Ocular toxicities associated with antibody drug conjugates.

PURPOSE OF REVIEW: To review the structure, mechanism of action, and pathophysiology of antibody-drug conjugates (ADCs) used to treat gynecological malignancies associated with ocular adverse effects. RECENT FINDINGS: Recent research shows tisotumab vedotin causes ocular toxicity localized to the conjunctiva, with common adverse effects being conjunctivitis, dry eye, blepharitis, and keratitis. Toxicity is likely due to targeting tissue factor (TF) in the conjunctiva, leading to direct delivery of the cytotoxic payload resulting in apoptosis and bystander killing. Mirvetuximab soravtansine causes blurred vision, keratitis, or dry eye with toxicity often localized in the cornea. Off-target inflammation appears to cause ocular adverse effects, with nonreceptor mediated macropinocytosis by corneal stem cells. SUMMARY: Collaboration between oncologists and ophthalmologists with adherence to mitigation protocols can decrease the risk of ocular adverse events.

Factors influencing treatment and time spent with physicians in patients with uveitis compared to other ophthalmology subspecialties in the National Ambulatory Medical Care Survey.

BACKGROUND: Cases of uveitis can necessitate long-term treatment resulting in recurrent follow-up appointments. Analysing the demographic distribution and patient factors influencing treatment and time spent with physicians in this population compared to other subspecialties of ophthalmology using the National Ambulatory Medical Care Survey (NAMCS) has not previously been studied. METHODS: Data were extracted from the NAMCS database, a large, nationally representative survey of office-based specialists, entered between 2012-2016 and 2018. Demographics, time with physician, and payor types were compared between patients with a uveitis-related diagnosis codes versus all other ophthalmic subspecialty diagnoses. RESULTS: Overall, 12,870 ophthalmic patients were included of which 300 had uveitis-related diagnosis codes. Uveitis patients were more likely to be non-Caucasian (p < 0.0001 to p = 0.022), visiting the physician's office due to flare of or treatment for a chronic medical problem (p < 0.0001 to p = 0.022). Adjusted for age, sex, race, and ethnicity, uveitis patients spent a significantly longer time (mean 27.5 min) compared to comprehensive ophthalmology patients (mean 25.5 min) with their physician (p = 0.0041). Among the uveitis patient population, African American patients (p = 0.0053), Hispanic or Latino (p = 0.034), and Medicaid (p = 0.035) patients had increased office visit times. CONCLUSIONS: Those with uveitis spent more time with the physician than comprehensive patients. Race, ethnicity, payor type, and the major reason for the visit all significantly impacted uveitis office visit times. In order to manage their schedules, providers should be aware of the additional support and time needed by these patients during office visits.

Investigating the Accuracy and Completeness of an Artificial Intelligence Large Language Model About Uveitis: An Evaluation of ChatGPT.

PURPOSE: To assess the accuracy and completeness of ChatGPT-generated answers regarding uveitis description, prevention, treatment, and prognosis. METHODS: Thirty-two uveitis-related questions were generated by a uveitis specialist and inputted into ChatGPT 3.5. Answers were compiled into a survey and were reviewed by five uveitis specialists using standardized Likert scales of accuracy and completeness. RESULTS: In total, the median accuracy score for all the uveitis questions (n = 32) was 4.00 (between "more correct than incorrect" and "nearly all correct"), and the median completeness score was 2.00 ("adequate, addresses all aspects of the question and provides the minimum amount of information required to be considered complete"). The interrater variability assessment had a total kappa value of 0.0278 for accuracy and 0.0847 for completeness. CONCLUSION: ChatGPT can provide relatively high accuracy responses for various questions related to uveitis; however, the answers it provides are incomplete, with some inaccuracies. Its utility in providing medical information requires further validation and development prior to serving as a source of uveitis information for patients.

Effectiveness of difluprednate in addition to systemic therapy for the treatment of anterior scleritis.

