95%. No, sorry, I'm impressed. That's why the immunology department was called. Okay, that's impressive. Keep going. Sorry.

Dr. Stephen Betschel:

Yeah, so it's very high if you have those features. And then the other thing, once you suspect it, it's fairly easy to diagnose. The difficulty is just in considering it and thinking about it. It's a rare disease. One in 50,000 patients will have it, and you can't expect emergency rooms to be aware of these rare conditions all the time. But once they suspect it and they're sent in our direction, doing the C4, C1 inhibitor level, and function should be very easy no matter where you practice.

Dr. Mariam Hanna:

Which leads into current best practices for diagnosing HAE. So I heard C4, C1 inhibitor level, titer, and function. Is genetic screening routine nowadays?

Dr. Stephen Betschel:

So you raised a good point, and you're right. C4, C1 inhibitor level, and function should be done and not only done but repeated to confirm the diagnosis. Now, where does genetics come in? For type 1 and type 2, often genetics isn't required; it's a biochemical diagnosis. It can be helpful, though, and where it can be helpful is if you're going to screen patients where it's a little uncertain, they may be in the same family, but the mutation is known. The difficulty is randomly doing testing. There are over 600 different mutations in the gene that encodes C1 inhibitor that are associated with type 1 and type 2. So in and of itself, it is not very helpful as a screening method unless you have the confirmed variant in a family member. And where it can be very helpful is screening in children before they may present with symptoms and before the biochemistry is consistent with type 1 and type 2. It can be falsely diagnosed early on in infancy where if you have the genetic mutation you can screen to confirm the diagnosis.

Dr. Mariam Hanna:

I see. How often do you end up repeating laboratory testing on patients that you are seeing or suspecting the diagnosis?

Dr. Stephen Betschel:

Yeah, so there is very little reason once you've confirmed the diagnosis of type 1 or type 2 HAE, there's really no reason to repeat the testing. There has been some talk that if patients are on C1 inhibitor replacement, you might be able, if you get the C1 inhibitor functional assay above a certain level, they might be less likely to swell. That's really theoretical at this point. And really, you would titrate any treatments, which we might talk about, based on the clinical response, not to any biochemical level. So once the diagnosis is there, there'd be very little reason to reassess that.

Dr. Mariam Hanna:

Okay. So then let's flip on to treatment then, since we're not following it biochemically. Let's talk about first advancements made in the treatment of HAE, what's available now, particularly in medications and approaches to managing HAE.

Dr. Stephen Betschel:

So treatment just broadly can be divided into on-demand. So when patients have an attack, what do they use to rescue themselves from that attack? The greatest risk with somebody with hereditary angioedema and procedures are those upper airway manipulations, invasive dental surgery, intubations, they can lead to localized angioedema. So protecting around that time of that intervention to minimize the risk of an attack. Now, so for acute therapy, the current treatments that are available in Canada would be Icatibant, which is a subcutaneous bradykinin 2 receptor antagonist. Then there's also intravenous C1 inhibitor, so giving back that C1 inhibitor that's missing and that's an intravenous infusion. Then all patients, even if they're on long-term prophylaxis and they're doing well, must have access to at least two treatments to enough treatment to treat two attacks. And then what about long-term prophylaxis? So there are a number of agents and Canada sort of led the way in this in terms of access to some of those therapies. But the first modern therapy you can think of is just giving back the C1 inhibitor. So intravenously Berinert was and still is available and it's usually given every three to four days. That can also be given subcutaneously in the form of Haegarda that's recently approved and licensed in Canada and available. And that again is a subcutaneous C1 inhibitor infusion every three to four days. There also is though a monoclonal antibody that's directed against kallikrein, and kallikrein is a key mediator in the development of bradykinin. So this is a small volume subcutaneous injection every two or even up to every four weeks that's given to block kallikrein production. Now kallikrein's important and you can inhibit it with the injection. There's also an oral agent called Berotralstat or Orladeyo, and that is an oral therapy that can be used to prevent attacks for types 1 and type 2.

