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PurposeTo compare the diagnostic utility of metagenomic deep sequencing (MDS) to cytology, flow cytometry and gene rearrangement by PCR in ocular samples of patients with suspected vitreoretinal lymphoma (VRL).MethodsPatients with suspected VRL underwent ocular sampling of one or both eyes at the Emory Eye Center from September 2017 to June 2022. Ocular samples were evaluated with MDS and conventional diagnostics. MDS was performed at the Ralph and Sophie Heintz Laboratory at the F.I. Proctor Foundation. Relevant demographic and clinical data were retrospectively collected from medical records. Patients were diagnosed with VRL based on clinical assessment and conventional diagnostic testing.ResultsThis study included 13 patients with suspected VRL who underwent diagnostic vitrectomy, including 1 patient who had an additional subretinal biopsy. Six patients (46.2%) were diagnosed with VRL. Among patients diagnosed with VRL, MDS detected pathogenic mutations in 5 out of 6 patients (83.3%) while cytology was positive for VRL in 4 out of 6 patients (66.7%), flow cytometry in 4 out of 4 patients (100.0%) and PCR in 4 out of 4 patients (100.0%). MDS detected mutations in MYD88 in 2 out of 6 patients diagnosed with VRL. In 7 patients (53.8%) not diagnosed with VRL, MDS detected pathogenic lymphoma mutations in 2 patients (28.6%).DiscussionMDS detected pathogenic mutations in five out of six patients diagnosed with VRL, including in two patients with negative cytology, demonstrating its potential to improve diagnostic rates of VRL as an adjunctive test.

PURPOSE: To describe the use of anti-osteoclastic medications (i.e., bisphosphonates and receptor activator of nuclear factor kappa beta (RANK) ligand inhibitors) in treating choroidal osteoma. METHODS: A 42-year-old male with bilateral posterior choroidal osteomas showed extensive outer retinal atrophy in the right eye secondary to decalcification of a choroidal osteoma and progressive extension of retinal pigment epithelial atrophy in the left eye encroaching on the macula with subtle changes in the choroidal osteoma. Bisphosphonates (i.e., oral alendronate 70 mg weekly) or RANK ligand inhibitors (i.e., subcutaneous denosumab 60 mg every six months) were initiated to prevent calcium resorption. RESULTS: After the introduction of more directed therapy, there was stabilization of the patients condition over the next nine years while under bisphosphonate treatment, followed by a switch to RANK ligand inhibitor therapy and later bisphosphonate treatment again. This was made evident through stability in fundus photography, enhanced depth imaging optical coherence tomography, and B-scan ultrasonography regarding outer retinal layers thickness, and choroidal osteoma thickness and calcification. CONCLUSION: Anti-osteoclastic therapy using bisphosphonates or RANK ligand inhibitors could be a new treatment paradigm to prevent resorption of choroidal osteomas and prevent the subsequent atrophy of outer retinal layers. SUMMARY STATEMENT: A patient with bilateral posterior choroidal osteomas was treated with bisphosphonates and RANK ligand inhibitors to prevent osteoma resorption in the better-seeing left eye. This has led to stability over six years of outer retinal layers thickness, choroidal osteoma thickness, and choroidal osteoma calcification.

PURPOSE: The diagnosis and management of dry eye disease (DED) could be complicated by the discordance between DED-related symptoms and signs. We performed a cross-sectional study to investigate the factors of and develop predictive models for the discrepancy in DED symptomatology. METHODS: We used data from 3455 participants, 21 to 89 years old, from the Sjögrens International Collaborative Clinical Alliance study. We performed a multivariable stepwise linear regression model with backward elimination and Bayesian information criteria to select predictors for the discordance in DES symptomatology, which was defined as the difference between the rank score of Ocular Surface Disease Index 6 (OSDI-6) and the rank score of ocular staining score (OSS). RESULTS: Ten predictors, such as vitality, immunomodulating drugs, sensory symptoms, and ethnicity, remained in the final models, achieving an adjusted R2 (aR2) of 0.35 (95% confidence interval [CI], 0.32-0.39). Specifically, medication use explained 19% (95% CI, 0.17-0.22) of the variance in the outcome, followed by medical history (aR2 = 0.18; 95% CI, 0.15-0.21). Health-related quality of life contributed 16% to the variance in the outcome (95% CI, 0.13-0.19), and, last, demographics contributed 11% (95% CI, 0.09-0.13). CONCLUSIONS: Our results suggest that individuals of Asian descent and those using immunomodulating medications often present with severe ocular signs that necessitate regular ophthalmological evaluations, even in the absence of proportionate ocular symptoms. Additionally, ocular symptoms, when accompanied by abnormal sensations in other parts of the body, could indicate systemic conditions that require further investigation and medical care.

