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Graves orbitopathy is both disabling and disfiguring. Medical therapies to reduce inflammation are widely used, but there is limited trial data beyond 18 months of follow-up. Methods Three-year follow-up of a subset of the CIRTED trial (N = 68), which randomized patients to receive high-dose oral steroid with azathioprine/placebo and radiotherapy/sham radiotherapy. Results Data were available at 3 years from 68 of 126 randomized subjects (54%). No additional benefit was seen at 3 years for patients randomized to azathioprine or radiotherapy with regard to a binary clinical composite outcome measure (BCCOM), modified European Group on Graves’ Orbitopathy score, or Ophthalmopathy Index. Clinical Activity Score (CAS), Ophthalmopathy Index, and Total Eye Score improved over 3 years (P < .001). However, quality of life at 3 years remained poor. Of 64 individuals with available surgical outcome data, 24 of 64 (37.5%) required surgical intervention. Disease duration of greater than 6 months before treatment was associated with increased need for surgery [odds ratio (OR) 16.8; 95% CI 2.95, 95.0; P = .001]. Higher baseline levels of CAS, Ophthalmopathy Index, and Total Eye Score but not early improvement in CAS were associated with increased requirement for surgery. Conclusion In this long-term follow-up from a clinical trial, 3-year outcomes remained suboptimal with ongoing poor quality of life and high numbers requiring surgery. Importantly, reduction in CAS in the first year, a commonly used surrogate outcome measure, was not associated with improved long-term outcomes.

Introduction: Ibrutinib is a small-molecule drug approved for the treatment of haematological disorders and is known to be associated with visual disturbances, but uveitis has not yet been reported as an adverse effect of this medication. We present two cases of ibrutinib-associated severe uveitis in patients with chronic lymphocytic leukaemia. Case description: Our first case is a 65-year-old woman who presented with acute onset of bilateral fibrinous anterior uveitis 1 day after starting ibrutinib. Her vision was hand movements in the right eye and 20/120 in the left with hyperaemic discs and subretinal fluid. Ibrutinib was stopped and she experienced a significant improvement under local and oral steroid treatment. The second case is a 64-year-old male with subacute onset of bilateral hypertensive anterior uveitis with pupillary seclusion and right eye hyphaema. He was on ibrutinib for the past 9 months. His vision at presentation was 20/80 and 20/60 for the right and left eye, respectively. He responded poorly to local steroid treatment until ibrutinib was stopped due to cardiac side-effects, after which his uveitis resolved and treatment was stopped. Conclusion: The temporal association between changes in ibrutinib treatment and our patients’ ocular inflammation suggests a causative link. Ibrutinib increases Th1-based immune responses which is proposed as a mechanism for drug-induced uveitis. Its antiplatelet effect may explain the fibrinous nature of the inflammation and hyphaema.

The current dogma in ophthalmology and vision research presumes the intraocular environment to be sterile. However, recent evidence of intestinal bacterial translocation into the bloodstream and many other internal organs including the eyes, found in healthy and diseased animal models, suggests that the intraocular cavity may also be inhabited by a microbial community. Here, we tested intraocular samples from over 1000 human eyes. Using quantitative PCR, negative staining transmission electron microscopy, direct culture, and high-throughput sequencing technologies, we demonstrated the presence of intraocular bacteria. The possibility that the microbiome from these low-biomass communities could be a contamination from other tissues and reagents was carefully evaluated and excluded. We also provide preliminary evidence that a disease-specific microbial signature characterized the intraocular environment of patients with age-related macular degeneration and glaucoma, suggesting that either spontaneous or pathogenic bacterial translocation may be associated with these common sight-threatening conditions. Furthermore, we revealed the presence of an intraocular microbiome in normal eyes from non-human mammals and demonstrated that this varied across species (rat, rabbit, pig, and macaque) and was established after birth. These findings represent the first-ever evidence of intraocular microbiota in humans.

Objectives The West London lung screening pilot aimed to identify early-stage lung cancer by targeting low-dose CT (LDCT) to high risk participants. Successful implementation of screening requires maximising participant uptake and identifying those at highest risk. As well as reporting pre-specified baseline screening metrics, additional objectives were to 1) compare participant uptake between a mobile and hospital-based CT scanner and 2) evaluate the impact on cancer detection using two lung cancer risk models. Methods From primary care records, ever-smokers aged 60–75 were invited to a lung health check at a hospital or mobile site. Participants with PLCOM2012 6-yr risk ≥1.51 % and/or LLPv2 5-yr risk ≥2.0 % were offered a LDCT. Lung cancer detection rate, stage, and recall rates are reported. Participant uptake was compared at both sites (chi-squared test). LDCT eligibility and cancer detection rate were compared between those recruited under each risk model. Results Of 8366 potential participants invited, 1047/5135 (20.4 %) invitees responded to an invitation to the hospital site, and 702/3231 (21.7 %) to the mobile site (p = 0.14). The median distance travelled to the hospital site was less than to the mobile site (3.3 km vs 6.4 km, p Conclusion Targeted screening is effective in detecting early-stage lung cancer. Similar levels of participant uptake at a mobile and fixed site scanner were demonstrated, indicating that uptake was driven by factors in addition to scanner location. The LLPv2 model was more permissive; recruitment with PLCOM2012 alone would have missed several cancers.

To report the clinical findings, anatomical features, and treatment outcomes in subjects with ocular tuberculosis (OTB) at 24 months in the Collaborative Ocular Tuberculosis Study (COTS)-1. Of the ...

