High Polygenic Risk Is Associated with Earlier Initiation and Escalation of Treatment in Early Primary Open-Angle Glaucoma.

PURPOSE: To assess the association between a glaucoma polygenic risk score (PRS) and treatment outcomes in primary open-angle glaucoma. DESIGN: Prospective, observational cohort study. PARTICIPANTS: Participants from the Progression Risk of Glaucoma: Relevant SNPs with Significant Association Study were divided into a cohort with suspect glaucoma who were treatment naive at enrollment and one with early manifest and suspect glaucoma receiving treatment at enrollment. METHODS: A per-allele weighted glaucoma PRS was calculated for 1107 participants. Multivariable mixed-effects Cox proportional regression analysis assessed the association between PRS and time to commencement of intraocular pressure (IOP)-lowering therapy in 416 patients with suspect glaucoma who were treatment naive at study enrollment. Secondary analysis evaluated the association between PRS and escalation of IOP-lowering therapy among 691 patients with suspect and early manifest glaucoma who were receiving IOP-lowering therapy at enrollment. MAIN OUTCOME MEASURES: Commencement or escalation of IOP-lowering therapy. RESULTS: A higher PRS was associated with a greater risk of commencing IOP-lowering therapy within 5 years (hazard ratio [HR], 1.45 per 1 standard deviation [/SD]; 95% confidence interval [CI], 1.27-1.62; P < 0.001). Participants in the upper population-based quintile showed a 3.3 times greater risk of commencing therapy by 5 years than those in the lowest quintile (HR, 3.30; 95% CI, 1.63-6,70; P < 0.001) and a 5.4 times greater risk of commencing IOP-lowering therapy by 2 years than the those in the lowest quintile (HR, 5.45; 95% CI, 2.08-14.25; P < 0.001). A higher PRS was associated with a greater risk of treatment escalation among patients receiving treatment at enrollment (HR, 1.19/SD; 95% CI, 1.09-1.31; P < 0.001). In combined analysis of all participants, participants in the top population-based quintile were at 2.3 times greater risk of requiring initiation or escalation of IOP-lowering therapy than those in the lowest quintile (HR, 2.33; 95% CI, 1.75-3.01; P < 0.001). CONCLUSIONS: This study demonstrated novel associations between glaucoma polygenic risk and risk of commencement or escalation of IOP-lowering therapy, building on previous work highlighting the potential clinical usefulness of genetic risk stratification in glaucoma. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Classification of Visual Field Abnormalities in Highly Myopic Eyes without Pathologic Change.

PURPOSE: To develop a classification system of visual field (VF) abnormalities in highly myopic eyes with and without glaucoma. DESIGN: Secondary analysis of VF data from a longitudinal cohort study. PARTICIPANTS: One thousand eight hundred ninety-three VF tests from 1302 eyes (825 individuals). METHODS: All participants underwent VF testing (Humphrey 24-2 Swedish interactive threshold algorithm standard program; Carl Zeiss Meditec) and detailed ophthalmic examination. A comprehensive set of VF defect patterns was defined via observation of the 1893 VF reports, literature review, and consensus meetings. The classification system comprised 4 major types of VF patterns, including normal type, glaucoma-like defects (paracentral defect, nasal step, partial arcuate defect, arcuate defect), high myopia-related defects (enlarged blind spot, vertical step, partial peripheral rim, nonspecific defect), and combined defects (nasal step with enlarged blind spot). A subset (n = 1000) of the VFs was used to evaluate the interobserver and intraobserver agreement and weighted κ values of the classification system by 2 trained readers. The prevalence of various VF patterns and their associated factors were determined. MAIN OUTCOME MEASURES: The classification of VF in highly myopic eyes and its associated risk factors. RESULTS: We found that normal type, glaucoma-like defects, high myopia-related defects, and combined defects accounted for 74.1%, 10.8%, 15.0%, and 0.1% of all unique VF tests, respectively. The interobserver and intraobserver agreements were > 89%, and the corresponding κ values were 0.86 or more between readers. Both glaucoma-like and high myopia-related VF defects were associated with older age (odds ratios [ORs], 1.07 [95% confidence interval (CI), 1.04-1.10; P < 0.001] and 1.06 [95% CI, 1.04-1.10; P < 0.001]) and longer axial length (ORs, 1.65 [95% CI, 1.32-2.07; P < 0.001] and 1.37 [95% CI, 1.11-1.68; P = 0.003]). Longer axial length showed a stronger effect on the prevalence of glaucoma-like VF defects than on the prevalence of high myopia-related VF defects (P = 0.036). CONCLUSIONS: We propose a new and reproducible classification system of VF abnormalities for nonpathologic high myopia. Applying a comprehensive classification system will facilitate communication and comparison of findings among studies.

Comparative study of 2-year outcomes for Hydrus or iStent inject microinvasive glaucoma surgery implants with cataract surgery.

