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Rituximab is extensively used for multiple sclerosis (MS) treatment. However, the best dosage remains to be established. It has been proposed that retreatment could be guided by B lymphocyte (BL) percentages.To establish the best BL value for retreatment with rituximab in MS and to confirm the safety and efficacy of this approach.A prospective study was done with an exploratory cohort and a confirmatory cohort of MS patients treated with rituximab between 2017 and 2021. The first one comprised 10 MS patients with BL assessed every 3 months after rituximab infusion and retreatment done when BL values were ≥0.5%. The confirmatory cohort included 41 MS patients (41.5% women, 87.8% with secondary progressive MS, median age = 46.3 (interquartile range: 41.3-52.1) years, disease duration = 14.1 (9-19.6) years, EDSS score = 5.5 (4.0-6.5)). The confirmatory cohort was treated with rituximab following the pattern established in the exploratory cohort.In the exploratory cohort, ≥0.2% BL was established as the best value for retreatment because in most cases, a substantial increase of BL counts was preceded by initial values of 0.2-0.3%. In the confirmatory cohort, rituximab reduced the annualized relapse rate (ARR 0.56 vs. 0.125, p 0.001), proportion of patients with appearance of new/enlarged T2 lesions (63.4% vs. 12.2%, p 0.001), gadolinium-enhancing lesions (39% vs. 0%, p 0.001), and confirmed disability progression (55% vs. 27.5%, p = 0.037). There were 22 patients (53.7%) who achieved NEDA-3. No patients had severe infections, and 10.7% cases had reduced IgG levels.Rituximab treatment guided by BL showed high effectiveness and a good safety profile for MS patients after one year of treatment.

Background: Multiple sclerosis is one of the most common causes of neurological disability in young adults with major consequences for their future lives. Improving communication strategies on prognosis may help patients deal with the disease and adjust their long-term life goals. However, there is limited information on patients' preferences of long-term prognosis (LTP) communication and associated factors. Objective: The aim of this study was to describe patients' preferences and assess the factors associated with LTP communication preferences in early-stage relapsing-remitting multiple sclerosis (RRMS) patients. Methods: A multicenter, non-interventional study was conducted. Adult patients with a diagnosis of RRMS, a disease duration from first attack

Serum neurofilament light chains (sNfL) are biomarkers of disease activity in multiple sclerosis (MS), but their value to predict response to treatment, and their association with patient immunological profile, need to be further explored. We studied 80 relapsing–remitting MS patients initiating dimethyl fumarate (DMF) treatment. sNfL levels were explored at baseline and at 3, 6 and 12 months by single molecule array. Blood lymphocyte subsets were measured at baseline and at 6 months by flow cytometry. Patients were followed a year and classified as NEDA (no evidence of disease activity) or ODA (ongoing disease activity). NEDA patients had lower sNfL levels at baseline (p = 0.0001), and after three (p = 0.004) and six (p = 0.03) months of DMF treatment. Consequently, low baseline sNfL values (≤ 12 pg/ml) increased the probability of NEDA (OR 5.8; CI 1.82–15.6; p = 0.002, after correcting by disease activity in the previous year), and associated with significant reductions of central memory CD4+ T lymphocytes, interferon-gamma+ CD8+ T lymphocytes, Natural Killer T cells, and memory B cells upon DMF treatment, being the highest differences in memory B cells (p

Disability accrual is mainly driven by progression independent of relapse activity, which is present even in early stages of relapsing-remitting multiple sclerosis (RRMS) and sometimes overlooked. This multicenter, non-interventional study evaluated whether patient-reported outcomes measures (PROMs) could capture disability in 189 early-stage RRMS patients (mean age: 36.1 ± 9.4 years, 71.4% female, mean disease duration: 1.4 ± 0.8 years, median EDSS: 1.0). The 9-Hole Peg Test (9-HPT), NeuroQoL Upper Extremity (NeuroQoL-UE), Timed 25-Foot Walk (T25-FW), Multiple Sclerosis Walking Scale (MSWS-12), Symbol Digit Modalities Test (SDMT), and Perceived Deficits Questionnaire (PDQ-5) were used to assess hand function, gait, and cognition, respectively. These functions were at least mildly affected in this early-stage population, finding significant correlations between PROMs and clinical assessments. PROMs could enable early-stage RRMS patients to communicate their perceived disability in different domains, assisting clinicians in disease monitoring and decision making.

