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CME / ABIM MOC

Practice Points in Hereditary Angioedema: Experts Weigh In on Challenging Cases

  • Authors: Marc Riedl, MD; Paula Busse, MD; H. Henry Li, MD, PhD
  • CME / ABIM MOC Released: 7/11/2022
  • Valid for credit through: 7/11/2023
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  • Credits Available

    Physicians - maximum of 0.50 AMA PRA Category 1 Credit(s)™

    ABIM Diplomates - maximum of 0.50 ABIM MOC points

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Target Audience and Goal Statement

This activity is intended for allergists, clinical immunologists, primary care physicians, and pediatricians.

The goal of this activity is that learners will be better able to improve the quality of life of patients with HAE by focusing on patient-centric treatment aims.

Upon completion of this activity, participants will:

  • Demonstrate improved performance associated with
    • Communicating treatment expectations to patients with HAE
    • Aligning treatment recommendations to patient preferences
  • Demonstrate greater confidence in their ability to
    • Navigate the differential diagnosis of HAE


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Moderator

  • Marc Riedl, MD

    Professor of Medicine
    Clinical Director
    US HAEA Angioedema Center
    University of California San Diego
    San Diego, California

    Disclosures

    Marc Riedl, MD, has the following relevant financial relationships:
    Consultant or advisor for: Astria; Biocryst; Biomarin; CSL Behring; Cycle Pharma; Ipsen; Kalvista; Ono Pharma; Pharming; Pharvaris; RegenexBio; Takeda
    Speaker or member of speakers bureau for: CSL Behring; Grifols; Pharming; Takeda
    Research funding from: Biocryst; Biomarin; CSL Behring; Ionis; Kalvista; Pharvaris; Takeda

Faculty

  • Paula Busse, MD

    Associate Professor
    Department of Medicine
    Division of Clinical Immunology
    The Mount Sinai Hospital
    New York, New York

    Disclosures

    Paula Busse, MD, has the following relevant financial relationships:
    Consultant or advisor for: Biocryst; CVS; Kalvista; Novartis; Regeneron
    Research funding from: Amgen; Biocryst; CSL Behring; Kalvista; Takeda

  • H. Henry Li, MD, PhD

    Allergist and Immunologist
    Institute for Asthma and Allergy
    Wheaton and Chevy Chase, Maryland

    Disclosures

    H. Henry Li, MD, PhD, has the following relevant financial relationships:
    Consultant or advisor for: Biocryst; CSL Behring; Ionis; Kalvista; Pharming; Pharvaris; Takeda
    Speaker or member of speakers bureau for: Biocryst; CSL Behring; Pharming; Takeda
    Research funding from: Biocryst; CSL Behring; Kalvista; Pharming; Pharvaris; Takeda

Editor

  • Karen Badal, MD, MPH

    Senior Medical Education Director, Medscape, LLC

    Disclosures

    Karen Badal, MD, MPH, has no relevant financial relationships.

Compliance Reviewer

  • Susan L. Smith, MN, PhD

    Associate Director, Accreditation and Compliance, Medscape, LLC

    Disclosures

    Susan L. Smith, MN, PhD, has no relevant financial relationships.

Peer Reviewer

This activity has been peer reviewed and the reviewer has disclosed no relevant financial relationships.


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CME / ABIM MOC

Practice Points in Hereditary Angioedema: Experts Weigh In on Challenging Cases

Authors: Marc Riedl, MD; Paula Busse, MD; H. Henry Li, MD, PhDFaculty and Disclosures

CME / ABIM MOC Released: 7/11/2022

Valid for credit through: 7/11/2023

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Activity Transcript

Marc Riedl, MD: Hello, I'm Dr Marc Riedl, professor of medicine and clinical director at the US HAEA Angioedema Center at the University of California, San Diego, in San Diego, California. Welcome to this program titled, "Practice Points in Hereditary Angioedema: Experts Weigh In on Challenging Cases." Joining me today are Dr Paula Busse, associate professor in the Department of Medicine in the Division of Clinical Immunology at the Mount Sinai Hospital in New York. And Dr Henry Li, an allergist-immunologist at the Institute of Asthma and Allergy in Chevy Chase, Maryland. Welcome Paula and Henry.

Paula Busse, MD: Thank you very much.

