Advancements in the management of uveitis

Best Practice & Research Clinical Rheumatology xxx (2016) 1e12

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Advancements in the management of uveitis Sergio Schwartzman Weill Medical College of Cornell University Hospital for Special Surgery, New York Presbyterian Hospital, USA

a b s t r a c t Keywords: Autoimmune ophthalmic disease Uveitis Biologic therapy Ocular complications

Uveitis may exist as a clinical manifestation of an underlying systemic disease or may represent an idiopathic entity, sometimes with a very characteristic pattern. Different forms of uveitis have been defined on the basis of three important variables: chronicity, anatomic location, and underlying etiology. The evolving understanding of the immune system has resulted in a more targeted approach to manage patients with different forms of uveitis, although clearly this approach is at a very early stage. Altered patterns of cellular processing and different cytokine expression, including TNF, IL-1, IL-2, IL-6, and IL17, have been defined in uveitis, and this has laid the pathway for targeted therapy. Furthermore, approved biologic therapies for some of the more common autoimmune illnesses have now been tested in uveitis. Adalimumab and infliximab have been the best studied anti-TNF agents and indeed have now been recommended by an expert panel as the first line of treatment for ocular manifestations of Behçet's disease and the second line of treatment for other forms of uveitis. Adalimumab has been recently approved for intermediate uveitis, posterior uveitis, and panuveitis. Other biologic agents have been tested, including daclizumab, a monoclonal antibody directed against IL-2, anti-IL1, and anti-IL-6 receptor agents and therapies that block antigen-presenting cell and T-cell interaction, such as abatacept. In small case series, other biologics such as interferon and rituximab have also been evaluated. Although these biologic therapies have provided a larger armamentarium to treat uveitis, challenges remain. Uveitis is not a disease, but a manifestation of many potential systemic diseases that may have specific individual therapeutic targets. Identification and characterization of these underlying diseases are not always possible and, more importantly, the most effective therapies for

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each entity have not been defined. In this study, an approach to manage patients with uveitis is presented and current therapy is reviewed. © 2016 Published by Elsevier Ltd.

Introduction Different forms of uveitis have been defined on the basis of three variables: chronicity, anatomic location, and underlying etiology. Uveitis can exist as a primary, idiopathic ophthalmic entity or as a comanifestation of an established underlying disease. Further, uveitis may be the presenting manifestation of a systemic illness that evolves over time. In approximately 50% of patients presenting with uveitis, a recognized illness will be identified, although this is to some extent determined by the healthcare professional or center where the patient is evaluated. There is a paucity of data defining the incidence and prevalence of uveitis and, more importantly, the prognostic implications of this group of diseases. In a northern California cross-sectional managed care study using a retrospective database and medical record review of 731,895 participants, a uveitis incidence of 52.4/100,000 person-years and a prevalence of 115.3/100,000 persons was noted [1]. Before the emergence of the concept of aggressive immunosuppression for autoimmune diseases and use of biologic therapies, it was estimated that in the United States, uveitis was responsible for an estimated 30,000 cases of blindness annually [2]. In a more recent retrospective cohort study of uveitis patients managed at a tertiary care center, outcome evaluated was best-corrected visual acuity at initial referral and after 1 year. In 133 patients, at 1-year follow-up, bilateral visual impairment was observed in only 4%, but at least one ocular complication developed in 66% of patients. In 30% of patients, intraocular surgery was required and 8% of patients required hospitalization [3]. Over the last two decades, the rates of ocular and systemic morbidity have decreased. Ideally, therapy for an identified systemic disease should be successful in controlling uveitis; however, this is not always the case. The therapeutic approach to uveitis requires careful consideration of etiology, anatomic site involved, chronicity, prior treatment failure, and potential ophthalmic and systemic risks of proposed therapy. Patients with uveitis need to be