to the next topic here topic to new breath of the wild info oh boys if you don't want breath of the wild spoilers you need to just stop listening right now skip ahead like I literally just like skip this entire segment I don't know how long it is at this point so I can't I can't tell you where to skip to in the video maybe I'll try to put it well in the video it'll be its own thing so just skip this whole segment if you don't want to get spoiled audio is gonna be audio I just just skip ahead to hear us talking about something it's not Zelda right um so breath of the wild game informer all those fine folks at game informer they got to do something that as far as we're aware no other media all that has gotten to do when the switch event was happening and there was the the two breath of the wild demos that we knew about there was the one they got to play on the show floor or it's not show floor it was just a floor where the media got to play the game and it was just the demo that we got to play back at E3 yeah and then there was a second demo that they weren't allowed to touch that apparently was the full game and that's where they showed up where Nintendo employee would like answer questions and just show up one of the stables and a few of the things out in the world that they wanted to show you but they didn't want to show you everything like there was a one shrine they would do that looked really easy but then they wouldn't actually talk to the person at the shrine and show you it yeah because spoilers are right right whatever reason it might be so there apparently was a third thing going on at least for just game informer as far as we know and basically the way they said it because they had posted out like their own their podcast their game informer show and on there they said well we got there we were playing the demo and all of a sudden they just like pull this aside to a back room and like two of us got to sit down and just play breath of the wild for like three plus hours that's ridiculous like and for starters really jealous for starters right sorry sorry for audio version I was doing something a little inappropriate but the they got taken to a back room and got to play breath of the wild not just like playing from the beginning for three hours they were as they described it it looks like there was already save files and they were just dropped into different save files to experience different parts of the game and one of the save files gonna drop them in at a stable and they got to learn a whole bunch of new things about the stables like they're like every stable is ran by unique a unique character so it's not like one character runs all the state no and then just magically appears at each one yeah they're like video games man video games right and that each stable is gonna have its own unique characters that you know go to it and leave from there to go back to wherever their villages or something and they have a purpose to be there and it's also like it's kind of also serves as a bizarre like in Skyward Sword in the main village where you go in and it's really like your potions and your upgrades and you know whatever your storage you can also sleep they also have like it like it I can go in kind of hotel yeah you can you sleep at it and here's the cool thing this is the first time we've heard of this is that when you go to sleep you have an option that you can pay extra rupees and I don't know if I wish this was true in real life you just pay money and you get to deep sleep or something right but somehow you pay money and then you wake up and you have a temporary extra heart until you get damage done and like you know you however much you pay determine how many extra hearts you get so say say you have you come in come in with your four hearts and then you pay a hundred rupees you wake up the next day with four extra hearts on top of those four but they're yellow and as soon as you get hit and they don't replenish yeah it's kind of like a kind of like a temporary shield that you get in some games so like that was really cool to find out we know that we've known in the past that there's like some food items you can make that do the same thing so I guess this is just another way to do it if you don't happen to have the supplies and you know there's a really difficult boss coming up or something and you just want to really pad your health as much as you can really cool thing personally but I think you know beyond that you know by the way we are gonna be talking about a dungeon soon they got to go into the world and just do anything they want they weren't told what to do and this is she threw was kind of like that yeah or they didn't kind of try to force you what to do yeah and and you know it because this was the full game you would figure oh they don't want you to find things no they did and this is probably game informer specific because they were under massive NDAs and because game informer has now stretched what they've done into a month-long coverage lead up to Breath of the Wild so it's kind of like every day they're releasing new info so even by the time you hear this there's gonna be new info that we're not discussing because we don't know it right and it's it's interesting that they got that opportunity and I had I think it's because they're magazine entity so they got a plan out ahead but like there are some really cool things that they discovered like we knew horses could die but even them knowing that going in it shocked them when it actually happened yeah yeah actually he shot his own horse I think he was using bomb arrows and in the midst of using them the horse ran through and it like the horse died from the rules and it's like he's like man like that really impacted him because like even though he didn't get that horse it was named Kyle or something yeah it was Kyle yeah like he still felt the connection to the horse because this never happened as all the before right like you especially in this game it seems like the horses develop relationships with you because you sue them you feed them you can make them like you better so they do things for you which I know sounds like a slave like I'm like you so they do exactly what you want to do but it's a horse yeah it's just yeah what do we do the horses anyway right races in real life yeah like come on but in this game that's how it although that's like the literal sense of what's happening you're doing it to get a reward at the same time it feels like you're developing a relationship with a horse unlike in the past when you're just kind of handy to Pona right yeah like this is your horse like in Twilight Princess if one is already your horse or in Ocarina of Time it really doesn't feel like you earn the horse per se like you don't have a choice like that's just the way the game goes here you got to choose horses you have some of them are really really hard to sneak up on and they have all different stats different personalities and I think they have personalities right that that I mean not personality or they're talking to you but just how they behave right like some are gonna be a lot rougher with you than others and take a lot be a lot harder to tame and you need to have for a lot longer and treat them differently like maybe it's even possible no one's asked this question yet but it's even possible that you know the horse is because of those different personalities you might have to do you might have to tame them in different ways like yeah you always have your soothe right if you give one horse an apple another horse might say screw that yeah right apples actually pissed me off and give me hives yeah you know spit it out at you and get angry at you and actually prefer something different maybe they want or maybe for some reason they want cooked horse meat I don't know why not why not so like maybe they're one of the four horsemen of the apocalypse you never know and like this is like the smallest thing in here that that but but it kind of brings in this sense of this world being alive right because you learn to care for this thing that you or an enemy killed I'm assuming you didn't mean to get the horse killed so right yeah accident and things you can do you can actually use the horse and you can like kick things to yeah and actually some of them had actually they all have I think different strengths yes stuff like that so you can actually use them in combat encouraged you but at the same time you take a risk and use them in combat so it was really strange to hear that this thing that they didn't they didn't capture they had already felt something for and it died and it was like a big shocking thing like an emotional moment that's like whoa yeah like games don't do this right and not like they weren't saying just like Zelda games don't do this like games don't do this like yeah they don't when you have your horse in the Witcher 3 that's your horse yeah right it doesn't die it might run away doesn't die yeah so like games just don't don't do this to you let you spend all this time training something and just rip it from you and by an accident I don't know another thing speaking of horses being different to from other Zelda games you cannot just call your horse from anywhere you have to be within a certain distance to which which again makes sense yeah I'm like cell phoning my horse across the world to run to me hey how you doing how are you coming over so so that was kind of cool and then they talked about the weather so now explain what they got surprised about with the weather so apparently they were in a giant lightning storm and they decided that they were carrying a metal shield and no I think it was short and sword and shield actually and they were struck by lightning and died yeah that is amazing yes um couple reasons it's amazing one that that's even in the game at all and that basically a right lightning rod and and as they describe it they kind of make death fun yeah right well I mean like like you died from it you're just like wait what yeah I mean we had the we had the one video for me three where you just decided to go when you died and we just turn it into a death video because I dive in ice cold water and survive with no clothes on for a little bit you can for like more than a half a second yeah right you better hope you're there's something to grab on to so it's like man that that lightning though and they said like apparently when they were doing the center rupture like we didn't know this was going to happen like like they're just like okay and it's kind of like what a Ajay Anoma said in the past he doesn't even know everything that's there is the find in this game because everything is so dynamic and so free flowing that there are situations that are gonna come up where not everybody on the Zelda team knows that's even a thing that could happen not everybody might know you can get struck by lightning or right or maybe they knew you can get struck by lightning they didn't know they put in the game where your metal will attract it like just like it logically would right especially when you're in a world like this where it's basically here's a wide open field and you're the only metal thing in it you probably would buy one attracts tracks the lightning you know obviously people getting hit in real life by lightning is rarity but we have a lot more metal