Guest guest Posted January 10, 2008 Report Share Posted January 10, 2008 Inflammatory Eye Disease: An Expert Interview With Schwartzman, MD http://www.medscape.com/viewarticle/562587?src=mp Schwartzman, MD Medscape Rheumatology. 2007; ©2007 Medscape Editor's Note: The pathophysiologic causes of uveitis are several and include autoimmune disorder, infection, idiopathic conditions, and complications of surgery. Symptoms range from pain, photophobia, and blurred or reduced vision to floaters, loss of vision, and blindness. Treatment may include corticosteroids, nonsteroidal anti-inflammatory drugs, immunomodulatory therapy, or ophthalmic implant surgery. This interview focuses on the autoimmune causes of uveitis, such as rheumatic diseases, in both children and adults. Helen Fosam, PhD, Medscape Rheumatology, spoke with Schwartzman, MD, Franchellie M. Cadwell Associate Professor of Medicine, Weill Medical College, The Hospital for Special Surgery and New York Presbyterian Hospital, Cornell University, New York, NY, about the issues surrounding the management of uveitis associated with rheumatic diseases. They discussed diagnostic challenges from a rheumatologist's perspective and recent advances in treatment with immunomodulatory agents, particularly for chronic refractory uveitis. Medscape: Autoimmune uveitis is closely associated with inflammatory arthritis. Do all arthritic conditions have a risk for uveitis? Are some forms of arthritis more of a risk than others? Dr. Schwartzman: If we look at the host of rheumatic diseases that exist, the reality is that there are certain diseases that have much more of a risk for developing uveitis than others. In that regard, the diseases that are most closely associated with uveitis and seen by rheumatologists include juvenile idiopathic arthritis, the spondyloarthropathies, as well as conditions such as sarcoidosis and Behcet's disease; these are the group of diseases that have the highest risk of developing uveitis.[1-4] There are other conditions with lower risk for uveitis, including inflammatory bowel disease and psoriatic arthritis. So, in terms of risks, there is clearly a differential among the different rheumatic diseases, and probably juvenile idiopathic arthritis and the spondyloarthropathy group of diseases such as ankylosing spondylitis have the highest risk of developing uveitis. Medscape: Is the risk for uveitis the same in adults and children? Dr. Schwartzman: The reality is that it is very different, depending on the specific diseases. However, we generally cannot categorize the risk according to age; we more accurately categorize risk according to disease entity. For example, if you look at ankylosing spondylitis, which is one of the spondyloarthropathies, the risk of developing uveitis at some point in the disease is anywhere from 30% to 40%. This means that a patient who has ankylosing spondylitis has a 30% to 40% risk for developing uveitis, and usually a specific type of uveitis called anterior uveitis. However, if you look at juvenile idiopathic arthritis, which is one of the most common diseases that affects children who develop uveitis, uveitis manifests in approximately 13% of these patients.[5] Even within the realm of juvenile idiopathic arthritis, there is a differential in terms of risk for developing uveitis in that the group that is most likely to develop uveitis is the very young oligoarticular girl who has juvenile idiopathic arthritis and positive antinuclear antibodies. So the risk differs across different arthritic diseases, it clearly differs between children and adults, and I think it is more dependent on the disease process than the age. Medscape: Apart from the arthritic condition, are there other risk factors for uveitis? How should rheumatologists recognize and manage them? Dr. Schwartzman: The reality is that uveitis can occur as part of the underlying autoimmune disease, and if we look at all patients with uveitis, approximately 50% will have an underlying systemic disease, whereas in the other 50%, there is likely no systemic disease that can be identified. We classify the latter group of patients as presenting with idiopathic uveitis. In terms of other potential risk factors that are perhaps tangentially related to the uveitis, from a clinical perspective, as mentioned for juvenile idiopathic arthritis, the patterns of disease is very important in defining risk. Other potential risk factors are not well delineated, although HLAB27 positivity, for example, has been found to be more common in people who have uveitis in general, irrespective of whether they have rheumatic disease. Medscape: What is the role of the rheumatologist in making a diagnosis for uveitis? Should they refer to, and work collaboratively with, an ophthalmologist? Dr. Schwartzman: I think that this is a critical issue. The rheumatologist and the ophthalmologist need to work together. The reason I say this is that the rheumatologist is generally very familiar with the medications that are used to treat uveitis, except for perhaps the topical agents; however, the rheumatologist cannot determine response to therapy, so unless the rheumatologist has the necessary diagnostic tools and can actually quantify the degree of inflammation, they are going to be at a loss in terms of understanding whether the medicines they are using are helping the patient. So the need for collaboration between the 2 subspecialties, the ophthalmologist and the rheumatologist, is critical. Frequently, at my clinic, I monitor the patient for their extraophthalmic disease and potential toxicity to the medications that I am using to treat a patient with resistant uveitis. However, to gauge whether the medicine is working or not, I am completely dependent on the ophthalmologist, and in that setting I always discuss the cases with the ophthalmologist. In terms of the diagnostic approach to uveitis, I would argue strongly that it should be dependent on the medical history and physical examination performed by the rheumatologist. There are specific tests to screen patients with uveitis, and, unfortunately, frequently patients with uveitis will present to the rheumatologist with a panel of blood tests and sometimes invasive procedures and x-rays that may or may not be appropriate. I would argue strongly that the history and physical exam dictates what laboratory tests are done. I should tell you, though, that in the work up for these patients, you need to be very secure in ruling out an infectious cause for uveitis, and to some extent we depend on the ophthalmologist for that. At the very minimum, I generally do a chest x-ray, PPD, syphilis serologies, and routine laboratory tests on my patients with uveitis; and then anything outside of that is dependent on the clinical presentation. For example, if a patient presents with inflammatory back pain, I will additionally obtain sacroiliac radiographs and perhaps check the HLAB27. If a patient presents with a history of gastrointestinal complaints, I frequently will have a gastroenterology work up to ensure that there is no inflammatory bowel disease. I think patient history and physical exam are very important from a rheumatologist's perspective. Medscape: Is it reasonable to advise all patients with rheumatic diseases to be screened for uveitis? Dr. Schwartzman: I do not think that routine screening is necessary. I think the reality is that in adults who do not have any ophthalmic complaints, one can be reasonably secure in knowing that there is no ophthalmic disease. However, children with juvenile idiopathic arthritis should be frequently seen by the ophthalmologist, because in this cohort of children, uveitis can be asymptomatic. The child may not complain of any symptoms yet have significant inflammatory disease. Medscape: What is the consequence of failure to treat uveitis? Dr. Schwartzman: The reality is that for patients who are not treated, the incidence of complications from uveitis -- synechiae, glaucoma, cataracts -- is quite high and, in that setting, will lead to significant visual loss.