BACKGROUND: To compare real-world 24-month outcomes of phacoemulsification combined with either iStent inject or Hydrus Microstent. METHODS: Analysis of data from the Fight Glaucoma Blindness (FGB) international registry. Anonymized data from 344 eyes with mild-to-moderate open-angle glaucoma, normal-tension glaucoma or ocular hypertension that underwent phacoemulsification combined with either iStent inject (224) or Hydrus Microstent (120) were included. Data were adjusted for baseline characteristics using linear regression and propensity score matching. The primary endpoint was a comparison of mean intraocular pressure (IOP) at 24 months. RESULTS: At 24 months, there was no significant difference in IOP reduction between the two groups, consistent across all analyses. The matched cohort showed iStent inject achieved 3.1 mmHg reduction and Hydrus a 2.3 mmHg reduction (p = 0.530) and a mean medication reduction of 1.0 for iStent inject versus 0.5 for Hydrus (p = 0.081). 5.4% of eyes in the iStent inject group and 7.5% of eyes in the Hydrus group required subsequent procedures to improve IOP control within 24 months. Complications were rare with no significant differences between the groups. CONCLUSIONS: Twenty-four-month outcomes showed sustained IOP reduction with a good safety profile for both groups. There was no significant difference in IOP outcomes between the groups. There may be a small additional reduction in glaucoma medication usage following cataract surgery with iStent inject compared to Hydrus.

Corneal Stiffness Parameters Are Predictive of Structural and Functional Progression in Glaucoma Suspect Eyes.

PURPOSE: To investigate corneal stiffness parameters (SPs) as predictors of future progression risk in glaucoma suspect eyes. DESIGN: Prospective, longitudinal study. PARTICIPANTS: Three hundred seventy-one eyes from 228 primary open-angle glaucoma suspects, based on optic disc appearance, with normal baseline Humphrey Visual Field (HVF; Carl Zeiss Meditec) results. METHODS: Baseline corneal SPs were measured using Corvis ST (Oculus Optikgeräte GmbH). Participants were followed up every 6 months with clinical examination, HVF testing, and OCT. The baseline SP at first applanation (SP-A1) and highest concavity predicted the prospective outcome measures. MAIN OUTCOME MEASURES: Structural progression was measured by the OCT rate of thinning of the retinal nerve fiber layer (RNFL) and ganglion cell-inner plexiform layer (GCIPL). Functional progression was assessed by permutation analysis of pointwise linear regression criteria on HVF testing. RESULTS: Stiffness parameters correlated positively with central corneal thickness (CCT), which was adjusted for in all analyses. A higher SP-A1, suggestive of a stiffer cornea, was associated with a faster rate of RNFL thinning (P < 0.001), synergistic with thinner CCT (P = 0.004) over a mean follow-up of 4.2 years. Eyes with higher SP-A1 and thinner CCT (thin and stiff corneas) showed accelerated RNFL thinning by 0.72 µm/year relative to eyes with lower SP-A1 and thicker CCT (95% confidence interval [CI], 0.17-1.28; P = 0.011) and were at 2.9-fold higher likelihood of fast RNFL progression of more than 1 µm/year (95% CI, 1.4-6.1; P = 0.006). Consistent results also were observed with GCIPL thinning. Furthermore, a higher SP-A1 was associated with a greater risk of visual field progression (P = 0.002), synergistic with thinner CCT (P = 0.010). Eyes with higher SP-A1 and thinner CCT were at 3.7-fold greater risk of visual field progression relative to eyes with thicker CCT and lower SP-A1 (95% CI, 1.3-10.5; P = 0.014). CONCLUSIONS: Glaucoma suspect eyes with higher corneal SPs and lower CCT, suggestive of thin and stiff corneas, are at greater risk of progression. Corneal SPs seem to act synergistically with CCT as risk factors for glaucoma progression.

Cardiovascular Disease Predicts Structural and Functional Progression in Early Glaucoma.

