 All right, so I'm going to start off by talking about juvenile idiopathic arthritis and really focusing on the management and some of the challenges that we face and decisions that have to be made in managing this disease. We're going to go through this with a case of a patient of Dr. by Tally's, which really is a great case to illustrate a lot of the things that we have to think about in ways to manage this disease. This is a three-year-old boy, and when he first presented, he had the diagnosis of oligoarticular JIA, and he's A&A positive. So he initially was seen by ophthalmology in 2002, just for a screening exam for any ocular inflammation, which was found to be negative. An overview and just some important points about JIA and UVitis associated with JIA, most of the children who are diagnosed with joint disease have that diagnosis first, and then have ocular complications secondary to that or after that. 15 to 47% of pediatric UVitis associate, or 15 to 47% of pediatric UVitis is associated with JIA, and that's a huge range of numbers, but there's differing reports. But the main takeaway is that this disease does account for a lot of the pediatric patients that we'll see with UVitis. 27 to 56% of kids with oligoarticular arthritis will develop UVitis, so it is important in this particular subset of kids that we really follow the screening guidelines and have the eye exams as kind of outlined, which we'll talk about. And then 30 to 50% of patients have structural ocular complications already at the time of diagnosis of UVitis, which is really not ideal, and that pretends a poor prognosis. So there's screening guidelines for when these kids need to be seen. Kind of the important things to remember is that oligoarticular JIA, RF negative polyarticular JIA, and psoriatic arthritis are kind of in the category where they may need to be seen more frequently, and then if they have a positive ANA and a diagnosis at less than six years of age, that kind of puts them in the high-risk category, and then a kid who's had the disease for less than four years is one that needs to be seen every three months, which is what category our patient falls into or it fell into when he first presented. So moving along this boy, he, in June of 2003, was started on methotrexate, 10 milligrams a week, and this was for the purpose of controlling his arthritis. He still hasn't had any ocular inflammation at this time. In August of 2003, he had his first documented uveitis flare, and at this time he had some leg pain, no eye pain, no eye injection, so parents, you know, no indication that he did have any eye problems, but on examination, he had one-plus-cell inflare and the right eye, two-plus-cell inflare and the left eye and some KP. So he was started on topical cortical steroids, and then he is also on methotrexate at this time as well, and he's continued on that. Kind of a, this is a very simplified version of the treatment paradigm, but basically, topical steroids are the first-line treatment, but as Dr. Vitale mentioned, there's complications of using these long-term, and so if this isn't controlling the inflammation, we move to anti-metabolites, most commonly methotrexate, and then adding on biologic therapies or using them in place of the anti-metabolites. And then there's little role, I mean, there's some role for oral or regional cortico-steroids, but that has to be short-term, and it's really not a long-term treatment plan. So the cortico-steroids, I mean, the goal is to get, to eliminate inflammation and to keep them at the lowest dose as possible and taper off as soon as you can without having the intraocular inflammation recur. There is a paper put out by Thorn and colleagues that looked at how what a reasonable long-term dose of low-dose cortico-steroids would be in kids with uveitis and looking at the risk of cataract development, and there's some controversy to this, but they did find that the risk having drops from increasing the drops per day from three to four drops per day was an independent risk factor for the development of cataracts, independent of uveitis, activity of the severity and type of cortico-steroids. So they, in their paper, they kind of concluded that a three-day, three-drop per day or less treatment regimen for what they defined as a moderate, moderate course, which was three to five years might be appropriate. Again, there's some controversy to that, but at least we can think of three-drops per day as less being something we can continue. And then even with this, though, up to 60% of patients will require other anti-metabolites or biologic therapies to control their uveitis. So in terms of anti-metabolites, methotrexate is kind of the first line therapy, and there's been some studies that have been done, and there's good evidence that it does control the uveitis in JIA patients, and for the, for time we'll kind of skip through, but there's evidence to support the fact that this is an effective at controlling ocular inflammation. You, what's been reported as kind of appropriate or a good response to methotrexate is a two-step decrease in AC grading, or AC, anterior chamber cell grading from in about 70 to 80% of patients within three to four months. That's kind of something we can expect, and then of course there's a lot of side, there can be a lot of side effects and any time we have these patients on anti-metabolites or any of these biologic therapies they need to be monitored with labs, and we need to pay attention to all the potential side effects and they need to have supplementation with folic acid. All right, so back to our patients. So in December of 2004, he had another uveitis flare. His methotrexate was increased to 15 milligrams a week, and then over the next kind of year and a half or so he continued to have uveitis flares. He's still on the 15 milligrams per week of methotrexate, and he's been treated for these flares with topical corticosteroids, but really things aren't as controlled as we would like. And then in June of 2007, he has an arthritis flare, and this is in the context of having these kind of recurrent uveitis flares. So his methotrexate was switched to subcutaneous administration. He's still on 15 milligrams a week, and he was started on infliximab at every six weeks. And then in March of 2009, so he was on infliximab for almost two years, and he had another arthritis flare, and this time it was independent of any uveitic flares, and he was switched to adelibimab and started on a very short, a weak prednisone course. And then at this point, their methotrexate dose had kind of been started to be tapered a little bit, but he was on 12.5 milligrams a week. So in 2007, his eye-examely, this is when he was started on infliximab. He just had one and a half plus cell in KP. And then this in March in 2009, kind of the next time he had his arthritis flare and they switched to adelibimab, but of note, he didn't