Lecture: Uveitis: Therapeutics Update

The therapy for non-infectious uveitis has continued to evolve during the pandemic. During this webinar, we will highlight the following: the two-year data from the FAST trial comparing the efficacy of mycophenolate mofetil to methotrexate, the VISUAL III data on adalimumab, outcomes of the clinical trials on the fluocinolone acetonide 0.18mg intravitreal implant, and the POINT trial on efficacy of the dexamethasone implant vs. periocular corticosteroid. Questions received during the registration process and the webinar will be discussed. (Level: All)

Lecturer: Dr. Ramana S. Moorthy, Ophthalmologist, AVRUC and Indiana University School of Medicine, USA


DR. MOORTHY: Good morning, everyone, my name is Ramana Moorthy, but I go by Bach. I am going to talk to you a little bit about an update of management of uveitis that as changed so everyone will be brought to what we’re doing in the US and parts. So, it may be a little US-centric. But I think it has some international studies as well. And we’ll talk a little bit about uveitis management. So, I know there are in — I looked at the — some of the questions and I’ve looked at the people that are joining the webinar and so forth and I know that the various stages of learning about uveitis. Some of you are experts and far, far smarter than I am, I’m sure. And some of you are beginning your training, perhaps, and beginning to understand about uveitis. I’m going to spend just a very few minutes and I’m gonna move quickly. So, there is a recording available and I apologize if I’m too quick, I will try not to do that. But you can always review this talk. So, let me start by telling you the basics here. I don’t have any financial disclosures to report. So, the purpose of the uveitis evaluation is really to assess the situation of what the patient has. Find the cause of the inflammation. Whether it’s infectious or non-infectious, and identify what the best treatment is and tell them about the prognosis. And the most important thing about uveitis patient is taking a good history. Because if you don’t take a good history, you’ll continuously be lost as to what’s going on with the patient. So, really going into — digging into the depths of history of present illness, past medical history, their surgical history. And about their symptom specifically. When did it start? What are the problems? Are they coming back? Are they recurrent? Chronic? What other illnesses and problems that may be relate ready you — do we need to know about. Where r there skin findings, zoster, lupus pernio or vitiligo or other issues. Are there spaces with users? Pulmonary symptoms indicating bad sarcoidosis like in this picture. Gastrointestinal, inflammatory disease or rare things like — disease. Things in the genitourinary system, and musculoskeletal, arthritic conditions? Exposure to zoonotic, cats, biting insects, et cetera. Travel history, especially knowledge of knowing the endemic diseases that are present in certain areas of the world can be very helpful in teasing out the cause. Then we move to the examination. And the most important tool in the examination is the thing in the center, your brain. So, if you don’t use your brain when you do the examination, it doesn’t matter. You can have millions of dollars invested in imaging and equipment but you got to have a good brain to put the findings together. And you need a slit lamp, it’s very important — it’s in Spanish. Maybe this is to go with the international flare of this talk. But the slit lamp is very important. The slit lamp tells you how much information there is. Eyes can be wide and quiet. Don’t always have to be red when there’s inflammation. pediatric uveitis, it’s wide and white, only with celling in the anterior chamber, using a lamp with a high intensity beam, a 1 by 2 millimeter beam looking at the cells that you will tell the activity. El criterions and flare are important. Looking at the posterior synechiae formation. And looking for chronic inflammation. That’s super important. And looking at back of the eye cannot be over-emphasized. Just because there’s inflammation in the front doesn’t mean your examination stops there. There are things going on in the back that tells you different information and the clues as to what the information may be. The uveitis specialist more than any other is a master of the ophthalmic and in some cases the systemic examination. You get to look at the whole patient. I’m not going through the details, you are experts. But it’s important to assess the conjunctiva for nodules, cornea, the iris for presence of inflammatory, synechiae, gonioscopy, often forgotten. And looking at cataracts. Remember, acute inflammation, red, painful eye. Intraocular pressures may be low. Can be a hypopyon or in chronic, there’s lots of structural damage like with the synechiae in the lens. And look at the vitreous, determine the amounts of cells and haze. Not grading systems with vitreous cells, but there are grading systems for haze. And look at cornea and the optic nerve, edema, lesions, cupping, pallor, look for inflammatory lesions, retinal hemorrhages, vascular sheathing, cystoid macular edema, and neovascularization. Those things can be helpful and give clues as to what’s going on. Look at the other parts of the body on the exam, skin, mucosa, joints and things I have talked about. If you’re not sure about doing the full examination of the patient, rely on patterns of recognition. There are certain patterns of disease. For example, the patient in the upper left has zoster and they have zoster-related inflammation in the eye. The patient in the middle a has evidence of a syphilitic rash. And the patient on the bottom, Lyme borreliosis with the typical thing. And after cataract surgery, hypopyon, that’s edematous until proven otherwise. Sometimes the vitritis is severe and looking in the back can be difficult. You have to use an ultrasound machine or another agent. Sometimes it’s easy, and redial vascular sheathing, indicates toxoplasmosis. And in parts of the world TB uveitis is important to recognize. There are different variations that can be quite severe. Bartonellosis is important. And patients who are immunocompromised or have AIDS. In certain parts of the world, high numbers of patients with AIDS, and looking for the cytomegalovirus, looking