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BACKGROUND AND OBJECTIVES: No evidence of disease activity (NEDA)-4 has been suggested as a treatment target for disease-modifying therapy (DMT) in relapsing-remitting multiple sclerosis (RRMS). However, the ability of NEDA-4 to discriminate long-term outcomes in MS and how its performance compares with NEDA-3 remain uncertain. We conducted a systematic review and meta-analysis to evaluate (1) the association between NEDA-4 and no long-term disability progression in MS and (2) the comparative performance of NEDA-3 and NEDA-4 in predicting no long-term disability progression. METHODS: English-language abstracts and manuscripts were systematically searched in MEDLINE, Embase, and the Cochrane databases from January 2006 to November 2021 and reviewed independently by 2 investigators. We selected studies that assessed NEDA-4 at 1 or 2 years after DMT start and had at least 4 years of follow-up for determination of no confirmed disability progression. We conducted a meta-analysis using random-effects model to determine the pooled odds ratio (OR) for no disability progression with NEDA-4 vs EDA-4. For the comparative analysis, we selected studies that evaluated both NEDA-3 and NEDA-4 with at least 4 years of follow-up and examined the difference in the association of NEDA-3 and NEDA-4 with no disability progression. RESULTS: Five studies of 1,000 patients (3 interferon beta and 2 fingolimod) met inclusion criteria for both objectives. The median duration of follow-up was 6 years (interquartile range: 4-6 years). The prevalence of NEDA-4 ranged from 4.2% to 13.9% on interferon beta therapy and 24.9% to 25.1% on fingolimod therapy. The pooled OR for no long-term confirmed disability progression with NEDA-4 vs EDA-4 was 2.14 (95% confidence interval: 1.36-3.37; I2 = 0). We did not observe any significant difference between NEDA-4 and NEDA-3 in the comparative analyses. DISCUSSION: In patients with RRMS, NEDA-4 at 1-2 years was associated with 2 times higher odds of no long-term disability progression, at 6 years compared with EDA-4, but offered no advantage over NEDA-3.

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OBJECTIVE: We conducted a systematic review and meta-analysis to evaluate the relationship between No Evidence of Disease Activity (NEDA) and no long-term disability progression on low and high efficacy therapy in relapsing-remitting multiple sclerosis (RRMS). METHODS: MEDLINE, Embase, and the Cochrane Database were searched from January 1, 2006 to January 26, 2021. We selected studies which evaluated NEDA-3 (no relapse, new MRI lesion, or confirmed disability progression) at one or two years and had a minimum of four years' follow-up for determination of disability progression. Data were extracted by two independent reviewers and were meta-analyzed using a random effects model. Primary outcome of no disability progression was defined as no confirmed progression on the Expanded Disability Status Scale (EDSS) during follow-up. We assessed the odds ratio for no disability progression with NEDA vs. Evidence of Disease Activity (EDA). Positive predictive value of NEDA for no disability progression was summarized for studies with prevalence of no progression >80% vs. <80% separately. RESULTS: We included 29 studies in our qualitative synthesis of which 27 (16 low efficacy, 11 high efficacy) were included in the meta-analysis (n=10,935 participants). Median follow-up was 5.6 years (IQR: 4.3, 8.0 years). The pooled odds ratios for no progression with NEDA-3 vs. EDA were 2.32 (95% CI: 1.58-3.42; I2=73%) for low efficacy therapy and 3.19 (1.86-5.47; I2=86%) for high efficacy therapy. Among studies with prevalence of no progression at follow-up >80%, the pooled positive predictive value for low efficacy therapy was 91% (95% CI: 89-93%) and for high efficacy therapy was 92% (95% CI: 88-94%). Among studies with prevalence of no progression <80%, the pooled positive predictive value for low efficacy therapy was 81% (95% CI: 75-86%) and for high efficacy therapy was 86% (95% CI: 80-90%). CONCLUSIONS: NEDA-3 is associated with no long-term disability progression in RRMS on both low and high efficacy therapies. Further studies of early composite outcome measures incorporating easily measurable biomarkers, and longer follow-up, may help to improve on prognostic value of NEDA-3 in RRMS.

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INTRODUCTION: Among survivors of intensive care, many remain dependent on mechanical ventilation and are discharged to long-term chronic ventilator units or to skilled nursing facilities. Few long-term outcome data are available on patients transferred from long-term chronic ventilator units. METHODS: We retrospectively followed subjects discharged from a long-term chronic ventilator unit from 2010-2012. We determined where these subjects went, evaluating whether location of discharge had an effect on mortality. RESULTS: We followed 79 subjects who were 64.9 ± 15.9 y old. Average stay in the long-term chronic ventilator unit was 38.5 ± 20.1 d. Within the first year after discharge, 24 (30.3%) subjects died: 17 in a skilled nursing facility, 7 at home. Of those who survived the first year, 28 had been discharged to a skilled nursing facility and 27 to home. Survivors were younger (62.6 ± 12.4 vs 70.4 ± 13.1 y, P = .03), had shorter intensive care unit lengths of stay (10.4 ± 5.0 vs 16.4 ± 11.5 d, P = .03), and were more likely discharged home from long-term chronic ventilator unit (49.0% vs 29.1%, P = .040). CONCLUSIONS: Subjects discharged from an long-term chronic ventilator unit and were alive at 1 y had shorter stays in the ICU and were more likely to be discharged home. Further attention is warranted to assure the survival of critical care patients once they are discharged from intensive care units.

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