Natalizumab treatment significantly reduced the annualised relapse rate and MRI activity over 2 years compared with placebo in phase III trials when administered as monotherapy in AFFIRM or in ...combination with interferon β-1a (IFNβ) in SENTINEL. The post hoc analyses reported here sought to determine the effect of natalizumab treatment on relapse activity in the minority of patients who continued to show MRI activity (ie, ≥ 1 gadolinium enhancing (Gd+) lesions or new or enlarging T2 hyperintense lesions) over 2 years in these trials. These analyses demonstrated that natalizumab treatment, both alone (AFFIRM) and in combination with IFNβ (SENTINEL), resulted in a reduced annualised relapse rate despite the presence of Gd+ lesions (p=0.004 and p=0.008, respectively) or new or enlarging T2 hyperintense lesions (each p<0.0001). Thus patients treated with natalizumab show clinical benefit even in the presence of continued MRI activity. Long term clinical outcome of these patients has not been studied.
This paper deals with thyroid disease that can occur after treatment with alemtuzumab (humanized monoclonal anti-CD52) for relapsing–remitting multiple sclerosis (MS). The 5-year incidence of thyroid ...adverse events in phase 3 clinical trials is up to 40.7%. In most cases, the thyroid dysfunction is mild and easily manageable and only few serious thyroid adverse events have been reported. The need for patient education on the risk of thyroid dysfunction, as well as regular clinical and biochemical thyroid function screening is well described. However, practical clinical guidance in case of abnormal thyroid-related findings prior to or after alemtuzumab treatment is currently lacking. Therefore, a Belgian taskforce consisting of MS and thyroid experts was created in 2016, with the objective of issuing a clinical thyroid management algorithm based on available scientific evidence and personal experience with regard to alemtuzumab treatment-related thyroid adverse events.
It was observed that interferon β (IFN-β) prevents the down-regulation of the interleukin-3 receptor α chain (IL-3Rα), which spontaneously occurs during culture of human monocytes. The functionality ...of IL-3R was demonstrated by the fact that IL-3 rescued IFN-β–treated monocytes from apoptosis. Monocytes cultured in the presence of IFN-β and IL-3 acquire a dendritic morphology and express high levels of HLA antigen class I and class II and costimulatory molecules. When stimulated by either lipopolysaccharide or fibroblasts expressing CD40 ligand (CD40L) transfectants, dendritic cells (DCs) generated in IFN-β and IL-3 secreted high levels of IL-6, IL-8, and tumor necrosis factor-α but low levels of IL-12 in comparison with DCs generated in IL-4 and granulocyte-macrophage colony-stimulating factor (GM-CSF). In mixed leukocyte culture, IL-3–IFN-β DCs induced a vigorous proliferative response of allogeneic cord blood T cells and elicited the production of high levels of IFN-γ and IL-5 by naive adult CD4+ T cells. Finally, IL-3–IFN-β DCs were found to produce much higher levels of IFN-α than IL-4–GM-CSF DCs in response to Poly (I:C) but not to influenza virus. It was concluded that monocytes cultured in the presence of IL-3 and IFN-β differentiate into DCs with potent helper T-cell stimulatory capacity despite their low secretion of IL-12.
Background: The Konectom™ smartphone-based cognitive processing speed (CPS) test is designed to assess processing speed and account for impact of visuomotor function on performance. Objective: ...Evaluate reliability and validity of Konectom CPS Test, performed in clinic and remotely. Methods: Data were collected from people with multiple sclerosis (PwMS) aged 18–64 years and healthy control participants (HC) matched for age, sex, and education. Remote test–retest reliability (intraclass correlation coefficients, ICC); correlation with established clinical measures (Spearman correlation coefficients); group analyses between cognitively impaired/unimpaired PwMS; and influence of age, sex, education, and upper limb motor function on CPS Test measures were assessed. Results: Eighty PwMS and 66 HC participated. CPS Test measures from remote tests had good test–retest reliability (ICC of 0.67–0.87) and correlated with symbol digit modalities test (highest |ρ| = 0.80, p < 0.0001). Remote measures were stable (change from baseline < 5%) and correlated with MS disability (highest |ρ| = 0.39, p = 0.0004) measured by Expanded Disability Status Scale. CPS Test measures displayed sensitivity to cognitive impairment (highest d = 1.47). Demographics and motor function had the lowest impact on CPS Test substitution time, a measure accounting for visuomotor function. Conclusion: Konectom CPS Test measures provide valid, reliable remote measurements of cognitive processing speed in PwMS.
