Efficacy and safety of infliximab or adalimumab in severe mucocutaneous Behçet's syndrome refractory to traditional immunosuppressants: a 6-month, multicentre, randomised controlled, prospective, parallel group, single-blind trial.

INTRODUCTION: Evidence from randomised controlled trials on anti-tumour necrosis factor (TNF) agents in patients with Behçet's syndrome (BS) is low. METHOD: We conducted a phase 3, multicentre, prospective, randomised, active-controlled, parallel-group study to evaluate the efficacy and safety of either infliximab (IFX) or adalimumab (ADA) in patients with BS. Adults patients with BS presenting with active mucocutaneous manifestations, occurring while on therapy with either azathioprine or cyclosporine for at least 3 months prior to study entry, were eligible. Participants were randomly assigned (1:1) to receive IFX or ADA for 6 months. The primary study outcome was the time to response of manifestations over 6-month anti-TNF alpha agents' treatment. RESULTS: 42 patients underwent screening visits, of whom 40 were randomly assigned to the IFX group (n=22) or to the ADA group (n=18). All patients at the time of randomisation had active mucocutaneous manifestations and a smaller proportion had concomitant vital organ involvement (ie, six and three patients with ocular and neurological involvement, respectively). A total of 14 (64%) responders in the IFX group and 17 (94%) in the ADA group were observed. Retention on treatment was 95% and 94% in the IFX and in the ADA group, respectively. Quality of life resulted to be significantly improved in both groups from baseline, as well as Behçet's Disease Current Activity Form assessment. We registered two adverse events (one serious) in the ADA group and three non-serious adverse events in the IFX group. DISCUSSION: The overall results of this study confirm the effectiveness of both IFX and ADA in achieving remission in patients with BS affected by mucocutaneous involvement.

Long-term outcome of Graves' orbitopathy following treatment with sirolimus.

OBJECTIVES: Sirolimus was found to be associated with a better outcome of Graves' orbitopathy (GO) at 24 weeks compared to methylprednisolone. We conducted a retrospective study to investigate its efficacy and safety over a longer period. METHODS: Data from 40 consecutive patients with moderate-to-severe, active GO, 20 treated with sirolimus and 20 with methylprednisolone, were collected. PRIMARY OUTCOME: overall outcome (composite evaluation) of GO at 48 weeks. SECONDARY OUTCOMES: (1) GO outcome at 24 weeks, and, at 24 and 48 weeks: (2) outcome of single eye features; (3) quality of life (GO-QoL); (4) TSH-receptor antibodies; (5) GO relapse at 48 weeks; (6) adverse events. RESULTS: The overall GO outcome at 48 weeks did not differ between the two groups (responders: 55% vs 55%). At 24 weeks, prevalence of responders was greater in sirolimus group (65% vs 25%; P = 0.01). A reduction ≥ 1 point in clinical activity score (CAS) was more frequent in sirolimus patients at 24 (85% vs 40%; P = 0.005) and 48 weeks (75% vs 60%; P = 0.03). The proportion of GO-QoL responders (appearance subscale) at 24 weeks was greater in sirolimus group (62.5% vs 26.3%; P = 0.03). No difference was observed for the remaining outcome measures. CONCLUSIONS: Treatment with sirolimus is followed by a greater overall response of GO compared with methylprednisolone at 24 weeks, but not at 48 weeks, when only CAS is affected. A more prolonged period of treatment may be required for a better outcome to be observed over a longer period.

A deep learning approach to investigate the filtration bleb functionality after glaucoma surgery: a preliminary study.

PURPOSE: To distinguish functioning from failed filtration blebs (FBs) implementing a deep learning (DL) model on slit-lamp images. METHODS: Retrospective, cross-sectional, multicenter study for development and validation of an artificial intelligence classification algorithm. The dataset consisted of 119 post-trabeculectomy FB images of whom we were aware of the surgical outcome. The ground truth labels were annotated and images splitted into three outcome classes: complete (C) or qualified success (Q), and failure (F). Images were prepared implementing various data cleaning and data transformations techniques. A set of DL models were trained using different ResNet architectures as the backbone. Transfer and ensemble learning were then applied to obtain a final combined model. Accuracy, sensitivity, specificity, area under the ROC curve, and area under the precision-recall curve were calculated to evaluate the final model. Kappa coefficient and P value on the accuracy measure were used to prove the statistical significance level. RESULTS: The DL approach reached good results in unraveling FB functionality. Overall, the model accuracy reached a score of 74%, with a sensitivity of 74% and a specificity of 87%. The area under the ROC curve was 0.8, whereas the area under the precision-recall curve was 0.74. The P value was equal to 0.00307, and the Kappa coefficient was 0.58. CONCLUSIONS: All considered metrics supported that the final DL model was able to discriminate functioning from failed FBs, with good accuracy. This approach could support clinicians in the patients' management after glaucoma surgery in absence of adjunctive clinical data.

