 So, my name is Brent Price and I'm the administrator of the Moran Ice Center and it's really my pleasure today to be able to introduce to you this version of our DocTalks. We do this frequently and we specialize or we have different specialties come in and talk about their interests, their results and things that are happening in their area of the medical field. And so, really my pleasure to introduce Dr. Albert Fatali today. He is someone here at the Moran Ice Center that is deeply respected and loved by all of us. I was fortunate in the early days, 15 years ago, to be involved in helping get Dr. Fatali here to the University of Utah. His specialty is a really unique specialty, uveitis, and it's certainly one that is unique in the Intermountain West. He has, part of the design I'd like to say, but Dr. Fatali brought the specialty here for us and then since then has really built the Intermountain West specialty in uveitis and it has been able to recruit some other wonderful providers, some that you may know and we actually have another one who will be starting next month. So, it's a great testimony to what Dr. Fatali has been able to build inside of our national circles and international circles, the University of Utah Moran Ice Center and the uveitis program, it has become recognized as one of the leading programs in the country and when you say in the country that means also in the world. So, Dr. Fatali is of course a retina specialist as well and I'm assuming many of you know him because you've been in his clinics and in his partner's clinics and we're just really glad to have you here. We're glad for your interest and we hope that this really is informative for you and we know there are also families here. A couple of things to know about Dr. Fatali that I really appreciate is Dr. Fatali is really interested and concerned in our outreach program. What that means is taking healthcare to individuals who don't have good access to this healthcare. There's a fourth street clinic here in Salt Lake City and when Dr. Fatali came he introduced our residents, our medical students, himself going down to the clinic and volunteering their time. We have probably one of the best ophthalmology outreach programs in the country where we go throughout the world and he's participated in those activities as well, a deep interest for him and we love what he brings to us. It's kind of like giving back to the community and we have a program that he participates in where we go monthly down to the Navajo Nation and take healthcare to really that part of our state, we call it locally, that needs it. He helped introduce one of the things I'm very proud of here at the Moran Ice Center. It's quite glamorous to go throughout the world and these wonderful places like Ghana or I'm trying to think, Al, you're going to Myanmar, you've got a program at Myanmar and Mongolia but yet here locally we still have needs and so Dr. Fatali was instrumental in putting together a program where twice a year we're able to bring into our center into the Moran Ice Center where the employees volunteer their time, the doctors and residents volunteer their time and coordinate with even pharmaceutical companies and we bring them into our, we bring people who don't have access to care, couldn't pay for it, bring them here on a Saturday and we line up these surgeries on a Saturday for indigent patients, patients who just don't have access to care and we're able to provide that care and I love the fact that it's local and that we're giving back to the community but also that it's easy for individuals here at the Moran Ice Center to participate and not having to fly across the globe. So a couple of interesting facts about Dr. Fatali is that he loves to ski so hopefully you get to see him up on the mountain with his family. He also plays the guitar. He's in a band and the name of the band is vital signs so there you go, kind of the life of a doctor and the personal life never really get disconnected as you know as Dr. Fatali was preparing for this talk he's on his cell phone taking care of a patient just minutes ago and so that's the life of a doctor. We're very fortunate to have Dr. Fatali here at the Moran Ice Center. We're grateful for all that he does and so please give him a warm welcome. Thank you very much Brent for that generous introduction really I'm really I forgot one thing may I yeah size is taller than me so I didn't forget that part. Each of you have cards, comment cards and so if you have questions write them on your card we'll push them over to this side of the table and we'll have some individuals pick those cards up as we get to the point where you may have questions. Sorry, no problem. Well thank you once again I'm I see a lot of familiar faces in the audience some of you are retina patients some of you are uveitis patients and the topic of today's talk is really about inflammatory ocular disease so the other hats that I wear the uveitis kind of hat so many of you may or may not be familiar with you know an entertainer Brock started named Sting he wrote a he was a member of the police he wrote a song in which one of the lyrics was pour over everything in my CV and you still know nothing about me so I thought I'd tell you a little bit about myself in addition to what Brent has told you so in a previous lifetime before I came to the Moran Ice Center I was doing much of what I was doing here at the King Khaled Ice Specialist Hospital in Saudi Arabia and I spent seven years doing doing that after I finished my fellowship training in actuality my real job title is wild animal trainer this is my wife and these are the four wild animals that I have had the pleasure of training throughout my lifetime here they are your your eyes don't deceive you these are actually the same age they're triplets this is the older son who's was just you know a year and a half older and this is the day that we decided to move to this is in Kennedy Airport before embarking on a plane to Saudi Arabia and I think my son here is kind of looking at me like sure you know you're doing here dad and said no no really the the the housing is tremendous in Saudi Arabia you're gonna love it ultra-modern incredibly beautiful and the sandboxes are just phenomenal this is actually 45 minutes from our home and we used to go there regularly it's weirdly prescient of Southern Utah anyhow and this was my wife who is was getting extremely good at juggling with four objects a art that she is mastering to this day and about six years into our journey there I got a call from and Randy Olson I asked me if I would consider coming to Utah I didn't have to think twice about that and so I pitched the idea to my wife and she's kind of like here's saying now let me get this straight okay so you you bring me to Saudi Arabia okay and you want me to go to Utah desert to desert you know religious fundamentalism to read a list to conservatism prohibitions on alcohol and and what is this with more than one wife I don't get this so I said no but seriously desert blooms there are absolutely more beautiful than they are in Saudi Arabia this is a view out of our front door down immigration can during the springtime this is the view out our front door during the wintertime you can see there are a few more houses there there was a day when I used to say follow me guys when we'd ski together as a family and sure enough here's my son crossing eights and we're getting buried in powder the most feared words on the mountain these days for me are follow me dad I long past the you know the time of getting upside down on skis if you this is my son Ryan who is also a competitive longboarder if you want a interesting YouTube video look up when reindeer attack it is a YouTube video that was taken purely by chance of him in a warm-up run clotting with a deer going about 45 miles an hour fortunately both the deer and he are fine my daughters are I actually accomplish the question they everybody seems to like speed or getting air in my family my son and I are surfing partners we surf a lot down in Mexico together and my brother and I are also serving partners and we share a similar passion for music and we play together sometimes I sit in on his band his band is the vital signs my band used to be called you feel blues so this is my family now we they certainly grown in size and we flourished here in Utah this is my family getting while we also it's grown in number we have you know our unofficial adopted son nephew Kellan the black sheep of the family and we also have a an extended extended family here you may recognize some of the people here is Dr. Shakur over Thanksgiving and one of our residents here and then our kind of extended family in Mexico so the we're not quite