New observations and emerging ideas in diagnosis and management of non-infectious uveitis: A review

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New observations and emerging ideas in diagnosis and management of non-infectious uveitis: A review James T. Rosenbauma,b,*, Bahram Bodaghic, Cristobal Coutod, Manfred Zierhute, Nisha Acharyaf, Carlos Pavesiog, Mei-Ling Tay-Kearneyh,i, Piergiorgio Nerij, Kevin Douglask, Sophia Pathail, Alexandra P. Songm, Martina Kronn, C. Stephen Fostero,p a

Department of Ophthalmology and Medicine, Oregon Health and Sciences University, Portland, OR, United States Legacy Devers Eye Institute, Portland, OR, United States Department of Ophthalmology, Sorbonne University DHU ViewRestore, AP-HP, Paris, France d Uveitis, Retina and Cornea Clinics, Department of Ophthalmology, University of Buenos Aires, Buenos Aires, Argentina e Centre for Ophthalmology, University Tuebingen, Tuebingen, Germany f Francis I. Proctor Foundation and Department of Ophthalmology and Epidemiology, University of California, San Francisco, CA, United States g Moorfields Eye Hospital and Biomedical Research Center, NHS Foundation Trust, London, United Kingdom h Centre for Ophthalmology and Visual Science (Incorporating the Lions Eye Institute), The University of Western Australia, Nedlands, WA, Australia i Department of Ophthalmology, Royal Perth Hospital, Perth, WA, Australia j The Eye Institute, Cleveland Clinic Abu Dhabi, Abu Dhabi, United Arab Emirates k AbbVie Inc., North Chicago, IL, United States l AbbVie Ltd, Maidenhead, United Kingdom m AbbVie Deutschland GmbH & Co. KG, Knollstraße 67061 Ludwigshafen, Germany n Massachusetts Eye Research and Surgery Institution, Waltham, MA, United States o Ocular Immunology and Uveitis Foundation, Waltham, MA, United States p Harvard Medical School, Boston, MA, United States b c

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Keywords: Adalimumab Biologics Corticosteroid-sparing therapy Immune-mediated disease Noninfectious uveitis

A B S T R A C T

Background: Non-infectious uveitis (NIU) is an immune-mediated disease with clinical symptoms such as eye pain, redness, floaters, and light sensitivity. NIU is one of the leading causes of preventable blindness. Objective: This review describes current and emerging therapies for NIU. Methods: PubMed searches were conducted using the terms uveitis, therapy, corticosteroids, immunomodulators, biologics, intravitreal injections, intraocular implants, and adverse events deemed relevant if they presented data relating to prevalence, diagnosis, and treatment of uveitis. Results: Diagnosis and management of NIU may require collaboration among different healthcare providers, including ophthalmologists and rheumatologists. Although many patients with NIU respond to corticosteroid (CS) therapy, long-term CS use can be associated with potentially severe adverse events. Localized CS therapies have been developed to reduce adverse events; however, some intravitreal injections and intraocular implants were linked to elevated intraocular pressure and cataracts. CS-sparing therapies such as biologics have demonstrated efficacy and safety while reducing CS burden. Biologics targeting tumor necrosis factor provide CS-sparing options for patients with NIU. Additional studies are needed to address long-term efficacy and safety of biologics targeting IL-6 and inhibitors of JAK/STAT.

Abbreviations: AE, adverse event; BCVA, best corrected visual acuity; CS, corticosteroids; DUET, Dublin Uveitis Evaluation Tool; ETDRS, Early Treatment Diabetic Retinopathy Study; HLA, human leukocyte antigen; IL, interleukin; IOP, intraocular pressure; JAK/STAT, Janus kinase/signal transducers and activators of transcription; JIA, juvenile idiopathic arthritis; NIU, non-infectious uveitis; SpA, spondyloarthritis; SUN, Standardization of Uveitis Nomenclature; TF, treatment failure; TNF, tumor necrosis factor; TTF, time to treatment failure Declaration of interest: CSF has served as a consultant for Aldeyra, Bausch & Lomb Surgical, EyeGate, Novartis, pSivida, and Xoma; has served as a paid speaker for Alcon and Allergan; and has received grants or has grants pending from Alcon, Aldeyra, Bausch & Lomb, Clearside Biomedical, Dompe, Icon, Novartis, Santen, Xoma, Aciont, and pSivida. JTR was a consultant for AbbVie, Gilead, Regeneron, UCB, Novartis, Topivert, Janssen, Roche, Santen, and Eyevensys; has received financial support from Pfizer; owns stock in Novartis and has received royalties from UpToDate. BB has served on the advisory boards of AbbVie, Allergan, and Santen and has received financial support from Novartis, Bayer, and Roche. CC has nothing to disclose. MZ has served on scientific advisory boards for AbbVie and Santen. NA has served as a consultant for AbbVie and Santen. CP has received a research grant from Alcon; has served as a consultant for Xoma, Servier, and Santen; and has served on the advisory board for Xoma, Servier, Santen, Alcon, and Bausch & Lomb. MLTK was an investigator in the HURON clinical trial for AbbVie and has received speaking fees from AbbVie. PN has served as a consultant for AbbVie, Santen, and Allergan. KD and APS are employees of AbbVie Inc. SP is an employee of AbbVie Ltd. UK. MKron is an employee of AbbVie Deutschland GmbH & Co KG. Funding source: This review was sponsored by AbbVie Inc. (North Chicago, IL). The sponsor participated in the manuscript preparation, review, and approval. * Corresponding author at: Legacy Devers Eye Institute, 1040 NW 22nd Ave, Suite 200, Portland, OR 97210, United States. E-mail address: [email protected] (J.T. Rosenbaum). https://doi.org/10.1016/j.semarthrit.2019.06.004 0049-0172/© 2019 Published by Elsevier Inc.

