Role of B Cell Profile for Predicting Secondary Autoimmunity in Patients Treated With Alemtuzumab

Células B; Alemtuzumab; AutoinmunidadLimfòcits B; Alemtuzumab; AutoimmunitatB cells; Alemtuzumab; AutoimmunityObjective: To explore if baseline blood lymphocyte profile could identify relapsing remitting multiple sclerosis (RRMS) patients at higher risk of developing secondary autoimmune adverse events (AIAEs) after alemtuzumab treatment. Methods: Multicenter prospective study including 57 RRMS patients treated with alemtuzumab followed for 3.25 [3.5-4.21] years, (median [interquartile range]). Blood samples were collected at baseline, and leukocyte subsets determined by flow cytometry. We had additional samples one year after the first cycle of alemtuzumab treatment in 39 cases. Results: Twenty-two patients (38.6%) developed AIAEs during follow-up. They had higher B-cell percentages at baseline (p=0.0014), being differences mainly due to plasmablasts/plasma cells (PB/PC, p=0.0011). Those with no AIAEs had higher percentages of CD4+ T cells (p=0.013), mainly due to terminally differentiated (TD) (p=0.034) and effector memory (EM) (p=0.031) phenotypes. AIAEs- patients also showed higher values of TNF-alpha-producing CD8+ T cells (p=0.029). The percentage of PB/PC was the best variable to differentiate both groups of patients. Baseline values >0.10% closely associated with higher AIAE risk (Odds ratio [OR]: 5.91, 95% CI: 1.83-19.10, p=0.004). When excluding the 12 patients with natalizumab, which decreases blood PB/PC percentages, being the last treatment before alemtuzumab, baseline PB/PC >0.1% even predicted more accurately the risk of AIAEs (OR: 11.67, 95% CI: 2.62-51.89, p=0.0007). The AIAEs+ group continued having high percentages of PB/PC after a year of alemtuzumab treatment (p=0.0058). Conclusions: A PB/PC percentage <0.1% at baseline identifies MS patients at low risk of secondary autoimmunity during alemtuzumab treatment.​This work was supported by grants from Red Española de Esclerosis Múltiple (REEM) (RD16/0015/0001; RD16/0015/0004; RD16/0015/0006; RD16/0015/0013) and PI18/00572 integrated in the Plan Estatal I+D+I and co-funded by ISCIII-Subdirección General de Evaluación and Fondo Europeo de Desarrollo Regional (FEDER, “Una manera de hacer Europa”)

Role of B Cell Profile for Predicting Secondary Autoimmunity in Patients Treated With Alemtuzumab

UDHEBRONTo explore if baseline blood lymphocyte profile could identify relapsing remitting multiple sclerosis (RRMS) patients at higher risk of developing secondary autoimmune adverse events (AIAEs) after alemtuzumab treatment. Multicenter prospective study including 57 RRMS patients treated with alemtuzumab followed for 3.25 [3.5-4.21] years, (median [interquartile range]). Blood samples were collected at baseline, and leukocyte subsets determined by flow cytometry. We had additional samples one year after the first cycle of alemtuzumab treatment in 39 cases. Twenty-two patients (38.6%) developed AIAEs during follow-up. They had higher B-cell percentages at baseline (p=0.0014), being differences mainly due to plasmablasts/plasma cells (PB/PC, p=0.0011). Those with no AIAEs had higher percentages of CD4+ T cells (p=0.013), mainly due to terminally differentiated (TD) (p=0.034) and effector memory (EM) (p=0.031) phenotypes. AIAEs- patients also showed higher values of TNF-alpha-producing CD8+ T cells (p=0.029). The percentage of PB/PC was the best variable to differentiate both groups of patients. Baseline values >0.10% closely associated with higher AIAE risk (Odds ratio [OR]: 5.91, 95% CI: 1.83-19.10, p=0.004). When excluding the 12 patients with natalizumab, which decreases blood PB/PC percentages, being the last treatment before alemtuzumab, baseline PB/PC >0.1% even predicted more accurately the risk of AIAEs (OR: 11.67, 95% CI: 2.62-51.89, p=0.0007). The AIAEs+ group continued having high percentages of PB/PC after a year of alemtuzumab treatment (p=0.0058). A PB/PC percentage <0.1% at baseline identifies MS patients at low risk of secondary autoimmunity during alemtuzumab treatment.