Thyroid Hormone Signaling in Retinal Development and Function: Implications for Diabetic Retinopathy and Age-Related Macular Degeneration.

Thyroid Hormones (THs) play a central role in the development, cell growth, differentiation, and metabolic homeostasis of neurosensory systems, including the retina. The coordinated activity of various components of TH signaling, such as TH receptors (THRs) and the TH processing enzymes deiodinases 2 and 3 (DIO2, DIO3), is required for proper retinal maturation and function of the adult photoreceptors, Müller glial cells, and pigmented epithelial cells. Alterations of TH homeostasis, as observed both in frank or subclinical thyroid disorders, have been associated with sight-threatening diseases leading to irreversible vision loss i.e., diabetic retinopathy (DR), and age-related macular degeneration (AMD). Although observational studies do not allow causal inference, emerging data from preclinical models suggest a possible correlation between TH signaling imbalance and the development of retina disease. In this review, we analyze the most important features of TH signaling relevant to retinal development and function and its possible implication in DR and AMD etiology. A better understanding of TH pathways in these pathological settings might help identify novel targets and therapeutic strategies for the prevention and management of retinal disease.

Managing the ocular surface after glaucoma filtration surgery: an orphan topic.

BACKGROUND: Ocular surface (OS) disorders before glaucoma filtration surgery (GFS) have been considered to play a crucial role influencing the surgical outcome. Conversely, the impact of surgery itself on the OS is almost completely overlooked, though evidence suggest that ocular surface disease (OSD) may be induced in patients by GFS. This review analyzes the determinants involved in the OSD development after GFS, the clinical features and related consequences, the main diagnostic hallmarks, as well as the therapeutic strategies for its management. METHODS: The PubMed database was utilized for the literature examination. Keywords that were searched included ocular surface disease, glaucoma filtration surgery, filtration bleb, post-surgical management, and quality of life. RESULTS: After GFS, OSD is promoted by peri- and post-operative factors, such as the filtration bleb (FB) development, combined surgical approach with phacoemulsification, the use of antifibrotic agents and the reintroduction of antiglaucoma medications. This particular form of OSD that present similar clinical features to mild to moderate dry eye, can be named as post-glaucoma surgery-OSD (PGS-OSD). PGS-OSD may negatively affect the FB functionality, thus potentially hindering the disease control, and significantly worsen the patient quality of life (QOL). CONCLUSIONS: Clinicians are encouraged to routinely include the OS evaluation after GFS and to consider proper management when the occurrence of PGS-OSD worsen the patient's QOL or exert negative effects to the FB functionality. An outline summarizing the main risk factors and the most appropriate therapeutic options to mitigate the PGS-OSD was proposed to support the routine practice.

One year in review 2021: systemic vasculitis.

Large- and small-vessel vasculitis are complex potentially life-threatening systemic autoimmune diseases that have recently been subjected to considerable immunologic and clinical research. Following the other reviews of this series, here we aim to summarise some of the most significant studies that have been recently published on the pathogenesis, clinical features and novel treatments of systemic vasculitis.

Beneficial effect of low-dose radioiodine ablation for Graves' orbitopathy: results of a retrospective study.

OBJECTIVE: Graves' orbitopathy (GO) reflects an autoimmune response against antigens expressed by the thyroid and orbital tissues. Elimination of thyroid antigens may be beneficial for GO. Total thyroid ablation (TTA) [thyroidectomy (Tx), followed by 30 mCi of radioiodine] was shown to exert a beneficial effect on GO following intravenous glucocorticoids (ivGC) compared with Tx alone. Here, we investigated retrospectively whether TTA performed with a 15 mCi of radioiodine still maintains advantages over Tx. METHODS: Thirty-two subjects, 13 treated with TTA (performed with 15 mCi of radioiodine) and 19 with Tx alone, all with moderately severe, active GO, treated with ivGC, were studied. The primary objective was the outcome of GO at 24 weeks based on a composite evaluation. RESULTS: The two groups did not differ at baseline in terms of sex, age, smoking habits, TSH, anti-TSH receptor autoantibodies, GO duration and eye features. The proportion of GO responders at 24 weeks was greater in the TTA (61.5%) than in the Tx group (26.3%, P = 0.046). In contrast, GO outcome at 48 weeks did not differ between the two groups (69.2% vs 52.6% of responder in TTA and Tx group, respectively). The outcome of the individual GO features did not differ between the two groups both a 24 and 48 months. CONCLUSIONS: The advantage of total thyroid ablation seems to be a more rapid response for GO to ivGC treatment. Prospective, randomized studies in a larger number of subjects are needed to confirm our findings.

