 Right, ladies and gentlemen, Professor Zone, ladies and gentlemen, thank you for coming for the Class 6 Grand Rounds. When we organize this specialist Grand Rounds, the lads and I, we've given it some considerable thought as to the topic we choose, why we discuss it. We go to Grand Rounds after Grand Rounds, we discuss cases, procedures, how to do things. And we sort of wanted to introduce a little bit of a discussion as to what we do, why we do, what can we do differently, and is there a way to improve some things. I think one of the most rubbish books that I was made to read, not so long ago, was Pugul by Cheese. It's about 70 pages long. It's probably the most idiotic book I've ever read. And more people in the world have read it than I think the Bible, because it was the craze until about 2004. And basically it says change is good. It's done over 70 or 80 pages. And certainly change is good, as long as you focus in on the appropriate types of changes that not simply keep on changing. Directly as a reason, and directly from the use of that particular book, I'm afraid you're all condemned to having to weekly review our press of gaining reports that have been sort of stuck in that delivering life, I would say. So good things and bad things in life that come up in these meetings and books and things that we read. There are two sides to today's presentation. The first one is a subject that I think we need to make some changes in our management as an institution, as a division, as a department, as a group. The second one is a more philosophical one. When King Solomon was having his good days, he once had a sad day, so he got his wise men together and he said, I want you to do something that will make me feel happy when I'm sad. And so they came up with a ring and on the ring's inscription is that phrase that has now been used over the over the centuries, which the popes recite when they when they get inaugurated, which is this two shall pass. And so the point was made to him that you just look at your ring which says this two shall pass in Latin, and the sad days will pass. So he got the wise men together one day and he said, you made my life miserable because I'm more happy than I'm sad. And every time I look at the ring I realize that my happy days will pass too. So you can never feel them today. So this business about these two shall pass applies to our second presentation today. We forget that we are. We all know the sayings, the momento mori, the sick gloria mundi, all the phrases over the years that we've used to remind us of mortality and how life passes and that we're not invincible. And yet I was in the changing room a few weeks ago and a fellow plastic surgeon was changing and I heard the rattle of a bottle and he took out about, it must be 60 or 70 pills and he swallowed them. It was 7.30 in the morning. And I said, what are you taking? I can't imagine you're that ill. He says, oh, vitamin this, vitamin that, blah, blah, blah. You're supposed to anti-age and reduce your age in all this sort of business. I think we forget the fact that we are after all mortals and that the multiplication of our cells has an infinite number of times that we can split before our cells die. So that comes into play in our second discussion. As far as the first discussion goes, when we talk about diseases, we mustn't simply talk about what's the best treatment. There's an organization called NICE, which is present in the UK. There are similar organizations in Europe, National Institute of Clinical Excellence. We don't have such an organization in the United States. It's high time we had one. And what NICE does is it looks at those treatments that give you the most cost-effective results in a disease management process. So if something is excessively expensive and it only helps a very few patients for a very short time, they do not allow you to use it. I think this is not a matter of death panels. It is a very sensible approach. The converse to that is if you have a treatment that really works very well and in Charles' company, I can't say to you, you can't use this because the NICE organization basically tells you this is the best treatment for it. There's published proof that works. So before I let the first presentation be given, I want you to just listen to this little summary from the paper that was published just three or four years ago. This was forwarded to us by Professor Zohn. This control study had six patients who were in the study group and six patients who were in the control group. It was easy to choose the patients that fell into the control group because these were the patients who were refused the immunosuppressive treatment that we requested from the Charles' companies. So they automatically fell into the control group. All six of these patients were blind in both eyes. As it happens, the study group went on to show, or was suspected from other case reports, that by the way, been around for about 12 years, that you can save vision in at least one if not both eyes to a very significant extent and leave people independent. This is something we're dealing with in 2016. We still have this problem of treatment, controls, who can we treat, who can't we treat? So the first disease we're discussing is one that we all put our minds to as to what do we do, what do we change, how do we treat? And I hope most of you got a chance to see one of the two patients we're presenting upstairs. The juice is going to present the first one and stack the second one. Thank you. Thanks. Good morning everyone. So for those of you who didn't get a chance to see the patient upstairs, that's case number one that I'm going to go over briefly. There's a lot of different dates and details about the case, but I'll just try to summarize them as concisely as possible. So case one, she's a 57-year-old woman with history of diabetes. She presented back in February of 2015 to her optometrist, complaining of ocular irritation and sensitivity over the past three months. She'd actually been taping her lower eyelids to her cheeks because she'd found that that had improved her irritation. At that time, I just want to... This is important just to see where she started. Her vision was 2070 and 2040 with correction. She had some corneal staining that day and bilateral oral intropion. She was referred to oculoplastic service here at Moran. About a month, you know, six weeks later, she arrived at her oculoplastic consultation. She said both her lids were bothering her, but she had denied any previous problem with her lids. At that time, without correction, so this may not be as bad as it actually is, 2150 and 2100 in right and left eyes. She was diagnosed with bilateral lower lid secretricial intropion. And about two weeks later, she underwent a bilateral lower lid intropion repair and actually had a conjunctival biopsy of