Efficacy of TNF-Alpha Inhibitors to Control Inflammation and Prevent Secondary Complications in Non-Infectious Uveitis: A Real-Life Experience from Switzerland.

PURPOSE: To evaluate the efficacy of systemic tumor necrosis factor-alpha inhibitors (TNFi) in the treatment of non-infectious uveitis (NIU). METHODS: This Swiss multicenter retrospective cohort study included patients with NIU requiring TNFi during the period from 2001 to 2018. Risk factors for the occurrence of new complications were identified using Cox regression analysis and hazard ratios (HR). RESULTS: Seventy-one patients (126 eyes; mean age 40.6 ± 14.4 years, mean duration of uveitis 46.0 ± 61.8 months) were followed for 40.2 ± 17.3 months after addition of TNFi. Under TNFi, visual acuity improved from 0.2 ± 0.3 to 0.1 ± 0.3 logMAR (p < 0.001). The portion of patients under systemic corticosteroids decreased from 81.7% to 25.4% (p < 0.001), while that for conventional synthetic disease-modifying anti-rheumatic drugs insignificantly decreased from 63.4% to 50.7% (p > 0.05). In 80.2% of eyes, complications were present at baseline with epiretinal gliosis (39.7%), cataract (41.3%) and macular edema (ME; 27.8%) being the most common. New complications under TNFi were encountered in 49.2% of eyes, also including recurrence (5 eyes) or new onset of ME (14 eyes). The need for switching of TNFi was associated with further complications (HR 3.78, p = 0.012). CONCLUSION: Although the efficacy and tolerability of TNFi in a real-life setting are favorable, treatment is often initiated late, i.e., after many eyes have already developed complications. Even with TNFi, new complications, particularly ME, cannot be completely avoided. Further research is needed to assess the impact of earlier initiation of TNFi therapy.

Long-term Efficacy of TNF-alpha Inhibitors on Persistent Uveitic Macular Edema: A Swiss Multicenter Cohort Study.

PURPOSE: To assess the efficacy of tumor necrosis factor-alpha inhibitors (TNFi) on uveitic macular edema (ME) unresponsive to conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs). METHODS: This multicenter retrospective study included patients with uveitic ME persisting despite csDMARDs. The effect of an additional TNFi on central retinal thickness (CRT), best corrected visual acuity (BCVA) and corticosteroid need was evaluated. RESULTS: Thirty-five eyes (26 patients, mean age 42.9 ± 15.2 years) were included. CRT decreased from 425 ± 137 µm to 294 ± 66 µm (p < .001) and 280 ± 48 µm (p < .001) at 1 and 4 years of follow-up, respectively. BCVA improved from 0.28 ± 0.22 to 0.21 ± 0.48 (1 year, p = .013) and 0.08 ± 0.13 logMAR (4 years, p = .002). The proportion of patients requiring systemic corticosteroids decreased from 88.5% to 34.8% (1 year) and 15.4% (4 years). CONCLUSION: The addition of a TNFi resulted in an improvement of CRT and BCVA for up to 4 years in uveitic ME but rescue treatments were needed for some patients.

Risks and Challenges in Interpreting Simultaneous Analyses of Multiple Cytokines.

Purpose: To determine the inherent risks of handling results below the lowest detectable value in the analysis of multiple cytokines in the aqueous humor of patients with retinal diseases by comparing possible statistical strategies to lower the risk of mis interpretation or over interpretation of results. Furthermore, in analyzing multiple cytokines simultaneously, the challenge of multiple comparison arises. Methods: The analyses were based on parallel testing of 43 cytokines in 58 aqueous humor samples from patients with macular hole or epiretinal membrane. Substitution of values below the detection limit with 0.1 ×, 0.5 ×, or 1.0× of the lowest level of quantitation was compared with handling as missing value. The impact of correction for multiple comparisons was assessed using the Holm correction. Results: When comparing macular hole with epiretinal membrane, not substituting the missing data revealed a difference (P < 0.05) for five compared with wight cytokines after their substitution, indicating an increased risk for under-estimating group differences (type II error). Correcting for multiple comparisons revealed a relevant risk of over estimating group differences (type I error). Conclusions: Physiologic cytokine concentrations in ocular fluids typically range at or below the lowest level of quantitation. Handling of results below this cutoff as missing leads to increased type II errors. Not correcting for multiple comparisons increases the risk of a type I error. Taken together, both harbor a systematic inherent risk of misinterpretation of the results. Translational Relevance: Ignoring the inherent risks of data misinterpretation in analyses of ocular fluid samples may result in mis leading conclusions regarding their biological relevance.

