Activity Transcript

Joseph Han, MD: Hello. I'm Dr Joseph Han, professor of otolaryngology, head and neck surgery, chief for the division of rhinology, endoscopic sinus and skull based surgery, as well as the chief for the division of allergy at Eastern Virginia Medical School in Norfolk, Virginia. Welcome to this program titled "Improving Outcomes in Chronic Rhinosinusitis With Nasal Polyps With Novel Targeted Therapies: From Guidelines to Clinical Practice." Joining me today is Dr Claire Hopkins, professor of rhinology at King's College in London. Welcome, Claire.

Claire Hopkins, FRCS (ORLHNS) DM: Good morning.

Dr Han: All right. So let's go ahead and talk a little bit about chronic sinusitis. So we know that about 25% of patients with chronic sinusitis have nasal polyps. And in fact, that percentage may be a little bit higher based on some of the recent literature and research looking at how much patients with chronic sinusitis have nasal polyps and may be a little bit higher. And we know that patients with nasal polyps have significant morbidity and have worse quality of life than those of patients without nasal polyps. The typical symptoms that we see in patients with chronic sinusitis are nasal discharge, nasal congestion, facial pressure, and loss of smell. And we know that patients with nasal polyps tend to have more symptoms with loss of smell. So when patients have chronic sinusitis, it doesn't lead to high mortality, but it leads to high morbidity, meaning that patients, when they have chronic sinusitis, really suffer.

So even though they're able to go to work, they have decreased productivity. The severity of their symptoms is so bad, it's similar to patients with moderate asthma and congestive heart failure. So because it really debilitates our patients, it's important to improve their symptoms and decrease the recurrence of nasal polyps in our patients. In today's discussion, we will review the clinical care pathway for the management of chronic sinusitis with nasal polyps, evaluating patients, and selecting the best treatment plan.

So Claire, after you diagnose a patient with chronic sinusitis, what is your initial approach to treating these patients?

Dr Hopkins: So usually, many patients will already have received an intranasal corticosteroid spray, and often saline irrigation in primary care before they're referred into ENT. So we tend to see the more moderate to severely affected patients. So for these patients, I'm going to look at them with endoscopy, get an idea of the severity of the polyps, and also try and judge the severity of their symptoms. Typically, I'll start the patient on intranasal corticosteroid drops. I also typically use a single course of an oral corticosteroid, provided they haven't had multiple courses for comorbid asthma, for example, really bearing in mind the risk of cumulative dosing. And I want to assess their response to that initial course of what I would call appropriate medical therapy to help guide me on how I'm going to treat them next, hopefully achieve adequate relief of symptoms and be able to set them up with a long term maintenance plan. But if they fail to derive adequate benefit from that course of treatment, then I can make a decision as to whether I need to move up the ladder.

Dr Han: How comfortable are you in giving patients oral corticosteroids for their nasal polyps?

Dr Hopkins: Well, as I said, I'm mindful that many of these patients have comorbid asthma and other conditions that might also require oral corticosteroids, so I try to avoid multiple dosing. We're increasingly aware now that the risks of oral corticosteroids, even with single short courses, are cumulative over a lifetime. So there's some data that show more than 2 courses in a year or more than 4 courses in a lifetime significantly increase your risk of adverse events. If they haven't had another course in a 12-month period, then I'll try. And certainly I don't go above more than 2 courses in a year for nasal polyps or with other conditions as well.

Dr Han: And certainly in the US, we have other treatment options available. We have different ways of delivering topical steroids. We have an isolation delivery system. And another way to deliver topical steroids is using a steroid sinus implant. And I think you're right, I really try to minimize the use of systemic corticosteroids and trying to rely on the topical steroids in, like you said, the topical steroid drops. It is something that I often have in my toolbox in treating patients with nasal polyps, even though it's not FDA approved.

So how long do you wait before you say the medical treatment isn't effective? And how do you decide when to do surgery for these patients?