PurposeTubulointerstitial nephritis syndrome with uveitis (TINU) is a rare, acquired syndrome characterized by interstitial nephritis with bilateral uveitis. We report a case of TINU with typical bilateral anterior uveitis complicated by an atypical, delayed-onset neuroretinitis in a 12-year old patient.ObservationA 12-year-old female with a 21-month history of TINU featuring chronic bilateral anterior uveitis presented with one week of blurred vision in her left eye. On exam she was found to have new-onset disc edema in the right eye and neuroretinitis in the left eye. After a negative infectious disease workup, the patient was treated with a course of intravenous (IV) solumedrol with prednisone taper and advancement of her systemic immunosuppression. In follow up she demonstrated resolution of her disc edema and neuroretinitis with improved visual acuity and clinical exam.ConclusionThis case stresses the importance of monitoring for additional ocular manifestations including neuroretinitis years after the onset of anterior uveitis in TINU. In comparison to the two published cases of TINU with neuroretinitis, this case shares features of uveitis progression, and thus highlights the value of further description of TINU-associated neuroretinitis.

PURPOSE: This study aims to explore the potential subgroups of sarcoidosis-associated uveitis (SAU) within a multicenter cohort of uveitis participants. DESIGN: Cross-sectional study. PARTICIPANTS: A cohort of 826 uveitis patients from a uveitis registry from 19 clinical centers in 12 countries between January 2011 and April 2015. METHODS: We employed a latent class analysis (LCA) incorporating recommended tests and clinical signs from the revised International Workshop on Ocular Sarcoidosis (IWOS) to identify potential SAU subgroups within the multicenter uveitis cohort. Additionally, we assessed the performance of the individual tests and clinical signs in classifying the potential subclasses. MAIN OUTCOME MEASURES: Latent subtypes of SAU. RESULTS: Among 826 participants included in this analysis, the 2-class LCA model provided a best fit, with the lowest Bayesian information criteria of 7218.7 and an entropy of 0.715. One class, consisting of 548 participants, represented the non-SAU, whereas the second class, comprised of 278 participants, was most representative of SAU. Snowballs/string of pearls vitreous opacities had the best test performance for classification, followed by bilaterality and bilateral hilar lymphadenopathy (BHL). The combination of 4 tests with the highest classification importance, including snowballs/string of pearls vitreous opacities, periphlebitis and/or macroaneurysm, bilaterality, and BHL, demonstrated a sensitivity of 84.8% and a specificity of 95.4% in classifying the SAU subtypes. In the exploratory analysis of the 3-class LCA model, which had comparable fit indices as the 2-class model, we identified a candidate non-SAU subtype, candidate SAU subtype with pulmonary involvement, and a candidate SAU with less pulmonary involvement. CONCLUSIONS: Latent class modeling, incorporating tests and clinical signs from the revised IWOS criteria, effectively identified a subset of participants with clinical features indicative of SAU. Though the sensitivity of individual ocular signs or tests was not perfect, using a combination of tests provided a satisfactory performance in classifying the SAU subclasses identified by the 2-class LCA model. Notably, the classes identified by the 3-class LCA model, including a non-SAU subtype, an SAU subtype with pulmonary involvement, and an SAU subtype with less pulmonary involvement, may have potential implication for clinical practice, and hence should be validated in further research. FINANCIAL DISCLOSURES: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

BACKGROUND/AIMS: We aimed to examine risk factors for corneal ulcer in a rural and peri-urban setting in Nepal. METHODS: This population-based matched case-control study was nested in a cluster randomised trial in 24 village development committees in Nepal. Incidence density sampling was used to match incident corneal opacity cases to controls, matching on time of opacity, age, sex and location. Cases and controls were invited to participate in a survey of risk factors for corneal ulcer. Risk factors were evaluated using conditional logistic regression to account for matching. RESULTS: Of the 540 participants with incident opacities identified in the trial, 433 were willing to participate in this substudy and matched to a control. Compared with controls, cases had lower odds of having any education vs no education (adjusted OR, aOR 0.60, 95% CI 0.39 to 0.94), working in non-manual labour occupations vs manual labour occupations (aOR 0.64, 95% CI 0.42 to 0.95) and preferring medical shops for ocular trauma versus eye care system centres (aOR 0.58, 95% CI 0.37 to 0.92). Cases had higher odds of protective goggle use versus no protection (aOR 3.8, 95% CI 1.3 to 11.0) and having an ocular injury vs none (aOR 7.7, 95% CI 4.3 to 13.6) compared with controls. CONCLUSION: We found ocular injury, manual labour and lower education to be strongly associated with the development of corneal ulcer. Given the persistent burden of corneal blindness in this area, prevention efforts could target efforts to increase access to care in areas where these factors are common.

