Activity Transcript

Marc Riedl, MD: Hello. I'm Dr Mark Riedl, professor of medicine and clinical director of the US HAEA Angioedema Center at the University of California San Diego. Welcome to this program titled, "How Will You Manage These Patients With Recurrent Angioedema?" I'm joined today by my friend, Dr William Lumry, clinical professor of internal medicine at the University of Texas Southwestern Medical School in Dallas, Texas. Welcome, Bill.

William Lumry, MD: Thanks, Mark. It's a pleasure to be here.

Dr Riedl: In this program, Bill and I will use patient cases to discuss strategies for testing, diagnosis, and management of patients with recurrent angioedema. Specifically, we'll review how to evaluate patients with symptoms of angioedema, how to define goals of treatment once a diagnosis of hereditary angioedema is made, and how to formulate a comprehensive management plan that incorporates both acute on demand treatments and prophylaxis. We'll also discuss the important issue of quality of life with patients with HAE and the need for planning and counseling patients so they can manage their condition and safely return to normal activities. Bill, let's introduce our first case. This is one of your patients. Could you walk us through the initial presentation and patient history?

Dr Lumry: I'll be happy to, Mark. This is a 23-year-old woman who presented to the emergency room with abdominal pain that had increased in severity over the past couple of days. This was accompanied by nausea and vomiting. She denied having any diarrhea, melena, hematemesis, fever, or dyspnea. Initial evaluation showed that her white blood cell was in normal range. Further medical history revealed that she had been having episodes like this since the age of 13. She was actually hospitalized at the age of 14 for one of these episodes. In between the episodes, the evaluations have not shown any abnormalities. The patient also said that her father experienced similar episodes, which typically would resolve several days regardless of treatment or lack of treatment.

Dr Riedl: Bill, this case provides a few important clues as to what may be going on with the patient. Could you run us through what those clues could be? Most importantly, how do you evaluate a patient like this?

Dr Lumry: I think the most important clue was the recurring nature of her symptoms as well as the lack of finding of any abnormalities in between the episodes that she had. The fact that there's a family history of similar episodes should also make you think about a possible hereditary condition. To evaluate someone like this, obviously as we all do we need to obtain a detailed medical history, a family history, and do a full physical examination on these individuals. The findings during an event may be completely different from what we see in between events. Often times, the pain will present similarly to an acute abdomen. What's happening in heredity angioedema is that there's a functional bowel obstruction. This may cause bloating, this may cause decreased bowel sounds, this may cause other symptoms that might make us think that there's something catastrophic going on in the abdomen.

Dr Lumry: However, these patients often have normal routine lab values. Occasionally, the white blood cell count will be elevated due to third spacing and dehydration. A CT scan or an abdominal ultrasound of the abdomen can be useful in diagnosing angioedema if dilated loops of bowel are seen or if ascites is found in the abdomen, but it's not definitive for a diagnosis for hereditary angioedema. I should remind everyone that the lack of a family history does not rule out hereditary angioedema. There are de Novo C1 inhibitor mutations that account for at least 25% of HAE cases without a family history. When the GI tract is the only site of attack, it's often a situation that's quite difficult to diagnose. These individuals often experience many years of delayed diagnoses that are inappropriate food allergies. I mentioned surgical abdomens, they often may go through multiple emergency room visits, hospitalizations, many imaging tests, and often unnecessary surgeries.

Dr Riedl: Thanks, Bill. I think this case really highlights the abdominal pain or these GI attacks can be one of the most prominent symptoms in HAE, so it's important to recognize that. In some patients, it is the predominant symptom even over the skin swelling that we commonly associate with HAE. Bill, once we have this clinical suspicion of HAE due to the clinical presentation of a patient, as you outlined very well the medical and family history, how do you confirm the diagnosis? What are the specific tests that one should be ordering to evaluate for hereditary angioedema?