empty nesters the two people that are living at home our dogs Ian Zeus and then my daughter Sophia but my wife and I are still doing fine and crazy after all these years so today the objectives of this talk is really to introduce you to a broad overview of the diagnosis and treatment of ocular inflammatory disease okay I would like to define it try to give you an appreciation for the magnitude of the problem our diagnostic approach our treatment approach including immunomodulation and new therapies that are available and then some important clinical trials that we have been involved in at the Moran eye center since I've been here so what is uveitis uveitis per se the definition the uveal tract is actually the inner layer of the eye inflammation of the inner layer of the eye but when we talk about uveitis it really refers to intraocular inflammation inflammation inside the eye and uveitis is not just one disease but it's about it's more than 30 separate diseases with defined clinical features with specific treatment indications they can be broadly thought of as either being infectious or not infectious and many of them the non-infectious ones are of an auto-inflammatory or autoimmune ideology we also there are also entities that simulate inflammation the eye such as neoplasms or cancers in the eye it is the third leading cause of blindness worldwide so this is not a small problem in the United States it accounts for about 10 to 15 percent of blindness and is the fifth to sixth leading cause of blindness behind diabetes in age-related macular degeneration the fact that this disease has its peak onset in the 30s and 40s suggests that maybe the personal economic impact of uveitis maybe even worse and greater than that of age-related diseases how do we approach the patient with uveitis it's it's more like the experience you have with your internist okay so that the history of the ophthalmic and the medical history is extremely important in patients with uveitis sir William Osler the father of American medicine said listen to your patient he's telling you your diagnosis so actually taking a good history both in the clinic and by means of a questionnaire is very important then we conduct an accurate examination and a general medical examination to the extent that we can perform it in the clinic sometimes just looking at a patient's hands or skin can give us some clues about the diagnosis and then we formulate a differential diagnosis this is the key to diagnosis in patients with uveitis what are the likely diagnostic entities based on this information so we generated differential diagnosis by characterizing inflammation along several different dimensions where it is located in the eye the anatomic location what is the presentation is it acute is it chronic is it one eye or both eyes what did the lesions look like in front of the eye or in the back of the eye how many are there and describe them what are the host factors that is what are the things about the person is this part of a systemic disease entity that we know about in patient or is it purely disease that's confined to the eye there are certain diseases such as sarcoidosis that is a systemic disease or infectious systemic disease such as syphilis or not our West Nile disease then the immunocompetence of the patient is key is the patient otherwise healthy or are they on medications that suppress their immune system to begin with or do they have a immunosuppressive disease such as HIV AIDS then the demographics that means where in the world are they from you know I mean certain diseases are more common in certain parts of the world and with our shrinking world these days with air travel and the fact that the Moran eye center is a tertiary care referral center this is quite important and then the associated signs and the associated symptoms so if you take a look at these pictures here this is a a rash that is called erythema migrans and then the right clinical context this is diagnostic of Lyme disease whereas this lady her natural pigmentation is dark and she has vitiligo and whitening of her eyelashes is associated with systemic illness called vkh or voitinagi herata syndrome then based on this information we direct our laboratory tests and then formulate a treatment plan based based on our our laboratory results and our diagnosis then we assess the treatment and monitor for side effects of toxicity that's a broad overview of how we approach the patient so when I first arrived here I was fortunate enough to participate in a workshop called the standardization of uviatus nomenclature or the sun working group in which a group of uviatus experts from around the world got together and decided to agree upon what we're going to agree on what we call uviatus and how we're going to classify it so to facilitate our communication together for research purposes and then in the literature and then of course when we're talking to each other about inflammatory diseases so we have classified there are many ways to classify uviatus but the way we have generally agreed to classify it is on an anatomic basis that is is the inflammation located primarily in the front of the eye that we call anterior uviatus or intermediate uviatus in which the inflammation is located in the vitreous gel of the eye in the peripheral retina or posterior uviatus which by definition involves inflammation of the retina and coroid or pan uviatus where the inflammation exists throughout the eye in all three chambers so to illustrate this we can see this patient having a red eye with an inflammatory collection of material in the front of the eye an anterior uviatus this patient has intermediate uviatus this is what we see when we look at the eye with these cell these accumulations of cells in the gel or the vitreous of the eye this is a posterior uviatus patient with toxoplasmosis with an active focus of inflammation of in the retina here and this is a patient with vkh disease with inflammation throughout the eye and an exudative retinal detachment we also agreed to what we mean when we talk about acute and chronic disease so an acute illness is one that has a sudden onset and a limited duration. Recurrent disease are episodes that are marked by periods of inactivity arbitrarily defined as three months off of medication and chronic disease is inflammation that persists despite tapering off of medications so i just thought i'd just run through give you some examples and some pictures of the major anterior uviatic diseases so we can again classify them as infectious or those associated with systemic disease this is an example of a patient with herpetic anterior uviatus this is a patient with HLAB27 associated disease these patients will present with an acute onset with pain redness and difficulty vision and photophobia difficulty with lights this is an accumulation of inflammatory cells in the front part of the eye. Contrast that to the more insidious and chronic onset of juvenile idiopathic arthritis associated disease in this young child with a white eye with chronic inflammation which has resulted in this cataract this is a patient with sarcoid associated uviatus with these deposits on the cornea of the eye with a chronic inflammatory course and this is a patient with you will notice has two different colored irises this is fuchs heterochromic ergo cyclitis which is a chronic disease the major disease of intermediate uviatus again is inflammation centered in the gel of the eye and the peripheral retina can be infectious or that can be part of a systemic condition one sees inflammatory exudates in the peripheral retina and what is commonly called a snow bank this is what we see when we look inside of the eye visual acuity is frequently affected by leaking of blood from blood vessels in the center of the vision this is a fluorescein angiogram which shows leakage of dye in the center of the vision so-called macular demons will talk about a little bit more detail these are the inflammatory exudates that we see in patients with intermediate type of uviatus we also frequently see patients with involvement of their blood vessels so-called vasculitis and this is seen also on fluorescein angiography this is a new modality a wide field fluorescein angiogram which shows in very magnificent detail the involvement of the peripheral blood vessels this is an indicator of active inflammation in the eye posterior uviatus by definition involves inflammation either in the retina such as this patient with with toxoplasmic retina corditis or in the chloride which is the the layer behind the retina deeper to the retina in this patient with tuberculosis disease it's important for us to characterize delusions their morphology the number their location whether or not