Expert Panel Recommendations for the Use of Anti–Tumor Necrosis Factor Biologic Agents in Patients with Ocular Inflammatory Disorders

Expert Panel Recommendations for the Use of AntieTumor Necrosis Factor Biologic Agents in Patients with Ocular Inflammatory Disorders Grace Levy-Clarke, MD,1 Douglas A. Jabs, MD, MBA,2 Russell W. Read, MD, PhD,3 James T. Rosenbaum, MD,4,5 Albert Vitale, MD,6 Russell N. Van Gelder, MD, PhD7 Purpose: To provide recommendations for the use of anti-tumor necrosis factor a (TNF-a) biologic agents in patients with ocular inflammatory disorders. Background: Ocular inflammatory diseases remain a leading cause of vision loss worldwide. AntieTNF-a agents are used widely in treatment of rheumatologic diseases. A committee of the American Uveitis Society performed a systematic review of literature to generate guidelines for use of these agents in ocular inflammatory conditions. Methods: A systematic review of published studies was performed. Recommendations were generated using the Grading of Recommendations Assessment, Development, and Evaluation group criteria. Results: Numerous studies including controlled clinical trials have demonstrated that antieTNF-a biologic agents (in particular infliximab and adalimumab) are effective in the treatment of severe ocular inflammatory disease. Based on these studies, the expert panel makes the following recommendations. Conclusions: Infliximab and adalimumab can be considered as first-line immunomodulatory agents for the treatment of ocular manifestations of Behçet’s disease. Infliximab and adalimumab can be considered as secondline immunomodulatory agents for the treatment of uveitis associated with juvenile arthritis. Infliximab and adalimumab can be considered as potential second-line immunomodulatory agents for the treatment of severe ocular inflammatory conditions including posterior uveitis, panuveitis, severe uveitis associated with seronegative spondyloarthropathy, and scleritis in patients requiring immunomodulation in patients who have failed or who are not candidates for antimetabolite or calcineurin inhibitor immunomodulation. Infliximab and adalimumab can be considered in these patients in preference to etanercept, which seems to be associated with lower rates of treatment success. Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references. Ophthalmology 2014;-:1e12 ª 2014 by the American Academy of Ophthalmology.

Cytokines are effector paracrine proteins that mediate many aspects of the inflammatory response. Cytokines, including the interleukins (ILs), the interferons, and tumor necrosis factor (TNF), are produced by both resident cells and immune effector cells. These proteins affect local processes including recruitment of leukocytes, vascular permeability changes, and programmed development of the adaptive immune response. Pharmacologic blockade of specific cytokines can result in marked attenuation of immunemediated inflammation. The pathogenesis of ocular inflammatory disease remains incompletely understood; however, cytokines seem to be critical mediators of ocular inflammation. The cytokines IL2 and tumor necrosis factor a (TNF-a) and Th1 mediators such as interferon-g and IL-12 are believed to be the primary factors contributing to the pathogenesis of uveitis. Recent studies also suggest that Th17 T-cells may be critical to some forms of uveitis. Supporting these hypotheses, these cytokines are found to be elevated in eyes with active  2014 by the American Academy of Ophthalmology Published by Elsevier Inc.

uveitis. Interferon-g and IL-2 are found in ocular tissues with concomitantly infiltrating T cells. Similarly, elevated levels of IL-6 are found in the aqueous humor of patients with noninfectious ocular inflammatory diseases. Elevated levels of TNF-a and IL-1 also have been demonstrated in both peripheral sera and in aqueous humor samples of patients with uveitis compared with controls. Although these data inherently are correlative, animal studies also suggest that these cytokines are required for intraocular inflammation. Experimental autoimmune uveitis (EAU) is a model of uveitis produced by immunization of rodents with specific retinal proteins. The resulting inflammation closely resembles several human panuveitis conditions, including sympathetic ophthalmia. Tumor necrosis factor a administration exacerbates the development of EAU, whereas IL-10 seems to have protective effects in EAU development. Consistent with findings in humans, Th1 cytokines are elevated in the ocular tissues of EAU animals and can be correlated with diseases course. Pharmacologic ISSN 0161-6420/14/$ - see front matter http://dx.doi.org/10.1016/j.ophtha.2013.09.048

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Ophthalmology Volume -, Number -, Month 2014 blockade of TNF-a minimizes ocular damage in EAU. Although not all observations in experimental uveitis support the apparent role of these cytokines in uveitis (EAU, for example, develops in mice that lack interferon-g, and endotoxin-induced uveitis occurs in mice whose IL-6 gene has been deleted or in those with a deletion of both receptors for TNF-a), on the whole, these data suggest that specific cytokines such as TNF-a and IL-2 are necessary for the full expression of intraocular inflammation in several models of experimental uveitis. Corticosteroids have been the mainstay of therapy for ocular inflammatory disease since their introduction in the early 1950s. Corticosteroids alone, however, are not sufficient for treatment of many cases of chronic uveitis. Some diseases such as Behçet’s disease, serpiginous choroiditis, and mucous membrane pemphigoid are corticosteroid resistant and require immunomodulation early in the disease course for favorable outcomes.1 Long-term corticosteroid therapy also incurs significant risk of unacceptable side effects including cushingoid changes, iatrogenic diabetes, osteoporosis, and hypercholesterolemia. A previous American Uveitis Society expert panel strongly endorsed the use of immunomodulatory agents such as antimetabolites, T-cell inhibitors, and alkylating agents as corticosteroid-sparing agents in chronic and severe uveitis to provide for corticosteroid-sparing control of disease.1 Biologic agents are recombinant proteins or antibodies directed at specific protein targets such as cytokines or cell surface receptors. These agents target individual molecules in the inflammatory cascade, thus resulting in suppression of specific immune effectors that potentially can cause severe ocular damage. There are many different classes of biologic agents, including anti-TNF agents, anti-IL agents,

antieB-cell agents, interferons, antievascular endothelial growth factor agents, and antibodies against specific interleukin receptors. Currently, there are substantial data accumulated on the anti-TNF agents; these data form the basis of the current study. In this review, we summarize the literature concerning the use of the anti-TNF biologic agents in the treatment of ocular inflammation and make recommendations on their appropriate use.

Methods A subcommittee of the Executive Committee of the American Uveitis Society reviewed all available published clinical studies (searching the United States National Library of Medicine PubMed.gov database using search terms in combination, including uveitis, ocular inflammation, scleritis, Behçet, juvenile arthritis, seronegative arthritis, ankylosing spondylitis, HLA-B27, sarcoidosis, choroiditis, TNF, tumor necrosis factor, infliximab, adalimumab, etanercept, golimumab, and certolizumab through May 1, 2013) to examine the role of biologic agents in the treatment of ocular inflammatory disorders. Approximately 400 publications were identified and reviewed. Recommendations were established using the Grading of Recommendations Assessment, Development and Evaluation methodology,2,3 which is based on methods from the Scottish Intercollegiate Guideline Network (SIGN) assessment system for individual studies,4 as implemented for Preferred Practice Patterns by the American Academy of Ophthalmology (Table 1). The goal of this review was to assist clinicians in determining when a biologic agent may be appropriate for treatment of ocular inflammatory disease and to provide recommendations for the use of these drugs in this setting. Because of journal limitations on the size of a published bibliography, we have included all background references in Appendix 1 (available at http://aaojournal.org).

Table 1. Implementation of Strength of Evidence Recommendations Using Scottish Intercollegiate Guideline Network and Grading of Recommendations Assessment, Development, and Evaluation Criteria To rate individual studies, a scale based on SIGN is used. The following definitions and levels of evidence to rate individual studies were used. Iþþ High-quality meta-analyses, systematic reviews of RCTs, or RCTs with a very low risk of bias Iþ Well-conducted meta-analyses, systematic reviews of RCTs, or RCTs with a low risk of bias I Meta-analyses, systematic reviews of RCTs, or RCTs with a high risk of bias IIþþ High-quality systematic reviews of case-control or cohort studies or high-quality case-control or cohort studies with a very low risk of confounding or bias and a moderate probability that the relationship is causal IIþ Well-conducted case-control or cohort studies with a low risk of confounding or bias and a high probability that the relationship is causal II Case-control or cohort studies with a high risk of confounding or bias and a significant risk that the relationship is not causal III Nonanalytic studies (e.g., case reports, case series) Recommendations for care are formed based on the body of the evidence. The following body of evidence quality ratings are defined by GRADE. Good quality Further research is very unlikely to change our confidence in the estimate of effect Moderate quality Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate Insufficient quality Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate; any estimate of effect is very uncertain Key recommendations for care are defined by GRADE3 as follows. Strong recommendation Used when the desirable effects of an intervention clearly outweigh the undesirable effects or clearly do not Discretionary recommendation Used when the tradeoffs are less certaindeither because of low-quality evidence or because evidence suggests that desirable and undesirable effects are closely balanced GRADE ¼ Grading of Recommendations Assessment, Development, and Evaluation; RCT ¼ randomized controlled trial; SIGN ¼ Scottish Intercollegiate Guideline Network.

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Review of Use of AntieTumor Necrosis Factor Agents Biology. The primary production of TNF-a is thought to arise from inflammatory cells in the monocyte and macrophage lineages, with additional production attributed to neutrophils, mast cells, eosinophils, retinal pigment epithelium, glia, Müller cells, and activated endothelial cells. Cytotoxic chemicals, activated T-cells, ultraviolet light, x-irradiation, and other cytokines are all thought to stimulate the production of TNF-a. It is postulated that stimulated cells release chemokines, which in turn activate transcription factors in the nucleus, resulting in the expression of the transmembrane form of the TNF-a molecule. This molecule binds to the TNF-a receptor-1, initiating a cascade that triggers the secretion of effector molecules, such as adhesion molecules, growth and proliferation factors, metalloproteinases, immunoglobulins, and additional cytokines and chemokines. Approved Agents. Five anti-TNF biologic agents currently are approved by the United States Food and Drug Administration (FDA) in the United States. The most recently approved agents, golimumab (Simponi; Janssen Biotech, Horsham, PA) and certolizumab (Cimzia; UCB, Brussels, Belgium) have not been in clinical use for a sufficient period to assess their usefulness for treatment of uveitis. The other 3 approved agents are: Etanercept (Enbrel; Amgen, Thousand Oaks, CA). Etanercept is a humanized, recombinant fusion protein. It consists of the p75 TNF-a receptor II, combined with the Fc tail domain of the human immunoglobulin (IgG) 1. Etanercept blocks the interaction of TNF with cell surface TNF receptors. There are 2 distinct receptors for TNF, p55 and p75. Etanercept renders TNF biologically inactive by preventing binding to both TNF receptors. Pharmacokinetically, the time to reach maximum serum concentration in an adult administered a single subcutaneous 25-mg dose is 6934 hours (meanstandard deviation), with a mean half-life of 10230 hours. In juvenile idiopathic arthritis (JIA) patients, studies indicate that the clearance is reduced slightly in children 4 to 8 years of age. Etanercept holds FDA indications for rheumatoid arthritis, polyarticular JIA (patients 2 years and older), psoriatic arthritis, ankylosing spondylitis, and plaque psoriasis (patients 17 years and older). For rheumatoid arthritis, psoriatic arthritis, or ankylosing spondylitis, etanercept is dosed 50 mg weekly or 25 mg twice weekly, given as subcutaneous injection. It can be used concurrently with methotrexate, corticosteroids, and nonsteroidal antiinflammatory medication. For plaque psoriasis, a 50-mg dose is given twice weekly for 3 months, followed by a reduction to a maintenance dose of 50 mg weekly. For JIA, the dosage is 0.8 mg/ kg weekly, up to a maximum of 50 mg weekly. The 25-mg prefilled syringe is not recommended for patients weighing less than 31 kg (68 pounds); the 50-mg prefilled syringe may be used for patients weighing up to 63 kg (138 pounds). Infliximab (Remicade; Janssen Biotech, Horsham, PA). Infliximab is a monoclonal, chimeric (mouse/human) IgG1 k antibody, directed at the TNF-a molecule. The murine constant region of the antibody is replaced by human sequences and is combined with the murine variable regions. Infliximab binds to the soluble and transmembrane forms of TNF-a and also inhibits its binding to its receptors, thus neutralizing its biological activity. A single intravenous infusion of 5 mg/kg infliximab results in a median maximum serum concentration of 118 mg/ml, with a terminal half-life of 9.5 days. Infliximab carries FDA approval for rheumatoid arthritis, Crohn’s disease, ankylosing spondylitis, psoriatic arthritis, plaque psoriasis in adults, and ulcerative colitis. Infliximab is dosed for rheumatoid arthritis as 3 mg/kg given as an intravenous infusion at weeks 0, 2, and 6 and then every 8 weeks. It is recommended as a combination therapy with methotrexate. For

