This lecture reviews how to approach the diagnostic work up of a uveitis patent based on clinical history and presentation, pattern recognition, and laboratory work up. Cases will be presented with didactic material.

Lecturer: Dr. Ramana Moorthy

Transcript

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DR RAMANA MOORTHY: This is Dr. Ramana Moorthy. I wanted to thank Orbis for giving me the opportunity to talk to you today about the treatment of uveitis. Let me share my slides with you, and we can start. The program today will really focus on basically the treatment of noninfectious uveitis. But I will say a few words on infectious uveitis, because there are several questions that I’ve already gotten about uveitis. You know, the key here is, of course, when we start treatment of inflammatory disease, we have to know the underlying cause. We have to make sure that it’s noninfectious. And how do we know that? Sometimes we don’t. Sometimes we take chances, because we have done testing to rule out the most common inflammatory causes — infectious causes, excuse me — of inflammation. And these include syphilis, tuberculosis, in some selected cases we may rule out Bartonellosis, we may rule out the other pathogens, such as bacterial or fungal or viral pathogens, viral uveitis, based on the clinical appearances, as we discussed in the lecture two weeks ago. Once we have effectively ruled out those causes, then the treatment of noninfectious uveitis can really begin full force. But until then, it is probably of little risk to start treatment of inflammatory disease at least with strong or potent topical steroidal medications, before we consider more aggressive steroid therapy, because we don’t know what the inflammatory disease may be. In posterior uveitis, that presents a bigger conundrum or dilemma. So if there is an infectious component to the inflammatory disease, we have to make sure that we have to control that infectious component first, and start the patient on antimicrobials, and then begin corticosteroid therapy aggressively. Without appropriate antimicrobial therapy, infectious uveitis gets worse. The paradigm, the treatment of noninfectious uveitis, is to basically control the inflammation. Control cells in the anterior chamber, control vitreous cells, and hopefully as a result of doing that, you can eliminate the risk of vision loss from structural and functional complications resulting from that inflammation. So you have to consider that specific diagnosis. Consider if there is any other underlying systemic disease. Does the patient have juvenile idiopathic arthritis? Do they have a systemic vasculitis that is causing their necrotizing scleritis? These kinds of things will make a big difference in terms of the choice of agents and your approach to the treatment. You also look at the patient’s existing level of ocular function. Obviously if the patient is 20/20 with no other symptoms and chronic uveitis with no structural damage to the eye, how you treat the patient is going to be milder and not as aggressive as a patient who has significant vision loss, structural complications such as cystoid macular edema and vitreal inflammation. Now, there are some exceptions to those generalized rules. For example, children may present with excellent vision with JIA associated uveitis, white, quiet eyes, but the anterior segment may show 2+ cells and they may have severe structural complications with 20/20 vision. So chronic disease can be much more difficult to control. Not only because it’s difficult to control to begin with, but because it’s hard to convince the patient — hey, you have problems, and we need to take care of this, before you get into more trouble with complications from the inflammation. The initial goal of any therapy, especially for acute disease, is to control inflammation rapidly. But the same goes for chronic disease. So how do you do that? Corticosteroids are the most effective agents, with a few exceptions. Those exceptions probably include cases where you have explosive onset, ocular Behcet’s disease. In those case, we use infliximab, directed against tumor necrosis alpha. Fortunately this is widely available in Western Europe and the United States, and in some portions of East Asia, it may be much more difficult to obtain and in Sub-Saharan African countries. But these agents, such as infliximab, have their own niche role to play, and they can be effective agents even for more recalcitrant disease. But corticosteroids are typically used topically, regionally, and systemically. The multicenter uveitis steroid treatment trial, or MUST trial, is an important trial to remember, because this showed the effectiveness of corticosteroids, specifically the corticosteroid implant. At 50 months follow-up, the most recent publication, it was clear that there are some specific advantages and disadvantages to both the systemic therapy, as well as the local therapy. And it turned out that the main advantage to local therapy was fewer systemic side effects, but both appeared to have equal efficacy, in terms of maintaining vision, and controlling inflammation. The Retisert implant, used for the treatment of uveitis in many places, is extremely expensive to buy out of pocket. It costs $15,000 to $18,000 in the United States to obtain this implant. But it lasts for three years. It’s very effective in controlling inflammation. But 40% of patients who get this implant get glaucoma. Everybody gets a cataract who has it. So you’re guaranteeing that patient that they will have at least one surgery — maybe 1.4 surgeries in their future, while they have this implant. So this is something to consider in patients who have uveitis. Remember, these kinds of surgical interventions can be very difficult. Sometimes mild scleritis or episcleritis can be treated with nonsteroidal antiinflammatory agents. We’re not gonna spend much time on those today. But there are some conditions where steroid sparing immunosuppressive therapy in noninfectious uveitis should be considered very early. Behcet’s disease, in the posterior segment especially, sympathetic ophthalmia, necrotizing scleritis, and serpiginous choroidopathy, and of course birdshot chorioretinopathy, juvenile — these are all the usual suspects for steroid sparing immunosuppressive therapy. When we start patients on steroids, we start at high doses and taper very gradually. One of the questions I had at the meeting was how do you taper the steroids once the inflammation is controlled? The key is to get the inflammation controlled at high doses. And for example — I’ll talk about anterior uveitis as an example. If somebody has 3+ cells on presentation in the anterior chamber, you start them on every hour prednisolone acetate drops. Or you start them on every two hour Durezol or difluprednate drops and get the inflammation rapidly controlled. The next step would be, over the course of the next two weeks, use that very frequent interval, and every two weeks, decrease the dosing based on the response. Generally when we use steroids so frequently, we get rapid control of the anterior segment inflammation, and then we can start tapering the medication. But the key is to do a slow taper. And start tapering once you have the inflammation controlled, at the highest dose possible. And that may sound aggressive. But you need to be aggressive in acute disease to control it rapidly, and then begin taper. And taper, even for acute uveitis, most acute anterior uveitis cases last 8 to 12 weeks. If you’re tapering patients off of steroids in less than that, you’re probably undertreating the vast majority of those patients, and the risk of developing recurrences in chronic disease is