AIM: To describe the effectiveness and side-effect profile of adding difluprednate therapy to patients with anterior scleritis being treated systemically. METHODS: Retrospective chart review. Charts from all patients with anterior scleritis who were treated with topical difluprednate in addition to systemic therapy from 1 January 2018 to 1 January 2020 were reviewed. Data collected included: demographics, scleritis type, systemic diagnosis, presence of nodules or necrosis, changes in scleritis activity, intraocular pressure (IOP), number of difluprednate drops used, type of systemic treatment used, best-corrected visual acuity (BCVA) and lens status. The primary outcome was clinical resolution of scleritis. Secondary outcomes included BCVA loss ≥2 lines, change in lens status or cataract surgery and IOP ≥24 mm Hg. RESULTS: Thirty-two patients (44 eyes) were analysed. The median age was 57 years (IQR 52, 72); 59% were female; 72% were Caucasian. An associated systemic disease was present in 59%. Systemic therapies used when difluprednate was added were: 65% immunosuppressive agents, 43% prednisone and 25% non-steroidal anti-inflammatory drugs. The addition of difluprednate resulted in clinical resolution in 79.6% of the treated eyes. Median time to inactivity was 9 weeks (IQR 5, 20). Eyes initially using 2-4 drops per day had a higher response rate (89%, p=0.005). Over a median follow-up of 34 weeks (IQR 21, 74), 11 eyes had IOP elevation; 6 eyes lost ≥2 lines of BCVA, 5 eyes had cataract progression. CONCLUSION: Most eyes treated with difluprednate achieved inactivity. The addition of difluprednate to systemic therapies provides an alternative to achieve control of inflammation.

Quantitative Ocular Surface Changes in Patients Undergoing Immune Checkpoint Inhibitor Therapy.

PURPOSE: To describe the clinical course and evaluate treatment of ocular surface changes in patients receiving immune checkpoint inhibitor (ICI) therapy. METHODS: Multiple markers of ocular surface dryness were evaluated in 16 patients on ICI therapy. The Wilcoxon rank-sum test was used to determine the significant change in the initial and final ocular surface indices. RESULTS: Fifty percent of the eyes demonstrated worsening Schirmer I scores; 29% showed an increase in lissamine green staining. During follow-up, 43% of patients experienced a decline in OSDI scores. Treatments included preservative-free artificial tears (88%), cyclosporine (25%), topical corticosteroids (31%), warm compresses (25%); punctal plugs (13%). Median follow-up time was 3.4 months (range:0-79 ); median ICI treatment duration was 7 months (range:1-40). Four patients died during the observation period. CONCLUSION: A significant proportion of patients experience changes in ocular surface markers while treated with ICIs. Medical intervention can lead to stabilization of ocular surface disease.

Referral to Vision Rehabilitation Services for Uveitis Patients: Referral Criteria and Barriers.

PURPOSE: Despite the benefits of vision rehabilitation services (VRS) for uveitis patients, limited literature has examined issues in VRS access within uveitis. We surveyed American Uveitis Society members regarding VRS referral practices, criteria, and barriers. METHODS: Survey responses were collected from November 2022 to January 2023. Analysis summarized responses and compared response patterns of frequently-referring and infrequently-referring providers through Fisher's exact tests and logistic regression. RESULTS: Most of the 33 respondents completed 1 to 5 monthly referrals using criteria of visual acuity loss, visual field loss, and difficulty performing vision-related activities. Key referral barriers included cost of services and insufficient patient-provider communication regarding vision loss. The practice of speaking to patients about vision loss during clinic visits was correlated with higher VRS referral rates (P = 0.047). CONCLUSIONS: Greater patient-provider communication about vision loss may represent an opportunity to increase access to VRS.

A Man With Kaleidoscope Vision.

A 63-year-old man with a history of stage 3 cutaneous melanoma of the scalp and chronic lymphocytic leukemia presents with kaleidoscope vision. What would you do next?

TACROLIMUS FOR IMMUNOSUPPRESSION IN PATIENTS WITH NONINFECTIOUS INTERMEDIATE, POSTERIOR, OR PANUVEITIDES.

