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ANDREA TOOLEY: Welcome to the Mayo Clinic Ophthalmology Podcast, brought to you by Mayo Clinic. I'm your host, Dr. Andrea Tooley.

ERICK BOTHUN: And I'm Dr. Erick Bothun. We're here to bring you the latest and greatest in ophthalmology medicine and more. In today's episode, we are joined by Dr. Wendy Smith.

She is a uveitis expert here at the Mayo Clinic. She is going to take us through run-of-the-mill cases in uveitis and what every ophthalmologist needs to know and some of the really tough ones with advances in therapeutics that you'll want to understand.

ANDREA TOOLEY: Dr. Wendy Smith is a uveitis and medical retina specialist here at Mayo Clinic in Rochester, Minnesota. Dr. Smith did her clinical fellowship in uveitis and medical retina at the National Eye Institute, NEI, NIH. She is the current chair for the Basic and Clinical Science Course on Uveitis and Ocular Inflammation Section for the AAO and directs the Medical Retina Fellowship here at Mayo. Welcome, Dr. Smith.

WENDY SMITH: Thank you.

ERICK BOTHUN: It's great to have you part of our podcast. We've been excited to have you on in particular because of your expertise with some of the toughest patients.

ANDREA TOOLEY: Yes, you get the hardest ones in the department.

ERICK BOTHUN: I can speak of one even today I saw that I was like, thank you for seeing Wendy yesterday. Certainly, you do manage some of the conditions that make us all nervous. And yet, you also manage uveitis conditions that are sort of run-of-the-mill or simple.

Share with us a little bit about the types of patients you see and the workups you do and what you think about when patients hit your door. We'll talk about some of the zebras, but just, what's your practice like on a day-to-day basis?

WENDY SMITH: Yeah, well, my waiting room is really mixed. I definitely have children. Maybe about 10% of my patients with uveitis are pediatric. And then, I have younger working age patients. And I have older patients as well. So uveitis can affect anyone.

Common, I mean, we are a tertiary care center, so we do get a lot of fifth opinion patients, but we provide primary care here, too, for our region. So we get a lot of newer diagnoses of uveitis. So common is definitely anterior uveitis, and some of the relatively simple cases may never need to come and see me, which is fine. [LAUGHS] But I would say certainly a common cause of anterior uveitis can be HLA-B27, which is a genetic association.

And there are some characteristic ways that uveitis may present. And I think the great thing about our training program is that most of the residents have a chance to see an HLA-B27 uveitis patient present. Because it can be quite dramatic with high grade inflammation and needing a lot of treatment and follow-up initially. And so I think getting a handle on that is great for our residents because we want them to be wonderful, comprehensive ophthalmologists when they finish. And they are, which is great. [CHUCKLES]

ANDREA TOOLEY: We do get a lot of different varieties from the really basic to the really complex uveitis. And I'm so glad that you mentioned HLA-B27 and anterior uveitis or iritis. Talk to us about when a comprehensivist is OK to manage basic iritis, anterior uveitis, and then when to refer and what your algorithm for treatment is there. Because I think that's always the question-- how long can you keep this patient, and then when do you need to send them off to a uveitis specialist?

WENDY SMITH: Yeah, so certainly, usually, the first line of treatment for anterior uveitis, after you've established that it's not infectious, would be steroid drops and cycloplegics initially, but not usually chronically. And so if you're able to quiet the uveitis with a tapering course of topical prednisolone, for example, they're able to get off drops after about six weeks and remain off drops for at least three months, then this is something that could potentially continue to be managed with steroid drops as needed.

But if they recur very soon after tapering off, within a week, within a month, even three months, if they have complications from the steroids, cataracts progressing, elevated eye pressure that can't be controlled, or the topical steroids are definitely not sufficient-- so they have macular edema, other complications-- then that's something where it would may be appropriate to seek further evaluation.

ANDREA TOOLEY: That's a really good overview. I'd be curious, too, about the general workup for straightforward, without complication, anterior uveitis. How much testing-- blood tests and workup do you do? And then how much do you just kind of say idiopathic?

WENDY SMITH: Yeah, I mean, I think what we try to teach the residents is that the first workup should be your history. [LAUGHS] So I don't very often get to see acute-- new cases of anterior uveitis because those often will go through the resident clinic, or they will see their local eye doctor, optometrist, or ophthalmologist first.