PURPOSE: In the absence of a gold-standard diagnostic test for different subtypes of dry eye disease (DED), we aimed to identify latent subtypes of DED within a well-characterized cohort. DESIGN: This is a cross-sectional study of participants enrolled in the Sjögren International Collaborative Clinical Alliance (SICCA). METHODS: A latent class analysis was applied to different dry eye-related signs/tests and symptoms of ocular pain (particularly those that aligned with corneal neuropathic pain) giving relative specificities and sensitivities of each diagnostic test or symptom in the SICCA population. RESULTS: Four subtypes of DED were identified with putative designations including normal, asymptomatic dry eye, symptomatic dry eye, and corneal neuropathic pain. CONCLUSIONS: More specific classification criteria are needed for DED. Latent class analysis applied to the signs and symptoms captured in the SICCA cohort may allow for the development and refinement of classification criteria for specific subtypes of dry eye.

PURPOSE: Small-fiber neuropathy (SFN) is known to be associated with Sjögren disease (SjD), and in vivo corneal confocal microscopy can identify features compatible with SFN. Here, we performed a descriptive study to identify features of SFN of the corneal subbasal nerve plexus using in vivo confocal microscopy. METHODS: We recruited 10 participants from the Sjögrens International Collaborative Clinical Alliance (SICCA), 1 new participant (in an effort to expand the SICCA cohort), and 22 healthy controls. All participants underwent slit-lamp examination and in vivo confocal microscopy of the central corneal subbasal nerve plexus centered about the central whorl to create a 30-image montage. Each image was analyzed with automated software (ACCmetrics, Manchester, United Kingdom) to produce 7 nerve metrics. We performed t-tests and age-adjusted regressions to make comparisons of nerve metrics between participants with SjD and healthy controls. RESULTS: Most nerve metrics were significantly lower in participants with SjD compared with healthy controls. The mean corneal nerve fiber density was found to be 3.5 mm/mm 2 in participants with SjD compared with 10.6 mm/mm 2 in healthy controls (95% confidence interval, -8.4 to -0.93; P = 0.02). Within the 11 participants with SjD, 22 eyes were analyzed on confocal microscopy, and 16 of those eyes (from 9 individuals) did not have an identifiable central whorl. Within the 22 healthy controls, 22 eyes (right eye alone) were analyzed on confocal microscopy, and 21 of those eyes had an identifiable central whorl. CONCLUSIONS: SjD exhibits lower corneal nerve metrics compared with healthy controls. These findings suggest that features compatible with SFN can distinguish SjD from healthy controls and may serve as a potential novel biomarker in identifying SjD.

PurposeTo evaluate the diagnostic accuracy of smartphone corneal photography in detecting corneal opacities in a community-based setting.MethodsA case-control, diagnostic accuracy study was nested in a cluster-randomized trial of a corneal ulcer prevention intervention in Nepal. Smartphone corneal photography was performed annually on community members self-reporting a potential risk factor for a corneal infection. Corneal photographs were graded for the presence or absence of an opacity. All cases with an opacity on smartphone photography and an equal number of controls were invited for a comprehensive eye examination with a slit lamp biomicroscope at an eye hospital. A mobile team visited participants unable to come to the hospital, conducting a limited examination with a penlight.ResultsOf 1332 study participants (666 cases and 666 controls), 1097 had a penlight examination (535 cases and 562 controls) and 191 had a slit lamp examination (120 cases and 71 controls). When penlight examination was considered the reference standard, smartphone diagnosis of a corneal opacity had a positive predictive value (PPV) of 47% (95% confidence interval 43-52%) and negative predictive value (NPV) of 95% (93-97%). When slit lamp examination was considered the reference standard, the overall PPV and NPV were 71% (62-78%) and 80% (70-88%), respectively. The NPV was greater for detection of opacities > 1mm, estimated at 95% (90-98%).ConclusionsCorneal photography performed in a resource-limited community-based setting using a smartphone coupled to an external attachment had acceptable diagnostic accuracy for detection of corneal opacities large enough to be clinically meaningful.

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.

We report a case of a 53-year-old HIV-negative patient in San Francisco, California, USA, with no classic mpox prodromal symptoms or skin lesions who experienced fulminant, vision-threatening scleritis, keratitis, and uveitis. Deep sequence analysis identified monkeypox virus RNA in the aqueous humor. We confirmed the virus on the cornea and sclera by PCR.

BackgroundThe 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 bodyThis 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.ConclusionRetinal 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.

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.

