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Today, it's all about the eyes, which are somewhat the extension of our brain, so treating ANY condition with them can be scary. I've gotten a lot of questions from listeners about dupilumab (Dupixent) and the side effects specifically when it comes to the eyes. So to dive in on this topic, I brought in today's guest, Dr. Roselie Achten, since her PhD focuses on ocular surface disease in atopic dermatitis patients before and during dupilumab treatment.
Dr. Roselie Achten is a medical doctor and PhD student at the Department of Dermatology at the University Medical Center Utrecht in the Netherlands, and I am so excited to have her on the show! You can find some of her research findings in the links section below.
Have you ever experienced any side effects with your eyes after starting dupilumab? I'd love to hear about it in the comments!
Or, listen on your favorite app: iTunes (Apple Podcasts) | Spotify | Stitcher | TuneIn | Subscribe on Android
In this episode:
- Stats on how many patients develop Dupixent eye side effects (aka. dupilumab-associated ocular surface disease)
- Eye symptoms of patients commonly complain about
- How long does it typically take to develop eye problems from Dupixent?
- What puts you more at risk for developing Dupixent eye side effects?
- What are your options if you develop Dupixent eye side effects?
- Can reducing the use of Dupixent help?
Quotes
“We were also quite surprised by the fact that the majority of the patients with moderate to severe atopic dermatitis already had characteristics of the ocular surface disease. So of the 70 patients that were analyzed, 90% of them already had characteristics of ocular surface disease before the start of Dupilumab treatment.” [11:09]
“If patients have these signs and symptoms of dupilumab associated ocular surface disease, we first start with tacrolimus skin ointment for the external eyelids. We also start with ketotifen, which is an antihistamine eye drop… also the artificial tears, it's more for if you experience a dry eye sensation, it could lead to improvement of that symptom for a little time.” [17:12]
Links
Find Dr. Roselie Achten online here
276: Dupixent Eye Side Effects: What's Going On? {RESEARCH} w/ Dr. Roselie Achten FULL TRANSCRIPT
Jennifer Fugo: Dr. Achten, welcome to the show. I'm so glad you're here.
Dr. Roselie Achten: Yes, thank you for the invitation on your podcast.
Jennifer: You're welcome. I've gotten a lot of questions from listeners about Dupilumab and its side effects. Specifically, when it comes to the eyes. And it seems like a lot of people, not everyone, but some people do experience certain eye issues. They complain about a level of eye irritation that can develop, and I don't know, maybe you know, maybe you don't, when that may develop in terms of starting Dupilumab. But it seemed like from the research, it wasn't one of the side effects that was discussed in the clinical trials and those original papers. Can you tell us why is it that these side effects are impacting the eye, and how common is it?
Dr. Achten: Yes, thank you for this first question. So, indeed, the most frequently reported side effect in Dupilumab treating atopic dermatitis patients is conjunctivitis, and we also call it Dupilumab-associated ocular surface disease. And in the Dupilumab phase-three trials in atopic dermatitis patients, it was reported in 8% to 22% of the patients. But it's increased over time, as they became more aware of the adverse events. So, it became more or less at 30% of special interest. And also if we look in daily practice, we see that approximately one-third of the patients develop the Dupilumab-associated ocular surface disease.
Jennifer: Wow.
Dr. Achten: Yes, and we see that approximately after the first four months of treatment with Dupilumab, most patients develop this side effect.
Jennifer: Oh wow. I know that there's a loading dose series. Does it normally happen then or does it seem to take maybe a little more time?
Dr. Achten: Yes, sometimes already within the first two weeks we see in daily practice, but it can also take a little bit longer and usually patients present with eye complaints of both eyes. So both eyes are affected and symptoms that patients report often are, for example, redness of the eyes, but also itch, sometimes in burning sense or pain. And sometimes patients experience excessive tear fluid in their eyes.
Jennifer: Any possible like visual changes or like blurry vision?
Dr. Achten: No. [inaudible 00:02:51].
Jennifer: Okay. So no visual issues.
Dr. Achten: No.
Jennifer: More so just the feel of the eyeball and the look of the eyeball, the white of the eyeball itself?
Dr. Achten: Yes.
Jennifer: Okay. So I should tell everyone that the reason we're having this conversation is my associate came across a Medscape article of a poster. Is it a poster or it was a study that you're working on right now. So some things we can talk about, some things we can't.
Dr. Achten: Yes, indeed.
