 Okay guys, I'm going to get started, okay? Because we have a lot of material to get through. This is, I'm Al Vitale, I'm in the Uveitis Division, but in the Division as well. And so we're going to, the goal of this is to give you kind of a general overview. The general principles, epidemiology, classification, and diagnostic approach to each Uveitis. So in a former life, I was actually doing a similar thing at the King Colored Eye Specialist Hospital in Saudi Arabia, where I spent seven years prior to coming to the Moran Eye Center. But in real life, my real job is a wild animal trainer, and this is my wife, and four monkeys, so my training began actually in Boston with these kids. So you can see I'm much younger there, and there are three children that are the same age, and a kid that's just a year and a half older. So this is our gang of four. We, I finished fellowship training once in Saudi Arabia, and this is actually a picture of us in front of Kennedy Airport on the day that we're leaving, and that is a triplet stroller. And my son seems to be looking at me like, you sure you know what you're doing here? We're really going to Saudi Arabia. And it turns out it was a pretty good place. My wife, with her hands full, literally, at a place near Saudi Arabia on the beach during the first time that we actually had a break. About six years into Saudi Arabia, we were on a camping trip out in the empty quarter, and I suggested to my wife that maybe we had this great opportunity to come to Utah, and she said Utah, really? Again, I mean, you know, desert to desert, fundamentalism to fundamentalism, prohibitions on alcohol, you know, cultural conservatism, and what's with this polygamy thing, you know? You know, because, you know, in Saudi Arabia, it's big, and I said, no, really, we can do what we like to do outside of our front door, and indeed, we love to ski. And, you know, there was a time when I, I mean, I still ski with my boys and my daughters, and there was a time when follow me guys was actually a safe thing to say, and really what's more dreaded is, like, follow me dad because I really don't want to ski behind my boys anymore because they get, you know, upside down and dangerous. This is my son, Ryan, who was a competitive longboarder. These guys pretty much are going about 65 miles an hour on concrete roads. If you want some entertainment, go on YouTube and kind of search when reindeer attack, he has this collision at about 55 miles an hour of this reindeer, which is pretty impressive. We've got a lot of hits on YouTube. He's alive and doing well. My daughters like to get air as well. They have been competitive equestrians, and my daughter, Sophia, continues to do that. My son and I like to surf a lot, and we go to a lot of different places to do that. The photo on the bottom right is a place called Scorpion Bay where I hope to be in a week, so hopefully there will be some surf there. My family has really thrived in Utah. These are my kids who have grown well, and then on the right, my kids and our adopted friend, Helen, there. We frequently have get-togethers around the holidays that involve people from the rent. Ice Enters, you can see Dr. Shakur, who is that there? Renee Choi and a couple of other people. And then we have our other families in Mexico and around. So people that are living at home now are two dogs. My daughter is living there for their time being. So they're really, we're not quite empty nesters, and we're still kind of crazy after all those years. So I just want to give you a little introduction about me as well as UVitis. So here we go, we're getting into the meat of this. So UVitis, really, the word UVA comes from the Greek, from the Latin for great. UVitis really is a generic term that refers to intraocular inflammation, intraocular inflammation. It really comprises about 30, more than 30 separate entities, which can be distinguished based on their clinical features and disease-specific treatments. Broadly speaking, I think it's helpful to think of ocular inflammatory disease as either infectious or not infectious. Many of the not infectious entities are auto-inflammatory or autoimmune. And of course, you always have to keep it in plastic, masquerade syndromes in mind. It is a leading cause of blindness worldwide, probably the fourth or fifth cause of blindness in the United States. It represents about 10 to 15% of total blindness in the United States. And maybe the fourth or fifth cause of visual loss after diabetes and age-related macular degeneration, making it an important cause of visual loss, given the fact that it affects people of working age and the economic and personal impact may be greater than that of age-related disease. The approach to the patient with uveitis, for the interns here, for Ariana, you never really escape being a doctor in uveitis. As William Osler said, if you want to know what your patient has, talk to them, listen to your patient, he's giving you the diagnosis. So history is really important, both ophthalmic, medical, that means of a review of systems which we conduct with the patient and ask them to fill out before their visit. Then, of course, the ocular examination and general medical examination to the extent that you can perform it in the clinic. You can get a lot of information by looking at skin lesions and the joints of patients. And then the formulation of the differential diagnosis, which is probably the single most important thing in the workup of a patient with uveitis. We can create a differential diagnosis. You characterize the intracurricular inflammation along several different dimensions. One, where is it located in the eye? What is the anatomic location? Two, what is the presentation course in laterality? Is it unilateral, bilateral? Is it acute or chronic? Then a description of the lesion morphology, the number of lesions, the descriptors of the lesions themselves will go into all of these. And then there are host factors. Is this an intracurricular inflammatory condition that is associated with a systemic disease, or is it a purely ocular condition? A corollary to that is, obviously, is it infectious or not infectious? Probably the most important, one of the most important differential distinctions that you need to make, obviously, because you do not want to treat an infectious disease with steroid medications. And then, what is the immunocompetence of the patient? The typical characteristic morphology and phenotype of certain types of disease in an immunocompetent