@article {1181, title = {Association between Quality of Life and Visual Acuity in a Randomized Clinical Trial of Patients with Uveitis Taking Antimetabolites.}, journal = {Ocul Immunol Inflamm}, year = {2023}, month = {2023 Feb 07}, pages = {1-9}, abstract = {

PURPOSE: To evaluate how changes in visual acuity are associated with changes in quality of life (QoL) among patients with non-infectious uveitis taking antimetabolites.

METHODS: This secondary analysis of the multicenter First-line Antimetabolites as Steroid-sparing Treatment (FAST) Uveitis Trial involves 216 participants randomized to methotrexate or mycophenolate mofetil. Vision-related (NEI-VFQ and IND-VFQ) and health-related (PCS and MCS SF-36v2) QoL and visual acuity were measured at baseline and 6-month primary endpoint.

RESULTS: Visual acuity was significantly associated and correlated with all QoL measures (Spearman correlation coefficients\ =\ 0.5, 0.5, 0.3, and 0.4 for NEI-VFQ, IND-VFQ, SF-36v2 MCS and PCS, respectively). All observed changes in QoL met or exceeded the minimal clinically important difference definition on each scale. Treatment group was not significantly associated with any QoL measure.

CONCLUSION: By adding insight beyond visual acuity, QoL provides a more comprehensive picture of the patient experience during uveitis treatment. QoL = quality of life; VR-QoL = vision-related quality of life; HR-QoL = health-related quality of life; FAST = First-line Antimetabolites as Corticosteroid Sparing Treatment; NEI-VFQ = National Eye Institute Visual Functioning Questionnaire; IND-VFQ = Indian Visual Functioning Questionnaire; SF-36v2 = Medical Outcomes Study 36-Item Short Form Survey; PCS = physical component score; MCS = mental component score; 95\% CI = 95\% confidence interval; MCID = minimal clinically important difference.

}, issn = {1744-5078}, doi = {10.1080/09273948.2023.2169714}, author = {Chattopadhyay, Aheli and Rathinam, S R and Gonzales, John A and Kelly, Nicole K and Thundikandy, Radhika and Kanakath, Anuradha and Murugan, S Bala and Vedhanayaki, R and Lim, Lyndell L and Suhler, Eric B and Al-Dhibi, Hassan A and Doan, Thuy and Ebert, Caleb D and Porco, Travis C and Acharya, Nisha R} } @article {1171, title = {Reduced Dose Methotrexate and Mycophenolate Mofetil in Noninfectious Uveitis: A Sub-Analysis from the First-Line Antimetabolites as Steroid Sparing Therapy (FAST) Trial.}, journal = {Ocul Immunol Inflamm}, year = {2023}, month = {2023 Jan 26}, pages = {1-6}, abstract = {

PURPOSE: Some patients taking methotrexate (MTX) or mycophenolate mofetil (MMF) experience intolerable side effects at full doses. We evaluated whether dose reduction affected treatment outcomes in uveitis patients.

METHODS: Subanalysis of the First-line Antimetabolites as Steroid-sparing Treatment (FAST) uveitis trial. Patients were randomized to receive MTX (25 mg weekly) or MMF (3\ g daily). A pre-specified dose reduction protocol could be employed for intolerable side effects. Primary analysis was performed at 6\ months.

RESULTS: 43/194 patients (22\%) required dose reduction. 88/151 patients (58\%) on maximum doses and 32/43 patients (74\%) on reduced doses were deemed treatment successes at 6 months. The odds ratio point estimate (1.60, 95\% CI 0.72-3.74) favored dose-reduction but this was not significant. Following reduction, adverse events improved at the subsequent study visit (79 events reduced to 63 events).

CONCLUSION: Dose reduction of antimetabolites was not associated with worse outcomes in this subanalysis of a uveitis trial.

}, issn = {1744-5078}, doi = {10.1080/09273948.2023.2165949}, author = {Sura, Amol A and Sun, Yuwei and Reddy, Amit K and Rathinam, S R and Gonzales, John A and Thundikandy, Radhika and Vedhanayaki, Rajesh and Kanakath, Anuradha and Murugan, Bala and Doan, Thuy A and Lim, Lyndell L and Suhler, Eric B and Al-Dhibi, Hassan A and Acharya, Nisha R} } @article {1231, title = {Risk of failing both methotrexate and mycophenolate mofetil from the First-line Antimetabolites as Steroid-sparing Treatment (FAST) uveitis trial.}, journal = {J Ophthalmic Inflamm Infect}, volume = {13}, year = {2023}, month = {2023 Jun 09}, pages = {29}, abstract = {

BACKGROUND: The antimetabolites methotrexate (MTX) and mycophenolate mofetil (MMF) are commonly used as initial corticosteroid-sparing treatment for uveitis. There is little data examining risk factors for failing both MTX and MMF. The objective of this study is to determine risk factors for failing both MTX and MMF in patients with non-infectious uveitis.

MAIN BODY: This is a sub-analysis of the First-line Antimetabolites as Steroid-sparing Treatment (FAST) uveitis trial, which was an international, multicenter, block-randomized, observer-masked, comparative effectiveness trial comparing MTX and MMF as initial treatments for non-infectious uveitis. This study was undertaken at multiple referral centers in India, the United States, Australia, Saudi Arabia and Mexico between 2013 and 2017. A total of 137 patients who completed all 12 months of follow-up from the FAST trial, were included in this study. The primary outcome was failing both antimetabolites over the 12 months of the trial. Potential predictors included: age, sex, bilateral involvement, anatomic location of the uveitis, presence of cystoid macular edema (CME) and retinal vasculitis at baseline visit, uveitis duration, and country/study sites as risk factors for failing both MTX and MMF. The presence of retinal vasculitis posterior to the equator on fluorescein angiogram was associated with failing both MTX and MMF.