things on the right and it's also not as funny but this is also a game so anybody out there who's got been struck by lightning we're not saying it's funny at all but it's funny in this game in the game and the thing is like it's just another layer to the game like you need to de-equip your metal items and equip wood ones or equip like you know maybe you have one of the stalfos arms that you can beat things with that's not metal right equip stuff that lets you progress to the world without having as big of a threat like I think you could still randomly get hit by lightning but yeah like lightning hit trees hit the ground like you can still get hit but it's not like specifically going to target you and they even said like there's cool things you can do with this like if you have a metal shield you can just take it throw it at a group of enemies and the lightning will strike that yeah and then I'll hit the enemies that that is pretty awesome yeah it's it's just that extra layer like we we saw in person through playing it how amazing the physics engine was oh definitely but we didn't see how weather is affected by it I don't think we even saw much weather at all no no I mean it was just cold the only weather we saw were like on the the actual fake weather in the booth when you find the plates on the ground oh yeah and it would be a thunderstorm thunder thunder thunderstorm quote unquote no so man well it makes me curious like how well what happens in a snowstorm right like is there actual blizzards and they mentioned actually there is because they didn't mention that they were walking through the through the snow and all of a sudden a couple enemies just came out of nowhere and surprised that kind of them because they didn't see them yeah so like they what what's really curious to me about this is the the the attention to detail like did you know who's I said several times like he's so proud of like the sound of the hooves and everything and I know that's just one thing and he's repeating it because he must be like really really proud of how that turned out but like that's not it that's one minor detail in a game that pays a lot of attention to minor details as an example when you're running the snow you move slower yeah real life when you run in the snow you move slower that that makes sense yes yes for people who don't know what snow is yes you do actually run slower yeah it's it's just crazy all the stuff that they experienced that no one else outside of Nintendo themselves is probably experienced at that point and just how they said there's constantly something going on so like a lot of people a lot of fears with Breath of the Wild have been that there it's such an expansive game that it's gonna feel empty and I guess based on their experience now they got off the plateau and got to explore freely and said they mostly tried to go north who knows maybe they're trying to get to the mountain I don't know but they just got to go north for a few hours and it just kind of there was always something like even if you weren't fighting there was something going on in the environment that would draw your attention to it and you never felt like you were bored and and I think that's the big thing people were worried about oh it's empty I'm gonna get bored apparently not there's so much going on no right there's there's can with nature and with the physics engine yeah you know with you know with weather you know like I said you know they were in snow they were in sand they were I mean they were all over the place and you know these few hours and everything just worked and this is where now now we get into the stuff that that's extra spoiler spoiler extra spoiler and that's a they actually got to do a dungeon and we're not talking about a shrine yeah they literally said this is a dungeon it has a boss at the end of it they tell the name of the boss so like they described the boss and they've now released a screenshot of the boss which I'll probably throw up in the video version somewhere here and it it sounds like the dungeon that they played isn't something that's as long as say a dungeon in Twilight Princess and Twilight Princess arguably have the longest dungeons in the series the game was basically here's a bunch of dungeons everything else is in between yeah and the dungeons were really long and really elaborate they said this feels more like dungeons and Zelda one where they're shorter but there are a lot of clever puzzles so instead of focusing on having a massive dungeon and figuring out how to traverse it you have a smaller dungeon but there's a lot of very very unique puzzle elements to it that aren't always obvious and actually if I remember right they did say there is actually multiple ways to solve each puzzle to yes because as they point out in this particular dungeon there is a Sheikah site place where you like the dungeons movie and the Sheikah site thing allows you to manipulate the dungeon let's you twist it or whatever and that let that that gives you access to different things and let's you try out different ideas like there's this what are they we finally know what that black gunk is called that that emanates that from Calamity Ganon oh I I don't forget yeah I don't remember but like in that in that gunk there's eyes Zelda thing sure didn't the eye like that's how you beat everything in Zelda right um so you defeat these eyes and it clears out the gunk so like that's what some of the puzzles are but a lot of the puzzles are physics-based and it sounds like that's kind of the gist of what dungeons are gonna be in here like it's all about physics and manipulating the environment and I am totally for that oh yeah totally like one thing I always said about Zelda over after all these years is that okay I've done 17,000 block pushing puzzles yeah none of these feel different anymore yeah right it feels like something I've done before maybe the answer is different maybe I gotta push to a different spot but I've done this yeah like a bunch of times and I think that's what's really unique about how these dungeons are having approaches you have no idea this is a physics engine yeah it's all being done with something Zelda's never done before um that's crazy to me and they said it's extremely fun and when they got to the boss it kind of opened up and if you look at the screenshot you could tell it almost looks like they're outside somewhere I don't know they don't really go over the fight too much outside of saying that like it's a faceless boss which you can see in the screenshot and it has like an arm cannon shooting missiles at you and like shooting spikes or shooting spikes at you and some other stuff crazy stuff going on and they did beat it they didn't tell us what happens after you beat it like do you gain a heart like they didn't go over that at least they haven't gone over that yet right yeah it wasn't talked about in the in the article and gave a former as magazine so and the thing apparently is like part of calamity Ganon maybe that's why it's faceless I have no idea but it's called Cole calamity something yeah I can't I really apologize for not knowing the name off the top of my head right now and it it is said at some point during the battle or before after that it is part of calamity again and so it's possible that all the big bosses in the game are like come together in or like or like part of calamity again and himself yeah part of his entity that come together at the end a lot of theories we could throw around for that and I gotta say none of this sounds bad to me no no not at all it sounds amazing so we learn all this stuff and there's been a slew of things there was some new like Nintendo released some new official art showing off like an all brand new design for a specific Korak that we've never seen before and there's just new information trickling out every day so as I said by the time you listen to this there'll be even more stuff out that we're not going to be discussing so having sat down and you read that you read the article for sure yep you sit down and read it yep well it's awesome it I didn't quite like the flow of it but yeah well the flow of the article yes yeah it kind of jumped from here to there so and I think you know I don't know if that's a I don't know it's hard cuz I'm not behind the scenes of them I think there's things they weren't allowed to talk about right and I don't feel like it felt like it was supposed to be one cohesive story but it wasn't yeah and I again like it if you haven't read the article yet I you know go purchase the digital copy game informer if you're interested it's like a four or five no it's a 12 page piece or something it's really long but get my it's a yeah so like there's a lot of big images so it's not as long as it appears right but it does have new screenshots in there so enjoy those they're nice so like you yeah it kind of felt like there was clear sections but there was no flow between yeah no not at all and again I think that's a lot of because they just they played for a few hours they're trying to summarize that down to you know right yeah no I get it and they either weren't allowed to talk about certain things or it wasn't something that was not worthy enough to really bring up it's just part of the experience that you're gonna experience every time you play yeah and I don't know if the pages that I read were out of order anything no they were in order okay so yeah yeah like I said it just kind of felt something felt a little off about it but I mean it was good informational around yeah yeah so you know that about the information setting aside you know the abruptness of some of some of the flow of the piece knowing all this new stuff what do you think I mean you you are as hyped for this game as I am and that's crazy because I've like this has been what I do yeah it is March 3rd here yet that's that's that's all I can say I mean it needs to get here like now yesterday yeah yesterday and you know I'm still still pressing my contact at Nintendo I'm a client and when am I gonna know what right really like if anything not just to review the game right oh definitely I just want to play it so like I applaud game of former yes definitely yeah lucky them you know go ahead and go over to the site if you're looking for more information about it obviously I'd love to say come visit internal prime net but we're slowing our news coverage down a little bit in anticipation of some new hires and some other things going on at the site but we will be picking it up as we get closer to launch but game of former themselves like what we're posting about the games coming from them so I go to the site check them out you know they posted a game of former show where they spend like the first hour of the show almost the first hour of the show talking about their experience with this game behind the scenes and in it they show footage of a lot of what they did so like if you want to see this in action not just read about it in the magazine that go there they did an awesome job another thing they did and this was pretty obvious if they got to do something that most other people do they also got to interview Shigeru Miyamoto and Eiji Anebo and I got to say it's the most entertaining interview I've ever seen you will go with that I don't know how informational it was yeah yeah it was either