BackgroundClinical trials established the efficacy and safety of natalizumab. Data are needed over longer periods of time and in the clinical practice setting.ObjectiveTo evaluate long-term safety of natalizumab and its impact on annualised relapse rate and Expanded Disability Status Scale (EDSS) progression in patients with relapsing-remitting multiple sclerosis (RRMS).MethodsThe Tysabri (natalizumab) Observational Program (TOP) is an open-label, multinational, 10-year prospective study in clinical practice settings.ResultsIn this 5-year interim analysis, 4821 patients were enrolled. Follow-up for at least 4 years from natalizumab commencement in 468 patients and at least 2 years in 2496 patients revealed no new safety signals. There were 18 cases of progressive multifocal leucoencephalopathy reported, following 11–44 natalizumab infusions. Mean annualised relapse rate decreased from 1.99 in the 12 months prior to baseline to 0.31 on natalizumab therapy (p<0.0001), remaining low at 5 years. Lower annualised relapse rates were observed in patients who used natalizumab as first MS therapy, in patients with lower baseline EDSS scores, and in patients with lower prenatalizumab relapse rates. Mean EDSS scores remained unchanged up to 5 years.ConclusionsInterim TOP data confirm natalizumab's overall safety profile and the low relapse rate and stabilised disability levels in natalizumab-treated patients with RRMS in clinical practice.Trial registration numberNCT00493298.

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ObjectiveTo compare treatment efficacy and persistence in patients who switched to natalizumab versus those who switched between glatiramer acetate (GA) and interferon-beta (IFNβ) after an on-treatment relapse on IFNβ or GA using propensity score matched real-world datasets.MethodsPatients included were registered in MSBase or the TYSABRI Observational Program (TOP), had relapsed on IFNβ or GA within 12 months prior to switching to another therapy, and had initiated natalizumab or IFNβ/GA treatment ≤6 months after discontinuing prior therapy. Covariates were balanced across post switch treatment groups by propensity score matching at treatment initiation. Relapse, persistence, and disability measures were compared between matched treatment arms in the total population (n = 869/group) and in subgroups defined by prior treatment history (IFNβ only [n = 578/group], GA only [n = 165/group], or both IFNβ and GA [n = 176/group]).ResultsCompared to switching between IFNβ and GA, switching to natalizumab reduced annualized relapse rate in year one by 65–75%, the risk of first relapse by 53–82% (mean follow-up 1.7–2.2 years) and treatment discontinuation events by 48–65% (all P ≤ 0.001). In the total population, switching to natalizumab reduced the risk of confirmed disability progression by 26% (P = 0.036) and decreased the total disability burden by 1.54 EDSS-years (P < 0.0001) over the first 24 months post switch.InterpretationUsing large, real-world, propensity-matched datasets we demonstrate that after a relapse on IFNβ or GA, switching to natalizumab (rather than between IFNβ and GA) led to superior outcomes for patients in all measures assessed. Results were consistent regardless of the prior treatment identity.

Background Atopic dermatitis (AD) is characterized by abnormal skin lipids that are largely driven by hyperactivated type 2 immune responses. The antibody to the α‐subunit of interleukin (IL)‐4 receptor, dupilumab, was recently approved to treat AD and demonstrated strong efficacy. However, the role of dupilumab therapy in the regulation of skin barrier structure and function has not been fully explored. Methods We have evaluated the content of lipids and transepidermal water loss (TEWL) in lesional and non‐lesional skin of adults and adolescents with moderate‐to‐severe AD over the course of 16‐week treatment with dupilumab and compared those values with that of matched healthy volunteers. Results Dupilumab treatment provided a significant decrease in TEWL in AD lesions, lowering it almost to the levels seen in the skin of healthy subjects. Blocking IL‐4/IL‐13 signaling with dupilumab normalized lipid composition (decreased levels of ceramides with non‐hydroxy fatty acids and C18‐sphingosine and increased the level of esterified omega‐hydroxy fatty acid‐containing ceramides) and increased ceramide chain length in lesional as well as non‐lesional stratum corneum of AD patients. Partial changes for these parameters were already observed after 2 weeks, with a full response achieved after 8 weeks of dupilumab treatment. Conclusions Inhibition of IL‐4/IL‐13 signaling by dupilumab allows restoration of skin lipid composition and barrier function in patients with moderate‐to‐severe AD.