H. Henry Li, MD, PhD: Thank you.

Dr Riedl: Today we're going to talk about hereditary angioedema (HAE). And by way of introduction, I'll just say a few words on HAE. This is a rare genetic condition that follows an autosomal dominant disease inheritance pattern. And the mutations that cause HAE cause a deficiency in C1 esterase inhibitor protein. This can cause either a quantitative deficiency or a functional deficiency of the protein. Either way, HAE is characterized by recurrent episodes of fairly severe subcutaneous or submucosal angioedema. This most often affects the skin, the gastrointestinal tract, or the airway.

Now, because HAE is a rare condition and most studies show it affects somewhere between 1 in 50,000 to 1 in 70,000 people, it often goes unrecognized and undiagnosed for quite a number of years. In fact, most studies show that on average patients go between 10 and 15 years before they're appropriately diagnosed with HAE. And these delays, of course, lead to significant problems because patients receive inappropriate or ineffective care for their angioedema symptoms. This ineffective care leads to an impaired quality of life. And unfortunately, when the airway is involved, it can lead to fatal events due to the risk of asphyxiation from this airway angioedema. So it's vitally important that clinicians be aware of, recognize and then effectively treat HAE as early as possible. Once a diagnosis of HAE is made, it's then very important to develop an effective management plan for the condition. And currently, we have multiple therapeutic options to effectively manage HAE. This makes it increasingly important that we individualize these management plans and focus on making them patient-centric, what's going to work best for an individual patient with HAE.

So with that background on HAE, let's turn to our discussion. We're going to go through a couple of cases. We'll review how to make a diagnosis of HAE, recognizing the clinical symptoms and the laboratory parameters; how to align treatment recommendations to meet patient preferences; and importantly, how to communicate with patients and their caregivers about the treatment options and the management expectations. So I'll turn to you Paula. I've mentioned a little bit about the symptoms of HAE. But I wonder if you could elaborate on the burden of this condition as it affects individuals and families with HAE?

Dr Busse: Sure. So, the burden of HAE really has kind of come into play recently. We recognize HAE is a disease where often the attacks are not predictable, and they can lead to mortality and morbidity if not treated correctly. So again, there's quite a bit of anxiety or depression associated with HAE. One is, "When is an attack going to come?" Two, "Am I going to have medications?" Three, "What is the potential outcome?" And not only during an attack, but between attacks, "Exactly when is the attack going to happen?" And again, this impacts not only the patient, but also the patient's family. It can impact the caregivers, it can impact the patient if the patient has children, "Am I going to pass the disease to my child?" Another impact that it really can have, is that HAE is a rare disease. Many times there are physicians who are not familiar with how to appropriately treat HAE, so patients often may know more than the physician about HAE and how to care for it, which again, leads to high levels of dissatisfaction with the patients. Again, the swelling can also impact the quality of daily life. Patients may have difficulty putting on shoes if they're having swelling of their hands or their feet. They may not be able to function with the severe stomach or abdominal attacks. So again, it really can impact the daily activities. And the attacks, as we'll talk about, are quite prolonged, they can last for 3 to 5 days. So it again, can impact the patient's ability to function over several days, which can not only impact quality of life, but also work and school.

Dr Riedl: Yes, it's an excellent point. And I think we often focus on the attacks themselves, when certainly, the more often they happen, the more they involve the intestinal tract, the airway. Those are sort of obvious how those can affect patients. But as you just pointed out, it's even between attacks, this unpredictability. And studies have shown lots of anxiety because of that unpredictability, depression because people can't carry out their usual work, school activities, or travel, or have their family events. I think that is a really important point we have learned; it's not just the attacks but even between the attacks that really impact patients and families.

So let's move to our first case and I'll just introduce the case, and then open it up for discussion. This is a 12-year-old girl. She's otherwise healthy and has been a very active 12 year old, but she's now in the emergency department with severe abdominal pain, she's had nausea and vomiting for the last 24 hours. And on physical exam, her abdominal exam shows some mild tenderness to deep palpation, but no rebound or guarding, no hepatomegaly, no ascites that are apparent on exam. Her extremities are normal. Her skin looks normal and her laboratories actually look quite normal. The routine labs don't show anemia or liver abnormalities. An abdominal ultrasound shows perhaps a very small amount of free fluid in her abdomen, but her inflammatory markers and other labs all look fine.

