Real-world management of treatment-naïve diabetic macular oedema : 2-year visual outcome focusing on the starting year of intervention from STREAT-DMO study

Background/aims To investigate the yearly change of real-world outcomes for best corrected visual acuity (BCVA) after 2-year clinical intervention for treatment-naïve diabetic macular oedema (DMO). Methods Retrospective analysis of aggregated, longitudinal medical records obtained from 27 retina specialised institutions in Japan from Survey of Treatment for DMO database. A total of 2049 treatment-naïve centre involving DMO eyes of which the initial intervention started between 2010 and 2015, and had been followed for 2 years, were eligible. As interventions, antivascular endothelial growth factor (VEGF) agents, local corticosteroids, macular photocoagulation and vitrectomy were defined. In each eye, baseline and final BCVA, the number of each intervention for 2 years was extracted. Each eye was classified by starting year of interventional treatment. Results Although baseline BCVA did not change by year, 2-year improvement of BCVA had been increased, and reached to +6.5 letters in the latest term. There is little difference among starting year about proportions of eyes which BCVA gained >15 letters, in contrast to those which lost >15 letters were decreased by year. The proportion of eyes receiving anti-VEGF therapy was dramatically increased, while those receiving the other therapies were gradually decreased. The proportion of eyes which maintained socially good vision of BCVA>20/40 has been increased and reached to 59.0% in the latest term. Conclusion For recent years, treatment patterns for DMO have been gradually but certainly changed; as a result, better visual gain, suppression of worsened eyes and better final BCVA have been obtained. Anti-VEGF therapy has become the first-line therapy and its injection frequency has been increasing

Real-world management of treatment-naïve diabetic macular oedema in Japan : two-year visual outcomes with and without anti-VEGF therapy in the STREAT-DME study

Background/Aims To investigate real-world outcomes for best-corrected visual acuity (BCVA) after 2-year clinical intervention for treatment-naïve, centr-involving diabetic macular oedema (DME). Methods Retrospective analysis of longitudinal medical records obtained from 27 institutions specialising in retinal diseases in Japan. A total of 2049 eyes with treatment-naïve DME commencing intervention between 2010 and 2015 who were followed for 2 years were eligible. Interventions for DME included anti-vascular endothelial growth factor (VEGF) therapy, local corticosteroid therapy, macular photocoagulation and vitrectomy. Baseline and final BCVA (logMAR) were assessed. Eyes were classified by the treatment pattern, depending on whether anti-VEGF therapy was used, into an anti-VEGF monotherapy group (group A), a combination therapy group (group B) and a group without anti-VEGF therapy (group C). Results The mean 2-year improvement of BCVA was −0.04±0.40 and final BCVA of >20/40 was obtained in 46.3% of eyes. Based on the treatment pattern, there were 427 eyes (20.9%) in group A, 807 eyes (39.4%) in group B and 815 eyes (39.8%) in group C. Mean improvement of BCVA was −0.09±0.39, –0.02±0.40 and −0.05±0.39, and the percentage of eyes with final BCVA of >20/40 was 49.4%, 38.9%, and 52.0%, respectively. Conclusion Following 2-year real-world management of treatment-naïve DME in Japan, BCVA improved by 2 letters. Eyes treated by anti-VEGF monotherapy showed a better visual prognosis than eyes receiving combination therapy. Despite treatment for DME being selected by specialists in consideration of medical and social factors, a satisfactory visual prognosis was not obtained, but final BCVA remained >20/40 in half of all eyes

Ocular surface inflammation impairs structure and function of meibomian gland

Dysfunction of the meibomian glands alters secreted meibum quantitatively and qualitatively that can lead to damage to the ocular surface epithelium. In response to an unstable tear film cause by meibomian gland dysfunction, ocular surface epithelium is damaged and expresses inflammatory cytokines leading to secondary ocular inflammation. In turn, inflammatory disorders of the palpebral conjunctiva and lid margin may affect the structure and function of meibomian gland. The disorders include allergic conjunctivitis, long-term usage of contact lenses, dermatological diseases that affect conjunctival homeostasis, Stevens-Johnson's syndrome or chemical burning of the ocular surface and lid margin

Ocular surface alkali injury damages meibomian glands in mice

PurposeTo examine effects of alkali injury of the ocular surface on meibomian gland pathology in mice.MethodsThree μL of 1 N NaOH were applied under general anesthesia to the right eye of 10-week-old BALB/c (n = 54) mice to produce a total ocular surface alkali burn. The meibomian gland morphology was examined at days 1, 2, 5, 10, and 20 by stereomicroscopy and non-contact infrared meibography. Mice were then sacrificed and eyelids processed for histology with hematoxylin-eosin and immunohistochemistry for ELOVL4, PPARγ, myeloperoxidase (a neutrophil marker) and F4/80 macrophage antigen, as well as TUNEL staining. Another set of specimens was processed for cryosectioning and Oil red O staining.ResultsAlkali injury to the ocular surface produced cellular apoptosis, infiltration of neutrophils and macrophages, degeneration of the meibomian gland, and ductal dilation. Inflammation in and destruction of acunal stricture seemed more prominent in the lower eyelid, while duct dilation was more frequently observed in the upper eyelid during healing. Surviving acinar cells were labeled for ELOVL4 and PPARγ. Oil red O staining showed that the substance in the dilated duct contained predominantly neutral lipid.ConclusionsAlkali injury to the ocular surface results in damage and destruction of the eyelid meibomian glands. The pattern of the tissue damage differs between glands of the upper and lower eyelids