Secondary epiretinal membrane after Ex-Press glaucoma filtration device implant.

PURPOSE: To estimate the frequency of epiretinal membrane (ERM) in eyes with primary open-angle glaucoma (POAG) treated with Ex-Press shunt implant. Secondarily, we aimed to assess the role of concomitant cataract surgery and the impact of the ERM on central foveal thickness and macular volume. METHODS: In this prospective, consecutive, case-control study, we enrolled 54 patients affected by PAOG and scheduled for Ex-Press device implant with or without contemporary phacoemulsification. Contralateral eyes affected by POAG and receiving anti-glaucomatous eyedrops constituted the control group. Complete ophthalmologic evaluation and spectral-domain optical coherence tomography (OCT) were performed before and 1, 3 and 6 months after surgery. RESULTS: Twenty-six eyes received the Ex-Press implant alone, and 28 eyes underwent the combined procedure. Six months postoperatively, we observed 18 (33%) cases of ERM: 15 (28%) of cellophane macular reflex (CMR) and 3 (6%) of pre-macular fibrosis (PMF). In the control group, 9 (17%) eyes developed an ERM: 8 (15%) were CMR, and 1 (2%) was PMF. The frequency of ERM statistically differs between treated and contralateral eyes (P = 0.032, χ2 test). The ERM frequency did not statically differ between eyes subjected to simple or combined surgery (P = 0.846, χ2 test). Mean central foveal thickness and mean macular volume did not significantly differ between groups. CONCLUSION: The Ex-Press glaucoma shunt may increase the risk of ERM onset regardless of the concomitant cataract surgery; however, most cases were cellophane macular reflex with limited functional and anatomical impact.

Behçet's syndrome and ocular involvement: changes over time.

Ocular involvement in Behçet's syndrome still represents a challenge for both rheumatologists and ophthalmologists; over the past 20 years the availability of new diagnostic tools and the concomitant introduction of biologic drugs led to a significant improvement in the management of these patients. The lack of uniform definitions and the diversity of the outcome measures still represent an obstacle for the prompt and correct management of ocular manifestations. The aim of the present review is to summarise the current evidences related to correct diagnosis and proper management of patients with Behçet's syndrome and ocular involvement.

One year in review 2020: vasculitis.

Systemic vasculitides are a group of diseases that could potentially affect any organ with heterogeneous clinical manifestations that usually depend on the size of the most involved vessels. These diseases could be associated with a relevant burden of mortality and morbidity if not early recognised and treated. Moreover, even if they are usually rare diseases, their incidence and prevalence seem to be increasing in the last decade, partially because of improved awareness and management of vasculitis from physicians. Like in the previous annual reviews of this series, in this paper we revised the most recent literature on pathogenesis, clinical manifestations and treatment options in small- and large-vessel vasculitis.

Aqueous humour concentrations after topical apPlication of combinEd levofloxacin-dexamethasone eye dRops and of its single components: a randoMised, assEssor-blinded, parallel-group study in patients undergoing cataract surgery: the iPERME study.