Risk and outcomes of COVID-19 in patients with multiple sclerosis

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.post-print996 K

Hopelessness in Patients with Early-Stage Relapsing-Remitting Multiple Sclerosis

Hopelessness; Relapsing-remitting multiple sclerosis; SuicideDesesperanza; Esclerosis múltiple recurrente-remitente; SuicidioDesesperança; Esclerosi múltiple recurrent-remitent; SuïcidiBackground: Hopelessness is a risk factor for depression and suicide. There is little information on this phenomenon among patients with relapsing-remitting multiple sclerosis (RRMS), one of the most common causes of disability and loss of autonomy in young adults. The aim of this study was to assess state hopelessness and its associated factors in early-stage RRMS. Methods: A multicenter, non-interventional study was conducted. Adult patients with a diagnosis of RRMS, a disease duration ≤ 3 years, and an Expanded Disability Status Scale (EDSS) score of 0– 5.5 were included. The State-Trait Hopelessness Scale (STHS) was used to measure patients´ hopelessness. A battery of patient-reported and clinician-rated measurements was used to assess clinical status. A multivariate logistic regression analysis was conducted to determine the association between patients’ characteristics and state hopelessness. Results: A total of 189 patients were included. Mean age (standard deviation-SD) was 36.1 (9.4) years and 71.4% were female. Median disease duration (interquartile range-IQR) was 1.4 (0.7, 2.1) years. Symptom severity and disability were low with a median EDSS (IQR) score of 1.0 (0, 2.0). A proportion of 65.6% (n=124) of patients reported moderate-to-severe hopelessness. Hopelessness was associated with older age (p=0.035), depressive symptoms (p=< 0.001), a threatening illness perception (p=0.001), and psychological and cognitive barriers to workplace performance (p=0.029) in the multivariate analysis after adjustment for confounders. Conclusion: Hopelessness was a common phenomenon in early-stage RRMS, even in a population with low physical disability. Identifying factors associated with hopelessness may be critical for implementing preventive strategies helping patients to adapt to the new situation and cope with the disease in the long term.This study was funded by Roche Medical Department, Spain (ML42064)

Dabigatran in Secondary Stroke Prevention: Clinical Experience with 106 Patients

Introduction. Our aim was to analyze our clinical experience with dabigatran etexilate in secondary stroke prevention. Methods. We retrospectively included patients starting dabigatran etexilate for secondary stroke prevention from March 2010 to December 2012. Efficacy and safety variables were registered. Results. 106 patients were included, median follow-up of 12 months (range 1–31). Fifty-six females (52.8%), mean age 76.4 (range 50–95, SD 9.8), median CHADS2 4 (range 2–6), CHA2DS2-VASc 5 (range 2–9), and HAS-BLED 2 (range 1–5). Indication for dabigatran etexilate was ischemic stroke in 101 patients and acute cerebral hemorrhage (CH) due to warfarin in 5 (4.7%). Dabigatran etexilate 110 mg bid was prescribed in 71 cases (67%) and 150 mg bid was prescribed in the remaining. Seventeen patients (16%) suffered 20 complications during follow-up. Ischemic complications (10) were 6 transient ischemic attacks (TIA), 3 ischemic strokes, and 1 acute coronary syndrome. Hemorrhagic complications (10) were CH (1), gastrointestinal bleeding (6), mild hematuria (2), and mild metrorrhagia (1), leading to dabigatran etexilate discontinuation in 3 patients. Patients with previous CH remained uneventful. Three patients died (pneumonia, congestive heart failure, and acute cholecystitis) and 9 were lost during follow-up. Conclusions. Dabigatran etexilate was safe and effective in secondary stroke prevention in clinical practice, including a small number of patients with previous history of CH

Three-Year Effectiveness of Dimethyl Fumarate in Multiple Sclerosis: A Prospective Multicenter Real-World Study

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 financiación5.754 JCR (2020) Q1, 36/208 Clinical Neurology1.565 SJR (2020) Q1, 61/372 Neurology (clinical)No data IDR 2020UE

Early predictive risk factors for dimethyl fumarate-associated lymphopenia in patients with multiple sclerosis

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 financiación4.808 JCR (2021) Q2, 64/212 Clinical Neurology1.006 JCR (2021) Q1, 472/2489 Medicine (miscellaneous)No data IDR 2020UE

Predicting aggressive multiple sclerosis with intrathecal IgM synthesis among patients with a clinically isolated syndrome

