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OBJECTIVE: CHAMPION-NMOSD (NCT04201262) is a phase 3, open-label, externally controlled interventional study evaluating the efficacy and safety of the terminal complement inhibitor ravulizumab in adult patients with anti-aquaporin-4 antibody-positive (AQP4+) neuromyelitis optica spectrum disorder (NMOSD). Ravulizumab binds the same complement component 5 epitope as the approved therapeutic eculizumab but has a longer half-life, enabling an extended dosing interval (8 vs 2 weeks). METHODS: The availability of eculizumab precluded the use of a concurrent placebo control in CHAMPION-NMOSD; consequently, the placebo group of the eculizumab phase 3 trial PREVENT (n = 47) was used as an external comparator. Patients received weight-based intravenous ravulizumab on day 1 and maintenance doses on day 15, then once every 8 weeks. The primary endpoint was time to first adjudicated on-trial relapse. RESULTS: The primary endpoint was met; no patients taking ravulizumab (n = 58) had an adjudicated relapse (during 84.0 patient-years of treatment) versus 20 patients with adjudicated relapses in the placebo group of PREVENT (during 46.9 patient-years; relapse risk reduction = 98.6%, 95% confidence interval = 89.7%-100.0%, p < 0.0001). Median (range) study period follow-up time was 73.5 (11.0-117.7) weeks for ravulizumab. Most treatment-emergent adverse events were mild/moderate; no deaths were reported. Two patients taking ravulizumab experienced meningococcal infections. Both recovered with no sequelae; one continued ravulizumab treatment. INTERPRETATION: Ravulizumab significantly reduced relapse risk in patients with AQP4+ NMOSD, with a safety profile consistent with those of eculizumab and ravulizumab across all approved indications. ANN NEUROL 2023;93:1053-1068.
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Neuromielitis Óptica , Adulto , Humanos , Neuromielitis Óptica/tratamiento farmacológico , Acuaporina 4 , Inactivadores del Complemento/uso terapéutico , RecurrenciaRESUMEN
BACKGROUND: The risk-benefit relationship of immunosuppressive therapies (ISTs) for elderly patients with neuromyelitis optica spectrum disorder (NMOSD) is not well established. This study aimed to investigate the safety and efficacy of IST in elderly patients with NMOSD. METHODS: This retrospective study analysed IST efficacy and safety in 101 patients with aquaporin-4 antibody-positive NMOSD aged over 65 years, treated for at least 6 months at five Korean referral centres, focusing on relapse rates, infection events and discontinuation due to adverse outcomes. RESULTS: The mean age at disease onset was 59.8 years, and female-to-male ratio was 4:1. Concomitant comorbidities at NMOSD diagnosis were found in 87 patients (86%). The median Expanded Disability Status Scale score at the initiation of IST was 3.5. The administered ISTs included azathioprine (n=61, 60%), mycophenolate mofetil (MMF) (n=48, 48%) and rituximab (n=41, 41%). Over a median of 5.8 years of IST, 58% of patients were relapse-free. The median annualised relapse rate decreased from 0.76 to 0 (p<0.001), and 81% experienced improved or stabilised disability. Patients treated with rituximab had a higher relapse-free rate than those treated with azathioprine or MMF (p=0.022). During IST, 21 patients experienced 25 severe infection events (SIEs) over the age of 65 years, and 3 died from pneumonia. 14 patients (14%) experienced 17 adverse events that led to switching or discontinuation of IST. When comparing the incidence rates of SIEs and adverse events, no differences were observed among patients receiving azathioprine, MMF and rituximab. CONCLUSION: In elderly patients with NMOSD, IST offers potential benefits in reducing relapse rates alongside a tolerable risk of adverse events.