Dr Hopkins: I tend to give a combination of topical and oral steroids at the beginning of my pathway for that moderate to severe group, because I'm hoping they'll have a significant reduction, both in terms of symptom severity and polyps score that we can then maintain. So I tend to see my patients at 4 weeks after that first burst of treatment to make sure that they've had improvement in symptoms. Often they get dramatic improvement on that first course of oral steroids, and that gives me useful information that they're steroid responsive and likely type 2. I then set them up on a maintenance plan of topical steroids to see how long we can keep them going for and hopefully keep them in a well-controlled position. But if at that 4 weeks of treatment with oral and topical steroids, they fail to get adequate response, then I'm going to start thinking about escalating my treatment, checking compliance, of course, and looking for other conditions, comorbid conditions, thinking about a CT scan, and perhaps starting to plan surgery in the patients that haven't responded well.

Dr Han: Claire, do you mind if we go to the case presentation then?

Dr Hopkins: I've got a 43-year-old woman who has come out with polyps having had surgery 6 years ago. Now, she's done pretty well in that time. And like many patients, when she goes through a good phase, her symptoms improve, she stops taking her intranasal corticosteroids. She's had 1 or 2 courses of oral steroids over that 6 year period, but largely has been well controlled, although symptoms have gradually increased. She's now come back with loss of smell, facial pain and pressure, nasal obstruction to the point that it's affecting her sleep. So she's got some loss of productivity in the workplace. Now, she's got no history of underlying asthma and no other comorbid conditions of relevance.

When I look in her nose, she's got grade 2 polyps on both sides, and the CT scan shows fairly diffused mucosal thickening in all of the sinuses with a Lund McKay score of 16 out to 24. Serum IgE is moderately elevated at 150, and her blood eosinophil count is 300. So in my mind, this is a patient that has done pretty well with surgery. One of the problems is she's been poorly compliant with her topical steroids, and she doesn't have any other risk factors, such as asthma, that predicts a high risk of failure. So my gut feeling is that she will likely do pretty well with surgery again. And if I can get patients through 5 to 6 years with reasonable control, then perhaps that's a good option. And in my mind, I'm not jumping to a biologic, but I wonder if you think that I should be offering her a biologic. She has had previous surgery and failed, so what would you do with this lady?

Dr Han: Well, I think this is a very typical patient that we see in our office, and this is a patient we would deem as chronic sinusitis with nasal polyps that have recurred after sinus surgery. But there are a lot of factors in this case that tells us that even though the patient has type 2 inflammation, it's probably not too severe. Some of the factors or things that you mentioned, like no history of asthma. I think asthma is a very good predictor of a higher systemic inflammation.

Another way to look at it is some of the biomarkers that you measured, the serum IgE, which is about 150, which is not that much higher than the upper limit of normal, as well as a blood eosinophils being only about 300. So that tells me that it is probably on the higher end, but not too high. The fact that they only need systemic steroids twice in a 6 year period also tells me that this isn't severe. So I agree with you. This is a patient that I think will do well with sinus surgery, removing all the polyps. And if she is able to stay on the top of the steroids, the likelihood the polyps coming back is probably very low.

Dr Hopkins: I think compliance is a big issue. And it happens so many times, the patients are doing really well, so they stop all of their medication until polyps come back. And I think that's where some of those enhanced delivery devices, the steroid diluting stents really come into their own, because we overcome that poor compliance. So I think that might even be an option for this patient to try and avoid the need for surgery. But yeah, my gut feeling is that actually, many of the current treatment options that we have will likely do this patient well if we can bring her on board with good compliance with medical therapy at the same time.

Dr Han: Yeah, absolutely, completely agree.

Dr Hopkins: So our lady is quite interesting, because if we go to the guidelines, many of the guidelines will say: "surgery first, but then if surgery fails move to a biologic." But as we've both discussed in this case, it's still a slightly gray area in that patient that's failed surgery. And you've got patients that fail surgery very early and get a significant recurrence of symptoms. Whereas you get those patients that actually do pretty well after surgery, and if we really optimize all of the treatment around it, we might get better outcomes. So it just shows how the guidelines try to simplify things, but there are still many any nuances in that pathway.