Summary Background Interferon beta is commonly used to treat patients with relapsing-remitting multiple sclerosis; however, the treatment is only partially effective in reducing relapses and ...progression of disability. Corticosteroids are used to treat relapses in patients with multiple sclerosis. We therefore aimed to investigate the combination of cyclic methylprednisolone and interferon beta for the treatment of relapsing-remitting multiple sclerosis. Methods In 2001, we designed a multicentre, double-blind, randomised, parallel-group trial, termed the methylprednisolone in combination with interferon beta-1a for relapsing-remitting multiple sclerosis (MECOMBIN) study. Patients were recruited between October, 2002, and March, 2005 from 50 neurology departments in eight countries. We included treatment-naive patients with relapsing-remitting multiple sclerosis who had an expanded disability status scale (EDSS) score of 4 or less. Patients all started to receive interferon beta-1a and after 3 months were randomly assigned to add-on methylprednisolone or placebo 500 mg/day orally for 3 consecutive days per month for 3–4 years. Placebo tablets were identical to methylprednisolone tablets. Treating physicians, examining physicians, and patients were masked to treatment allocation. Patients were clinically assessed every 3 months and had brain MRI at baseline and 3 years later. The primary outcome was time to onset of disability progression, according to an increase in EDSS score sustained over 6 months. All patients who received at least one dose of study drug were included in all planned analyses. This trial is registered with ClinicalTrials.gov , NCT00168766. Findings 341 patients were randomly assigned to methylprednisolone (n=172) or placebo (n=169); 171 patients in the methylprednisolone group and 167 in the placebo group received at least one dose of study drug. 90 patients had sustained disability progression: 44 of 167 in the methylprednisolone group and 46 of 171 in the placebo group. The time to sustained progression did not differ between groups (hazard ratio 0·879, 95% CI 0·566–1·365; p=0·57). There were 1436 adverse events, 24 of which were serious, in the methylprednisolone group and 1070 events, 35 of which were serious, in the placebo group. Interpretation Monthly pulses of methylprednisolone in combination with interferon beta-1a do not seem to affect disability progression any more than interferon beta-1a treatment alone. More research is required to assess whether this treatment regimen might benefit particular subsets of patients. Funding Biogen Idec.
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.
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.
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.
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.
Biogen.
We studied the secretion of gelatinase B by dendritic cells (DC) generated by culturing human peripheral blood monocytes in granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-4 ...(IL-4). First, we found the intracellular expression of gelatinase B on sections of fixed DC pellets. Zymography analysis of the supernatants of DC cultured for 72 h demonstrated the presence of gelatinase B. To determine if DC produce net enzymatic activity, bioactive gelatinase, a novel sensitive fluorescent-activated substrate conversion (FASC) assay was used to complement the zymography data. Culture media of unstimulated DC demonstrated reproducible net gelatinolytic activity. Tumor necrosis factor-alpha (TNF-alpha) IL-1beta but not lipopolysaccharide (LPS) stimulation caused a significant increase in gelatinase B production in zymography analysis. Both types of stimulation failed to increase net gelatinase activity in FASC assay. Interestingly, interferon-beta (IFN-beta) significantly diminished both the total zymolytic production and the net bioactive gelatinase produced by DC in a dose-dependent manner. We conclude that human monocyte-derived DC secrete bioactive gelatinase B and that IFN-beta inhibits this production.
bibelle.iyoma@biogen.com (B. Iyoma).
Le test CPS de KonectomTM, similaire au SDMT (Symbol Digit Modalities Test) inclut des codes fixe et dynamique. Le code dynamique restreint l’utilisation de la ...mémoire de travail.
Examiner l’impact du type de code sur les performances au test CPS ainsi que la validité convergente de ce test avec le SDMT.
DigiToms recrutait des patients atteints de SEP avec un EDSS ≤ 6,0. Le SDMT était évalué avec une neuropsychologue à l’hôpital. Le test CPS était auto-administré à distance 1 fois par jour jusqu’à 28jours et à l’hôpital. Le type de code est alternativement fixe ou dynamique à chaque réalisation. L’impact du code est étudié sur le nombre de réponses correctes, temps moyens de réponse (TR) correcte et de substitution correcte (TS) au S2D.
Les données préliminaires de 35 patients sont présentées. Le nombre de réponses correctes est plus élevé (différence moyenne de 6 réponses correctes) ; le TR et TS du S2D sont plus courts (différence moyenne de 320 millisecondes) avec le code fixe versus dynamique (p<0,0001). Il y a zéro réponse incorrecte pour la plupart des tests indépendamment du code. Les corrélations sont significatives (p<0,0001) et d’ampleur similaire (|r|=0,739–0,793) entre les résultats des tests SDMT et CPS indépendamment du code.
Des RT et ST plus courts suggèrent que la mémoire de travail contribue à la performance du CPS en utilisant un code fixe mais la force de corrélation entre les résultats du CPS et les performances du SDMT ne différaient pas selon le code de référence utilisé. De futurs travaux examineront différentes composantes du CPS et caractériseront les domaines cognitifs impliqués.
Le code de référence impacte la performance du CPS.
Despite increasing burden of stroke in Africa, prospective descriptive data are rare. Our objective was to describe, in The Gambia, the clinical outcome of stroke patients admitted to the Royal ...Victoria Teaching Hospital in the capital Banjul, to assess mortality and morbidity, and propose preventive and therapeutic measures.
Prospective data were collected on consecutive patients older than 15 years old admitted between February 2000 and February 2001 with the diagnosis of nonsubarachnoid stroke. Risk factors, clinical characteristics, and social consequences were assessed using a modified National Institutes of Health Stroke Scale (mNIHSS), the Barthel Activity in Daily Living scale, the Siriraj score for subtypes, and the Bamford criteria for location/extension. Patients were followed-up at home up to 1 year after discharge.
Ninety-one percent (148/162) of eligible patients were enrolled and followed-up. Hypertension and smoking were the most prevalent risk factors. Severity was high at admission, especially in women, and was strongly correlated to the outcome. mNIHSS and consciousness level on admission were strong predictors of the mortality risk. Swallowing difficulties at admission, fever, lung infection, and no aspirin treatment were, independently, risk factors for a lethal outcome susceptible to being addressed by treatment. Mortality was 41% in-hospital and 62% after 1 year. In survivors, autonomy levels improved over time. Drug compliance was poor. At home, family members provided care. Long-term socioeconomic and cultural activities were affected in most patients.
Case-fatality was high compared with Western cohorts. Preventive measures can be developed. Rational treatment, in the absence of head imaging for initial assessment, requires adapted protocols. Providers should be trained, both at hospital and community levels.
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