When you dig into the history of this young woman, she has had previous episodes of abdominal pain. And in fact, she's had hand and foot swelling in the past, repeatedly without any clear trigger for those events. The hand and foot swelling typically are asymmetrical, one hand or the other. They go away after 3 or 4 days spontaneously. She has been to the urgent care for some of these other skin swelling episodes, but again, has never had a diagnosis made and was told perhaps she was allergic to something, treated with allergy medications. She has missed some school, some activities, because of the swelling. She did have some allergy testing done in the past which did not reveal any specific food or environmental allergies. So Henry, I'll turn to you first. How do you go about narrowing down what might be happening here with this 12-year-old girl?

Dr Li: This is almost a typical case of what we see. When considering differential diagnoses for angioedema, look for past history of extremity swelling and also consider the severe abdominal pain. Often, clinicians may not consider angioedema as a possible diagnosis for a patient who presents with severe abdominal pain. And so abdominal pain can present with skin symptoms in these patients. For this patient, all routine labs are clearly negative and normal, no signs of inflammation, no clear trigger. This is a case where we need to do further lab testing specific for HAE or complement deficiency as further investigation of the diagnosis. One question I may ask this patient is whether she has started her period, and whether the abdominal pain is related to her period or not? I think that is relevant and certainly past medical history, we already know. How about the family history? Are there any family member with similar presentation of swelling, unexplained swelling, unexplained abdominal pain? Those are some things we can consider to help with the case.

Dr Riedl: Right, there are a number of clues here. The age of onset, as you said, that the teenage years are very common for HAE to become more active. The linking the abdominal pain with the skin symptoms, as you just pointed out. The estrogen sensitivity which can sometimes be a clue with the menstrual cycle for women. And then, asking about the family history. These are all things that one has to think of. Paula, what other questions are important to ask? You have a girl with swelling, with abdominal pain, what other clues are important in the history? 

Dr Busse: When I'm looking at patients who are presenting with abdominal pain or angioedema, I kind of lump in my head whether this is a histamine-mediated or bradykinin-mediated, because that's really going to direct how you're going to treat. So looking at this patient here, I'm going to ask about the time of onset and how long the swelling or abdominal pain lasted. That's really going to help me determine if this is histamine-mediated vs bradykinin-mediated.

With histamine-mediated, the onset of swelling is usually pretty quick. Whereas with bradykinin-mediated, it's a little bit longer. And the reason we want to know about, or associate if it's histamine-mediated or bradykinin-mediated, is it's really going to direct our treatment approach. So again, with this patient, we're going to ask how long swelling symptoms have been going on. And then, in this patient here, they say that she had been treated with antihistamines. So my question for the patient and the patient's family is, how they have been treated with antihistamines? Is it to prevent symptoms or is it for the onset of symptoms? Because with histamine-mediated angioedema, sometimes patients will say, "Oh, the swelling didn't get better with histamine." But we really need to possibly evaluate to see if it could be prevented with the use of antihistamines.

Another important point is that we're going to ask patients about the quality of the swelling. Does it itch? In this patient here, they said there is no associated rash. Again, an important point to distinguish between histamine-mediated and bradykinin-mediated, is that histamine-mediated is often going to have urticaria. An important point to make is that patients with bradykinin-mediated angioedema, such as HAE, can have a rash called erythema marginatum, which is not urticaria. But again, they may possibly confuse it with urticaria, although it does not itch. As Dr Li mentioned before, we're going to ask about family history. We don't have a family history here. But again, even if a patient with HAE or we're suspecting HAE doesn't have a family history, it does not exclude it. Twenty-five percent of the time there can be a new mutation in the C1 inhibitor. So again, these are some of the points that I'm thinking about, because it's really going to address how I approach treatment as well as diagnosis.

Dr Riedl: Great, thank you. So, we've taken the history, we've asked these important questions, the presence or absence of hives, the family history, the trajectory, or how long did the symptoms last, which can be a clue to the mechanism. The response to treatment, which as you mentioned, is really important to dig into the history, what's worked or not worked to either treat or prevent these symptoms. So, we've got that information, we've got some clues, but we'd like to have a definitive answer here. Henry, I think you mentioned, there are some laboratory tests we need to be thinking about. Walk us through what kind of testing one needs to consider if HAE shows up in our minds as a possibility.

Dr Li: Certainly. If it's a screening test, and the patient is in the emergency room or urgent care, then you  want to test for C4 levels. If we are in a more relaxed setting, a well-established lab, or hospital, or clinic, usually we recommend C1 esterase inhibitor, both antigen and the functional level, to be checked. And of course, it also depends on the patient’s age. For a 12-year-old patient, a C1q test is not usually mandatory. So there are 4 laboratory tests that can really help establish the diagnosis of HAE. These are C4 levels, C1 inhibitor antigen and function, and the C1q, which has become somewhat optional. And those are the tests we usually order as a first step for establishing the diagnosis.

