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Stefan Diem,1–3,* Mirjam Fässler,2,* Omar Hasan Ali,2,4 Marco Siano,1 Rebekka Niederer,2 Fiamma Berner,2 Guillaume-Alexandre Roux,2 Christoph Jakob Ackermann,1 Sabine Schmid,1 Sabine Güsewell,5 Martin Früh,1,6 Lukas Flatz1,2,4,7 1Department of Oncology/Haematology, Kantonsspital St. Gallen, St. Gallen, Switzerland; 2Department of Immunobiology, Kantonsspital St. Gallen, St. Gallen, Switzerland; 3Department of Oncology/Haematology, Spital Grabs, St. Gallen, Switzerland; 4Department of Dermatology, University Hospital Zürich, Zürich, Switzerland; 5Clinical Trial Unit, Kantonsspital St. Gallen, St. Gallen, Switzerland; 6University of Bern, Bern, Switzerland; 7Department of Dermatology/Allergology, Kantonsspital St. Gallen, St. Gallen, Switzerland *These authors contributed equally to this work Background: Prognosis of metastatic non-small cell lung cancer significantly improved with the availability of checkpoint inhibitors (anti-PD-1/PD-L1). Unfortunately, reliable biomarkers to predict treatment benefit are lacking.Patients and methods: We prospectively collected clinical and laboratory data of 56 non-small cell lung cancer patients treated with a checkpoint inhibitor. The aim was to identify baseline parameters correlating with worse outcome and to create a risk score that enabled to stratify patients into different risk groups. As inflammation is known to promote tumor growth, we focused on inflammation markers in the blood. Disease control (DC) was defined as complete response, partial response, and stable disease on CT scan according to RECIST 1.1.Results: Half of the patients achieved DC. Four parameters differed significantly between the DC group and the no disease control group: Eastern Cooperative Oncology Group performance status (P=0.009), number of organs with metastases (P=0.001), lactate dehydrogenase (P=0.029), and ferritin (P=0.005). A risk score defined as the number of these parameters (0= no risk factor) exceeding a threshold (Eastern Cooperative Oncology Group performance status ≥2, number of organs with metastases ≥4, lactate dehydrogenase ≥262U/L, and ferritin ≥241 µg/L) was associated with overall survival and progression-free survival. Overall survival at 6 and 12 months is as follows: Scores 0–1: 95% and 95%; Score 2: 67% and ≤33%; Scores 3–4: 15% and 0%. Progression-free survival at 6 and 12 months is as follows: Scores 0–1: 81% and 50%; Score 2: 25% and ≤25%; Scores 3–4: 0% and 0%.Conclusion: We propose an easy-to-apply risk score categorizing patients into different risk groups before treatment start with a PD-1/PD-L1 antibody. Keywords: NSCLC, checkpoint inhibitor, biomarkers, risk score, response, survival

Aims: Ethnic disparities have been observed in treatment at first specialist appointments across various specialties within New Zealand. This study aimed to examine documentation and treatment decisions for diabetic retinopathy by ethnicity., Methods: Retrospective audit of first specialist diabetic retinopathy clinic appointments for 388 patients at the Department of Ophthalmology, Te Whatu Ora Te Toka Tumai Auckland. Multiple domains of care were assessed, including comprehensiveness of history taking, examination, investigations and treatment decisions., Results: Europeans comprised 42%, Māori only 9.5%, Pacific peoples 13.19%, Asian 32.7% and Middle Eastern/Latin American/African in 2%. Māori patients were eligible for a significantly greater number of treatments (p=0.001). The comprehensiveness of history taking (p=0.809), examination (p=0.513), investigations (p=0.623) and proportion of eligible treatments provided (p=0.788) was similar but did not reach the gold standard of care across all ethnicities., Conclusions: The standard of care provided in first specialist appointments for diabetic retinopathy appear to be similar across all ethnic groups, although Māori were underrepresented and had a higher disease burden at presentation. Our data highlights the need to reduce barriers faced by Māori in accessing GP, optometry and retinopathy screening referrals in Auckland, and improving local consultation and treatment guidelines., Competing Interests: None to declare., (© PMA.)