ImportanceThe value of serum neurofilament light chain (sNfL) levels for predicting long-term disability in patients with multiple sclerosis (MS) remains controversial.ObjectiveTo assess whether high sNfL values are associated with disability worsening in patients who underwent their first demyelinating MS event.Design, Setting, and ParticipantsThis multicenter cohort study included patients who underwent their first demyelinating event suggestive of MS at Hospital Universitario Ramón y Cajal (development cohort; June 1, 1994, to September 31, 2021, with follow-up until August 31, 2022) and 8 Spanish hospitals (validation cohort; October 1, 1995, to August 4, 2020, with follow-up until August 16, 2022).ExposuresClinical evaluations at least every 6 months.Main Outcomes and MeasuresThe main outcomes were 6-month confirmed disability worsening (CDW) and an Expanded Disability Status Scale (EDSS) score of 3. Levels of sNfL were measured in blood samples obtained within 12 months after disease onset using a single molecule array kit. The cutoffs used were sNfL level of 10 pg/mL and a standardized score (z score) of 1.5. Multivariable Cox proportional hazards regression models were used to evaluate outcomes.ResultsOf the 578 patients included in the study, 327 were in the development cohort (median age at sNfL analysis, 34.1 years [IQR, 27.2-42.7 years]; 226 female [69.1%]) and 251 patients were in the validation cohort (median age at sNfL analysis, 33.3 years [IQR, 27.4-41.5 years]; 184 female [73.3%]). The median follow-up was 7.10 years (IQR, 4.18-10.0 years). Levels of sNfL greater than 10 pg/mL were independently associated with higher risk of 6-month CDW and an EDSS of 3 in the development cohort (6-month CDW: hazard ratio [HR], 2.39; 95% CI, 1.39-4.12; P = .002; EDSS of 3: HR, 4.12; 95% CI, 2.18-7.77; P P = .02; EDSS of 3: HR, 2.03; 95% CI, 1.23-3.33; P = .005). Highly effective disease-modifying treatments were associated with lower risks of 6-month CDW and an EDSS of 3 in patients with high baseline sNfL values.Conclusions and RelevanceThis cohort study found that high sNfL values obtained within the first year of disease were associated with long-term disability worsening in MS, suggesting that sNfL level measurement may help identify optimal candidates for highly effective disease-modifying treatments.

Dimethyl fumarate (DMF) tolerability and safety in multiple sclerosis (MS) has been analyzed in randomized clinical trials. Real-life studies are needed to assess possible harms of this therapy in a wider MS population. To evaluate DMF tolerability, safety and persistence in MS in a real-world setting. We conducted a multicenter prospective study of patients who started DMF, attended in 16 public hospitals of Spain. A specific database was elaborated to collect data on most frequent adverse events (AE). Regression models were used to analyze the effect of demographic and clinical characteristics on risk of AEs and DMF discontinuation. We collected data of 886 patients (2681 patients/years-exposition) with median 39.5 (IQR 23, 51.5) months on DMF exposure; 25.3% were treatment naive and 74.7% switched to DMF from other disease-modifying therapies. DMF was discontinued in 29.9% of patients, in 13.2% due to AEs and in 13.5% to inefficacy. AEs were experienced by 71.2%, being flushing the most frequent (44.1%), 5.4% developed grade III lymphopenia, without cases of grade IV. Females showed a higher risk of flushing and gastroenteric symptoms (OR 1.49, p = 0.011; OR 1.69, p = 0.001, respectively); lymphopenia was associated with older age (OR 1.04, p

Background: Multiple sclerosis is one of the most common causes of neurological disability in young adults with major consequences for their autonomy and capacity to maintain employment. Objective: The aim of this study was to assess the impact on work productivity in early-stage relapsing-remitting multiple sclerosis (RRMS). Methods: A multicenter, non-interventional study was conducted. Adult patients with a diagnosis of RRMS, a disease duration

Background: Lymphopenia is a major concern in MS patients treated with dimethyl-fumarate (DMF) as it increases the risk of progressive multifocal leukoencephalopathy. A pronounced reduction in absolute lymphocyte counts (ALCs) early after treatment initiation has been suggested to be associated with the occurrence of lymphopenia thereafter. Objectives: To identify risk factors for DMF-induced lymphopenia and evaluate whether the degree of decrease in the ALCs three months after initiation of DMF treatment is a predictor of the subsequent development of lymphopenia. Methods: In this real-world Spanish prospective multicenter study conducted in MS patients who started DMF between 2014 and 2019, we analyzed the association between DMF-related lymphopenia and the percentage of early ALCs decline using regression models, considering both, significant lymphopenia (grades 2 + 3) and severe lymphopenia (grade 3). The cutoff values of early ALCs declines were obtained using the ROC curve. Results: Among 532 MS patients treated with DMF, 193 (36.3%) developed any grade of lymphopenia. Older age and lower ALCs at treatment onset predicted the risk for lymphopenia but the best predictive risk factor was the reduction of ALCs within the three first months of treatment. Specifically, a reduction in ALCs≥21.2% was associated with a 6.5-fold higher risk of developing significant lymphopenia, and a decrease in ALCs≥40.2% with a 12.7-fold higher risk of developing severe lymphopenia. Conclusions: A pronounced reduction in ALCs early after initiation of DMF in MS patients is the best predictive risk factor for the subsequent development of significant lymphopenia. Sin financiación 4.808 JCR (2021) Q2, 64/212 Clinical Neurology 1.006 JCR (2021) Q1, 472/2489 Medicine (miscellaneous) No data IDR 2020 UEM

Background and purpose Limited information is available on incidence and outcomes of COVID‐19 in patients with multiple sclerosis (MS). This study investigated the risks of SARS‐CoV‐2 infection and COVID‐19‐related outcomes in patients with MS, and compared these with the general population. Methods A regional registry was created to collect data on incidence, hospitalization rates, intensive care unit admission, and death in patients with MS and COVID‐19. National government outcomes and seroprevalence data were used for comparison. The study was conducted at 14 specialist MS treatment centers in Madrid, Spain, between February and May 2020. Results Two‐hundred nineteen patients were included in the registry, 51 of whom were hospitalized with COVID‐19. The mean age ± standard deviation was 45.3 ± 12.4 years, and the mean duration of MS was 11.9 ± 8.9 years. The infection incidence rate was lower in patients with MS than the general population (adjusted incidence rate ratio = 0.78, 95% confidence interval [CI] = 0.70–0.80), but hospitalization rates were higher (relative risk = 5.03, 95% CI = 3.76–6.62). Disease severity was generally low, with only one admission to an intensive care unit and five deaths. Males with MS had higher incidence rates and risk of hospitalization than females. No association was found between the use of any disease‐modifying treatment and hospitalization risk. Conclusions Patients with MS do not appear to have greater risks of SARS‐CoV‐2 infection or severe COVID‐19 outcomes compared with the general population. The decision to start or continue disease‐modifying treatment should be based on a careful risk–benefit assessment., In this multicenter registry‐based cohort study, patients with multiple sclerosis did not have an increased risk of becoming infected with COVID‐19 compared with the general population, and were not more likely to have a severe outcome of COVID‐19 (i.e., admission to an intensive care unit or death). No relationship was found between the use of any disease‐modifying treatment and the development of severe COVID‐19 disease.