Dr. Mariam Hanna:

So what do you typically monitor in patients that are on long-term management for HAE to know that you have them on the right level of control? What are markers that we've accomplished our job as allergists in managing these patients?

Dr. Stephen Betschel:

And that's a good question because it used to go with the older therapies and the side effects with the androgens, you would have to titrate effect to side effects. Now we're not really seeing side effects with these modern therapies. Really nothing significant or severe related to those treatments. So the focus really has been, and this is borne out in the guidelines, it's been borne out in a Delphi goals of treatment for HAE. The goal of treatment really is to normalize patient's lives, allow them to have a quality of life. They almost don't have HAE and that really is often predicated on the idea of reducing the number of attacks to zero or total control, and that has been achievable in some patients with some of these therapies. So you really want to make sure that patients are having the least number of attacks as possible, and if that is occurring, then you can almost be guaranteed that their quality of life is improving as well. There are very specific measuring tools that can be used. So there's the angioedema control test, that's one that can go back over the past month to see how many attacks and how bothered patients are by those attacks. So now it's gone away from monitoring for side effects to really trying to optimize that attack control and ultimately control quality of life, sorry, improve quality of life. I meant,

Dr. Mariam Hanna:

I actually remember during fellowship we had somebody that was on androgen therapy and we talked about side effects and titrating for effect and monitoring side effects. Do you discuss any common side effects routinely now for the newer generation of HAE therapies that we have? And if so,

Dr. Stephen Betschel:

So not so much. So C1 inhibitor, we've had experience with C1 inhibitor for a very long time, and we have not just us in Canada, but where it's been used in Germany for many decades, there really are no known side effects other than the intravenous administration, if it's being used intravenously or local side effects, intolerance issues when it's used subcutaneously, the other agents such as lanadelumab, again, it's a subcutaneous injection, so local side effects reactions, but very uncommon to have anything more than that. Orladeyo, the oral kallikrein inhibitor side effects associated with that tend to be more gastrointestinal. They tend to be short-lived and often get better as patients continue on treatment. There are some drug interactions with Orladeyo that need to be considered, but side effects just really are not a concern with these modern therapies like we saw with the older therapies.

Dr. Mariam Hanna:

Fantastic. Okay. And so Canadians, as you said, have led the charge on many aspects of HAE, but I'm curious because of the tables that you sit at Dr. Betschel, how is HAE managed differently around the world and what can we learn from the international community that may be coming down the pipeline for us?

Dr. Stephen Betschel:

Yeah, so Mariam, I'm so glad you asked me this question because I must say we're somewhat privileged in Canada. Canada is often seen as a bit of a beacon in terms of availability of therapies and almost universal availability of therapies to treat a rare condition. So we really do lead the way in that regard and other countries have similar access and reimbursement for these treatments as well. What I think we're trying to do on these international, with these international groups and the patient international advocacy group, HAEI, has been very good at trying to ensure that patients all around the world get access to these therapies. Now when that's done, great strides will be made, but there are great strides coming even for countries who have therapies that are available to them now. And what we may be seeing in the not too distant future is an oral treatment. So an orally administered treatment for an attack. So right now it's either a subcutaneous or an intravenous injection, but there may be in the not too distant future an oral agent that you can take first sign of an attack. So that'll be a considerable advancement for availability and access and ease of treatment for patients. Also, some of the things that are being investigated are kallikrein inhibitors that can go on with half of up to 90 days. So the frequency of injections may be three or six months. So really decreasing the burden of treatment. Gene therapy is being looked at as well. There were some recent clinical trials, they've been paused, unfortunately not because as I understand any safety concerns, but more because of the marketplace concerns of gene therapy. But the future is certainly bright, it's been bright for the past 10 years with these new therapies and it's not stopping. The patients will have a lot of options and hopefully continue to see that grow in our country and other countries and really hopefully make life-saving therapy to patients in countries that don't have that currently.

