Literature review and proposal of best practice for ophthalmologists: monitoring of patients following intravitreal brolucizumab therapy.

Brolucizumab is a novel humanised, single-chain, variable fragment inhibitor of Vascular Endothelial Growth Factor-A for the treatment of neurovascular age-related macular degeneration. Brolucizumab gained US Food and Drug Administration and European Medicines Agency approval following the Phase III HAWK (NCT02307682) and HARRIER (NCT02434328) trials which compared brolucizumab with aflibercept, presenting a tolerable safety and favourable efficacy profile. The mean change (least squares [LS] mean ± standard error) in best-corrected visual acuity letters from baseline to week 96 in the HAWK trial was 5.9 ± 0.78 for brolucizumab (6 mg) versus 5.3 ± 0.78 for aflibercept, and in the HARRIER trial, 6.1 ± 0.73 (6 mg) for brolucizumab (6 mg) and 6.6 ± 0.73 for aflibercept. Within both trials, greater reductions were noted in the central subfield thickness from baseline to week 96 in the brolucizumab (6 mg) groups versus the aflibercept group. Subsequent post-marketing reports detailed intraocular inflammation (IOI) after brolucizumab treatment and in response an independent safety review committee conducted a post hoc data review. While comparable, the rate of brolucizumab-associated IOI was higher in the post hoc analysis than the trials (4.6% and 4.4%, respectively). Findings from trials and real-world data indicate there may be pre-defining risk factors that predispose patients to IOI following brolucizumab treatment. With a thorough understanding of IOI classification and best practice management, ophthalmologists can use brolucizumab confidently and, should a case arise, they should act quickly to prevent vision loss. Herein, we provide information and guidance to support clinical decision-making related to brolucizumab use.

Long-term heavy silicone oil intraocular tamponade.

Heavy silicone oil tamponade is intended to be temporary, but may occasionally be indefinite in patients who refuse, or are deemed unsuitable for, further surgery. The aim of this study is to compare the outcomes of patients with temporary versus indefinite heavy silicone oil intraocular tamponade. This retrospective, comparative case series identified 75 patients who underwent heavy silicone oil instillation (Oxane HD) over a 6 year period (2006-2012) in one institution. Thirty-nine patients had temporary heavy oil tamponade and 36 patients had indefinite tamponade. The majority (68 %) of patients had a history of previous vitreoretinal surgery prior to oil instillation and 66.7 % had pre-existing proliferative vitreoretinopathy (PVR). The mean final logMAR best corrected visual acuity (BCVA) was significantly better in the temporary tamponade group (1.34 ± 0.66) than the indefinite tamponade group 1.82 ± 0.64 (p = 0.003). Ambulatory BCVA (≥ 4/200) was retained in 76.3 % of temporary tamponade patients versus 54.3 % of indefinite tamponade patients (p = 0.093). Successful retinal reattachment was significantly more likely in temporary tamponade patients (92.3 %) than indefinite tamponade patients (75 %; p = 0.04). Complications in the patients with indefinite heavy silicone oil tamponade included redetachment (38.9 %), corneal pathology (13.8 %), secondary glaucoma (11.1 %) and anterior segment emulsification (8.3 %).While temporary tamponade patients had better outcomes than those with indefinite tamponade, the majority of indefinite tamponade patients still retained ambulatory vision in the affected eye. Indefinite heavy silicone oil tamponade remains a viable option for those who cannot undergo removal of oil surgery.

Tumor necrosis factor polymorphisms associated with tumor necrosis factor production influence the risk of idiopathic intermediate uveitis.