they're involved in the back of the eye or in the periphery so some of the descriptors that we often use are amoeboid if you see a patient with an amoeboid type of picture like this this is characteristic of a disease entity that we call serpiginous corditis these lesions are flat we call these placoid this is characteristic of a inflammatory condition called ampy or acute posterior multifocal placoid posterior apophiliopathy these are orange ovoid lesions that are characteristic of a patient with birdshot retina cordopathy these are the more punched out lesions that are pigmented that are characteristic of a patient with multifocal corditis in panneuvietis and this patient has a scar near the center of the vision due to a cordal nevascular membrane which can complicate this disease and decrease central vision this you could hardly see the white dots here and these are this is part of an entity called multiple evanescent white dots syndrome beautiful name isn't and the white dots are indeed evanescent they come and they go and they one may miss them and be just left with this kind of granularity in in the macular in that back of the eye the major diseases a posterior visual listed here both infectious and non-infectious this is a patient with a cmv retinitis a viral condition that we see sometimes in immunocompromised patients and patients with hiv aids this is a non-infectious disease of sarcoidosis with very bad involvement in the back of the eye affecting not only the retina but the chloride and the gel and the red blood vessels and this is a peculiar white dot syndrome called relentless placoid cordopathy in which the inflammation starts from the periphery and has relentlessly kind of involved the entire retina fortunately for this patient sparing their central vision and then there's panneuvietis the major disease is called panneuvietis you'll notice that syphilis and sarcoidosis are two entities that are listed here because they are classically known as the great imitators they can do anything they want they can show up anywhere in the eye and really present in any fashion this happens to be a patient with syphilitic posterior cordorotinitis this is a example of a patient with void kinyagi herata syndrome i showed you the picture of the lady with the depigmented face this was actually a young saudi woman and if to the trained eye one can see that the details of the retina are obscured because there's fluid underneath the retina indeed when we perform a fluorescein angiogram on this patient we can see these large pockets of fluid that are characteristic of this disease and then these are the lesions of a patient with sympathetic ophthalmia that had had surgery or rather had trauma in their fellow eye and unfortunately had developed an inflammatory condition in their better eye a very unusual disease indeed so we are in the business of vision as uvi specialist and i vision the best corrective vision is really an important thing to assess when we examine the patient we assess their intraocular pressure and then we have come up with a a kind of a standardized way to grade the inflammation and i just like to show you what we see when we look in the eye in a patient with inflammation so these are cells in the anterior chamber you may hear me say or there are there one plus two plus three plus cells in the anterior chamber and we grade them according to the number of cells that we can identify in a slit beam when we examine the eye and we grade it accordingly similarly we grade flare flare is due to leakage of protein in patients with chronic uviitis in the anterior chamber and it's very similar to the chefs of light that you see after a rainstorm or some of you may remember going to a movie theater and having someone smoke in the movie theater and seeing chefs of light due to particulate matter in the air so the particulate matter is protein in the eye and flare is actually graded to the degree to which it obscures the structures in the front part of the eye similarly when we look into the back of the eye we get a a large a picture of the posterior aspect of the eye this is the optic nerve and the blood vessels coming off of here and this is a very clear view we can see the structures very clearly but in patients with intraocular inflammation in the back of the eye that can become progressively more obscured depending upon the degree of inflammation in the eye so we grade it on a scale of zero to four plus to the degree to which it obscures the structures in the eye so why do we work patients up with laboratories well it's very important to exclude infections we don't want to treat a patient with infection with a steroid medication which would make an infection worse then we want to identify systemic diseases they may that may impact on the health of our patients and i'll show you some examples of that and then this will guide appropriate treatment as to whether or not we use a steroid or an immunomodulator or antimicrobial medication and then to provide some prognostic information for the patient because not all information is the same in the eye the workup is selective based upon our history and our review of systems we start from the more common to the more rare we always consider the masqueraders such as syphilis, sarcoid and tb in our differential diagnosis because these are syphilis is a disease that everybody is at risk for if you're alive and we can cure it with penicillin and then we always consider masquerade syndromes what i mean by masquerade syndromes are those entities that simulate inflammation but are actually not inflammatory but they are due to cancers or lymphomas or other vision threatening and then life threatening entities in the eye sometimes it's we perform a very targeted screen for example if we see something like this in the eye this is called neural retinitis we see that the optic nerve is involved and there are these what we call a macular star get these exudates around the center of the vision this is characteristic of neural retinitis and we know statistically speaking that the most common cause of neural retinitis is infectious agent due to bartonella the group of bacteria called bartonella which is responsible for cat scratch disease similarly if we see these kind of these punched out lesions in a patient in september that has had a episode of encephalitis and they're diabetic we would we might think of west null virus because that's the time of year that comes and this is very characteristic of west null virus and then if we see a patient for example of these necrotizing lesions in their peripheral retina that coalesce we would certainly want to get a sample of fluid from the front part of the rye because this is a viral infection that can destroy the eye quickly we don't routinely screen patients for some of these agents such as viruses and toxoplasmosis because they have a very high prevalence in the in the population so we don't take the blood to look for that but we targeted based upon what we're seeing in the eye if we took 100 patients that came in with isolated anterior uveitis that was acute 50 of those patients would be positive for this gene HLAB 27 and the importance of that is that HLAB 27 is associated with an immune response gene but it is also associated with a group of diseases that cause arthritis particularly in young people so if we can and about two-thirds of patients that present with anterior uveitis will have an undiagnosed arthritis so when we're we see a patient that has this we will screen for that and we'll ask them in our history do you have back pain have you do you have skin lesions and things like that that they do we send them to a rheumatologist because the treatment this is systemic treatment that we can offer that patient may prevent that patient from having severe deforming arthritis later in on in their life sarcoidosis is a disease you've all probably heard of it is a inflammatory granulomas disease can affect almost any organ in the body usually the most common organs affected are the lungs the skin the lymph nodes and the eye and in about 25 percent of patients with sarcoidosis may have uveitis and it may look like these nodules in the front part of the eye or this very severe inflammatory picture that I showed you earlier so we work patients up for specific for specific laboratories that may help us in the diagnosis of sarcoidosis but this only gives us a clue because the diagnosis of this condition is really one of exclusion and requires a biopsy chest x-ray is a very useful screening test for patients with sarcoidosis because they have characteristic changes in their lungs and if and they also have characteristic changes on CT scan but the definitive diagnosis is a diagnosis