Lecture: Drug Interactions and Drug-Induced Uveitis

DR MOORTHY: Good morning, everybody. I wanted to introduce myself. My name is Ramana Moorthy, and I want to welcome everybody from all over the world. I hope you guys are dealing with the pandemic better than we are. And I hope this will soon come to an end so we at some point — I can meet many of you in person. Some of you I’ve met in person, probably. But I wanted to welcome you today. So today I wanted to focus a little bit on drug induced uveitis. This talk also includes a little brief interlude into drug interactions, initially. And one specific interaction that I wanted to highlight, that is very important for ophthalmologists, and uveitis specialists, or retina specialists, because we tend to use corticosteroids, and subsequently, talk about some of the more common causes or common associations of drugs and uveitis. Causation is a difficult thing to determine in medicine. We can go by statistical anomalies. But in this case we use specific criteria that I will discuss with you. These criteria were developed by pharmacologists, with a great deal more experience on adverse events than I had, many years ago, and I’ll discuss that with you. I have no financial disclosures. And we’ll start off with a poll question to begin with. And I’ll read the question. You’ll have 30 seconds to answer. The highest risk and incidence of peptic ulceration occurs with which of the following therapies? A, systemic corticosteroids alone, B, systemic NSAIDs alone, C, systemic NSAIDs combined with systemic corticosteroids, or D, systemic corticosteroids combined with systemic methotrexate? Which has the highest risk and highest incidence of peptic ulceration? Okay. Excellent. So most of you got this right. And I’m gonna close this off here. But you’re right. The combination of NSAIDs and corticosteroids substantially put patients at a higher risk for developing peptic ulcerations. There are many drug interactions that ophthalmologists and uveitis specialists should be aware of, because we use corticosteroids quite frequently. Of course, many of us use them topically, but we have to use them systemically from time to time for various disease processes. Immunomodulatory therapy and biologics are really kind of relegated to other specialists. I’m gonna go back here for just a second. I think this slide show is on autoadvance, for some reason. But the immunomodulatory therapy has various mechanisms of action. I won’t go through the details of this. Obviously corticosteroids ultimately inhibit the transcription — translation processes that occur in the cell nucleus, and subsequently the translation processes are inhibited more of course of the cytoplasm of the cells. But there are other agents that we use, like the immunosuppressive medications, that have different effects on the cell cycle, as well as the way that they modulate interleukins and ultimately inhibition of the cell cycle indirectly. So if we look at some of the most important interactions between systemic corticosteroids, by far the greatest problems that we encounter when we use corticosteroids with systemic and non-steroidal antiinflammatory medications. Nonsteroidal antiinflammatory medications produce a 20 fold increased risk of peptic and gastric ulcers. Originally people saw ulcers with the use of IV corticosteroids, but these patients had other issues that put them at risk for that. These were from reports in the 1970s and 1980s. So many times when we start oral steroids, we often place patients on medications to reduce the risk of ulceration. We might place patients on PPIs, proton pump inhibitors, or H2 blockers, prophylactically. But I think the most important thing is that these… The NSAIDs produce a much greater risk for the patient and induce the development of gastric and peptic ulcerations much more significantly than steroids alone. So the most important thing is to probably avoid using NSAIDs in combination with corticosteroids, when you use systemic corticosteroids, probably the patient is on NSAIDs for other reasons — you probably should avoid putting them together and avoid having them use the NSAIDs while they’re on the steroids, if at all possible, and in addition, if they’ve been on chronic NSAID therapy, you might want to institute PPI or you might want to institute H2 blockers in association with the internist. There are other things… Many times, the induction of hepatic cytochrome P450 system and the metabolism of other medications like anticonvulsants and so forth can change corticosteroids — how effective they are. So decreased corticosteroids may be seen with anticonvulsants and many different antiinfectives. The anticoagulant effects of warfarin, for example, are increased by corticosteroids, because again, the anticoagulants kind of compete with the cytochrome 3A4 system, which is important for the metabolism of these agents, and corticosteroids are also similarly metabolized by those, so they compete for the enzyme activity, and that can alter the metabolism of those medications. I won’t bore you with these lists. But you can see that there are many different things that we have to consider. One other thing I would point out is that fluoroquinolones, when used with systemic corticosteroids, appear to increase the risk of developing tendinitis and tendon rupture. But here’s the pathophysiology that we see in terms of corticosteroid induced enteropathies. Corticosteroids decrease gastric bicarbonate production and decrease mucus production. This is made worse by the NSAIDs, which also have similar effects on mucus synthesis and prostaglandin synthesis. And as a result, there are significant changes that occur in the mucus production and blood flow to the intestinal mucosa. Compounded by the decrease in bicarbonate production by corticosteroids, and that results in significant cell injury, increased intestinal permeability, to bacteria, bile acids, proteolytic enzymes, and toxins which are normally — the mucus and prostaglandin tend to coat and prevent the activity of these proteolytic enzymes, and that is inhibited when you have all of these agents together. The NSAIDs as well as the corticosteroids. And that increases the risk of you developing significant erosion, ulceration, bleeding, protein loss, all those things that were developed in this corticosteroid plus NSAID induced enteropathy. So this is important to keep in mind, and this is one concept I wanted to go over. The other things we won’t have to spend too much time on, because most of you may not be using these agents. Methotrexate, for example, a commonly used immunomodulatory therapeutic agent for non-infectious uveitis and chronic conditions — its effects can be altered by antibiotics. Certain antibiotics increase the effects of methotrexate, and some decrease these. And many of these are due to displacement of plasma protein bound methotrexate in the serum, and some of them are due to inhibition at the level of the renal tubules. Mycophenolate, another commonly used antimetabolite, very important in cell cycle inhibition and prevention of cell cycle inhibition, and this agent can have multiple different drugs that can actually inhibit its activity. And most of the drugs that you can see here, outside of the antivirals, appear to reduce the efficacy of mycophenolate. Mainly through GI absorption. As you know, that’s a very important mechanism by which mycophenolate gets into the body when it’s taken orally, and many of the side effects of mycophenolate are gastrointestinally related, so as you can imagine, the GI system is very important in the way the drug is metabolized, and the viability of this drug is affected when you have other agents used concomitantly. Azathioprine, again, methyltransferase inhibition. This drug has increased amounts — the effects of azathioprine can be seen when allopurinol is utilized. ACE inhibitors — very commonly used. If you give this with azathioprine, you can see leukopenia or anemia — and I have seen this in patients who are chronically on azathioprine therapy and have hypertension. Cyclosporine and tacrolimus — drugs that use the P450 system can cause cyclosporine levels to be modulated. You can see the different agents. Any time you see antifungal agents like fluconazole come up very commonly, these agents tend to inhibit cytochrome P450, so they cause significant elevation of cyclosporine levels. This has appeared on board questions in the past. Fluconazole, ketoconazole, itraconazole, those increase the cyclosporine levels and increase the significance of toxicity and nephrotoxicity associated with the drug. Excuse me. I think I’ve got… I apologize. I had some audio that was mixed in here. Alkylating agents, cyclophosphamide, et cetera, a few drugs that they interact with. And tacrolimus can interact with rapamycin. We won’t go into the details of some of these. These are probably beyond the scope — because these agents are very rarely used. I can come back and answer specific questions about these drugs if you have them, but these are just informational slides, for the most part. You know, there’s drug interactions with biologics that are very different from chemical drugs, because biologics are high molecular weight molecules, they’re complex and heterogeneous, strongly dependent on manufacturing processes, and difficult to characterize in terms of how do they act, et cetera, in terms of — compared to how you characterize chemical