Jennifer: Just yet. But your research team is actually looking for reasons why people are experiencing this side effect with Dupilumab. So what did your study look like and what did it find?
Dr. Achten: Yes, so indeed our research team is looking for reasons why this drugs impacts the eye and we have a team with dermatologists but also ophthalmologists and also pharmacologists and people who do translational research. So it's a large team. We've done different researches, so for example, we did look at risk factors. So which patients developed Dupilumab-associated ocular surface disease and which do not. And in this study we included 469 patients, that were treated with Dupilumab and had atopic dermatitis. And of these patients approximately one-third developed Dupilumab-associated ocular surface disease. So we found that one third of these patients had Dupilumab-associated ocular surface disease. And of these patients significantly more patients had atopic dermatitis on their eyelids in the past years. So that suggests that this is association between the eyelid eczema and the development of the Dupilumab-associated ocular surface disease.
Jennifer: So are you saying, because I want to make sure that everyone hears this. Your team is considering or thinking that possibly having had eczema on the eyelids themselves could potentially put you at a greater risk for developing this?
Dr. Achten: Yes. The study that we did showed that there was an association between those two factors.
Jennifer: Okay.
Dr. Achten: Yes. And another factor that we found was that people that had a history of any eye disease and also used atopic medication at the start of Dupilumab also had increased risk of developing Dupilumab-associated ocular surface disease. So yeah, this might indicate that these patients already have ongoing ophthalmic pathology for example, which leads to a higher risk of the development of Dupilumab-associated ocular surface disease.
Jennifer: Okay. Do you know, just out of curiosity, when you say using medication on the eyes. Could it be like any type of, some sort of dry eye medication or a glaucoma medication?
Dr. Achten: Yeah, so in this study it was very broad because it was already a quite small group. So if we divided it in more small groups we could not do any analysis with it anymore. Yes, so I don't know if there's one particular medication that increases the risk.
Jennifer: That's interesting though. It's interesting. It's so cool that you're digging into this and that's at least from the get go, that's a large group of people to even just look at. So even if we can pull out some little nuggets and then you guys can dig into this further in the future, I'm sure you're going to find even more information as well.
Dr. Achten: Yes, and we also are currently investigating the eyes by using an ophthalmologic examination. So the study that I mentioned about your risk factors was based on patient reported diagnosis and now we're also doing an ophthalmic examination in patients that are starting with Dupilumab treatment. So this is a prospective study and we do an ophthalmic examination before the start of Dupilumab and also during treatment. And our ophthalmologist developed a score system, the [inaudible 00:07:00] Ophthalmic Inflammatory and Allergic Disease Score. Also called the Utopia Score, which focuses on the different parts of the eye. So for example, eyelids but also the [inaudible 00:07:12] and [inaudible 00:07:12] of the eye with white part of the eye and the [inaudible 00:07:18] and the limbus. And this will assess an overall severity score of the ocular surface disease that no mild moderate of severe ocular surface disease.
Jennifer: Can I ask quickly, do you know, did your study look at whether this is, in terms of this side effect. Does it go away if you stop Dupilumab?
Dr. Achten: Yes. We did not do this in the study that I mentioned now, but we did a previous study in which we followed 33 case series, there was a case series of 33 patients and we found a discontinuation of Dupilumab which was necessary in three patients lead to improvements of the ocular side effects. But there is also some treatment that can be prescribed for the Dupilumab-associated ocular surface disease. Yes.
Jennifer: Wow. Okay. So you, boy you've really been digging into this. This is not actually your first study into this and you're continuing on, this is really cool. My listeners should be familiar with the term Cytokines. If you guys aren't, you should go back and listen to specifically the episode with Dr. Heather's Wiki and we'll put that link directly into the show notes if you did not hear that where we discussed what cytokines are.
But you can think of them as signaling molecules in your body that for those of you who know, different diseases can have an increase in certain cytokines. And so with Dupilumab we see that it targets IL-13 and IL-four. So in your paper I thought this was really interesting. So you said that IL-13 because it's blocked by Dupilumab you mentioned in regards to that something called Goblet Cells. Can you describe to the listeners what are these goblet cells? Yes, it sounds like goblet, like a little goblin running around but goblet. Although it's not a monster by the way, everyone listening. What do these cells do and how might Dupilumab actually impact the cells in the eye region?
