Immunology and Uveitis

Patel AK, Newcomb CW, Liesegang TL, Pujari SS, Suhler EB, Thorne JE, Foster SC, Jabs DA, Levy-Clarke GA, Nussenblatt RB, Rosenbaum JT, Sen NH, Artornsombudh P, Kothari S, Kempen JH, for Group SITEDR. Risk of Retinal Neovascularization in Cases of Uveitis. Ophthalmology 2016;123(3):646-54.Abstract

PURPOSE: To evaluate the risk of and risk factors for retinal neovascularization (NV) in cases of uveitis. DESIGN: Retrospective cohort study. PARTICIPANTS: Patients with uveitis at 4 US academic ocular inflammation subspecialty practices. METHODS: Data were ascertained by standardized chart review. Prevalence data analysis used logistic regression. Incidence data analysis used survival analysis with time-updated covariates where appropriate. MAIN OUTCOME MEASURES: Prevalence and incidence of NV. RESULTS: Among uveitic eyes of 8931 patients presenting for initial evaluation, 106 of 13 810 eyes had NV (prevalence = 0.77%, 95% confidence interval [CI], 0.60-0.90). Eighty-eight more eyes developed NV over 26 465 eye-years (incidence, 0.33%/eye-year; 95% CI, 0.27-0.41). Factors associated with incident NV include age <35 years compared with >35 years (adjusted hazard ratio [aHR], 2.4; 95% CI, 1.5-3.9), current cigarette smoking (aHR, 1.9; 95% CI, 1.1-3.4), and systemic lupus erythematosus (aHR, 3.5, 95% CI, 1.1-11). Recent diagnosis of uveitis was associated with an increased incidence of NV (compared with patients diagnosed >5 years ago, aHR, 2.4 [95% CI, 1.1-5.0] and aHR, 2.6 [95% CI, 1.2-6.0] for diagnosis within <1 year vs. 1-5 years, respectively). Compared with anterior uveitis, intermediate uveitis (aHR, 3.1; 95% CI, 1.5-6.6), posterior uveitis (aHR, 5.2; 95% CI, 2.5-11), and panuveitis (aHR, 4.3; 95% CI, 2.0-9.3) were associated with a similar degree of increased NV incidence. Active (aHR, 2.1, 95% CI, 1.2-3.7) and slightly active (aHR, 2.4, 95% CI, 1.3-4.4) inflammation were associated with an increased incidence of NV compared with inactive inflammation. Neovascularization incidence also was increased with retinal vascular occlusions (aHR, 10, 95% CI, 3.0-33), retinal vascular sheathing (aHR, 2.6, 95% CI, 1.4-4.9), and exudative retinal detachment (aHR, 4.1, 95% CI, 1.3-13). Diabetes mellitus was associated with a somewhat increased incidence of retinal NV (aHR, 2.3, 95% CI, 1.1-4.9), and systemic hypertension (aHR 1.5, 95% CI, 0.89-2.4) was associated with nonsignificantly increased NV incidence. Results were similar in sensitivity analyses excluding the small minority of patients with diabetes mellitus. CONCLUSIONS: Retinal NV is a rare complication of uveitis, which occurs more frequently in younger patients, smokers, and those with intermediate/posterior/panuveitis, systemic vasculopathy, retinal vascular disease, or active inflammation. Inflammation and retinal NV likely are linked; additional studies are needed to further elucidate this connection.

Sainz-de-la-Maza M, Molina N, Gonzalez-Gonzalez LA, Doctor PP, Tauber J, Foster SC. Scleritis associated with relapsing polychondritis. Br J Ophthalmol 2016;100(9):1290-4.Abstract