PURPOSE: Idiopathic intermediate uveitis (IIU) is a potentially sight-threatening inflammatory disorder with well-defined anatomic diagnostic criteria. It is often associated with multiple sclerosis, and both conditions are linked to HLA-DRB1*15. Previously, we have shown that non-infectious uveitis (NIU) is associated with interleukin 10 (IL10) polymorphisms, IL10-2849A (rs6703630), IL10+434T (rs2222202), and IL10+504G (rs3024490), while a LTA+252AA/TNFA-238GG haplotype (rs909253/rs361525) is protective. In this study, we determined whether patients with IIU have a similar genetic profile as patients with NIU or multiple sclerosis. METHODS: Twelve polymorphisms were genotyped, spanning the tumor necrosis factor (TNF) and IL10 genomic regions, in 44 patients with IIU and 92 population controls from the UK and the Republic of Ireland. RESULTS: IIU was strongly associated with the TNFA-308A and TNFA-238A polymorphisms. We found the combination of TNFA-308 and -238 loci was more strongly associated with IIU than any other loci across the major histocompatibility complex, including HLA-DRB1. CONCLUSIONS: TNF polymorphisms, associated with increased TNF production, are highly associated with IIU. These results offer the potential to ascribe therapeutic response and risk (i.e., the influence of HLA-DRB1*15 status and TNFR1 polymorphism) to anti-TNF therapy in IIU.

Punctate inner choroidopathy and multifocal choroiditis with panuveitis share haplotypic associations with IL10 and TNF loci.

PURPOSE: The white-dot syndromes are a heterogenous group of chorioretinal disorders that have many common clinical features. Whether these disorders represent distinct clinical entities or different manifestations of the same disease warrants further interrogation. Two white-dot syndromes were investigated, with closely overlapping phenotypes--multifocal choroiditis with panuveitis (MFCPU) and punctate inner choroidopathy (PIC)--for differences in clinical course and genotype frequency at IL10 and TNF loci, known to be associated with noninfectious uveitis. METHODS: Twelve polymorphisms were genotyped, spanning the TNFA and IL10 genomic regions, in 61 patients with MFCPU or PIC and 92 population controls from the United Kingdom and Republic of Ireland. RESULTS: There were clear differences in clinical course between patients with MFCPU and PIC which had prognostic significance. However, both patient groups demonstrated similar associations with the IL10 haplotype, IL10htSNP2(-2849)AX/htSNP5(+434)TC and negative associations with the TNF haplotype, LTA+252A/TNFhtSNP1(-308)G/TNFhtSNP2(-238)G/TNFhtSNP3(+488)A/TNFd3. CONCLUSIONS: Despite clear differences in clinical course and outcome, MFCPU and PIC may still represent two manifestations of the same disease, given their similar genetic associations with IL10 and TNF loci, which are known to be associated with noninfectious uveitis and autoimmunity, in general. Definitive proof will necessitate genomewide sequence analysis. However, the data also support the notion that epigenetic factors have a strong effect on clinical phenotype.

Cytokine polymorphism in noninfectious uveitis.

PURPOSE: Noninfectious uveitis is a sight-threatening immune-mediated intraocular inflammatory disorder. The inheritance of uveitis in multiplex families and its association with known monogenic and polygenic immunologic disorders suggests that common genetic variants underlie susceptibility to uveitis as well as to other immunologic disorders. TNFA and IL10 are strong candidate genes, given the influence of these cytokines on inflammation, immune tolerance, and apoptosis. METHODS: The role of 12 polymorphisms spanning the TNFA and IL10 genomic regions was investigated in 192 uveitis patients and 92 population control subjects from four regional centers in the United Kingdom and Republic of Ireland. RESULTS: The results demonstrate that uveitis is associated with three haplotype-tagging SNPs (htSNPs) in the IL10 gene: htSNP2 (rs6703630), htSNP5 (rs2222202), and htSNP6 (rs3024490). IL10htSNP2AG/htSNP5TC was the most significantly associated haplotype (P = 0.00085), whereas the LTA+252AA/TNFhtSNP2GG haplotype was protective (P = 0.00031). Furthermore, subgroup analysis showed that the frequency of the TNFd4 allele was higher in patients with nonremitting ocular disease and/or those requiring higher levels of maintenance immunosuppression. Although these associations lost significance after Bonferroni correction, they infer a relationship that may be validated by a larger study. CONCLUSIONS: Since these variants are implicated in the susceptibility and severity of several immunologic disorders, the results support the hypothesis that common genetic determinants influence shared mechanisms of autoimmunity.

