Inflammation and glucose intolerance. A prospective study of gestational diabetes mellitus

WSTĘP. Podwyższony poziom leukocytów w surowicy krwi jest wskaźnikiem procesu zapalenia, który, jak wykazują badania prospektywne, wiąże się z rozwojem cukrzycy typu 2. Chociaż cukrzyca ciążowa oraz cukrzyca typu 2 mają dużo wspólnych mechanizmów patofizjologicznych, w niewielu pracach badano związek zapalenia z rozwojem cukrzycy ciążowej. MATERIAŁ I METODY. W badaniu oceniano w sposób prospektywny liczbę leukocytów w próbkach krwi pobranych podczas pierwszej rutynowej wizyty kontrolnej w grupie 2753 kobiet w ciąży &#8212; wieloródek z prawidłową wartością glikemii. U 98 (3,6%) z nich wystąpiła później cukrzyca ciążowa. Pacjentki podzielono na podgrupy w zależności od kwartyla liczby leukocytów i porównano wyniki przeprowadzanego w trzecim trymestrze przesiewowego testu tolerancji glukozy oraz częstość cukrzycy ciążowej wśród kobiet należących do poszczególnych kwartyli. Zastosowano test regresji logistycznej, aby obliczyć skorygowane względem jednego i wielu czynników względne ryzyko wystąpienia cukrzycy ciążowej w zależności od kwartyla leukocytozy. WYNIKI. U kobiet, u których doszło do rozwoju cukrzycy ciążowej, stężenie leukocytów w surowicy krwi było wyższe (10,5 &plusmn; 2,2 vs. 9,2 &plusmn; 2,2 × 103 komórek/ml; p < 0,01) niż u pacjentek, u których metabolizm węglowodanów pozostał prawidłowy. Wraz ze wzrostem kwartyla leukocytozy obserwowano liniowy wzrost glikemii po obciążeniu glukozą (p < 0,01), pola pod krzywą testu tolerancji glukozy (p < 0,01) oraz częstości cukrzycy ciążowej (kwartyl 1. &#8212; 1,1%; kwartyl 2. &#8212; 2,5%; kwartyl 3. &#8212; 4,2% i kwartyl 4. &#8212; 6,4%; p < 0,01). W analizie wieloczynnikowej, wraz ze wzrostem kwartyla leukocytozy, liniowy trend względnego ryzyka (RR, relative risk) rozwoju cukrzycy ciążowej pozostał statystycznie istotny [kwartyl 1. &#8212; referencyjny, kwartyl 2. &#8212; RR 2,3 (95% CI 0,9-5,7), kwartyl 3. &#8212; RR 3,3 (1,4&#8211;7,8), kwartyl 4. &#8212; RR 4,9 (2,1&#8211;11,2); p < 0,01]. WNIOSKI. Podwyższony poziom leukocytów we wczesnym okresie ciąży jest w sposób niezależny, liniowy związany z wynikami testów przesiewowych w kierunku cukrzycy ciążowej oraz ryzykiem wystąpienia tej choroby. Brak wyraźnej granicy w rozkładzie liczby leukocytów sprawia, że wskaźnik ten nie może mieć zastosowania klinicznego, chociaż dane sugerują, że proces zapalenia wiąże się z rozwojem cukrzycy ciążowej. Może to być kolejny mechanizm patofizjologiczny, łączący występowanie cukrzycy ciążowej z rozwojem w przyszłości cukrzycy typu 2.INTRODUCTION. Increased leukocyte count is a marker of inflammation that has been associated with the development of type 2 diabetes in prospective studies. Although gestational diabetes mellitus (GDM) and type 2 diabetes share certain pathophysiological mechanisms, few studies have examined inflammation and risk of GDM. MATERIAL AND METHODS. We prospectively examined routine leukocyte counts collected at the first prenatal visit in a cohort of 2,753 nulliparous euglycemic women, 98 (3.6%) of whom were later diagnosed with GDM. Subjects were divided into quartiles of leukocyte count, and the results of third-trimester glucose screening tests and the incidence of GDM among these quartiles were compared. Logistic regression was used to calculate univariate and multivariable-adjusted relative risks (RRs) of GDM according to leukocyte quartiles. RESULTS. Leukocyte counts were increased among women who subsequently developed GDM compared with those who remained free of GDM (10.5 &#177; &#177; 2.2 vs. 9.2 &#177; 2.2 × 103 cells/ml; P < 0.01). There was a linear increase in postloading mean glucose levels (P for trend < 0.01), the area under the glucose tolerance test curves (P for trend < 0.01), and the incidence of GDM (quartile 1, 1.1; quartile 2, 2.5; quartile 3, 4.2; and quartile 4, 6.4%; P for trend < 0.01) with increasing leukocyte quartiles. In the multivariable-adjusted analysis, the linear trend in the RR of GDM with increasing leukocyte quartiles remained statistically significant (quartile 1, reference; quartile 2, RR 2.3 [95% CI 0.9&#8211;5.7]; quartile 3, 3.3 [1.4&#8211;7.8]; quartile 4, 4.9 [2.1&#8211;11.2]; P for trend < 0.01). CONCLUSIONS. Increased leukocyte count early in pregnancy is independently and linearly associated with the results of GDM screening tests and the risk of GDM. Although overlap in the leukocyte count distributions precludes it from being a clinically useful biomarker, these data suggest that inflammation is associated with the development of GDM and may be another pathophysiological link between GDM and future type 2 diabetes