However, when I see them, to recreate that what happened at the beginning, I want to know how the symptoms started, if they had any infections in the month before, if they had any recent vaccinations or medication changes, what are their other medical conditions, to try to get a sense of what risk factors there might be out there.

And then it really depends on what you see. If a patient presented with elevated, intraocular pressure, that's not typical for iritis. So that might make you start thinking about a herpetic cause. Otherwise, really, there's not a lot of workup that you would do if they don't have any other symptoms outside their eyes.

So, pretty much always, for any new case of uveitis should still rule out syphilis. It can occasionally present just as anterior uveitis. Now, if the patient is four years old, OK, probably we don't need to do the test then. But otherwise, the most common type of anterior uveitis is idiopathic, undifferentiated. So without any other clues, you don't have to do a very extensive workup.

So just straight-up anterior uveitis, it's a very acute presentation, I'm going to check HLA-B27 and syphilis. If it's a little more indolent or chronic, then I may also do ACE and lysozyme and a chest X-ray, looking for evidence of sarcoidosis.

And after that, a lot of the other labs that are kind of done as what people think might be a standard uveitis workup aren't really appropriate. ANA, for example, almost never is relevant without any other symptoms outside the eyes, and rheumatoid factor, same thing. Uveitis is actually very rarely associated with rheumatoid arthritis. So without any other symptoms, no other joint pain, or no history of something that sounds like inflammatory arthritis, you wouldn't need to do that lab either.

ANDREA TOOLEY: So helpful. That is just so, so helpful. Thank you for saying all that.

WENDY SMITH: And then the last thing I'll say that seems to go commonly into a uveitis workup, but most uveitis specialists don't think is appropriate is Lyme testing. So we are in a Lyme endemic area. But actually uveitis is only very rarely associated with Lyme disease. So I need other history that would make me think the patient could have Lyme.

So you pulled a tick off of yourself. You show me your bull's eye rash. You have migratory arthritis. You have been camping and rolling around in ticks, then, yes. But otherwise, not just you have anterior uveitis, I'm going to check Lyme. That's not part of the workup for that kind of presentation.

ANDREA TOOLEY: OK.

ERICK BOTHUN: So a comprehensive ophthalmologist may be listening, and I think typically greatly appreciate the opportunity of sending a patient your way to say, please help me fix this situation. But there's also so often becomes a chronicity to them.

What's your ideal model, especially someone that is a patient from three, four hours away or more? Do you find that your average uveitis patient is best co-managed or is best kind of staying home to the more advanced care site? I know there's a timidness for referring doctors to know if they're doing enough for their uveitis patients. So just share, what do you recommend for when relationships with colleagues, and when is it OK to co-manage and when is it not?

WENDY SMITH: Yeah, that's a great question. So there's a couple of reasons why patients come to Mayo in general. And sometimes a big part of it is education and the chance for the patient to ask questions about their condition.

So, for some of these patients who may have had chronic anterior uveitis for five, even 10 years, I'll do an overview of their exam and their history and see if they have any complications from the uveitis or the treatment thus far. I'll explain everything to them, what I'm seeing and what I'm thinking. And if it seems like there's any holes in the workup, then we might recommend additional testing.

And then, depending on what's going on, if they clearly have uncontrolled uveitis, or they're coming up on needing cataract surgery, for example, and they don't have control, then I'll make an outline of suggestions for management locally.

And then it depends on the patient. Some patients, I'm not going to be able to make those recommendations right away. I need to see them a couple of times to see how things change, if we're going to change treatment a little bit. So I may ask if the patient is able to come back so I can follow along for a little while and then transition care back.

Sometimes they definitely come from way too far away, or it's just not going to be convenient. So then, again, I'll put some guidelines in my summary, saying, if this happens, then try that. And then, at the end of it all, I say, welcome to come back for re-evaluation if there are additional questions or something changes.

As we all know, we have patients that come from far away, and it's a major burden, potentially, to come here. So yeah, I really, really do like to try to co-manage, if at all possible.

For the health systems, there are several of our optometrists and some of the general ophthalmologists that sometimes I will electronic consult through the chart. So they'll send me an update and tell me what happened, and then I'll try to, in a timely fashion-- not always as timely as I wish-- advise them on what they could do to save the patient a trip back to Rochester.

