 Good morning guys. Good morning. I can't believe it's July 30th. I mean the kids going back to school are saying, summer's over. Oh my god. I feel like summer began. Anyway, so we're going to kind of pick it up where we left off. And I'm going to provide you with an overview of treatment of UVIS. Plug it in. Fundamental to treating UVIS is establishing a diagnosis. So as we were talking about last time, it's really essential to establish a diagnosis, even if it's idiopathic to exclude an infection or a legacy. If you have an infection, it's treated with appropriate anti-microbial therapy. And then if it's a non-infectious or disease-specific implications of treatment, which we're going to kind of go over a little bit. And then kind of a step-lighter algorithm. I hate the word algorithms in UVIS because really, therapy's individualized the patient. But it's an approach. It's basically a kind of philosophy of taking care of patients. I think one should always be willing to step back, reconsider your diagnosis, particularly if you have an atypical response to treatment or if new findings emerge. The diagnosis may be different or you actually may be treating something that you don't want to be treating. So the goals of treatment, okay? We want to eliminate inflammation with prompt control of acute activity, suppress chronic or recurrent disease, and an attempt to reduce an induced remission, which is difficult to do in a lot of cases with UVIS. This whole approach is an effort to prevent, reduce ocular structural complications, which can interfere with vision, such as cataract, macrodema, scarring, quadrilateral scars, and to minimize potential systemic complications or ocular complications of therapy. So in essence, we want to have our cake and eat it. And I think that in many cases it's possible, but it takes some doing and a little bit of, you know, empiric therapy sometimes. So this stepladder approach, basically very broadly speaking, is we start out with steroids, okay? Steroids are the first line treatment for patients with UVIS. Frequent steroids, topically or systemically, but for edgier segment inflammation topical steroids and psychoplegics. I don't really use oral non-steroidal anti-inflammatory medications very often, except when they are indicated for a patient that already has disease from which they're taking it, such as certain types of spinal or throat disease, in which I think in some cases it may be somewhat steroid-sparing. Then periocular and intervitrial steroids, which will go over brief systemic steroids, you know, dividing the length of time with oral prednisone, usually about a milligram per kilogram, tapering, and then the early implementation of steroid-sparing immunomodulatory therapy in patients that are not responsible for development of side effects. And then finally there is, I think, a role for retracting in UVIS, although that is really not well-defined therapeutically. So we have the route and the choice of medications really determined by the anatomic location we were talking about last time of the inflammation. The accurate complications that it can induce, and really the systemic health of the patient. So tapering steroids, for example, are adequate for purely anti-ov-UVIS, but they will not penetrate to the back of the eye. So here are our choices, topical periocular implantable devices, systemic steroids, immunomodulatory therapy. We use them depending upon the location of the UVIS, so anti-UVIS, topical steroids are really the choice. In intermediate UVIS, usually, we begin with periocular injections and sometimes systemic diseases, and then advanced therapy is needed. Post-UVIS similarly, and then in pan-UVIS, this inflammation affects all segments of the eye. We can use, we have everything available to us. So just topical steroids, I don't want to insult your intelligence or anything like this, but when we use topical therapy, if you have inflammation in the eye, use it frequently enough to put out the fire, to put out the inflammation, so don't start out with BIT topical steroids. Treat it frequently, a high dose delivered directly of the anterior segment, and then once the inflammation is under control, taper it sometimes slowly, depending upon the disease, but taper it and then there is limited delivery of the posterior segment with the exception of a couple of situations. So diphenyl prednate does have pretty good posterior segment delivery. A caution about that is four times more potent than predfortag, and is much more steroid, side-effect-inducing with elevated interaction pressure and cataract. And it particularly produces those problems with age children. The other thing is that in a betrachromized eye, you may have better posterior segment penetration of wall drops, so non-stroidals as well. So as I was saying, you start out with high-frequency taper over about six to eight weeks. Frequently, we will employ cycle-pleagian that cases of anterior uveitis for comfort for the patient to avoid ciliary spasm and also to prevent sneakiness. I prefer to use a sure-acting cycle-plegic such as home matrimony or cycle gel, cycle petalate to move the pupil rather than to keep it in a fixed dilated position where I think the sneaky would be more apt to perform. Regional steroids provide local sustained delivery for about three to four months and minimize systemic adverse events, and they're very useful, particularly in acute non-remitting disease that is unilateral, particularly intermediate uveitis, and the kind of indications are obviously an infectious disease, so you would never want to administer