CONCLUSION: Retinal vasculitis may be a risk factor for failing multiple antimetabolites. Clinicians could consider more quickly advancing these patients to other medication classes, such as biologics.

}, issn = {1869-5760}, doi = {10.1186/s12348-023-00350-5}, author = {Reddy, Amit K and Miller, D Claire and Sura, Amol A and Rathinam, S R and Gonzales, John A and Thundikandy, Radhika and Kanakath, Anuradha and Murugan, Bala and Vedhanayaki, Rajesh and Lim, Lyndell L and Suhler, Eric B and Doan, Thuy and Al-Dhibi, Hassan A and Goldstein, Debra A and Arellanes-Garcia, Lourdes and Acharya, Nisha R} } @article {976, title = {Detection of Leptospirosis Genome from the Aqueous Humor of a Patient with Bilateral Uveitis.}, journal = {Ocul Immunol Inflamm}, year = {2022}, month = {2022 Apr 29}, pages = {1-3}, abstract = {

BACKGROUND: Leptospira species are difficult to culture. Thus, when there is suspicion for an infectious etiology to uveitis, bacterial cultures may fail to identify Leptospira. We describe a case of leptospirosis-associated uveitis that evaded culture and molecular assays. DNA sequencing of the aqueous fluid showed the presence of Leptospira spp.

METHODS: Retrospective case review of clinical and laboratory features of a patient with ocular leptospirosis is presented.

RESULTS: DNA sequencing identified the genome of Leptospirosis spp. in the aqueous humor.

CONCLUSION: Metagenomic sequencing, by virtue of its unbiased nature, can be a helpful adjunctive test when a strong clinical suspicion for intraocular infection persists despite negative routine culture and molecular assays.

}, issn = {1744-5078}, doi = {10.1080/09273948.2022.2067779}, author = {Gonzales, John A and Sundararajan, Miel and Qian, Ying and Hwang, Thomas and Doan, Thuy} } @article {961, title = {Intraocular Inflammation Associated with IRAK4 Deficiency.}, journal = {Ocul Immunol Inflamm}, year = {2022}, month = {2022 Apr 20}, pages = {1-3}, issn = {1744-5078}, doi = {10.1080/09273948.2022.2059523}, author = {Gonzales, John A and Nortey, Jeremy and Reddy, Amit and Doan, Thuy and Acharya, Nisha R} } @article {971, title = {Occult cause of uveitis-glaucoma-hyphema syndrome diagnosed during treatment with endocyclophotocoagulation (ECP).}, journal = {Am J Ophthalmol Case Rep}, volume = {26}, year = {2022}, month = {2022 Jun}, pages = {101537}, abstract = {

Purpose: To describe uveitis-glaucoma-hyphema (UGH) syndrome secondary to a posterior chamber intraocular lens (PCIOL) within the capsular bag in which pathogenic changes to the ciliary body were observed and treated with endocyclophotocoagulation (ECP).

Observations: An 85-year-old woman who had cataract surgery in her right eye four years ago presented with recurrent, unilateral, open-angle, hypertensive uveitis in her right eye. Her presentations were characterized by decreased vision, elevated intraocular pressure, corneal edema, a mixed anterior chamber reaction, and pigmented anterior vitreous cells. She had a frank vitreous hemorrhage during two episodes. Ultrasound biomicroscopy revealed a dense Soemmerring ring in her right eye without evidence of PCIOL-iris or PCIOL-ciliary body chafe. Subsequent ECP revealed whitened and atrophic ciliary processes adjacent to a tilted haptic within the capsular bag, consistent with chronic PCIOL-ciliary body chafe. ECP was applied to the affected ciliary processes, which successfully eliminated recurrences.

Conclusions and importance: UGH can rarely occur due to an PCIOL within the capsular bag. In cases where ultrasound biomicroscopy (UBM) does not show abnormalities and clinical suspicion remains high, ECP can be a useful adjunct to observe and treat abnormalities of the ciliary body.

}, issn = {2451-9936}, doi = {10.1016/j.ajoc.2022.101537}, author = {Sura, Amol A and Reddy, Amit K and Babic, Kelly and Saifee, Murtaza and Acharya, Nisha R and Gonzales, John A and Han, Ying and Doan, Thuy A} } @article {921, title = {Outcomes of uveitic macular edema in the First-line Antimetabolites as Steroid-sparing Treatment (FAST) Uveitis Trial.}, journal = {Ophthalmology}, year = {2022}, month = {2022 Feb 07}, abstract = {

PURPOSE: To evaluate the outcomes of uveitic macular edema at 6 months and 12 months in patients treated with methotrexate or mycophenolate mofetil.

DESIGN: Subanalysis of a block-randomized, observer-masked, multi-center clinical trial.

SUBJECTS/PARTICIPANTS: Patients were enrolled into the First-line Antimetabolites as Steroid-sparing Treatment (FAST) uveitis trial between August 2013 and August 2017.

METHODS/INTERVENTION/TESTING: Patients were randomized to oral methotrexate 25mg weekly or mycophenolate mofetil 1.5g twice daily for 12 months, along with a corticosteroid taper. In addition to standardized clinical examination, all patients underwent spectral domain optical coherence tomography imaging at each visit. At the 6-month primary endpoint, patients who achieved treatment success continued the same treatment for a subsequent 6 months and treatment failures switched to the other treatment group.

