Immunology and Uveitis

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Sen NH, Vitale S, Gangaputra SS, Nussenblatt RB, Liesegang TL, Levy-Clarke GA, Rosenbaum JT, Suhler EB, Thorne JE, Foster SC, Jabs DA, Kempen JH. Periocular corticosteroid injections in uveitis: effects and complications. Ophthalmology 2014;121(11):2275-86.Abstract
PURPOSE: To evaluate the benefits and complications of periocular depot corticosteroid injections in patients with ocular inflammatory disorders. DESIGN: Multicenter, retrospective cohort study. PARTICIPANTS: A total of 914 patients (1192 eyes) who had received ≥ 1 periocular corticosteroid injection at 5 tertiary uveitis clinics in the United States. METHODS: Patients were identified from the Systemic Immunosuppressive Therapy for Eye Diseases Cohort Study. Demographic and clinical characteristics were obtained at every visit via medical record review by trained reviewers. MAIN OUTCOME MEASURES: Control of inflammation, improvement of visual acuity (VA) to ≥ 20/40, improvement of VA loss attributed to macular edema (ME), incident cataract affecting VA, cataract surgery, ocular hypertension, and glaucoma surgery. RESULTS: Among 914 patients (1192 eyes) who received ≥ 1 periocular injection during follow-up, 286 (31.3%) were classified as having anterior uveitis, 303 (33.3%) as intermediate uveitis, and 324 (35.4%) as posterior or panuveitis. Cumulatively by ≤ 6 months, 72.7% (95% CI, 69.1-76.3) of the eyes achieved complete control of inflammation and 49.7% (95% CI, 45.5-54.1) showed an improvement in VA from <20/40 to ≥ 20/40. Among the subset with VA <20/40 attributed to ME, 33.1% (95% CI, 25.2-42.7) improved to ≥ 20/40. By 12 months, the cumulative incidence of ≥ 1 visits with an intraocular pressure of ≥ 24 mmHg and ≥ 30 mmHg was 34.0% (95% CI, 24.8-45.4) and 15.0% (95% CI, 11.8-19.1) respectively; glaucoma surgery was performed in 2.4% of eyes (95% CI, 1.4-3.9). Within 12 months, among phakic eyes initially ≥ 20/40, the incidence of a reduction in VA to <20/40 attributed to cataract was 20.2% (95% CI, 15.9-25.6); cataract surgery was performed within 12 months in 13.8% of the initially phakic eyes (95% CI, 11.1-17.2). CONCLUSIONS: Periocular injections were effective in treating active intraocular inflammation and in improving reduced VA attributed to ME in a majority of patients. The response pattern was similar across anatomic locations of uveitis. Overall, VA improved in one half of the patients at some point within 6 months. However, cataract and ocular hypertension occurred in a substantial minority.
Sharon Y, Anesi SD, Martinez CE, Huang AJW, Foster CS, Chu DS. Repository Corticotropin Injection as an Alternative Treatment for Refractory Ocular Mucous Membrane Pemphigoid. Cornea 2021;Abstract
PURPOSE: The purpose of this study was to report the clinical course and outcome of patients with refractory ocular mucous membrane pemphigoid (MMP) treated by repository corticotropin injection (RCI). METHODS: Patients with biopsy-proven ocular MMP treated with RCI from 3 tertiary medical centers were evaluated. Medical records between January 2013 and January 2021 were reviewed and deidentified to retrieve relevant disease-related data. Primary outcome measures included conjunctival inflammatory activity, change in Foster clinical conjunctival scarring staging after RCI treatment, and the development of ocular and systemic complications. RESULTS: Included were 15 patients (10 women and 5 men; 36-95 yrs of age) with a mean follow-up of 4.5 years. Most of the patients (80%) had Foster stage 3 at presentation, and all patients had active MMP. Each patient had failed to respond to at least 1 immunomodulatory drug during the follow-up, and 9 (60%) patients had treatment failure of at least 2 other agents before the use of RCI. The mean duration of RCI treatment was 21 months (range, 3-54 mo). Foster stage did not change in any of the 15 patients at the last follow-up. Nine patients continued RCI therapy at the last follow-up, and in all of them, the disease activity of MMP was well controlled. No serious adverse events because of RCI were documented during the follow-up in any treated patient. CONCLUSIONS: RCI may serve as an alternative or an adjunctive treatment in patients with severe and refractory ocular MMP. Treatment with RCI seems to be safe and well-tolerated.