for that is important. And in all individuals, caused by zoster HSV. And don’t miss the findings in the sclera. A patient like this with the necrotizing area of scleritis that’s very painful, you have to look for the possibility of underlying systemic vascularities. And rely on additional data by getting imaging. Fluorescein, angiography, fluoresceins, if you have those tools available, great! You don’t need them all the time, but they can be so helpful to look at the macula and the retina and assess things and really to do a really thorough assessment for uveitis, you often need these to help you. Put it all together. In a single statement like on the top here. A 27-year-old male, for example, with a hypopyon uveitis, joint redness and patchy psoriatic skin rash. I can tell you the diagnostics are very small here. I would get two tests, an HLA-B27 and HLA. Most likely associated with reactive arthritis or — looking at the problem, it has to be problem-focused. Don’t do a million dollar lab work up and getting CBCs or a SED rate or other useless information unless you have a reason to get that. If you think of something that you forgot based on exam or imaging, go back and look again. This is a workup of the uveitis patient is a work in progress. And the laboratory testing is only supportive of what your presumptive diagnosis is. It’s not a substitute for your exam. It’s definitely not a substitute for your history. And remember, you get more than one chance to work up the uveitis patients because many of these patients have chronic diseases and they have significant severe vision loss. They need to be monitored and treated very carefully and monitored closely and recurrently. Don’t order tests that are not gonna help you. Or, you know, lupus and rheumatoid arthritis are clinical diagnosis. And labs such as ANA, rheumatoid factor are not worked up in the adult unless they have scleritis or retinal vasculitis it’s worked up in children, we want to rule out idiopathic arthritis and determine the sub-type. I almost never do it in a adult unless they have scleritis or retinal vasculitis. You don’t want to order some of the testing, it’s useless. Order HLA-B27 and maybe an HBB. 5% of patients are positive. It only means something when the clinical findings of retinal cortisol rate with the A-29 when it fits together. Other invasive testing that we will cover a little bit more in the updates. This includes anterior chamber tap or vitreous tap, and chain reaction studies, looking for DNA fingerprinting of infectious agents that may be causing the uveitis. And others that are part of the uveitis and retina specialists.
There are diagnosis of uveitis that you don’t to want miss. You continent want to miss infectious causes of uveitis. Don’t miss necrotizing herpetic retinitis, that causes blindness. Syphilis has tremendous social and life implications. Don’t miss tuberculosus uveitis. And don’t miss systemic like the patient with the scleritis I showed. They have significant increase in mortality, not just morbidity, but mortality when not treated. And don’t miss primary CNS lymphoma that can masquerade and that can kill them. And cancers that may masquerade, and other syndromes. Don’t miss things that aren’t uveitis, chronic retinal detachments or hereditary. The detachments are treated with surgery. Hereditary retinal dystrophies are treated differently if at all. These are important to know. Start with the first polling question. What is the most important reason for performing a diagnostic workup of uveitis patient? To determine the etiology of autoimmune? To determine if topical steroids can be used safely? To determine if systemic immunosuppressives are needed? Or to determine if the etiology is infectious or non-infectious?
Okay. So, good. Excellent. So, that’s right. The most important thing that we want to know is if it’s infectious or non-infectious. I’m glad you’re awake and paying attention. Here in Indiana, it’s 9, I have been up since 5, but you’re later in the day, I hope you’re not too tired. This is important. We want to know the diagnostics — from the diagnostics what’s the cause?
So, what are the advances that have happened in diagnostics? Polymerase chain reactions described first in 1985, amplify small regions of the DNA. Now we have things automated to the level that we can do tremendous and very quick analysis qualitatively and quantitatively. Even in places that are remote, we have access to small, very simple machines that do sophisticated analysis of sputum samples, for example. To determine if the patient has mycobacterium TB. Many of you are using that in your clinics to determine and very quickly using the P CR techniques to amplify small pieces of DNA that may be present without significant, long cultures that take a long time to get back results so we know immediately. Sometimes we can even speciate the organisms based on the DNA findings. So, beyond that in the last ten years, we have had tremendous advances in the development of what we call multiplex PCR, many target genomic DNAs at one time. And sometimes in the hundreds and thousands, and they have high sensitivity, but also high false positivity. They pick up so little bits of DNA. So, it’s really — you have to use this with a grain of salt when you’re evaluating this. There’s also real-time PCR. This is what I’m talking about when you’re looking at 16 ribosomal DNA, ribosomal RNA pieces and using conserved genomic regions like mycobacteria and fungi in the field and making a rapid, real-time diagnosis. And finally, within the last 7 or 8 years, meta genomic deep sequencing is a field in itself where we can use a — basically a bit shotgun approach and look at a broad identification of all possible pathogens in a sample. But these needs primers from the large data bank, but provide rapid diagnosis, but provide also tremendous clues and can be forensically evaluate the cause of the uveitis. The uveitis may be chronic lasting 50 years, maybe go back to the inciting event which is quite remarkable. That requires a lot of experience in meta genomic deep sequencing and access to big datasets and complicated equipment. This may not be immediately available to us. But I suspect in the next 10 to 15 years we’ll be seeing machines and laboratories that will be able to do this regionally in many parts of the world.