Background Lymphopenia is a major concern in MS patients treated with dimethyl-fumarate (DMF) as it increases the risk of progressive multifocal leukoencephalopathy. Objective To identify factors associated with lymphopenia in DMF-treated patients and explore changes in blood lymphocyte subsets associated with DMF-induced lymphopenia. Methods Prospective longitudinal study including 106 patients initiating DMF treatment followed for a median time of 24.67 months. Blood lymphocyte subsets were studied in 64 patients by flow cytometry at baseline and 6 months after. Results Mean absolute lymphocyte counts (ALCs) decreased by 29% during the first year of DMF-treatment. Patients developing lymphopenia showed a faster decline within the three first months. A reduction of ALCs higher than 38% at this time was associated to subsequent development of grade 2–3 lymphopenia (OR = 5.93, 95% CI: 1.9–18.6, p = 0.002). All patients showed a significant decrease in different T and B lymphocyte subsets upon DMF therapy. In addition, lymphopenic patients experienced a selective decrease in natural killer T (NKT) cell percentages (p = 0.01), and a high drop in NKT total counts (p Conclusions Patients who experience a drop in ALCs by >38% at three months of DMF-treatment are about 6-times more likely to develop significant lymphopenia. This decrease is clearly associated with a considerable loss of NKT cells.

Objectives Teriflunomide, a disease‐modifying treatment approved for multiple sclerosis (MS), inhibits reversibly dihydroorotate dehydrogenase, an enzyme involved in de novo pyrimidine biosynthesis and down‐regulates proliferation of activated lymphocytes. We aimed to study the impact of this drug in the lymphocyte profiles of MS patients. Methods Fifty‐five patients with relapsing‐remitting MS who initiated teriflunomide treatment were included in the study. We studied peripheral blood mononuclear cells obtained before and 6 months after treatment initiation and explored effector, memory, and regulatory cells by flow cytometry. Wilcoxon matched pair tests were used to assess differences between basal and 6 months after treatment results. P‐values were corrected with Bonferroni test. Results When explored T and B cell subsets, we observed a decrease in the percentages of terminally differentiated CD4+ T cells (P = 0.001) and plasmablasts (P < 0.0001) after 6 months of treatment. These results were confirmed with the total cell number. When studied immunomodulatory cells, we observed a clear increase of monocytes expressing programmed death‐ligand 1 (PD‐L1) (P = 0.005), which correlated negatively with all effector CD8+ T cell subsets. We also observed an increase in the percentage of CD8+ T cells (P = 0.028) and monocytes (P = 0.04) producing IL‐10. Conclusions Teriflunomide induces a specific reduction in effector T and B cells that have shown to play a role in MS course and an increase in immunomodulatory cells. Particularly, this drug induces the expression of PD‐L1, a molecule involved in tolerance to autoantigens, which can contribute to inhibit the abnormal immune response taking place in MS.

The potential influence of the timing of high-efficacy disease-modifying therapies (heDMTs) on processing speed (PS) performance is critically lacking in current literature.To assess the extent to which early commencement of heDMTs would be associated with a better PS evolution as compared to moderate efficacy disease-modifying therapies (meDMTs) and delayed commencement of heDMTs.In this ongoing prospective longitudinal study, the 695 MS patients that have received a PS evaluation at 12-month of follow-up measured by the iPad®-based Processing Speed Test (PST) were retained for the analysis. All patients who had ever been prescribed a high efficacy disease-modifying therapy (heDMT) were classified in tertiles according to the proportion of their disease duration that had been on heDMTs. Based on these tertiles and the time to the first heDMT from the disease onset, patients were divided into the early heDMT group and the delayed heDMT group. Between-group differences in mean PST standardized (Z-score) change from baseline were analyzed using a linear mixed model.In the multivariable model, each year of delay in starting a heDMT was associated with increased odds of cognitive worsening at 12-month (OR = 1.0324, 95% CI = 1.014-1.062, p0.05). MeDMT-treated patients were at a significantly higher risk for cognitive worsening than early heDMT patients (OR= 2.57, 95%CI = 1.02-6.17). Linear mixed model-based adjusted mean change in PST Z-score from baseline was significantly better in those patients with the longest proportion of their disease duration treated with heDMT (highest tertile) compared to the lowest tertile (difference 0.37 [95%CI 0.02-0.92;p=0.036) and medium tertile (difference 0.39 [95%CI 0.06-0.31;p=0.037).Early he-DMT-treated patients are at significantly lower risk for cognitive worsening. Early administration of heDMTs is associated with greater cognitive functioning improvements than delayed commencement or meDMTs.