PURPOSE: To evaluate the effectiveness of tacrolimus in patients with noninfectious intermediate, posterior, or panuveitis needing a two-immunosuppressive-agent regimen. METHODS: Design: Retrospective cohort study. Setting: Two tertiary-care uveitis practices at academic medical centers. Patient population: Thirty-two patients with noninfectious intermediate, posterior, or panuveitides in whom single-agent immunosuppression was inadequate to effect successful corticosteroid sparing. Intervention: tacrolimus, added as the second immunosuppressive agent. Main outcome measure: successful corticosteroid sparing, defined as inactive uveitis at a dose of prednisone ≤7.5 mg/day. RESULTS: Active uveitis was present in 65.6% of patients at initiation of tacrolimus, and the median time to inactive uveitis was 1.5 months (95% confidence interval 1.2, 4.08). The median time to successful corticosteroid sparing was 3.9 months (95% confidence interval 1.41, 6.67), and by 6 months of follow-up successful corticosteroid sparing was achieved in 75% of patients. Tacrolimus was discontinued for side effects in five patients, three for tremor, and two for hyperglycemia. All side effects were reversible with tacrolimus discontinuation. CONCLUSION: Tacrolimus seems to have efficacy as a second immunosuppressive agent in two-immunosuppressive drug regimens, when a single agent does not permit successful corticosteroid sparing. Side effects were reversible with tacrolimus discontinuation.

Therapeutic Outcomes of Non-Infectious Scleritis Treated with Tumor Necrosis Factor-Alpha Inhibitors.

PURPOSE: We determine the efficacy of tumor necrosis factor-α (TNF) inhibitors in establishing scleritis quiescence. METHODS: We conducted a multicenter retrospective chart review of patients with non-infectious scleritis treated with a TNF inhibitor for at least 6 months. The primary endpoint was scleritis quiescence at 6 months. Secondary endpoints included scleritis quiescence at 12 months, TNF inhibitor effects on concurrent doses of systemic corticosteroids and visual acuity outcomes at 6 and 12 months. RESULTS: At 6 months, 82.2% (37/45) of subjects obtained scleritis quiescence with TNF inhibition. At 12 months, 76.2% (32/42) of subjects remained quiescent. Baseline daily corticosteroid use (21.5 ± 21.6 mg) decreased to 5.4 ± 8.3 mg by 6 months (p < 0.0001) and 2.8 ± 6.1 mg by 12 months (p < 0.001). There was no significant difference between the baseline and 6-month BCVA (p = 0.52). CONCLUSIONS: TNF inhibitors are an effective scleritis therapy with significant systemic corticosteroid sparing effect.

Analyzing the demographics of patients with uveitis in an indigent, urban population.

PURPOSE: To study the types of uveitis examined in a hospital serving indigent populations in need of low-cost care. METHODS: A retrospective chart review examined the electronic medical records of all patients with uveitis-related at Drexel Eye Physicians. Data collected included demographics, anatomic location of the uveitis, systemic disease associations, treatment modalities and insurance. Statistical analysis was performed using χ² or Fischer exact tests. RESULTS: 270 patients (366 eyes) were included for analysis, 67% of patients identified as African American. Most eyes (95.3%, N = 349) were treated with topical corticosteroid drops, and only 6 (1.6%) received an intravitreal implant. Immunosuppressive medications were started in 24 patients (8.9%). Nearly 80% depended to some extent on Medicare or Medicaid Assistance for treatment coverage. There was no association between insurance type and use of biologics or difluprednate. CONCLUSION: We found no association between insurance type and the prescription of medications for uveitis that should be used at home. There was a minimal number of patients prescribed medications for implantation in the office. The adherence of use of medications at home should be investigated.

A Geodemographic Analysis of Travel Time to Uveitis Specialists in the United States.