Crohn’s disease and ulcerative colitis, infliximab is dosed 5 mg/kg intravenously at weeks 0, 2, and 6, and then every 8 weeks. For ankylosing spondylitis, the dosage is 5 mg/kg intravenously at weeks 0 and 6, then every 6 weeks thereafter. For plaque psoriasis and psoriatic arthritis, the dosage is 5 mg/kg intravenously at weeks 0, 2, and 6, and then every 8 weeks. The dosage can be increased up to 10 mg/kg or as often as every 4 weeks. The risk of serious infections, however, is increased at higher doses. Adalimumab (Humira; AbbVie, North Chicago, IL). Adalimumab is a recombinant human IgG1 monoclonal antibody specific for TNF-a. The antibody is created with human-derived heavy- and light-chain variable regions and human IgG1 k constant regions. Adalimumab binds TNF-a and blocks its interaction with its 2 known receptors. The time to reach maximum serum concentration is 13156 hours, after a 40-mg subcutaneous administration to a healthy adult subject, with an average absolute bioavailability estimated at 64%. The mean terminal half-life is approximately 2 weeks (range, 10e20 days). There was a trend toward higher apparent clearance in the presence of antiadalimumab antibodies and lower clearances with increasing age from 40 to 75 years. Combination therapy with methotrexate reduces adalimumab clearance after single and multiple dosing by 29% to 44%. Adalimumab is approved for JIA in children and for rheumatoid arthritis, ulcerative colitis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, and plaque psoriasis in adults. For rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis, adalimumab is given as a 40-mg dose administered by subcutaneous injection every other week. It may be used concomitantly with methotrexate, corticosteroids, and nonsteroidal medications. In JIA, for children weighing 15 to 30 kg, adalimumab is dosed 20 mg every other week; for children weighing more than 30 kg, the dose is 40 mg every other week. For Crohn’s disease, the treatment regimen is a loading dose of 160 mg at day 1, 80 mg at day 15, and initiation of maintenance at day 29 with 40 mg every other week. For plaque psoriasis, treatment consists of a loading dose of 80 mg, 1 week later transitioning to maintenance therapy at 40 mg every other week. Adverse events common to all anti-TNF agents include increased risk of infection, development of autoimmune disease while receiving treatment, and development of immune-mediated resistance to drug. Serious infections and sepsis, including fatalities, have been reported, although rates of these infections may not be significantly higher than those in the general population. Reactivation of tuberculosis and invasive opportunistic fungal infections in particular have been documented. The risk of tuberculosis is higher for patients receiving anti-TNF monoclonal antibodies compared with patients receiving soluble TNF receptor therapy. There has also been a report of tuberculous uveitis after treatment with etanercept. The use of TNF-blocking agents has been associated with the development of new or exacerbated autoimmune disease, particularly development or worsening of demyelinating disorders. A subset of patients treated with TNF inhibitor therapy have developed positive antinuclear antibody (ANA) and antiedoublestranded DNA titers. Infliximab use in ulcerative colitis has been associated with a 44% seroconversion rate for ANA, a 9% incidence of mild lupus-like symptoms, and a 1% risk of severe lupuslike disease. In one uveitis trial, 3 of 31 subjects treated with infliximab demonstrated drug-induced lupus. There have been several reports of new-onset uveitis in patients treated with antiTNF agents for nonocular manifestations of rheumatologic diseases (SIGN level III). Lim et al5 concluded that etanercept therapy in particular was associated with a significantly greater number of new uveitis cases, compared with infliximab and adalimumab (although this must be considered in the overall context of etanercept treatment being associated with a nearly 2-fold overall

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Ophthalmology Volume -, Number -, Month 2014 reduction in uveitis flares in patients with underlying ankylosing spondylitis).6 Other rare, paradoxical autoimmune adverse events have been described in patients taking anti-TNF agents, including new-onset inflammatory bowel disease, sarcoidosis, psoriasis, and anterior scleritis. Patients treated with chimeric monoclonal antibodies can develop antibodies to the nonhumanized portions of the antibody. Even with the humanized agents, such as adalimumab, low titers of antibodies have been detected. Patients treated concomitantly with methotrexate typically show a lower rate of antibody development than patients treated with TNF-inhibitor monotherapy. Several studies have suggested an increased risk of lymphoma in patients with rheumatoid arthritis who are taking anti-TNF agents. A metareview of the available studies7 suggests that there are not sufficient data to establish a causal relationship (SIGN level Iþ). It should be noted that patients with rheumatoid arthritis, especially those with highly active disease, may be at a higher baseline risk for the development of lymphoma; thus, the exact role that these agents may play in the development of lymphoma is still not known. However, a retrospective study of patients taking several classes of immunomodulating drugs for uveitis did report an increased relative risk for death and for cancer death in patients taking TNF inhibitors, compared with individuals taking antimetabolites or calcineurin inhibitors.8 In the pediatric and adolescent population, postapproval surveillance by the United States FDA documented 48 malignancies in children taking any of the TNF inhibitors, including 10 cases of hepatosplenic T-cell lymphoma occurring primarily in patients with inflammatory bowel disease taking concomitant purine inhibitors. This has led to a black box warning for these medications with respect to malignancy risk in this setting (available at: http://www.accessdata.fda.gov/drugsatfda_docs/ label/2009/103772s5234lbl.pdf; accessed August 31, 2013). However, 2 large observational databases of 13 001 and 19 591 patients with good follow-up (approximately 49 000 and 89 710 person-years, respectively) detected no increased risk of malignancy with anti-TNF monoclonal antibody therapy (odds ratios for cancer, approximately 1.0 vs. no anti-TNF therapy),9e11 except for nonmelanotic skin cancer in one study (odds ratio, 1.5).11 These studies did demonstrate an increased risk of cancer for patients with rheumatic diseases that was not affected by anti-TNF therapy. A recent large meta-analysis of more than 29 000 subjects participating in randomized controlled clinical trials examining biologic agents in the treatment of rheumatoid arthritis found no evidence of increased malignancy risk with any of the biologic agents (SIGN level Iþ).12 Contraindications of this class of medications include any evidence of active infection, prior lymphoproliferative disorder diagnosed or treated within the previous 5 years, moderate or severe heart failure, New York Heart Association class III/IV heart failure, chronic hepatitis B or C, presence of any demyelinating disorders, pneumonitis (inflammatory, as seen in rheumatoid arthritis [RA]), or use in the perioperative period (1 week before and 1 week after surgery)13 (SIGN level IIeIII). However, ocular surgery is considered low risk, and these medicines generally are not discontinued for intraocular procedures. Infliximab, etanercept, and adalimumab all have been categorized as FDA category B for use in pregnancy (animal reproduction studies have failed to demonstrate a risk to the fetus and there are no adequate and well-controlled studies in pregnant women). Before initiation of treatment with anti-TNF agents, baseline laboratory screening consisting of complete blood count; comprehensive metabolic panel including liver function, renal function, and electrolytes; and screening for tuberculosis (following Centers for Disease Control and Prevention guidelines)

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are recommended. If latent tuberculosis is detected, appropriate antitubercular therapy should be initiated. The anti-TNF treatment may be started 1 month after initiation of tuberculosis therapy. Patients initiating anti-TNF therapy should be up-to-date for pneumococcal, influenza (nonlive virus), and hepatitis B vaccines. Patients receiving anti-TNF therapy should not have live virus vaccine, including varicella zoster, oral polio, or rabies vaccination. Infliximab, adalimumab, and etanercept are all FDA approved for systemic administration. Intravitreal injection of infliximab in animal models seems to be well tolerated; however, adalimumab and infliximab do not bind to nonhuman TNF, and so full assessment of potential toxicity is not possible in animal models. Several pilot studies have assessed intravitreal infliximab for treatment of uveitis, macular degeneration, and macular edema. However, significant adverse effects, including decline in electroretinogram amplitudes and microperimetry and development of de novo uveitis in one study,14 have led to a call for a moratorium on use of anti-TNF biologic agents intravitreally outside of wellcontrolled clinical trials.

Summary of Evidence Uncontrolled case series, nonrandomized, retrospective clinical studies, and prospective open-label trials of antiTNF agents indicate they are effective for the treatment of noninfectious uveitis. Although the preponderance of published literature to date has documented use of infliximab in treatment of uveitis, there have been few comparative studies to address the question of superiority of adalimumab or infliximab in the treatment of any uveitic condition, nor are data available to suggest which agent should be used primarily. In this review, evidence for each agent is presented in turn, with data for infliximab presented first because of its relative preponderance; this is not meant to imply any recommended bias toward using infliximab in preference to adalimumab. There are, however, substantial data (see below) suggesting that etanercept has lower efficacy for treatment of some forms of uveitis than either infliximab or adalimumab. Efficacy has been suggested for the ocular inflammatory manifestations of a number of specific conditions as detailed in the following sections.