Purpose: To evaluate corneal donation demographics in New Zealand (NZ) and explore changes over time., Methods: Data were collected from all donated corneas processed by the New Zealand National Eye Bank over a 10-year period from January 2013 until December 2022. Demographic data including age, self-identified ethnicity, and gender were collected, along with location and cause of death. National death data for the corresponding period were collected online from Statistics New Zealand., Results: A total of 1842 donors were processed; 1414 (76.8%) were sourced from Aotearoa-New Zealand and the remainder from Australia/United States. There was a small but statistically significant median age difference between NZ donors (68 years, interquartile range 55-76) and overseas donors [66 years (interquartile range) 51-70]. Most (n = 1151 81.4%) of NZ donors died in hospital settings, with the most common cause of death being cerebrovascular (n = 444 31.4%). Individuals were less likely to donate their cornea if they were female, [incidence rate ratio (IRR) 0.746, P < 0.001] older age (IRR 0.968, P < 0.001), or if they were of Māori (IRR 0.178, P < 0.001) or Pasifika ethnicity (IRR 0.125, P < 0.001). There was also a statistically significant decrease in donation rates over time (IRR 0.945, P < 0.001)., Conclusions: There remains a profound gap between the demand for corneal transplantation and corneal tissue donation, which is worsening with time. Donor age, gender, and ethnicity seem to influence corneal donation rates. These demographic differences may be ameliorated by increased education, cultural safety, further research into those willing to donate, and the establishment of an organ/tissue donation registry., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background and Objectives: Ocular involvement is common in sarcoidosis. Our study aimed to evaluate the role of screening for uveitis in subjects with sarcoidosis., Methods: Retrospective case series of 88 subjects with a pre-existing diagnosis of sarcoidosis, with no previous diagnosis of uveitis, reviewed by Ophthalmology at Auckland District Health Board between January 2016 and May 2022., Results: Among those undergoing a screening examination, uveitis was observed in 27.8% (15 out of 54 subjects). In those presenting with acute eye symptoms, uveitis was observed in 94.1% (32 out of 34 subjects). Sarcoid uveitis was diagnosed in a total of 50 out of 88 subjects (56.8%). 45 subjects required ocular treatment. Sarcoid uveitis was observed in 6 out of 27 subjects (22.2%) who were entirely asymptomatic at screening. On multivariate analysis, blurring of vision (OR 26.2 p < 0.001), eye pain (OR 7.3 p = 0.014) and respiratory disease (OR 7.1 p = 0.044) were associated with increased risk of sarcoid uveitis. In the 41 subjects with no uveitis at initial examination, 3 subjects (7.3%) subsequently developed uveitis., Conclusion: Our study highlights the importance of ophthalmic screening of all patients with systemic sarcoidosis, even in asymptomatic patients. With a high correlation of ocular symptoms in diagnosis of sarcoid uveitis, ophthalmologists should educate patients to look out for the development of symptoms of ocular inflammation, and clinicians who continue follow up for systemic sarcoidosis should remind patients to watch carefully for these symptoms to facilitate timely diagnosis and intervention., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Purpose: To examine the real-world management and outcomes of uveitic cystoid macular oedema (CME)., Design: Retrospective study., Methods: Patients with uveitic CME were identified from the Inflammatory Eye Disease database. 248 eyes of 218 patients with uveitic CME were identified. Main Outcome Measures : Time to resolution, time to recurrence and vision loss., Results: Median age at time of CME was 51.7 years [IQR 37.3-63.9]. Overall likelihood of resolution was 209/248 eyes (85.3%). Resolution occurred in 34.1% with topical therapy, 69.2% treated with oral prednisone (72.9% if prednisone dose ≥ 60 mg/day), 73.5% treated with orbital floor steroid, and 86.7% treated with intravitreal steroid. On multivariate analysis, ERM was associated with decreased resolution of CME (HR 0.735 p  = 0.045). Additionally, infectious aetiology approached significance (HR 0.635 p  = 0.059) for CME resolution. Recurrence occurred in 85 eyes (36.5%). Predictors of increased likelihood of recurrence were current smoking status (HR 1.818 p  = 0.042) and subretinal fluid at diagnosis (HR 1.577 p  = 0.043). Eyes with infectious aetiology had lower chance of CME resolution, but those that did resolve had lower probability of recurrence (HR 0.891 p  = 0.019). Moderate vision loss (20/50-20/200) occurred in 24 eyes (9/7%) and severe vision loss (≤20/200) in 17 eyes (6.9%)., Conclusions: Management of CME is challenging given the heterogeneous aetiologies, severity of the macular edema as well as response to the therapy. A high rate of resolution was observed, given sufficient time, but recurrence occurs in one-third. Current smoking status plays an important role in the risk of recurrence of CME and patients should be encouraged to stop smoking.

Blood-retinal barrier (BRB) disruption is a common accompaniment of intermediate, posterior and panuveitis causing leakage into the retina and macular oedema resulting in vision loss. It is much less common in anterior uveitis or in patients with intraocular lymphoma who may have marked signs of intraocular inflammation. New drugs used for chemotherapy (cytarabine, immune checkpoint inhibitors, BRAF inhibitors, EGFR inhibitors, bispecific anti-EGFR inhibitors, MET receptor inhibitors and Bruton tyrosine kinase inhibitors) can also cause different types of uveitis and BRB disruption. As malignant disease itself can cause uveitis, particularly from breast, lung and gastrointestinal tract cancers, it can be clinically difficult to sort out the cause of BRB disruption. Immunosuppression due to malignant disease and/or chemotherapy can lead to infection which can also cause BRB disruption and intraocular infection. In this paper we address the pathophysiology of BRB disruption related to intraocular inflammation and malignancy, methods for estimating the extent and effect of the disruption and examine why some types of intraocular inflammation and malignancy cause BRB disruption and others do not. Understanding this may help sort and manage these patients, as well as devise future therapeutic approaches., Competing Interests: Declaration of competing interest The authors make the following declaration of interest: OTN is on the advisory board of AbbVie inc. and Roche inc. RN is a consultant for GSK. JG is a scientific founder and member of the scientific advisory board of a company spun out by UCL Business to commercialise a LRG1 function-blocking therapeutic antibody developed through the UK Medical Research Council DPFS funding scheme. He is also a shareholder of this company and named inventor on three patents related to LRG1 as a therapeutic target. The authors have no other relevant competing interest to declare., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Diabetes mellitus is a growing global public health issue estimated to affect around 600 million people by 2040 [1]. It occurs in populations throughout the world, is increasing in both the developing world and high-income countries and also affects young, working-age people. Ocular involvement in diabetes occurs early in the disease and is present in over a third of diabetes mellitus Type 2 patients at the time of diagnosis. Blindness due to diabetic retinopathy (DR) remains a leading cause of adult-onset blindness, [1] which results from disruption of retinal vasculature, ischemia and its consequences and exudation causing macular edema. The prevalence of diabetic retinopathy is increasing at a greater rate than other causes of blindness including cataract, refractive errors, age-related macular degeneration and glaucoma. Compared to cataract and refractive error, management of diabetic retinopathy requires vast medical resources, including trained medical practitioners able to perform ocular injections and ophthalmologists for laser treatments and retinal surgery. This creates a significant burden on medical services as care for these patients lasts decades., (Copyright © 2022. Published by Elsevier Inc.)