[6] In the United States, it is estimated that uveitis results in approximately 10% of the overall significant visual loss reported, which is a very high percentage, when you consider diseases such as glaucoma and diabetes. I think it is critical to treat uveitis both in adults and in children. Medscape: Is uveitis a progressive disease? Dr. Schwartzman: Generally, it is variable. It depends on the type of uveitis. In patients who have acute anterior uveitis, depending on the clinical syndrome, sometimes it can be a very transient or single event. However, there is a subgroup of patients who have resistant uveitis; the uveitis can be anterior uveitis, posterior uveitis, or panuveitis, and in that group it is progressive. Medscape: For chronic cases of uveitis, or cases refractory to treatment, biologics such as anti-TNF agents have emerged as promising options. Can you comment on studies supporting a biologic approach to treatment? Dr. Schwartzman: Once you have a patient with resistant uveitis, there isn't a single paradigm for how to treat them. In that regard, various medications have been used, most commonly in addition to topical steroids. Systemic steroids are used when topical treatments fail. If systemic steroids fail, multiple remittive medications have been tried, and these have included medicines such as cyclosporine, azathioprine, mycophenolate, and methotrexate. In terms of the role of biologics, treatment with these agents is currently evolving, and there are a number of studies and abstracts that suggest that the monoclonal antibodies infliximab and adalimumab seem to be effective for the treatment of resistant uveitis, whereas etanercept does not appear to be effective.[7-10] Other studies have also investigated patients who have uveitis and a systemic underlying disease such as a spondyloarthropathy to ascertain whether treatment with an anti-TNF agent will result in a decrease in their uveitis flares.[11] In these studies, again it appears that the monoclonal antibodies infliximab and adalimumab are effective, whereas etanercept does not prevent uveitis flares. So there are a number of studies looking at anti-TNF-treated patients with underlying systemic diseases and uveitis as well as those with idiopathic uveitis. In these settings, the effectiveness of the monoclonal antibodies is superior to etanercept. Of note, in Japan, inflixamab has been approved for Behcet's disease with refractory uveoretinitis, so worldwide there is at least one approval for a form of uveitis for infliximab. The problem with the studies on anti-TNF agents is that most of them are retrospective. They are usually cases that have been accumulated at a treatment center; there are no prospective, double-blind, randomized trials. There is one very good phase 2 study by Suhler[12] from the Casey Institute on the use of infliximab to treat resistant uveitis. The study involved 23 patients from a uveitis clinic who were treated with infliximab. Patients who responded to treatment were continued on infliximab, and there was clearly some significant benefit from the use of infliximab in this cohort of patients. Unfortunately, this study is the only prospective trial currently available, although others are being contemplated. The side effects noted in this cohort of patients were far more than what is described in the literature for other autoimmune disease. Medscape: You mentioned that not all the anti-TNF agents are effective; is this related the differences in their structure and mechanism of action? Dr. Schwartzman: That is a good question. I don't think anybody knows the answer to that. Although they all target TNF, we know that the pharmacokinetics of these drugs differ; we know that the half-lives also differ. The other issue that needs to be considered in uveitis, in terms of treatment, is that there is a blood ocular barrier, and there may be different permeabilities to different agents, and this may be related to molecular structure and dosing. But there are clear differences between the anti-TNF agents. There are also other issues; for example, effects on lymphotoxin -- etanercept affects lymphotoxin, whereas the monoclonal antibodies do not, so nobody really knows the reason why there are differences in the treatment effects with anti-TNF agents. Medscape: Are the monoclonal antibodies infliximab and adalimumab equally effective for all uveitis conditions? Dr. Schwartzman: There are a lot more data on infliximab than adalimumab. Most of the studies with adalimumab are on juvenile uveitis, whereas for infliximab, there are a lot more data for all forms of resistant uveitis. So in terms of the published literature, there is currently a difference in the volume of studies, although there are ongoing studies with adalimumab in nonpediatric patients. Furthermore, there is currently no head-to-head trial for infliximab and adalimumab, so it is impossible to compare their effectiveness for uveitis, but my assumption is that both work similarly. Medscape: From your experience, when should a decision be made to use a biologic agent for uveitis, and what are the key considerations for the choice of a biologic therapy? Dr. Schwartzman: Currently, there is no paradigm for timing the use of an anti-TNF agent, and if you look at the literature critically, in most, if not all, circumstances, it is for patients who have chronic disease that is resistant to traditional treatment. In fact, the term resistant is questionable --resistant to what? Is it someone who is just resistant to systemic corticosteroids? Someone who is resistant to one of the DMARDs? There is no consensus. My honest sense, though, is that the 2 circumstances where I will use an anti-TNF agent in a patient with resistant uveitis are: (1) when a patient has failed tapering of systemic steroids and at least 1 remittive medication; and (2) in a patient that the ophthalmologist does not feel that we have much time, that is a patient whose uveitis is significantly vision threatening. I probably would try the steroids first, and if that is not effective, I would then treat with an anti-TNF agent. I should also say that in terms of the anti-TNF agents, the one prospective trial by Suhler[12] noted an interesting and surprising finding that in the group of 23 study patients with treatment-resistant uveitis, side effects from anti-TNF therapy used in the study (infliximab) were significantly greater than what we have seen in patients with traditional rheumatic disease for whom the anti-TNF agents are approved. Of note, side effects noted in this cohort included pulmonary embolus, congestive heart failure, lupus-like disease, and vitreous hemorrhage. The frequency of these side effects has not been noted in trials of patients with rheumatoid arthritis, psoriatic arthritis, ankylosing spondlylitis, or inflammatory bowel disease. Furthermore, there are studies that suggest new-onset uveitis can be seen in patients treated with anti-TNF agents.