Dr. Dareen Siri was invited to share her experience in “Simplifying the Science, the Root Cause of HAE”, which is part one of the HAE podcast series where in each episode is a conversation with another HAE expert trying to dig into some of the nuances of hereditary angioedema, also known as HAE. They address different challenges that their patients or the providers might face in managing, diagnosing, and treating this condition. They discuss some of the approaches, communication techniques, and management tips in helping patients manage their disease, or their caregivers and loved ones help them as well.
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…Allergists are involved in managing HAE because during this discovery process, the patient may think their swelling or perhaps their doctor thinks their swelling is from an allergy. And of course, they find out that later it’s an immunological disease… When we’re able to make a diagnosis and figure out that it’s not allergy, which can be a time consuming and harrowing process for many patients, it can take years even to get the diagnosis because not everyone’s familiar with the disease. I think it can give us a lot of relief, satisfaction in that we know what causes it, we know the treatment plan, and we can see if we can control some of that unpredictability that occurs with the disease.
This educational program is sponsored by Pharming Healthcare, Inc. The information contained within this podcast is for educational purposes only and is not intended to be medical advice.
Patient experiences may be discussed in this episode. It is important to recognize that these experiences may not be representative, as every patient has a unique disease course. This activity is not intended for continuing medical education credits.
Excerpts:
Dr. Anderson: My name is John Anderson. I’m an allergist here in Alabama. I’ve been blessed to have an opportunity to treat patients with HAE for over a decade now. …Today we’ll be talking about HAE, which is a C1 esterase inhibitor disease or a C1 disease, and we’ll talk about what we can do as healthcare providers to help translate what this mechanism is to our colleagues or to our patients. And of course, we’re blessed to have Dr. Dareen Siri to make it all easy for us. And so, Dareen, tell us a little bit about you. What got you interested in treating HAE?
Dr. SirI: Welcome. First of all, thank you so much for inviting me today on this program. I’m really excited to talk about HAE. It’s one of my passions. Just like you, I practice in private practice and also have an academic affiliation. I’m located in central Illinois. I practice in the largest combined allergy and respiratory practice in our region. And we have a lot of referrals because we’ve not really shied away from treating patients with complex medical conditions. So this has become a bit of a referral center for managing patients with severe, complicated rare conditions like HAE.
And I think it’s important for us to have these types of referral centers where people have familiarity, expertise. That way, patients can really get the best care and coordinate with their local physicians in order to get diagnosis more quickly, get treatment plans more effectively, and certainly get therapies. I think that as an allergist immunologist, just like you, I treat a lot of immunology patients.
At some point, allergists are involved in managing HAE because during this discovery process, the patient may think their swelling or perhaps their doctor thinks their swelling is from an allergy. And of course, they find out that later it’s an immunological disease. And luckily for you and me, John, we treat both conditions, right? So that’s great for us.
And finally, when we’re able to make a diagnosis and figure out that it’s not allergy, which can be a time consuming and harrowing process for many patients, it can take years even to get the diagnosis because not everyone’s familiar with the disease. I think it can give us a lot of relief, satisfaction in that we know what causes it, we know the treatment plan, and we can see if we can control some of that unpredictability that occurs with the disease.
Dr. Anderson: So in thinking about that we acknowledge that this is a rare disease. We’ll often publish that this is like one in 50,000. And yet, depending upon where you practice, you might have a higher density of patients. Certainly, where I live and work, we’re known to have a large family cohort. But as we’re thinking about this and sharing it with our colleagues about what to look for, and what is it like how would you describe to somebody who doesn’t have HAE but is on the lookout for it? What does HAE look like and feel like?
Dr. Siri: I would love to address that. It’s really important for us to get that diagnosis because it is rare, and many people may not be familiar. As you and I both know, hereditary angioedema is a rare genetic disorder. And although it can be autosomal dominant it can manifest later in life, it can manifest early in life, the features being variable can make it difficult to diagnose. And many patients who are diagnosed are what we call de novo, which means that there was no one in the family who had it before. As you know, HAE is characterized by recurrent episodes of swelling, it can infect various parts of the body, the face, the limbs, the GI tract. As we both know, it is caused by deficiency of C1 inhibitor, which means there are low levels in the body, or it may be caused by dysfunction of the protein. So the protein may look like it’s a normal level, but actually that doesn’t work that well. And we know that C1 inhibitor is involved in regulating certain immune reactions.
