Autologous hematopoietic stem cell transplantation for multiple sclerosis: Long-term follow-up data from Norway.

BACKGROUND: Autologous hematopoietic stem cell transplantation (HSCT) is a potent treatment option for patients with aggressive relapsing-remitting multiple sclerosis (RRMS). OBJECTIVE: To evaluate long-term outcomes of HSCT in MS. METHODS: National retrospective single-center observational study of patients with aggressive RRMS that underwent HSCT in Norway from January 2015 to January 2018. Criteria for receiving HSCT included at least two clinical relapses the last year while on disease modifying treatment (DMT). RESULTS: In total, 29 patients, with a mean follow-up time of 70 months (standard deviation:14.3), were evaluated. Twenty patients (69%) had sustained no evidence of disease activity (NEDA-3) status, 24 (83%) were relapse-free, 23 (79%) free of magnetic resonance imaging (MRI) activity, and 26 (90%) free of progression. Number of patients working full-time increased from 1 (3%), before HSCT, to 10 (33%) after 2 years and 15 (52%) after 5 years. CONCLUSION: HSCT offers long-term disease-free survival with successively increasing work participation in patients with aggressive MS resistant to DMTs.

Defining a standard set of health outcomes for patients with relapsing-remitting multiple sclerosis.

BACKGROUND: Standardizing health outcomes is challenging in clinical management, but it also holds the potential for creating a healthcare system that is both more effective and efficient. The aim of the present study is to define a standardized set of health outcomes for managing Relapsing-Remitting Multiple Sclerosis (RRMS). METHODS: The project was led and coordinated by a multidisciplinary scientific committee (SC), which included a literature review, a patient-focused group, three nominal group meetings, and two SC meetings. RESULTS: 36 outcome variables were included in the standard set: 24 clinical (including weight, smoking habit, comorbidities, disability, mobility, diagnosis of secondary progressive multiple sclerosis, relapsed-related variables, radiological variables, cognitive status and disease-related symptoms), nine treatment-related (pharmacological and non-pharmacological information), and 3 related to the impact of RRMS on the patient's life (quality of life, pregnancy desire, work-related difficulties). In addition, experts also agreed to collect 10 case-mix variables that may affect but cannot be controlled as part of the management of the condition: 4 sociodemographic (age, sex, race, and employment status) and 6 clinical (height, date of diagnosis and first episode, serological status, early symptoms, and number of relapses pre-diagnosis). CONCLUSION: The information provided through the present standard set of outcome variables can improve the management of RRMS and promote patient-centred quality care.

Evaluating Relapse Knowledge in People with Multiple Sclerosis: A Cross-Sectional Study on the Development and Validation of the Relapse Knowledge Questionnaire.

BACKGROUND: Multiple sclerosis (MS) knowledge is a prerequisite for active patient engagement in medical decision-making. Treatment of relapses in MS is a clinical field with many uncertainties and each acute relapse requires decisions regarding possible options for action, indicating the need for patient involvement. However, there is no validated instrument assessing relapse knowledge in people with MS. Our study aims to develop a valid MS relapse questionnaire for use as an outcome instrument for educational interventions. METHODS: A multidisciplinary panel developed the relapse knowledge questionnaire (RKQ) based on a previously developed questionnaire. We tested the RKQ on MS patients for comprehensibility, usability and acceptance in qualitative think-aloud interviews and conducted a cross-sectional quantitative online survey to validate the questionnaire. People with suspected or confirmed relapsing-remitting MS and a recent relapse experience were eligible for inclusion. We checked normal distribution of the RKQ score and determined the item difficulty. Construct validity was analysed using correlational analysis. RESULTS: The final RKQ consists of 10 items. After minor changes of the RKQ during pre-testing (n = 2), pilot testing (n = 10) confirmed the usability and acceptance of the instrument. The subsequent validation study (n = 203) resulted in a mean item difficulty of 0.44, ranging from 0.18 to 0.83. Seven items were particularly difficult and answered incorrectly by more than 50 % of participants. Construct validity of the RKQ was satisfactory. The RKQ score correlated only weakly with participants' degree of education (|rp|>0.1), years since diagnosis (|rp|>0.1), and the intention to receive corticosteroids (|rp|>0.1). CONCLUSION: This study indicates the validity of the RKQ and proposes that the RKQ is a suitable instrument to assess relapse knowledge in people with MS participating in educational interventions.