So, how do we use this in practice? Well, in one study, for example, aqueous and vitreous samples of nine common pathogens were evaluated and found that specificities and sensitivities were very, very high. And the intent of the authors was to use real-time PCR and provide high level of fidelity and correlated to quantitative PCR which takes a lot more instrumentation and techniques. They found in the field that you can do a multiplex PCR strip and within a few minutes or an hour, find the cause of the inflammation where it used to take days sometimes to do it. That’s where we’re going with this. I’m gonna now switch bases here a little bit and talk a little bit about what most of the rest of this talk is going to be. In the developing world, you know that you all know outside of the US and the western world, for example, that the most common cause of uveitis is probably infectious. You don’t want to miss infections, syphilis, tuberculosis, toxoplasmosis. Don’t want to miss regional infection problems. But the mundane, day-to-day activity for me in my practice is the treatment of non-infectious, chronic ocular inflammatory diseases. Why is that? Because chronic inflammatory diseases are incredibly frustrating, very difficult to treat, and often require the expertise of somebody who has some experience in ocular etiology in the use of things that are steroids sparing. Steroids by themselves are not the final answer. They’re the initial step for the treatment of these patients. Once we know that the uveitis is non-infectious and it’s not caused by an infectious organism, treatment is different. If you have an infectious cause of uveitis, how do you treat infections? You treat them with antibiotics, right? That’s the most important thing to remember. If you have somebody who has infectious uveitis and can’t give steroids, they’re going to get worse. There may be some exceptions. Most cases in the short-term they’re going to get worse if you miss the diagnosis of infectious uveitis. It’s important to understand if it’s infectious or not. That’s why you have to do the laboratory testing, serological testing and aqueous testing. Once you know that it’s not an infection, then you can move on to treatment. So, treatment guidelines are that once you know it’s non-infectious, the paradigm is to control the inflammation that is non-infectious and eliminate the risk to the vision and try to avoid structural complications of the disease. The choice of the agent that you use initially is based on the specific diagnosis, the current ocular disease, and the existing level of ocular function compromised. And whether they have bilateral or unilateral disease. And also what desires of the patient may be. Now, the initial therapy is to control information rapidly, okay? When somebody presents to you. When they have non-infectious uveitis. Particularly in acute versus chronic. Regardless, the goal is to control inflammation rapidly. That means using corticosteroids for the most part. There are some examples of that corticosteroids are the be toast get it controlled quickly. Topically, regionally, and systemically. Regional use of corticosteroid can be you have to be careful. You don’t to want give regional — for example, periocular or intraocular for those with herpesvirus, if you give them that, the eye will be blind and never recover. It’s very important that they be on antibiotics first and treated with antibiotics before you start covering them with more aggressive corticosteroids when it’s infectious. We’re talking about non-infectious uveitis, corticosteroids are the most effective way to control inflammation quickly. The multi-center uveitis treatment trial looked at local, the fluocinolone acetonide implant versus systemic steroids. And I will go over final results from that. But this showed us both can be faithfully effective in controlling the disease and macular edema. But there are caveats to both of these. Quality of life caveats and complications caveats from corticosteroids. So, for certain conditions such as mild scleritis, et cetera, you don’t need to use corticosteroids. You can get away with non-steroidal anti-inflammatory medications. There are certain cases, certain disease processes, where early initiation of immunomodulatory therapy is important. And there’s an exception to getting it under control. Patients with Behcet’s disease, in Eastern Europe and India and South-East Asia who see a lot of Behcet’s disease, especially posterior uveitis, retinal vasculitis, the best way to get it under control is with inflixamab, it can be effective in controlling inflammation. And often times even faster than corticosteroid in controlling the inflammation in Behcet’s disease. There are other cases where immuno-modular therapy is important, but corticosteroids are still the initial step, and scleritis, birdshot uveitis, juvenile idiopathic — all these things require immuno-modular therapy. With steroids, start high, taper. For example, if they have a lot of anterior uveitis that’s non-infectious. Put them on topical steroid drops every hour and gradually taper those drops over the course of probably many months. You can’t taper them very quickly if they have severe inflammation. If the inflammation gets under control or the patient reports, my symptoms went away, inflammation is still there. It will take a long time for severe inflammation to gradually decrease. It may take two to three months to decrease in the anterior chamber for non-infectious uveitis. Tapering of the steroids is done very gradually. And if the disease activity recurs with the taper, determine the dose to determine the next step. If you’re on oral steroids and started at 60 milligrams a day and flare at 20 milligrams a day, they’re probably not going to do well on steroids alone and may require immunosuppressive therapy. When you can’t control them with the first line corticosteroid therapy, then you think about using immunosuppressive medications. There are multiple classes of drugs that well will get to. And these include alkylating agents, biologic response modifiers. All of these things are talks in themselves and I don’t have a lot of time to go over each one of these. There are lectures that I have given about each one of these that you can see in the Orbis database. But beyond the second line therapy, then our options become more severely limited because some of the drugs that we use are off-label in these cases. And then we have also combination drug therapy. Or sometimes surgical therapy in your patients. There are special considerations for the use of these — of these non-steroid medications. For example in pregnancy. People who are of childbearing age and also vaccine recommendations are particularly important because if they’re on immunosuppressive therapy, you should probably not take live viral vaccines such as the oral polio vaccine. Now the zoster doesn’t apply because it’s replaced by a killed viral antigen vaccine. Rabies and influenza vaccine sometimes has a live virus. Avoid that in patients who are immunosuppressed. The updates come from the MUST trial in the United States and abroad. And the multi-centered treatment trial. And also the systemic immunosuppressive therapy for eye diseases, SITE cohort study, a retrospective. There’s a randomized clinical trial, and then the systemic immunosuppressive site cohort is looking at specific therapies, complications, and mortality and morbidity. Let me ask you the first question and then I’ll show you the answer. The next polling question. Which of the following statements are true regarding corticosteroid therapy for non-infectious uveitis? One, fluocinolone, this is for — and the second is periocular corticosteroids are more likely to cause significant elevations compared to intravitreal dexamethasone implant. Third, all local therapies call IOP elevation. And finally, corticosteroid therapy is not the first line therapy for non-infectious uveitis.