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The diagnosis of brain metastases (BMs) in patients with lung cancer (LC) predominantly relies on magnetic resonance imaging (MRI), a method that is constrained by high costs and limited accessibility. This study explores the potential of serum neurofilament light chain (sNfL) and serum glial fibrillary acidic protein (sGFAP) as screening biomarkers for BMs in LC patients. We conducted a retrospective analysis of 700 LC cases at the National Cancer Center, Korea, from July 2020 to June 2022, measuring sNfL and sGFAP levels at initial LC diagnosis. The likelihood of BM was evaluated using multivariate analysis and a predictive nomogram. Additionally, we prospectively monitored 177 samples from 46 LC patients initially without BM. Patients with BMs (n= 135) had significantly higher median sNfL (52.5 pg/mL) and sGFAP (239.2 pg/mL) levels compared to those without BMs (n = 565), with medians of 17.8 pg/mL and 141.1 pg/mL, respectively (p < 0.001 for both). The nomogram, incorporating age, sNfL, and sGFAP, predicted BM with an area under the curve (AUC) of 0.877 (95% CI 0.84-0.914), showing 74.8% sensitivity and 83.5% specificity. Over nine months, 93% of samples from patients without BM remained below the cutoff, while all patients developing BMs showed increased levels at detection. A nomogram incorporating age, sNfL, and sGFAP provides a valuable tool for identifying LC patients at high risk for BM, thereby enabling targeted MRI screenings and enhancing diagnostic efficiency.
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Biomarcadores de Tumor , Neoplasias Encefálicas , Proteína Ácida Fibrilar de la Glía , Neoplasias Pulmonares , Proteínas de Neurofilamentos , Humanos , Proteínas de Neurofilamentos/sangre , Femenino , Masculino , Neoplasias Pulmonares/sangre , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/diagnóstico , Proteína Ácida Fibrilar de la Glía/sangre , Persona de Mediana Edad , Anciano , Biomarcadores de Tumor/sangre , Neoplasias Encefálicas/sangre , Neoplasias Encefálicas/secundario , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/diagnóstico , Estudios Retrospectivos , Nomogramas , Adulto , Imagen por Resonancia Magnética/métodos , Anciano de 80 o más AñosRESUMEN
INTRODUCTION: This study evaluated the influence of facial width on the perception of lip protrusion and investigated the concordance between 2-dimensional (2D) profile images and 3-dimensional (3D) video clips in assessing lip protrusion. METHODS: An Asian female standard head model was created using 3D modeling software. Eight head models were constructed by modifying the standard head model in terms of facial width (broad, neutral, and slim) and lip protrusion (retrusive, straight, and protrusive). Overall, 97 Asian raters rated the lip protrusion from the 2D profiles and 3D rotation video clips of the 9 models. RESULTS: No significant differences were found in the perception of lip protrusion in terms of sex, age, or occupation. Compared with the 2D profiles, the 3D video clips were rated as more protrusive in 8 of the 9 head models, with the retrusive broad, retrusive neutral, straight broad, and straight slim faces showing statistical significance (P <0.01). The rating is significantly higher in slim faces than in broad faces across the 3 groups of 2D profiles (P <0.01). For 3D video clips, the rating was higher in slim faces than in broad faces in all 3 groups, whereas differences were significant in the straight and protrusive groups only (P <0.01). CONCLUSIONS: In this study, 3D video clips were more sensitive to the perception of lip protrusion than were 2D profiles to some extent. The lips were rated relatively more protrusive in a slim face than in a broad face. Therefore, the relationship between facial width and lip protrusion should be considered in orthodontic treatment goals and treatment plans.
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Cara , Labio , Humanos , Femenino , Labio/anatomía & histología , Programas Informáticos , Pueblo Asiatico , PercepciónRESUMEN
INTRODUCTION: This study aimed to analyze the load-deflection characteristics of an orthodontic cantilever by using the large deflection elastic model. METHODS: We experimentally measured the vertical deflections of a cantilever with round or rectangular cross-sections, with lengths of 20 mm and 30 mm, and made of either stainless steel or titanium molybdenum alloy. The measurements were obtained under clinically relevant loading ranges (20-60 g of force for round and 20-140 g of force for rectangular wires) and compared with theoretical predictions derived from small and large deflection elastic models. Load-deflection and tangent stiffness curves were subsequently plotted. RESULTS: The impact of a permanent deformation was clinically insignificant. The stiffness of the cantilever increased with the load or deflection rather than remaining constant. Within the clinical loading range, we identified stiffness reversal loading values at which the stiffness of titanium molybdenum alloy surpassed that of stainless steel. The textbook guidelines on cantilevers can apply only when the vertical deflection remains within 16% of its length. CONCLUSIONS: Within the typical clinical loading range, the load-deflection relationship of a cantilever deviates from Hooke's law because of the prominent deflection trait. The conventional model remains effective when the vertical deflection is within 16% of the cantilever length. Otherwise, it is advisable to determine the load and stiffness on the basis of actual measurements rather than relying on theoretical predictions.
