MOG Antibodies Restricted to CSF in Children With Inflammatory CNS Disorders.

OBJECTIVES: To assess the clinical significance of myelin oligodendrocyte glycoprotein antibodies (MOG-abs) restricted to CSF in children with inflammatory CNS disorders. METHODS: Patients included 760 children (younger than 18 years) from 3 multicenter prospective cohort studies: (A) acquired demyelinating syndromes, including acute disseminated encephalomyelitis (ADEM); (B) non-ADEM encephalitis; and (C) noninflammatory neurologic disorders. For all cases, paired serum/CSF samples were systematically examined using brain immunohistochemistry and live cell-based assays. RESULTS: A total of 109 patients (14%) had MOG-abs in serum or CSF: 79 from cohort A, 30 from B, and none from C. Of these, 63 (58%) had antibodies in both samples, 37 (34%) only in serum, and 9 (8%) only in CSF. Children with MOG-abs only in CSF were older than those with MOG-abs only in serum or in both samples (median 12 vs 6 vs 5 years, p = 0.0002) and were more likely to have CSF oligoclonal bands (86% vs 12% vs 7%, p = 0.0001) and be diagnosed with multiple sclerosis (6/9 [67%] vs 0/37 [0%] vs 1/63 [2%], p < 0.0001). DISCUSSION: Detection of MOG-abs in serum or CSF is associated with CNS inflammatory disorders. Children with MOG-abs restricted to CSF are more likely to have CSF oligoclonal bands and multiple sclerosis than those with MOG-abs detectable in serum.

Multiscale networks in multiple sclerosis.

Complex diseases such as Multiple Sclerosis (MS) cover a wide range of biological scales, from genes and proteins to cells and tissues, up to the full organism. In fact, any phenotype for an organism is dictated by the interplay among these scales. We conducted a multilayer network analysis and deep phenotyping with multi-omics data (genomics, phosphoproteomics and cytomics), brain and retinal imaging, and clinical data, obtained from a multicenter prospective cohort of 328 patients and 90 healthy controls. Multilayer networks were constructed using mutual information for topological analysis, and Boolean simulations were constructed using Pearson correlation to identified paths within and among all layers. The path more commonly found from the Boolean simulations connects protein MK03, with total T cells, the thickness of the retinal nerve fiber layer (RNFL), and the walking speed. This path contains nodes involved in protein phosphorylation, glial cell differentiation, and regulation of stress-activated MAPK cascade, among others. Specific paths identified were subsequently analyzed by flow cytometry at the single-cell level. Combinations of several proteins (GSK3AB, HSBP1 or RS6) and immune cells (Th17, Th1 non-classic, CD8, CD8 Treg, CD56 neg, and B memory) were part of the paths explaining the clinical phenotype. The advantage of the path identified from the Boolean simulations is that it connects information about these known biological pathways with the layers at higher scales (retina damage and disability). Overall, the identified paths provide a means to connect the molecular aspects of MS with the overall phenotype.

Examining the environmental risk factors of progressive-onset and relapsing-onset multiple sclerosis: recruitment challenges, potential bias, and statistical strategies.

It is unknown whether the currently known risk factors of multiple sclerosis reflect the etiology of progressive-onset multiple sclerosis (POMS) as observational studies rarely included analysis by type of onset. We designed a case-control study to examine associations between environmental factors and POMS and compared effect sizes to relapse-onset MS (ROMS), which will offer insights into the etiology of POMS and potentially contribute to prevention and intervention practice. This study utilizes data from the Primary Progressive Multiple Sclerosis (PPMS) Study and the Australian Multi-center Study of Environment and Immune Function (the AusImmune Study). This report outlines the conduct of the PPMS Study, whether the POMS sample is representative, and the planned analysis methods. The study includes 155 POMS, 204 ROMS, and 558 controls. The distributions of the POMS were largely similar to Australian POMS patients in the MSBase Study, with 54.8% female, 85.8% POMS born before 1970, mean age of onset of 41.44 ± 8.38 years old, and 67.1% living between 28.9 and 39.4° S. The POMS were representative of the Australian POMS population. There are some differences between POMS and ROMS/controls (mean age at interview: POMS 55 years vs. controls 40 years; sex: POMS 53% female vs. controls 78% female; location of residence: 14.3% of POMS at a latitude ≤ 28.9°S vs. 32.8% in controls), which will be taken into account in the analysis. We discuss the methodological issues considered in the study design, including prevalence-incidence bias, cohort effects, interview bias and recall bias, and present strategies to account for it. Associations between exposures of interest and POMS/ROMS will be presented in subsequent publications.