Dr Han: I agree. And there are some studies, albeit there are smaller studies, but there are some studies that show that if you have sinusitis with nasal polyp, doing sinus surgery, about 10% or 15% of these patients don't have recurrence of nasal polyps without doing anything, which was a little bit surprising. But I have seen those patients in my practice where, these patients who do surgery, they do well. They get lost to follow-up and they come in just to get a routine checkup a couple years later. And I'm really worried that their polyps are going to come back and that it's going to start coming out of their nose. But surprisingly, a lot of these patients, the polyps are gone and, but it's a minority of patients. It's definitely not majority. I think majority of patients, once you have nasal polyps, you have polyps for life.

Dr Hopkins: I think we're learning much more about how to pick out those predictors, aren't we? The comorbid asthma, particularly the aspirin exasperated respiratory disease, the patients with very high levels of the eosinophils in their polyps at their first surgery, we can get a pretty good idea now which ones we're going to see back in the near future.

I think we're also learning a lot more about how to really optimize the surgery. And I always think of the really nice Cochrane review by Richard Harvey's group that really shows that in a patient pre-surgery, intranasal corticosteroids really have very little effect, but that improves significantly after surgery because we're better delivering the intranasal corticosteroids into the sinus cavities. So I am much more mindful that I want my polyp patients to have complete surgery, really opening all of the sinus groups to good delivery of topical steroids afterwards. And I think again, if we can really make sure that we are treating, when we use surgery in those patients, we are really doing it to its best extent, we're going to give those patients the longest duration of benefit from our surgery too.

Dr Han: No, I think you bring up a very good point. Not all sinus surgeries are the same. So the way I operate on patients with severe nasal polyps is very different than those who don't have nasal polyps. So I completely agree that sinus surgery is not the same for everyone. And even when people do sinus surgery, they sometimes may have different outcomes.

Dr Hopkins: Yeah. I think it's a nice comparative study, really looking at sort of the more minimally invasive techniques. And for me, they just don't really work in these patients with polyps. We need large openings, open cavities, good delivery of steroids afterwards, and the ability to place steroid diluting stents and so on, I think, would be optimized as well.

Dr Han: So Claire, I was hoping to present a case to you. So this is a 37-year-old male, history of nasal polyps with their typical symptoms, facial pressure, reduced sense of smell and congestion and postnasal drainage. The symptoms at first weren't too bad, but over time became worse and worse, to the point where his congestion was so bad that he had difficulty sleeping. In terms of his history, the patient had adult onset asthma, has been on high dose ICS and LABA, including montelukast, and often, even with these medications, still has to use albuterol once, sometimes twice a week. And he states that he has continued exacerbations where he has to visit the emergency room once or twice a year. He did have sinus surgery about a year ago and felt like his symptoms got better. But over time, his symptoms started coming despite using topical corticosteroid irrigation. And at times, he's often asked for systemic steroids or oral corticosteroids at times. And so what would you do for this patient and what do you think about this patient?

Dr Hopkins: So this is a patient who's clearly uncontrolled, both with respect to his asthma and his nasal polyps. He's having multiple courses of steroids, which we've already discussed will have a cumulative risk of adverse events. He's really had the best treatment for both conditions, yet he's still failing. So to me, this is a patient that I really am considering a biologic to be the best treatment option for. I want to think about whether there's anything else that might be driving his symptoms. For example, aspirin exacerbated respiratory disease springs to mind, particularly in this patient. I want to look at other markers for the level of inflammation, but I'm really heading towards a biologic in my mind.

Dr Han: So in terms of the biomarkers, we did draw a CBC with differential, looking for a blood eosinophil, and it was 900. We also checked for total IgE and it was 49. And when we did allergy testing on him, skin prick testing on him, the number of allergies were very minimal. There were a couple of molds and not that much more. So what do you think about those results then?

