Assessing illness-related uncertainty in relapsing-remitting multiple sclerosis: A psychometric analysis of the Mishel Uncertainty of Illness Scale.

A multicenter study involving 204 adults with relapsing-remitting multiple sclerosis (RRMS) assessed the dimensionality and item characteristics of the Mishel-Uncertainty of Illness Scale (MUIS), a generic self-assessment tool. Mokken analysis identified two dimensions in the MUIS with an appropriate item and overall scale scalability after excluding nonclassifiable items. A refined 12-item MUIS, employing a grade response model, effectively discriminated uncertainty levels among RRMS patients (likelihood ratio test p-value = .03). These findings suggest the potential value of the 12-item MUIS as a reliable measure for assessing uncertainty associated with the course of illness in RRMS.

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.

Effectiveness and Safety of Teriflunomide in Relapsing-Remitting Multiple Sclerosis and Improvements in Quality of Life: Results from the Real-World TERICARE Study.

INTRODUCTION: Teriflunomide is a once-daily oral immunomodulator approved for relapsing forms of multiple sclerosis (MS) or relapsing-remitting multiple sclerosis (RRMS; depending on the local label), based on extensive evidence from clinical trials and a real-world setting on efficacy, tolerability and patient-reported benefits. The TERICARE study assessed the impact of teriflunomide treatment over 2 years on health-related quality of life (HRQoL) and some of the most common and disabling symptoms of MS, such as fatigue and depression. METHODS: This prospective observational study in Spain included RRMS patients treated with teriflunomide for ≤ 4 weeks. The following patient-reported outcomes (PROs) were collected at baseline and every 6 months for 2 years: the 29-item Multiple Sclerosis Impact Scale version 2 (MSIS-29), the 21-item Modified Fatigue Impact Scale (MFIS-21), the Beck Depression Inventory (BDI-II), the Short Form (SF)-Qualiveen and the Treatment Satisfaction Questionnaire for Medication v1.4 (TSQM). Annualised relapse rate (ARR), disability progression according to the Expanded Disability Status Scale (EDSS), and no evidence of disease activity (NEDA-3) were also assessed. RESULTS: A total of 325 patients were analysed. Patients had a mean (SD) age of 43.2 years (10.4), a mean baseline EDSS score of 1.75 (1.5), a mean number of relapses in the past 2 years of 1.5 (0.7), and 64% had received prior disease-modifying therapy (DMT). Patients showed significant improvements in the psychological domain of MSIS-29 from 35.9 (26.6) at baseline to 29.4 (25.5) at 18 months (p = 0.004) and 29.0 (24.6) at 24 months (p = 0.002). Levels of fatigue and depression were also reduced. After 2 years of treatment with teriflunomide, ARR was reduced to 0.17 (95% CI 0.14-0.21) from the baseline of 0.42 (95% CI 0.38-0.48), representing a 60.1% reduction. Mean EDSS scores remained stable during the study, and 79.9% of patients showed no disability progression. 54.7% of patients achieved NEDA-3 in the first 12 months, which increased to 61.4% during months 12-24. Patients reported increased satisfaction with treatment over the course of the study, regardless of whether they were DMT naive or not. CONCLUSION: Teriflunomide improves psychological aspects of HRQoL and maintains low levels of fatigue and depression. Treatment with teriflunomide over 2 years is effective in reducing ARR and disability progression.

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.

Detecting disability using self-reported and clinical assessments in early-stage relapsing-remitting multiple sclerosis: Looking for a complementary approach.

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.

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.

Consensus on early detection of disease progression in patients with multiple sclerosis.