both lower eyelids at that time. This was repaired using a lateral tarsal strip technique and a reinsertion of lower lid retractors. This is a picture right before surgery, so you can see she's taped her lower lids here. A lot of conjunctival hyperemian injection and bilateral lower lid intropiants are with lashes touching the eye there. So the biopsy results came back a few days later from dermatopathology. The right conjunctival biopsy was completely normal. It showed some connective tissue fibers here, but in terms of the immunoglobulins here, they were all negative. So this really shows the utility of taking two biopsies in a patient, which was done here very wisely, and it shows the predominance of IgG IgG4 in the basement membrane zone and also IgA. So the interpretation from the dermatology department was that this was a predominantly IgA, but also a linear IgG, making a diagnosis of Pemphagoid and specifically linear IgA disease. So after the positive biopsy, this patient was called several times to the office to discuss the results. Unfortunately, she didn't show up several times and we actually made a formal appointment after the biopsy was confirmed to discuss this with her and she didn't show up a third time. So the patient obviously lost the follow-up, which will show why she progressed here. So she finally made it to the office a couple months after the biopsy and she's reporting that she cannot look up at that time. You can see her vision dropped to counting fingers in her right eye and her left eye as well. We requested an urgent referral to dermatology with Dr. Zone, who's present here today. In the meantime, we decided to have her follow-up with us and she canceled her appointment to Mr. Dermatology appointment with Professor Zone. So you can see the pattern here of poor follow-up. Urgently she called in a month and a half later saying that she was having problems, no specifics to that, but she'd actually developed bilateral corneal ulcers and upper lidentropian with chakrasis and here's a picture of how she looked when she called in that day. These are the quote problems that she was having. It's quite obvious what's going on. Bilateral ulcers, a ton of ton of inflammation here in the conjectiva with early fibrosis and you can see the symblephron formation and shortening the inferior fornix. So we urgently sent her to the, excuse me, the cornea service. At that time she was just light, clear light perception in both eyes. The left eye was soft, however the anterior chamber was formed, but it was shallow. They didn't see an active leak, but they suspected that there was kind of intermittent slow leak from that left eye. At that point cultures were taken, which grew staph aureus, or excuse me, just staph, I don't remember exactly what bug, but staph. She started on fortified vancomycin drops, also doxycycline and vitamin C to help with the corneal ulcers. The next day she underwent an upper lidentropian repair by this modified Trabu procedure and also the tracheitis was treated with the almond unit to both lower lids. She got in to see Professor Zohn later that week. At that time the history revealed that she'd been suffering from severe dysphagia, blistering of her throat and mouth and I actually had been reporting badinal symptoms for years, but those are unclear if that's a blistering in the vagina. She started on dapsone 25 mg daily and they submitted an insurance request here for IVIG and Rituximab infusions. We'll go over, that's the article Dr. Patel was alluding to before and we'll go over the benefit of those treatments. Her labs, after she saw Dr. Zohn, I'll go over this in more detail too, but there's an ELISA serum test that you can use to detect adenobodies and hers were obviously in the abnormal range here in red. She also had positive titers of both IGA and IgG in the basement membrane zone and the interpretation to this is similar to the conductive obiopsy, a mixed pattern of IgG and IgA and this was interpreted by Dr. Zohn to say maybe this has implications for her disease severity and possibly treatment monitoring. So in the meantime, next couple weeks she was following up with cornea molecule plastics and she had progressive thinning, new vascularization, congenitalization, some blepharone and I'll show some pictures of that. She started an oral prednisone to try to prevent further scarring and then you can see the timeline here up until, I think she saw Dr. Zohn here on the 14th a couple weeks later she finally started Rituximab, no IVIG but with solumendrol. Here's a picture of how she looked the next month and you can see this persistent staining of her corneas. This is after the upper lid procedure you see a nice eversion of the upper lids with the lashes away from the corneas that's really important. You can actually see some recurrence of the entropion on the lower lids here as well. So just some following of her labs we increased her dapsone further and followed this BP-180 lab that I referred to before and it's on a trend downwards however, because it was not completely normalized they considered starting IVIG which was not started. Overall she received 8 infusions of Rituximab as we followed her labs. Here's how she looks just last month in December. You can see this basically end stage disease here with conditivalization and scarring of the corneas, keratinization severe some blepharone and you can see that's how she looks today as well. Here's just from a couple weeks ago and this is how she looks today. You can see this basically 360 degrees of some blepharone and shortening of the fornex here just complete obliteration of the fornex. So very kind of end stage picture here. So the future plans for her there's nothing definite but Dr. Patel is planning some more lid surgery for her next month with a fornex reconstruction and a lower lid reconstruction as well. In the meantime she's been kept on dapsone lubrication with the rithromycin ointment and also a low-dose prednisone. We continue to epilator lash just to try to protect the cornea and then she's visited with cornea and the possible options cornea can comment on this later on but there's possibly a keratolimbal autographed with a transplant or possibly a keratoprosthesis and we'll discuss a little bit about that later. I just want to talk briefly about case number two who's not here today but a little bit different case given his long history but he's a 75-year-old man with history of diabetes. He was diagnosed with mucus membrane pemphagoid 12 years ago based on a pharyngeal biopsy. This was formally diagnosed as linear IgA bolus dermatosis. He also has a history of glaucoma in the right eye with steroid response. He's also had catarx surgery in the right eye. He was previously treated with cyclophosphamide and prednisone. He later went off of those immunosuppressants and then was