extremely informational or hoax hoax or it was partially in between yeah like they label that you know here's 51 questions posed I think it said was about breath of the wild but a couple of the questions weren't above us a while all right yeah there is that like in here there's things like you know like they asked about paper Mario and then like did you know what basically said like we're working on that and it's like wait are you saying you're making paper Zelda yeah right yeah or are you just like working on a paper Mario for the switch or yeah it was really weird well I mean he did pointed his shirt so I know and then like then like Miyamoto did like a pose and I was like okay is this joking and like this cuz kind of kind of brings back to like Eiji Anebo way back in 2014 when he said oh I didn't explicitly say that was like and it blew up in this big thing I was in a female yeah blah blah blah and it almost felt like a lot like that where it's like they're kind of going along with it so I don't know right but then there's things like there's some things that feel like it's a joke but then it's actually legit in other cases as an example Eiji Anebo has asked what Link's last name is he looked over at Shigeru Miyamoto because yeah they did he did not create like so yeah you know this is not a question he's ever answered and Shigeru Miyamoto is like it's like Mario and then and then the game so guys like what so it's a Link Mario's last name is Mario yeah and it's like no Link Link yeah because Mario's last name is Mario it's Mario Mario and it's Luigi Mario that's a little weird last name of the Mario Bros. well I guess it makes sense yeah Mario Brothers yeah that is true Mario Mario yeah that is true it's like it makes sense it kind I mean I'd never really thought of it that way yeah like in Zelda's was Link Link that's like why not is he joking or well I don't know because then they both that like turned to each other kind of laughed at it because Eiji Anebo was like well I'm not something we've ever thought about you're right yeah I mean more like instantly he's like it's like Mario and it's like so is he thought about it or yeah or is he just coming up with this like in a fly different news sites out there they're like oh man links last name is link and it's like yeah do we know for sure you're right but but at the same time Mario's last name is Mario's it's like they literally referenced it's like Mario yeah right it's like what for Mario it is Mario Mario so it could be link link it's honestly a completely irrelevant thing right especially since there's multiple links interesting question yeah it was a very interesting interview there were maybe my favorite question was when they were like hey can we trust these translators right and they paint over the translators translators smiling yeah so and they said yes you could trust them yeah but um you know because obviously they were probably surprised with some of the the translated answers they were getting back like really yeah like what yeah you know like oh or the screw your favorite Mario so I don't know it's just a fun interview we you can go on YouTube I think they finally have it on YouTube now and look up 51 questions about for a while or something it should pop up as like top video just crazy I don't know what to believe from it so I don't want to talk about yeah more more information we could possibly lean from just I don't I don't know what we can lean from it even at Zelda and Farmer you know Darren was asking me or yeah just asking like in general like what to what to do with this thing because like we break it up like normal and make a bunch of stories out of it or like what now just like yeah I don't this is what the only interview I've ever seen or watched or read that I'm just like throw the video up and it could be true or it could be BS and I think we should just make a single post about these again I agree so that's exactly what they did at Zelda and Farmer so yeah it's just fun it's great and I think it's gonna do it for for brought the wild I do have one more thing to add yeah I know right right holy cow stop the presses I actually have something to add I don't remember whether it's in the article or if it was in the interview but I know I can't remember which one of them said that actually I and to what you were saying before I don't know if anybody actually knows everything in this game because they had so many different groups of people working on it they had one per one group specifically working on animals just just animals in their movement and everything else like that and then another one's working on like trees and another one working on this and that they had so many different teams working on this that I don't know if there is one person that really knows everything in this game which is kind of crazy yeah like the one guy there was this is back to the switch event when they were doing a live stream the one guy I think it was maybe Nintendo UK that was doing it one of the Nintendo Ruts was playing through it and he went yet he lit a torch and went over to a beehive and the bees dissipated so he was able to knock on the hive and get the chest and yeah you got it and the guy said oh you know the the person who was doing also talking was like yeah as you see like you know that that's the thing you can do in the game and the guys like actually I didn't know that's like the guy who did he's like actually I didn't know that was a thing like I just found that out now yeah he works in Nintendo so it's like yeah like it's crazy that there's so much in this game that no no one person knows yeah I like it's probably impossible no one person knows even everything that's possible in the game not just the stuff that's in it but how things can be done like there's gonna be things done with this physics engine by gamers that Nintendo had never even thought oh yeah yeah I just hope it doesn't like start flinging you off of cliffs like and what the heck is it Skyrim yeah you know and you know I'm just I'm just broadens all inform and I'll look and if there's anything we missed right and we do recommend going over there yeah it is great site like the great site I'm still technical editor chief of it for a couple months and like they are really doing an excellent job you know I so I've had some people ask me in the past about Zeldin former like since Zeldin former kind of works on a process of posting content that other people have done like you know maybe they went to Nintendo everything and saw the report or they went to go to Nintendo or they went to Game Informer in this case or someone on Twitter so it's all like second or third-hand information trickling down the Zeldin former posts about and I've often had people say well why like why go there why not just go to Nintendo everything when they get it up faster and all I could say is that in just now like when I want to look up stuff it is so much easier to go to one site that has everything so they're going to Nintendo yeah everything and having to type in Breath of the Wild and you know if they didn't take something correctly it's not you're not gonna find it in there right which actually I went back through some of my posts and I realized I didn't have tags so so it's like one of those things that I guess it's just it has everything in one spot yeah anything you want to know about Breath of the Wild that is out there is gonna is either on or going to be on Zeldin former I won't write and it's like that for every game so you know when obviously I'm a little biased because I know right you know I've been at her in chief almost eight years there but it's just now now that I'm kind of transitioning on my way out as emotional as that is for me I still find it as like an excellent source even like over what I do at Nintendo Prime even if we were on top of the Zeldin news I would still tell you the ones on the news side on the internet Zeldinformer.com definitely there yeah if you just want to gather up Zeldin news and that's all you care about Zeldin formers place to be come to us for we'll have Zeldin news but we also have a lot of other things right easy to bury it and it's not gonna get buried here you know as an example like at the time that we're recording this you know like the top thing Zeldin's lullaby can be heard in Breath of the Wild now I know because I read this earlier today it's not just that it can be heard it can be heard in various different forms all over the overworld it's not to be like the general overworld theme and every time you hear it in front of the overall it's completely different and you might not even recognize it as I know for this report here one person heard it only by speeding up the video but like five times as fast oh geez you can hear it and it sounds like a master doing oh yeah like there was a trailer once for it was I think it was the first trailer for Skyward Sword where if you play the music in it backwards it was something like that very nice it was crazy I yeah I think it was Skyward Sword so like Nintendo is really cool doing the stuff and what does this mean who knows and I must have a greater context if this is the overall theme for the overworld and there's no music in the overworld there's music it's just subtle yeah it's subtle it's there to give you some ambient noise but it's not there to detract you from like you shouldn't be traveling the overworld to hear the music you should be traveling it to enjoy the world and this is gonna help enhance that experience right rather than like when you are playing Twilight Princess you go on the thing you got this big epic music team it really doesn't matter what's going on around you you're just enjoying this epic song as you're riding horse and it's great it's sweet I love yeah Princesses Hyrule Field music but you know it's just I'm not there's nothing in that world to enjoy right and that's that's the point I think to give you something to enjoy this is a lot more to enjoy so a lot of things you want to pay attention like I said you earlier enemy surprised you know I'm like use all your senses yeah you might have heard of something that tipped you off that there was an enemy with the fly you can do six hearts damage yeah yeah that's right they got jumped out of the snow and then just destroyed just wrecked difficult game they they they spoke at length on their game and former show about this is a difficult Zelda game and it takes you if you're a Zelda veteran it takes you by surprise because Zelda hasn't really been difficult like this in a long long time not since Zelda 1 Zelda 2 like this is well when they went back to the roots to build an open world Zelda game it wasn't just the exploration it was yeah like this is a dangerous world man yeah it's dangerous these aren't just enemies you just waggle around and dominate you're just randomly waiting for old man to pop up it's dangerous and they didn't know they didn't know and this is something we knew from our experience it probably didn't stand out to you because you don't have as much experience with Zelda games but most other games even when you have multiple enemies on screen say you have five oh yeah yeah they wait to attack you at once like you're only really dealing with one at once yep not this time now there's no need in turn you can be trying to dodge one and then you three more of my turn to just drill you yeah it's crazy it's I almost said expected I don't expect it no but it's real yeah that's what like if like when you watch movies and it's a gang of people game around one guy and he's fighting well that's not holding work hold on guys one at a time guys one at a time yeah yeah like that's not how things work no like as someone who's gotten beaten up before like no they all come at you at once yeah I mean yeah there's a risk they might hit each other but they're probably gonna hit you a huck of a lot more oh yeah you know you always hope that the one guy sucks the other guy too hard by accident and then that starts to fight with them they leave you alone but that just doesn't happen right they just get mad and then they just hit you even harder so we'll get into yeah yeah more of that but yeah it's just a really cool thing there's this game yeah I think just wrap this up it's amazing marks third needs to get here this game right dude this is all right