Background Potential increase of cancer incidence is one of the main safety concerns of the disease-modifying therapies employed in Multiple Sclerosis (MS). Objective Detailed description of patients who developed cancer among a prospective cohort of Spanish MS patients on dimethyl fumarate (DMF) treatment. Methods We describe patients who developed cancer among a cohort of 886 MS patients on DMF treatment (2681 patient-years), with a median time of exposure of 39.5 months (IQR 23-51.5), who participated in a multicentre and prospective real-world study conducted in 16 Spanish National Health System hospitals from February 2014 to May 2019. Local researchers were periodically contacted by the investigation team to monitor safety issues. Cancer histories were collected from the medical records and the information was updated at July 30th 2020. Results Eight Caucasian women developed cancer, which accounts for 0.9% and an accumulated malignancy rate of 298.39 cases per 100,000 patient-years of DMF exposure. At the time of cancer diagnosis, age was between 33 to 67 years and median time on DMF treatment 16.5 months (range 1-53). Two patients had familiar history of cancer. No specific cancer lines were found (breast cancer in 2 cases, thyroid in 3, urothelial carcinoma, cervix and a progression to leiomyosarcoma from a mitotically active leiomyoma). DMF was withdrawn during cancer treatment in 6 patients and reintroduced later. All cancers except one are in complete remission. The patient with leiomyosarcoma died by cancer progression. Conclusion A relationship between cancers and DMF is unlikely because the malignancy rate was similar to that of the age-and sex-matched general population, and because of the absence of specific tumour cell lines. Nevertheless, as with other immunosuppressive DMTs, clinicians treating MS should be aware of any potential cancer symptom and demand proper testing.

Immunosuppression (IS) and autoimmune disease (AD) are prevalent in patients with severe coronavirus disease 2019 (COVID-19), but their impact on its clinical course is unknown. We investigated relationships between IS, AD, and outcomes in patients hospitalized with COVID-19. Data on consecutive admissions for COVID-19 were extracted retrospectively from medical records. Patients were assigned to one of four cohorts, according to whether or not they had an AD (AD and NAD) or were immunosuppressed (IS and NIS). The primary endpoint was development of severe acute respiratory distress syndrome (ARDS); secondary endpoints included death, and a composite of mechanical ventilation (MV) or death. A total of 789 patients were included: 569 (72.1%) male, 76 (9.6%) with an AD, and 63 (8.0%) with IS. Relative to the NIS-NAD cohort, patients in the IS-AD cohort had a significantly reduced risk of severe ARDS (adjusted hazard ratio [aHR] 0.42; 95% confidence interval [CI] 0.23–0.80; p = 0.008). No significant relationships between IS or AD status and either death or the composite of MV and death were identified, although a trend towards higher mortality was identified in the IS-NAD cohort (aHR vs NIS-NAD 1.71; 95% CI 0.94–3.12; p = 0.081). Patients in this cohort also had higher median serum levels of interleukin-6 compared with IS-AD patients (98.2 vs 21.6 pg/mL; p = 0.0328) and NIS-NAD patients (29.1 pg/mL; p = 0.0057). In conclusion, among patients hospitalized with COVID-19, those receiving immunosuppressive treatment for an AD may have a reduced risk of developing severe ARDS. Supplementary Information The online version contains supplementary material available at 10.1007/s10875-020-00927-y.

Dimethyl fumarate (DMF) has demonstrated efficacy in phase III studies. However, real-world data are still limited.The objective of this study was to describe the profile of patients who receive DMF and to assess the effectiveness of DMF regarding relapses, disability progression, magnetic resonance imaging activity, and NEDA (No Evidence Disease Activity)-3 status in a Spanish population in a real-world setting.We conducted a multicenter prospective study of patients who started DMF between 2014 and 2019 in Spain. Three subgroups were considered: naïve, switch to DMF because of inefficacy, and switch to DMF because of adverse effects. The effects of DMF on clinical and radiological measures were evaluated.Among 886 patients, 25.3% were naïve, 28.8% switched because of adverse effects, and 45.9% because of inefficacy. Median follow-up was 38.9 (interquartile range 22.6-41.8) months. Annualized relapse rates were 0.15, 0.10, and 0.10 at 12, 24, and 36 months respectively, and 77.7% of patients were relapse free at month 42. At 12, 24, and 42 months, 96.1%, 87.4%, and 79.7% of patients were progression free, respectively. The number of T1 gadolinium-enhancement (T1Gd+) lesions was 0.19, 0.14, and 0.18 at 12, 24, and 36 months. NEDA-3 status at month 42 was maintained by 49.8% of patients. Relapsing was associated with higher annualized relapse rates the year before (hazard ratio 1.34, p0.001) and to the inefficacy switch vs naïve group (hazard ratio 1.76, p = 0.003). A higher baseline Expanded Disability Status Scale score was associated with disability progression (hazard ratio 1.15, p = 0.003) and more T1Gd+ lesions (hazard ratio 1.07, p0.001) with radiological progression. A higher baseline Expanded Disability Status Scale score, a larger number of T1Gd+ lesions, and a switch because of inefficacy (vs adverse events) were all risk factors for losing NEDA-3 status. DMF was discontinued in 29.9% of patients, in 13.5% because of inefficacy.Our findings confirm the sustained effectiveness of DMF on the clinical and radiological activity of multiple sclerosis in a real-world setting, both in naïve patients and in those switching from other multiple sclerosis therapies.