So a person who presents with an HAE attack, which is oftentimes how they get diagnosed because they’re having one attack, multiple attacks. One, they’ll get swelling. The swelling typically occurs without warning. It can affect different areas, as we talked about, it can vary from mild to severe. There are some areas of the body that may look milder and some areas of the body that may be more severe. And the same patient may have varying severities over time, depending on triggers and things like that. So typically, when the patient has these areas of swelling, it is painful.
Many of my patients present with abdominal symptoms, and that can be severe pain, nausea, vomiting, diarrhea. And unfortunately for these patients who manifest only a gastrointestinal disorder, it can lead to misdiagnosis because when they present to an ER or see a doctor for the first time and don’t have a diagnosis, people think that they have an acute abdomen or appendicitis or some other primary abdominal gastrointestinal issue.
We can talk about triggers as well. Your patients probably have a lot of triggers. My patients it’s psychological or physical stress, sometimes trauma, surgery, dental procedures, even when they’re having hormonal changes, certain times of the month when they’re menstruating, certain medications like oral contraceptives, infections.And then certainly many patients don’t have any identifiable trigger. And so this can be really distressing for them.
Dr. Anderson: We talk a lot about how unpredictable this is. And I think a lot of that stress that you mentioned, part of it is the worry about when am I going to have another attack? And is it going to happen while I’m out of the house or when I’m on the road? And all of that lack of control, I think really adds to a burden as far as managing this. Yet some patients talk about having early warning signs or a way to kind of tell. And I was going to ask you are there early indicators or how does a person know if an attack is coming or if the attack is imminent?
Dr.Siri: I think that those early warning signs or what we call, as medical professionals, prodromal symptoms are really important to recognize. And not everybody has them. But if the patient does have them, whether it’s with some attacks or with others, it’s important for them to document those, keep a diary, let us know who are treating them so that perhaps we can develop a better plan in preventing or treating early or resolving that for them more quickly.
But some of my patients have prodromal symptoms such as fatigue. They just feel exhausted before they have an HA attack. A lot of them have this muscle aching. They have discomfort in their joints, their limbs, their muscles, especially perhaps in the area that may be swelling. They can experience mood changes. And then a lot of our patients, especially the ones who are having a progression of a GI attack or gastrointestinal attack, they can have some nausea to start with.
Dr. Anderson: So most every week I see patients in my practice who are presenting with hives. Sometimes they’ll have associated swelling or angioedema. They’re very itchy and you had started to differentiate how this might be different than our HAE patients. For these patients who are having more hives, we’ll do a workup. It can include labs and skin testing. And when we start talking about treatment, we really focus on antihistamines as our pathway that we’re trying to modify. In what ways does that more common or typical hives with angioedema patient look similar to or differentiate from HAE? What’s the overlap and what’s unique?
Dr. Siri: I think that is a really important consideration because certainly common things are common.Patients come in with urticaria, allergic issues or other forms of swelling. And we have to take our knowledge of the patients who are not responding and don’t look classical or maybe have associated features to say, hey, this isn’t classically what we think of as allergic urticaria or angioedema and urticaria in that condition. I think that one of the things that I look for when I’m thinking about hereditary angioedema versus urticaria or allergic triggers is the duration of the swelling. For many patients, as you and I have seen that the typical hives start and very quickly resolves oftentimes in 24 hours. In HAE, the swelling typically lasts for longer than that. As we talked about, sometimes 72 hours or more in some of the patients. And also with the appearance, it’s non-pitting. It’s not that kind of edema that we think about. And so when we press it, there’s no indentation. It looks fairly continuous in terms of the skin. There’s not a clear demarcated area, at least in the later parts of the swelling. And certainly that itch component is not driving people crazy. There’s really not a lot of itch. And certainly we know that urticaria and other forms of allergic rashes is characterized by really intense itching. And so HAE is really not like that.
And certainly you talked about treatment, like antihistamines. Antihistamines don’t work in HAE. It doesn’t really provide that much relief. Corticosteroids and epinephrine, those medications don’t work. So if we keep having a patient come into our prompt care ER as a primary care, we give them these medications and they’re not really resolving the patient’s symptoms. I think we need to look for an alternative diagnosis.