Dr Lumry: Mark, there are actually a variety of tests that we can utilize. A screening test that we recommend be obtained in the emergency room or possibly by a primary care physician is a C4 level. The C4 level is low in individuals who have C1 inhibitor deficiency associated hereditary angioedema. It actually drops to very low levels during an attack. If that's obtained in the emergency department, it's often diagnostic. Even between attacks, patients with hereditary angioedema 95% of the time will have a low C4 level. This test is available very widely. It does not require any very special handling of the specimen for the test to be accurate. To confirm a diagnosis of hereditary angioedema, we do a couple of other tests. First would be a C1 inhibitor level. The second would be a C1 inhibitor functional assay. We typically will also do a serum C1q level, which is low in another type of angioedema that's not hereditary known as acquired angioedema.

Dr Lumry: Approximately 85% of patients with hereditary angioedema have a reduced quantity of circulating C1 inhibitor. These individuals are known to have HAE type 1. Fifteen percent of patients have a dysfunctional C1 inhibitor even though their level is actually normal. These individuals are known as type two. Low C4, low C1 inhibitor level, or a low C1 inhibitor functional activity with normal C1Q are confirmatory tests for hereditary angioedema. Type 1 if both the activity and levels are low, type 2 if the levels are normal, but the activity is low. Mark, what are the options for management of patients like this when they have an acute attack? Do we have a variety of things they can turn to, to control the attacks when they do occur?

Dr Riedl: We do, Bill. That's one of the most important first steps in putting together an HAE management plan. After diagnosis, we want to ensure that an affected individual has an effective medication to stop these attacks when they occur. We call this acute or on demand HAE treatment. We actually have 4 FDA approved medications to treat these HAE attacks or symptoms when they occur. There are two C1 inhibitor concentrates that are available. There's a plasma derived C1 inhibitor. There's also a recombinant human C1 inhibitor medication. These are both dosed based on weight and both are intravenously administered. These are very useful, have been shown to be very effective. As may be obvious, these replace the C1 inhibitor protein that's missing in these affected patients. Thereby are quite effective at stopping HAE attacks when they occur. There's 2 other FDA-approved products, a kallikrein inhibitor called ecallantide and a bradykinin receptor antagonist called icatibant. Both of these medicines are administered subcutaneously. They have different age indications with icatibant being approved for 18 and older, and ecallantide for 12 and older.

Bill, I went over some of the acute treatments. We have options to discuss with patients and set up an effective way to treat these HAE attacks, but there are some other important considerations with acute treatments. Could you walk us through some of the important information that clinicians need to know and discuss with patients when it comes to treating these HAE attacks?

Dr Lumry: Mark, as you pointed out, this is very and actually the first step in creating a management plan for patients. Obviously, these attacks are unpredictable, but with the patients being able to treat them when they occur, the morbidity and potentially the mortality of an attack can be lessened dramatically. Any patient with a diagnosis of hereditary angioedema should have an on demand treatment. That treatment should be readily accessible. We recommend that patients have 2 doses available to treat any given attack. 90% of attacks will respond to 1 treatment, but there are occasional patients that require a second dose when the attack is not completely controlled or returns. Mark, could you talk a little bit about how you might select an on demand treatment for a patient?

Dr Riedl: Some of the considerations of course include the efficacy of the medicine. We have again data to show these are all effective, but sometimes it's worthwhile to touch on that with the patient and also considerate ourselves. The safety and side effects of the medication, we want this to be tolerable for patients. We also want them to know what side effects to be cognizant of and watch for. Then, route of administration is something that's important for some patients, intravenous versus subcutaneous administration.

As we've discussed, C1 inhibitor concentrates replace the missing protein. Whereas ecallantide and icatibant are very targeted treatments either blocking kallikrein activity or blocking the bradykinin receptor respectively. While this may not matter as much to patients, I think it's important for us to know the mechanism of action as the prescribing specialist. There may be instances where that's an important consideration in individual patients.

Bill, we've talked about diagnosis, we've talked about the on demand or acute treatment plan. Now, we have to, when we're sitting with a patient, put this together in an overall management plan. I'm wondering if you could talk a little bit about creating that management plan, then what the goals of that management plan may be as we follow a patient over time.