Dr Riedl: Great. Excellent. And so Henry's ordered the tests. Paula, walk us through how we interpret those tests. What do they mean at the end of the day?

Dr Busse: So as Dr Li said, ordering a C4 test is really going to be very helpful. But unfortunately, in the emergency room, it's not a quick turnaround like a CBC would be, so we may not get the results of a low C4 until 24 hours later. But basically what we're going to be looking for is that HAE can be classified as type I and type II. There's also a third type, which has been labeled as HAE with normal C1 inhibitor.

So when we look at the tests, what we're going to first look at is our C4 level. So if we see the C4 level is low, we're going to be thinking HAE type I or type II. We may be thinking, not in a 12 year old as Dr Li mentioned, but acquired C1 inhibitor deficiency, where the C4 is going to be low. And usually in these patients, it's actually very low. The next important step that we're going to be looking at when we're considering the labs, is looking at the C1 inhibitor function. So for both type I and type II, there's going to be a low function. Acquired C1 inhibitor deficiency, there will also be a low function. But again, in a 12 year old, I'm really not going to be thinking that. Acquired C1 inhibitor deficiency is usually seen in patients who are a little bit older.   

So you look for the C4. You look for the C1 inhibitor function, it should be low for type I and type II. And then, you're going to look at the C1 inhibitor protein level. So, a C1 inhibitor protein level will be low in type I, but normal in type II. So again, it's not going to make a difference in how we approach treatment, but it will make a difference in diagnosis. For patients with HAE with normal C1 inhibitor, all of the testing, C4, C1 inhibitor protein and function are going to be normal. So this is when we're going to have to really look, dive a little bit deeper into the clinical response to antihistamines to see if antihistamines, high dose antihistamines prevent angioedema or abdominal pain. If we're thinking about acquired C1 inhibitor deficiency, which we're not in this patient, most likely because of the age, we're going to look for a C1q level, which is going to be low. So, that's how I would look through some of the initial tests. But unfortunately, we're probably not going to have these available in the emergency room.

Dr Riedl: Great. Thanks. And yes, absolutely right. It's important for these patients to get outpatient follow-up to complete the testing or to follow up on any testing that's been done because it does take some time for these labs to come back. So there are, of course, published algorithms and various guidelines suggesting when to send these tests. But I think as you both outlined, in any patient with recurrent angioedema and in particular, those that don't have hives, itching, signs of a mast cell or histaminergic process, these are really critical tests to send because it's the only way to exclude or confirm the diagnosis of HAE and in particular, C1 inhibitor deficiency, which is the most common cause.

I'd only add, of course, that we always want to look at the medication list, because we know ACE inhibitor-associated angioedema is quite common, particularly in adults, not in a 12 year old in this case. But it's important to exclude that as a possible common cause of isolated recurrent angioedema. And to a much lesser extent, ARB medicines, which there are reports of, though it seems to be much less common compared to ACE inhibitors.

All right. So let's get back to our 12 year old. Her test results showed a low C1 inhibitor level at 5, a low C1 inhibitor function at 15% and a low C4 level at 5, with a normal C3. And again, worth mentioning that the C3 level is not affected by C1 inhibitor deficiency, so that will be normal if you send a panel that includes that. And so, this does confirm this 12 year old has type I HAE with insufficient production of C1 esterase inhibitor which would, of course, fit with her recurrent abdominal pain, her recurrent cutaneous angioedema. And so we've made the diagnosis, which is very important to get her appropriate treatment. 

So, let's shift gears a little bit now and talk about the treatment of HAE. And Paula, I'll turn to you. Tell us a little bit about the options for managing HAE and maybe we start with the on-demand treatments for HAE.

Dr Busse: So with HAE, we group our treatments into several different categories. One is on-demand, when attacks are occurring, one is to prevent and one is a short term prophylaxis. So, for on-demand treatments, all patients should have on-demand therapy available. This is a must. And again, when patients have an on-demand therapy, they should have at least 2 doses.