Despite the increasing evidence of the benefit of corticosteroids for the treatment of moderate-severe coronavirus disease 2019 (COVID-19) patients, no data are available about the potential role of high doses of steroids for these patients. We evaluated the mortality, the risk of need for mechanical ventilation (MV), or death and the risk of developing a severe acute respiratory distress syndrome (ARDS) between high (HD) and standard doses (SD) among patients with a severe COVID-19. All consecutive confirmed COVID-19 patients admitted to a single center were selected, including those treated with steroids and an ARDS. Patients were allocated to the HD (≥ 250 mg/day of methylprednisolone) of corticosteroids or the SD (≤ 1.5 mg/kg/day of methylprednisolone) at discretion of treating physician. Five hundred seventy-three patients were included: 428 (74.7%) men, with a median (IQR) age of 64 (54–73) years. In the HD group, a worse baseline respiratory situation was observed and male gender, older age, and comorbidities were significantly more common. After adjusting by baseline characteristics, HDs were associated with a higher mortality than SD (adjusted OR 2.46, 95% CI 1.59–3.81, p

BACKGROUND: Coronavirus disease 2019 (COVID-19) is an emerging infectious disease that has spread rapidly worldwide. The role of immunosuppression among COVID-19 patients has not been elucidated and management may be challenging. OBJECTIVE: To assess differences in severe outcomes of hospitalized patients with COVID-19 according to immune system state. DESIGN: Retrospective single-center observational study with confirmed COVID-19 patients admitted to Hospital Universitario Ramón y Cajal from March 18, 2020 to April 04, 2020. The final date of follow-up was April 09, 2020.PARTICIPANTS: Confirmed COVID-19 patients. MAIN MEASURES: The primary endpoint was development of moderate-severe acute respiratory distress syndrome (ARDS). Time to moderate-severe ARDS, the need for mechanical or non-invasive ventilation (MV/NIV), death, and a composite of death or MV/NIV were secondary endpoints. KEY RESULTS: Of 138 patients included, 27 (19.6%) were immunosuppressed (IS), with 95 (68.8%) male patients and a median (Q1, Q3) age of 68 (54–78) years. Among the baseline characteristics, no relevant or significant differences were observed between IS and non-immunosuppressed (non-IS) patients, detecting a non-severe immunosupression among IS. A significantly lower proportion of IS patients (22.2% [95%CI, 9.8–43.0%]) compared to non-IS patients (49.5% [95%CI, 40.2–58.9%]) developed moderate-severe ARDS, in both unadjusted (OR 0.29 [95%CI, 0.11–0.76], p=0.014) and adjusted (aOR 0.16 [95%CI, 0.05–0.55], p=0.004) analyses. After stratifying by pathologies, only IS autoimmune diseases remained significant (aOR 0.12 [95%CI, 0.03–0.57], p=0.007). Non-significant trends toward a longer time to moderate or severe ARDS, a lower need for MV/NIV, and a lower risk of death or MV/NIV were detected in IS. CONCLUSIONS: In our cohort of COVID-19 patients, non-severe immunosuppression was associated with a lower risk of moderate-severe ARDS, especially among AD. This suggests a potential protective effect from a hypothesized host hyper-inflammatory response and warrants reconsideration of management of IS patients.

INTRODUCTIONDespite the increasing evidence of the benefit of corticosteroids for the treatment of moderate-severe Coronavirus disease 2019 (COVID-19) patients, no data are available about the potential role of high doses of steroids for these patients.METHODSAll consecutive confirmed COVID-19 patients admitted to a single center were selected, including those treated with steroids and an acute respiratory distress syndrome (ARDS). Patients were allocated to the high doses (HD, ≥250mg/day of methylprednisolone) of corticosteroids or the standard doses (SD, ≤1.5mg/kg/day of methylprednisolone) at discretion of treating physician. The primary endpoint was the mortality between both cohorts and secondary endpoints were the risk of need for mechanical ventilation (MV) or death and the risk of developing a severe ARDS.RESULTS573 patients were included: 428 (74.7%) men, with a median (IQR) age of 64 (54–73) years. In HD cohort, a worse baseline respiratory situation was observed and male sex, older age and comorbidities were significantly more common. After adjusting by baseline characteristics, HD were associated with a higher mortality than SD (adjusted-OR 2.46, 95% CI 1.58 – 3.83, pCONCLUSIONOur real-world experience advises against exceeding 1-1.5mg/kg/day of corticosteroids for severe COVID-19 with an ARDS, especially in older subjects. This reinforces the rationale of modulating rather than suppressing immune responses in these patients.SUMMARYIn patients with severe COVID-19, high doses of corticosteroids are associated with a higher mortality and risk of need for mechanical ventilation or death compared to standard doses. This deleterious effect is mainly observed in the elderly.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is an emerging infectious disease that has spread rapidly worldwide. The role of immunosuppression among COVID-19 patients has not been elucidated and management may be challenging.OBJECTIVE: To assess differences in severe outcomes of hospitalized patients with COVID-19 according to immune system state.DESIGN: Retrospective single-center observational study with confirmed COVID-19 patients admitted to Hospital Universitario Ramón y Cajal from March 18, 2020 to April 04, 2020. The final date of follow-up was April 09, 2020.PARTICIPANTS: Confirmed COVID-19 patients.MAIN MEASURES: The primary endpoint was development of moderate-severe acute respiratory distress syndrome (ARDS). Time to moderate-severe ARDS, the need for mechanical or non-invasive ventilation (MV/NIV), death, and a composite of death or MV/NIV were secondary endpoints.KEY RESULTS: Of 138 patients included, 29 (21%) were immunocompromised (IC), with 95 (68.8%) male patients and a median (IQR) age of 68 (54 – 78) years. Among the baseline characteristics, no relevant or significant differences were observed between IC and non-immunocompromised (non-IC) patients. A significantly lower proportion of IC patients (24.1% [95% CI, 11.4 – 44.0%]) compared to non-IC patients (49.5% [95% CI, 40.1 – 59.0%]) developed moderate-severe ARDS, in both unadjusted (OR 0.32 [95% CI, 0.13 – 0.82], p=0.018) and adjusted (aOR 0.16 [95% CI, 0.05 – 0.52], p=0.003) analyses. A positive non-significant trend toward a longer time to moderate or severe ARDS, a lower need for MV/NIV, and a lower risk of death or MV/NIV were detected in IC. A trend toward a shorter- hospitalization in IC was observed.CONCLUSIONS: In our cohort of COVID-19 patients, immunosuppression was associated with a lower risk of moderate-severe ARDS. This suggests a potential protective effect from a hypothesized host hyper-inflammatory response and warrants reconsideration of drug discontinuation in IC patients.

