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Immunology and Uveitis

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Hall N, Douglas VP, Ivanov A, Ross C, Elze T, Kempen JH, Miller JW, Sobrin L, Lorch A. The Epidemiology and Risk Factors for the Progression of Sympathetic Ophthalmia in the United States: An IRIS Registry Analysis. Am J Ophthalmol 2024;258:208-216.Abstract
PURPOSE: To investigate the demographic and clinical characteristics of patients with sympathetic ophthalmia (SO) and define the risk factors for its incidence following trauma and ophthalmic procedures. DESIGN: Retrospective cohort study. PARTICIPANTS: Patients in the American Academy of Ophthalmology's (Academy) IRIS Registry (Intelligent Research in Sight) who were (n=1523) or were not diagnosed with SO following a documented procedure or trauma between January 1, 2013, and December 31, 2019. METHODS: Multiple demographic and clinical factors were collected, descriptive statistics and prevalence were calculated, and multivariate linear regression models were fit to the data. MAIN OUTCOME MEASURES: Prevalence of SO, demographic and clinical characteristics, and beta coefficient (β) estimates of demographic and clinical characteristics impacting time to SO onset after procedure (Procedure Only cohort) or trauma (Trauma cohort). RESULTS: Of 65,348,409 distinct IRIS Registry patients, 1523 (0.0023%) were diagnosed with SO between 2013 and 2019, and also had a documented preceding trauma or procedure. Of these, 927 (60.87%) were female, 1336 (87.72%) belonged to the Procedure Only cohort, and 187 (12.28%) belonged to the Trauma cohort. The prevalence of SO after trauma was 0.0207%, whereas after procedures it was 0.0124%. The highest risk of procedure-related SO was seen in patients with history of "other anterior segment" (0.122%) followed by glaucoma (0.066%) procedures, whereas the lowest prevalence was noted with cataract surgeries (0.011%). The average time to onset of SO across both cohorts combined was 527.44 (±715.60) days, with statistically significant differences between the 2 cohorts (P < .001). On average, the time to onset from inciting event to SO was shorter with increasing age, by 9.02 (95% CI: -11.96, -6.08) days for every 1-year increase. CONCLUSIONS: SO following trauma and ophthalmic procedure is potentially rarer than previously reported, as measured in this large ophthalmic medical record database. Female sex may be a risk factor for SO. Older age may be a risk factor for quicker onset. These findings can guide clinical decision-making and management.
He B, Tanya SM, Wang C, Kezouh A, Torun N, Ing E. The Incidence of Sympathetic Ophthalmia After Trauma: A Meta-analysis. Am J Ophthalmol 2022;234:117-125.Abstract
PURPOSE: Sympathetic ophthalmia (SO) is a rare, bilateral panuveitis that occurs following open globe injury (OGI), with a variable incidence reported in the literature. Our objective was to determine the incidence proportion and incidence rate of SO following OGI to help guide shared physician-patient decision making. DESIGN: Systematic review and meta-analysis. METHODS: A systematic literature search was performed using the MEDLINE, EMBASE, and Cochrane databases from inception to November 2020 for population-based studies on OGI and SO in adults and children. Two reviewers independently screened search results. Random-effects meta-analyses were performed to calculate the incidence proportion and incidence rate. The Risk Of Bias In Non-Randomized Studies - of Interventions (ROBINS-I) tool was used to assess the risk of bias. The study was registered on PROSPERO CRD42020198920. RESULTS: A total of 24 studies were utilized in the meta-analyses. After OGI, the estimated overall incidence proportion of SO was 0.19% (95% CI 0.14%-0.24%) and the incidence rate of SO was 33 per 100,000 person-years, (95% CI 19.61-56.64) with I2 of 13% and 72%, respectively. CONCLUSIONS: SO after OGI is rare. The estimated incidence proportion and incidence rate are useful when counselling patients regarding management options after OGI. Further studies are needed to examine the influence of age, the extent and location of trauma, timing of repair, and prophylactic eye removal on the incidence of SO.
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.