PURPOSE: Travel time to a patient's medical provider represents a significant component of access to care. We examined travel time to the nearest uveitis specialist for the American population and characterize its impact on access to uveitis care. DESIGN: Observational studies using the American Community Survey and American Census Bureau population estimates. METHODS: Addresses of fellowship-trained uveitis specialists were collected from the American Uveitis Society (AUS) and the Ocular Immunology and Uveitis Foundation (OIUF) websites and geocoded using ArcGIS Pro 2.9. Service areas were defined as all locations within a 60-min drive time from each specialist's location. Demographic and population data for total population, racial groups, household poverty levels, population in dependent groups (younger than 18, older than 65), and health insurance status were overlaid. Data were aggregated for census tracts within and outside service areas and compared using chi-square analysis. Main Outcome Measures: Differences in population demographics for people within and outside service area coverage. RESULTS: 223 uveitis specialist addresses were geocoded into ArcGIS. Of specialist locations, 94% were found in urban areas. Of the total United States population, 63.3% were found to be within service areas. Of these, 55.9% were White and 14.7% were African American, whereas 70% of the people outside service areas were White and 10.1% were African American (p < 0.0001) (Table 1). Only 8.3% of the people within service area coverage had no health insurance compared with 9.5% outside service areas (p < 0.0001). Within coverage areas, 12.7% of the households had a total income below the federal poverty level versus 15.1% of the households outside service area coverage (p < 0.0001). Within service area coverage, 37.4% of the people were in a dependent age group compared with 40.4.% outside service area coverage (p < 0.0001). CONCLUSIONS: Our analysis shows a significant travel burden to the nearest uveitis specialist for a large proportion of Americans. More providers are needed in rural areas, as patients there are more likely to live under the poverty line, be uninsured, or belong to a dependent age group.

Clinical Outcomes in Vitrectomized versus Non-vitrectomized Eyes in Patients with Primary Vitreoretinal Lymphoma.

AIM: To evaluate if there is a difference in the clinical course of primary vitreoretinal lymphoma (PVRL) in vitrectomized versus non-vitrectomized eyes. METHODS: Observational multicenter retrospective case series of patients diagnosed with PVRL between 2007 and 2019, at three tertiary centers. The main outcomes were relapse rates, inflammatory parameters, and best-corrected visual acuities (BCVA). Statistical methods used were an adjusted generalized estimating equation model, and a proportional Cox model. RESULTS: Eighty patients (150 eyes) were followed for a median of 1.7 years. At presentation, there were no clinical differences between the groups. The relapse rate was 0.091/eye-year (EY) for vitrectomized eyes and 0.087/EY for non-vitrectomized eyes (p = .35). Vitrectomized eyes had better BCVA than non-vitrectomized eyes (p < .001). CONCLUSIONS: Vitrectomy had no effect on the relapse rate in eyes with PVRL. However, the decrease in vitreous cell and debris led to vitrectomized eyes having better visual acuity than non-vitrectomized eyes.

Using the Electronic Medical Record to Increase Laboratory Test Monitoring in Ocular Inflammation Patients: A Quality Improvement Study.

BACKGROUND AND OBJECTIVES: Treatment of chronic, noninfectious ocular inflammation includes corticosteroids, disease-modifying antirheumatic medications, and biologics. To mitigate adverse effects associated with the use of these medications, routine laboratory test monitoring is recommended throughout treatment. We evaluated the effectiveness of an alert added to the electronic medical record (EMR) to aid in laboratory test monitoring for patients prescribed these high-risk medications. METHODS: A prospective, interventional study assessed the effect of the alert within the EMR on laboratory test ordering at the Division of Ocular Immunology at the Wilmer Eye Institute. The primary outcome measure was the change in number of ordered laboratory tests at 3, 6, and 12 months after the alert activation compared with pre-intervention levels and overall through the study period. The laboratory tests that were monitored included complete blood count, comprehensive metabolic panel, dual-energy x-ray absorptiometry (DXA) scanning, fasting lipid panel, and interferon gamma release assays. RESULTS: The laboratory test orders for 153 patients on high risk medications were analyzed. Only the frequency of ordering the DXA and interferon gamma release assays increased significantly, compared with baseline, throughout the study. Conversely, there was a significant decrease in the frequency of ordering of fasting lipid profiles and hemoglobin A 1c at each time point and for complete blood count and comprehensive metabolic panel at the 6-month time point. CONCLUSION: An EMR alert results in increased laboratory test ordering initially for tests drawn on a yearly basis, but the effect on more frequently ordered tests wanes with time if the alert can be silenced by the provider. Nonetheless, it provides a novel mechanism to increase laboratory ordering in patients on high-risk medications that can be adapted for use in other EMR software. Future studies are needed to assess whether physician laboratory test ordering behavior is altered throughout the study period with the use of a non-silencable alert.