This article provides a summary of available data on Māori ocular health, highlighting significant disparities between Māori and non-Māori populations. Māori are more likely to develop diabetes, sight-threatening retinopathy and keratoconus, and present for cataract surgery earlier with more advanced disease. Limited data exists for macular degeneration and glaucoma, but there is some suggestion that Māori may have lower prevalence rates. The article emphasises the urgent need for robust national data on Māori ocular health to enable targeted interventions and funding allocation. Achieving equity for Māori in all aspects of health, including ocular health, requires concerted efforts from all stakeholders., (© 2023 The Authors. Clinical & Experimental Ophthalmology published by John Wiley & Sons Australia, Ltd on behalf of Royal Australian and New Zealand College of Ophthalmologists.)

Background: Immune checkpoint inhibitors (ICIs) are among the most promising treatment options for melanoma and non-small cell lung cancer (NSCLC). While ICIs can induce effective anti-tumor responses, they may also drive serious immune-related adverse events (irAEs). Identifying biomarkers to predict which patients will suffer from irAEs would enable more accurate clinical risk-benefit analysis for ICI treatment and may also shed light on common or distinct mechanisms underpinning treatment success and irAEs., Methods: In this prospective multi-center study, we combined a multi-omics approach including unbiased single-cell profiling of over 300 peripheral blood mononuclear cell (PBMC) samples and high-throughput proteomics analysis of over 500 serum samples to characterize the systemic immune compartment of patients with melanoma or NSCLC before and during treatment with ICIs., Findings: When we combined the parameters obtained from the multi-omics profiling of patient blood and serum, we identified potential predictive biomarkers for ICI-induced irAEs. Specifically, an early increase in CXCL9/CXCL10/CXCL11 and interferon-γ (IFN-γ) 1 to 2 weeks after the start of therapy are likely indicators of heightened risk of developing irAEs. In addition, an early expansion of Ki-67 + regulatory T cells (Tregs) and Ki-67 + CD8 + T cells is also likely to be associated with increased risk of irAEs., Conclusions: We suggest that the combination of these cellular and proteomic biomarkers may help to predict which patients are likely to benefit most from ICI therapy and those requiring intensive monitoring for irAEs., Funding: This work was primarily funded by the European Research Council, the Swiss National Science Foundation, the Swiss Cancer League, and the Forschungsförderung of the Kantonsspital St. Gallen., Competing Interests: Declaration of interests L.F. has/had advisory roles for Novartis, Sanofi, Philogen, and Bristol-Myers Squibb, all which took place outside the submitted work. P.A.A. has/had consultant/advisory roles for Bristol-Myers Squibb, Roche-Genentech, Merck Sharp & Dohme, Novartis, Array BioPharma, Merck Serono, Pierre Fabre, Incyte, MedImmune, AstraZeneca, Syndax, Sun Pharma, Sanofi, Idera, Ultimovacs, Sandoz, Immunocore, 4SC, Alkermes, Italfarmaco, Nektar, Boehringer-Ingelheim, Eisai, Regeneron, Daiichi Sankyo, Pfizer, Oncosec, Nouscom, Takis, Lunaphore Technologies, Seattle Genetics, ITeos Therapeutics, Medicenna, Bio-Al Health, and ValoTx; he also received research funding from Bristol-Myers Squibb, Roche-Genentech, Array, Sanofi, and Pfizer, as well as travel support from Merck Sharp & Dhome and Pfizer, all which was outside the submitted work. T.A. served as consultant to Bristol-Myers Squibb, Novartis, and CeCaVa; received travel support from Bristol-Myers Squibb and Novartis; received speaker fees from Novartis, Bristol-Myers Squibb, Pierre Fabre, and CeCaVa; received institutional funding from Neracare, Novartis, Sanofi, and SkylineDX; and received institutional research grants from Novartis outside the submitted work. R.D. has intermittent, project-focused consulting and/or advisory relationships with Novartis, Merck Sharp & Dhome, Bristol-Myers Squibb, Roche, Amgen, Takeda, Pierre Fabre, Sun Pharma, Sanofi, Catalym, Second Genome, Regeneron, Alligator, T3 Pharma, MaxiVAX SA, Pfizer, and touchIME, all which took place outside the submitted work. W.v.d.V. declares research support from the Novartis research foundation and the PROMEDICA Stiftung and serves as a consultant for Mabylon outside the submitted work. S.U. declares research support from Bristol-Myers Squibb and Merck Serono; speakers and advisory board honoraria from Bristol-Myers Squibb, Merck Sharp & Dohme, Merck Serono, Novartis, and Roche; and travel support from Bristol-Myers Squibb, Merck Sharp & Dohme, and Pierre Fabre outside the submitted work. L.Z. declares speakers and advisory board honoraria from Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Sanofi, and Sunpharma; research support from Novartis; and travel support from Merck Sharp & Dohme, Bristol-Myers Squibb, Pierre Fabre, Sanofi, Sunpharma, and Novartis outside the submitted work. F.D. receives/received honoraria and travel support from Merck Sharp & Dohme, Bristol-Myers Squibb, and Sun Pharma outside the submitted work. L.H. declares research support from Therakos and speakers and advisory board honoraria from Amgen, BiomeDx, Bristol-Myers Squibb, Curevac, Merck, Merck Sharp & Dohme, Myoncare, Novartis, Pierre Fabre, Sanofi, SUN, and Roche, outside the submitted work. M.E. declares honoraria and travel support from Bristol-Myers Squibb, Immunocore, and Novartis outside the submitted work. R.K. declares travel support from Pierre Fabre and Sun Pharma outside the submitted work. M.J. declares advisory roles (institutional) for Novartis, AstraZeneca, Basilea Pharmaceutica, Bayer, Bristol-Myers Squibb, Debiopharm, Merck Sharp & Dhome, Roche, and Sanofi; research funding from Swiss Cancer Research; and travel grants from Roche, Sanofi, and Takeda. D.S. has/had consultant/advisory roles in the last 3 years for Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Array, Merck Serono, Pfizer, Pierre Fabre, Sun Pharma, Sanofi, Regeneron, Ultimovacs, Sandoz, Immunocore, 4SC, Neracare, Nektar, Daiichi Sankyo, Oncosec, Amgen, BioCon, Immatics, InFlarX, Innovent, Labcorp, Replimune, and Haystack; his institution also received research funding from Bristol-Myers Squibb, Roche-Genentech, Array, and Merck Sharp & Dhome, all of which took place outside the submitted work. N.K. received personal fees, travel costs, and speaker’s honoraria from Astellas, Novartis, Ipsen, and Photocure, all of which took place outside the submitted work. M.P.L. has received project-specific research funding from Roche, Novartis, Molecular Partners, and Oncobit., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Cancer treatment with immune checkpoint blockade (ICB) often induces immune-related adverse events (irAEs). We hypothesized that proteins coexpressed in tumors and normal cells could be antigenic targets in irAEs and herein described DITAS (discovery of tumor-associated self-antigens) for their identification. DITAS computed transcriptional similarity between lung tumors and healthy lung tissue based on single-sample gene set enrichment analysis. This identified 10 lung tissue-specific genes highly expressed in the lung tumors. Computational analysis was combined with functional T cell assays and single-cell RNA sequencing of the antigen-specific T cells to validate the lung tumor self-antigens. In patients with non-small cell lung cancer (NSCLC) treated with ICB, napsin A was a self-antigen that elicited strong CD8 + T cell responses, with ICB responders harboring higher frequencies of these CD8 + T cells compared with nonresponders. Human leukocyte antigen (HLA) class I ligands derived from napsin A were present in human lung tumors and in nontumor lung tissues, and napsin A tetramers confirmed the presence of napsin A-specific CD8 + T cells in blood and tumors of patients with NSCLC. Napsin A-specific T cell clonotypes were enriched in lung tumors and ICB-induced inflammatory lung lesions and could kill immortalized HLA-matched NSCLC cells ex vivo. Single-cell RNA sequencing revealed that these T cell clonotypes expressed proinflammatory cytokines and cytotoxic markers. Thus, DITAS successfully identified self-antigens, including napsin A, that likely mediate effective antitumor T cell responses in NSCLC and may simultaneously underpin lung irAEs.