a periocular or an inferior steroid in a patient that has toxoplasmosis or in whom you might suspect of having arm scolitis, or you would be loathed to do this in your circumspect in a patient that has a really large steroid, high steroid responder. So the preparation we most often use is a triapicillone acetate of 40 milligrams per mil. You can deliver it either in a posterior subtenance injection or an orbital floor, and they have equal efficacy. It is effective in both reducing inflammation and in macular edema in about greater than 50% of the time, and there is additional benefit for repeated injection. There is, of course, the risk of steroid-associated side effects of cataract and intraocular pressure, which are not actually minimal. Similarly, with intravitual corticosteroids, triapicillone acetate has been used most frequently in two to four milligrams. It is quite effective in reducing CME in about 85% of cases, improving vision, and decreasing vitritis in the duration is about depending upon the eye or eye as it protects my astronaut in about three to six months. There's no tachyphylaxis to repeat injection, so it's equally effective each time, but the cataract, it induces cataract and intraocular pressure more often. One study showed that basically cataract requiring surgery occurs after the fifth injection in a large percentage. You're familiar with the Ozardax or dexamethasone delivery system, so it's a different steroid in dexamethasone. This was approved for use in uveitis through the Huron trial. It had advocacy in reducing haze, macular DMA, and as opposed to sham with, you know, at least initially where it got approved with minimal intraocular elevations of pressure and cataract, but this was a six month trial. Patients that were steroid responders were excluded from the trial, so they had to wait for kind of post-marketing experience where the efficacy is actually still effective in patients with even greater inflammation that was required for the trial with reduction of macular thickness in patients with macular DMA. Elevation in the intraocular pressure a little bit more, you know, 40% of patients, more instance of filtering surgery and cataract surgery. And while the studies show, you know, a reinjection frequency of a mean of about six months, I think in clinical practice most people find that you have to re-inject people more like three or four months. When you're determining whether or not to use something like ozardex, like intravitrile versus periocular, like what are you thinking about, like in terms of like when would you use periocular versus ozardex? Yeah, well that's actually a good question and it was something that we attempted to you know, there's a study called the point trial which was included which I'm going to talk to you about a little bit that may answer that question. But in general, okay, I am using periocular stearers a lot less frequently than I was previously. I think periocular stearers have a role in patients with very mild macular DMA that may for example be macular DMA that is peri-phovial but not quite underneath the phobia in which you don't, the patient may be adverse to an injection because it is effective, post-operatively after the tractomy surgery in patients that have vitreous haze with no macular DMA and intermediate uveitis you know, it's your first encounter with a patient, they may have a little bit of leakage from their on their angiogram, they may benefit from a periocular injection. So that's what I'd be thinking but in more severe inflammation, I think more go to is intravitrile. So, I'm, Ogedex has actually shown efficacy you know, in the pediatric population and in, it is it has a similar disillusion rate in a vitrectomized eye and not a vitrectomized eye. So, I mean, I think that is helpful in a patient that has a vitrectomy for example and if you put an intravitrile triacinth into their eye, they're going to have the dispersive effect of all this with these crystals in their eye and they won't be able to see very well for a day or two or maybe longer whereas in Ogedex this thing is floating around and they're similarly effective. So, regional corticosteroids the problem, they're relatively short acting they're less effective for chronic inflammation so you'd have to continue to repeat the injections there's theoretically and I think that in practice with each relapse of inflammation that a patient may have or with chronic inflammation there's this kind of sawtooth decline in retinal function with each relapse or in chronic disease progressive dysfunction so you, a approach where you're injecting a patient every two months is probably not really a viable approach for chronic therapy so those patients might need systemic therapy which we'll discuss. And then of course is the cumulative risk of ocular side effects, right, cataract and glaucoma and also the cumulative effects of endothelitis. So to your point Brad, there was a trial that we were the PIs for here called the point trial, the periocular and intubitrile corticosteroids for umidic macchiordema trial with clinical impression that intubitrile therapy may be more effective than periocular therapy but may have a less favorable side effect for a trial. And that the impression, clinical impression is that objects in intubitrile time cell may be similarly effective but you know the studies that went for the approval of the medicine seem to indicate that maybe objects were safer. So a less controlled trial was conducted to evaluate, you know, what's the best first line treatment for macchiordema in patients with