Okay, good morning, everyone. I think we'll get started. Welcome to UVitis Grand Rounds or the ophthalmology rheumatology interface. I will begin with an overview of non-infectious UVitis new treatments and current treatments. This will be followed by two case presentations illustrating the treatment of accurate only inflammation and then accurate inflammation associated with systemic diseases. And then that will be followed by a talk on an update on biological agents for the treatment of non-infectious UVitis by Dr. Gobi Pemmetza, who is a assistant professor of ophthalmology rheumatology and our collaborator. So for some reason this is not advancing. Okay, so our approach to the treatment of non-infectious UVitis begins with establishing a diagnosis and of course excluding infection and then putting out inflammation with corticosteroids by any means necessary from any route necessary, depending upon the type of inflammation we have in the diagnosis. And then having a very low threshold for the implementation of immunomodulatory therapy in patients with chronic inflammation in order to either spare steroids or use as a first line agent. And this consists of both conventional and biological agents. In essence, the goals of our treatment are to eliminate inflammation with prompt control of activity and hopefully induce a remission in an effort to prevent a structural damage that is essential for vision and to avoid or minimize systemic complications in essence to have our cake and eat it. And I think that this is possible. In essence, the choice of treatment with steroids and immunomodulatory therapy will depend upon several factors including the anatomic site of the inflammation, the severity of the inflammation, the laterality of the information and the underlying diagnosis. So topical steroids is appropriate for anterior uveitis only. Periocular steroids is appropriate for unilateral intermediate uveitis. Implantable devices are also appropriate for unilateral, more severe unilateral, intermediate uveitis and as adjunctive therapy for posterior and pan-uveitis. And systemic steroids are appropriate for more severe inflammation, particularly bilateral inflammation in which we expect a more prolonged course. And then of course immunomodulatory therapy in order to spare steroids or as first line agent. Here are our choices today. Most for regional corticosteroids. Periocular corticosteroids can be administered transceptively or via posterior subtenance injections in the slide above or intravitrally as triampicinolone or as the approved dexamethasone implant or Ozadex as I'm sure you are all familiar. We were a principal study investigator for the point trial which was a randomized controlled trial to evaluate the safety and efficacy of regional corticosteroids for patients with active uveitis and macular dima. So we compared periocular versus intravitrile approaches and the Ozadex. And as you can see in this graph here, these are the intravitrile approaches and this is the periocular approaches. There's a statistically significant clinically significant decrease in central macular thickness at eight weeks which is the primary endpoint. In addition, there was a statistically significant and clinically significant improvement in resolution of macular dima in the intravitrile approaches as opposed to periocular. And there was elevation intraocular pressure in all three groups, although this was greater for the intravitrile groups. So really in conclusion, all treatment groups had improvement in central subfield thickness and in best corrected visual acuity. However, this difference was much greater and much better for patients with intravitrile therapy and it suggests that the intravitrile approach may be the indicated approach for patients with central involving and vision-threatening macular dima. We are also a principal investigator for a sister trial called the Merit Study that is investigating non corticosteroid and intravitrile alternatives for macular dima. And this is comparing dexamethasone implant, which we just saw here, to intravitrile anti-vegif, random bismab and intravitrile methotrexate, data is locked and we're analyzing it so stay tuned. The problem with regional corticosteroids is that they are relatively short acting and hence less effective for chronic inflammation. And so associated with the cumulative risks of steroid exposure such as cataract and intraocular pressure problems and of course of the procedure itself. Back in 2005, in order to address this issue, a flucinolone setonide implant was approved by the FDA, which provides sustained intravitrile steroids for about two and a half to three years. And this is surgically implanted in the operating room. This provides effective anti-inflammatory therapy with improvement of visual acuity, but as expected adverse effects of cataract and a hundred percent of eyes and a very high percentage of elevated intraocular pressure and the need for incisional glaucoma surgery, not too unexpected for marinating an eye in steroids. In 2018, a variation on the steam of the flucinolone insert was approved by the FDA. And this is an office-based injection of the same medication yet at a lower dose. And this was shown to have efficacy versus sham at 12 and 36 months with respect to inflammation and a reduction in the loss of visual acuity but was associated with cataract formation and elevation of the intraocular pressure, but certainly not as great as that with the red assert implant. Probably its greatest utility is in a mild to moderate chronic inflammation in the eye as it is a lower dose and for eyes that are complicated by chronic macrodema. So I anticipate that the UT is going to be used for adjunctive therapy more often as primary therapy because many of these, many eyes with severe inflammation just, will not respond to the dose of this medication. A really novel approach, which has recently been approved like a month ago by the FDA for the treatment of macrodema in non-infectious CBI, this is supercoital administration of triampicinolone. So animal models have shown that supercoital administration may be better than the intervitral as that higher amounts of drug get to the point of interest in the retina and the coroid and lower exposure to the anterior segment and hence less intraocular pressure problems. And this was trialed in the peach tree trial at phase three randomized control trial, which compared this supercoital administration to different time points to quote sham injection. They were sham injected, but they were actually injected with local steroids. And the primary endpoint was visual acuity and it met the primary endpoint with 47% of study eyes getting greater than three lines of vision from baseline as compared to 17% of controls. What was really remarkable was this robust decreased in central macular thickness, which was sustained throughout the trial at 24 weeks of central macular thickness. So it appeared to be a very good treatment for macrodema. There were very few cataract events as compared to control and very few intraocular pressure events and no need for institutional glaucoma surgery. So this is a promising technique. So almost two decades ago, there were guidelines that were published for the use of immunosuppressive drugs in patients with more severe posterior and panuviatus that was non-infectious that had been on corticosteroids that require immunomodulation. And the recommendations of this panel were failure of systemic corticosteroids, unacceptable side effects. Disease is known to be poorly responsive to steroids and we can go through some of those. And of course, the requirement for chronic corticosteroids are greater than 7.5 milligrams per day, which is associated with systemic side effects. In addition, this publication recommended that immunomodulatory therapy be commenced at the onset of treatment for certain diseases. Those included certain diseases associated with systemic diseases such as Bechette's disease or necrotizing scleritis and purple ulcerative characterized with or without the association of an underlying systemic vasculitis. And then a whole host of just ocular only inflammatory disease including mucous membrane pemphagoid, serpigens cordopathy, sympathetic epilomina, VKH. And then it also recommended the early institution of corticosteroids in which we know that natural history is to poorly respond to steroid monotherapy such as Bruchat rent or cordopathy, certain cases of multiple corditis, intermediate uveitis and certainly JIA associated with your cyclitis. So just for a review, we can think of immunomodulatory as conventional therapy and biologic therapy. So the conventional agents are listed here and they begin with anti metabolites that you are familiar with and methotrexate, mycopenylate and aziphthyprin, T cell transduction or calcineurin inhibitors such as cyclosporin, tachrylimus. And finally the acylating agents when I'm using cyclophosphamide which we use less frequently as we have now biologics available to us. But it's these agents that actually are the most likely to induce remission of severe inflammatory disease. So there are numerous case studies and case series that show the effectiveness of conventional immunomodulatory therapy in JIA, in Bruchat rent or cordopathy, multipocal corditis in PIC, VKH and in serpigens cordopathy. You are probably familiar with the MUST trial which was a multi-centered randomized controlled trial which compared the Redisoc implant that I just showed to you earlier versus conventional therapy with steroids and then conventional immunomodulatory therapy. And so local steroids versus systemic steroids. And this was a very interesting study. At two years, the visual outcomes were about the same in both groups but inflammatory control was achieved a little quicker and a little faster with the implant as compared to systemic therapy. Systemic therapy was very well tolerated. So many of you were not poisoning our patients or harming them. And of course there was the expected ocular complications of cataract and elevation intractor pressure. But at seven years, you can see that the implant did great for a while and then there was a crossover at about five years in which the systemic group actually did better at seven years. And this was due to recurrent choreoretinal inflammation