carefully evaluated by both an ophthalmologist and a physician trained in internal medicine (preferably a rheumatologist or immunologist) to establish a diagnosis and assure that an infectious, primary neurologic, or malignant process is not present, as therapy in these circumstances is very different from that for other forms of autoimmune uveitis. In this study, we focus on the current use of different therapeutic modalities in patients with uveitis. Nonbiologic therapeutic approach to uveitis The most frequent type of uveitis is acute and anterior uveitis, and the conditions responsible for this type of uveitis generally respond well to topical corticosteroids and cycloplegic and/or mydriatic agents. Patients with chronic disease, intermediate uveitis, posterior uveitis, or panuveitis, who have the highest morbidity require aggressive therapy. High-dose systemic steroids are generally the first therapeutic intervention. The recommended initial therapy is usually prednisone at doses of 40e80 mg per day. In severe cases, parenteral steroids are used, and there are data for “pulse dose” steroids in uveitis. As was the case in rheumatology several decades ago, there is currently an ophthalmology-led emphasis being placed on using second-line agents earlier in patients with poor prognosis. Methotrexate and mycophenolate are frequently the first agents used, although cyclosporine, tacrolimus, and azathioprine are used as well. Methotrexate has been used to treat noninfectious uveitis as an oral agent, parenterally and as an intra-ocular injection. It is a folate antagonist that inhibits dihydrofolate reductase. This enzyme is critical in the synthesis of nucleic acid, and therefore methotrexate inhibits rapid cell growth and Please cite this article in press as: Schwartzman S, Advancements in the management of uveitis, Best Practice & Research Clinical Rheumatology (2016), http://dx.doi.org/10.1016/j.berh.2016.07.005

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proliferation [4]. Although studies on both high- and low-dose methotrexate in uveitis have been published [5,6], generally doses between 15 and 25 mg per week orally or parenterally are effective. There are no prospective, randomized, masked studies evaluating the efficacy of this agent, although it is very frequently used. The data supporting its use are predominantly case series and reviews [7,8]. In one large retrospective noncomparative interventional case series of 160 patients with different types of uveitis, inflammation control was achieved in 76.2% of patients, steroid-sparing effect was achieved in 56%, and visual acuity was maintained or improved in 90% of patients [6]. Mycophenolate mofetil is a prodrug of mycophenolic acid, which is an inhibitor of inosine-50 monophosphate dehydrogenase. This therapy depletes guanosine nucleotides preferentially in T and B lymphocytes and inhibits proliferation, thereby suppressing cell-mediated immune responses and antibody formation [9]. Mycophenolate dosing generally requires 2e3 g/day in divided doses [10,11]. In a retrospective case series that evaluated 84 consecutive patients with inflammatory eye disease who were treated with mycophenolate, of which 61% had uveitis, the median dose of prednisone at the start of mycophenolate mofetil therapy was 40 mg per day. The majority of the patients (82%) were considered treatment success cases, as judged by the ability to control inflammation and taper prednisone to 10 mg daily [12]. Cyclosporine is a specific T-cell inhibitor that forms a complex with cyclophilin, which then inhibits the phosphatase activity of calcineurin. This effect regulates nuclear translocation and subsequent activation of transcription factors [13]. Dosing range in autoimmune ophthalmic diseases is generally between 2.5 and 5 mg/kg, and it is administered twice daily, although in some studies, lower doses have been used. Cyclosporine has been studied in a number of uncontrolled trials in various forms of uveitis [14e16]. In a larger randomized and controlled study of 96 patients, it succeeded in decreasing the frequency and severity of disease flares [17]. This medication has been used broadly across different autoimmune ophthalmic disease and it does appear to be fairly effective. Tacrolimus, a macrolide antibiotic, although structurally unrelated to cyclosporine A, has a similar mode of action. It binds to immunophilin, an FK506 binding protein, which then inhibits calcineurin phosphatase [18]. Its dose range is 0.03e0.08 mg/kg/day. In a randomized trial of patients with various etiologies of posterior uveitis comparing cyclosporine to tacrolimus, both groups responded equally. A total of 13 patients (68%) taking tacrolimus and 12 patients (67%) taking cyclosporine responded to treatment [19]. Some long-term studies following patients treated with tacrolimus have been successful [20]. Azathioprine is an imidazolyl derivative and a prodrug for mercaptopurine, which is incorporated into replicating DNA, blocking the pathway of purine synthesis and therefore impeding T and B cell replication [21]. In a study of 21 patients with corticosteroid-resistant noninfectious uveitis, who were treated with azathioprine (2.5 mg/kg/day), visual acuity evaluated resulted in complete success observed in 62.5%, partial response in 20.9%, and failure in 16.6% of patients. Inflammation as an outcome measure after azathioprine treatment resulted in complete success in 70.8%, partial response in 29.1%, and failure in 16.6%. Complete response of steroid sparing was observed in 85.7% of patients and complete success of the three listed criteria was observed in 57.1% of patients [22]. Other nonbiologic therapies for uveitis include the use of chlorambucil and cyclophosphamide. These medications are now very infrequently used because of their potential toxicity and the availability of more targeted therapy with biologic agents. Both are alkylating agents and function by interfering with DNA replication and damaging DNA, which results in cell cycle arrest and cellular apoptosis with an immunosuppressant effect on the function of both T cells and B cells [23]. In a retrospective case series of 28 patients who were refractory to other immunomodulatory therapy and systemic steroids, 68% showed response to chlorambucil. The median duration of treatment was 12 months and the median daily dose was 8 mg. The medication was discontinued in 25% of patients because of side effects [24]. Cyclophosphamide can be administered either orally or by intravenous infusion. Most studies published actually combine numerous autoimmune ophthalmic illnesses, as this agent is infrequently used. In a retrospective cohort study of 215 patients with noninfectious ocular inflammation, where only 20.4% had uveitis, 49.2% gained sustained control of inflammation within 6 months and 76% within 12 months. Corticosteroid-sparing success was achieved in 30.0% at 6 months and 61.2% at 12 months. Cyclophosphamide was discontinued by 33.5% of patients within 1 year because of side effects [25]. Please cite this article in press as: Schwartzman S, Advancements in the management of uveitis, Best Practice & Research Clinical Rheumatology (2016), http://dx.doi.org/10.1016/j.berh.2016.07.005

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Comparator trials have recently been initiated, but as these require large numbers of patients with the same types of uveitis, they are difficult to perform and interpret. In a multicenter, randomized, observer-masked clinical trial, patients with noninfectious posterior uveitis, intermediate uveitis, or panuveitis were randomized to receive 25 mg weekly oral methotrexate or 1000 mg twice daily oral mycophenolate mofetil. There were 35 methotrexate- and 32 mycophenolate mofetil-treated patients. A proportion of 69% of patients achieved treatment success with methotrexate and 47% with mycophenolate mofetil (p ¼ 0.09). There was no statistically significant difference in corticosteroid-sparing capacity [26]. At present, a larger comparative effectiveness study entitled First-line Antimetabolites as Steroid-sparing Treatment (FAST trial) (clinicaltrials.gov) is ongoing. Biologic therapeutic approach to uveitis Biologic agents are defined by the FDA as: “Virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, protein (except any chemically synthesized polypeptide), or analogous product, or arsphenamine or derivative of arsphenamine (or any other trivalent organic arsenic compound), applicable to the prevention, treatment, or cure of a disease or condition of human beings” (FDA. Scientific Considerations in Demonstrating Biosimilarity to a Reference Product: Guidance for Industry, April 2015). From a practical perspective, these include agents such as antibodies, bioengineered receptor complexes, Fab fragments, and agents such as interferons that affect the expression of pro- and anti-inflammatory components of the immune system. Biologic therapy for autoimmune rheumatic disease was first approved in 1998. For uveitis, the published literature, with exceptions, has suffered from differences in study designs, incorrect power calculations, differences in inclusion criteria, and a lack of consensus regarding outcome measures. However, published literature exists for many different classes of biologic agents including anti-TNF, anti-IL1, anti-IL6 receptor, anti-IL17, anti-IL2 