either inactive or active inflammation. And I don't have time to go through all the nuances of that trial but the bottom line is that all three are effective, but that intubitrile approach is more effective in reducing macchiordema, both azuredex and dexamethasone than stearoids. And that that was clinically and statistically significant and that that was at the cost of a moderately elevated intraocular pressure rise in the intubitrile group that could be managed with stearoids. Again, this is a pretty short study. The other interesting aspect of this was that the intubitrile dex was not inferior to the intubitrile approach. In fact, although it was empowered this way, we're studying it seemed because of some of the complications of the study design it seemed that the may have a not statistically significant advantage over intubitrile therapy terms of efficacy. The other thing that we learned was the peak efficacy of the seems to be about 8 weeks rather than 8 weeks. And that intubitrile dex monthly implant did not seem to have an advantage with respect to intraocular elevation of the pressure. There is another trial that is a sister trial to this with related to macrodema called the Merrick trial that is ongoing. Again, we are principal investigators for this site and there have been some other non-steroidal agents that have been shown to be actually useful in the treatment of macrodema including anti-veg agents, both Avastin and Lucentus and intervirtual methotrexate which has been used as you know in the treatment of intraocular lymphoma but also in terms of patients with uveitis. And one large retrospective cohort showed that induced a durable remission in over 70% of patients. So what is the best treatment? So one of the big problems in uveitis is that patients with apparently controlled inflammation can still have persistent macrodema up to 40% of patients in fact. And in the MUST trial 62% of patients in systemic therapy are additional periocular or intubitrile injections. So what is the best treatment for patients with controlled inflammation who have already had an exposure according to steroids? So your choices are to give another steroid in the eye or maybe try something else, so that's what we're studying in that MUST trial. For more longer acting steroid delivery, there's the red assert. This was approved back in 2005 and it showed definitive efficacy with respect to reduced recurrences and compared to the fellow eye, decreased requirement for junctive therapy and improvement of stabilization in vision eventually in 80% of the patient. But at the cost of not unexpected, frequent eye-ocular complications by marinating an eyeball in steroids for two and a half years. So this implant will release flucinolone and setinine for just moderately potent according to steroid for two and a half years. So everybody in my experience gets a cataract. Medical therapy is required about three quarters of patients. That's pretty why. And filtering surgery both in the trials that led to the approval of the implant and in the MUST trial was necessary in 30 to 40% of patients. So that's not insignificant. I think that we'll talk about this and we can talk about it offline as I say. But I think this is a great device in terms of the cost of significant eye-ocular side effects and you have to this is where individualization is important. So our job I think particularly younger people is to prevent eye-ocular complications and create them. There is a long term people will say what's the big deal of cataracts and you can always do a cataract with it. I would agree with that. But there is a big deal about glaucoma surgery I think. So there is a long term risk of that. There is also an alona set-night insert which is an office-based delivery. Sorry, the red assert is a device that needs to be implanted in the operating room. I just have a minor detail so the patient needs to go to the OR and you know there is a you have to implant this with a paris plana incision into the eye and suturing it into the eye. So it would be great to have a similarly effective implant that you could inject into the office. And indeed this has been developed by alomarous sciences and by eye point. The aluvian implant is confusing but aluvian was from alomarous sciences. This is the implant that was approved for the use of diabetic macular or the eye point product. It has been approved recently in October for uveitis. So there are slightly different there are different companies that own them. And there is no indication for the use of aluvian in uveitis although some people have used them. But now we do have a device as you can see here which is an office-based inject injection of flucinolone into the eye and it's a bioerotable device that is it's contained in a polyamide cylinder that elutes in phase one kinetics into the eye once it's injected. So you are left with this little thing that kind of floats around in the eye but it usually lodges in the vitreous. I personally do not have enough experience to tell you whether or not patients see these things or not. But Glenn Jaffee who pioneered this has not really had that experience. So it's the efficacy of this has been shown in pivotal randomized controlled clinical trials with significant reduction and lowering the currents rate as compared to sham decreased incidence of loss of 15 letters of vision and it allows less adjunctive therapy to be used but then a higher rate of cataract development and note again this is fairly early I am sure that you are going to see more cataract development and probably more elevated intravenous