That’s right. All corticosteroid therapies, every one of them, can actually cause intraocular concentrations. I have seen patients after injection develop intraocular pressure elevation 10 years after their last injection. And develop really severe, rapidly progressive glaucoma. Now, can I blame my periocular corticosteroid injection alone? Maybe. But maybe the patient had a propensity to develop glaucoma from a genetic propensity. But regardless, once you give regional corticosteroids, for example, or even oral corticosteroids, you may change structurally the trabecular meshwork permanently in some patients. And may have a lifetime risk of glaucoma, and even after it’s in quiescence. And many years after they stopped the corticosteroids. It’s very important to keep that many mind. What the MUST steroid implant versus systemic showed is at the 7 year — now we have longer data — the systemic therapy, especially therapies with immunized therapy, better outcome at 7 years compared to the implant compared with quality of life and safety data. That’s important to remember. So, long-term patients did well with either therapy, but steroids plus immuno– oral steroids and the therapy together, low dose oral steroids, of course. But the combination of the system and steroids work very well, provided reasonably good quality of life compare the to fluocinolone implant and had better visual outcomes than the steroid implant alone. We have two types of steroid implant, the Retisert, Bausch + Lomb, that’s the large dose implant. It’s very different than the fluocinolone insert, the .19 Iluvien is not used for uveitis, it’s used for diabetes, for example. But the Yutiq is used for posterior uveitis, not approved for anterior uveitis. When utilized, the Yutiq implant has significantly greater duration to the first recurrence. You know, we’re talking about a ten-fold almost 657 days compared to 70 days with sham injection and using oral steroids. There are fewer reoccurrences with the implant at 36 months after insertion. And, you know, it provided — significantly reduces macular edema. But it does cause more frequent cataracts and glaucoma with this lower dose implant seem to be comparable to the sham — I wouldn’t say it’s less frequent. It seemed less frequent in the studies. But likely it’s comparable and didn’t seem to make a huge difference in glaucoma development. Although intraocular pressures should be measured in these patients. This is an implant that lasts three years that you can implant in the office. Many of you may have done this, the Yutiq implant. Which is the trademark, but the fluocinolone acetonide .1 implant. This is shown in a large randomized clinical trial to be highly effective in the treatment of posterior pan-uveitis. And the POINT trial, three types of corticosteroid approaches, the periocular triamcinolone and the other implants. And the intravitreal were superior to the exterior treatment. All caused intraocular pressure elevations, but they were greatest for the intravitreal treatments. And there was not much difference between the two treatments. You needed fewer injections it looked like to control inflammation in the intravitreal groups compared to the periocular groups. So, but all of the treatments did improve vision and improve central subfield thickness in the treatment of uveitic macular edema. Next polling question. Update question. Steroid-sparing immunosuppressive agents increase risk of cancer mortality. True or false? So, this is very interesting. You know, this goes back to what the results tell me that what we have in the treatment paradigm as uveitis specialists in the treatment of non-infectious uveitis still needs to be kind of — we need to kind of too late our horns here. Because the use of steroid-sparing immunosuppressive medications in the treatment of non-infectious uveitis has been shown to not increase cancer mortality. You know, the old paradigm was you’re poisoning patient when is you treat them with these immuno modulatory agents, but these are indeed generally very safe when monitored and taken care of appropriately for patients and administered appropriately. And they tend to be very well-tolerated with low — some have virtually no risk. Methotrexate has zero risk of cancer-associated mortality. And secondary cancers in general. The other agents are very, very low risk. How do we know that? Well, we know that from a large cohort from the site studies. So, what the site studies showed us is that, you know, that azathioprine, methotrexate, and others had cancer mortality rates similar to that of patient who is never took immunosuppressive medications. Isn’t that impressive? But there are those that are toxic, cyclophosphamide, that drug, the overall mortality, when we use it for non-infectious uveitis, cancer mortality was not significantly increased to those who didn’t get it. Isn’t that interesting? When we use it appropriately, given appropriately, and there are guidelines for use of agents like cyclophosphamide that help us. Tumor necrosis factors were slightly increased hazard ratio, about two times greater of overall risk in cancer mortality. There is some increased risk of cancer mortality associated with the inhibitors like adalimumab. Schizophrenia of the following clinical features of chronic anterior uveitis is determinant of reduced rate of disease or remission? Excuse me. I think I will go forward — sorry. Which is associated with reduced rates of disease remission? Longer duration at presentation? Unilateral disease, older age at presentation, or absence of underlying systemic disease?