PURPOSE: To investigate the association between cardiovascular disease and baseline structural defects and disease progression in glaucoma. DESIGN: Prospective, longitudinal study of preperimetric and perimetric glaucoma. PARTICIPANTS: Two thousand six hundred twenty-eight eyes from 1314 participants recruited to the Progression Risk of Glaucoma: Relevant SNPs with Significant Association (PROGRESSA) study were evaluated for baseline and longitudinal structural thinning using spectral-domain OCT and for visual field progression on Humphrey visual field (HVF) assessment. METHODS: Patients were classified as either predominantly macula ganglion cell-inner plexiform layer (mGCIPL), predominantly peripapillary retinal nerve fiber layer (pRNFL), or both mGCIPL and pRNFL structural change at enrollment, and then evaluated for longitudinal OCT or HVF progression. Cardiovascular disease and medication characteristics of the participants were compared with a reference group of stable patients. MAIN OUTCOME MEASURES: OCT and HVF baseline status and longitudinal progression. RESULTS: After accounting for age and cardiovascular characteristics, patients with predominantly mGCIPL thinning at baseline showed a higher prevalence of hypertension (odds ratio [OR], 2.70; 95% confidence interval [CI], 1.66-4.41; P < 0.001), antihypertensive use (OR, 2.03; 95% CI, 1.20-3.46; P = 0.008), and statin use (OR, 1.98; 95% CI, 1.07-3.66; P = 0.029) than reference patients. Patients with predominantly pRNFL thinning exhibited a comparable prevalence of cardiovascular disease or medication with reference patients. Review of longitudinal OCT and HVF data (mean follow-up, 5.34 ± 1.29 years) showed that hypertension was associated with an increased risk of both OCT (OR, 1.79; 95% CI, 1.17-2.75; P = 0.006) and HVF progression (OR, 1.92; 95% CI, 1.18-3.15; P = 0.013). A 1-standard deviation (approximately 21 mmHg) increase in systolic blood pressure at baseline was associated with a greater risk of OCT progression (OR, 1.27; 95% CI, 1.01-1.63; P = 0.041) and HVF progression (OR, 1.32; 95% CI, 1.01-1.73; P = 0.043). The association between systolic blood pressure and structural progression was comparable to that observed between intraocular pressure and structural progression (OR, 1.30; 95% CI, 1.01-1.67; P = 0.039). CONCLUSIONS: Cardiovascular disease is an important risk factor for glaucoma progression.

eFOCUS 2: A randomised crossover trial of smartphone fundoscopy and direct ophthalmoscopy aiming to improve optic disc interpretation by medical students with e-learning support.

BACKGROUND: Ophthalmoscopy and its interpretation are complex. We aimed to compare the diagnostic accuracy of smartphone fundoscopy with traditional direct ophthalmoscopy for optic disc interpretation, with e-learning support. METHODS: We conducted a randomised, crossover study of 102 medical students. Students were offered e-learning for optic disc interpretation. A fundoscopy objective structured clinical examination was conducted after an introductory lecture and 10-min practical training session on smartphone fundoscopy and traditional ophthalmoscopy. Participants examined patients and simulator slides with a randomised crossover between smartphone [D-eye (Padova, Italy) or iExaminer (Welch Allyn, Macquarie Park, Australia)] and traditional ophthalmoscopy (Welch Allyn). Optic discs were graded independently by three masked ophthalmologists. The primary outcome was the ability to interpret an optic disc as normal or abnormal. Secondary outcomes included other optic disc aspects; student preferences; and e-learning performance. RESULTS: Students' agreement with the gold standard for an abnormal or normal disc was significantly greater using a smartphone (74.4%) than with direct ophthalmoscopy (68.1%, p = 0.032). More students preferred smartphone (74%) over direct ophthalmoscopy (26%, p < 0.001). E-learning led to an improvement in optic disc interpretation scores (mean improvement = 4.5%, 95% CI = 3.7-5.2, p < 0.001). CONCLUSIONS: Medical students are more accurate at recognising an abnormal optic disc using smartphone fundoscopy than traditional direct ophthalmoscopy, and have a strong preference for smartphone fundoscopy. E-learning may improve the interpretation of optic disc abnormalities. Smartphone fundoscopy may mitigate some technical challenges of fundoscopy and reinvigorate use of this valuable clinical examination.

Tofacitinib as Induction and Maintenance Therapy for Ulcerative Colitis.

BACKGROUND: Tofacitinib, an oral, small-molecule Janus kinase inhibitor, was shown to have potential efficacy as induction therapy for ulcerative colitis in a phase 2 trial. We further evaluated the efficacy of tofacitinib as induction and maintenance therapy. METHODS: We conducted three phase 3, randomized, double-blind, placebo-controlled trials of tofacitinib therapy in adults with ulcerative colitis. In the OCTAVE Induction 1 and 2 trials, 598 and 541 patients, respectively, who had moderately to severely active ulcerative colitis despite previous conventional therapy or therapy with a tumor necrosis factor antagonist were randomly assigned to receive induction therapy with tofacitinib (10 mg twice daily) or placebo for 8 weeks. The primary end point was remission at 8 weeks. In the OCTAVE Sustain trial, 593 patients who had a clinical response to induction therapy were randomly assigned to receive maintenance therapy with tofacitinib (either 5 mg or 10 mg twice daily) or placebo for 52 weeks. The primary end point was remission at 52 weeks. RESULTS: In the OCTAVE Induction 1 trial, remission at 8 weeks occurred in 18.5% of the patients in the tofacitinib group versus 8.2% in the placebo group (P=0.007); in the OCTAVE Induction 2 trial, remission occurred in 16.6% versus 3.6% (P<0.001). In the OCTAVE Sustain trial, remission at 52 weeks occurred in 34.3% of the patients in the 5-mg tofacitinib group and 40.6% in the 10-mg tofacitinib group versus 11.1% in the placebo group (P<0.001 for both comparisons with placebo). In the OCTAVE Induction 1 and 2 trials, the rates of overall infection and serious infection were higher with tofacitinib than with placebo. In the OCTAVE Sustain trial, the rate of serious infection was similar across the three treatment groups, and the rates of overall infection and herpes zoster infection were higher with tofacitinib than with placebo. Across all three trials, adjudicated nonmelanoma skin cancer occurred in five patients who received tofacitinib and in one who received placebo, and adjudicated cardiovascular events occurred in five who received tofacitinib and in none who received placebo; as compared with placebo, tofacitinib was associated with increased lipid levels. CONCLUSIONS: In patients with moderately to severely active ulcerative colitis, tofacitinib was more effective as induction and maintenance therapy than placebo. (Funded by Pfizer; OCTAVE Induction 1, OCTAVE Induction 2, and OCTAVE Sustain ClinicalTrials.gov numbers, NCT01465763 , NCT01458951 , and NCT01458574 , respectively.).