of exclusion and shows these the systopathologic alteration and the most common place that this may maybe in the lungs but we also look for other sites that may not be as invasive such as the skin or underneath the eyelid where we might actually obtain a biopsy make a diagnosis and save a patient a trip to bronchoscopy so we also perform imaging such as MRI scanning on patients that may have systemic conditions that may masquerade as or be involved in inflammation such as tuberculosis and lymphoma this is a patient that has swelling of their parotid gland with sarcoidosis in patients in which we don't have no view into the back of the eye we can perform ultrasound on their eye to get an idea of what's going on in the back of the eye certainly this patient has all these large caroidal masses in the back of the eye this is a patient you don't want to have a surgical immature in until you know it's back in the back of their eye fluorescein angiography is a extremely sensitive and valuable modality in which we eject dye into a peripheral vein and take a series of photographs into the back of the eye and look at the vascular pattern that is produced here you can see that there's leakage here around the blood vessels and in patients with the inflammation in the eye many patients will have leakage of their blood vessels and it can be used very well diagnostically in certain conditions and it can also be helpful for us in terms of monitoring the response treatment there's another imaging modality called ICG angiography which actually looks at it layer deeper than the retina so in entities in which the coroid is involved such as tuberculosis or in patients with deep lesions such as birdshot retina cordopathy we see these defects in the back of the eye which can be very helpful diagnostically and in terms of following the patient in time the this is a anatomic picture of the back of the eye as seen by OCT ocular coherence tomography which has kind of been a game changer in our assessment of patients both retinal diseases and with ocular inflammatory disease because it can provide us with quantitative real-time information in a non-invasive fashion so it's just like going to have a picture taken this is a normal appearing retina in the back of the eye this is clearly abnormal which has a lot of clear spaces and swelling both under the retina and within the retina and we can actually quantify the amount of swelling that's there sometimes the swelling is not due to inflammation but could be due to pulling on the retina from the gel of the eye so this has given us a lot of info can give us a lot of information about why they're swelling in the back of the eye it also gives us an idea of what the layers of the retina look like back here that can help us tell the patient why they might be having visual loss finally there is a newer modality called autofluorescence which gives us an idea of what's happening in the pigment epithelium which is the layer on which the retina rests certain types of inflammatory disease will produce these atrophic black areas on autofluorescence and sometimes they may produce these brighter areas which suggest there may be active inflammation in those areas so these are clues that help us decide on what's active what's not what needs to be treated and then how we can follow patients in time so a lot of what i've shown you is kind of pattern recognition and certainly retina specialists depend a lot on pattern recognition making their diagnosis but look at these two slides here i mean things aren't always what they appear to be right okay so to a trained uveitis specialist or retina specialist if we looked at this in the right clinical context we would make the diagnosis of toxoplasmic retinal corditis without ordering a laboratory test similarly if a patient with HIV AIDS entered my clinic and had this picture we would make a diagnosis of CMD retinitis however if an immunosuppressed patient came in and had a picture like this i couldn't tell whether or not that was toxoplasmosis or whether it was due to an infection due to a bacteria whether or it was due to a viral infection similarly in this particular case in an older patient with these types of infiltrates underneath their retina we cannot tell whether or not that's due to an infection or due to an infiltrate from say for example lymphoma so we can't just tell by looking so we need a little bit more information and sometimes it's it's necessary to actually obtain tissue from the eye inside the eye or in the retina and the core in order to make that determination so we have to biopsy the fluids from the eye or the tissue of the eye and it is extremely important when the clinical presentation is insufficient to make the diagnosis or it's atypical or if the patient hasn't responded to therapy in the way that you think that they might have so for example you might give a patient some steroids and they get worse and the first thing that i would think about is maybe they have an infection that i've missed so we have to it's extremely helpful in patients with suspected intraocular infection or suspected intraocular malignancy because the biopsy has the power to really alter your management of that patient because the treatment of those things is completely different and how do we do that well we can take a sample from the front part of the eye we can take a sample from the gel of the eye with just a needle which we do sometimes on an emergent basis and a patient that may have had an infection after an operation from their eye and then there are other times in which we perform a vitrectomy in the operating room that gives us a controlled removal of the gel from the eye and allows us to take large samples for example when the differential diagnosis is very broad and we have to order a number of tests in order to try to narrow the diagnosis so just we're halfway there okay so that's the diagnostic approach just to recap we do a comprehensive medical examination or review of systems okay we come do a complete auger examination and a medical examination to the extent that we can do it and then we form a differential diagnosis the key then we order laboratory tests and ancillary investigations based upon this information make a diagnosis and have a working diagnosis what do we want what are the goals of treatment well we want to eliminate inflammation that's the key we want to eliminate inflammation to control acute activity that can destroy the eye quickly promptly we want to suppress chronic and recurrent disease and hopefully induce a remission of this disease in the patient this is all in an effort to prevent ocular structural damage to the eye which can impair vision we want to do all of this and to avoid side effects and systemic complications to the patient so we want to have our cake and we want to eat it at the same time and i think it's possible to do this in most cases so what's the approach well we have a working diagnosis there are certain diseases which we there are specific indications for therapy so if we have an infectious disease we treat it with an antibiotic if we have a non-infectious disease we employ a step ladder algorithm which i'm going to describe to you in more detail and there are certain diseases that are non-infectious for which we have specific treatments for but we always in the back of our minds are willing to reconsider our diagnosis because patients may have an atypical response to treatment or new findings may emerge which may change your mind about the about the diagnosis patient patients eyes don't always read textbooks okay and you know so so things change in time so this algorithm i hate the word algorithm because it implies that this is what we do all the time but in general this is this is our approach and our approach is to use steroids for patients that don't that patients that don't have infection in the right to use steroids by every route that we possibly can to suppress inflammation so topical steroids that is drops for anterior uvias periocular and intravitral steroids that is injectable steroids in and around the eye systemic steroids if we need to do that steroids sparing immunomodulatory therapy which i'll talk to you about both conventional and and employing newer biological agents and then sometimes we perform we need to perform ocular surgery both diagnostically and then therapeutically for the complications that may arise from chronic inflammation in the eye so the route and the and the choice of treatment are really determined by where the inflammation is located in the eye okay the ocular complications that we see and the systemic health of the patient so if a patient has purely anterior uvias topical steroids or drops will suffice the exception