BackgroundOcular rosacea is common and is often managed with long-term antibiotic treatment. Doxycycline is the most commonly selected antibiotic for the treatment of rosacea. As there is no established standard of care treatment dose for rosacea, prescribed doses of doxycycline vary widely. The FDA classifies 40 mg daily dose of doxycycline for ocular rosacea as sub-microbial in comparison to an antibiotic dose of 200 mg daily. However, this "sub-microbial" dose has never been evaluated in patients with ocular rosacea, and even the sub-microbial dose has potential to alter systemic mucosa flora. Here, we present a randomized controlled trial using RNA sequencing to fully characterize the impact of sub-microbial antibiotic dosing of doxycycline on antimicrobial resistance and bacterial composition of the ocular and gut flora.MethodsIn a triple-masked parallel randomized control trial, patients with ocular rosacea will be randomized to three arms: a 40-mg dose of doxycycline, a 200-mg antibiotic dose of doxycycline, or placebo. Collected rectal and lower eyelid samples will be compared for frequency of antimicrobial resistance genetic determinants and microbiome diversity. A subjective ocular surface disease index survey and objective tear breakup time measurement will be determined.DiscussionThese results will enhance our understanding of the overall systemic impact of long-term systemic sub-microbial antibiotic dosing for the treatment of chronic recurrent ocular inflammatory diseases.Trial registrationThis trial was registered on ClinicalTrials.org (NCT05296837) on March 22, 2022.

PurposeTo identify peripheral blood transcriptome differences in uveitis patients with sarcoidosis compared to those with Vogt-Koyanagi-Harada (VKH) syndrome and controls.MethodsTen 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.ResultsTen 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.ConclusionsThis 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.

PurposeTo report a case of bilateral anterior intermediate uveitis after recovery from SARS-CoV-2 associated multisystem inflammatory syndrome in children (MIS-C).Case reportA 9-year-old male presented with bilateral anterior intermediate uveitis with fluorescein angiography (FA) leakage of the disc and peripheral vasculature 1 month after recovery from MIS-C. He was treated with difluprednate 0.05% in both eyes with resolution of FA leakage, but our patient has required an extended treatment of topical therapy and the need long term immunosuppression.ConclusionsThis is a case of uveitis presenting after recent MIS-C related to SARS-CoV-2. Ongoing follow up and monitoring is required, and it is important for the ophthalmologist and rheumatologist to be aware of this rare complication during the current COVID-19 pandemic.

PurposeTo 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).ObservationsAn 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 importanceUGH 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.

BackgroundCorneal ulcers are a common cause of blindness in low-income and middle-income countries, usually resulting from traumatic corneal abrasions during agricultural work. Antimicrobial prophylaxis of corneal abrasions can help prevent corneal ulcers, but delays in the initiation of therapy are frequent. We aimed to assess whether a community-based programme for corneal ulcer prevention would reduce the incidence of corneal ulceration.MethodsA cluster-randomised trial was performed in village development committees (VDCs) in Nepal. VDCs in the catchment area of Bharatpur Eye Hospital, Nepal with less than 15 000 people were eligible for inclusion. We randomly assigned (1:1) VDCs to either an intervention group or a control group. In the intervention VDCs, existing female community health volunteers (FCHVs) were trained to diagnose corneal abrasions and provide a 3-day course of ophthalmic antimicrobials to their patients. In the control VDCs, FCHVs did not provide this intervention. Participants were not masked given the nature of the intervention. Both groups were followed up for 3 years for photographic evidence of corneal ulceration. The primary outcome was the incidence of corneal ulceration, determined by masked assessment of corneal photographs. The analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, NCT01969786.FindingsWe assessed 112 VDCs, of which 24 were enrolled. The study was performed between Feb 4, 2014, and Oct 20, 2017. 12 VDCs were randomly assigned to the intervention group and 12 to the control group. 252 539 individuals were included in the study (130 579 in the intervention group and 121 960 in the control group). FCHVs diagnosed and provided antimicrobials for 4777 corneal abrasions. The census identified 289 corneal ulcers among 246 893 person-years in the intervention group (incidence 1·21 cases [95% CI 0·85-1·74] per 1000 person-years) and 262 corneal ulcers among 239 170 person-years in the control group (incidence 1·18 cases [0·82-1·70] per 1000 person-years; incidence rate ratio 1·03 [95% CI 0·63-1·67]; p=0·93). Medication allergy was self-reported in 0·2% of participants.InterpretationWe did not detect a reduction in the incidence of corneal ulceration during the first 3 years of a community-based corneal ulcer prevention programme. Further study might be warranted in more rural areas where basic eye care facilities are not available.FundingNational Eye Institute.