An Intraocular Pressure Polygenic Risk Score Stratifies Multiple Primary Open-Angle Glaucoma Parameters Including Treatment Intensity.

PURPOSE: To examine the combined effects of common genetic variants associated with intraocular pressure (IOP) on primary open-angle glaucoma (POAG) phenotype using a polygenic risk score (PRS) stratification. DESIGN: Cross-sectional study. PARTICIPANTS: For the primary analysis, we examined the glaucoma phenotype of 2154 POAG patients enrolled in the Australian and New Zealand Registry of Advanced Glaucoma, including patients recruited from the United Kingdom. For replication, we examined an independent cohort of 624 early POAG patients. METHODS: Using IOP genome-wide association study summary statistics, we developed a PRS derived solely from IOP-associated variants and stratified POAG patients into 3 risk tiers. The lowest and highest quintiles of the score were set as the low- and high-risk groups, respectively, and the other quintiles were set as the intermediate risk group. MAIN OUTCOME MEASURES: Clinical glaucoma phenotype including maximum recorded IOP, age at diagnosis, number of family members affected by glaucoma, cup-to-disc ratio, visual field mean deviation, and treatment intensity. RESULTS: A dose-response relationship was found between the IOP PRS and the maximum recorded IOP, with the high genetic risk group having a higher maximum IOP by 1.7 mmHg (standard deviation [SD], 0.62 mmHg) than the low genetic risk group (P = 0.006). Compared with the low genetic risk group, the high genetic risk group had a younger age of diagnosis by 3.7 years (SD, 1.0 years; P < 0.001), more family members affected by 0.46 members (SD, 0.11 members; P < 0.001), and higher rates of incisional surgery (odds ratio, 1.5; 95% confidence interval, 1.1-2.0; P = 0.007). No statistically significant difference was found in mean deviation. We further replicated the maximum IOP, number of family members affected by glaucoma, and treatment intensity (number of medications) results in the early POAG cohort (P ≤ 0.01). CONCLUSIONS: The IOP PRS was correlated positively with maximum IOP, disease severity, need for surgery, and number of affected family members. Genes acting via IOP-mediated pathways, when considered in aggregate, have clinically important and reproducible implications for glaucoma patients and their close family members.

Effect of phacoemulsification cataract surgery on intraocular pressure in early glaucoma: A prospective multi-site study.

IMPORTANCE: Cataract and primary open-angle glaucoma (POAG) commonly co-exist, and cataract surgery is thought to reduce intraocular pressure (IOP), the major modifiable risk factor of POAG. BACKGROUND: Previous studies exploring the effect of cataract surgery on IOP are limited by retrospective design, lack of a control group, medication use and washout and loss to follow up. DESIGN: Prospective, multicentre, matched case-control Australian study. PARTICIPANTS: 171 eyes of 108 POAG patients who underwent cataract surgery, matched to 171 control eyes. METHODS: Serial longitudinal IOP measurements were compared before and after cataract surgery, and relative to the controls. A mixed-effect model was used for the longitudinal data. MAIN OUTCOME MEASURES: Change in IOP. RESULTS: The mean follow-up time was 4.8 (1.4) years. Cataract surgery reduced mean IOP by 2.22 mmHg (95% confidence interval: 1.93-2.52 mmHg, P < .001) with 59 eyes (34%) achieving at least 3 mmHg reduction. Compared to matched controls, the mean reduction in IOP was 1.75 mmHg (95% confidence interval 1.15-2.33 mmHg; P < .001). Higher preoperative IOP and being on fewer topical glaucoma medications preoperatively were strongly predictive of a larger IOP reduction in a multivariable model. Anterior chamber depth was not associated with IOP reduction. Eyes with preoperative IOP ≥24 mmHg had a mean IOP reduction of 4.03 mmHg with 81% experiencing at least 3 mmHg reduction. Sub-analysis of medication naïve and pseudoexfoliation patients showed similar results. CONCLUSIONS AND RELEVANCE: Cataract surgery has a confirmed effect in reducing IOP in a "real world" setting of early glaucoma patients.