drugs. And they may be very sensitive to external conditions, as opposed to a tablet that you take. Biologics have to be stored in a specific way, injected in a specific way, or given in a specific way orally. And they can be potently immunogenic in many cases. Whereas chemical drugs typically are not. And so these are obviously differences. And so when we talk about interaction of the biologics versus pharmaceutical agents, we have to think about a very different approach to these. And the route of administration, the absorption, the distribution, all of these are very different. And in fact, even the effect of the drugs, pharmacokinetically, may be very long in duration, when we use monoclonal antibodies, for example, compared to chemical medications. Although the biologics don’t appear to interfere with other systemically traditional pharmacotherapy, systemically administered traditional pharmacotherapy, these interactions are pretty underappreciated. I’m gonna go to the next question. And this will kind of segue into the main topic. And I’ll spend more time here discussing drugs and uveitis. This question is: Drug induced uveitis should be considered in which of the following scenarios? A, only if the uveitis is bilateral. B, only if other causes of uveitis have been ruled out. C, only if inflammation resolves upon drug discontinuation, and D, only if the inflammation recurs on rechallenge of the drug. So this is kind of a tough question. And I apologize for that. But my point in asking this question is that when we think about causality, when we think about: What is causing uveitis? It’s a very difficult question sometimes to answer. A laboratory test may be elevated or may be positive, for example, and we may say: Well, this is the possible cause. Probably what we mean to say is: This is the possible or probable association. But, you know, we have to combine what we see clinically and historically in the patient to ultimately make that diagnosis. For example, if somebody has a hypopyon uveitis and they’re HLAB27 positive, are we sure that that is the underlying cause of the hypopyon uveitis? We’ve of course ruled out the possibility of other causes of inflammation. So the point of this question is: Only if other causes of uveitis have been specifically ruled out… That is, we have done a uveitis workup on patients… Then we can come up with the diagnosis that perhaps this drug or drugs may be the underlying cause of the inflammatory disease. So causality is very important and very difficult, potentially, to determine, and so that is the reason that I put this question. So other causes of uveitis must be ruled out, before you can say: Oh, this is drug induced uveitis. A laboratory workup in uveitis patients is important, as well as a good history and physical, in order to determine what is the underlying cause. So drug induced uveitis is really kind of based on an accurate history and physical examination. It is a diagnosis of exclusion. That being said, many times the effect of the drug is known. It has been well described. And so we can make and jump and leap to that conclusion. Hey, this is what it is. We know for sure this is what it is. We probably don’t need to do as extensive a laboratory workup that we would otherwise. But we are faced sometimes with situations where this is a new drug. And this is an inflammation that we’re seeing. And we’re worried… Hey, is this drug induced or something else? There we’re going to do a much more extensive laboratory evaluation as well as a much more thorough physical, and ultimately make this diagnosis of drug induced uveitis by exclusion. Even commonly used drugs are not immunologically benign. This is my daughter who, unfortunately, a week before starting college, got a severe drug induced inflammatory reaction and serum sickness, as a result of minocycline exposure. She had developed severe transaminase elevation, high fevers, and this very severe rash. And she recovered, but required systemic corticosteroid therapy. And we were very concerned about her, obviously. She became very ill. Drug induced uveitis causation determination is based on multiple criteria. It is based on previous conclusive reports of this reaction. The adverse reaction appears when the drug was administered and improved when the drug was discontinued. This adverse reaction reappeared when the drug was readministered, and alternative causes other than the drug have been excluded. And the adverse reaction reappears… If the adverse reaction reappears with placebo, that tells you that maybe that’s not the cause. Toxic concentrations of the drug have been measured. That can help you. Adverse reaction was dose dependent. A dose escalation results in worsening of the reaction. That tells you also that this is a causality. And then finally, the last two, the adverse reaction to drugs in the same class, other drugs in the same class produce the same event. And then of course, you have objective evidence to show what these adverse events are. For example, the skin rash I showed you in the picture or the fevers or the transaminase elevation. These criteria were developed by Naranjo back in 1981. They’re extremely important toxicologic principles regarding drug induced uveitis. Let me go back for just a couple seconds. Do we know why drugs produce uveitis? We really don’t. Some mechanism such as direct toxicity may be playing a role. Because those toxicity changes induce an imbalance between interleukin 2 and interleukin 17, resulting in free radicals, cytokines, and inflammation. Sometimes the drug itself can induce vasculitis or lupus. For example, the original reports of quinidine and quinine derivatives associated with lupus, or even more recently, infliximab causing sarcoid-like inflammatory granulomatous inflammatory disease. This are some factors regarding drug induced uveitis that we don’t understand. Why is that some drugs only cause unilateral uveitis? For example, rifabutin or bisphosphonates, or immune checkpoint inhibitors? Why do some agents in the same class cause uveitis even with rechallenge? And others in the same class do not? For example, etanercept has a much greater risk of inducing de novo inflammation in the eye, versus adalimumab, which is much less likely to do so. Is causation definitive? How do we prove it? We won’t be able to unless we elucidate the mechanisms of drug induced uveitis. So causation is something we have to think hard about. We can say: Hey, this is likely the underlying cause, but we might have to back off in terms of saying definitively the cause. But how can we say… How can we help ourselves? By using those ten criteria. If we weight some of these criteria, that may help us, in terms of making sure that we have a definitive versus probable or possible causes. So this table was developed about five or six years ago, by a group of us, looking at those Naranjo criteria, and putting a weight on it. So, for example, some of these are weighted heavily. If there was a rechallenge and you get the same reaction, that’s very important, because it tells us… Yes, causation is likely. If the reaction occurred right after the drug was administered. But if alternative causes of the reaction were found, you’re less likely — you’re gonna actually detract from that number. And so we tally up all of this for each drug. And we come up with a number. And so that number or cumulative score, if you will, will determine whether or not there’s a definite likelihood, causal likelihood, a probable causal likelihood, possible, or doubtful causal likelihood. I hope that makes sense. And this slide does require a little bit of studying. And I’ll try to make this slide available to you guys, hopefully through Cybersight. And then we can… There are many systemic medications that are associated with the uveitis. That we’ll cover quickly. But some I want to spend a little bit more time on. And there are also intraocular medications that are associated with uveitis. Anti-VEGF agents, unpreserved triamcinolone, and of course topical medications such as brimonidine, propranolol, prostaglandin analogs, along with topical cutaneous medicines, associated with inflammation. And we’ll talk about a more controversial topic, drug induced uveitis with vaccinations. The first drug I want to talk about is systemic and intraocular cidofovir. It’s a selective inhibitor of viral DNA polymerase, originally developed for cytomegalovirus in the AIDS epidemic in the early 1990s. It has a long intracellular half-life, so it was advantageous to use and administer intravitreally and intravenously. Unfortunately, there was a significant risk, whether given systemically or intraocularly. This drug appeared to produce non-granulomatous anterior uveitis and hypotony. It also induced severe nephrotoxicity, and the risk factors appeared to be that in patients who were HIV positive, on protease inhibitors, treated for CMV retinitis, who had chronic and recurrent retinitis and immune recovery — those were at greater risk. And those who received intravitreal therapy of four or more injections appeared to be at greater risk. The side effects of this drug also appeared to be reduced by using oral probenecid. Which inhibits secretion of cidofovir from the ciliary body. So by using probenecid orally, the risk of uveitis and some of the other complications such as nephrotoxicity appeared to be decreased. But ultimately, the mechanism of hypotony and uveitis was not