Dr Lumry: I think we should talk about the goals before we talk about the components of the plan. I think our overall goal is to allow these individuals to have a normal life to prevent significant morbidity including interference with school, work, or social activities. Certainly, trying to prevent mortality, which unfortunately still occurs in individuals who have an untreated laryngeal or airway attack. There are a variety of things that we can do. We've talked about education specifically with the on demand therapies, but patient and caregiver education about the disease, what the triggers of that individual's attacks are, how to assess an attack, and how to treat it when it does occur. Obviously even though this disease has a common pathway that causes the swelling, everybody's disease is a little different. The plans that we put together for our patients need to be individualized and usually put together on a shared decision making process that the patient and the caregiver have buy in to the process of how they're going to manage their disease. We recommend that at some point in the course of treatment and creating a management plan that they consult an HAE specialist who may be best able to put the components of the plan together that will work best for the patient.

Obviously, once a treatment plan is put in place, we need to monitor it, be sure that we're achieving the goals that we stated previously, and follow these patients along so that they may continue to have access to medications and receive appropriate care. Mark, I think you have a case to present that's a little bit different from the first one. Would you give information about that one?

Dr Riedl: Sure. The second case is a 40-year-old man. He was previously diagnosed with HAE about 10 years ago after a delay of several years, which we know is not uncommon with this condition. He initially was having attacks of his hands, feet, and face about every 3 months at the time of presentation. He was treating these attacks quite effectively with a subcutaneous on demand HAE medication, but in the last several months his symptomatology has changed and he's now experiencing more facial and laryngeal attacks. In addition to that, his attack frequency has substantially increased. He reports that over the past 6 months, he's had about 2 attacks per month, sometimes 3 attacks per month with much more involvement of his face, his tongue, and some airway symptoms that have been quite serious.

He's also started to have more abdominal attacks which are very painful and debilitating. Despite having his on demand HAE medication, which has continued to work, the frequency and the severity of his attacks have led to a couple of hospital visits in the last few months. He's also found the attacks to be extremely disruptive to his work. He has a job that's very public facing, so any facial swelling is difficult. He's also been missing some days of work due to the attacks even with acute treatment, he still doesn't feel well for a few hours with each attack. He's also had to cancel some family events and some family travel, which has been disruptive to his family life and relationships.

Dr Lumry: Mark, what do you think is going on here? This guy has obviously been diagnosed. He's been treated appropriately, he's done very well. What kinds of things do we need to be thinking about when there's such a dramatic change in symptom frequency, lack of control, what sort of factors do we need to consider as we approach this gentleman?

Dr Riedl: Bill, I think the first important point is to recognize the wide variability in HAE symptoms. Certainly, we see that between various patients even within the same family, but within a given individual that has this condition, you can see these sorts of changes overtime where things may be going along quite stably and then for various reasons or unknown reasons even, you see a dramatic change in the symptomatology, which can lead to a lot of disability and dangerous situations. Because we see this change in his symptoms, the first thing I think is to assess whether there's any triggers that may have cause this. In a gentleman like this, I'd want to make sure he hasn't been put on an ace inhibitor for instance as a blood pressure medicine that we know can exacerbate HAE attacks. We'd be asking about infections or other health conditions that may be flaring that sometimes will cause an increase in HAE symptoms. Then, changes in his life. We know of course that stress is a trigger for attacks in some people, whether that's good stress of getting married, having a child, or bad stress with sick relatives or being over worked at his job. Those sorts of life stressors are unavoidable, so we're not going to be restrictive as a treatment plan, but it's good for us to explore that so the patient may identify reasons why things have changed in terms of symptoms.

That being said, I think that overall what we're trying to do in HAE management is improve quality of life. You included that as part of your overall management plan as one of the goals that we're focused on. I think with each assessment including the follow-up for this gentleman, we need to be asking about things that affect quality of life. The obvious ones are, how often are the attacks occurring? What's the severity? What types of attacks, whether that be airway, GI, or cutaneous? We need to review those components of the treatment plan that you laid out. Are they using their on demand medicine? Is it effective? Are they having side effects? Are they having supply issues and having enough to treat their attacks? Over and beyond those medical components that we should always be thinking about as clinicians, we also need to assess the impact of HAE on their overall life activities. How are the symptoms or the treatments even affecting their ability to carry out their activities? That includes many areas of life. Work, school, but also their family life, their social life, their ability to travel, their ability to exercise and carry out their hobbies, and physical activities that are meaningful in all of our lives.