Predicting disease severity in multiple sclerosis using multimodal data and machine learning.

BACKGROUND: Multiple sclerosis patients would benefit from machine learning algorithms that integrates clinical, imaging and multimodal biomarkers to define the risk of disease activity. METHODS: We have analysed a prospective multi-centric cohort of 322 MS patients and 98 healthy controls from four MS centres, collecting disability scales at baseline and 2 years later. Imaging data included brain MRI and optical coherence tomography, and omics included genotyping, cytomics and phosphoproteomic data from peripheral blood mononuclear cells. Predictors of clinical outcomes were searched using Random Forest algorithms. Assessment of the algorithm performance was conducted in an independent prospective cohort of 271 MS patients from a single centre. RESULTS: We found algorithms for predicting confirmed disability accumulation for the different scales, no evidence of disease activity (NEDA), onset of immunotherapy and the escalation from low- to high-efficacy therapy with intermediate to high-accuracy. This accuracy was achieved for most of the predictors using clinical data alone or in combination with imaging data. Still, in some cases, the addition of omics data slightly increased algorithm performance. Accuracies were comparable in both cohorts. CONCLUSION: Combining clinical, imaging and omics data with machine learning helps identify MS patients at risk of disability worsening.

Seroprevalence of SARS-CoV-2 in Patients with Multiple Sclerosis under Disease-Modifying Therapies: A Multi-Centre Study.

BACKGROUND: The EMCOVID project conducted a multi-centre cohort study to investigate the impact of COVID-19 on patients with Multiple Sclerosis (pwMS) receiving disease-modifying therapies (DMTs). The study aimed to evaluate the seroprevalence and persistence of SARS-CoV-2 antibodies in MS patients enrolled in the EMCOVID database. The DMTs were used to manage MS by reducing relapses, lesion accumulation, and disability progression. However, concerns arose regarding the susceptibility of pwMS to COVID-19 due to potential interactions between SARS-CoV-2 and the immune system, as well as the immunomodulatory effects of DMTs. METHODS: This prospective observational study utilized data from a Multiple Sclerosis and COVID-19 (EMCOVID-19) study. Demographic characteristics, MS history, laboratory data, SARS-CoV-2 serology, and symptoms of COVID-19 were extracted for pwMS receiving any type of DMT. The relationship between demographics, MS phenotype, DMTs, and COVID-19 was evaluated. The evolution of SARS-CoV-2 antibodies over a 6-month period was also assessed. RESULTS: The study included 709 pwMS, with 376 patients providing samples at the 6-month follow-up visit. The seroprevalence of SARS-CoV-2 antibodies was higher among pwMS than the general population, with Interferon treatment being significantly associated with greater seroprevalence (16.9% vs. 8.4%; p 0.003). However, no other specific DMT showed a significant association with antibody presence. A total of 32 patients (8.5%) tested positive for IgG, IgM, or IgA antibodies against SARS-CoV-2 at baseline, but then tested negative at 6 months. Most of the pwMS in the cohort were asymptomatic for COVID-19 and, even among symptomatic cases, the prognosis was generally favourable. CONCLUSION: pwMS undergoing DMTs exhibited a higher seroprevalence of COVID-19 than the general population. Interferon treatment was associated with a higher seroprevalence, suggesting a more robust humoral response. This study provides valuable insights into the seroprevalence and persistence of SARS-CoV-2 antibodies in pwMS and contributes to our understanding of the impact of COVID-19 amongst this population.

Serum biomarker levels predict disability progression in patients with primary progressive multiple sclerosis.