Hua J, Inomata T, Chen Y, Foulsham W, Stevenson W, Shiang T, Bluestone JA, Dana R. Pathological conversion of regulatory T cells is associated with loss of allotolerance. Sci Rep 2018;8(1):7059.Abstract
CD4CD25Foxp3 Regulatory T cells (Tregs) play a critical role in immune tolerance. The plasticity and functional adaptability of Tregs in an inflammatory microenvironment has been demonstrated in autoimmunity. Here, using a double transgenic mouse model that permits Foxp3 lineage tracing, we investigated the phenotypic plasticity of Foxp3 Tregs in a well-characterized murine model of corneal transplantation. In order to subvert the normal immune privilege of the cornea and foster an inflammatory milieu, host mice were exposed to desiccating stress prior to transplantation. Treg frequencies and function were decreased following desiccating stress, and this corresponded to decreased graft survival. A fraction of Tregs converted to IL-17 or IFNγ 'exFoxp3' T cells that were phenotypically indistinguishable from effector Th17 or Th1 cells, respectively. We investigated how Foxp3 expression is modulated in different Treg subsets, demonstrating that neuropilin-1 peripherally-derived Tregs are particularly susceptible to conversion to IL-17/IFNγ exFoxp3 cells in response to cues from their microenvironment. Finally, we show that IL-6 and IL-23 are implicated in the conversion of Tregs to exFoxp3 cells. This report demonstrates that the pathological conversion of Tregs contributes to the loss of corneal immune privilege.
Hunter RS, Skondra D, Papaliodis G, Sobrin L. Role of OCT in the diagnosis and management of macular edema from uveitis. Semin Ophthalmol 2012;27(5-6):236-41.Abstract
Uveitis is a potentially visually threatening disease accounting for 10% of vision loss in the developed world. The most common cause of vision loss in patients with uveitis has been shown to be macular edema (ME). The early detection and management of ME is critical to preserve vision in these patients. Optical coherence tomography (OCT) is a valuable tool in the management of many ocular diseases. The use of OCT has revolutionized the diagnosis and management of macular edema from a wide variety of ophthalmological diseases, including uveitis. In this review, we evaluate the role of OCT in the diagnosis and management of uveitic macular edema.
Huynh E, Elhusseiny AM, Nihalani BR. Paediatric anterior uveitis management in the USA: a single-centre, 10-year retrospective chart review exploring the efficacy and safety of systemic immunomodulatory therapy. Eye (Lond) 2023;37(7):1325-1330.Abstract
OBJECTIVE: To evaluate the efficacy of immunomodulatory therapy (IMT) in paediatric anterior uveitis. METHODS: Chart review of all patients ≤ 18 years treated for anterior uveitis using a stepladder approach during a 10-year period. The type and duration of IMT were noted. The data were analysed depending on chronicity, aetiology, and type of IMT using appropriate statistical tests. The outcome measures included ocular complications, the need for surgical intervention, and visual outcomes. RESULTS: One hundred and thirty-four patients (191 eyes) were analyzed. The median age at diagnosis was 7 years (interquartile range (IQR): 7.5 years). The median follow-up was 4 years (IQR: 6 years). The most common causes of anterior uveitis were Juvenile idiopathic arthritis (64 patients, 47.8%) and undifferentiated (33 patients, 24.6%). All patients were started on topical steroids and cycloplegics. 94 (70%) patients required IMT. 92 (68.6%) were started on Methotrexate as the first agent, of which 21 (22%) were switched to a different agent owing to side effects. Biologic agent was added in 55 (41%) patients. 21 (16%) required switch to a second biologic agent, 5 (3.7%) to third, and 1 (0.8%) to fourth biologic agent. At the last exam, 11 (8%) had persistent inflammation. 55 (41%) had ocular complications, and 113 (84%) had a best corrected visual acuity ≥ 20/40. CONCLUSION: Early introduction of IMT and switch to different agents may be required to control anterior uveitis and reduce the complications in children. IMT is safe and effective in treating paediatric anterior uveitis.
