Fundamentals III: Treatment Strategies for Severe Asthma by Leveraging Pathophysiology and Current Guidelines

Dr Louie: Now we are going to look at treatment strategies for severe asthma. Specifically, we are going to leverage not pathophysiology but pathophysiology and an understanding of immunology. I am going to basically try and get to the very end because it is challenging. But I hope to make it simple because your patients need to learn about the immunology of asthma. They need to learn about eosinophils and type two inflammation.

[00:56:52]

Approved Targeted Biologics for Severe Asthma

The next slide shows you basically the currently FDA-approved biologics for severe asthma available for prescription. To read off the names and going from left to right: omalizumab, first FDA-approved in 2003; mepolizumab, 2015; reslizumab is the only IV formulation given to patients that was FDA approved in 2016; benralizumab, 2017; dupilumab, 2018; and tezepelumab, 2021. And there are at least three more coming, so hop on board now. Learn immunology, understand how these biologics target the immunology of dysregulated asthma inflammation.

The targets basically for mepolizumab, reslizumab is circulating interleukin-5. I mentioned earlier the pillars of type two inflammation are IL-4, IL-5, and IL-13. Benralizumab, on the other hand, basically binds to the receptor for interleukin-5. These receptors are most often found on eosinophils.

Again, we are targeting eosinophilic inflammation. We are targeting type two inflammation. Dupilumab, on the other hand, is the only biologic that causes dual inhibition of two cytokine pathways. It basically blocks interleukin-4 and interleukin-13 activation. How does it do that? It binds to the interleukin-4 receptor, which is necessary for the type one receptor for interleukin-4 and type two receptor for interleukin-13.

Tezepelumab works completely differently. It actually goes to very high up. It acts on what I call the dermatology of asthma. It works on the epithelium. As many of you know, there are so-called alarmins. These are epithelial cytokines that are released. You have probably heard about interleukin-33, interleukin-25. Thymic stromal lymphopoietin basically is the alarmin that tezepelumab binds to.

The frequency basically can vary. At the very end of this session, we are going to talk about and have to see the spelling of the name. There is a upcoming biologic that you can administer hopefully, if it is FDA approved, every six months. A lot of excitement on this front. Safety never happens by accident.

There are basically two of these biologics which have boxed warnings, and these are patients that should have an EpiPen prescribed in addition to the biologic. That goes for omalizumab, otherwise known as Xolair, and for reslizumab, otherwise known as Cinqair.

With that background, we are going to basically walk through very quickly what these biologics do.

[00:59:43]

Omalizumab in Severe Asthma

Omalizumab, as I said, it binds to circulating IgE. It downregulates mast cell activation and degranulation. It basically is prescribed in those patients who have evidence of a perennial aeroallergen, like the cockroach, to dust mite dander that Jennifer talked about. You really have to convince the insurance company that the patient has asthma, number one. You have to do testing for these specific IgEs.

[01:00:12]

Anti-IgE: Omalizumab for Severe Asthma

Does it work? Yes, it does. In fact, all the biologics, including omalizumab, can reduce exacerbations and the need for hospitalization. It is approved for children six years and older. All the biologics reduce exacerbations by 50% to 60% at best. They are all different. They are like antibiotics. They are all different. I have had patients fail three biologics. They work on paper, ladies and gentlemen, but it does not work in the real world, which is why it is so important to integrate your clinical experience, your real-world experience, into the practice of medicine.

Try and resist using algorithms. Treat the patient. Be patient-centric. You have to be disease-centric as well as patient-centric in all cases.

Again, it does reduce exacerbations, as these graphs show you. Remember, these studies were done in very controlled circumstances. There were strict inclusion and exclusion criteria. In the real world, I cannot turn away patients who walk through my door, or I know you cannot do the same in your case. Again, you have to do a clinical trial of one.

Remember, all patients are created equally different. Once you or your family needs healthcare, you will begin to remember what we just talked about.

[01:01:32]

Omalizumab: Safety

Safety. Anaphylaxis occurs like two in 1,000 patients. 60% to 70% of the cases anaphylactic occurs during the first three doses. If I prescribe it, my team basically uses it. We will basically monitor the patient in the clinic for the first three visits. There is report of malignancy that was basically reviewed by the FDA together with Genentech. Again, it has led to a cautionary paragraph in the prescribing information.

[01:02:03]

Omalizumab in Severe Asthma

What you need to take home is that it is indicated as an add-on maintenance to inhaled steroids, six years and older. The IgE level has to be between 30 and 700. There is basically a dosing regimen. It can be once a month or twice a month. You have to convey to the patient and to the non-paid caregiver the risk of anaphylaxis. That is omalizumab or Xolair.

[01:02:30]

IL-5 in Severe Asthma

Interleukin-5, we hit on this earlier. This is growth hormone for eosinophils. Eosinophils in asthma, and also in COPD are not the normal eosinophils. They are slightly bigger. They have less granules. They are very angry. They release their granules at will. They may release, and there is no parasite or worm inside. They will release the major basic protein, they are eosinophil peroxidase, eosinophil cationic protein, and you get basic tissue damage, particularly in epithelium, and you get airway fibrosis.

Again, mepolizumab and reslizumab target circulating IL-5, whereas benralizumab targets the alpha subunit to the receptor that is on the surface of the eosinophils, but it does much more than the block. It also brings in natural killer cells, which will terminate the eosinophils life.

[01:03:30]

Mepolizumab in Adults and Adolescents 12 Yr and Older

Does mepolizumab work? Yes, it works. It is FDA-approved for six years and older. This is just data showing you. Remember, this is really a discussion. Please read the original article that was published back in 2014. Do not rely totally on up-to-date or open evidence. It is like reading Reader's Digest. Read the article, and you begin to understand what I am pointing out. This is very much a population-based study. You have to learn how to do a clinical trial. I know you know how to do a clinical trial of one.

[01:04:05]

          Mepolizumab in Children

It works in children.

[01:04:08]

Mepolizumab: Safety

Side effects. Again, very similar to placebo. Again, no cases of anaphylaxis reported with mepolizumab, but all these monoclonal antibodies are raised in hamster ovary cells. Again, they are proteins and patients can develop severe hypersensitivity.