receptor, co-stimulatory blockade, interferon, and CD20 B cell-directed therapy. Adalimumab is now approved for the management of non-infectious, intermediate, posterior and panuveitis. Anti-TNF agents The anti-TNF agents have been predominantly studied in a retrospective manner, although some prospective studies have now been successfully completed. Recently, three studies have been conducted with adalimumab, with subsequent FDA and EMA approval, for the management of noninfectious intermediate uveitis, posterior uveitis, and panuveitis. There are more publications on the use of anti-TNF therapy for the treatment of uveitis than any other group of biologic therapies, and the majority of them focus on the use of infliximab. This may reflect the fact that this therapy was approved in 1998. Currently, there are over 65 published articles on the use of this medication in uveitis. Infliximab, a chimeric mouse/human monoclonal antibody, is unique in the anti-TNF group of therapies in that it is approved for the treatment of many rheumatic illnesses in a wide range of doses, thus providing dosing flexibility that can range from 3 mg/kg every 8 weeks to 10 mg/kg every 4 weeks. It is not formally approved for the management of uveitis, although it is frequently used for this group of illnesses. Given the potential impediment of the blood ocular barrier and the frequent need for high-dose medications to treat ophthalmic inflammatory disease, this may be an important advantage. Infliximab has been used to treat various forms of uveitis in many systemic illnesses, where uveitis is a common manifestation, and in patients with idiopathic forms of uveitis. It has been used in juvenile idiopathic arthritis (JIA) [27e34], spondyloarthritis [35e37], Crohn's disease [38,39], sarcoidosis [32,40], and Behcet's disease. In Japan, infliximab is approved for the treatment of Behcet's diseaseassociated uveoretinitis. Prospective data from eight tertiary uveitis centers were analyzed in 50 patients. At 1 year, uveoretinitis had improved in 69%, improved somewhat in 23%, was unchanged in 8%, and had worsened in none [41]. One of the few prospective studies enrolled 23 patients with various underlying etiologies of resistant uveitis. At 10 weeks, 78% of patients met criteria for clinical success as judged by a composite clinical end point of visual acuity, control of intraocular inflammation, ability to taper concomitant therapy, and improvement of fluorescein angiography and/or ocular coherence Please cite this article in press as: Schwartzman S, Advancements in the management of uveitis, Best Practice & Research Clinical Rheumatology (2016), http://dx.doi.org/10.1016/j.berh.2016.07.005

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tomography. Serious adverse events experienced by the cohort included pulmonary embolus, congestive heart failure, lupus-like reaction in two patients, and vitreous hemorrhage in two patients. Although infliximab was effective, the number of potential toxicities differed from other studies published across all indications for this medication. In a 2-year followeup, a 60% retention rate was noted [42]. In a large observational retrospective study of 88 patients from a single center with recalcitrant uveitis treated with infliximab, 81.8% of the patients achieved clinical remission and only 58.3% required additional immunomodulatory medications. In this study, 36.4% of the patients experienced at least one side effect, but only 19.3% discontinued treatment. The most commonly reported adverse effects were skin rash (9.1%) and fatigue (8%). Interestingly, in contrast to the Suhler study [43], in this large study, potential serious adverse events included only one case of autoimmune hepatitis, two chronic infections, and one case of drug-induced lupus [44]. In patients with JIA, infliximab has been frequently used to treat uveitis [27e34]. In an interesting retrospective study focusing on the importance of aggressive therapy to control recalcitrant uveitis in children, 17 children with chronic uveitis were administered high-dose infliximab (10e20 mg/kg/ dose). All 17 patients showed a dramatic, rapid response, with no observed inflammation in 13 patients after the second infusion [27]. Adalimumab, a human monoclonal antibody against TNF approved for the therapy of many autoimmune diseases, has also been used to treat recalcitrant uveitis [32,34,45e73] and has been recently approved for the management of noninfectious intermediate uveitis, posterior uveitis, and panuveitis. In a prospective, multicenter, open-label trial to assess the effectiveness and safety of adalimumab in treating refractory uveitis patients with multiple