Sheppard JD, Foster SC, Toyos MM, Markwardt K, Da Vanzo R, Flynn TE, Kempen JH. Difluprednate 0.05% versus Prednisolone Acetate 1% for Endogenous Anterior Uveitis: Pooled Efficacy Analysis of Two Phase 3 Studies. Ocul Immunol Inflamm 2017;:1-13.Abstract
PURPOSE: To analyse pooled data from 2 similar phase 3 noninferiority studies comparing difluprednate 0.05% versus prednisolone acetate 1% in patients with endogenous anterior uveitis. METHODS: Patients received difluprednate alternating with vehicle or prednisolone acetate for 14 days (8 drops/day in both groups), followed by tapering from day 14 to 28. All patients were observed until day 42. RESULTS: More patients on difluprednate than on prednisolone acetate were cleared of anterior chamber cells on day twenty one (71.3% vs 54.7%; p = 0.02); results were similar at the other time points. Treatment withdrawals were higher with prednisolone acetate than difluprednate (19.8% vs 7.4%; log-rank p = 0.02). Study discontinuation due to lack of efficacy was also higher with prednisolone acetate than difluprednate (14.0% vs 0%; p = 0.0002 [pre-specified exploratory analysis]). CONCLUSIONS: More difluprednate-treated eyes were quiet following 21 days of treatment, and difluprednate-treated patients were much less likely to be withdrawn from the study because of treatment failure.
Sheppard J, Garg S, Lievens C, Brandano L, Wirostko B, Korenfeld M, Raizman M, Foster SC. Iontophoretic Dexamethasone Phosphate Compared to Topical Prednisolone Acetate 1% for Noninfectious Anterior Segment Uveitis. Am J Ophthalmol 2019;Abstract
PURPOSE: To evaluate the safety and efficacy of dexamethasone phosphate ophthalmic solution (EGP-437) delivered by transscleral iontophoresis using the EyeGate® II Drug Delivery System, compared to topical prednisolone acetate 1% (PA 1%), in subjects with noninfectious anterior uveitis. DESIGN: Prospective, randomized, double-masked, parallel-group, non-inferiority clinical trial METHODS: A total of 193 subjects with active noninfectious anterior uveitis (anterior chamber [AC] cell count ≥11 cells) were randomized to EGP-437 delivered via iontophoresis (Days 0 and 7) or self-administered PA 1% daily (tapered schedule, Days 0-28). Masking was maintained with placebo iontophoresis/eyedrops. The primary efficacy endpoint was the proportion of subjects with an AC cell count of zero on Day 14; noninferiority of EGP-437 was defined if the lower limit of the confidence interval for the difference (EGP-437 minus PA 1%) was less than -10%. RESULTS: At Day 14, 32/96 (33.3%) EGP-437 subjects and 32/97 (33.0%) PA 1% subjects had an AC cell count of zero (difference [95% confidence interval], 0.34 [-12.94, 13.63]; P=0.064). Efficacy trended better with EGP-437 among patients with more severe baseline uveitis (AC cell count >25). Safety and tolerability were good with both treatments. EGP-437 subjects experienced fewer IOP elevations ≥6 mm Hg versus PA 1% subjects (13 vs 24 incidents through Day 28). CONCLUSIONS: Despite clinically similar response rates, statistical noninferiority of EGP-437 versus a tapered regimen of PA 1% was not achieved. Numerical trends suggesting fewer IOP elevations with EGP-437, similar efficacy overall, and possibly better efficacy in more severe disease warrant further study.
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.