[01:04:29]

Mepolizumab in Severe Asthma

In summary, it was the first anti-eosinophil drug. Xolair can also work, but you have to use basically what is appropriate based on the nomogram. There is no anaphylaxis warning, and the eosinophil count has to be 150 or greater. This is where it is very important to remember that inhaled steroids, particularly high-dose inhaled steroids can lower the eosinophil count by 20% to 40%.

If you are like me, having to deal with peer review, I bring that to the discussion, literally advocating for my patients, or some of you may say, I am begging for the patient, and I am begging for the patient because safety never happens by accident.

[01:05:12]

Reslizumab in Severe Asthma

Reslizumab is the only intravenous biologic that you can prescribe, and it can reduce exacerbations, again, about between 40% and 60%.

[01:05:23]

Reslizumab Improves Lung Function in
Severe Asthma with Baseline EOS ≥ 400 cells/μL

Just a graph showing you the data here, the requirement according to the package insert the information, the eosinophil count has to be originally 400 or greater, but again, 150 is the threshold. That is 150 or greater.

[01:05:43]

Reslizumab in Severe Asthma

Anaphylaxis. This is not approved for children.

[01:05:48]

Benralizumab Significantly Reduces Exacerbation Rates and OCS Dosage in Severe Asthma (EOS ≥300 cells/μL)

Benralizumab. again, I basically remiss in not mentioning the names. Omalizumab is Xolair, mepolizumab is Nucala, reslizumab is Cinqair, benralizumab is Fasenra, significantly reduces both the exacerbation as well as oral corticosteroids. The need for oral corticosteroids, in my opinion, is also a clinical phenotype. Nucala or mepolizumab, as well as benralizumab and dupilumab have shown in clinical studies to help patients either reduce their dose of oral corticosteroids or eliminate the need for oral corticosteroids on a daily basis.

Again, these are FDA-approved for efficacy and safety. Again, but they are add on. They cannot stand alone, which is why one of the answers to one of the other questions was wrong.

[01:06:43]

Benralizumab: Safety

Here are the side effects. Very similar to placebo, headache, pyrexia. Again, no pneumonia. Please remember, inhaled corticosteroids, particularly moderate to high-dose, is equivalent to about 7.5 to 10 milligrams of prednisone a day. If you do not know that, own the information. Now own the knowledge. Again, somebody who has continued need for high-dose inhaled corticosteroids are at risk not only for pneumonia, but also for diabetes.

As I said, for diabetes, where basically incubating patients that will need diabetic care, we leave them in high-dose inhaled corticosteroids.

[01:07:24]

Benralizumab in Severe Asthma

Again, benralizumab is approved for six and older. No anaphylaxis. It can be given every eight weeks after two months of giving it every four weeks. Again, available for office and home use.

[01:07:44]

Dupilumab in Severe Asthma

Dupilumab again gained worldwide fame for dealing with atopic dermatitis or eczema. That was in 2017, I believe. In 2018, it was approved for asthma 12 years and older, and it took a few more years for it to be approved in six years. Again, this is the only biologic that causes dual inhibition. It knocks out IL-4 and 13.

Can we, in fact, use Nucala and Dupixent and call it a day? No insurance company will let you, but it does not make any sense, particularly when you want to champion patient safety. There is efficacy with dupilumab at 200, 300 doses. Here in the Sacramento Valley, we have relied on 300 primarily for our patients. Again, it is given every two weeks subcutaneously at home via auto injector, reduces exacerbations. No surprise.

[01:08:42]

Dupilumab Improves Exacerbation Rates in Severe Asthma

Then why are we not employing these biologics? Look at the CHRONICLE study. It is ongoing. No more than 20% of patients appropriate for biologics are getting it. What is holding us back? You heard Jennifer talk about the healthcare disparities who are not getting a chance to try biologics children, women, Blacks, Hispanics, Native Americans. I will throw in Asians for kids[?] because we are invisible to everybody.

[01:09:06]

Clinical Response to Dupilumab per Eosinophil Count and FeNO

Again, dupilumab works as the other biologic across eosinophil counts and exhaled nitric oxide because you are trying to reduce inflammation, specifically type two inflammation. You can use this, but remember all these studies were done in population. We are seeing a distillation. We are seeing mean or average values.

[01:09:26]

Dupilumab Reduces OCS Dose in Steroid-Dependent Severe Asthma

Dupilumab again is the only biologic that has a specific FDA label. It is indicated for the patient who is dependent or on steroids. As I said earlier, if you look at the current studies published, both Nucala, mepolizumab, and benralizumab have published studies which also show impressive reduction in the need for prednisone or Medrol if that is your go-to oral corticosteroid.

[01:09:53]

Dupilumab: Safety

As far as safety, again, overall, it is well tolerated. Again, this is all available. I know you have the PowerPoint slides you can review it at your leisure.

[01:10:02]

Dupilumab in Asthma

Please remember six years and older. Dupilumab has eight different indications in different diseases. Bullous pemphigoid, atopic dermatitis, eosinophilic esophagitis, asthma, nasal polyposis. How can that be? It is because dupilumab basically addresses uncontrolled dysregulated type two inflammation. That is the immunological concept I want you to take home.

[01:10:33]

Thymic Stromal Lymphopoietin in Asthma

What about TSLP or thymic stromal lymphopoietin? I told you this is an alarmin or epithelial cytokine that is released whenever the skin inside our airways come in contact with the environment or virus. Again, it triggers the alarm systems like your car alarm or your house alarm, and interleukin 25 and 33 are also part of it. That can cause downstream effects. This looked like a very logical target.

[01:11:01]

Tezepelumab in Severe Asthma

They developed an antibody against the TSLP, and that is basically a tezepelumab that has demonstrated reduction in asthma patient [inaudible] has not been shown to reduce oral corticosteroid use. In fact, it failed. I think there are studies in play right now to show because we have, in clinical practice, used tezepelumab in our own clinical practice to take away prednisone, but it did not show superiority over placebo in the clinical trials that were published in the New England Journal of Medicine.