Dimethyl fumarate (DMF) tolerability and safety in multiple sclerosis (MS) has been analyzed in randomized clinical trials. Real-life studies are needed to assess possible harms of this therapy in a wider MS population.To evaluate DMF tolerability, safety and persistence in MS in a real-world setting.We conducted a multicenter prospective study of patients who started DMF, attended in 16 public hospitals of Spain. A specific database was elaborated to collect data on most frequent adverse events (AE). Regression models were used to analyze the effect of demographic and clinical characteristics on risk of AEs and DMF discontinuation.We collected data of 886 patients (2681 patients/years-exposition) with median 39.5 (IQR 23, 51.5) months on DMF exposure; 25.3% were treatment naïve and 74.7% switched to DMF from other disease-modifying therapies. DMF was discontinued in 29.9% of patients, in 13.2% due to AEs and in 13.5% to inefficacy. AEs were experienced by 71.2%, being flushing the most frequent (44.1%), 5.4% developed grade III lymphopenia, without cases of grade IV. Females showed a higher risk of flushing and gastroenteric symptoms (OR 1.49, p = 0.011; OR 1.69, p = 0.001, respectively); lymphopenia was associated with older age (OR 1.04, p 0.001), and a higher EDSS with lymphopenia (OR 1.10, p = 0.035) and DMF withdrawal (HR 1.43, p = 0.012). No safety problems were reported.Our findings confirm good tolerability and safety of DMF in real-world setting and suggest that women have an increased risk of AEs and higher baseline disability involves greater risk of drug discontinuation.

Overview: We assessed the role of age and disease activity as new factors contributing to establish the risk of progressive multifocal leucoencephalopathy in multiple sclerosis patients treated with natalizumab in 36 University Hospitals in Europe. We performed the study in 1,307 multiple sclerosis patients (70.8% anti-John Cunninghan virus positive antibodies) treated with natalizumab for a median time of 3.28 years. Epidemiological, clinical, and laboratory variables were collected. Lipid-specific IgM oligoclonal band status was available in 277 patients. Factors associated with progressive multifocal leucoencephalopathy onset were explored by uni- and multivariate logistic regression. Results: Thirty-five patients developed progressive multifocal leucoencephalopathy. The multivariate analysis identified anti-John Cunninghan virus antibody indices and relapse rate as the best predictors for the onset of this serious opportunistic infection in the whole cohort. They allowed to stratify progressive multifocal leucoencephalopathy risk before natalizumab initiation in individual patients [area under the curve (AUC) = 0.85]. The risk ranged from, This study was supported by grants PI15/00513, PI18/00572, and RD17/0015 (Red Espanola de Esclerosis Multiple) from Instituto de Salud Carlos III, Ministerio de Economia y Empresa, Spain.

Background: Dimethyl fumarate (DMF) has demonstrated efficacy in phase III studies. However, real-world data are still limited. Objective: The objective of this study was to describe the profile of patients who receive DMF and to assess the effectiveness of DMF regarding relapses, disability progression, magnetic resonance imaging activity, and NEDA (No Evidence Disease Activity)-3 status in a Spanish population in a real-world setting. Methods: We conducted a multicenter prospective study of patients who started DMF between 2014 and 2019 in Spain. Three subgroups were considered: naïve, switch to DMF because of inefficacy, and switch to DMF because of adverse effects. The effects of DMF on clinical and radiological measures were evaluated. Results: Among 886 patients, 25.3% were naïve, 28.8% switched because of adverse effects, and 45.9% because of inefficacy. Median follow-up was 38.9 (interquartile range 22.6-41.8) months. Annualized relapse rates were 0.15, 0.10, and 0.10 at 12, 24, and 36 months respectively, and 77.7% of patients were relapse free at month 42. At 12, 24, and 42 months, 96.1%, 87.4%, and 79.7% of patients were progression free, respectively. The number of T1 gadolinium-enhancement (T1Gd+) lesions was 0.19, 0.14, and 0.18 at 12, 24, and 36 months. NEDA-3 status at month 42 was maintained by 49.8% of patients. Relapsing was associated with higher annualized relapse rates the year before (hazard ratio 1.34, p < 0.001) and to the inefficacy switch vs naïve group (hazard ratio 1.76, p = 0.003). A higher baseline Expanded Disability Status Scale score was associated with disability progression (hazard ratio 1.15, p = 0.003) and more T1Gd+ lesions (hazard ratio 1.07, p < 0.001) with radiological progression. A higher baseline Expanded Disability Status Scale score, a larger number of T1Gd+ lesions, and a switch because of inefficacy (vs adverse events) were all risk factors for losing NEDA-3 status. DMF was discontinued in 29.9% of patients, in 13.5% because of inefficacy. Conclusions: Our findings confirm the sustained effectiveness of DMF on the clinical and radiological activity of multiple sclerosis in a real-world setting, both in naïve patients and in those switching from other multiple sclerosis therapies. Sin financiación 5.754 JCR (2020) Q1, 36/208 Clinical Neurology 1.565 SJR (2020) Q1, 61/372 Neurology (clinical) No data IDR 2020 UEM