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Conclusion: Biologics, JAK/STAT inhibitors, and improved localized therapies may provide additional options for patients with NIU. © 2019 Published by Elsevier Inc.

Introduction Uveitis refers to a diverse group of intraocular inflammatory diseases of the uvea (i.e., the iris, ciliary body, and choroid) and adjacent structures, including the cornea, vitreous humor, retina, and optic nerve. Uveitis is one of the leading causes of preventable blindness in the United States [1,2], and account for 15% of the causes of total blindness in Western countries [3]. Among patients treated for uveitis in academic ophthalmology clinics and referral centers, 20% to 70% experience major vision loss [4]. Up to 50% of patients will experience reduced visual function, and 10% to 15% will become blind [1,5,6]. Studies have shown a strong correlation between delayed treatment and the likelihood of poor visual outcomes [7,8]. Vision loss associated with uveitis has a negative impact on quality of life and activities of daily living [9,10]. Uveitis can be classified based on the primary anatomical site of inflammation (i.e., anterior, intermediate, and posterior; Fig. 1). Panuveitis is the inflammation of all 3 components of the uvea [11]. Uveitis also may be categorized by etiologic origin, including infectious (e.g., bacterial, viral, fungal causes), non-infectious (known or unknown systemic causes), or masquerade (neoplastic or non-neoplastic causes) [12]. The Standardization of Uveitis Nomenclature (SUN) Working Group has provided additional descriptors of the disease, such as onset (sudden or insidious), duration (limited [3 months] or persistent [>3 months]), and course (acute, recurrent, or chronic) [13]. This review focuses on non-infectious uveitis (NIU). Reported prevalence and incidence estimates vary widely, largely owing to the heterogeneity of the disease and differences in diagnostic work-up [14]. Moreover, different study designs and case ascertainment methods result in estimates that vary by geographic region, age, race/ethnicity, and disease origin. Prevalence estimates better reflect patients at risk for developing ongoing disease, whereas incidence estimates likely reflect the population at risk for experiencing a first episode of uveitis. In a northern California epidemiology study, uveitis prevalence was estimated to be 115/ 100,000 people, and incidence ranged from 47.1 to 52.4/100,000 person-years [15]. NIU prevalence estimates based on administrative claims from 14 million privately insured individuals throughout the United States was 121/100,000 people [16]. Anterior uveitis is the most common form of uveitis [17]. Based on the results from the

US retrospective claims analysis, anterior NIU made up 81% of all NIU cases, with a prevalence of 98/100,000 adults; non-infectious intermediate, posterior, and panuveitis were 0.9% (prevalence, 1/100,000), 8.6% (prevalence, 10/100,000), and 9.6% (12/100,000), respectively [16]. Methods Literature searches were conducted using the PubMed engine with combinations of search terms including uveitis, therapy, corticosteroids, immunomodulators, biologics, intravitreal injections, intraocular implants, and adverse events. Search results were screened for relevance; articles (full papers, short communications, abstracts, and review articles) were deemed relevant if they presented data on prevalence, diagnosis, and treatment of uveitis. Additional papers were identified using reference citations from the articles obtained in the initial searches. Search results were supplemented based on authors’ expertise and knowledge of the literature. This manuscript provides a descriptive review of the literature search results and interpretation by the authors. Diagnosis Diagnosis of uveitis can be challenging; a multi-disciplinary approach is needed to improve identification and management of patients with NIU. Specifically, closer collaboration between ophthalmologists and rheumatologists, who play a major role in diagnosing and providing an appropriate treatment for patients with systemic immune disease, may benefit long-term outcomes. Non-infectious uveitis is an immune-mediated ocular disease that can be associated with systemic diseases such as inflammatory bowel disease and sarcoidosis (Table 1) [18,19]. Patients with noninfectious intermediate, posterior, or panuveitis present an increased risk of developing glaucoma, cataract, visual disturbance, retinal detachment, and other retinal disorders, as well as blindness or low vision [4]. In anterior uveitis, which includes iritis and iridocyclitis, the anterior chamber is the primary site of inflammation (Table 2) [13]. Clinical signs and symptoms can include corneal findings (such as keratic precipitates), pupillary changes, anterior and posterior synechiae,

Fig. 1. Classification of uveitis by inflammation site: anterior, intermediate, and posterior uveitis.