[No abstract]

Purpose To investigate the potential of utilizing the expression of genes for glucocorticoid receptor (GR) and mitogen-activated protein kinase phosphatase-1 (MKP-1) as biomarkers of corticosteroid (CS) refractoriness and disease activity in patients with Vogt-Koyanagi-Harada (VKH) disease. Design Prospective cohort study. Methods Twenty VKH patients receiving their first cycle of CS treatment in the absence of additional systemic immunosuppressive therapy and a control group of fifteen healthy volunteers were recruited from the University of Chile (Santiago, Chile) and US National Institutes of Health (Bethesda, United States). Intraocular inflammation was clinically quantified at enrolment and all follow-up visits. CS refractoriness was defined as an ocular reactivation of VKH upon CS withdrawal at a daily oral prednisone dose of 10 mg or more. Quantitative Reverse transcription polymerase chain reaction (qRT-PCR) was performed to measure the mRNA levels of the alpha (α) and beta (β) isoforms of GR and MKP-1 in peripheral blood mononuclear cells (PBMC) after in vitro stimulation with either anti-CD3/anti-CD28 antibodies, lipopolysaccharide (LPS), or phytohemagglutinin (PHA), in the presence or absence of dexamethasone (Dex). Results After 6 hours of stimulation in the presence of Dex, PBMC from CS-refractory VKH patients had an impaired elevation in GRα expression (P = .03). Furthermore, inactive patients showed a significant Dex-induced upregulation of MKP-1 (P = .005). Conclusions In this pilot study, the expression of GR isoforms and MKP-1 corresponded with patients' clinical response to systemic CS treatment and disease activity, respectively. Hence, these candidate biomarkers have potential clinical utility in the early identification of CS refractoriness and subclinical inflammation in patients with VKH disease.

Susac syndrome is a rare condition presumed to be immune-mediated occlusion of small arterial vasculature principally of the brain, inner ear, and retina. Clinically, the syndrome manifests as a pathognomonic triad of encephalopathy, hearing loss, and branch retinal artery occlusion. Early recognition and diagnosis is important as delayed treatment may be profound and result in deafness, blindness, dementia, and other neurological deficits. The plethora of imaging technology, including magnetic resonance imaging, retinal fluorescein angiography, optical coherence tomography, and optical coherence tomography angiography, allows deeper and more discrete anatomical-physiological correlation of underlying pathology, early diagnosis, and imaging biomarkers for early detection of relapse during follow-up. We highlight the current clinical classification of Susac syndrome, available investigations, treatment, and care pathways.

Background/Aim To report the efficacy and tolerability of antitumour necrosis factor-alpha therapy (TNF inhibitors [TNFi]) in the management of non-infectious ocular inflammation, including uveitis and scleritis, in adult patients over an 8-year period.Materials and methods This is a prospective cohort study of infliximab and adalimumab in the treatment of non-infectious ocular inflammatory disease. 43 of 85 adult patients on TNFi (34 infliximab, 9 adalimumab) for ≥1 year with non-infectious uveitis or scleritis were followed from 2006 to 2014. Clinical assessments, medication, adverse events and history of steroid rescues were collected at 6 monthly intervals. General quality of life (Short Form Health Survey (SF-36)) and visual quality of life (Vision-related quality of life Core Measure (VCM1)) were assessed annually. Outcome measures included rate of sustained remission, rate of relapse, systemic corticosteroid reduction, adverse events, and VCM1 and SF-36 scores.Results The median time on infliximab was 3.2 years (IQR 4.3) and on adalimumab was 2.4 years (IQR 1.8). Sustained remission was induced in 39 patients (91%) (0.5 per patient year) after a median of 1.2 years on a TNFi. 22 (51%) experienced one relapse, and 5 (12%) had two relapses. 23 (54%) had at least one adverse event; serious adverse events necessitating hospitalisation or cessation of medication occurred in four (9%) patients. 10 patients (23%) switched from the initiation of TNFi, at 1.7 years after starting, to another TNFi or another class of biologic therapy.Conclusion TNFi treatment is associated with long-term drug-induced remission of ocular inflammation, visual stability and corticosteroid reduction. Adverse events were common and no new safety signals occurred. Relapse of inflammation occurs in half of the treated population.This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

Early cancer diagnosis is a clinical and research priority of the UK government. Earlier cancer diagnosis should enable identification of cancers at an earlier stage, leading to improved outcomes.1 This must be balanced with the potential physical and psychological harms of over-investigation and over-diagnosis. The ‘two-week wait’ (2WW) referral pathway represents the most common route to cancer diagnosis. However, only 39% of cancer diagnoses were made via 2WW pathways in 2017, while significant proportions of diagnoses are made via other outpatient clinics (32%) or emergency presentation (19%), representing potentially missed diagnostic opportunities.2 Approximately 50% of cancer patients present with non-specific but concerning symptoms of cancer (NSCS).3 Compared to ‘alarm symptoms’ these have low predictive values for cancer and are less indicative of site-specific disease; consequently, they are not reflected in 2WW referral criteria.3 These patients frequently are referred later for specialist investigation and have more advanced disease.4 A principal goal for the new NHS Rapid Diagnostic Centres (RDCs) is to provide a pathway for patients with NSCS to detect cancer earlier, where treatment outcomes are more favourable.1 NHS England aims to provide full population coverage with RDCs by 2024.5 Despite their low predictive value and association with multiple diseases, many NSCS are considered as characteristic warning signs of cancer. These include unexpected weight loss, malaise, unexplained pain, new dyspnoea, and persistently abnormal blood tests.4,6,7 Unexpected weight loss was the most common symptom seen within an RDC pilot (66%) between 2016 and 2018;7 however, it has a relatively low predictive value for cancer.6,8,9 While patients with weight loss in isolation may not warrant further investigation, considering other clinical variables …