BACKGROUND AND PURPOSE Different biological and radiological biomarkers predict clinical conversion to multiple sclerosis (MS) after a clinically isolated syndrome (CIS). The aim was to explore their role in predicting the outcome of patients with optic neuritis (ON), a CIS considered to have a benign prognosis. METHODS Sixty-eight consecutive ON patients were followed prospectively. Magnetic resonance imaging (MRI) and cerebrospinal fluid studies including oligoclonal immunoglobulin G (IgG) bands (OCGBs), lipid-specific oligoclonal IgM bands (LS-OCMBs) and neurofilament light chain quantification were performed at disease onset. Conversion to clinically definite MS (CDMS) was monitored. RESULTS The mean time of follow-up of our series was 46.4 months. Twenty-five patients (36.7%) developed CDMS during follow-up. Neurofilament light chain levels did not predict clinical conversion. By contrast, an abnormal MRI increased the risk of CDMS [hazard ratio (HR) 12.5, P = 0.013]. The clearest association was found in patients with more than three T2 lesions. OCGBs also predicted the onset of CDMS (HR 21.3, P = 0.003) and LS-OCMBs were associated with a shorter time to CDMS (HR = 116.6, P

Response to interferon-beta (IFN-beta) treatment is heterogeneous in multiple sclerosis (MS). We aimed to search for biomarkers predicting no evidence of disease activity (NEDA) status upon IFN-beta treatment in MS. 119 patients with relapsing-remitting MS (RRMS) initiating IFN-beta treatment were included in the study, and followed prospectively for 2 years. Neutralizing antibodies (NAb) were explored in serum samples obtained after 6 and 12 months of IFN-beta treatment. Soluble cytokines and blood lymphocytes were studied in basal samples by ELISA and flow cytometry, respectively. 9% of patients developed NAb. These antibodies were more frequent in patients receiving IFN-beta 1b than in those treated subcutaneous (p = 0.008) or intramuscular (p

Background: The precise mechanism of action of dimethyl fumarate (DMF) treatment in MS remains unknown. Objective: To identify the changes in the blood lymphocyte profile of MS patients predicting no evidence of disease activity (NEDA) status after DMF treatment. Methods: We studied blood lymphocyte subsets of 64 MS patients treated with DMF at baseline and after 6 months of treatment by flow cytometry. NEDA (41 patients) or ongoing disease activity (ODA, 23 patients) were monitored after a year of follow-up. Results: During treatment, all patients experienced an increase in the naive T cells and a decrease in effector memory ones. However, only NEDA patients showed a significant reduction in central memory CD4+ and CD8+ T cells, memory B cells, CD4+ T cells producing interferon (IFN)-gamma, CD8+ T cells producing tumor necrosis factor-alpha (TNF-alpha), and IFN-gamma and B cells producing TNF-alpha. Additionally, they had an increase in regulatory CD56bright cells not observed in ODA group. After treatment, there was a negative correlation between CD56bright cells and CD8+ T cells producing IFN-gamma and TNF-alpha. Conclusion: A pro-tolerogenic shift in the blood leukocyte profile associates with an optimal response to DMF in MS.

ObjectiveTo analyze the changes induced by ocrelizumab in blood immune cells of patients with primary progressive MS (PPMS).MethodsIn this multicenter prospective study including 53 patients with PPMS who initiated ocrelizumab treatment, we determined effector, memory, and regulatory cells by flow cytometry at baseline and after 6 months of therapy. Wilcoxon matched paired tests were used to assess differences between baseline and 6 months' results. p Values were corrected using the Bonferroni test.ResultsOcrelizumab reduced the numbers of naive and memory B cells (p < 0.0001) and those of B cells producing interleukin (IL)-6, IL-10, granulocyte-macrophage colony-stimulating factor (GM-CSF), and tumor necrosis factor-alpha (TNFα) (p < 0.0001 in all cases). By contrast, the proportions of plasmablasts and B cells producing GM-CSF and TNFα increased significantly, suggesting the need for treatment continuation. We also observed a decrease in CD20+ T-cell numbers (p < 0.0001) and percentages (p < 0.0001), and a clear remodeling of the T-cell compartment characterized by relative increases of the naive/effector ratios in CD4+ (p = 0.002) and CD8+ (p = 0.002) T cells and relative decreases of CD4+ (p = 0.03) and CD8+ (p = 0.004) T cells producing interferon-gamma. Total monocyte numbers increased (p = 0.002), but no changes were observed in those producing inflammatory cytokines. The immunologic variations were associated with a reduction of serum neurofilament light chain (sNfL) levels (p = 0.008). The reduction was observed in patients with Gd-enhanced lesions at baseline and in Gd− patients with baseline sNfL >10 pg/mL.ConclusionsIn PPMS, effector B-cell depletion changed T-cell response toward a low inflammatory profile, resulting in decreased sNfL levels.