complications in this device. Just with respect to macadamia in the one year 12 year results about 74% versus 48% patients in sham had resolution of their macadamia so as we will see this may end up becoming actually a very useful device but patient selection is really important so it is the slowest releasing of the devices and it may be useful adjunctively in the office in patients that are on systemic treatment that have persistent macadamia or in patients with moderate inflammation in their eye and unilateral disease such as in patient with intermediate EVIs there is another delivery system that is being pioneered supercruital delivery of a triumphal by clear side biomedical and there is animal model that supports this versus intermittent injection that this may give you a higher amount of medication to where you want it to the core and RPE cells with a lower exposure of medication to the anterior segment so when you plan to read a certain into the eye it is right behind the ciliary body so it is thought that location is important with respect to the induction of cytokinesis we are not in this trial but I did try using this device it is pretty fast some patients will report some pain associated with this injection by injecting medicine into the supercruital space as they do when they develop supercruital hemorrhages but it is a very actually unique device and again there are phase 3 randomized controlled trials NDA has been submitted to the FDA for its approval remain known by academy of time whether or not this is the approval and it reached its primary outcome measurement which was basically visual duty outcome 46 or 47 percent of patients versus 50 percent of sham team layers of vision it is also a significant reduction in central macular thickness and it reduced a requirement for rescue that is local steroid rescue versus sham so sham patients were not treated they were treated with periocular and so far there is a low incidence of intraocular pressure and cataract so far stay tuned so systemic corticosteroids are really the main state of severe disease particularly when it is bilateral prednisone has a terrible reputation among patients and maybe people don't use it but it is a very effective medication used properly I think without creating a lot of the litany of steroid side effects that you would read about if you were to open up all the side effects of this medication I think that they are manageable and in our clinic we weigh patients, we check their blood pressure we check their blood sugar and their fasting limits and we don't have patients on steroids for super long periods of time so we have a defined interval of about 3 months we set goals with the patient in terms of how much we always supplement them with D and calcium because one of the major side effects of the medication is blossom calcium and use angiobesortable agents is necessary immunomodulation immunomodulatory therapy is necessary in patients that fail to respond to corticosteroids in patients with unacceptable side effects of corticosteroids or diseases that are known to be poorly responsive to monotherapy with corticosteroids and we'll go over some of that or when you're tapering a patient often they get to 20 milligrams prednisone and they have recurrence it's just you're not going to gain anything by continuing to elevate their prednisone continuously and giving them chronic exposure steroids you need to add something else or spare steroids in the long run so there are certain diseases we know that need immunomodulatory therapy at the outset those include Bechette's disease severe ocular ocular supragenous chordopathy tyrosine scleritis and sympathetic ophthalmia there are some other diseases in which the experience suggests that really early implementation if not at the outset may be beneficial in the long run in terms of the progress of those patients those include birdshot, multi-vocal certain cases with JIA and some cases with HIV-AIDS so what are these agents so I like to think of them again because I think I try to think broadly stupidly but in broad categories so there are so many agents available or coming available so I think you one useful way is conventional therapy biologic therapy so conventional agents and biologic agents actually by definition modify some specific aspects of the immune system so conventional agents are more broadly acting they interfere with either DNA or protein synthesis and affect the body all the cells in the body like methotrexate will affect immune cells but also the gut other agents will have specific receptor ligand antagonism such as IL-2 for cyclosporin there is receptor blockade and there are others for which really the anti-inflammatory mechanisms are not quite known so the conventional agents again thinking in broad categories are the anti-metabolites that those include methotrexate mycophenolate, monochial or cell sept calcinerine inhibitors or T-cell transduction inhibitors such as cyclosporin and tecrolimus and then the alkylating agents chloribus cell and cyclophosphide which we don't use that frequently these days because we have more we have alternatives such as the biological agents these agents are actually useful in certain disease states in inducing remission to my knowledge there are not very many agents that actually do that the alkylating agents are the only ones that do really so for patients for example with Baciasis disease remission induction has been shown with chlorimus cell and cyclophosphide for patients with necrotizing scilaritis associated disease angiopositive disease we do have retuximab