restarted on celsept a couple of years later. I think the last time he had been on immunosuppression was about 2009. His visual acuity after his first bad, bad flare of pemphagoid he ended up blind basically blind in the left eye counting fingers. His right eye did not suffer any bad scarring of disease so he's fortunate to keep keep his one eye. In 2010 he had some blepharone surgery but he basically represented over Christmas in 2014 with new blistering in his nose, mouth and irritation of his eyes. Over almost about a month later he received a rituximab infusion and the same lab was drawn here. Nine is kind of the cutoff of normal but you can see this is elevated because below nine is normal and then he also elevated BP230 and another rituximab infusion. These are the only two infusions he received as far as I can tell from the records. His right eye dropped from 2030-2040 all the way to hand motion so now he's effectively blind in both eyes, legally blind in both eyes. He was seen in the dermatology clinic and this is I'll point out this gentleman's from St. George he had difficulty coming up to Salt Lake City and follow up so that was one kind of impedance to treatment here. He was started on dapsone 50 milligrams a day in prednisone. Over the course of three months he received three courses of solimedrol as well as some courses of IVIG that I'll show later and then we followed his labs. His BP-180 dropped down to the normal range so the BP230 he was kept on dapsone. At that point because of his antibodies were negative there was no more rituximab was recommended. His ocular surface was protected and tried to be treated with prednisone, restasis and tears and we also kept him on his alfagand to try to limit the damage due to his glaucoma. He received a total a total of 17 IVIG treatments I don't have the exact dates of those in the records though however. Back in September he had an ocular surface reconstruction with Dr. Patel. The plan for him was to try to blunt the inflammatory response by using prednisone a couple of days prior and up to two weeks after in a taper however the patient was confused about these instructions and did not do it unfortunately. The procedure Dr. Patel performed was amicus membrane graft. He resected some scarring from his cornea and resected some scar tissue. Next he was approved to 2050 from this count fingers hand motions type vision he had so a good improvement but as you can see what happens three weeks postoperatively you can see some chemosis and edema here where the reconstruction took place but his cornea is fairly clear you don't see that new vascularization his lashes look like they're in pretty good position away from the cornea and then about seven weeks postop you can see this progressive sub epithelial fibrosis shortening of his fornix he's got some irregular epithelium here and this beginning of this unfortunately it sounds like the procedure did not particularly take well and he's starting to progress despite immunomodulation so he was on the DAPS zone but he developed anemia he developed some heart problems as well he was taken off the DAPS zone and we saw him over Christmas time and at that time professor's own planned for further rituximab infusions and IVIG every month for six months and I don't know if this has been approved he's getting it now so that's a good news and then from the cornea standpoint what to do with this gentleman kind of the same plan possibly limbo autograph versus a K-PRO so that's where we stand with him so any comments from the audience so far just on these two cases maybe Dr. Patel or professor's own have any comments of anything I missed I have a lot of comments go ahead so I'm just going to review so mucous membrane pimphagoid is a group of chronic inflammatory and blistering diseases they affect the mouth, pharynx, larynx genital and anal mucosa it's characterized by these linear deposits of IgG, IgA or complement 3 in the basement membrane zone of the epithelium OCP is a type of mucous membrane pimphagoid that presents as a chronic sigatizing conjunctivitis the epidemiology of this it's relatively rare disease incidences quoted between 1 in 8000 and 1 in 46000 in ophthalmic patients there's differing numbers on there but they usually range in that in those numbers snow geographic or racial predilection average age of diagnosis is more elderly patients 60 to 70 years old however this disease may smolder along and present as kind of just a chronic low grade conjunctivitis for years and years before patients actually declare themselves or undergo a biopsy patients that are younger may present with more severe or rapidly progressive disease there's a slight female to male increase in the ratio there and it's actually rare in children there's only less than fewer than 20 patients reported in the pediatric literature pathogenesis of this is a systemic autoimmune disorder you can see of all the other sites that are involved there is an aberrant production of antibodies against antigens in the mucosal epithelial basement membrane zone there's several targets that have been identified this is a beta 4 of alpha 6 beta 4 integrin is one that's commonly cited in the literature and then this is the other one that I was referring to that people used to detect in the serum for possibly to follow the disease to see the response to treatment if it is positive so there's a couple of theories of why this occurs basically there's these autoantibodies bind to these antigens in the basement membrane zone this stimulates an inflammatory cascade release of pro-inflammatory cytokines and pro-fibrotic cytokines which lead to scarring there's a couple of proposed theories but nothing's particularly been proven there is some HLA haplitides that have been associated with it and there's also some links to topical ophthalmic and systemic medications that they term these as pseudopemphagoid and a lot of the glaucoma medications that I'll point out later have been shown to be associated with this the presentation the ophthalmic findings they can be unilateral as in the second case the gentlemen seem to have unilateral presentation but bilateral involvement is usually within two to four years the eye is the first side of involvement in one third of these patients they typically present with the chronic relapsing conjunctivitis redness, tearing, burning decrease in vision, mucus drainage form body sensation, etc the extraocular findings are present in the oral cavity in about 42% of patients with erosive gingivitis in erosions of the buccal mucosa etc can also present in the nose, pharynx, larynx and other areas in the body non-mucosal skin sites can be involved in 16% and then you have to remember this is actually a potentially lethal disease patients can asphyxiate from esophageal or tracheal stricture so it's something to keep in