underlying systemic conditions, 68% of patients were responders at 10 weeks and 39% showed durable response at 50 weeks. No patient experienced treatment-limiting toxicity related to the study therapy [49]. Two studies, VISUAL I and VISUAL II, were responsible for the approval of adalimumab for the treatment of uveitis. In the first study, VISUAL I, 233 adults with noninfectious intermediate uveitis, posterior uveitis, or panuveitis with active uveitis despite 2 weeks of prednisone were randomized to receive placebo or adalimumab subcutaneously 80 mg at week 0, followed by 40 mg every other week. All patients received a prednisone burst followed by taper to 0 mg by week 15. The primary end point was the time to treatment failure. Risk of treatment failure was reduced by 44% in the adalimumab arm. Median time to treatment failure was 3 months for placebo and 4.8 months for adalimumab. In VISUAL II, 258 patients with inactive disease dependent on 10e35 mg/day of prednisone to maintain inactivity were randomized and treated similarly. Median time to treatment failure was 5.6 months for placebo but not estimable for adalimumab, as more than half of the patients did not show treatment failure by week 80 (reference [114]). In an interesting study, comparing infliximab to adalimumab in anterior uveitis, a higher benefit for adalimumab was demonstrated. A total of 48 patients were treated with infliximab and 43 with adalimumab. Fifty-three percent achieved remission, 32.9% had recurrent anterior uveitis, and 11.8% did not respond. A higher remission rate was observed with adalimumab 67.4% versus 42.8% with infliximab (p ¼ 0.025). Caution needs to be exercised in interpretation of this study, given the trial design and the fact that these were patients with only anterior uveitis [34]. Golimumab, a fully human anti-TNF monoclonal antibody, which is available as a subcutaneous and intravenous preparation approved for the treatment of a number of autoimmune diseases, has been used to treat uveitis. In a series of patients with JIA and HLA B-27 associated uveitis (13 patients with JIA, 4 with HLA-B27) who showed a failed response to other biologics, 70.5% response was achieved [74]. Studies on this agent are ongoing [75]. Etanercept is a fusion protein containing IgG1 Fc and TNF receptor 2. Although etanercept was first thought to play a potential role in treating resistant uveitis [35,76e78], further studies have shown no benefit from this therapy [79,80]. A controversial area that requires clarification and further study is the potential paradoxical role of anti-TNF agents as a cause of uveitis. A pivotal study published in 2010 clarifies this topic by demonstrating that while the incidence of uveitis is higher in patients treated with etanercept than infliximab and adalimumab, the overall incidence of new-onset uveitis with all three agents is very low. Cases of uveitis in patients treated with anti-TNF agents reported to the World Health Organization adverse drug events database or the National Registry of Drug-Induced Ocular Side Effects (Casey Eye Institute) from 1 January 1998 to 1 January 2006 were reviewed. There were 43 cases of uveitis associated with etanercept, 14 associated with infliximab, and 2 associated with Please cite this article in press as: Schwartzman S, Advancements in the management of uveitis, Best Practice & Research Clinical Rheumatology (2016), http://dx.doi.org/10.1016/j.berh.2016.07.005

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adalimumab. After normalizing for the estimated number of patients treated with each medication, etanercept was associated with a higher number of uveitis cases than those of infliximab (p < 0.001) and adalimumab (p < 0.01), while no such association was found between adalimumab and infliximab (p > 0.5). The authors conclude that if there was an association between etanercept and uveitis, the incidence of uveitis should have been much higher [81]. A difficult question that remains is whether to use etanercept in patients with underlying diseases that in and of themselves have a risk for the development of uveitis. Previous studies showed that in ankylosing spondylitis trials in which etanercept was used, there was no higher incidence of uveitis [82]; yet, it is well accepted that uveitis can occur in 20e40% of patients with any of the HLA B-27associated inflammatory conditions [83]. In a published paper, an expert panel has made recommendations for the use of anti-TNF agents in ocular inflammatory diseases [84]. A subcommittee of the Executive Committee of the American Uveitis Society, using PubMed, reviewed all published clinical studies on the use of anti-TNF agents to treat ocular