BACKGROUND: We aimed to investigate the potential of serum biomarker levels to predict disability progression in a multicentric real-world cohort of patients with primary progressive multiple sclerosis (PPMS). METHODS: A total of 141 patients with PPMS from 18 European MS centres were included. Disability progression was investigated using change in Expanded Disability Status Scale (EDSS) score over three time intervals: baseline to 2 years, 6 years and to the last follow-up. Serum levels of neurofilament light chain (sNfL), glial fibrillar acidic protein (sGFAP) and chitinase 3-like 1 (sCHI3L1) were measured using single-molecule array assays at baseline. Correlations between biomarker levels, and between biomarkers and age were quantified using Spearman's r. Univariable and multivariable linear models were performed to assess associations between biomarker levels and EDSS change over the different time periods. RESULTS: Median (IQR) age of patients was 52.9 (46.4-58.5) years, and 58 (41.1%) were men. Median follow-up time was 9.1 (7.0-12.6) years. Only 8 (5.7%) patients received treatment during follow-up. sNfL and sGFAP levels were moderately correlated (r=0.43) and both weakly correlated with sCHI3L1 levels (r=0.19 and r=0.17, respectively). In multivariable analyses, levels of the three biomarkers were associated with EDSS changes across all time periods. However, when analysis was restricted to non-inflammatory patients according to clinical and radiological parameters (n=64), only sCHI3L1 levels remained associated with future EDSS change. CONCLUSIONS: Levels of sNfL, sGFAP and sCHI3L1 are prognostic biomarkers associated with disability progression in patients with PPMS, being CHI3L1 findings less dependent on the inflammatory component associated with disease progression.

Predictive value of retinal atrophy for cognitive decline across disease duration in multiple sclerosis.

BACKGROUND: We investigated the association between changes in retinal thickness and cognition in people with MS (PwMS), exploring the predictive value of optical coherence tomography (OCT) markers of neuroaxonal damage for global cognitive decline at different periods of disease. METHOD: We quantified the peripapillary retinal nerve fibre (pRFNL) and ganglion cell-inner plexiform (GCIPL) layers thicknesses of 207 PwMS and performed neuropsychological evaluations. The cohort was divided based on disease duration (≤5 years or >5 years). We studied associations between changes in OCT and cognition over time, and assessed the risk of cognitive decline of a pRFNL≤88 µm or GCIPL≤77 µm and its predictive value. RESULTS: Changes in pRFNL and GCIPL thickness over 3.2 years were associated with evolution of cognitive scores, in the entire cohort and in patients with more than 5 years of disease (p<0.01). Changes in cognition were related to less use of disease-modifying drugs, but not OCT metrics in PwMS within 5 years of onset. A pRFNL≤88 µm was associated with earlier cognitive disability (3.7 vs 9.9 years) and higher risk of cognitive deterioration (HR=1.64, p=0.022). A GCIPL≤77 µm was not associated with a higher risk of cognitive decline, but a trend was observed at ≤91.5 µm in PwMS with longer disease (HR=1.81, p=0.061). CONCLUSIONS: The progressive retinal thinning is related to cognitive decline, indicating that cognitive dysfunction is a late manifestation of accumulated neuroaxonal damage. Quantifying the pRFNL aids in identifying individuals at risk of cognitive dysfunction.

Neurological adverse events related to immune-checkpoint inhibitors in Spain: a retrospective cohort study.