Background: Early identification of the transition from relapsing-remitting multiple sclerosis (RRMS) to secondary progressive MS (SPMS) can be challenging for clinicians, as diagnostic criteria for SPMS are primarily based on physical disability and a holistic interpretation. Objective: To establish a consensus on patient monitoring to identify promptly disease progression and the most useful clinical and paraclinical variables for early identification of disease progression in MS. Methods: A RAND/UCLA Appropriateness Method was used to establish the level of agreement among a panel of 15 medical experts in MS. Eighty-three items were circulated to the experts for confidential rating of the grade of agreement and recommendation. Consensus was defined when ≥66% agreement or disagreement was achieved. Results: Consensus was reached in 72 out of 83 items (86.7%). The items addressed frequency of follow-up visits, definition of progression, identification of clinical, cognitive, and radiological assessments as variables of suspected or confirmed SPMS diagnosis, the need for more accurate assessment tools, and the use of promising molecular and imaging biomarkers to predict disease progression and/or diagnose SPMS. Conclusion: Consensus achieved on these topics could guide neurologists to identify earlier disease progression and to plan targeted clinical and therapeutic interventions during the earliest stages of SPMS.

Delayed cognitive processing and treatment status quo bias in early-stage multiple sclerosis.

BACKGROUND: The evolving therapeutic landscape requires more participation of patients with relapsing remitting multiple sclerosis (RRMS) in treatment decisions. The aim of this study was to assess the association between patient's self-perception, cognitive impairment and behavioral factors in treatment choices in a cohort of patients at an early stage of RRMS. METHODS: We conducted a multicenter, non-interventional study including adult patients with a diagnosis of RRMS, a disease duration ≤18 months and receiving care at one of the 21 participating MS centers from across Spain. We used patient-reported measures to gather information on fatigue, mood, quality of life, and perception of severity of their MS. Functional metrics (Expanded Disability Status Scale [EDSS], cognitive function by the Symbol Digit Modalities Test [SDMT], 25-foot walk test) and clinical and radiological data were provided by the treating neurologist. The primary outcome of the study was status quo (SQ) bias, defined as participant's tendency to continue taking a previously selected but inferior treatment when intensification was warranted. SQ bias was assessed based on participants treatment preference in six simulated RRMS case scenarios with evidence of clinical relapses and radiological disease progression. RESULTS: Of 189 participants who met the inclusion criteria, 188 (99.5%) fully completed the study. The mean age was 36.6 ± 9.5 years, 70.7% female, mean disease duration: 1.2 ± 0.8 years, median EDSS score: 1.0 [IQR=0.0-2.0]). Overall, 43.1% patients (n = 81/188) had an abnormal SDMT (≤49 correct answers). SQ bias was observed in at least one case scenario in 72.3% (137/188). Participant's perception of their MS severity was associated with higher SQ bias (ß coeff 0.042; 95% CI 0.0074-0.076) among those with delayed cognitive processing. Higher baseline EDSS and number of T2 lesions were predictors of delayed processing speed (OR EDSS=1.57, 95% CI: 1.11-2.21, p = 0.011; OR T2 lesions=1.50, 95% CI: 1.11-2.03, p<0.01). Bayesian multilevel model accounting for clustering showed that delayed cognitive processing (exp coeff 1.06; 95% CI 1.04-1.09) and MS symptoms severity (exp coeff 1.28; 95% CI 1.22-1.33) were associated with SQ bias. CONCLUSION: Over 40% of patients in earlier stages of RRMS experience delays in cognitive processing that might affect their decision-making ability. Our findings suggest that patients' self-perception of disease severity combined with a delay in cognitive processing would affect treatment choices leading to status quo bias early in the course of their disease.

Long-term prognosis communication preferences in early-stage relapsing-remitting multiple sclerosis.

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 ≤ 3 years, and an Expanded Disability Status Scale (EDSS) score of 0-5.5 were included. The Prognosis in MS questionnaire was used to assess how much patients want to know about their LTP. Different patient-reported measures were administered to gather information on symptom severity, pain, fatigue, mood/anxiety, quality of life, stigma, illness perception, feeling of hopelessness, self-efficacy, information avoidance and coping strategies. Cognition was assessed using the Symbol Digit Modalities Test (SDMT). A multivariate logistic regression analysis was performed to assess the association between LTP information preference and demographic and clinical characteristics, as well as patients' perspectives. RESULTS: A total of 189 patients were included (mean age: 36.1  ±  9.4 years, 71.4% female, mean disease duration: 1.2  ±  0.8 years). Median EDSS score was 1.0 (IQR = 0.0-2.0). A proportion of 68.5% (n  =  126) of patients had never discussed LTP with their neurologists, whereas 69.2% (n = 126) reported interest in knowing it (73.5% at diagnosis). Bivariate analyses suggested that patients were significantly more likely to have higher LTP information preferences if they were male and had a lower SDMT score. Male gender and a lower SDMT score were predictors of LTP information preferences. CONCLUSIONS: Patients with early-stage RRMS want to discuss their LTP shortly after diagnosis. Understanding the factors involved may be useful to design individualized communication strategies.