Effect of high frequency repetitive transcranial magnetic stimulation (rTMS) on the balance and the white matter integrity in patients with relapsing-remitting multiple sclerosis: A long-term follow-up study.

OBJECTIVES: Repetitive Transcranial Magnetic Stimulation (rTMS) is considered as a safe and non-invasive developing technique used as a therapeutic method for patients with Relapsing-Remitting Multiple Sclerosis (RRMS) who suffer from disturbances in gait and balance. The aim of our study is to evaluate the long-term effect of high frequency rTMS as a therapeutic option for truncal ataxia in RRMS patients and to assess its impact on the integrity of the white matter (WMI), measured in the form of anisotropy metrics using diffusion tensor imaging (DTI). METHODS: The study was conducted in two phases: phase I; a randomized, single-blind, sham-controlled phase and phase II was a 12 months longitudinal open-label prospective phase. Phase I of the trial involved the randomization of 43 patients with RRMS and truncal ataxia to either real (n = 20) or sham (n = 19) rTMS (2 participants from each treatment group were excluded from the study; one developed a relapse before treatment, 2 declined to participate, and one did not show up). Phase II involved providing 12 actual treatments cycles to all patients; each cycle length is 4 weeks, repeated four times on a trimonthly basis, forming a total of 48 sessions. DTI was used for assessment of the WMI. All patients performed DTI 3 times: Imaging sessions were conducted at the screening visit, at the end of phase I, and after the last session in phase II for the first, second and third sessions respectively. A figure-of-8-shape coil, employing rTMS protocol and located over the cerebellum, was used. rTMS protocol is formed of 20 trains formed of 50 stimuli with 20 s apart (5 Hz of 80 % of resting Motor Threshold "MT"). The Berg Balance Scale (BBS), Time up and go (TUG) test, and 10-m walk test (10MWT) were first evaluated at the start of each cycle and just after the final rTMS session. RESULTS: The genuine rTMS group's 10MWT, TUG, and BBS showed substantial improvement (p < 0.01), which is continued to be improved throughout the study Timeline, with a significant difference observed following the final rTMS session (P< 0.001). A longitudinal increase in FA was observed in both the Cerebello-Thalamo-Cortical (CTC) and Cortico-Ponto-Cerebellar (CPC) bilateral, as indicated by means of Fractional Anisotropy (FA) measures (p < 0.05). CONCLUSION: In ataxic RRMS patients, high frequency rTMS over the cerebellum has a long-term beneficial impact on both balance and WMI.

Evoked potentials after autologous hematopoietic stem cell transplantation for multiple sclerosis.

OBJECTIVE: To investigate the effect of autologous hematopoietic stem cell transplantation (AHSCT) on functional aspects of the nervous system assessed by visual (VEP), somatosensory (SEP), and motor (MEP) evoked potentials in patients with relapsing-remitting multiple sclerosis. BACKGROUND: Several studies have demonstrated the efficacy of AHSCT on inflammatory activity and disability progression in patients with multiple sclerosis. However, the impact of AHSCT on evoked potentials has not been evaluated before. METHODS: Twelve AHSCT-treated patients from Uppsala University Hospital were consecutively recruited. Evoked potentials (EP) were collected at baseline and two follow-up visits, 3 and 12 months post-AHSCT. We calculated a composite EP score for each participant and compared it between different time points. RESULTS: The median total EP score decreased from 5 at baseline, to 2.5 at 12 months post-ASHCT (p = 0.008). A significant improvement in tibial SEP (tSEP) latencies was observed (42.7 vs 41.5 ms, p < 0.001), with a similar trend for MEP latencies 12 months post-ASHCT. No significant changes in median SEP or VEP latencies were observed. CONCLUSIONS: Treatment with AHSCT was associated with improved transmission in some central nervous system pathways in multiple sclerosis patients.

Clinical characterization of long-term multiple sclerosis (COLuMbus) patients in Argentina: A cross-sectional non-interventional study.