MAIN OUTCOME MEASURES: Pre-specified primary outcome at 6 months and 12 months outcomes of central subfield thickness and visual acuity.

RESULTS: Of 216 patients in the FAST Trial, 42 eyes of 30 patients in the methotrexate group and 55 eyes of 41 patients in the mycophenolate group had uveitic macular edema. Baseline median central subfield thickness was 359μm and 342μm in the methotrexate and mycophenolate groups, respectively. At 12 months, for those who stayed on the same treatment, macular thickness decreased from baseline by 23 μm (IQR, -39.0 to 13) and 18 μm (IQR, -68.5 to 9), in the methotrexate and mycophenolate groups, respectively, (P=0.76). In patients who switched treatment at 6 months, macular thickness decreased from baseline by 12.5 μm (IQR, -29.8 to -2.3) and 92 μm (IQR, -240 to -18) in the methotrexate and mycophenolate groups, respectively, (P=0.23). At 12 months, 7/19 (37\%) eyes on methotrexate had resolution of macular edema compared to 15/25 (60\%) eyes on mycophenolate (P=0.10). For those that switched treatments, 8/17 (47\%) eyes on methotrexate and 6/11 (55\%) eyes on mycophenolate had improvement of macular edema, (P=0.92) CONCLUSIONS: Treatment with methotrexate or mycophenolate mofetil for uveitic macular edema results in similar improvements in macular thickness at 6 and 12 months. At 12 months, approximately half of eyes in each antimetabolite group still had persistent macular edema.

}, issn = {1549-4713}, doi = {10.1016/j.ophtha.2022.02.002}, author = {Tsui, Edmund and Rathinam, Sivakumar R and Gonzales, John A and Thundikandy, Radhika and Kanakath, Anuradha and Balamurugan, S and Vedhanayaki, R and Lim, Lyndell L and Suhler, Eric B and Al-Dhibi, Hassan A and Doan, Thuy and Keenan, Jeremy and Ebert, Caleb D and Kim, Eric and Madow, Brian and Porco, Travis C and Acharya, Nisha R} } @article {896, title = {Time to Uveitis Control with Methotrexate and Mycophenolate Mofetil.}, journal = {Ophthalmology}, year = {2022}, month = {2022 Jan 24}, abstract = {

This subanalysis from the First-line Antimetabolites as Steroid-sparing Treatment Trial found no significant difference in the time to achieve a corticosteroid-sparing dosage of prednisone for patients with noninfectious uveitis treated with methotrexate versus mycophenolate mofetil.

}, issn = {1549-4713}, doi = {10.1016/j.ophtha.2022.01.020}, author = {Bui, Anh D and Kong, Christina L and Kelly, Nicole K and Rathinam, S R and Gonzales, John A and Thundikandy, Radhika and Kanakath, Anuradha and Murugan, Bala and Vedhanayaki, R and Lim, Lyndell L and Suhler, Eric B and Al-Dhibi, Hassan A and Doan, Thuy and Acharya, Nisha R} } @article {731, title = {Comprehensive pathogen detection for ocular infections.}, journal = {J Clin Virol}, volume = {136}, year = {2021}, month = {2021 Feb 11}, pages = {104759}, abstract = {

BACKGROUND: Molecular diagnostics such as pathogen-directed PCRs have transformed testing for ocular infections since the late 1990s. Although these assays remain important diagnostic tools for samples with low biomass, the lack of diagnostic range motivates alternative molecular approaches for ocular infections. The aim of this study was to determine the performance of a high-throughput RNA sequencing approach, RNA-seq, to detect infectious agents in ocular samples from patients with presumed ocular infections.

METHODS: We compared the performance of RNA-seq to pathogen-directed PCRs using remnant nucleic acids from 41 aqueous or vitreous samples of patients with presumed ocular infections. Pathogen-directed PCRs were performed at the CLIA-certified Stanford Clinical Virology Laboratory. RNA-seq was performed in a masked manner at the Proctor Foundation at the University of California San Francisco. Percent positive and negative agreement between the two testing approaches were calculated. Discordant results were subjected to orthogonal testing.

RESULTS: The positive percent agreement between RNA-seq and pathogen-directed PCRs was 100\% (95\% confidence interval (CI): 78.5\%-100\%). The negative percent agreement was 92.6\% (95\% CI: 76.6\%-97.9\%). RNA-seq identified pathogens not on the differential diagnosis for 9.7\% (4/41) of the samples. Two pathogens solely identified with RNA-seq were confirmed with orthogonal testing.

CONCLUSIONS: RNA-seq can accurately identify common and rare pathogens in aqueous and vitreous samples of patients with presumed ocular infections. Such an unbiased approach to testing has the potential to improve diagnostics although practical clinical utility warrants additional studies.