really very well known. The treatment could have been very frustrating, because we needed to use topical corticosteroids in the face of chronic retinitis in those days, before we had highly active retroviral therapy. It was quite difficult. And many times cidofovir had to be continued from saving the life of the patient because they had systemic CMV but sometimes we had to stop it. We had decreased intraocular pressures, and that made the drug very difficult. The next drug we’re going to talk about is rifabutin. I have a question for you. Rifabutin associated uveitis can be confused with which of the following uveitis entities? A, HLA B27 associated hypopyon uveitis, B, retinal vasculitis, C, necrotizing scleritis, and D, VKH syndrome? I’m asking these questions ahead of time to see how much you know so I can gauge the level of the talk by that. Let’s see what you guys got. Most of you got it. 42%. So the hypopyon anterior uveitis, often unilateral, was a characteristic finding of rifabutin induced uveitis. It’s a derivative of rifampin, used in immunocompromised patients, and it was characterized by hypopyon development. The eye looked relatively quiet. It wasn’t severely inflamed with fibrin. Relatively clean-looking hypopyon like you might see in Behcet’s. But most of these patients were using a high dose of rifabutin. This was a high dose response, and when the dose was lord from 600 milligrams to 300, it became much less likely, versus 30% of cases when they were at 600 milligrams per day. Usually it developed 6 months after initiation of the drug and there was rechallenge induced recurrence and reversibility with drug discontinuation. There are a few cases of other forms of uveitis, panuveitis, retinal vasculitis, intermediate uveitis reported, but by and large, hypopyon uveitis, very common. Here’s a picture that Dr. Sen from the NIH shared kindly with me, and here’s another picture of a hypopyon on one of my patients. The hypopyon can be small. Remember, unless you pull down that lower lid, you’re going to miss all hypopyons. And sometimes even putting a gonio lens on and looking in the inferior portion of the angle may be necessary, especially when you see a lot of cells in the anterior chamber, 3 to 4 plus inflammatory cells in the anterior chamber. Often mean that you’re going to have some kind of congregation of these cells in the inferior angle and the development of a small hypopyon. So don’t miss this. It’s embarrassing when you miss a hypopyon that’s small, just because the eye looked relatively quiet. So dosage and duration of use are important risk factors for rifabutin. There are other drugs. Because of the inhibition of cytochrome P450, and we touched on this earlier in drug induced side effects, but agents such as clarithromycin and ritonavir, often given in early portions of the AIDS era to treat infections and HIV disease appeared to inhibit the cytochrome P450 system and exacerbated the side effects of rifabutin. Intensive topical steroid therapy and reduction of dose appeared to be curative of inflammation without significant long-term side effects, thankfully. And these patients initially did get laboratory workup, including HLAB27 and antitreponemal IgG as part of the workup for the uveitis patient in this setting, and those are negative. And again, that establishes — helped establish more clearly — the underlying diagnosis of the drug induced uveitis. Sulfonamides are one of the oldest classes of systemic antibiotics, but they have been associated with a non-granulomatous anterior uveitis, first reported 30 years ago. And often bilateral, and the rechallenge — there was recurrence of inflammation at least in one report. So this achieved a fairly high score of causality. And the treatment is usually topical corticosteroids or medication discontinuation. A big player in drug induced uveitis: Do not ignore our bisphosphonates. These agents are used very commonly in those — particularly in women who are at higher risk for osteoporosis after menopause. So they’re very commonly used and more aggressively used nowadays, to prevent the osteoporosis and prevent pathologic fractures, caused by metastatic malignant disease. They’re typically very well tolerated. But let’s talk a little bit about the characteristics of bisphosphonate induced uveitis. Is it, A, more common with intravenously administered bisphosphonates? B, is it more commonly unilateral? C, is it more commonly a panuveitis? Or D, is it more commonly associated with non-nitrogen containing bisphosphonates? So yes. More commonly, it’s associated with intravenous bisphosphonate use. That’s correct. Some of these newer agents such as Prolia, these are given — zoledronic acid, for example, given IV, and Pamidronate, given IV, has been associated with a fairly high risk of ocular inflammatory disease. Excuse me. I’m gonna… Take a drink of water here. But all of these agents have been linked to ocular inflammatory disease. It is more commonly bilateral. Scleritis, when it occurs, can be unilateral. Episcleritis and even orbital inflammation has been reported. With intravenous pamidronate, more than 40 cases have been reported in the literature as of 2019, and it’s probably a little higher now. And we can see that anterior uveitis is probably the most common manifestation, and usually occurred within one to six days of infusion. And again, there was a dosage variation. So there wasn’t a specific dose dependence here. But there was recurrence with rechallenge of inflammation in most cases. This is a patient who had fairly severe scleritis, as well as — he’s got a little subconjunctival hemorrhage, unfortunately. I apologize for that. But this is a case of scleritis with significant pain, and she had mild anterior uveitis associated with zoledronic acid. The mechanism is thought to be a release of inflammatory cytokines, specifically from nitrogen containing bisphosphonates. Nitrogen containing bisphosphonates are more commonly associated with this inflammatory disease, as opposed to the non-nitrogen bisphosphonates. Nitrogenated bisphosphonates presumably are proinflammatory, from various mechanisms. They cause significant elevations of C-reactive protein and interleukin 1 and 6, and this results in immune dysregulation. And all of this has been previously reported in other conditions with anterior uveitis. Many of these patients will have a flu-like illness with the infusion and have infusion reactions as well. The therapy is sometimes requiring drug discontinuation, or switching to a different agent that does not contain nitrogen. Topical corticosteroids and occasionally oral non-steroidals can be utilized and in severe cases, oral corticosteroids may be needed as well, but usually this is self-limited, and the disease recovers once the drug is discontinued on the corticosteroid therapy. Fluoroquinolones have been associated with — I put uveitis in quotes here. Because it’s not really a typical uveitis. And it can be bilateral and occur with standard doses of medications. And it can develop within two weeks after drug initiation. There can be bilateral ocular pain and visual impairment. I’ll say that “uveitis” in quotes, because there’s more pigment disruption in the iris than there is actual inflammatory cell in these patients. We often will see some inflammatory cell when there’s this massive disruption of the iris pigment. And iris pigment loss. But oral fluoroquinolones have been associated with this. But moxifloxacin has been most commonly implicated. Interestingly, topical moxifloxacin has not been implicated. Intraocular moxifloxacin has been associated with inflammation, but not the kind of changes that we see with the systemic medications. And I’ll show you the signs here. There’s usually fine pigmented KPs seen, prominent pigment in the anterior chamber, and minimal non-pigmented cells and diffuse iris transillumination and atonic pupil appearance. 50% of patients actually develop ocular hypertension. So it could be confused even for herpetic disease. The treatment is usually drug discontinuation, and topical corticosteroids can be helpful early on, but unfortunately the iris damage can be permanent. Here’s a picture, a very nice picture, from Dr. Soukiasian, of anterior chamber pigment cells in this reaction. You can see that almost the small tobacco dust-type appearance of cells are the granules in the anterior chamber. Fluid. And then you can see this significant loss of pigmentation of the iris. This patient had a brown iris. And you can see these small clumps of pigment granules on the surface of the iris. Like freckles. Little tiny freckles on the surface of the iris. That’s typical appearance. And look at this on transillumination of the same iris. This is a beautiful slide, showing the loss of the posterior and superficial pigment epithelium from the iris, resulting in this atonic pupil, with significant transillumination defects. So it’s really kind of a pseudouveitis. It’s almost a phototoxicity kind of reaction. For those who have autoimmune predisposition, have other autoimmune diseases, may be more at risk for this, and these patients may more likely have HLAB27 or B51 haplotypes, and because this was found in 20% to 40% of patients who were tested, respectively, so there is some autoimmune association. It has not been described with either topical or intraocular injection of fluoroquinolones. I have seen vitritis from intraocular moxifloxacin injection