Purpose: To compare visual outcome and recurrence rates of eyes with noninfectious inflammatory choroidal neovascularization (CNV) treated with or without anti-vascular endothelial growth factor (VEGF) injections and immunosuppression., Design: Retrospective, nonrandomized clinical study., Methods: Participants: Patients with CNV secondary to noninfectious inflammatory causes who attended uveitis clinics at Moorfields Eye Hospital between January 2000 and April 2016. Data were gathered from the clinical notes of all subjects examined in clinic., Main Outcome Measures: change in best-corrected visual acuity (BCVA), mean time to CNV recurrence, moderate vision loss (≤20/50), and severe vision loss (≤20/200)., Results: A total of 166 patients (204 eyes) with noninfectious inflammatory CNV were included in this study with a median follow-up of 6.9 years (interquartile range: 2.9-11.7; 1652 eye-years). The mean BCVA at the time of CNV diagnosis was 0.38 ± 0.05 logarithm of the minimum angle of resolution (logMAR) (Snellen equivalent 20/47) in the eyes that received the first-line anti-VEGF treatment and 0.44 ± 0.03 logMAR (Snellen equivalent 20/55) in the eyes on other treatment modalities (P = .39). Eyes treated first with anti-VEGF (n = 55) received the mean of 4.35 ± 0.53 injections and showed a statistically significant improvement in vision at all time points (P < .001) except for a 5-year visit (P = .25). The rest of the eyes demonstrated no significant change in vision throughout follow-up (all P > .05). At the final visit, the mean BCVA was 0.26 ± 0.11 logMAR (Snellen equivalent 20/36) in the former and 0.35 ± 0.06 logMAR (Snellen equivalent 20/44) in the latter. The mean time to CNV recurrence was 186 ± 15.1 months, and the risk was significantly reduced by treatment with oral corticosteroids (adjusted hazard ratio = 0.32, confidence interval: 0.17-0.59, P < .001) or anti-VEGF injections (adjusted hazard ratio = 0.31, confidence interval: 0.18-0.52, P < .001)., Conclusions: Eyes that developed inflammatory CNV were at risk of vision loss. Those receiving early anti-VEGF injections achieved a better visual outcome and had a reduced risk of CNV recurrence. Oral corticosteroids also had an effect that reduces the risk of recurrence in eyes previously treated., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Purpose: Immune checkpoint inhibitor (ICI)-induced hepatitis belongs to the frequently occurring immune-related adverse events (irAEs), particularly with the combination therapy involving ipilimumab and nivolumab. However, predisposing factors predicting the occurrence of ICI-induced hepatitis are barely known. We investigated the association of preexisting autoantibodies in the development of ICI-induced hepatitis in a prospective cohort of cancer patients., Methods: Data from a prospective biomarker cohort comprising melanoma and non-small cell lung cancer (NSCLC) patients were used to analyze the incidence of ICI-induced hepatitis, putatively associated factors, and outcome., Results: 40 patients with melanoma and 91 patients with NSCLC received ICI between July 2016 and May 2019. 11 patients developed ICI-induced hepatitis (8.4%). Prior to treatment, 45.5% of patients in the hepatitis cohort and 43.8% of the control cohort showed elevated titers of autoantibodies commonly associated with autoimmune liver diseases (p = 0.82). We found two nominally significant associations between the occurrence of ICI-induced hepatitis and HLA alleles associated with autoimmune liver diseases among NSCLC patients. Of note, significantly more patients with ICI-induced hepatitis developed additional irAEs in other organs (p = 0.0001). Neither overall nor progression-free survival was affected in the hepatitis group., Conclusion: We found nominally significant associations of ICI-induced hepatitis with two HLA alleles. ICI-induced hepatitis showed no correlation with liver-specific autoantibodies, but frequently co-occurred with irAEs affecting other organs. Unlike other irAEs, ICI-induced hepatitis is not associated with a better prognosis., (© 2021. The Author(s).)