mind that this is just not localized to the eye can be deadly these are just a couple pictures that you may have the patient open their mouth and see this inflammatory response here of the gingiva and this is Frank blistering an ulceration of the gingiva here this is a kind of a confusing diagram I put together to confuse you all but so it basically starts with the inflammatory process and leading to sub-epithelial fibrosis and then there's three little three areas here that you can go down but they are all usually involved there's these lid changes that cause malposition of the lids and lashes there's the conjectival changes that lead to shrinkage, some blepharone and possibly ankle blepharone and then there's also destruction of the tear film in all three aspects of the tear film, the goblet cells, mybomine glands and the echorine glands so what does this lead to? Leads to dry-eye state leads to malposition of the lids, abnormal blinking and mechanical trauma from the lashes and exposure to keratopathy and then eventually the end stage is this corneal keratinization, neovascularization conjectivalization scarring and eventual blindness so the staging of this disease is proposed by Dr. Foster in the 80s stage one, this has been also been modified however stage one is a chronic inflammatory state with mucus discharge used as a rosemongal as a staining and shows sub-epithelial fibrosis I'll show some pictures of this next stage two is foreshortening of the interferophonics and this can be graded A through D depending on a percentage of how much it is shortened some blepharone is the next stage and also graded as a percentage A through D and stage four is the end stage and I'll show a picture of that and I think that's the category you'd put our patient upstairs so here's a picture of stage one disease, you see this white band underneath the conjectiva here, this is some beginnings of sub-epithelial fibrosis so this is kind of chronic conjectival inflammation here stage two you see some foreshortening of the interferophonics here, it's not as deep as it should be interferophonics is usually involved first as it was in our patients this is stage three, you can see the sub-blepharone formation here not all the way across but you can see a focal area of sub-blepharone and then stage four, just horrible, horrible disease keratinization of the cornea scarring, conjectitilization neovascularization, opacity of the cornea ankle of blepharone, just complete obliteration here of the foreshortening of this, just very, very sad end stage picture here in terms of diagnosis a biopsy is typical of what people do, a lot of people actually go ahead and biopsy an extra-ocular site if it's involved if this is negative there is high suspicion for the disease then the bulbaric conjectiva is frequently used I believe, I don't know where the biopsy is taken from in your case of our patient upstairs Dr Patel in fear of conjectiva they recommend taking a perilegional biopsy to avoid false negatives you don't want to biopsy the super, super inflamed conjectiva that may just show chronic inflammation and scarring and not give you the picture you're looking for negative biopsy however does not exclude the diagnosis of OCP direct immunofluorescence is done on all specimens at least at this institution it is 52% sensitive however if it's negative then they suggest using immunoperoxidase which increases the sensitivity to 83% and then positive immunohistochemistry does not rule out other diagnoses such as epidermolysis bullis aquisata or linear IgA bullis dermatosis so here's a picture of what you'd see on the direct immunofluorescence this is standing positively for IgG in the basement membrane zone here you can also see some other areas that look positive however this is normally inflamed conjunctivitis IgG is found in the conic taba there's also IgG found in the substantia propa here in normal specimens but this is what you're looking for here at the basement membrane zone so this is the test I was referring to earlier the BP 180 and BP 230 this is an ELISA test serum levels of this IgG basically BP 180 and BP 230 are these molecular structures found in the basement membrane zone that serve as antigens for the IgG to bind to they're in the negative range in normal individuals these antibodies are present in about 80% of both Pemphagoid patients and 20% of mucous membrane Pemphagoid patients it is highly sensitive and specific for Pemphagoid so this is just a long list of the differential diagnosis of a chronic secretarizing conjunctivitis the things that we as ophthalmologists would probably see more often would be maybe an atopic carotid conjunctivitis, ocular rosacea and there's actually a lot of association with Pseudo-Pemphagoid and topical glaucoma medication a lot of patients have intolerance of their glaucoma medications you try switching medications they still have conical time inflammation you may want to put this Pseudo-Pemphagoid type picture on your differential when you have a patient like that Pseudo-Pemphagoid the biopsy is negative for the linear stain that we showed however the topical glaucoma medications and systemic practology is a beta blocker we don't really use anymore has been associated with this and this is just a paper that showed the proportion of patients with drug induced Pseudo-Pemphagoid and what drops they're on it's kind of small here but the top of the list here was the beta blockers next was alpha agonist then goes down with pilocarpin, myotics and then latinoprost and the carbonic anhydrase are the lowest Pseudo-Pemphagoid picture so the goals of treatment in Pemphagoid number one suppress and control inflammation is a systemic disease this is your first and most important goal of treatment second is to promote healing number three prevent secretarization we cannot reverse scarring but we can hopefully prevent further scarring 75% of these patients may require systemic immunosuppression other tenants of treatment like I said is a systemic disease first and foremost immunosuppressive therapy should be administered only by those with experience not many of us ophthalmologists have experience with these immunomodulatory therapies however there are other medical subspecialists that we frequently work with that are very experienced in this make the appropriate referrals these patients need to see a corneal specialist someone that's very skilled in the anterior segment reconstruction perhaps down the line ocular plastics needs to be very very involved and also at this institution we frequently work with dermatology or basically always work with dermatology because of the systemic medications needed and it is a systemic disease these patients do need to commit to frequent follow-up that was a big problem in our patient here both the physician and the patient need to commit to having