This is a tough question. So, let’s see what people think so. So, inpatients with chronic uveitis, white eyes, chronic inflammation. That’s right. So, the features that really are determinant for reduced rates of disease remission, that means they’re unlikely to go into remission. Are if they have longer duration of disease at presentation. In other words, they’ve had the disease for many years when they come and see a uveitis specialist, those folks are not gonna do well. There are other factors too that I’ll review with you in some of the studies that were — some of the site studies and other studies that have shown what these predictors are of remission. But it turns out that bilateral disease, younger age although presentation — because they have to live with their disease longer — and systemic disease associations like JIA or spondyloarthropathy, those tend to be bad prognostic indicators at disease — they don’t go into remission. How do we know that? The SITE study in 2019, recently, looked at this particular issue. About a third of all the patients, 2795 eyes, 1634 patients were admitted within five years. But the two-thirds that had reduced remission incidence they looked at very carefully. Those patients that have that had reduced remission incidence, longer duration of disease, more often bilateral. More often had structural complications, presentation in particular, and required surgical intervention. And younger at presentation. And these patients often had a systemic diagnosis associated with their inflammatory disease. Specifically things like JIA or spondyloarthropathy. Those patients when they’re on immunosuppressive therapy, may need to stay on immunosuppressive therapy for many, many, many years. Sometimes 10, 15, 20. Maybe a lifetime in some cases. I have now after being in practice for more than 30 years, I have patients who I saw as children now coming back as adults having inflammatory problems when they have very severe uveitis as children. So, this is very important to keep in mind that, you know, bad diseases, chronic inflammatory diseases tend to not necessarily burn out or go away completely. There are many agents that we use to spare the use of steroids. Anti-metabolites like methotrexate, and mycophenolate mofetil, and what do we know about the metabolites? A remarkable study updated in 2022 is the FAST trial, many may have participated in the trial in India and in the US and abroad. But this trial was remarkable. They looked at a steroid taper. And patients then were randomized to either methotrexate or mycophenolate as the agent to spare the use of corticosteroid as it was tapered. At one year, it was a little bit more advantageous, and then there were — 2 drops of — with very little active inflammation. It looked like the methotrexate group was having more success in the study. But in follow-up evaluation three years later what we found is that the time to reach treatment success, defined as less than 7.5 milligrams a day, less than or equal to 7.5 milligrams a day for maintenance for chronic, intermediate panuveitis was equal for both methotrexate and mycophenolate. Both are highly effective in getting the inflammatory disease under control and minimizing the need for oral corticosteroids. And both appeared to be equally effective in controlling inflammation, and both allowed reduction of prednisone to maintenance. This is really important information for the uveitis specialist who is relying on these agents. You can choose the agent based on tolerability on the patient and the patient’s individual choice. And sometimes may have a favorite medicine that we use. And it’s purely up to the practicing uveitis specialist to determine this. So, there are other agents that we use less frequently like calcineurin inhibitors. And, of course, these heavy duty agents like alkylating are used for really bad types of uveitis like necrotizing scleritis, for example. TNF-alpha inhibitors changed the landscape of uveitis in the last 15 years as steroid-sparing agents. They have been found initially to be highly effective in pediatric juvenile uveitis. But in adults, used for the treatment of non-infectious uveitis in patients who have intermediate pan-uveitis or posterior uveitis. There’s an upstream inhibitor of interleukin 1, a pro-inflammatory cytokine that causes tissue destruction in the joint, cartilage and the eye. Inflixamab, it’s an antibody with a human — and a mouse variable fragment on side. It blocks TNF-alpha and finds to TNF-alpha. There’s a fully humanized IgG, one antibody, that binds the necrosis factor alpha, upstream inhibitor of IL-1. And finally, the receptor analog that binds alpha. It has caused inflammation in patients who never had inflammation. We don’t use it in the treatment of uveitis. And patients sometimes come to see us who have taken it for inflammatory disease processes, Etanercept. It’s not really better than placebo for treatment. And Humira was tested in large clinical trials. There are many collections of TNF-alpha inhibitors to keep in mind. Exacerbate demyelinating disease. Exacerbate congestive heart failure. Exacerbate histoplasmosis. Cause drug induced lupus and secondary neoplasia, lymphoma and leukemia. Next polling question, adalimumab therapy for non-infectious uveitis can cause which of the following adverse effects? I just went over them. Chronic gastritis, demyelinates disease of the CNS, central nervous system, cardiac arrhythmias, or capacitation of the tinea capitis.