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Background and Objectives: This study aimed to evaluate the effects of subtalar joint axis-based balance exercises on the anterior talofibular ligament (ATFL) thickness, ankle strength, and ankle stability after an arthroscopic modified Broström operation (AMBO) for chronic ankle instability (CAI). Materials and Methods: The study included 47 patients diagnosed with CAI who underwent AMBO and were randomly divided into three groups: control (n = 11), general balance exercise (n = 17), and subtalar joint axis balance exercise (n = 19), regardless of the affected area. Participants in the exercise rehabilitation group performed exercises for 60 min twice a week for six weeks, starting six weeks after AMBO. ATFL thickness, ankle strength, and ankle dynamic stability were measured using musculoskeletal ultrasonography, Biodex, and Y-balance test, respectively, before and after treatment. Results: Compared with the remaining groups, the subtalar joint axis balance exercise group had reduced ATFL thickness (p = 0.000), improved ankle strength for eversion (p = 0.000) and inversion (p = 0.000), and enhanced ankle stability (p = 0.000). Conclusions: The study results suggest that subtalar joint axis-based balance exercises may contribute to the early recovery of the ankle joint after AMBO.
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Inestabilidad de la Articulación , Ligamentos Laterales del Tobillo , Articulación Talocalcánea , Humanos , Tobillo , Articulación Talocalcánea/cirugía , Articulación del Tobillo/cirugía , Ligamentos Laterales del Tobillo/cirugía , Resultado del Tratamiento , Inestabilidad de la Articulación/cirugíaRESUMEN
OBJECTIVE: To investigate relationships between serum neurofilament light chain (sNfL), ubiquitin C-terminal hydrolase L1 (sUCHL1), tau (sTau) and glial fibrillary acidic protein (sGFAP) levels and disease activity/disability in neuromyelitis optica spectrum disorder (NMOSD), and the effects of inebilizumab on these biomarkers in N-MOmentum. METHODS: N-MOmentum randomised participants to receive inebilizumab or placebo with a randomised controlled period (RCP) of 28 weeks and an open-label follow-up period of ≥2 years. The sNfL, sUCHL1, sTau and sGFAP were measured using single-molecule arrays in 1260 scheduled and attack-related samples from N-MOmentum participants (immunoglobulin G (IgG) autoantibodies to aquaporin-4-positive, myelin oligodendrocyte glycoprotein-IgG-positive or double autoantibody-negative) and two control groups (healthy donors and patients with relapsing-remitting multiple sclerosis). RESULTS: The concentration of all four biomarkers increased during NMOSD attacks. At attack, sNfL had the strongest correlation with disability worsening during attacks (Spearman R2=0.40; p=0.01) and prediction of disability worsening after attacks (sNfL cut-off 32 pg/mL; area under the curve 0.71 (95% CI 0.51 to 0.89); p=0.02), but only sGFAP predicted upcoming attacks. At RCP end, fewer inebilizumab-treated than placebo-treated participants had sNfL>16 pg/mL (22% vs 45%; OR 0.36 (95% CI 0.17 to 0.76); p=0.004). CONCLUSIONS: Compared with sGFAP, sTau and sUCHL1, sNfL at attack was the strongest predictor of disability worsening at attack and follow-up, suggesting a role for identifying participants with NMOSD at risk of limited post-relapse recovery. Treatment with inebilizumab was associated with lower levels of sGFAP and sNfL than placebo. TRIAL REGISTRATION NUMBER: NCT02200770.
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Neuromielitis Óptica , Humanos , Neuromielitis Óptica/sangre , Neuromielitis Óptica/tratamiento farmacológico , Biomarcadores , Anticuerpos Monoclonales Humanizados/uso terapéutico , Método Doble CiegoRESUMEN
With the increased clinical interest in myelin-oligodendrocyte glycoprotein-antibody-associated disease (MOGAD), the international MOGAD panel's proposed criteria were recently released. To evaluate its diagnostic performance, the criteria were applied to a single-center cohort. Among the enrolled 100 patients, 93 fulfilled the criteria throughout the median 24 months of follow-up. All 36 patients with a clear-positive MOG-immunoglobulin G (IgG) satisfied the supporting features, except one who did not undergo magnetic resonance imaging (MRI) scan at disease onset. The criteria also contributed significantly to the confirmation of MOGAD in 57 of 64 patients without clear-positive MOG-IgG. When limited to the first attack, 51 of 61 patients (84%) satisfied the criteria, 4 of whom were initially negative for MOG-IgG. These results support the diagnostic utility of the International MOGAD Panel criteria.