inflammatory disorders. A total of 400 articles were identified, and using the validated Grading of Recommendations Assessment Development and Evaluation methodology [85], recommendations were made. Although five anti-TNF agents have been approved for the treatment of various autoimmune diseases, the Executive Committee chose to evaluate only the data for etanercept, infliximab, and adalimumab. Of note, for one of the excluded medications, golimumab, which was approved in 2009 for RA, published literature is available on its use in uveitis [74,75,86e89]. The committee reviewed the structure, pharmacokinetics, indications, and safety of these agents besides addressing their use in autoimmune ophthalmic diseases. For the ocular manifestations of Behcet's disease, based on SIGN level IIeIII data, there was a strong recommendation and high-quality evidence for the use of infliximab and moderate quality evidence for the use of adalimumab to treat the ocular manifestations of this disease as first- or second-line corticosteroid-sparing agents. There was insufficient quality evidence for the use of etanercept and hence discretionary recommendations for its use in Behcet's disease-associated uveitis. For the ophthalmic manifestations of JIA, based on SIGN level IIeIII data and high-quality evidence, there was strong recommendation to use infliximab or adalimumab as second-line agents after MTX to treat patients with JIA-associated uveitis. There was a strong recommendation based on the high-quality evidence that etanercept should not be used in this condition. Recommendations for the ocular diseases in spondyloarthritis are more complicated as these diseases, although sharing a common genetic link, present with different phenotypes. Similarly, the ocular inflammatory manifestations of these illnesses vary across the specific entities. Nonetheless, on the basis of SIGN level IeIII data, there were strong recommendations for the use of infliximab or adalimumab as corticosteroid-sparing agents for chronic uveitis and discretionary recommendations for the use of either one of these two agents as adjunctive therapy for sight-threatening uveitis. The recommendations for the treatment of autoimmune ophthalmic disease associated with sarcoidosis were based on SIGN level IeIII data. Discretionary recommendations were made for the use of infliximab or adalimumab and against the use of etanercept. Data for other less common forms of uveitis were addressed, including birdshot chorioretinitis, different forms of choroiditis, and panuveitis. In summary, across all indications, there seems to be concrete evidence and therefore recommendations supporting the potential use of infliximab or adalimumab to treat uveitis. Interleukin blockers Daclizumab, a monoclonal antibody directed against the 55k subunit of the IL-2 receptor, has been used to treat uveitis. Initial reports on the use of this agent in patients with uveitis were published in 1999 [90] with subsequent supporting efficacy data [91]. It has now been studied as both an intravenous and subcutaneous mode of administration [92,93]. In a study on the use of daclizumab that included 39 patients with a follow-up of 40 months, 29 patients underwent intravenous administration with the standard regimen, 5 patients received a highdose intravenous regimen, and 5 patients received subcutaneous administration. Visual acuity improved by two lines or more in 7 patients and worsened by two lines or more in 6 patients. There was no statistically significant association between baseline anterior chamber cells, vitreous haze, and vitreous cells. During the treatment period, the mean number of immunosuppressant medications Please cite this article in press as: Schwartzman S, Advancements in the management of uveitis, Best Practice & Research Clinical Rheumatology (2016), http://dx.doi.org/10.1016/j.berh.2016.07.005

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decreased from 1.89 per patient at baseline to 1.17 medications at the end of the follow-up. The mean number of flares was of 2.05 per patient with a rate of 0.62 per patient-year [94]. Therapy targeting IL-17A has thus far not been successful. Secukinumab, a fully human monoclonal antibody that targets interleukin-17A and is approved for psoriasis, psoriatic arthritis, and ankylosing spondylitis, has been studied in uveitis. This medication was studied in three independent studies to evaluate efficacy and safety. A total of 118 patients with Behcet's uveitis (SHIELD study); 31 noninfectious, active non-Behcet's uveitis (INSURE study); and 125 patients with quiescent, noninfectious, non-Behcet's uveitis (ENDURE study) have been studied. Reductions of uveitis