We were very excited to take on tezepelumab into our black bag or black medical bag because it showed efficacy in those patients who were non-eosinophilic or had low eosinophil counts less than 100. We found that it actually helped control patients' symptoms and reduce the rate of exacerbation in that group. It has a place for not only type two high asthma but type two low. Do not feel this is a rescue biologic. This is a first-line biologic that you can use, as the other biologics are all first-line. This is why you must all develop an acquaintance. You all must develop experience with all the biologics.

Again, it works. It works again.

[01:12:32]

Tezepelumab: Safety

The side effects are really very few. If you look at placebo, 3%; pharyngitis, arthralgia, 3%; back pain 3%. All of them cause back pain. I cannot explain it, but if you look at tezepelumab or Tezspire, 4%.

[01:12:48]

Tezepelumab in Asthma

No anaphylaxis or warning, 12 years and older, and very recently approved for nasal polyposis, if I am correct.

[01:13:04]

Investigational: Depemokimab in Severe Asthma

Here is what is really exciting, and I have to pronounce this correctly, depemokimab. Published in New England Journal of Medicine this clinical trial, SWIFT-1 and SWIFT-2. Very exciting. This is a monoclonal antibody targeting circulating interleukin-5. It is given every six months, not every four weeks, every six months. The reason why I am excited is because adherence is a huge problem. I said earlier, up to 80% of patients with asthma do not know how to use their inhaler. Only at most 25% to 30% follow their asthma action plan and their prescribed treatment. This may help adherence. It may, but it may not. Again, you got to make sure you have the right diagnosis.

[01:13:53]

Depemokimab: Safety

This is maybe a dawn of a new era. The side effect profile, very similar to placebo.

[01:13:59]

Choosing a Biologic

This leads us to the overview from the World Health Organization through the GINA guidelines. How do you choose a biologic? Remember, the crime is not to prescribe one when a patient has uncontrolled asthma with medium to high-dose inhaled corticosteroids. Why not just high-dose? Because high-dose it is like giving somebody prednisone.

If somebody is not doing better on medium or high-dose, it is very important to consider adding a biologic earlier. If you are worried about prior authorization, why should you be? All of you are very familiar with the GLP-1 agonist. It is no different. Patients need to understand that their treatment has to be escalated.

Why? Patient safety. You are trying to reduce symptoms and, most importantly, exacerbation. Consider omalizumab if patients have IgE level and you are concerned primarily about allergic asthma. If somebody has eosinophilic asthma, it does not mean you cannot prescribe omalizumab. But the thought leaders that we have recommend the biologics that target eosinophils directly, and that is basically mepolizumab, reslizumab, and benralizumab. Of course, dupilumab has two indications.

One for asthma with eosinophilic phenotype, that is, uncontrolled asthma, and also for uncontrolled asthma patients who are dependent on steroids. Tezepelumab, far right, again, it works for all of them. The key thing is you are driven by patients who continue to have exacerbation, which gets back to the earlier point. How many exacerbations would you allow your patient to experience? Is it zero? Is it one, two, three, or four? In the past, we let patients have as many as they want to. Now it is very clear, we will tolerate no more than one a year.

[01:16:11]

Choosing a Biologic: Predictors of Response

How about looking at biomarkers? Higher eosinophils, actually. Omalizumab works when people have higher eosinophil counts. Works better. Again, you can directly attack the eosinophils with all the anti-IL-5 and anti-IL-5 receptor drugs, anti-IL-4 receptor, that is dupilumab and anti-TSLP, that is tezepelumab. eNO not done in a lot of places, unfortunately, because of cost and politics.

Again, you are really talking about measuring type two inflammation, and I would probably say all six of these will be helpful. I am quibbling with the GINA guidelines here. This is why you need to bring your own experience into play. You know what is best for your community.

Adult-onset asthma. Well, again, I think they all work, but GINA says think about using mepolizumab or benralizumab. For childhood-driven onset asthma, anti-IgE, again, in my opinion, you could do that, but you can also consider mepolizumab and benralizumab as well as dupilumab. They are all basically FDA-approved for six years and older.

These are just opinions. What matters is what you do for your patients in the name of patient safety. It is about making sure you have the right diagnosis.

[01:17:41]

Choosing a Biologic: Comorbidities

Comorbidities. We hit this earlier. You cannot find trauma unless you look for it. Examine the patient's skin. Look up the nose. Dupilumab is indicated for eosinophilic esophagitis. Go from left to right. We did have a case study in this program where the patient had eosinophilic granulomatosis with polyangiitis.

Mepolizumab, for seven years, was the only biologic that was FDA approved, was able to get, I think it was like 24% of people off of prednisone. I have had experience. I would like to hear if Jennifer has had experience with EGPA and mepolizumab. But very recently, benralizumab was also FDA approved. Now we have two biologics that can spare the patients the need for the toxic side effects of oral corticosteroids.

That is a very quick overview of biologics, so any tips on getting the patient? What is the trigger? The trigger is uncontrolled symptoms and exacerbation. If you have an Asthma Control Test score consistently below 20, patient who requires prednisone more than once a year, that is enough for me to fight for the patient's health and for their well-being.

[01:19:12]

Skill Building and Feedback III

Okay. Tyler, we need to try and help Samir. Can we help Samir, ladies and gentlemen?

Tyler Kuhk: Let us try, and great on timing. I think we will have a good couple of minutes here to have a little discussion and maybe get to some questions if we have a little bit of time. We will start with Samir. He is a 50-year-old auto mechanic who has frequent asthma flares despite using his high-dose ICS/LABA. He is required three prednisone bursts. High-dose ICS/LABA, he is on tiotropium.

His labs show his eosinophils at 140 cells per microliter, but his FeNO was elevated at 55. He has nasal polyps and atopic dermatitis, and his asthma remains poorly controlled with frequent exacerbations. I think, Dr Louie, your slides really went through this, which I found actually really helpful. I was snapping the pictures there in terms of how you choose based on comorbidities and things like that. We can chat with you and Jennifer about what therapy you think best targets the inflammatory pathway in this specific case for Samir’s symptoms.