Dr Hopkins: So the eosinophil count is certainly pretty normal for this type of patient with comorbid upper and lower respiratory disease. At the back of my mind, with an elevated eosinophil count, I'm always wanting to think, could this be EGPA? Could there be something going on? But the count itself isn't abnormal. But I do want to make sure I'm not going to miss that presentation, particularly with some of the biologics that can push the eosinophil count up a little bit further.

Dr Han: Yeah. And I think you made a really good point about ruling out aspirin triad or A-ERD or N-ERD in this patient. Because especially in those with adult-onset asthma, I've noticed that they tend to develop or become aspirin intolerant or NSAID intolerant, and so I think that's a very good point that you pointed out.

Dr Hopkins: I think it's often late in diagnosis, but we see it increasingly more frequently in patients that more severe the disease. And we know that these patients will have a very high risk of recurrence after nasal surgery. So if we could make the diagnosis before surgery, this is one group I might consider putting straight on a biologic from the outset. The challenge is they often don't get diagnosed till they've had 2, 3, 4 surgeries and before the diagnosis is picked up. So it's having it in the back of the mind really.

Dr Han: And certainly, for this patient, the options are we could do sinus surgery. I think he is a good candidate for biologic. Certainly, since he's had sinus surgery, I think a steroid sinus implant is a reasonable option. I really hate the option of giving him systemic steroids because he's already taken so much. And like you said, it's the cumulative amount of systemic steroids that they get that are related to risk and so I really hate that. But that is still an option. So what would you do for this patient?

Dr Hopkins: Well, I think we've also got to bear in mind the patient's preferences and also speak with our pulmonologist because the asthma is uncontrolled as well. To me, the huge advantage of the biologic in this case is that we're going to achieve better control of both the upper and the lower airway, and I think that's a significant win for this patient. So as I said, to me, this is a patient who is an ideal candidate for a biologic therapy.

Dr Han: Yeah. That's a great point. And it helps us understand that it really should be a multidisciplinary approach. It's not an isolated decision. I think so commonly, many people just look at the nasal polyp and just think about how severe it is, but don't think about the asthma and the lower respiratory system.

Dr Hopkins: Ideally, we want to be working in combined clinics for these difficult to treat patients, because the treatments that we give have an impact on the lower airway and vice versa. And really, we want to be working together to give the patient the best outcome.

Dr Han: Yeah. And I do think that biologic is a very reasonable option for this patient because the patient just had sinus surgery. One of the things you mentioned earlier, you want to make sure that the patient had a complete sinus surgery and that they opened up all the sinus cavities to allow topical steroids to get in there. But I do think that biologic is a very reasonable option for this patient.

And in the US, fortunately, we have 3 biologics that have been approved. The first one that was approved was dupilumab, which is an IL-4 receptor alpha antagonist. And the 2 phase 3 studies that were used to prove that dupilumab was effective were SINUS-24 and 52, and it reduced the nasal polyps size as well as reduced symptoms, as well as improving their sense of smell.

The other biologic that was approved next was omalizumab, which targets circulating IgE. And the 2 phase 3 studies were POLYP 1 and POLYP 2. And similar to the dupilumab study, it also improved the nasal poly score and congestion, which were the two primary endpoints. They did see that patients did have improvement in their smell as well. They did an open-label study looking omalizumab for a year, and when they stopped the omalizumab, the symptoms started getting worse again, similar to what we saw with dupilumab.

And the one that was most recently approved in the US by FDA was mepolizumab, which targets circulating IL-5. SYNAPSE was the phase 3 study that evaluated use of mepolizumab in patients with nasal polyps. And again, similar to the other biologics, mepolizumab was effective in reducing the nasal polyp size as well as decreasing patients' symptoms. And the study, similar to dupilumab, showed that there was a reduced need for use of sinus surgery, as well as use of systemic steroids. And so I think basically, all 3 studies showed that they're effective in treating nasal polyps and well tolerated. I think the most common adverse effect that we saw was the local site reaction.