Behçet’s Disease Behçet’s disease is a multisystem inflammatory disease. It presents with a constellation of clinical signs, including but not limited to uveitis, occlusive vasculitis, aphthous stomatitis, genital ulceration, and arthritis. In 1990, the International Study Group for Behçet’s Disease published a set of accepted diagnostic criteria.15 Typically, Behçet’s disease is treated with systemically administered corticosteroids in conjunction with 1 or more immunomodulatory agents.1 A recent meta-analysis of the literature for use of antiTNF agents in 369 patients with systemic Behçet’s disease16 has suggested very high response rates (>90%) for improvement in all major classes of Behçet’s signs and symptoms in patients with disease inadequately controlled by traditional immunomodulatory treatment (SIGN level I; see Table 1 for explanation of SIGN system). An expert panel reviewed this literature and concluded that

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use of anti-TNF agents in Behçet’s disease is warranted for patients whose disease is incompletely controlled by or who are intolerant of standard immunomodulatory agents.17 Numerous small open-label series have reported response rates for ocular disease treated with infliximab at approximately 90% (SIGN level II to III).18,19 In studies with a longer follow-up of 16 to 36 months, responses were sustained in most patients and relapse rates were less than half of baseline rates obtained before infliximab treatment, with improvement or stabilization of vision in most patients.20e23 Several studies have compared patients treated with infliximab retrospectively with those treated with other immunosuppressive therapies. Yamada et al24,25 retrospectively compared patients treated with either cyclosporine A or infliximab in addition to corticosteroids for ocular Behçet’s disease. Both groups had an average of approximately 3 disease exacerbations per year before medication. This was reduced to 1.2 exacerbations in the cyclosporine A group and 0.4 exacerbations in the infliximab group (SIGN level IIþ). Similarly, Tabbara and Al-Hemidan,26 in a retrospective study of 43 patients with retinal vasculitis resulting from Behçet’s disease, compared relapse rates and visual acuities between patients receiving conventional immunosuppressive medications and infliximab. With a mean follow-up of 36 months, this group found the relapse rate of disease to be significantly higher in the group receiving standard therapy than in the group receiving infliximab. At 24 months, visual acuity was significantly better in the infliximab-treated cohort than in those receiving standard treatment (SIGN level IIþ). Markomichelakis et al27 prospectively compared a single infusion of infliximab with high-dose systemic oral corticosteroids or intravitreal corticosteroids in the treatment of acute exacerbations of ocular Behçet’s disease. This group found significantly faster resolution of ocular signs of inflammation in patients receiving infliximab, as well as superior resolution of retinal vasculitis, posterior uveitis, and cystoid macular edema compared with individuals receiving corticosteroid by either route (SIGN level IIþ). Okada et al28 prospectively studied 63 patients with Behçet’s disease with ocular manifestations treated with infliximab at 8 tertiary referral centers. At the 1-year time point, 69% of patients showed full improvement in ocular manifestations and 23% showed partial improvement. Only 8% showed no improvement, and no patients showed worsening. The mean number of ocular attacks in a 6-month period decreased from 2.66 at baseline to 0.44 for the first 6 months of therapy. Side effects were noted in 46% of patients, including 3 infusion reactions. However, none of these were considered serious adverse events (SIGN level IIþ). Adalimumab has been studied for Behçet’s disease in small case studies and generally for patients who were intolerant of infliximab.29e34 These studies suggest continued control of disease in transition from infliximab to adalimumab (SIGN level III). Etanercept has been investigated less thoroughly than infliximab for treatment of Behçet’s-related ocular inflammation. Of note, etanercept has been shown to be effective for the mucocutaneous manifestations of Behçet’s disease in a randomized, placebo-controlled clinical trial35 (SIGN level

Iþ). Otherwise, etanercept use in uveitis has been limited to case reports and small series.36e38 At least 1 report notes successful treatment of a patient with infliximab after ineffective therapy with etanercept.39

Panel Recommendation for Ocular Manifestations of Behçet’s Disease Strong Recommendation. Treatment with anti-TNF therapy with infliximab (good-quality evidence) or adalimumab (moderate-quality evidence) may be considered as first- or second-line corticosteroid-sparing therapy for patients with ophthalmic manifestations of Behçet’s disease, and infliximab may be considered as first- or second-line treatment for acute exacerbations of pre-existing Behçet’s disease. Discretionary Recommendation. Etanercept may be considered for Behçet’s patients with uveitis who are intolerant to infliximab and adalimumab (insufficient-quality evidence).

Juvenile Idiopathic Arthritis Juvenile idiopathic arthritis, a multisystemic primary autoimmune disorder, is the most common form of chronic arthritis of childhood and the most common identifiable systemic association with iridocyclitis, occurring in 10% to 15% of patients. Risks for the development uveitis include the oligoarticular subtype of JIA, ANA positivity, younger age at onset of arthritis, and female gender. Juvenile idiopathic arthritis-associated iridocyclitis presents insidiously as an asymptomatic chronic, bilateral, nongranulomatous uveitis typically between 6 months and 4 years of age. Complications associated with visual loss are common and include cataract, band keratopathy in the visual axis, posterior synechiae, hypotony, glaucoma, and macular edema, with an incidence of any complication occurring at 33% per eye per year. Juvenile idiopathic arthritis is a visually debilitating disease, with an estimated frequency of visual loss in 30% to 20/50 or worse and in 24% to 20/200 or worse over a 3-year period in patients referred to tertiary referral centers. The therapeutic approach to JIA-associated iridocyclitis involves the elimination of all active inflammation and the early introduction of immunomodulatory therapy when needed to reduce both risk of vision loss resulting from complications of inflammation and to limit total corticosteroid exposure. A variety of immunomodulatory medications have been used in this context, with methotrexate being the first line drug of choice. However, methotrexate may not always achieve inflammatory control and alternative immunomodulatory agents may be less desirable both in terms of efficacy and their associated systemic toxicities. Numerous prospective and retrospective studies of pediatric patients have reported on the efficacy of infliximab in the treatment of refractory, noninfectious uveitis.40e44 Taken together, these studies demonstrate that the use of infliximab results in a consistent reduction in intraocular inflammation, albeit at higher doses and with shorter infusion intervals than those used for the treatment of rheumatoid arthritis, a reduction in the requirement for topical and systemic steroids permitting systemic immunomodulatory

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Ophthalmology Volume -, Number -, Month 2014 therapy to be tapered, differential efficacy with respect to etanercept, and few serious adverse events. Some patients also have experienced rapid anti-inflammatory control with maintenance of remission. Kahn et al42 performed a retrospective study of 17 children with refractory, chronic, noninfectious uveitis who were treated with high induction doses of infliximab (10e20 mg/kg) and methotrexate (6 of 17 children), followed by 10 mg/kg per dose every 2 to 4 weeks or monthly 20-mg/kg doses for a mean of 13 months (SIGN level III). The doses were tapered and the intervals extended depending on the clinical response. Ten patients had JIAassociated anterior uveitis. All 17 patients experienced a dramatic, rapid response to treatment with no observed inflammation in 13 patients after the second infusion, whereas 4 patients required 3 to 7 infusions to achieve inflammatory quiescence. In all patients receiving systemic steroids and nonmethotrexate immunomodulation (tacrolimus, cyclosporine, mycophenolate mofetil, and cyclophosphamide), as well as 88% of those receiving topical steroids, these medications were able to be tapered off. In 6 patients, methotrexate prophylaxis against the possible development of human antichimeric antibodies was continued. Ardoin et al45 reported a retrospective study of 16 children (29 eyes) with refractory noninfectious uveitis, 10 of whom had exclusively ocular disease, who were treated with infliximab and methotrexate (15 of 16 patients) and were followed up for a mean of 26 months (SIGN level III). Patients were treated with a standard 3-dose intravenous load over 1 month (5 mg/kg at weeks 0, 2, and 4) followed by monthly infusions, titrated to the clinical response. The median maintenance dose of infliximab was 8.2 mg/kg, whereas the median infusion interval was 5.6 weeks. Four children had JIA and 1 child had psoriatic arthritis-associated iridocyclitis, whereas the remainder were deemed to have idiopathic disease. However, 11 patients were found to be ANA positive and 4 had positive HLAB27 test results. At 1 year, 64% of patients had 0 ocular inflammation, whereas 79% of patients achieved a 2-step reduction in ocular inflammation or 0 inflammation at this time point. These results were highly statistically significant. Topical steroids were discontinued in 69% of patients; 58% remained free of recurrent inflammation and visual acuity remained stable at 1 year. No serious infusion reactions, infections, or other adverse events were reported over a total of 362 infliximab infusions. Adalimumab is a potentially effective treatment option for patients in whom methotrexate treatment fails and may be useful as maintenance therapy after induction doses with infliximab.46e48 Adalimumab has the advantage of being less immunogenic than infliximab and may be administered subcutaneously rather than intravenously. The optimal dosage and treatment protocols are not defined and must be individualized for each patient. Tynjala et al47 reported on the efficacy of adalimumab in a retrospective study of 20 children with recalcitrant JIA-associated uveitis using Standardization of Uveitis working group nomenclature criteria to assess the treatment response (SIGN level III). The mean age at the initiation of treatment was 13.4 years and the mean duration of uveitis was 8.7 years, with 19 of

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20 patients having had previous anti-TNF therapy, in 90% of whom infliximab treatment was deemed to have failed. Patients were treated with standard doses of adalimumab ranging from 20 to 40 mg subcutaneously every 2 weeks with a mean duration of 18.7 months of therapy. Uveitis activity was noted to improve in 7 (35%) patients, was unchanged in 12 (60%) patients, and worsened in 1 (5%) patient. Improved activity was noted among younger patients and those with a shorter disease duration. There was a reduction in the mean number of uveitis flares from 1.9 to 1.4 per year during adalimumab treatment. Serious adverse events and side effects were not observed. Seven patients discontinued adalimumab therapy during the follow-up, 6 patients because of inefficacy and 1 patient because of inflammatory quiescence. A prospective study of 131 patients with uveitis treated with adalimumab, of whom 30% had JIA-associated uveitis, demonstrated substantial and significant improvement at 6 months in measures of inflammation (anterior chamber cells, vitreous inflammation), structural complications (e.g., macular edema in 70%), visual acuity, and in the need for other immunosuppression (SIGN level IIþ).49 Studies reporting the efficacy of etanercept in the treatment of JIA-associated uveitis are limited. The initial enthusiasm surrounding the apparent efficacy of etanercept in a small, uncontrolled, prospective study of 10 children with chronic, recalcitrant uveitis, 7 of whom had JIA, has been tempered by the long-term follow-up of this same group of patients and by the lack of efficacy of etanercept in a small (n ¼ 12), randomized, placebo-controlled clinical trial in the treatment of JIA-associated uveitis (SIGN level IIþ).50e52 Moreover, etanercept showed no significant efficacy over placebo in preventing uveitis relapse in a patients being tapered from methotrexate in another small (n ¼ 20) randomized, controlled trial (SIGN level IIþ).53 Although there have been several reports of uveitis occurring in children with JIA while being treated with etanercept,54e56 anti-TNF treatment per se was shown not to alter the risk for the development of uveitis in a cohort of 1109 children with JIA.55 Those who did have JIA, however, displayed identifiable at-risk characteristics (in particular, rheumatoid factor-negative, ANA-positive disease), and most of these (71%) had been treated with etanercept. Although etanercept may not cause uveitis directly, patients receiving this drug should be monitored closely for the development of uveitis. Differential efficacy of infliximab with respect to etanercept in treatment of JIA-associated uveitis has been demonstrated in several studies.54,57e59 Galor et al54 performed a retrospective analysis of 22 patients with refractory noninfectious uveitis ranging in age from 11 to 79 years who were treated with either infliximab or etanercept (SIGN level IIþ). Most were female (19/22) and had systemic arthritis, including 7 with JIA. Diagnosis of Crohn’s disease, sarcoidosis, ankylosing spondylitis, relapsing polychondritis, and birdshot retinochoroidopathy were included. After 1 year of treatment, 100% of patients taking infliximab showed a decrease in ocular inflammation, in contrast to 33% of those taking etanercept, whereas 94% of individuals in the