ObjectiveSjögren's syndrome (SS) is frequently undetected or misdiagnosed as other rheumatologic diseases. We aimed to develop an SS screening questionnaire for the rheumatology practice.MethodsWe developed the Sjögren's Syndrome Screening Questionnaire (SSSQ) via secondary analysis of data from 974 participants referred by rheumatologists to the Sjögren's International Collaborative Clinical Alliance (SICCA) study. Participants answered 88 questions regarding symptoms, medical history, and demographics. They underwent ocular, dental, and serologic tests and were classified as SS or non-SS using the 2016 American College of Rheumatology/European League Against Rheumatism classification criteria. We conducted univariate and multivariate logistic regression to identify questions most discriminative of SS, from which we derived an individual's likelihood of SS ("SSSQ score").ResultsFive questions were significantly discriminative of SS in the multivariate analysis (p < 0.05): (1) Can you eat a cracker without drinking a fluid/liquid? (no: odds ratio [OR], 1.39; 95% confidence interval [CI], 1.06-1.82]); (2) How would you describe your dental and oral health in general? (fair/poor: OR, 1.68; 95% CI, 1.04-2.75); (3) During the last week, have you experienced tearing? (none of the time: OR, 2.26; 95% CI, 1.23-4.34); (4) Are you able to produce tears? (no: OR, 1.62; 95% CI, 1.12-2.37); and (5) Do you currently smoke cigarettes? (no: OR, 2.83; 95% CI, 1.69-4.91). SSSQ score ≥7 (possible range, 0-11) distinguishes SS from non-SS patients with 64% sensitivity and 58% specificity (area under receiver operating characteristic curve, 0.65).ConclusionsThe SSSQ is a simple 5-item questionnaire designed to screen for SS in clinical practice, with a potential impact to reduce delays in diagnosis.

ObjectiveThe objective of this study was to examine the association of smoking with Primary Sjögren syndrome (pSS) classification and pSS diagnostic test results. We hypothesized that past and current smokers would have lower odds of being classified as having Sjögren syndrome (SS) and lower odds of having abnormal individual SS diagnostic test results compared with nonsmokers.MethodsParticipants with suspected or established pSS were enrolled into the Sjögren's International Collaborative Clinical Alliance (SICCA) registry and had oral, ocular, and rheumatologic examinations performed; blood and saliva samples collected; and labial salivary gland biopsy examinations performed; they also completed questionnaires at baseline. Logistic regression was used to determine whether smoking status was associated with pSS classification and individual pSS diagnostic test results.ResultsA total of 3514 participants were enrolled in SICCA. A total of 1541 (52.9%) met classification criteria for pSS. Compared with never smokers, current smokers had reduced odds of being classified as having pSS, reduced odds of having a focus score ≥ 1 and serologic positivity for anti-SSA/anti-SSB antibodies, and lower odds of having abnormal signs or test results of dry eye disease. Compared with never smokers, past smokers did not have a statistically significant reduction in odds of being classified as having pSS and of having abnormal individual pSS diagnostic test results.ConclusionCompared with never smokers, current smokers in the SICCA cohort had lower odds of being classified as having pSS, lower odds of exhibiting abnormal signs and test results for dry eye disease, and lower odds of having a labial salivary gland biopsy supportive of pSS classification. Such negative associations, however, do not suggest that current smoking is of any benefit with respect to pSS.

PurposeSub-analysis of the FAST Trial comparing change in CD4 (∆CD4) from baseline through 12 months in uveitis patients treated with mycophenolate mofetil (MMF) and methotrexate (MTX).MethodsPatients were randomly allocated to 1.5 g twice daily MMF or 25 mg weekly MTX. Individuals with CD4 counts at baseline, 6 months (or treatment failure prior), and 12 months (or treatment failure between 6 and 12 months) were included. The association between treatment and ∆CD4 (cells/μL) was analyzed using multivariable linear regression.ResultsThere was no significant difference in ∆CD4 between MMF and MTX at 6 months (-31.7 cells/μL for MMF compared to MTX; 95% CI: -358.2 to 294.8, P = .85) and 12 months (-78.3 cells/μL for MMF compared to MTX; 95% CI: -468.0 to 311.3; P = .69).ConclusionThere was no significant difference in ∆CD4 between MMF and MTX from baseline to 12 months, suggesting that MMF does not confer additional risk of CD4 lymphopenia in uveitic patients.ClinicalTrials.gov Identifier: NCT01829295.

Purpose of Review: Corneal neuropathic pain can be difficult to treat, particularly due to its lack of response to standard dry eye therapies. We describe a variety of topical therapeutic options that are available to treat corneal neuropathic pain with a significant or primary peripheral component. We also describe possible mechanisms of action for such topical therapies. Recent Findings: Topical corticosteroids and blood-derived tear preparations can be helpful. Newer therapies, including topical lacosamide and low-dose naltrexone are emerging therapeutic options that may also be considered. Summary: Corneal neuropathic pain with a significant peripheral component may be managed with a variety of topical therapeutic options.