to that is children with idiopathic arthritis that have chronic disease topical steroids will not penetrate to the back of the eye so for patients with intermediate and posterior impending vitis we have to employ a different route so we need to inject steroids either in or around the eye or use systemic corticosteroids or implantable devices which i'm going to show you about so as far as topical steroids are concerned we use them frequently we try to get a response and then we taper once we have a response frequently we'll put patients on a dilating drop a cycloplegic because this helps with comfort in the for patients with anterior uvias and also we attempt to move the pupil so that the iris does not become stuck to the lens in the back of the eye periocular steroids means injectable steroids in or around the eye and this can provide locals drug delivery for about three months the indications for this would be the ideal patient would have an acute and remitting intermediate posterior or pan uvias that is it has defined periods of activity and non activity and the ideal patient with had it would have unilateral disease that you only need to inject one eye or in patients with swelling in the back of the eye which i'll talk to you about a little bit more so how can we inject the steroids we can inject it underneath the eye through in the orbital floor we can inject it on the surface of the eye as depicted here we can inject it into the eye such as an intervictural steroid as you see here and then there's a company that's come up with a kind of fancy method for injecting dexamethasone this so-called azuredex implant implantable device that injects a pellet of a steroid into the back of the eye all of these are effective for a while in treating inflammation in the eye the problem with steroid administration particularly frequent topical steroids or injectable steroids is the accurate complications that can arise including cataract and glaucoma which do happen eventually if steroids are given often enough in patients the the problem therapeutically is also that it is relatively short acting so it would be a less effective choice for a patient with a chronic disease right it is helpful as an adjunctive measure for patients that may be having flare-up or may have edema in their eye but there is subtle structural damage with each relapse with cumulative damage with inflammation at each time a steroid might be injected so you might be missing the opportune time to to treat the patient plus there's the cumulative risk of steroid exposure that I just mentioned in terms of cataract and intraocular pressurize so some very clever people got together and said well why don't we just kind of design a device that we can implant into the eye that will release steroids for three years okay so such a device has has been devised and approved by the FDA the so-called reticent implant this is the implant this was actually modeled on the vitro cert implant which was initially used for treatment of patients with CNP retinitis in the AIDS epidemic so this device is surgically implanted into the eye in the operating room and releases flucinolone acetylide which is a long-acting medium potency steroid for about three years it is very effective in suppressing inflammation as has been shown in studies that led to its approval by the FDA but it has frequent adverse effects auger effects as expected so most patients will develop cataract 100% patients will develop cataract and many patients will have elevated pressure on the eye that need treatment medically and about 40% of those at least in this trial needed actually incisional glaucoma surgery in order to manage their problem there is another device with the same steroid that has been developed and has been approved for the for the treatment of macular edema that is swelling in the eye due to diabetic disease the so-called alluvian implant and we think that it will also be approved for the treatment of non-infectious uveotas the advantage to this approach is that it says it's a lower dose of this steroid medication and it can be injected in the office rather than taking the patients to the operating room other injectable medications in the eye people have thought well gosh you know steroids have all these bad side effects let's why don't we use medications that are non-steroidal and see if they are effective one such medication that we use systemically is methotrexate that has actually been shown to be quite effective in treating inflammation in the eye and in macular edema rhinobisemab is and lucentus or a vasin are medications that have been used frequently in patients with edema due to vein occlusions and macular degeneration and they have also shown been shown to be effective in patients with swelling in the back of the eye due to macular edema in patients with uveotas some patients you cannot treat with just local injections patients with bilateral severe disease require more sustained systemic therapy and they require system therapy with systemic corticosteroids systemic corticosteroids predisone is the mainstay of treatment of patients with non-infectious uveotas and it is usually administered orally at high dose until inflammation starts to get better and then it is tapered that we taper it off but we also supplement patients with calcium and vitamin d and we monitor them closely because there are many side effects that are associated with a systemic corticosteroids which I think in my opinion are manageable most of the time if we keep an eye on patients so these are the if you it's a scroll a long list of side effects but I think that many of these side effects are certainly manageable if we have a defined period of time in which we're using these medications we do not want patients to be on corticosteroids for a long period of time because we know that the long-term side effects of chronic corticosteroids are not good for patients for for all of those reasons reasons that we just cited so what do we do for patients that have inflammation that in which you know they respond to steroids but you can't get them off of steroids or you can't get them to an acceptable low dose well you have to give them a alternative medication that's where we use immunomodulatory therapy and this very important paper back in 2000 were actually guidelines for the use of immunomodulation failure of systemic corticosteroids unacceptable side effects of steroids or disease known to be poorly responsive to steroids and we'll talk about that in a minute or the requirement for chronic steroids at a dose of greater than 7.5 milligrams per day so those are kind of the guidelines that we use what is immunomodulatory therapy well immunomodulatory therapy by definition is systemic therapy that modifies some limb of the immune system so it modifies it dampens the immune response by a variety of mechanisms interfering with DNA or protein synthesis or interfering with certain types of receptors or signals cellular signals in the eye that are responsible for inflammation the this expert group decided that there were certain recommended that there are certain diseases for which immunomodulatory therapy should be commenced at the outset of the diagnosis and those disease entities are listed here because we know that those patients will either do very very poorly with steroids alone or they have a an underlying systemic disease that require it and that you you may be actually saving these patients life such as a patient with Wegener's granulomatosis that has inflammation in their eye there are a whole group of other other diseases that we know require long-term therapy and that the option of having long-term therapy with systemic corticosteroids is probably not how you want to treat these patients so you have a very low threshold to treat those patients with immunomodulation in addition to corticosteroids and they are listed here such as birchod and multifocal corditis so and certain children with immuno with juvenile adiopathic arthritis so what are these medications some of you may be familiar with them because maybe some of you have been on them we I can classify them into large groups the anti metabolites such as methotrexate, mycophenolate or celsapt or azathioprene then there are the t-cell or calcineurine inhibitors such as cyclosporine and tachrylimus and then there are more potent agents such as the alkylating agents such as chloramysil and cyclophosphamide which are used less frequently today because of the very serious side effects that can be associated with these medications and because we now have biological agents that may work just as well as these medications so the principles of treatment with these medications we individualize it to the patient