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infliximab-treated group showed a reduced need for topical steroids versus 29% in the etanercept group during the same period. Moreover, only 1 infliximab-treated patient was deemed a treatment failure, whereas all etanercept-treated individuals eventually required a change in their medication to control ocular inflammation. Two episodes of de novo anterior scleritis were attributed to etanercept therapy, whereas 1 patient had severe uveitis recurrence immediately after an etanercept injection. No significant differences in the use of systemic steroids or other immunomodulatory therapy were noted between the 2 groups. These findings, together with the superior differential efficacy of infliximab over etanercept, relegate etanercept to third-line immunomodulatory status in the treatment of JIA-associated uveitis. Simonini et al60 compared the frequency of uveitis flares in children taking infliximab versus adalimumab in an openlabel, prospective study (SIGN level IIþ). Most subjects in both arms had a JIA diagnosis. Thirty-three subjects were followed up using primary outcome measures of time to disease remission and time to first relapse. This group found that time to achieve remission was identical between the 2 groups, but patients taking adalimumab had a higher probability of long-lasting remission while taking medication. By 40 months of follow-up, 60% of children taking adalimumab had not had a disease recurrence compared with 19% of children receiving infliximab. Sen et al61 performed a similar prospective cohort study on the use of adalimumab in children who had failed treatment with corticosteroids and an immunomodulatory agent (SIGN level IIþ). Of 17 patients enrolled, 50% of eyes had improved, 16% had stable inflammation, and 3% had worsened, whereas 31% remained without anterior chamber cells. Six patients required courses of oral steroids for uveitis and 7 patients received intraocular or periocular injections of steroids, suggesting that adalimumab monotherapy was not sufficient for control of disease in a subset of subjects. A second prospective study by Simonini et al62 (SIGN level IIþ) assessed the efficacy of adalimumab initiated as first anti-TNF therapy in children compared with the use of the agent only after infliximab failure. In this prospective, comparative case series and open-label study of 26 children either treated primarily with adalimumab or only after loss of efficacy of infliximab, the authors found substantially longer induced disease remission in subjects receiving adalimumab primarily compared with those whose adalimumab treatment began after infliximab failure (18 vs. 4 months). A joint working group of the German Ophthalmological Society, the Society for Childhood and Adolescent Rheumatology, and the German Society for Rheumatology reviewed the literature to propose evidence-based treatment guidelines for anti-inflammatory treatment of uveitis associated with JIA63 (SIGN level I). Using a rating system similar to that used in the present study, this group found level II (good quality) evidence for use of infliximab and level III (moderate quality) evidence for use of adalimumab as second-line immunomodulatory agents in the treatment of JIA. The group concluded as well that etanercept had lower efficacy for the treatment of JIA than the other 2 studied anti-TNF agents.

Panel Recommendation for Treatment of Juvenile Idiopathic Arthritis-Associated Ocular Disease with AntieTumor Necrosis Factor Therapy Strong Recommendation. Infliximab (good-quality evidence) or adalimumab (good-quality evidence) should be considered as a second-line immunomodulatory agent after methotrexate for treatment of JIA-associated uveitis. The combination of infliximab with methotrexate should be considered, unless medically contraindicated. Close monitoring with an ophthalmologist and pediatric rheumatologist is highly recommended. Strong Recommendation. Etanercept should not be used as the primary immunomodulatory agent for patients with JIA-associated uveitis (good-quality evidence).

Seronegative Spondyloarthropathy The seronegative spondyloarthropathies are a group of chronic inflammatory diseases strongly associated with HLAB27 positivity. They include reactive arthritis (formerly Reiter syndrome), ankylosing spondylitis, inflammatory bowel disease (Crohn’s disease and ulcerative colitis), and psoriatic arthritis. These conditions are associated strongly with the occurrence of acute anterior uveitis. A chronic form of uveitis may occur as well, although less commonly. Therapy of seronegative spondyloarthropathy-associated acute anterior uveitis consists primarily of short-term courses of corticosteroids administered topically, periocularly, or systemically. Seronegative spondyloarthropathyassociated acute anterior uveitis typically is recurrent. Patients with HLA-B27eassociated recurrent acute anterior uveitis have on average approximately 1 attack per year, lasting on average approximately 6 weeks, which usually responds to topical corticosteroids. However, a small percentage has frequent recurrences, which may warrant prophylactic immunosuppressive therapy to reduce disease occurrence. In a meta-analysis of 4 placebo-controlled trials of TNF inhibitor therapy for ankylosing spondylitis and 3 openlabel studies, Braun et al6 analyzed data from 717 total patients treated for anterior uveitis (SIGN level Iþ). Follow-up data on 397 patients revealed that the frequency of acute anterior uveitis flares in patients receiving TNF inhibition via either infliximab or etanercept had a mean of 6.8 flares per 100 patient-years, whereas those exposed to placebo had a mean of 15.6 flares (P ¼ 0.01). In a similar study, Rudwaleit et al64 reviewed data from 1250 patients with active ankylosing spondylitis treated with adalimumab as part of a multinational, open-label, uncontrolled clinical trial (SIGN level IIþ). The uveitis flare rate before trial entry was 15 per 100 patient-years for all patients. Adalimumab treatment decreased the overall flare rate by 51%, with a 58% reduction in those with a prior history of anterior uveitis, and by 68% in those with a recent history of anterior uveitis (all P < 0.001). Seronegative spondyloarthropathy-associated acute anterior uveitis may be resistant to conventional therapy with corticosteroids or a patient may have a contraindication to corticosteroid use, necessitating use of additional or

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Ophthalmology Volume -, Number -, Month 2014 alternate anti-inflammatory therapy.1 El-Shabrawi and Hermann65 used infliximab as the sole therapy in the treatment of seronegative spondyloarthropathy-associated acute anterior uveitis (SIGN level III). In this prospective, noncomparative trial in 7 patients, infliximab was infused at 10 mg/kg on a one-time basis. Uveitis resolved in a mean of 812 days. In the above-referenced adalimumab trial by Rudwaleit et al,64 a 50% reduction in flares occurred during treatment (P ¼ 0.001) among 28 patients with symptomatic anterior uveitis at enrollment. Seronegative spondyloarthropathy-associated acute anterior uveitis may become chronic. As such, standard therapeutic paradigms for chronic disease should be followed, including the use of additional immunosuppressive agents if corticosteroids alone are insufficient at a safe dose.1 Rudwaleit et al64 reported a 45% reduction in uveitis flares in 43 patients with a history of chronic uveitis treated with adalimumab (P ¼ 0.002).

Panel Recommendations for SpondyloarthropathyAssociated or HLA-B27eAssociated Uveitis Strong Recommendation. Infliximab or adalimumab also may be used as corticosteroid-sparing treatment for patients with chronic uveitis resulting from seronegative spondyloarthropathy (good-quality evidence). Discretionary Recommendation. Infliximab or adalimumab may be used for patients with severe, visionthreatening or debilitating uveitis requiring systemic immunosuppressive agents or as adjunctive therapy to corticosteroid treatment in acute disease (good-quality evidence).

Sarcoidosis Sarcoidosis is also a multisystem disease, characterized by noncaseating granuloma formation in multiple organs. The respiratory tract is most commonly involved, but up to 26% of patients may have ocular involvement. Infliximab has been shown to be effective in the treatment of pulmonary sarcoidosis in a randomized controlled trial (SIGN level Iþ).66 Efficacy of infliximab also has been suggested in several case series of sarcoidosis patients with ocular involvement (SIGN level III).19,67e69 Adalimumab also seems to have efficacy in the treatment of posterior segment findings associated with sarcoidosis in a cohort study of 41 patients with disease refractory to treatment with prednisone and methotrexate and followed up for 12 months (SIGN level II). In this study, 85% of patients showed improvement in ocular signs and 15% showed stabilization at the 1-year time point. Etanercept has been tested in a very small, masked, randomized controlled clinical trial of patients with ocular sarcoidosis.70 In this study of 12 subjects, all patients were already receiving immunomodulation and corticosteroid therapy at randomization. No difference could be discerned between etanercept-treated and placebo-treated patients in inflammation at end of the study nor in corticosteroid-sparing effect at the 6-month end point (SIGN level III). Etanercept additionally has been associated with the development and worsening of granulomatous uveitis in

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the setting of sarcoidosis71,72 and the development of other sarcoid-like granulomas.73e76

Panel Recommendation for Treatment of Ocular Involvement of Sarcoidosis with Infliximab or Adalimumab Discretionary Recommendation. Infliximab or adalimumab may be considered as second-line immunomodulatory therapy for patients failing or intolerant of standard immunomodulatory agents (moderate-quality evidence). Discretionary Recommendation. Etanercept should not be used in the treatment of ocular sarcoidosis (moderatequality evidence). Clinical effectiveness of anti-TNF therapy has also been reported in the following ocular inflammatory disorders.

Scleritis Infliximab has been reported as a viable option for patients with scleritis recalcitrant to immunosuppressive therapy or requiring protracted periods of oral corticosteroid therapy77e81 (SIGN level III). A small, prospective, randomized, open-label pilot study showed positive results for patients with anterior scleritis treated with infliximab82 (SIGN level III). Patients with specific underlying systemic disease, such as granulomatosis with polyangiitis (formerly known as Wegener’s granulomatosis), may show varying responses.83 Etanercept was not effective for the treatment of granulomatosis with polyangiitis in a prospective, randomized controlled trial84 (SIGN level Iþ), whereas the rituximab, a monoclonal antibody that depletes B cells, was found to be noninferior to cyclophosphamide for this indication (SIGN level Iþ).85

Panel Recommendation for Treatment of Scleritis with Infliximab Discretionary Recommendation. Infliximab may be considered as second-line corticosteroid-sparing therapy for chronic and severe scleritis (moderate-quality evidence).

Other Posterior Uveitides and Panuveitis Syndromes Several small case series19,23,68 as well as one prospective open-label clinical trial86,87 examining the response of uveitis to infliximab have included patients with birdshot chorioretinitis (BSCR), a bilateral posterior uveitis generally treated with systemic immunomodulation. In each study, patients with BSCR showed clinical response to infliximab therapy (SIGN level III). One study of 22 patients with BSCR refractory to other therapies suggested successful control of the inflammation in 89% of patients88 (SIGN level IIþ). Several small series and case reports have suggested efficacy for Vogt-Koyanagi-Harada disease,89e91 multifocal choroiditis with panuveitis,92 serpiginous choroiditis,93 and idiopathic pars planitis,23,41 but use of TNF inhibition specifically in these conditions has not been tested widely or directly. Furthermore, the prospective study on the use of infliximab for mostly idiopathic uveitis found a high rate of adverse events that may indicate that this form of TNF inhibition could have more

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risk if inflammation is not systemic, but instead confined to the eyes.86,87 Suhler et al94 prospectively evaluated the efficacy of adalimumab in a cohort of 31 patients with a variety of uveitic conditions, most of which were idiopathic panuveitis, but also including several with VogtKoyanagi-Harada disease or BSCR (SIGN level IIþþ). Patients in this study had uveitis refractory to corticosteroids and had received at least 1 disease-modifying agent. The authors in this multisite study used a well-defined clinical end point for control of uveitis and found a 68% response rate to adalimumab at the 10-week time point, although this decreased to 39% at 50 weeks, suggesting significant efficacy for adalimumab as second-line agent for panuveitis recalcitrant to corticosteroid and traditional steroid-sparing therapy.