recurrence or vitreous haze score during withdrawal of concomitant immunosuppressive medication were the main outcomes studied. The primary efficacy endpoints of the three studies were not met [95]. Interleukin-1 is found in the vitreous fluid of patients with active uveitis [96]. Anakinra, an anti-IL-1 receptor antagonist, has been studied in a small number of patients with uveitis [97,98]. Gevokizumab, a monoclonal antibody that binds to interleukin-1 beta, had been granted Orphan Drug Designation for the treatment of noninfectious intermediate uveitis, posterior uveitis, and panuveitis, or chronic noninfectious anterior uveitis on the basis of a small exploratory study. Seven patients with acute posterior or panuveitis, and/or retinal vasculitis, resistant to azathioprine and/or cyclosporine were enrolled. Immunosuppressive agents were discontinued at the baseline and patients received a single infusion of gevokizumab. All patients responded and no serious adverse events were reported [99]. Larger phase III multicenter studies that were subsequently conducted were not supportive of pursuing an indication for this condition, and Xoma Corporation may halt efforts to seek approval in uveitis. IL-6 has also been identified as one of the cytokines overexpressed in the vitreous fluid of patients with uveitis [100]. Tocilizumab, a monoclonal IL-6 receptor antibody with approved indications in RA, polyarticular JIA, and systemic onset JIA, has been reported as an effective therapy to treat uveitis in a small number of patients. Patients with uveitis and various underlying illnesses who previously failed second-line agents, anti-TNF therapies, and abatacept have been successfully treated with tocilizumab [101,102]. In a series of patients with JIA, Adan reported on five patients with uveitis refractory to conventional therapy, including at least one biologic agent [103]. The patients received tocilizumab (8 mg/kg) every 4 weeks. At the mean follow-up of 8.4 months, 50% of the affected eyes studied showed improvement in visual acuity and 25% remained stable. All patients sustained uveitis remission at 6 months [104]. A current multicenter, randomized study of tocilizumab in intermediate uveitis, posterior uveitis, and panuveitis is currently underway. Sarilumab, a second anti-IL-6 receptor monoclonal antibody that is not yet approved, has completed phase II studies for the treatment of posterior segment noninfectious uveitis. IFN-a has been studied in uveitis, and there are a number of small studies demonstrating efficacy, particularly in multiple sclerosis-associated uveitis. In a retrospective study of Behcet's uveitis unresponsive to conventional immunosuppressive therapy, among 44 patients who had been treated with IFN-a, 36.4% remained relapse free during treatment, whereas 63.6% had recurrent attacks. There was a significant improvement in visual acuity, and this was preserved throughout follow-up in 38 (95%) of 40 patients [105]. In a small prospective study of 12 patients with sight-threatening uveitis that failed to respond to one or more immunosuppressive therapies, IFN-alpha-2b was administered subcutaneously daily. After a mean observational period of 11 months, a favorable clinical response was observed in 83% of patients [106].

Other targets In a small case series, other biologic agents have been used as therapy for uveitis. Abatacept, an agent that blocks the CD 28 co-stimulatory signaling that normally leads to T cell activation, has been used to treat autoimmune uveitis. This agent is currently approved for the treatment of rheumatoid arthritis as both an intravenous and subcutaneous medication. In a series of seven patients with JIA and uveitis, abatacept was found to be efficacious in maintaining clinical remission in six of the seven patients for a period of 9.2 months [107]. The patients were found to have decreased uveitis flares after 6 months of therapy. There have been other smaller series of reports using abatacept to treat uveitis, Please cite this article in press as: Schwartzman S, Advancements in the management of uveitis, Best Practice & Research Clinical Rheumatology (2016), http://dx.doi.org/10.1016/j.berh.2016.07.005