chlorimus cell and cyclophosphide so treatment principles you got a fire, you want to put out the fire with a fire hose not a squirt gun so you want to use a large dose by whatever as Nalcomax would say by whatever means necessary so by whatever route you need to use to put out the fire and then you want to keep the fire out so you taper the medication and then if there's recurrence think about immunomodulatory therapy or if it's disease that doesn't respond well to monotherapy then immunomodulatory therapy so in order to do that you need to know something about your drug so using steroids as a bridge is useful in patients for example for whom you're going to put on any metabolite because most medications will require two to three months to become actually biologically active so you want to have something on board tapering your prednisone while methotrexiders cell systems become biologically effective so with immunomodulatory therapy as opposed to steroids where we start out with a higher dose and then taper down we start out with a moderately high dose and then taper up with monitoring side effects so we want to closely monitor these patients both clinically to see how they're doing on their medications then with laboratory investigations at baseline and at regular intervals to exclude infection and then to monitor the hematopoietic side effects or renal side effects for example cyclosporin will produce renal side effects and those patients need to be followed for PUN creatinine whereas liver function is more metabolites so there was a very large registered study called the site study that is still kind of ongoing and it's collected a lot of important and informative data from five huge Iveitis practices in the United States on the use of these agents and it has shown that basically the anti-metabolites work about 60 to 70% of the time so that means that you have a fairly high percentage of patients in whom you don't have a response and at the remission rate for patients with anti-metabolites is fairly low whereas the remission rate for patients with cytoxin is high higher however it comes at a price of significantly higher toxicity there was a trial called the must trial the multi-centric Iveitis steroid treatment trial which is a very important study that I encourage you to read the reports on both their two and seven-year data which I'll just briefly here is a randomized controlled trial of the flucinolone implant versus standard of therapy that is steroids first and then the addition of conventional basically immunomodulatory therapy to see which is better or whether or not there was equivalence because a lot of people would say oh my god you're poisoning these patients with immunomodulatory therapy why can't we just inject something into the eye so the two-year results showed that both with respect to the implant and to the systemic therapy that the visual outcomes at two years the study was designed as a two-year study but there was a follow up for seven years I think that's an important point of argument that we can talk about some other time but the end point of the study was at two years and it showed similar visual outcomes their inflammatory control was statistically significantly better with the implant but vision was the same and systemic therapy was incredibly well tolerated so we learned some very important pieces of information so inflammation was slightly better with the implant vision was the same and patients really did well with systemic therapy other than having to have more prescriptions written for infection so a person's on methotrexate they get a cold, they go to their GP and they say oh you're on methotrexate here's an antibiotic prescription that's really what I'm talking about but it came at the cost as I was saying significantly increased the amount of cataract IOP requiring therapy and glaucoma surgery and a large number of patients the results at seven years were interesting so this is not a designed end point but a large portion of these patients followed up to seven years and what it showed was that at seven years there was actually a switch to a more favorable response to systemic therapy and that switch occurred at about five years and it occurred probably concomitant with the decrease in the efficacy of the implant implantation was not required in this trial although patients were re-implanted but it was not a requirement and that overall favorable visual outcome in the systemic arm and that there was a higher proportion of patients that had legal blindness in the implant arm benefit systemic arm so these graphs kind of show that with respect to inflammation there is a statistically significant difference up until about 54 months and then at about five to six years this switched your favoring systemic therapy both groups had anti-inflammatory coverage which is probably why the systemic arm did better because they had continuous anti-inflammatory therapy with respect to macurodema not so much only a statistically significant difference at about six months for the implant that again switched at about 54 months favoring systemic therapy all of your complications you know as I mentioned to you in the trial at seven years similar cataract glaucoma surgery then systemic adverse events were similar as in the two-year study with more antibiotic treatment infections and similar quality of life for both groups so what does that mean you know I mean you can interpret this data in two in two very different ways but that long-term visual outcome favor systemic therapy versus the implant and the reason for the