PURPOSE: To evaluate the penetration of levofloxacin and dexamethasone sodium phosphate into the aqueous humour (AH) after administration in combination and as single molecules. Evaluation of the penetration of those agents in the site of action and their pharmacodynamic potential activity in view of the intended clinical use after cataract surgery. METHODS: Randomised, assessor-blinded, parallel-group. Patients scheduled for cataract surgery were assigned in a 1:1:1 ratio to: levofloxacin + dexamethasone sodium phosphate (L-DSP), Levofloxacin (L) or Dexamethasone sodium phosphate (DSP) eye drops. Either test or reference drugs were instilled in the cul-de-sac twice, 90 and 60 min before paracentesis. RESULTS: A total of 125 patients completed the study. Fraction of dose absorbed in the anterior chamber was 3.8-4.2 · 10-4 for levofloxacin and 0.3-0.4 · 10-4 for dexamethasone, respectively. No notable differences in concentration of levofloxacin were found between L-DSP arm (1.970 nmol/ml) and L arm (2.151 nmol/ml). The concentrations of levofloxacin were well above the MICs for the most frequent Gram-positive and Gram-negative eye pathogens. Dexamethasone concentrations were slightly lower in L-DSP arm (0.030 nmol/ml) than in DSP arm (0.042 nmol/ml), but still in the pharmacodynamically active range in the site of action. The difference was not clinically relevant. DSP was not detected in any HA sample, suggesting its full hydrolysis to free dexamethasone. CONCLUSION: Our results confirm that no interaction is evident on the corneal penetration of levofloxacin and dexamethasone which reach pharmacologically active concentrations when instilled as fixed combination eye drops to patients undergoing cataract surgery. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03740659.

Pachychoroid neovasculopathy: a type-1 choroidal neovascularization belonging to the pachychoroid spectrum-pathogenesis, imaging and available treatment options.

PURPOSE: The purpose of this paper is to provide a meaningful literature review about the epidemiology, pathogenesis, imaging and treatment of pachychoroid neovasculopathy (PNV). METHODS: A computerized search from inception up to December 2019 of the online electronic database PubMed was performed using the following search string: "pachychoroid neovasculopathy". The reference list in each article was scanned for additional relevant publications. RESULTS: PNV is a type-1 choroidal neovascularization, overlying focal areas of choroidal thickening and dilated choroidal vessels. It can develop in patients affected by pachychoroid pigment epitheliopathy or chronic central serous chorioretinopathy. The absence of drusen, the presence of pachydrusen, younger age of onset and choroidal thickening distinguish it from neovascular age-related macular degeneration (AMD). PNV incidence and prevalence data are lacking. Its pathophysiology is not fully understood, but angiogenic mechanisms involved in neovascular AMD may be different from those in PNV. Due to optical coherence tomography (OCT) improvements, PNV can be diagnosed more easily than before. In particular, PNV shows a shallow pigment epithelium detachment with an undulating retinal pigment epithelium over a subfoveal choroidal thickening, associated with vein enlargement in Haller's layer (named pachyvessels) and choriocapillaris thinning. On OCT angiography, PNV reveals tangled hyper-reflective filamentous neovessels in the choriocapillaris itself. The current first-line PNV treatment is intravitreal anti-VEGF (vascular endothelial growth factor) injections with a treat-and-extend regimen. In particular, aflibercept shows a higher rate of fluid absorption than others. In the case of fluid recurrence or persistence, photodynamic therapy is a valid alternative. CONCLUSION: Ongoing research into pathophysiology and imaging improvements may be helpful in defining prognostic criteria and stratifying patient risk, allowing responsible monitoring and management of PNV.

Changes in visual function and ocular morphology in women who have undergone ART treatment and children born as a result of ART treatment: a systematic review.

As all the structures of the human eye are characterized by sex hormone receptors, this study tested the hypothesis that assisted reproductive technology (ART) treatment influences visual function and ocular morphology in women who have undergone ART treatment and children born as a result of ART treatment. A systematic literature search of all original articles published up to August 2018 was performed using the PubMed database, including all original studies available in the literature. Review articles, studies in which participants underwent mixed interventions (i.e. other than ART treatment), studies reporting data on ocular malformations in ART offspring, and studies written in languages other than English were excluded. All selected articles were analysed to assess the level of evidence according to the Oxford Centre for Evidence-Based Medicine 2011 guidelines, and the quality of evidence according to the Grading of Recommendations Assessment, Development and Evaluation system. Although sparse data suggest that ART treatment can influence visual function and ocular morphology in women who have undergone ART treatment and children born as a result of ART treatment, the available evidence is inconclusive given its low level and quality. More high-quality research is needed to assess the potential interaction between ART treatment and the eye.

One year in review 2019: vasculitis.

Systemic vasculitis are disabling complex disorders potentially involving any organ and system. Tremendous efforts have been made recently in this field with novel insights into pathogenesis and new therapy in the pipeline. Following the previous annual reviews of this one year in review series, in this paper we provide a critical digest of the most recent literature regarding pathogenesis, clinical manifestations and therapy, with the ultimate aim of addressing whether the existing data may open new avenues for precision medicine in these disorders.

Effect of Resveratrol on In Vitro and In Vivo Models of Diabetic Retinophathy: A Systematic Review.