significant. And as you taper the medications, you’re going to keep in mind the complications of topical steroids, if you’re overutilizing them. Intraocular pressure elevation and glaucoma. In the case of systemic steroids, we have other considerations that we have to consider. Like bone loss, when we’re using chronic low doses of oral prednisone, we have the issue of bone loss or calcium loss from bone and thinning of bones, osteopenia and osteoporosis development is one complication. But there are myriad systemic associations with systemic steroids, which I’ll talk about in a moment. If the control isn’t achieved with initial therapy, second line therapy is usually transitioned to fairly quickly. And it’s used when chronic disease cannot be controlled by a safe dose of corticosteroids. If somebody still has active inflammation and they’re religiously using prednisolone drops every hour and they’re on 60 milligrams of prednisone, and after six weeks of therapy, they still have significant inflammation, we have to be very cautious of how aggressive we are at that point to control inflammation. The possibilities here include that you’ve made the wrong diagnosis and you have an inflammatory condition, that you don’t have appropriately diagnosed, which is probably unlikely, but more than likely you have a very severe inflammatory condition that is just not responding to a corticosteroid therapy alone. So in these cases, you’re going to be looking especially for long-term use of steroid-sparing agents. There are multiple drug classes that we’ll talk about, and the selection of agent is really empiric, in my opinion, although there are certain considerations, such as systemic disease, that will help you make the final choice. The antimetabolites, such as methotrexate, azathioprine, and mycophenolate, are the most commonly used agents, and then the calcineurin inhibitors are also utilized. Alkylating agents are reserved for the worst diseases, and of course, the biological response modifiers are finding an increasing role, especially with the recent FDA approval in the United States, of adalimumab, or Humira, for the treatment of non-infectious posterior and pan-uveitis. Beyond second line therapy, sometimes we use combination therapy. Occasionally surgical interventions, such as a pars plana vitrectomy, in patients who have severe vitritis that is unresponsive. In women of child bearing age and of course men who are interested in having children — we have to consider specifically the issues of sterility in men and of course the potential risk to the fetus in pregnancy. And this may also alter our choice of agents. Vaccinations in patients who are under immunosuppressive therapy we have to be cautious about as well. We should avoid live virus vaccine in anybody who is receiving anti-TNF therapy, and I would do this in any patient receiving immunomodulatory therapy. Any vaccine made with live virus. We’ll start now with talking initially about topical cycloplegics, which I think are overlooked. This may sound like a mundane topic, but any time I see patients who have anterior chamber involvement, I will use cycloplegics. If there’s mild cellular inflammation, I generally use something that is mild mydriatic cycloplegic agents. However, if the inflammation is very severe, with fibrin, hypopyon development, and the patient already has fairly dense fibrinous synechiae formation, we need to lyse those, so I will put them on 1% atropine drops, or hyoscine is also an option. In addition to that, in the office, use a cotton-tipped applicator soaked with topical phenylephrine, 2.5%, 1% mydriacyl, 1% cyclogyl, and place it at the edge of the limbus, where the synechiae are, to break them. If they’re fibrotic and chronic and have been there for years, they’re not gonna break for you. But those associated with acute disease will, and they need to be treated aggressively. If somebody is allergic to these, we don’t use these medications, obviously. And we also check the angle depth to make sure that the patient is not going to develop angle closure as a result of the use of these agents. The dose is adjusted according to the desired duration effect, and also based on how severe the inflammation is. And these medications are listed in order of duration of activity here. Atropine lasts the longest. Can last up to two weeks, once you give a drop. As can scopolamine. Cyclopentolate lasts about 24 hours or so. tropicamide about 12 hours. You have to monitor the pupil size, and when you’re monitoring the effectiveness of these patients, you have to look at the anterior segment. Look at the synechiae. Document exactly where they are in clock hours, or by drawing, and follow them. Sometimes you can see creeping synechiae formation and you may not recognize that the disease is not well controlled. You may think that it is, and it’s not. And you’re seeing progressive synechiae formation, indicating that there’s ongoing chronic inflammation. There are complications from cycloplegics. Psychosis, especially from atropine, is more common in pediatric agents and the elderly. Tachycardia, fever — muscarinic side effects, that are more common especially with atropine or hyoscine, the scopolamine. They can cause blurry vision. Reading glass may be necessary. And sometimes we give atropine to dilate the pupil, but their inflammation is not well controlled and they develop synechiae, and the pupil is left stuck wide open. In order to avoid that, once you get the severe inflammation well controlled on atropine, I switch the patients over when they have milder anterior segment inflammation. To something like cyclogyl. That’s rarely an issue, but it can happen. Corticosteroids are the mainstay for the treatment of noninfectious ocular inflammatory disease, but they’re also indicated after the infection has been treated, as I mentioned earlier. Especially when there’s an inflammatory component to the infectious disease, treat the infection first, and 24 to 48 hours after the initiation of systemic or local antibiotic therapy, you can start corticosteroid therapy. You should not use corticosteroids alone for the treatment of infectious uveitis ever. There was a question about toxoplasmosis treatment, et cetera. I will kind of mention in passing the treatment of infectious conditions, but let me just say here for the record, there are two questions. One was on toxoplasmosis treatment. Toxoplasma, retinochoroiditis — I usually will still rely on the classic triad, triple therapy, of using sulfadiazine, oral pyrimethamine, and oral prednisone. Now, pyrimethamine has had significant controversy in the United States, because of a lone pharmaceutical company buying up the rights to distribute the medication, and charging exorbitant amounts of money. If pyrimethamine is not readily available, other options can include clindamycin. Usually I will use these agents — and another option could be azathioprine, 250 milligrams, BID, to 500 milligrams a day. That could be used as well, along with corticosteroids, once the antitoxoplasma medication is started. The treatment is usually given for a 6 to 8-week period. We also use intravitreal clindamycin. That can be effective method of treatment, between 300 to 500 micrograms and a 10th of a CC intravitreally could be utilized. And the other question was on cat scratch disease. Forgive me for digressing. I just want to get these questions out of the way. I usually will use doxycycline at 100 milligrams BID, and I will treat usually between 4 and 6 weeks in duration. Sometimes I use corticosteroids a few days after starting the oral antibiotic. So let’s move on here. There are contraindications for the corticosteroids, as I mentioned. Mainly