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Jabs DA, Sugar EA, Burke AE, Altaweel MM, Dunn JP, Gangaputra S, Kempen JH, Pepple KL, Stawell RJ, Holbrook JT, and Group MUST (MUST) TF-up SR. Cataract Surgery in Patients With Uveitis Treated With Systemic Therapy in the Multicenter Uveitis Steroid Treatment (MUST) Trial and Follow-up Study: Risk Factors and Outcomes. Am J Ophthalmol 2023;254:210-220.Abstract
PURPOSE: To evaluate the rate of, risk factors for, and outcomes of cataract surgery in patients with intermediate, posterior, and panuveitides treated with systemic corticosteroids and immunosuppression. DESIGN: Cohort study of participants from a randomized clinical trial. METHODS: A multicenter clinical trial with extended follow-up comprised the study setting. From the cohort of participants assigned to systemic therapy in the Multicenter Uveitis Steroid Treatment (MUST) Trial and Follow-up Study, 125 phakic eyes of 74 patients with intermediate, posterior, or panuveitides treated with systemic therapy were included. The main outcome measures were cataract surgery and visual acuity after cataract surgery. RESULTS: The cumulative incidence of cataract surgery was 43% at 7 years of follow-up, and the risk did not plateau. Risk factors for cataract surgery included age >50 years (hazard ratio [HR] 2.86, 95% CI 1.52, 5.42; P = .001), topical corticosteroid use (time-updated HR 3.13, 95% CI 1.42, 6.94; P = .005), glaucoma medication use (HR 2.75, 95% CI 1.38, 5.47; P = .004), and possibly history of anterior chamber inflammation (HR 1.90, 95% CI 0.95, 3.84; P = .07). Median gain in acuity and median best corrected visual acuity 1 year after cataract surgery were 4.8 lines and 20/25, respectively, among 42 eyes undergoing cataract surgery with 1-year follow-up data. CONCLUSIONS: Among patients with intermediate, posterior, and panuveitides, treated with oral corticosteroids and immunosuppression, there is a substantial long-term risk of cataract surgery. Visual acuity outcomes after cataract surgery are generally good.
Jaffe GJ, Foster SC, Pavesio CE, Paggiarino DA, Riedel GE. Effect of an Injectable Fluocinolone Acetonide Insert on Recurrence Rates in Chronic Noninfectious Uveitis Affecting the Posterior Segment: Twelve-Month Results. Ophthalmology 2019;126(4):601-610.Abstract
PURPOSE: To assess the safety and efficacy of an intravitreal fluocinolone acetonide (FA) insert to manage inflammation associated with chronic noninfectious posterior uveitis. DESIGN: Multicenter, randomized, prospective, doubled-masked, sham-controlled, 3-year phase 3 clinical trial. PARTICIPANTS: One hundred twenty-nine participants with recurrent noninfectious posterior uveitis were assigned randomly to FA insert (n = 87) or sham injection (n = 42). The more severely affected eye in participants with bilateral disease was designated as the study eye. METHODS: The insert (FA, 0.18 mg) was injected into the vitreous cavity; sham injection mimicked the insert delivery procedure. Ophthalmic examinations, OCT, and ocular tolerability and discomfort assessments were conducted; study visits were on days 7 and 28 and months 2, 3, 6, 9, and 12. Uveitis recurrence was treated as needed. The 6-month recurrence rate was the primary outcome measure. RESULTS: The 6-month (28% and 91%) and 12-month (38% and 98%) uveitis recurrence rates were significantly lower (P < 0.001) with FA insert vs. sham, respectively. Fewer recurrences per study eye (mean, 0.7 vs. 2.5), lower incidence of 15-letter or more decrease in best-corrected visual acuity (14% vs. 31%), and reduced systemic (19% vs. 40%) and local (7% vs. 62%) uveitis adjunctive treatments were observed with FA insert vs. sham, respectively. The FA insert group showed higher rates of cataract. Intraocular pressure-lowering treatment use was similar between groups. No deaths, treatment-related study discontinuations, or unanticipated safety signals were observed through 12 months. CONCLUSIONS: Chronic noninfectious posterior uveitis was managed successfully in this study population; FA insert eyes experienced fewer uveitis recurrence episodes, required fewer adjunctive treatments, and demonstrated less visual acuity loss compared with sham eyes. The FA insert treatment group showed higher rates of cataract; delivery by injection was not associated with an increase in ocular adverse events or any other safety measures not typically associated with local steroid use, suggesting the procedure is appropriate for an office setting.
