Development of a Core Outcome Set for Clinical Trials in Non-infectious Uveitis of the Posterior Segment.

PURPOSE: To develop an agreed upon set of outcomes known as a "core outcome set" (COS) for noninfectious uveitis of the posterior segment (NIU-PS) clinical trials. DESIGN: Mixed-methods study design comprising a systematic review and qualitative study followed by a 2-round Delphi exercise and face-to-face consensus meeting. PARTICIPANTS: Key stakeholders including patients diagnosed with NIU-PS, their caregivers, and healthcare professionals involved in decision-making for patients with NIU-PS, including ophthalmologists, nurse practitioners, and policymakers/commissioners. METHODS: A long list of outcomes was developed based on the results of (1) a systematic review of clinical trials of NIU-PS and (2) a qualitative study of key stakeholders including focus groups and interviews. The long list was used to generate a 2-round Delphi exercise of stakeholders rating the importance of outcomes on a 9-point Likert scale. The proportion of respondents rating each item was calculated, leading to recommendations of "include," "exclude," or "for discussion" that were taken to a face-to-face consensus meeting of key stakeholders at which they agreed on the final COS. MAIN OUTCOME MEASURE: Items recommended for inclusion in the COS for NIU-PS. RESULTS: A total of 57 outcomes grouped in 11 outcome domains were presented for evaluation in the Delphi exercise, resulting in 9 outcomes directly qualifying for inclusion and 15 outcomes being carried forward to the consensus meeting, of which 7 of 15 were agreed on for inclusion. The final COS contained 16 outcomes organized into 4 outcome domains comprising visual function, health-related quality of life, treatment side effects, and disease control. CONCLUSIONS: This study builds on international work across the clinical trials community and our qualitative research to construct the world's first COS for NIU-PS. The COS provides a list of outcomes that represent the priorities of key stakeholders and provides a minimum set of outcomes for use in all future NIU-PS clinical trials. Adoption of this COS can improve the value of future uveitis clinical trials and reduce noninformative research. Some of the outcomes identified do not yet have internationally agreed upon methods for measurement and should be the subject of future international consensus development.

Dual-target, real-time PCR for the diagnosis of intraocular Toxoplasma gondii infections.

BACKGROUND: Toxoplasma gondii is the most common infectious cause of posterior uveitis worldwide. Two multicopy targets (B1 and Rep529) are commonly used in T. gondii PCR assays, but studies evaluating these targets in ocular fluid samples are limited. Herein, we determine the analytical characteristics of a single-reaction, internally controlled, dual-target, real-time T. gondii PCR and evaluate the clinical performance of this assay in intraocular fluid samples obtained at a reference ophthalmologic centre in the USA. METHODS: Lower limits of detection for the B1 and Rep529 components of the dual-target assay were determined using serial dilutions of cultured T. gondii strain Z185. The dual-target assay was then used to test 148 archived intraocular samples (132 vitreous,16 aqueous humour) collected at the Francis I. Proctor Foundation between January 2010 and December 2015 for testing by a nested, conventional PCR targeting the B1 gene. RESULTS: The 95% lower limits of detection for the dual-target assay was determined to be 1.05 tachyzoites/mL for B1 and 0.83 tachyzoites/mL for Rep529. Using archived clinical intraocular specimens, the dual-target assay demonstrated 97.2% positive per cent agreement (n=35/36; 95% CI 83.7% to 99.9%) and 99.1% negative per cent agreement (n=111/112; 95% CI 94.4% to 100%) compared with the nested, conventional B1 PCR. CONCLUSION: This single-reaction, internally controlled, dual-target (B1, Rep529) real-time PCR for the detection of T. gondii DNA in intraocular specimens demonstrated excellent agreement with nested, conventional, B1 PCR. The dual-target design may ensure T. gondii detection when variation is present in one of two target regions.

Longitudinal Vision-Related Quality of Life for Patients with Noninfectious Uveitis Treated with Fluocinolone Acetonide Implant or Systemic Corticosteroid Therapy.

PURPOSE: To evaluate longitudinal vision-related quality of life (VRQoL) in patients with noninfectious uveitis. DESIGN: Cohort study using randomized controlled trial data. PARTICIPANTS: Patients with active or recently active intermediate uveitis, posterior uveitis, or panuveitis enrolled in the Multicenter Steroid Treatment Trial and Follow-up Study. METHODS: Data from the 25-item National Eye Institute Visual Functioning Questionnaire (NEI-VFQ-25) for the first 3 years after randomization were evaluated semiannually. Analyses were stratified by assigned treatment (129 implants vs. 126 systemic therapies) because of substantial differences in the trajectories of VRQoL. The impact of baseline measurements of visual function (visual acuity and visual field), demographics, and disease characteristics was assessed using generalized estimating equations. MAIN OUTCOME MEASURES: Primary outcome was the NEI-VFQ-25 composite score over 3 years after randomization. RESULTS: Individuals in both treatment groups showed similar improvement in NEI-VFQ-25 scores after 3 years of follow-up (implant: 11.9 points; 95% confidence interval [CI], 8.6-15.2; P < 0.001; systemic: 9.0 points; 95% CI, 5.6-12.3; P < 0.001; P = 0.21 for interaction). Individuals in the implant group showed a substantial improvement during the first 6 months followed by stable scores, whereas individuals in the systemic group showed a steady improvement over the course of follow-up. Worse initial visual acuity and visual fields were associated with lower initial NEI-VFQ-25 scores for both treatment groups. In the systemic group, these differences were maintained throughout follow-up. In the implant group, individuals with initial visual acuity worse than 20/40 showed additional improvement in NEI-VFQ-25 score to come within -7 points (95% CI, -15.0 to 0.9) of those with visual acuity 20/40 or better initially, a clinically meaningful but not statistically significant difference (P = 0.081). Results based on sensitivity analyses showed similar patterns. CONCLUSIONS: Both treatment groups demonstrated significant improvements in NEI-VFQ-25 scores; however, the improvement was immediate for the implant group as opposed to gradual for the systemic group. Poorer visual function was associated significantly with initial differences in NEI-VFQ-25 scores. However, only individuals in the implant group with poor visual acuity were able to overcome their initial deficits by the end of 3 years.