okay based upon their diagnosis and the systemic disease associations the age and sex of the patient their medical status their visual prognosis we don't want to treat patients with no prognosis for vision the access and cost to the medications and the and the patient preferences so how do we go about using conventional immunological therapy well we have we treat the acute inflammation with steroids okay to get the inflammation under control the analogy would be if you have a fire you want to use a fire hose not a squirt gun in order to dampen the inflammation but you want to keep the fire out as you taper off of steroids or you take the fire hose away and that's where immunomodulatory therapy comes in so we usually begin them simultaneously we need to know the response times of these medications because the immunomodulated making medicines that I mentioned to you the conventional agents take about two to three months to become active so that we want patients to be protected with steroids while we're tapering the steroids coming down the immunomodulatory medication may become active we monitor the patients clinically at each visit for any signs of toxicity we perform laboratory evaluations on the patients depending upon the medication that they are on so that they don't develop any untoward side effects of the medications so we can adjust their dose or stop the medication if they're developing a problem with the medicine there was a very important clinical trial that many that some of your some of the patients here and in my clinic participated in the must trial which was a randomized controlled clinical trial involving 24 centers that studied this implant device that releases steroids for three years versus the use of conventional immunomodulatory therapy that I just described to you and the results of this were very interesting because at two years it seemed though the visual outcome between the two were about the same but in the implant group they seem to achieve a faster and better control of inflammation which was statistically more significant however by seven years and this this information was just published there was clearly an advantage visually in patients that had had systemic therapy over the implant and there was also a more favorable outcome in terms of inflammatory control and I think that this had to do with the fact that the implant itself started to actually lose efficacy by about year five so the implant I seem to control inflammation a little bit longer than we had anticipated but by year five patients that had implants in their eyes began to have more recurrence of inflammation the good news is that overall there was a visual favorable outcome in both treatment arms this just graphically represents the fact that here you have the implant and the systemic treatment arms and then initially there was it seemed to favor the implant but by five years they became less significant and by said by seven years there was an advantage to the patients that had the systemic treatment the accurate complications of the implant versus systemic were pretty predictable that is patients that had implants had cataracts and glaucoma surgery as we had predicted before but the good news in patients with in terms of systemic adverse events was that the immunomontatory therapy was taller way better than anybody anticipated before the major statistically significant finding from this was that patients that were treated with these medications seemed to have more antibiotic treated infections which is kind of understandable patients on methotrexate and they develop a cough their the doctor might write them a prescription for an antibiotic but there were no really serious consequences of treating patients with systemic therapy so this group the must research group has formed a research consortium internationally of which I'm a member and a member of the executive committee and we have come up with important questions to ask about the treatment of patients with intraocular inflammatory disease one of which is how to treat patients with uveic macular edema what is the role of therapeutic vitro retinal surgery and the use of other biological agents macular edema as I told you before is the leading cause of acute decrease of central vision in patients with inflammation here is a normal macular this is a fluorescent angiogram showing the cystic spaces and this is the swelling of the retina we see in patients with macular edema you know it's very very common in this in this large database they showed you you know well over a third of patients had macular edema when they entered the study and about 62 about 40 percent of the patients 40 percent of those patients had not resolved in two years so it's there can be a persistent problem and it can be a recurrent problem so how do we treat macular edema well we try to control the uveitis we treat the patients to control their intraocular inflammation we advise patients on modifiable risk factors such as smoking which we know is about fourfold confers a fourfold increased risk of macular edema and then we use these adjunctive regional steroids these injectable steroids into the eye as adjunctive therapy in patients with they're even on systemic therapy we are in the process of performing two randomized controlled trials which my colleague with which i and my colleagues have actually designed the first is called the point study which has just been concluded and that study looked at compared tried to find out what is the best initial treatment for patients with uveatic macular edema is it periocular steroids underneath the eye or is it an injection of steroids into the eye or is it an injection with that pellet that i described we don't know the answer yet we just concluded that one in patients that have had previous exposure to an intravitral steroid to an injection of steroid into their eye if they have a recurrence of their edema or persists what we what we have to offer the patient these days is just another steroid injection and we know that those additional steroid injections can confer risk in terms of cataract and glaucoma to the patient so the second trial is to look at what offers the best balance of efficacy and safety among three different options with repeated intravitral injections either a azure dex implant that fancy device that i showed you or intravitral anti-vegeth round abyss map that i talked to you about before or intravitral methotrexate both of these are non-steroidal okay not steroids alternatives that we think are equally as effective as a steroid so we'll be awaiting those studies and some of you are participating in that study so the other the other type of therapy that has really expanded our therapeutic ornamentarium are the emergence of biological response modifiers biological agents these are therapeutic proteins that are bio-engineered as antagonists to immunoreactive molecules that is to molecules in the immune system that are specifically associated with inflammation in the eye so they block these cytokines and receptors and self-surface proteins and the idea is to provide specific more targeted therapy that hopefully would result in less generalizable side effects that you might see in a patient for example on systemic corticosteroids this is a long list of some of the biological response modifiers that we currently use that are available to us in the clinic and they target different receptors in the eye not important to know all what these are but the ones that you're probably the most familiar or may have heard about are the so-called tnf alpha inhibitors tnf alpha is a molecule that is very important in the inflammatory cascade so blocking that molecule might dampen the the inflammatory response and the two medications that are used most frequently in intracranial inflammation are infliximab or remiccate and alimumab or humera remiccate infliximab is a monoclonal antibody that is a that is a bio-engineered as a combination of a mouse and a human antibody okay and is delivered by intravenous infusion basically on a monthly basis as opposed to humera or adalimumab which is fully humanized molecule that is administered subcutaneously often by the patient themselves every two weeks there was a important opinion paper about the use of anti-tnf agents in patients with uveitis and this paper called the literature and concluded that infliximab and adalimumab or remiccate and humera biological agents are recommended as first-line agents for certain patients with bachet disease an uncommon disease here but a blinding disease in parts of the world where it is endemic is also they are also very important second-line agents in patients that that fail conventional immunomodulatory therapy particularly