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Kempen JH, Gewaily DY, Newcomb CW, Liesegang TL, Kaçmaz OR, Levy-Clarke GA, Nussenblatt RB, Rosenbaum JT, Sen NH, Suhler EB, Thorne JE, Foster SC, Jabs DA, Payal A, Fitzgerald TD, for Group SITED (SITE) R. Remission of Intermediate Uveitis: Incidence and Predictive Factors. Am J Ophthalmol 2016;164:110-117.e2.Abstract

PURPOSE: To evaluate the incidence of remission among patients with intermediate uveitis; to identify factors potentially predictive of remission. DESIGN: Retrospective cohort study. METHODS: Involved eyes of patients with primary noninfectious intermediate uveitis at 4 academic ocular inflammation subspecialty practices, followed sufficiently long to meet the remission outcome definition, were studied retrospectively by standardized chart review data. Remission of intermediate uveitis was defined as a lack of inflammatory activity at ≥2 visits spanning ≥90 days in the absence of any corticosteroid or immunosuppressant medications. Factors potentially predictive of intermediate uveitis remission were evaluated using survival analysis. RESULTS: Among 849 eyes (of 510 patients) with intermediate uveitis followed over 1934 eye-years, the incidence of intermediate uveitis remission was 8.6/100 eye-years (95% confidence interval [CI], 7.4-10.1). Factors predictive of disease remission included prior pars plana vitrectomy (PPV) (hazard ratio [HR] [vs no PPV] = 2.39; 95% CI, 1.42-4.00), diagnosis of intermediate uveitis within the last year (HR [vs diagnosis >5 years ago] =3.82; 95% CI, 1.91-7.63), age ≥45 years (HR [vs age <45 years] = 1.79; 95% CI, 1.03-3.11), female sex (HR = 1.61; 95% CI, 1.04-2.49), and Hispanic race/ethnicity (HR [vs white race] = 2.81; 95% CI, 1.23-6.41). Presence/absence of a systemic inflammatory disease, laterality of uveitis, and smoking status were not associated with differential incidence. CONCLUSIONS: Our results suggest that intermediate uveitis is a chronic disease with an overall low rate of remission. Recently diagnosed patients and older, female, and Hispanic patients were more likely to remit. With regard to management, pars plana vitrectomy was associated with increased probability of remission.

Kempen JH, Pistilli M, Begum H, Fitzgerald TD, Liesegang TL, Payal A, Zebardast N, Bhatt NP, Foster SC, Jabs DA, Levy-Clarke GA, Nussenblatt RB, Rosenbaum JT, Sen NH, Suhler EB, Thorne JE, for Group SITED (SITE) CSR. Remission of Non-Infectious Anterior Scleritis: Incidence and Predictive Factors. Am J Ophthalmol 2021;223:377-395.Abstract
PURPOSE: To assess how often non-infectious anterior scleritis remits and identify predictive factors. METHODS: Our retrospective cohort study at four ocular inflammation subspecialty centers collected data for each affected eye/patient at every visit from center inception (1978, 1978, 1984, 2005) until 2010. Remission was defined as inactivity of disease off all suppressive medications at all visits spanning at least three consecutive months or at all visits up to the last visit (to avoid censoring patients stopping follow-up after remission). Factors potentially predictive of remission were assessed using Cox regression models. RESULTS: During 1,906 years' aggregate follow-up of 832 affected eyes, remission occurred in 214 (170 of 584 patients). Median time-to-remission of scleritis = 7.8 years (95% confidence interval [CI]: 5.7, 9.5). More remissions occurred earlier than later during follow-up. Factors predictive of less scleritis remission included scleritis bilaterality (adjusted hazard ratio [aHR] = 0.46, 95% CI: 0.32-0.65); and diagnosis with any systemic inflammatory disease (aHR = 0.36, 95% CI: 0.23-0.58), or specifically with Rheumatoid Arthritis (aHR = 0.22), or Granulomatosis with Polyangiitis (aHR = 0.08). Statin treatment (aHR = 1.53, 95% CI: 1.03-2.26) within ≤90 days was associated with more remission incidence. CONCLUSIONS: Our results suggest scleritis remission occurs more slowly in anterior scleritis than in newly diagnosed anterior uveitis or chronic anterior uveitis, suggesting that attempts at tapering suppressive medications is warranted after long intervals of suppression. Remission is less frequently achieved when systemic inflammatory diseases are present. Confirmatory studies of whether adjunctive statin treatment truly can enhance scleritis remission (as suggested here) are needed.