That’s right. So, demyelinating disease, that’s the most important side effect here that you need to keep in mind. Demyelinating CNS is significant, and very particular potential risk factor associated with the use of adalimumab. Move on to the next one. So, adalimumab was studied in a very robust randomized clinical trial. Looking at control of non-infectious intermediate pose tear and panuveitis in adult patients. It was proved based on the Visual I and Visual II studies. And what did we find? Well, adalimumab increases the interval of treatment failure from 13 to 24 weeks. And increases the flare from 4.8 months to 10 months. There was a statistically significant difference. An 87% increase to the time of treatment failure — I’m sorry, for the treatment failure from 13 weeks to 24 weeks which is remarkable. So, we know that it is a highly effective treatment — steroid-sparing agent for the treatment of uveitis. And increased vitreous haze grade. This study is important, uveitis is a multi-faceted disease. It’s not just about celling and flare. It’s about vision, it’s about macular edema, and a lot of other things. And this trial was very beautifully designed and looked at a lot of different aspects of uveitis management and really was a home run in the way that it was designed and executed. And it’s become a model for future clinical trials in uveitis as we may see in the next several years. Keep my eyes and ears peeled for the new agents. The primary endpoint was the treatment of this — of this — of the treatment failure. And the treatment failure was, you know, dramatically — the time to treatment failure was dramatically increased with the treatment of adalimumab from this study. I’m gonna keep moving here. In terms of this — so, I’ve already gone over the conclusions. There were adverse events, but the adverse events in the original visual trials were similar between the steroid group and the adalimumab group. The VISUAL III trial, a follow-up, a pooled data follow-up. And this showed that the amount of steroid that patients were utilizing at the end of 78 weeks, a longer duration here, was even less. Many were on 2.5 milligrams a day of prednisone for maintenance while they’re on adalimumab. And patients who have inactive uveitis at entry tended to stay inactive on very, very low doses or minimal doses of corticosteroids. This follow-up data confirmed the efficacy of adalimumab in the treatment of non-infectious, intermediate, and non-uveitis. And we have data now to suggest that — and adalimumab is typically given every two weeks. But there’s data to suggest that for patients that failed every other week, weekly can improve inflammatory control in half of those patients. This is a retrospective study at a single academic institution. This is a newer study from Dr. Goldstein’s group. That showed that weekly adalimumab can also be effective if every other week doesn’t work. And even more important than that, there was a placebo control trial looking at adalimumab plus methotrexate versus methotrexate alone. And I’m sorry, methotrexate and placebo versus methotrexate plus adalimumab. And what this particular study showed, the SYCAMORE trial, showed that the placenta-controlled trial was important. They actually administered placebo versus adalimumab. So, they were — what they Showed was that there were — there was better control with adalimumab plus methotrexate. But patients who received adalimumab had more adverse events. They had adverse infectious events, mainly — and these types of serious adverse events required treatment, you know, discontinuation of treatment and treatment of those complications. So, that’s something important to remember. So, this adalimumab therapy controlled inflammation was associated with a lower rate of treatment failure in adolescents and children. But with children with JIA-associated uveitis taking this methotrexate plus adalimumab, adalimumab had a much higher incidence
Adverse events and serious adverse events than those who received placebo with methotrexate. That’s very important to remember. And it’s important when giving adalimumab to children that a pediatric rheumatologist be involved in the care of those patients. There are other biologic agents adalimumab that can be used for severe inflammatory disease, but they’re toxic, anti-CD20 Rituximab has been available for many years. It wipes out cells and it’s effective in the treatment of things such as GPA. It has the role, but it’s an off-label use and it’s highly toxic. Can produce profound lymphopenia, and other reaction. There are many other things that are coming out with biologic response modifiers that I don’t have the time to go through. But many of these are newer agents that provide us with abilities to control inflammation better and in patients who have non-infectious uveitis when they’ve failed the traditional available medications. I’ve listed a few things here. But I think this is less important. I’m gonna try to briefly cover some of the complications of uveitis management. That’s changed a little bit too. Uveitic glaucoma, and here are a couple patients with tube shunts from this. Here’s a patient, statistically significant risk factors from the SITE studies associated with ocular hypertension. What are the takeaway points here? You know, the important is that the risk factors for ocular — and glaucoma in the treatment of non-chronic uveitis in the SITE trial suggested that the patients who had a history of ocular tension in the fellow eye are at greater risk for developing glaucoma. Patients who had history of acetylene implants, higher risk. And prior use of drops, they have issues with glaucoma, they’re gonna have problems with contractive pressures as the studies progress. Patients who are on more than, you know, current topical steroid use especially. Those on frequent use of drops like eight or more times a day, they’re at greater risk. Periocular steroid risk within the last three months, greater risk for IOP elevations. Previous ocular surgeries like vitrectomy are at greater risk. And people on more than 7.5 maintenance of oral prednisone, those folks are at greater risk. Chronic inflammation that’s not well-controlled, those folks are at greater risk. All of these are important risk fact for the development of ocular hypertension and glaucoma. Those we know. It’s important to remember that controlling inflammation is an important paradigm. Reducing the amount of steroids that the patients are on is an important paradigm for control of intraocular pressures and knowing prior history, family history or propensity for glaucoma is another major risk factor. So, here is a patient with uveitic cataract, it’s poorly controlled. Cataract surgery, the MUST trial showed — that’s a prospective study — over patients who underwent primary cataract surgery in the 479 enrolled eyes overall did well and the vision improved and the patients had no preoperative factors for pre-op vision had an impact on final visual outcome. Systemic therapy and fluocinolone implant had similar outcomes. If you’re on appropriate therapy and getting good control of your inflammation, doing cataract surgery in patients that had control on appropriate immunosuppressive therapy and corticosteroid therapy had good outcomes following cataract surgery. So, you know, if you look at all the patients who have cataract surgery, the — about 1.2% of patients of all eyes undergoing cataract surgery have uveitis, okay? And if you look at that, they have a higher incidence of ocular — glaucoma — and small pupils. This is something we know in patients who undergo cataract surgery and have underlying uveitis, tend to have a poorer prognosis overall. And if you look at the cataracts associated with uveitis, the patients don’t do as well visually. But if they’re well-controlled according to the MUST trials, seen by a specialist and good control, the outcomes are better. Next polling question. Which of the following is not an important risk factor for cataract formation in children with uveitis? Greater number of uveitis flares per year, use of systemic immunosuppressive therapies, presence of posterior synechiae, local corticosteroid injections? Which is not important risk factor for cataract formation in children with uveitis?
