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Glaucoma filtration surgery is one of the most effective methods for lowering intraocular pressure in glaucoma. The surgery efficiently reduces intra-ocular pressure but the most common cause of failure is scarring at the incision site. This occurs in the conjunctiva/Tenon's capsule layer overlying the scleral coat of the eye. Currently used antimetabolite treatments to prevent post-surgical scarring are non-selective and are associated with potentially blinding side effects. Developing new treatments to target scarring requires both a better understanding of wound healing and scarring in the conjunctiva, and new means of delivering anti-scarring drugs locally and sustainably. By combining plastic compression of collagen gels with a soft collagen-based layer, we have developed a physiologically relevant model of the sub-epithelial bulbar conjunctiva/Tenon's capsule interface, which allows a more holistic approach to the understanding of subconjunctival tissue behaviour and local drug delivery. The biomimetic tissue hosts both primary human conjunctival fibroblasts and an immune component in the form of macrophages, morphologically and structurally mimicking the mechanical proprieties and contraction kinetics of ex vivo porcine conjunctiva. We show that our model is suitable for the screening of drugs targeting scarring and/or inflammation, and amenable to the study of local drug delivery devices that can be inserted in between the two layers of the biomimetic. We propose that this multicellular-bilayer engineered tissue will be useful to study complex biological aspects of scarring and fibrosis, including the role of inflammation, with potentially significant implications for the management of scarring following glaucoma filtration surgery and other anterior ocular segment scarring conditions. Crucially, it uniquely allows the evaluation of new means of local drug delivery within a physiologically relevant tissue mimetic, mimicking intraoperative drug delivery in vivo.

On 21st January 2020, the FDA approved Tepezza (teprotumumab-trbw) for the treatment of active Graves' orbitopathy (GO) in adults. This approval was based on positive results from two multinational randomised double-blind placebo-controlled clinical trials. This article discusses the outcomes of those trials and the potential role of teprotumumab in altering current treatment paradigms in Graves' orbitopathy. Future challenges are explored, including the need to confirm its disease-modifying effect, to establish its optimal position in the treatment pathway, and to define the appropriate subset of patients who would benefit from its use. The results from these two large clinical trials have shown teprotumumab to have remarkable effects on multiple clinical outcomes in GO, particularly in its ability to reverse proptosis. It may herald a new era in the treatment of thyroid eye disease and could offer an alternative to surgery and its associated complications. Additional studies will continue to shape the treatment of GO and define the role of teprotumumab within the treatment paradigm.

Trachoma is a conjunctiva scarring disease, which is the leading infectious cause of blindness worldwide. Yet, the molecular mechanisms underlying progressive fibrosis in trachoma are unknown. To investigate the contribution of local resident fibroblasts to disease progression, we isolated conjunctival fibroblasts from patients with scarring trachoma and matching control individuals, and compared their gene expression profiles and functional properties in vitro. We show that scarring trachoma fibroblasts substantially differ from control counterparts, displaying pro-fibrotic and pro-inflammatory features matched by an altered gene expression profile. This pro-inflammatory signature was exemplified by increased IL-6 expression and secretion, and a stronger response to macrophage-mediated stimulation of contraction. We further demonstrate that scarring trachoma fibroblasts can promote Akt phosphorylation in macrophages in an IL-6 -dependent manner. Overall this work has uncovered a distinctive molecular fingerprint for scarring trachoma fibroblasts, and identified IL-6- as a potential contributor to the chronic conjunctival fibrosis, mediating reciprocal pro-fibrotic/pro-inflammatory interactions between macrophages and fibroblasts.