}, issn = {1873-5967}, doi = {10.1016/j.jcv.2021.104759}, author = {Doan, Thuy and Sahoo, Malaya K and Ruder, Kevin and Huang, ChunHong and Zhong, Lina and Chen, Cindi and Hinterwirth, Armin and Lin, Charles and Gonzales, John A and Pinsky, Benjamin A and Acharya, Nisha R} } @article {846, title = {Detection of Tropheryma whipplei Genome From the Aqueous Humor by Metagenomic Sequencing.}, journal = {Ann Intern Med}, year = {2021}, month = {06/2021}, issn = {1539-3704}, doi = {10.7326/L20-1470}, author = {Gonzales, John A and Doan, Thuy and VanZante, Annemieke and Stewart, Jay M and Sura, Amol and Reddy, Amit and Rasool, Nailyn} } @article {761, title = {Peripheral Blood Transcriptome in Patients with Sarcoidosis-Associated Uveitis.}, journal = {Ocul Immunol Inflamm}, year = {2021}, month = {2021 Mar 04}, pages = {1-4}, abstract = {

: To identify peripheral blood transcriptome differences in uveitis patients with sarcoidosis compared to those with Vogt-Koyanagi-Harada (VKH) syndrome and controls.: Ten patients with uveitis compatible with sarcoidosis (eight with pulmonary sarcoidosis, one with central nervous system sarcoidosis, and one with conjunctival sarcoidosis), nine patients with VKH, and nine healthy controls were prospectively enrolled.: Ten genes exhibited a four-fold difference in expression in sarcoidosis patients compared to controls, many being involved in regulating inflammatory processes or cellular responses to microbes.: This research suggests that the transcriptome in sarcoidosis is robust enough to be detected in the peripheral blood and that sarcoidosis can be distinguished from healthy controls. Differentially expressed genes may serve as candidates warranting further investigation with respect to disease pathophysiology and may provide additional information, such as ability to stratify patients based on associated disease severity and anatomical location of inflammation within the eye.

}, issn = {1744-5078}, doi = {10.1080/09273948.2020.1861306}, author = {Gonzales, John A and Takhar, Jaskirat S and Joye, Ashlin and Acharya, Nisha R and Chen, Cindi and Hinterwirth, Armin and Doan, Thuy} } @article {736, title = {Vitreoretinal Lymphoma: A Literature Review and Introduction of a New Diagnostic Method.}, journal = {Asia Pac J Ophthalmol (Phila)}, volume = {10}, year = {2021}, month = {2021 01 19}, pages = {93-98}, abstract = {

PURPOSE: The aim of this study was to briefly review the clinical and diagnostic features of vitreoretinal lymphoma (VRL) and to introduce the recent introduction of metagenomic deep sequencing in this ocular lymphomatous disease.

DESIGN AND METHODS: Review and description of the process of using metagenomic deep sequencing for ocular specimens at the Proctor Foundation, University of California, San Francisco, CA.

RESULTS: VRL masquerades as a uveitis, but clinical signs of subretinal lesions, and vitritis should prompt the inclusion of VRL in a differential diagnosis. Imaging features such as hyporeflective infiltrative lesions between the retinal pigment epithelium and Bruch{\textquoteright}s membrane are compatible with VRL, but diagnosis requires satisfying specific cytopathological and immunohistochemical or molecular features. Diagnosis, then, is subject to the cellularity, viability, and volume of the specimen submitted for these tests. Metagenomic deep sequencing has the ability to detect numerous lymphoma-associated mutations and is able to utilize minute volume samples and cell-free nucleic acid, so is well-suited for ocular tissues.

CONCLUSIONS: Metagenomic deep sequencing may offer an additional tool in the future with which to diagnose VRL.

}, issn = {2162-0989}, doi = {10.1097/APO.0000000000000365}, author = {Takhar, Jaskirat and Doan, Thuy and Gonzales, John A} } @article {181, title = {Clinical Course of Preexisting Uveitis during Treatment of Lung Cancer with Durvalumab.}, journal = {Ocul Immunol Inflamm}, volume = {28}, year = {2020}, month = {2020 05 18}, pages = {566-570}, issn = {1744-5078}, doi = {10.1080/09273948.2019.1678652}, author = {Ahmad, Tessnim R and Doan, Thuy and Gonzales, John A and Acharya, Nisha R and Tsui, Edmund} } @article {156, title = {Metagenomic Deep Sequencing to Investigate for an Infectious Etiology of Iridocorneal Endothelial Syndrome.}, journal = {Cornea}, volume = {39}, year = {2020}, month = {2020 Oct}, pages = {1307-1310}, abstract = {

PURPOSE: Iridocorneal endothelial (ICE) syndrome is a group of rare ocular conditions that result from abnormal corneal endothelial cells, leading to secondary glaucoma, iris distortions, and corneal edema. The etiology of ICE is unknown, although it has been associated with viral infections, such as herpes simplex virus. In this study, we sought to identify an infectious etiology for ICE using advanced molecular techniques.

METHODS: Metagenomic RNA sequencing (MDS) is a high-throughput sequencing approach that can identify all pathogens in any clinical sample, including RNA viruses. Descemet membrane and aqueous fluid from patients with ICE syndrome were subjected to MDS testing.

RESULTS: Samples from 3 patients with ICE were analyzed. MDS was performed on the aqueous fluid of 3 patients and Descemet membrane and endothelial cell tissue from 1 patient. Viral pathogens were not identified in any of the samples.

CONCLUSIONS: We were unable to identify a viral etiology in the tissues of patients with the Chandler variant of ICE syndrome, although this study was limited by sample size.

}, issn = {1536-4798}, doi = {10.1097/ICO.0000000000002368}, author = {Sutra, Plern and Rose-Nussbaumer, Jennifer and Gonzales, John A and Wang, Kaidi and Hinterwirth, Armin and Seitzman, Gerami and Bloomer, Michele and Acharya, Nisha and Doan, Thuy} } @article {101, title = {Association Between Noninfectious Uveitis and Psychological Stress.}, journal = {JAMA Ophthalmol}, volume = {137}, year = {2019}, month = {2019 02 01}, pages = {199-205}, abstract = {

Importance: Uveitis involves dysregulation of the ocular immune system. Stress has been shown to affect immune function, but it is unclear whether there is an association between stress and uveitis.