frequent follow-ups here so the treatment there's some stepwise treatments that have been proposed in talking with Professor Zohn in his articles that he's written the mild to moderate ocular disease you provide ocular care patients are typically started on DAPS zone between 50 and 200 milligrams a day for about 12 weeks there is less data on methotrexate celsaptase, ethylprin, but these have also been used with success in these patients severe refractor disease traditionally they've been used with psychophosphamine psychophosphamide does take a while to work there for your patients are covered with prednisone the role of steroids in this disease both of our patients were on oral prednisone a lot of that is to try to kind of cover them while they're getting heavier systemic immunosuppression but it can also control scarring but it's not enough to control this disease activity and basically the side effect profile of prednisone is not something that you would keep patients on long term I'll discuss IVIG and rituximab here but the basics of it is it can shorten the duration of conventional therapy in a study it reduced the duration of therapy from 8 to 4 months rituximab can provide long lasting improvement in 3 quarters of the patients over 24 months and then there's a combination of IVG and rituximab so that's what our second patient received here's the paper by Dr. Foster's group that Dr. Patel alluded to before 6 of 6 of patients in the control in the study group had no progression of their Pemphagoid disease and had no changes in their best corrective visual acuity that's really great numbers even though it's a small sample size and then 6 of 6 of the control patients those patients were put on infliximab cyclophosphamide and IVIG I believe these patients 6 of 6 became bilaterally blind there's no adverse effects noted from the rituximab group patients in terms of ophthalmic care when you see a patient like this aggressive lubrication is very very important some authors propose use of protecting the ocular surface with the bandage contact lens to prevent mechanical irritation from the lashes punctal occlusion is an option to provide more lubrication to the ocular surface topical steroids cyclosporine, tachrylimus there's kind of a limited role to those however they won't control the disease effectively but they can possibly limit the amount of scarring in the eye also it's important to treat patients for blepharitis to try to optimize their tear secretion management of trichiasis and distichiasis can be done in the office by epilating lashes however this is something that needs to be done monthly and there's also an ophthalmologist there's a high association of ocp and glaucoma some papers say up to 25% of patients actually have glaucoma that have this disease as well there's a little confusion is this glaucoma medication induced picture of ocp or is there just actually an association between the two diseases it's not really totally understood surgical considerations for these patients you want to make sure they're completely completely quiet before doing any type of surgery on them and these prior some studies you'll see that patients have been on disease modifying therapy for over a year to try to control their disease before any surgeries tried perioperative oral steroids as we suggested in our second patient lid procedures are typically addressed first if there's a stage procedure to be done with ocular surface reconstruction and then some authors recommend continued immunosuppression postoperatively for at least six months the nidus of inflammation from creeping out there eyelid surgery there's several techniques recommended for intropion repair which we won't go over tracheosis several techniques used to relieve that some blepharons Dr. Foster recommends just a simple license of some blepharon with the some blepharon ring placement and there's also techniques for foreignage reconstruction and several things available for use here mucus membrane grafting brain transplantation is quite popular anchoring sutures to try to deepen the forenecks and then some people will have to use mydomycin C to try to prevent the scarring effect that is of course not without complications with scleral melting and persistent epithelial defects so that needs to be used very cautiously this is a paper from a couple years back I think they had seven patients that they did 11 eyes and repaired the intropion and just this there's a lot of text here but basically the highlights of this is that the pre-operative immunosuppression was so so important these patients had a mean pre-operative immunosuppressions of over 15 months so it just goes to show these patients need to be so so well controllable for any surgeries tried they also really pushed for ocular surface protection pre-operatively with bandage contact lenses local entomical therapy and oral prednisone to try to prevent scarring then these patients underwent lid construction pre-operatively they had they used immunosuppression for at least six months so this just goes through the things I just mentioned on the last slide and all their patients had surgical success they had no disease progression control of inflammation and I believe their follow-up was over two years so in terms of cornea options I'm not a cornea specialist but there are several papers out there on what to do in these patients ocular surface reconstruction with amniotic membrane stem cell transplantation has been moderately successful there's a study of 11 patients where six of them were successful penetrating keratoplasty and lamella keratoplasty pretty poor success in the literature and then there's the option of keratoprosthesis type 1 has a very very poor retention rate at three years and not many patients better than 2200 type 2 keratoprosthesis where it actually goes through the lid has a much higher retention rate at three years all and so there's also some reports of using osteodontal keratoprosthesis however in these chronic psychotrizing diseases ocular psychotritional panphagoid is kind of towards the bottom in terms of success with osteodontal keratoprosthesis so what about cataract surgery some of these patients are going to go on to recover and be quiet for a while and then they may develop cataracts from being on chronic steroids etc and just in the age group they're in so I think it's important just to keep technique in mind clear corneal incisions are very very important here you want to try to manipulate the contractiva as minimally as possible there's some case series that document that the surgery can be very successful in ocp patients but they do recommend periopter steroids before after for at least ten days these patients also should be on there if they're on chemotherapeutic agent at least six months post-operatively judicious use of topical steroids with