Macular Ganglion Cell-Inner Plexiform Layer Loss Precedes Peripapillary Retinal Nerve Fiber Layer Loss in Glaucoma with Lower Intraocular Pressure.

PURPOSE: To investigate which clinical measures influence whether an individual demonstrates earliest glaucomatous structural progression on peripapillary retinal nerve fiber layer (pRNFL) or macular ganglion cell-inner plexiform layer (mGCIPL). DESIGN: Prospective, longitudinal cohort study. PARTICIPANTS: Two hundred seventy-one eyes from 207 individuals with statistically significant evidence of glaucomatous progression on OCT Guided Progression Analysis (GPA) software were drawn from a total of 1271 eyes from 686 individuals categorized as glaucoma suspect or having early manifest glaucoma undergoing glaucoma surveillance. METHODS: Individuals demonstrating earliest evidence of longitudinal progression on mGCIPL GPA event analysis were compared with individuals demonstrating evidence of earliest longitudinal progression on pRNFL GPA event analysis. MAIN OUTCOME MEASURES: Correlation of OCT event change analysis with intraocular pressure (IOP), clinical variables, and baseline thickness of the pRNFL and mGCIPL. RESULTS: Intraocular pressure, baseline pRNFL thickness, baseline mGCIPL thickness, and systemic hypertension were associated with location of first progression. Eyes demonstrating earliest longitudinal progression on mGCIPL had significantly lower maximum-recorded pretreatment IOP (mean difference, 3.90 mmHg; 95% confidence interval [CI], 2.37-5.43 mmHg; P < 0.001). The interval between progression on pRNFL and progression on mGCIPL increased by 12.4 months for every 5-mmHg increase in IOP (95% CI, 10.32-15.72 months). Eyes demonstrating earliest longitudinal progression on mGCIPL showed significantly lower baseline average pRNFL thickness than eyes progressing on pRNFL first (mean difference, 7.07 µm; 95% CI, 4.38-9.77 µm; P < 0.001). Eyes progressing first on mGCIPL parameters were 3.03 times more likely to demonstrate a new paracentral field defect than eyes progressing first on pRNFL parameters (odds ratio, 3.03; 95% CI, 1.26-7.28; P = 0.01). CONCLUSIONS: Clinical features, particularly pretreatment IOP, influence whether structural glaucoma progression is detected earlier with mGCIPL or pRNFL imaging. These data support the usefulness of mGCIPL imaging in addition to pRNFL analysis for detection of glaucoma progression, particularly in patients with normal IOP.

Psychometric validation of the SF-36® Health Survey in ulcerative colitis: results from a systematic literature review.

PURPOSE: To conduct a systematic literature review of the reliability, construct validity, and responsiveness of the SF-36® Health Survey (SF-36) in patients with ulcerative colitis (UC). METHODS: We performed a systematic search of electronic medical databases to identify published peer-reviewed studies which reported scores from the eight scales and/or two summary measures of the SF-36 collected from adult patients with UC. Study findings relevant to reliability, construct validity, and responsiveness were reviewed. RESULTS: Data were extracted and summarized from 43 articles meeting inclusion criteria. Convergent validity was supported by findings that 83% (197/236) of correlations between SF-36 scales and measures of disease symptoms, disease activity, and functioning exceeded the prespecified threshold (r ≥ |0.40|). Known-groups validity was supported by findings of clinically meaningful differences in SF-36 scores between subgroups of patients when classified by disease activity (i.e., active versus inactive), symptom status, and comorbidity status. Responsiveness was supported by findings of clinically meaningful changes in SF-36 scores following treatment in non-comparative trials, and by meaningfully larger improvements in SF-36 scores in treatment arms relative to controls in randomized controlled trials. The sole study of SF-36 reliability found evidence supporting internal consistency (Cronbach's α ≥ 0.70) for all SF-36 scales and test-retest reliability (intraclass correlation coefficient ≥0.70) for six of eight scales. CONCLUSIONS: Evidence from this systematic literature review indicates that the SF-36 is reliable, valid, and responsive when used with UC patients, supporting the inclusion of the SF-36 as an endpoint in clinical trials for this patient population.

Tofacitinib for induction and maintenance therapy of Crohn's disease: results of two phase IIb randomised placebo-controlled trials.