Panel Recommendation for Treatment of Birdshot Chorioretinitis, Multifocal Choroiditis with Panuveitis, Serpiginous Choroiditis, or Undifferentiated Panuveitis with AntieTumor Necrosis Factor Therapy. Discretionary Recommendation. Infliximab or adalimumab may be considered corticosteroid-sparing therapy for chronic and severe disease in patients intolerant of or unresponsive to traditional immunomodulatory therapies (moderate-quality evidence). Discretionary Recommendation. Given the association of demyelinating disease and pars planitis and the known exacerbating effects of anti-TNF agents on demyelinating diseases, other corticosteroid-sparing therapies may be favored in this condition (moderate-quality evidence). If anti-TNF therapy is considered in a patient with intermediate uveitis (e.g., pars planitis), magnetic resonance testing of the brain should be performed to exclude multiple sclerosis. In conclusion, since their introduction more than a decade ago, anti-TNF agents have become mainstays in the treatment of a variety of systemic immunologically mediated diseases, including rheumatoid arthritis, inflammatory bowel disease, JIA, seronegative spondyloarthropathies, and psoriatic arthritis. None of these agents presently carry FDA indication for treatment of ocular inflammatory disorders. Thus, recommendations for use of these agents in these heterogeneous diseases must rely on analysis of literature, including small controlled clinical trials, open-label prospective clinical trials, and retrospective analyses. Our recommendations were derived from a comprehensive review of the literature, weighing the quality of evidence using established methodologies (SIGN4 for individual studies and Grading of Recommendations for Assessment, Development and Evaluation3 recommendations), as specified by the American Academy of Ophthalmology. The methodology of this review, however, did not fully implement the Preferred Reporting Items for Systematic Reviews and Meta-Analysis checklist95 (embodying Cochrane review-type methodology), which has been adopted by other organizations and journals

for reporting systematic reviews. Because we have not excluded studies on the basis of design, follow-up period, or design methodology (but have considered these issues implicitly in assigning SIGN grading), it is possible that biases inherent in the reviewed studies have affected our recommendations. As such, we have labeled our study an expert panel recommendation rather than an evidence-based review. In analyzing more than 400 publications from the past 15 years examining use of anti-TNF therapies in the treatment of various forms of ocular inflammatory disease, we find substantial evidence supporting use of anti-TNF therapies for several well-recognized forms of uveitis: 1. Strong recommendation. Anti-TNF therapy with infliximab (good-quality evidence) or adalimumab (moderate-quality evidence) should be considered early in management of patients with visionthreatening ocular manifestations of Behçet’s disease. 2. Strong recommendation. Anti-TNF therapy with infliximab (good-quality evidence) or adalimumab (good-quality evidence) should be considered as second-line immunomodulatory therapy for children with vision-threatening uveitis secondary to JIA in whom methotrexate therapy is insufficiently effective or not tolerated. Methotrexate therapy, if tolerated, may be combined with infliximab therapy. 3. Strong recommendation. Anti-TNF therapy with infliximab or potentially adalimumab should be considered as second-line immunomodulatory therapy in patients with vision-threatening chronic uveitis from seronegative spondyloarthropathy (good- to moderate-quality evidence). 4. Discretionary recommendation. Anti-TNF therapy with infliximab or adalimumab for other forms of ocular inflammation, including sarcoidosis, scleritis, and panuveitis, may be considered in patients with vision-threatening, corticosteroid-dependent disease who have failed first-line immunomodulatory therapies such as antimetabolites or calcineurin inhibitors (moderate-quality evidence). The literature for adalimumab is less developed than for infliximab, but these agents seem to show similar efficacy in most studies. Until more comparative data are available, no recommendation can be made as to preferred agent, although numerous studies have suggested that adalimumab may be effective in patients who have become intolerant to or have developed reduced clinical responsiveness to infliximab. 5. Strong recommendation. Use of infliximab or adalimumab should be considered before etanercept therapy for treatment of ocular inflammatory disease. Etanercept may have efficacy for treatment of some forms of ocular inflammatory disease such as mucocutaneous Behçet’s disease, but it has been associated with development of uveitis in JIA patients and development of sarcoid-like disease in others. Patients presently taking etanercept for other

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Ophthalmology Volume -, Number -, Month 2014 indications with existing, incompletely controlled uveitis or new ocular inflammatory disease should consider switching to infliximab or adalimumab if possible.

19. 20.

References 21. 1. Jabs DA, Rosenbaum JT, Foster CS, et al. Guidelines for the use of immunosuppressive drugs in patients with ocular inflammatory disorders: recommendations of an expert panel. Am J Ophthalmol 2000;130:492–513. 2. Glasziou P, Vandenbroucke JP, Chalmers I. Assessing the quality of research. BMJ 2004;328:39–41. 3. Balshem H, Helfand M, Schunemann HJ, et al. GRADE guidelines: 3. Rating the quality of evidence. J Clin Epidemiol 2011;64:401–6. 4. Keaney M, Lorimer AR. Auditing the implementation of SIGN (Scottish Intercollegiate Guidelines Network) clinical guidelines. Int J Health Care Qual Assur Inc Leadersh Health Serv 1999;12:314–7. 5. Lim LL, Fraunfelder FW, Rosenbaum JT. Do tumor necrosis factor inhibitors cause uveitis? A registry-based study. Arthritis Rheum 2007;56:3248–52. 6. Braun J, Baraliakos X, Listing J, Sieper J. Decreased incidence of anterior uveitis in patients with ankylosing spondylitis treated with the anti-tumor necrosis factor agents infliximab and etanercept. Arthritis Rheum 2005;52:2447–51. 7. Dommasch E, Gelfand JM. Is there truly a risk of lymphoma from biologic therapies? Dermatol Ther 2009;22:418–30. 8. Kempen JH, Daniel E, Dunn JP, et al. Overall and cancer related mortality among patients with ocular inflammation treated with immunosuppressive drugs: retrospective cohort study. BMJ 2009;339:b2480. 9. Wolfe F, Michaud K. Lymphoma in rheumatoid arthritis: the effect of methotrexate and anti-tumor necrosis factor therapy in 18,572 patients. Arthritis Rheum 2004;50:1740–51. 10. Chakravarty EF, Michaud K, Wolfe F. Skin cancer, rheumatoid arthritis, and tumor necrosis factor inhibitors. J Rheumatol 2005;32:2130–5. 11. Wolfe F, Michaud K. The effect of methotrexate and antitumor necrosis factor therapy on the risk of lymphoma in rheumatoid arthritis in 19,562 patients during 89,710 personyears of observation. Arthritis Rheum 2007;56:1433–9. 12. Lopez-Olivo MA, Tayar JH, Martinez-Lopez JA, et al. Risk of malignancies in patients with rheumatoid arthritis treated with biologic therapy: a meta-analysis. JAMA 2012;308: 898–908. 13. Saag KG, Teng GG, Patkar NM, et al. American College of Rheumatology 2008 recommendations for the use of nonbiologic and biologic disease-modifying antirheumatic drugs in rheumatoid arthritis. Arthritis Rheum 2008;59:762–84. 14. Giganti M, Beer PM, Lemanski N, et al. Adverse events after intravitreal infliximab (Remicade). Retina 2010;30:71–80. 15. International Study Group for Behçet’s Disease. Criteria for diagnosis of Behçet’s disease. Lancet 1990;335:1078–80. 16. Arida A, Fragiadaki K, Giavri E, Sfikakis PP. Anti-TNF agents for Behçet’s disease: analysis of published data on 369 patients. Semin Arthritis Rheum 2011;41:61–70. 17. Sfikakis PP, Markomichelakis N, Alpsoy E, et al. Anti-TNF therapy in the management of Behçet’s diseasedreview and basis for recommendations. Rheumatology (Oxford) 2007;46:736–41. 18. Ohno S, Nakamura S, Hori S, et al. Efficacy, safety, and pharmacokinetics of multiple administration of infliximab in

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22. 23.

24. 25. 26. 27.

28.

29. 30. 31. 32. 33.

34.

35. 36. 37.

Behçet’s disease with refractory uveoretinitis. J Rheumatol 2004;31:1362–8. Lindstedt EW, Baarsma GS, Kuijpers RW, van Hagen PM. Anti-TNF-alpha therapy for sight threatening uveitis. Br J Ophthalmol 2005;89:533–6. Accorinti M, Pirraglia MP, Paroli MP, et al. Infliximab treatment for ocular and extraocular manifestations of Behçet’s disease. Jpn J Ophthalmol 2007;51:191–6. Niccoli L, Nannini C, Benucci M, et al. Long-term efficacy of infliximab in refractory posterior uveitis of Behçet’s disease: a 24-month follow-up study. Rheumatology (Oxford) 2007;46: 1161–4. Tognon S, Graziani G, Marcolongo R. Anti-TNF-alpha therapy in seven patients with Behçet’s uveitis: advantages and controversial aspects. Ann N Y Acad Sci 2007;1110:474–84. Petropoulos IK, Vaudaux JD, Guex-Crosier Y. Anti-TNFalpha therapy in patients with chronic non-infectious uveitis: the experience of Jules Gonin Eye Hospital. Klin Monbl Augenheilkd 2008;225:457–61. Yamada Y, Sugita S, Tanaka H, et al. Timing of recurrent uveitis in patients with Behçet’s disease receiving infliximab treatment. Br J Ophthalmol 2011;95:205–8. Yamada Y, Sugita S, Tanaka H, et al. Comparison of infliximab versus ciclosporin during the initial 6-month treatment period in Behçet disease. Br J Ophthalmol 2010;94:284–8. Tabbara KF, Al-Hemidan AI. Infliximab effects compared to conventional therapy in the management of retinal vasculitis in Behçet disease. Am J Ophthalmol 2008;146:845–50. Markomichelakis N, Delicha E, Masselos S, et al. A single infliximab infusion vs corticosteroids for acute panuveitis attacks in Behçet’s disease: a comparative 4-week study. Rheumatology (Oxford) 2011;50:593–7. Okada AA, Goto H, Ohno S, Mochizuki M, Ocular Behçet’s Disease Research Group of Japan. Multicenter study of infliximab for refractory uveoretinitis in Behçet disease. Arch Ophthalmol 2012;130:592–8. van Laar JA, Missotten T, van Daele PL, et al. Adalimumab: a new modality for Behçet’s disease [letter]? Ann Rheum Dis 2007;66:565–6. Takase K, Ohno S, Ideguchi H, et al. Successful switching to adalimumab in an infliximab-allergic patient with severe Behçet disease-related uveitis. Rheumatol Int 2011;31:243–5. Mushtaq B, Saeed T, Situnayake RD, Murray PI. Adalimumab for sight-threatening uveitis in Behçet’s disease. Eye (Lond) 2007;21:824–5. Perra D, Alba MA, Callejas JL, et al. Adalimumab for the treatment of Behçet’s disease: experience in 19 patients. Rheumatology (Oxford) 2012;51:1825–31. Olivieri I, Leccese P, D’Angelo S, et al. Efficacy of adalimumab in patients with Behçet’s disease unsuccessfully treated with infliximab. Clin Exp Rheumatol 2011;29(suppl): S54–7. Leccese P, Latanza L, D’Angelo S, et al. Efficacy of switching to adalimumab in a patient with refractory uveitis of Behçet’s disease to infliximab [letter]. Clin Exp Rheumatol 2011;29(suppl):S93. Melikoglu M, Fresko I, Mat C, et al. Short-term trial of etanercept in Behçet’s disease: a double blind, placebo controlled study. J Rheumatol 2005;32:98–105. Curigliano V, Giovinale M, Fonnesu C, et al. Efficacy of etanercept in the treatment of a patient with Behçet’s disease. Clin Rheumatol 2008;27:933–6. Atzeni F, Sarzi-Puttini P, Capsoni F, et al. Successful treatment of resistant Behçet’s disease with etanercept [letter]. Clin Exp Rheumatol 2005;23:729.