probably slow taper the prognosis for these patients it is a slowly progressive disease over ten to thirty years in most cases you would like to try to attempt to cease therapy after two years of patients being quiet there are long periods of remission off therapy achievable and about a third of patients however the relapse rate is unpredictable and these patients may flare just out of the blue and some studies say that up to 30% of patients with advanced contractival fibrosis do eventually become blind and like I said it's kind of unpredictable but despite optimum immunosuppression some of these patients still progress our patients both received retuximab and adequate immunosuppression however both of our patients are unfortunately effectively legally blind at this point some of the problems that I encountered through going through these cases of our two patients so this is a very complex disease there's multiple specialists involved different doctors different clinics sometimes it's hard to know who is it appropriate to refer to when do we have to refer these patients how soon do they need to be seen do they have to see a certain doctor can they see somebody else there are insurance issues and delays that I think definitely played a role in these cases and unfortunately the patients pay the price for that there's also access to care issues with our patient being from St. George and maybe not being able to come up here as often our other patient was maybe a little bit confused about the importance of follow up and no showed several appointments these patients just need to make sure that they're aware that this is a lifelong disease that they need very very regular follow up for some of my conclusions so like I said this is a systemic autoimmune condition patients need prompt delivery of immunomodulatory therapy and I think overall the university needs a better system as a whole to care for these patients some institutions have what's called a corneoplastic unit or corneoplastic team I think maybe a better collaboration between the cornea team and the plastics team to make sure these patients are seen maybe on the same day or maybe in conjunction with one another in disgust and what the treatment plan would better serve these patients obviously we work very closely with dermatology and professor zone I think maybe understanding the referral process and how to get these patients better seen more efficiently more quickly would also better serve these patients are there other physicians besides professor zone that if professor zones unavailable for some reason that we can see and get this patient in quicker I think that would also help the patients and then of course we all have problems with insurance but professor zone may be able to comment on this because he's probably intimately familiar with the insurance process of getting rituximab and IVIG approved but making sure starting the insurance process very early and if there's a system that we could use to try to expedite that for these patients of course rituximab is approved for lymphoma and rheumatoid arthritis and lupus it's not approved for this disease by the FDA so insurance companies aren't necessarily too excited to approve this for an off-label type use so that's obviously a kind of a barrier to treatment as well so I'd open any comments here that's the end of my presentation Dr. Lin I just want to make two comments I'm glad that you emphasized the importance of preoperative systemic human suppression because even with clear corneal cataract surgery if someone has OCP and is not even suppressed it can cause complete blood and titillization and the numbers that they were giving as far as success rates of Boston OCP was even more dismal than what you have presented so they're saying that the type 1 K-Pro which is the more common type has a 100% chance of failure in OCP and the type 2 K-Pro which is OCP has an 80% chance of failure even worse I don't know where those numbers come from but that was the general those are just the exposure rates I believe and not in us I guess that's a failure but those are over 3 years I don't know how long their study was Dr. Badi I have a few comments so I second Amy's in terms of the K-Pro Dr. Dolman told me I have a few comments first you do have a IVIG subconjunctival injection we have an option for IVIG we can try a subconjunctival IVIG it would be free to the patient second topical hydroxyprogesterone topical vitamin E ointment can be useful for these patients to help reduce the characterization and help improve the epithelialization third I believe Genentech does have a patient assistance program which would be eligible for that but Jim Rosenbaum in Oregon has an overview lastly just to give you some part of our good side to enjoy doing that Rutaksen I just checked the next website Rutaksen the UK is approved by NICE for as Zach mentioned similar diseases for which an anchor vasculitis is not approved for OCP and so like other biologics are often not available in that clinical trial in Oregon patients would have to travel to that site I know it's a multi-center okay I've dealt with this a lot for the past 40 years so I have a lot of comments 5 minutes please to start out with the diagnosis in the first case he showed something very very bothersome to us we get about 1,800 specimens from around the country a year and I would say probably 10% of those are conjunctival biopsies maybe 5% but we get a lot of them we do the reference laboratory, serology and direct amino fluorescence for ERUP what he showed was that when I was negative and one was positive that's very very bothersome because making the diagnosis is very important only about 20% of the people are positive on serum I would say 80% are negative so the first thing is making the diagnosis and biopsying conjunctival that is not so inflamed is very important as he mentioned because the inflammation if there's intense inflammation it will destroy the reactants that we're trying to find on direct amino fluorescence and that becomes a false negative or some people actually give us a piece of this for example those are almost universally negative scarring is a bad place to biopsy if you can get relatively quiet conjunctival I know a lot of these people don't really have quite conjunctival but stay away from the scar and stay away from the bright red stuff we have a much higher chance of positivity and we can increase that by 20% we don't really know I've had a lot of conversations with him in the article you were talking about in Up to Date he contributed that we've had conversations about it and he's done everything to try to increase his positivity by those immunoperoxidase things that you mentioned up to 70% so just because it's negative doesn't mean they don't have it and the second biopsy may be in order depending upon what your