in those eyes. And so basically the bottom line I think is that either one of these approaches is certainly acceptable. Systemic therapy seemed to be better in providing sustained inflammatory control in these eyes and hence better visual outcome at seven years. So the availability of biological agents has revolutionized the treatment of rheumatology certainly and we have stolen many of these approaches and drugs for the treatment of UV-itis. This is a kind of a short list of the biological agents that are currently used in UV-itis treatment. The ones that you're most familiar with I'm sure are the TNF inhibitors. Infleximab which is a chimeric monoclonal anti-TNF antibody which is given IV and adelimumab or chimeric which is a humanized monoclonal antibody which is administered subcutaneously and was FDA approved, the only biologic agent to be FDA approved for intermediate, posterior and pan-UV-itis 2016. Again, a expert panel recommended the use of these biologic agents as first line agents for patients with Bay-Schett's disease. And as second line agents after failure of conventional immunosuppress therapy in patients with JA-associated erosyclitis and as potential second line agents for patients that may not tolerate or do well with conventional therapy which include severe post-year UV-itis or scleritis. I would just bring your attention to the fact that there is a randomized controlled clinical trial, multi-centered trial that is going on which we are participating called the advised trial and this is looking at humera versus conventional immunomodulatory therapy as a primary out point of steroid sparing therapy in patients with intermediate, posterior and pan-UV-itis. So it will answer some important questions like can you just go straight to a biologic? Other biologic response modifiers that are used in auto inflammatory disease include interleukin and receptor antagonists such as a badisept which is a co-stimulatory blocker which has been shown to be semi-effective in refractory JIA. Rituximab and monoclonal anti-CD-20 on B-cells which has been extremely effective in patients with refractory scleritis, mucous membrane tempoid and refractory eubiotics. Other biologic agents that have been used intraferon and alpha-2A, the European experience suggests it's extremely effective in Bechette's disease although there are numerous side effects associated with this medication. A application that is extremely effective is in patients with recalcitrant macular edema. Intervenous immunoglobulin has been useful in patients with autoimmune retinitis, retinopathy and cancer-associated retinopathy. Emerging data suggests that tosylizumab and IL-6 blocker, which is a humanized anti-monoclonal antibody, which is an approval for various inflammatory diseases, is also effective in refractory eubiases, particularly those complicated with macular edema, as we'll see. And this has been shown in two phase two studies and some numerous case reports and we'll see some of that later. So in summary, there are disease-specific indications for treatment of eubiotics, both for ocular only and for inflammation of the eye that is associated with systemic diseases. We take a kind of a stepped approach using corticosteroids, which is guided by the anatomic location, the diagnosis, lidaralline severity of the disease, and we employ conventional immunomodulatory and biologic agents when needed in order to spare steroids or is a primary therapy and or using sustained release implants as either primary or more commonly as a junctive therapy for recurrent macular edema and inflammation in eyes that are already on systemic therapy. So the currently guarded prognosis for patients with severe inflammatory disease is possible with effective and sustained suppression of intraocular inflammation, the early introduction of steroid sparing immunomodulatory therapy, I think identifying eyes at risk for complications is likewise important. And then of course, studying the safety and efficacy of early introduction of these agents and regional therapies in well-designed clinical trials. So I hope that provides a backdrop for what's ahead here. I would invite Rachel Patel to come up and give us a case presentation on what's next. Okay. So I'm gonna talk about a particular patient who might be well-known to many people at Marani Center as well as to Dr. Pemetza. And so this is called still active what now part one. So this is a 59-year-old woman. She first comes to establish care and rheumatology clinic. She has a history of chronic erosive rheumatoid arthritis for what she's been previously treated in Mexico prior to immigrating to the United States. And it primarily affects her hands, her shoulders and her feet. She also has diabetes and high blood pressure. She's on a tenor sept or embryo every week as well as methotrexate every week. And after one year with reasonable control of her joints, her methotrexate is stopped. One month after stopping her methotrexate, she comes to the U of U ER and she has a right eye pain and redness. And the good Dr. Bear was on primary call at this point and he accurately diagnosed her with scleritis and said, sounds like we need something to help treat the scleritis. And she says, I've actually been seen as ophthalmologist in town. His name is Dr. Wyatt. She's been treating me with a sub-tenus kinologue every couple of months or so. And it's getting better, but it's not fully completely treated. So she is in coordination with Dr. Wyatt. She's discharged from the ER. She follows up in rheumatology clinic at which point she started on oral prednisone and to treat the bilateral disease at 50 milligrams daily. She's restarted on her methotrexate with a consideration that potentially that was one of the reasons why her scleritis got much worse after stopping that. And it's recommended that she switched from enverol to Adelima map or humera. As many of you know, itanercept has very little efficacy in uveitis and therefore humera, the approved medication was something that could be an alternative to treat both her scleritis and her rheumatoid arthritis. However, she was getting her enverol through a hospital assistance program because she's uninsured. And so the Adelima map switch was a little bit limited by her lack of insurance. She was lost to follow up for a couple of months, but then showed up in the uveitis clinic. At this point, you can see here that she's got diffused scleritis of both eyes. You can see a little bit of the depot of the residual subtenance catalog on the top of her right eye. She doesn't have any evidence of necrotizing scleritis at this point, which is great, but she also has had recent try and send alone injection in the last three months. So potentially we're not seeing how severe this could actually be. Therefore, her methotrexate is maxed to 25 milligrams a week, switched to subcutaneous to help increase the theoretical bioavailability. And she is given instructions to apply for the Hemera assistance program and that started every two weeks. She's also given samples of Hemera to help her along the way. However, four months later, while, although she's improving it initially, her scleritis in the right eye flares much more severely also followed by, for the first time, peripheral ulcerative keratitis in this eye. I don't have a picture unfortunately at this point, but you can see that she's got marginal ulceration of the right cornea with also some epithelial loss and fluorescein staining. So she started an oral prednisone. This is not great for her diabetes and also she develops GI bleeding on prednisone. Her Humira, which is conventionally prescribed every two weeks is increased to weekly with some evidence that that can increase some disease remission and people who are minimally responsive to every two weeks. However, during this process, she keeps running out of Hemera samples and sometimes the methotrexate, which she's paying for out of pocket. And so the idea is maybe this isn't the best regimen for her. So she's moved to apply for inflixin on a Remicade assistance. With the idea is this is an infusion that she'll get at the hospital every four weeks. Maybe that's a little bit more helpful for her to get it. She stops the Humira and she starts inflixin out at 10 milligrams per kilogram every four weeks. And five months after this, however, her left eye now starts to develop PUK. So this is what it looks like. She with this would indicate that she is also inadequately controlled at the current dose of inflixin. Even though she's been receiving this reliably. So she has started on oral prednisone again. Her inflixin is increased even farther to 15 milligrams per kilogram as to tide her over while she is waiting for approval for the manufacturer of Rituximab to approve her for assistance as well. When approved, she is switched to Rituximab. Rituximab is given in two doses and then six months later is her next dose. So she is actually doing well on this. The reason for choosing Rituximab in these cases is probably because there's evidence for the last several years that Rituximab is particularly effective in patients with scleritis and peripheral ulcerative keratitis as well as initially in rheumatoid arthritis as well. So we have something that could potentially treat all three of her conditions. In this review by Dr. Cunningham, they looked at 120 patients with scleritis who were treated with a Tuximab and 112 of them, so 93% had a positive response. So pretty good. Puk is a little less common, but the evidence we have, I'm trying to move that away, suggests that of the patients who were treated with anti-TNF inhibitors, such as humera or infliximab with Puk, about half of them had to switch to a different agent to achieve disease control over the first year, but all of those who were treated with the Tuximab did not. The idea behind this is that scleritis and Puk are considered a vascular process and Rituximab is particularly efficacious in these conditions. However, you'll also note in the same picture that she's got more going on in her Puk. She's also got a pretty dense cataract, her vision as at best, 20, 70 in both eyes, and she's been on and off topical and stomach steroids for the last year or so. So now that she is under good control for several months on Rituximab, without arthritis, scleritis, or Puk, she's signed up for cataract surgery. I got this video from Dr. Chaya, so kudos to him. You can see here that the main wound is made directly through the Puk, which causes a little bit of leakage around the fecotip, which means that during the surgery, they have to sew up the sides of the wounds to enable the rest of the nucleus removal, making the surgery a little bit more interesting. And at the end, all of the pairs, including also how to be tied down. So Puk does not make easy cataract surgery. However, she does well and postoperatively in both eyes, she's uncorrected 20, 30 vision, and she's maintained disease stability and pliescence on Rituximab every six months and methotrexate weekly. So just some lessons that this patient taught us. Local and systemic therapy each have their own side effects, such as the cataracts that her drafts have caused, as well as the GI bleeding on her oral prednisone is caused. Options for escalating treatment with IMT include increasing the dose or frequency, as was done