Immunology and Uveitis

Oray M, Abusamra K, Ebrahimiadib N, Meese H, Foster SC. Long-term side effects of glucocorticoids. Expert Opin Drug Saf 2016;15(4):457-65.Abstract

INTRODUCTION: Glucocorticoids represent the standard therapy for reducing inflammation and immune activation in various diseases. However, as with any potent medication, they are not without side effects. Glucocorticoid-associated side effects may involve most major organ systems. Musculoskeletal, gastrointestinal, cardiovascular, endocrine, neuropsychiatric, dermatologic, ocular, and immunologic side effects are all possible. AREAS COVERED: This article analyzes English-language literature and provides an update on the most recent literature regarding side effects of systemic glucocorticoid treatment. EXPERT OPINION: The risk/benefit ratio of glucocorticoid therapy can be improved by proper use. Careful monitoring and using appropriate preventive strategies can potentially minimize side effects.

Maleki A, Swan RT, Silpa-Archa S, Preble JM, He Y, Foster SC. Short-Wavelength Automated Perimetry Parameters at Baseline and Following Remission in Patients With Birdshot Retinochoroidopathy. Am J Ophthalmol 2016;163:83-92.e6.Abstract

PURPOSE: To identify changes in short-wavelength automated perimetry patterns and parameters between the active and inactive states. DESIGN: Retrospective cohort study with age-matched, normal controls. METHODS: setting: Private tertiary referral center. STUDY POPULATION: Seventy-five eyes of 38 patients with active birdshot retinochoroidopathy and 37 eyes of 37 historical normal controls. INTERVENTION: Thirty-seven patients received immunomodulatory therapy. A fluocinolone acetonide intravitreal implant (Retisert) was implanted in both eyes of 1 patient as an initial treatment. MAIN OUTCOME MEASURES: Changes in short-wavelength automated perimetry total deviation scores, pattern deviation scores, mean deviation, and pattern standard deviation in the active phase and the remission state. RESULTS: Mean deviation (P = .006), pattern standard deviation (P = .001), total deviation score (P = .002), and pattern deviation score (P = .007) were significantly different from the active phase to the remission state. The length of time required to achieve remission did not significantly affect the changes in mean deviation (regression coefficient = 0.01; P = .92), pattern standard deviation (regression coefficient = 0.01; P = .87), total deviation score (regression coefficient = -0.1; P = .32), or pattern deviation score (regression coefficient = 0.1; P = .36) from the active phase to the remission state. CONCLUSION: There was significant improvement in total deviation score, pattern deviation score, mean deviation, and pattern standard deviation on short-wavelength automated perimetry as patients achieved remission. Short-wavelength automated perimetry appears to be a useful and complementary modality in monitoring disease activity in birdshot retinochoroidopathy.

Foster SC, Kothari S, Anesi SD, Vitale AT, Chu D, Metzinger JL, Cerón O. The Ocular Immunology and Uveitis Foundation preferred practice patterns of uveitis management. Surv Ophthalmol 2016;61(1):1-17.Abstract

Ocular inflammatory disease is a leading cause of vision loss worldwide. Uveitis encompasses a wide spectrum of pathology, both with respect to its etiology and the anatomic location within the eye. Inflammation can be confined to the eye and may also be seen systemically. The cornerstone of management of ocular inflammatory disease historically has been corticosteroids, which are invaluable in the immediate control of inflammation; however, corticosteroids are inappropriate for long-term use as they are associated with a wide array of toxic side effects. As we continue to learn more about the various etiologies and elucidate the basic science pathways and mechanisms of action that cause intraocular inflammation, new therapeutic approaches have evolved. They include employment of immunomodulatory agents (corticosteroid-sparing therapies) that have expanded our treatment options for these vision-threatening diseases. These pharmacologics provide therapy for ocular and systemic inflammation in an individualized, patient-tailored, stepladder approach with the ultimate goal of durable, corticosteroid-free remission. We review the preferred practice patterns of a tertiary care center specializing in ocular inflammatory disease.