Silpa-Archa S, Ittharat W, Chotcomwongse P, Preble JM, Foster SC. Analysis of Three-Dimensional Choroidal Volume with Enhanced Depth Imaging Findings in Patients with Recurrent Vogt-Koyanagi-Harada Disease. Curr Eye Res 2021;46(7):1010-1017.Abstract
Purpose: To demonstrate changes in three-dimensional choroidal volume with enhanced depth imaging optical coherence tomography (EDI-OCT) in patients with recurrent stage of Vogt-Koyanagi-Harada disease (VKH).Materials and Methods: This prospective comparative case series included 9 patients with recurrent VKH, 10 patients with quiet VKH, and 15 healthy controls after sample size was calculated. All VKH cases with recurrences underwent raster scanning with EDI-OCT at active and inactive stages of the disease.Results: All choroidal parameters in the active stage significantly reduced when the inflammation subsided: total choroidal volume (P = .02), central choroidal volume (P = .01), central choroidal thickness (P = .03). The changes in central choroidal volume over the resolution phase were more pronounced than the changes in central choroidal thickness in 56% of cases. Two cases presenting with only subclinical posterior segment recurrence had their choroidal parameters recovered after prompt treatment.Conclusions: In the recurrent stage of VKH, alteration in choroidal volume was evident by EDI-OCT even in an absence of anterior segment inflammation. Central choroidal volume may serve as a biomarker for detecting choroidal morphological change.
Silpa-Archa S, Oray M, Preble JM, Foster CS. Outcome of tocilizumab treatment in refractory ocular inflammatory diseases. Acta Ophthalmol 2016;94(6):e400-6.Abstract

PURPOSE: To report the outcomes of tocilizumab treatment for refractory ocular inflammatory diseases. METHODS: A retrospective case series of 17 patients (28 eyes) diagnosed with recalcitrant ocular inflammatory diseases including uveitis (10 cases), scleritis (six cases) and orbital pseudotumour (one case), who received tocilizumab between April 2010 and March 2015. All patients were initiated with treatment of 4 mg/kg or 8 mg/kg tocilizumab. The primary outcome was absence of inflammation and achievement of steroid sparing at 6 and 9 months. Secondary outcomes were change in visual acuity and major adverse effects of tocilizumab causing discontinuation of the treatment. RESULTS: Mean age at initiation of tocilizumab was 41 ± 16 years. Prior to tocilizumab treatment, all patients underwent unsuccessful conventional immunosuppressive therapy while 94% of patients (16/17) failed treatment with various biological agents. After tocilizumab administration, control of inflammation and steroid sparing were achieved in 63% and 71% of uveitis patients at 6 and 9 months, while 50% of scleritis patients achieved the primary outcome at 6 and 9 months. Mean duration of tocilizumab therapy was 12.6 ± 10.0 (range, 2-35) months. Three of four patients who had a follow-up of at least 18 (range, 18-35) months experienced quiescent inflammation for up to 32 months of tocilizumab use until last visit. Four patients (24%) discontinued tocilizumab due to serious side effects including neutropenia, unacceptable dizziness and nausea, severe angioedema and severe abdominal pain. CONCLUSION: Our series demonstrated moderate efficacy of tocilizumab in recalcitrant uveitis and scleritis. Serious adverse effects were not uncommon.

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.

Silpa-Archa S, Silpa-Archa N, Preble JM, Foster SC. Vogt-Koyanagi-Harada syndrome: Perspectives for immunogenetics, multimodal imaging, and therapeutic options. Autoimmun Rev 2016;15(8):809-19.Abstract

Vogt-Koyanagi-Harada syndrome (VKH) is a bilateral, diffuse granulomatous uveitis associated with neurological, audiovestibular, and dermatological systems. The primary pathogenesis is T-cell-mediated autoimmune response directed towards melanocyte or melanocyte-associated antigens causing inflammation of the choroidal layer. This phenomenon usually leads to diffuse inflammatory conditions throughout most parts of eye before ocular complications ensue. The diagnosis is achieved mainly by clinical features according to the revised diagnostic criteria of VKH published in 2001, without confirmatory serologic tests as a requirement. However, ancillary tests, especially multimodal imaging, can reliably provide supportive evidence for the diagnosis of early cases, atypical presentations, and evaluation of management. Prompt treatment with systemic corticosteroids and early non-steroidal immunosuppressive drug therapy can lessen visually threatening ocular complications and bring about good visual recovery. Close monitoring warrants visual stabilization from disease recurrence and ocular complications. This article review aims not only to update comprehensive knowledge regarding VKH but also to emphasize three major perspectives of VKH: immunogenetics as the major pathogenesis of the disease, multimodal imaging, and therapeutic options. The role of anti-vascular endothelial growth factor therapy and drug-induced VKH is also provided.