Cytokine gene polymorphism in sympathetic ophthalmia.

PURPOSE: Sympathetic ophthalmia (SO) is a prototypical autoimmune disease in which injury to one eye causes sight-threatening inflammation in the otherwise normal contralateral eye. Previous work found that human leukocyte antigen alleles HLA-DRB1*04 and DQA1*03 are markers of increased susceptibility and severity in British and Irish patients. Evidence is accumulating that single nucleotide polymorphisms (SNPs) in cytokine genes can also influence the development of autoimmune disease through their effect on levels of cytokine production. The purpose of this study was to determine whether polymorphisms in the cytokine genes are important markers for disease severity and outcome in patients with SO. METHODS: Twenty-six British and Irish patients meeting well-defined criteria for the diagnosis of SO were compared with 48 matched controls. Genotyping of SNPs in the TNFalpha, TNFbeta, and IL-10 genes was performed using the polymerase chain reaction and sequence-specific primers (SSP-PCRs) and of the CTLA-4 and TNF receptor 2 genes using restriction length polymorphism-PCR (RFLP-PCR). RESULTS: Significant associations were found between the IL-10 -1082 SNP and disease recurrence from previously stable disease and the level of steroids required for maintenance therapy. In addition, the GCC IL-10 promoter haplotype (IL-10 -1082G, -819C, -592C) was found to be protective against disease recurrence. CONCLUSIONS: These results show that cytokine gene polymorphisms are markers for the severity of disease in SO. They were found to be associated with recurrence of previously stable disease and with the level of maintenance steroid treatment required to control inflammatory activity.

Risk factors for endothelial cell loss after phacoemulsification surgery by a junior resident.

PURPOSE: To assess the risk factors for endothelial cell loss after phacoemulsification cataract surgery performed by a junior resident. SETTING: Ophthalmic teaching hospital, Dublin, Ireland. METHODS: This prospective study included 40 eyes having divide-and-conquer phacoemulsification cataract surgery by a junior resident under the supervision of an experienced surgeon. Nine variables were examined to assess the risk for corneal endothelial cell loss postoperatively. RESULTS: The mean overall endothelial cell loss was 11.6%. Longer surgery time, longer absolute and effective phaco time, higher mean ultrasound power, and higher cataract density were significantly associated with endothelial cell loss on univariate analysis. Multivariate analysis identified a grade 3 nucleus (severely dense) and long absolute phaco time as independent predictors for endothelial cell loss, with longer absolute phaco time the stronger predictor. CONCLUSIONS: Divide-and-conquer phacoemulsification cataract surgery was a safe technique in the hands of an ophthalmic trainee. This study supports advice to junior surgeons to choose cases with less dense cataracts as this will help reduce the absolute phaco time and thus minimize endothelial cell loss.

Grading of pars planitis by ultrasound biomicroscopy--echographic and clinical study.

OBJECTIVE: To determine the value of high frequency ultrasound biomicroscopy (UBM) in the assessment of pars planitis, and in particular to correlate UBM findings and ophthalmoscopy findings. METHODS: All patients with pars planitis were identified from the uveitis database of the Department of Ophthalmology, University of Aberdeen. Fifteen consecutive patients (age 14-52 years) underwent complete ophthalmological examination. UBM was performed at a sound frequency of 50 MHz on 17 eyes of 10 patients to determine the extent of disease. UBM findings were evaluated by two investigators in a blinded fashion and graded from 0 to 3 according to the following grading criteria: 0=no cells, 1=mild cells, 2=marked cells, 3=organization of cells. Opthalmoscopy findings were also graded using the same criteria. UBM and ophthalmoscopy findings were independently graded and compared. RESULTS: We found a good inter-observer correlation for the UBM grading of pars planitis (rho=0.86). There was no significant difference in the grading of pars planitis by indirect ophthalmoscopy as compared to grading by UBM (P>0.05). CONCLUSION: UBM appears to be a valuable and reliable diagnostic technique for the evaluation of patients with pars planitis and may be useful especially in patients with media opacities to diagnose and/or monitor efficacy of treatment.