OBJECTIVE: Tofacitinib is an oral, small-molecule Janus kinase inhibitor that is being investigated for IBD. We evaluated the efficacy and safety of tofacitinib for induction and maintenance treatment in patients with moderate-to-severe Crohn's disease (CD). DESIGN: We conducted two randomised, double-blind, placebo-controlled, multicentre phase IIb studies. Adult patients with moderate-to-severe CD were randomised to receive induction treatment with placebo, tofacitinib 5 or 10 mg twice daily for 8 weeks. Those achieving clinical response-100 or remission were re-randomised to maintenance treatment with placebo, tofacitinib 5 or 10 mg twice daily for 26 weeks. Primary endpoints were clinical remission at the end of the induction study, and clinical response-100 or remission at the end of the maintenance study. RESULTS: 180/280 patients randomised in the induction study were enrolled in the maintenance study. At week 8 of induction, the proportion of patients with clinical remission was 43.5% and 43.0% with 5 and 10 mg twice daily, respectively, compared with 36.7% in the placebo group (p=0.325 and 0.392 for 5 and 10 mg twice daily vs placebo). At week 26 of maintenance, the proportion of patients with clinical response-100 or remission was 55.8% with tofacitinib 10 mg twice daily compared with 39.5% with tofacitinib 5 mg twice daily and 38.1% with placebo (p=0.130 for 10 mg twice daily vs placebo). Compared with placebo, the change in C-reactive protein from baseline was statistically significant (p<0.0001) with 10 mg twice daily after both induction and maintenance treatments. CONCLUSIONS: Primary efficacy endpoints were not significantly different from placebo, although there was evidence of a minor treatment effect. No new safety signals were observed for tofacitinib. TRIAL REGISTRATION NUMBERS: NCT01393626 and NCT01393899.

Efficacy and safety of an interleukin 6 monoclonal antibody for the treatment of systemic lupus erythematosus: a phase II dose-ranging randomised controlled trial.

OBJECTIVES: This phase II trial evaluated the efficacy and safety of an interleukin (IL) 6 monoclonal antibody for systemic lupus erythematosus (SLE). METHODS: Patients with active disease were randomised to placebo or PF-04236921 10 mg, 50 mg or 200 mg, subcutaneously, every 8 weeks with stable background therapy. SLE Responder Index (SRI-4; primary end point) and British Isles Lupus Assessment Group-based Composite Lupus Assessment (BICLA) were assessed at week 24. Post hoc analysis identified an enriched population based upon planned univariate analyses. RESULTS: 183 patients received treatment (placebo, n=45; 10 mg, n=45; 50 mg, n=47; 200 mg, n=46). The 200 mg dose was discontinued due to safety findings and not included in the primary efficacy analysis. The SRI-4 response rates were not significant for any dose compared with placebo; however, the BICLA response rate was significant for 10 mg (p=0.026). The incidence of severe flares was significantly reduced with 10 mg (n=0) and 50 mg (n=2) combined versus placebo (n=8; p<0.01). In patients with greater baseline disease activity (enriched population), the SRI-4 (p=0.004) and BICLA (p=0.012) response rates were significantly different with 10 mg versus placebo. Four deaths (200 mg, n=3; 10 mg, n=1) occurred. The most frequently reported adverse events included headache, nausea and diarrhoea. CONCLUSIONS: PF-04236921 was not significantly different from placebo for the primary efficacy end point in patients with SLE. Evidence of an effect with 10 mg was seen in a post hoc analysis. Safety was acceptable for doses up to 50 mg as the 200 mg dose was discontinued due to safety findings. TRIAL REGISTRATION NUMBER: NCT01405196; Pre-results.

Myocilin Predictive Genetic Testing for Primary Open-Angle Glaucoma Leads to Early Identification of At-Risk Individuals.

PURPOSE: To assess the difference in severity of disease in primary open-angle glaucoma (POAG) patients with a Myocilin (MYOC) disease-causing variant who presented through normal clinical pathways (Clinical cases) versus those who were examined following genetic testing (Genetic cases). DESIGN: Retrospective clinical and molecular study. PARTICIPANTS: Seventy-three MYOC mutation carriers identified through the Australian and New Zealand Registry of Advanced Glaucoma. METHODS: Individuals were classified based on how they first presented to an ophthalmologist: Clinical cases were referred by their general practitioner or optometrist, and Genetic cases were referred following positive results from genetic testing for the previously identified familial MYOC variant (cascade genetic testing). All cases were then sub-classified into 4 groups (unaffected, glaucoma suspect, glaucoma, advanced glaucoma) according to the severity of disease at the time of their first examination by an ophthalmologist. MAIN OUTCOME MEASURES: Glaucoma clinical parameters and age at presentation. RESULTS: At their first examination, 83% of Genetic cases were unaffected and 17% were glaucoma suspect, whereas among Clinical cases 44% were glaucoma suspect, 28% had glaucoma, and 28% had advanced glaucoma. Genetic cases were significantly younger at presentation than Clinical cases (40.6±12.5 vs. 47.5±16.7 years; P = 0.018). The mean highest intraocular pressure (32.2±9.7 vs. 17.6±3.6 mmHg; P < 0.001), cup-to-disc ratio (0.65±0.27 vs. 0.48±0.13; P = 0.006), and mean deviation on visual field testing (-10.0±10.3 vs. -1.2±1.2; P < 0.001) were all significantly worse in Clinical cases compared with Genetic cases. Individuals with common MYOC p.Gln368Ter variant were further analyzed separately to account for the phenotypic variability of different disease-causing variants. All findings remained significant after adjusting for the common MYOC p.Gln368Ter variant. CONCLUSIONS: Our findings demonstrated that MYOC cascade genetic testing for POAG allows identification of at-risk individuals at an early stage or even before signs of glaucoma are present. To our knowledge, this is the first study to demonstrate the clinical utility of predictive genetic testing for MYOC glaucoma.