Silpa-Archa S, Cao JH, Boonsopon S, Lee J, Preble JM, Foster SC. Birdshot Retinochoroidopathy: Differences in Clinical Characteristics between Patients with Early and Late Age of Onset. Ocul Immunol Inflamm 2016;:1-7.Abstract

PURPOSE: To describe differences in the clinical characteristics of birdshot retinochoroidopathy (BSRC) patients diagnosed early and later in life. METHODS: This is a retrospective cohort study. Age was primarily analyzed and 50 years of age at diagnosis was selected as a cut-off point. RESULTS: A total of 144 patients (288 eyes) were included; 68 with early-onset and 76 with late-onset BSRC. The younger group had a statistically significant higher rate of more severe iritis (p = 0.04); an average number of non-steroidal immunosuppressants and biologic agents (NSIB) (p = 0.04); and a prolonged time to initiation of NSIB (p = 0.01). There were only four patients (3%) who had >0.5+ cells in the anterior chamber. CONCLUSIONS: Patients with early-onset BSRC carried a higher risk for anterior segment inflammation, had a more prolonged delay to initiation of treatment with NSIB, and required a greater number of NSIBs to achieve remission.

Silpa-Archa S, Preble JM, Foster SC. VITREOUS TREPONEMAL ANTIBODY AS A SUPPLEMENTARY TEST TO SEROLOGY FOR THE CONFIRMATION OF SYPHILITIC CHORIORETINITIS. Retin Cases Brief Rep 2020;14(2):166-169.Abstract
PURPOSE: To report the novel application of nontreponemal and treponemal antibody to confirm diagnosis of ocular syphilis from vitreous samples. METHODS: Two distinct case reports emphasizing the importance of confirmatory vitreous treponemal antibody. Multimodal imaging of patients was also applied. RESULTS: We report two distinct cases with positive serum treponemal antibody but opposing vitreous treponemal antibody results. One case with a positive vitreous test responded well to antisyphilitic treatment. By contrast, a case with a negative vitreous result was changed to serpiginous choroiditis, eventually cured by immunomodulatory treatment. CONCLUSION: Intraocular fluid analysis of nontreponemal and treponemal antibody may play an important role in ruling out suspected ocular syphilis in settings without a polymerase chain reaction facility, especially immunocompromised patients who are at risk of multiple infections. Further studies are needed to establish the sensitivity and specificity of nontreponemal and treponemal antibody test on vitreous samples.
Silpa-Archa S, Ponwong A, Preble JM, Foster SC. Culture-Positive Endogenous Endophthalmitis: An Eleven-Year Retrospective Study in the Central Region of Thailand. Ocul Immunol Inflamm 2017;:1-10.Abstract
PURPOSE: To report the characteristics of infection and prognostic factors of endogenous endophthalmitis (EE) over an 11-year period. METHODS: The clinical records of 41 eyes of 36 patients diagnosed with culture-proven EE at the Rajavithi Hospital were retrospectively reviewed. RESULTS: Median age at presentation was 58 years. Liver abscess (19%) and urinary tract infections (19%) were the most common sources of infection. The most common causative agents were gram-negative organisms (48%). The most commonly isolated microorganism was Klebsiella pneumoniae (26.8%). Worse initial visual acuity and severe intraocular inflammation at first presentation were equally associated with poor visual outcome in the multivariate model (adjusted odds ratio, 20.32; 95% confidence interval [1.12-357.45]; P = 0.040). CONCLUSIONS: Endogenous endophthalmitis usually has a poor visual prognosis. Liver abscess and urinary tract infections are common primary sites of infection. Poor initial visual acuity and severe intraocular inflammation at the initial presentation are predictors of poor visual outcome.