Kempen JH, Van Natta ML, Friedman DS, Altaweel MM, Ansari H, Dunn JP, Elner SG, Holbrook JT, Lim LL, Sugar EA, Jabs DA, and Group MUST (MUST) TF-up SR. Incidence and Outcome of Uveitic Glaucoma in Eyes With Intermediate, Posterior, or Panuveitis Followed up to 10 Years After Randomization to Fluocinolone Acetonide Implant or Systemic Therapy. Am J Ophthalmol 2020;219:303-316.Abstract
PURPOSE: To evaluate long-term risk and outcomes of glaucoma in eyes with intermediate, posterior, and panuveitis managed with systemic or fluocinolone acetonide (0.59 mg, "implant") therapy. DESIGN: Prospective Follow-up of the Multicenter Uveitis Steroid Treatment (MUST) Clinical Trial Cohort. METHODS: Patients with intermediate, posterior, or panuveitis randomized to implant or systemic therapy (corticosteroid plus immunosuppression in >90%) were followed prospectively for glaucoma incidence and outcome. RESULTS: Among 405 uveitic at-risk eyes of 232 patients (median follow-up = 6.9 years), 40% (79/196) of eyes assigned and treated with implant and 8% (17/209) of eyes assigned and treated with systemic therapy (censoring eyes receiving an implant on implantation) developed glaucoma (hazard ratio [HR] = 5.9, 95% confidence interval [CI] 3.2, 10.8; P < .001). Adjustment for intraocular pressure (IOP) elevation during follow-up only partially mitigated the association of implant treatment with glaucoma incidence: HR = 3.1 (95% CI 1.6, 6.0); P = .001. Among 112 eyes of 83 patients developing glaucoma, the 5-year cumulative incidence following diagnosis of sustained (2 or more consecutive visits) worsening of mean deviation by ≥6 dB was 20% (95% CI 12%, 33%); 5-year cumulative incidence of sustained worsening of cup-to-disc ratio by ≥0.2 was 26% (95% CI 17%, 39%). CONCLUSIONS: The implant has substantially higher risk of glaucoma than systemic therapy, a difference not entirely explained by posttreatment IOP elevation. Management of IOP elevation was effective in preventing worsening of glaucoma for the large majority of cases, but even under expert clinical management, some glaucoma worsened. Uveitis cases should be monitored carefully for IOP elevation and glaucoma indefinitely.
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.

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.
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Lasave AF, You C, Ma L, Abusamra K, Lamba N, Valdes Navarro M, Meese H, Foster SC. LONG-TERM OUTCOMES OF RITUXIMAB THERAPY IN PATIENTS WITH NONINFECTIOUS POSTERIOR UVEITIS REFRACTORY TO CONVENTIONAL IMMUNOSUPPRESSIVE THERAPY. Retina 2018;38(2):395-402.Abstract
PURPOSE: To assess long-term effectiveness of rituximab therapy for refractory noninfectious uveitis affecting the posterior segment. METHODS: Retrospective case series. Patients diagnosed with recalcitrant noninfectious posterior uveitis who were treated with rituximab intravenous infusions between 2010 and 2015 were included. Patients underwent best-corrected visual acuity testing and fluorescein angiography evidence of disk or vascular staining at 6, 12, 18, and 24 months. Patients had at least 24 months of follow-up. RESULTS: Eleven patients (21 eyes) with refractory posterior uveitis treated with intravenous rituximab were included. Nine (81.8%) patients were female. Mean follow-up was 29.3 ± 7.8 months. rituximab was administered as complementary therapy because of previous inefficacy of other therapies in 7 (63.7%) patients, and it was the only treatment in four (36.3%) patients who did not tolerate other drugs. Inflammation signs by fluorescein angiography were controlled in nine (81.8%) patients at the end of follow-up. Baseline best-corrected visual acuity was 20/80 (logarithm of the minimal angle of resolution 0.6 ± 0.4), and final best-corrected visual acuity was 20/40 (0.3 ± 0.5) (P = 0.005). No significant side effects were reported. CONCLUSION: Rituximab therapy was associated with stability and remission of recalcitrant noninfectious posterior uveitis in patients who did not tolerate or did not respond to other therapies.