decreased vision was thought to be the increased in the amount of macular damage and cortiretinal inflammatory lesions there was initials better control with the implant you know that initially with the implant then later on at seven years obligation rate as expected with the implant so I think that you know the treatment implications is that systemic therapy works okay that it may be better for a lot of patients as initial therapy but the implant has excellent control of information I think again I would never I can think about this data in two very different ways because I think it really needs to be individualized to the patient there are patients that are intolerable of corticosteroids there are patients that just don't want to be on systemic therapy that will do well with this medication there are patients that have had unacceptable side effects of systemic therapy for which implants are actually very good options as I mentioned the the adjunctive use of intervitual therapy with more longer acting maybe extremely useful particularly in patients that are on systemic therapy that have small recurrences of say for example macular so biological therapy the other large arm they are therapeutic bioengineered proteins that are antagonists against immunoactive molecules not that you should memorize this but this is really what is you know available these days that we use in patients with with their RISO inhibitors the CD20 inhibitors IL-6 inhibitors IL-1 inhibitors they are we have borrowed really heavily from the rheumatologic colleagues in terms of using these medications as they have pioneered the use of these arthritis but just to go over the things that you will see most frequently in clinic so the TNF inhibitors there are many of them but the ones you will see most often are N-Brol influx map and Adaluma map N-Brol is a recombinant fusion protein that really is great for arthritis it was one of the first to come up but it really has been shown to be ineffective in patients with with uveitis so we will see children for example more adults that have inflammatory arthritis that are being treated with N-Brol that come in for screening and they may not have any inflammation in their eye okay let's not rock the boat okay you're doing fine well if they developed inflammation I would switch them to another agent such as influx map or Adaluma map which is more effective there is evidence based medicine and there is evidence based medicine and so it's hard to conduct large clinical trials but it is useful to get people's experience and particularly when you're trying to get medications approved by insurance companies so prior to the visual one two and three trials it was published in which we had expert opinion with respect to the use of biologic agents and basically the bottom line was that influx map and Adaluma map are really the preferred first line agents for Bechette's disease nothing else seems to work very well with Bechette's disease everything's been tried but these agents seem to work well they are not remittive but they do get disease under control and then second line agents are patients with GA-associated urocyclitis and then potentially second line agents when you have failure of conventional immunomodulatory therapy in patients with severe intermediate posterior panheubitis so influx map is a chimeric monoclonal antibody that is a mouse-human combination that shows efficacy in heubitis with reduced retopical steroids from its IMT taper and is differentially more effective than in tenor sept it is administered by IV infusion on basically a monthly basis after an induction the fact that it's a chimeric antibody a little bit problematic and that one can develop antibodies to the molecule so that patients that are on this medicine usually require concomitant metabolites such as methotrexate one of the advantages to using this cellular drug is in a poorly adhering patient at least you know that they're getting their medicine right so they're coming in for an infusion every month and then the variable with respect to the dose and the frequency with which you administer it so rheumatologists like to administer this at a much lower dose than for ocular inflammation three to five milligrams per kilogram we usually start it out at about 10 we can go up to 20 and then infuse patients on a monthly basis rather than eight weeks and then extend their infusion interval out Adalimumab has been approved by the FDA is the first biological agent to be approved for use of intermediate post-European UBI's but on the basis of two visual one and visual two trials it is fully humanized so it's less immunogenic though people do develop antibodies to the medication it is delivered subcutaneously so it's a little bit easier to administer and to the credit of ABV supports this product they have a fantastic program for patients in terms of support and use of this it's usually dosed every two weeks although in ophthalmology there are patients that have recalcitrant disease in which we may have to dose them weekly and that can be a bear in terms of getting that approved so there are some concerns with respect to TNF inhibition the major I mentioned some of them to you you know there can be a anti-chomeric antibodies which can reduce the efficacy of the drug drug-induced lupus syndrome but really the most important thing is that patients are at increased risk for developing severe infections particularly TB and histoplasmosis so any patient that undergoes biologic therapy has screening for tuberculosis there are studies in the literature depending upon what