Bill, as we move along, one of the major management questions I guess facing us as clinicians is when to use or when to initiate prophylactic therapy for patients with hereditary angioedema. This comes in a couple of varieties, short term prophylaxis, more commonly we're making decisions about long-term prophylactic use in addition to on demand treatment plans. How do you decide when and where to initiate prophylactic therapy?

Dr Lumry: Mark, I think we need to define the difference between short-term and long-term prophylaxis. As we talked about in the discussion of triggering attacks, one of the common triggers of attacks is trauma. When patients are having dental procedures, particularly tooth extractions or other extensive procedures in their mouth, or undergoing other medical procedures like endoscopy or intubation, we should pretreat them if you will to try to prevent that activity from causing a swelling attack. That type of pre-treatment can take a couple of forms, which we can discuss in a minute. As far as the other form of prophylaxis, more long-term disease-controlling prophylaxis, there are a variety of things that we need to think about.

What's the burden if you will of the disease? How frequently are you having attacks? What's your access to an emergency room or urgent care? Obviously, this disease is so unpredictable that many patients have significant anxiety about, when is the next attack going to occur? That anxiety can be quite paralyzing to the patient and disruptive to their family and other activities.

As you've mentioned previously, this all comes under quality of life. We would like to have these individuals have as near normal life as possible. If this disease is interfering with that possibility, then certainly doing something to decrease the frequency or maybe eliminate the attacks by using a long-term prophylactic agent is something we should consider. There's a variety of prophylactic options. I think they're getting better each year. Mark, as you know we've had these now since 2008. We've seen an improvement primarily in the burden of treatment, the ease at which patients can use these agents and side effect profiles have decreased. Can you tell us a little bit about what's available and what you do in your practice for prophylaxis?

Dr Riedl: Sure, Bill. To review quickly first, the short term prophylactic options and as you already mentioned, these are medicines given just prior to a surgical, medical, or dental procedure that has a high risk of triggering HAE attacks. There's really 2 approaches to short-term prophylaxis. The first is androgen therapy. Androgens are oral medications, but they work fairly slowly, so androgen therapy should be started generally about a week before a procedure that may trigger attacks and often these are continued for a couple of days after the procedure. This is generally effective, but takes a little bit of planning ahead. The other approach, which is generally favored now due to the efficacy data that we have that's been published is C1 inhibitor products. These are IV and infused generally just before the procedure, so usually if given within a few hours prior to a medical or surgical procedure, it's been quite effective at preventing HAE complications from the procedure. The long-term prophylactic options, we have more of those, and as you alluded to, there's been significant progress in long-term prophylactic options for HAE in recent years.

The C1 inhibitor products, these are plasma derived C1 inhibitor products. We've had intravenous C1 inhibitor prophylaxis for a little over a decade now. More recently developed is a subcutaneous form of C1 inhibitor prophylaxis, which has become I would say favored over IV because it's easier for patients to administer this on a long-term basis subcutaneously. It also maintains a more steady state level of the C1 inhibitor protein within the blood. That has led to better, more effective prevention of HAE attacks based on the clinical trials that have been done with the SC C1 inhibitor product. Secondly in the last few years, there has been development of a monoclonal antibody against plasma kallikrein. This is the drug lanadelumab. This is a monoclonal treatment that's administered subcutaneously. Generally, given every 2 weeks. Although if people do well over time, there is an option to space that out to every 4 weeks. Again, we've seen this to be very effective in clinical trials at preventing hereditary angioedema attacks, so it's another useful option to consider in patients that will benefit from long-term prophylaxis.