Objective: To determine whether having uveitis is associated with psychological stress.

Design, Setting, and Participants: A cross-sectional, case-control study including a self-administered survey, medical records review, and diurnal salivary cortisol test was conducted at a university-based uveitis clinic and comprehensive eye clinic. Participants included 146 consecutive adults with noninfectious uveitis and age-matched controls with no eye disease. The study was conducted from December 1, 2017, to March 14, 2018.

Main Outcomes and Measures: Participants completed the self-administered, Cohen 10-item Perceived Stress Scale (PSS-10), a demographics questionnaire. Responses to each question were categorized on a 5-point Likert scale, with total scores ranging from 0 (no stress) to 40 (high stress). In addition, participants submitted 3 salivary cortisol samples. Those with uveitis were classified as having recently active or controlled disease through medical records review. The prespecified primary analysis was a linear regression of PSS-10 score and uveitis correcting for age, sex, educational level, employment, and median income. Secondary analyses included comparing PSS-10 scores in patients with recently active and controlled uveitis, determining predictors of stress, and comparing diurnal salivary cortisol between uveitis and control groups.

Results: Of 146 eligible patients, 17 declined participation and 9 consented but were excluded because they did not complete both questionnaires, resulting in 120 patients (80 uveitis; 40 controls) in the final analysis. Eighty participants (66.7\%) were women, and 70 (58.3\%) were white. Median age was 40 years (interquartile range, 29-59 years). Having uveitis was associated with a 4.3-point increase in PSS-10 score (95\% CI, 1.8 to 6.9; P = .002). There was no significant difference in PSS-10 scores between patients with recently active and controlled uveitis (1.0 point greater for patients with active uveitis; 95\% CI, -2.0 to 3.9; P = .52). Factors associated with increased PSS-10 score in patients with uveitis included female sex (coefficient, 4.0; 95\% CI, 1.6 to 6.5; P = .002), current immunomodulatory therapy (coefficient, 2.5; 95\% CI, -0.3 to 5.2; P = .08), history of depression (coefficient, 3.8; 95\% CI, 0.8 to 6.8; P = .02), and having posterior or panuveitis (coefficient, 2.6; 95\% CI, 0.8 to 4.4; P = .006). Of the 70 participants (58.3\%) who had testable samples for cortisol analysis, diurnal salivary cortisol levels did not significantly differ between uveitis and nonuveitis groups.

Conclusions and Relevance: These findings suggest that patients with uveitis have higher levels of psychological stress compared with controls, yet no significant difference was identified in the stress of patients with active vs controlled uveitis. Consequently, comprehensive treatment for noninfectious uveitis may be able to address the psychological results of this disease.

}, keywords = {Adult, Case-Control Studies, Cross-Sectional Studies, Eye Infections, Female, Humans, Male, Middle Aged, Risk Factors, Stress, Psychological, Surveys and Questionnaires, Uveitis, Vision, Ocular, Visual Acuity}, issn = {2168-6173}, doi = {10.1001/jamaophthalmol.2018.5893}, author = {Berlinberg, Elyse J and Gonzales, John A and Doan, Thuy and Acharya, Nisha R} } @article {96, title = {Association of Ocular Inflammation and Rubella Virus Persistence.}, journal = {JAMA Ophthalmol}, volume = {137}, year = {2019}, month = {2019 04 01}, pages = {435-438}, abstract = {

Importance: Metagenomic deep sequencing (MDS) demonstrates that persistent and active rubella virus (RV) infection is associated with Fuchs heterochromic iridocyclitis (FHI).

Objective: To assess the utility of MDS in identifying RV infection in patients with uveitis.

Design, Setting, and Participants: This case series assessed 6 patients diagnosed by MDS with RV-associated uveitis at a tertiary uveitis referral center in the United States.

Exposures: Prior RV infection.

Main Outcomes and Measures: Clinical examination findings, slitlamp photography, corneal confocal imaging, and infectious pathogen genome obtained from RNA sequencing.

Results: Six white men (age range, 36-61 years) were diagnosed with RV-associated uveitis by MDS. Three patients exhibited iris heterochromia associated with their uveitis in classic FHI fashion. The other 3 patients had less classic FHI features and exhibited anterior vitritis. Three patients had in vivo corneal confocal microscopy, with 2 demonstrating stellate keratic precipitates in addition to endothelial infiltration, spotlike holes, and enlarged intercellular boundaries. Of these 3 patients, 1 patient exhibited polymorphism and polymegathism of the endothelial cells.

Conclusions and Relevance: These findings suggest that persistent RV infection is associated with recurrent or chronic anterior or anterior-intermediate uveitis as well as corneal endothelial cell damage. Ophthalmologists should consider RV infection as a potential cause of hypertensive anterior and intermediate uveitis.