and even anterior uveitis occurred following cataract surgery, because some of these proprietary medications, like Trimoxi, when there is triamcinolone injected with moxifloxacin, I have seen inflammatory reactions, and persistent inflammation following cataract surgery in some patients who have received that. Here’s another picture of systemic moxifloxacin associated iris transillumination. Next question I’m gonna jump over to are TNF alpha inhibitors. Which of the following TNF alpha inhibitors are associated with uveitis? Infliximab, adalimumab, etanercept, or all of the above? This is a little bit of a trick question. I mentioned the answer earlier. You got it. Excellent. So all of them have been associated with inflammation. But etanercept can cause de novo inflammatory disease. These TNF alpha inhibitors — TNF alpha is a proinflammatory cytokine. And in addition, this cytokine has been very effective in the treatment of a variety of inflammatory diseases, as you know. Most recently, adalimumab in the last few years has been FDA approved for the treatment of non-infectious intermediate posterior and panuveitis, and all of you are familiar probably with the visual one, two, and three clinical trial results from Abbott Pharmaceuticals. But three agents fall into this category. There’s a fourth agent, but infliximab, adalimumab, and etanercept have been most extensively studied. And etanercept is a soluble TNF alpha receptor, conjugated to the Fc region of human IgG and administered subcutaneously. Etanercept inhibits both TNF alpha and TNF beta. Whereas infliximab and adalimumab exclusively inhibits TNF alpha. The differences in mechanism of action of inhibition of TNF alpha versus TNF alpha and beta with etanercept may explain differences in their side effects. As you know, TNF alpha antagonists have been associated with lupus-like syndromes, demyelinating disease that mimics multiple sclerosis, autoimmune hepatitis, and interstitial lung disease. And uveitis has been associated as well. Usually uveitis develops one to twelve months after initiating therapy. It resolves after discontinuing the agent, and more than 10% were kind of paradoxical new onset intraocular inflammation after initiating therapy in the case of etanercept. For example, someone with rheumatoid arthritis, treated with etanercept — now, in rheumatoid arthritis, do we see iritis as a manifestation? No, we don’t typically see that. But etanercept, when given to RA patients, appears to induce this kind of inflammatory disease. There was some question of its effect. And the problem is that many of these uveitic cases required long-term therapy, courses of steroids, and other immunosuppressive agents besides the TNF alpha antagonists, we had to stop those, and there was a poor visual inflammatory control outcome in these cases. All three agents have been implicated, however. When you look at the national database registry, there have been nearly 60 cases of drug induced uveitis that have been reported, probably underreported, with these agents. Most of which are associated with etanercept. The second most common, however, is infliximab. That makes sense because it’s a Murine chimeric antibody, versus adalimumab, which is more fully humanized. There have been dechallenge and rechallenge data for some patients, so the association is fairly strong between these agents and uveitis. So anterior uveitis, periphlebitis, and chorioretinitis have been reported. And biopsy proven sarcoid has also been seen. I’ve seen this with adalimumab and infliximab, the sarcoid type of inflammatory disease. You often have to use systemic corticosteroids in the more severe cases of this kind of drug induced uveitis, to get rid of the inflammation. But there’s recovery once you stop the agent. Here’s a patient that was — examples of kind of a diffuse granulomatous KPs. And you can see this kind of sarcoid-like perivascular sheathing. And these vitreous snowball opacities and preretinal inflammatory opacities in the inferior periphery of the patient who has a sarcoid-like inflammatory response to etanercept. The mechanisms may be related. The inverse relationship between TNF alpha and interferon, and also interleukin 2, a proinflammatory cytokine. If interferon levels are high, due to TNF alpha inhibition, immune cell activation can occur, and autoantibody formation can occur, and immune complex deposition and autoimmune disease occur. And there’s a differential risk of uveitis between the various TNF alpha inhibitors, as I mentioned. So etanercept is likely to cause even de novo inflammation in patients who shouldn’t be prone to inflammation, but is more likely associated with uveitis than some of the other agents. Let me move on to the next thing. Immune checkpoint inhibitors. This is a really hot topic today, because we’re seeing a lot of patients getting cancer chemotherapy with these agents. Most commonly, these agents induce what kind of uveitis? Intermediate uveitis, panuveitis, anterior uveitis, or posterior uveitis? What is the most common type of uveitis that is seen with immune checkpoint inhibitors? This is more common sense, whether you know the information or not. Yeah. So anterior uveitis, although all of them have been reported, anterior uveitis by far accounts for close to 2/3 of the reported cases of uveitis associated with immune checkpoint inhibitors. Immune checkpoint inhibitors — they were developed when we realized that tumor cells evade the immune system, because they possess specific ligands. The so-called PD-L1 ligand, and the specific CTLA4 receptor, if you will, or antigen, that will bind to this CTLA4, that when bound inhibits T-cell activation and so by this method, these tumor cells were able to evade the immune system. So when the T-cell receptors, the CTLA4 molecule, CD28 molecule, bound to the B7 receptor on the antigen presenting cell, along with the specific major histocompatibility complex from an antigen presenting cell — when that binding occurs, the T-cell was inactivated. Now, in the case of tumor cells, they can do the same thing. They can kind of fake out, if you will, the immune system. By blocking the activation of the T-cell, by actually binding these T-cell receptors. So what we do with an inhibition of these… The CTLA4, or the PD1 or the PD-L1 ligand — by blocking that, we’re blocking that interaction, so we’re allowing the T-cells then to become active, and once they’re active, they become natural killer cells or T killer cells, and result in significant tumor cell death. And this is how we’ve been able to kind of modify how we treat metastatic melanoma, metastatic cutaneous melanoma, and other metastatic cancers, such as non-small cell lung cancer, et cetera. So these agents are ubiquitously used, and because they tend to prime the immune system, they tend to induce inflammation, because they prime activated T-cells in a broad, non-clonal sense, if you will. There are many agents in the immune checkpoint inhibitor category that have been associated with this. So this is a list of them. Ipilimumab, Pembrolizumab, and Nivolumab have been commonly used. Some of the newer agents, such as Cemiplimab, atezolizumab, and others have been associated with these reports. There’s a very high association of causality between these agents and uveitis. PDL — so pembrolizumab results in PD1 blockade. We talked about the mechanism briefly. You can go back and review my slides later if you wish. I don’t want to spend a lot of time regarding this. But when you bind the PD1 to the PDL1, this inhibits the cytotoxic cell of the activated T-cells. So when you inhibit this, that results in tumor cell death. The same goes for the CTLA4 checkpoint molecule that is present on the surface of activated T-cells. It negatively regulates T-cell proliferation. So it inhibits CTLA4 and upregulates T-cell proliferation. And again, used for metastatic cancers. So PD1 blockade is probably the more common mechanism of action among these agents. The Ipilimumab is the main CTLA4 inhibitor currently available. There’s also the PDL1 ligand. Antibodies that bind to that ligand and inhibit PDL1 interaction that way are also available, and these have also been associated with inflammatory disease, although inflammatory disease is a little bit more different there. It looks like a vasculitic process in the retina, as opposed to choroidal or uveal inflammation. There are many immune adverse reactions associated with immune checkpoint inhibitors. Specifically we know that hypophysitis was described as a classic response. But pneumonitis and colitis. By far, immune colitis is the most common adverse event that occurs with immune checkpoint inhibitor therapy. There is a significant kind of terminology that was developed for adverse event description. And anterior uveitis — there are grades of severity that you can see here, that was developed because of the number of adverse events reported in national database registries and drug registries about these agents over the last approximately 10 years or so. The immune-related events, as I mentioned, they’re numerous, but uveitis originally was thought to be about 1% of events. But probably it’s more like about 2%, because it’s somewhat underreported. And so far, we have about 94 cases, as of the February-March of 2020. The number of inflammatory events. That we see in association with these agents. Probably that number is closer to 100 or 110 at the end of this year. So