AIMS: To evaluate ocular disease characteristics and successful therapeutic regimens in patients with scleritis associated with relapsing polychondritis (RP). To compare these features with those seen in patients with scleritis associated with other systemic immune-mediated diseases (SIMD). METHODS: Electronic health records of 13 scleritis patients associated with RP were analysed and compared with those of 113 scleritis patients associated with other SIMD seen at two tertiary referral centres. RESULTS: Scleritis in patients with RP was often bilateral (92.3%), diffuse (76.9%), recurrent (84.6%), sometimes with decreased vision (46.2%), anterior uveitis (38.5%), peripheral keratitis (15.4%) and ocular hypertension (30.8%). Patients with scleritis associated with RP more often had bilateral scleritis (p=0.001), necrotising scleritis (23.1%; p=0.02), recurrences (p=0.001) and decreased vision (three of the six with legal blindness; p=0.012), as compared with patients who had scleritis associated with other SIMD. Nine patients (69.2%) had one or more SIMD other than RP, including systemic vasculitis (4) or other autoimmune disease (8); they antedated RP by 9 years (range 2-21 years). Successful therapy included cyclophosphamide (5), methotrexate (3), azathioprine (3), mycophenolate mofetil (2), infliximab (2) and adalimumab (1). CONCLUSIONS: Scleritis may be the first manifestation whose study leads to the diagnosis of RP. Scleritis associated with RP is more often bilateral, necrotising, recurrent and associated with decrease of vision than scleritis associated with other SIMD. About 69.2% of patients will have an additional SIMD disorder. Scleritis associated with RP most often will require immunomodulatory therapy. Occasionally, scleritis with RP may appear while using antitumor necrosis factor α agents.

Smith RE, Reyes NJ, Khandelwal P, Schlereth SL, Lee HS, Masli S, Saban DR. Secondary allergic T cell responses are regulated by dendritic cell-derived thrombospondin-1 in the setting of allergic eye disease. J Leukoc Biol 2016;100(2):371-80.Abstract

Allergic eye disease, as in most forms of atopy, ranges in severity among individuals from immediate hypersensitivity to a severe and debilitating chronic disease. Dendritic cells play a key role in stimulating pathogenic T cells in allergen re-exposure, or secondary responses. However, molecular cues by dendritic cells underpinning allergic T cell response levels and the impact that this control has on consequent severity of allergic disease are poorly understood. Here, we show that a deficiency in thrombospondin-1, a matricellular protein known to affect immune function, has subsequent effects on downstream T cell responses during allergy, as revealed in an established mouse model of allergic eye disease. More specifically, we demonstrate that a thrombospondin-1 deficiency specific to dendritic cells leads to heightened secondary T cell responses and consequent clinical disease. Interestingly, whereas thrombospondin-1-deficient dendritic cells augmented activity of allergen-primed T cells, this increase was not recapitulated with naïve T cells in vitro. The role of dendritic cell-derived thrombospondin-1 in regulating secondary allergic T cell responses was confirmed in vivo, as local transfer of thrombospondin-1-sufficient dendritic cells to the ocular mucosa of thrombospondin-1 null hosts prevented the development of augmented secondary T cell responses and heightened allergic eye disease clinical responses. Finally, we demonstrate that topical instillation of thrombospondin-1-derived peptide reduces T cell activity and clinical progression of allergic eye disease. Taken together, this study reveals an important modulatory role of dendritic cell-derived thrombospondin-1 on secondary allergic T cell responses and suggests the possible dysregulation of dendritic cell-derived thrombospondin-1 expression as a factor in allergic eye disease severity.

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.

Silpa-Archa S, Lee JJ, Foster SC. Ocular manifestations in systemic lupus erythematosus. Br J Ophthalmol 2016;100(1):135-41.Abstract

Systemic lupus erythematosus (SLE) can involve many parts of the eye, including the eyelid, ocular adnexa, sclera, cornea, uvea, retina and optic nerve. Ocular manifestations of SLE are common and may lead to permanent blindness from the underlying disease or therapeutic side effects. Keratoconjunctivitis sicca is the most common manifestation. However, vision loss may result from involvement of the retina, choroid and optic nerve. Ocular symptoms are correlated to systemic disease activity and can present as an initial manifestation of SLE. The established treatment includes prompt systemic corticosteroids, steroid-sparing immunosuppressive drugs and biological agents. Local ocular therapies are options with promising efficacy. The early recognition of disease and treatment provides reduction of visual morbidity and mortality.