We report a case of ocular-only mpox infection in a 53-year-old man in San Francisco, California, USA. His medical history included chronic lymphocytic leukemia (CLL), inactive 2 years after treatment [...]

PurposeTo evaluate changes in health-related and vision-related quality of life (VRQoL) among patients with noninfectious uveitis who were treated with antimetabolites.DesignSecondary analysis of a randomized controlled trial.ParticipantsPatients with noninfectious uveitis from India, the United States, Australia, Saudi Arabia, and Mexico.MethodsFrom 2013 through 2017, 216 participants were randomized to receive 25 mg weekly oral methotrexate or 1.5 g twice daily oral mycophenolate mofetil. Median changes in quality of life (QoL) were measured using Wilcoxon signed-rank tests, and differences between treatment groups were measured using linear mixed models, adjusting for baseline QoL score, age, gender, and site. Among Indian patients, VRQoL scores from a general scale (the National Eye Institute Visual Function Questionnaire [NEI-VFQ]) and a culturally specific scale (the Indian Visual Function Questionnaire [IND-VFQ]) were compared using Pearson correlation tests.Main outcome measuresVision-related QoL (NEI-VFQ and IND-VFQ) and health-related QoL (HRQoL; physical component score [PCS] and mental component score [MCS] of the Medical Outcomes Study 36-Item Short Form Survey [SF-36v2]) were measured at baseline, the primary end point (6 months or treatment failure before 6 months), and the secondary end point (12 months or treatment failure between 6 and 12 months).ResultsAmong 193 participants who reached the primary end point, VRQoL increased from baseline by a median of 12.0 points (interquartile range [IQR], 1.0-26.1, NEI-VFQ scale), physical HRQoL increased by a median of 3.6 points (IQR, -1.4 to 14.9, PCS SF-36v2), and mental HRQoL increased by a median of 3.0 points (IQR, -3.7 to 11.9, MCS SF-36v2). These improvements in NEI-VFQ, SF-36v2 PCS, and SF-36v2 MCS scores all were significant (P < 0.01). The linear mixed models showed that QoL did not differ between treatment groups for each QoL assessment (NEI-VFQ, IND-VFQ, PCS SF-36v2, and MCS SF-36v2; P > 0.05 for all). The NEI-VFQ and IND-VFQ scores for Indian participants were correlated highly at baseline and the primary and secondary end points (correlation coefficients, 0.87, 0.80, and 0.90, respectively).ConclusionsAmong patients treated with methotrexate or mycophenolate mofetil for uveitis, VRQoL and HRQoL improved significantly over the course of 1 year and did not differ by treatment allocation. These findings suggest that antimetabolites could improve overall patient well-being and daily functioning.

ObjectiveTo evaluate how ocular, oral, and bodily neuropathic pain symptoms, which characterize small fiber neuropathies, are associated with Sjögren's syndrome (SS) classification based on the American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) criteria.MethodsParticipants enrolled in the Sjögren's International Collaborative Clinical Alliance (SICCA) registry had ocular, rheumatologic, oral, and labial salivary gland (LSG) biopsy examinations, blood and saliva samples collected, and completed questionnaires at baseline. We used mixed effects modeling with age, country, gender, and depression being fixed effects and study site, a random effect, to determine if neuropathic pain indicators (assessed via questionnaires) were associated with being classified as SS.ResultsA total of 3,514 participants were enrolled into SICCA, with 1,541 (52.9%) meeting the 2016 ACR/EULAR classification criteria for SS. There was a negative association between being classified as SS and experiencing bodily neuropathic pain features of needle-like pain, prickling/tingling sensation, ocular neuropathic pain of constant burning, and constant light sensitivity, and having a presumptive diagnosis of neuropathic oral pain.ConclusionsWe found that those classified as SS had lower scores/reports of painful neuropathies compared with those classified as non-SS. Non-SS patients with dry eye disease or symptoms could benefit from pain assessment as they may experience painful small-fiber neuropathies (SFNs). Pain questionnaires may help identify pain associated with SFNs in patients with SS and non-SS dry eye. Future studies would be helpful to correlate self-reports of pain to objective measures of SFNs in those with SS, non-SS dry eye, and healthy controls.