there’s a fair number of cases that have been reported and well documented. Most cases have been caused by those first three agents, ipilimumab, nivolumab, and pembrolizumab. Some have involved with BRAF and MEK inhibitors, which I’ll touch on. And most of these were treated systemic corticosteroids. And about 40% were able to continue ICPI therapy. Remember, these agents are highly effective in tumor control, so we’re talking about life and death when we’re talking about stopping these agents. So in most of these cases of uveitis, the uveitis was managed independently of the immune checkpoint inhibitor continuation. So 60% we were able to continue therapy with the immune checkpoint inhibitors because it prolonged the life of the patient, and the quality of life improved when we treated the uveitis with local and/or regional or systemic corticosteroids. You can see here I tabulated — this took me a long time to do. But all of the cases — this is a very important piece of information for me. It shows the distribution of the uveitic cases. It’s interesting. Pembrolizumab, for example, had far more cases of panuveitis that were described, compared to anterior uveitis. Whereas Ipilimumab and Nivolumab were mainly anterior uveitis. What’s interesting to note is that many of these cases of uveitis in the panuveitis case look like Vogt-Koyanagi-Harada syndrome. These cases were more common in the metastatic melanoma cases that were being treated with the immune checkpoint inhibitors. We think the reason for that is that tumor lysis and cell death in melanoma results in proteins that are inherently immunogenic to activated T-cells. And as a result, that activation causes those locations of melanin that are normally hidden away from the immune system, if you will, or immunologically segregated, to be exposed, then, through the choroidal circulation, and those activated T-cells are plentiful enough that they go into the choroid, go into the uveal tract, through the blood flow, natural movement of the cells, and that results in the binding of those T-cells to the melanin associated proteins, and induce this VKH-like inflammatory disease process. Most cases develop within three months of starting therapy. Most cases were bilateral, almost always, and there was a rechallenge, which resulted in recurrence in many cases. Dose-response was not possible to determine, because these were typically fixed doses. Although frequency can be adjusted, and more frequent administration of the drugs resulted in more inflammatory reactions. And there were different drugs in the same group, in the immune checkpoint inhibitors. For example, patients who had a reaction to Pembrolizumab, if they switched to another agent, they got the disease. At least one patient who was on ipilimumab developed disease when switched to pembrolizumab. So this meets the definition of definitive causality here. This was a beautiful case — one of the first cases of nivolumab uveitis, where the patient developed cystoid macular edema. This patient developed panuveitis, disc edema, and almost a neuroretinitis picture, severe choroidal thickening, here’s one of my patients who developed the choroiditis panuveitis type picture. You can see even the vascular inflammation occurring in this agent, along with choroidal inflammation. Here’s a beautiful report of a VKH syndrome associated with Pembrolizumab, and you can see very dramatic appearance that looks clinically exactly like VKH. This is a bilateral case. Optic neuropathy has been associated. There’s also melanoma associated retinopathy in patients treated with metastatic cutaneous melanoma, along with immune checkpoint inhibitors. This is much more difficult to parse out and understand, because of the association and the nature of how these drugs work and the nature of metastatic cancer itself. There are other agents. BRAF and MEK inhibitors. These enable cell cycle proliferation, and they’ve been used in conjunction with immune checkpoint inhibitors. And they’ve also been associated with inflammation, although less commonly so. All of these agents can cause uveitis, alone or in combination with PD1 and CTLA4 inhibition. There have been cases of uveitis when the agents were used alone as well. So we know that these occur, but they’re not quite as — the data is not quite as robust, and the cases aren’t quite as common. But these are also agents that are used together, and so you need to keep these agents also in mind as causes of inflammation. The treatment is usually for the uveitis — is usually with topical, periocular, and systemic corticosteroid therapy. You do not need to discontinue immune checkpoint inhibitor therapy in most cases, unless the uveitis is extremely severe and sight threatening. There are also other agents, such as Erlotinib, an epidermal growth factor receptor tyrosine kinase inhibitor. There have been reports of bilateral anterior uveitis, a couple cases required drug cessation, but these were treated with local corticosteroid therapy. There are many other agents that are less associated with inflammatory disease. Diethylcarbamazine is a filaricidal agent, which can induce death of the filaria in the eye, which can induce this Mazzotti reaction. So many of these are from the death of the filaria rather than the drug itself. We use anti-VEGF agents, and preserved triamcinolone, both of which have been associated with inflammation as well. We don’t use preserved triamcinolone intraocularly anymore. There’s a black box warning associated with it. Pegaptanib, which we don’t use much anymore — it was the first of the anti-VEGF agents — this agent did produce inflammation. It was thought to be due to the preparation of the drug. We don’t use it. It’s kind of more of a historical interest. Ranibizumab, of course, Lucentis, is very commonly used for the treatment of diabetic retinopathy, as well as neovascular macular degeneration. And this has been associated with inflammation in 2% of treated eyes in the MARINA and ANCHOR trials, but uveitis appeared to be more common in some of the other studies. But these were a little less well controlled, and fewer patients involved. Bevacizumab has also been associated with inflammation, although less commonly so. In a little less than 1% of patients. So we think that it’s about 0.5%. Most of these are generally anterior segment inflammation with mild spillover vitritis, but occasionally they can be quite severe. Fibrin and hypopyon — it can look like a sterile endophthalmitis. In these cases, when we see inflammation like this develop after infection, we have to think about the possibility that it could be infectious. Especially if there’s fibrin and a hypopyon, I tend to treat these patients as an infectious endophthalmitis if they develop this reaction after treatment, rather than a sterile inflammatory process. But it’s a clinical impression that you have to have. If the patient got the injection and within three days presents with pain and vision loss, likely that’s an endophthalmitis. If the patient presents two or three weeks after an injection with anterior chamber inflammation, mild corneal edema, in those cases, I’m going to be more likely to think about the possibility that the drug is actually producing an immunologic reaction because the patient has autoantibodies or antibodies directed toward that specific drug. Again, anti-VEGF agent, the induced inflammation is relatively uncommon. But because we do so many injections now, millions of injections being done around the globe, we’re going to see these cases. You need to keep these in mind. Often we have to discontinue the agent, or switch to a different anti-VEGF agent, and we often treat these just with topical corticosteroids or cycloplegics. I’m gonna move on and talk a little bit about an important agent that has received a lot of press recently. That’s brolucizumab. Brolucizumab associated uveitis causes visual loss through which mechanism? A, occlusive retinal vasculitis, B, cystoid macular edema, C, exudative retinal detachment, or D, uveitic glaucoma. Okay. So occlusive vasculitis was the most commonly reported. The thing that was causing significant amount of vision loss in patients was occlusive vasculitis. That was present even in the milder cases, when wild field angiography was performed. Brolucizumab is a single chain antibody. The newest of the anti-VEGF agents. It has a very small molecular weight, and appeared to — in the HAWK and HARRIER trials for neovascular macular degeneration have significant efficacy and better than non-inferiority in terms of its effect, and non-inferiority when used every eight weeks after the initial first three monthly injections. Brolucizumab or Beovu has been associated with significant uveitis and uveitis-related complications, the most severe of which was occlusive retinal vasculitis and severe vision loss. We think the prevalence is probably closer to 3% or 4%, as opposed to 1%, because the reports appear to be increasing, as more of the drug is being used. The inflammation can be treated and managed with topical agents. Or systemic corticosteroids. But when occlusive retinal vasculitis and choroidal vasculitis occur, unfortunately in those cases vision loss can be permanent, and there have been patients with profound vision loss associated with this, one case of bilateral profound vision loss in a patient who received bilateral injections on the same day. So it’s a very, very important thing to kind of keep in mind. The morphology appears to be mainly anterior uveitis. But posterior uveitis and the combinations were not uncommon. And if you look at the totals, retinal vasculitis was reported in 85%, and occlusive vasculitis. So you have to really look at it with wide field angiography, when you see inflammation on brolucizumab. It can be quite severe and extend into the posterior segment like this, and result with profound vision loss. Even with an active neovascular lesion here on the OCT, you can see the dramatic vasculo-occlusive nature of the reaction. This is another severe vaso-occlusive — this involves the choroidal as well as the retinal vasculature. Profound vision loss in this patient. The visual outcomes can be quite severe. 