Ulcerative Colitis Treatment Patterns and Cost of Care.

OBJECTIVES: To examine treatment patterns, dosing, health care resource utilization, and cost of tumor necrosis factor inhibitors (TNFi), adalimumab (ADA) and infliximab (IFX), among patients enrolled in US Humana insurance plans who have been diagnosed with ulcerative colitis (UC). METHODS: This retrospective cohort study identified the first pharmacy or medical claim for ADA or IFX (from January 1, 2007, to December 31, 2014) in patients with continuous enrollment for 6 months or more preindex and 12 months or more postindex, with one or more UC diagnosis claim 6 months pre- or postindex. TNFi discontinuation was defined as a therapy gap of 56 days or more for ADA and 112 days or more for IFX. TNFi switch was defined as nonindex TNFi initiation. Health care resource utilization and costs were characterized quarterly according to treatment patterns. RESULTS: The study population comprised 295 patients: mean age 50.9 years, 50.5% females, and 61.7% in southern United States. At the index date, 17% of patients received ADA and 83% received IFX. Treatment discontinuation was observed in 52% of ADA and 45% of IFX users through 12 months postindex (mean time 19 and 22 weeks, respectively). Among discontinuers, 46% of ADA and 68% of IFX users did not restart/switch TNFi. ADA and IFX showed mean times to switch of 18 and 30 weeks, respectively. TNFi discontinuers had the lowest mean quarterly total health care cost ($3,935) versus patients who initiated/switched TNFi ($15,004). Nevertheless, discontinuers had higher UC-related hospitalization versus patients receiving therapy. CONCLUSIONS: Approximately half of ADA and IFX users discontinued, with approximately half of discontinuers not restarting/switching therapies. Further investigation of treatment patterns and outcomes after TNFi discontinuation is required.

Efficacy and cost-effectiveness of intracameral vancomycin in reducing postoperative endophthalmitis incidence in Australia.

BACKGROUND: Endophthalmitis is a rare but devastating postoperative complication of cataract surgery. We aimed to describe the incidence of acute postoperative endophthalmitis in an Australian population over a 14-year period. DESIGN: This was a retrospective longitudinal cohort study performed at Westmead Hospital, a major tertiary hospital in Sydney, Australia. PARTICIPANTS: Patients who had acute postoperative endophthalmitis within 6 weeks of their cataract surgery at Westmead Hospital were included. METHODS: Endophthalmitis cases from 2000 to 2014 were identified from computerized diagnostic coding. These were cross-referenced with the cataract surgery list over this time period. The routine use of intracameral vancomycin at the end of cataract surgery was introduced in Westmead Hospital in 2004. MAIN OUTCOME MEASURES: We quantified the incidence of acute postoperative endophthalmitis pre and post the routine use of intracameral vancomycin. RESULTS: A total of 14 805 cataract cases were performed at Westmead Hospital from 2000 to 2014. Seventeen cases of endophthalmitis were within 6 weeks post cataract surgery performed at Westmead Hospital. In the period 2000 to 2003, the incidence of postoperative endophthalmitis was 0.43% (11/2539). From 2004 to 2014, there was a dramatic decrease in the incidence of postoperative endophthalmitis to 0.049% (6/12 266, P < 0.0001). CONCLUSIONS: There has been a nine-fold reduction in the rate of acute postoperative endophthalmitis with the use of intracameral vancomycin in cataract surgery. Post-cataract surgery endophthalmitis is now a relatively rare cause of endophthalmitis in this Australian population. Our study supports the routine use of intracameral vancomycin as postoperative endophthalmitis prophylaxis.

Randomized trial of tofacitinib in active ulcerative colitis: analysis of efficacy based on patient-reported outcomes.