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.

Impact of Neuromyelitis Optica Spectrum Disorder on Quality of Life from the Patients' Perspective: An Observational Cross-Sectional Study.

INTRODUCTION: Neuromyelitis optica spectrum disorder (NMOSD) is associated with a reduced health-related quality of life (HRQoL). The purpose of this study was to describe the impact of NMOSD on HRQoL from the patients' perspective and its relationship with other disease factors. METHODS: An observational, cross-sectional study was conducted at 13 neuroimmunology clinics in Spain. Patients with NMOSD diagnosis (2015 Wingerchuk criteria) were included. The 29-item Multiple Sclerosis Impact Scale (MSIS-29) was used to assess the HRQoL. Different questionnaires were used to measure symptom severity, stigma, mood disorders, pain, fatigue, and difficulties in the workplace. Factors that impact HRQoL were identified by Spearman's correlation and multivariate linear regression analysis. RESULTS: Seventy-one patients were included (mean age 47.4 ± 14.9 years, 80.3% female, mean time since disease onset 9.9 ± 8.1 years). The median Expanded Disability Status Scale score was 3.0 (1.5-4.5). The mean (± SD) physical and psychological MSIS-29 sub-scores were 41.9 ± 16.8 and 20.9 ± 8.3, respectively. Fatigue and body pain were the most prevalent symptoms. Depressive symptoms were found in 44.3% (n = 31) of patients. The physical MSIS-29 dimension showed the highest correlation with symptom severity (ρ = 0.85584, p < 0.0001), whereas the highest correlations for psychological MSIS-29 dimension were pain, MSIS-29 physical dimension, and depression (ρ = 0.76487, 0.72779, 0.71380; p < 0.0001, respectively). Pain was a predictor of both dimensions of MSIS-29. CONCLUSION: Fatigue, pain, and depressive symptoms are frequent problems among patients with NMOSD, impacting on their quality of life. Assessment of patient-oriented outcomes may be useful to achieve a holistic approach, allowing early specific interventions.

Measuring productivity loss in early relapsing-remitting multiple sclerosis.

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 ≤ 3 years, and an Expanded Disability Status Scale (EDSS) score of 0-5.5 were included. Absenteeism, presenteeism, and unpaid work loss due to RRMS were measured using the Valuation of Lost Productivity (VOLP) questionnaire. The EDSS, SymptoMScreen, 5-item Modified Fatigue Impact Scale, Hospital Anxiety and Depression Scale, Symbol Digit Modalities Test, and Multiple Sclerosis Work Difficulties Questionnaire were used to gather information on disability, patients' perception of symptom severity, fatigue, mood/anxiety, cognition, and problems in the workplace, respectively. Associations between the VOLP and clinical and work outcomes were analyzed using Spearman's rank correlations. RESULTS: A total of 189 patients were included. Mean age (SD) was 36.1 ± 9.4 years and 71.4% were female. Mean disease duration was 1.2 ± 0.8 years. Median EDSS score was 1.0 (IQR 0, 2.0). One hundred thirty patients (68.8%) were working for pay or self-employed. Fifty-three patients (40.8%) reported absence from work in the past 3 months with an average of 14.3 absent workdays. Their health problems resulted in the loss of 3.4% of their actual work time in the past 7 days. Thirty patients got help (11.8 h) with their unpaid work activities in the past 7 days. Absenteeism was significantly correlated with anxiety and depression (rho=0.298 and 0.291, p<0.001), fatigue (rho=0.214, p = 0.014), and symptom severity (rho=0.213, p = 0.015). Presenteeism was significantly correlated with fatigue (rho=0.375, p<0.001), symptom severity (rho=0.373, p<0.001), depression (rho=0.263, p = 0.008), and disability (rho=0.215, p = 0.031). CONCLUSIONS: Productivity loss even in a RRMS population with short disease duration stresses the need for more efficient treatment control of disease activity from earlier stages.