That’s right. Systemic immunosuppressive therapy is not a risk factor. It’s probably protective. You’re minimizing corticosteroids. If they have flares and significant anatomic complications like posterior synechiae, they’re going to get cataracts more frequently. We know that because of a significant and very important study that was done. There are two important studies. So, the main risk factors from the British study that showed and retrospective study, the main risk factors for cataract development were number of uveitis flares, cystoid macular edema and macular edema, and the use of local corticosteroid injection. Treatment with topical steroids were not risk factors that study suggested. What that study implied, controlling inflammation, even using higher dose of steroids is important in preventing ocular — this is important. However, the next study, a retrospective study from the US showed us from the Hopkins group that when they looked at patients who — in children in particular with uveitis, that topical steroid use alone was associated with cataract development. Especially when the patients were using three or more drops of corticosteroids daily. Three is the magic number. You want to try to reduce the corticosteroid drop use to three or less drops per day in order to help reduce the development of cataracts. Other risk factors include the things in the other studies with active inflammatory disease, posterior synechiae associated with the development of cataracts. The authors concluded that topical corticosteroid of less than or equal to three drops daily associated with 80% lore risk of cataract development in JIH patients. There are some caveats with the retrospective studies. And the key for any surgical intervention in a uveitis patient, get the disease well-controlled for at least three months and pulse the patient’s topical and oral corticosteroids starting a week before surgery and gradually taper the steroids. You want to avoid doing surgery in actively inflamed eyes because the inflammation is really going to go out of control after the surgery. And you want to be aware and treat all of the steroid-related — I’m sorry, the inflammation-related complications such as macular edema prior to this. And looking at macular edema itself, the MUST trials showed even when macular edema was under control, macular edema is chronic problem. It must be controlled long-term to achieve stable visual outcomes according to the study from 2021. And Uveitic macular edema can episodically relapse even when controlled. These relapses result in significant vision loss. Macular edema and the chronic uveitis continues to be a long-term problem and needs to be monitored for patients. So, I think that’s another important factor. I’m gonna stop there. The rest of it is actually parts of other talks that I’ve given about cataract management, et cetera. I’m going open it up for questions. But I think — I think that we’re towards the end here. And so, I don’t want to take up too much of your time. I hope that this update was helpful to you. And try to bring to light some of the newer studies that I thought were important to discuss. I didn’t discuss the S UN Group’s fantastic reports that were — that were published in the American Journal of Ophthalmology. An entire issue I think was dedicated to the SUN criteria. And the — this process — excuse me — my timer is going off telling me that I’m done. Okay. There with go. I can’t stop this.