patient will look completely different in an immunosuppressed patient. Then, what is the demographics? Where in the world is the patient? Coming from, what is their ethnic background? As the world is smaller, you will see unusual diseases here. Plus, there are certain disease entities that are more common among certain ethnic groups. And then, of course, the associated signs and symptoms. So, here you have a patient with a rash, an erythema, migransotargetoid rash, which in the clinical context is diagnostic of Lyme disease. No more tests, right? So, directed laboratory investigation and I underlined directed laboratory injection investigation, which is based upon your differential diagnosis and your leading candidates for diagnosis is used to exclude infection to identify the systemic condition that may impact on the systemic health of the patient and to provide prognostic information for the patient. So, there are certain laboratories that may allow you to characterize the information. So, HLA-B27, as we will see, is associated with acute anterior recurrent uveitis and you can, if you identify that, you know that up to 83% of those patients can have an associated spondyloarthopathy and so referral to a rheumatologist is critical and then you can also tell the patient that you're going to have a kind of recurrent type of disease, not something that requires anti-inflammatory medication for a lifetime. And then the formulation of a treatment plan. That involves antimicrobial therapy, you know, the case of an infectious disease, and then anti-inflammatory therapy and a step-ladder approach, which we will discuss and assessing your treatment, see if it's working, right, and then to monitor for the side effects and toxicity of your treatment. So, there is a group called the Sun Working Group, the standardization of you guys nomenclature, and we met about a decade ago to try to agree on what we are talking about when we describe inflammation in the eye. So, we agreed to agree that we would characterize inflammation based on an anatomical classification. There are many different ways to classify inflammation in the eye, but a useful classification is anatomy. Where in the eye is the predominance of the inflammation? Is it in the anterior segment, anterior uveitis? Is it intermediate uveitis, which is concentrated in the gel, the vitreous, and the peripheral retina? Posterior uveitis. Posterior uveitis, by definition, requires a lesion in the retina or chloride, not a structural complication like macrodema or optic nerve head smell or even vasculitis. So, lesion in the retina or chloride. Or a pan-uveitis, where there is inflammation in all three compartments. So, these are some just graphic examples of, you know, anterior uveitis with hypopion uveitis and a patient with big chest disease, intermediate uveitis. This is looking beyond the lens into the gel of the eye and you can see it is chock full of cellular material. This is posterior uveitis with a core retinal scar and adjacent satellite lesion, which is characteristic of toxoplasmosis. And this is an exudative retinal attachment in a patient with VKH, which, taking my word for it, is a pan-uveitis. So, this classification system is good, but it does not include, I think, some important, very important entities, which we didn't address or are important to consider, and that includes carotid uveitis. So, inflammation or infection, involving the cornea and the anterior chamber. So, carotid uveitis, in my mind, is herpetic until proven otherwise. Scleroid uveitis, likewise, in patients that have scleritis, will not infrequently have anterior uveitis or posterior uveitis or, you know, sub-retinal fluid. That's important because in about 50% of the time it can be associated with a systemic condition and rarely systemic conditions that are potentially lethal, such as GPA. Then there's the whole problem of retinal vasculitis, which can be primary or secondary. So, the vessels can be involved in a variety of diseases, either as a primary vasculitis, or secondary to infection or inflammatory disease, or as a part of a systemic vasculitis, which is uncommon. However, it's important to identify those systemic conditions, such as lupus or GPA or polyartist, because that impacts the systemic health of the patient. And then the differential diagnosis can also be further honed down by identifying which vessels are involved. So there are certain entities that predominantly involve the arteries, such as herpetic necrotizing retinitis, or those that predominantly involve the veins, such as sarcoid and associate uveitis or intermediate uveitis. What do you mean when you'd say, you know, acute or chronic or recurrent disease? Okay, so you... When we talk about the onset of inflammation, it's either sudden or insidious, and the duration is either limited or it is persistent, and limited arbitrarily would be something that lasts less than or equal to three months, so that an acute disease is one that is of sudden onset and limited duration. Recurrent disease is an acute disease that has episodes that is punctuated by periods of inactivity for greater than three months, and a chronic disease would be persistent inflammation that has inflammation with prompt relapse after tapering treatment. So it's important that, you know, people communicate that correctly, you know? There is no such thing as, you know, an acute chronic disease. I mean, people put these words together all the time, not really thinking about what it is that, you know, they're saying, so I think that it's important to, you know, use these kind of words correctly because it's useful in communicating what it is that you're talking about, because it can tell you what the disease is, and I'll show you what I mean. So another way that you guys had been classified is kind of a clinical description of whether or not it's granulomatous or non-granulomatous. This is not a pathologic definition, but more of a clinical definition based upon the appearance of the inflammatory precipitates on the cornea or on the iris, and these are non-granulomatous fine, carotid precipitates, which are not particularly specific, but these are granulomatous in contradistinction that look like kind of greasy, larger, so-called mutton fat, you know, stuck-on precipitates, and this is an inflammatory nodule on the iris. Okay, so if you see this, then your differential is a little bit more narrow because there are a limited number of diseases that can present as granulomatous disease, such