[13,14] So one question that I think is still unanswered is whether these patients with resistant uveitis, some of whom have underlying systemic diseases, are at a higher risk of developing side effects from treatment with anti-TNF agents. Having said that, if you look at all of the other literature on the use of the anti-TNF agents in resistant uveitis, a significantly increased side effect profile is not generally seen. Medscape: What determines the choice of anti-TNF? Dr. Schwartzman: For the treatment of resistant uveitis, I think pretty much unanimously, my sense is that etanercept is not used to treat resistant uveitis. Of the anti-TNF agents, the only one that has been potentially found to cause uveitis is etanercept. We clearly need more studies with regards to this concept. Deciding between adalimumab and infliximab is a little bit more difficult in that, again, there are no head-to-head trials comparing the 2. My sense is that both are efficacious. There are more data published for infliximab, but this is one of those circumstances where I think the data currently cannot support one over the other, although one must say that there is much more published for infliximab. I think other issues play into the decision about adalimumab or infliximab, and they include issues such as insurance coverage, patient preference, and dosing flexibility. Currently there is no a clear-cut answer between these 2 agents, and obviously we await more data on adalimumab. With regard to uveitis associated with juvenile idiopathic arthritis, most of the current literature is with adalimumab. There is some literature with infliximab in juvenile idiopathic arthritis, but there isn't as much of a focus. Additionally, infliximab is not approved for the treatment of juvenile idiopathic arthritis, whereas adalimumab has been submitted to the FDA for approval. In view of the limited data and lack of head-to-head trials, it is not possible to conclude at the present time that one monoclonal antibody is better than the other. My sense is that they both work, and to prove that one is better than the other, we need a head-to-head trial. Medscape: From a patient perspective, what should be the consideration before making a choice to use a biologic agent to treat uveitis? Dr. Schwartzman: I think we tend to use the same exclusions that we would for the use of anti-TNF agents in other diseases in that in someone who has had an active infection, for example, or a lymphoproliferative disease, we would be very reluctant to use an anti-TNF agent. The risk of tuberculosis obviously needs to be considered, and all of these patients should be very carefully screened for tuberculosis. Multiple sclerosis (MS) also needs to be considered in that, at times, certain forms of uveitis have been associated with this condition, and anti-TNF agents can worsen MS. The one exception that you must be aware of, if you are treating patients with underlying uveitis, is that there is an association of one form of uveitis with multiple sclerosis. Clearly, caution must be exercised in using the anti-TNF agents because they may worsen multiple sclerosis. So I think that the issues associated with lymphoproliferative malignancies, potential infections, and potential neurologic disease would be key considerations as potential contraindications to the use of an anti-TNF agent in this patient group. Medscape: What do you see as the key educational needs among rheumatologists who treat autoimmune uveitis in adults and children? Dr. Schwartzman: One issue is that although most rheumatologists will see autoimmune eye disease, I would argue that most clinical rheumatologists see these patients relatively infrequently, depending on the referral patterns. The other issue is that their patients with rheumatic diseases will at some point develop autoimmune eye diseases, and the reality is that when that happens, most rheumatologists are at a disadvantage in terms of understanding the disease and therapies available to treat these conditions. So from an educational needs perspective, I think rheumatologists need to be more cognizant of the association between uveitis and systemic autoimmune diseases. But they also need to understand that idiopathic uveitis is an autoimmune disease, and probably the most important area that needs to be highlighted here is that there has to be a marriage between the ophthalmologist and the rheumatologist in terms of treating these groups of patients. It is important to understand the essential and different roles of the physicians involved in managing a patient with inflammatory uveitis. Quote Link to comment Share on other sites More sharing options...
Guest guest Posted January 11, 2008 Report Share Posted January 11, 2008 Thanks Georgina thats a great article. Is it recent? One thing that confuses me though is that this guy considers psoriatic arthritis separate from a spondylarthropathy. I thought it was a subcategory of spondy. & Grant/10,PsA/Uveitis > > Inflammatory Eye Disease: An Expert Interview With Schwartzman, MD > http://www.medscape.com/viewarticle/562587?src=mp > > Schwartzman, MD > Medscape Rheumatology. 2007; ©2007 Medscape > > Editor's Note: > The pathophysiologic causes of uveitis are several and include autoimmune > disorder, infection, idiopathic conditions, and complications of surgery. > Symptoms range from pain, photophobia, and blurred or reduced vision to > floaters, loss of vision, and blindness. Treatment may include > corticosteroids, nonsteroidal anti-inflammatory drugs, immunomodulatory > therapy, or ophthalmic implant surgery. > > This interview focuses on the autoimmune causes of uveitis, such as > rheumatic diseases, in both children and adults. Helen Fosam, PhD, Medscape > Rheumatology, spoke with Schwartzman, MD, Franchellie M. Cadwell > Associate Professor of Medicine, Weill Medical College, The Hospital for > Special Surgery and New York Presbyterian Hospital, Cornell University, New > York, NY, about the issues surrounding the management of uveitis associated > with rheumatic diseases. They discussed diagnostic challenges from a > rheumatologist's perspective and recent advances in treatment with > immunomodulatory agents, particularly for chronic refractory uveitis. > > Medscape: Autoimmune uveitis is closely associated with inflammatory > arthritis. Do all arthritic conditions have a risk for uveitis? Are some > forms of arthritis more of a risk than others? > > Dr. Schwartzman: If we look at the host of rheumatic diseases that exist, > the reality is that there are certain diseases that have much more of a risk > for developing uveitis than others. In that regard, the diseases that are > most closely associated with uveitis and seen by rheumatologists include > juvenile idiopathic arthritis, the spondyloarthropathies, as well as > conditions such as sarcoidosis and Behcet's disease; these are the group of > diseases that have the highest risk of developing uveitis.[1-4] There are > other conditions with lower risk for uveitis, including inflammatory bowel > disease and psoriatic arthritis. So, in terms of risks, there is clearly a > differential among the different rheumatic diseases, and probably juvenile > idiopathic arthritis and the spondyloarthropathy group of diseases such as > ankylosing spondylitis have the highest risk of developing uveitis. > > Medscape: Is the risk for uveitis the same in adults and children? > > Dr. Schwartzman: The reality is that it is very different, depending on the > specific diseases. However, we generally cannot categorize the risk > according to age; we more accurately categorize risk according to disease > entity. For example, if you look at ankylosing spondylitis, which is one of > the spondyloarthropathies, the risk of developing uveitis at some point in > the disease is anywhere from 30% to 40%. This means that a patient who has > ankylosing spondylitis has a 30% to 40% risk for developing uveitis, and > usually a specific type of uveitis called anterior uveitis. However, if you > look at juvenile idiopathic arthritis, which is one of the most common > diseases that affects children who develop uveitis, uveitis manifests in > approximately 13% of these patients.