infection. So treat the infection first and then start corticosteroids. People who have existing peptic ulcers or erosive gastritis. Poorly controlled diabetic, definitely contraindication for corticosteroids. And elevation of intraocular pressure just means that you have to monitor those patients very carefully, because corticosteroids obviously will cause intraocular pressure elevation. The paradigm treatment that I want to really kind of stress here is to start at high doses, with frequent interval dosing of topical steroids initially, every hour, and gradually taper when you’re dealing with anterior uveitis. Anterior uveitis is the most common thing by far that the general practitioner is going to see in their day-to-day practice. For intermediate and panuveitis, posterior uveitis, in those cases you’re going to have to use periocular, intraocular corticosteroids, or systemic corticosteroids, depending on the nature of the inflammatory disease process. And patient factors. And if you do oral corticosteroids, you need to use prednisone at about a milligram per kilogram per day, usually that means 60 to 80 milligrams daily of prednisone, tapered gradually over a period of — minimum of 6 to 12 weeks, with a maintenance regimen, hopefully, of less than 10 milligrams a day of prednisone. Prednisone is our equivalent to corticosteroids that we use in the United States. Prednisolone acetate is usually started hourly, when we treat anterior segment inflammation, and tapered every two weeks, by basically half. I go every one hour for two weeks, every two hours for two weeks, every three hours for two weeks. Very, very gradually. I usually take my time. In HLA-B27 associated uveitis — most episodes last 8 to 12 weeks. Some longer, especially in severe cases. If you’re tapering the patient off of steroids too quickly, you’re going to guarantee that the patient is going to get chronic disease, and that is going to be very difficult to control. So I urge my residents in our university here and in my practice to use steroids aggressively, early on, if it’s a noninfectious uveitis, and taper gradually. You don’t want to start prednisolone four times daily and then try to catch up and increase, because it’s not responding. You want to start high. Hourly drops and then gradually taper. Durezol, or difluprednate, is twice as potent as prednisolone. And appears to penetrate not only the anterior chamber, but the anterior vitreous. So in mild cases of uveitis where the patient has good vision and mild vitritis, those patients can be managed by difluprednate, but it does carry with it a substantial risk of intraocular pressure elevation. Around half of patients who are on it, especially children, intraocular pressure elevation can be quite severe on difluprednate. And that can happen any time. On initiation of therapy, or even a year afterwards. Be aware of that. Taper these slowly, and start systemic corticosteroid therapy only 48 hours after appropriate antimicrobial therapy for infectious conditions. The most common that we use are difluprednate and prednisolone. I use fluorometholone because it’s a potent steroid and at low concentrations is almost as effective as prednisolone acetate, but tends to be a little bit more friendly, in terms of intraocular pressure elevation. It does not cause as much intraocular pressure elevation as difluprednate, certainly, and probably less than prednisolone as well. I don’t use topical dexamethasone very much. And loteprednol, Lotemax, and rimexolone I don’t use at all. Periocular corticosteroids — I usually use triamcinolone. A longer duration corticosteroid, about 20 to 40 milligrams, usually. 20 milligrams in pediatric patients and about 40 milligrams in adult patients. These I often repeat every 2 to 3 weeks or so. And these can be given multiple times, around each eye, depending on the response to inflammation, and on whether the patient develops intraocular pressure elevation. If you give sub-Tenons, it can be very difficult to manage, because those patients may end up needing surgery for glaucoma. Because it’s very difficult to go back and remove the corticosteroids. I’ve done that before. Gone and done a tenon-ectomy and removed the corticosteroids, to reduce the steroid response. That’s a desperate measure. Often these patients go on to see a glaucoma specialist and undergo appropriate glaucoma management. Intraocular steroids — I use preservative-free triamcinolone. But smaller doses can be utilized with fairly effective treatment. Of course, we can give intraocular antibiotics and VEGF inhibitors as well, along with corticosteroids, as I alluded to, with toxoplasma therapy. I will usually give — in case of toxoplasmosis — I will not use triamcinolone, because it’s a long acting steroid. I’ll use clindamycin intravitreally and usually dexamethasone. It’s a short acting agent. I’ll avoid triamcinolone in cases of infectious posterior uveitis, because intravitreal triamcinolone can make things much worse. You can have uncontrolled infectious disease, where you can have severe necrotizing retinitis developing. And also the same goes for viral necrotizing herpetic retinitis. Avoid using intravitreal corticosteroids. I just don’t do that. If you want to use corticosteroids, use systemic, once the systemic antivirals have been on board for a few days. The triamcinolone is the main agent. I use Depo-Medrol or methylprednisolone acetate. It’s also available periocular. And the shorter acting agents I do not use as periocular injections. This is another recapitulation of the same thing. This is how I give a retroseptal — excuse me, posterior sub-Tenon’s infection using the Nozik technique. Bob Nozik was the first to describe this technique, more than four decades ago. And I use a 25-gauge short 5/8-inch needle on a 3-CC syringe with about 1-CC of triamcinolone or Kenalog, where we draw up about 40 CC in the adult patient. Here’s a patient receiving a retroseptal injection. I use a 1/2-inch needle. Steve Foster turned me on to this. It’s minimally painful. 25 can hurt more going through the skin. 27 doesn’t hurt as much. And I go straight back, penetrate the septum, and inject intraseptally. You get a little festoon under the lid from the steroid injection. Intravitreally — there are many options now. In addition to intravitreal triamcinolone, the fluocinolone implant, which was studies in clinical trials from Bausch and Lomb, as well as more recently, with the MUST clinical trial that I mentioned earlier, conducted by the National Institutes of Health, that’s highly effective, but again, associated with significant complications that we’ll get to. The dexamethasone implant, it’s continuous release for about a month. The clinical effectiveness in uveitis for the dexamethasone implant is probably a little less than 3 months. I typically will see it effective for 2 months. So these are all methods of delivery. The Ozurdex is done in the office. The Iluvien I have not talked about. That’s still pending for uveitis treatment. It shows some promise in terms of being — as an office procedure and lasting longer, but it’s not biodegradable. Whereas the Ozurdex is biodegradable and goes away. In the case of the Retisert, you’ll see these have to be surgically implanted and sutured in position. They may have to be removed and replaced every three years, based on the severity of the inflammation. Oral agents — prednisone is the one I use. For the most severe uveitic cases, for example, Behcet’s disease, I will use IV prednisolone, 1 gram a day, typically divided into three doses, IV, and the patient is hospitalized for this, because we monitor blood sugar, blood pressure, and other parameters. They