Immune checkpoint inhibitors (ICIs) have improved the survival of patients with non-small cell lung cancer (NSCLC) by reinvigorating tumor-specific T cell responses. However, the specificity of such T cells and the human leukocyte antigen (HLA)-associated epitopes recognized, remain elusive. In this study, we identified NSCLC T cell epitopes of recently described NSCLC-associated antigens, termed keratinocyte differentiation antigens. Epitopes of these antigens were presented by HLA-A 03:01 and HLA-C 04:01 and were associated with responses to ICI therapy. Patients with CD8 + T cell responses to these epitopes had improved overall and progression-free survival. T cells specific for such epitopes could eliminate HLA class I-matched NSCLC cells ex vivo and were enriched in patient lung tumors. The identification of novel lung cancer HLA-associated epitopes that correlate with improved ICI-dependent treatment outcomes suggests that keratinocyte-specific proteins are important tumor-associated antigens in NSCLC. These findings improve our understanding of the mechanisms of ICI therapy and may help support the development of vaccination strategies to improve ICI-based treatment of these tumors., Competing Interests: No potential conflict of interest was reported by the author(s)., (© 2021 The Author(s). Published with license by Taylor & Francis Group, LLC.)

Competing Interests: The authors have no conflicts of interest to declare.

Aim: Drug-induced ocular inflammation is rare and may be overlooked as a cause of uveitis. The main objective was to describe the causes of drug-induced ocular inflammation. Secondary objectives included uveitis complications and drug rechallenge reactions., Methods: A retrospective chart review at Auckland District Health Board's tertiary uveitis clinic (Auckland, New Zealand) was performed. Participants were identified using the uveitis database, which consists of 2,750 subjects. Fifty eyes of 35 subjects had drug-induced inflammation., Results: Drug-induced inflammation occurred in 1.3% of subjects with uveitis. Mean age was 66.8±15.6 years, and 25 subjects (71.4%) were female. Drugs responsible were bisphosphonates (24 subjects, 68.6%), brimonidine (one subject, 2.9%), etanercept (three subjects, 8.6%), immune checkpoint inhibitors (two subjects, 5.7%), BRAF inhibitors (three subjects, 8.6%), EGFR inhibitors (one subject, 2.9%) and allopurinol/perindopril (one subject, 2.9%). In subjects with bisphosphonate inflammation, anterior uveitis occurred in 22 (91.7%) and scleritis in two (8.3%). A positive rechallenge reaction occurred in two subjects with zoledronate and one with alendronate. Uveitis occurred in six subjects (17.1%) treated with cancer drugs including immune checkpoint inhibitors, BRAF inhibitors and EGFR protein kinase inhibitors. Subjects with cancer-drug-induced uveitis were managed with corticosteroids and five subjects were able to continue therapy; in one subject uveitis was uncontrollable and required drug cessation., Conclusions: Ocular inflammation caused by bisphosphonates is usually mild and resolves on medication withdrawal. Uveitis seen in association with newer cancer medications can be more severe, but in most cases it can be managed without medication cessation., Competing Interests: Nil.