Quantifying the patient´s perspective in neuromyelitis optica spectrum disorder: Psychometric properties of the SymptoMScreen questionnaire.

BACKGROUND: The assessment of self-reported outcomes in neuromyelitis optica spectrum disorder (NMOSD) is limited by the lack of validated disease-specific measures. The SymptoMScreen (SyMS) is a patient-reported questionnaire for measuring symptom severity in different domains affected by multiple sclerosis (MS), but has not been thoroughly evaluated in NMOSD. The aim of this study was to assess the psychometric properties of the SyMS in a sample of patients with NMOSD. METHODS: A non-interventional, cross-sectional study in adult subjects with NMOSD (Wingerchuk 2015 criteria) was conducted at 13 neuroimmunology clinics applying the SyMS. A non-parametric item response theory procedure, Mokken analysis, was performed to assess the underlying dimensional structure and scalability of items and overall questionnaire. All analyses were performed with R (v4.0.3) using the mokken library. RESULTS: A total of 70 patients were studied (mean age: 47.5 ± 15 years, 80% female, mean Expanded Disability Status Scale score: 3.0 [interquartile range 1.5, 4.5]). Symptom severity was low (median SyMS score: 19.0 [interquartile range 10.0, 32.0]). The SyMS showed a robust internal reliability (Cronbach's alpha: 0.90 [95% confidence interval 0.86, 0.93]) and behaved as a unidimensional scale with all items showing scalability coefficients > 0.30. The overall SyMS scalability was 0.45 conforming to a medium scale according to Mokken's criteria. Fatigue and body pain were the domains with the highest scalability coefficients. The SyMS was associated with disability (rho: 0.586), and physical and psychological quality of life (rho: 0.856 and 0.696, respectively). CONCLUSIONS: The SyMS shows appropriate psychometric characteristics and may constitute a valuable and easy-to-implement option to measure symptom severity in patients with NMOSD.

Perception of Stigma in Patients with Neuromyelitis Optica Spectrum Disorder.

BACKGROUND: Perception of stigma was associated with low self-esteem, psychological problems, and decreased health-seeking behavior among patients with different neurological disorders. The purpose of this study was to assess stigmatization and its impact in patients with neuromyelitis optica spectrum disorder (NMOSD). METHODS: A non-interventional study was conducted at thirteen neuroimmunology clinics in Spain. Patients with a diagnosis of NMOSD (2015 Wingerchuk criteria) were included. The 8-item Stigma Scale for Chronic Illness (SSCI-8), the Expanded Disability Status Scale (EDSS), the 29-item Multiple Sclerosis Impact Scale (MSIS-29), the Beck Depression Inventory-Fast Screen (BDI-FS), the MOS Pain Effects Scale (MOS-PES) and the Fatigue Impact Scale for Daily Use (D-FIS) were used to assess the perception of stigma, disability, quality of life, mood, pain, and fatigue, respectively. Associations between outcome measures were analyzed using Spearman's rank correlation. RESULTS: Seventy-one patients were studied (mean age: 47.4 years ± 14.9, 81.7% female, mean time since disease onset: 9.9 years ± 8.1). The median EDSS score was 3.0 (interquartile range 1.5, 4.5). Stigma prevalence was 61.4% (n=43). Thirty-one patients (43.6%) had depression. The SSCI-8 score showed a significant correlation with both physical (rho=0.576, p<0.0001) and psychological (rho=0.608, p<0.0001) MSIS-29 scales scores, EDSS score (rho=0.349, p=0.0033), BDI-FS score (rho= 0.613, p<0.0001), MOS-PES score (rho= 0.457, p<0.0001), and D-FIS score (rho=0.556, p<0.0001). CONCLUSION: Stigma is a common phenomenon affecting over 6 out of 10 patients with NMOSD. Understanding stigma may be useful to develop educational strategies improving NMOSD knowledge.