can be very ill when they get this therapy. Once I complete 3 days of intravenous therapy, I will switch them to oral. And this is the most severe cases of explosive Behcet’s. I have done that in the past. All forms of steroids can cause PSC cataracts and increased intraocular pressure. For example, intraocular pressure increase can occur at any point in the disease process. So if you gave a corticosteroid injection to a patient periocularly six months ago, it’s still possible that they might get intraocular pressure elevation. Once you’ve committed to that form of therapy, it’s very important to monitor their intraocular pressure, even after the inflammation is gone, or if they’re in between episodes, if they have recurrent disease, for example. Let me go to the first polling question, before we talk about some of the side effects of steroids. If a patient was treated with prednisone, 60 milligrams daily, and the dose was tapered and discontinued over a 6-week period, which of the following complications is least likely to occur during that period? Weight gain, aseptic necrosis of the hip, hypertension, or mood disturbances? And we’ll see if the answer comes up here. This is a little bit of a trick question. Everybody who’s on corticosteroids is going to experience some element of weight gain. Underlying diabetes can become worse, underlying hypertension can become worse, and mood disturbances are very common. But the least common and most idiosyncratic — most of you got it right — is aseptic necrosis of the hip. This is a serious complication, often presenting with severe hip pain, inability to walk, and the patient will have softening of the femoral head. Sometimes the humoral head as well, in some cases. So this can be a devastating complication, requiring joint replacement surgery. So this is completely idiosyncratic, but tends to occur at higher doses, when patients are on 40 to 60 milligrams of prednisone or higher. And so monitor for this very, very carefully. There are many other short-term complications. And I joke that corticosteroids, if there is a complication or a systemic symptom that has ever been reported, that symptom is probably listed in the Physician’s Desk Reference for corticosteroids. In other words, every side effect known to man has probably been attributed to corticosteroids. It’s humorous in some ways. But that tells us that these agents, although effective, we need to counsel patients when using them systemically, as to potential risks. If they’re diabetic, I avoid using systemic corticosteroids if I can. If I have no choice, in those cases, I will have them be aggressively monitored by their medical doctor and also have the patient self-monitor blood sugars. Fluid retention, hypertension, worsening of heart failure. With chronic and aseptic necrosis of the hip — all those things we talked about already. Very rarely there are patients who have hypersensitivity reactions, such as urticaria, to prednisone. That’s often strange and paradoxical. We often use those agents to treat allergies. But it’s probably the vehicle or something in the agent that they’re allergic to. People can, with long-term use, most seriously, develop osteoporosis, osteopenia, impaired wound healing, fragile skin, multiple recurrences of subconjunctival hemorrhage with topical steroids, for example. Topical steroids can cause fragility of the conjunctiva and recurrent hemorrhages. Pancreatitis, fatty liver — lots of different complications. So many I don’t want to list all of these. Fat redistribution and development of a cushingoid state is something we see frequently. As early as 2 months after initiation of systemic corticosteroids. Here’s another potential complication that we need to talk about. Which of the following is most likely to induce peptic ulcers? Again, this is a medical question. It’s not a uveitis question. But it’s important, because we use systemic corticosteroids frequently, as uveitis specialists and as ophthalmologists. And we should be aware of some of these issues. And let’s see what the results show here. So kind of a mixed bag here. So I think 39% of you said systemic corticosteroids and about 30%, almost an equal number, said all are equally likely to cause peptic ulcers. It’s interesting. Corticosteroids alone — in the original reports, they’ve been associated with gastric ulcers and GI hemorrhage. But these are probably uncontrolled studies and spurious observations. It turns out that really although corticosteroids can exacerbate and make worse preexisting gastritis or peptic ulcer disease, combining corticosteroids and non-steroidals increases the risk of peptic ulcers and gastric ulcers by 10 to 20-fold. That was impressive. It’s well known in the medical literature. So I am very, very cautious about combining these two. So you may have patients with scleritis you have on steroids, and they’re taking non-steroidals to control pain or something. That’s a bad combination. Can result in a lot of problems. Those patients should be monitored carefully for the development of ulcers, and if you’re gonna use both of those agents together, I would suggest an H2 blocker, or some of these other new proton pump inhibitors, et cetera, that can be utilized for the treatment of these. Corticosteroids can be utilized with injection into the choroidal or retinal circulation. That’s not a good thing. Those patients can lose vision and become permanently blind. Perforation of the globe, ptosis, proptosis, orbital fat atrophy are more cosmetic issues, but the orbital fat prolapse, subconjunctival hemorrhage or periorbital hemorrhage, pain, syncope, et cetera, scarring — all these things are potential risks. And intravitreal risks, in terms of the corticosteroid implants, the Retisert implant, 100% of phakic patients will need cataract surgery within two years of placement of the Retisert implant. 40%… About 50% will develop glaucoma. 40% will need surgical intervention for glaucoma within 2 years. The good news is, when you do surgery for cataract or glaucoma, when you have these implants, generally patients have good control of inflammation already, and tend to do well surgically. So this is something to keep in mind. Some patients develop vitreous opacities or vitreous hemorrhage as well. Surgical complications such as macular edema, retinal hemorrhage, hypotony, choroidal detachment, retinal detachment, sterile endophthalmitis — all of these are potential risks as well. Lens damage at the time of insertion. Rarely… It doesn’t happen anymore, but the old implants used to dissociate. So the cap of the implant fell off and they needed to be explanted. Those can be very difficult to remove. Sometimes you have conjunctival erosions. These patients need to be monitored carefully for glaucoma and cataract progression. Topical use. You have to be very careful for topical corticosteroids, because if you have underlying herpetic corneal disease, you may make that worse. So you have to make sure you’ve ruled out infectious diseases before using topical steroids. And again, development of spontaneous subconjunctival hemorrhage. Here’s the next poll question, going back to systemic steroids. Again, when we use these chronically, we have to keep these in mind. Which of the following tests has to be performed for patients on long-term management doses of prednisone? Monthly liver function tests, monthly BUN and create nine, annual complete blood count, or annual bone density scan? Let’s see if anybody is paying attention this morning. I’m sure you all are. So we have… So any time that we have somebody who is on chronic systemic corticosteroid therapy, no matter what dosage, even 7.5 or less than 10 milligrams a day, those