It has been suggested that autoantibodies may induce axonal damage in multiple sclerosis (MS). Optical coherence tomography (OCT) showed that thinning of peripapillary retinal nerve fiber layer (RNFL) and ganglion cell layer/inner plexiform (GCIPL) measurements reflect axonal loss in the disease. We investigated whether the intrathecal synthesis of lipid-specific oligoclonal IgM bands (LS-OCMB) associates with thinning of these structures in MS patients.58 consecutive MS patients and 70 age-matched healthy controls were assessed. LS-OCMB was studied in cerebrospinal fluid by isoelectric focusing and immunoblotting. RNFL and GCIPL imaging were quantified by spectral domain OCT.RNFL and GCIPL were significantly reduced in MS patients compared to controls (p0.01). RNFL thickness was further reduced in LS-OCMB positive MS patients compared to LS-OCMB negative MS subjects mainly in papillomacular bundle (p0.05), temporal and inferior quadrants (p0.05) and inferotemporal sector (p=0.01).The presence of LS-OCMB associates with increased retinal axonal loss in MS. This reinforces the relationship found between the intrathecal synthesis of IgM and the axonal damage observed in immunological and pathological studies even in normal-appearing white matter. OCT seems an optimal tool to monitor axonal damage in LS-OCMB positive patients, relevant for therapeutic decisions and quantification of the effects of new neuroprotective treatments.

Substantia nigra hyperechogenicity (SN+) detected by transcranial ultrasound (TUS) is useful for Parkinson’s disease (PD) diagnosis. Approximately 15% false negative results of unknown significance are reported. However, most TUS studies are transversal, and diagnosis of PD may change during follow-up. Analysis of our prospective registry of TUS in clinical practice, selecting patients with sufficient bone window, to whom TUS was performed because of suspected PD, and a minimum of 3-year follow-up. Subjects were classified regarding SN echogenicity (SN+/SN−). 172 patients (122 SN+, 50 SN−), mean age 71 years (25–90), were included. At the end of follow-up, PD diagnosis was retained by 91% SN+ vs. 54% SN− subjects (p

Neurological manifestations associated with HHV-7 have been described in primary infection in children, and very occasionally in immunocompromised adult patients. However, the role of HHV-7 reactivation as a cause of central nervous system (CNS) diseases in immunocompetent adults has not yet been defined. We retrospectively analyzed clinical and microbiological features of adults with neurological symptoms who underwent lumbar puncture and a multiplex polymerase chain reaction (PCR) for herpesviruses (HHV-1–8) and enteroviruses performed in cerebrospinal fluid (CSF), during a 4-year period. A total of 251 subjects were included. Mean age was 55 years, ranging 15–89. Globally, HHV-7 DNA was detected in CSF in 14 patients (5.6%). It was detected in 1 of 36 patients with microbiologically confirmed CNS infections, and in 7 of 172 patients with diagnoses of non-infectious neurological disorders (Specificity 0.96, 95% confidence interval 0.93–0.99). Additionally, HHV-7 DNA was detected in 6 of 21 patients (28.6%) with probable CNS infections (compatible clinical syndrome and CSF changes) in the absence of other causative agent: four meningitis, one myelitis, and one encephalitis. Treatment with foscarnet was effective in achieving improvement of symptoms and clearance of HHV-7 DNA in CSF in the cases of encephalitis and myelitis, while ganciclovir was ineffective in the case of encephalitis. Our results show that HHV-7 reactivation may cause CNS disease in immunocompetent adults and that detection of HHV-7 DNA in CSF as a false-positive result or as asymptomatic reactivation in adult patients with neurological diseases is uncommon. Foscarnet seems the first-line treatment for HHV-7 CNS disease.

Background HHV7 reactivation has been occasionally reported as a cause of encephalitis or myelitis in transplant recipients, but to our knowledge it has never been associated with neurological disease in HIV-infected patients. We report a case of acute myelitis in an HIV-infected patient, with sustained HHV-7 DNA amplification in cerebrospinal fluid (CSF) and a favourable response to foscarnet. Case report A 40 year-old man with HIV infection was admitted with asymmetric hypoesthesia in legs and paraparesis. He was receiving treatment with efavirenz, emtricitabine and tenofovir, his CD4 count was 580/mm3 and HIV viral load was undetectable. Magnetic resonance imaging showed a focal central hyperintensity on T2 and STIR sequences, on the torathic spinal cord, with slight enhancement after intravenous gadolinium. All microbiological studies were negative except for HHV-7 DNA amplification in CSF. With a diagnosis of idiopathic transverse myelitis, treatment with high-dose intravenous methylprednisolone was initiated. However, paraparesis continued worsening, and a second CSF obtained 12 days after the first one resulted again in HHV-7 amplification. Results The patient was treated with a 2 week course of foscarnet, and a rapid neurological improvement was noted. After treatment, PCR for HHV-7 in CSF was negative. Neurological exam was normal one month after treatment initiation. Conclusion HHV-7 reactivation may cause neurological disease in patients with HIV infection. Foscarnet is an effective treatment in HHV-7 associated myelitis.