ERICK BOTHUN: And then I imagine, because so often, you're co-managing with other colleagues here at Mayo, I mean, uveitis can spill over into other ocular disease consistent with glaucoma or retinal disease and also systemically. Share with us, just in your average recommendation, that they see someone else in our department or else here at Mayo. Which specialists are you reaching out to the most? And which should a referring doctor think about, well, maybe I need more than one with this visit to be consulted?

WENDY SMITH: Yeah, so sometimes, I, far and away, outside of ophthalmology, work with rheumatology the most. We have an amazing rheumatology department here. We are spoiled [LAUGHS] with the number of rheumatologists that we have.

And so I also require that we have ophthalmic records before we schedule a new patient with me. And either I review them, or my technician reviews them. Because we like to pre-schedule as much as possible. So if it looks like they are going to also need to see oculoplastics, then we'll already reach out to try to set that up so that we can coordinate within a day or so of the visit with me.

And similarly, sometimes, it's not clear if they want to see rheumatology here. So then we'll ask the scheduler to talk to the patient and say, did you want to see rheumatology here or the referring doctor? Was that your intent?

Occasionally, the referral gets triaged to rheumatology and if the patient seems to only have uveitis, rheumatology may recommend that they only see me. Or I'll review it and say no, we need both of us at the same time. So it varies. But as much information ahead of time really helps us preschedule. Because people are really accommodating at Mayo, but sometimes there's just things we're not going to be able to get within the same week of a patient's visit. Yeah.

ANDREA TOOLEY: Along with that, the rheumatology vein and coordinating with room, a lot of the care for some of these complex uveitis are biologic medications and immunosuppressives. And I know there's a lot of new exciting therapeutics kind of on the horizon. We briefly talked about that. Could you give us a little crash course in some of the therapeutics for uveitis, what common ones you use, and then what are exciting new developments?

WENDY SMITH: Yeah, so when you move on to systemic medication-- for acute inflammation, it's still corticosteroids, whether it's drops or injections or oral or IV. And those, often, I will manage on my own, unless it's a pediatric patient. And then I want to involve rheumatology or pediatrics.

After that, you break it down, indeed, into mechanism of drug. And so the conventional immunosuppressives, which are, for the most part, oral, are still pretty much the first line of treatment. And, again, spoiled here with so many rheumatologists, but many ophthalmologists will be comfortable prescribing and managing oral immunosuppressives on their own.

After that, for sure, the major game changer in the past, just about 15 years, are the biologics. And so the only systemic medication that is FDA-approved to treat noninfectious uveitis is the TNF inhibitor adalimumab. And this medication is increasingly used for all types of ocular inflammation. Some of that would be off-label, like scleritis, for example.

And that particular biologic, adalimumab, increasingly is the first choice for some patients. There are fewer side effects, potentially. And patients tend to tolerate it a little better. It works a little faster than conventional immunosuppressive. So that's been a medication that we increasingly use.

Something that will change how we use it is that there will now be a biosimilar, which is the equivalent of a generic of adalimumab. Biosimilars, just like other generic type drugs, are not entirely exactly the same as the original drug. And I think most of us anticipate that insurance companies will require us to use biosimilars. So whether there will be any concerns that it's not-- doesn't work the same for certain disease entities like uveitis, I don't think we know yet. But I know we'll be using them.

ANDREA TOOLEY: I have two kind of questions along those lines. One is, are you starting with conventional immunosuppressants? You're starting with oral prednisone, and then doing something like methotrexate before, then, you move on to biologics. And we can use brand names here. I think we're talking about Humira or rituximab or whatever. Are you kind of going along that line, or are you jumping right to Humira? And then I have a follow-up question, but answer that first.

WENDY SMITH: Yeah, that's a good one. Yep, so we do tend to-- acute inflammation, use steroids. Still, for most patients, we go to a conventional one like methotrexate. And then if you can't get off steroids or you still have active inflammation, you might add Humira.

ANDREA TOOLEY: Got it.

WENDY SMITH: But for some types of uveitis, for example, birdshot uveitis, which we have a lot of here in the upper midwest, I often want the combination of the conventional immunosuppressive and the TNF inhibitor, most commonly Humira, right away. Because it's often a later diagnosis. It's a more chronic and can be very destructive to the retinal function. So you want to be more aggressive sooner, I think, for birdshot.

And then for some other entities, you may want to go also first to Humira. Again, it's the side effect profile that will tend to push people that way a little bit. Plus, the severity of uveitis might make one think about using a biologic like Humira first.