Dr. Achten: Yes, indeed. My colleagues investigated some of the corneal biopsies of patients with Dupilumab associated ocular surface disease and they found a scarcity of the [inaudible 00:09:51] goblet cells. And the goblet cells in the co-unified tissue are mucusy creating cells that are vital for the ocular server function. And as you mentioned, Dupilumab is affecting the IL-13 and we hypothesize that because normally IL-13 has a positive effect on the mucus production of the [inaudible 00:10:12] goblet cells and also on the growth of the goblet cells. And we hypothesis that due to the blocking effect by Dupilumab on IL-13, this might lead to less mucus production and less goblet cells.
And we're currently investigating these counified goblet cells in patients that are being treated with Dupilumab. We're using a technique which is called [inaudible 00:10:36] impression cytology. So it's very easy to perform a non-invasive technique and you can collect the first cell layers of the co-unified tissue and then look at the goblet cells. So we're still working on the number of goblet cells during the PI treatment. So we are already analyzing patients that are starting with Dupilumab treatments and we found that these patients already had lower goblet cell members compared to healthy controls.
Jennifer: Oh, interesting.
Dr. Achten: Yes. And what I also wanted to mention is that we were also quite surprised by the fact that the majority of the patient with moderate to severe atopic dermatitis already had characteristics of the ocular surface disease. So of the 70 patients that were analyzed, 90% of them already had characteristics of ocular surface disease before the start of Dupilumab treatment, which quite a lot.
Jennifer: Can I ask, you've mentioned ocular surface disease a lot.
Dr. Achten: Yes.
Jennifer: And for someone listening, they may never have heard of this before, if someone is considering Dupilumab but they're nervous that they could be impacted by this. Could they go to an ophthalmologist and be checked beforehand for ocular surface disease?
Dr. Achten: Yes, that's a good question. We are doing that in our study and we see that many patients already have ocular surface disease before the start of the Dupilumab treatment. And even 31% of the 70 patients that were analyzed had moderate to severe eye complaints before the start of Dupilumab. And what makes it a little bit hard is that not all patients report symptoms of the ocular surface disease.
Jennifer: Ah.
Dr. Achten: So you really need the ophthalmic examination. But we do see that, again in these patients we found that patients with moderate to severe ocular surface disease had more frequently the eyelid eczema and also more severe atopic dermatitis. So maybe if it's not feasible to refer all patients to an ophthalmologist before the start of Dupilumab. We recommend to refer for example, the patient with more severe eyelid eczema or more severe atopic dermatitis at all.
Jennifer: That that is good to know. And I think that might be helpful for people to hear because I know a lot of people are on the fence and for those of you listening. I am you do you. So if you feel that medication is a good next step for you, I will never judge you for that. I don't think anyone should be judged whether they choose to do meds or they choose to go an alternative route or they choose to mix both. So if you're concerned about this, this might be something you could do to help advocate for yourself and inform yourself about what the potential risks are and maybe if you are at greater risk for this type of side effect. So we'll get a little nerdy for a second. In your research and I know you're going to try and make this as simple as you can for everyone listening because when we start to talk about Immunology. I will even admit I don't have a background in immunology and I understand so much thanks to all of the wonderful experts here on the Healthy Skin Show and my own personal curiosity.
But it gets confusing. And so I read something in the Medscape paper and then you had shared some more details with us before this interview about how Dupilumab might lead to this imbalance between the two different sides of the immune system. TH-2 and then the TH-1, TH 17. And this somehow could possibly feed into that concept that remember we talked about a moment ago everybody, how Dupilumab impacts IL-4, that cytokine. So as best you can, if you're going to explain this to a patient listening to this, what does that mean and how could that imbalance maybe show up just symptom wise, what would they feel in their body or see show up in terms of symptoms?
Dr. Achten: Yes. So as you mentioned, Dupilumab affects the immune pathways of both IL-4 and IL-13, which are the TH-2 cells. And normally there's a balance between the TH-2 cells and the TH-1, Th-17 cells and due to the inhibition of TH-2 cells by Dupilumab. In some patients a disbalance may appear and that might lead to an increase of the Th-1 and Th-17 cells. And we've already seen this in some case reports describing that during Dupilumab treatments, other TH-1 related adverse event could appear for example, psoriasis. And our hypothesis is that the disbalance between the TH-2, TH-1, and TH-17 might lead to and TH-1 inflammation in the eye. And my colleagues already investigated some biopsies of the conjunctival tissue of patients with the Dupilumab-associated ocular surface disease and they found an increased local TH-1 related cytokine production in the biopsies. But this was very small study. So we need to learn more about this and need to do a larger study and we will conduct that later on.