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Autoanticuerpos , Inmunoglobulina G , Humanos , Glicoproteína Mielina-OligodendrócitoRESUMEN
BACKGROUND: The N-MOmentum trial investigated safety and efficacy of inebilizumab in participants with neuromyelitis optica spectrum disorder (NMOSD). OBJECTIVE: Evaluate the attack identification process and adjudication committee (AC) performance in N-MOmentum. METHODS: Adults (n = 230) with NMOSD and Expanded Disability Status Scale score ⩽8 were randomized (3:1) to inebilizumab 300 mg or placebo. The randomized controlled period was 28 weeks or until adjudicated attack. Attacks were adjudicated according to 18 predefined criteria. Magnetic resonance imaging (MRI) and biomarker (serum glial fibrillary acidic protein [sGFAP]) analyses were performed. RESULTS: A total of 64 participant-reported neurological events occurred; 51 (80%) were investigator-determined to be attacks. The AC confirmed 43 of the investigator-determined attacks (84%). There was high inter- and intra-AC-member agreement. In 25/64 events (39%) and 14/43 AC-adjudicated attacks (33%), MRI was reviewed during adjudication. Retrospective analysis revealed new domain-specific T1 and T2 MRI lesions in 90% of adjudicated attacks. Increased mean sGFAP concentrations (>2-fold change) from baseline were observed in 56% of adjudicated attacks versus 14% of investigator-determined attacks rejected by the AC and 31% of participant-reported events determined not to be attacks. CONCLUSION: AC adjudication of NMOSD attacks according to predefined criteria appears robust. MRI lesion correlates and sGFAP elevations were found in most adjudicated attacks.
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Anticuerpos Monoclonales Humanizados , Neuromielitis Óptica , Neuromielitis Óptica/tratamiento farmacológico , Humanos , Imagen por Resonancia Magnética , Biomarcadores/sangre , Proteína Ácida Fibrilar de la Glía/sangre , Anticuerpos Monoclonales Humanizados/uso terapéutico , Estudios RetrospectivosRESUMEN
BACKGROUND: Microfibrillar-associated protein 4 (MFAP4) is an extracellular matrix protein not previously described in the human central nervous system (CNS). OBJECTIVES: We determined MFAP4 CNS expression and measured cerebrospinal fluid (CSF) and serum levels. METHODS: Tissue was sampled at autopsy from patients with acute multiple sclerosis (MS) (n = 3), progressive MS (n = 3), neuromyelitis optica spectrum disorder (NMOSD) (n = 2), and controls (n = 9), including 6 healthy controls (HC). MFAP4 levels were measured in 152 patients: 49 MS, 62 NMOSD, 22 myelin oligodendrocyte glycoprotein-associated disease (MOGAD), and 19 isolated optic neuritis (ION). RESULTS: MFAP4 localized to meninges and vascular/perivascular spaces, intense in the optic nerve. At sites of active inflammation, MFAP4 reactivity was reduced in NMOSD and acute MS and less in progressive MS. CSF MFAP4 levels were reduced during relapse and at the onset of diseases (mean U/mL: MS 14.3, MOGAD 9.7, and ION 14.6 relative to HC 17.9. (p = 0.013, p = 0.000, and p = 0.019, respectively). Patients with acute ON (n = 68) had reduced CSF MFAP4 (mean U/mL: 14.5, p = 0.006). CSF MFAP4 levels correlated negatively with relapse severity (rho = -0.41, p = 0.017). CONCLUSION: MFAP4 immunoreactivity was reduced at sites of active inflammation. CSF levels of MFAP4 were reduced following relapse and may reflect disease activity.