Scleritis in Lyme Disease.

PURPOSE: To estimate the incidence of scleritis in Lyme disease and report clinical features. DESIGN: Incidence rate estimate and case series. METHODS: Data were collected from an electronic medical record on patients with scleritis presenting to the Wilmer Eye Institute between January 1, 2012 and December 31, 2020. A diagnosis of Lyme disease was made using the Infectious Diseases Society of America, American Academy of Neurology, and the American College of Rheumatology 2020 joint criteria plus a response to antibiotic therapy. After identifying all new-onset cases of scleritis in the database, the proportion of new-onset scleritis with Lyme disease was calculated. The proportion of Lyme disease cases with scleritis was estimated using the number of cases with Lyme disease from the Baltimore metropolitan area reported to the Centers for Disease Control and Prevention. After querying other major eye centers in the area for any cases of Lyme disease scleritis, none were identified, and the incidence of Lyme disease scleritis was estimated using published U.S. Census data for the greater Baltimore metropolitan area. RESULTS: Six cases of Lyme disease scleritis were identified in the 8-year time frame; 1 additional case was identified in the following year. Lyme disease scleritis accounted for 0.6% of all cases of scleritis, and 0.052% of patients with Lyme disease had scleritis. The estimated incidence of Lyme scleritis was 0.2 per 1,000,000 population per year (95% confidence interval 0-0.4), whereas the estimated incidence of Lyme disease in the area was 3 per 10,000 population per year (95% confidence interval 2.9-3.1). All scleritis cases were anterior, unilateral, without necrosis, and resolved with antibiotic use without relapse in a median of 39.5 days (range 29-57 days). Other features of Lyme disease were present in 4 of 7 patients, including a history of erythema migrans in 2 of 7 patients. CONCLUSIONS: Lyme disease is an uncommon cause of scleritis in endemic areas.

The Conundrum of Clinical Trials for the Uveitides: Appropriate Outcome Measures for One Treatment Used in Several Diseases.

The uveitides consist of >30 diseases characterized by intraocular inflammation. Noninfectious intermediate, posterior, and panuveitides typically are treated with oral corticosteroids and immunosuppression, with a similar treatment approach for most diseases. Because these uveitides collectively are considered a rare disease, single-disease trials are difficult to impractical to recruit for, and most trials have included several different diseases for a given protocol treatment. However, measures of uveitis activity are disease specific, resulting in challenges for trial outcome measures. Several trials of investigational immunosuppressive drugs or biologic drugs have not demonstrated efficacy, but design problems with the outcome measures have limited the ability to interpret the results. Successful trials have included diseases for which a single uveitis activity measure suffices or a composite measure of uveitis activity is used. One potential solution to this problem is the use of a single, clinically relevant outcome, successful corticosteroid sparing, defined as inactive uveitis with a prednisone dose ≤7.5 mg/day coupled with disease-specific guidelines for determining inactive disease. The clinical relevance of this outcome is that active uveitis is associated with increased risks of visual impairment and blindness, and that prednisone doses ≤7.5 mg/day have a minimal risk of corticosteroid side effects. The consequence of this approach is that trial visits require a core set of measures for all participants and a disease-specific set of measures, both clinical and imaging, to assess uveitis activity. This approach is being used in the Adalimumab Versus Conventional Immunosuppression (ADVISE) Trial.

Bilateral anterior and posterior scleritis in a patient with acute myelogenous leukemia.