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Differential diagnosis

Table 1 Systemic diseases associated with uveitis Autoimmune disease

Most commonly associated uveitis

Estimated prevalence

Spondyloarthritis Inflammatory bowel disease Psoriatic arthritis

Anterior Anterior and/or intermediate Anterior and/or intermediate Anterior

10% 50% 2% 12%

Intermediate Anterior/intermediate/ panuveitis

1% 10% 20% develop eye disease (30% 50% develop uveitis in bone sarcoidosis) 67% of patients present with anterior uveitis 90% (ocular involvement)

Juvenile idiopathic arthritis Multiple sclerosis Sarcoidosis

Beh¸c et’s disease Vogt-Koyanagi-Harada disease

3

7% 10% 30%

Posterior and panuveitis Anterior (less common) Panuveitis Posterior uveitis (with thickening of the choroid, and serous retinal detachments)

Table 2 Classification of uveitis by primary anatomic site of inflammation Classification

Primary site of inflammation

Includes

Anterior

Anterior chamber

Intermediate Posterior

Vitreous humor Retina and/or choroid

Panuveitis

Anterior chamber, vitreous humor, retina, and/or choroid

 Iritis (iris)  Iridocyclitis (iris and ciliary body)  Pars planitis (pars plana)  Focal, multifocal, or diffuse choroiditis  Retinal vasculitis  Iritis (iris)  Iridocyclitis (iris and ciliary body)  Pars planitis (pars plana)  Focal, multifocal, or diffuse choroiditis

Adapted from Jab DA, et al. Am J Ophthalmol 2005;140:510 [13].

redness, pain, blurred vision, light sensitivity, and floaters [20]. Representative associated systemic diseases include juvenile idiopathic arthritis (JIA), ankylosing spondylitis, Beh¸c et’s disease, sarcoidosis, tubulointerstitial nephritis and uveitis (TINU), and inflammatory bowel disease [21]. In intermediate uveitis, the primary site of inflammation is the vitreous humor (Table 2) [13]. Clinical symptoms include blurry vision, floaters, and light sensitivity. Representative origins include malignancies, sarcoidosis, and multiple sclerosis [21]. Pars planitis corresponds to the idiopathic form of intermediate uveitis and is characterized by the presence of “snowbanks” (white exudates over the pars plana and ora serrata) and “snowballs” (aggregates of inflammatory cells in the vitreous). In posterior uveitis, the primary sites of inflammation are the retina and/or choroid and include focal, multifocal, or diffuse presentations of choroiditis (Table 2) [13]. Clinical symptoms include floaters, and there is usually no pain or redness. Representative associated diseases include autoimmune disorders, Beh¸c et’s disease, and sarcoidosis [21]. In panuveitis, the anterior chamber, vitreous humor, and retina and/or choroid are involved (Table 2) [13]. Clinical symptoms include floaters, pain, redness, and light sensitivity. Representative associated diseases include autoimmune disorders, sarcoidosis, Vogt-KoyanagiHarada syndrome, and Beh¸c et’s disease [22].