The other biologics, the other TNF inhibitors, rituximab you mentioned, which is a CD20, biologic CD20 targeting, those are, again, not FDA-approved. And so if you don't have any other systemic diagnosis, it will be more difficult to get those approved by insurance. And so often, we also start with conventional immunosuppressives to say, hey, we used these other medications. And now we need to do the next step.

ANDREA TOOLEY: Yeah, you said exactly what my next question was, which was on the insurance line, how often are you having to do this fail first or proving that they failed, either conventional or prednisone, before they let you go to the--

WENDY SMITH: Yeah, I think, I mean, again, we still tend to-- we won't even-- unless it's very severe uveitis, we're not going to try to go often to a biologic first for many types of uveitis. But I think the bar is being moved higher and higher by insurance companies. And more and more approvals and appeals and letters and denials seem to be happening. And so I anticipate it will only get harder.

ANDREA TOOLEY: That's so frustrating when you know what a patient needs, and you can't get it directly to them.

WENDY SMITH: Yep.

ERICK BOTHUN: Question about the side effect profile. You mentioned risks with any of these drugs. And I remember at the start of COVID, everyone that was-- all my patients that were on immunosuppression were quite worried about what this new infection was going to bring to their lives. What is your-- when you discuss-- most people are comfortable with methotrexate and prednisone. They've been around so long.

But in terms of the biologics, what are the side effects that you see the most commonly generating a change in care or generating symptoms that the patient isn't quite even aware of? But what are the ones that you think of the most, or do we need to keep in mind as ophthalmologists?

WENDY SMITH: Yeah, so before I answer that question-- and if I forget it, remind me-- [LAUGHS] there is good data in the uveitis literature looking at the risks of immunosuppression. Because that's definitely something that patients are worried about, and parents of children with uveitis worry about when we talk about using systemic immunosuppression.

And if you think about the worst side effects that can happen with medications, the likelihood of a really severe-- something that will impact your life for a long time happening is the highest with chronic use of prednisone. So that's actually one of the relatively more dangerous things we can use if we use it the wrong way and too long.

For the non-prednisone immunosuppressives, there was a big study that looked at patients with uveitis on systemic immunosuppression compared to patients with uveitis who were not on systemic immunosuppression and compared to patients in the general population who don't have uveitis at all.

And the two questions they ask are, if you're on immunosuppression and you have uveitis, are you more likely to die sooner? And are you more likely to die from cancer? And the answer is no, which should be reassuring. But of course, the answer is still-- the question is still, but what about-- you could still get cancer even if it doesn't kill you. And obviously, none of us would willingly want to put that-- increase that risk too much for any patient.

So for pretty much all of the classes of medications, except for the very old class, the alkylating agents, which is cyclophosphamide and chlorambucil, there does not seem to be a significantly increased risk of cancer beyond some of the risks that you can also see in general from having a systemic inflammatory disease.

The original version of that study had kind of incomplete data on the TNF inhibitors, Humira. And so there was a thought that perhaps there was a signal there that suggested some additional risks for patients. But now with another seven-plus years of data, that signal has not borne out.

So in terms of what you think about for patients and risks, actually, with the TNF inhibitors, you don't need as much lab monitoring compared to methotrexate or mycophenolate. So you don't tend to see the effects on blood counts as much as you might with those other medications. As I said, many patients don't have much in the way of day-to-day symptoms.

But there can be-- some patients may describe kind of an overall fatigue. I've had a few patients who seem to have headaches that correlate with being specifically on Humira. There can be some weight gain issues with the TNF inhibitors, including Humira.

And sometimes, very rarely, there can be some sort of not well-defined effects on mood and psychiatric issues. I've had a few patients who just wouldn't tolerate the medication for that reason, but it's pretty rare. Most commonly, we stopped using Humira because it's not working for uveitis, I would say, above and beyond.

For the immunosuppression that you're concerned with COVID, yeah, we were all scared, very scared. And I delayed many people for a while, delayed putting patients on immunosuppression for the first time, as we tried to figure out what their risk would be.

We learned that the risk is a little bit different depending-- the risk of infection is different depending on the mechanism of the drug, and that your response to the vaccination is affected depending on the immunosuppression that you're on. So that has influenced the recommendations that have been made over the past few years in terms of vaccination and prophylaxis, if you're exposed to COVID. And of course, as COVID has changed, so have the recommendations.

ANDREA TOOLEY: Yeah, I've had quite a few patients on rituximab who just cannot develop an antibody response to the COVID vaccine, no matter what. Their B-cells are just so deplete that it's not going to happen.