BACKGROUND: Most Multiple Sclerosis (MS) clinical trials fail to assess the long-term effects of disease-modifying therapies (DMT) or disability. METHODS: COLuMbus was a single-visit, cross-sectional study in Argentina in adult patients with ≥10 years of MS since first diagnosis. The primary endpoint was to determine patient disability using the Expanded Disability Status Scale (EDSS). The secondary endpoints were to evaluate the distribution of diagnoses between relapsing-remitting MS (RRMS) and secondary progressive MS (SPMS), patient demographics, disease history, and the risk of disability progression. The relationship between baseline characteristics and the current disability state and the risk of disability progression was assessed. RESULTS: Out of the 210 patients included, 76.7 % had a diagnosis of RRMS and 23.3 % had been diagnosed with SPMS, with a mean disease duration of 17.9 years and 20.5 years, respectively. The mean delay in the initial MS diagnosis was 2.6 years for the RRMS subgroup and 2.8 years for the SPMS subgroups. At the time of cut-off (28May2020), 90.1 % (RRMS) and 75.5 % (SPMS) of patients were receiving a DMT, with a mean of 1.5 and 2.0 prior DMTs, respectively. The median EDSS scores were 2.5 (RRMS) and 6.5 (SPMS). In the RRMS and SPMS subgroups, 23 % and 95.9 % of patients were at high risk of disability, respectively; the time since first diagnosis showed a significant correlation with the degree of disability. CONCLUSIONS: This is the first local real-world study in patients with long-term MS that highlights the importance of recognizing early disease progression to treat the disease on time and delay disability.

Long-term effectiveness of a cognitive behavioural therapy (CBT) in the management of fatigue in patients with relapsing remitting multiple sclerosis (RRMS): a multicentre, randomised, open-label, controlled trial versus standard care.

BACKGROUND: Fatigue is a disabling symptom of multiple sclerosis (MS). The lack of effective therapeutics has promoted the development of cognitive behavioural therapy (CBT)-based fatigue management programmes. However, their efficacy does not sustain over time. We proposed to test the long-term effectiveness of a 6-week fatigue programme supplemented with four booster sessions ('FACETS+') in patients with relapsing remitting MS (RRMS) and fatigue. METHODS: This multicentre, randomised, controlled, open-label, parallel-group trial versus standard care enrolled patients with RRMS and fatigue. Participants were randomised to either FACETS+ plus standard care or standard care alone. The primary outcome measure was fatigue impact (Modified Fatigue Impact Scale (MFIS) at 12 months) based on intention-to-treat analyses. RESULTS: From May 2017 to September 2020, 162 patients were screened; 105 were randomly assigned to FACETS+ (n=57) or standard care (n=48) and 88 completed the primary outcome assessment for the MFIS. At month 12, participants showed improved MFIS compared with baseline in the intervention group (mean difference (MD)=14.0 points; (95% CI 6.45 to 21.5)) and the control group (MD=6.1 points; (95% CI -0.30 to 12.5)) with a significant between-group difference in favour of the intervention group (adjusted MD=7.89 points; (95% CI 1.26 to 14.52), standardised effect size=0.52, p=0.021). No trial-related serious adverse events were reported. CONCLUSIONS: A 6-week CBT-based programme with four booster sessions is superior to standard care alone to treat MS-related fatigue in the long term (12 months follow-up). The results support the use of the FACETS+ programme for the treatment of MS-related fatigue. TRIAL REGISTRATION NUMBER: NCT03758820.

Humoral response to Epstein-Barr virus in patients with multiple sclerosis treated with B cell depletion therapy.