body of literature you read that there's an increased risk of lymphoma in this group of patients particularly among patients with rheumatologic disease that are already at risk for lymphoma anyways patients with rheumatoid disease it has not been shown in the GI literature it's actually very there is actually increased risk of demyelination so this is actually an important point especially with respect to the treatment of UV-itis as we maybe touched on last time intermediate UV-itis one of the major differentials in intermediate UV-itis is multiple sclerosis which can occur in more often in young women that are HLA-DR2 positive in any case multiple sclerosis is not a diagnosis you make by a laboratory test but we know that those patients are at increased risk so you need to talk to patients about it and then as intermediate UV-itis or porous planets patients are at risk for development I would not start this without actually screening them with an MRI scan the latest and greatest is always met with great enthusiasm and just take a more circumspect approach and that is kind of wait and see I would certainly adopt new therapy not everybody responds to TNF inhibition right so there are other by launch agents that are available to us that work by different mechanisms so if a patient doesn't respond to one anti-TNF medication such as Adelum you might want to switch them to another one like infliximab where you control over the dosing there are a couple of other anti-agents such as golymumab and sirtoluminsumab which also may be effective but there are third line agents and we don't really have time to go through them but they work by different receptor antagonism such as abatosept or rituximab which is a medication that actually inhibits B-cells don't ask me the exact mechanism of how inhibiting a B-cell it's complicated but a B-cell inhibition seems to work in rheumatoid arthritis in which it's thought to be a bit insimilarly in certain patients with EVitis which we think is more of a TH-17 or CD4. There are other medications that will inhibit other cytokines such as IL-1. One promising which inhibits intralocon-6 which is a cytokine found in the eyes that are inflamed that potentiate the activation of T-17 cells is tosylizumab which is an IL-6 inhibitor. One of the other interesting aspects of this molecule is not only is an IL-6 inhibitor but also inhibits anti-veget. So systemic administration of this medication is not only effective but also for macchaedema actually there is a phase 2 trial called the STOP EVitis trial which was a multi-center phase 2 trial which looked at the safety and efficacy of IV tosylizumab in two different doses and it showed an improvement of best corrected visual acuity, decrease in vitreous haze and decrease in macular thickness which was significant interestingly in the lower dose rather than the higher dose of this molecule. So this there is a few more about ectema or tosylizumab just for the sake of completeness there are other biologic agents such as the interferons interferon and alpha 2a is a molecule that can be given three times a week or weekly and has been actually very useful in bachette's disease in the European experience it's really not useful here but it's actually very useful in recalcitrant macular edema I know of one patient that nothing worked other than this and that patient is still on interferon alpha 2a and then IVIG which has been useful based on autoimmune retinopathy so what about the outcomes you know there is no question that in JIA associated urocyclicitis that treating patients with immunomodulatory therapy decreases the risk of auto complications and blindness and the better CEI and the site cohort which is that large cohort that I mentioned to you there is a significant decrease in the risk of visual loss particularly worse than 2050 outcome in patients that are managed with there is a concern for what about the induction of cancer and mortality there have been a couple of studies on this and it's quite interesting and I think that the information is evolving about this suffice to say that in the published literature thus far there is no increased risk of cancer mortality or cancer risk in patients on anti metabolites or in metabolites or cyclosporine inhibitors there is a slightly increased risk of mortality in patients with cytotoxic agents although this seems to be driven completely to the right of the cell a word of caution is that and then just kind of like hot off the press kind of information is lost over this and that the site data the initial site data of the TNF inhibition did seem to suggest an increase of mortality and cancer risk in patients that are on biological agents although this is a very small number of patients and that subsequent data has suggested this does not actually hold patients that are on immunomodulatory therapy even patients that are on anti metabolites are at increased risk of non-mole skin cancer so you have to advise them about that and that is also another area of study so in summary there are disease specific indications for treatment we apply a stepladder algorithm with the early implementation of steward sparing steward sparing immunotherapy either is conventional biologic therapy and there is definitely a place for multiple diseases and hopefully with effective control we can modify the prognosis of uveitis with the early introduction of these agents and I think that will also require identifying allies that are at the most risk for developing a lot of complications and which limits marketing surveillance with randomized control trials thanks