Differential diagnosis of NIU is affected by various factors, including geographic, environmental, and demographic. Diagnosis can be a challenge because the cause is often not apparent [23]. Differential diagnosis also depends on the recognition that uveitis is not a single disease but is considered a group of syndromes based on its potential associations with primary ocular conditions as well as systemic inflammatory diseases [19,23]. Idiopathic uveitis is the most common diagnosis of patients with NIU; however, it is critical that infections or other masquerade syndromes (such as malignancy) are ruled out first. In the Dublin Uveitis Evaluation Tool (DUET) study, Haroon et al. found that by administering an algorithm to a validation cohort of 74 patients with idiopathic acute anterior uveitis, 40% had undiagnosed spondyloarthritis (SpA) [17]. Additionally, anterior uveitis can be associated with sarcoidosis, JIA, inflammatory bowel disease, and TINU [24 28]. These findings highlight the importance of collaboration among specialists, including ophthalmologists and rheumatologists. To this end, the SENTINEL study was initiated to increase such collaboration, with the aim of improving the management of patients with anterior uveitis and facilitating the timely diagnosis of underlying SpA. By describing and analyzing the prevalence of SpA in patients with anterior uveitis, investigators found that among the 798 patients with anterior uveitis, 50% and 18% were diagnosed with axial and peripheral SpA, respectively, per Assessment of SpondyloArthritis International Society criteria [29]. Moreover, the proportion of patients with SpA, and in particular axial SpA, was higher in patients who had HLA-B27 positive anterior uveitis versus those who had recurrent HLA-B27 negative anterior uveitis (71% vs 20%, respectively; P < 0.0001). Peripheral SpA was also more frequent in patients who were HLA-B27 positive versus HLA-B27 negative (22% vs 11%, respectively; P < 0.0001). However, either axial or peripheral arthritis were common among patients who were HLA-B27 negative with recurrent anterior uveitis. Intermediate uveitis is associated with sarcoidosis, multiple sclerosis, and infectious conditions (i.e., Lyme disease) [30], whereas posterior and panuveitis may be associated with sarcoidosis, VogtKoyanagi-Harada syndrome, and Beh¸c et’s disease, as well as bacterial (i.e., tuberculosis), fungal, and viral infections [22]. Anterior uveitis can be associated with infectious conditions caused by herpes simplex virus, varicella zoster virus, and cytomegalovirus [31]. Laboratory tests (e.g., urinary b2 microglobulin) and polymerase chain reaction analysis may be used to identify tubulo-interstitial nephritis, sarcoidosis, and infectious uveitis [32,33]. Because uveitis can encompass a diverse group of syndromes, selecting appropriate disease-specific endpoints in uveitis clinical studies can be challenging. Endpoints that assess therapeutic effectiveness need to be applicable to patients with different types of uveitis and may not fit all diagnoses equally. For example, different endpoints would be needed for studies in patients with uveitis associated with JIA versus patients with pars planitis [34]. Collaboration between ophthalmologists and rheumatologists plays a primary role in facilitating the understanding of NIU and associated systemic immune-mediate diseases, as well as providing appropriate diagnostics methods and improving long-term outcomes in patients with NIU. Disease management The goals of therapy for NIU are to reduce inflammation and attain complete remission, thereby mitigating or avoiding ocular complications, permanent cumulative damage, and long-term vision loss [35,36]. NIU severity can be assessed based on the graded variables corresponding to inflammation of the anterior segment of the eye and vitreous. Inflammation of the anterior segment of the eye (i.e.,

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anterior chamber cell grade) is scored on a scale of 0 to 4+ according to the SUN Working Group criteria, whereby a higher score indicates greater disease severity [13]. Inflammation of the vitreous (i.e., vitreous haze grade) is scored on a scale of 0 to 4+ according to National Eye Institute criteria adapted by the SUN Working Group, in which a higher score indicates greater severity [37]. Further evidence of inflammation can be seen as the number of active inflammatory lesions in the choroid or retina increase, in which a greater number of inflammatory lesions corresponds to greater disease severity. Visual acuity can also be a quantifiable outcome in NIU clinical studies [13]. Visual acuity can be quantified using an Early Treatment Diabetic Retinopathy Study (ETDRS) logMAR chart, where logMAR of 0 is equivalent to Snellen chart of 20/20 in feet (6/6 in meters). According to the World Health Organization and the International Council of Ophthalmology, the range for normal vision is between 0.1 and 0.2 logMAR (Snellen 20/25 to 20/12.5) and low vision (i.e., worse) is between 0.5 and 1.3 logMAR (Snellen 20/63 to 20/400). Log MAR of 1.0 (Snellen 20/200) corresponds to legally blind in the United States [38,39]. General therapeutic progression for treating patients with noninfectious uveitis is (1) topical corticosteroids (especially for anterior uveitis), (2) systemic treatment with low-dose corticosteroids (i.e., prednisone) or high-dose oral or intravenous corticosteroids for patients with severe uveitis, (3) systemic immunomodulators (i.e., T-cell inhibitors or antimetabolites), and (4) biologics (i.e., adalimumab or infliximab; Fig. 2) [40,41]. The specifics of the treatment will also depend on the clinical form of non-infectious uveitis (i.e., acute episode, inter-outbreak phase, or chronic). Short-term therapy will be more aggressive for patients with acute uveitis and may involve higher-dose corticosteroids, while a therapeutic plan that aims to control inflammation with the lowest possible doses of drugs to minimize side effects will be used in patients with recurrent episodes or chronic uveitis [42]. Conventional therapy Patients with NIU typically receive first-line therapy with corticosteroids (CS) to control inflammation [43]; oral prednisone is a commonly used systemic CS. The typical maintenance dose is 7.5 mg/d to minimize systemic toxicity [44]; however, higher doses up to 60 to 80 mg/d are sometimes required (used in the acute phase and typically corresponds to the 1- to 1.5-mg/kg dose) [43]. Once the antiinflammatory response is achieved, the dose is gradually tapered. High-dose methylprednisolone (Solu-Medrol; Pfizer Inc, New York, NY, USA) can be administered intravenously to deliver 1000 mg/d, usually over 3 days, when a rapid response is essential [45]. The use of high-dose systemic CS is critical for achieving immediate control of inflammation, but immunosuppressive agents also may

Fig. 2. Guidelines for management of non-infectious uveitis.