Jennifer: Oh wow. Well at least it's helpful to know, I think for everyone listening who has maybe even experienced this side effect. It's not in your head, something's going on, it's a clue that there's some sort of imbalance going on. I think it's helpful for people to hear. So in terms of you'd mentioned discontinuing Dupilumab can be helpful in at least reducing the severity of this ocular surface disease that shows up in some individuals if say you want to stay on Dupilumab because it's really helping you, but this is the one thing that's driving you nuts and making you not feel great. Is there any way to treat it or manage it while you're on Dupilumab that you know of?
Dr. Achten: Yes, yes. And maybe it's good to know that most of the patients can continue Dupilumab regardless of the Dupilumab associated ocular surface disease. So only few patients need to stop with their treatment. So the majority of patients can continue the treatment and what we already always do, if patients have these signs and symptoms of Dupilumab associated ocular surface disease. We first start with tacrolimus skin ointment for the external eyelids. We also start with Ketotifen, which is an antihistamine eye drop.
Jennifer: Yes, Ketotifen is also helpful for stabilizing mass cells. So I'm familiar with this and I think some of the listeners may be too, but that's good to know.
Dr. Achten: Yes, also the artificial tears, it's more for if you experience a dry eye sensation, it could lead to improvement of that symptom for a little time. Because it's not improving the ocular inflammation. And if that's not helpful, then we recommend to refer the patients to an ophthalmologist.
Jennifer: And the person who would prescribe this. So for those listening, they know my dad was an ophthalmologist and an eye surgeon. So I understand most of the things, probably the words and terms that you've used. I probably understand more than most if you are experiencing this issue. I think most people, the first phone call they're going to make is to their dermatologist. Does the dermatologist prescribe these eye medications or?
Dr. Achten: Yes, in our outpatient clinic, all patients first call the dermatologist, indeed.
Jennifer: Okay.
Dr. Achten: And we prescribe tacrolimus and ketotifen indicate and the lubricant eye drops. Yeah, the lubricant eye drops. And sometimes we also prolong the dosing interval of Dupilumab. So for example, once every four weeks or once every five weeks, we see that the inflammation becomes less if we taper down the dose. We've described that in a case series of 33 patients. So that's also an option if for example, the tacrolimus and the ketotifen are not working or the medication prescribed by the ophthalmologist is not effective enough.
Jennifer: Okay. So right now it sounds like the treatment option if you want to stay, I just want to recap for everybody listening if you want to stay on Dupilumab would be some Tacrolimus, it sounded like cream.
Dr. Achten: Yes.
Jennifer: Like you apply a cream to the eyelid. And just for everybody listening, please talk to your doctor in case you have some tacrolimus cream. I just know some med formulations are not appropriate to be put around the eyes. I know that from working with my dad in his office. So just check with your doctor. Don't go and put things around the eyes if you weren't advised to because sometimes they can cause damage to the eyes and the eyes are kind of like an extension of your brain. So just keep that in mind. So talk with your doctor. So tacrolimus cream, ketotifen eye drops, and then you said dry eye drop.
Dr. Achten: Yes.
Jennifer: Those hydrating eye drops for dry eyes and then possibly instead of doing your shots, I think, what are they normally every two weeks?
Dr. Achten: Every two weeks, yes.
Jennifer: So every two weeks you would perhaps space them out further to once every four or five weeks. But obviously you would do that in conjunction with your doctor and their advice. Don't ever change your medication, because this is a biologic drug, we don't want to start messing things up and nobody knows what's going on and taking medications or stopping medications without their support and help.
Dr. Achten: Yes. And sometimes the ophthalmologist can also prescribe some therapies that are more effective. So if the tacrolimus for example is not working, then first go to the ophthalmologist and if that's not working. You can think about the interval dose.
Jennifer: Yes. Perfect. Well thank you so much for sharing all of this, Roselie. I honestly was so thrilled when I saw this paper. I'm excited for the research that you're doing. So I hope that you'd be willing to come back once you have more data to share with everyone. I know everyone's going to appreciate this so much. That you're actually looking into this because I think people have felt like this was a really big side effect, that there really wasn't that information coming out about. And it's very refreshing that we finally have some info that also patients could bring back to their doctor if their doctor is not aware of what is going on with the eye side effect. This could be a really great resource for them. And I will link to the Medscape article in the show notes so you can also share that with your physician. But thank you so much for being here. I really appreciate
Dr. Achten: Yes, thank you for the invitation again.