So it's nice to have all these biologics that are available. And usually what I do is when I talk to patients about the use of biologics in our patients with chronic sinusitis with nasal polyps. I offer these 3 different biologics with different mechanism for it. And one of the things that I think patients are interested is how frequently the patients have to get the biologic, because what I have to tell them, these biologics are proteins and we want to treat it as such. And because of that, you can't take it by mouth. You have to give them through SC injection. So Claire, once you put a patient on biologic, how long do you wait to see if there's a response from the biologic?

Dr Hopkins: So I think it's important to advise the patient that while many patients will see quite a rapid response, we need to allow a reasonable period of 4 to sometimes 6 months before we determine whether they're a responder or not. We need to stress the importance of continuing to use their intranasal corticosteroids. This is an add-on treatment and not a replacement. And again, for some of those really early responders, their temptation is to stop their intranasal corticosteroids. And we've got, again, keep them on side with good education. So I would see the patient at 16 weeks. I will look at the polyp score to see if they're reducing. I'll look at their symptom scores to make sure they're responding.

And at that point, I'm going to decide if there's no response, in which case I might consider likely stopping and switching the biologic, whether there's a partial response, where there might be an add-on place for surgery, or whether they're doing well and will continue. And what we see in many of the trials is the patients that have gone out to 12 months, there's almost a complete reduction in polyps. Their Lund McKay scores look better than any surgery. So I'm trying to put my patients into 1 of those 3 categories. What I think we need to avoid is really rushing in and going straight to surgery in the patient on whom we've just started on the biologic. We really want to give it a chance to work and avoid the need for surgery, if possible.

Dr Han: And I think that's a such a great point, because just this week, I had a patient who was started on a biologic, and the patient had a good response, to the point where she felt like she didn't need the topical steroids and so she stopped using topical steroids. And so I emphasized to her, just like you said, "you need to still be on topical steroids." And then she continued on the topical steroids and then when she came back in 3 months this week, she said she felt remarkably better and she felt like she was to the point where she didn't need further treatment and just wanted to continue with the biologic and topical steroids. But that is a common situation that I find myself in, when patients, they had a good response with the biologic and they stopped using topical steroids.

We see that similar pattern in patients who were given a biologic with asthma, where they stopped their ICS and LABA, when in fact, if you look at these real life experiences, about 80% of the patient who are on biologics still need their ICS and LABA. And we actually just presented our data, looking at our real-life experience, looking at biologics in patients with nasal polyp, we're finding out a very similar number, where a little more than 80% of the patients still needed their topical steroids. And when they stopped the topical steroids, the symptoms weren't as good as the patients wanted it to be. And so I think you're absolutely right. The biologic is really still meant to be an add-on therapy to topical steroids, whether it be asthma or nasal polyps.

Dr Hopkins: I think it could be even more dramatic in those difficult to treat asthma patients that have been on a low dose of oral corticosteroids in the background. Suddenly, their asthma is controlled and they stop all of their steroids and they often have a slight increase in polyps for a while. So it is really important to keep them on side, to give time for the biologic to work well before you make any other decision.

Dr Han: As you adeptly have pointed out, the asthma wasn't under good control. And so this is a patient where I would talk to the pulmonologist and say: "hey, the asthma's not under good control. The polyp is difficult to manage." And I talk to the pulmonologist and ask them: "what biologic would you consider for this patient?" And we have so many difficult patients that we created a severe asthma consortium in the Hampton Roads area, which is where I live. We meet often regularly and talk about new treatment options and talk about some of these difficult to manage patients who often have comorbid asthma and nasal polyps.