Aim: This study was conducted to describe the epidemiology of thyroid eye disease (TED) in New Zealand., Methods: One hundred and sixty-one subjects with TED seen over a 14-year period in Auckland, from a combined ophthalmology-endocrinology clinic, had data extracted from clinical notes., Results: Median age at onset was 47.0±15.1 years and 77.6% were female. Crude yearly incidence of TED (per 1,000,000) was 12.6 in non-smokers and 67.3 in smokers (p<0.001).  On univariate analysis, female gender, Māori ethnicity and smoking were associated with incidence of TED. On multivariate analysis, female gender and smoking status were associated with risk of TED, and the difference in ethnicity was explained by smoking status. Māori subjects with TED were more likely to be current smokers (72.7%) compared to European (39.2%), Pacific Peoples (33.3%), Asian (8.3%) and Other (12.5%). Māori ethnicity and current smokers were associated with a higher clinical activity score at presentation (p=0.049 and p=0.027)., Conclusion: A strong association was demonstrated with female gender and smoking status and rate of TED. Māori have increased rates of TED; however, this difference was explained by smoking. Eliminating smoking would result in at least a 28.1% reduction in TED incidence in New Zealand., Competing Interests: Nil.

Aim: To evaluate the impact of public health campaigns for glaucoma and age-related macular degeneration compared to breast cancer and prostate cancer using Google Trends data., Methods: Relative search volumes for the terms 'glaucoma', 'macular degeneration', 'breast cancer' and 'prostate cancer' for New Zealand from October 2008-September 2018 were obtained via Google Trends. Intervention time-series analyses were used to compare observations before and after each awareness campaign., Results: Of the campaigns occurring in the 10-year study period, statistically significant increases in search behaviour were observed for breast cancer (45%, p<0.01), prostate cancer (32%, p<0.01) and glaucoma (16%, p<0.01). Macular degeneration search behaviour increased on average 14% but this was not statistically significant (p>0.1), although increased activity (294%) was observed in December 2016, corresponding with the release of a report, public meeting and media release on the socioeconomic impact of macular degeneration., Conclusions: Glaucoma and macular degeneration search behaviour in New Zealand has a low impact following health awareness campaigns in comparison to breast and prostate cancer. This implies there is scope for improvement with these campaigns and a large increase in macular degeneration activity following a public meeting, and report release suggests that increased funding may increase impact. This study also highlights the utility of internet data for cost-effective monitoring of public interest in health issues., Competing Interests: Nil.

Purpose: The aim of this study was to identify the factors associated with positive culture sample in patients with endophthalmitis based on clinical presentation and multimodal intraocular sampling., Design: Retrospective review., Methods: A total of 259 subjects with a diagnosis of endophthalmitis presented to a tertiary ophthalmic referral center between 2006 and 2018. Patient demographics, presenting clinical findings and the results of aqueous and vitreous sampling were analyzed., Results: Mean age was 64.2 (± 22.6) years with 52.9% female. Endophthalmitis followed cataract surgery in 84 eyes (32.4%) and was the most common precipitant; intravitreal injections were the next common cause involving 60 eyes (23.2%). Mean visual acuity on presentation was hand movements with a hypopyon present 134 eyes (52%). In total, 135 cases (52.1%) were culture positive. Aqueous sampling was performed in 112 eyes [culture positive 36 (32.1%)]; vitreous sample in 122 eyes [positive in 56 (45.3%)]. Vitrectomy was performed in 169 eyes with 149 sent for culture [70 (47.0%) positive]. A positive vitrectomy culture was observed in 14 eyes (36.9%) of 38, despite initial treatment with intravitreal antibiotics. Factors associated with positive culture were aqueous tap [odds ratio (OR) 2.06, P = 0.02], vitrectomy (OR 2.86, P = 0.001), and absent red reflex (OR 2.73, P = 0.001)., Conclusions: A multimodal approach to intraocular sampling should be considered in those presenting with endophthalmitis, with both aqueous tap and vitrectomy associated with an increased probability of achieving a positive culture.

Myocarditis can develop into inflammatory cardiomyopathy through chronic stimulation of myosin heavy chain 6-specific T helper (T H )1 and T H 17 cells. However, mechanisms governing the cardiotoxicity programming of heart-specific T cells have remained elusive. Using a mouse model of spontaneous autoimmune myocarditis, we show that progression of myocarditis to lethal heart disease depends on cardiac myosin-specific T H 17 cells imprinted in the intestine by a commensal Bacteroides species peptide mimic. Both the successful prevention of lethal disease in mice by antibiotic therapy and the significantly elevated Bacteroides- specific CD4 + T cell and B cell responses observed in human myocarditis patients suggest that mimic peptides from commensal bacteria can promote inflammatory cardiomyopathy in genetically susceptible individuals. The ability to restrain cardiotoxic T cells through manipulation of the microbiome thereby transforms inflammatory cardiomyopathy into a targetable disease., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Importance: Immunotherapy with checkpoint inhibitors targeting the PD-1 (programmed cell death 1) axis has brought notable progress in patients with non-small cell lung cancer (NSCLC) and other cancers. However, autoimmune toxic effects are frequent and poorly understood, making it important to understand the pathophysiologic processes of autoimmune adverse effects induced by checkpoint inhibitor therapy., Objective: To gain mechanistic insight into autoimmune skin toxic effects induced by anti-PD-1 treatment in patients with non-small cell lung cancer., Design, Setting, and Participants: This prospective cohort study was conducted from July 1, 2016, to December 31, 2018. Patients (n = 73) with non-small cell lung cancer who received anti-PD-1 therapy (nivolumab or pembrolizumab) were recruited from 4 different centers in Switzerland (Kantonsspital St Gallen, Spital Grabs, Spital Wil, and Spital Flawil). Peripheral blood mononuclear cells, tumor biopsy specimens and biopsies from sites of autoimmune skin toxic effects were collected over a 2-year period, with patient follow-up after 1 year., Main Outcomes and Measures: Response to treatment, overall survival, progression-free survival, and development of autoimmune toxic effects (based on standard laboratory values and clinical examinations)., Results: Of the cohort of 73 patients with NSCLC (mean [SD] age, 68.1 [8.9] years; 44 [60%] men), 25 (34.2% [95% CI, 24.4%-45.7%]) developed autoimmune skin toxic effects, which were more frequent in patients with complete remission or partial remission (68.2% [95% CI, 47.3%-83.6%]) than those with progressive or stable disease (19.6% [95% CI, 11.0%-32.5%]) (χ2 = 14.02, P < .001). Nine T-cell antigens shared between tumor tissue and skin were identified. These antigens were able to stimulate CD8+ and CD4+ T cells in vitro. Several of the antigen-specific T cells found in blood samples were also present in autoimmune skin lesions and lung tumors of patients who responded to anti-PD-1 therapy., Conclusions and Relevance: These findings highlight a potential mechanism of checkpoint inhibitor-mediated autoimmune toxic effects and describe the association between toxic effects and response to therapy; such an understanding will help in controlling adverse effects, deciphering new cancer antigens, and further improving immunotherapy.