To test, in a two-arm, single center, superiority, randomized controlled trial, the effectiveness of and costs associated with a patient-initiated treatment model for people with hemifacial spasm (HFS) and blepharospasm (BEB) in comparison to usual care. One hundred and thirty patients with HFS or BEB, aged 18 years or over, were recruited from a nurse-led botulinum toxin type A clinic at an eye hospital in the United Kingdom (UK), completed baseline measures and were randomized (1:1). The intervention group determined their own botulinum toxin type A (BoNT/A) treatment schedule during the trial period (9 months) and received an information leaflet with a \"hotline\" number to book an appointment. Usual care appointments were scheduled by treating clinicians. Data analysts were blind to study group. The primary outcomes were disease severity and functional disability, as measured by the Jankovic Rating Scale and Blepharospasm Disability Index, respectively. Secondary outcomes included quality of life, anxiety and depression, satisfaction with care, confidence in the service, economic costs and employment days lost. Sixty-five patients were randomized to each group. The intervention demonstrated no statistically significant difference to usual care for any of primary outcomes. On secondary outcomes the levels of anxiety differed significantly (F  = 1.65, p = 0.02), with the intervention arm exhibiting a decrease and the control arm an increase (Hedges' g = - 0.26 [99% CI -0.83, 0.32]). No other statistically significant differences were found for secondary outcomes. Overall healthcare costs and costs to the patient were on average £198.95 less (95% CI -£256.76, £654.67; p = 0.10) per participant for those in the intervention compared to usual care, although this finding was not significant. We did not observe differences between the patient-initiated treatment model and usual care for people with BEB or HFS, on any primary outcome measure, quality of life, or depression. The patient-initiated treatment model may, however, have the potential to save healthcare costs and reduce anxiety. Patients using this new model were also equally as satisfied in the service and confident in their care as those receiving treatment as usual. Clinicaltrials.gov ID NCT02577224 , 16th October 2015.

Sebaceous gland carcinoma (SGC) is a rare, but life-threatening condition with a predilection for the periocular region. Eyelid SGC can be broadly categorised into two subtypes, namely either nodular or pagetoid with the latter being more aggressive and requiring radical excision to save life. We have identified key altered microRNAs (miRNA) involved in SGC shared by both subtypes, hsa-miR-34a-5p and hsa-miR-16-5p. However, their gene targets BCL2 and MYC were differentially expressed with both overexpressed in pagetoid but unchanged in nodular suggesting different modes of action of these two miRNAs on BCL/MYC expression. Hsa-miR-150p is nodular-specifically overexpressed, and its target ZEB1 was significantly downregulated in nodular SGC suggesting a tumour suppressor role. Invasive pagetoid subtype demonstrated specific overexpression of hsa-miR-205 and downregulation of hsa-miR-199a. Correspondingly, miRNA gene targets, EZH2 (by hsa-miR-205) and CD44 (by hsa-miR-199a), were both overexpressed in pagetoid SGC. CD44 has been identified as a potential cancer stem cell marker in head and neck squamous cell carcinoma and its overexpression in pagetoid cells represents a novel treatment target. Aberrant miRNAs and their gene targets have been identified in both SGC subtypes, paving the way for better molecular understanding of these tumours and identifying new treatment targets.

Graves' orbitopathy (GO) is a disfiguring and sometimes blinding disease, characterised by inflammation and swelling of orbital tissues, with fibrosis and adipogenesis being predominant features. Little is known about the disease aetiology and the molecular mechanisms driving the phenotypic changes in orbital fibroblasts are unknown. Using fibroblasts isolated from the orbital fat of undiseased individuals or GO patients, we have established a novel in vitro model to evaluate the dual profile of GO cells in a three-dimensional collagen matrix; this pseudo-physiological 3D environment allows measurement of their contractile and adipogenic properties. GO cells contracted collagen matrices more efficiently than control cells following serum or TGFβ1 stimulation, and showed a slightly increased ability to proliferate in the 3D matrix, in accordance with a fibro-proliferative phenotype. GO cells, unlike controls, also spontaneously differentiated into adipocytes in 3D cultures - confirming an intrinsic adipogenic profile. However, both control and GO cells underwent adipogenesis when cultured under pathological pressure levels. We further demonstrate that a Thy-1-low population of GO cells underlies the adipogenic - but not the contractile - phenotype and, using inhibitors, confirm that the contractile and adipogenic phenotypes are regulated by separate pathways. In view of the current lack of suitable treatment for GO, we propose that this new model testing the duality of the GO phenotype could be useful as a preclinical evaluation for the efficacy of potential treatments.