Silpa-Archa S, Dejkong A, Kumsiang K, Chotcomwongse P, Preble JM, Foster SC. Poor prognostic factors in post-traumatic endophthalmitis following open globe injury. Int J Ophthalmol 2020;13(12):1968-1975.Abstract
AIM: To demonstrate prognostic factors for poor visual outcome in patients with post-traumatic endophthalmitis (PTE) following open globe injury. METHODS: A retrospective study was conducted on 66 patients (66 eyes) with PTE following open globe injury from 2005 to 2015. Potential factors accounting for good and poor visual outcome were statistically analyzed by Chi-square test and Logistic regression model. RESULTS: In 66 cases, 39 cases (59%) had a poor visual outcome. Univariate and multivariate Logistic regression analysis identified retained intraocular foreign body (IOFB) as the only factor significantly associated with poor visual outcome [adjusted odds ratio, 4.62; 95% confidence interval (1.04-20.53); =0.04]. The most common causative agents were gram-positive organisms (83%), of which (33%), was the most common pathogen. All cases received intravitreal antibiotic injections. Oral ciprofloxacin was the most used systemic antibiotic (33%). Pars plana vitrectomy was performed in 83% (55/66) of cases. At 6mo follow-up, mean BCVA was 1.74±0.72 logMAR units. CONCLUSION: In patients with PTE following open globe injury, the only predictor of poor visual outcome is the presence of IOFB. is the most isolated microorganism.
Singh RB, Sinha S, Saini C, Elbasiony E, Thakur S, Agarwal A. Recent advances in the management of non-infectious posterior uveitis. Int Ophthalmol 2020;40(11):3187-3207.Abstract
PURPOSE: To review the current regimens and novel therapeutic modalities in various stages of research and development for the management of non-infectious posterior uveitis (NIPU). METHODS: We performed a thorough review of current literature using PubMed, Google Scholar and Clinicaltrials.gov to identify the published literature about the available therapeutics and novel drugs/therapies in different stages of clinical trials. RESULTS: The current management regimen for non-infectious posterior uveitis includes corticosteroids, immunomodulatory therapies and anti-metabolites. However, NIPU requires long-term management for efficacious remission of the disease and to prevent disease relapse. Long-term safety issues associated with steroids have led to efforts to develop novel therapeutic agents including biological response modulators and immunosuppressants. The current therapeutic agents in various stages of development include calcineurin inhibitors, biologic response modifiers and a more a comprehensive modalities like ocular gene therapy as well as novel drug delivery mechanisms for higher bioavailability to the target tissues, with minimal systemic effects. CONCLUSION: Novel efficacious therapeutic modalities under development will help overcome the challenges associated with the traditional therapeutic 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.

Sobrin L, Stone JH, Huang AJ, Niles JL, Nazarian RM. Case 14-2020: A 37-Year-Old Man with Joint Pain and Eye Redness. N Engl J Med 2020;382(18):1750-1758.