New Algorithms Improving PML Risk Stratification in MS Patients Treated With Natalizumab.

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 <1/3,300 in patients with anti-John Cunninghan virus antibody indices <0.9 and relapse rate >0.5, to 1/50 in the opposite case. In patients with lipid-specific IgM oligoclonal bands assessment, age at natalizumab onset, anti-John Cunninghan virus antibody indices, and lipid-specific IgM oligoclonal band status predicted progressive multifocal leucoencephalopathy risk (AUC = 0.92). The absence of lipid-specific IgM oligoclonal bands was the best individual predictor (OR = 40.94). The individual risk ranged from <1/10,000 in patients younger than 45 years at natalizumab initiation, who showed anti John Cunningham virus antibody indices <0.9 and lipid-specific IgM oligoclonal bands to 1/33 in the opposite case. Conclusions: In a perspective of personalized medicine, disease activity, anti-lipid specific IgM oligoclonal bands, anti Jonh Cunninghan virus antibody levels, and age can help tailor natalizumab therapy in multiple sclerosis patients, as predictors of progressive multifocal leucoencephalopathy.

Different clinical response to interferon beta and glatiramer acetate related to the presence of oligoclonal IgM bands in CSF in multiple sclerosis patients.

OBJECTIVE: To study the efficacy of interferon beta (IFNß) and glatiramer acetate (GA) related to the presence of oligoclonal M bands (OCMB) in the cerebrospinal fluid in relapsing-remitting multiple sclerosis (RRMS). METHOD: This is an observational, multicenter and retrospective study with prospectively collected data of patients that started treatment with IFNß or GA. Treatment decision was made blinded to the OCMB status. Time to first attack after starting therapy was compared by using Kaplan-Meier curves, and adjustment by Cox regression analysis was performed. RESULTS: Two hundred and fifty-six patients entered in the study (141-55% received IFNß; 115-45% received GA). After a mean follow-up of 41 and 65 months, 54.7% of patients remained free from further attacks (RF). The proportion of RF patients was higher in the GA group than in the IFNß group (72.2 vs. 40.4%, p < 0.001). The IFNß patients with OCMB+ presented the poorest response, 31.3% RF vs. 48.1% in IFNß without OCMB, p = 0.03. CONCLUSION: OCMB in CSF could be a biomarker of treatment response in multiple sclerosis.

Relapsing-Remitting Multiple Sclerosis Is Characterized by a T Follicular Cell Pro-Inflammatory Shift, Reverted by Dimethyl Fumarate Treatment.

Multiple sclerosis (MS) is considered a T cell-mediated autoimmune disease, although several evidences also demonstrate a B cell involvement in its etiology. Follicular T helper (Tfh) cells, a CXCR5-expressing CD4+ T cell subpopulation, are essential in the regulation of B cell differentiation and maintenance of humoral immunity. Alterations in circulating (c)Tfh distribution and/or function have been associated with autoimmune diseases including MS. Dimethyl fumarate (DMF) is a recently approved first-line treatment for relapsing-remitting MS (RRMS) patients whose mechanism of action is not completely understood. The aim of our study was to compare cTfh subpopulations between RRMS patients and healthy subjects and evaluate the impact of DMF treatment on these subpopulations, relating them to changes in B cells and humoral response. We analyzed, by flow cytometry, the distribution of cTfh1 (CXCR3+CCR6-), cTfh2 (CXCR3-CCR6-), cTfh17 (CXCR3-CCR6+), and the recently described cTfh17.1 (CXCR3+CCR6+) subpopulations of CD4+ Tfh (CD45RA-CXCR5+) cells in a cohort of 29 untreated RRMS compared to healthy subjects. CD4+ non-follicular T helper (Th) cells (CD45RA-CXCR5-) were also studied. We also evaluated the effect of DMF treatment on these subpopulations after 6 and 12 months treatment. Untreated RRMS patients presented higher percentages of cTfh17.1 cells and lower percentages of cTfh2 cells consistent with a pro-inflammatory bias compared to healthy subjects. DMF treatment induced a progressive increase in cTfh2 cells, accompanied by a decrease in cTfh1 and the pathogenic cTfh17.1 cells. A similar decrease of non-follicular Th1 and Th17.1 cells in addition to an increase in the anti-inflammatory Th2 subpopulation were also detected upon DMF treatment, accompanied by an increase in naïve B cells and a decrease in switched memory B cells and serum levels of IgA, IgG2, and IgG3. Interestingly, this effect was not observed in three patients in whom DMF had to be discontinued due to an absence of clinical response. Our results demonstrate a possibly pathogenic cTfh pro-inflammatory profile in RRMS patients, defined by high cTfh17.1 and low cTfh2 subpopulations that is reverted by DMF treatment. Monitoring cTfh subsets during treatment may become a biological marker of DMF effectiveness.