Purpose: To report a novel case of bilateral anterior and posterior scleritis in a patient with acute myelogenous leukemia (AML). Observations: A 69-year-old African American man was admitted to the hospital for relapse of AML. After admission, but prior to induction of chemotherapy, the patient developed ocular redness and proptosis. The diagnosis of bilateral anterior and posterior scleritis was made following an ophthalmic examination, infectious and autoimmune lab work-up, and neuroimaging. The patient was administered immunosuppressive therapy, clinically monitored, and initiated on chemotherapy for AML relapse. About one week later, the patient showed clinical improvement and resolution of the scleritis and proptosis. Conclusion: Scleritis may present during AML relapse, and it may be due to a paraneoplastic syndrome or a reactive anti-leukemic inflammatory response. Clinicians should monitor patients with AML relapse for symptoms such as ocular redness, proptosis, pain, photophobia, and decreased vision, which may indicate development of scleritis.

Management of Immunotherapy-Related Toxicities, Version 1.2022, NCCN Clinical Practice Guidelines in Oncology.

The aim of the NCCN Guidelines for Management of Immunotherapy-Related Toxicities is to provide guidance on the management of immune-related adverse events resulting from cancer immunotherapy. The NCCN Management of Immunotherapy-Related Toxicities Panel is an interdisciplinary group of representatives from NCCN Member Institutions, consisting of medical and hematologic oncologists with expertise across a wide range of disease sites, and experts from the areas of dermatology, gastroenterology, endocrinology, neurooncology, nephrology, cardio-oncology, ophthalmology, pulmonary medicine, and oncology nursing. The content featured in this issue is an excerpt of the recommendations for managing toxicities related to CAR T-cell therapies and a review of existing evidence. For the full version of the NCCN Guidelines, including recommendations for managing toxicities related to immune checkpoint inhibitors, visit NCCN.org.

Attitudes toward parental leave and breastfeeding during ophthalmology residency.

INTRODUCTION: As mandated by the Accreditation Council for Graduate Medical Education (ACGME), residency programs are required to have parental leave policies. A lack of standardized requirements leads to a lack of uniformity among programs. We discuss resident and program director attitudes toward parental leave and examine the range of policies on parental leave and breastfeeding within ophthalmology residency programs. METHODS: Two electronic surveys assessing perceptions toward parental leave during residency and breastfeeding on return to clinical duties were created individually for completion by ophthalmology residents or residency program directors, respectively, with responses collected over 4 weeks. RESULTS: Of residents who took parental leave, 23 (87%) denied taking time off without pay. The most commonly reported effects on training by residents were missed surgical training and impact on research. Nearly 60% of residents (N = 26) reported receiving negative feedback or actions prior to or after the leave. The majority of residents felt program directors and coresidents were supportive (53.8%, 48.1%, respectively), but parental leave negatively affected their coresidents (46.2%). Twenty-five program directors reported that there are written parental leave policies in place at their institution. Sex disparities were noted, with program directors reporting more negative impacts on surgical training in female residents (p = 0.035). There was no statistically significant difference between program director attitudes on clinical training, well-being, or burnout by resident sex. All program directors were supportive of breastfeeding; half reported an institutional breastfeeding policy. CONCLUSION: A national discussion on standardizing parental leave and breastfeeding policies over all ophthalmology residency programs is warranted.

Effectiveness of the Dexamethasone Implant in Lieu of Oral Corticosteroids in Intermediate and Posterior Uveitis Requiring Immunosuppression.

PURPOSE: To evaluate dexamethasone intravitreal implant effectiveness in lieu of high-dose oral prednisone for short-term treatment of noninfectious intermediate and posterior uveitis in patients requiring immunosuppression. METHODS: This is a proof-of-concept, open-label, non-comparative clinical trial with 12-month follow-up. The primary outcome was uveitis control without additional prednisone at 6 and 12 months. Secondary outcomes were need for multiple implants or additional prednisone, and safety data. RESULTS: 20 patients (28 eyes) were enrolled- 16 eyes had control by 6 months; 20 by 12 months. No patients required high-dose prednisone. 6 patients enrolled on prednisone: 2 stopped; 4 tapered to 7.5 mg daily or less by 12 months. 16 eyes required multiple implants; five required cataract surgery; 12 required drops to control IOP; 2 underwent glaucoma surgery. CONCLUSIONS: The dexamethasone implant was effective in lieu of high-dose prednisone although the majority required multiple implants. All patients decreased or discontinued prednisone during follow-up.