Immune thrombocytopenia (ITP) is thought to result from an aberrant adaptive autoimmune response, involving autoantibodies, B and T lymphocytes, directed at platelets and megakaryocytes. Previous reports have demonstrated skewed CD4+ T-helper subset distribution and enhanced production of pro-inflammatory cytokines such as interleukin 17A and interferon gamma. The role of monocytes (MCs) in ITP is less widely described, but innate immune cells have a role in shaping CD4+ T-cell phenotypes. Glucocorticoids (GCs) are commonly used for first-line ITP treatment and modulate a broad range of immune cells including T cells and MCs. Using multiparameter flow cytometry analysis, we demonstrate the expansion of intermediate MCs (CD14++ CD16+ ) in untreated patients with newly diagnosed ITP, with these cells displaying a pro-inflammatory phenotype, characterised by enhanced expression of CD64 and CD80. After 2 weeks of prednisolone treatment (1 mg/kg daily), the proportion of intermediate MCs reduced, with enhanced expression of the anti-inflammatory markers CD206 and CD163. Healthy control MCs were distinctly different than MCs from patients with ITP before and after GC treatment. Furthermore, the GC-induced phenotype was not observed in patients with chronic ITP receiving thrombopoietin receptor agonists. These data suggest a role of MCs in ITP pathogenesis and clinical response to GC therapy.

BackgroundCorticosteroids remain the first line treatment for patients with Immune Thrombocytopenia (ITP). However, 20-30% of patients do not respond to treatment at tolerable doses. This variation in corticosteroid efficacy is replicated in other autoimmune diseases and may have an adaptive immune basis.ObjectiveTo test the hypothesis that CD4+ T cell responses to corticosteroids are different in patients with clinically defined corticosteroid refractory ITP.MethodsIn this prospective cohort study, CD4+ T cells from patients with ITP were cultured in the presence or absence of dexamethasone (Dex). Intracellular cytokine expression was then quantified by flow cytometry and compared with patients’ clinical response to corticosteroid treatment. A control cohort of patients with autoimmune uveitis was also studied to evaluate whether our findings were limited to ITP or are potentially generalizable across autoimmune diseases. ResultsThe ratio of interleukin (IL)-10 to IL-17 expression following CD4+ T cell culture with Dex was able to discriminate between ITP patients with a clinically defined complete (n=33), partial (n=12) or non-response (n=11) to corticosteroid treatment (p=0.002). These findings were replicated in patients with autoimmune uveitis (complete response n=14, non-response n=22; p=0.01) ConclusionsThere is a relative abrogation of IL-10 and persistence of IL-17 expression in the CD4+ T cells of patients who clinically fail corticosteroid therapy. This observation has potential to inform both our mechanistic understanding of the action of corticosteroids in the treatment of ITP, and as a biomarker for steroid refractory disease, with potential application across a range of haematological and non-haematological conditions.

To examine disease profile of tubercular uveitis (TBU) in Paediatric population. Among 945 patients of the retrospective multinational study by the Collaborative Ocular Tuberculosis Study (COTS)-1,...

Immune thrombocytopenia (ITP) is thought to result from an aberrant adaptive autoimmune response, involving autoantibodies, B and T lymphocytes, directed at platelets and megakaryocytes. Previous reports have demonstrated skewed CD4

[No abstract]

Corticosteroids remain the first-line treatment for patients with immune thrombocytopenia (ITP). However, 20% to 30% of patients do not respond to treatment at tolerable doses. This variation in corticosteroid efficacy is replicated in other autoimmune diseases and may have an adaptive immune basis.To test the hypothesis that CD4In this prospective cohort study, CD4The ratio of interleukin (IL)-10 to IL-17 expression following CD4There is a relative abrogation of IL-10 and persistence of IL-17 expression in the CD4

The integrity of ocular anatomy and physiology, the function of the visual system, and the perception of vision, our most prized sense, are intimately connected with our general health. Subtle visual signs and symptoms may therefore be the first manifestation of occult systemic disease. With a basic history and examination of the eyes and vision, the physician can narrow the differential diagnosis and ascertain whether there is any immediate threat to vision or even life. The major focus of this chapter is the eye in the context of a range of vascular, haematological, neoplastic, inflammatory, endocrine, genetic, metabolic, toxic, and nutritional disorders. This chapter also considers the leading causes of blindness globally, and common ocular presentations in primary care and general medical practice. Other isolated ocular conditions are excluded and neuro-ophthalmological conditions are referred to elsewhere in this book (Chapters 24.6.1 and 24.6.2).

