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Age-related macular degeneration (AMD), a degenerative disease in the central macula area of the neuroretina and the supporting retinal pigment epithelium, is the most common cause of vision loss in the elderly. Although advances have been made, treatment to prevent the progressive degeneration is lacking. Besides the association of innate immune pathway genes with AMD susceptibility, environmental stress- and cellular senescence-induced alterations in pathways such as metabolic functions and inflammatory responses are also implicated in the pathophysiology of AMD. Cellular senescence is an adaptive cell process in response to noxious stimuli in both mitotic and postmitotic cells, activated by tumor suppressor proteins and prosecuted via an inflammatory secretome. In addition to physiological roles in embryogenesis and tissue regeneration, cellular senescence is augmented with age and contributes to a variety of age-related chronic conditions. Accumulation of senescent cells accompanied by an impairment in the immune-mediated elimination mechanisms results in increased frequency of senescent cells, termed “chronic” senescence. Age-associated senescent cells exhibit abnormal metabolism, increased generation of reactive oxygen species, and a heightened senescence-associated secretory phenotype that nurture a proinflammatory milieu detrimental to neighboring cells. Senescent changes in various retinal and choroidal tissue cells including the retinal pigment epithelium, microglia, neurons, and endothelial cells, contemporaneous with systemic immune aging in both innate and adaptive cells, have emerged as important contributors to the onset and development of AMD. The repertoire of senotherapeutic strategies such as senolytics, senomorphics, cell cycle regulation, and restoring cell homeostasis targeted both at tissue and systemic levels is expanding with the potential to treat a spectrum of age-related diseases, including AMD.

Age-related macular degeneration (AMD) is the most common cause of blindness among the elderly in the developed world. While treatment is effective for the neovascular or “wet” form of AMD, no therapy is successful for the non-neovascular or “dry” form. Here we discuss the current knowledge on dry AMD pathobiology and propose future research directions that would expedite the development of new treatments. In our view, these should emphasize system biology approaches that integrate omic, pharmacological, and clinical data into mathematical models that can predict disease onset and progression, identify biomarkers, establish disease causing mechanisms, and monitor response to therapy. No effective therapies exist for dry age-related macular degeneration. In this perspective, the authors propose that research should emphasize system biology approaches that integrate various ‘omics’ data into mathematical models to establish pathogenic mechanisms on which to design novel treatments, and identify biomarkers that predict disease progression and therapeutic response.

In a randomized trial, children with uveitis associated with juvenile idiopathic arthritis who were taking a stable dose of methotrexate were significantly less likely to have treatment failure but more likely to have adverse events with adalimumab than with placebo. Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease in children. Children with JIA are at risk for inflammation of the uvea (uveitis). Uveitis develops in approximately 12 to 38% of patients with JIA within 7 years after the onset of arthritis. 1 , 2 Despite current screening and therapeutic options, visual impairment in both eyes may develop in up to 15% of children with JIA-associated uveitis, and they may be certified as legally blind. 3 , 4 Experimental models of autoimmune uveitis have shown that tumor necrosis factor α (TNF-α) plays a pivotal role in the pathogenesis, 5 findings that have been borne . . .

Non-infectious uveitis is a potentially sight-threatening ocular disorder caused by chronic inflammation and its complications. Therapeutic success is limited by systemic adverse effects associated with long-term corticosteroid and immunomodulator use if topical medication is not sufficient to control the inflammation. We aimed to assess the efficacy and safety of adalimumab in patients with inactive, non-infectious uveitis controlled by systemic corticosteroids. We did this multicentre, double-masked, randomised, placebo-controlled phase 3 trial at 62 study sites in 21 countries in the USA, Canada, Europe, Israel, Australia, and Latin America. Patients (aged ≥18 years) with inactive, non-infectious intermediate, posterior, or panuveitic uveitis controlled by 10–35 mg/day of prednisone were randomly assigned (1:1), via an interactive voice and web response system with a block size of four, to receive either subcutaneous adalimumab (loading dose 80 mg; biweekly dose 40 mg) or placebo, with a mandatory prednisone taper from week 2. Randomisation was stratified by baseline immunosuppressant treatment. Sponsor personnel with direct oversight of the conduct and management of the study, investigators, study site personnel, and patients were masked to treatment allocation. The primary efficacy endpoint was time to treatment failure, a multicomponent endpoint encompassing new active inflammatory chorioretinal or inflammatory retinal vascular lesions, anterior chamber cell grade, vitreous haze grade, and visual acuity. Analysis was done in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01124838. Between Aug 10, 2010, and May 14, 2015, we randomly assigned 229 patients to receive placebo (n=114) or adalimumab (n=115); 226 patients comprised the intention-to-treat population. Median follow-up time was 155 days (IQR 77–357) in the placebo group and 245 days (119–564) in the adalimumab group. Treatment failure occurred in 61 (55%) of 111 patients in the placebo group compared with 45 (39%) of 115 patients in the adalimumab group. Time to treatment failure was significantly improved in the adalimumab group compared with the placebo group (median not estimated [>18 months] vs 8·3 months; hazard ratio 0·57, 95% CI 0·39–0·84; p=0·004). The 40th percentile for time to treatment failure was 4·8 months in the placebo group and 10·2 months in the adalimumab group. No patients in either group had opportunistic infections (excluding oral candidiasis and tuberculosis). No malignancies were reported in the placebo group whereas one (1%) patient in the adalimumab group reported non-serious squamous cell carcinoma. The most common adverse events were arthralgia (12 [11%] patients in the placebo group and 27 [23%] patients in the adalimumab group), nasopharyngitis (16 [17%] and eight [16%] patients, respectively), and headache (17 [15%] patients in each group). Adalimumab significantly lowered the risk of uveitic flare or loss of visual acuity upon corticosteroid withdrawal in patients with inactive, non-infectious intermediate, posterior, or panuveitic uveitis controlled by systemic corticosteroids. No new safety signals were observed and the rate of adverse events was similar between groups. These findings suggest that adalimumab is well tolerated and could be an effective treatment option in this patient population. An open-label extension study (NCT01148225) is ongoing to provide long-term safety data for adalimumab in patients with non-infectious uveitis. AbbVie.