BACKGROUND: Neurological immune-related adverse events associated with immune checkpoint inhibitors can have several clinical manifestations, but the syndromes and prognostic factors are still not well known. We aimed to characterise and group the clinical features, with a special focus in patients presenting with encephalopathy, and to identify predictors of response to therapy and survival. METHODS: This retrospective observational study included patients with neurological immune-related adverse events from 20 hospitals in Spain whose clinical information, serum samples, and CSF samples were studied at Hospital Clinic de Barcelona, Barcelona, Spain. Patients with pre-existing paraneoplastic syndromes or evidence of alternative causes for their neurological symptoms were excluded. We reviewed the clinical information, classified their clinical features, and determined the presence of neural antibodies. Neurological status was assessed by the treating physician one month after adverse event onset (as improvement vs no improvement) and at the last evaluation (complete recovery or modified Rankin Scale score decrease of at least 2 points, indicating good outcome, vs all other modified Rankin Scale scores, indicating poor outcome); if the participant had died, the date and cause of death were recorded. We used Fisher's exact tests and Mann-Whitney U tests to analyse clinical features, and multivariable logistic regression to analyse prognostic factors. FINDINGS: From Jan 1, 2018, until Feb 1, 2023, 83 patients with suspected neurological immune-related adverse events after use of immune checkpoint inhibitors were identified, of whom 64 patients were included. These patients had a median age of 67 years (IQR 59-74); 42 (66%) were male and 22 (34%) were female. The predominant tumours were lung cancer (30 [47%] patients), melanoma (13 [21%] patients), and renal cell carcinoma (seven [11%] patients). Neural antibodies were detected in 14 (22%) patients; 52 (81%) patients had CNS involvement and 12 (19%) had peripheral nervous system involvement. Encephalopathy occurred in 45 (70%) patients, 12 (27%) of whom had antibodies or well defined syndromes consistent with definite paraneoplastic or autoimmune encephalitis, 24 (53%) of whom had encephalitis without antibodies or clinical features characteristic of a defined syndrome, and nine (20%) of whom had encephalopathy without antibodies or inflammatory changes in CSF or brain MRI. Nine (14%) of 64 patients had combined myasthenia and myositis, five of them with myocarditis. Even though 58 (91%) of 64 patients received steroids and 31 (48%) of 64 received additional therapies, 18 (28%) did not improve during the first month after adverse event onset, and 11 of these 18 people died. At the last follow-up for the 53 remaining patients (median 6 months, IQR 3-13), 20 (38%) had a poor outcome (16 deaths, one related to a neurological immune-related adverse event). Mortality risk was increased in patients with lung cancer (vs those with other cancers: HR 2·5, 95% CI 1·1-6·0) and in patients with encephalopathy without evidence of CNS inflammation or combined myocarditis, myasthenia, and myositis (vs those with the remaining syndromes: HR 5·0, 1·4-17·8 and HR 6·6, 1·4-31·0, respectively). INTERPRETATION: Most neurological immune-related adverse events involved the CNS and were antibody negative. The presence of myocarditis, myasthenia, and myositis, of encephalopathy without inflammatory changes, or of lung cancer were independent predictors of death. Most deaths occurred during the first month of symptom onset. If our findings are replicated in additional cohorts, they could confirm that these patients need early and intensive treatment. FUNDING: The Instituto de Salud Carlos III and the European Union.

mRNA COVID-19 Vaccination Does Not Exacerbate Symptoms or Trigger Neural Antibody Responses in Multiple Sclerosis.

BACKGROUND AND OBJECTIVE: In people with multiple sclerosis (pwMS), concern for potential disease exacerbation or triggering of other autoimmune disorders contributes to vaccine hesitancy. We assessed the humoral and T-cell responses to SARS-CoV-2 after mRNA vaccination, changes in disease activity, and development of antibodies against central or peripheral nervous system antigens. METHODS: This was a prospective 1-year longitudinal observational study of pwMS and a control group of patients with other inflammatory neurologic disorders (OIND) who received an mRNA vaccine. Blood samples were obtained before the first dose (T1), 1 month after the first dose (T2), 1 month after the second dose (T3), and 6 (T4), 9 (T5), and 12 (T6) months after the first dose. Patients were assessed for the immune-specific response, annualized relapse rate (ARR), and antibodies to onconeuronal, neural surface, glial, ganglioside, and nodo-paranodal antigens. RESULTS: Among 454 patients studied, 390 had MS (22 adolescents) and 64 OIND; the mean (SD) age was 44 (14) years; 315 (69%) were female; and 392 (87%) were on disease-modifying therapies. Antibodies to the receptor-binding domain were detected in 367 (86%) patients at T3 and 276 (83%) at T4. After a third dose, only 13 (22%) of 60 seronegative patients seroconverted, and 255 (92%) remained seropositive at T6. Cellular responses were present in 381 (93%) patients at T3 and in 235 (91%) patients at T6 including all those receiving anti-CD20 therapies and in 79% of patients receiving fingolimod. At T3 (429 patients) or T6 (395 patients), none of the patients had developed CNS autoantibodies. Seven patients had neural antibodies that were already present before immunization (3 adult patients with MS had MOG-IgG, 2 with MG and 1 with MS had neuronal cell surface antibodies [unknown antigen], and 1 with MS had myelin antibody reactivity [unknown antigen]. Similarly, no antibodies against PNS antigens were identified at T3 (427 patients). ARR was lower in MS and not significantly different in patients with OIND. Although 182 (40%) patients developed SARS-CoV-2 infection, no cases of severe COVID-19 or serious adverse events occurred. DISCUSSION: In this study, mRNA COVID-19 vaccination was safe and did not exacerbate the autoimmune disease nor triggered neural autoantibodies or immune-mediated neurologic disorders. The outcome of patients who developed SARS-CoV-2 infection was favorable.