patients need to be very carefully monitored for the development of osteoporosis. I don’t — we don’t need to check liver function tests or renal functions or CBCs on patients who are on chronic maintenance oral prednisone therapy. The CBC will show margination or elevation of the white blood cell count. Occasionally patients can get fatty liver with corticosteroids. That usually happens in higher doses. But that’s very, very uncommon. So these are things to keep in mind. Again, on this therapy, it’s very important that the patients on systemic corticosteroids be monitored carefully for blood pressure, weight, diabetes, all these things that we talked about already, and of course, long-term monitoring of bone density scanning. The patients should have a total bone density scan if that’s available, and be monitored for osteoporosis. And of course, topical, regional, and intravitreal corticosteroids we need to monitor for the development of intraocular pressure elevation cataract status. So I’m gonna switch gears and talk about those really bad diseases, where we need to use immunosuppressives. So serpiginous choroiditis. In the left eye there, in the superior temporal quadrant, you can see there’s active serpiginous choroiditis. And this patient has juxtafoveal or subfoveal involvement already. And they’ve lost the other eye. The other eye is on the left. Here’s a patient with birdshot retinal choroiditis. Most patients with this condition will require long-term therapy, either with the intravitreal implant, Retisert, or long-term therapy with immunomodulatory therapy, such as CellCept, cyclosporine, or low dose prednisone. Antimetabolites such as Imuran or alkylating agents or sometimes a complication. Behcet’s disease will require long-term immunomodulatory therapy, and acute vasculitic flare-ups as you see in the bottom left and bottom right here — sometimes these flare-ups can look like necrotizing retinitis and can be indistinguishable from acute retinal necrosis syndrome or acute herpetic retinitis. In the case of Behcet’s that look like that, those need to be managed with anti-TNF therapy. Vogt-Koyanagi-Harada disease. Patients that have chronic inflammation, as in the bottom, those patients will require immunomodulatory agents. Necrotizing scleritis. This is a patient of mine who had evidence of relapsing polychondritis with cartilage loss in the ear and nose. This patient is going to die without cytotoxic therapy. Today we use agents such as Rituxan or infliximab, along with some of the alkylating agents. Mooren’s ulcer, where we have to use aggressive immunomodulatory therapy. Here is a patient with peripheral ulcerative keratitis, associated with positive P-ANCA test. He had microscopic polyangiitis. This patient required cytoxan, or cyclophosphamide therapy. So these are the corneal indications. For immunomodulatory therapy. And I mentioned already some of the posterior panuveitic complications. JIA is where we use these early. Specifically methotrexate, along with topical corticosteroids, to try to control inflammation in young children. We’ve ruled out infection, we try to treat the inflammation, steroids aren’t enough, so we use immunomodulatory therapy. If somebody is requiring greater than 10 milligrams of prednisone to control inflammation, they’re gonna need immunosuppressive therapy. If somebody is requiring every two week periocular corticosteroid therapy, and they’re not responding, those patients probably will likely require aggressive intervention with immunomodulatory therapy. I’m a purist. I tend to use systemic agents much more frequently than I use local therapy. Especially because I tend to e I tend to see in my uveitis practice much more — generally we tend to use immunomodulatory therapy much more commonly. We don’t know which is the best agent to use. We have some ideas. But we don’t know how long to continue therapy. Immunosuppressive therapy… (no audio) I hope you can hear me. I’m gonna share my screen here. I’m deeply sorry for this. It’s a technical glitch of some kind. Let me… Go to the case where we were at here, at the treatment paradigm. So we were talking about immunomodulatory therapy. Can you hear me okay? I hope you can hear me okay. I’m assuming that you can. I’ll try to speak up, so you can hear me well. Let me… So immunomodulatory therapy… When we use these, there are numerous mechanisms of action. This is from an old article I picked up several years ago that shows where all these agents act in the immune cascade and looking specifically at the T-cell. T-helper cells are the main source of much of the inflammatory activity that we see in noninfectious and even in infectious — but in noninfectious uveitis. Corticosteroids, for example, work at the level of the antigen presenting cell, but also at the nuclear level, nuclear transcription. And also we have the T-cell inhibitors, such as cyclosporine and tacrolimus that are calcineurin inhibitors, that actually work indirectly, in terms of affecting the cell cycle, and we have mycophenolate and azathioprine, that have an effect on the synthesis of DNA and rapidly dividing cells. So something that’s more interesting, because it’s now being tested as an intravitreal agent for noninfectious uveitis… All of these are important in the armamentarium for the treatment of inflammatory disease. Now, in this slide, we don’t have anything showing what the effect of TNF alpha inhibitors are, which are important for the treatment of ocular inflammatory disease. The patients who are treated with immunomodulatory therapy… I’m trying to get this slide to move here… Patients who are treated with immunomodulatory therapy need to have baseline testing of CBC, liver function tests, and in the case of azathioprine, sometimes I will use the thiopurine methyltransferase activity test. I’ve stopped doing that, because it’s an expensive test, but I will evaluate these patients monthly, complete blood counts and liver function tests, I’ll continue monitoring these patients, and once they’re on a stable dosage, I’ll reduce the frequency of these tests. So let me ask the next question. Which immunosuppressive agent can be used safely during pregnancy? We didn’t talk about any of these agents, but we will in a moment, and discuss them. Methotrexate is an abortifacient. Obviously you can’t use it during pregnancy because it was used originally as an abortive agent. Cyclophosphamide is certainly not safe in pregnancy. It’s destructive and severely, profoundly neutropenic inducing. So the safest agents are the TNF alpha inhibitors. Adalimumab can be used safely. And other agents that can be used with caution are azathioprine and cyclosporine. These are important agents to consider. There are significant fetal and maternal risks we need to consider. Moderate fetal harm can come from cyclophosphamide, methotrexate, et cetera. And selectively, we can use, as I mentioned, some of these agents, specifically TNF inhibitors, azathioprine, et cetera. Corticosteroids can be used in pregnancy as well, with little risk to the fetus. Let’s start talking a little bit about the antimetabolites. Methotrexate is the oldest, and it impacts directly the formation of thymidine. And it’s basically a folic acid analog. But its antiinflammatory activity is probably more subtle than this. More complex. And probably it’s due to the extracellular release of adenosine that actually causes the antiinflammatory effect from methotrexate. It’s given subcutaneously or orally, weekly, because it’s a slow onset of action. It takes up to six weeks to have full intraocular effect, and even children I use the full dosing of 25 milligrams a week to control, as long as their liver function