6 to 7 lines when you have vision loss from this drug. So I’ve been quite cautious. I have a few patients that are tolerating the drug well. And the key to this, in my humble opinion, is you have to be very careful of the dosing. You don’t want to give any more than 0.05ccs of the drug. There may be a dose-related response. It’s not been proven. But I think that may be an issue here. There have been rechallenge data too. And I’ve seen someone referred to me who was rechallenged multiple times with brolucizumab, who developed a fairly severe inflammation with repeated reinjections. Triamcinolone acetonide, when it was preserved and injected in the eye, produced inflammation, but sometimes inflammation can be a sterile endophthalmitis like this. And was treated and improved with intensive topical corticosteroids. And/or periocular corticosteroids. But infectious endophthalmitis was suspected and empirically treated, based on whether or not there was pain and severe vision loss in some of these cases. But it probably was a toxic reaction to the drug and possibly to the vehicle, especially when we had preservatives. Now with preservative-free formulations such as Triesence, we’re not seeing so much endophthalmitis. Sometimes we see a pseudouveitis when the drug is deposited into the anterior chamber. That did not need to be treated. It went away with repositioning of the patient. Here are particles that you can see. I will spend a little bit of time on drug induced topical medications. I think we’re running very late. I apologize. But this is a very important topic that I thought I would share. If you want me to finish the rest of it, I can try to go more quickly. I know that we’re getting late. Let me know. Lawrence, you can chime in and let me know if I need to stop and answer questions. But I’ll spend a few more minutes on topical medications, before we kind of just briefly end on vaccine induced inflammation. Metipranolol is not very often used anymore. It’s a non-selective topical beta blocker for the treatment of glaucoma. It was associated with granulomatous anterior uveitis. Very strong data in association. Drug discontinuation, topical steroids were the key to treatment. But mechanism remains unknown. I’m gonna skip the next one. Brimonidine is a very important one. We use this very commonly. But this can be associated with granulomatous anterior uveitis associated with IOP elevation and often these patients have follicular conjunctivitis associated with brimonidine use. This reaction is almost universal, along with the uveitis, when you did see the uveitis, to help you make the diagnosis. Here’s a patient of mine that had bilateral brimonidine induced inflammation. We stopped the drug and put the patient on a weak topical steroid and the inflammation went away within a couple of weeks. This patient also had severe conjunctival follicular reaction to the drug and had chronic red eyes as well. So many of these patients will have this kind of presentation with brimonidine. So brimonidine is an important cause of granulomatous anterior uveitis that you need to keep in mind. Latanoprost, Travoprost, and Bimatoprost have been associated with changes in iris color, conjunctival hyperemia, growth of eyelashes, which we know about, it can cause the development of cystoid macular edema, and sometimes we’ve seen herpes viral keratitis with these agents. They cause breakdown of blood-aqueous barrier, and they can sometimes act like prostaglandins, but low concentrations are specifically designed to address this side effect, to avoid kind of excessive inflammatory response. But even with this, we do see mild amounts of anterior uveitis with this drug. Many patients… Many people have asked me about use of prostaglandins in uveitis patients. And uveitic glaucoma. As long as you have topical corticosteroid therapy, I don’t think that prostaglandins are necessarily a contraindication in patients who have chronic uveitis or uveitis associated with glaucoma. The concomitant use of some topical steroids, along with the prostaglandin analogs, often mitigate any prostaglandin analog associated inflammation. So they’re not a contraindication for the treatment of uveitic glaucoma. Drug discontinuation, if you saw significant inflammation or CME, maybe you considered it and you might want to use other antiglaucoma medications, and topical steroids and non-steroidals may be useful as an adjunctive treatment to the drug associated inflammation. Again, this is probably resulting from proinflammatory effects of the prostaglandin analogs. And increased production of IL-1 and IL-6, which appear to be present in the tear film of these patients who are using these medications. And that probably results in anterior chamber inflammation. I’ll skip the podophyllin and capsaicin. These are interesting things that have been reported with anterior uveitis. There’s modest data to suggest these are associated. Vaccines have been associated with uveitis. I want to ask you a question. Which of the following statements is true regarding vaccine associated uveitis? A, it often results in irreversible vision loss, B, it is recalcitrant to usual treatment modalities, C, it is so common that vaccinations should be abandoned, or D it is often mild and self-limited. This is the main point I want to take away with vaccine associated uveitis. We’re almost done with the lecture, guys. I’m sorry for the length and duration. And yes, exactly. So vaccines by far are far, far, far more beneficial than any associated side effects. These side effects that we see are more curiosities. Fortunately, in the vast majority of these diseases, mild and self-limited. You’re exactly right. So you guys already know this lecture. But we talked about this in a couple of recent editorials about the value of vaccines. Billions of vaccines are given around the globe. And only a handful of cases have been reported. So if you look at the total number of vaccine associated uveitis reports, about 300 cases have been reported so far. Through multiple database registries that we have. The most important database registry — I want to give a shoutout to Dr. Fraunfelder, who started this years ago, the national registry of drug induced ocular side effects, in Portland. You can see that the hepatitis B vaccine is the one that’s been most commonly associated, followed by the HPV vaccine, which was more recently introduced, followed by the influenza vaccine, which is given more commonly, and the BCG inoculation, vaccination, that’s given in certain parts of the world, has also been associated. Other ones that are less commonly associated — more commonly occurs in vaccine associated uveitis cases, more common in women and younger patients, and commonly occur within weeks of the vaccination, but can occur as late as two or three months after vaccine. The mechanisms remain unclear, but there may be molecular mimicry. Specific cell and antibody mediated hypersensitivity reaction, and there may be a couple of other mechanisms, such as the adjuvants — induced inflammation, because the adjuvants are an important part of vaccines, and more relevant to vaccines that only contain a part or component of the antigen. There is something called Shoenfeld syndrome that is associated with adjuvants, or the ASIA syndrome. This is a postvaccination phenomenon, probably the underlying pathogenesis for macrophage myofasciitis syndrome, a very rare syndrome, Gulf War syndrome, siliconosis, so many of these patients have an underlying condition and are more at risk of developing these conditions. Adjuvants include aluminum salts, et cetera. If someone has had prior exposure to antigens, it’s more likely that they’ll get inflammation. I won’t bore you with BCG vaccine. This has been used intravesicularly, for bladder cancers, as well as for tuberculosis around the world. It responds to topical steroids, there are rare cases of VKH syndrome associated with this. Hepatitis B vaccine, even though there are a lot of reported cases, there’s not a lot of robust information because rechallenge data is limited and the causation has not been clearly established. Same with influenza vaccine. Interestingly, recently, I’ve seen influenza vaccine associated with APMPPE and MEWDS. A couple of interesting cases of that. Varicella zoster vaccine. This is a controversial area. The Shingrix vaccine, the antigenic vaccine, has been replaced by the new Zostavax vaccine. Both of these have been associated with systemic inflammatory reactions, as well as local ocular inflammatory reactions that have been varied. The results have been some report of de novo development of necrotizing herpetic retinitis associated with some of