Lee DJ, Preble J, Lee S, Foster SC, Taylor AW. MC5r and A2Ar Deficiencies During Experimental Autoimmune Uveitis Identifies Distinct T cell Polarization Programs and a Biphasic Regulatory Response. Sci Rep 2016;6:37790.Abstract

Autoantigen-specific regulatory immunity emerges in the spleen of mice recovering from experimental autoimmune uveitis (EAU), a murine model for human autoimmune uveoretinitis. This regulatory immunity provides induced tolerance to ocular autoantigen, and requires melanocortin 5 receptor (MC5r) expression on antigen presenting cells with adenosine 2 A receptor (A2Ar) expression on T cells. During EAU it is not well understood what roles MC5r and A2Ar have on promoting regulatory immunity. Cytokine profile analysis during EAU revealed MC5r and A2Ar each mediate distinct T cell responses, and are responsible for a functional regulatory immune response in the spleen. A2Ar stimulation at EAU onset did not augment this regulatory response, nor bypass the MC5r requirement to induce regulatory immunity. The importance of this pathway in human autoimmune uveitis was assayed. PBMC from uveitis patients were assayed for MC5r expression on monocytes and A2Ar on T cells, and comparison between uveitis patients and healthy controls had no significant difference. The importance for MC5r and A2Ar expression in EAU to promote the induction of protective regulatory immunity, and the expression of MC5r and A2Ar on human immune cells, suggests that it may be possible to utilize the melanocortin-adenosinergic pathways to induce protective immunity in uveitic patients.

Levin MH, Pistilli M, Daniel E, Gangaputra SS, Nussenblatt RB, Rosenbaum JT, Suhler EB, Thorne JE, Foster SC, Jabs DA, Levy-Clarke GA, Kempen JH. Incidence of visual improvement in uveitis cases with visual impairment caused by macular edema. Ophthalmology 2014;121(2):588-95.e1.Abstract
PURPOSE: Among cases of visually significant uveitic macular edema (ME), to estimate the incidence of visual improvement and identify predictive factors. DESIGN: Retrospective cohort study. PARTICIPANTS: Eyes with uveitis, seen at 5 academic ocular inflammation centers in the United States, for which ME was documented to be currently present and the principal cause of reduced visual acuity (<20/40). METHODS: Data were obtained by standardized chart review. MAIN OUTCOME MEASURES: Decrease of ≥ 0.2 base 10 logarithm of visual acuity decimal fraction-equivalent; risk factors for such visual improvement. RESULTS: We identified 1510 eyes (of 1077 patients) with visual impairment to a level <20/40 attributed to ME. Most patients were female (67%) and white (76%), and had bilateral uveitis (82%). The estimated 6-month incidence of ≥ 2 lines of visual acuity improvement in affected eyes was 52% (95% confidence interval [CI], 49%-55%). Vision reduced by ME was more likely to improve by 2 lines in eyes initially with poor visual acuity (≤ 20/200; adjusted hazard ratio [HR] 1.5; 95% CI, 1.3-1.7), active uveitis (HR, 1.3; 95% CI, 1.1-1.5), and anterior uveitis as opposed to intermediate (HR, 1.2), posterior (HR, 1.3), or panuveitis (HR, 1.4; overall P = 0.02). During follow-up, reductions in anterior chamber or vitreous cellular activity or in vitreous haze each led to significant improvements in visual outcome (P <0.001 for each). Conversely, snowbanking (HR, 0.7; 95% CI, 0.4-0.99), posterior synechiae (HR, 0.8; 95% CI, 0.6-0.9), and hypotony (HR, 0.2; 95% CI, 0.06-0.5) each were associated with lower incidence of visual improvement with respect to eyes lacking each of these attributes at a given visit. CONCLUSIONS: These results suggest that many, but not all, patients with ME causing low vision in a tertiary care setting will enjoy meaningful visual recovery in response to treatment. Evidence of significant ocular damage from inflammation (posterior synechiae and hypotony) portends a lower incidence of visual recovery. Better control of anterior chamber or vitreous activity is associated with a greater incidence of visual improvement, supporting an aggressive anti-inflammatory treatment approach for ME cases with active inflammation.