Sobrin L, Stanwyck LK, Pan W, Hubbard RA, Kempen JH, VanderBeek BL. Association of Hypovitaminosis D With Increased Risk of Uveitis in a Large Health Care Claims Database. JAMA Ophthalmol 2018;136(5):548-552.Abstract
Importance: Understanding the role of vitamin D-which regulates inflammatory responses-in noninfectious uveitis (an inflammatory disease) may provide insight into treatment and prevention of this disease. Objective: To investigate whether there is an association between hypovitaminosis D and incident noninfectious uveitis. Design, Setting, and Participants: In a retrospective case-control study, data from a health care claims database containing deidentified medical claims from a large private insurer were used to identify 558 adults enrolled from January 1, 2000, to December 31, 2016, who received a diagnosis of noninfectious uveitis from an eye care clinician (with receipt of a confirmatory diagnosis within 120 days of the initial diagnosis) and who had a vitamin D level measured within 1 year before the first diagnosis. Exclusion criteria included having systemic disease or receiving medication known to lower vitamin D levels, having undergone intraocular surgery, and having infectious uveitis. Each case patient was matched with 5 controls on the basis of age, sex, race/ethnicity, and index date (2790 controls). The controls had vitamin D level determined either within 1 year before or within 6 months after receiving an eye examination with normal findings. Multiple logistic regression models were used to examine the association between hypovitaminosis D and noninfectious uveitis. Main Outcomes and Measures: The primary, prespecified analysis assessed the association of noninfectious uveitis with hypovitaminosis D (vitamin D level ≤20 ng/mL). Results: The 558 cases and 2790 controls were matched on age, and each group had a mean (SD) age of 58.9 (14.7) years. Among the cohort of 3348 patients, 2526 (75.4%) were female, and the racial/ethnic distribution in the matched samples was 2022 (60.4%) white, 552 (16.5%) black, 402 (12.0%) Hispanic, 162 (4.8%) Asian, and 210 (6.3%) unknown. Patients with normal vitamin D levels had 21% lower odds of having noninfectious uveitis than patients with low vitamin D levels (odds ratio [OR], 0.79; 95% CI, 0.62-0.99; P = .04). In a race-stratified analysis, an association between vitamin D and uveitis was found in black patients (OR, 0.49; 95% CI, 0.30-0.80; P = .004) and was qualitatively similar but nonsignificant in white patients (OR, 0.87; 95% CI, 0.62-1.21; P = .40) and Hispanic patients (OR, 0.60; 95% CI, 0.33-1.10; P = .10). Conclusions and Relevance: This and other reports have found an association between hypovitaminosis D and noninfectious uveitis. However, these studies cannot establish a causal relationship. Prospective studies are warranted to evaluate whether hypovitaminosis D causes increased risk of uveitis and the role of vitamin D supplementation in prevention and treatment of uveitis.
Sobrin L, Pistilli M, Dreger K, Kothari S, Khachatryan N, Artornsombudh P, Pujari SS, Foster SC, Jabs DA, Nussenblatt RB, Rosenbaum JT, Levy-Clarke GA, Sen NH, Suhler EB, Thorne JE, Bhatt NP, Kempen JH, for Group SITEDCSR. Factors Predictive of Remission of Chronic Anterior Uveitis. Ophthalmology 2020;127(6):826-834.Abstract
PURPOSE: To estimate the incidence of medication-free remission of chronic anterior uveitis and identify predictors thereof. DESIGN: Retrospective cohort study. PARTICIPANTS: Patients diagnosed with anterior uveitis of longer than 3 months' duration followed up at United States tertiary uveitis care facilities. METHODS: Estimation of remission incidence and identification of associated predictors used survival analysis. MAIN OUTCOME MEASURES: Incidence of medication-free remission. For the primary analysis, remission was defined as inactive uveitis while off treatment at all visits spanning an interval of at least 90 days or-for patients who did not return for follow-up after 90 days-remaining inactive without receiving suppressive medications at all of the last visits. Association of factors potentially predictive of medication-free remission was also studied. RESULTS: Two thousand seven hundred ninety-five eyes of 1634 patients with chronic anterior uveitis were followed up over 7936 eye-years (4676 person-years). The cumulative medication-free, person-year remission incidence within 5 years was 32.7% (95% confidence interval [CI], 30.4%-35.2%). Baseline clinical factors predictive of reduced remission incidence included longer duration of uveitis at presentation (for 2 to 5 years vs. less than 6 months: adjusted hazard ratio [aHR], 0.61; 95% CI, 0.44-0.83), bilateral uveitis (aHR, 0.75; 95% CI, 0.59-0.96), prior cataract surgery (aHR, 0.70; 95% CI 0.56-0.88), and glaucoma surgery (aHR, 0.63; 95% CI, 0.45-0.90). Two time-updated characteristics were also predictive of reduced remission incidence: keratic precipitates (aHR, 0.36; 95% CI, 0.21-0.60) and synechiae (aHR, 0.62; 95% CI, 0.41-0.93). Systemic diagnosis with juvenile idiopathic arthritis and spondyloarthropathy were also associated with reduced remission incidence. Older age at presentation was associated with higher incidence of remission (for age ≥40 years vs. <40 years: aHR, 1.29; 95% CI, 1.02-1.63). CONCLUSIONS: Approximately one third of patients with chronic anterior uveitis remit within 5 years. Longer duration of uveitis, younger age, bilateral uveitis, prior cataract surgery, glaucoma surgery, presence of keratic precipitates and synechiae, and systemic diagnoses of juvenile idiopathic arthritis and spondyloarthropathy predict reduced remission incidence; patients with these factors should be managed taking into account the higher probability of a longer disease course.