}, keywords = {Adult, Eye Infections, Viral, Humans, Male, Middle Aged, Rubella, Uveitis}, issn = {2168-6173}, doi = {10.1001/jamaophthalmol.2018.6185}, author = {Gonzales, John A and Hinterwirth, Armin and Shantha, Jessica and Wang, Kaidi and Zhong, Lina and Cummings, Susie L and Qian, Ying and Wilson, Michael R and Acharya, Nisha R and Doan, Thuy} } @article {76, title = {A double masked randomised 4-week, placebo-controlled study in the USA, Thailand and Taiwan to compare the efficacy of oral valganciclovir and topical 2\% ganciclovir in the treatment of cytomegalovirus anterior uveitis: study protocol.}, journal = {BMJ Open}, volume = {9}, year = {2019}, month = {2019 12 19}, pages = {e033175}, abstract = {

INTRODUCTION: Cytomegalovirus (CMV) anterior uveitis is a recognised cause of anterior uveitis in immunocompetent patients and is preventable cause of vision loss. Ocular sequelae include corneal endothelial damage which can cause corneal oedema and failure, as well as glaucoma. Recurrences of inflammation are common and therefore patients are often exposed to long-term therapy. Oral therapy is available in the form of valganciclovir, although with the caveat of systemic side effects such as bone marrow suppression and renal failure necessitating regular interval laboratory monitoring. Recent reports have demonstrated that topical 2\% ganciclovir solution may offer promising treatment outcomes in patients with CMV anterior uveitis with superior safety, cost-effectiveness and convenience profiles. An investigation into the relative equipoise of these therapies is warranted for these reasons.

METHODS AND ANALYSIS: The Systemic and Topical Control of Cytomegalovirus Anterior uveitis: Treatment Outcomes (STACCATO) trial is designed as a multicentre, block randomised by site, double-masked, placebo-controlled trial comparing the efficacy of oral valganciclovir, 2\% topical ganciclovir and placebo in treating PCR-proven CMV anterior uveitis. Participant clinical evaluation will occur at three study time points by a masked study ophthalmologist over a 28-day period to assess resolution of ocular inflammation (secondary outcome). A control group will provide additional information about the possible impact that the infected host{\textquoteright}s immune response may play in controlling local viral replication. The primary analysis is an analysis of covariance (three arms) correcting for baseline to compare quantitative CMV viral load in the anterior chamber (AC) aqueous fluid before and 7 days after treatment.

ETHICS AND DISSEMINATION: The University of California San Francisco Committee on Human Research and the Khon Kaen University Institutional Review Board have given ethical approval. The results of this trial will be presented at local and international meetings and submitted for peer-reviewed journals for publication.

TRIAL REGISTRATION NUMBER: NCT03576898.

}, keywords = {Administration, Oral, Administration, Topical, Antiviral Agents, Cytomegalovirus Infections, Double-Blind Method, Ganciclovir, Humans, Multicenter Studies as Topic, Randomized Controlled Trials as Topic, Taiwan, Thailand, United States, Uveitis, Anterior, Valganciclovir, Viral Load}, issn = {2044-6055}, doi = {10.1136/bmjopen-2019-033175}, author = {Takhar, Jaskirat S and Joye, Ashlin S and Somkijrungroj, Thanapong and Laovirojjanakul, Wipada and Lin, Chang-Ping and Lietman, Thomas M and Porco, Travis C and Keenan, Jeremy D and Gebreegziabher, Elisabeth A and Seitzman, Gerami D and Rose-Nussbaumer, Jennifer and Thuy A Doan and Acharya, Nisha R and Gonzales, John A} } @article {41, title = {Effect of Corticosteroid-Sparing Treatment With Mycophenolate Mofetil vs Methotrexate on Inflammation in Patients With Uveitis: A Randomized Clinical Trial.}, journal = {JAMA}, volume = {322}, year = {2019}, month = {2019 09 10}, pages = {936-945}, abstract = {

Importance: Methotrexate and mycophenolate mofetil are commonly used immunomodulatory therapies for achieving corticosteroid-sparing control of noninfectious uveitis, but there is uncertainty about which drug is more effective.

Objective: To compare the effect of methotrexate and mycophenolate for achieving corticosteroid-sparing control of noninfectious intermediate uveitis, posterior uveitis, and panuveitis.

Design, Setting, and Participants: The First-line Antimetabolites as Steroid-sparing Treatment (FAST) uveitis trial screened 265 adults with noninfectious uveitis requiring corticosteroid-sparing immunosuppressive therapy from 9 referral eye centers in India, the United States, Australia, Saudi Arabia, and Mexico between August 22, 2013, and August 16, 2017. Follow-up ended on August 20, 2018.

Interventions: Patients were randomized to receive oral methotrexate, 25 mg weekly (n = 107), or oral mycophenolate mofetil, 3 g daily (n = 109).

Main Outcomes and Measures: The primary outcome was treatment success at 6 months, which was defined as having control of inflammation in both eyes, no more than 7.5 mg prednisone daily and less than or equal to 2 drops of prednisolone acetate 1\%, and no treatment failure due to safety or intolerability. Patients underwent follow-up to 12 months while receiving the same treatment or switched to the other antimetabolite, depending on their 6-month outcome.

Results: Among 216 patients who were randomized (median age, 38 years; 135 (62.5\%) women), 194 (89.8\%) completed follow-up through 6 months. Treatment success occurred in 64 (66.7\%) patients in the methotrexate group vs 56 (57.1\%) in the mycophenolate group (difference, 9.5\% [95\% CI, -5.3\% to 21.8\%]; odds ratio [OR], 1.50 [95\% CI, 0.81 to 2.81]; P = .20). Among patients with posterior uveitis or panuveitis, treatment success was achieved in 58 (74.4\%) in the methotrexate group vs 42 (55.3\%) in the mycophenolate group (difference, 19.1\% [95\% CI, 3.6\% to 30.6\%]; OR, 2.35 [95\% CI, 1.16 to 4.90]; P = .02); whereas among patients with intermediate uveitis treatment success occurred in 6 (33.3\%) in the methotrexate group vs 14 (63.6\%) in the mycophenolate group (difference, -30.3\% [95\% CI, -51.6\% to 1.1\%]; OR, 0.29 [95\% CI, 0.08 to 1.05]; P = .07; P for interaction = .004). Elevated liver enzymes were the most common nonserious laboratory adverse event, occurring in 14 patients (13.0\%) in the methotrexate group and 8 patients (7.4\%) in the mycophenolate group.