these things. It’s a little bit of a dicey area when as a uveitis specialist, people ask me if I should get the zoster vaccine, I usually tell them that the Zostavax is safe and it’s highly unlikely they’re gonna get a problem from this. Patients do okay, but they have a poorer visual prognosis, and it can be a devastating illness, obviously. But those cases are so rare, I don’t think it’s a reason to avoid them. Even yellow fever vaccine has been associated with uveitis reports. But I wanted to kind of wrap things up, and say that drug interactions that we use in ophthalmology are common. And dose adjustments may be necessary. You need to make sure that you don’t use corticosteroids with non-steroidals, and then number two, drugs must be considered as an etiology in the evaluation of uveitis patients as a cause of the inflammation. You do this through a thorough history and physical examination, and laboratory testing, but history and physical examination may help you in delineating the cause of the inflammation, without having to do expensive laboratory tests. But when you’re not sure, laboratory testing is part of the laboratory workup — part of the workup of this patient. And often these types of inflammatory diseases can be cured, because you remove the offending agent, and institute corticosteroids and they get better. I appreciate your attention. I’m gonna see if I can answer some questions. I’m sorry that I went over. I knew it would be a long lecture. I’m gonna see if I can answer the questions here quickly. Can long-term topical moxifloxacin also cause iris changes and uveitis? Typically we find that it’s an idiosyncratic response. I don’t know that long-term there’s any data to suggest that long-term moxifloxacin — topical moxifloxacin absolutely has not been associated with any kinds of iris changes that we are aware of, based on reports. The next question is: In your experience, can vaccines, for instance measles mumps and rubella induce inflammatory reactions? I just showed you that it can. There have been reports of that. MMR vaccine has been associated with that. So the treatment is corticosteroids. Sometimes systemic corticosteroids may be necessary. How do you diagnose uveitis with a history if you have no slit lamp? Very difficult. Almost impossible. So a slit lamp exam — and I know many of you consult with me on the uveitis — so when you send me information, I really can’t say, because chronic uveitis, remember, doesn’t cause any symptoms. And so you may have a lot of inflammation and chronic changes, structurally, in the eye, but you can’t see it unless you look at them under the slit lamp with the microscope. Okay? And you have to dilate their pupil and look at the back of the eye. And so you need a really good slit lamp, in order to do a thorough ophthalmic examination. So uveitis… That’s why I can’t do telemedicine. In this COVID era. You know? We can’t make a diagnosis. Even acute anterior uveitis, unless you look at the slit lamp, and see cells in the anterior chamber, you can’t make that diagnosis. Just because the eye is red and they’re photophobic. Okay? So wear an N95 mask, have the patient wear a mask, and limit your exposure. But unfortunately, you have to look at them with the slit lamp to make the diagnosis. With a normal torch light, can we see and tell the condition of the iris? Unfortunately you’re not going to be able to tell, unless the patient has severe chronic disease and posterior synechiae and the pupil doesn’t dilate. You’re not gonna be able to tell whether there’s anterior chamber cell or flare. You need a slit lamp in order to examine the patient for uveitis. In your experience can a vaccine such as MMR induce neuroretinitis? I think yes. Our patient developed JIA. Parent suggested it was after vaccination. You know, this is where you, as a specialist, then need to kind of sort out what came first. The chicken or the egg. Vaccinations for MMR are very common. Uveitis induced from that is very uncommon. And then you have JIA, which is probably more common than the vaccine associated inflammatory disease processes. Okay? So there are specific types of inflammatory changes that occur from vaccines, but these reports are very narrow. Very small numbers. Whereas we have lots of information about chronic anterior uveitis that occurs in JIA, particularly pauciarticular JIA. So history, physical, and then if the patient is… If the young girl with inflammation in both eyes that’s chronic and asymptomatic at presentation — then you know that it’s more likely going to be JIA associated inflammatory disease, as opposed to the vaccination. And being vaccinated as a child against mumps, measles, and rubella is going to save her life. Okay? So the JIA is most likely the cause of the inflammation. What is the difference between infectious endophthalmitis and immune endophthalmitis? So this is an excellent point. Infectious endophthalmitis, as I mentioned, in my experience, presents more than two days — two or more days, excuse me, after an intravitreal anti-VEGF injection, and is associated with pain and severe vision loss. They often have fibrin and hypopyon in the anterior chamber. Those patients need vitrectomy, vitreous tap, injection with intravitreal antibiotics, and that’s how you make that diagnosis. Now, if the patient presents with milder inflammation that occurs weeks, two weeks, two to three weeks after an intravitreal anti-VEGF injection, that is an inflammatory reaction. Okay? That is more likely not an endophthalmitis. However, you have to use your clinical gestalt to make the diagnosis. And again, if you suspect endophthalmitis, you’re much better off to tap and inject that patient than to leave that patient alone and not treat it. Because then you have irreversible vision loss. How to differentiate sterile… Okay. The next one is: Does brimonidine cause intraocular pressure to be elevated? So brimonidine associated inflammation, when it occurs, the granulomatous uveitis, almost always is associated with elevated intraocular pressure. And almost always has concomitant follicular conjunctivitis associated with it. Okay? So pilocarpine causes inflammation too. Yes, it can. I didn’t cover that. But pilocarpine also has a proinflammatory effect. It can exacerbate inflammation. So we typically avoid pilocarpine in uveitis patients. And it can also have profoundly negative effects on uveoscleral outflow. So we tend to avoid it in patients who have chronic uveitis anyway. But I have seen a breakdown of blood-aqueous barrier and increased cell and flare on patients on pilocarpine, occasionally. Can moxifloxacin induce BADI and BAIT? I’m not sure what those… I’m sorry. I’m not sure what those acronyms stand for. I apologize. Can COVID infection result in irreversible visual loss or amaurosis and how? Okay. So COVID infection, in my experience, causes vision loss mainly through chronic ventilator induced keratopathy. The patient is face down on a ventilator for two weeks or more. Without appropriate corneal protection. And they can get severe keratopathy. That is the most common cause of vision loss. And I have had several patients who have had that, over the course of the last seven months. Now, the other things that are not reported are in the vasculitic nature. So there have been reports of post-COVID associated vasculitic changes. Immune vasculitis changes. Specifically involving the coronary arteries in children. And there may be a vasculitic condition affecting the cerebral vasculature as well, in patients who have had COVID. I am not an expert in this area. So I have to… But I have not seen it affect the retina, specifically. I have one patient who has COVID induced uveitis, I think. Had. And she had perivascular inflammation, which is probably commonly associated with those RNA viruses. But I cannot prove it. Because no lab was willing to do aqueous sample evaluation for the COVID-19 virus, because they had no standardization of that PCR… The reverse transcriptase PCR assay. You had a slide that listed topical steroids as possible causation. However, this is often used as treatment. Can you clarify? I think that the issue here is… In the 1960s, a couple of reports of African American patients who received topical corticosteroids, who then got inflammation on topical corticosteroids. But the reports were muddled. The reports were muddled by the fact that many of those patients were found later to have syphilis. And syphilitic uveitis. So editorially, I had to include that in one of the papers that I wrote about 25 years ago. But I had some concerns about including that slide. So the causation is kind of… Moderate. But some people who originally used the formulations of corticosteroids that were made in the 1960s also thought that vehicular induced inflammatory disease may have played a role. I don’t know. And I have not seen anything like it, with modern topical corticosteroids. So I wouldn’t worry about that. So that’s my clarification. Do COVID-19 vaccines have any uveitic side effects? I have not seen the released data, because I don’t know that that data will be released yet. From the phase 3 clinical studies, from the three companies that have currently usable vaccines in phase 3 clinical trials. Pfizer, Moderna, et cetera. I have not seen their data. I suspect that there may be some reports, but again, we have so many patients affected that the… I can’t emphasize this enough. Vaccinations have provided more