have any ocular inflammation. And so one of the other things that this case does illustrate very well is that the joint disease and eye disease isn't synchronous, and it really is important that we follow very closely with rheumatology and have a really good working relationship and communication so that these patients do get their medications adjusted and changed if necessary and when necessary. So kind of the next step in the treatment after we've tried topical corticosteroids and then the anti-metabolites, the biologic response monobisers and there's a handful that we can use. So there's the tumor necrosis factor, alpha inhibitors, infliximab and adelibimab are two. They infliximab when we use it in JIA will need, we use about five milligrams per keg to 20 milligrams per keg and it's a shorter interval than with the adults in rheumatoid arthritis. It has been shown to have a consistent reduction in intraocular inflammation and it can be effective in permitting systemic immunomodulatory therapy taper and reducing the overall requirement of steroid use. It does have a waning efficacy over time and then adelibimab potentially is effective as well. The problem is just limited data and studies and limited comparisons between the two in this disease. Important things to remember about using these medications, the anti-double stranded DNA antibodies can form so you can have a rare drug induced lupus and then the anti-chimeric human antibodies can also form which can reduce the efficacy and cause infusion reactions and then with all of these there's an increased risk of infectious disease, increased risk of lymphoma but importantly in this category of medications there's an increased risk of demyelination and optic neuropathy and so not related necessarily to GIA but just remember if you're ever treating someone with intermediate UVitis or parisplanitis we need to make sure that they do not have any, that they do not have multiple sclerosis. It's a contraindication to use them. This medication with multiple sclerosis then you can have neuropsychiatric complications. Rutexamab is another biologic response modifier. It's an anti-b-cell mass human monoclonal antibody. Small case series showed some ocular quiescence with Rutexamab and refractory UVitis cases. It's a very small sample. I mean a lot of these studies are fairly small power but it's what we have. So back to our patient again. We're now in November of 2010 and he had a UVitis and an arthritis flare. He was switched to abatosept and he's still on methotrexate 12.5 milligrams. He was actually switched to abatosept six weeks prior to this visit and that was kind of again for his joint involvement but on his exam he still has inflammation more so in the left eye which is kind of chronically what he's had and he was started again on topical corticosteroids. Abatosept is another biologic response modifier. It's a selective two-cell co-simulation modulator. There's again a few very small series that showed some efficacy and clinical remission of UVitis but eight patients in the first series and then two reported cases in the second series and then our patient it didn't really, it wasn't effective in controlling his ocular inflammation. So March 2011 he continues to have low grade ocular inflammation, he continues to have flare ups of arthritis and the decision was made to switch back to infliximab because it did, looking kind of back at the course of his disease, it did seem to be fairly effective and at least more effective in controlling his disease than abatosept and adelimumab and his methotrexate was increased to 20 milligrams a week. So then, and I'll go back here for just, so after that switch he was actually had a pretty good response and was quiescent and has been quiescent since and didn't, hasn't had any ocular inflammation. So the question is how long does he need to stay on all these medications and what's an appropriate length to keep someone who has controlled UVitis on methotrexate. So there's a good paper that came out by ISO and colleagues and in 2011 it was a retrospective chart review between 1989 and 2009. And they basically took patients who had been started on methotrexate for UVitis associated with JIA and looked at what length of time they were on methotrexate and the length when they were taken off of it if they had any relapses and tried to kind of elucidate what the best kind of treatment paradigm for decreasing and tapering off methotrexate would be. They found that 69% of patients that had inactive UVitis at the time of methotrexate withdrawal had a relapse and most were in within the first year. And so looking at all the data they found that a longer period of inactivity combined with an older age or longer treatment with methotrexate might protect against relapses. And kind of just to highlight this the one year increase of duration of inactive UVitis being treated with methotrexate resulted in a decrease of hazard of new relapse in 93%. So really it's important to keep these patients when they're quiet on methotrexate for at least two years before we think about tapering them off. And the duration of inactivity before the withdrawal was an independent risk factor for the relapse of UVitis. So this paper was nice in showing actually providing data to what a lot of UVitis practitioners do in keeping the kids on methotrexate but now we have data to support why we want to keep someone on methotrexate for years after they're actually diseases controlled. And so he has like I said still been had control of his UVitis and so his vision now with 2020 in the right eye, 2025 in the left eye when he was seen most recently in January there was no ocular inflammation. He's on methotrexate seven point five milligrams a week at this point and his infliximab intervals are being extended and he's kind of going through a slow taper. So this case obviously extends and over many years and he's had kind of a chronic course of flare ups and trying to control it with different medications and I think it brings a few important points and how we have to manage this disease. It's a chronic disease and we can see that here and it involves a lot of persistence and just frequent visits and just making sure that everyone is on the same page and the parents understand what's happening. And the pediatric UVitis can have a guarded prognosis but this is potentially modifiable with early and aggressive steroids bearing immunomontulatory therapy and this disease and a lot of other UVatic entities really requires very good coordination and communication between different subspecialists to provide the best patient care and joint disease and eye disease are not synchronous so when there's an ocular flare up we have to communicate to the rheumatologist and vice versa to really get these kids on the treatment that they need. That is it. So thank you to Dr. Vitale, Dr. Shakur, Dr. Bell and Dr. Zimmerman.