Background: Uveitis associated with juvenile idiopathic arthritis is a cause of major ocular morbidity. A substantial proportion of children are refractory to systemic methotrexate and TNF inhibitors. Our aim was to study the safety and efficacy of tocilizumab in children with juvenile idiopathic arthritis-associated uveitis refractory to both methotrexate and TNF inhibitors.Methods: This multicentre, single-arm, phase 2 trial was done following a Simon's two-stage design at seven tertiary hospital sites in the UK. Patients aged 2-18 years with active juvenile idiopathic arthritis-associated uveitis were eligible. All patients had been on a stable dose of methotrexate for at least 12 weeks and had not responded to treatment with a TNF inhibitor. Patients weighing 30 kg or more were treated with 162 mg subcutaneous tocilizumab every 2 weeks for 24 weeks, and participants weighing less than 30 kg were treated with 162 mg every 3 weeks for 24 weeks. The primary outcome was treatment response defined as a two-step decrease, or decrease to zero, from baseline in the level of inflammation (anterior chamber cells) at week 12, per the standardisation of uveitis nomenclature criteria. A phase 3 trial would be justified if more than seven patients responded to treatment. An interim analysis was planned to assess whether the trial would be stopped for futility, with futility defined as two or fewer treatment responses among ten participants. Adverse events were collected up to 30 calendar days after treatment cessation. The primary analysis was done in the intention-to-treat population and the safety analysis was done in all patients who started the treatment. This trial is registered with the International Standard Randomised Controlled Trial Number registry (ISRCTN95363507) and EU Clinical Trials Register (EudraCT 2015-001323-23).Findings: 22 participants were enrolled to the trial between Dec 3, 2015, and March 9, 2018, and 21 participants received treatment. One participant was found to be ineligible immediately after enrolment and was therefore withdrawn. Seven of 21 (median unbiased estimate of proportion 34% [95% CI 25-57]) responded to treatment (p=0·11). Safety results were consistent with the known safety profile of tocilizumab.Interpretation: The primary endpoint was not met, and thus the results do not support a phase 3 trial of tocilizumab in patients with juvenile idiopathic arthritis-associated uveitis. Importantly, data on the use of tocilizumab in clinical practice is now captured in national registries. Despite this trial not meeting the threshold required to justify a larger phase 3 trial, several patients responded to treatment; as such, tocilzumab might still be a therapeutic option in some children with uveitis refractory to anti-TNF drugs, given the absence of other treatment options.Funding: Versus Arthritis and the National Institute for Health Research Clinical Research Network: Children.

PURPOSE: To analyze the role of polymerase chain reaction (PCR) of ocular fluids in management of tubercular (TB) anterior, intermediate, posterior, and panuveitis. METHODS: In Collaborative Ocular Tuberculosis Study (COTS)-1 (25 centers, n = 962), patients with TB-related uveitis were included. 59 patients undergoing PCR of intraocular fluids (18 females; 53 Asian Indians) were included. RESULTS: 59 (6.13%) of COTS-1 underwent PCR analysis. PCR was positive for Mycobacterium TB in 33 patients (23 males; all Asian Indians). 26 patients were PCR negative (18 males). Eight patients with negative PCR had systemic TB. Anti-TB therapy was given in 18 negative and 31 PCR cases. At 1-year follow-up, five patients with positive PCR (15.15%) and three with negative PCR (11.54%) had persistence/worsening of inflammation. CONCLUSIONS: Data from COTS-1 suggest that PCR is not commonly done for diagnosing intraocular TB and positive/negative results may not influence management or treatment outcomes in the real world scenario.

PurposeThe aim of this study was to determine a sequence of structural changes in acute posterior multifocal placoid pigment epitheliopathy (APMPPE) using optical coherence tomography-angiography (OCT-A) and comparing with other imaging modalities.Patients and methodsPatients with a new diagnosis of acute-onset APMPPE referred to a regional specialist centre from October 2015 to October 2016 were included. Multimodal imaging employed on all patients from diagnosis included the following: fundus fluorescein angiography, indocyanine green angiography, fundus autofluorescence, spectral domain-OCT (SD-OCT), and OCT-A. All non-invasive imaging processes were repeated during follow-up.ResultsTen eyes of five patients were included in the study, three males and two females, with a mean age of 26.2 years (range: 21–32) and a mean follow-up of 6.4 months (range: 2.6–13.3). All patients presented with bilateral disease and macular involving lesions. OCT-A imaging of the choriocapillaris was supportive of hypoperfusion at the site of APMPPE lesions during the acute phase of this condition with normalisation of choroidal vasculature during follow-up. Multimodal imaging consistently highlighted four sequential phases from presentation to resolution of active disease.ConclusionsMultimodal imaging in patients with APMPPE in acute and long-term follow-up demonstrates a reversible choroidal hypoperfusion supporting the primary inciting pathology as a choriocapillaritis. The evolution shows resolution of the ischaemia through a defined sequence that results in persistent changes at the level of the retinal pigment epithelium and outer retina. OCT-A was able to detect preclinical changes and chart resolution at the level of the choriocapillaris.

Since lung cancer (LC) is still the leading cause of cancer deaths worldwide [1], early detection through screening represents an important opportunity to improve LC survival and is a priority area for cancer care. The National Lung Screening Trial (NLST) aimed to compare low-dose helical computed tomography (LDCT) with chest radiography in LC screening of current or former heavy smokers. The trial found a relative reduction in mortality from LC of 20% in those who had undergone LDCT screening. LC screening has regained prominence in the thoracic oncology literature with the completion of NELSON and other European trials, which support the role of LC screening in achieving early diagnosis and reducing mortality. A growing number of implementation pilots are providing an impetus towards organised, national programmes for LC screening, which are in need of long-term follow-up data such as those presented in this study., The extended follow-up of the NLST represents a timely and important update to the NLST data, alongside full results of the NELSON and the LUSI trials, as Europe begins to set out a vision for lung cancer screening. http://bit.ly/2MYXedI

Aim of the study was to examine extent, natural history, and clinical features associated with visual impairment (VI) in patients diagnosed with ocular tuberculosis (OTB) by the Collaborative Ocula...