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Esclerosis Múltiple Crónica Progresiva , Esclerosis Múltiple , Neuromielitis Óptica , Humanos , Glicoproteína Mielina-Oligodendrócito , Neuromielitis Óptica/líquido cefalorraquídeo , Sistema Nervioso Central , Inflamación , Autoanticuerpos , Acuaporina 4/líquido cefalorraquídeo , Proteínas Portadoras , Glicoproteínas , Proteínas de la Matriz ExtracelularRESUMEN
BACKGROUND/PURPOSE: The pathogenesis of chronic actinic dermatitis (CAD) is more complicated than other photodermatoses. However, the relationship between the clinical severity of CAD and the offending photocontact or contact allergens or both, and the correlations of CAD immunopathogenesis with the immunoregulatory molecules involved in adaptive immunity are yet to be investigated. METHODS: We performed phototesting with broad-spectrum ultraviolet (UV) B, UVA, and visible light to establish the presence of photosensitivity in 121 patients with CAD, together with photopatch and contact patch testing. Nine patients with CAD were selected according to their clinical severity score for CAD (CSS-CAD), and triple direct immunofluorescence analysis was performed with paraffin-embedded skin biopsy samples. RESULTS: As CSS-CAD was closely correlated with the multiplicity of photo(contact) allergens, particularly photoallergens, three or more photoallergens were detected in the severe CAD group (52.5%); less in the moderate group (32.8%); and only one in the mild group (14.8%; P = .025). In the groups showing greater severity of disease, the absolute numbers of IFN-γ+ , IL-17+ , CD4+, CD8+, common-γ chain receptor (common-γCR)+ , and CD69+ tissue-resident memory cells increased on average; there was also an increase in the CD4+/CD8+ cell ratio, with the more severely affected groups. However, the levels of TNF-α+ and FoxP3+ regulatory T (Treg) cells and the mean IL-17/IFN-γ cell ratio decreased in the more severely affected CSS-CAD subgroups. CONCLUSIONS: Based on the clinical analysis and immunopathogenic results, avoidance of excessive sun exposure, and topical and systemic blocking agents for photo(contact) allergens are recommended. Additionally, conventional immunomodulators and emerging agents including JAK-STAT inhibitors may be administered for CAD treatment in the future.
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Trastornos por Fotosensibilidad , Linfocitos T Reguladores , Células Th17 , Humanos , Inmunidad Adaptativa , Alérgenos/uso terapéutico , Interleucina-17 , Trastornos por Fotosensibilidad/patología , Linfocitos T Citotóxicos/patología , Linfocitos T Reguladores/patología , Receptores de Antígenos de Linfocitos T gamma-deltaRESUMEN
Pesticides effectively reduce the population of various pests that harm crops and increase productivity, but leave residues that adversely affect health and the environment. Here, a simultaneous multicomponent analysis method based on ultra-high-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UHPLC-QTOF-MS) pretreated by the QuEChERS method was developed to control the maximum residual levels. Among the 140 pesticides with high frequency of detection in agricultural products in Gyeongnam region in Korea for 5 years, 12 pesticides with high detection frequency in sweet pepper were selected. The analytical method is validated, linearities are r2 > 0.999, limit of detection (LOD) ranges from 1.4 to 3.2 µg/kg, and limit of quantification (LOQ) ranges from 4.1 to 9.7 µg/kg, and the recovery rate was 81.7-99.7%. In addition, it was confirmed that a meaningful value of these parameters can be achieved by determining the measurement uncertainty. The results proved that parameters such as recovery rate and relative standard deviation of the analysis method were within international standards. Using the developed method, better and safer sweet peppers will be provided to consumers, and effective pesticide residue management will be possible by expanding to other agricultural products.
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Capsicum , Residuos de Plaguicidas , Plaguicidas , Cromatografía Líquida de Alta Presión/métodos , Plaguicidas/análisis , Espectrometría de Masas/métodos , Residuos de Plaguicidas/análisisRESUMEN
INTRODUCTION: This study aimed to determine the minimum required length of microimplants (MIs) to prevent excessive micromotion during MI healing that can lead to MI failure. METHODS: Hypothesizing that the implantation depth of MI in cancellous bone (IDcancel) is the key to the control of micromotion during MI healing, we numerically investigated the minimum IDcancel required to maintain MI micromotion to below the threshold (30 µm) that would threaten MI survival. Twenty MI and bone models were built using MIs of 4 lengths and bone specimens with 5 different cortical bone thicknesses to create IDcancel in the 0.5-5.5 mm. Then, applying a horizontal force of 1.5 N on the MI head, we calculated the micromotion (peak and average MI micromotions) and determined the minimum IDcancel. A clinical test was performed to verify the numerical result by placing 160 MIs in the posterior maxilla and mandible. RESULTS: A strong correlation (r2= 0.694) was found to exist between IDcancel and MI micromotion. A minimum of 2.5 mm of IDcancel was needed to maintain the level of MI micromotion (peak micromotion) <30 µm threshold. The 6-month survival rate of MI was strongly correlated with IDcancel (r2= 0.744) and decreased sharply when IDcancel was ≤2 mm. CONCLUSIONS: The minimum lengths of MIs to provide the minimum IDcancel of 2.5 mm required to promote successful MI healing in the posterior maxilla and mandible are 5.2 and 6.5 mm, respectively.