26th Annual Computational Neuroscience Meeting (CNS*2017): Part 3 - Meeting Abstracts - Antwerp, Belgium. 15–20 July 2017

This work was produced as part of the activities of FAPESP Research,\ud Disseminations and Innovation Center for Neuromathematics (grant\ud 2013/07699-0, S. Paulo Research Foundation). NLK is supported by a\ud FAPESP postdoctoral fellowship (grant 2016/03855-5). ACR is partially\ud supported by a CNPq fellowship (grant 306251/2014-0)

Amyloid-Related Imaging Abnormalities in 2 Phase 3 Studies Evaluating Aducanumab in Patients with Early Alzheimer Disease

Importance: The EMERGE and ENGAGE phase 3 randomized clinical trials of aducanumab provide a robust data set to characterize amyloid-related imaging abnormalities (ARIA) that occur with treatment with aducanumab, an amyloid-β (Aβ)-targeting monoclonal antibody, in patients with mild cognitive impairment due to Alzheimer disease or mild Alzheimer disease dementia. Objective: To describe the radiographic and clinical characteristics of ARIA that occurred in EMERGE and ENGAGE. Design, Setting, and Participants: Secondary analysis of data from the EMERGE and ENGAGE trials, which were 2 double-blind, placebo-controlled, parallel-group, phase 3 randomized clinical trials that compared low-dose and high-dose aducanumab treatment with placebo among participants at 348 sites across 20 countries. Enrollment occurred from August 2015 to July 2018, and the trials were terminated early (March 21, 2019) based on a futility analysis. The combined studies consisted of a total of 3285 participants with Alzheimer disease who received 1 or more doses of placebo (n = 1087) or aducanumab (n = 2198; 2752 total person-years of exposure) during the placebo-controlled period. Primary data analyses were performed from November 2019 to July 2020, with additional analyses performed through July 2021. Interventions: Participants were randomly assigned 1:1:1 to high-dose or low-dose intravenous aducanumab or placebo once every 4 weeks. Dose titration was used as a risk-minimization strategy. Main Outcomes and Measures: Brain magnetic resonance imaging was used to monitor patients for ARIA; associated symptoms were reported as adverse events. Results: Of 3285 included participants, the mean (SD) age was 70.4 (7.45) years; 1706 participants (52%) were female, 2661 (81%) had mild cognitive impairment due to Alzheimer disease, and 1777 (54%) used symptomatic medications for Alzheimer disease. A total of 764 participants from EMERGE and 709 participants from ENGAGE were categorized as withdrawn before study completion, most often owing to early termination of the study by the sponsor. Unless otherwise specified, all results represent analyses from the 10-mg/kg group. During the placebo-controlled period, 425 of 1029 patients (41.3%) experienced ARIA, with serious cases occurring in 14 patients (1.4%). ARIA-edema (ARIA-E) was the most common adverse event (362 of 1029 [35.2%]), and 263 initial events (72.7%) occurred within the first 8 doses of aducanumab; 94 participants (26.0%) with an event exhibited symptoms. Common associated symptoms among 103 patients with symptomatic ARIA-E or ARIA-H were headache (48 [46.6%]), confusion (15 [14.6%]), dizziness (11 [10.7%]), and nausea (8 [7.8%]). Incidence of ARIA-E was highest in aducanumab-treated participants who were apolipoprotein E ϵ4 allele carriers. Most events (479 of 488 [98.2%]) among those with ARIA-E resolved radiographically; 404 of 488 (82.8%) resolved within 16 weeks. In the placebo group, 29 of 1076 participants (2.7%) had ARIA-E (apolipoprotein E ϵ4 carriers: 16 of 742 [2.2%]; noncarriers, 13 of 334 [3.9%]). ARIA-microhemorrhage and ARIA-superficial siderosis occurred in 197 participants (19.1%) and 151 participants (14.7%), respectively. Conclusions and Relevance: In this integrated safety data set from EMERGE and ENGAGE, the most common adverse event in the 10-mg/kg group was ARIA-E, which occurred in 362 of the 1029 patients (35.2%) in the 10-mg/kg group with at least 1 postbaseline MRI scan, with 94 patients (26.0%) experiencing associated symptoms. The most common associated symptom was headache. Trial Registrations: ClinicalTrials.gov Identifiers: NCT02484547, NCT02477800