Concepts of how the immune system functions have evolved during the last half century. From widespread acceptance of Self-Nonself Discrimination to explain adaptive immunity, to increasing understanding of receptor-mediated activation of innate immunity through the Danger Model, understanding of the role of the immune response continues to grow with ever broader models such as the Damage Response Framework and the Discontinuity Model. The realisation that the majority of foreign antigens, such as those comprising the microbiome, are tolerated by the immune system, allows a re-appraisal of immune tolerance and how it relates to these conceptual shifts. Disease induced by both autoantigens and foreign antigens occurs most readily when the abundantly redundant immune system is defective, for genetic or other reasons, in one or more critical component. When fully competent, the primary role of the immune system is to “physiologically manage” both foreign and self-antigens by quietly engaging in activities such as waste disposal, autophagy, removal of apoptotic cell debris, tissue repair and metabolism. This is evidenced for foreign antigens by the limited incidence of clinical disease in pandemics despite widespread exposure of the population to the infectious agent: instead, many asymptomatic infected individuals harbour latent infections controlled by a healthy immune system, and are mainly at risk of developing overt disease when immune competency is impaired. In the case of autoantigens, by definition, exposure is 100% yet disease incidence is minimal and similarly requires a failure of immune competence, initiated by the same aberrant response to a coincident foreign antigen.

Background/aimsAnterior segment optical coherence tomography (AS-OCT) assessment of anterior chamber inflammation is an emerging tool. We describe the performance of AS-OCT in a paediatric population.MethodsA mixed-methods prospective study, using routine clinical assessment as reference standard, and AS-OCT, with Tomey CASIA2 or Heidelberg Spectralis HS1, as index test, with data collected on patient perceptions of imaging. Repeatability, diagnostic indices, responsiveness to clinical change and clinical correlations of imaging-based metrics (image cell count, size, density and brightness) were assessed, with construction of receiver operated characteristic curves. Exploratory thematic analysis of responses from families was undertaken.ResultsA total of 90 children (180 eyes) underwent imaging. Bland Altman limits of agreement for CASIA2 repeatability ranged from +17 cells (95% CI 13.6 to 21.1) to −19 cells (95% CI −15.6 to −23.2) and HS1 from +1 (95% CI 0.9 to 1.2) to −1.0 (−1.2 to −0.8) cells. CASIA2 imaging had higher sensitivity of 0.92 (95% CI 0.78 to 0.97) vs HS1 imaging 0.17 (95% CI 0.07 to 0.34), with positive correlation between clinical grade and CASIA2 cell count (coefficient 12.8, p=0.02, 95% CI 2.2 to 23.4). Change in clinical grade at follow-up examinations correlated with change in image based ‘cell’ count (r2=0.79, p<0.001). Patients reported a potential positive impact of seeing their disease activity.ConclusionOur findings suggest that OCT-based imaging holds the promise of deeper understanding of disease, improved patient experience and more granular monitoring of activity with resultant improved outcomes, but further work is needed to refine acquisition and analysis protocols.