Llop SM, Davoudi S, Stanwyck LK, Sathe S, Tom L, Ahmadi T, Grotting L, Papaliodis GN, Sobrin L. Association of Low Vitamin D Levels with Noninfectious Uveitis and Scleritis. Ocul Immunol Inflamm 2018;:1-8.Abstract
PURPOSE: To determine whether an association between Vitamin D and noninfectious ocular inflammation exists. METHODS: Retrospective case-control study with 765 patients (333 uveitis cases, 103 scleritis cases, 329 controls). Logistic regression models examined the relationship between hypovitaminosis D and ocular inflammation. RESULTS: The odds of having uveitis were 1.92 times higher for patients with hypovitaminosis D compared to patients with normal Vitamin D levels in the multivariate analysis [odds ratio (OR) = 1.92, 95% Confidence Interval (CI) = 1.36-2.72, p = 2.32 × 10]. A secondary analysis demonstrated that the odds of developing uveitis or scleritis were 5% lower and 4% lower, respectively, for every unit increase in Vitamin D level (uveitis: OR = 0.95, 95% CI = 0.94-0.97, p = 9.87 × 10; scleritis: OR = 0.96, 95% CI = 0.93-0.99, p = 0.009). CONCLUSION: Hypovitaminosis D was associated with increased risk of ocular inflammation in this retrospective study.
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Ma L, You C, Hernandez M, Maleki A, Lasave A, Schmidt A, Stephenson A, Zhao T, Anesi S, Foster SC. Management of Ocular Cicatricial Pemphigoid with Intravenous Immunoglobulin Monotherapy. Ocul Immunol Inflamm 2018;:1-7.Abstract
PURPOSE: To assess the long-term efficacy and safety of IVIg monotherapy in patients with recalcitrant ocular cicatricial pemphigoid (OCP). METHODS: A chart review of all OCP patients seen at the Massachusetts Eye Research and Surgery Institution (MERSI) between 2005 and 2015 was completed. Stage was graded by using the Foster grading system. IVIg infusion was 2g/kg/cycle administered in 3 consecutive days monthly. RESULTS: Of 512 OCP patients, 17 patients (34 eyes) treated with IVIg monotherapy were identified. Seven were female and ten were male. The average age at diagnosis was 60.7-year-old. The follow up time ranged from 12 to 140 months. Twenty-six eyes (76.5%) achieved remission. Nine remission eyes received cataract surgeries, and 2 of them had relapse (22.2%). The other 17 eyes did not undergo ocular surgery and remained in remission. IVIg monotherapy showed high efficacy in stage 1 OCP (7/7, 100%). Ocular surgery can be associated with OCP relapse (Table 2). CONCLUSIONS: IVIg monotherapy is an effective and safe therapy in patients with recalcitrant OCP. Ocular surgery can be associated with OCP relapse.
Maleki A, Meese H, Sahawneh H, Foster SC. Progress in the understanding and utilization of biologic response modifiers in the treatment of uveitis. Expert Rev Clin Immunol 2016;12(7):775-86.Abstract

Uveitis is the third most common cause of blindness in developed countries. Considering the systemic and local complications of long-term corticosteroid therapy and the intolerance due to side effects and ineffectiveness of conventional chemotherapy, use of biologic response modifiers is a reasonable alternative in the treatment of non-infectious uveitis and persistent uveitic macular edema. The majority of the evidence presented here comes from open uncontrolled analyses. Based on these studies, tumor necrosis factor alpha inhibitors, especially infliximab and adalimumab, have been shown to be effective in the treatment of non-infectious uveitis in numerous studies. More research is necessary, particularly multi-center randomized clinical trials, to address the choice of biologic response modifier agent and the length of treatment as we employ biologic response modifiers in different types of uveitis and persistent uveitic macular edema.

Maleki A, Swan RT, Lasave AF, Ma L, Foster SC. Selective Laser Trabeculoplasty in Controlled Uveitis with Steroid-Induced Glaucoma. Ophthalmology 2016;123(12):2630-2632.

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