Sobrin L, Yu Y, Han S, Susarla G, Kempen JH, Hubbard RA, VanderBeek BL. Risk of Non-infectious Uveitis with Metformin Therapy in a Large Healthcare Claims Database. Ocul Immunol Inflamm 2021;:1-7.Abstract
PURPOSE: To determine if metformin is associated with noninfectious uveitis (NIU). METHODS: Patients in an insurance claims database who initiated metformin (n = 359,139) or other oral anti-diabetic medications (n = 162,847) were followed for NIU development. Both cohort and case-control analyses were performed to assess differing exposure lengths using Cox and conditional logistic regression, respectively. RESULTS: The hazard ratio (HR) for incident NIU was not significantly different between the metformin and non-metformin cohorts [HR = 1.19, 95% Confidence Interval (CI): 0.92-1.54, = .19]. The case control analysis similarly showed no association between any metformin use 2 years before the outcome date and NIU [odds ratio (OR) = 0.64, 95% CI: 0.39-1.04, = .07]. However, there was a protective 20 association between cumulative metformin duration [(445-729 days) adjusted OR (aOR) = 0.49, 95% CI: 0.27-0.90, = .02] and dosage (>390,000 mg aOR = 0.44, 95% CI: 0.25-0.78, = .001) compared with no metformin use. CONCLUSIONS: Our results suggest metformin use for longer durations may be protective of NIU onset.
Sobrin L, Yu Y, Li A, Kempen JH, Hubbard RA, VanderBeek BL. Angiotensin Converting Enzyme-Inhibitors and Incidence of Non-infectious Uveitis in a Large Healthcare Claims Database. Ophthalmic Epidemiol 2021;:1-6.Abstract
: To determine if angiotensin converting enzyme-inhibitors (ACE-I) alter the incidence of non-infectious uveitis (NIU). Patients in a large healthcare claims database who initiated ACE-I (n = 695,557) were compared to patients who initiated angiotensin receptor blockers (ARB, n = 354,295). A second comparison was also made between patients who initiated ACE-I (n = 505,958) and those who initiated beta-blockers (BB, n = 538,109). The primary outcome was incident NIU defined as a first diagnosis code for NIU followed by a second instance of a NIU code within 120 days. For the secondary outcome, a corticosteroid prescription or code for an ocular corticosteroid injection within 120 days of the NIU diagnosis code was used instead of the second NIU diagnosis code. Data were analyzed using Cox regression modeling with inverse probability of treatment weighting (IPTW). Sub-analyses were performed by anatomic subtype. When comparing ACE-I to ARB initiators, the hazard ratio (HR) for incident NIU was not significantly different for the primary outcome [HR = 0.95, 95% Confidence Interval (CI): 0.85-1.07, = .41] or secondary outcome [HR = 0.96, 95% CI: 0.86-1.07, = .44]. Similarly, in the ACE-I and BB initiators comparison, the HR for incident NIU was not significantly different comparing ACE-I and BB initiators for either outcome definition or any of the NIU anatomical subtypes. Our results suggest there is no evidence that ACE-I have a protective effect on NIU.

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