PurposeThe purposes of this study were to assess the reproducibility of a novel standardized technique for capturing corneal subbasal nerve plexus images with in vivo corneal confocal microscopy and to compare nerve metrics captured with this method in participants with dry eye and control participants.MethodsCases and controls were recruited based on their International Statistical Classification of Diseases and Related Health Problems (ICD-10) diagnoses. Participants completed the following 3 ocular symptom questionnaires: the Ocular Surface Disease Index, Neuropathic Pain Symptom Inventory, and Dry Eye Questionnaire 5. A novel eye fixation-grid system was used to capture 30 standardized confocal microscopy images of the central cornea. Each participant was imaged twice by different operators. Seven quantitative nerve metrics were analyzed using automated software (ACCmetrics, Manchester, United Kingdom) for all 30 images and a 6-image subset.ResultsForty-seven participants were recruited (25 classified as dry eye and 22 controls). The most reproducible nerve metrics were corneal nerve fiber length [intraclass correlation (ICC) = 0.86], corneal nerve fiber area (ICC = 0.86), and fractal dimension (ICC = 0.90). Although differences were not statistically significant, all mean nerve metrics were lower in those with dry eye compared with controls. Questionnaire scores did not significantly correlate with nerve metrics. Reproducibility of nerve metrics was similar when comparing the entire 30-image montage to a central 6-image subset.ConclusionsA standardized confocal imaging technique coupled with quantitative assessment of corneal nerves produced reproducible corneal nerve metrics even with different operators. No statistically significant differences in in vivo corneal confocal microscopy nerve metrics were observed between participants with dry eye and control participants.

BackgroundMolecular 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.MethodsWe 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.ResultsThe 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.ConclusionsRNA-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.

PurposeTo develop a screening questionnaire to identify patients with dry eye with a high likelihood of having underlying Sjögren syndrome (SS).MethodsThis was a cross-sectional study of participants with dry eye complaints who were self-referred or referred by an ophthalmologist to the Sjögren's International Collaborative Clinical Alliance study. Symptoms and ocular surface examination findings were candidate predictors. Univariable and multivariable logistic regression analyses were performed to estimate odds ratios (ORs) and 95% confidence intervals (95% CI) for the association of a symptom and/or ocular sign with SS. Area under the receiver operating characteristic curve (AUC) was used to summarize the predictive ability of different regression models and the derived likelihood score.ResultsFour questions were statistically significant in the final multivariable model: 1) Is your mouth dry when eating a meal? [Yes = OR 1.63 (1.18-2.26)]; 2) Can you eat a cracker without drinking a fluid or liquid? [No = OR 1.46 (1.06-2.01)]; 3) How often do you have excessive tearing? [None of the time = OR 4.06 (1.81-9.10)]; and 4) Are you able to produce tears? [No = OR 2.24 (1.62-3.09)]. The SS likelihood score had an AUC of 0.70 (95% CI, 0.66-0.73), and when including tear break-up time and conjunctival staining, it yielded an AUC of 0.79 (95% CI, 0.77-0.82).ConclusionsThis questionnaire can be used to identify patients with dry eye with a high likelihood of having SS. With future refinement and validation, this screening tool could be used alone or in combination with examination findings to identify patients with SS earlier, thereby facilitating better clinical outcomes.

PurposeThe 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 methodsReview and description of the process of using metagenomic deep sequencing for ocular specimens at the Proctor Foundation, University of California, San Francisco, CA.ResultsVRL 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'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.ConclusionsMetagenomic deep sequencing may offer an additional tool in the future with which to diagnose VRL.

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.

PurposeTo evaluate the ocular signs and tests for keratoconjunctivitis sicca (KCS) in the absence of a gold standard.MethodsCross-sectional study of participants from the Sjögren's International Collaborative Clinical Alliance (SICCA) registry. Participants had oral/ocular/rheumatologic examinations, blood/saliva samples collected, and salivary gland biopsy. Latent class analysis (LCA) identified clusters of patients based on 3 to 4 predictor variables relating to signs or tests of KCS. The resulting model-based "gold standard" classification formed the basis for estimated sensitivity and specificity associated with these predictors.ResultsA total of 3514 participants were enrolled into SICCA, with 52.9% classified as SS. LCA revealed a best-fit model with 2 groups. For the gold standard-positive group, an abnormal tear breakup time, ocular staining score (OSS), and Schirmer I had a sensitivity of 99.5%, 91.0%, and 47.4%, respectively. For the gold standard-negative group, an abnormal tear breakup time, OSS, and Schirmer I had a specificity of 32.0%, 84.0%, and 88.5%, respectively. OSS components (fluorescein and lissamine staining), exhibited a sensitivity of 82.6% and 90.5%, respectively, in the gold standard-positive group, whereas these signs in the gold standard-negative group had a specificity of 88.8% and 73.0%, respectively.ConclusionsOSS and its components (fluorescein and lissamine staining) differentiated 2 groups from each other better than other KCS parameters and had relatively high sensitivity and specificity.