Levy-Clarke et al



Anti-TNF Therapy in Ocular Inflammation

38. Sommer A, Altmeyer P, Kreuter A. A case of mucocutaneous Behçet’s disease responding to etanercept [letter]. J Am Acad Dermatol 2005;52:717–9. 39. Estrach C, Mpofu S, Moots RJ. Behçet’s syndrome: response to infliximab after failure of etanercept [letter]. Rheumatology (Oxford) 2002;41:1213–4. 40. Richards JC, Tay-Kearney ML, Murray K, Manners P. Infliximab for juvenile idiopathic arthritis-associated uveitis. Clin Experiment Ophthalmol 2005;33:461–8. 41. Rajaraman RT, Kimura Y, Li S, et al. Retrospective case review of pediatric patients with uveitis treated with infliximab. Ophthalmology 2006;113:308–14. 42. Kahn P, Weiss M, Imundo LF, Levy DM. Favorable response to high-dose infliximab for refractory childhood uveitis. Ophthalmology 2006;113:860–4. 43. Gallagher M, Quinones K, Cervantes-Castaneda RA, et al. Biological response modifier therapy for refractory childhood uveitis. Br J Ophthalmol 2007;91:1341–4. 44. Simonini G, Zannin ME, Caputo R, et al. Loss of efficacy during long-term infliximab therapy for sight-threatening childhood uveitis. Rheumatology (Oxford) 2008;47: 1510–4. 45. Ardoin SP, Kredich D, Rabinovich E, et al. Infliximab to treat chronic noninfectious uveitis in children: retrospective case series with long-term follow-up. Am J Ophthalmol 2007;144: 844–9. 46. Biester S, Deuter C, Michels H, et al. Adalimumab in the therapy of uveitis in childhood. Br J Ophthalmol 2007;91: 319–24. 47. Tynjala P, Kotaniemi K, Lindahl P, et al. Adalimumab in juvenile idiopathic arthritis-associated chronic anterior uveitis. Rheumatology (Oxford) 2008;47:339–44. 48. Vazquez-Cobian LB, Flynn T, Lehman TJ. Adalimumab therapy for childhood uveitis. J Pediatr 2006;149:572–5. 49. Diaz-Llopis M, Salom D, Garcia-de-Vicuna C, et al. Treatment of refractory uveitis with adalimumab: a prospective multicenter study of 131 patients. Ophthalmology 2012;119: 1575–81. 50. Reiff A. Long-term outcome of etanercept therapy in children with treatment-refractory uveitis [letter]. Arthritis Rheum 2003;48:2079–80. 51. Reiff A, Takei S, Sadeghi S, et al. Etanercept therapy in children with treatment-resistant uveitis. Arthritis Rheum 2001;44:1411–5. 52. Smith JA, Thompson DJ, Whitcup SM, et al. A randomized, placebo-controlled, double-masked clinical trial of etanercept for the treatment of uveitis associated with juvenile idiopathic arthritis. Arthritis Rheum 2005;53:18–23. 53. Foster CS, Tufail F, Waheed NK, et al. Efficacy of etanercept in preventing relapse of uveitis controlled by methotrexate. Arch Ophthalmol 2003;121:437–40. 54. Galor A, Perez VL, Hammel JP, Lowder CY. Differential effectiveness of etanercept and infliximab in the treatment of ocular inflammation. Ophthalmology 2006;113:2317–23. 55. Saurenmann RK, Levin AV, Feldman BM, et al. Risk of newonset uveitis in patients with juvenile idiopathic arthritis treated with anti-TNFalpha agents. J Pediatr 2006;149:833–6. 56. Schmeling H, Horneff G. Etanercept and uveitis in patients with juvenile idiopathic arthritis. Rheumatology (Oxford) 2005;44:1008–11. 57. Saurenmann RK, Levin AV, Rose JB, et al. Tumour necrosis factor alpha inhibitors in the treatment of childhood uveitis. Rheumatology (Oxford) 2006;45:982–9. 58. Tynjala P, Lindahl P, Honkanen V, et al. Infliximab and etanercept in the treatment of chronic uveitis associated with

59.

60.

61.

62.

63.

64.

65.

66.

67.

68. 69. 70. 71. 72. 73. 74.

75.

refractory juvenile idiopathic arthritis. Ann Rheum Dis 2007;66:548–50. Foeldvari I, Nielsen S, Kummerle-Deschner J, et al. Tumor necrosis factor-alpha blocker in treatment of juvenile idiopathic arthritis-associated uveitis refractory to second-line agents: results of a multinational survey. J Rheumatol 2007;34:1146–50. Simonini G, Taddio A, Cattalini M, et al. Prevention of flare recurrences in childhood refractory chronic uveitis: an openlabel comparative study of adalimumab versus infliximab. Arthritis Care Res (Hoboken) 2011;63:612–8. Sen ES, Sharma S, Hinchcliffe A, et al. Use of adalimumab in refractory non-infectious childhood chronic uveitis: efficacy in ocular diseaseea case cohort interventional study. Rheumatology (Oxford) 2012;51:2199–203. Simonini G, Taddio A, Cattalini M, et al. Superior efficacy of adalimumab in treating childhood refractory chronic uveitis when used as first biologic modifier drug: adalimumab as starting anti-TNF-alpha therapy in childhood chronic uveitis. Pediatr Rheumatol Online J [serial online] 2013;11:16. Available at: http://www.ped-rheum.com/content/11/1/16. Accessed September 28, 2013. Heiligenhaus A, Michels H, Schumacher C, et al. Evidencebased, interdisciplinary guidelines for anti-inflammatory treatment of uveitis associated with juvenile idiopathic arthritis. Rheumatol Int 2012;32:1121–33. Rudwaleit M, Rodevand E, Holck P, et al. Adalimumab effectively reduces the rate of anterior uveitis flares in patients with active ankylosing spondylitis: results of a prospective open-label study. Ann Rheum Dis 2009;68:696–701. El-Shabrawi Y, Hermann J. Anti-tumor necrosis factor-alpha therapy with infliximab as an alternative to corticosteroids in the treatment of human leukocyte antigen B27-associated acute anterior uveitis. Ophthalmology 2002;109:2342–6. Rossman MD, Newman LS, Baughman RP, et al. A doubleblinded, randomized, placebo-controlled trial of infliximab in subjects with active pulmonary sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 2006;23:201–8. Cruz BA, Reis DD, Araujo CA; Minas Gerais Vasculitis Study Group. Refractory retinal vasculitis due to sarcoidosis successfully treated with infliximab. Rheumatol Int 2007;27: 1181–3. Baughman RP, Bradley DA, Lower EE. Infliximab in chronic ocular inflammation. Int J Clin Pharmacol Ther 2005;43:7–11. Doty JD, Mazur JE, Judson MA. Treatment of sarcoidosis with infliximab. Chest 2005;127:1064–71. Baughman RP, Lower EE, Bradley DA, et al. Etanercept for refractory ocular sarcoidosis: results of a double-blind randomized trial. Chest 2005;128:1062e47. Suzuki J, Goto H. Uveitis associated with sarcoidosis exacerbated by etanercept therapy [letter]. Jpn J Ophthalmol 2009;53:439–40. Hashkes PJ, Shajrawi I. Sarcoid-related uveitis occurring during etanercept therapy. Clin Exp Rheumatol 2003;21: 645–6. Samimi M, Lorette G, Machet L, et al. Facial granulomatous nodules during etanercept treatment for psoriasis [letter]. Int J Dermatol 2009;48:1025–7. Toussirot E, Pertuiset E, Kantelip B, Wendling D. Sarcoidosis occurring during anti-TNF-alpha treatment for inflammatory rheumatic diseases: report of two cases. Clin Exp Rheumatol 2008;26:471–5. Kudrin A, Chilvers ER, Ginawi A, et al. Sarcoid-like granulomatous disease following etanercept treatment for RA [letter]. J Rheumatol 2007;34:648–9.

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Ophthalmology Volume -, Number -, Month 2014 76. Gonzalez-Lopez MA, Blanco R, Gonzalez-Vela MC, et al. Development of sarcoidosis during etanercept therapy. Arthritis Rheum 2006;55:817–20. 77. Ahn SJ, Oh JY, Kim MK, Wee WR. Treating refractory scleritis with infliximab [letter]. Jpn J Ophthalmol 2009;53:286–7. 78. Huynh N, Cervantes-Castaneda RA, Bhat P, et al. Biologic response modifier therapy for psoriatic ocular inflammatory disease. Ocul Immunol Inflamm 2008;16:89–93. 79. Prendiville C, O’Doherty M, Moriarty P, Cassidy L. The use of infliximab in ocular inflammation. Br J Ophthalmol 2008;92:823–5. 80. Cazabon S, Over K, Butcher J. The successful use of infliximab in resistant relapsing polychondritis and associated scleritis [letter]. Eye (Lond) 2005;19:222–4. 81. Murphy CC, Ayliffe WH, Booth A, et al. Tumor necrosis factor alpha blockade with infliximab for refractory uveitis and scleritis. Ophthalmology 2004;111:352–6. 82. Sen HN, Sangave A, Hammel K, et al. Infliximab for the treatment of active scleritis [report online]. Can J Ophthalmol 2009;44:e9–12. 83. Kontkanen M, Paimela L, Kaarniranta K. Regression of necrotizing scleritis in Wegener’s granulomatosis after infliximab treatment [letter][report online]. Acta Ophthalmol 2010;88:e96–7. 84. Wegener’s Granulomatosis Etanercept Trial (WGET) Research Group. Etanercept plus standard therapy for Wegener’s granulomatosis. N Engl J Med 2005;352:351–61. 85. Stone JH, Merkel PA, Spiera R, et al; RAVE-ITN Research Group. Rituximab versus cyclophosphamide for ANCAassociated vasculitis. N Engl J Med 2010;363:221–32. 86. Suhler EB, Smith JR, Giles TR, et al. Infliximab therapy for refractory uveitis: 2-year results of a prospective trial [letter]. Arch Ophthalmol 2009;127:819–22.