Diffusion-based structural connectivity patterns of multiple sclerosis phenotypes.

BACKGROUND: We aimed to describe the severity of the changes in brain diffusion-based connectivity as multiple sclerosis (MS) progresses and the microstructural characteristics of these networks that are associated with distinct MS phenotypes. METHODS: Clinical information and brain MRIs were collected from 221 healthy individuals and 823 people with MS at 8 MAGNIMS centres. The patients were divided into four clinical phenotypes: clinically isolated syndrome, relapsing-remitting, secondary progressive and primary progressive. Advanced tractography methods were used to obtain connectivity matrices. Then, differences in whole-brain and nodal graph-derived measures, and in the fractional anisotropy of connections between groups were analysed. Support vector machine algorithms were used to classify groups. RESULTS: Clinically isolated syndrome and relapsing-remitting patients shared similar network changes relative to controls. However, most global and local network properties differed in secondary progressive patients compared with the other groups, with lower fractional anisotropy in most connections. Primary progressive participants had fewer differences in global and local graph measures compared with clinically isolated syndrome and relapsing-remitting patients, and reductions in fractional anisotropy were only evident for a few connections. The accuracy of support vector machine to discriminate patients from healthy controls based on connection was 81%, and ranged between 64% and 74% in distinguishing among the clinical phenotypes. CONCLUSIONS: In conclusion, brain connectivity is disrupted in MS and has differential patterns according to the phenotype. Secondary progressive is associated with more widespread changes in connectivity. Additionally, classification tasks can distinguish between MS types, with subcortical connections being the most important factor.

Disability accrual in primary and secondary progressive multiple sclerosis.

BACKGROUND: Some studies comparing primary and secondary progressive multiple sclerosis (PPMS, SPMS) report similar ages at onset of the progressive phase and similar rates of subsequent disability accrual. Others report later onset and/or faster accrual in SPMS. Comparisons have been complicated by regional cohort effects, phenotypic differences in sex ratio and management and variable diagnostic criteria for SPMS. METHODS: We compared disability accrual in PPMS and operationally diagnosed SPMS in the international, clinic-based MSBase cohort. Inclusion required PPMS or SPMS with onset at age ≥18 years since 1995. We estimated Andersen-Gill hazard ratios for disability accrual on the Expanded Disability Status Scale (EDSS), adjusted for sex, age, baseline disability, EDSS score frequency and drug therapies, with centre and patient as random effects. We also estimated ages at onset of the progressive phase (Kaplan-Meier) and at EDSS milestones (Turnbull). Analyses were replicated with physician-diagnosed SPMS. RESULTS: Included patients comprised 1872 with PPMS (47% men; 50% with activity) and 2575 with SPMS (32% men; 40% with activity). Relative to PPMS, SPMS had older age at onset of the progressive phase (median 46.7 years (95% CI 46.2-47.3) vs 43.9 (43.3-44.4); p<0.001), greater baseline disability, slower disability accrual (HR 0.86 (0.78-0.94); p<0.001) and similar age at wheelchair dependence. CONCLUSIONS: We demonstrate later onset of the progressive phase and slower disability accrual in SPMS versus PPMS. This may balance greater baseline disability in SPMS, yielding convergent disability trajectories across phenotypes. The different rates of disability accrual should be considered before amalgamating PPMS and SPMS in clinical trials.

The Acute Optic Neuritis Network (ACON): Study protocol of a non-interventional prospective multicenter study on diagnosis and treatment of acute optic neuritis.