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and interestingly, this medication has been effective in a few patients who did not respond or were intolerant to anti-TNF agents [108e110]. Although the role of B cells is unknown in uveitis, in a pathologic study of an enucleated eye of a patient with JIA-associated uveitis, focal aggregates of CD20-positive cells with CD3 and CD8 positive cells were noted [111]. Therefore, there may be rationale for using anti-B cell therapy in the management of uveitis. In one study of eight patients with JIA-associated uveitis, seven were responders [112]. In another study, 10 patients with JIA and severe uveitis with sight-threatening complications resistant to traditional therapy, including anti-TNF agents, responded after one cycle of rituximab [113]. Conclusion Over the last two decades, an evolving understanding of immunology has led to the development of therapies for autoimmune disease that specifically targets unique cytokines, receptors, and cell surface molecules. The strategy of treating uveitis has also morphed into an approach where early and aggressive intervention is viewed as the therapeutic goal. A recent expert panel has recommended the use of two antiTNF agents, infliximab and adalimumab, as first-line therapy for the treatment of ocular manifestations of Behcet's disease [84]. Adalimumab is now approved to treat some form of uveitis. Other identified targeted therapies including anti-IL1, anti-IL6 receptor, anti-IL17, anti-IL2 receptor, co-stimulatory blockade, interferon, and anti CD-20 B cell are increasingly being evaluated in patients with autoimmune ophthalmic diseases. However, the challenges remain. Clinical trials in uveitis are difficult to perform given the rarity and heterogeneity of this group of illnesses and defining appropriate outcome measures. Uveitis is not a disease, but a phenotypic expression of an abnormality in the immune system. The exact genetic, cellular, and cytokine etiology of specific forms of uveitis need to be better defined, and once this is accomplished, appropriate targets in individual patients with uveitis will be identified. Conflict of interest statement Potential conflict of interest: Abbvie, Genentech, Janssen, Novartis, UCB, Regeneron, Pfizer. References [1] Gritz DC, Wong IG. Incidence and prevalence of uveitis in Northern California; the Northern California epidemiology of uveitis study. Ophthalmology 2004 Mar;111(3):491e500. discussion PubMed PMID: 15019324. *[2] Nussenblatt RB. The natural history of uveitis. Int Ophthalmol 1990 Oct;14(5e6):303e8. PubMed PMID: 2249907. *[3] Groen F, Ramdas W, de Hoog J, et al. Visual outcomes and ocular morbidity of patients with uveitis referred to a tertiary center during first year of follow-up. Eye 2016 Mar;30(3):473e80. PubMed PMID: 26742865. Pubmed Central PMCID: 4791707. [4] Cutolo M, Sulli A, Pizzorni C, et al. Anti-inflammatory mechanisms of methotrexate in rheumatoid arthritis. Ann Rheum Dis 2001 Aug;60(8):729e35. PubMed PMID: 11454634. Pubmed Central PMCID: 1753808. [5] Durrani K, Zakka FR, Ahmed M, et al. Systemic therapy with conventional and novel immunomodulatory agents for ocular inflammatory disease. Surv Ophthalmol 2011 Nov-Dec;56(6):474e510. PubMed PMID: 22117884. *[6] Samson CM, Waheed N, Baltatzis S, et al. Methotrexate therapy for chronic noninfectious uveitis: analysis of a case series of 160 patients. Ophthalmology 2001 Jun;108(6):1134e9. PubMed PMID: 11382642. [7] Ali A, Rosenbaum JT. Use of methotrexate in patients with uveitis. Clin Exp Rheumatol 2010 Sep-Oct;28(5 Suppl. 61): S145e50. PubMed PMID: 21044449. [8] Gangaputra S, Newcomb CW, Liesegang TL, et al. Methotrexate for ocular inflammatory diseases. Ophthalmology 2009 Nov;116(11):2188e2198 e1. PubMed PMID: 19748676. Pubmed Central PMCID: 3785935. [9] Allison AC. Mechanisms of action of mycophenolate mofetil. Lupus 2005;14(Suppl. 1):s2e8. PubMed PMID: 15803924. [10] Deuter CM, Doycheva D, Stuebiger N, et al. Mycophenolate sodium for immunosuppressive treatment in uveitis. Ocul Immunol Inflamm 2009 Nov-Dec;17(6):415e9. PubMed PMID: 20001262. [11] Klisovic DD. Mycophenolate mofetil use in the treatment of noninfectious uveitis. Dev Ophthalmol 2012;51:57e62. PubMed PMID: 22517204. *[12] Thorne JE, Jabs DA, Qazi FA, et al. Mycophenolate mofetil therapy for inflammatory eye disease. Ophthalmology 2005 Aug;112(8):1472e7. PubMed PMID: 16061096. [13] Matsuda S, Koyasu S. Mechanisms of action of cyclosporine. Immunopharmacology 2000 May;47(2e3):119e25. PubMed PMID: 10878286. [14] Nussenblatt RB, Palestine AG, Chan CC. Cyclosporin A therapy in the treatment of intraocular inflammatory disease resistant to systemic corticosteroids and cytotoxic agents. Am J Ophthalmol 1983 Sep;96(3):275e82. PubMed PMID: 6614105. [15] Nussenblatt RB, Palestine AG, Rook AH, et al. Treatment of intraocular inflammatory disease with cyclosporin A. Lancet 1983 Jul 30;2(8344):235e8. PubMed PMID: 6135075.

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Please cite this article in press as: Schwartzman S, Advancements in the management of uveitis, Best Practice & Research Clinical Rheumatology (2016), http://dx.doi.org/10.1016/j.berh.2016.07.005