87. Suhler EB, Smith JR, Wertheim MS, et al. A prospective trial of infliximab therapy for refractory uveitis: preliminary safety and efficacy outcomes. Arch Ophthalmol 2005;123: 903–12. 88. Artornsombudh P, Gevorgyan O, Payal A, et al. Infliximab treatment of patients with birdshot retinochoroidopathy. Ophthalmology 2013;120:588–92. 89. Wang Y, Gaudio PA. Infliximab therapy for 2 patients with Vogt-Koyanagi-Harada syndrome. Ocul Immunol Inflamm 2008;16:167–71. 90. Khalifa YM, Bailony MR, Acharya NR. Treatment of pediatric Vogt-Koyanagi-Harada syndrome with infliximab. Ocul Immunol Inflamm 2010;18:218–22. 91. Niccoli L, Nannini C, Cassara E, et al. Efficacy of infliximab therapy in two patients with refractory Vogt-Koyanagi-Harada disease [letter]. Br J Ophthalmol 2009;93:1553–4. 92. Benitez-del-Castillo JM, Martinez-de-la-Casa JM, PatoCour E, et al. Long-term treatment of refractory posterior uveitis with anti-TNFalpha (infliximab). Eye (Lond) 2005;19: 841–5. 93. Seve P, Mennesson E, Grange JD, et al. Infliximab in serpiginous choroiditis [letter][report online]. Acta Ophthalmol 2010;88:e342–3. 94. Suhler EB, Lowder CY, Goldstein DA, et al. Adalimumab therapy for refractory uveitis: results of a multicentre, openlabel, prospective trial. Br J Ophthalmol 2013;97:481–6. 95. Moher D, Liberati A, Tetzlaff J, et al; PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med [serial online] 2009;6(7): e1000097. Available at: http://www.plosmedicine.org/article/ info%3Adoi%2F10.1371%2Fjournal.pmed.1000097. Accessed September 28, 2013.

Footnotes and Financial Disclosures Originally received: October 30, 2012. Final revision: September 24, 2013. Accepted: September 30, 2013. Available online: ---.

Russell N. Van Gelder: Financial supportdAlcon Research Laboratories, Inc, and Novartis Manuscript no. 2012-1645.

1

St. Luke’s Cataract and Laser Institute, Tarpon Springs, Florida. Departments of Ophthalmology and Medicine, the Mount Sinai Medical School, New York, New York; Department of Epidemiology, the Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland. 3 Department of Ophthalmology, University of Alabama at Birmingham School of Medicine, Birmingham, Alabama. 2

James T. Rosenbaum: ConsultantdAbbott, Amgen, Allergan, Novartis, Pfizer, Elan, Xoma, Lux, Teva, Sanofi, Santen, Regeneron, and Genentech; Financial supportdCentocor, Genentech, Lux, Novartis, Eyegate, and Abbott Douglas A. Jabs: ConsultantdAbbott Pharmaceuticals, Alcon Laboratories, Allergan, Inc, Corcept Therapeutics, Genentech, Genzyme Corporation, GlaxoSmithKline, and Roche Pharmaceuticals; Data and Safety Monitoring CommitteedApplied Genetic Technologies Corporation and Novartis Pharmaceutical Corporation

4

Departments of Ophthalmology and Medicine, Division of Rheumatology, Oregon Health & Science University, Portland, Oregon.

Russell W. Read: ConsultantdAbbott, Allergan, Lux, and Eleven BioTherapeutics; Financial supportdLux, Abbott, and Eyegate

5

Supported by The Clinician Scientist Award in Translational Scientist from Burroughs-Wellcome Foundation, Research Triangle Park, NC (R.V.G.); unrestricted grants from Research to Prevent Blindness, Inc, New York, New York (to the University of Washington, University of Alabama, and Mt. Sinai Medical School); and the Physician-Scientist award of Research to Prevent Blindness, Inc, New York, NY.

Department of Ophthalmology, Legacy Devers Eye Institute, Portland, Oregon.

6

Department of Ophthalmology, Moran Eye Institute, University of Utah School of Medicine, Salt Lake City, Utah.

7

Departments of Ophthalmology, Pathology, and Biological Structure, University of Washington School of Medicine, Seattle, Washington. Dr. Levy-Clarke is now affiliated with the Ophthalmology Projects Division, Vistakon, Jacksonville, FL 32256. Financial Disclosure(s): The author(s) have made the following disclosure(s): Grace Levy-Clarke: EmployeedVistakon

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Correspondence: Russell N. Van Gelder, MD, PhD, Department of Ophthalmology, University of Washington School of Medicine, Campus Box 359608, 325 9th Avenue, Seattle, WA 98104. E-mail: [email protected].

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Appendix 1: Supplementary references 1. Horai R, Caspi RR. Cytokines in autoimmune uveitis. J Interferon Cytokine Res 2011;31:733–44. 2. Commodaro AG, Bueno V, Belfort R Jr, Rizzo LV. Autoimmune uveitis: the associated proinflammatory molecules and the search for immunoregulation. Autoimmun Rev 2011;10:205–9. 3. Caspi R. Autoimmunity in the immune privileged eye: pathogenic and regulatory T cells. Immunol Res 2008;42:41–50. 4. Amadi-Obi A, Yu CR, Liu X, et al. TH17 cells contribute to uveitis and scleritis and are expanded by IL-2 and inhibited by IL-27/STAT1. Nat Med 2007;13:711–8. 5. Mohler KM, Torrance DS, Smith CA, et al. Soluble tumor necrosis factor (TNF) receptors are effective therapeutic agents in lethal endotoxemia and function simultaneously as both TNF carriers and TNF antagonists. J Immunol 1993;151:1548–61. 6. Wooley PH, Dutcher J, Widmer MB, Gillis S. Influence of a recombinant human soluble tumor necrosis factor receptor FC fusion protein on type II collagen-induced arthritis in mice. J Immunol 1993;151:6602–7. 7. Hooks JJ, Chan CC, Detrick B. Identification of the lymphokines, interferon-gamma and interleukin-2, in inflammatory eye diseases. Invest Ophthalmol Vis Sci 1988;29:1444–51. 8. van Laar JA, van Hagen PM. Cytokines in uveitis. Clin Med Res 2006;4:248–9. 9. Scallon BJ, Moore MA, Trinh H, et al. Chimeric anti-TNFalpha monoclonal antibody cA2 binds recombinant transmembrane TNF-alpha and activates immune effector functions. Cytokine 1995;7:251–9. 10. van Dullemen HM, van Deventer SJ, Hommes DW, et al. Treatment of Crohn’s disease with anti-tumor necrosis factor chimeric monoclonal antibody (cA2). Gastroenterology 1995;109:129–35. 11. Murray PI, Hoekzema R, van Haren MA, et al. Aqueous humor interleukin-6 levels in uveitis. Invest Ophthalmol Vis Sci 1990;31:917–20. 12. Franks WA, Limb GA, Stanford MR, et al. Cytokines in human intraocular inflammation. Curr Eye Res 1992;11(Suppl):187–91. 13. Palexas GN, Sussman G, Welsh NH. Ocular and systemic determination of IL-1 beta and tumour necrosis factor in a patient with ocular inflammation. Scand J Immunol Suppl 1992;11:173–5. 14. Caspi RR. Experimental autoimmune uveoretinitis in the rat and mouse. Curr Protoc Immunol 2003. Chapter 15: Unit 15.6. 15. Dick AD, McMenamin PG, Korner H, et al. Inhibition of tumor necrosis factor activity minimizes target organ damage in experimental autoimmune uveoretinitis despite quantitatively normal activated T cell traffic to the retina. Eur J Immunol 1996;26:1018–25. 16. Nakamura S, Yamakawa T, Sugita M, et al. The role of tumor necrosis factor-alpha in the induction of experimental autoimmune uveoretinitis in mice. Invest Ophthalmol Vis Sci 1994;35:3884–9. 17. Robertson M, Liversidge J, Forrester JV, Dick AD. Neutralizing tumor necrosis factor-alpha activity suppresses activation of infiltrating macrophages in experimental autoimmune uveoretinitis. Invest Ophthalmol Vis Sci 2003;44:3034–41. 18. Rizzo LV, Xu H, Chan CC, et al. IL-10 has a protective role in experimental autoimmune uveoretinitis. Int Immunol 1998;10: 807–14. 19. Tarrant TK, Silver PB, Chan CC, et al. Endogenous IL-12 is required for induction and expression of experimental autoimmune uveitis. J Immunol 1998;161:122–7. 20. Caspi RR, Sun B, Agarwal RK, et al. T cell mechanisms in experimental autoimmune uveoretinitis: susceptibility is a

21. 22.

23. 24.

25. 26. 27.

28. 29. 30. 31. 32.

33. 34.

35. 36. 37. 38. 39.

function of the cytokine response profile. Eye (Lond) 1997;11(Pt 2):209–12. Busch M, Bauer D, Hennig M, et al. Effects of systemic and intravitreal TNF-alpha inhibition in experimental autoimmune uveoretinitis. Invest Ophthalmol Vis Sci 2013;54:39–46. Jones LS, Rizzo LV, Agarwal RK, et al. IFN-gamma-deficient mice develop experimental autoimmune uveitis in the context of a deviant effector response. J Immunol 1997;158: 5997–6005. Rosenbaum JT, Kievit P, Han YB, et al. Interleukin-6 does not mediate endotoxin-induced uveitis in mice: studies in gene deletion animals. Invest Ophthalmol Vis Sci 1998;39:64–9. Rosenbaum JT, Han YB, Park JM, et al. Tumor necrosis factoralpha is not essential in endotoxin induced eye inflammation: studies in cytokine receptor deficient mice. J Rheumatol 1998;25:2408–16. Goldfeld AE, Tsai EY. TNF-alpha and genetic susceptibility to parasitic disease. Exp Parasitol 1996;84:300–3. Reimold AM. TNFalpha as therapeutic target: new drugs, more applications. Curr Drug Targets Inflamm Allergy 2002;1: 377–92. Cheng YJ, Yang BC, Hsieh WC, et al. Enhancement of TNFalpha expression does not trigger apoptosis upon exposure of glial cells to lead and lipopolysaccharide. Toxicology 2002;178:183–91. Kavanaugh AF. Anti-tumor necrosis factor-alpha monoclonal antibody therapy for rheumatoid arthritis. Rheum Dis Clin North Am 1998;24:593–614. Illei GG, Lipsky PE. Novel, non-antigen-specific therapeutic approaches to autoimmune/inflammatory diseases. Curr Opin Immunol 2000;12:712–8. Zhou H. Clinical pharmacokinetics of etanercept: a fully humanized soluble recombinant tumor necrosis factor receptor fusion protein. J Clin Pharmacol 2005;45:490–7. Keystone EC. Tumor necrosis factor-alpha blockade in the treatment of rheumatoid arthritis. Rheum Dis Clin North Am 2001;27:427–43. Thyagarajan V, Norman H, Alexander KA, et al. Risk of mortality, fatal infection, and fatal malignancy related to use of anti-tumor necrosis factor-alpha biologics by rheumatoid arthritis patients. Semin Arthritis Rheum 2012;42:223–33. Gan J, Manadan AM, Sequiera W, Block JA. Tuberculosis infections and tumor necrosis factor alpha antagonists. Am J Ther 2013;20:73–8. Tubach F, Salmon D, Ravaud P, et al. Risk of tuberculosis is higher with anti-tumor necrosis factor monoclonal antibody therapy than with soluble tumor necrosis factor receptor therapy: the three-year prospective French Research Axed on Tolerance of Biotherapies registry. Arthritis Rheum 2009;60: 1884–94. Fonollosa A, Segura A, Giralt J, Garcia-Arumi J. Tuberculous uveitis after treatment with etanercept. Graefes Arch Clin Exp Ophthalmol 2007;245:1397–9. Lozeron P, Denier C, Lacroix C, Adams D. Long-term course of demyelinating neuropathies occurring during tumor necrosis factor-alpha-blocker therapy. Arch Neurol 2009;66:490–7. Louis M, Rauch J, Armstrong M, Fitzcharles MA. Induction of autoantibodies during prolonged treatment with infliximab. J Rheumatol 2003;30:2557–62. Caramaschi P, Bambara LM, Pieropan S, et al. Anti-TNFalpha blockers, autoantibodies and autoimmune diseases. Joint Bone Spine 2009;76:333–42. Laffitte E, Janssens JP, Roux-Lombard P, et al. Tuberculosis screening in patients with psoriasis before antitumour necrosis factor therapy: comparison of an interferon-gamma release