tests are tolerable. We know from numerous studies, especially the SITE studies, the therapeutic studies, retrospective therapeutic studies on the treatment of immunosuppressive therapy for the treatment of noninfectious uveitis that we’ve been doing in the United States in multiple trials, multiple agents have specifically been evaluated, and methotrexate shows about a 66% reduction in the need or ability to control, I should say, the inflammation in patients with no inflammation after a year of therapy, and more than half have reduced prednisone doses to low levels. The good thing about methotrexate is there is no long-term increased risk of neoplasia, and there also appears to be a potential risk of course with leukopenia, elevated liver function test and development of cirrhosis and pulmonary fibrosis — these are unusual complications with the doses that we use, but these are potential risks. Patients should be monitored with CBCs and liver function tests on these medications. There is zero risk of long-term neoplasia. This is why this is safe to use in children. Folic acid is usually used as a supplement to prevent side effects, and I tell all patients to avoid alcohol. Abstinence is important. And two dual forms of contraception should be utilized by women of child bearing age and even for three months after discontinuing the medication, because of its profound effect on oogenesis, and spermatogenesis as well. So patients on this should practice appropriate contraception and avoid trying to get pregnant on these medications. Azathioprine is an antimetabolite, it incorporates a nonsensical nucleotide into DNA that stops replication of rapidly dividing cells. It’s been around for 40-plus years. Used in organ transplantation, can be used effectively for patients who have autoimmune noninfectious uveitis. We used to obtain thiopurine methyltransferase enzyme activity levels. It’s known that most patients tolerate azathioprine well, but about 11% of patients have a heterozygous deficiency in the activity of this enzyme, which is important for the metabolism of this agent. And so toxic levels can develop if TPMT is not available in appropriate amounts. So we either need to do a dose adjustment or avoid Imuran altogether in patients with this. There are some patients who are homozygous and they have minimal activity and cannot tolerate azathioprine at all. It takes a few months to be effective, and two thirds of patients on this medication had no inflammation after a year according to SITE studies, and similar to methotrexate, about half had a reduction in indeed for corticosteroids. Headaches are common side effects. Leukopenia can be potentially rapid and serious, especially in patients with TPMT mutations. I would avoid that. Elevation in liver enzymes can occur in patients with TPMT mutations as well. And there is some potential for long-term increase in malignancy, although this is not clearly demonstrated in the SITE studies. Mycophenolate is one of my favorites. It’s an inosine phosphate dehydrogenase inhibitor. It’s interesting that this particular enzyme — it appears that CellCept is about 5 times more… Has 5 times more affinity in binding this enzyme in activated T-cells. So it’s very specific. It knocks out rapidly dividing T-cells, and it selectively does so. That’s what makes it a very attractive agent theoretically. This is well tolerated. The most common side effect is diarrhea. 18% can develop this, and usually it’s how they take it or the dose. So we can do dose adjustment or adjust how the patients are on this medication. But nearly three quarters of patients on this medication didn’t have inflammation after a year of use, and more than half were able to reduce prednisone dose to less than 10 milligrams a day. And is excellent for preventing rejection in organ transplantation as well. Risk of neoplasia are rare, but need to be considered. We monitor the patients the same way. Typical dose for an adult is 2,000 to 3,000 milligrams daily cumulative dose of mycophenolate. I use less cyclosporine than I used to in the 1990s, since CellCept or mycophenolate became available. But cyclosporine and tacrolimus are both calcineurin inhibitors. They bind cyclophilin, and this prevents the activation of the IL-2 gene and the production of large amounts of mRNA and replication of rapidly dividing T-cells, and production of cytokines. So it has significant antiinflammatory effect, by multiple mechanisms. But it’s a T-cell inhibitor. It inhibits the production of cytokines from activated T-cells, so it’s a significant effect in controlling inflammation. The SITE data is not as impressive as the other agents. About half had no inflammation after a year, and only a third were able to reduce prednisone dose to less than 10 milligrams. And especially tacrolimus is used in organ transplant to prevent rejection. The dosage — I usually use less than 5 milligrams per kilogram per day. When it’s combined with other agents, I may utilize 1 to 2.5 milligrams per kilogram per day, and to avoid some of the side effects and to reduce the other agent as well. So when used in combination, the dose adjustments have to be lower. So you have the combined effect of both of those agents with fewer side effects. There are lots of side effects with cyclosporine. Hirsutism, reduction in creatinine clearance. We used to measure drug levels with radioimmunoassay. Now we just measure renal function to determine renal toxicity. Trembling of hands, paresthesias, acne. These are all known side effects of this. Sirolimus is interesting. It’s similar to tacrolimus and cyclosporine, but it targets the other side of the cyclophilin pathway. In terms of how it attaches to the nuclear factor, activating the target. In that situation, what happens with sirolimus is that it inhibits the activity of serine in MTOR. So when it does that, it has a very specific inflammatory effect, just like inactivated T-cells. Just like the cyclophilin binding does. And results in reduction of inflammatory cytokine release. So it’s very effective when it’s given intravitreally, according to the SAKURA phase III trials. So we’re very interested in this as an intravitreal injection for panuveitis. This is a new area, kind of on the verge of breakthrough here soon. And it may change how we treat chronic uveitic disease. Alkylating agents are used in the most severe cases. As you know, cytoxan, for example, is basically — prevents DNA — results in DNA crosslinking and cell death, apoptosis, of rapidly dividing cells. It causes localized protein damage as well. One of the by-products, the metabolites, of cyclophosphamide, is acrolein. It causes cell toxicity. So a poll question here. The highest rate of durable remission of disease is most likely to be achieved by use of which agent? We talked about a lot of agents, but which are most effective in causing durable remission? No inflammation off of medications? So that’s durable remission. Being free of inflammation on no medication. And let’s see what you guys all thought. So it’s kind of… Yeah, nobody chose the agent that’s the right answer. So this is interesting. If you look at chronic non-infectious inflammatory disease, cytoxan and chlorambucil have the highest degree of remission. Cyclosporine and infliximab are good at controlling inflammation, but it takes a long time to reach durable remission of disease, and stopping the agent is always associated with significant trepidation. But with chlorambucil and cyclophosphamide, the rates are much higher than with any other agent. Isn’t that interesting? All of you got that wrong. So cyclophosphamide is usually given at 100 to 150 milligrams daily. These agents I will give