COVID-19 in Patients with Multiple Sclerosis: Associations with Disease-Modifying Therapies

Background Disease-modifying therapies (DMTs) for multiple sclerosis (MS) target immunity and have the potential to increase the risk of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection and alter its clinical course. We assessed these risks in patients with MS (PwMS). Objective The objective of this study was to describe the overall risk of coronavirus disease 2019 (COVID-19) infection, severe disease course, and potential population-level predictors of COVID-19 infection in PwMS, and to provide a context using a cohort of patients with systemic lupus erythematosus (SLE). In addition, the association of different MS DMTs with the incidence and clinical course of COVID-19 was evaluated. Safety data from the Biogen Global Safety Database are also presented on reported cases of COVID-19 in patients treated with Biogen MS therapies. Methods The IBM(R) Explorys electronic health record database of &gt; 72,000,000 patients from US healthcare networks identified patients with MS or SLE, with and without polymerase chain reaction-confirmed COVID-19. COVID-19 cumulative incidence, hospitalization, and deaths among DMT classes were compared using logistic regression (adjusted for age, sex, body mass index, comorbidities, and race/ethnicity). As a secondary data source to assess safety data, COVID-19 reports for Biogen MS therapies were extracted and described from Biogen's Global Safety Database. Results 30,478 PwMS with an open DMT prescription were identified within Explorys; 344 were COVID-19 positive. The most significant risk factors for acquiring COVID-19 were comorbidity score &gt;= 1, body mass index &gt;= 30, and Black/African ancestry. Similar risk factors were also identified for patients with SLE. Patients with MS were less likely to develop COVID-19 when treated with interferons (0.61%) and glatiramer acetate (0.51%), vs all other MS DMTs (both p &lt; 0.001); anti-CD20 therapy was associated with the highest risk (3.45%; p &lt; 0.0001). In the Biogen Global Safety Database, we identified 1217 patients who were COVID-19 positive treated with intramuscular interferon beta-1a, peginterferon beta-1a, natalizumab, dimethyl fumarate, diroximel fumarate, or fampridine. Conclusions Comorbidities, obesity, and Black/African ancestry, but not age, were associated with a higher risk of SARS-CoV-2 infection in PwMS. Interferons and glatiramer acetate were associated with a reduced COVID-19 risk, whereas anti-CD20 therapies were associated with an increased risk, within the treated MS cohort. COVID-19 safety reports for patients receiving Biogen MS therapies were consistent with the Explorys database and MS literature, illustrating the replicability and power of this approach