Dr Louie: Right now, as I mentioned earlier, there are four biologics that actually work in asthma that have been approved for nasal polyposis. I need Jennifer to keep me honest. Dupixent or dupilumab was the first one that was FDA-approved. Then came Nucala or mepolizumab, very recently tezepelumab was FDA-approved, but I am missing one other one.

Jennifer: Omalizumab.

Dr Louie: Thank you, Jennifer.

Tyler Kuhk: There is too many.

Dr Louie: Again, how do you choose? This is why you have to basically have experience because on paper, they all work. That is a lie. They do not all work. I remember my first patient I tried on benralizumab. He was ready to die after going through omalizumab, going through mepolizumab, going through reslizumab, and he was only 39 years old with five children. He was ready to give it up.

I said, no, no, no, we are not done yet. On paper, it should have worked. This is why it is so important to take all these clinical trials in context. They are done in populations highly regulated. They are designed to get FDA approval for safety and efficacy. But again, in the real world, the responsibility becomes yours to choose the right one. You have to do a clinical trial of one, and let patients go for no more than three months on one biologic and be ready to switch, which is why you have to be familiar with all, not just one or two. You have to be familiar with all of them.

[01:22:00]

Poll 8

Tyler Kuhk: I am curious to see what our audience thinks, and we will continue the discussion. Based on Samir's presentation, everybody, we want to survey on which biologic therapy that you think would be most appropriate. If you had the choice, would you choose:

1. Omalizumab;
2. Mepolizumab;
3. Depemokimab, which is not approved yet, but it could be option; or
4. Dupilumab.

We will give you a few moments on answering that.

Dr Louie: Okay. While your audience is listening, notice that we are not looking at X-rays. We are not looking at FEV1. We are looking at the patient's clinical history and the available biomarkers we have currently.

Tyler Kuhk: Actually, here is the spread now. 68% of you actually would have went with D, so dupilumab. 17% was right behind that with omalizumab. Maybe it opens our discussion now, you guys, about how do you discuss biologics with patients? The million-dollar question, how do you pick that up? There is a couple of questions here. We probably have a little bit of time for. So we will just start off with you, Dr Louie, and then Jennifer pipe in, and we will go from there.

[01:23:33]

Faculty Discussion

Dr Louie: Again, as I said earlier, Tyler, I try to frame the discussion as a failure of the treatment plan. I never blamed the patient. I tried my best beforehand to make sure the patient uses their inhaler correctly, and they are using it every day. We begin to talk about basically the advanced therapy. One of the things early on that I had to do with a lot of patients here in Northern California thought these were vaccines, and they are not vaccines. The drugs delivered with a needle, but they are not vaccines.

They can help you, and you literally have to hold their hand. You can show them the guidelines, but there is so little trust in the healthcare system presently. They really want to know would you treat your sister, your brother, your mom, your dad, your wife, your husband with these biologics? Again, this is all part of the shared decision-making mechanics that Jennifer's going to go through very expertly, very shortly.

Trust has to be earned every single day. Usually, I give patients at least three choices, and they may want to go home and do some work, or they say, what would you do, Sam? I will pick one, and I use them all. I do not really have outstanding favorites. The favorite biological habit is the one that works for the patient.

Jennifer Weber: I could not agree with that more. People ask me that all the time when we discuss, okay, it is time to start a biologic. They just say, “Well, put me on what you think is going to work best.” Patients are not just cases on paper, as we all know, and Dr Louie has hinted towards this too.

There are so many different things that I think need to come into play when having this conversation with patients about which biologic is best for you. Things that may seem silly to us, but it means a lot to patients. Do they have a needle phobia, for example? Are they petrified to take injections at home? Would it be too difficult to get to our clinic every two weeks to get it? Or can we not get them into an infusion center to get it?

Is insurance going to cover it? Of course, that is a whole other conversation for another day. We are doing prior authorizations and appeals on these all the time. That being said, it is important to consider they might have a preferred medication in their formulary. If that is a medication that the patient qualifies for, maybe that is the best one to start with. Ultimately, when I am having this conversation, I will start it by saying to these patients that are in the emergency room all the time on prednisone, way too much.

I tell them about the risks of those things, risks about uncontrolled asthma and oral glucocorticoid use. Then I say, we have things that work better. You do not have to live like this anymore. Let us work together to find something that works for you. These are highly effective medications with excellent safety profiles. I show them actually a graphic that is from the Asthma and Allergy Foundation with all of the different treatment options. I say, here are the six different biologics that are available right now.

Let me explain to you what these are for. Let us talk about how they are dosed. Yes, this takes a ton of time. I am not going to lie or sugarcoat it, but it is worth it. Sometimes we are not able to get that biologic started right then and there. I am trying to think ahead of the curve with these patients that I know are severe, frequent exacerbators. I try to bring it up as early as I can in the course of disease before I am like, “Oh, shoot, we really need to get them on it right now.”

I can find that very helpful if you are just introducing the concept a little bit earlier than you think might be necessary.

Tyler Kuhk: Great answers. I think we have time for one question. I wanted to pull this. Catherine had asked, and it is I do not think we talked about it, but a lot of people ask about pregnancy. Perhaps your experience in using biologics with pregnancy, do you start them on pregnant patients? Do you keep patients that might become pregnant while they are on them? You want to talk a little bit about that? Maybe Dr Louie and Jennifer, if you want to add? We have maybe two minutes here to discuss that, which is not that much time.

Dr Louie: The data for pregnancy is not available, although there are registries for all the biologics except for tezepelumab. I have personally prescribed biologics for patients. I have a colleague who is a surgeon, and she lost her baby during the pandemic. She had uncontrolled asthma. It was devastating.

Based on her phenotype and endotype, she had high eosinophils. She had a high exhaled nitrous oxide. I happened to recommend to her three biologics, and then she asked the question, as most of your colleagues in healthcare would ask you, what would you choose, Sam? I said, let us try benralizumab, Fasenra.

Long story short, he went on to have twin boys, and she is very lucky to have an older daughter, who is two years old. It has been wonderful for the family. Let me tell you, the boys are naughty as hell.