The Collaborative Ocular Tuberculosis Study (COTS) Group sought to address the diagnostic uncertainty through retrospective cohort analysis of treatment regimens and therapeutic outcomes for patien...

An international, expert led consensus initiative was set up by the Collaborative Ocular Tuberculosis Study (COTS) group to develop systematic, evidence, and experience-based recommendations for the treatment of ocular TB using a modified Delphi technique process. In the first round of Delphi, the group identified clinical scenarios pertinent to ocular TB based on five clinical phenotypes (anterior uveitis, intermediate uveitis, choroiditis, retinal vasculitis, and panuveitis). Using an interactive online questionnaires, guided by background knowledge from published literature, 486 consensus statements for initiating ATT were generated and deliberated amongst 81 global uveitis experts. The median score of five was considered reaching consensus for initiating ATT. The median score of four was tabled for deliberation through Delphi round 2 in a face-to-face meeting. This report describes the methodology adopted and followed through the consensus process, which help elucidate the guidelines for initiating ATT in patients with choroidal TB.

Purpose: Tubercular intermediate uveitis (TIU) and panuveitis (TBP) are difficult to manage because of limitations in diagnostic tools and lack of evidence-based treatment guidelines. The Collabora...

Purpose: To standardize a nomenclature system for defining clinical phenotypes, and outcome measures for reporting clinical and research data in patients with ocular tuberculosis (OTB).Methods: Uveitis experts initially administered and further deliberated the survey in an open meeting to determine and propose the preferred nomenclature for terms related to the OTB, terms describing the clinical phenotypes and treatment and reporting outcomes.Results: The group of experts reached a consensus on terming uveitis attributable to tuberculosis (TB) as tubercular uveitis. The working group introduced a SUN-compatible nomenclature that also defines disease "remission" and "cure", both of which are relevant for reporting treatment outcomes.Conclusion: A consensus nomenclature system has been adopted by a large group of international uveitis experts for OTB. The working group recommends the use of standardized nomenclature to prevent ambiguity in communication and to achieve the goal of spreading awareness of this blinding uveitis entity.

It is not currently possible to reliably visualise and track immune cells in the human central nervous system or eye. Previous work demonstrated that indocyanine green (ICG) dye could label immune cells and be imaged after a delay during disease in the mouse retina. We report a pilot study investigating if ICG can similarly label immune cells within the human retina. Twelve adult participants receiving ICG angiography as part of routine standard of care were recruited. Baseline retinal images were obtained prior to ICG administration then repeated over a period ranging from 2 hours to 9 days. Matched peripheral blood samples were obtained to examine systemic immune cell labelling and activation from ICG by flow cytometry with human macrophage cultures as positive controls. Differences between the delayed near infrared ICG imaging and 488 nm autofluorescence was observed across pathologies, likely arising from the retinal pigment epithelium (RPE). Only one subject demonstrated ICG signal on peripheral blood myeloid cells and only three distinct cell-sized signals appeared over time within the retina of three participants. No significant increase in immune cell activation markers were detected after ICG administration. ICG accumulated in the endosomes of macrophage cultures and was detectable above a minimum concentration, suggesting cell labelling is possible. ICG can label RPE and may be used as an additional biomarker for RPE health across a range of retinal disorders. Standard clinical doses of intravenous ICG do not lead to robust immune cell labelling in human blood or retina and further optimisation in dose and route are required.

Graves orbitopathy, also known as thyroid eye disease or thyroid-associated orbitopathy, is visually disabling, cosmetically disfiguring and has a substantial negative impact on a patient’s quality of life. There is increasing awareness of the need for early diagnosis and rapid specialist input from endocrinologists and ophthalmologists. Glucocorticoids are the mainstay of treatment; however, recurrence occurs frequently once these are withdrawn. Furthermore, in >60% of cases, normal orbital anatomy is not restored, and skilled rehabilitative surgery is required. Clinical trials have shown that considerable benefit can be derived from the addition of antiproliferative agents (such as mycophenolate or azathioprine) in preventing deterioration after steroid cessation. In addition, targeted biologic therapies have shown promise, including teprotumumab, which reduces proptosis, rituximab (anti-CD20), which reduces inflammation, and tocilizumab, which potentially benefits both of these parameters. Other strategies such as orbital radiotherapy have had their widespread role in combination therapy called into question. The pathophysiology of Graves orbitopathy has also been revised with identification of new potential therapeutic targets. In this Review we provide an up-to-date overview of the field, outline the optimal management of Graves orbitopathy and summarize the research developments in this area to highlight future research questions and direct future clinical trials.

Background: Tuberculosis (TB) is a major infection that can affect the eye as first and sole presentation without features of systemic disease. Controversy exists regarding diagnosis and management of tubercular uveitis (TBU), further compounded by regional variations in disease expression. Purpose: Collaborative Ocular Tuberculosis Study (COTS)-1 aims to address knowledge deficits through collaboration amongst uveitis specialists across the globe by sharing the data of patients with TBU presented at participating centers from January 2004 to December 2014. Methods: Data collection was facilitated by a novel method of real-time encrypted web-based data entry allowing regular updates as new data and recommendations become available. Results: Information on clinical features, investigation findings, management, and treatment outcomes were reviewed to get an idea about real world scenario. Conclusion: The current review aims to focus on methodology and briefing of published reports from COTS group in COTS-1 study to highlight key messages from this large data.