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.

In patients with thyroid-associated ophthalmopathy, responses to treatment are rare and usually minor. Teprotumumab, an antibody to the insulin-like growth factor I receptor, led to significant responses in 69% of patients and to decreased proptosis. Medical therapies for moderate-to-severe thyroid-associated ophthalmopathy (Graves’ orbitopathy) that have proved to be effective and safe in adequately powered, prospective, placebo-controlled trials are lacking. This unmet need is due to the incompletely understood pathogenesis of the disease. 1 Current treatments are inconsistently beneficial and often associated with side effects, and their modification of the ultimate disease outcome is uncertain. 1 – 3 Previous clinical trials, which were rarely placebo-controlled, suggest that high-dose glucocorticoids, alone 3 – 5 or with radiotherapy, 6 , 7 can reduce inflammation-related signs and symptoms in patients with active ophthalmopathy. However, glucocorticoids and orbital radiotherapy minimally affect proptosis and can cause dose-limiting adverse . . .

Background/AimsThe COVID-19 has facilitated a paradigm shift in the sphere of ophthalmic telemedicine: its utility is no longer limited to providing care to remote regions, rather it is expeditiously being adopted as the new standard of care. The aim of our paper is to explore the current attitudes of oculoplastic surgeons towards telemedicine and its utility in the present landscape and its prospects in the future.MethodsA 39-item questionnaire was distributed to consultant oculoplastic surgeons practising across the UK and anonymised responses were collected and analysed.ResultsThe COVID-19 pandemic has allowed rapid implementation of telemedicine services in oculoplastic departments across the UK with 86.6% of the respondents incorporating telemedicine into the routine clinical practice. Clinicians reported a statistically significant increase in utility of telemedicine, confidence in using telemedicine and quality of infrastructure available to employ telemedicine following the COVID-19 outbreak. The greatest utility of telemedicine is in triaging, postoperative assessment and eyelid lesion assessment. Main barriers to implementation of telemedicine included difficulties in conducting clinical examinations, lack of administrative support and poor access to digital technologies for patients. Overall, most clinicians were satisfied with the impact of telemedicine services and almost all experts foresee themselves continuing to use telemedicine in the future.ConclusionsTelemedicine has become an integral part of the oculoplastic service delivery since the COVID-19 pandemic its use is likely to continue. Further development of digital infrastructure and improvement of clinical examination capabilities are required to enable its wider adoption.

Graves' orbitopathy (GO) is an autoimmune inflammatory disease affecting the orbit. Orbital fibroblasts are a key component in GO pathogenesis, which includes inflammation, adipogenesis, hyaluronic acid (HA) secretion, and fibrosis. Macrophages are thought to participate in the immunological stage of GO, but whether they can directly affect the fibroblasts phenotype and modulate disease progression is unknown. We previously showed that GO adipogenic and fibrotic phenotypes could be modelled in a pseudo-physiological 3D environment in vitro. Here, we introduced macrophages in this 3D culture model to investigate role for macrophages in modulating adipogenesis, HA production, and contractility in orbital fibroblasts. Macrophages had a minimal effect on lipid droplet formation in fibroblasts, but significantly increased HA production and cell contractility, suggesting that they may promote the fibrotic phenotype. This effect was found to be mediated at least in part through phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) activation and linked to an increase in actin polymerization and protrusive activity in fibroblasts. Overall our work shows for the first time a direct role for macrophages in modulating the fibroblasts' phenotype in GO, supporting a role for macrophages in the progression of the fibrotic phenotype through induction of HA production and stimulation of the contractile phenotype in orbital fibroblasts.