Again, that is my story. I have other patients who have tried other biologics. What I did with this particular surgeon was to let her speak to the pharmaceutical company for the data that they do have on pregnancy. The biologic does pass through the placenta. It is in mother's milk. They continue to do very well. The boys are walking now, and it is really scary. Both of them look like Terminators. They destroy everything in their way, but they are very cute. Jennifer, do you have any story?

Jennifer Weber: I sure do. Actually, funny enough, asthma and pregnancy is one of my special interests. I have done a couple of talks just on this topic, so I am not going to go into extreme detail. But what I would urge you to do if you are taking care of young women of childbearing potential, take a look at the quad AI statement about use of biologics in pregnancy. There is a lot of great data links directly to articles in there about case reports of use of biologic and pregnant women.

Mother to baby is the reference that Dr Louie was referring to that is where you can get patients enrolled in data repositories of monitoring the safety and administration of biologics during pregnancy. Any patients that are pregnant that you might be taking care of on biologic really should be registered on mother to baby if the trials are open. I will say, based on my clinical experience and the data, omalizumab is the oldest biologic. It came to market in 2003.

With that being said, it has the most amount of data by far. However, it is still a scarce amount of data. That is, of course, because we cannot ethically study pregnancy and use of these medications or fetal development in the use of these medications.

With that being said, all available data for omalizumab in particular has been very reassuring.

In our practice within our clinic, if we know that we have a young woman who is looking to conceive in the next few years, omalizumab will be our drug of choice if the patient qualifies for that.

The next biologic with most available data is mepolizumab. Again, that would have been the next released biologic. It is basically how old are these medications? I do not have any pregnant patients on tezepelumab, but I do have a colleague with a patient with very severe asthma. I am talking about patients that have had multiple ICU stays due to asthma, who was on tezepelumab prior to conceiving, and then decided to continue it throughout the pregnancy.

Another place I would draw your attention to is ACOG, American College of Obstetricians and Gynecologists, and they have a position statement on asthma management and pregnancy as well. Their bottom line is that controlling asthma in pregnancy is so important that any potential or theoretical risk of these medications is likely outweighed by the benefit of keeping the asthma controlled, especially if they are going to use medications that can be toxic when they are in the ICU, for example.

This is always something that you need to bring up with these patients and talk about. There is not a lot of data. Here is what you can look at. Talk to your OB/GYN about this and just have an open conversation with all team members.

[01:32:31]

Posttest 3

Tyler Kuhk: Thank you so much for those answers, you guys. We are just going to move along to our post-test real quick. We have this 48-year-old man with severe asthma that is currently on the high-dose ICS/LABA and tiotropium. Blood eosinophil count is 420 cells per microliter, and he is required two courses of systemic steroids in the past four months. He has a history of eosinophilic granulomatosis with polyangiitis. Which of the following biologics would be the most appropriate next step in his management? Would that be:

1. Omalizumab;
2. Mepolizumab;
3. Dupilumab; or
4. Tezepelumab.

We will give you a few moments to answer that and do the pre and post.

[01:33:25]

          Posttest 3: Rationale

Most people chose dupilumab 64% in the pre-test and post-test. We have dupilumab at 36% and mepolizumab at 26%. The correct answer is B, mepolizumab. Remember, that is the preferred agent given that patient has that history of EGPA. We can maybe talk a little bit about that after Jennifer's next session, because we are just running a little bit behind time here, but we have plenty of time, hopefully, for questions at the end.

[01:33:53]

Fundamentals IV:
Engaging Patients in Collaborative Care for Severe Asthma

Jennifer, I am going to hand it back to you to finish things off, and then I will see you at the next case study.

[01:33:57]

Asthma Management Requires Ongoing Assessment

Jennifer Weber: Let us get right into it. Any of you familiar with the GINA asthma guidelines may have seen this graphic before. This is like cannon in asthma management. You assess your patient. You adjust their therapies, and you review. And the cycle continues forever.

I am not going to read off of this, but what I am really going to drive home to you guys here is we do not want patients on high-dose ICS for long periods of time. Every six months, at a minimum, maybe even every three months, if you have that timing where you can see the patient and availability in your clinics, we should see if we can reduce that ICS dose if it is safe to do so, if they are stable, they are not flaring. We will use fluticasone salmeterol 550 as an example.

They should not be on that inhaler for years and years, especially if their therapy is not optimized. Always look at dose reduction and then, of course, step up as well. If they are not controlled, their exacerbating you have to add those therapies in. Step up, step down. Always key in asthma management.

[01:35:08]

Utilizing Asthma Action Plans

Asthma action plans are interesting because they exist, I think, a little bit more in pediatrics. They exist in guidelines. There is actually an interesting asthma action plan in the GINA guidelines that talks about single maintenance and reliever therapy, and how that can be modified for patients that are using ICS formoterol for both maintenance and relief of their asthma.

This is like a traditional asthma action plan here. Some patients do love this, and it really helps them, especially if their asthma diagnosis is newer, because it tells them what you do and like your regular or green zone. When things are going well, what do you do? When things are getting a little bit iffy in the yellow zone, when should you call your healthcare provider?

Then, of course, the red zone that is when you have to call us, and maybe you are even going to the emergency room. A simpler way to do this, I find, just in clinical practice, is talking to patients about how much reliever inhaler is too much. I would say general rule of thumb, if they are using a reliever inhaler two to three times a day for two consecutive days or more, they need to call.

I really want to know about that. I did see a question somewhere from someone in the chat. When do we want to know about mild asthma exacerbations? If a patient is using reliever inhaler more frequently than baseline, that is how we would define that mild asthma exacerbation. I would want to know about that because we need to keep track of poorly controlled symptoms when we are thinking about that review, assess, adjust cycle, and increasing asthma therapies.

[01:36:44]

What Can We Do to Empower Patients?

How can we empower our patients? We have talked about this a little bit. Provide information to your patient. Keep it clear, concise, unbiased. Make sure you are meeting the patient where they are at. Try not to use medical jargon. I know it is hard sometimes, but putting things into like a seventh-grade level, eighth-grade level, somewhere in there is usually that sweet spot where patients feel like you are not speaking down to them, but it is understandable. Make sure you are giving them verbal and written instructions.