clinical suspicion is because of the diagnosis of cyclotrizing conjunctivitis obviously those people who have pseudo-pempegoid for the most part are going to be negative and are always a concern of ours because especially the ones we get in the mail we have no idea what things are on or anything like that so first point was diagnosis the second thing is 30 to 40% of the people have mucosal disease besides the mouth, the gingiva I do it all the time people have a little scar on their mouth or their eyes are pink I'll biopsy their mouth so if they have even a little bit of mouth disease we reported 8 people with esophageal stenosis back in the 90s and we biopsy esophagus anything to get a piece to make certain of the diagnosis especially those people who have IgA it turns out are more sensitive to dafts than people who have IgG so diagnosis, diagnosis, diagnosis really helps us like in this case when you can see the antibody levels going down in response to your treatment that kind of warms your heart from an immunotherapy standpoint so my entire clinical career has been devoted to immunosuppressing people and I would say probably 60% of the people I see are immunosuppressed I've treated probably a couple hundred people with rituxin so I don't really know I see a lot of Pemphagos and a lot of Pemphagoi so I would emphasize eukosmembrane involvement if they have just look in their mouth ask them do they have probably swallowing do they have sores in their mouth because if they do we can get a biopsy and make a diagnosis the next thing is treatment as was alluded to that the reflex is always treated with a lot of steroids that will cut down on the inflammation of the disease and it doesn't get rid of the antibody so it boils down to immunosuppression back in the 90s the only thing we had that worked was cyclophosphamide and foster and the people at Hopkins would always say if you don't give them cyclophosphamide that's bad I now have three of those patients that I'm following with bladder cancer so it's not without its complications and right now I don't think anyone would give cyclophosphamide when he was saying that things aren't approved because this is an orphan disease it's going to be very very unlikely that it's going to get approved so steroids, immunosuppresses I don't use much cyclophosphamide anymore I'm a great believer in rituxin and IVIG and as you alluded to that's a crisis with the insurance so I love that paper that Foster wrote on this topic six people got immunosuppression they're blind, six people got IVIG plus rituxin they can see you're responsible for this you make the choice I send that paper with usually a very nasty note I try to be very nasty to these people on the telephone I have to sometimes gather it up but it is in my nature so because I think if you don't fight for it first the first patient was obviously negligent we just see this in April when her first appointment was we might have been able to IVIG this way and rituxin but she just didn't show up and she I don't know, she had a bizarre opinion of what she had I personally believe that the best treatment is IVIG and rituxin if this institution that runs about $25,000 to $30,000 a month for that dosing $11,000 for the IVIG $11,000 for the rituxin and it's about $1,000 for the infusion so we're not talking small amounts it's usually I figure $30,000 a month for six months is the cost of this so it's very important that clinical trials be done to see whether or not it works we have a clinical trial on a B-cell poison for pemphagous right now for pemphagois the other thing that he mentioned that as a real disaster in this area is people who live a distance away I take care of these people and I have a junior associate Dr. Hull who I've worked with for a number of years and I'm encouraging him to see more and more of these people and he is and we see patients together on Thursday afternoons so there is hope to treat them but I always ask the question when I talk about this topic nationally and internationally actually and I always ask the question what would I do if I had this disease that's the essence of severe immunosuppression and aggressive therapy because this is aggressive therapy I've produced two microbial hemics who are on IVIG the rest of their life I've had some nasty infections I've never had anybody die on rituximab and the number of people I've treated IVIG I've had thrombi I've thrombosed the superior vena cava these things are not without problems so it's aggressive therapy but the question still becomes in the title of the talk I give what would I do if I had pephagoid not just skin but esophageal oral and if I had pephagoid and if I had pephagoid in my eye I would get rituximab and IVIG I would just take it for sixth grade months and neither of these people the one lady, the insurance company agreed to the rituximab and not to the IVIG and in the second one they agreed to one course of rituximab and IVIG and then I sent them the letter sent them the email or the the article and started arguing with them you know unfortunately in our system insurance companies are making these choices the medical person who is making them is usually a general practitioner or a family practitioner of some sort so that's a real crisis but I agree with your idea that we should have a more uniform approach when Maureen Lundergum is here she and I used to meet regularly to discuss these people but if we could have more of a group approach I think we'd be better off on managing them because the things that you were saying about and lip repair I know virtually nothing about but I can immunosuppress just about any case thank you I don't want to leave this hanging I think we should come to some sort of conclusion I go to too many meetings where we shake our heads and say insurance company this, insurance company that I'm beginning to see 30-year-olds and 40-year-olds with positive confirmed results for the past at least about 40-50 years of life and we need a team approach where we're courting as interested and that immunosuppression in some places it comes from rheumatology in other places we're lucky enough to have people like your team that needs to be established we had this problem with Maladoma we based a solid plan board and I and Antpaka got together a few years ago we set up a website-based approach where we have everything available for insurance companies to go to but we suggest to them that somebody needs a sentinel load biopsy we still have the same problem with getting approval and so on and we managed to overcome that by setting up a sort of a unit where we work together and it's very successful now and we rarely have problems with getting approval for biopsy sentinel load biopsy is lived under sanctions the major facial reconstruction that I do and so on and I think we need to set this up if Hal is