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Hueso Cortical , Mandíbula , HumanosRESUMEN
BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) is a relapsing, autoimmune, inflammatory disorder that typically affects the optic nerves and spinal cord. At least two thirds of cases are associated with aquaporin-4 antibodies (AQP4-IgG) and complement-mediated damage to the central nervous system. In a previous small, open-label study involving patients with AQP4-IgG-positive disease, eculizumab, a terminal complement inhibitor, was shown to reduce the frequency of relapse. METHODS: In this randomized, double-blind, time-to-event trial, 143 adults were randomly assigned in a 2:1 ratio to receive either intravenous eculizumab (at a dose of 900 mg weekly for the first four doses starting on day 1, followed by 1200 mg every 2 weeks starting at week 4) or matched placebo. The continued use of stable-dose immunosuppressive therapy was permitted. The primary end point was the first adjudicated relapse. Secondary outcomes included the adjudicated annualized relapse rate, quality-of-life measures, and the score on the Expanded Disability Status Scale (EDSS), which ranges from 0 (no disability) to 10 (death). RESULTS: The trial was stopped after 23 of the 24 prespecified adjudicated relapses, given the uncertainty in estimating when the final event would occur. The mean (±SD) annualized relapse rate in the 24 months before enrollment was 1.99±0.94; 76% of the patients continued to receive their previous immunosuppressive therapy during the trial. Adjudicated relapses occurred in 3 of 96 patients (3%) in the eculizumab group and 20 of 47 (43%) in the placebo group (hazard ratio, 0.06; 95% confidence interval [CI], 0.02 to 0.20; P<0.001). The adjudicated annualized relapse rate was 0.02 in the eculizumab group and 0.35 in the placebo group (rate ratio, 0.04; 95% CI, 0.01 to 0.15; P<0.001). The mean change in the EDSS score was -0.18 in the eculizumab group and 0.12 in the placebo group (least-squares mean difference, -0.29; 95% CI, -0.59 to 0.01). Upper respiratory tract infections and headaches were more common in the eculizumab group. There was one death from pulmonary empyema in the eculizumab group. CONCLUSIONS: Among patients with AQP4-IgG-positive NMOSD, those who received eculizumab had a significantly lower risk of relapse than those who received placebo. There was no significant between-group difference in measures of disability progression. (Funded by Alexion Pharmaceuticals; PREVENT ClinicalTrials.gov number, NCT01892345; EudraCT number, 2013-001150-10.).
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Acuaporina 4/inmunología , Complemento C5/antagonistas & inhibidores , Inactivadores del Complemento/uso terapéutico , Inmunosupresores/uso terapéutico , Neuromielitis Óptica/tratamiento farmacológico , Adulto , Anticuerpos Monoclonales Humanizados/efectos adversos , Autoanticuerpos/sangre , Inactivadores del Complemento/efectos adversos , Evaluación de la Discapacidad , Progresión de la Enfermedad , Método Doble Ciego , Quimioterapia Combinada , Femenino , Cefalea/inducido químicamente , Humanos , Inmunoglobulina G/sangre , Inmunosupresores/efectos adversos , Masculino , Neuromielitis Óptica/inmunología , Calidad de Vida , Infecciones del Sistema Respiratorio/etiología , Prevención SecundariaRESUMEN
BACKGROUND: Despite rigorous confirmation with reliable assays, some individuals showing the neuromyelitis optica spectrum disorder (NMOSD) phenotype remain negative for both aquaporin-4 (AQP4) and myelin oligodendrocyte glycoprotein (MOG) antibodies. OBJECTIVE: We aimed to investigate whether double seronegative NMOSD (DN-NMOSD) and NMOSD with AQP4 antibody (AQP4-NMOSD) share the same pathophysiological basis, astrocytopathy, by measurement of cerebrospinal fluid (CSF) glial fibrillary acidic protein (GFAP) levels as a marker of astrocyte damage. METHODS: Seventeen participants who (1) satisfied the 2015 diagnostic criteria for NMOSD, and (2) tested negative for AQP4 and MOG antibodies confirmed with repeated cell-based assays, and (3) had available CSF samples obtained at the point of clinical attacks, were enrolled from 4 medical centers (South Korea, Germany, Thailand, and Denmark). Thirty age-matched participants with AQP4-NMOSD, 17 participants with MOG antibody associated disease (MOGAD), and 15 participants with other neurological disorders (OND) were included as controls. The concentration of CSF GFAP was measured using enzyme-linked immunosorbent assay. RESULTS: CSF GFAP levels in the DN-NMOSD group were significantly lower than those in the AQP4-NMOSD group (median: 0.49 versus 102.9 ng/mL; p < 0.001), but similar to those in the OND (0.25 ng/mL) and MOGAD (0.39 ng/mL) control groups. The majority (90% (27/30)) of participants in the AQP4-NMOSD group showed significantly higher CSF GFAP levels than the highest level measured in the OND group, while no participant in the DN-NMOSD and MOGAD groups did. CONCLUSIONS: These results suggest that DN-NMOSD has a different underlying pathogenesis other than astrocytopathy, distinct from AQP4-NMOSD.