Boonsopon S, Maghsoudlou A, Kombo NE, Foster SC. A therapeutic trial of valganciclovir in patients with uveitis and positive Epstein-Barr virus early antigen D IgG titers. Eur J Ophthalmol 2015;26(1):30-5.Abstract

PURPOSE: To evaluate the effectiveness of a therapeutic trial of valganciclovir in patients with uveitis with positive Epstein-Barr virus early antigen D immunoglobulin G titers (EBV EA-D). METHODS: We performed a retrospective chart review of 14 patients at the Massachusetts Eye Research and Surgery Institution who had uveitis with positive EBV EA-D but negative studies for all other causes of uveitis and were treated with valganciclovir 450 mg twice a day or valganciclovir 900 mg twice a day between January 2010 and August 2014. RESULTS: Nine of 14 patients, who had presumed EBV reactivation with associated intraocular inflammation, were successfully treated with valganciclovir: 3 of these were treated with valganciclovir 450 mg twice a day and 6 were treated with valganciclovir 900 mg twice a day. Five of 14 patients failed to respond to valganciclovir with persistent inflammation after at least 2 weeks of valganciclovir therapy, and were subsequently treated with immunomodulatory therapy to control inflammation. CONCLUSIONS: Uveitis can be caused by EBV infection/reactivation. A therapeutic trial with valganciclovir 450 mg twice a day for 1 month in patients with uveitis with positive EBV EA antibody may be beneficial.

Shoda H, Yanai R, Yoshimura T, Nagai T, Kimura K, Sobrin L, Connor KM, Sakoda Y, Tamada K, Ikeda T, Sonoda K-H. Dietary Omega-3 Fatty Acids Suppress Experimental Autoimmune Uveitis in Association with Inhibition of Th1 and Th17 Cell Function. PLoS One 2015;10(9):e0138241.Abstract

Omega (ω)-3 long-chain polyunsaturated fatty acids (LCPUFAs) inhibit the production of inflammatory mediators and thereby contribute to the regulation of inflammation. Experimental autoimmune uveitis (EAU) is a well-established animal model of autoimmune retinal inflammation. To investigate the potential effects of dietary intake of ω-3 LCPUFAs on uveitis, we examined the anti-inflammatory properties of these molecules in comparison with ω-6 LCPUFAs in a mouse EAU model. C57BL/6 mice were fed a diet containing ω-3 LCPUFAs or ω-6 LCPUFAs for 2 weeks before as well as after the induction of EAU by subcutaneous injection of a fragment of human interphotoreceptor retinoid-binding protein emulsified with complete Freund's adjuvant. Both clinical and histological scores for uveitis were smaller for mice fed ω-3 LCPUFAs than for those fed ω-6 LCPUFAs. The concentrations of the T helper 1 (Th1) cytokine interferon-γ and the Th17 cytokine interleukin-17 in intraocular fluid as well as the production of these cytokines by lymph node cells were reduced for mice fed ω-3 LCPUFAs. Furthermore, the amounts of mRNAs for the Th1- and Th17-related transcription factors T-bet and RORγt, respectively, were reduced both in the retina and in lymph node cells of mice fed ω-3 LCPUFAs. Our results thus show that a diet enriched in ω-3 LCPUFAs suppressed uveitis in mice in association with inhibition of Th1 and Th17 cell function.

Kothari S, Foster SC, Pistilli M, Liesegang TL, Daniel E, Sen NH, Suhler EB, Thorne JE, Jabs DA, Levy-Clarke GA, Nussenblatt RB, Rosenbaum JT, Lawrence SD, Kempen JH, for Eye Diseases Group SITR. The Risk of Intraocular Pressure Elevation inPediatric Noninfectious Uveitis. Ophthalmology 2015;122(10):1987-2001.Abstract