In humans, the three main circulating monocyte subsets are defined by their relative cell surface expression of CD14 and CD16. They are all challenging to study because their characteristics are strongly context specific, and this has led to a range of conflicting reports about their function, which is especially so for CD14++CD16+ (intermediate) monocytes. Ex vivo cultures are also often confounded by the concomitant use of immunosuppressive drugs. We therefore sought to characterize the phenotype and function of intermediate monocytes in the setting of acute inflammation prior to treatment in a cohort of 41 patients with acute alcoholic hepatitis (AH). Circulating intermediate monocytes were enriched in patients with AH and had an activated phenotype with enhanced expression of CCR2 and CD206 compared with healthy controls. Proinflammatory cytokine expression, including IL-1β and IL-23, was also higher than in healthy controls, but both classical (CD14++CD16−) and intermediate monocytes in AH were refractory to TLR stimulation. Compared with healthy controls, both AH monocyte subsets had greater phagocytic capacity, enhanced ability to drive memory T cell proliferation in coculture, and skewed CD4+ T cells to express an increased ratio of IL-17/IFN-γ. Furthermore, liver tissue from AH patients demonstrated an enrichment of monocytes including the intermediate subset compared with controls. These data demonstrate that intermediate monocytes are expanded, functionally activated, induce CD4+ T cell IL-17 expression, and are enriched in the liver of patients with AH.

Introduction The NLST and NELSON studies demonstrated lung cancer mortality reduction from low-dose CT (LDCT) lung cancer screening. Local implementation pilots of ‘Lung Health Checks’ indicate feasibility in the NHS. NHS England will now fund 10 aligned projects for a national Lung Health Check pilot as a major centre-piece of the early diagnosis agenda of the NHS Long Term Plan. We report on methodological approaches to deliver this project and progress towards deployment. Methods Sites selected from Clinical Commissioning Groups in 10 Cancer Alliances had highest incidence and mortality from lung cancer, excluding those where screening pilots or research projects were already underway. Approximately 600,000 individuals will be invited with an expected 200,000 scans over the next four years, including baseline and 24 month incident round scanning. To support quality and governance, NHS England published a National Protocol (January 2019), are developing a Quality Assurance Framework, minimum dataset, Incidental Findings Protocol and Research Standard (assisted by CRUK). NHSE are supported by the CT Screening Advisory Committee, a sub-group of the Clinical Expert Group for Lung Cancer, NHSE. Cancer Alliances are being assisted in developing detailed delivery plans by the National Cancer Programme team. Results Detailed delivery plans have been provided by all regions. 47 radiologists will attend a national education program with clearly defined metrics for a national quality assurance training standard including volumetry and computer-aided detection. Standard participant materials are in production and QA evaluator appointed. Data on infrastructure readiness, progress against delivery milestones and final supporting documents relating to quality and governance will be presented. Conclusions The Lung Health Check program will be a major national flagship for respiratory medicine and a key component of the Long Term Plan aspirations to achieve early stage diagnosis in 75% of cancer cases. The program will inform the international literature on implementation of potentially revolutionary lung cancer screening but careful adherence to QA and demonstration of efficacy through appropriate evaluation is critical. Potential barriers include participant uptake; workforce capacity and data flow/information governance. The Standard Protocol is already being used by several European countries as a template for local protocol development. On behalf of the CT Screening Advisory Group, Clinical Expert Group for Lung Cancer and NHS England National Cancer Team.

Purpose: Macular edema (ME) is a leading cause of visual loss in a range of retinal diseases and despite the use of antivascular endothelial growth factor (anti-VEGF) agents, its successful treatment remains a major clinical challenge. Based on the indirect clinical evidence that interleukin-6 (IL-6) is a key additional candidate mediator of ME, we interrogated the effect of IL-6 on blood-retinal barrier (BRB) integrity in vitro.Methods: Human retinal pigment epithelial cell (ARPE-19) and human retinal microvascular endothelial cell (HRMEC) monolayers were used to mimic the outer and inner BRB, respectively. Their paracellular permeability was assessed by measuring the passive permeation of 40 kDa fluorescein isothiocyanate (FITC)-dextran across confluent cells in the presence of IL-6. Transendothelial/epithelial electrical resistance (TEER) then was measured and the distribution of the tight junction protein ZO-1 was assessed by immunofluorescence using confocal microscopy.Results: Treatment with IL-6 for 48 hours significantly increased the diffusion rate of FITC-dextran, decreased TEER, and disrupted the distribution of ZO-1 in ARPE-19 cells, which constitutively express the IL-6 transmembrane receptor, and this was reversed with IL-6R blockade. In contrast, IL-6 did not affect the paracellular permeability, TEER, or ZO-1 distribution in HRMECs.Conclusions: These in vitro data support the hypothesis that IL-6 reversibly disrupts the integrity of ARPE-19 cells, but it does not affect HRMECs.Translational Relevance: IL-6 is a candidate therapeutic target in the treatment of outer BRB driven ME.