Long-term Outcome of Intravitreal Aflibercept Treatment for Neovascular Age-Related Macular Degeneration Using a "Treat-and-Extend" Regimen.

PURPOSE: To report outcomes in patients with neovascular age-related macular degeneration (nAMD) after treatment with aflibercept for up to 4 years using a treat-and-extend (T&E) regimen. DESIGN: Observational study. PARTICIPANTS: Patients with newly diagnosed nAMD treated with aflibercept in a T&E protocol. METHODS: Subjects received 3 injections of aflibercept at monthly intervals followed by a T&E protocol for at least 12 months. At each clinical visit after the loading phase, OCT and best-corrected visual acuity (BCVA) testing were performed to monitor disease activity. MAIN OUTCOME MEASURES: Change in BCVA over time, number of injections and visits per year, and percentage of patients reaching a treatment interval of ≥12 weeks. RESULTS: Of 231 consecutive eyes (231 patients) with a mean follow-up time of 2.9 (1-5.5) years, 173 were followed up for ≥2 years, 112 were followed up for ≥3 years, and 62 were followed up for ≥4 years. Mean BCVA increased from 59.8 letters (20/60) at diagnosis to 65.8 letters (20/50) after the loading phase (+6.0 letters; standard deviation [SD], 11.1) and to 65.5 letters at 12 months (+5.7 letters; [SD], 17). After 4 years of treatment, mean BCVA was maintained insignificantly better than baseline (63.4 letters, +3.6 letters gain, SD, 20.6; P > 0.05). To achieve this, a mean of 7.7 (±1.2) injections and 4.4 (±1.6) clinic visits in the first year and 4.4 (±1.9) injections and 4.3 (±1.3) clinical visits per year thereafter were required. By 2 years of follow-up, 46.9% of patients reached a treatment interval of ≥12 weeks. CONCLUSIONS: By using a T&E regimen, patients with nAMD maintained stable visual function over 4 years in a real-world setting with a reasonable treatment burden.

Cytokine profiles in the aqueous humor and serum of patients with dry and treated wet age-related macular degeneration.

PURPOSE: To identify disease-specific cytokine profile differences in the aqueous humor (AH) (other than the vascular endothelial growth factor) between patients with dry and treated wet age-related macular degeneration (AMD) and healthy controls. METHODS: This retrospective study drew on a case-series of patients diagnosed with dry AMD (n = 25) and treated wet AMD (n = 19), as well as on healthy controls (no systemic therapy; n = 20) undergoing phacoemulsification or vitrectomy. Samples of AH and serum were collected in parallel at the beginning of surgery. The levels of 43 cytokines were simultaneously determined using the Bio-Plex® multiplex beads system. Differences between the three groups were statistically compared using the Kruskal-Wallis H-Test after applying the Bonferroni correction for multiple comparisons (p<0.0012). RESULTS: The concentrations of three cytokines were elevated in the AH of patients with dry AMD (CXCL6; p = 0.00067) and treated wet AMD (CXCL5, CXCL6, MIG/XCXL; all p<0.001) relative to those in the healthy controls. No other differences between the three groups were identified. The AH levels of seven cytokines (16%), including CXCL6, ranged below the lower limit of quantitation of the assay. Without the correction for multiple comparisons (p<0.05), the levels of 31 of the 43 cytokines in the AH of patients with AMD would have differed significantly from those in the control. The systemic cytokine profiles (serum) were similar in all three groups. CONCLUSIONS: No systematic differences in the AH cytokine environment were identified between patients with dry AMD and those with treated wet AMD. This finding might indicate that AMD is either the result of a persistent imbalance in the physiological tissue milieu, or that the localized process induces no significant change in the cytokine environment of the anterior ocular segment.