So we have a couple different options. We have 2 different forms of C1 inhibitor, so patients can replace the C1 inhibitor for acute therapy, this is administered IV. So again, thinking of a 12 year old, it might be a little bit difficult, in sense that you have to decide who is going to administer the IV therapy? Is a parent going to do that? Are you going to bring the child to emergency room? What is the plan going to be? There's a plasma-derived option as well as the recombinant C1 inhibitor replacement. There are other options which are subcutaneous. Icatibant, a bradykinin receptor antagonist, has been approved in the US for adults, and in Europe for patients over 2 years of age. We have ecallantide, also subcutaneous administered; however, with ecallantide there's a small risk of allergic reactions, so it must be administered either in a hospital or clinic setting, or by nursing staff.

Dr Riedl: Great, thanks. And as you said, but worth repeating, every patient with a diagnosis of HAE needs one of these FDA-approved effective medicines. It may vary which one, depending on their preference, the route of administration, the age of indication, as you mentioned, is a bit different for some of these medicines. But that's the first step, is setting up an effective, reliable treatment plan to deal with these attacks, and stop these attacks when they occur. As you mentioned, Paula, the other approaches are prophylactic or preventative. And so, long-term prophylaxis (LTP) has become a very important consideration for many patients. Henry, tell us a little bit about when we might consider LTP and then how we go about making that decision.

Dr Li: We consider LTP for patients whose HAE is more burdensome or in those who have more frequent attacks. These are patients who are already taking rescue or acute treatments, but continue to have frequent attacks, more than a couple of attacks in months, or they just don’t respond adequately to their acute treatment, where they may need more than one treatment for each attack. Also, the patient’s attack may be very severe, leading to laryngeal swelling. These attacks can be very disruptive, and patients may not be able to adequately treat the attack in a timely fashion. So when considering LTP, we will consider patients’ quality of life, how much they are affected, and also their preference. When we speak with patients about their options, they often don’t want to have an attack to start with. So in these patients, we take into account preference, other factors (severity and frequency of attacks, response to rescue medications) and come up with the best treatment plan to prevent attacks from occurring. 

Dr Riedl: And so there are many factors to consider and these are all outlined in the evidence-based guidelines, either the World Allergy Organization or the US HAEA guidelines, listing these factors that we need to consider. It's more than just how many attacks or what types of attacks, but as you mentioned Henry, patient preference and quality of life. Paula, do you want to very briefly mention the long term prophylactic options that we have to treat patients with for HAE?

Dr Busse: Sure. We have a couple different options. And again, the nice thing is that the landscape is changing. And one thing that we're going to discuss is how these medications really have improved patients’ quality of life. So we have plasma-derived C1 inhibitor. This can be administered intravenously or subcutaneously. For someone who's 12 or young, a child, I would probably opt for a subcutaneous rather than an IV, because it's going to be administered every 3 to 4 days. We have a subcutaneous plasma kallikrein inhibitor, lanadelumab, which is approved for over 12 years of age. This can be administered every other week. If patients do well, meaning after 6 months of therapy using every other week dosing without any attacks, the dosing interval can be lengthened to every 4 weeks, which is a nice option. It's been again approved for age over 12. We have an oral plasma kallikrein inhibitor, which has been approved for over 12 years of age. This is administered on a daily basis. So again, this is another option.

So, when we're looking at these options, we really have to discuss with the patient, see what he or she is comfortable with, see what the family's comfortable with. And really, I think the important thing is to let the patient make the decision. I think as a physician you're there to guide them, but this really is a patient-physician partnership, because the patients are the ones who truly know their disease and they're the ones taking the medications. So again, it's a shared decision.

Dr Riedl: So I'll just wrap up this first case with a couple of points to recap. When we make a new diagnosis or for any patient, we really have to discuss a comprehensive management plan. And that includes an on-demand treatment plan for every patient to be able to terminate an attack that occurs, but also discussing the options of LTP, which as has been pointed out, has become a very important piece of management to try to prevent these attacks, lead to predictability. And then of course, we have to review this plan periodically for efficacy, for safety, for adherence to the plan, because this is a condition that can change over time.

And that brings us to a second case, which I'd like to introduce. This is a 24-year-old gentleman, he was diagnosed with HAE about a decade ago and he's been on acute treatments as he should be. He uses this and it works well to stop his attacks, but increasingly he's had to use this multiple times a month, sometimes 4, 5, 6 times a month for frequent HAE attacks. So not surprisingly, these episodes have become quite disruptive to his schooling. He's in graduate school, a very stressful time in life and his activities have been substantially impacted by these frequent treatments for HAE. So, I'll open it up to either one of you, maybe Henry, you can start, does this patient need LTP? And how do we think about this?