Conclusions and Relevance: Among adults with noninfectious uveitis, the use of mycophenolate mofetil compared with methotrexate as first-line corticosteroid-sparing treatment did not result in superior control of inflammation. Further research is needed to determine if either drug is more effective based on the anatomical subtype of uveitis.

Trial Registration: ClinicalTrials.gov Identifier: NCT01829295.

}, keywords = {Adult, Anti-Inflammatory Agents, Drug Therapy, Combination, Enzyme Inhibitors, Female, Humans, Immunosuppressive Agents, Liver Function Tests, Male, Methotrexate, Middle Aged, Mycophenolic Acid, Prednisolone, Uveitis}, issn = {1538-3598}, doi = {10.1001/jama.2019.12618}, author = {Rathinam, S R and Gonzales, John A and Thundikandy, Radhika and Kanakath, Anuradha and Murugan, S Bala and Vedhanayaki, R and Lim, Lyndell L and Suhler, Eric B and Al-Dhibi, Hassan A and Doan, Thuy and Keenan, Jeremy D and Rao, Maya M and Ebert, Caleb D and Nguyen, Hieu H and Kim, Eric and Porco, Travis C and Acharya, Nisha R} } @article {111, title = {Letermovir for the Management of Cytomegalovirus-associated Uveitis.}, journal = {Ocul Immunol Inflamm}, year = {2019}, month = {2019 Oct 22}, pages = {1-6}, abstract = {

: To investigate the use of letermovir 480 mg daily for the treatment of cytomegalovirus (CMV)-associated uveitis (AU). : Retrospective case series of CMV-AU patients on letermovir. : Six eyes of five patients (mean age 54 years) were included. Mean follow-up time was 10 months. Four patients had CMV anterior uveitis and one patient had bilateral CMV retinitis. All were treated initially with valganciclovir 900 mg twice daily. Transition to letermovir was due to cytopenias (n = 3), transaminitis (n = 1), and persistent inflammation on valganciclovir (n = 1). At the initiation of letermovir, mean visual acuity (VA) was 0.35 logMAR and IOP was 14 mmHg. One of the six eyes had a recurrence of anterior uveitis due to self-discontinuation of letermovir. No adverse events were observed. At last follow-up, no patients had active inflammation. Mean VA was 0.08 logMAR and IOP was 9 mmHg. : Letermovir may be an alternative treatment for CMV-AU in patients with persistent inflammation or side effects on valganciclovir.

}, issn = {1744-5078}, doi = {10.1080/09273948.2019.1662062}, author = {Tsui, Edmund and Gonzales, John A and Shantha, Jessica G and Acharya, Nisha and Doan, Thuy} } @article {91, title = {Primary vitreoretinal lymphoma: empowering our clinical suspicion.}, journal = {Curr Opin Ophthalmol}, volume = {30}, year = {2019}, month = {2019 Nov}, pages = {491-499}, abstract = {

PURPOSE OF REVIEW: Vitreoretinal lymphoma (VRL) is well known as a masquerade syndrome. However, delays in diagnosis are common particularly because of the small volume of tissue that is used for investigative studies. We outline the current diagnostic tests available to clinicians and provide a glimpse of possible future novel diagnostics.

RECENT FINDINGS: The use of spectral domain ocular coherence tomography to identify subretinal lesions has proven to be a reliable ally to clinicians. Nevertheless, the diagnostic gold standard remains cytology, which requires a skilled pathologist. Molecular tests, including MYD88 polymerase chain reaction testing has further refined our diagnostic capabilities. Metagenomic deep sequencing is a newer molecular test that offers the ability to identify any mutation associated with lymphoma development and may offer more sensitive testing in the future.

SUMMARY: Clinicians have developed a strong acumen for suspecting VRL based upon clinical features, which can further be supported by a variety of imaging modalities. Delays in diagnosis continue to occur particularly because of the small volume of ocular fluid available for testing and because current tests offer a biased approach in terms of limited scope of detecting a specific mutation or cytopathologic feature(s). Newer molecular techniques feature an expanded scope of detecting any mutation associated with lymphomatous development.

}, keywords = {Eye Neoplasms, Humans, Intraocular Lymphoma, Molecular Diagnostic Techniques, Myeloid Differentiation Factor 88, Retinal Neoplasms, Vitreous Body}, issn = {1531-7021}, doi = {10.1097/ICU.0000000000000620}, author = {Takhar, Jaskirat S and Thuy A Doan and Gonzales, John A} } @article {116, title = {Time Trade-off Utility Values in Noninfectious~Uveitis.}, journal = {Am J Ophthalmol}, volume = {208}, year = {2019}, month = {2019 12}, pages = {47-55}, abstract = {

PURPOSE: To investigate time trade-off (TTO) utility values in patients with noninfectious uveitis and determine whether patient demographics and clinical characteristics are associated with utility scores.

DESIGN: Time trade-off utility analysis.

METHODS: Setting: A tertiary care uveitis center in San Francisco, California, USA.