be required to (1) attain complete remission owing to disease severity or chronic flares and (2) reduce CS doses to avoid adverse effects and potential complications [43]. Although complete remission is the desired outcome, it is difficult to achieve, and the main use of immunosuppressants is to reduce steroid exposure. In patients taking oral systemic CS to control disease, a daily dose >7.5 mg administered chronically can contribute to long-term adverse effects [36,46]. Thus, immunosuppressive therapy is recommended as a CS-sparing approach when inflammation cannot be controlled with oral systemic CS 7.5 to 10 mg/d within 3 months [13,36,43]. Immunosuppressants used to supplement systemic CS and reduce the CS burden include antimetabolites (azathioprine, methotrexate, mycophenolate mofetil), T-cell inhibitors (cyclosporine, tacrolimus), and alkylating agents (cyclophosphamide, chlorambucil). Although the latter are rarely used because of higher risk of serious complications, especially in young patients [47,48], a number of studies have demonstrated therapeutic efficacy of cyclophosphamide and chlorambucil in patients with NIU [49 52]. To avoid adverse events (AEs) associated with systemic therapies, localized treatment such as intravitreal injection or intraocular implants have been developed. In small retrospective studies (54 and 44 patients, respectively), intravitreal CS injections, such as triamcinolone acetate (Bristol-Meyers Squibb, Middlesex, UK, and Alcon, Fort Worth, TX, USA) at 4 mg/0.1 mL improved visual acuity in patients with uveitic cystoid macular edema, a complex retinal condition that represents a major cause of visual loss. However, these therapies were associated with an elevated intraocular pressure (IOP), for which approximately half of the eyes required IOP-lowering medication, and progression of cataract [53,54]. Additionally, the improvements in visual acuity have been reported to have a limited duration, and repeat injections may be needed [53,54]. Other local therapies include CS-delivering technologies that use intravitreal sustained-release implants and inserts. Retisert implants (Bausch & Lomb, Rochester, NY, USA) contain 0.59 mg fluocinolone acetonide and release it for up to 3 years at a rate of approximately 0.5 mg/d. Although Retisert reduced the rates of non-infectious posterior uveitis recurrences in the 34-week study and the 3-year followup, the implants were associated with complications [55,56]. The 3-year follow-up study of 278 patients found that at least two-thirds of all eyes treated with Retisert had IOP elevated by 10 mmHg from baseline. A significantly higher proportion of eyes treated with Retisert required IOP-lowering medication compared with control eyes (78% vs 36%; P < 0.01); glaucoma surgery was also significantly more common in eyes with Retisert versus those without Retisert (40% vs 2%; P < 0.01). Additionally, almost all patients developed cataracts within 3 years after implantation [55]. A 7-year follow-up study of 255 patients found that those who received systemic therapy had better visual acuity compared with those who received a fluocinolone acetonide implant; additionally, 45% of eyes with implants had surgery to lower IOP, and 90% of eyes with implants had cataract surgery [57]. Iluvien insert (Alimera Sciences, Alpharetta, GA, USA) releases 0.2 or 0.5 mg/d fluocinolone acetonide for 3 years and has been shown to improve visual acuity in patients with diabetic macular edema; however, a significant proportion of patients receiving Iluvien versus those receiving control experienced elevated IOP (37% [low dose] and 46% [high dose] vs 12% [control]) or required cataract surgery (80% [low dose] and 87% [high dose] vs 27% [control]) in a 3-year followup of 956 patients with diabetic macular edema [58,59]. At the time of this report, Iluvien was not approved for the treatment of NIU. Ozurdex (Allergan Inc., Irvine, CA, USA) implant delivers 700 mg dexamethasone over 6 months; 6-month studies showed that it improved vitreous haze and visual acuity in patients with non-infectious intermediate or posterior uveitis (n = 229) [60,61]. The percentage of patients with IOP 25 mmHg was < 10% across all treatment groups; IOP-lowering medication was required for 23%