your man who knows gender and interest in this and I accept it establish a team where people can reverse those patients too I'm all for it I'll do whatever I can to make that happen from our side I think that people need to be seen regularly the other thing he said is I don't think these people realize it's a very bizarre disease and I try to and then they get oh you're just trying to scare me no not really and so what do we what do we need to do as the next step to set that up do you think we'll be well first of all we're presenting this here because for the last three or four years I've been frustrated a little bit I've managed to get him sorted out this lady I've got three young patients now who are positive in the beginning to show signs of information coming on some of them you recognize plastics is almost an orphan child here we're dealing with the end stage this is the entropion this is a systemic disease it's inflammation that has to be controlled so whereas at the end of your segment the corneoplastic type of thing we're going to try to have a cornea that needs to be actively involved here there's some controversy about topical subcontinent travel as Mala was saying we need to be actively involved here so I think what we'll do to induce an eye is contact you and Hal and then we'll identify amongst our corneal corneal team who might be interested I used to do a lot of this with Hosefa and as you know between you and I Hosefa we still handle this pretty well so we just need somebody actively involved where we can say they should get seen on time every month by all three of us in an ideal way we'd have a clinic on the same day we can work towards that some time so look out for we'll send you an email we can play a web page and have some of this basic information available when you argue with an insurance company all the time some of these papers like Foster's paper there are a few others we didn't discuss which actually show there are more case reports than the study he did 6 and 6 we can have all that data available so in the next month we'll get this website paid setup hopefully we'll identify corneal that's interesting we'll set those numbers as a service that's provided when somebody gets a positive pharmacy or suspicion of Pemphloin because it's a stomach disease we'll get it seen by you all straight away Dr. Vitale? Yes, but thanks for this great presentation I couldn't emphasize more the importance of pre-operative in the expression of operative in the first patient reasons why I couldn't answer rapidly but in terms of the collaboration this is a disease it's like horrendous UDI outside of the office similar approach at least in UDI service we have a seamless liaison with rheumatology and with pediatric rheumatology so everybody is on board and it's been a forge over years of necessity because we have a very large number of patients as opposed to two patients with OCP that might come but it's been meet on a fairly regular basis and there's cross-fertilization in terms of educating one another about the drugs and the diseases so it's a seamless kind of referral that we have with pediatric rheumatology with all of the members of that department and in adult rheumatology it has been a little bit more difficult but we have identified individuals that are willing to take on some of these patients so part of the problem that you encounter is you have to suppress the patient with heavy duty immunosuppression for indications that they're not labeled and it requires a lot of work and so we work together to try to do these things and pre-office and manage them together communication is really, really important it can work I have a whole stack of doctors and insurance companies and I'm just like I have instances in which they just refuse it's a really bad situation John, the video upstairs is still active did you get a chance to see her today? No I didn't So she's still active we've been controlling the drugs so it's just with imagination I don't want to do big experiment drugs and more aggressive invasion so we'll make sure you get a chance to do it The insurance company improved 8 treatments with Rituximab they wouldn't improve the IVIG I'm sure the B-cell count is still 0 probably should treat her with IVIG intra sub-conjunctival IVIG is a fascinating idea there's actually papers of intra-oral Rituximab which makes almost no sense but intra-oral Rituximab working sub-mucosally and I wonder I have a sneaky feeling that intra-ocular sub-conjunctival Rituximab would work for a whole bunch of reasons that would take a long time to explain so I won't She's had a lot of Rituximab I think if we could get IVIG approved for her her insurance company under the exchange would broke that didn't help us she was insured by Arches which is one of the groups that wasn't supposed to be backed up by the federal government on the exchange and they weren't so somebody's got to come up with 20,000 a month if we're going to treat her with IVIG like we do with the guy in Boise who you know I go up to Boise and see Pentecost and Pentevoid people because they were being lost to follow-up up there every three months and see them all this guy's been on IVIG forever it's a struggle what is all of this stuff real expensive do you guys do what do you treat with is it real expensive do you do IVIG and Rituximab or anything like that biologics for UVIGs absolutely sure there are only a handful of patients that need treatments but you know what's mad it's always a problem it's not so much a problem in obtaining approval for those patients that have an indication so for example through the JIA there are people that fail to mention on immobulations that require biologics therapy and there you have a problem it's all insurance dependent and how aggressive in terms of most of the time we are able to as far as Rituximab is concerned we have the most common indication for Rituximab is actually intravitrile Rituximab for patients with intraocular lymphoma so we don't have a problem with that we just formulated here and the IRV is approved for that there are maybe two patients who are on Rituximab for Rituximab and one patient with autoimmune and one patient it's hard to get to use a lot of Rituximab okay in this bill Trump and ISIS refugees, Kardashians stags presentation is absolutely excellent it demands our presidents to discuss this in great detail it actually affects all of them how we practice this position I don't want to dilute it by having it presented for two minutes I'm going to organize another special day and I guess it's just as important a topic that we can present as this first one which I think will actually make a difference to our patients care now that we've had professors over here we've got an idea about how to at least put this together that was a superb prayer thanks thank you sorry about that