You are showing them pictures, graphics as much as you can, and to not go on diatribes or spiels about medication. Give them a couple of sentences. Let them respond to you. Let them ask questions. That is always going to be more effective than just talking at your patient.

Then, of course, what is really key with patients is you are giving them all these choices. It is their choice at the end of the day. We are there to provide recommendations. It is their life. It is their body.

They are in control of their asthma. I always say that to my patients. I am here to help you, support you, provide recommendations. This is your life, your body. You tell me what you need. You tell me what you are actually going to take, what you are actually going to do. I always make it clear I am not here to judge you, especially when we are talking about smoking, for example, or drug use. I am not here to judge. I am just here to help.

[01:38:08]

The Process of Motivational Interviewing

Motivational interviewing is another key thing we can use when we are empowering our patients, interviewing them, talking to them just about where they are at in their treatment plan, where their goals are at. You want to ask patients permission if it is okay to talk about things. I will use smoking cessation as an example. Just saying to a patient, :Hey, is it okay if we talk about your smoking today?”

That will just give you a really good idea of where they are at, because if they are honest with you and they say, “No, that is not going to happen.” Great, you are not wasting your time. Maybe you could bring it up at the next appointment, but you are understanding where they are at, and then we can meet them where they are at.

You want to focus in on what the patient really needs from you. You do not necessarily every time you have to see a patient go over their inhaler technique. That might make them feel stupid, for lack of a better term. They might feel belittled. You might want to say, “Do you feel good with your inhalers? Do you have any issues accessing medications? What are your concerns? What are your barriers? What can I help you with?” Just always putting it back on them and waiting and listening. You want to hear their ideas, their opinions, and keep questions open-ended when you can.

Then when you make a plan for a patient, you always want it to be collaborative as much as you possibly can. There are, of course, outlying situations where patients just really need something, and you are like, “Hey, you need to go to the emergency room today. That is really my recommendation, and if you do not follow that, I am a little concerned.” Barring those situations, you really need the patient to understand, I am doing this because and I want to take this medication because and they feel more supported in those situations.

[01:39:51]

Engaging Patients in Treatment Selection

I have already talked a little bit about this. How do we engage patients in treatment selection? Some things to consider. Route of administration. Some patients love biologics because they are taken so infrequently compared to inhalers that are usually dosed at a minimum once a day, twice a day, or they are taking pills, multiple things. For some people, that is a great selling point to be like you need step up in therapy.

This can reduce your overall medication burden, and that is helpful for them to understand. Time constraints are certainly an issue for some patients. An example here is a patient with a very low FEV1. We may be tempted to say, “Hey, you would benefit from nebulized therapies. These are likely going to be the best delivered medications to you, but they work.”

They do not have time to take nebs two to three times a day. They are not going to do it. Just things we need to understand.

Insurance concerns, the never-ending saga we have to deal with, but if we are prescribing a really expensive or novel therapy, that might be hard. If we know that our patient's insurance is not the best and they have a high out-of-pocket cost, they are less likely to take those expensive medications and something else that might be covered and might still be effective enough at managing their asthma.

We also want to make sure we are going over treatment expectations with patients. I think something that is really critical, in particular with starting biologics or stepping up asthma therapy, is telling patients that we are not going to give you this injection today, and you will feel better tomorrow. That is not going to happen. It should work relatively fast. Within a couple of months, we should get some response. But this is not immediate.

This is not like IV steroids. We are going to need to take some time. We are going to need to keep reassessing what is going on here. We are going to need you to be patient while we figure that out and stay on your medications that you are currently on.

When patients say things like, “I never want to end up intubated in the ICU again”, that is the perfect time to say, “We can get this under control. Let us talk about how we do this. Let us come up with a plan. Let us talk about when you need to call me.”

[01:42:13]

Nonadherence Behaviors and Interventions

Nonadherence. At least in my practice, this is very common. As Dr Louie said, we have to be gentle and compassionate with these patients and not be like, “Hey, you are not doing what I asked”, and get annoyed. Oftentimes, it is multifactorial. It is systemic. It is because of things they cannot control in their life. Really complicated psychosocial barriers. We want to say, I am not here to lecture you. I am not here to judge you, but let us talk about what we can do to make this work for you and get this under control. It is your life. I am here to help.

Frequently miss doses of medication. Forgetfulness is a really common one. I will often see patients that are on an inhaler that they are supposed to use twice a day. They just forget that second dose. We can say, set an alarm on your phone, put it on top of your toothbrush, or next to your toothbrush. Put it on top of your coffee. Something like that to get creative, or maybe we consider switching them to a once-daily medication.

Whatever is going to work for the patient. If their medications are not being taken correctly, if they are overusing inhalers, underusing inhalers, that is just a conversation you need to have with them. Reiterate again, provide both verbal and written instructions, and ask for them to just quickly tell you, “Tell me how you are going to take your inhalers when you are going home today? What are you going to do tomorrow when you wake up? How are you going to use the inhaler? Show it to me. Mime it out.”

A lot of patients, too, unfortunately, have a poor understanding of asthma, even when they are seeing an asthma specialist. So do not feel bad if you see this all the time. Even when we are focusing 100% on their airway disease, this still happens, where patients just think, “ Well, I am on these medications, I feel great. I do not have symptoms anymore.” A couple of months go by, they are not using any meds at all. In particular, no ICS, and then they have a big flare, and we are playing catch-up, and they end up needing prednisone because their airway inflammation is just going up until they tip over into flare.

Telling these patients, “I know you feel good now that you are on a biologic, for example, but you still need to take your ICS. Let us talk about how to do that. Let us talk about how to minimize medication use but keep you safe, or if they are not taking meds at all.” This is unfortunately becoming more and more common with insurance barriers and just financial strains that too many people seem to be dealing with.

