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.

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.

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.

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.

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.

Health system wide "big data" analysis of rheumatologic conditions and scleritis.

BACKGROUND: The development of scleritis in the setting of autoimmune conditions has been well documented. Prior series have assessed the relationship between systemic autoimmune disorders and scleritis only in patients referred for rheumatologic or ocular inflammation. This can lead to a referral bias. We reviewed all charts within the electronic medical record (EMR) of a health system for patients with systemic autoimmune and scleritis diagnoses to determine the prevalence of both and which disorders had the highest relative risk of developing scleritis. METHODS: The EMR was searched for scleritis and systemic inflammatory diagnoses in the past medical history and diagnosis tabs, and for associated disease specific laboratory values. The intersection of scleritis and systemic inflammatory conditions was assessed through searching both SNOMED Clinical Terminology and ICD-10 codes for diagnoses. The prevalence of each autoimmune disorder, scleritis prevalence, the percentage of patients with an autoimmune condition having scleritis, the percentage of patients with scleritis having an autoimmune condition; the relative risk (RR) of scleritis patients having a specific autoimmune disorder were calculated. RESULTS: A total of 5.9 million charts were searched with autoimmune conditions identified in 148,993 patients. The most common autoimmune conditions overall were HLA-B27-associated diseases (n = 26,680; prevalence 0.45%); rheumatoid arthritis (RA)(N = 19,923; prevalence 0.34%). Conversely, 2702 patients were identified with scleritis (prevalence 0.05%), of which 31.4% had an associated autoimmune condition. Patients with RA represented the highest percentage of patients with an autoimmune condition having scleritis. Granulomatosis with polyangiitis (GPA) represented the highest the percentage of patients with scleritis having an autoimmune condition. Sjogrens was the third most common condition associated with scleritis- making up 4.5% of cases. An association with juvenile idiopathic arthritis (JIA) was seen in 0.3% of patients. CONCLUSIONS: While this is the largest retrospective review examining the association between autoimmune disease and scleritis, the findings are similar to prior studies with nearly a third of scleritis patients having an underlying autoimmune diagnosis. Limitations of the study included accurate chart coding; having laboratory results within the searchable EMR. Future research is needed to delineate associations of systemic disease with the anatomic location of scleritis using EMR.

Changes in patient visits and diagnoses in a large academic center during the COVID-19 pandemic.

BACKGROUND: To minimize the risk of viral transmission, ophthalmology practices limited face-to-face encounters to only patients with urgent and emergent ophthalmic conditions in the weeks after the start of the COVID-19 epidemic in the United States. The impact of this is unknown. METHODS: We did a retrospective analysis of the change in the frequency of ICD-10 code use and patient volumes in the 6 weeks before and after the changes in clinical practice associated with COVID-19. RESULTS: The total number of encounters decreased four-fold after the implementation of clinic changes associated with COVID-19. The low vision, pediatric ophthalmology, general ophthalmology, and cornea divisions had the largest total decrease of in-person visits. Conversely, the number of telemedicine visits increased sixty-fold. The number of diagnostic codes associated with ocular malignancies, most ocular inflammatory disorders, and retinal conditions requiring intravitreal injections increased. ICD-10 codes associated with ocular screening exams for systemic disorders decreased during the weeks post COVID-19. CONCLUSION: Ophthalmology practices need to be prepared to experience changes in practice patterns, implementation of telemedicine, and decreased patient volumes during a pandemic. Knowing the changes specific to each subspecialty clinic is vital to redistribute available resources correctly.

Neurosarcoidosis and Ocular Inflammation: A Case Series and Literature Review.

OBJECTIVE: To describe the ocular findings of neurosarcoidosis (NS) through a case series and review the current literature on the ocular complications of NS. METHODS: Case series of 4 patients with a literature review. RESULTS: Ophthalmic involvement in NS includes scleritis, cranial nerve palsies, uveitis, optic nerve granulomas, and occlusive retinal vasculitis. CONCLUSION: NS is an uncommon, but potentially life-threatening, manifestation of sarcoidosis with ocular involvement up to 25% of patients. Patients presenting with neuro-ophthalmic manifestations of sarcoidosis are more likely to have other sites of involvement requiring ophthalmologists to maintain a high index of suspicion for systemic disease.

Encephalopathy, Chiasmal Compression, Ophthalmoplegia, and Diabetes Insipidus in Pituitary Apoplexy.

Pituitary apoplexy with haemorrhage is a potentially life-threatening condition, and a rare cause of third nerve palsies. The range of vision loss and ophthalmoplegia seen in cases of apoplexy reflects the variability of cranial structures compressed by mass effect. The pathophysiology of extraocular muscle limitation and facial paraesthesia occurs with compression of the cavernous sinus, which contains cranial nerves III, IV, VI, and the ophthalmic branch of V. Blood supply to adjacent structures may be also compromised, causing additional loss of function. This case report of a patient with diabetes insipidus and a third nerve palsy illustrates the anatomic basis of the presenting signs of pituitary apoplexy, and the necessity for prompt neuroimaging if it is suspected.

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.

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.

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.

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.

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.

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.

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.