Checkpoint inhibitors have improved survival of metastatic melanoma. However, reliable biomarkers to predict response are still needed. Immunoglobulin G (IgG) antibody subclasses reflect immunocompetence in individuals and are known to be involved in essential functions in our immune system. This prospective study evaluated the association between serum IgG with its subclasses IgG1, IgG2, IgG3, and IgG4 and antitumor response according to RECIST 1.1. Serum samples from 49 patients were prospectively collected before the start of treatment with a checkpoint inhibitor. We observed a statistically significant association of baseline IgG2 with response to therapy (P=0.011). After defining optimal cutpoints, we found significant associations between total IgG (>9.66 g/L, P=0.038), IgG1 (>6.22 g/L, P=0.025), IgG2 (>2.42 g/L, P=0.019), and IgG3 (>0.21 g/L, P=0.034) with progression-free survival. Prolonged overall survival was associated with elevated IgG2 (>2.42 g/L, P=0.043). Together, these findings define total IgG and subclasses as predictors of clinical successful checkpoint inhibition in metastatic melanoma patients.

Background: Long-term survival of stage IV melanoma patients has improved significantly with the development of immune checkpoint inhibitors (CIs). Reliable biomarkers to predict response and clinical outcome are needed., Methods: We investigated the role of melanoma-associated antibodies as predictive markers for CI therapy in two independent cohorts. In cohort 1, a prospective study, we measured specific antibodies before treatment, after one week and after six to nine weeks of treatment. Cohort 2 consisted of serum samples prior to CI therapy initiation. ELISA assays were performed to quantify specific IgG directed against melanocyte differentiation antigens tyrosinase-related proteins 1 and 2 (TRP1/TYRP1 and TRP2/TYRP2), glycoprotein 100 (gp100), MelanA/MART1, and the cancer-testis antigen NY-ESO-1. Response was defined as either complete or partial remission on CT scan according to RECIST 1.1., Results: In cohort 1, baseline levels of these antibodies were higher in the responder group, although statistical significance was only reached for NY-ESO-1 (p = 0.007). In cohort 2, significantly higher antibody baseline levels for MelanA/MART1 (p = 0.003) and gp100 (p = 0.029) were found. After pooling the results from both cohorts, higher levels of MelanA/MART1 (p = 0.013), TRP1/TYRP1 (p = 0.048), TRP2/TYRP2 (p = 0.047) and NY-ESO-1 (p = 0.005) specific antibodies at baseline were independently associated with response., Conclusions: Melanoma-associated antibodies may be candidate biomarkers for response and survival in metastatic melanoma patients being treated with CIs. These markers may be used to complement patient assessment, in combination with PD-L1 status, tumor-infiltrating lymphocytes and tumor mutational burden, with the aim to predict outcome of CI treatment in patients with metastatic melanoma., Trial Registration: Ethikkommission Ostschweiz, EKOS 16/079 https://ongoingprojects.swissethics.ch/runningProjects&#95;list.php?q=%28BASECID~contains~2016-00998%29&orderby=dBASECID .

Purpose: Mutations in the visual system homeobox 1 (VSX1) gene have been described at a low frequency in keratoconus and posterior polymorphous corneal dystrophy (PPCD). The putative role is controversial for several reasons, including a lack of mutations detected in other population cohorts. This study aims to determine whether VSX1 contributes to the genetic pathogenesis of keratoconus and PPCD in a New Zealand population, and includes analysis of a Polynesian population., Methods: Recruitment of patients with keratoconus and PPCD, comprehensive clinical examination including corneal topography and pachymetry, and collection of biologic samples for DNA extraction were undertaken. Mutational analysis of VSX1 (exons 1-7) with PCR and sequencing with bioinformatic assessment of variants was performed. Probable pathogenic variants were screened for in a control population using high-resolution melting analysis., Results: Forty-seven patients with keratoconus, including 15 familial cases, and ten unrelated patients with PPCD were recruited. Two pathogenic changes were detected; a novel change c.173C>T (p.Pro58Leu) was found in a patient with PPCD, predicted to be pathogenic, and not seen in 200 ethnically matched control alleles. The previously reported c.731A>G (p.His244Arg) was detected in a patient with sporadic keratoconus, and not present in the controls. No family members were available for segregation analysis., Conclusions: This study reports the presence of pathogenic mutations in VSX1 in PPCD and keratoconus, including a novel disease-causing variant. The affected numbers are small, but given the growing body of evidence of pathogenic segregating changes in VSX1 in disease cohorts, the expression in keratocytes as part of wound healing, and the documented association of PPCD and keratoconus, it seems likely that the role of VSX1 as a genetic factor contributing to disease is real.