The specific pathogenesis of idiopathic nephrotic syndrome (NS) is poorly understood, and the role of immune mediators remains contentious. However, there is good evidence for the role of a circulating factor, and we recently postulated circulating proteases as candidate factors. Immunosuppressive therapy with glucocorticoids (GCs) and T cell inhibitors are widely used in the clinical treatment of NS. Given that T helper (CD4+) cells expressing IL-17A (so-called Th17 cells) have recently been reported to be resistant to GC treatment, and GC resistance remains a major challenge in the management of NS, we hypothesized that Th17 cells produce a circulating factor that is capable of signaling to the podocyte and inducing deleterious phenotypic changes. To test this, we generated human Th17 cells from healthy volunteers and added the supernatants from these T cell cultures to conditionally immortalized human podocytes in vitro. This demonstrated that podocytes treated with Th17 cell culture supernatant, as well as with patient disease plasma, showed significant stimulation of JNK and p38 MAPK pathways and an increase in motility, which was blocked using a JNK inhibitor. We have previously shown that nephrotic plasma elicits a podocyte response via protease-activated receptor-1 (PAR-1). Stimulation of PAR-1 in podocytes elicited the same signaling response as Th17 cell culture supernatant treatment. Equally, protease inhibitors with Th17 cell culture treatment blocked the signaling response. This was not replicated by the reagents added to Th17 cell cultures or by IL-17A. Hence, we conclude that an undefined soluble mediator produced by Th17 cells mimics the deleterious effect of PAR-1 activation in vitro. Given the association between pathogenic subsets of Th17 cells and GC resistance, these observations have potential therapeutic relevance for patients with NS.

Purpose To investigate the comparative efficacy of bevacizumab (Avastin) and ranibizumab (Lucentis; both Genentech, Inc, South San Francisco, CA) for diabetic macular edema (DME) using a crossover study design. Design Randomized, double-masked, 36-week, 3-period crossover clinical trial. Participants Fifty-six subjects with DME involving the center of the macula in one or both eyes. Methods Monthly intravitreous injections of bevacizumab (1.25 mg) or ranibizumab (0.3 mg). Main Outcome Measures Comparison of mean changes in visual acuity and central retinal thickness, tested using a linear mixed-effects model. Results Based on the linear mixed-effects model, the 3-month estimated mean improvement in visual acuity was 5.3 letters for bevacizumab and 6.6 letters for ranibizumab (difference, 1.3 letters; P = 0.039). Estimated change in optical coherence tomography (OCT) central subfield mean thickness (CSMT) was −89 μm for bevacizumab and −137 μm for ranibizumab (difference, 48 μm; P Conclusions This trial demonstrated a statistically significant but small relative clinical benefit of ranibizumab compared with bevacizumab for treatment of DME, using a markedly reduced sample size relative to a full comparative efficacy study. The effects on visual acuity and central retinal thickness for the 2 drugs are consistent with those reported at 1 year for the concurrent parallel-group trial by the Diabetic Retinopathy Clinical Research Network testing bevacizumab, ranibizumab, and aflibercept for DME. The 3-period crossover design allowed for meaningful and efficient comparison, suggesting that this approach may be useful for future comparative efficacy studies of anti–vascular endothelial growth factor drugs for DME.

Highlights • The immediate morbidity from COVID-19 is high in UK thoracic cancer patients. • Mortality, hospitalisation and treatment interruption rates were high. • All patients who died were current or ex-smokers., Background UK COVID-19 mortality rates are amongst the highest globally. Controversy exists on the vulnerability of thoracic cancer patients. We describe the characteristics and sequelae of patients with thoracic cancer treated at a UK cancer centre infected with COVID-19. Methods Patients undergoing care for thoracic cancer diagnosed with COVID-19 (RT-PCR/radiology/clinically) between March-June 2020 were included. Data were extracted from patient records. Results Thirty-two patients were included: 14 (43%) diagnosed by RT-PCR, 18 (57%) by radiology and/or convincing symptoms. 88% had advanced thoracic malignancies. Eleven of 14 (79%) patients diagnosed by RT-PCR and 12 of 18 (56%) patients diagnosed by radiology/clinically were hospitalised, of which four (29%) and 2 (11%) patients required high-dependency/intensive care respectively. Three (21%) patients diagnosed by RT-PCR and 2 (11%) patients diagnosed by radiology/clinically required non-invasive ventilation; none were intubated. Complications included pneumonia and sepsis (43% and 14% respectively in patients diagnosed by RT-PCR; 17% and 11% respectively in patients diagnosed by radiology/clinically). In patients receiving active cancer treatment, therapy was delayed/ceased in 10/12 (83%) and 7/11 (64%) patients diagnosed by RT-PCR and radiology/clinically respectively. Nine (28%) patients died; all were smokers. Median time from symptom onset to death was 7 days (range 3–37). Conclusions The immediate morbidity from COVID-19 is high in thoracic cancer patients. Hospitalisation and treatment interruption rates were high. Improved risk-stratification models for UK cancer patients are urgently needed to guide safe cancer-care delivery without compromising efficacy.

BACKGROUND: Dynamic epigenetic alterations accompanying CD4+ T helper cell differentiation have been implicated in multiple autoimmune diseases. The bromodomain and extra-terminal (BET) proteins are epigenetic regulators that recognize and bind to acetylated histones in chromatin and are targets for pharmacological inhibition. In this study we tested a new BET inhibitor under clinical development, OTX015, to interrogate its effects on key CD4+ T cell subsets associated with autoimmunity.METHODS: Naïve and memory murine and human CD4+ T cells were isolated and differentiated into populations characterized by the expression of interferon (IFN)-γ and interleukin (IL)-17. Cultured cells were then exposed to varying concentrations of OTX015 in vitro, and its impact on cytokine expression was quantified by flow cytometry. In parallel, the expression of the transcription factors TBX21 and RORC was quantified by PCR. A previously studied BET inhibitor JQ1 was used as a pharmacological control.RESULTS: OTX015 suppressed both murine and human CD4+ T cell proliferation. Its impact on cytokine expression varied in murine and human naïve and memory subsets. OTX015 was similarly effective as JQ1 in the suppression of cytokines and T helper cell proliferation. Higher concentrations of OTX015 also had a greater impact on the viability of murine versus human cells. IL-17 and IFN-γ expression was not altered in murine memory CD4+ T cells, whereas in human memory CD4+ T cells, OTX015 inhibited IL-17, but not IFN-γ. Across all human T cell subsets OTX015 suppressed IL-17 more effectively than IFN-γ.CONCLUSION: Our studies demonstrate that OTX015 has anti-inflammatory effects by suppressing murine and human CD4+ T cell proliferation and subset-dependent proinflammatory cytokine expression, including the selective suppression of IL-17 in human memory CD4+ T cells.