PURPOSE: To characterize the risk and risk factors for intraocular pressure (IOP) elevation in pediatric noninfectious uveitis. DESIGN: Multicenter retrospective cohort study. PARTICIPANTS: Nine hundred sixteen children (1593 eyes) younger than 18 years at presentation with noninfectious uveitis followed up between January 1978 and December 2007 at 5 academic uveitis centers in the United States. METHODS: Medical records review by trained, certified experts. MAIN OUTCOME MEASURES: Prevalence and incidence of IOP of 21 mmHg or more and 30 mmHg or more and incidence of a rise in IOP by 10 mmHg or more. To avoid underascertainment, outcomes were counted as present when IOP-lowering therapies were in use. RESULTS: Initially, 251 (15.8%) and 46 eyes (2.9%) had IOP ≥21 mmHg and ≥30 mmHg, respectively. Factors significantly associated with presenting IOP elevation included age of 6 to 12 years (versus other pediatric ages), prior cataract surgery, pars plana vitrectomy, duration of uveitis ≥6 months, contralateral IOP elevation, presenting visual acuity worse than 20/40, and topical corticosteroid use (in a dose-response relationship). The median follow-up was 1.25 years (interquartile range, 0.4-3.66). The estimated incidence of any observed IOP elevation to ≥21 mmHg, to ≥30 mmHg, and increase in IOP by ≥10 mmHg was 33.4%, 14.8%, and 24.4%, respectively, within 2 years. Factors associated with IOP elevation included pars plana vitrectomy, contralateral IOP elevation (adjusted hazard ratio [aHR], up to 9.54; P < 0.001), and the use of topical (aHR, up to 8.77 that followed a dose-response relationship; P < 0.001), periocular (aHR, up to 7.96; P < 0.001), and intraocular (aHR, up to 19.7; P < 0.001) corticosteroids. CONCLUSIONS: Intraocular pressure elevation affects a large minority of children with noninfectious uveitis. Statistically significant risk factors include IOP elevation or use of IOP-lowering treatment in the contralateral eye and local corticosteroid use that demonstrated a dose-and route of administration-dependent relationship. In contrast, use of immunosuppressive drug therapy did not increase such risk. Pediatric eyes with noninfectious uveitis should be followed up closely for IOP elevation, especially when strong risk factors such as the use of local corticosteroids and contralateral IOP elevation are present.

Cordero-Coma M, Sobrin L. Anti-tumor necrosis factor-α therapy in uveitis. Surv Ophthalmol 2015;60(6):575-89.Abstract

Since the first reported use in 2001 of an anti-tumor necrosis factor-alpha (TNF-α) agent, infliximab, for the treatment of uveitis, several new anti-TNF-α agents have emerged for the treatment of refractory noninfectious uveitides, although their use remains off-label in the US. These agents have demonstrated remarkable clinical antiinflammatory efficacy and a potential immunoregulatory role in selected uveitis patients, but it is currently unclear whether they can modify the natural history of disease. We review the rationale and clinical indications for this therapy, the differences between agents, how to manage dosing and intervals, and how to screen for and identify potential side effects. We also present a summary of the science behind the use of anti-TNF-α agents in ocular inflammation and the evidence for their efficacy.