A large number of preclinical studies suggest the involvement of resveratrol in the prevention and treatment of eye diseases induced by oxidative stress and inflammation. We tested the hypothesis that resveratrol influences many pathways of in vitro and in vivo models of diabetic retinopathy through a systematic literature review of original articles. The review was conducted in accordance with the PRISMA guidelines. A literature search of all original articles published until April 2019 was performed. The terms "resveratrol" in combination with "retina", "retinal pathology", "diabetic retinopathy" and "eye" were searched. Possible biases were identified with the adopted SYRCLE's tool. Eighteen articles met inclusion/exclusion criteria for full-text review. Eleven of them included in vitro experiments, 11 studies reported in vivo data and 3 studies described both in vitro and in vivo experiments. Most of the in vivo studies did not include data that would allow exclusion of bias risks, according to SYRCLE's risk of bias tool. Both in vitro and in vivo data suggest anti-apoptotic, anti-inflammatory and anti-oxidative actions of resveratrol in models of diabetic retinopathy. However, results on its anti-angiogenic effects are contradictory and need more rigorous studies.

Macular spectral-domain optical coherence tomography values and correlations in healthy children.

PURPOSE: The aim of this study is to investigate potential correlations between age, gender, spherical equivalent and optical coherence tomography (OCT) retinal parameters among healthy children. METHODS: A macular spectral-domain OCT was performed in all patients using a Spectralis® OCT device, and the macular thickness and volume of each of the early treatment diabetic retinopathy study (ETDRS) subfields were analysed. RESULTS: Ninety-four children were enrolled. Mean central macular thickness was 274.968 ± 18.28 µm, while mean central macular volume was 0.216 mm3. Statistical analysis showed a significant correlation between the factor age and central macular thickness (F(3,90) = 4.96, p = 0.003, η2 = 0.14) and central macular volume (F(3,90) = 4.98, p = 0.003, η2 = 0.14). Statistical analysis showed a significant correlation between the factor gender and macular thickness/volume of several ETDRS subfields. A significant correlation between refractive error and macular thickness/volume was also noted. CONCLUSIONS: This study shows significant correlations between macular thickness/volume and the factors age, gender and spherical equivalent. Paediatric spectral-domain optical coherence tomography ranges need further investigations since many significant correlations are still to be confirmed.

One year in review 2018: systemic vasculitis.

Systemic vasculitis are heterogeneous, complex and disabling disorders. Following the previous annual reviews of this series, this paper gives a brief overview on current knowledge about recent literature on small- and large-vessel systemic vasculitis, with a specific focus on pathogenetic and clinical aspects, novel possible disease-related biomarkers and current and future therapies that are in the pipeline.

A pilot study on Langerhans cells in keratoconus patients by in vivo confocal microscopy before and after corneal cross-linking and correlation with eye rubbing.

PURPOSE: The aim of this study was to investigate the corneal microstructure and Langerhans cells using in vivo confocal microscopy in keratoconus patients before and after cross-linking, and to correlate the morphologic findings with clinical and patient-reported outcomes, including eye rubbing (ER) behavior. METHODS: Patients with progressive keratoconus undergoing iontophoresis-assisted epithelium-on cross-linking (I-CXL) were consecutively enrolled. In vivo confocal microscopy was performed before and 6 months after treatment. Patients were asked to quantify their ER behavior on a Visual Analogue Scale (VAS) and completed the Keratoconus Outcomes Research Questionnaire and the Ocular Surface Disease Index questionnaires at the same time points. Visual acuity, tear osmolarity, topography, aberrometry, and pachymetry of both eyes were assessed. RESULTS: Thirteen patients were included in this pilot study. Preoperatively, the mean Langerhans cells density was 35,615 cells per mm2, and the median morphology was 3. The mean ER VAS before treatment was 7,077 out of 10. The ER VAS showed significant positive correlations with both Langerhans cells density and morphology of the study eye. After treatment, a statistically significant reduction in ER VAS and in Langerhans cells variables was observed. The mean sub-basal plexus nerve density was comparable to pre-operative values 6 months after I-CXL. CONCLUSIONS: Based on this preliminary evidence, the presence of high density of mature Langerhans cells in the central cornea of keratoconus patients and its correlation with eye rubbing support the role of inflammation in keratoconus. The reduction in these markers after treatment may suggest a potential of CXL in moderating immune-related inflammation and eye rubbing in the medium term.