Abusamra K, Maghsoudlou A, Roohipoor R, Valdes-Navarro M, Lee S, Foster SC. Current Treatment Modalities of JIA-associated Uveitis and its Complications: Literature Review. Ocul Immunol Inflamm 2016;24(4):431-9.Abstract

Uveitis is a common and serious complication of juvenile idiopathic arthritis. Up to 75% of all cases of anterior uveitis in childhood are associated with juvenile idiopathic arthritis. Despite the remarkable progress in early detection and treatment of inflammation, vision-threatening complications of uveitis still occur in almost 60% of patients. Structural complications include band keratopathy, maculopathy (macular edema, macular cysts, and epiretinal membrane), glaucomatous optic neuropathy, and cataracts. The management of complications in juvenile idiopathic arthritis is usually complex and requires early surgical intervention. In this paper, we review the general concepts of common ocular complications seen in patients with JIA-associated uveitis, with special attention to the recent diagnostic and preferred treatment approaches at the Massachusetts Eye Research and Surgery Institution. Received 9 March 2015; revised 30 September 2015; accepted 30 October 2015; published online 14 January 2016.

Cao JH, Oray M, Cocho L, Foster SC. Rituximab in the Treatment of Refractory Noninfectious Scleritis. Am J Ophthalmol 2016;164:22-8.Abstract

PURPOSE: To describe the outcomes of the use of rituximab in the treatment of refractory noninfectious scleritis. DESIGN: Retrospective case series. METHODS: Review of the medical charts of patients with noninfectious scleritis refractory to conventional immunomodulatory therapy who were seen at the Massachusetts Eye Research and Surgery Institution between 2005 and 2015. The primary outcome measure in this study was steroid-free remission. Secondary outcomes were favorable response (decrease in scleritis activity score) and decrease in steroid dependence. RESULTS: There were 15 patients, with a mean follow-up duration of 34 months. Fourteen patients (93.3%) showed a clinical improvement, with 13 (86.6%) achieving a scleritis activity score of zero at 6 months. To date, 2 patients continue to enjoy durable drug-free remission (28 and 32 months follow-up). There was only 1 adverse effect recorded (infusion hypotension) requiring cessation of rituximab. CONCLUSION: Rituximab can be an effective treatment modality for recalcitrant noninfectious scleritis and, in some, can result in long-term durable drug-free remission.

Faez S, Lobo A-M, Unizony SH, Stone JH, Papaliodis GN, Sobrin L. Ocular inflammatory disease in patients with polymyalgia rheumatica: A case series and review of the literature. Clin Rheumatol 2016;35(1):251-8.Abstract

Scleritis and uveitis are potentially blinding conditions that can be associated with systemic inflammatory diseases. Polymyalgia rheumatica (PMR) is a common rheumatic disorder of the elderly of uncertain etiology. Although there are a few published reports of scleritis and uveitis in PMR patients, the association of PMR to ocular inflammation has not been well established. The aim of this study is to report a series of PMR patients with scleritis and/or uveitis and review the prior published reports of this potential association. We retrospectively reviewed the medical charts of patients with PMR and scleritis or uveitis who were examined in the Ocular Immunology Service of Massachusetts Eye and Ear Infirmary. We also performed a systematic literature search (PubMed; January 1990 until January 2014) to identify earlier published reports. Seven PMR patients with ocular inflammatory disease (OID) were included in our study: two with scleritis, three with anterior uveitis, and two with panuveitis. The onset of PMR preceded the occurrence of OID in six patients, and in one patient uveitis developed 2 months prior to PMR. Five patients demonstrated a temporal association between flares of PMR and OID. In four patients, OID flares developed during tapering of systemic prednisone prescribed for PMR. Four of the five patients who had relapsing PMR had recurrent or persistent uveitis over the course of follow-up. PMR may be associated with both scleritis and uveitis and should be considered as a possible underlying cause of OID.

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.

Pages