as sarcoid-sympathetic, lens-induced disease, and drug or form body, VKH. Notice that herpes and syphilis can do whatever it likes, so it is not specific, okay, and always keep in mind that herpes and syphilis are the masqueraders that can do pretty much anything they like. So this very busy slide just kind of lists on this axis the anatomic location in this, whether it's infectious, systemic, non-systemic. The point of this slide is to point out that syphilis, tuberculosis, and sarcoidosis, and where it's endemic Lyme disease, can really do and can present in all different anatomic locations of the eye. So always have that in mind when you're thinking about uveitis patients. So here are some illustrations of the major anterior uveidities. They are listed here in infectious, systemic, and non-systemic disease. This is an example of a patient with herpedic carotid uveitis with sectoral irisography, which, by the way, is not parthenumonic of varicella infection, so it can happen in simplex as well. This is a patient with B27-associated disease with a hypopion uveitis, a collection of white blood cells in the anterior chamber that layers out. This, in contradiction, is a patient with chronic uveitis and a child that has a white eye with juvenile idiopathic arthritis and a structural complication of the cataract. This is a patient with mutton-fat Kp, posterior sneakia, in a patient with anterior uveitis and sarcoidosis. And this is a guy with two different color irides with fuchs-heterochoromic iridocyclitis. The major entities I had to think about in intermediate uveitis are infectious disease such as syphilis and Lyme disease. The major systemic illnesses that can occur with it include multiple sclerosis, which is an important consideration in select patients, and sarcoidosis. And then, if there is no associated systemic condition, it is termed parisplanitis. Parisplanitis is idiopathic intermediate uveitis. One of the most common structural complications and cause for visual loss is macurodema. There are frequently collections of what we call snowballs or inflammatory excites in the red at this. These would be non-well-circumstried vitreous opacities, which would be indicative of active disease. That is, inflammation affecting the veins. As you can see, there's sheathing of these vessels, and it's more prominent on wide-field fluorescein angiography, as you can see here. Post-year uveitis you want to know where the primary level of inflammation is, whether or not it's in the retina or in the chloride. I showed you this example previously. This is toxoretinitis where the inflammation is in the retina. This is tuberculous corditis which you can appreciate clinically that maybe the lesions are a little bit deeper than in the retina. It's important to identify the location of lesions but also the character of lesions themselves. Whether or not there's one or two lesions, or there are multi-focal lesions. This is B-possifocal. This is multi-focal. Whether or not it's located or if it's peripherally located or it's diffusely located throughout the fundus. Then the color, size, and shape of lesions. So for example, this is an amoeboid geographic corretal lesion that is characteristic of serpigenous corditis. This is a plaquoid lesion at the level of the pigment epithelium that is characteristic of ampic. These are orange, yellow, ovoid lesions with a streaking appearance in the corret which are very characteristic of burgshot. These are punched out lesions with atrophic appearance and hyperpigmentation rather than that we see in patients with multi-focal corditis. And these are barely discernible small white cartwheel type of lesions that come and go in our so-called I don't know characters, evanescent white dots. In the posterior segment major infectious entities are listed here. This is a patient with CMV retinitis which is a multi-focal retinitis. This is a patient with sarcoidosis with many with multiple things happening here. There's vasculitis, there's vitritis. There are coriorentinal atrophic spots there is retinitis as well. This is a patient with an unusual kind of variant of ampii on the spectrum of ampii that is more relentless really, it's called relentless plaqueoid coriorentinopathy which is characterized by multiple spots that kind of progress towards the posterior pole and recur, ampii usually doesn't recur but they have similar characteristics in the angiographical. And then panneuvias always think about syphilis seriously, always think about syphilis. Lyme disease is similar in a endemic area and then some systemic conditions include VKH disease this is actually related with VKH disease which may be difficult for you to appreciate but there is neurosensory detachment of the retina here which is more easily seen on fluorescent angiography which shows this pooling of dye into these large areas of neurosensory detachment which is characteristic of that disease and this is a patient with multifocal cortis and sympathetic talvian. Okay so you have all this kind of nomenclature and you have these descriptors of the disease in your mind and enables you to actually communicate effectively when you're describing disease so a unilateral alternating recurrent anterior uveitis first thing I'm thinking about is an HLA B27 associated disease as opposed to a unilateral chronic anterior uveitis there are a couple of entities that I will think about so folks that are a chronic unilateral recurrent focal retinitis as we showed a couple of examples here toxoplasmosis those would be the kinds of things that would come to mind as opposed to a bilateral or chronic multifocal cortitis that you might see in patient with BIRC shot or multifocal cortitis. So when we assess a patient we're in the business of vision so critical things to look at are best corrected visual acuity interact your pressure and a standardized grading system to kind of quantitate the level of inflammation in the eye so the sun group have come up with this classification system which classifies inflammation on a scale of zero to four plus based on actually counting the number of cells in the eye on a one by one millimeter slit as you can see here so there is variation between about 95% agreement with a variation of one grade which I think is pretty good one also assesses flare so flare is analogous to this jungle kind of scene I saw in India where I was traveling there which this is moisture in the air but flare in the eye is leakage of protein from incompetent vessels and it is a marker