Age-related decreases in autophagy contribute to the progression of age-related macular degeneration (AMD). We have now studied the interaction between autophagy impaired in retinal pigment epithelium (RPE) and the responses of macrophages. We find that dying RPE cells can activate the macrophage inflammasome and promote angiogenesis. In vitro , inhibiting rotenone-induced autophagy in RPE cells elicits caspase-3 mediated cell death. Co-culture of damaged RPE with macrophages leads to the secretion of IL-1β, IL-6 and nitrite oxide. Exogenous IL-6 protects the dysfunctional RPE but IL-1β causes enhanced cell death. Furthermore, IL-1β toxicity is more pronounced in dysfunctional RPE cells showing reduced IRAK3 gene expression. Co-culture of macrophages with damaged RPE also elicits elevated levels of pro-angiogenic proteins that promote ex vivo choroidal vessel sprouting. In vivo , impaired autophagy in the eye promotes photoreceptor and RPE degeneration and recruitment of inflammasome-activated macrophages. The degenerative tissue environment drives an enhanced pro-angiogenic response, demonstrated by increased size of laser-induced choroidal neovascularization (CNV) lesions. The contribution of macrophages was confirmed by depletion of CCR2 + monocytes, which attenuates CNV in the presence of RPE degeneration. Our results suggest that the interplay between perturbed RPE homeostasis and activated macrophages influences key features of AMD development.

Background/aimsCataract is an important source of visual loss in patients with uveitis. Whether or not outcomes of cataract surgery in eyes with uveitis are worse compared with non-uveitic eyes have to date been compromised by lack of reliable estimates of benefit and harm, which require data from large cohorts.MethodsElectronic medical record data were extracted from eight independent UK clinical sites for eyes undergoing cataract extraction between January 2010 and December 2014. 1173 eyes with a recorded diagnosis of uveitis were compared with a reference group of 95 573 eyes from the same dataset.ResultsUveitic eyes represented 1.2% of all eyes undergoing cataract surgery. Eyes in the uveitic group had worse preoperative visual acuity (0.87 vs 0.65 logarithm of the minimum angle of resolution (logMAR) units), were from younger patients and had shorter axial lengths and a higher incidence of ocular copathology including glaucoma. A greater number had documented small pupils, required additional surgical procedures, developed more intraoperative complications and had poorer postoperative visual acuity at all time points measured up to 6 months (0.41 vs 0.27 logMAR units at 12–24 weeks).ConclusionsThis large study cohort of eyes with a diagnosis of uveitis undergoing cataract surgery highlights more precisely the complex surgical demands, copathology and worse visual outcomes in this group. These data will allow more accurate preoperative counselling and planning. Although improvement in visual acuity is achieved in most cases, prognosis should be guarded, so that patient expectations are met. Compared with the non-uveitic population, the mean postoperative visual acuity is between one and two lines worse at all time points.

Background There is a paucity of data on the ocular outcomes in paediatric non-infectious uveitis since the introduction of the biologic agents. The purpose of this study was to outline the clinical characteristics of children with non-infectious uveitis and determine the visual outcomes and ocular complication rates in the modern era. Methods Children with non-infectious uveitis from January 2011 to December 2015 were identified. Data was collected at baseline, 1, 3, 5, and 10 years post diagnosis. The incidence rates of visual impairment, structural ocular complications and surgical intervention were calculated. Using logistic regression the association between various baseline characteristics and later visual impairment was investigated. Results Of the 166 children, 60.2% ( n  = 100) had a systemic disease association. 72.9% ( n  = 121) children received methotrexate, 58 children progressed to a biologic. The incidence rates of visual acuity loss to > 0.3 LogMAR (6/12) and to ≥1.0 LogMAR (6/60) were 0.05/Eye Year (EY) and 0.01/EY, respectively. Visual outcomes in the Juvenile Idiopathic Arthritis associated Uveitis (JIA-U) and Idiopathic Uveitis cohorts were not statistically significant. Of the 293 affected eyes, posterior synechiae was the predominant complication on presentation, while cataract had the highest incidence rate (0.05/EY). On direct comparison, children with JIA-U were statistically significantly more likely to develop glaucoma while children with Idiopathic Uveitis were statistically significantly more likely to develop macular oedema. Conclusion One third of children received a biological therapy, reflecting increasing utilisation and importance of biological agents in the management of inflammatory conditions. Rates of visual impairment and ocular complications are an improvement on previously published data.

Age-related macular degeneration (AMD), a retinal degenerative disease, is the leading cause of central vision loss among the elderly population in developed countries and an increasing global burden. The major risk is aging, compounded by other environmental factors and association with genetic variants for risk of progression. Although the etiology of AMD is not yet clearly understood, several pathogenic pathways have been proposed, including dysfunction of the retinal pigment epithelium, inflammation, and oxidative stress. The identification of AMD susceptibility genes encoding complement factors and the presence of complement and other inflammatory mediators in drusen, the hallmark deposits of AMD, support the concept that local inflammation and immune-mediated processes play a key role in AMD pathogenesis that may be accelerated through systemic immune activation. In this regard, increased levels of circulating C-reactive protein (CRP) have been associated with higher risk of AMD. Besides being a risk marker for AMD, CRP may also play a role in the progression of the disease as it has been identified in drusen, and we have recently found that its monomeric form (mCRP) induces blood retinal barrier disruption . In this review, we will address recent evidence that links CRP and AMD pathogenesis, which may open new therapeutic opportunities to prevent the progression of AMD.