WENDY SMITH: Yep, so then when the prophylaxis was available, the Evusheld worked. That was an option. And then those are the patients that would still be treated with Paxlovid, I think, right now, until that changes.

ANDREA TOOLEY: Yeah, yeah.

ERICK BOTHUN: I think your comment about the psychiatric conditions, the psychological responses of disease is something that I don't think we give enough attention to, at least in my peds population. I think there's a component of an uncommunicated stress response.

Even if it's not communicated, the fear of the parents over the child losing vision, how that can play out in the child's life is quite an interesting journey to have empathy for, to communicate through, to address. And it's just, I think, one to be for these chronic conditions to continue to revisit and talk through.

I don't know too many of my young patients with uveitis that are on methotrexate that like the color yellow because methotrexate is yellow. And they'll see something yellow, even a school bus, and they get this sort of visceral reaction in their gut that just, they don't like the color yellow. And it's interesting how often our medical diseases are having influence on their overall behavior.

And so it's just important. It's nice that you brought that up. And I think it's important for our listeners to just appreciate. And not just uveitis patients, but all of our patients, but certainly in these ones with chronic diseases.

ANDREA TOOLEY: Yeah, wow.

WENDY SMITH: Yeah, I think for some of the pediatric patients, sometimes there's also a fear that it's something that they've done wrong or when the uveitis flares up, that they feel like it's their fault. And now, there is an adherence to medication component. But otherwise, we don't know why people get uveitis, for the most part. We don't know why people flare up.

And so, sometimes, yeah, I try to feel out how a patient is feeling about things. And it is a lot of stress, both adult and children with uveitis. Because they really want their disease to be controlled. They don't want to be on medication. Everybody, of course, hopes for the magic wand treatment that makes it all go away. And for the most part, with uveitis as a chronic condition, it's an ongoing fight.

ERICK BOTHUN: I think our residents are quite in tune with encouraging patients with diabetes or high blood pressure to keep those things under control because their eye health long-term are going to be impacted in ways that we've richly studied. It's hard with uveitis.

I think we've grown to realize very few of them, especially some of the childhood ones for me, but you now others, that just, they're not expected to burn out. They're going to be chronically with them. And this overlying curiosity, fear, dark cloud on the horizon, is certainly something that affects them.

And just the importance of, as you're saying, compliance. There's a certain transition, whether in youth or adults, but in youth, going from the parents doing this to me, to, I need to manage this myself. And those are all important windows to have supportive care.

I appreciate the teamwork you've been to our side. Any advice on others in terms of managing these meds? I assume your average comprehensive ophthalmologist, working with a patient with uveitis, knows their resources in their area, but other plugs for the medication side? Is it just know your rheumatologist well?

WENDY SMITH: Yeah I think, certainly, many uveitis specialists are going to be comfortable managing medications. The big hurdle can be administrative help. So if you need to get prior authorizations of medications, the TNF inhibitors-- Humira, for example, has to be sent by a specialty pharmacy.

So you need to know how to send the prescription properly to the specialty pharmacy. So that takes a lot of administrative support even for a uveitis specialist. So some people will have a nurse that works with their practice, for example, or another administrative type person.

Otherwise, indeed, the average ophthalmologist, we wouldn't expect somebody to have the experience to do that. So partnering with a rheumatologist in the community is important. And unfortunately, not all every rheumatologist may be comfortable treating a patient with uveitis because they can't evaluate the inflammation at all.

So there, what's really important from the ophthalmologists is really good communication. And it can't be in our hieroglyphics or our abbreviations. It needs to be, "Dear Dr. So-and-so, the uveitis is well-controlled. Can we please continue this regimen if it's medically safe?" And if it's not, being really clear about that.

Because sometimes I have patients referred to me by rheumatologists outside of Mayo, saying, what's the situation? We don't know what to do because we can't tell what's going on with the uveitis. So we all need to be really good about communication with each other.

ANDREA TOOLEY: Yeah, this is such a high yield, really fantastic overview. Thank you so much for breaking it down. I think it's super helpful to anyone out there seeing patients with uveitis. So much to recognize and appreciate in caring for these patients. So thank you so much for your expertise. It was wonderful to chat with you.

You can find all episodes of the Mayo Clinic Ophthalmology Podcast on our website.

ERICK BOTHUN: Thank you for listening, and we definitely look forward to sharing more.

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