Okay. All right. There we go. Sorry. So, let me answer questions and I’ll go to the chat here. And let’s see what the Q&A. What to do to decrease inflammation after cataract surgery in chronic uveitis patient. First of all, don’t operate on a patient who has inflammation. You want to make sure that the inflammation is well-controlled for at least three months before you do cataract surgery. That means no cells. To me, inflammation well-controlled means no cells. That doesn’t mean minimal amount of steroids. Whatever it takes to control the inflammation first, get it done. Get the inflammation with zero cells in the anterior chamber and then do cataract surgery. If patients have posterior synechiae and a lot of flare, they’re going to do badly regardless of the level of control. Those patients need to be monitored carefully. Use of intraocular lens implants in uveitis patients should be done very judiciously. Patients can remain aphakic and wear a contact lens than a patient who has poorly-controlled inflammation in an eye with an implant especially in children that ultimately need the implant removed. It’s very important in these cases to talk with a pediatric ophthalmologist, and a uveitis specialist. These can be complex cases. What is your preferred method for treating bilateral Mac already edema and intermediate uveitis with little inflammation. If it’s bilateral, I use methotrexate or I use mycophenolate. If that doesn’t work, may use intravitreal or corticotropes for non-infectious uveitis. Colleagues around the country used interferon. It has significant side effects, but it can be highly effective in the treatment of cystoid macular with uveitis. What is the most common cause of scleritis in 7 month old baby? I would look for infectious causes in that first before you look for autoimmune disease causes. That’s very rare for babies to present with scleritis. I would look for infectious causes. What in your experience has been the maximum duration of steroid therapy for uveitis? I have patients who are on 5 milligrams every other day of maintenance oral corticosteroids for 20 years. The treatment of chronic non-infectious inflammatory disease probably requires some corticosteroids. Ideally, I would love to remove corticosteroids from the equations, often this is not possible. We try therapy to minimize the use. Chronic diseases require chronic therapy. You don’t treat diabetes for one day and say it’s cured. Don’t treat diabetes for three months and say it’s cured. Similarly with chronic inflammatory disease. Chronic inflammatory eye disease is disease that lasted more than three months without remission. Can you summarize the challenges for treatment? I just did. I think I talked about that. The challenges are trying to reduce corticosteroids, trying to reduce the structural uveitis and the corticosteroids and balancing that with the use of immunotherapy for the — the other challenge is making sure you don’t miss the diagnosis of infectious uveitis. Is it okay to start treatment with topical steroids only in the first week if the patient shows vitreous — I don’t know what — and USG? I’m sorry. I’m not sure of what that means. Yes. So, if you suspect — I think that the question is if the patient may have — if you’re thinking that it might be infectious and there’s something going on, is it okay to start steroids topically? Yes. In most infectious uveitic cases, the only thing it if you have prophetic corneal disease and infection with the corneal disease, you will make that worse with topical steroids. So, that’s one exception. The — is any recent study for Fuchs’ uveitis. Nothing recently other than the most important finding is the association of prior rubella virus. And rubella virus RNA was discovered in patients in the anterior chamber who had Fuchs’ uveitis. And the serologic evidence of a greater prevalence of patients who have exposure to rubella who have Fuchs’. And there’s also chronic CMV can cause that as well. There’s a lot of work in Singapore on this. But in patients who present with chronic inflammatory disease, look very much like Fuchs’ disease caused by cytomegalovirus. And you need to check the patients every few weeks depending on the severity of the infection. I check many patients on a monthly basis. Somebody said I have — uveitis past three months reoccurring soon after stopping steroids. What can I do? So, the — in post-retinal detachment, depending on what was done, a vitrectomy, and those patients can be difficult to manage. You have to prove that it’s not infectious first of all. So, I would look for if they have a lot of yells in the anterior chamber, tap the AC and send it off for a PCR evaluation to make sure you’re not looking at viral causes. Do it in a laboratory workup and a review of systems to make sure they don’t have underlying systemic inflammatory disease processes that are non-infectious. And then based on that, I would start treatment with more aggressive — more aggressively than just with topical medications if necessary. Occasionally it can be because of an inflammatory reaction to an ex-planted material like a sickle cell or buckle implant that you see scleritis. Removal of that can make it better. This is a tough problem. What’s your opinion for pred mutation use in intermediate uveitis? 50% of the patients develop glaucoma or severe intraocular pressure, sometimes rapidly. That’s important to keep in mind. It can be almost as effective as giving a steroid injection in the eye. It does penetrate into the anterior vitreous, it can affect treatment positively and cystoid edema positively. But it has to be used with caution because of IOP issues. If mycophenolate or methotrexate or second line treatment fails, what is the next? I use the second line or third line, I guess. For — immunocompromised patients, when do you decide to top intravitreal and continue — when it’s well-controlled and don’t see progression, then I leave on maintenance oral van– and advice would you give for a 50-year-old female? Needs immunotherapy and evaluated by a rheumatologist. Make sure she has testing, ANA testing, rheumatoid factor testing and evaluated by a rheumatologist. And what’s the most common cause for uveitis in a 4-year-old? Depends on the presentation, acute versus chronic inflammatory disease, the eyes are white and chronic and bilateral, it’s likely JIA-associated. That’s the most common identifiable cause. And if it’s intermediate, most common is pars planitis. And it’s possible, including toxoplasmosis. And that’s globally and in the western world. What do you do in cases that all recalcitrant to all treatment modalities. Maybe refer it to you, my anonymous participate. I have patients with those problems, unfortunately. We have to do multiple medications. You have to have the help of your colleagues and discuss cases. And use things that are off-label and often not utilized regularly. Can the patient free from uveitis be controlled functional finally? Eventually, there are many patients who can be free of uveitis. Non-infectious uveitis. But the, you know, the patients that I see are very — the toughest cases. I don’t want to say that it’s not possible. Certainly it’s possible. But it may take years in many cases. What would be your choice of immunosuppress, TNF alpha inhibitors, and oral prednisone is relatively safe in pregnancy. Well, thank you so much. And I will let you guys go. I hope you have a wonderful rest of the week and weekend. Thank you for your attention. I hope you learned something. I certainly learned something from your questions.

Last Updated: May 24, 2024

1 thought on “Lecture: Uveitis: Therapeutics Update”

Leave a Comment