Background: To establish demographics, referral patterns and clinical characteristics of patients attending an emergency eye service within a major public tertiary teaching hospital and to identify possible targets to improve delivery of patient care., Methods: Retrospective study of all patients (N=504) attending an acute eye clinic over a representative 2-week period within Greenlane Clinical Centre, Auckland., Results: Mean age was 42.4 plus or minus 20.6 years with mean visual acuity of 6/10. Referrals came from: general-practitioners (GP) (26.2%), self-referrals (18.6%), hospital medical-officers (7.4%), accident and emergency clinics (6.6%) and optometrists (2.2%). 39.1% of patients were follow-up reviews. Main presenting symptoms were pain, red eye and reduced vision. Average waiting-time was 119 plus or minus 98 min. Major diagnoses were trauma, uveitis and adenoviral keratoconjunctivitis (AKC). Males were more likely to present with ocular trauma, whereas females were more likely to exhibit uveitis, contact-lens related keratitis and AKC. Outcomes included follow-up (48.2%), referral to speciality ophthalmology care (19.0%), referral to other clinics (5.75%), and discharge (33.7%)., Conclusion: A significant proportion of presentations could have been appropriately referred to outpatient departments or potentially managed by primary healthcare providers. Potential initiatives to manage excessive workload demands might target prevention of ocular trauma, improved contact-lens education, limiting the spread of AKC and improved GP education.

Confocal microscopy enables microstructural analysis of the in vivo cornea, allowing fresh insight into corneal microstructure in health, and in inherited and acquired corneal disease. This method of corneal examination is evolving in an exponential fashion, with rapid advances in technology being mirrored by rapid growth in both research and clinical applications. Whilst initially the evidence base for in vivo confocal microscopy consisted largely of small case studies, in recent years there has been a trend towards collecting quantitative data in an effort to better delineate between heath and disease. Confocal microscopy has been utilised clinically to aid in the diagnosis of infectious keratitis, in particular Acanthamoeba and fungal keratitis, and has also established a role in the diagnosis and phenotyping of corneal dystrophies. This article reviews in vivo confocal microscopy of the human cornea in health and disease and examines clinical and research applications of this new technology.

Aims: To establish rates of HLAB27-positive uveitis and ankylosing spondylitis in a New Zealand population and to examine characteristics of patients with ankylosing spondylitis that present with uveitis., Methods: A retrospective audit of 124 consecutive patients presenting to the Acute Eye Clinic at Auckland City Hospital with a diagnosis of either bilateral uveitis or their second episode of uveitis was undertaken. All patients underwent full blood count, erythrocyte sedimentation rate, HLAB27 typing, and radiographs of the sacroiliac joints and lumbar spine., Results: The HLAB27 antigen was detected in 36% of patients undergoing uveitis screening tests. Ankylosing spondylitis was diagnosed on lumbar spine and sacroiliac joint X-ray in 41% of HLAB27-positive patients and in none of the HLAB27-negative patients. No correlation was identified between age at first presentation and diagnosis of ankylosing spondylitis. Ankylosing spondylitis was not associated with elevated white cell count or erythrocyte sedimentation rate. Male gender and detection of the HLAB27 antigen were strongly associated with a diagnosis of ankylosing spondylitis (p<0.001)., Conclusions: Ankylosing spondylitis was detected in 41% of the HLAB27-positive patients and in 0% of the HLAB27-negative patients. Routine lumbar spine and sacroiliac joint X-rays are only recommended for HLAB27-positive patients.

Objective: To compare the results of Proview pressure phosphene tonometry (PPPT) performed by the patient and an examiner with Goldmann applanation tonometry (GAT)., Methods: A comparative case series of 96 (192 eyes) consecutive patients from a glaucoma clinic was conducted. Intraocular pressure (IOP) was measured with GAT by one examiner, PPPT by another examiner, and PPPT by the patient. All examiners were masked to the results from any preceding IOP measurement., Results: The coefficient of repeatability for repeated measurements for the GAT was +/-0.48 mmHg. The limits of agreement for self-measurement of IOP with the PPPT and examiner measured IOP with PPPT were 6.3 mmHg and 4.8 mmHg, respectively. The limits of agreement between GAT and self assessed PPPT were +/-11.8 mmHg (mean difference of 0.63 mmHg). When the same comparison was made between GAT and examiner assessed PPPT, the results were limits of agreement of +/-10 mmHg (mean difference of 2.86 mmHg). No significant difference was identified in the agreement of the GAT and the PPPT when subanalysed for age of patient or diagnosis (P > 0.05). The limits of agreement between self-assessed IOP with the PPPT and the GAT were +/-8.2 for those with IOP <20 mmHg and +/-14.9 mmHg for those with IOP>20 mmHg., Conclusions: Poor agreement exists between IOP measured by GAT and PPPT measured by an examiner or by the patient.