Let us just think about what is going to be the most affordable. Let us look into alternative strategies of getting the medications. Can we refer them to cost-plus drugs? Is that going to be cheaper than a traditional commercial pharmacy? Can they self-pay somewhere that is going to be cheaper? That is all about shared decision-making and just really talking to your patient about what they are willing to do, how to overcome that. And of course, instilling trust between you and the patient, knowing that having them know that you have their back and you are willing to try to figure out what is going to be best for them.

Sometimes patients will also just discontinue treatment and not tell us. This can be really frustrating because let us just say they are on a biologic. They have a skin reaction, so they think they are having an allergic reaction, and they stop, and they never take it again, and we do not know that until their three-month follow-up.

A helpful way to overcome this is to tell them ahead of time, “Hey, here is the expectation of what some common side effects are with this treatment, or if you have anything that you think could represent a reaction, give me a call.” It is hard to get it through. Have a good conversation about that after the fact, but if you can try to prevent it from happening, that is really helpful.

[01:46:00]

Monitoring of Patients on Biologics

The way I monitor patients on biologics is pretty much exactly what is on this slide. After we initiated, I do like to see them usually within four to six weeks. If I am really busy and do not have the time, eight weeks is okay. We can expand this too. If you have other support staff in your clinic, clinical pharmacists, if you do nursing visits, even just getting the patient in the clinic so they can do a quick check-in, get an asthma control score, see where they are at. Are they having any side effects? Just something to monitor the patient, that is ideal.

Really, they should be seeing you as the provider. If you need to think of a workaround, think of a workaround. Make them feel supported and safe while they are starting this new medication.

Repeating spirometry and FeNO, I will usually do at the six-month mark, or when the patient starts to notice that benefit to see if we can physically document. You know what? There has been an FEV1 increase, in your FeNO is down. This is awesome. I will say looking just at numbers is not as helpful as getting the patient's input too. What I really care more about is their symptom burden reducing and are they free from exacerbation.

I mentioned it before, but stepping down those inhaled medications. Ultimately, we want patients on the smallest safe dose of inhaled corticosteroid as possible. I am realistic with my patients. These truly severe patients, if they are on high-dose ICS or dual ICS, I tell them it might take us two years to get that down, but we are going to do it slowly, and we are going to do it safely. I am going to keep a close eye on you while we do it. Usually with that, they are on board.

If you say. “We are just going to cut it three months in, I think you will be fine.” You do not really explain it. You do not go through like this is what I want you to monitor for. I think they are less likely to have buy-in.

Me and my colleagues will generally consider alternative biologic therapy, I would say at the four to six month mark. Some of the biologics, I will say tezepelumab seems to take a little bit longer to work. That is just my clinical experience. I do not know if there is data to back that up. Sometimes with those patients, I will say, let us wait the full six months and see unless they are having an adverse reaction or having exacerbations landing them in the emergency room, or they are using prednisone recurrently. In those cases, we may need to do something a little bit sooner. Looks like we are on our last case.

[01:48:21]

Skill Building and Feedback IV

Tyler Kuhk: I know we all want to pick the brains of our amazing speakers. I am going to just get through this pretty quickly so that we can get to some of the questions that are piling up. I think there are great questions. Let us just talk about Carla real quick. Jennifer did a really good talk about some of these social challenges. She is a 62-year-old woman.

She is tired of all her inhalers. She has frequent nighttime symptoms and confusion about her medications. Her daughter helps to organize them. Carla's missed follow ups and is concerned about steroid adverse effects. She says she does not feel confident managing her asthma alone. Thinking about Jennifer's great talking during that section is how could we potentially engage someone like Carla to improve her understanding and adherence?

[01:49:06]

Poll 9

I am going to pull the audience on which strategy might best support shared decision-making for Carla. Would we:

1. Simplify her regimen and review inhaler technique using teach-back;
2. Emphasize adherence and increase the dose of her controller medication;
3. Provide printed materials at the end of her appointment; or
4. Reschedule a follow-up visit for further counseling.

Let us see what you guys think. 83% went with that answer A, so that is great.

[01:49:50]

Faculty Discussion

I think we already had a really good discussion with Jennifer about how she engages her patients in shared decision-making. Thanks for sharing all those pearls with us, Jennifer. I think it was really helpful.

[01:50:00]

Poll 10

Again, just a poll question for data collection from the audience is, what barriers do you encounter when discussing treatment options with your patients? Feel free to enter an answer there. Just give you a couple of moments there.

[01:50:33]

Posttest 4

Then just our post-test four question. How confident are you in your ability to use shared decision-making to discuss asthma treatments with your patients with severe asthma? Are you:

1. Not confident at all;
2. Somewhat not confident;
3. Somewhat confident;
4. Confident;
5. Very confident.

We definitely see an increase in confidence after the talk. Great job to our speakers.

[01:51:20]

Poll 11

Last question before we get to Q&A. This is again just data collection is, how often do you plan to suggest biologic therapies for patients with severe asthma?

1. Never;
2. Rarely;
3. Sometimes;
4. Frequently; or
5. Always.

[01:51:40]

Q&A

We have about 10 minutes for question and answers. There has been a lot of questions submitted through the presentation. I am just going to jump into a few right now, and Jennifer, Dr Louie, just jump in on what you are thinking here.

One question here from Justine is, what are your clinical thresholds for implementing biologics outside of severity and asthma control? You are looking at eosinophils, PFT findings, and then maybe speak to your use of biologics and COPD asthma overlap.

Dr Louie: Well, presently there is no drug that is approved for the asthma COPD overlap syndrome. It is an ongoing, very fierce debate about asthma and COPD. Is asthma an early form of COPD? Is COPD a late form of asthma?

I think the controversy will continue, but to-date, there is only two biologics are FDA approved for COPD again as an add-on to inhaled therapy, typically triple therapy. I think what we are seeing are two different populations because we look at the clinical trials, Tyler, and hope Jennifer will help me here.

If you look at the demographics, the patients in COPD are usually about 65 or 66 years old. All the asthma studies for biologics, the mean age was like 48 to 50. You are looking at about a 15-year difference. That 15-year difference, I think, is oftentimes overlooked when people are trying to compare asthma with COPD. Want to compare apples with apples, not apples with oranges or bananas.