for this world than any side effects that they’ve induced. Okay? It is incredibly essential that we get on board with COVID-19 vaccines. So we can get our lives back to normal. How do you treat recurrent CMV anterior uveitis? CMV anterior uveitis was described originally in Singapore, and in the Far East, with anterior chamber paracentesis. It has two presentations. One is an acute hypertensive uveitis that mimics the old Posner-Schlossman syndrome, and another one that mimics the more common chronic Fuchs uveitic syndrome appearance. The treatment is difficult. Topical Zirgan gel can be utilized in some cases. Oral valacyclovir can be utilized, but it is very expensive and extremely myelosuppressive and cytotoxic. So it is a difficult inflammatory disease to treat. Most patients respond to low doses of topical steroids alone. So I often manage them with that, and occasionally when they flare up, with topical Zirgan. Oral acyclovir and oral valacyclovir are probably not as helpful as valganciclovir — if I said valacyclovir, I meant valganciclovir. Oral valganciclovir is cytotoxic and myelosuppressive, profoundly so, and has to be used carefully. Vancomycin intraocularly has been associated with a hemorrhagic vasculitis. It’s more of a direct drug toxicity than an immunologic phenomenon, because it occurs immediately after drug instillation in the eye. So intravitreal injection of vancomycin should be done very carefully, 1 milligram in 0.1cc is the maximum tolerable dose and concentration of drug. Does topical corticosteroid cause uveitis? I think — modern corticosteroids don’t. Bottom line is, I wouldn’t worry about that. What is your approach treating vaccine associated uveitis and what kind of uveitis to expect? Anterior uveitis is the most common, typically I use topical and oral corticosteroids. Typically they improve very quickly. Intracameral adrenaline? When you inject things in the eye, that can cause cell and flare. Remember, when you inject something in the eye, you’re violating the blood-aqueous barrier immediately. Even that can cause a few cells to come into the anterior chamber. And this is a direct mechanism with intraocular adrenaline. So how long after vaccination should we see uveitic changes? Typically two or more weeks afterwards. Finally, how you treat recurrent… Topical antivirus… Econopred… Yes, topical Zirgan gel, which is a topical ganciclovir gel, or topical prednisolone drops… Yes. In advanced glaucoma treated with brimonidine… How do I… So there’s a question about glaucoma and uveitis. In advanced glaucoma, you’re going to have to stop the drug and see how the inflammation responds. And use a very low… Use a topical steroid that will not cause pressure elevation, such as loteprednol, Lotemax, or fluorometholone may be utilized. Somebody says… I’m pro vaccines, but patient has a sibling and the parents are not quite sure if they should vaccinate or not the other child. You have to talk to them and come up with a consensus decision. I wish I had a crystal ball, but I don’t know the answer to that. I suspect the value of the vaccine is far greater than the potential risk that it will have some immunological side effects. For immune endophthalmitis, do you still do anterior chamber tap? If it’s immune and you think it’s non-infectious, I would follow them closely, put them on topical steroids, and see them daily until you see where it’s going. If you think it’s not infectious. I would use topical prednisolone or Durezol very frequently, like every hour or every two hours, and monitor them closely to see what they do. How long to discontinue the uveitis for brimonidine? You have to keep them off for about a month before the inflammation goes away. For uveitis associated with CME, we use anti-VEGF, so if the patient develops uveitis due to anti-VEGF, how can we differentiate between the primary uveitis and the anti-VEGF? Uveitis with anti-VEGF therapy — in cases where I’m using anti-VEGF for the treatment of CME in uveitic cases, number one, I typically don’t. Okay? I don’t do that. Number two, I think that if you use anti-VEGF therapy, often the CME is recalcitrant, whereas the inflammation is well controlled. So if you have well controlled… No anterior chamber cell and no significant vitreous cell, and you have CME and you give an anti-VEGF agent and subsequently two weeks later, they develop inflammation, that might give you a clue. These are clinical questions that are very difficult to parse out sometimes. So you’re asking a very good question. That I don’t think there’s a definitive answer to. I think the best thing is, if you suspect it, avoid the drug and see if you can manage it in different ways. Manage the CME and uveitis in the traditional methods. Can paracentral acute middle maculopathy be linked to COVID? I think in this situation… I don’t know. I think that you can certainly see vasculitic… Secondary vasculitic changes related to this. To post-COVID syndrome. I think it’s possible. The reports have not come out. There have been cases of cotton wool spots and other types of vascular changes that occur in COVID infection. The Brazilian group has reported that probably most extensively in hospitalized patients, having retinal evaluation who did show that they developed cotton wool spots and PAMM-like lesions, so I know that’s been reported. Okay. What is the best treatment for anterior uveitis in children? Chronic antiuveitis immunosuppressive therapy, topical corticosteroids, and the help of a pediatric rheumatologist. Without going into greater detail, that’s a big question. To what extent do laboratory testing and uveitis… What do you use aqueous and vitreous humor testing… Yes, the answer to laboratory testing — drug induced uveitis is a diagnosis of exclusion. History and physical examination and a detailed drug history for the patient will tell you the answer, most of the time. Okay? However, in cases where you can’t sort it out, a laboratory evaluation should include the ability to rule out three important causes of inflammation: One, tuberculosis, two, syphilis, and three, sarcoidosis. Those are the most common causes of uveitis that we need to rule out. So I would check for those things. So you get a treponemal-specific test such as antitreponemal IgG, you would do a quantiferon PPD skin test, and you would do a chest x-ray and serologic testing for sarcoid, along with serum calcium. Those can be helpful to you, to evaluate. If you think that the patient has unilateral hypertensive uveitis with corneal changes and you think it’s herpetic disease, I would do an anterior chamber paracentesis with PCR, vitreous testing — vitreous cytology testing, and vitreous sampling for PCR should be reserved for viral retinitis, toxoplasmosis, and other conditions where you don’t have a definitive diagnosis and the patient is worsening on traditional therapy. Can topical steroids and NSAIDs for eye treatment associated with steroid cause uveitis? Can topical treatment with NSAIDs for eye treatment associated with… Not in my experience. I think NSAIDs can cause significant corneal — topical NSAIDs can cause significant corneal toxicity. I have seen that. But not anterior uveitis. Can topical cyclosporine be used for drug induced uveitis? I have no experience with it. Topical cyclosporine comes usually in an oil emulsion. Topical Restasis, for example. 2% topical cyclosporine solution. I have very little experience with it. It tends to be quite irritating to the ocular surface when it’s in higher concentrations. I don’t know that it has any great benefit in the treatment of anterior uveitis. Combining topical treatment for… Eye pathology? I’m sorry. I don’t know what the previous… I forgot the previous question about combining… Moxifloxacin is used as one of the COVID treatments in pulmonary infections. What does it mean, long time use of moxifloxacin, more than a week? I use moxifloxacin orally for a couple of weeks in some patients for infectious conditions, two weeks, three weeks. I think it is okay. But when it’s combined with corticosteroids, it may increase the risk of tendon rupture. It can also be associated with that ocular response with pigment loss that I told you about. It’s just something they need to be monitored for. Those responses, Dr. Tandili, are pretty uncommon, but I think just monitoring and making the patients aware. Which drugs can cause acute angle closure like anterior uveitis? The classic ones that have been associated are the antimigraine medications. I’m blanking on it. I didn’t talk about these medications. It’s an excellent point here. But there are a couple of drugs that have been associated with forward rotation of the ciliary body, choroidal effusions, and angle closure. And I’m sorry… You caught me offguard. It’s a migraine drug. I can’t believe I’m not remembering it. But… I’ll have to get back to you on that. I’m sorry. I’m embarrassed. I should know this. I always ask the patient about this drug, and I’m blanking on the name. But… Anyway, I appreciate all your… Yeah, topiramate. Thank you, Vijaya. That’s the drug. Topamax. We call it Topamax here. But topiramate. Thank you so much. You guys are extremely good. Thank you so much for your participation. It’s a real pleasure. I really enjoyed this. I hope that you learned a little bit, and I know I learned that I shouldn’t forget topiramate. So have a great week. I hope you all stay safe and healthy, and have a good day. Good evening. Bye-bye.