of chronic inflammation and chronic disease and one grades flare by grading it zero to four plus depending upon the degree to which it obscures the structures in the anterior chamber similarly when grades the haze in the vitreous this is the NEI grading system from vitreous haze it is not a perfect scale by any question by any stretch of the imagination that is haze in the gel of the eye that is obscuring structures in the back of the eye obviously there are other things that can produce haze right so corneal capacity or nuclear capacity so one attempts to mentally you know take into consideration those those entities so you know grade of zero is crystal clear and grade of four is like no view to any structures in the back of the eye and then it's graded between three traits in between that so the sun group could not agree on a vitreous cell scoring system predominantly because it's really kind of you know unwieldy to think about even starting to count these numbers of cells in the eye but I think that it is still something that people use okay in grading inflammation to denote active or inactive inflammation so when you look into the back of the eye and we will do this in our clinic some patients with chronic inflammation will have cells in their eye that are not active that are stuck onto the vitreous fibers or that are pigmented whereas other patients will have cells that are floating around in the clear or free lacunae spaces of the eye which are more indicative of active inflammation one may also see aggregates of cells so called snowballs in the eye those with fluffy borders would be indicative of active inflammation whereas those that have been treated the cellular aggregate may not completely go away and it may remain with well circumscribed borders in addition when you know this toxoplasmic lesion that I showed you previously I should probably put that in here but what can see actually cellular inflammation in the vitreous gel over the lesion and it's important to note that because when you treat that lesion that inflammation should dissipate so these are all kind of markers are of inflammation so when we work up a patient why in the world do we do this you know well we talked about this you exclude an infection identify systemic disease impacting health, guide appropriate treatment and provide prognosis for inflammation so the principles are to be selective right based upon your differential diagnosis what are the most what are the leading causes that you're thinking about right so if you look in the back of the eye and you identify toxoplasmosis on your indirect alfamoscopy HLAB 27 is not a test that you want to work on you want to stage the work up from the more common to the more rare as I mentioned to you always consider the masqueraders such as syphilis infectious diseases sarcoid and TB patients that may have an impact or exposure history and then always think about masquerade symptoms just always have it in the back of your mind to think a little bit outside of the box that is neoplastic disease that may simulate infectious or inflammatory disease so syphilis testing in general we screen with both a specific and a non-specific trepanema test as you there is a new recommendation from the CDC which I won't get into reverse sequence testing but in essence one uses two different tests to exclude the possibility that patient may have had actual syphilis that has become dormant either in time or with treatment because tertiary syphilis is something that you don't want to miss and one can see that in patients with EVIs so RPR and FDA or the reverse sequence testing which this lab doesn't do on a routine basis Lyme disease testing is I think important in patients that have a history of exposure in an endemic area sometimes the history will tell you what the patient has seriously I had my mother-in-law called me on the telephone and said from New Jersey my face is all droopy and I said really have them draw a Lyme titer when you go see your doctor so you have facial palsy due to Lyme disease and you know it's very very common it's common in New Jersey it's common where she lives it's a common man of physician disease testing for duerculosis well you know testing for duerculosis with PBT and paudifuron gold is pretty sensitive and specific routine testing for every patient for duerculosis with uveitis is that the prevalence of the disease in the general population is really really low so that the positive predictive value of that test would be very poor to be used as a screening test on the other hand it is very helpful in patients in whom you think you want to exclude that diagnosis so a person that presents with iris nodules and chronic anterior uveitis patient with a chorotal tuberculomas you see in this picture there is an entity called surpigenous like corditis that you must exclude tuberculosis exposure and then multifocal corditis in an immunocompromised patient then of course there are patient factors you know so we see refugees here, immigrants elderly people and then those with significant exposure risk and then of course in anybody in whom you're considering placing chronic immunosuppressive therapy especially biological therapy targeted laboratory testing is useful in patients with for example they present with a neural retinitis as you see here so bartonella is the leading cause of neural retinitis and should probably be excluded history of cat scratch is always helpful but not always forthcoming West Nile virus in a patient that presents with kind of these targetoid type of lesions that may you know in September and August or October which is West Nile season seriously I was giving a talk last year to you know some people here in September and our fellow called me and said this patient has these funny lesions blah blah blah and the patient ended up having a West Nile virus so we got West Nile virus and she had drenching fevers you know oh okay maybe we can talk a little talk about this in detail but it's useful you wouldn't get West Nile virus on a patient with anterior uveitis right so there's no clinical indication to do that and then PCR the aqueous or vitreous is extremely useful in confirming the diagnosis confirming the clinical diagnosis of necrotizing retinitis on the other hand routine screening is of limited value in patients for varicella or herby simplexities because the majority of the patient population is going to be seropositive for that similarly toxoplasmosis routine screening is not going to be valuable