children with juvenile idiopathic arthritis associated inflammatory ocular disease or in patients that have other posterior segment inflammatory disease that fail conventional immunomodulation so that we can actually advance them to these therapies so remiccate is one of those medications that is used in rheumatology frequently we use it at higher doses and more frequent infusion intervals than rheumatologists do humera is a another agent that is potentially effective treatment option and the the word about humera is that it's been recently approved in April of 2016 by the FDA for use in uveitis specifically so there are two visual there are two trials that we participated in as well at the miran icenter the visual one and visual two trial that led to the first FDA approval of a biological agent for uveitis this is a big deal for patients with uveitis and because most of the agents that i've discussed with you are used off-label that is there is no FDA indication for their use although it is the standard of care so this medication has been shown to be useful in both patients with active disease and then in preventing patients to having recurrent disease while we're tapering them off of steroids our tnf inhibitors completely safe well you know they're not they do we do know that they are associated with increased risk of infection so that any patient that is placed on these medications is screened thoroughly for infections particularly tuberculosis there is a reported increased risk of lymphoma associated with some of these medications but usually among patients that have systemic conditions that for which they are already at increased risk for these for lymphoma such as patients with rheumatoid arthritis and then of course we use them with caution in patients that have risk of demyelination that is patients that are at risk for developing multiple sclerosis and in one of the entities they showed you intermediate uveitis associated with parthenitis in a certain subgroup of those people they are at risk for developing there are more risk for developing multiple sclerosis so we use these agents with caution in that group of patients there is a very good response to this these medications it is not a magic bullet it does not cure uveitis there are some patients that are not responders sometimes the response kind of wanes in time and there are treatment related side effects for which we need to which we need to decrease the we need to discontinue the medication so there are alternative medications within the same class and then there are third line biologics that i have mentioned to you before that target different receptors for which there is less experience but we do use in patients with with recalcitrant disease so does it work well i think it does work if it must trial seven-year results i think show that this approach is effective and then specifically in patient youngsters with juvenile associated arthritis associated irdocycletus there's a definitive reduced risk of auger complications in patients that are managed with these medications with improvement of visual acuity with effective immunomodulation in a very recent in a fairly recently reported study the site study which looked at five very large university uveitis practices there was a significant decrease in the risk for visual loss in patients treated with immunomodulation um is immunomodulatory therapy completely safe well for certain classes of medications the anti metabolites and t-cell inhibitors we think that there is no increased risk of malignancy or mortality and there is a slightly increased risk for non-millennic skin cancers which we advise patients about the outglading agents like cyclophosphamide we know is associated with an increased risk of malignancy and then what about these tnf inhibitors well this large study that i cited before called the site data suggests there may be an increased signal for mortality associated with these agents but there are other large databases in other diseases such as rheumatoid arthritis that do not show an increased risk of cancer so the jury is out because these are relatively new agents and we must monitor patients very closely so how do we modify the prognosis of this potentially blinding disease i think effective and early suppression of intraocular inflammation the early introduction of steroid sparing immunomodulation and the identification of eyes at risk for complications of visual loss there are multiple treatment options which need to be individualized to the patient and their disease we need to have continued vigilant post marketing surveillance and more and more randomized control trials to see which patients would benefit most from biological agents and from immunomodulatory therapy and of course continued areas of active research in terms of the immunologic mechanisms of uveitis that we can design drugs that are specific for their inflammation the development and application of targeted non-steroidal drug therapies that we talked about before such as individual methotrexate new drug delivery systems there are many of them out there such as nanoparticles and microparticular and then driving molecules across the eye with electrical current and then finally the role of therapeutic protracting in uveitis you know they say that i started my talk out you know describing my family to you they say that it takes a village to raise you know a child i think it takes moving to Saudi Arabia to raise triplets but i think that i just wanted to acknowledge my colleagues in the uveitis team it really takes a really excellent team actually to to manage patients with uveitis for a long time for about 12 years i was the only provider of uveitis in the inter-mountain west in 2015 dr akbar Shakur joined me which enabled us to greatly expand our clinical capacity in seeing patients our ability to become involved in many of these research protocols and then to develop a teaching program and a uveitis fellowship program to train the next generation of experts in intraocular inflammatory disease dr marisa laura shell was our first fellow last year and she will be joining our faculty in october 1st this is our very talented fellow this year lim hasman the care of patients is not just the doctors in fact it may goes way way beyond that the ophthalmic lead texts are instrumental in caring for the patient while they're in the clinic i know many of you spend very many long hours in the clinic and then in calling in on the clinic to get information these are our uveitis team leaders past diana ramirez and canis garcia our very talented team of uveitis team leaders henry berrera emily peterson amanda dickie and marisa long and then the people that you meet when you when you come in okay carlos and steven couldn't do it without with carlos with these guys you know managing people up at the front end bang down the doors to get into our clinic and then once you're finally in there you meet this these these guys the imagers the very talented imagers that we have here led by jim jim gillman melissa janiel becky and glenn jenkins so it wouldn't also be impossible for me to do any of this without the administrative everything of stevy stevens who is he plugs the left side of my brain when it needs plugging thank you very much for your attention i'd be happy to answer any questions so the first two of these questions are really retina related questions that are not specific to the talk that i gave to you one of them has to do with the treatment of central retinal vein occlusion and central retinal vein occlusions utilize these anti anti anti-vegeta medications and unfortunately you know sometimes it requires monthly injections with these medications what we try to do is treat the patient until the swelling in their eye goes down to zero and then extend the interval out to find what the sweet spot is where they no longer have swelling in the in their eye and then try to extend it out so that they no longer require it but sometimes patients will require treatment for many years i know that answers carls question i think can you obtain all the lutein and zeaxanthine from food i think you can but you have to eat a very well balanced diet i i think that you know there is the arates to vitamin supplement for patients with moderate macular degeneration that is actually recommended for patients with that which gives you the recommended amount of lutein and zeaxanthine in a single pill so i think it's easier rather than you know having to you know have a large whole bunch of leafy green vegetables sometimes you know i think it's impractical sometimes to obtain that kind of supplementation from purely from diet i'm going to try to look at questions that are related to to inflammation