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of patients receiving 700-mg Ozurdex. Additionally, cataract formation was not significantly different in eyes treated with or without Ozurdex (12% [low dose] and 15% [high dose] vs 7% [control]; P = 0.769) [61]. Sirolimus (Santen Pharmaceutical, Osaka, Japan) is a locally injected immunosuppressant delivered intravitreally or subconjunctivally that blocks T-cell activation and proliferation. In a prospective, open-label study in patients with NIU (Sirolimus as a Therapeutic Approach for Uveitis; SAVE), there were improvements in vitreous haze grade in all patients and visual acuity improvement in about 30% of patients who received sirolimus [62]. The phase 3 Sirolimus Study Assessing Double-masKed Uveitis TreAtment (SAKURA) assessed efficacy and safety of intravitreal sirolimus in 347 patients with NIU and found improvement in vitreous haze grade; ocular AEs included iridocyclitis and elevated IOP [63]. This therapy is not currently approved by the US Food and Drug Administration. Additional clinical trials, including a phase 2 trial (SAVE-2) and a phase 3b extension of the SAKURA trial, will further assess safety and efficacy of sirolimus in patients with NIU [64]. Biologics The anti-tumor necrosis factor (TNF) agents provide alternative or concurrent options to immunomodulators as CS-sparing therapies to treat patients with NIU [48,65]. Adalimumab (AbbVie Inc., North Chicago, IL, USA), a human monoclonal antibody that blocks TNF-a signaling, has been approved for the treatment of non-infectious intermediate, posterior, and panuveitis [66]. The efficacy and safety of adalimumab have been assessed in randomized, controlled clinical trials [67,68]. The multicenter placebo-controlled VISUAL I trial assessed efficacy and safety of adalimumab as a CS-sparing therapy in adult patients with active non-infectious intermediate, posterior, and panuveitis (n = 223) [67]. Patients with active uveitis had 1 active inflammatory lesion, inflammation of the anterior segment of the eye (anterior chamber cell grade of 2+ or higher), or inflammation of the vitreous (vitreous haze grade of 2+ or higher) despite the use of corticosteroids for >2 weeks. Patients received placebo or adalimumab (80-mg loading dose, 40-mg dose every 2 weeks starting at week 1). Time to treatment failure (TTF), defined as inability to achieve anterior chamber cell grade or vitreous haze grade of 0 to 0.5 or worsening of anterior chamber or vitreous inflammation, new chorioretinal or retinal vasculitis lesion, or worsening of best corrected visual acuity (BCVA) was the primary outcome measure. After an initial 60-mg prednisone burst, patients were tapered to 0 mg CS by week 15 [67]. With CS discontinuation, adalimumab was shown to be an effective therapy in patients with active intermediate, posterior, or panuveitis. Adalimumab therapy reduced the risk of treatment failure (TF) by 50% (hazard ratio, 0.50; P < 0.001) and resulted in longer median TTF (24 vs 13 weeks in patients receiving adalimumab vs placebo, respectively). Additionally, adalimumab significantly reduced the worsening of the anterior chamber cell grade, vitreous haze grade, and BCVA compared with placebo (P  0.01) [67]. In the adalimumab group, there were 18 serious AEs (28.8 events/100 patient years [PY]); 6 of these (9.6 events/100 PY) were considered to be possibly related to adalimumab by investigators. Additionally, patients receiving adalimumab experienced 5 serious infections (8.0 events/100 PY), 2 malignancies (3.2 events/100 PYs), 1 event of active tuberculosis (1.6 events/100 PYs), and 1 event of latent tuberculosis (1.6 events/100 PYs). The placebo group experienced 6 serious AEs (13.6 events/100 PY) and 3 serious infections (6.8 events/100 PYs); there were no reports of malignancies or tuberculosis. Although patients receiving adalimumab experienced more treatment-related and serious AEs compared with patients receiving placebo, no unexpected safety signals were detected compared with other indications [67].

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The VISUAL II clinical trial addressed efficacy and safety of adalimumab as a CS-sparing therapy for preventing reactivation of uveitis in adults with inactive non-infectious intermediate, posterior, or panuveitis (n = 229) who received CS doses higher than the recommended maintenance therapy. Patients with inactive uveitis had no active inflammatory lesions, an anterior chamber cell grade 0.5+, and a vitreous haze grade 0.5+. Patients were dependent on 10 to 35 mg/d prednisone for maintaining inactive uveitis before the initiation of the study; CS were then tapered to 0 mg by week 19 [68]. Adalimumab therapy reduced the risk of TF in patients with inactive uveitis (hazard ratio, 0.57; P = 0.004) and resulted in longer median TTF (>18 vs 8.3 months in patients receiving adalimumab vs placebo, respectively). Based on the exploratory analyses, patients receiving adalimumab significantly improved TTF due to visual acuity compared with placebo (hazard ratio, 0.33; P = 0.002). Time to TF due to new active inflammatory lesions, increases in anterior chamber cell grade, and increases in vitreous haze grade were numerically lower in patients receiving adalimumab versus placebo, but were not significantly different. Patients receiving adalimumab and placebo had similar rates of AEs, serious AEs, and AEs leading to discontinuation [68]. Patients receiving adalimumab experienced 1 malignancy (1.1 events/100 PY) and 3 events of latent tuberculosis (3.2 events/ PY); patients receiving placebo experienced no malignancies and 1 event of latent tuberculosis (1.4 events/100 PY) [68]. Long-term efficacy and safety of adalimumab in adult patients with NIU (n = 424) were addressed in a multicenter, open-label clinical trial extension (VISUAL III) [69]. Results were analyzed through 78 weeks of follow-up, and adalimumab was assessed as a CS-sparing therapy. Patients were stratified by active (defined as patients who experienced TF in VISUAL I or VISUAL II trials) or inactive (defined as patients who completed the VISUAL I or II trials without TF) uveitis at study entry. Patients were permitted to initiate, continue, escalate, or taper concomitant therapy with CS and/or immunosuppressants while receiving 40 mg adalimumab every other week [69]. At week 78, about three-quarters of patients with active uveitis at VISUAL III entry achieved quiescence (defined as no active inflammatory lesions, anterior chamber cell grade 0.5+, and vitreous haze grade 0.5+) with no or low-dose (7.5 mg/day) systemic CS. Overall, 80% of patients were in quiescence at week 78 with no or low-dose uveitis-related CS. Additionally, adalimumab therapy improved BCVA in patients with active uveitis and maintained stable BCVA in patients with inactive uveitis throughout follow-up [69]. In the VISUAL III study, there were 157 serious AEs (16.5 events/100 PY); 36 of these (3.8 events/100 PY) were considered to be at least possibly related to adalimumab by the investigators. Additionally, there were 38 serious infections (4.0 events/100 PY), 12 malignancies (1.3 events/PY), 1 event of active tuberculosis (0.1 events/100 PY), and 15 events of latent tuberculosis (1.6 events/PY). No new safety signals were identified in this clinical trial extension [69]. Currently, there are limited adalimumab studies in pediatric populations with NIU. In a study of 90 pediatric patients receiving concomitant methotrexate, adalimumab was shown to be highly effective in patients with JIA-associated uveitis, which is primarily an anterior uveitis (SYCAMORE trial). Adalimumab therapy resulted in a significantly longer TTF, reducing the risk of treatment failure by 75% in the adalimumab group compared with the placebo group (hazard ratio, 0.25; P < 0.0001) and a reduction in the daily dose of glucocorticoids (P = 0.04) [70]. Another prospective, randomized, multicenter study (ADJUVITE; n = 32) has also shown adalimumab efficacy in patients with early onset idiopathic or JIA-associated chronic anterior uveitis. Ocular inflammation, evaluated by laser flare photometry, was significantly reduced in the adalimumab group as early as 2 months after initiation [71]. Recommendations derived from a comprehensive review of the literature before the approval of adalimumab suggested that infliximab (Janssen Biotech, Horsham, PA, USA) or adalimumab were the