OBJECTIVE: To determine the best method to measure intrathecal immunoglobulin (Ig) M synthesis (ITMS), a biomarker of worse prognosis in multiple sclerosis (MS). We compared the ability for predicting a poor evolution of 4 methods assessing ITMS (IgM oligoclonal bands [OCMBs], lipid-specific OCMBs [LS-OCMBs], Reibergram, and IgM index) in patients with a clinically isolated syndrome (CIS). METHODS: Prospective study with consecutive patients performed at a referral MS center. We used unadjusted and multivariate Cox regressions for predicting a second relapse, Expanded Disability Status Scale (EDSS) scores of 4 and 6, and development of secondary progressive MS (SPMS). RESULTS: A total of 193 patients were included, with a median (interquartile range) age of 31 (25–38) years and a median follow-up of 12.9 years. Among all methods, only OCMB, LS-OCMB, and Reibergram significantly identified patients at risk of some of the pre-established outcomes, being LS-OCMB the technique with the strongest associations. Adjusted hazard ratio (aHR) of LS-OCMB for predicting a second relapse was 2.50 (95% CI 1.72–3.64, p < 0.001). The risk of reaching EDSS scores of 4 and 6 and SPMS was significantly higher among patients with LS-OCMB (aHR 2.96, 95% CI 1.54–5.71, p = 0.001; aHR 4.96, 95% CI 2.22–11.07, p < 0.001; and aHR 2.31, 95% CI 1.08–4.93, p = 0.03, respectively). CONCLUSIONS: ITMS predicts an aggressive MS at disease onset, especially when detected as LS-OCMB. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that lipid-specific IgM oligoclonal bands can predict progression from CIS to MS and a worse disease course over a follow-up of at least 2 years

Blood CD8+ Naïve T-Cells Identify MS Patients with High Probability of Optimal Cellular Response to SARS-CoV-2 Vaccine

This single-center study included 68 multiple sclerosis (MS) patients who received the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination from one of several approved vaccine preparations in Spain. Blood samples were collected one to three months after the second dose of the vaccine had been administered. Cellular immune responses to the vaccine were assessed using QuantiFERON analysis, and peripheral blood mononuclear cell subsets were assayed using flow cytometry. Response associated with higher percentages of total lymphocytes, naïve CD4+ T-cells (p = 0.028), CD8+ T-cells (p = 0.013), and, mostly, naïve CD8+ T-cells (p = 0.0003). These results were confirmed by analyzing absolute numbers (p = 0.019; p = 0.002, and p = 0.0003, respectively). Naïve CD8 T-cell numbers higher than 17 cells/μL were closely associated with an optimal cellular response to SARS-CoV-2 vaccination (odds ratio: 24.0, confidence interval: 4.8–460.3; p = 0.0001). This finding clearly shows that independent of the treatment received, higher numbers of naïve CD8+ T-cells yield a strong cellular response to SARS-CoV-2 vaccines in MS patients. If this finding is validated with other viruses/vaccines, it could provide a good tool for identifying MS patients undergoing treatment who will develop strong cellular responses to anti-virus vaccines

Hopelessness in Patients with Early-Stage Relapsing-Remitting Multiple Sclerosis

Background: Hopelessness is a risk factor for depression and suicide. There is little information on this phenomenon among patients with relapsing-remitting multiple sclerosis (RRMS), one of the most common causes of disability and loss of autonomy in young adults. The aim of this study was to assess state hopelessness and its associated factors in early-stage RRMS. Methods: A multicenter, non-interventional study was conducted. Adult patients with a diagnosis of RRMS, a disease duration ≤ 3 years, and an Expanded Disability Status Scale (EDSS) score of 0– 5.5 were included. The State-Trait Hopelessness Scale (STHS) was used to measure patients´ hopelessness. A battery of patient-reported and clinician-rated measurements was used to assess clinical status. A multivariate logistic regression analysis was conducted to determine the association between patients’ characteristics and state hopelessness. Results: A total of 189 patients were included. Mean age (standard deviation-SD) was 36.1 (9.4) years and 71.4% were female. Median disease duration (interquartile range-IQR) was 1.4 (0.7, 2.1) years. Symptom severity and disability were low with a median EDSS (IQR) score of 1.0 (0, 2.0). A proportion of 65.6% (n=124) of patients reported moderate-to-severe hopelessness. Hopelessness was associated with older age (p=0.035), depressive symptoms (p=< 0.001), a threatening illness perception (p=0.001), and psychological and cognitive barriers to workplace performance (p=0.029) in the multivariate analysis after adjustment for confounders. Conclusion: Hopelessness was a common phenomenon in early-stage RRMS, even in a population with low physical disability. Identifying factors associated with hopelessness may be critical for implementing preventive strategies helping patients to adapt to the new situation and cope with the disease in the long term