because of the high seropovolence in the general population I mentioned this to you a patient that comes in with non-granulose anterior uveitis first episode may have a history of back pain half of those patients are going to be actually be 27 positive up to you know 80% will have an undiagnosed spondylorotherm that's a useful test ANA is not a useful test as a routine screening test for patients with uveitis lupus rarely causes inflammation in the eye it can cause vasculitis but rarely uveitis on the other hand children with anterior uveitis should be screened with ANA because oligoarticular juvenile idiopathic arthritis is a leading cause of chronic anterior uveitis similarly a beta-2 microglobulin and serum creatinine are useful screening tests in patients that present with bilateral simultaneous anterior uveitis for the diagnosis to be low institutional nephitis uveitis syndrome and then ANCA, rheumatoid factor would be useful in patients with squitis and systemic diseases are associated 50% of these sclerotic patients and rheumatoid and rheumatoid diseases is the number one systemic association just a word about sarcoidosis it can produce any type of uveitis the organs most likely affected are the lung skin, the endothelial system but really the joints, brain, heart are important organs that are frequently involved people will not frequently use ACE and lysozyme screening tests the utility of which is probably not very helpful I don't think unless the patient has active disease in which they are generally high similarly abnormal liver enzymes may point you in the direction of sarcoidosis they're very high in patients with liver involvement but really chest x-ray is probably the most useful screening tests for patients with sarcoidosis normal 90% of patients with active disease and in patients in whom you have a high clinical suspicion of sarcoidosis and I have a normal chest x-ray repeating that test with a high resolution CT scan may be very valuable because it may identify lesions that are missed on routine chest x-ray the diagnosis really the definitive diagnosis is that the tissue diagnosis particularly in the lungs but look for extra-ocular sites like the skin without having to do an invasive rock or even the lacrimal gland so ancillary imaging is also important in the workup of uveitis as we talked about with chest x-ray sacroiliac films CT and MRI but ultrasonography obviously in a patient with low capacity one would not want to have a surgical adventure in this eye with these attachments and UBM is helpful in identifying the causes of hypotomy which you can't really see on your examination so the identification of ancillary membrane or ancillary body attachment we will talk about multimodal imaging which is really critical in the evaluation of patients with posterior uveitis fluorescein angiography is alive and well I think in uveitis it is a very sensitive imaging modality for the detection of active disease particularly retinal vasculitis and it can also identify areas of non-perfusion which I think require treatment in patients with occlusive retinal vasculopathy which one sees in patients with uveitis then ICG angiography as we were discussing yesterday in fluorescein at last Thursday in fluorescein clinic it is useful adjunct in patients with chordal inflammatory disease obviously OCT is kind of revolutionized our view of the back of the eye providing quantitative information and structural information particularly as far as not only just macrodema but what is happening in terms of coronal neovascularization and in the outer retina and I think that OCT angiography will become very important in the identification and distinction between coronal retinal inflammatory disease and coronal neovascular disease and finally I find this a lot of fluorescence likewise is I think quite useful in identifying atrophic versus active diseases in certain types of white dot type of syndromes we do use full field electro retinography for global test function in certain diseases such as Bershade retinocortopathy with autoimmune type of retinopathy where the button is globally infected and then visual field testing likewise are useful objective modalities to follow patients that are being treated with immunosuppressive therapy so treatment in 20 minutes I just want to kind of go over some general principles of treatment so that you have an idea of how we approach patients so the really important thing in treatment is to establish a diagnosis you may not have a 40% of the diagnoses or maybe 35% are idiopathic diagnosis or you may not have a diagnosis etc but you have thought about what you need to do so it's important to exclude an infection so you don't want to treat an infection appropriately but you don't want to treat an infection with a anti-inflammatory regimen so establish the diagnosis rule out an infection in malignancy and then treat inflammation with anti microbial therapy treat the inflammatory disease in a step ladder approach and then always reconsider your diagnosis just watch the patient go down and rabbit hole and don't look back so some people will have an atypical response to their therapy maybe your diagnosis isn't right you really have to be prepared to rethink things and then be astute to new findings that today emerge when you see patients it's a new opportunity to reassess them so the goals elimination, inflammation suppress chronic activity try to induce remission which is hard to do treat and reduce, prevent, occur structural complications in order to preserve vision and to avoid and minimize systemic complications so you want to eat, have your cake and eat it this step ladder algorithm I really don't like algorithms in UVI I mean I think you think about each patient individually but this is just a general guideline you start with steroids okay, steroids is the first line treatment and from whatever, you know, route and frequently as you can so topical steroids periocular steroids, intravitural steroids and then systemic steroids for brief periods of time because we try to limit the total exposure of steroids from all routes as much as we can so we use them to put out acute inflammation but try to limit the total exposure of steroids given the steroid side effects and then have a low threshold for the introduction of steroids bearing immunomodulatory therapy which involves both conventional agents which we'll just give you an overview of and then biological agents and then there are cases in which diagnostic tractomy is necessary