Dr. Mariam Hanna:

If I may ask, what is the secret to the success of HAE research and developments that we can learn from for other areas and other diseases?

Dr. Stephen Betschel:

It goes back, I'm going to say again another shout out to Canada. Back to the first iteration of the guideline. The international guideline was a Canadian guideline that was put together by Tom Bowen, a pediatric allergist out in Calgary when he had a patient that he didn't know anything about and he decided to convene a number of international experts and immunologists across Canada to put together this consensus document back in 2003. So just over two decades ago, that community from that time forward has been extremely active and close-knit on a physician treater research side. Also, industry has been very much engaged with this community as well and always very interested to interact and to move things forward from a treatment perspective. What is also critical and has been extremely important in this is patient involvement and advocacy and the patients were involved in that first iteration of the consensus document. They continue to have a voice in all the subsequent iterations. After that, Canada has very cohesive patient organizations, HAE Canada as well as AOHQ and Quebec. And there's also a very strong advocacy voice from the international group who's really in the past 10 years has brought together, and I can't remember the number of countries, but I think there are about 86 to 90 countries that are linked into that umbrella patient organization. So it's no one thing that's brought it together. It's many things, treaters industry and most importantly patients have been key in pushing this forward, in getting this done. The other key differences, and I know compared to other conditions it's fairly, is homogeneous. So it is a fairly specific disease where we'd have an easy diagnosis. So that has also helped along the way, but it really has been an international multi-stakeholder engagement that has led to the success and the strides that have been made in many countries. But there's still more work.

Dr. Mariam Hanna:

Yeah, still more work to do, but truly an example for other diseases and other conditions that we manage in healthcare. Before we wrap up, I would like your perspective on key points that we should be emphasizing as allergists when we're educating our patients and their families about living with hereditary angioedema.

Dr. Stephen Betschel:

Yeah, and I think Mariam, I think there's overlap between what I try to reinforce with patients and also treaters, is that what we just talked about, there's been significant evolution in the ability to treat HAE and I think patients, particularly older patients who may have been familiar with that time when they would go to the hospital and not have a diagnosis, almost refrain from seeking healthcare, that it doesn't have to be like that. So there are treatments now that will really change how many of these patients have had to suffer historically and even currently. So I think that's important. So to engage your healthcare provider to consider treatments, to really optimize control of the attacks and normalize quality of life. Once you make that diagnosis, you can have a considerable impact, not just on that one patient, but a family of patients, potentially.

Dr. Mariam Hanna:

Powerful words to end by. Alright, time to wrap up. If there's any more wisdom, I will take it and ask today's allergist, Dr. Betschel, for his top three key messages to impart to patients and physicians on today's topic: hereditary angioedema. Dr. Betschel, we're all ears and willing to listen to any additional advice you give us over to you.

Dr. Stephen Betschel:

Right. So I think the key three takeaway messages are, understand that HAE is a different disease than it was because of the advancement of treatments. Keep up to date so you can keep your patients up to date and keep it top of mind to make sure that you're offering the best form of therapy available to patients and their families.

Dr. Mariam Hanna:

Fantastic. Thank you, Dr. Betschel, for joining us on today's episode of The Allergist.

Dr. Stephen Betschel:

Thank you, Mariam.

Dr. Mariam Hanna:

This podcast is produced by the Canadian Society of Allergy and Clinical Immunology. The Allergist is produced for CSACI by PodCraft Productions. The views expressed by our guests are theirs alone and do not necessarily reflect the views of the Canadian Society. This podcast is not intended to provide any medical advice to our listeners. Please visit www.csci.ca for show notes and any pertinent links from today's conversation. The Find an Allergist app on the website is a useful tool to locate an allergist in your area. If you like the show, please give us a five-star rating and leave a comment wherever you download your podcast and share it with your networks because in the journey of rare disorders, allergists are here to help. Thank you for listening. Sincerely, The Allergist.