myself, but often I will have a rheumatologist and/or oncologist involved. These are very risky agents to utilize. They are available more readily. But they have to be used very carefully. In India, I know that they use intravenous pulse therapy of cytoxan every month for 6 to 12 months at 500 to 1,000 milligrams IV. But when you look at the target leukocyte counts and try to dumb down the leukocyte counts to low levels of 3,000 to 4,000 cells per microliter and then off of all steroids and then taper them off the medication, we want to keep the maximum cumulative dose of cyclophosphamide down to 35 milligrams or less. After 35 milligrams cumulative dose, about 6 months of therapy, oral dosing, the risk of secondary leukemia substantially increases. Look at the SITE data. Almost a third can reduce prednisone to less than 10 milligrams a day. The oral form is associated with a greater risk of hemorrhagic cystitis, because of acrolein metabolite being present in the circulation. Chlorambucil also causes crosslinking of DNA and inhibition of DNA replication, but has a longer duration of effect. Short-term or short-term therapy can be utilized, and there’s significant information on the utilization of this short-term high dose therapy, which has been very effective, from the University of Illinois and Northwestern University. Complications are very severe. Pneumocystis carinii opportunistic infection, hemorrhagic cystitis, gonadal suppression, and permanent sterility can occur. So patients on these agents should consider — especially men — sperm banking. Biologic response markers are specialist agents. They’re used usually in conjunction with a rheumatologist. Very rarely do we use these on our own. But now adalimumab has been approved by the FDA for noninfectious uveitis. And I consider these second line immunosuppressive agents. I don’t go to adalimumab unless they’ve failed other immunosuppressants. So there are numerous biologic modifiers. The list continues to grow on an annual basis. But for our purposes, the top two that you see on the top right of the slide, infliximab and adalimumab, are the most important. And then we also have the rituximab, very important in the treatment of severe vasculitic conditions. We know that the rationale for use in ocular inflammatory disease is based on rheumatology clinical trials. But more recently, we’ve had some excellent clinical studies, especially for adalimumab, conducted by Abhi Pharmaceuticals, on the treatment of noninfectious uveitis. Dosing and treatment of choice is really empiric, based on patient tolerability as well. So tumor necrosis factor signals other inflammatory cytokines, and is kind of an upstream regulatory cytokine itself. So it’s released by an activated CD4 or T-helper cell, and it’s important for release of interleukin 1, other proinflammatory and antiinflammatory cytokines that are present. So regulation of TNF is an important aspect of inflammatory control in the eye. Adalimumab is a completely humanized IgG molecule that targets the soluble TNF as well as membrane-bound TNF. TNF alpha. So this is a very useful agent for the treatment. And infliximab has a slight variation and it’s kind of a both — it’s a chimeric antibody. The adalimumab is completely humanized. The infliximab is murine or mouse-derived. We don’t think of etanercept. It’s useful for joint disease, but it has no use for uveitis. Some people think it may potentiate the development of uveitis. So we don’t use it. Infliximab and adalimumab are what we use. Adalimumab has been approved for the treatment of noninfectious anterior, posterior, and panuveitis. We have to be very careful with these agents, and you should have a rheumatologist involved in dispensing these and treating the patients, because some require infusions, such as the infliximab, hypersensitivity reaction, exacerbation of demyelinating disease, congestive heart failure, exacerbation of TB and latent TB, very important in Third World countries, of course, and of course histoplasmosis in our neck of the woods, and drug induced lupus and leukemias have been reported. These are all important conditions, and make these agents very significant departures from antimetabolites in terms of the side effect profile. So they should not be taken lightly, and involvement of an internist, rheumatologist, is very important. Rituximab is a chimeric antibody, directed against B lymphocytes. It’s very effective when they’re producing a lot of antibody, for example in immune complex diseases, such as vasculitis. It’s gonna be very highly effective. It’s effective in refractory scleritis, systemic vasculitis — there’s a lot of ophthalmic evidence to show efficacy here. But complications can be profound lymphopenia, hypersensitivity, and infusion reactions. These definitely need to be given by an oncologist or rheumatologist. There are other agents that have limited utility in uveitis. Such as Abatacept, or Orencia. It blocks fusion protein for CTLA-4. And interferons can be utilized in Europe. They tend to be utilized much more commonly than they are in the United States. And I have little experience with the use of interferon alpha 2 for the treatment of uveitis. But it is very helpful in intermediate uveitis, associated with cystoid macular edema. If you read some of the articles by Dr. Jay Rosenbaum and his group in Oregon. There are now other T-cell inhibitors coming up that have a great role to play in the future by inhibiting IL-17. These IL-17 inhibitors, specifically Secukinumab has shown significant positive effects on controlling inflammation. So this is kind of a nutshell overview of what we have available in our armamentarium. For the treatment of inflammation. I’m gonna stop… I’m gonna take some Q and As. And I apologize that I cut out. I had some internet connectivity problems, and it’s been fixed at this point. So I’m actually running a little late. And I have a conference that I have to go to. But I hope that I’ve answered some of the questions. I don’t see a whole lot of Q and As here. Let me see if I have any… Do you all have any questions that I can quickly answer? I’m not seeing any questions coming up here. I hope that you were able to get some useful information from this. And if there’s… I’m gonna take a look at a few questions that was sent to me yesterday. What is the role of topical cyclosporine? Okay. Fuchs uveitis. You know, Fuchs iridocyclitis does not require immunosuppressive therapy. Should be treated with corticosteroids. In those cases, patients have 50% chance of developing cataracts or glaucoma. Cataract surgery can be done in Fuchs patients without preoperative corticosteroids. And this disease does not require immunosuppressive of any kind. This is a disease that does not produce structural complications from chronic inflammation, other than compressive glaucoma. Okay. Let me just go on here. Alternatives to IMTS. I’m not sure what IMTS stands for. Let me answer a couple of other questions here, and I’ll come back to that one. How long should we continue corticosteroids? I mentioned that corticosteroids, once the inflammation has been controlled, these need to be gradually tapered, over a period of 8 to 12 weeks, if we’re talking about topical corticosteroids. When can we safely stop the immunosuppressives in posterior panuveitis? We can safely stop immunosuppressives at 3 to 5 years, in my opinion, after control of inflammation. A minimum of 2 years after there’s no inflammation. The immunomodulatory therapy for chronic uveitis… Again, is, for granulomatous inflammation, it’s variable. I think it’s an idiosyncratic and very highly patient-dependent selection of agent. It’s an empiric selection. There’s no raw