Loss of TRPV4 Function Suppresses Inflammatory Fibrosis Induced by Alkali-Burning Mouse Corneas

<div><p>In humans suffering from pulmonary disease and a mouse model, transient receptor potential vanilloid 4 (TRPV4) channel activation contributes to fibrosis. As a corneal alkali burn induces the same response, we determined if such an effect is also attributable to TRPV4 activation in mice. Accordingly, we determined if the alkali burn wound healing responses in wild-type (WT) mice are different than those in their TRPV4-null (KO) counterpart. Stromal opacification due to fibrosis in KO (n = 128) mice was markedly reduced after 20 days relative to that in WT (n = 157) mice. Immunohistochemistry revealed that increases in polymorphonuclear leukocytes and macrophage infiltration declined in KO mice. Semi-quantitative real time RT-PCR of ocular KO fibroblast cultures identified increases in proinflammatory and monocyte chemoattractant protein-1 chemoattractant gene expression after injury. Biomarker gene expression of fibrosis, collagen1a1 and α-smooth muscle actin were attenuated along with macrophage release of interleukin-6 whereas transforming growth factor β, release was unchanged. Tail vein reciprocal bone marrow transplantation between WT and KO chimera mouse models mice showed that reduced scarring and inflammation in KO mice are due to loss of TRPV4 expression on both corneal resident immune cells, fibroblasts and infiltrating polymorphonuclear leukocytes and macrophages. Intraperitoneal TRPV4 receptor antagonist injection of HC-067047 (10 mg/kg, daily) into WT mice reproduced the KO-phenotype. Taken together, alkali-induced TRPV4 activation contributes to inducing fibrosis and inflammation since corneal transparency recovery was markedly improved in KO mice.</p></div

Effects of loss of TRPV4 function on TGFβ1 and IL-6 expression in ocular fibroblasts.

<p><b>Comparison of effects of TGFβ1 on VEGF and αSMA expression in WT and TRPV4 KO ocular fibroblasts. A:</b> Loss of TRPV4 gene function does not reduce TGFβ 1 since its levels were the same irrespective of the presence or absence of TRPV4 mRNA expression. <b>B:</b> Loss of TRPV4 gene function reduces IL-6 gene expression. <b>C.</b> Exogenous TGFβ1 increases VEGF mRNA expression levels that are dependent on TRPV4 gene expression. In loss of TRPV4 function fibroblasts, TGFβ1 fails to increase VEGF gene expression. <b>D:</b> Exogenous TGFβ1 induces increases in αSMA expression irrespective of the presence or absence of TRPV4 gene expression. TGFβ1 induced rises were larger in WT ocular fibroblasts than in their TRPV4 KO counterpart. mean ± SEM *<i>P</i> < 0.05, Scale bar = 100 μm.</p

TRPV4 antagonist (HC-067047) injection attenuates corneal inflammatory fibrosis induced by alkali burn in wild-type (WT) mice.

<p><b>A.</b> The corneas of WT mice treated with or without HC-030031 at 5, 10 or 20 days. Corneal transparency restoration is markedly improved in the mice treated with a TRPV4 antagonist HC-067047 at each time point. <b>B.</b> Eyeball diameter during wound healing after alkali burn shows untreated globes are smaller at 20 days than antagonist treated globes. <b>C and D.</b> Histology of burned corneas stained with HE and immunohistochemical stained at day 10 (C) and 20 (D). The stromal organization is more disorganized in untreated mice cornea than in antagonist treated mice. The antagonist treated mice cornea has lower levels of infiltration of MPO-labeled neutrophils and F4/80-positive macrophages as well as less marked αSMA staining at each time point. Scale bar is 100 μm.</p

Dependence of fibrogenic gene expression on gain of TRPV4 function in peritoneal macrophages.

<p><b>A:</b> Real-time RT-PCR showed that mRNA of MCP-1 was markedly suppressed by TRPV4 gene ablation. <b>B.</b> Difference in IL-6 gene expression between that in WT fibroblasts and TRPV4 KO macrophage was insignificant <b>C.</b> Difference in TGFβ1 gene expression between that in WT macrophage and TRPV4 KO macrophage was insignificant. <b>D:</b> Difference in VEGF gene expression between that in WT macrophage and TRPV4 KO macrophage were insignificant.</p

Identical histology of the wild type (WT) and TRPV4 knockout (KO) mouse corneas.

<p>There are no discernible differences in the corneal histology of WT <b>(A)</b> and <b>(B)</b> KO based on a comparison of hematoxylin-eosin (HE) staining patterns. Scale bar = 100 μm.</p

Expression of transient receptor potential vanilloid 4 (TRPV4) in corneas of wild type mice.

<p><b>A:</b> TRPV4 expression is more preponderant in the basal epithelial cell layer (arrowheads) in the intact mouse cornea (arrowheads) with some indication of expression in the suprabasal layers. However, there is no indication of its presence in the top tear-side layer. <b>B:</b> Stromal fibroblasts undergo TRPV4 upregulation during healing at day 10 post-alkali burn in (asterisk). Scale bar = 100 μm.</p