BACKGROUND: Tofacitinib, a novel, oral Janus kinase inhibitor, demonstrated a dose-dependent efficacy for induction of clinical response and remission in patients with active ulcerative colitis (UC). The objective of the current study was to determine the effect of tofacitinib on patient-reported outcomes (PROs). METHODS: Eligible patients (≥18 years of age) with a diagnosis of active UC (total Mayo score of 6-12 points and moderately-to-severely active disease on sigmoidoscopy) were randomized in a 2:2:2:3:3 ratio to receive oral tofacitinib 0.5 mg, 3 mg, 10 mg, or 15 mg, or placebo twice daily (BID) for 8 weeks. PROs were assessed by the Inflammatory Bowel Disease Questionnaire (IBDQ) and the Inflammatory Bowel Disease Patient-Reported Treatment Impact (IBD PRTI) survey. RESULTS: At Week 8, mean IBDQ total scores had improved relative to baseline across all five treatment groups (baseline range 123.2-134.5; Week 8 range 149.6-175.4). Improvement from baseline was significantly greater (P = 0.001) for tofacitinib 15 mg BID versus placebo. For tofacitinib 15 mg BID, most patients reported satisfaction or extreme satisfaction, definite preference for tofacitinib, and definite willingness to use tofacitinib again on the IBD PRTI at week 8. Patients achieving endoscopic remission (Mayo endoscopy score of 0) had significantly higher IBDQ scores and favorable PRTI scores than those not achieving endoscopic remission. CONCLUSIONS: Short-term treatment with tofacitinib BID was associated with dose-dependent improvement in health-related quality of life and patient preferences for tofacitinib. The results complement previously reported efficacy and safety data for the Phase II study. (NCT 00787202, November 6, 2008).

Influence of education and diagnostic modes on glaucoma assessment by optometrists.

PURPOSE: To evaluate the influence of different clinical examination techniques, including optic nerve head (ONH) photography, visual field tests, and adjunct imaging on the diagnosis of glaucoma by Australian and New Zealand optometrists. The effect of a short-term, didactic teaching module on these is also explored. METHODS: Clinical data of 30 patients previously seen at the Centre for Eye Health was collected and compiled into glaucoma diagnostic assessment modules. Each of six modules contained different combinations of clinical examination results and required a classification of the cases as normal, suspicious or glaucoma. A cohort of 54 Australian and New Zealand optometrists were recruited for the study and allocated into two cohorts. The intervention group completed a glaucoma training course prior to the assessment while the control group completed the assessment without additional training. Diagnostic accuracy was compared between modules and optometrist groups. RESULTS: High false negative rates were observed with ONH photography, which were drastically reduced with the addition of visual field, albeit at the cost of increased false positive rates. Addition of adjunct imaging techniques partially compensated for the increase in the false positive rate from the visual field, but had limited effect on false negative rate. Educational intervention resulted in larger improvement in the diagnostic ability when multiple imaging modalities were provided. CONCLUSION: The study highlighted the importance of combining both structural and functional assessments in glaucoma. Current imaging technology demonstrated limited usefulness for event diagnosis due to the persistent difficulties of defining structural and functional loss in glaucoma, thus highlighting the need for new glaucoma assessment techniques. Short-term didactic teaching programs may only result in limited improvement of glaucoma diagnostic ability in optometrists, and hence, it may need to be combined with long-term and/or non-didactic training components to obtain a greater effect.

Intraocular pressure-lowering medications and long-term outcomes of selective laser trabeculoplasty.

BACKGROUND: To investigate the effects of current intraocular pressure-lowering medications on the efficacy of selective laser trabeculoplasty. DESIGN: Retrospective chart review of records from an urban glaucoma clinic in Sydney, Australia. PARTICIPANTS: Patients who received their first selective laser trabeculoplasty between 2002 and 2005 were studied (grouped from 0 to 3 according to the number of pre-selective laser trabeculoplasty medications, and followed for 5 years). Those with previous argon laser therapy, trabeculectomy or angle-closure were excluded. METHODS: Selective laser trabeculoplasty (Ellex) used to deliver 180 or 360 degree of treatment, under the same protocol. MAIN OUTCOME MEASURES: Responders were defined by ≥20% reduction from baseline intraocular pressure. Data were censored when pressure-lowering intervention was required. The mean intraocular pressure, survivor, response rate, number and type of medications were compared. RESULTS: There were 206 patients with ocular hypertension, primary, pseudo-exfoliation, or pigmentary glaucoma who used none (n = 20), one (n = 33), two (n = 61) or three or more (n = 92) pre-selective laser trabeculoplasty topical anti-glaucoma medications. The mean baseline intraocular pressures for each group was 23.7, 22.2, 20.7 and 20.4 mmHg, respectively (P = 0.061). Post-treatment mean intraocular pressure was 17.9, 17.7, 15.5, and 15.7 mmHg; percentage reduction was similar between groups (23.6-25.6%, P = 0.20). Kaplan-Meier survival analysis showed comparable survival rates across groups (P = 0.445). At 60 months, 11.1, 17.1, 30.5 and 11.5% of responders remained in each group. Higher proportions of patients in groups 2 and 3 required further laser or surgery. CONCLUSION: The number of pre-selective laser trabeculoplasty medications did not affect the intraocular pressure-lowering effectiveness of selective laser trabeculoplasty; however, groups on more medications required more pressure-lowering interventions.