with influximab and humera. I'm switching to a medication in the same class, such as humera and influximab, or switching to a different class of therapy, like the CD20 antibody in Rituximab. Patients with EVitis and systemic disease, such as rheumatoid arthritis, have approved indications for several IMT options, but this of course requires close co-management with our colleagues in rheumatology, dermatology, and oncology. Sometimes the best treatment is the one that the patient can get. And visual rehabilitation with cataract surgery and EVitis requires complete disease class and it's for three months to achieve optimal outcomes. So here are my references, and thank you to all the people who are helping take care of. Okay, I'm Marissa Lavreshelle, one of the EVitis faculty here, and I'll be presenting the next case, which has its own set of distinct challenges and differences. This is a 60-year-old man that was referred to the EVitis Clinic for bird shot choreoretnopathy. As we know, bird shots really a prototype of an ocular inflammatory disease, that has a specific phenotype and a strong HLA association, but no systemic rheumatologic disease associated with it. And it has a known course without treatment of causing progressive visual decline from visual field loss and nyctalopia or night blindness with an abnormal ERG. It's characterized by these deep hypopigmented lesions. I don't know if I can get a pointer here. You can see that for the rheumatologists in the crowd. There's these deep sort of yellowish spots scattered throughout the posterior pole. And someone described it sort of as a bird shot, like a gunshot pattern. So it has this name bird shot. And this patient also had a diagnosis of hypertension, but no other past medical history. On the floor, seeing angiography, the photo on the left of the screen, we can see some segmental periflebitis indicating active disease. He has nerve edema and some angiographic CME. And then the photo on your right is an ICG. And we can see some small hypo fluorescent spots indicative of bird shot. Vision was slightly declined, 2050 in the right eye, 2030 in the left eye with elevated intraocular pressure of 35 and 31. Normal is 10 to 21. And in this photo, we can see a macular OCT with an epiretinal membrane, which is this line on top and then cystoid macular edema, which are the dark circles here. The patient is already on max dose of methotrexate, 25 milligrams oral weekly in conjunction with rheumatology. And his drops include three antihypertensive agents. COSOFT is a combination agent and then Bramonadine in hopes of treating the ocular hypertension. And he's on a topical steroid and a topical NSAID for the macular edema. So our recommendations at this point is to switch the oral methotrexate to the subcutaneous form, increasing bioavailability and then starting adelimumab. And that was bridged with an oral prednisone taper and then in hopes of treating or at least helping the ocular hypertension, trying to taper him off of the ocular steroids, the topical prednisone. The macular edema did improve but didn't completely resolve and the patient lives in Nevada. At some point his pressure was checked locally and it was still high despite tapering off the topical steroids. So he started on diamox and unfortunately the patient was suffering from one of the common side effects of oral prednisone which can be mood disturbances. He described feeling very angry or almost homicidal towards one of his roommates. So we're sort of left with the situation of a bilateral posterior uveitis with no known systemic disease that has improved but not completely resolved on our first two lines of treatment therapy being anti-metabolite and adelimumab and he still has macular edema. So in this case, the local therapy has the negative side effects of raising intraocular pressure. We could try a surgical intervention such as a paris plaintive atructomy with a membrane peel to relieve some of the tractional component of that macular edema from the epiretinal membrane. The patient is fake however, so we know that paris plaintive atructomy and definitely a red assert would induce a cataract requiring surgery and the red assert also tends to worsen the intraocular pressure leading to incisional glaucoma surgery. And systemic therapy also has its side effects that we have to deal with. So the psychiatric issues with the oral prednisone is this patient experienced. Cyclosporine is an agent that we can add as a third line in some patients for adjunctive therapy. However, he already has baseline hypertension and we know the cyclosporine can exacerbate that. And so we move on to other potential biologics which can be difficult in getting approved for a uveitis alone. So our recommendation is to try a flibrecept. That's an anti-vegeth intraocular injection aimed at macular edema. That does not have the issue with the steroids inducing IOP elevation. And we started operation for tosylizumab. And tosylizumab is thought to, IL-6 is thought to increase circulating levels of vegeth and so IL-6 inhibition then can act as a systemic anti-vegeth agent. This is a 24 month study of 16 eyes in 12 patients with refractory uveatic macular edema. In these patients, the uveitis itself was quiet, but the macular edema was persistent. And it was long-standing in this study that macular edema was present actually for over 13 years. And all the patients had been previously treated with other IMT agents and then they were initiated on tosylizumab, IV infusion, eight megs per gig every four weeks. And the outcome was a significant reduction in central macular thickness seen at one month and sustained through 12 months. So for our patient after the flibrecept injections, they did have resolution of the macular edema despite that epiretinal membrane in the right eye. However, the left eye still had some persistent cysts and they were awaiting approval of the tosylizumab at this point. So this case really highlights a real world patient with a challenging ocular systemic disease or sorry, an ocular inflammatory disease without a systemic disease. Rachel mentioned some of the techniques we used to advance immunosuppression such as increasing dose of frequency, switching medications, switching classes. And with this one, we saw that we switched the route of administration in hopes of improving bioavailability and then selecting a third agent with particular efficacy against macular edema. And so we really rely on our colleagues in the rheumatology department. We think these cases, once we move through the first and second line agents that we have a lot of experience in prescribing, albeit off-label with the exception of Adelimumab. And then we get to agents like tosylizumab that don't have a specific approval for but it's used to treat these ocular inflammatory diseases that really are vision threatening. And so the best approach to these is a sort of hand-in-hand collaboration with the rheumatology department and the UVitis department to get these patients these extra line of therapy that ultimately saves their vision. So we really appreciate the work that the rheumatologists do with us to help care for these very challenging patients. Thank you. Either any questions or points that anybody wanna raise about this? As Marissa is saying, it's real world stuff. Hands are often tied by what we get. Currents will cover and by the side effects of medication. For both, ocular only or systemic disease. Sorry, for both ocular and systemic disease. So we're talking about vision-threatening information no matter how you cut it. So it's difficult. So you have on the one hand, yay, humor has been approved, now what? I mean, humor is not a magic bullet. It doesn't induce remission in most patients. So we still have a long way to go. In this patient, there are UVitis practitioners that would present the patients and look, we can't get alternatives approved. Reducer works really well for this disease or birdshot retinocardopathy. We're gonna bite the bullet and do a combined FAKO tube in the eye and the patient might do well, but it's a lot of surgery, right? In a faking patient and then with an epiret on that thing. So my kind of approach would be, I mean, if you're against the wall, then maybe that's what you have to do, but I think it makes sense to try to avoid creating complications, okay? Rather than, you know, and treating them with agents that are alternative. So in any case, I'm really, really pleased that Dr. Pometza is here. He has been a great colleague and collaborator with many, many patients with particularly, you know, with ankylosing spondylitis and HLAB 27 associated disease, but much more. So he was certainly, he was very involved in that first case that we had and really I went to bat for this patient. So, you know, we have a patient that doesn't have insurance. We try to pull out all the stops at the Moran and the Department of Rheumatology to help our patients with cold systemic autism. So I'll give you Dr. Pometza. Okay, I want to thank Dr. White-Haley and Marisa for giving me this opportunity. So I'm going to focus more on the biologic therapies, what we have on the rheumatology side and which also work really well for UV-itis in autoimmune diseases. But I also want to briefly talk about the epidemiology, the immunopathology, because that's what helps us understand why these biologics do work in different forms of UV-itis. We often encounter both in the UV-itis clinic and the rheumatology clinic. So we know rheumatologic diseases can manifest as a variety of ophthalmology conditions from UV-itis, scleritis, retinal vascularitis, and xeroptalamia. And we know, like listed here, so predominantly every rheumatologic disease we take care of can cause some form of ocular manifestation. But the most common ones, we see are anchors and spawned alitis. Okay. So as I said, we know several rheumatologic conditions can cause different forms of ocular inflammation, but predominantly the most common ones we encounter in our rheumatology practice are anchoring spawned alitis, GIAs, sarcoidosis, and HLAB-20s and spawned arthritis which are the common cause of UV-itis. We know that the coexistence of UV-itis and arthritis happens quite frequently and this suggests there's some shared pathogenesis happening in these two conditions. This also is better understood because we know this inflammatory cytokines like TNF, IL-6, IL-17, they've been associated with increased evidence in inflammatory eye conditions. We also know both anchoring spawned alitis and UV-itis patients share so many common risk factors like B-27, IL-23 receptors, polymorphisms, and ERAP halotypes as well. So this will meta-analysis which looked at the different prevalence of rheumatologic conditions all over the world and it highlights that some rheumatologic conditions are more likely to cause UV-itis. The most common one is HLAB-27 and it showed the prevalence of this in UV-itis codes could be anywhere from 2% to 11% predominantly in Caucasians, this can be a significant cause of UV-itis. JIA sarcoidosis and anchoring spawned alitis are also very commonly associated with UV-itis. And BESHITs is of important because these patients can have severe forms of pan-UV-itis which can complicate vision due to retinal vasculitis and macular edema. So from the immunopathology, the majority of the