Comparison of switching to 6-week dosing of natalizumab versus continuing with 4-week dosing in patients with relapsing-remitting multiple sclerosis (NOVA): a randomised, controlled, open-label, phase 3b trial

Background: Treatment with natalizumab once every 4 weeks is approved for patients with relapsing-remitting multiple sclerosis, but is associated with a risk of progressive multifocal leukoencephalopathy. Switching to extended-interval dosing is associated with lower progressive multifocal leukoencephalopathy risk, but the efficacy of this approach is unclear. We aimed to assess the safety and efficacy of natalizumab once every 6 weeks compared with once every 4 weeks in patients with relapsing-remitting multiple sclerosis. Methods: We did a randomised, controlled, open-label, phase 3b trial (NOVA) at 89 multiple sclerosis centres across 11 countries in the Americas, Europe, and Western Pacific. Included participants were aged 18–60 years with relapsing-remitting multiple sclerosis and had been treated with intravenous natalizumab 300 mg once every 4 weeks with no relapses for at least 12 months before randomisation, with no missed doses in the previous 3 months. Participants were randomly assigned (1:1), using a randomisation sequence generated by the study funder and contract personnel with interactive response technology, to switch to natalizumab once every 6 weeks or continue with once every 4 weeks. The centralised MRI reader, independent neurology evaluation committee, site examining neurologists, site backup examining neurologists, and site examining technicians were masked to study group assignments. The primary endpoint was the number of new or newly enlarging T2 hyperintense lesions at week 72, assessed in all participants who received at least one dose of assigned treatment and had at least one postbaseline MRI, relapse, or neurological examination or efficacy assessment. Missing primary endpoint data were handled under prespecified primary and secondary estimands: the primary estimand included all data, regardless of whether participants remained on the assigned treatment; the secondary estimand classed all data obtained after treatment discontinuation or study withdrawal as missing. Safety was assessed in all participants who received at least one dose of study treatment. Study enrolment is closed and an open-label extension study is ongoing. This study is registered with EudraCT, 2018-002145-11, and ClinicalTrials.gov, NCT03689972. Findings: Between Dec 26, 2018, and Aug 30, 2019, 605 patients were assessed for eligibility and 499 were enrolled and assigned to receive natalizumab once every 6 weeks (n=251) or once every 4 weeks (n=248). After prespecified adjustments for missing data, mean numbers of new or newly enlarging T2 hyperintense lesions at week 72 were 0·20 (95% CI 0·07–0·63) in the once every 6 weeks group and 0·05 (0·01–0·22) in the once every 4 weeks group (mean lesion ratio 4·24 [95% CI 0·86–20·85]; p=0·076) under the primary estimand, and 0·31 (95% CI 0·12–0·82) and 0·06 (0·01–0·31; mean lesion ratio 4·93 [95% CI 1·05–23·20]; p=0·044) under the secondary estimand. Two participants in the once every 6 weeks group with extreme new or newly enlarging T2 hyperintense lesion numbers (≥25) contributed most of the excess lesions. Adverse events occurred in 194 (78%) of 250 participants in the once every 6 weeks group and 190 (77%) of 247 in the once every 4 weeks group, and serious adverse events occurred in 17 (7%) and 17 (7%), respectively. No deaths were reported. There was one case of asymptomatic progressive multifocal leukoencephalopathy (without clinical signs) in the once every 6 weeks group, and no cases in the once every 4 weeks group; 6 months after diagnosis, the participant was without increased disability and remained classified as asymptomatic. Interpretation: We found a numerical difference in the mean number of new or newly enlarging T2 hyperintense lesions at week 72 between the once every 6 weeks and once every 4 weeks groups, which reached significance under the secondary estimand, but interpretation of statistical differences (or absence thereof) is limited because disease activity in the once every 4 weeks group was lower than expected. The safety profiles of natalizumab once every 6 weeks and once every 4 weeks were similar. Although this trial was not powered to assess differences in risk of progressive multifocal leukoencephalopathy, the occurrence of the (asymptomatic) case underscores the importance of monitoring and risk factor consideration in all patients receiving natalizumab. Funding: Biogen