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Astrocitos , Proteína Ácida Fibrilar de la Glía , Neuromielitis Óptica , Acuaporina 4 , Astrocitos/patología , Autoanticuerpos , Proteína Ácida Fibrilar de la Glía/líquido cefalorraquídeo , Humanos , Glicoproteína Mielina-Oligodendrócito , Neuromielitis Óptica/líquido cefalorraquídeoRESUMEN
OBJECTIVE: During PREVENT (NCT01892345), eculizumab significantly reduced relapse risk versus placebo in patients with aquaporin-4 immunoglobulin G-positive neuromyelitis optica spectrum disorder (AQP4-IgG+ NMOSD). We report an interim analysis of PREVENT's ongoing open-label extension (OLE; NCT02003144) evaluating eculizumab's long-term safety and efficacy. METHODS: Patients who completed PREVENT could enroll in the OLE to receive eculizumab (maintenance dose = 1,200 mg/2 weeks, after a blinded induction phase). Safety and efficacy data from PREVENT and its OLE (interim data cut, July 31, 2019) were combined for this analysis. RESULTS: Across PREVENT and the OLE, 137 patients received eculizumab and were monitored for a median (range) of 133.3 weeks (5.1-276.9 weeks), for a combined total of 362.3 patient-years (PY). Treatment-related adverse event (AE) and serious adverse event (SAE) rates were 183.5 in 100 PY and 8.6 in 100 PY, respectively. Serious infection rates were 10.2 in 100 PY in eculizumab-treated patients versus 15.1 in 100 PY in the PREVENT placebo group. No patient developed a meningococcal infection. At 192 weeks (3.7 years), 94.4% (95% confidence interval [CI], 88.6-97.3) of patients remained adjudicated relapse-free. The adjudicated annualized relapse rate was 0.025 (95% CI = 0.013-0.048) in all eculizumab-treated patients versus 0.350 (95% CI = 0.199-0.616) in the PREVENT placebo group. During the OLE, 37% of patients (44 of 119 patients) stopped or decreased background immunosuppressive therapy use. INTERPRETATION: This analysis demonstrates that eculizumab's long-term safety profile in NMOSD is consistent with its established profile across other indications. This analysis also demonstrated the sustained ability of long-term eculizumab treatment to reduce relapse risk in patients with AQP4-IgG+ NMOSD. ANN NEUROL 2021;89:1088-1098.