Dr. Anderson: I can think about some of my patients in their journey to diagnosis, describing how, yeah, they were given antihistamines or given steroids and two days later they were better. And they’re debating about they’re kind of affirming, hey, maybe that helped. And I’m thinking, no, that’s a red flag that maybe it didn’t help.
Dr.Siri: To your point, that’s absolutely something really, really essential for us to understand is that sometimes the patient’s angioedema resolves in several days anyway. So do these medications really help or not? So I think it makes it sometimes hard to diagnose those patients.
Dr. Anderson: So if you have a patient who is having an HAE attack, what should that patient do?
Dr.Siri: That patient should respond with exactly what is outlined in the Hereditary Angioedema Association Medical Advisory Board Clinical Guidelines, which recommend that, first of all, all patients have access to an acute therapy, regardless of whether they’re on long-term prophylactic therapy. The second thing is that they should treat all attacks regardless of their location. The third component that is very important as well is early administration of the on-demand treatment to prevent attack progression.
So I typically classify the management of HAE into four pillars. One, the effective on-demand therapy, as we talked about. Second, that preventive therapy if needed. Third, an action plan developed by experts such as you and me in coordination with a patient to know how to treat, to self-inject if needed, to do self-care and treatment because certainly they may not have easy access to a tertiary medical facility. And then finally, when to escalate their therapy and seek help when appropriate if they need to go somewhere for additional treatment after they’ve already self-treated. And it’s really important terms of that educational component. So most of my patients do have definitely an on-demand medication and perhaps even more than one. How about your patients, John?
Dr. Anderson: So I totally agree with having access to on-demand medication and emphasizing that option of treatment. I do agree that patients are, when they decide this on their own, sometimes they’re electing not to treat and that’s a cause of concern.
I do try to put a human face to this and I acknowledge that there are reasons why a patient might choose that. Other times I’ll try to kind of use myself as an example. I have asthma and I’ll talk about, sometimes I’m on the couch and I’m wheezing and my rescue medication is all the way over there in the bathroom. And I’m like too lazy to go take my medicine. And it’s so easy. I mean, it’s just, why am I doing that? And I’m trying to at least appeal to that. This is a human behavior. We acknowledge that this is what we do. And then we try to break down why is that happening and try to then encourage them to be more proactive with their action plan.
So thinking about fellowship, I remember one of my attendings demonstrating the kallikrein pathway or the contact pathway and all of the different elements of that pathway and telling me that I’m going to just need to memorize this once so I can pass the test. And I don’t know how many of my colleagues out there can kind of remember sort of knowing this, but they’re not really remembering each of the different enzymes and the order and what happens when it happens. A lot of times when we talk about HAE, we focus on C1-esterase inhibitor.
It’s kind of that master regulator of this pathway. But for those who can identify with that foggy, dim memory of the contact pathway, what is the role of C1-esterase inhibitor? How does it affect kallikrein pathway? And what should our colleagues really kind of know about it?
Dr. Siri: I’m glad you asked that question. C1 inhibitor plays a really important role in regulating inflammation and the complement system in particular. So certainly when an inflammation occurs, then at some point that inflammation has to dissipate. So you think about all the players, whether they’re cytokines or chemicals or cells coming into an area, kind of like a flood of people going into an arena. And when the game is over and the inflammation is gone, you tell everybody, go home, folks empty out the stadium.
And so the inhibitor is almost like the ushers that are kind of telling people to time to go home guys. They’ve got to suppress things, regulate proteins, et cetera. And so when that process goes unchecked and there’s no C1 inhibitor, and there’s nobody to tell the folks to go home, it then of course continues. And this all drives the single important protein, which causes a lot of vasodilation and things like that called bradykinin. So we know that there are key roles in C1 inhibitor. And if we have low levels of C1 inhibitor, that’s a problem. And if we have a dysfunctional C1 inhibitor, that’s a problem. And so we know that C1 inhibitor, we think of it as activation of the classical pathway for complement, a really important part of the immune response. And then we also think of an important contact system regulatory pathway as well.
These then lead to, as we talked about, whether it’s suppressing or regulating factor 12, pre-kallikrein or high molecular weight kininogen. We talk about the fact that bradykinin, which then increases production and goes unregulated, it’s a potent mediator of inflammation and it causes blood vessels to become leaky and causes that swelling. So I think that it’s important for us to recognize the various important roles of C1 inhibitor and many pathways in inflammation, all leading to increased bradykinin production when they are not available to help suppress or regulate some of those inflammatory proteins.