PATIENT POPULATION: One hundred and four consecutive adults with noninfectious uveitis, enrolled between November 2016 and February 2017.

MAIN OUTCOME MEASURES: TTO utility values, as collected by an interviewer-guided survey. Information regarding general health, ocular symptoms, and religion was also collected and medical record review was conducted to record anatomic location of uveitis, disease activity, visual acuity, and treatments. Multivariable regression analysis with backward selection was used to identify variables associated with TTO values.

RESULTS: Median TTO score was 0.975 (interquartile range [IQR]: 0.8-1.0), corresponding to trading a median 1.28 years of remaining life for healthy eyes (IQR: 0-6.29). Regression analysis revealed that worse eye visual acuity, \>6\ months of oral corticosteroid use, and current antidepressant use were associated with lower TTO scores (P\ = .008, P\ = .006, P\ = .008, respectively), controlling for age and sex. In particular, patients who had been taking oral corticosteroids for more than 6\ months, regardless of dose, were 10.5 times more likely to trade 20\% or more years of remaining life (TTO <=0.8) than patients not taking oral corticosteroids (95\% confidence interval: 2.3, 48.1; P\ = .002).

CONCLUSIONS: Patients with noninfectious uveitis had measurable, though modest, reductions in quality of life, as assessed by TTO, and these decreases were significantly associated with visual acuity in the worse eye and long-term oral corticosteroid use.

}, keywords = {Administration, Oral, Adult, Antidepressive Agents, Cross-Sectional Studies, Female, Glucocorticoids, Health Status, Health Surveys, Humans, Male, Middle Aged, Quality of Life, Sickness Impact Profile, Surveys and Questionnaires, Tertiary Care Centers, Uveitis, Visual Acuity}, issn = {1879-1891}, doi = {10.1016/j.ajo.2019.06.005}, author = {Niemeyer, Katherine M and Gonzales, John A and Doan, Thuy and Browne, Erica N and Rao, Maya M and Acharya, Nisha R} } @article {146, title = {When to Consider Bisphosphonates in Patients on Steroids for Chronic Ocular Inflammatory Conditions.}, journal = {J Ocul Pharmacol Ther}, volume = {35}, year = {2019}, month = {2019 09}, pages = {379-380}, keywords = {Adrenal Cortex Hormones, Adult, Aged, Aged, 80 and over, Bone Density Conservation Agents, Diphosphonates, Eye Diseases, Female, Humans, Male, Middle Aged, Osteoporotic Fractures}, issn = {1557-7732}, doi = {10.1089/jop.2019.0058}, author = {Takhar, Jaskirat S and Pawar, Varun K and Marneris, Athanasios G and Thuy A Doan and Acharya, Nisha R and Gonzales, John A} } @article {266, title = {Illuminating uveitis: metagenomic deep sequencing identifies common and rare pathogens.}, journal = {Genome Med}, volume = {8}, year = {2016}, month = {2016 08 25}, pages = {90}, abstract = {

BACKGROUND: Ocular infections remain a major cause of blindness and morbidity worldwide. While prognosis is dependent on the timing and accuracy of diagnosis, the etiology remains elusive in ~50\ \% of presumed infectious uveitis cases. The objective of this study is to determine if unbiased metagenomic deep sequencing (MDS) can accurately detect pathogens in intraocular fluid samples of patients with uveitis.

METHODS: This is a proof-of-concept study, in which intraocular fluid samples were obtained from five subjects with known diagnoses, and one subject with bilateral chronic uveitis without a known etiology. Samples were subjected to MDS, and results were compared with those from conventional diagnostic tests. Pathogens were identified using a rapid computational pipeline to analyze the non-host sequences obtained from MDS.

RESULTS: Unbiased MDS of intraocular fluid produced results concordant with known diagnoses in subjects with (n = 4) and without (n = 1) uveitis. Samples positive for Cryptococcus neoformans, Toxoplasma gondii, and herpes simplex virus 1 as tested by a Clinical Laboratory Improvement Amendments-certified laboratory were correctly identified with MDS. Rubella virus was identified in one case of chronic bilateral idiopathic uveitis. The subject{\textquoteright}s strain was most closely related to a German rubella virus strain isolated in 1992, one year before he developed a fever and rash while living in Germany. The pattern and the number of viral identified mutations present in the patient{\textquoteright}s strain were consistent with long-term viral replication in the eye.

CONCLUSIONS: MDS can identify fungi, parasites, and DNA and RNA viruses in minute volumes of intraocular fluid samples. The identification of chronic intraocular rubella virus infection highlights the eye{\textquoteright}s role as a long-term pathogen reservoir, which has implications for virus eradication and emerging global epidemics.

}, keywords = {Aqueous Humor, Cryptococcosis, Cryptococcus neoformans, Herpes Simplex, Herpesvirus 1, Human, High-Throughput Nucleotide Sequencing, Humans, Metagenomics, Phylogeny, Rubella, Rubella virus, Toxoplasma, Toxoplasmosis, Uvea, Uveitis, Virus Replication}, issn = {1756-994X}, doi = {10.1186/s13073-016-0344-6}, author = {Doan, Thuy and Wilson, Michael R and Crawford, Emily D and Chow, Eric D and Khan, Lillian M and Knopp, Kristeene A and O{\textquoteright}Donovan, Brian D and Xia, Dongxiang and Hacker, Jill K and Stewart, Jay M and Gonzales, John A and Acharya, Nisha R and DeRisi, Joseph L} }