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preferred therapies for the treatment of ocular inflammatory disease, whereas there have been reports of uveitis exacerbations in children with JIA receiving etanercept (Amgen, Thousand Oaks, CA, USA) [72]. Additionally, a registry-based study found that etanercept has been linked with a higher number of reported uveitis cases compared with infliximab (P < 0.001; odds ratio, 5.375) [73]. The use of adalimumab as a CS-sparing systemic therapy was supported and received recommendation level A in a recently published guidance for the treatment of NIU provided by the Fundamentals Of Care for UveitiS (FOCUS) initiative [48]. Infliximab received recommendation level B/C; however, the FOCUS initiative reported there was no evidence to support etanercept therapy in patients with NIU [48]. In some studies, infliximab and adalimumab had similar efficacy, demonstrating equivalent response rates and providing CS-sparing inflammation control in patients with chronic NIU [74,75]. In the case of intravitreal application of infliximab, retinotoxicity has been observed, resulting in a call for a moratorium on the use of intravitreal infliximab outside of research studies [76 78]. Mixed results have been reported in patients with Beh¸c et’s disease related uveitis. A small study of infliximab treatment in patients (n = 23) with Beh¸c et’s disease found that more than half developed 1 episode of recurrent uveitis during treatment [79]. However, another study reported a reduction of frequency of ocular inflammatory attacks in patients with Beh¸c et’s disease receiving infliximab. In this study, patients who received treatment for 12 to 24 months (n = 43), 24 to 36 months (n = 62), 36 to 48 months (n = 42), and >48 months (n = 17) had a significantly lower frequency of ocular inflammatory attacks in the recent year compared with the year before infliximab treatment (P < 0.05) [80]. Recent guidelines recommend infliximab therapy in patients with Beh¸c et’s disease and acute sight-threatening uveitis; adalimumab could be an effective alternative to infliximab in some patients [81]. Other biologics that are being tested in patients with NIU include interleukin (IL) 6 receptor inhibitors such as tocilizumab (Roche, Nutley, NJ, USA) or sarilumab (Sanofi-Aventis, Bridgewater, NJ, USA). In the phase 1/2 STOP-Uveitis randomized clinical trial (n = 37), patients receiving 4 or 8 mg/kg intravenous tocilizumab for 6 months showed improvements in visual acuity and a reduction in vitreous haze; tocilizumab was well tolerated, and no unexpected AEs were detected [82]. Sarilumab has been previously shown to improve outcomes in patients with moderate to severe rheumatoid arthritis [83] and has been recently approved for the treatment of moderately to severely active rheumatoid arthritis in the United States, European Union, and Canada [84 86]. However, sarilumab has not been effective in patients with ankylosing spondylitis [83,87]. The SATURN study, a multicenter, phase 2 clinical trial addressing efficacy and safety of sarilumab in patients with NIU [64], was recently completed. Interferon-a therapy has been shown to be effective in patients with Beh¸c et’s disease and other causes of uveitis [88,89]. The efficacy and safety of secukinumab (Novartis Pharmaceutical, Basel, Switzerland), an IL-17A inhibitor, have been demonstrated in a phase 2 clinical trial in patients with NIU (n = 37) [90]. However, secukinumab failed to meet the primary efficacy endpoints in phase 3 trials (SHIELD, n = 118; INSURE, n = 31; and ENDURE, n = 125); no significant differences were observed in recurrence of uveitis or vitreous haze scores in patients receiving secukinumab versus placebo [91]. Additionally, a multicenter, randomized controlled study using filgotinib, a small molecule JAK/STAT inhibitor, to treat patients with NIU, is ongoing at the time of this publication. Conclusion Uveitis represents a group of diseases with complex etiologic origins and clinical symptoms that may include eye pain, redness, floaters, and light sensitivity. Collaboration among health providers, specifically, ophthalmologists and rheumatologists, is needed to