diagnostic tissue and fluid sampling so the best route and choice of medications is really determined by the location of the inflammation the laterality of the inflammation the potential ocular complications and the systemic health of the patient so topical steroids are very useful in patients with anterior uveitis but not so much for people with posterior uveitis because the medications don't penetrate to the back of the eye whereas periocular, intravitural or systemic steroids are useful with or without immunomodulatory therapy are useful in patients with intermediate posterior and pan-uveitis particularly when it's bilateral for systemic disease so this slide just kind of summarizes in a box fashion if you think better this way we use topical steroids for intermediate posterior and pan-uveitis in which there's anterior uveitis but periocular steroids are more preferentially used in intermediate and posterior uveitis so how to use topical therapy we deliver high doses of uveitis usually so you don't start out with twice a day but if you have inflammation now you want to treat the inflammation with a healthy frequency for to eight times a day of topical medication and then once there is the inflammation is down to 0.5 plus or zero then begin to taper the medication we frequently will also apply cycloplegics for patients with anterior uveitis both to move the pupil so that you protect the patient from developing posterior and also for pain management for posterior spasm periocular steroids can provide local and sustained drug delivery for about three months with no real systemic side effects and the indications are best really for acute and remitting disease intermediate posterior pan uveitis so this better for that then chronic disease it can be used primarily say for example in a patient with unilateral intermediate uveitis it can be used adjunctively in patients who develop macular demo or on systemic medication it is frequently useful in patients with macular uveitis the contraindications for periocular steroid injection I think just always think about it are infection so you don't want to treat a patient with toxoplasmosis with a periocular injection because you have a depo steroid back there that can make the infection run wild similarly scleritis and corticosteroid intraocular pressure responses are relative contraindications that need for that treatment there are a couple of different preparations we generally use trimesin alone here there are a couple of different ways to deliver it one can give a orbital floor injection a posterior or a subtenons injection I generally deliver it through the orbit it's an orbital floor injection when I do it which I've been doing a lot less often these days because I think it's better tolerated by the patient and it's easier to do and I think that the side effects although they are similar in terms of cataract and elevation intraocular pressure I think they're better tolerated actually with the orbital floor approach they are equally as efficacious at least in the studies that have been conducted so irrespective of the route you can get resolution inflammation in about 30-60% of the time with improvement of visual acuity there's a historically an additional benefit of repeated injection we will have some new data coming out in about 3-2 months which is comparing different routes which will be interesting we can inject the steroid into the eye an intraviginal injection it is quite effective in the reduction of macrodema and of inflammation in the eye with improvement of vision and decreased vitritus the duration really varies depending upon the disease and the and whether or not it is contractimized or not there is a formulation of dexamethasone the so-called azure dex injectable implant which is a biodegradable polymer with glycolic acid which is produced into carbon dioxide and water which has been approved for the use of intermediate posterior panneuviasis it is effective in reducing vitritus haze, macrodema and visual acuity compared to shem in the approval trial with little complications okay and no cataract but you have to remember that these studies are short term it's a six month study patients who were steroid responders so real life okay use of dexamethasone shows efficacy I think a reduced durability platform from rather than six months but more like two to four months in terms of its durability and indeed it is effective in reducing centromocular thickness in vitrius haze but it comes at a cost with repeated injections with elevated intracranial pressure and cataract so this is just a summary slide showing periocular steroids and intravitural steroids showing basically that they are moderately effective I think there is this clinical impression that intravitural injections may be more effective I think that is probably true but there is more of a problem with ocular side effects of elevated intracranial pressure and cataract and that there are additional benefits for repeated injections but it comes at a cost and then one interesting I think clinical observation is that patients that are on immunosystemic immunosuppressive therapy require fewer adjective treatments than patients that are not so the problem with regional ocular steroids is that they are relatively short acting and they are not really that effective for chronic inflammation because it would require multiple administrations of steroids in the eye with the cumulative risk of cataract and intracranial pressure with each relapse you are treating relapse so with each relapse you have this little hit structural function I think in the eye with kind of a soft decline of function and I think that has been pretty well demonstrated to these that have been managed that way historically in the past such as Birchot which does not respond well to intracranial therapy either with periocular intracranial or systemic corticosteroids there is a device called the Reticert device which has been shown to provide a sustained delivery of flucillone acetylene into the back of the eye and it's been approved by the FDA in 2005 reduction of rate of inflammation reduction of the rate of adjunctive corticosteroids and effective in the short term while the implant is still active but it comes at a cost and the cost is 100% development of cataract and fake it guys 70% development of the need for adjunctive topical anti glaucoma medications and 40% incidence of incisional glaucoma surgery that's pretty high so if you're it's effective but you have to keep