[5] Even within the realm of juvenile > idiopathic arthritis, there is a differential in terms of risk for > developing uveitis in that the group that is most likely to develop uveitis > is the very young oligoarticular girl who has juvenile idiopathic arthritis > and positive antinuclear antibodies. So the risk differs across different > arthritic diseases, it clearly differs between children and adults, and I > think it is more dependent on the disease process than the age. > > Medscape: Apart from the arthritic condition, are there other risk factors > for uveitis? How should rheumatologists recognize and manage them? > > Dr. Schwartzman: The reality is that uveitis can occur as part of the > underlying autoimmune disease, and if we look at all patients with uveitis, > approximately 50% will have an underlying systemic disease, whereas in the > other 50%, there is likely no systemic disease that can be identified. We > classify the latter group of patients as presenting with idiopathic uveitis. > In terms of other potential risk factors that are perhaps tangentially > related to the uveitis, from a clinical perspective, as mentioned for > juvenile idiopathic arthritis, the patterns of disease is very important in > defining risk. Other potential risk factors are not well delineated, > although HLAB27 positivity, for example, has been found to be more common in > people who have uveitis in general, irrespective of whether they have > rheumatic disease. > > Medscape: What is the role of the rheumatologist in making a diagnosis for > uveitis? Should they refer to, and work collaboratively with, an > ophthalmologist? > > Dr. Schwartzman: I think that this is a critical issue. The rheumatologist > and the ophthalmologist need to work together. The reason I say this is that > the rheumatologist is generally very familiar with the medications that are > used to treat uveitis, except for perhaps the topical agents; however, the > rheumatologist cannot determine response to therapy, so unless the > rheumatologist has the necessary diagnostic tools and can actually quantify > the degree of inflammation, they are going to be at a loss in terms of > understanding whether the medicines they are using are helping the patient. > So the need for collaboration between the 2 subspecialties, the > ophthalmologist and the rheumatologist, is critical. Frequently, at my > clinic, I monitor the patient for their extraophthalmic disease and > potential toxicity to the medications that I am using to treat a patient > with resistant uveitis. However, to gauge whether the medicine is working or > not, I am completely dependent on the ophthalmologist, and in that setting I > always discuss the cases with the ophthalmologist. > > In terms of the diagnostic approach to uveitis, I would argue strongly that > it should be dependent on the medical history and physical examination > performed by the rheumatologist. There are specific tests to screen patients > with uveitis, and, unfortunately, frequently patients with uveitis will > present to the rheumatologist with a panel of blood tests and sometimes > invasive procedures and x-rays that may or may not be appropriate. I would > argue strongly that the history and physical exam dictates what laboratory > tests are done. I should tell you, though, that in the work up for these > patients, you need to be very secure in ruling out an infectious cause for > uveitis, and to some extent we depend on the ophthalmologist for that. At > the very minimum, I generally do a chest x-ray, PPD, syphilis serologies, > and routine laboratory tests on my patients with uveitis; and then anything > outside of that is dependent on the clinical presentation. For example, if a > patient presents with inflammatory back pain, I will additionally obtain > sacroiliac radiographs and perhaps check the HLAB27. If a patient presents > with a history of gastrointestinal complaints, I frequently will have a > gastroenterology work up to ensure that there is no inflammatory bowel > disease. I think patient history and physical exam are very important from a > rheumatologist's perspective. > > Medscape: Is it reasonable to advise all patients with rheumatic diseases to > be screened for uveitis? > > Dr. Schwartzman: I do not think that routine screening is necessary. I think > the reality is that in adults who do not have any ophthalmic complaints, one > can be reasonably secure in knowing that there is no ophthalmic disease. > However, children with juvenile idiopathic arthritis should be frequently > seen by the ophthalmologist, because in this cohort of children, uveitis can > be asymptomatic. The child may not complain of any symptoms yet have > significant inflammatory disease. > > Medscape: What is the consequence of failure to treat uveitis? > > Dr. Schwartzman: The reality is that for patients who are not treated, the > incidence of complications from uveitis -- synechiae, glaucoma, cataracts -- > is quite high and, in that setting, will lead to significant visual loss.[6] > In the United States, it is estimated that uveitis results in approximately > 10% of the overall significant visual loss reported, which is a very high > percentage, when you consider diseases such as glaucoma and diabetes. I > think it is critical to treat uveitis both in adults and in children. > > Medscape: Is uveitis a progressive disease? > > Dr. Schwartzman: Generally, it is variable. It depends on the type of > uveitis. In patients who have acute anterior uveitis, depending on the > clinical syndrome, sometimes it can be a very transient or single event. > However, there is a subgroup of patients who have resistant uveitis; the > uveitis can be anterior uveitis, posterior uveitis, or panuveitis, and in > that group it is progressive. > > Medscape: For chronic cases of uveitis, or cases refractory to treatment, > biologics such as anti-TNF agents have emerged as promising options. Can you > comment on studies supporting a biologic approach to treatment? > > Dr. Schwartzman: Once you have a patient with resistant uveitis, there isn't > a single paradigm for how to treat them. In that regard, various medications > have been used, most commonly in addition to topical steroids. Systemic > steroids are used when topical treatments fail. If systemic steroids fail, > multiple remittive medications have been tried, and these have included > medicines such as cyclosporine, azathioprine, mycophenolate, and > methotrexate. > > In terms of the role of biologics, treatment with these agents is currently > evolving, and there are a number of studies and abstracts that suggest that > the monoclonal antibodies infliximab and adalimumab seem to be effective for > the treatment of resistant uveitis, whereas etanercept does not appear to be > effective.[7-10] Other studies have also investigated patients who have > uveitis and a systemic underlying disease such as a spondyloarthropathy to > ascertain whether treatment with an anti-TNF agent will result in a decrease > in their uveitis flares.