Optic neuritis (ON) often occurs at the presentation of multiple sclerosis (MS), neuromyelitis optica spectrum disorders (NMOSD), and myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD). The recommended treatment of high-dose corticosteroids for ON is based on a North American study population, which did not address treatment timing or antibody serostatus. The Acute Optic Neuritis Network (ACON) presents a global, prospective, observational study protocol primarily designed to investigate the effect of time to high-dose corticosteroid treatment on 6-month visual outcomes in ON. Patients presenting within 30 days of the inaugural ON will be enrolled. For the primary analysis, patients will subsequently be assigned into the MS-ON group, the aquapotin-4-IgG positive ON (AQP4-IgG+ON) group or the MOG-IgG positive ON (MOG-IgG+ON) group and then further sub-stratified according to the number of days from the onset of visual loss to high-dose corticosteroids (days-to-Rx). The primary outcome measure will be high-contrast best-corrected visual acuity (HC-BCVA) at 6 months. In addition, multimodal data will be collected in subjects with any ON (CIS-ON, MS-ON, AQP4-IgG+ON or MOG-IgG+ON, and seronegative non-MS-ON), excluding infectious and granulomatous ON. Secondary outcomes include low-contrast best-corrected visual acuity (LC-BCVA), optical coherence tomography (OCT), magnetic resonance imaging (MRI) measurements, serum and cerebrospinal fluid (CSF) biomarkers (AQP4-IgG and MOG-IgG levels, neurofilament, and glial fibrillary protein), and patient reported outcome measures (headache, visual function in daily routine, depression, and quality of life questionnaires) at presentation at 6-month and 12-month follow-up visits. Data will be collected from 28 academic hospitals from Africa, Asia, the Middle East, Europe, North America, South America, and Australia. Planned recruitment consists of 100 MS-ON, 50 AQP4-IgG+ON, and 50 MOG-IgG+ON. This prospective, multimodal data collection will assess the potential value of early high-dose corticosteroid treatment, investigate the interrelations between functional impairments and structural changes, and evaluate the diagnostic yield of laboratory biomarkers. This analysis has the ability to substantially improve treatment strategies and the accuracy of diagnostic stratification in acute demyelinating ON. Trial registration: ClinicalTrials.gov, identifier: NCT05605951.

Treatment of multiple sclerosis with rituximab: A Spanish multicenter experience.

Introduction: Rituximab (RTX) is considered a potential therapeutic option for relapsing-remitting (RRMS) and progressive forms (PMS) of multiple sclerosis (MS). The main objective of this work was to investigate the effectiveness and safety of rituximab in MS. Patients and methods: Observational multicenter study of clinical and radiological effectiveness and safety of rituximab in RRMS and PMS. Results: A total of 479 rituximab-treated patients were included in 12 Spanish centers, 188 RRMS (39.3%) and 291 (60.7%) PMS. Despite standard treatment, the annualized relapse rate (ARR) the year before RTX was 0.63 (SD: 0.8) and 156 patients (41%) had at least one gadolinium-enhanced lesion (GEL) on baseline MRI. Mean EDSS had increased from 4.3 (SD: 1.9) to 4.8 (SD: 1.7) and almost half of the patients (41%) had worsened at least one point. After a median follow-up of 14.2 months (IQR: 6.5-27.2), ARR decreased by 85.7% (p < 0.001) and GEL by 82.9%, from 0.41 to 0.07 (p < 0.001). A significant decrease in EDSS to 4.7 (p = 0.046) was observed after 1 year of treatment and this variable remained stable during the second year of therapy. There was no evidence of disease activity in 68% of patients. Infusion-related symptoms were the most frequent side effect (19.6%) and most were mild. Relevant infections were reported only in 18 patients (including one case of probable progressive multifocal leukoencephalopathy). Conclusion: Rituximab could be an effective and safe treatment in RRMS, including aggressive forms of the disease. Some selected PMS patients could also benefit from this treatment.

Comparative effectiveness in multiple sclerosis: A methodological comparison.