inflammatory diseases they happen due to dysregulation of your innate and your adaptive immune system and which includes your macrophages, your B cells, your T cells and genetic cells. And the end result of this dysregulation results in production of multiple pro-inflammatory cytokines like your TA tumor necrosis factor, IL-6, IL-17 and interferon. However, the primary cytokine target from changes with different inflammatory diseases. On the right, this demonstrates the different cytokines which are associated with the pathogenesis in BESHITs HLAB-27 and sarcoidosis. But the one common factor in all these three is TNF alpha. And that explains why TNF inhibitors seem to be effective in BESHITs, HLAB-27, some spondyloctritis. And even in sarcoidosis, we use it in off-label when patients do not respond to methotrexate. But if you look further down, there are differences in the underlying pathology. In sarcoidosis, macrophages play a huge role. They secrete serum amyloid which causes the granulomas and the inflammatory response. Whereas in HLAB-27, it's predominantly the TH-17 cells which secrete IL-17 and TNF alpha. And whereas in BESHITs, it's the combination of CD8 T cells and the TH-17 cells. And you can see there's a multiple cytokines involved in the pathogenesis. And that could explain the severity of UVITs in BESHITs disease. So immunosuppressive therapies have been successful in reducing the CVRT of UVITs and also induce remission. But the choice of immune suppressant therapy differs based on the underlying rheumatologic condition and the CVRT of UVITs. And this is where it's important for the rheumatologist coordinate with the ophthalmologist to identify which is the most appropriate therapeutic agent for each individual patient. And this therapy should be considered promptly in patients with recalcitrant or ithrating UVITs or if disease questions cannot be obtained with corticosteroids. And as ophthalmologists be in rheumatology, we're also concerned about prolonged courses of steroids. So in patients who are unable to achieve questions on glucoporticoids, we would like to use a steroid-sparing agent to reduce long-term toxicity. So methotrexate, mycophenolate, and azotypina are the most commonly used nonbiologic immune suppressant therapies. I just mentioned the mastrial, but Dr. White-Elly talked about it. I'm going to skip this, but this did confirm that patients on systemic immune suppressant therapy definitely do better in the long-term compared to the intravitous rheucinolone. So however, the treating provider should review the patient's comorbidities, the medication interactions, and assess risk factors of toxicity before choosing appropriate immune suppressant therapy. And methotrexate is the first choice of systemic immune therapy, but there are certain individuals where we should avoid methotrexate. If they have prior liver disease or previous exposure to have B or C, we should avoid methotrexate. Azotypine is a good alternative for methotrexate, but it's common practice in rheumatology. We check thiopurine methyl transferase enzyme levels before we initiate azotypine. So a small group of patients who are low on TPMT level, there are significant risk of azotypine toxicity where it can cause severe bone marrow suppression and result in pancytopenia. So we like to make sure they have adequate TPMT levels before we initiate azotypine. So this slide summarizes the evidence for different immune suppressant therapies which are shown to treat several different types of EVitis. The most data is available for mycophenolate, which is shown in like 13 different, either case series or small studies where it's very effective. It not only controls inflammation, it also improves visual acuity. Similarly as a type and also is shown to be effective to treat. However, it's not as effective in improving visual acuity, but it's shown to be very good to reduce inflammation and methotrexate is also very effective. I also listed cyclophosphamide and calcineuronimidus, but they have not been used as much lately because of the emergence of all the biologic therapies. So that has reduced the need for cyclophosphamide and calcineuronimidus. So anti-KNF agents were the first biologic therapy we approved for rheumatoid arthritis and that revolutionized how we treat rheumatologic diseases. So these biologic game arts are often considered when patients fail systemic immune therapies like methotrexate or is a type ring. And Adilumab was the first agent which was approved for EVitis and visual one in the visual two trials as Dr. White-Alley mentioned, proved the safety of efficacy. So there was one study called psychomore study. This looked at the effects of, as Adilumab, methotrexate versus methotrexate alone in GI patients with refractory EVitis. And this also confirmed Adilumab is very effective in inducing remission in GI patients with refractory EVitis. There was one comparative study which was done in Bechet's disease with refractory EVitis and they compared infliximab versus Adilumab. And they had 177 cases of Bechet's disease with refractory EVitis and failed steroids and immune suppressive therapy. And in this study, they followed up after one year and it showed Adilumab appears to be associated with better outcomes compared to infliximab. So from this study and other case series, Adilumab became the first choice anti-kinetic agent. And in patients who fail Adilumab, we often pursue infliximab. So there are certain advantages with infliximab. So one is it offers you to do a weight-based dosing and you can also type rate dose anywhere from five milligrams up to 10 milligrams. And rarely we can do up to 15 milligrams like we did in the previous patients. So patients who are in consistent refractory EVitis with no response to Adilumab, infliximab offers a great opportunities. So I want to quickly mention Certilismab. So the one good indication of Certilismab is in pregnant women as there is no placental transfer of Certilismab from moms to infants. So this is the preferred anti-kinetic agent in pregnant women who need a biologic agent. So this table also shows you the evidence of the different studies which prove the efficacy of infliximab, Adilumab and Golmumab. So infliximab has shown to be very effective to create different types of anterior posterior EVitis complicated by retinal vasculitis. It's also shown to be very effective to treat vicious disease and sarcoidosis patients with non-infectious EVitis. It's also shown to be effective to treat VKH disease and bird shot choreography. All of these are off-label use but definitely there is enough evidence to show infliximab and Adilumab are good alternative therapies for patients with refractory EVitis. However, we are running into trouble because there are a lot of patients who do not respond to an anti-TNF agent. So data from the RA trial showed us that 25 to 40% of the patients do not respond to an anti-TNF agent. So this is where it gets tricky what will be the next choice of treatment. So the TNF non-responders, we either deal with the primary non-responders or secondary non-responders. So these are people who had minimal or no response to an anti-TNF agent. Most likely these patients, the disease process is not driven by a TNF dependent pathway and that explains a lack of response. The data from RA trial shows that in primary non-responders, we do not recommend cycling through multiple TNF agents because either they're not going to improve the clinical response or you're risking disease progression. So in primary non-responders, we recommend to switch to different class of biologics. In secondary non-responders, these are patients that have good initial response, but over time, the low therapeutic response, this can happen either due to the patients develop a neutralizing antibody to the monoclonal antibody or there was disease progression. In these patients, you can try dose escalation like your patient is on a hemorrhage every two weeks, we can try to do it weekly or switch to infliximab and try high dosing infusions. And this lists several reasons why a patient may not respond to a certain biologic agent. So this is a flowchart of how we manage patients who fail an anti-TNF blocker. So in patients who are active RA and they try the TNF blocker and if they do not respond to a initial anti-TNF agent, the options we have are abatosep, riteximab and tosylizumab. So in patients who have a positive rheumatoid factor and a positive CCP antibody study showed they have a better chance of responding to riteximab. However, if the patients are negative for CCP antibody, they may not respond to riteximab. In those, you would either choose abatosep or tosylizumab. If this patient is a secondary non-responder, you can still consider a second TNF blocker or you can just switch to a different class of medication. And further down, if they do not respond to any of these biologics, you can pursue the Jack inhibitors which have been very effective for RA and other inflammatory arthritis. So this is a flowchart of what we have available options for HLA-B-272. Unfortunately, the options are limited in this patient population and so the managing TNF non-responders can be a little bit tricky. If they fail Humira 40 milligrams every two weeks, we still pursue either infliximab or symphony because the data on IL-17 is still in conclusive. So we either initiate infliximab or switch over to symphony. So one of the options is if patient has well-controlled AS in which predominantly to manage UVitis, we can add methotrexate or microfinolate and that has shown to be efficacious to control UVitis. If patient fails another anti-TNF agent, then we are bound to switch to an IL-17 inhibitor. So the evidence of IL-17 inhibitor, as I said, is still in conclusive. So if we're using this to treat recurrent UVitis, the recommendation is used to combine with methotrexate to improve the outcomes. And jack inhibitors are also now approved for HLAB 27 spawn lactritis. So I want to talk about each cytokine inhibitor. So IL-17 inhibitors, they have important role aid spawn lactritis and autoimmune UVitis and TH-17 cells are the major source of IL-17. We also have data from animal models and human models that suggest IL-17 is an important cytokine in UVitis. So we have two different IL-17 antagonists, Psechokinomab and Ixokinomab, and they're shown to be very effective in psoriasis, ankylosing spondylitis and psoriatic arthritis. So both the Psechokinomab and Ixokinomab predominantly block IL-17A, which is the most important isoform of IL-17. However, these IL-17 agents don't seem to help in RA or Crohn's disease or refractory UVitis. So there have been some studies for IL-17 inhibitors in UVitis patients. So there were three randomized studies which looked at the evidence of Psechokinomab in UVitis patients. Unfortunately, the primary outcome did not show any difference in the UVitis recurrence between the treatment group and the placebo group. However, on further analysis, the secondary efficacy data did suggest that Psechokinomab does have a beneficial effect in reducing the use of concomitant immune suppressing medications. So Dr. Deodar and Etal, what they did was did a pool analysis to study the incidence of UVitis in the trials of Psechokinomab. In pool analysis, they found the incident rates of UVitis was 1.4 episodes per 