Dr. Anderson: So I totally love the example of the Usher being the C1 esterase inhibitor. And this is just because when I was in college, I worked security at football and basketball games. So now I get to really identify, it brings it full circle. I was C1 esterase inhibitor and now I champion treatment with C1 esterase inhibitors. So I like that. I’m going to remember that one.
Dr. Siri: There’s a great video that’s presented by our colleague who we know well, another HAE expert, Dr. Michael Manning. I love hearing about how he presents the science of HAE in that video. Yeah, that’s a really great video.
Dr. Anderson: …So far, we’ve talked a lot about insights about what is HAE, certainly how we try to communicate some of these important factors to our colleagues, but it’s also important to kind of share this complexity with our patients and really promote patient understanding. What do you do to connect to patients on these topics and how do you kind of break down that complexity for them?
Dr. Siri: I like to think of inflammation as little fires being set off in the body and how C1 esterase inhibitor, C1 inhibitor works is that it’s a protein that puts out those fires, like a ranger checking on each campfire using his or her reserves in a fire truck to put out the fires. So when you don’t have an adequate ranger, or maybe that ranger is just inept, those fires can go unchecked and spread and then set fires in other areas. So you can think of that like excess kallikrein and then bradykinin causing that wave of inflammation and then tissue swelling and a lot of vasodilation.
So having the deficiency of C1 esterase is a lot like having a low tank in your fire truck. So in terms of treatment, we have to fill up the reserves of our fire truck to be ready for when a fire may break out and we’ve got to regulate it just like we might be the park ranger.
Dr. Anderson: That’s awesome. I too will use fire as an example of inflammation. And sometimes I’ll even talk about the difference between like a grease fire or an electrical fire that you don’t put them out the exact same way. And that kind of helps patients understand why we might do different treatments for different types of angioedema.
Dr. Siri: I think that it’s really important to underscore the fact that HAE with every single patient is very heterogeneous. No two patients are alike. As we talked about in the same family with the same mutation, the patients may be quite different. We know that there are hundreds of different mutations, several genes that are implicated certainly in regulating this process with C1 esterase inhibitor or C1 inhibitor production and function. But patients are surprised to know that they may have a different mutation than the other person in their support group that has HAE as well because it manifests in the same way and that’s swelling. So when I discuss the disease with them, I often talk about the fact that we are all hopefully in the center and we want to stay centered.
But when we have a crazy disease like this where it is really spontaneous, unpredictable, it’s like a yo-yo or a roller coaster and something comes along and puts them off center and now they’re out of their orbit. And then we’re trying to as quickly as we can get back to center because as we talked about, patients will stop going to work. They won’t go to school. They won’t go outside the house. They’re in a lot of pain. It’s very disruptive.
And so hopefully if we drive home the fact there are other people like them, we know what causes it. We know that there are effective treatments that they feel more confident about taking control of their life.
Dr. Anderson: Well, I think bringing it back to the individual is so important and letting the patients know that yes, there are those that are like them that have this but also letting them acknowledge that in some ways their circumstance is unique and that their fix or their plan hopefully can, as you say, it can be tailored to them.
And we’ve talked a lot about explaining that disease process or sharing or driving learning and education in that domain. And that naturally lends itself to making choices about treatment. So one of the things that I’m thinking about is that if we talk so much about C1 esterase inhibitor as that essential inhibitor or regulating enzyme, it highlights its role both in the process of HAE but also as a potential treatment for HAE.
And we’re going to talk about Ruconest as an option to treat acute attacks for patients who are having hereditary angioedema and treating their attacks. Ruconest is approved for acute treatment in adult and adolescent patients with hereditary angioedema. There was not enough data in the clinical studies to establish efficacy in patients with laryngeal attacks. And when you introduce Ruconest to your patients or to your colleagues, what do you highlight? How do you explain it to them?
Dr. Siri: This educational component is so important. I love the fact that we’re starting to talk about on-demand therapy, which of course is the primary treatment patients should have available. And one of the really, really important factors is this replacement therapy. In hereditary angioedema, we have to restore or supplement the deficient or the dysfunctional C1 inhibitor protein. And how do we do that? Well, we have to administer C1 inhibitor exogenously replacing it. And so it can help regulate the complement contact systems and prevent that excessive bradykinin. And as we both know that Ruconest works by providing functional C1 inhibitor.