data to suggest that this is the agent you should use. Infectious uveitis should not be treated with immunosuppressives, obviously. How do you fight recurrence of uveitis? Well, treat the acute uveitic condition aggressively. And for a significant duration of time, and make the inflammation go away. At the risk of overtreatment. So you can prevent recurrences. Developing countries’ treatment options are limited. Corticosteroids are readily available. Some of the older immunosuppressives, such as methotrexate and Imuran may be available. I know this is a huge problem, because many of you will see the most severe diseases in those that are the most economically disadvantaged. Obviously if nothing else is available, corticosteroids can be utilized effectively, I think, in the vast majority of cases, to control inflammation. And I think that if we realize that acute inflammatory disease, if it’s aggressively treated with steroids and brought under control, generally will do well in our hands. Especially in anterior uveitis. It’s the patients who are inadequately treated, with too rapid a taper of steroids, that result in chronic problems. So let me just see a few other questions here. Here’s a question… I have two questions, first one about Behcet’s disease. What is your first line therapy? Cyclosporine… Explosive onset Behcet’s disease I typically will recommend with posterior segment inflammation that infliximab will be utilized, and high dose or IV corticosteroids, in infliximab is not available. IV corticosteroids, followed by a gradual taper of oral corticosteroids, and I would use Imuran, because Imuran in the Japanese studies has been shown to be a little bit more effective than cyclosporine, but cyclosporine is fine as well. My problem with cyclosporine is that I have not been able to taper patients off of cyclosporine. Almost behaves like a steroid, with similar kinds of side effects. So I don’t use cyclosporine as much. So Humira is an excellent agent to switch to, if you’re not having a good effect with cyclosporine, if it’s available. Can we do refractive surgery after controlling uveitis? I tell patients with anterior uveitis that cataract surgery potentially can cause their disease to recur, even if they’re quiet. I’m very conservative. I tell patients that elective surgeries potentially carry that risk. Now, corneal surgeries alone, I suppose, can be done, but I would counsel the patient. I don’t think this is necessarily going to be straightforward. So I would be very cautious in recommending such aggressive kind of… More elective surgical procedures, such as refractive surgery. Do I give periocular corticosteroids for patients with Fuchs complaining of floaters or having a flare of vitritis? Vitreous surgery may be more effective in that setting. Yes, you can try that, but remember, these patients are high risk for glaucoma. Corticosteroids can help reduce symptoms. Sometimes people with Fuchs can have pain, can have floaters. Corticosteroids can be used, but remember that 50% get glaucoma, and 50% get cataract. So you’re gonna make cataracts and glaucoma worse with corticosteroids. So I would use these steroid agents gingerly. Perhaps you can use difluprednate, which can penetrate into the vitreous and control some vitreous cells. That might be useful. In resource-poor countries, without immunosuppressive therapies, how do we regularly monitor? Complete blood count and liver function tests should be available practically anywhere in the world. CBC — you can get a hemoglobin or hematocrit or white blood cell count, I think that can be easily obtained. Liver function tests should be obtainable. If you don’t have access to these, you’re gonna take some chances. Not monitoring a patient on immunosuppressive therapy is very risky. Herpetic uveitis long-term control. I use systemic antiviral therapy. Usually I use Valtrex, 1,000 milligrams daily maintenance, or acyclovir, 800 milligrams daily maintenance. Azathioprine. Yes, good agent. Azathioprine can be utilized especially in conditions like Behcet’s disease, but it has excellent immunosuppressive effect. And utilized between 100 to 200 milligrams daily. And again takes 3 to 6 months to take effect and used for a few years. What is the role of glaucoma shunt surgery in uveitis management? This is beyond the scope of this talk, because there are lots of questions about uveitis, because I know — and perhaps we should have a lecture on the complications of uveitis. And I’ll see if I can put that together for you. But inflammation, any time surgery is considered in uveitis patients with chronic uveitis, inflammation has to be as well controlled as possible, with essentially no cells in the anterior chamber, and whatever it takes to get to that level, keep them at that level, with no cells at that level of medications, even if it’s high doses of steroids, prednisone, keep that at that level for three months, and then you can do glaucoma surgery. Tube shunts work best, and that’s what I prefer. Chronic vitritis can be taken care of with vitrectomy. But these are temporary measures. If you’ve done everything to control the inflammation and vitreous opacities remain, it’s therapeutic and highly effective. But if you’ve not done everything to control the inflammation, you’re probably making it worse. Surgical options are limited. For implanting the implant, such as Retisert, yes, that’s highly effective. For chronic idiopathic anterior uveitis — it’s chronic. Do you stop treatment for chronic hypertension? Do you stop treatment for chronic diabetes? No. So you don’t stop treatment for chronic idiopathic anterior uveitis. It’s not going to go away. So you need to find the lowest dose of corticosteroids that is going to keep the inflammation well controlled. Who is a purist? By purist, I’m not a guy who likes to use local therapy as much. I like to use systemic therapy. Especially in chronic disease. Because of the nature of my practice. All of you are not going to be seeing the kinds of patients that I see, because I’m a uveitis specialist. But the chronic, really severe conditions require systemic immunosuppressive therapy to control. What is the best therapy for toxoplasmosis? Clindamycin is an appropriate alternative. Intravitreal clindamycin is an excellent alternative. Retinitis pigmentosa… Can be produce what appears to be occluded vessels, et cetera. And these patients don’t respond to immunosuppressive therapy. Idiopathic uveitis can be treated with chemotherapy… Yes, as long as it’s not infectious, it can definitely be treated with immunosuppressive therapy. But you need corticosteroids to control the inflammation initially, and then start immunosuppression. Retinal detachment with chronic uveitis is managed with the same vitreoretinal techniques that you would use with ordinary detachments, but I tend to be more aggressive in avoiding cryotherapy, I tend to use vitrectomy combined with scleral buckling surgery, because these patients have more risk of proliferative vitreoretinopathy development. So I’m more aggressive. I’m a retina specialist as well, so I do a lot of PVR surgery in uveitic patients. So I’ll try to put together a lecture — I’ll talk to the Orbis folks and see if we can get that to happen. How would you manage these patients? Well… Miserable patient. Yes. These are very, very difficult conditions to manage. If you can’t do it yourself, you have to seek out help from a person trained in ocular inflammatory diseases, such as a uveitis or retina specialist to help you. I have to go. Thank you very much for your attention.

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January 20, 2017

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