PurposeThis case report discusses an atypical case of cytomegalovirus (CMV) retinal necrosis with panretinal occlusive vasculopathy in a 77-year-old man who was immunosuppressed following treatment for giant cell arteritis (GCA).MethodsA case report is presented.ResultsClinical examination demonstrated a central retinal artery occlusion and pale disc suspicious for arteritic ischemic optic neuropathy in the right eye. Biopsy-proven GCA prompted treatment with oral prednisone. While on glucocorticoid immunosuppression, the patient suffered vision loss in the left eye from CMV-necrotizing retinitis with occlusive vasculopathy. Treatment controlled the CMV infection but tapering of his steroids resulted in worsening GCA, requiring a steroid-sparing treatment, tocilizumab.ConclusionsCorticosteroid immunosuppression for GCA may lead to immune dysfunction allowing for an atypical occlusive vasculitis with retinal necrosis from CMV. Early identification and treatment are essential to adjust the level of immunosuppression and consider alternate therapies to control the GCA and prevent worsening of this opportunistic infection.

Purpose:This is a retrospective case report illustrating the diagnostic and therapeutic challenges associated with a chronic rhegmatogenous retinal detachment masquerading as a severe panuveitis with intense anterior chamber inflammation. We have included clinical features, anterior segment and fundus photography, B-scan ultrasonography, fluorescein angiography, and intraoperative findings. Observations:A 26-year-old male presented with features of unilateral panuveitis: hypotony, anterior segment inflammation (posterior synechiae and anterior chamber cell with fibrin clumping), diffuse choroidal thickening, and retinal detachment. Laboratory investigations for infectious or rheumatologic processes were negative, and empiric systemic corticosteroid therapy was unsuccessful. This prompted suspicion for an alternate primary etiology, and pars plana vitrectomy revealed small retinal breaks as the underlying cause of the retinal detachment and inflammation. Conclusions:Rhegmatogenous retinal detachments are a known cause of intraocular inflammation. Nevertheless, it remains a challenge to recognize retinal breaks in this setting, particularly with robust anterior segment inflammation and posterior findings resembling severe exudative uveitis. Being aware of this unique presentation may prevent delays in diagnosis and have important prognostic implications.

IntroductionCytomegalovirus (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 analysisThe 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'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 disseminationThe 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 numberNCT03576898.

PurposeTo evaluate the prevalence of novel candidate autoantibodies associated with Sjögren syndrome (SS) and their ability to identify those with SS among participants with dry eye enrolled in the Sjögren's International Collaborative Clinical Alliance (SICCA) study at the University of Pennsylvania (Penn).MethodsAll participants previously underwent a full ocular and systemic evaluation for possible SS as part of the SICCA study. An enzyme-linked immunosorbent assay was used to detect IgG, IgA, and IgM autoantibodies to salivary protein 1 (SP-1), parotid secretory protein (PSP), and carbonic anhydrase 6 from previously banked baseline serum samples from SICCA study participants enrolled at Penn. The prevalence rate of each autoantibody, calculated by considering the presence of any isotype as antibody positive, was compared between participants with dry eye with SS (n = 81) or without SS (n = 129) using the Fisher exact test.ResultsThe prevalence of SP-1 IgM autoantibodies was higher in those with SS compared with those without SS (14% vs. 5%; P = 0.03). Similarly, the prevalence of PSP IgA autoantibodies was higher in those with SS compared with non-SS dry eye participants (21% vs. 11%; P = 0.048). There was no statistically significant difference in the prevalence of carbonic anhydrase 6 autoantibodies between those with or without SS (15% vs. 20%; P = 0.36).ConclusionsIn the Penn SICCA cohort, SP-1 IgM and PSP IgA autoantibodies were more prevalent in the serum of SS-related dry eye participants compared with those without SS. Further longitudinal studies are needed to determine the clinical significance of these findings.

PurposeTo 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.DesignTime trade-off utility analysis.MethodsSetting: A tertiary care uveitis center in San Francisco, California, USA.Patient populationOne hundred and four consecutive adults with noninfectious uveitis, enrolled between November 2016 and February 2017.Main outcome measuresTTO 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.ResultsMedian 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).ConclusionsPatients 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.

ImportanceMethotrexate 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.ObjectiveTo compare the effect of methotrexate and mycophenolate for achieving corticosteroid-sparing control of noninfectious intermediate uveitis, posterior uveitis, and panuveitis.Design, setting, and participantsThe 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.InterventionsPatients were randomized to receive oral methotrexate, 25 mg weekly (n = 107), or oral mycophenolate mofetil, 3 g daily (n = 109).Main outcomes and measuresThe 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.ResultsAmong 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 relevanceAmong 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 registrationClinicalTrials.gov Identifier: NCT01829295.