Dr. Anderson: So if we think about the clinical trial experience with Ruconest, what are some of the things that are important to highlight?
Dr. Siri: I love talking about clinical trials. As you know, I run a clinical research center and we both love doing local trials and as well as I’m talking to patients about them. So the clinical trial experience with Ruconest shows that it can effectively treat acute HA swelling attacks. The primary endpoint of that pivotal clinical trial, which means the median time to beginning of symptom relief in those 44 patients in the treatment arm was 90 minutes for patients receiving the 50 units per kilogram of Ruconest. This is compared to the placebo arm in which those patients, it was about a median time of 152 minutes.
So this was statistically significant. Certainly in the open label extension study, the symptom relief began at 75 minutes, 97% of the swells were treated with just one dose of Ruconest in the open label extension phase of the clinical study, 44 patients received a dose of 50 units per kilogram of Ruconest and this was over 170 attacks. So in the pivotal trial, approximately nine out of 10 patients achieved symptom relief with just that one dose at that 50 units per kilogram.
Dr. Anderson: Certainly what I like is to see that in that open label phase, the onset of symptom relief began a little sooner. And to me, that emphasizes that acknowledging that upon recognition of the attack, treating the attacks early is an important part of that management strategy. The other thing that we talk about with our patients, of course, is safety, what potential side effects or adverse events were experienced in the trials. What can you share about that?
Dr.Siri: I think safety is paramount in any therapy for patients, whether it’s a common or rare disease like HAE, we have to be comfortable with the safety profile and patients want to know and have confidence in information about safety. So some of the adverse event data during the phase three pivotal clinical trial, there was a serious adverse reaction reported, which was a case of anaphylaxis. The most common adverse reactions, however, were headache, nausea, and diarrhea. And these were reported in instances of 2% or greater.
Dr. Anderson: It is contraindicated in patients with a history of rabbit allergy or hypersensitivity reactions to other C1 inhibitor preparations. So that’s important to keep in mind. And of course, patients should be monitored and taught to monitor for signs and symptoms of allergic reactions, including hives, generalized urticaria, tightness of the chest, wheezing, hypotension, and or anaphylaxis. If any of those symptoms occur, discontinue Ruconest treatment and administer an appropriate therapy. Now, on to blood clots. Serious arterial and venous thromboembolic events have been reported with the use of C1 inhibitor products. And risk factors may include the use of ports or any sort of venous access device, history of previous clots, underlying atherosclerosis, use of oral contraceptives or certain androgens, morbid obesity, and immobility. Patients can be trained to self-administer Ruconest once they recognize an attack. But they should also know that if the attack is progressing or they are not able to properly prepare or administer Ruconest, they should have a plan in place to contact a health care professional to seek medical attention. They should not administer more than two doses within a 24-hour period. In terms of the most serious adverse reaction reported in clinical trials, it was anaphylaxis. During the clinical trials, the most common adverse reactions with an incidence of 2% or greater were headache, nausea, and diarrhea. Before prescribing Ruconest, please read the full prescribing information, including the patient product information.
We’re kind of getting to the end of our chat together, but what do you want to highlight for us? What are some of the key takeaways that we should be thinking about?
Dr. Siri: As we are talking about a complex disease, I think I want to emphasize, although rare, it’s a genetically based disorder. The deficiency is that C1 inhibitor or there may be a dysfunctional protein. This leads into uncontrolled activation of the complement and contact systems with increased bradykinin production that manifests as acute swelling attacks, which may be in various parts of the body and can range over time in any patient as well as range in severities. There is a really crucial role in replacement or augmentation of C1 inhibitor to help regulate that pathway to reduce attacks. It’s very important that patients treat all their HAE attacks and that they have availability to an on-demand acute therapy.
Dr. Anderson: One final thing I’ll mention about takeaways. To our broader audience, I imagine some of our listeners are very comfortable managing HAE and others might be looking for referral centers like yours and mine to help assist in that management once found. The other thing is just that encouragement to screen patients who are having those red flags that you mentioned earlier. When I think about my practice, the vast majority of patients that I manage were not diagnosed by me. In fact, I have actually only diagnosed very few patients who are presenting with angioedema who then later become patients with HAE. Most of the screening work is done by the broader community. So I’m very thankful for those who are ordering these labs and interpreting them and having that index of suspicion.
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