BACKGROUND: In the absence of evidence from randomised controlled trials, observational data can be used to emulate clinical trials and guide clinical decisions. Observational studies are, however, susceptible to confounding and bias. Among the used techniques to reduce indication bias are propensity score matching and marginal structural models. OBJECTIVE: To use the comparative effectiveness of fingolimod vs natalizumab to compare the results obtained with propensity score matching and marginal structural models. METHODS: Patients with clinically isolated syndrome or relapsing remitting MS who were treated with either fingolimod or natalizumab were identified in the MSBase registry. Patients were propensity score matched, and inverse probability of treatment weighted at six monthly intervals, using the following variables: age, sex, disability, MS duration, MS course, prior relapses, and prior therapies. Studied outcomes were cumulative hazard of relapse, disability accumulation, and disability improvement. RESULTS: 4608 patients (1659 natalizumab, 2949 fingolimod) fulfilled inclusion criteria, and were propensity score matched or repeatedly reweighed with marginal structural models. Natalizumab treatment was associated with a lower probability of relapse (PS matching: HR 0.67 [95% CI 0.62-0.80]; marginal structural model: 0.71 [0.62-0.80]), and higher probability of disability improvement (PS matching: 1.21 [1.02 -1.43]; marginal structural model 1.43 1.19 -1.72]). There was no evidence of a difference in the magnitude of effect between the two methods. CONCLUSIONS: The relative effectiveness of two therapies can be efficiently compared by either marginal structural models or propensity score matching when applied in clearly defined clinical contexts and in sufficiently powered cohorts.

Variability of the response to immunotherapy among subgroups of patients with multiple sclerosis.

BACKGROUND AND PURPOSE: This study assessed the effect of patient characteristics on the response to disease-modifying therapy (DMT) in multiple sclerosis (MS). METHODS: We extracted data from 61,810 patients from 135 centers across 35 countries from the MSBase registry. The selection criteria were: clinically isolated syndrome or definite MS, follow-up ≥ 1 year, and Expanded Disability Status Scale (EDSS) score ≥ 3, with ≥1 score recorded per year. Marginal structural models with interaction terms were used to compare the hazards of 12-month confirmed worsening and improvement of disability, and the incidence of relapses between treated and untreated patients stratified by their characteristics. RESULTS: Among 24,344 patients with relapsing MS, those on DMTs experienced 48% reduction in relapse incidence (hazard ratio [HR] = 0.52, 95% confidence interval [CI] = 0.45-0.60), 46% lower risk of disability worsening (HR = 0.54, 95% CI = 0.41-0.71), and 32% greater chance of disability improvement (HR = 1.32, 95% CI = 1.09-1.59). The effect of DMTs on EDSS worsening and improvement and the risk of relapses was attenuated with more severe disability. The magnitude of the effect of DMT on suppressing relapses declined with higher prior relapse rate and prior cerebral magnetic resonance imaging activity. We did not find any evidence for the effect of age on the effectiveness of DMT. After inclusion of 1985 participants with progressive MS, the effect of DMT on disability mostly depended on MS phenotype, whereas its effect on relapses was driven mainly by prior relapse activity. CONCLUSIONS: DMT is generally most effective among patients with lower disability and in relapsing MS phenotypes. There is no evidence of attenuation of the effect of DMT with age.

Predictors of treatment switching in the Big Multiple Sclerosis Data Network.

Background: Treatment switching is a common challenge and opportunity in real-world clinical practice. Increasing diversity in disease-modifying treatments (DMTs) has generated interest in the identification of reliable and robust predictors of treatment switching across different countries, DMTs, and time periods. Objective: The objective of this retrospective, observational study was to identify independent predictors of treatment switching in a population of relapsing-remitting MS (RRMS) patients in the Big Multiple Sclerosis Data Network of national clinical registries, including the Italian MS registry, the OFSEP of France, the Danish MS registry, the Swedish national MS registry, and the international MSBase Registry. Methods: In this cohort study, we merged information on 269,822 treatment episodes in 110,326 patients from 1997 to 2018 from five clinical registries. Patients were included in the final pooled analysis set if they had initiated at least one DMT during the relapsing-remitting MS (RRMS) stage. Patients not diagnosed with RRMS or RRMS patients not initiating DMT therapy during the RRMS phase were excluded from the analysis. The primary study outcome was treatment switching. A multilevel mixed-effects shared frailty time-to-event model was used to identify independent predictors of treatment switching. The contributing MS registry was included in the pooled analysis as a random effect. Results: Every one-point increase in the Expanded Disability Status Scale (EDSS) score at treatment start was associated with 1.08 times the rate of subsequent switching, adjusting for age, sex, and calendar year (adjusted hazard ratio [aHR] 1.08; 95% CI 1.07-1.08). Women were associated with 1.11 times the rate of switching relative to men (95% CI 1.08-1.14), whilst older age was also associated with an increased rate of treatment switching. DMTs started between 2007 and 2012 were associated with 2.48 times the rate of switching relative to DMTs that began between 1996 and 2006 (aHR 2.48; 95% CI 2.48-2.56). DMTs started from 2013 onwards were more likely to switch relative to the earlier treatment epoch (aHR 8.09; 95% CI 7.79-8.41; reference = 1996-2006). Conclusion: Switching between DMTs is associated with female sex, age, and disability at baseline and has increased in frequency considerably in recent years as more treatment options have become available. Consideration of a patient's individual risk and tolerance profile needs to be taken into account when selecting the most appropriate switch therapy from an expanding array of treatment choices.