improve management of patients with NIU and help identify previously undiagnosed conditions associated with uveitis, as demonstrated in the SENTINEL and DUET studies [17,29]. Although CS have been the mainstay therapy for patients with NIU, potential serious AEs associated with long-term systemic CS use highlight the need for additional therapies allowing patients to reduce their dependence on CS. CS-sparing therapies that demonstrate efficacy combined with a more favorable safety profile can be used to reduce CS burden in patients with NIU. Adalimumab has been shown to be effective in reducing the daily CS dose in adult patients while significantly increasing TTF and enabling most patients with non-anterior NIU to achieve or maintain quiescence. To date, adalimumab is the only biologic approved for the treatment of NIU. Other biologics targeting signaling molecules involved in the immune response (e.g., IL-6) may provide additional options for patients with NIU; further studies are needed to address long-term efficacy and safety of tocilizumab and sarilumab [64,82]. Future studies are also needed to optimize localized treatments to avoid elevated IOP and cataract associated with some intravitreal injections and intraocular implants. An appreciation of the interplay between uveitis and systemic inflammatory diseases will help ophthalmologists and rheumatologists to better treat their patients. Acknowledgments Medical writing support was provided by Natalia Zhukovskaya, PhD, of Complete Publication Solutions, LLC (North Wales, PA) and was funded by AbbVie Inc. AbbVie is committed to responsible data sharing regarding the clinical trials we sponsor. This includes access to anonymized, individual and trial-level data (analysis data sets), as well as other information (e.g., protocols and Clinical Study Reports), as long as the trials are not part of an ongoing or planned regulatory submission. This includes requests for clinical trial data for unlicensed products and indications. This clinical trial data can be requested by any qualified researchers who engage in rigorous, independent scientific research, and will be provided following review and approval of a research proposal and Statistical Analysis Plan (SAP) and execution of a Data Sharing Agreement (DSA). Data requests can be submitted at any time and the data will be accessible for 12 months, with possible extensions considered. For more information on the process, or to submit a request, visit the following link: https://www.abbvie.com/ourscience/clinical-trials/clinical-trials-data-and-information-sharing/ data-and-information-sharing-with-qualified-researchers.html. References [1] Durrani OM, Tehrani NN, Marr JE, Moradi P, Stavrou P, Murray PI. Degree, duration, and causes of visual loss in uveitis. Br J Ophthalmol 2004;88:1159–62. [2] Siddique SS, Shah R, Suelves AM, Foster CS. Road to remission: a comprehensive review of therapy in uveitis. Expert Opin Investig Drugs 2011;20:1497–515. [3] Denniston AK, Holland GN, Kidess A, Nussenblatt RB, Okada AA, Rosenbaum JT, et al. Heterogeneity of primary outcome measures used in clinical trials of treatments for intermediate, posterior, and panuveitis. Orphanet J Rare Dis 2015;10:97. [4] Dick AD, Tundia N, Sorg R, Zhao C, Chao J, Joshi A, et al. Risk of ocular complications in patients with noninfectious intermediate uveitis, posterior uveitis, or panuveitis. Ophthalmology 2016;123:655–62. [5] Miserocchi E, Modorati G, Mosconi P, Colucci A, Bandello F. Quality of life in patients with uveitis on chronic systemic immunosuppressive treatment. Ocul Immunol Inflamm 2010;18:297–304. [6] Vavvas D, Foster CS. Immunomodulatory medications in uveitis. Int Ophthalmol Clin 2004;44:187–203. [7] Dana MR, Merayo-Lloves J, Schaumberg DA, Foster CS. Prognosticators for visual outcome in sarcoid uveitis. Ophthalmology 1996;103:1846–53. [8] Krzystolik M, Power WJ, Foster CS. Diagnostic and therapeutic challenges of sarcoidosis. Int Ophthalmol Clin 1998;38:61–76. [9] Schiffman RM, Jacobsen G, Whitcup SM. Visual functioning and general health status in patients with uveitis. Arch Ophthalmol 2001;119:841–9.

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