Dr Li: So I think this is a great candidate to discuss about how do we approach to manage his case by preventing attacks rather than just responding to the attack. And so, I think bringing up the option of LTP will be part of the discussion for a treatment plan for this patient.

Dr Riedl: Yeah, an important conversation to have. And increasingly, we're looking at quality of life in HAE. And so, some of the prophylactic medicines now have looked at this question, quality of life with treatment. And Paula, do you want to say a few words about the studies that have looked at quality of life with prophylactic therapy?

Dr Busse: So, looking specifically at the AE-QoL tool, this has been used in the HELP study, looking at lanadelumab for prevention of HAE, and there was a met endpoint in the overall score, which, and the results of what the AE-QoL has different domains such as functioning, fatigue, fears or shame, nutrition. Again, so they were able to find that it met a significant improvement in all the areas of quality of life. Looking at other tools that have been used such as the EQ-5D, impact on work, WPAI, or other outcomes that we've measured in terms of quality of life, not necessarily specific to angioedema, but subcutaneous use of C1 inhibitor at two doses 40 and 60 IU/kg also met these changes in improvement of quality of life.

So again, we're seeing over several different treatment modalities, SC C1 inhibitor, a SC plasma kallikrein inhibitor, improvement in quality of life. Recently in the APeX-2 trial, we've also seen that an oral plasma kallikrein inhibitor at several points, including initial start of after 4 weeks of therapy and out to 48 weeks has also shown improved quality of life. This is measured upon using the AE-QoL. So again, we're seeing a theme here, that these new therapies for HAE, these new prophylactic therapies are significantly improving patient's quality of life. 

Dr Riedl: Thanks, Paula. And I think it really does highlight the importance of the impact that these treatments can have on our patients' quality of lives. It's the reason, of course, the evidence-based guidelines now recommend discussing LTP with every patient. It doesn't mean every patient is going to utilize those therapies, but certainly it's something we want to make sure patients and families are aware of and use them when appropriate to manage HAE. Well, this has been incredibly interesting. I want to give our panelists a quick chance to add one last thought of what you think is important to take from the program in terms of diagnosing and managing HAE. Paula, I'll start with you, any closing comments?

Dr Busse: It's a lot of information when you first diagnose patients with HAE, and you have to explain to the patient, this is going to be a learning experience, so don't expect to learn everything about your disease the first time. So again, that can be with a patient who's been newly diagnosed or a patient who's had a diagnosis of HAE and is learning about different triggers or different medications. So it's a process and it's a process that needs to be evaluated each time. And it needs to be evaluated upon whether is LTP working for this patient, or do we need to start LTP for the patient? Another important point is that even though patients are on LTP, it’s important that they must have acute therapy. Although our newer therapies for LTP work well and can prevent attacks, we can't guarantee that patients are not going to have an attack. So patients still need to have access to acute therapies.

Dr Riedl: And Henry, your take home points.

Dr Li: I think the point we are trying to convey to all healthcare providers is that angioedema is common, and whenever we see angioedema and swelling, especially those without accompanying hives, we need to consider a possible HAE diagnosis. Even for cases when you don't see swelling, you have unexplained severe abdominal pain, especially recurring severe abdominal pain, we need to consider angioedema as a differential diagnosis. And of course, once we are thinking about establishing a diagnosis, there are simple tests, pretty straightforward, when we do the tests and interpret the results, then the treatment is actually straightforward. Make the diagnosis and then figure out whether the patient needs some rescue medication to treat an acute attack, or if the patient is suffering much more from the condition, we may consider a newer option of preventing attacks, of which there are 4 currently available.

Dr Riedl: Thank you. So yes, think of the diagnosis. Once you make the diagnosis, listen to our patients, listen to what's important to them in terms of a management plan. And then of course, regular follow-up. Our second case highlighted that this does change over time. And so, what works for a patient last month may not work in the coming 6 months. We have to constantly follow up and make adjustments to the management plan to fit the activity of the condition in our patient's lives. So Paula and Henry, thank you very much for this great discussion. I appreciate your involvement.

Dr Busse: Thank you.

Dr Li: Thank you. 

Dr Riedl: And thank you to the audience for participating in this activity. Please continue on to answer the questions that follow and complete the evaluation.

This is a verbatim transcript and has not been copyedited.

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