Mars-like UV Flux and Ionizing Radiation Differently Affect Biomarker Detectability in the Desert Cyanobacterium Chroococcidiopsis as Revealed by the Life Detector Chip Antibody Microarray.

The effect of a Mars-like UV flux and γ-radiation on the detectability of biomarkers in dried cells of Chroococcidiopsis sp. CCMEE 029 was investigated using a fluorescence sandwich microarray immunoassay. The production of anti-Chroococcidiopsis antibodies allowed the immunoidentification of a reduced, though still detectable, signal in dried cells mixed with phyllosilicatic and sulfatic Mars regolith simulants after exposure to 6.8 × 105 kJ/m2 of a Mars-like UV flux. No signal was detected in dried cells that were not mixed with minerals after 1.4 × 105 kJ/m2. For γ-radiation (60Co), no detectable variations of the fluorescence signal occurred in dried cells exposed to 113 kGy compared to non-irradiated dried cells. Our results suggest that immunoassay-based techniques could be used to detect life tracers eventually present in the martian subsurface in freshly excavated materials only if shielded from solar UV. The high structural integrity of biomarkers irradiated with γ-radiation that mimics a dose accumulated in 13 Myr at 2 m depth from the martian surface has implications for the potential detectability of similar organic molecules/compounds by future life-detection missions such as the ExoMars Rosalind Franklin rover.

Disease modifying therapy switching in relapsing multiple sclerosis: A Delphi consensus of the demyelinating expert group of the Spanish society of neurology.

BACKGROUND: The increase in available disease modifying therapies (DMTs) for multiple sclerosis has led to greater emphasis on improving treatment sequencing paradigms. This article summarises the opinions from a panel of 25 experts on treatment switching approaches in relapsing multiple sclerosis (RMS). METHODS: A modified Delphi consensus process was carried out to develop clinically relevant statements for aiding treatment decisions in patients with RMS between the 16th January and the 9th October 2019. A sub-group of two experts (core group) carried out an extensive review of the literature and formulated 106 statements for the expert panel to evaluate. RESULTS: From a total number of 106 statements that were submitted to the expert panel for critical evaluation, consensus (at least 80% of the panelists agreed) was reached on 99 of them. These statements cover treatment objectives, reasons for DMT switching, suboptimal response criteria, strategies for treatment change and washout periods. CONCLUSION: The agreed statements provide up-to-date guidance on DMT sequencing for optimal patient management.

Cognitive Performance and Health-Related Quality of Life in Patients with Neuromyelitis Optica Spectrum Disorder.

Background: The frequency of cognitive impairment (CI) reported in neuromyelitis optica spectrum disorder (NMOSD) is highly variable, and its relationship with demographic and clinical characteristics is poorly understood. We aimed to describe the cognitive profile of NMOSD patients, and to analyse the cognitive differences according to their serostatus; furthermore, we aimed to assess the relationship between cognition, demographic and clinical characteristics, and other aspects linked to health-related quality of life (HRQoL). Methods: This cross-sectional study included 41 patients (median age, 44 years; 85% women) from 13 Spanish centres. Demographic and clinical characteristics were collected along with a cognitive z-score (Rao's Battery) and HRQoL patient-centred measures, and their relationship was explored using linear regression. We used the Akaike information criterion to model which characteristics were associated with cognition. Results: Fourteen patients (34%) had CI, and the most affected cognitive domain was visual memory. Cognition was similar in AQP4-IgG-positive and -negative patients. Gender, mood, fatigue, satisfaction with life, and perception of stigma were associated with cognitive performance (adjusted R2 = 0.396, p < 0.001). Conclusions: The results highlight the presence of CI and its impact on HRQoL in NMOSD patients. Cognitive and psychological assessments may be crucial to achieve a holistic approach in patient care.