I think COPD is a tough nut to crack. As the editors of the New England Journal of Medicine and JAMA said at the American Thoracic Society conference in May 2023. This is a dawn of a new era, particularly with dupilumab and mepolizumab available. I think it is much to say about formularies and algorithms.

I think the message people should leave the conference with is to really think about prescribing biologics earlier. Recognize the toxic side effects of inhaled steroids because I was lied to. Inhaled steroids are safe. They are just going to stay in the lung, which is a bunch of BS, because everything is absorbed systemically eventually. As I said earlier, there is no quibble about the dose. It is about 7.5 to 10 milligram for high dose, and medium dose is about 5 to 7.5 milligrams.

I agree with Jennifer. We need to get people off of high-dose inhaled steroids, and people continue to prescribe it a lot of times because of marketing. A lot of times, because people are just lazy, but again, this is where our empathy, our integrity, our accountability needs to step up. I really enjoy the slogan, a commitment to practice change. We do need to change.

The reason why we are changing is because of the patient safety and because we all have enormous pride in our profession and what we do. I will be damned if I let an algorithm or artificial intelligence take over what I do in my remaining years.

Tyler Kuhk: Great answer. Jennifer, I was going to ask you a question while we are talking about oral steroid use. There was a question from Paul about how do you keep track of oral steroid use, because this can be a challenge I know in clinical practice. Do you have any pearls to share with the audience, and how you might track that with your patients?

Jennifer: Absolutely. I will be honest. My clinical notes are a bit wordy because I like to keep things in my notes, like prednisone exposure, emergency room visits, hospitalizations. I will usually keep a little section somewhere that says, like, disease history course. I will put in 2023, they had four courses of OCS, or they had an emergency room visit where they had IV corticosteroids. I just have an idea of what their exposure is.

How do I get that data? I ask the patient first and foremost. Second, with all of our fancy EMR, I look at other health systems through care everywhere. I look within our own health system, and I also can run a report. I use Epic. There is a report I can run that is about medication dispenses, and I will look and see, are they getting prednisone every month at the pharmacy, because I have seen that happen many times. I will say to the patient, “Hey, it looks like you have had six different prescribers give you prednisone over the last six months. Where is this coming from? Are you going to urgent care?” Then they will be like, “Oh, yeah, I forgot about that.” Sometimes those tools can be really helpful. I do like to keep track because bottom line here, two courses of oral glucocorticoids in one year puts your patient at unnecessary risk. I will tell people like full stop. If they are using their inhalers and they are on OCS twice a year, they need step up in therapy, or they need reassessment of their asthma in general.

There is studies to, I do not remember the exact reference, but even just five burst doses of OCS in a lifetime, so that is our typical like prednisone, 40 milligrams for five days. That increases the risk of osteoporosis, diabetes, obesity, infections. I will also mention because we all have this pulmonology focus, increases risk of NTM infections, MAC, MAI, we are seeing it more and more. We are seeing this asthma bronchiectasis more and more. We really do not want to be giving these patients boatloads of steroids if we do not have to. I hope that answers it. Sorry, it was a little wordy.

Dr Louie: I would like to interject. If you follow the GINA guidelines, step one, step two, step three, step four, step five, and you see the patient ideally every six weeks to reassess asthma control. The patient should be evaluated for a while after about six months, not four to six years. I am sure most of us up here in the conference I have seen patients who have been suffering for years, not months with their asthma. Sorry, Tyler.

Tyler Kuhk: I was just going to say we need buy-in for a PDMP for prednisone. It would be helpful because I type in the search bar on Epic, I type in prednisone, and I can see, but if they are going to an outside place, and you cannot tell. I think more creative solutions, and there is a lot of data saying that steroids are bad.

Dr Louie, I want to go back to Devon, the ICU nurse case. One of the questions during that we were talking about asthma mimickers. Becky[?] was wanting to know some of the top diagnoses that you see that are asthma mimickers. I know Jennifer had alluded to VCD. Anything else on the top of your mind for our clinicians to consider?

Dr Louie: Reflux. I am sure, Tyler, you have seen esophageal reflux. Please remember, inhaled steroids and albuterol basically can make reflux worse. I am talking about gastroesophageal reflux. That can lead to all kinds of upper airway issues, including vocal cord or vocal fold dysfunction, GERD in particular. A lot of my nurses, for better or for worse, they continue to smoke cigarettes. It went up tremendously during the pandemic. You really have to work on getting them to stop once again.

Not easy to do once you go back to smoking. I think I mentioned earlier about use of NSAIDs Motrin, Aleve. See too much aspirin, much anymore, I think they primarily go to allergies. People have Samter's syndrome or Francis triad if you are on the East Coast. I think GERD overwhelmingly is the big one to worry about besides smoking cigarettes and marijuana, which is legal in California.

Tyler Kuhk: Jennifer, if you do not have anything to add, I think we have time for one more question before we do closing remarks and start to close things out, and I think this is probably just an important point to hit home is do we keep these patients on their inhalers and biologics simultaneously, or do we discontinue inhalers? I am curious to hear.

Jennifer: I love this question. Can we safely discontinue ICS/LABA when we initiate a patient on a biologic? No. That is not what the guidelines say. GINA, CHEST, and ATS will say they need to remain on their ICS/LABA when they first initiate. However, again, back to that cycle, they review, assess, reassess cycle, you have to start seeing when you have the opportunity to decrease their medications. If that is six months, if that is eight months a year, whatever it is, try your best to decrease that ICS in the patients safely.

I will say I take care of many patients that have remission level control on biologic, which is wonderful. We have been able to safely reduce them to anti-inflammatory reliever therapy. This is all outlined in GINA. It is a hefty document, but it is worth a read through that goes through a lot of this stuff in great detail how to safely reduce their ICS, what the schedule is, and how to empower the patient to and tell them this might be something you would expect some increased chest tightness or wheezing when you first do this. Keep an eye.

See if, instead of decreasing to as-needed therapy right away or that anti-inflammatory reliever, maybe take your inhaler three times a week for a month. Then try it once a week for a month. See how it goes. Then see if you can handle straight up as needed, so you can taper ICS how you would taper oral steroids as well.