Kruh JN, Yang P, Suelves AM, Foster SC. Infliximab for the treatment of refractory noninfectious Uveitis: a study of 88 patients with long-term follow-up. Ophthalmology 2014;121(1):358-364.Abstract
OBJECTIVE: To establish the safety and efficacy of infliximab for the treatment of refractory noninfectious uveitis. DESIGN: Retrospective, interventional, noncomparative cohort study. PARTICIPANTS: Eighty-eight patients from a single-center private practice. METHODS: Patients with chronic, recalcitrant uveitis treated with infliximab (Remicade; Janssen Biotech, Inc., Titusville, NJ) were identified through an electronic medical record database. All charts were reviewed for sex, diagnosis, location of inflammation, presence of vasculitis, prior immunomodulatory treatments, duration of infliximab treatment, dose received, secondary side effects, and other medications continued while receiving treatment with infliximab. MAIN OUTCOME MEASURES: The primary outcome measures were the rate of remission, time to remission, relapse rate, failure rate, and patient tolerance. Additional analysis aimed to identity risk factors that would predict a higher success rate of infliximab to treat various types of noninfectious uveitis. RESULTS: Of the 72 patients (81.8%) who achieved clinical remission while being treated with infliximab, 42 (58.3%) required additional immunomodulatory medications. At 7, 18.1, and 44.7 weeks, 25%, 50%, and 75% of patients, respectively, achieved clinical remission off all corticosteroids. Thirty-two patients (36.4%) experienced at least 1 side effect while on infliximab therapy, and 17 patients (19.3%) discontinued treatment secondary to 1 or more intolerable side effects. The most common adverse effects were skin rash (9.1%) and fatigue (8%). Factors associated with a higher chance to achieve clinical remission were nonidiopathic uveitis (P < 0.001), intermediate or panuveitis (P < 0.001), absence of vasculitis (P < 0.001), and a starting dose ≥5 mg/kg (P < 0.011). CONCLUSIONS: Infliximab induces a high rate of complete clinical remission in recalcitrant uveitis and is well tolerated by most patients.
Hsu S-M, Mathew R, Taylor AW, Stein-Streilein J. Ex-vivo tolerogenic F4/80⁺ antigen-presenting cells (APC) induce efferent CD8⁺ regulatory T cell-dependent suppression of experimental autoimmune uveitis. Clin Exp Immunol 2014;176(1):37-48.Abstract
It is known that inoculation of antigen into the anterior chamber (a.c.) of a mouse eye induces a.c.-associated immune deviation (ACAID), which is mediated in part by antigen-specific local and peripheral tolerance to the inciting antigen. ACAID can also be induced in vivo by intravenous (i.v.) inoculation of ex-vivo-generated tolerogenic antigen-presenting cells (TolAPC). The purpose of this study was to test if in-vitro-generated retinal antigen-pulsed TolAPC suppressed established experimental autoimmune uveitis (EAU). Retinal antigen-pulsed TolAPC were injected i.v. into mice 7 days post-induction of EAU. We observed that retinal antigen-pulsed TolAPC suppressed the incidence and severity of the clinical expression of EAU and reduced the expression of associated inflammatory cytokines. Moreover, extract of whole retina efficiently replaced interphotoreceptor retinoid-binding protein (IRBP) in the preparation of TolAPC used to induce tolerance in EAU mice. Finally, the suppression of EAU could be transferred to a new set of EAU mice with CD8⁺ but not with CD4⁺ regulatory T cells (T(reg)). Retinal antigen-pulsed TolAPC suppressed ongoing EAU by inducing CD8⁺ T(reg) cells that, in turn, suppressed the effector activity of the IRBP-specific T cells and altered the clinical symptoms of autoimmune inflammation in the eye. The ability to use retinal extract for the antigen raises the possibility that retinal extract could be used to produce autologous TolAPC and then used as therapy in human uveitis.
Wentworth BA, Freitas-Neto CA, Foster SC. Management of pediatric uveitis. F1000Prime Rep 2014;6:41.Abstract
Pediatric uveitis is a topic of special interest not only because of the unique diagnostic and therapeutic challenges but also because of the lifetime burden of vision loss if the problem is not adequately treated, as well as the economic and psychological toll on the family. Often, uveitis in children is discovered as part of a routine eye exam; this silent, insidious inflammation can be difficult to treat and can lead to further complications if not handled skillfully. Corticosteroids have long been the mainstay of therapy; however, the significant associated side effects mandate a corticosteroid-sparing therapeutic regimen in pursuit of remission. In this review, we cover the therapeutic options for pediatric uveitis, specifically focusing on the most common non-infectious varieties, juvenile idiopathic arthritis-associated uveitis and pars planitis.
Suelves AM, Siddique SS, Schurko B, Foster SC. Anterior chamber intraocular lens implantation in patients with a history of chronic uveitis: five-year follow-up. J Cataract Refract Surg 2014;40(1):77-81.Abstract
PURPOSE: To compare the incidence of long-term complications after cataract surgery with primary anterior chamber intraocular lens (AC IOL) implantation in uveitic patients and patients without a history of intraocular inflammation (control group). SETTING: Single-center private practice. DESIGN: Retrospective clinical study. METHODS: The study comprised patients who between November 2005 and August 2010 had cataract extraction followed by AC IOL implantation because conventional placement was not possible. Outcome measures were the incidence of intraoperative and postoperative complications, preoperative corrected distance visual acuity (CDVA), and CDVA after 1 year. RESULTS: Of the 39 patients identified through electronic medical records, 17 (17 eyes) had a history of chronic uveitis and 22 (23 eyes) had no intraocular inflammatory disease. There were no significant differences in the incidence of intraoperative and postoperative complications between the 2 groups during follow-up (range 12 to 68 months) (P=.702). Although uveitic eyes had a greater risk for epiretinal membrane formation, the incidence of uveitis flareups attributed to the IOL and deposits on IOL surfaces was comparable to that in the control group (P<.001). The CDVA improved significantly in both groups 1 year after surgery (P<.01 and P<.001, respectively). CONCLUSION: In uveitic eyes with inadequate capsule support, AC IOL implantation restored visual function without a significant increase in long-term postoperative complications compared with eyes that had no history of uveitis.

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