those risks in mind there is an NDA's been submitted to the FDA for a flucillone acetylene intracranial insert which is similar idea similar compound liver in an office setting so the medication is actually alluded on to a palli amide cylinder which is injected to the eye like death's meth so we will see it preliminarily is actually pretty effective it may be a really great adjunct systemic corticosteroids are used frequently in patients with bilateral disease for acute therapy we can also dose it at a milligram per kilogram or usually at a maximum about 60 milligrams a day the reason for that dose is that data from the rheumatologic literature suggest that doses greater than 60 milligrams a day are associated sometimes with or more places patients at greater risk for aseptic necrosis so usually around 60 milligrams for a couple weeks and then then tapering the medication we can also give it by IV pulse as the neurons frequently will do for optic nerve disease and then we always supplement patients with calcium and vitamin D and then use antiresorptive agents I think in patients that are postmenopausal or greater at risk which we obtain on a yearly basis of patients including and we also monitor their weight just to keep them honest and to help them with side effects of that medication there are guidelines for the use of immunomodulation immunomodulatory drugs this was a paper that I think you should all read at some point in time it was published in 2000 but I think it has some very useful information by the lead authors Doug Jabbs and AJO in 2000 and basically one uses immunomodulation in patients that fail systemic steroids and that would be patients with unacceptable side effects of the medication disease is known to be poorly responsive to chronic steroids and then requirements for chronic steroids that would be at doses of greater than 7.5 milligrams for three months as this dose is likely to produce more serious side effects over the long term there are some disease entities that require immunomodulation and the outset of disease given the natural history of those diseases and those include patients with Bechette's disease with posterior segment involvement and retinal vasculitis patients with Ocure Mucous Membrane Pepicoid Stripidgenous Chordopathy patients with Necrotizing Chloridis and Sympathetic Ophthalmia and there are a whole group of diseases in which we actually are immunospecific therapy pretty early given the fact that we know that the natural history of those diseases is poor with steroid monotherapy Birchheut is a good example of disease Juvenile Idiopathic Arthritis is another good example of that disease in which you don't want to treat children with long courses of systemic corticosteroids nor do you want them to be on topical steroids for long periods of time with both systemic and Ocure side effects of steroids so convention it's useful I think to think about immunomodulation in two large categories conventional immunomodulation and biological immunomodulation conventional immunomodulation by definition modifies some specific limb of the immune system the mechanisms include interfering with DNA or protein synthesis specific receptor or ligand antagonism such as two receptor in patients with cyclosporin or signal transduction receptor blockade and then the anti-inflammatory effects it's not really well known even in patients with methotrexate where it's less immunospressive and more of an anti-inflammatory medication so the major drugs that we use in UVIs that are conventional agents are listed here again I'm simply I like to think of things in groups so anti-metabolites where are the anti-metabolites methotrexate mycophenolate that's what we use mostly T-cell transduction cyclosporin and then the alkylating agents heavy heavy guns so we use them less frequently because we now have biologic agents but the ones that we have used and those medications do come at a cost you know at least some increased mortality in patients in certain groups with alkylating agents more severe side effects but they are I think the only medications that have been shown to really induce true remission of inflammatory disease so as I was alluding to earlier how do we treat patients acute care with steroids whatever route we need if we're contemplating placing a patient on say for example in a conventional agent like methotrexate we use systemic steroids frequently as a bridge or maybe an intraocular steroid as a steroid bridge because the time with which anti-metabolites become active maybe two to three months so we want steroids to ramp down and then the other medications to ramp up the patients with the development of toxicity and then we tell the patients that they need to be monitored in the laboratory because the medications are may suppress the immune system and are metabolized usually by the liver with the exception of tychrolimus and cyclosporin in which renal indices need to be monitored this is kind of a summary slide of data from the site study, which is a really great study of five very large UVIS practices which glean a lot of information about the use of these medications and it basically shows what is the outcome of monotherapy with these medications and as you can see methotrexate and mycophenolate are about the same in terms of their efficacy in steroid sparing and toxicity. Cyclosporin is a little less effective and it's not usually used as monotherapy but it's useful in combination with these other medications I think because it has a different mechanism in action and azothyroidine is used less commonly but may be used and then psychophosphamide has the highest rate of inactivity and the greatest rate of remission but also the greatest rate of complications. Let's just know about the must trial this is a trial that I looked at that it was a randomized clinical trial that compared the flucinolone implant versus this kind of systemic algorithm that I just described the bottom line of this study depends on when you look at it so the two-year results of the study show that the visual outcome was similar for both groups inflammatory control was a little bit faster and greater with the implants than systemic therapy that was statistically significant and that systemic therapy was well tolerated as expected, acute complications were seen of cataract and intraocular pressure elevated glaucoma surgery in patients that were implanted however when these patients were followed over 7 years at about year 5 there was a crossover in terms of