Purpose To determine longer-term outcomes of participants enrolled from a single center in the SYCAMORE trial, a randomized placebo-controlled trial of adalimumab versus placebo in children with juvenile idiopathic arthritis-associated uveitis (JIA-U) uncontrolled on methotrexate. Design Retrospective interventional case series. Methods Medical records of all 28 SYCAMORE participants recruited at the Bristol Eye Hospital were reviewed at approximately 3-monthly intervals up to 5 years from the trial randomization date. Uveitis activity, treatment course, visual outcomes, ocular complications and adverse events were recorded. Data are presented using summary statistics. Results Following withdrawal of the investigational medicinal product (IMP), 25 of the 28 participants were started on adalimumab for active juvenile idiopathic arthritis-associated uveitis (JIA-U). Of the 12 participants in the active treatment arm of the SYCAMORE study, 11 (92%) were restarted on adalimumab after withdrawal of the IMP for active JIA-U (median time to flare 188 days (range 42-413)). Two participants stopped adalimumab for uncontrolled JIA-U. One participant had a reduction in vision to 0.3 due to cataract. Mean visual acuity for the remaining 27 participants was -0.04 (right eye) and -0.05 (left eye). Conclusions Drug-induced remission of JIA-U did not persist when adalimumab was withdrawn after 1-2 years treatment. Adalimumab was well tolerated and visual acuity outcomes were excellent.

Purpose: To contribute a global description of the spectrum of choroidal involvement in tubercular uveitis (TBU).Methods: Retrospective cohort study of TBU patients with choroidal involvement from ...

Background: Standard treatment for thyroid eye disease is with systemic corticosteroids. We aimed to establish whether orbital radiotherapy or antiproliferative immunosuppression would confer any additional benefit. Methods: CIRTED was a multicentre, double-blind, randomised controlled trial with a 2 × 2 factorial design done at six centres in the UK. Adults with active moderate-to-severe thyroid eye disease associated with proptosis or ocular motility restriction were recruited to the trial. Patients all received a 24 week course of oral prednisolone (80 mg per day, reduced to 20 mg per day by 6 weeks, 10 mg per day by 15 weeks, and 5 mg per day by 21 weeks) and were randomly assigned via remote computerised randomisation to receive either radiotherapy or sham radiotherapy and azathioprine or placebo in a 2 × 2 factorial design. Randomisation included minimisation to reduce baseline disparities in potential confounding variables between trial interventions. Patients and data analysts were masked to assignment, whereas trial coordinators (who monitored blood results), pharmacists, and radiographers were not. The radiotherapy dose was 20 Gy administered to the retrobulbar orbit in ten to 12 fractions over 2 to 3 weeks. Azathioprine treatment was provided for 48 weeks at 100–200 mg per day (dispensed as 50 mg tablets), depending on bodyweight (100 mg for interaction=0·86). The adjusted odds ratio (ORadj) for improvement in the binary clinical composite outcome measure was 2·56 (95% CI 0·98–6·66, p=0·054) for azathioprine and 0·89 (0·36–2·23, p=0·80) for radiotherapy. In a post-hoc analysis of patients who completed their allocated therapy the ORadj for improvement was 6·83 (1·66–28·1, p=0·008) for azathioprine and 1·32 (0·30–4·84, p=0·67) for radiotherapy. The ophthalmopathy index, clinical activity score, and numbers of adverse events (161 with azathioprine and 156 with radiotherapy) did not differ between treatment groups. In both groups, the most common adverse events were mild infections. No patients died during the study. Interpretation: In patients receiving oral prednisolone for 24 weeks, radiotherapy did not have added benefit. We also did not find added benefit for addition of azathioprine in the primary analysis; however, our conclusions are limited by the high number of patients who withdrew from treatment. Results of post-hoc analysis of those who completed the assigned treatment suggest improved clinical outcome at 48 weeks with azathioprine treatment. Funding: National Eye Research Centre, Above and Beyond, and Moorfields Eye Charity.

Purpose: To report a case of juxtafoveal choroidal neovascularization in a patient with candida chorioretinitis successfully treated with intravitreal bevacizumab. Methods: Case report. Results: A 45-year-old woman previously treated for candida chorioretinitis was presented with reduced vision in the left eye. The patient was investigated with ophthalmoscopy, fluorescein angiography, and optical coherence tomography (OCT). Following initial treatment, fundus examination, fluorescein angiography, and OCT of the right eye revealed a secondary juxtafoveal classic choroidal neovascularization. Following a single intravitreal injection of bevacizumab, the patient had excellent visual recovery, with absence of subretinal or intraretinal fluid in the OCT. Conclusions: Bevacizumab was effective in treatment of choroidal neovascularization associated with candida chorioretinitis.