100 patient years. Majority of these patients are HLAB 27 and 17% of them had prior risk of UVitis. So they compared the exposure-adjusted incident rates of IL-17 with TNF agents. In TNF agents, the incident rates were 2.6 to 3.5 per 100 patient years. So their difference wasn't bad. So overall, this pool analysis suggested that there is no increased risk of UVitis in Psechokinomab exposed cohorts. IL-12 and IL-23 cytokines are also associated with inflammatory diseases. So Psechokinomab is the only IL-12 and 23 monoclonal antibody, which is approved to treat psoriasis, PSA, and Crohn's disease. There are multiple monoclonal antibodies, which target the P-19 subunit of IL-23, but it does not block IL-12. These monoclonal antibodies seem to have a very limited role. They're only going to be effective in psoriasis. And unfortunately, this IL-23 inhibition did not seem to work in agile spawn law arthritis. So overall, we know that IL-23 inhibition may have a role in UVitis, but currently we don't have enough evidence to support the use in refractory UVitis. I think there are some few small case theories of which used Psechokinomab in patients' disease with some improved outcomes. So this slide summarizes the different IL-12, 23 antibodies and IL-17 antibodies. So the Psechokinomab and Psechokinomab has been approved by FDA for psoriasis, psoriatic arthritis, and ankylosing spondylitis. Psechokinomab, which I mentioned earlier, blocks IL-12, 23 also is very effective in psoriasis, psoriatic arthritis, and it's also effective in Crohn's disease, but these IL-23 monoclonal antibodies have a limited efficacy in psoriasis. So this briefly summarizes the algorithm or approach for treating UVitis in JIA. So I'm going to skip the stop part, like Dr. White already mentioned, if you fail systemic steroids and you can initiate as a type prurin or methotrexate, but once you try a systemic immune surface therapy, if patients continue to have refractory UVitis, you can consider edulomab or inphyxomab as I mentioned, edulomab is the preferred agent which has superior efficacy compared to inphyxomab. If patients fail these, you can switch over to abatocet protexomab or the tosylozomab. So IL-16 inhibitors, so studies showed patients who have glaucoma or ocular inflammatory diseases they're elevated serum IL-6 levels. IL-6 is also associated with complications like deovascularization and macular edema. So in patients who have UVitis secondary to RA or JIA, tosylozomab is shown to be very effective in inducing remission. Tosylozomab is only approved for RA, JIA, GCA, but it's quite often used off-label in patients' disease, tachiasis, stills disease and relapsing polychondritis. The common adverse effects associated with this are upper respiratory infections, neutropenia and gastrointestinal perforation. So patients who have history of divertical ITS or gastrointestinal perforation, they should avoid tosylozomab. The other IL-6 and monoclonal antibody is cerilumab which is also approved for RA and it's also shown to be very effective to treat non-infectious UVitis. And also want to quickly list that there are several other inflammatory diseases which are shown to respond to IL-6 inhibition. So there have been few randomized control styles which study the efficacy of tosylozomab. One of them is the stop UVitis and there was other study predominantly in refractory UVitis in JIA patients which also confirmed efficacy and safety of tosylozomab. In RA trials, we know both subcutaneous tosylozomab and intravenous tosylozomab are equally effective. However, in UVitis patients, IV tosylozomab is preferred over subcutaneous tosylozomab. So there was one case series of refractory UVitis where they compared IV versus subcutaneous tosylozomab. So these patients initially sustained remission with IV tosylozomab, but when they were switched over to subcutaneous tosylozomab, they had relapsed UVitis. So from this data, it's been decided that IV tosylozomab is preferred compared to subcutaneous injections. So T-cell inhibitors briefly, the one agent we have is abatosep which binds to CD86 and inhibits T-cell activation. It's only approved for RA. It can be used in TNF naive RA and also patients who failed anti-TNF agents. So abatosep has been shown in small case series to be very effective to treat refractory UVitis in JIA patients. IL-1 inhibitors have been approved in the last decade. So IL-1 is a primary cytokine that's involved in rheumatoid arthritis. So IL-1 inhibitors are approved in systemic JIA, adults on the stills disease, but it's still off-label for several conditions like BESHETs, UVitis, and other auto-inflammatory syndromes. So we have an echinol and kinamab which are very effective to treat BESHETs related UVitis. So Riteximab is a CD20 inhibitor which has been shown to be very effective for rheumatoid arthritis. And one of the pioneering trial is the reflex trial. So there are several different dosings of Riteximab, but the one we often use in rheumatology is 1,000 milligrams times two doses on day one and day 15. The other is the weekly dosing 375 milligrams per meter square, which is still often used sometimes in anchor vasculitis. Riteximab is recommended for patients if they fail one or two anti-TNF agents. It's also approved for inflammatory myositis and anchor vasculitis. But Riteximab has now become one of the go-to medication for patients with systemic lupus erythematosis or systemic sclerosis with systemic organ involvement like interstitial lung disease or lupus nepritis, but it's still off-label as of now. So we predominantly use the 1,000 milligram two doses, but there have been some trials to compare low dose Riteximab, which is 500 milligrams, two doses was 1,000 milligrams. And in this study, the most of the outcomes favored the high dose Riteximab. However, low dose Riteximab can be considered for maintenance treatment in patients who had a good response with initial therapies. So the maintenance treatment is every six months for active disease. However, in patients who had remission initially, you can wait and monitor for disease activity and you can delay the maintenance of infusions if patients are not manifesting any active disease. So one of the advantages of Riteximab is they have a sustained treatment response for up to six months or beyond. But however, it should be used with caution due to the increased infection and infusion reactions. So this was one study which looked at the long-term outcomes of Riteximab and which has shown to be very effective for non-infectious posterior uveitis. And the majority of these patients had either pan-uveitis with combined retinal vasculitis due to lupus or granuloma, polyangitis, and HLA-B27. In all of these patients, they had a good response to Riteximab. So Riteximab can also be considered for other inflammatory conditions we see in the setting of lupus and anchor vasculitis. So biosimilars are available for Riteximab and hopefully that will reduce the cost of these biologics. So jacked inhibitors have been approved for RA, AS, and PSA in the last decade. But there have been several other jacked inhibitors currently being studied in GI, hematology, and dermatology. So the current approved by jacked inhibitors include trophacetinib, baracetinib, and opacetinib. And they all block different giant kinases. And all of them have shown to be very effective to treat RA refractory tube biologic therapies. They have been some case reports of patients with refractory HLA-B27, IVITs, and JIA patients who failed given blockers, Riteximab, and Tosalizumab. In this case, reports of patients who were either tried trophacetinib or baracetinib were able to achieve remission of IVITs. However, there are still ongoing randomized control trials to confirm efficacy. Currently, patients who fail multiple therapies can be considered for either trophacetinib or baracetinib. So this lists the history of the approval of trophacetinib and the different jacking because of the last decade. But there is a word of caution which has come to light in the last two years. So trophacetinib was first approved in 2012 and it was like a game changer and most of the rheumatology were invited to use in some refractory patients. However, FDA announced box warning last year that jacked inhibitors are associated with increased risk of cardiac events, blood clots, and cancer. So this comes from an oral surveillance study in patients who received trophacetinib and they had demonstrated increased risk of major cardiovascular events, thrombotic events, malignancy compared to TNF inhibitors. So ACR released a statement earlier this year that jacked inhibitors should be used with caution in RA, PSA, and AS in their inadequate response of intolerance. In certain patients like smokers, men, older than 65, they have a prior cardiovascular event or stroke, you should try other biologic agents before you consider a jacked inhibitor. So last optimization of biologic. So there have been some studies going on to see can we reduce the frequency and the dosing of biologics to potentially reduce the healthcare costs and also reduce the risk of side effects. So several trials have been done in rheumatologic conditions. All of them showed that you can do careful down titration of biologics and still maintain therapeutic response with no flare-ups. But the one thing we learned from this is you should never withdraw biologics because they have a high risk of relapse. So there was one study which looked at optimization of adaluminum ab in refractory VI test patients due to basiats. In this patients, physicians were able to reduce the frequency of adaluminum ab down up to four to six weeks without relapse. So patients who had successful remission on biologics you can consider either prolonging the dosing interval or reducing the dose with closed monitoring. And quickly, what are the challenges we face day-to-day? One of the big thing I did not mention here is the cost. So we have so many patients who are either uninsured or their insurance doesn't pay for biologics. So we often have difficult decisions how we can provide them the right therapy. But beyond that, as the treating providers we need to understand the patients underlying comorbidities their prior exposure to infections and immunization status before you choose appropriate therapy. Patients who have stage four or stage five CHF if they have demyelinating neurologic diseases malignancy of prior infections like latent TB you should avoid anti-tunip agents. And we should make sure all of them receive appropriate immunization before we initiate biologic therapies and thankfully have pharmacists in our clinic who help us review patients information and help us make their up to date in all the vaccines. So there is some data that reactivation of TB is less in IL-17 inhibitors. So if somebody have a latent TB, IL-17 inhibitors can be used prior to TNF agents. And obviously the COVID pandemic has been a difficult period for everyone in the last two years. And one of the challenges we've been having is several patients have to switch to a salism app because of lack of availability. And it's slowly getting better. And finally, Jack inhibitors are the way to go but we should avoid them in high risk patients until we get further data. And thank you so much. It's been a long time and I'm open for questions.