[11] In these studies, again it appears that the > monoclonal antibodies infliximab and adalimumab are effective, whereas > etanercept does not prevent uveitis flares. So there are a number of studies > looking at anti-TNF-treated patients with underlying systemic diseases and > uveitis as well as those with idiopathic uveitis. In these settings, the > effectiveness of the monoclonal antibodies is superior to etanercept. > > Of note, in Japan, inflixamab has been approved for Behcet's disease with > refractory uveoretinitis, so worldwide there is at least one approval for a > form of uveitis for infliximab. The problem with the studies on anti-TNF > agents is that most of them are retrospective. They are usually cases that > have been accumulated at a treatment center; there are no prospective, > double-blind, randomized trials. There is one very good phase 2 study by > Suhler[12] from the Casey Institute on the use of infliximab to treat > resistant uveitis. The study involved 23 patients from a uveitis clinic who > were treated with infliximab. Patients who responded to treatment were > continued on infliximab, and there was clearly some significant benefit from > the use of infliximab in this cohort of patients. Unfortunately, this study > is the only prospective trial currently available, although others are being > contemplated. The side effects noted in this cohort of patients were far > more than what is described in the literature for other autoimmune disease. > > Medscape: You mentioned that not all the anti-TNF agents are effective; is > this related the differences in their structure and mechanism of action? > > Dr. Schwartzman: That is a good question. I don't think anybody knows the > answer to that. Although they all target TNF, we know that the > pharmacokinetics of these drugs differ; we know that the half- lives also > differ. The other issue that needs to be considered in uveitis, in terms of > treatment, is that there is a blood ocular barrier, and there may be > different permeabilities to different agents, and this may be related to > molecular structure and dosing. But there are clear differences between the > anti-TNF agents. There are also other issues; for example, effects on > lymphotoxin -- etanercept affects lymphotoxin, whereas the monoclonal > antibodies do not, so nobody really knows the reason why there are > differences in the treatment effects with anti-TNF agents. > > Medscape: Are the monoclonal antibodies infliximab and adalimumab equally > effective for all uveitis conditions? > > Dr. Schwartzman: There are a lot more data on infliximab than adalimumab. > Most of the studies with adalimumab are on juvenile uveitis, whereas for > infliximab, there are a lot more data for all forms of resistant uveitis. So > in terms of the published literature, there is currently a difference in the > volume of studies, although there are ongoing studies with adalimumab in > nonpediatric patients. Furthermore, there is currently no head-to- head trial > for infliximab and adalimumab, so it is impossible to compare their > effectiveness for uveitis, but my assumption is that both work similarly. > > Medscape: From your experience, when should a decision be made to use a > biologic agent for uveitis, and what are the key considerations for the > choice of a biologic therapy? > > Dr. Schwartzman: Currently, there is no paradigm for timing the use of an > anti-TNF agent, and if you look at the literature critically, in most, if > not all, circumstances, it is for patients who have chronic disease that is > resistant to traditional treatment. In fact, the term resistant is > questionable --resistant to what? Is it someone who is just resistant to > systemic corticosteroids? Someone who is resistant to one of the DMARDs? > There is no consensus. My honest sense, though, is that the 2 circumstances > where I will use an anti-TNF agent in a patient with resistant uveitis are: > (1) when a patient has failed tapering of systemic steroids and at least 1 > remittive medication; and (2) in a patient that the ophthalmologist does not > feel that we have much time, that is a patient whose uveitis is > significantly vision threatening. I probably would try the steroids first, > and if that is not effective, I would then treat with an anti-TNF agent. > > I should also say that in terms of the anti-TNF agents, the one prospective > trial by Suhler[12] noted an interesting and surprising finding that in the > group of 23 study patients with treatment-resistant uveitis, side effects > from anti-TNF therapy used in the study (infliximab) were significantly > greater than what we have seen in patients with traditional rheumatic > disease for whom the anti-TNF agents are approved. Of note, side effects > noted in this cohort included pulmonary embolus, congestive heart failure, > lupus-like disease, and vitreous hemorrhage. The frequency of these side > effects has not been noted in trials of patients with rheumatoid arthritis, > psoriatic arthritis, ankylosing spondlylitis, or inflammatory bowel disease. > Furthermore, there are studies that suggest new-onset uveitis can be seen in > patients treated with anti-TNF agents.[13,14] So one question that I think > is still unanswered is whether these patients with resistant uveitis, some > of whom have underlying systemic diseases, are at a higher risk of > developing side effects from treatment with anti-TNF agents. Having said > that, if you look at all of the other literature on the use of the anti-TNF > agents in resistant uveitis, a significantly increased side effect profile > is not generally seen. > > Medscape: What determines the choice of anti-TNF? > > Dr. Schwartzman: For the treatment of resistant uveitis, I think pretty much > unanimously, my sense is that etanercept is not used to treat resistant > uveitis. Of the anti-TNF agents, the only one that has been potentially > found to cause uveitis is etanercept. We clearly need more studies with > regards to this concept. Deciding between adalimumab and infliximab is a > little bit more difficult in that, again, there are no head-to- head trials > comparing the 2. My sense is that both are efficacious. There are more data > published for infliximab, but this is one of those circumstances where I > think the data currently cannot support one over the other, although one > must say that there is much more published for infliximab. I think other > issues play into the decision about adalimumab or infliximab, and they > include issues such as insurance coverage, patient preference, and dosing > flexibility. Currently there is no a clear-cut answer between these 2 > agents, and obviously we await more data on adalimumab. > > With regard to uveitis associated with juvenile idiopathic arthritis, most > of the current literature is with adalimumab. There is some literature with > infliximab in juvenile idiopathic arthritis, but there isn't as much of a > focus. Additionally, infliximab is not approved for the treatment of > juvenile idiopathic arthritis, whereas adalimumab has been submitted to the > FDA for approval. In view of the limited data and lack of head-to- head > trials, it is not possible to conclude at the present time that one > monoclonal antibody is better than the other. My sense is that they both > work, and to prove that one is better than the other, we need a head-to-head > trial. > > Medscape: From a patient perspective, what should be the consideration > before making a choice to use a biologic agent to treat uveitis? > > Dr. Schwartzman: I think we tend to use the same exclusions that we would > for the use of anti-TNF agents in other diseases in that in someone who has > had an active infection, for example, or a lymphoproliferative disease, we > would be very reluctant to use an anti-TNF agent. The risk of tuberculosis > obviously needs to be considered, and all of these patients should be very > carefully screened for tuberculosis. Multiple sclerosis (MS) also needs to > be considered in that, at times, certain forms of uveitis have been > associated with this condition, and anti-TNF agents can worsen MS. The one > exception that you must be aware of, if you are treating patients with > underlying uveitis, is that there is an association of one form of uveitis > with multiple sclerosis. Clearly, caution must be exercised in using the > anti-TNF agents because they may worsen multiple sclerosis. So I think that > the issues associated with lymphoproliferative malignancies, potential > infections, and potential neurologic disease would be key considerations as > potential contraindications to the use of an anti-TNF agent in this patient > group. > > Medscape: What do you see as the key educational needs among rheumatologists > who treat autoimmune uveitis in adults and children? > > Dr. Schwartzman: One issue is that although most rheumatologists will see > autoimmune eye disease, I would argue that most clinical rheumatologists see > these patients relatively infrequently, depending on the referral patterns. > The other issue is that their patients with rheumatic diseases will at some > point develop autoimmune eye diseases, and the reality is that when that > happens, most rheumatologists are at a disadvantage in terms of > understanding the disease and therapies available to treat these conditions. > So from an educational needs perspective, I think rheumatologists need to be > more cognizant of the association between uveitis and systemic autoimmune > diseases. But they also need to understand that idiopathic uveitis is an > autoimmune disease, and probably the most important area that needs to be > highlighted here is that there has to be a marriage between the > ophthalmologist and the rheumatologist in terms of treating these groups of > patients. It is important to understand the essential and different roles of > the physicians involved in managing a patient with inflammatory uveitis. > Quote Link to comment Share on other sites More sharing options...
Guest guest Posted January 11, 2008 Report Share Posted January 11, 2008 Hi , I'm glad you found the posting informative. The interview was dated September 28, 2007 so it is pretty recent. Your comment about the classifications ... that's not so easy for me to answer. Hopefully someone who knows for sure will chime in. Personally, my area of greater understanding is with systemic JIA, since that's the type my son has. I had considered PsA a distinct entity from Spondylitis. Not to minimalize very serious health issues but in very simple and superficial terms, when I think of PsA I think of the skin and finger and toe joints and when I think of AS I think of the spine, back and neck (and heel). When I saw your message it made me question my assumptions. The first place I went was the Spondylitis Association of America. There, they say that arthritis appears in about 5 to 10% of people who have psoriasis ... I'd heard that before .... but also that about 20% of those with PsA will eventually have spinal involvement! I may have seen that before but it surprised me, how high the number was! So you may very well be correct. I'll look forward to seeing more replies about this. Thanks, Georgina Re: Inflammatory Eye Disease Thanks Georgina thats a great article. Is it recent? One thing that confuses me though is that this guy considers psoriatic arthritis separate from a spondylarthropathy. I thought it was a subcategory of spondy. & Grant/10,PsA/Uveitis > > Inflammatory Eye Disease: An Expert Interview With Schwartzman, MD > http://www.medscape.com/viewarticle/562587?src=mp > > Schwartzman, MD > Medscape Rheumatology. 2007; ©2007 Medscape > > Editor's Note: > The pathophysiologic causes of uveitis are several and include autoimmune > disorder, infection, idiopathic conditions, and complications of surgery. > Symptoms range from pain, photophobia, and blurred or reduced vision to > floaters, loss of vision, and blindness. Treatment may include > corticosteroids, nonsteroidal anti-inflammatory drugs, immunomodulatory > therapy, or ophthalmic implant surgery. > > This interview focuses on the autoimmune causes of uveitis, such as > rheumatic diseases, in both children and adults. Helen Fosam, PhD, Medscape > Rheumatology, spoke with Schwartzman, MD, Franchellie M. Cadwell > Associate Professor of Medicine, Weill Medical College, The Hospital for > Special Surgery and New York Presbyterian Hospital, Cornell University, New > York, NY, about the issues surrounding the management of uveitis associated > with rheumatic diseases. They discussed diagnostic challenges from a > rheumatologist's perspective and recent advances in treatment with > immunomodulatory agents, particularly for chronic refractory uveitis. > > Medscape: Autoimmune uveitis is closely associated with inflammatory > arthritis. Do all arthritic conditions have a risk for uveitis? Are some > forms of arthritis more of a risk than others? > > Dr. Schwartzman: If we look at the host of rheumatic diseases that exist, > the reality is that there are certain diseases that have much more of a risk > for developing uveitis than others. In that regard, the diseases that are > most closely associated with uveitis and seen by rheumatologists include > juvenile idiopathic arthritis, the spondyloarthropathies, as well as > conditions such as sarcoidosis and Behcet's disease; these are the group of > diseases that have the highest risk of developing uveitis.[1-4] There are > other conditions with lower risk for uveitis, including inflammatory bowel > disease and psoriatic arthritis. So, in terms of risks, there is clearly a > differential among the different rheumatic diseases, and probably juvenile > idiopathic arthritis and the spondyloarthropathy group of diseases such as > ankylosing spondylitis have the highest risk of developing uveitis. > > Medscape: Is the risk for uveitis the same in adults and children? > > Dr. Schwartzman: The reality is that it is very different, depending on the > specific diseases. However, we generally cannot categorize the risk > according to age; we more accurately categorize risk according to disease > entity. For example, if you look at ankylosing spondylitis, which is one of > the spondyloarthropathies, the risk of developing uveitis at some point in > the disease is anywhere from 30% to 40%. This means that a patient who has > ankylosing spondylitis has a 30% to 40% risk for developing uveitis, and > usually a specific type of uveitis called anterior uveitis. However, if you > look at juvenile idiopathic arthritis, which is one of the most common > diseases that affects children who develop uveitis, uveitis manifests in > approximately 13% of these patients.[5] Even within the realm of juvenile > idiopathic arthritis, there is a differential in terms of risk for > developing uveitis in that the group that is most likely to develop uveitis > is the very young oligoarticular girl who has juvenile idiopathic arthritis > and positive antinuclear antibodies. So the risk differs across different > arthritic diseases, it clearly differs between children and adults, and I > think it is more dependent on the disease process than the age. > > Medscape: Apart from the arthritic condition, are there other risk factors > for uveitis? How should rheumatologists recognize and manage them? > > Dr. Schwartzman: The reality is that uveitis can occur as part of the > underlying autoimmune disease, and if we look at all patients with uveitis, > approximately 50% will have an underlying systemic disease, whereas in the > other 50%, there is likely no systemic disease that can be identified. We > classify the latter group of patients as presenting with idiopathic uveitis. > In terms of other potential risk factors that are perhaps tangentially > related to the uveitis, from a clinical perspective, as mentioned for > juvenile idiopathic arthritis, the patterns of disease is very important in > defining risk. Other potential risk factors are not well delineated, > although HLAB27 positivity, for example, has been found to be more common in > people who have uveitis in general, irrespective of whether they have > rheumatic disease. > > Medscape: What is the role of the rheumatologist in making a diagnosis for > uveitis? Should they refer