Quality-of-Life Outcomes From a Randomized Clinical Trial Comparing Antimetabolites for Intermediate, Posterior, and Panuveitis.

PURPOSE: To evaluate the changes in quality of life in noninfectious uveitis patients treated with 2 of the most commonly prescribed antimetabolite treatments. DESIGN: Secondary analysis of a multicenter, block-randomized clinical trial. METHODS: Eighty patients at Aravind Eye Hospitals in Madurai and Coimbatore, India, with noninfectious intermediate, posterior, or panuveitis were randomized to receive oral methotrexate, 25 mg weekly, or oral mycophenolate mofetil, 1 g twice daily, and were followed up monthly for 6 months. Best-corrected visual acuity, Indian Vision Function Questionnaire (IND-VFQ), and Medical Outcomes Study 36-item Short Form Survey (SF-36) were obtained at enrollment and at 6 months (or prior, in the event of early treatment failure). RESULTS: IND-VFQ scores, on average, increased by 9.2 points from trial enrollment to 6 months (95% confidence interval [CI]: 4.9, 13.5, P = .0001). Although the SF-36 physical component summary score did not significantly differ over the course of the trial, the mental component summary score decreased by 2.3 points (95% CI: -4.4, -0.1, P = .04) and the vitality subscale decreased by 3.5 points (95% CI: -5.6, -1.4, P = .001). Quality-of-life scores did not differ between treatment arms. Linear regression modeling showed a 3.2-point improvement in IND-VFQ score for every 5-letter improvement in visual acuity (95% CI: 1.9, 4.3; P < .001). CONCLUSIONS: Although uveitis treatment was associated with increased vision and vision-related quality of life, patient-reported physical health did not change after 6 months of treatment, and mental health decreased. Despite improved visual outcomes, uveitis patients receiving systemic immunosuppressive therapy may experience a deterioration in mental health-related quality of life.

Quality of Life and Risks Associated with Systemic Anti-inflammatory Therapy versus Fluocinolone Acetonide Intraocular Implant for Intermediate Uveitis, Posterior Uveitis, or Panuveitis: Fifty-four-Month Results of the Multicenter Uveitis Steroid Treatment Trial and Follow-up Study.

PURPOSE: To evaluate the risks and quality-of-life (QoL) outcomes of fluocinolone acetonide implant versus systemic therapy with corticosteroid and immunosuppression when indicated for intermediate uveitis, posterior uveitis, and panuveitis. DESIGN: Additional follow-up of a randomized trial cohort. PARTICIPANTS: Two hundred fifty-five patients with intermediate uveitis, posterior uveitis, or panuveitis, randomized to implant or systemic therapy. METHODS: Randomized subjects with intermediate uveitis, posterior uveitis, or panuveitis (479 eyes) were followed up over 54 months, with 79.2% completing the 54-month visit. MAIN OUTCOME MEASURES: Local and systemic potential complications of the therapies and self-reported health utility and vision-related and generic health-related QoL were studied prospectively. RESULTS: Among initially phakic eyes, cataract and cataract surgery occurred significantly more often in the implant group (hazard ratio [HR], 3.0; P = 0.0001; and HR, 3.8; P < 0.0001, respectively). In the implant group, most cataract surgery occurred within the first 2 years. Intraocular pressure elevation measures occurred more frequently in the implant group (HR range, 3.7-5.6; all P < 0.0001), and glaucoma (assessed annually) also occurred more frequently (26.3% vs. 10.2% by 48 months; HR, 3.0; P = 0.0002). In contrast, potential complications of systemic therapy, including measures of hypertension, hyperlipidemia, diabetes, bone disease, and hematologic and serum chemistry indicators of immunosuppression toxicity, did not differ between groups through 54 months. Indices of QoL initially favored implant therapy by a modest margin. However, all summary measures of health utility and vision-related or generic health-related QoL were minimally and nonsignificantly different by 54 months, with the exception of the 36-item Short-Form Health Survey physical component summary score, which favored implant by a small margin at 54 months (3.17 on a scale of 100; P = 0.01, not adjusted for multiple comparisons). Mean QoL results were favorable in both groups. CONCLUSIONS: These results suggest that fluocinolone acetonide implant therapy is associated with a clinically important increased risk of glaucoma and cataract with respect to systemic therapy, suggesting that careful monitoring and early intervention to prevent glaucoma is warranted with implant therapy. Systemic therapy subjects avoided a significant excess of toxicities of systemic corticosteroid and immunosuppressive therapies in the trial. Self-reported QoL measures initially favored implant therapy, but over time the measures converged, with generally favorable QoL in both groups.