Neuromyelitis optica spectrum disorders: Comparison according to the phenotype and serostatus.

OBJECTIVE: To (1) determine the value of the recently proposed criteria of neuromyelitis optica (NMO) spectrum disorder (NMOSD) that unify patients with NMO and those with limited forms (NMO/LF) with aquaporin-4 immunoglobulin G (AQP4-IgG) antibodies; and (2) investigate the clinical significance of the serologic status in patients with NMO. METHODS: This was a retrospective, multicenter study of 181 patients fulfilling the 2006 NMO criteria (n = 127) or NMO/LF criteria with AQP4-IgG (n = 54). AQP4-IgG and myelin oligodendrocyte glycoprotein immunoglobulin G (MOG-IgG) antibodies were tested using cell-based assays. RESULTS: Patients were mainly white (86%) and female (ratio 6.5:1) with median age at onset 39 years (range 10-77). Compared to patients with NMO and AQP4-IgG (n = 94), those with NMO/LF presented more often with longitudinally extensive transverse myelitis (LETM) (p < 0.001), and had lower relapse rates (p = 0.015), but similar disability outcomes. Nonwhite ethnicity and optic neuritis presentation doubled the risk for developing NMO compared with white race (p = 0.008) or LETM presentation (p = 0.008). Nonwhite race (hazard ratio [HR] 4.3, 95% confidence interval [CI] 1.4-13.6) and older age at onset were associated with worse outcome (for every 10-year increase, HR 1.7, 95% CI 1.3-2.2). Patients with NMO and MOG-IgG (n = 9) had lower female:male ratio (0.8:1) and better disability outcome than AQP4-IgG-seropositive or double-seronegative patients (p < 0.001). CONCLUSIONS: In patients with AQP4-IgG, the similar outcomes regardless of the clinical phenotype support the unified term NMOSD; nonwhite ethnicity and older age at onset are associated with worse outcome. Double-seronegative and AQP4-IgG-seropositive NMO have a similar clinical outcome. The better prognosis of patients with MOG-IgG and NMO suggests that phenotypic and serologic classification is useful.

Adverse events during the titration phase of interferon-beta in remitting-relapsing multiple sclerosis are not predicted by body mass index nor by pharmacodynamic biomarkers.

BACKGROUND: This study aimed to correlate body mass index or biomarkers with the frequency of common adverse events (AEs) with subcutaneous IFN ß-1a during treatment titration in patients with relapsing-remitting multiple sclerosis previously naïve to IFN ß. METHODS: Eighty-four patients (66.3% females) were followed up during 8 weeks, 25.3% were overweight and 14.5% were obese. RESULTS: Biomarkers steadily increased during all study period by 45.3% for ß2-microglobulin, 262.8% for olygoadenylate synthetase-1, and 92.8% for neopterin. Overall AE reporting did not vary with the dose or treatment duration. CONCLUSIONS: BMI was not predictive of increased risk for AEs. Biomarkers did not discriminate on the frequency of any AE either.