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Inactivadores del Complemento/uso terapéutico , Neuromielitis Óptica/tratamiento farmacológico , Adulto , Anciano , Acuaporina 4/inmunología , Autoanticuerpos/inmunología , Autoantígenos/inmunología , Femenino , Humanos , Inmunoglobulina G/inmunología , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Neuromielitis Óptica/inmunología , RecurrenciaRESUMEN
BACKGROUND: Patients with anti-aquaporin-4 antibody seropositive (AQP4-IgG+) neuromyelitis optica spectrum disorders (NMOSDs) frequently suffer from optic neuritis (ON) leading to severe retinal neuroaxonal damage. Further, the relationship of this retinal damage to a primary astrocytopathy in NMOSD is uncertain. Primary astrocytopathy has been suggested to cause ON-independent retinal damage and contribute to changes particularly in the outer plexiform layer (OPL) and outer nuclear layer (ONL), as reported in some earlier studies. However, these were limited in their sample size and contradictory as to the localisation. This study assesses outer retinal layer changes using optical coherence tomography (OCT) in a multicentre cross-sectional cohort. METHOD: 197 patients who were AQP4-IgG+ and 32 myelin-oligodendrocyte-glycoprotein antibody seropositive (MOG-IgG+) patients were enrolled in this study along with 75 healthy controls. Participants underwent neurological examination and OCT with central postprocessing conducted at a single site. RESULTS: No significant thinning of OPL (25.02±2.03 µm) or ONL (61.63±7.04 µm) were observed in patients who were AQP4-IgG+ compared with patients who were MOG-IgG+ with comparable neuroaxonal damage (OPL: 25.10±2.00 µm; ONL: 64.71±7.87 µm) or healthy controls (OPL: 24.58±1.64 µm; ONL: 63.59±5.78 µm). Eyes of patients who were AQP4-IgG+ (19.84±5.09 µm, p=0.027) and MOG-IgG+ (19.82±4.78 µm, p=0.004) with a history of ON showed parafoveal OPL thinning compared with healthy controls (20.99±5.14 µm); this was not observed elsewhere. CONCLUSION: The results suggest that outer retinal layer loss is not a consistent component of retinal astrocytic damage in AQP4-IgG+ NMOSD. Longitudinal studies are necessary to determine if OPL and ONL are damaged in late disease due to retrograde trans-synaptic axonal degeneration and whether outer retinal dysfunction occurs despite any measurable structural correlates.
Asunto(s)
Acuaporina 4/sangre , Neuromielitis Óptica/fisiopatología , Retina/fisiopatología , Adulto , Astrocitos/patología , Autoanticuerpos , Estudios Transversales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Tomografía de Coherencia ÓpticaRESUMEN
The prevalence of cerebrospinal fluid-specific oligoclonal bands (CSF-OCBs) was reported to be low in Asian people with multiple sclerosis (pwMS) compared to that in Western pwMS. It is yet to be determined whether it is a genuine feature of Asian pwMS or a misapprehension owing to past mis-classification of MS-mimicking diseases as MS. We aimed to reappraise the prevalence of CSF-OCBs in Korean pwMS after carefully excluding other central nervous system-inflammatory demyelinating diseases since 2017. Among 88 subjects, 78 (88.6%) were positive for CSF-OCBs, which suggests the prevalence of CSF-OCBs is not different between Korean and Western pwMS.
Asunto(s)
Enfermedades del Sistema Nervioso Central , Esclerosis Múltiple , Asia , Humanos , Focalización Isoeléctrica , Esclerosis Múltiple/epidemiología , Bandas OligoclonalesRESUMEN
To evaluate the occurrence of attack-independent neuroaxonal and astrocytic damage in myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), serum neurofilament light chain (sNfL) and serum glial fibrillary acidic protein (sGFAP) levels were longitudinally measured in 102 sera using a single-molecule array assay. Sera from 15 adults with relapsing MOGAD with available longitudinal samples for the median 24-month follow-up and 26 age-/sex-matched healthy controls were analyzed. sNfL levels were significantly elevated in all clinical attacks, where the levels decreased below or close to cut-off value within 6 months after attacks. sNfL levels were consistently low during inter-attack periods. In contrast, sGFAP levels did not increase in most clinical attacks and remained low during follow-up. Significant neuroaxonal damage was observed at clinical attacks, while attack-independent neuroaxonal and astrocytic injury was absent in MOGAD.
Asunto(s)
Filamentos Intermedios , Proteínas de Neurofilamentos , Anticuerpos , Astrocitos , Biomarcadores , Humanos , Glicoproteína Mielina-Oligodendrócito , RecurrenciaRESUMEN
During PREVENT (a phase 3, randomized, double-blind, placebo-controlled, time-to-event study) and its open-label extension (interim analysis), 33 adults with aquaporin-4 immunoglobulin G-positive neuromyelitis optica spectrum disorder (AQP4-IgG + NMOSD) received eculizumab monotherapy for a median of 2.8 years (range, 14 weeks-5.2 years). At 192 weeks (~4 years), 96% of these patients were free from adjudicated relapses (Kaplan-Meier analysis; 95% confidence interval, 75.7-99.4). During PREVENT, 95% (20/21) of patients receiving eculizumab monotherapy had no disability worsening. Eculizumab monotherapy provides effective long-term relapse prevention, relieving the chronic immunosuppression burden in patients with AQP4-IgG + NMOSD. ClinicalTrials.gov; PREVENT: NCT01892345; open-label extension: NCT02003144.