if that's okay could we ask the amount of lutein well i can't i can't recall the exact milligram amount off the top of my head but it's the the correct amount is in the arates to formula by boushon loan preserver vision so this is a good question no you look through i wasn't sure which retinopathy of premature that's a good dr hartnett question yes but dr hartnett i know she was maybe going to be here but it didn't look like she so this is a general question about retinopathy of prematurity which you know dr hartnett's actually an expert on that but we know that the risk factors for retinopathy of prematurity have to do with low birth weight and exposure to oxygen so certainly we there's nothing you can do about low birth weight and unfortunately you're caught between a rock and a hard place where you have a low birth weight infant that in order to survive you need to supplement them with oxygen um yes oxygen is a definitive risk factor for for them as is um early gestational age so um a patient with b-27 associated uh disease um do you recommend immediate family screenings siblings no i don't think that that would make sense because it is not inherited in a uh in a manner that you're thinking of where where it's dominantly inherited that it would definitely be present in every generation family members are at risk for developing those things if you were if you have hla b-27 associated disease um members of your family may be at risk but i don't think it is uh it makes sense to screen those patients with that test unless they develop um symptoms that are associated with that uh well someone is asking why does the nonpoenation have such a high rate of of diabetic retinopathy environment diet genetics i think it's a combination of all those things you know in saudi arabia there was a very very high prevalence of um of diabetes that i think had to do with genetic predisposition developing the disease diet for sure has a lot to do with it poor access to medical care i think has a lot to do with it both in saudi arabia and in the navajo nation this is a great question what can i do to prevent my uvis from coming back or to prevent or minimize the severity of it when it does come back um i don't think there is anything that you personally can do other than to try to modify those risk factors that we know can be associated with inflammation so there's there are some patients that have kind of a crappy lifestyle you know in terms of their what they you know smoking and drinking uh and certain types of food allergies and things like that i think certainly um common sense modification of those risk factors such as smoking makes a lot of sense i do have some patients that have modified their diet to there are some patients that have have gluten sensitivity that they seem to have decreased in the severity of the inflammation but those are isolated cases um i i think that there isn't anything that one can specifically do to prevent it from coming back other than to be cognizant of the um of the signs and the symptoms of recurrent inflammation and to be seen uh promptly should you have the symptoms or signs um this same same person is asking you know if you get uvis once or twice a year will it continue the rest of your life um well you know if i gotta polish my crystal ball a little bit here but i think that it's impossible to predict the future okay but i think that in general um inflammatory conditions tend to wane in time okay so as our immune systems kind of kind of wind down as we age a little bit so do the severity of certain types of inflammation that being said um you know many many patients that have children with inflammatory disease will ask that question will my child have this forever the idea is to prevent the inflammation that is present now from causing structural damage to their eye later in their eye and so we need to do whatever it is that we need to do in order to prevent that from happening and if that requires uh placing the patient on an immunomodulation then that's what we need to do we hope to induce a remission of that disease and we hope that those children will outgrow that inflammatory condition as they get older there is a subset of kids okay that still have that disease into adulthood um so i i think that you know you can make a generalization but as i try to emphasize in this um in this talk disease treatment is really individualized the patient what is the difference between uveitis and iridus um it is there is really um in the in the one of the slides that i showed you before um uveitis is just a kind of a generic definition for inflammation in the eye iridus is a term that used to be used for inflammation around the iris so that would be anterior type of uveitis so iridus is a form of uveitis that is confined to the front of the eye or anterior uveitis uh how does humera work humera works by blocking a protein that is that is thought to be instrumental in the uh in inflammatory pathway so um humera works by blocking uh tnf alpha that's how it works um is tnf alpha the only thing that's involved in inflammation it isn't no there are many other pathways involved the immune response is extremely complicated there are probably other molecules that could be targeted that are upstream of tnf alpha that might actually be more efficacious and it is for patients with iridus that is associated with spondyloarthopathy so the b-27 people in the room that have multiple recurrences of this medication that may also have an arthritis that is associated with this we know that humera or um remicade is effective for their arthritis and that it reduces the um the the number of inflammatory occurrences and their severity by by 50 percent at least in large studies that we know about um for uveitis that is related to juvenile arthritis um are there links to lifestyle and diet that can help reduce inflammation great question i don't know the answer to that question i don't think that there are i think that there are genetic predispositions in developing this disease um i think common sense approach to diet and things like that is important but there isn't um anything specific that i would do to change that many patients will will ask me is it stress and well yes it is um you know stress is a part of life stress definitely is an important factor in the psycho neuro immunoaccess patients that experience great deal of stress in their lives sometimes will have episodes of inflammation it's been a question that many people have been interested in for a long time it's just very very difficult to study how that how to study that because there is no real proxy marker for stress i um someone is asking me and Dr. and Mr. Rippy uh do you know uh do do i work for the VA personally i do not uh work for the VA so when i first got here i used to um go over to the VA and see patients with uveitis and some retina but mostly to try to decrease the burden of uveitis but there uh it became impractical to hold a clinic there because uh patients came in so sporadically so what we do is we just fee service patients from the VA to the Moran Eye Center so there's a patient that's asking about alternative therapies aromatherapy uh oil and you know oils and things like that for uveitis has that been applied for uveitis itself not in any controlled scientific fashion to my knowledge there is a whole branch of alternative medication at the national Institute of Health that are looking into things like that it is very very difficult actually to study that in an isolated fashion when we have other therapies that are that are effective i have nothing against alternative therapies but i can't make a comment on whether or not they are effective or not when we're treating patients with other medications okay sort of oh just kind of his help with B-27 related uveitis and joint inflammation well it might help you be less aware of it but i don't i to my knowledge it doesn't help therapeutically with the medication you know or you may become more hyper aware of it i don't know so i don't mean to make light of that because there is a large and emerging literature about the this the alleged you know therapeutic benefit of cannabis and medicine and there's it's a real mixed bag you know it's really a mixed bag you would have to smoke a lot of pot and to get your and your interlock your pressure down in a consistent fashion well why don't just take it one drop a day you know i in terms of chemotherapy definitely to treat patients with you know they're having side effects of chemotherapy yes there there's good good studies to show that cannabinoids okay not necessarily you know smoking reefer itself is helpful for you know for nausea and things like that they're associated with that medication