Dr Hopkins: And I think that's a really good point. Again, it’s shared decision making. It's quite interesting, because often, the pulmonologist will direct the choice of the biologic. But when we reassess the patient at 4 to 6 months, we often find that the asthma has been controlled remarkably well, but sometimes the polyps don't respond in quite the same way. And I think at that point, there is a role for considering, does surgery have an add-on role? Because there's a lot of fibrous scaffold structure in the polyps. And I often, in my mind, think of the skeleton of the polyp being left behind even though the inflammation is treated. So at that point, there may be a role for keeping the patient on the biologic to clear all of the polyps with surgery and then see if it prevents the recurrence and continues to maintain good control of their asthma and then good control of their polyps. So I think that we are learning a lot more about how to think about biologics and surgery working in combination, rather than simply a choice of one or the other as well.

Dr Han: And I think being placed on a biologic doesn't necessarily exclude them from eventually needing surgery down the road. Just from our experience, looking at patients who have received biologics for nasal polyps, we're finding out that even though they had a great response for the biologic, their sense of smell and congestion got better. Like you said, some of the polyps still tend to linger and these patients have persistent symptoms of postnasal drainage. Fokkens recently wrote that patients who had biologics for year, a lot of the other symptoms got better except for the postnasal drainage. And we're seeing the same thing, a very similar experience, where these patients eventually say the postnasal drainage is severe enough where they want to have surgery again. So it doesn't necessarily mean that you can't do surgery in patients on biologics, but I think to your point, you have to give them enough time, and the topical steroids also work before you consider changing therapy.

Dr Hopkins: And at what point would you consider switching the biologic? Because that's something that we haven't really covered. If the biologic doesn't seem to work, would you try another before considering surgery? What would be your pathway?

Dr Han: Yeah. I think that's a great question. So again, looking at our presentation that we presented at the ARS Annual Meeting last fall, what we found that of the patients we gave biologic, about 75% to 80% of these patients, once they're put on a biologic, do well and stay on the same biologic, assuming that they're able to continue with the topical steroids. We're finding out that about 20% of these patients are switching a biologic. So I would say the majority of the patients probably don't need to switch, but that we are finding that a minority of the patients getting biologic for nasal polyps are switching. And the most common reason why they're switching is because of symptom relief. They're not getting the symptom improvement that they want, and so then that ends up being the major factor in changing the biologic. If we do change the biologic, it is a multidisciplinary approach in which we talk to the different specialists to try to choose what we think may be a better option.

Dr Hopkins: Yeah. I think one of our challenges at the moment is that we don't have biomarkers that allow us to predict the response for biologic before trying. So there is still that element of trial and error. But as we look to new biologics moving up the inflammatory cascade, we might be able to better treat those non-responders. And so certainly one of the exciting things is we still have many new drugs coming through trials and potentially coming to market.

Dr Han: Yeah, absolutely. There are multiple clinical studies right now ongoing looking at the new and different biologics. And in fact, there's actually a clinical study looking at dupilumab and omalizumab had to head to see which one would be better. So it'll be interesting to see what those clinical studies shows that are currently ongoing.

Dr Hopkins: Yeah, I think that would be a really valuable trial. Because one of the limiting factors of the data that we have at the moment is that the patients included in the trials differ slightly. The outcome measures are different. So it is hard to make any head to head comparison of the effectiveness of different biologics. And also, we need that data to predict the responders to help better guide our decision making.

Dr Han: We're getting close to the end, and so I want to talk about some key takeaway messages from our presentation today. So 1 is allow medical treatment adequate time to work before changing treatment plan. Number 2, determine factors that can predict the severity of respiratory inflammation in our patients with nasal polyps. And third, personalize patient care, which includes taking into consideration the patient's desire for certain treatment options. So Claire, thank you very much for joining us today. Appreciate it.

Dr Hopkins: It's been a pleasure as always. Thank you.

Dr Han: And I'd also like to thank the audience for participating in this activity. Please continue on to answer the questions that follow and complete the evaluation. Thank you.

This is a verbatim transcript and has not been copyedited.