to, and work collaboratively with, an > ophthalmologist? > > Dr. Schwartzman: I think that this is a critical issue. The rheumatologist > and the ophthalmologist need to work together. The reason I say this is that > the rheumatologist is generally very familiar with the medications that are > used to treat uveitis, except for perhaps the topical agents; however, the > rheumatologist cannot determine response to therapy, so unless the > rheumatologist has the necessary diagnostic tools and can actually quantify > the degree of inflammation, they are going to be at a loss in terms of > understanding whether the medicines they are using are helping the patient. > So the need for collaboration between the 2 subspecialties, the > ophthalmologist and the rheumatologist, is critical. Frequently, at my > clinic, I monitor the patient for their extraophthalmic disease and > potential toxicity to the medications that I am using to treat a patient > with resistant uveitis. However, to gauge whether the medicine is working or > not, I am completely dependent on the ophthalmologist, and in that setting I > always discuss the cases with the ophthalmologist. > > In terms of the diagnostic approach to uveitis, I would argue strongly that > it should be dependent on the medical history and physical examination > performed by the rheumatologist. There are specific tests to screen patients > with uveitis, and, unfortunately, frequently patients with uveitis will > present to the rheumatologist with a panel of blood tests and sometimes > invasive procedures and x-rays that may or may not be appropriate. I would > argue strongly that the history and physical exam dictates what laboratory > tests are done. I should tell you, though, that in the work up for these > patients, you need to be very secure in ruling out an infectious cause for > uveitis, and to some extent we depend on the ophthalmologist for that. At > the very minimum, I generally do a chest x-ray, PPD, syphilis serologies, > and routine laboratory tests on my patients with uveitis; and then anything > outside of that is dependent on the clinical presentation. For example, if a > patient presents with inflammatory back pain, I will additionally obtain > sacroiliac radiographs and perhaps check the HLAB27. If a patient presents > with a history of gastrointestinal complaints, I frequently will have a > gastroenterology work up to ensure that there is no inflammatory bowel > disease. I think patient history and physical exam are very important from a > rheumatologist's perspective. > > Medscape: Is it reasonable to advise all patients with rheumatic diseases to > be screened for uveitis? > > Dr. Schwartzman: I do not think that routine screening is necessary. I think > the reality is that in adults who do not have any ophthalmic complaints, one > can be reasonably secure in knowing that there is no ophthalmic disease. > However, children with juvenile idiopathic arthritis should be frequently > seen by the ophthalmologist, because in this cohort of children, uveitis can > be asymptomatic. The child may not complain of any symptoms yet have > significant inflammatory disease. > > Medscape: What is the consequence of failure to treat uveitis? > > Dr. Schwartzman: The reality is that for patients who are not treated, the > incidence of complications from uveitis -- synechiae, glaucoma, cataracts -- > is quite high and, in that setting, will lead to significant visual loss.[6] > In the United States, it is estimated that uveitis results in approximately > 10% of the overall significant visual loss reported, which is a very high > percentage, when you consider diseases such as glaucoma and diabetes. I > think it is critical to treat uveitis both in adults and in children. > > Medscape: Is uveitis a progressive disease? > > Dr. Schwartzman: Generally, it is variable. It depends on the type of > uveitis. In patients who have acute anterior uveitis, depending on the > clinical syndrome, sometimes it can be a very transient or single event. > However, there is a subgroup of patients who have resistant uveitis; the > uveitis can be anterior uveitis, posterior uveitis, or panuveitis, and in > that group it is progressive. > > Medscape: For chronic cases of uveitis, or cases refractory to treatment, > biologics such as anti-TNF agents have emerged as promising options. Can you > comment on studies supporting a biologic approach to treatment? > > Dr. Schwartzman: Once you have a patient with resistant uveitis, there isn't > a single paradigm for how to treat them. In that regard, various medications > have been used, most commonly in addition to topical steroids. Systemic > steroids are used when topical treatments fail. If systemic steroids fail, > multiple remittive medications have been tried, and these have included > medicines such as cyclosporine, azathioprine, mycophenolate, and > methotrexate. > > In terms of the role of biologics, treatment with these agents is currently > evolving, and there are a number of studies and abstracts that suggest that > the monoclonal antibodies infliximab and adalimumab seem to be effective for > the treatment of resistant uveitis, whereas etanercept does not appear to be > effective.[7-10] Other studies have also investigated patients who have > uveitis and a systemic underlying disease such as a spondyloarthropathy to > ascertain whether treatment with an anti-TNF agent will result in a decrease > in their uveitis flares.[11] In these studies, again it appears that the > monoclonal antibodies infliximab and adalimumab are effective, whereas > etanercept does not prevent uveitis flares. So there are a number of studies > looking at anti-TNF-treated patients with underlying systemic diseases and > uveitis as well as those with idiopathic uveitis. In these settings, the > effectiveness of the monoclonal antibodies is superior to etanercept. > > Of note, in Japan, inflixamab has been approved for Behcet's disease with > refractory uveoretinitis, so worldwide there is at least one approval for a > form of uveitis for infliximab. The problem with the studies on anti-TNF > agents is that most of them are retrospective. They are usually cases that > have been accumulated at a treatment center; there are no prospective, > double-blind, randomized trials. There is one very good phase 2 study by > Suhler[12] from the Casey Institute on the use of infliximab to treat > resistant uveitis. The study involved 23 patients from a uveitis clinic who > were treated with infliximab. Patients who responded to treatment were > continued on infliximab, and there was clearly some significant benefit from > the use of infliximab in this cohort of patients. Unfortunately, this study > is the only prospective trial currently available, although others are being > contemplated. The side effects noted in this cohort of patients were far > more than what is described in the literature for other autoimmune disease. > > Medscape: You mentioned that not all the anti-TNF agents are effective; is > this related the differences in their structure and mechanism of action? > > Dr. Schwartzman: That is a good question. I don't think anybody knows the > answer to that. Although they all target TNF, we know that the > pharmacokinetics of these drugs differ; we know that the half- lives also > differ. The other issue that needs to be considered in uveitis, in terms of > treatment, is that there is a blood ocular barrier, and there may be > different permeabilities to different agents, and this may be related to > molecular structure and dosing. But there are clear differences between the > anti-TNF agents. There are also other issues; for example, effects on > lymphotoxin -- etanercept affects lymphotoxin, whereas the monoclonal > antibodies do not, so nobody really knows the reason why there are > differences in the treatment effects with anti-TNF agents. > > Medscape: Are the monoclonal antibodies infliximab and adalimumab equally > effective for all uveitis conditions? > > Dr. Schwartzman: There are a lot more data on infliximab than adalimumab. > Most of the studies with adalimumab are on juvenile uveitis, whereas for > infliximab, there are a lot more data for all forms of resistant uveitis. So > in terms of the published literature, there is currently a difference in the > volume of studies, although there are ongoing studies with adalimumab in > nonpediatric patients. Furthermore, there is currently no head-to- head trial > for infliximab and adalimumab, so it is impossible to compare their > effectiveness for uveitis, but my assumption is that both work similarly. > > Medscape: From your experience, when should a decision be made to use a > biologic agent for uveitis, and what are the key considerations for the > choice of a biologic therapy? > > Dr. Schwartzman: Currently, there is no paradigm for timing the use of an > anti-TNF agent, and if you look at the literature critically, in most, if > not all, circumstances, it is for patients who have chronic disease that is > resistant to traditional treatment. In fact, the term resistant is > questionable --resistant to what? Is it someone who is just resistant to > systemic corticosteroids? Someone who is resistant to one of the DMARDs? > There is no consensus. My honest sense, though, is that the 2 circumstances > where I will use an anti-TNF agent in a patient with resistant uveitis are: > (1) when a patient has failed tapering of systemic steroids and at least 1 > remittive medication; and (2) in a patient that the ophthalmologist does not > feel that we have much time, that is a patient whose uveitis is > significantly vision threatening. I probably would try the steroids first, > and if that is not effective, I would then treat with an anti-TNF agent. > > I should also say that in terms of the anti-TNF agents, the one prospective > trial by Suhler[12] noted an interesting and surprising finding that in the > group of 23 study patients with treatment-resistant uveitis, side effects > from anti-TNF therapy used in the study (infliximab) were significantly > greater than what we have seen in patients with traditional rheumatic > disease for whom the anti-TNF agents are approved. Of note, side effects > noted in this cohort included pulmonary embolus, congestive heart failure, > lupus-like disease, and vitreous hemorrhage. The frequency of these side > effects has not been noted in trials of patients with rheumatoid arthritis, > psoriatic arthritis, ankylosing spondlylitis, or inflammatory bowel disease. > Furthermore, there are studies that suggest new-onset uveitis can be seen in > patients treated with anti-TNF agents.[13,14] So one question that I think > is still unanswered is whether these patients with resistant uveitis, some > of whom have underlying systemic diseases, are at a higher risk of > developing side effects from treatment with anti-TNF agents. Having said > that, if you look at all of the other literature on the use of the anti-TNF > agents in resistant uveitis, a significantly increased side effect profile > is not generally seen. > > Medscape: What determines the choice of anti-TNF? > > Dr. Schwartzman: For the treatment of resistant uveitis, I think pretty much > unanimously, my sense is that etanercept is not used to treat resistant > uveitis. Of the anti-TNF agents, the only one that has been potentially > found to cause uveitis is etanercept. We clearly need more studies with > regards to this concept. Deciding between adalimumab and infliximab is a > little bit more difficult in that, again, there are no head-to- head trials > comparing the 2. My sense is that both are efficacious. There are more data > published for infliximab, but this is one of those circumstances where I > think the data currently cannot support one over the other, although one > must say that there is much more published for infliximab. I think other > issues play into the decision about adalimumab or infliximab, and they > include issues such as insurance coverage, patient preference, and dosing > flexibility. Currently there is no a clear-cut answer between these 2 > agents, and obviously we await more data on adalimumab. > > With regard to uveitis associated with juvenile idiopathic arthritis, most > of the current literature is with adalimumab. There is some literature with > infliximab in juvenile idiopathic arthritis, but there isn't as much of a > focus. Additionally, infliximab is not approved for the treatment of > juvenile idiopathic arthritis, whereas adalimumab has been submitted to the > FDA for approval. In view of the limited data and lack of head-to- head > trials, it is not possible to conclude at the present time that one > monoclonal antibody is better than the other. My sense is that they both > work, and to prove that one is better than the other, we need a head-to-head > trial. > > Medscape: From a patient perspective, what should be the consideration > before making a choice to use a biologic agent to treat uveitis? > > Dr. Schwartzman: I think we tend to use the same exclusions that we would > for the use of anti-TNF agents in other diseases in that in someone who has > had an active infection, for example, or a lymphoproliferative disease, we > would be very reluctant to use an anti-TNF agent. The risk of tuberculosis > obviously needs to be considered, and all of these patients should be very > carefully screened for tuberculosis. Multiple sclerosis (MS) also needs to > be considered in that, at times, certain forms of uveitis have been > associated with this condition, and anti-TNF agents can worsen MS. The one > exception that you must be aware of, if you are treating patients with > underlying uveitis, is that there is an association of one form of uveitis > with multiple sclerosis. Clearly, caution must be exercised in using the > anti-TNF agents because they may worsen multiple sclerosis. So I think that > the issues associated with lymphoproliferative malignancies, potential > infections, and potential neurologic disease would be key considerations as > potential contraindications to the use of an anti-TNF agent in this patient > group. > > Medscape: What do you see as the key educational needs among rheumatologists > who treat autoimmune uveitis in adults and children? > > Dr. Schwartzman: One issue is that although most rheumatologists will see > autoimmune eye disease, I would argue that most clinical rheumatologists see > these patients relatively infrequently, depending on the referral patterns. > The other issue is that their patients with rheumatic diseases will at some > point develop autoimmune eye diseases, and the reality is that when that > happens, most rheumatologists are at a disadvantage in terms of > understanding the disease and therapies available to treat these conditions. > So from an educational needs perspective, I think rheumatologists need to be > more cognizant of the association between uveitis and systemic autoimmune > diseases. But they also need to understand that idiopathic uveitis is an > autoimmune disease, and probably the most important area that needs to be > highlighted here is that there has to be a marriage between the > ophthalmologist and the rheumatologist in terms of treating these groups of > patients. It is important to understand the essential and different roles of > the physicians involved in managing a patient with inflammatory uveitis. > Quote Link to comment Share on other sites More sharing options...
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