12.e1

Ophthalmology Volume -, Number -, Month 2014

40.

41.

42. 43. 44. 45.

46. 47.

48. 49.

50.

51. 52. 53. 54. 55. 56. 57. 58.

assay vs. tuberculin skin test. Br J Dermatol 2009;161: 797–800. Theis VS, Rhodes JM. Review article: minimizing tuberculosis during anti-tumour necrosis factor-alpha treatment of inflammatory bowel disease. Aliment Pharmacol Ther 2008;27: 19–30. Beigel F, Schnitzler F, Paul Laubender R, et al. Formation of antinuclear and double-strand DNA antibodies and frequency of lupus-like syndrome in anti-TNF-alpha antibody-treated patients with inflammatory bowel disease. Inflamm Bowel Dis 2011;17:91–8. Suhler EB, Smith JR, Giles TR, et al. Infliximab therapy for refractory uveitis: 2-year results of a prospective trial. Arch Ophthalmol 2009;127:819–22. Lim LL, Fraunfelder FW, Rosenbaum JT. Do tumor necrosis factor inhibitors cause uveitis? A registry-based study. Arthritis Rheum 2007;56:3248–52. Sieper J. Developments in the scientific and clinical understanding of the spondyloarthritides. Arthritis Res Ther 2009;11: 208. Scrivo R, Spadaro A, Spinelli FR, Valesini G. Uveitis following the use of tumor necrosis factor alpha inhibitors: comment on the article by Lim et al. Arthritis Rheum 2008;58: 1555–6. author reply 6e7. Sfikakis PP, Markomichelakis N. Tumor necrosis factor inhibitors and uveitis: comment on the article by Lim et al. Arthritis Rheum 2008;58:1554–5. author reply 6e7. Sheane BJ, Howard D, Doran MF, Cunnane G. Link between tumor necrosis factor inhibitors and onset of uveitis: comment on the article by Lim et al. Arthritis Rheum 2008;58:1554. author reply 6e7. Saurenmann RK, Levin AV, Feldman BM, et al. Risk of newonset uveitis in patients with juvenile idiopathic arthritis treated with anti-TNFalpha agents. J Pediatr 2006;149:833–6. Fouache D, Goeb V, Massy-Guillemant N, et al. Paradoxical adverse events of anti-tumour necrosis factor therapy for spondyloarthropathies: a retrospective study. Rheumatology (Oxford) 2009;48:761–4. Bouchra A, Benbouazza K, Hajjaj-Hassouni N. Guillain-Barre in a patient with ankylosing spondylitis secondary to ulcerative colitis on infliximab therapy. Clin Rheumatol 2009;28(Suppl 1):S53–5. Hashkes PJ, Shajrawi I. Sarcoid-related uveitis occurring during etanercept therapy. Clin Exp Rheumatol 2003;21:645–6. Sfikakis PP, Iliopoulos A, Elezoglou A, et al. Psoriasis induced by anti-tumor necrosis factor therapy: a paradoxical adverse reaction. Arthritis Rheum 2005;52:2513–8. Garrison L, McDonnell ND. Etanercept: therapeutic use in patients with rheumatoid arthritis. Ann Rheum Dis 1999;58(Suppl 1):I65–59. Bickston SJ, Lichtenstein GR, Arseneau KO, et al. The relationship between infliximab treatment and lymphoma in Crohn’s disease. Gastroenterology 1999;117:1433–7. Wolfe F, Michaud K. Lymphoma in rheumatoid arthritis: the effect of methotrexate and anti-tumor necrosis factor therapy in 18,572 patients. Arthritis Rheum 2004;50:1740–51. Bucher C, Degen L, Dirnhofer S, et al. Biologics in inflammatory disease: infliximab associated risk of lymphoma development. Gut 2005;54:732–3. Burger DC, Florin TH. Hepatosplenic T-cell lymphoma following infliximab therapy for Crohn’s disease. Med J Aust 2009;190:341–2. Dommasch E, Gelfand JM. Is there truly a risk of lymphoma from biologic therapies? Dermatol Ther 2009;22:418–30.

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59. Mariette X, Tubach F, Bagheri H, et al. Lymphoma in patients treated with anti-TNF: results of the 3-year prospective French RATIO registry. Ann Rheum Dis 2010;69:400–8. 60. Mellemkjaer L, Linet MS, Gridley G, et al. Rheumatoid arthritis and cancer risk. Eur J Cancer 1996;32A:1753–7. 61. Baecklund E, Ekbom A, Sparen P, et al. Disease activity and risk of lymphoma in patients with rheumatoid arthritis: nested case-control study. BMJ 1998;317:180–1. 62. Kempen JH, Gangaputra S, Daniel E, et al. Long-term risk of malignancy among patients treated with immunosuppressive agents for ocular inflammation: a critical assessment of the evidence. Am J Ophthalmol 2008;146:802e12 e1. 63. Diak P, Siegel J, La Grenade L, et al. Tumor necrosis factor alpha blockers and malignancy in children: forty-eight cases reported to the Food and Drug Administration. Arthritis Rheum 2010;62:2517–24. 64. Targeted tuberculin testing and treatment of latent tuberculosis infection. This official statement of the American Thoracic Society was adopted by the ATS Board of Directors, July 1999. This is a Joint Statement of the American Thoracic Society (ATS) and the Centers for Disease Control and Prevention (CDC). This statement was endorsed by the Council of the Infectious Diseases Society of America. (IDSA), September 1999, and the sections of this statement. Am J Respir Crit Care Med 2000;161:S221–47. 65. Hosseini H, Safaei A, Khalili MR, et al. Intravitreal infliximab in experimental endotoxin-induced uveitis. Eur J Ophthalmol 2009;19:818–23. 66. Theodossiadis PG, Liarakos VS, Sfikakis PP, et al. Intravitreal administration of the anti-TNF monoclonal antibody infliximab in the rabbit. Graefes Arch Clin Exp Ophthalmol 2009;247: 273–81. 67. Giansanti F, Ramazzotti M, Vannozzi L, et al. A pilot study on ocular safety of intravitreal infliximab in a rabbit model. Invest Ophthalmol Vis Sci 2008;49:1151–6. 68. Farvardin M, Afarid M, Mehryar M, Hosseini H. Intravitreal infliximab for the treatment of sight-threatening chronic noninfectious uveitis. Retina 2010;30:1530–5. 69. Farvardin M, Afarid M, Shahrzad S. Long-term effects of intravitreal infliximab for treatment of sight-threatening chronic noninfectious uveitis. J Ocul Pharmacol Ther 2012;28:628–31. 70. Wu L, Arevalo JF, Hernandez-Bogantes E, et al. Intravitreal tumor necrosis factor-alpha inhibitors for neovascular agerelated macular degeneration suboptimally responsive to antivascular endothelial growth factor agents: a pilot study from the Pan American Collaborative Retina Study Group. J Ocul Pharmacol Ther 2013;29:366–71. 71. Arias L, Caminal JM, Badia MB, et al. Intravitreal infliximab in patients with macular degeneration who are nonresponders to antivascular endothelial growth factor therapy. Retina 2010;30:1601–8. 72. Wu L, Arevalo JF, Hernandez-Bogantes E, Roca JA. Intravitreal infliximab for refractory pseudophakic cystoid macular edema: results of the Pan-American Collaborative Retina Study Group. Int Ophthalmol 2012;32:235–43. 73. Wu L, Hernandez-Bogantes E, Roca JA, et al. intravitreal tumor necrosis factor inhibitors in the treatment of refractory diabetic macular edema: a pilot study from the PanAmerican Collaborative Retina Study Group. Retina 2011;31:298–303. 74. Pulido JS, Pulido JE, Michet CJ, Vile RG. More questions than answers: a call for a moratorium on the use of intravitreal infliximab outside of a well-designed trial. Retina 2010;30:1–5.

Levy-Clarke et al



Anti-TNF Therapy in Ocular Inflammation

75. Woreta F, Thorne JE, Jabs DA, et al. Risk factors for ocular complications and poor visual acuity at presentation among patients with uveitis associated with juvenile idiopathic arthritis. Am J Ophthalmol 2007;143:647–55. 76. Thorne JE, Woreta F, Kedhar SR, et al. Juvenile idiopathic arthritis-associated uveitis: incidence of ocular complications and visual acuity loss. Am J Ophthalmol 2007;143: 840–6. 77. Kump LI, Castaneda RA, Androudi SN, et al. Visual outcomes in children with juvenile idiopathic arthritis-associated uveitis. Ophthalmology 2006;113:1874–7.

78. Richards JC, Tay-Kearney ML, Murray K, Manners P. Infliximab for juvenile idiopathic arthritis-associated uveitis. Clin Experiment Ophthalmol 2005;33:461–8. 79. Tam LS, Gu J, Yu D. Pathogenesis of ankylosing spondylitis. Nat Rev Rheumatol 2010;6:399–405. 80. Braun J, Baraliakos X, Listing J, Sieper J. Decreased incidence of anterior uveitis in patients with ankylosing spondylitis treated with the anti-tumor necrosis factor agents infliximab and etanercept. Arthritis Rheum 2005;52:2447–51. 81. Jabs DA, Johns CJ. Ocular involvement in chronic sarcoidosis. Am J Ophthalmol 1986;102:297–301.

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