efficacy so that at 7 years the treatment favored systemic therapy to the implant with a significant difference in visual acuity between the two eyes and this was thought to be due to the occurrence of new cord-rent illusions in the implant group despite crossover so you can see this at about year 5 or 6 where you have this crossover of these two curves here in the left there was initial improvement in macrodema and it became same at about 5 years and better for the systemic treatment so I think that the take home of this we can discuss this for an entire session and I think it's worthy of discussion but I think that the take home of that is that not that systemic therapy is better you have to utilize this to a patient so that initially systemic therapy may be preferred initial treatment for a patient that can tolerate systemic therapy due to the variable effect of regional steroid but the implant is an excellent alternative for patients that have un-controlled inflammation or intolerance to systemic medications biological response modifiers these are the other major category of immunomodulation I just if you give me 2 minutes I will go through it I know we're at 8 o'clock so what they are are recombinant antibody derived proteins these are the lists of about 8 biologics that are used in uveitis the ones that you will see more often in clinic include infliximab and adelumimab which are TNF alpha inhibitors nbril is a fusion protein which is very effective in treating arthritis but not effective in treating uveitis so an expert plan like the one that in 2000 was convened which included that infliximab and adelumab these 2 TNF inhibitors are useful as first line agents for patients with basis disease and a second line agents in JIA so it's here in Cicletus and then our potential second line agents in patients that fail to treat the infection and then the next one is the infliximab is a chimeric antibody human antibody is delivered IV we use it in combination with anti-metabolical to reduce the incidence of anti-chimeric antibody and before it's added to advocacy it is an effective medication which is steroid and sparing are not really primitive agents so you remove them and many patients will have recurrences of inflammation the advantage to using infliximab is that you can adjust the dose a little bit you can assure compliance so it's IV the patient has to be there to get it and then you can actually dose it monthly or every 8 weeks and there's variability in the dosage if the patient doesn't respond Adelumimab is a fully humanized anti-TNF antibody which has been approved by the FDA for uveitis so it's the first biological agent that's been approved for uveitis and we have been using it more and more frequently in our clinics I think the concerns that you need to know about the TNF inhibitors is that there's definitive increased risk for infection so all patients are screened for tuberculosis there is an increased risk at least in certain populations of lymphoma and I think that we need to talk to our patients about that but the patients that are the most risk for that are patients with autoimmune disease that would be at risk for the development of this anyway that's hard to it's a hard sell sometimes in some patients that are very risk-averse and then of course it can increase the risk of demyelination so in any patient that has any history of multiple sclerosis or in patients with miscellaneous who are at risk for developing multiple sclerosis one should be circumspecting just automatically prescribing it so in patients that we put on this medication that are young women with intermediate uveitis we get a thorough history and even in the absence of any history I will scan them so there's variable response to TNF therapies so TNF is in the answer right there are a whole bunch of other biological agents that are in the pipeline that we use so what do you do if a patient fails Humira well you can put them on another TNF and TNF medications as I mentioned to you so Humira is subcutaneously administered it's a fixed dose of 40 milligrams every two weeks sometimes patients will respond to an influx map who don't respond to Humira and they are dose monthly and higher doses of medication there are some other anti TNF agents that can also be used but there are a whole other classes of biological agents which target different receptors so influx map and Humira target TNF alpha which is a pro-inflammatory cytokine but there are many other pro-inflammatory cytokines that are up or downstream for that that have been shown to be very effective such as RituxMap which targets CD20 B-cells Anakinarum targets IL-1 IL-2 inhibitors and then Tocillizumab which is an anti IL-6 Interferon so are used actually very effectively based on Bacchus disease and chronic macular demon but the literature comes from Europe and for some reason it just is not caught on in the United States primarily because of the insurance hurdles and getting people on it and the 100% development of side effects that are kind of nasty flu-like illnesses and depression but I actually have a patient that is on this chronically for macular demon whereas nothing else has worked for them so is this stuff effective? Well it is actually effective in patients with JIA in reducing ocular complications such as hypotony, epiretal membrane and a better seeing eye and in this site cohort which is where probably the best data comes there is a significant reduction in the risk of visual loss particularly for patients with less than 20-15 vision Cancer risk is something that you should know about these agents can be associated with increased risk but this again the same site study showed that there was no increased risk of cancer related morbidity or mortality associated with anti-metabolites or calcinurian inhibitors. There was a signal for increased mortality in patients with biologics but that is a very small number of patients and there is actually very good literature in the non-niuvietic experience in GI and in rheumatology which shows much less risk of this. That's a lot of material and I don't expect you guys to take all these things home but I really wanted to give you a broad overview of how we approach the patient and what we treat them with. It is not a random process there really is a way to approach a patient both diagnostically and therapeutically. This will become a way to assist patients in the clinic. We will discuss these treatment and diagnostic modalities in more detail in coming lectures.