Then, there's a couple of oral options. Certainly, androgens have bene around for many years. There are attenuated androgens like Danazol that are FDA approved for HAE prophylaxis. The androgens have been utilized much less in recent years because of the concerns about long-term side effects. We'll cover the side effects and safety issues of each of the medicines in a moment. Suffice to say there has been concerns about the long-term use of androgens in all patients. Particularly in women and children, we see many unfavorable side effects. Androgen use remains an option. I do discuss is with my patients, but increasingly we've been using other effective and what appear to be safer treatments over the androgens in recent years. Lastly, there's an investigational oral drug, which is not yet been approved by the FDA. This is called berotralstat. This is an oral kallikrein inhibitor, so a targeted oral therapy that in pivotal clinical trials has again been shown effective at preventing HAE attacks when used for long-term prophylaxis. This is not approved yet, but we expect a decision in December of 2020 from the FDA. If approved, this would be a once daily oral pill that may be very useful for long-term prophylaxis in HAE.

Bill, would you take us through some of those adverse effects that we need to be aware of and council patients about?

Dr Lumry: Certainly, as you mentioned earlier, androgen therapy, which has been around since the 70s and is approved as a prophylactic therapy for this disease, although effective, it is associated with significant side effects both in men and in women. Some of those side effects include weight gain, which is almost universal. In women, there can be menstrual irregularities and virilization. Patients may complain of muscle aches and pains, as well as headaches, and other things. Because of those side effects as well as some medical side effects, which can include liver damage and an effect on serum levels of low density lipoprotein and cholesterol we've tended to move away from androgens as a primary prophylactic treatment, particularity as the newer agents have been approved and become available. C1 inhibitor prevention, initially available 10 years ago as an IV product is effective, but patients often have issues with vein fatigue when giving it every 3 to 4 days intravenously. With a subcutaneous product, there are some local injection site reactions, which are usually transient, and fairly well tolerated.

There's a rare individual or a potential for hypersensitivity with any plasma based product, but again at a very rare side effect and frankly one that I've not seen in my patients. With the monoclonal antibody lanadelumab again given subcutaneously, there are local injection site reactions that patients will complain about. Other side effects that were reported in this long-term trial, which I don't believe were related to the drug, included upper respiratory tract infections, headaches, some rash, some dizziness, and diarrhea. The berotralstat, which as you mentioned is still under investigation and may be approved later this year, particularly at the higher doses showed some gastrointestinal adverse effects. Some cramping, some diarrhea, some nausea, which seemed to with time abate. That is potentially a limiting side effect for use of this drug. We've got good news, we've got bad news, and we're moving along quite nicely with the ability to control this disease in these patients, which heretofore have been really under served.

Dr Riedl: Well, thanks so much, Bill. I really, appreciate your expertise. I think it's been a very informative discussion. I'll finish up with some concluding remarks. First, we always need to consider the diagnosis of HAE. Particularly, in patients that present with recurrent episodes of skin swelling, and we've also highlighted how abdominal pain is an important clue to the diagnosis of HAE. In fact, abdominal pain may the prominent feature in some patients with this rare condition. As far as lab testing, it's important to remember that the C4 level is a very useful screening test for HAE, but the confirmatory tests include C1 inhibitor levels and function.

We've reviewed today the importance of establishing an on-demand treatment plan for patients with HAE. This includes selecting an FDA approved acute treatment for hereditary angioedema. This really should be the first important step in overall comprehensive treatment plan. It's very important that patients are educated on how to use their acute medication, when to use it, as well as ongoing monitoring for any side effects as well as the efficacy of this acute treatment. We do emphasize that early treatments of these attacks with an effective medicine will allow for the optimal response and reduce the time of swelling as well as any complications.

We have very effective long-term prophylactic treatments that significantly reduce the frequency of these HAE attacks. It's important to discuss these options with patients. In fact, the newest evidence based guidelines suggest that we should discuss long-term prophylaxis with patients at each follow-up visit. Finally, we should remember that HAE is a highly variably condition. The symptoms vary between affected individuals. Also, may change dramatically over time in a single patient diagnosed with HAE. Because of this unpredictability, it's very important that we have close follow-up with these patients, see them regularly so that we can determine if the treatment plan is effective, we can assess their quality of life through an interview, but also perhaps using validated quality of life tools. Therefore, we can adjust the treatment plan to ensure that we're optimizing their treatment as much as possible.

Bill, I'd once again like to thank you for joining me today in this discussion.

Dr Lumry: Thank you, Mark. I've enjoyed our discussion and hopefully the audience has as well.

Dr Riedl: I'll thank you, the participants, for attending 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.