BACKGROUND: B cell depletion therapy is highly effective in relapsing-remitting multiple sclerosis (RRMS). However, the precise underlying mechanisms of action for its biological effects in MS have still not been clarified. Epstein-Barr virus (EBV) is a known risk factor for MS and seems to be a prerequisite for disease development. EBV resides latently in the memory B cells, and may not only increase the risk of developing MS, but also contribute to disease activity and disability progression. Therefore, the effects of B cell depletion in MS could be associated with the depletion of EBV-infected cells and the altered immune response to the virus. In this study, we investigate the impact of B cell depletion on the humoral immune response specific to EBV in patients with MS. METHODS: Newly diagnosed, treatment-naïve patients with RRMS were followed up to 18 months after initiation of B-cell depletion therapy in the Overlord-MS study, a phase III trial (NCT04578639). We analyzed serum sampled before treatment and after 3, 6, 12 and 18 months for immunoglobulin γ (IgG) against Epstein-Barr nuclear antigen 1 (EBNA1) and Epstein-Barr viral capsid antigen (VCA). We analyzed antibodies to cytomegalovirus (CMV) and total IgG in serum, as controls for viral and overall humoral immunity. The risk allele, HLA-DRB1*15:01, and the protective allele, HLA-A*02:01, were determined in all participants. In addition, polymerase chain reaction (PCR) for circulating EBV-DNA was performed in the first 156 samples drawn. The associations between time on B cell-depletion therapy and serum anti-EBV antibody levels were estimated using linear mixed-effects models. RESULTS: A total of 290 serum samples from 99 patients were available for analysis. After 6, 12 and 18 months, the EBNA1 IgG levels decreased by 12.7 % (95 % CI -18.8 to -6.60, p < 0.001), 12.1 % (95 % CI -19.8 to -3.7, p = 0.006) and 14.6 % (95 % CI to -25.3 to -2.4, p = 0.02) respectively, compared to baseline level. Carriers of the HLA-DRB1*15:01 allele had higher EBNA1 IgG levels at baseline (p = 0.02). The VCA IgG levels significantly increased by 13.7 % (95 % CI 9.4 to 18.1, p < 0.001) after 3 months, compared to baseline, and persisted at this level throughout the follow-up. CMV IgG levels decreased, but to a lesser extent than the decrease of EBNA1 IgG, and total IgG levels decreased during therapy. Circulating EBV-DNA was found in only three of 156 samples from 64 patients. CONCLUSIONS: EBNA1 IgG levels decreased, while VCA IgG levels increased, during B cell depletion therapy. This supports the hypothesis that the mechanism of action for B cell depletion therapy might be mediated by effects on EBV infection, which, in turn, mitigate immune cross-reactivity and disease perpetuation.

Effect of the COVID-19 pandemic on disease activity in multiple sclerosis patients treated with hematopoietic stem cell transplantation.

BACKGROUND AND PURPOSE: It is still debated whether the COVID-19 pandemic affected disease activity in people with autoimmune diseases, including multiple sclerosis (MS). The aim of this study, therefore, was to explore the impact of COVID-19 in people with MS (pwMS) not receiving continuative disease-modifying therapy (DMT) after previous treatment with autologous hematopoietic stem cell transplantation (AHSCT). MATERIALS AND METHODS: We included pwMS treated with AHSCT who were in disease remission without receiving DMTs during the pandemic and who were followed up at our centre during the study period. Data on SARS-CoV-2 infection and vaccination were recorded, with details of adverse events and clinical-radiological disease activity. RESULTS: A total of 36 pwMS (31 females; 86%) were included, of whom 23 (64%) had relapsing-remitting (RR-MS) and 13 had secondary progressive MS (SP-MS). Thirty-three pwMS (92%) received anti-SARS-CoV-2 mRNA vaccines. Thirteen patients (36%) developed mild to moderate COVID-19 a median (range) of 58 (4-224) months after AHSCT; seven (54%) of these patients were not yet vaccinated. Transient neurological symptoms after vaccination or infection were reported in 9% and 36% of the patients, respectively. The rate of new inflammatory events (relapses or asymptomatic magnetic resonance imaging [MRI] activity) after AHSCT increased from 0.006 (one asymptomatic new lesion/159 patient-years) before the pandemic to 0.083 (five relapses plus two cases of asymptomatic MRI activity/84 patient-years) since the pandemic start (p = 0.004). CONCLUSIONS: People with MS with a history of highly active disease, who are untreated or receiving moderate-efficacy DMTs might be more vulnerable to disease reactivation, possibly elicited by exogenous triggers. Careful monitoring and further investigation are warranted to ascertain whether special precautions are needed in these cases.

CSF Concentrations of CXCL13 and sCD27 Before and After Autologous Hematopoietic Stem Cell Transplantation for Multiple Sclerosis.

BACKGROUND AND OBJECTIVES: In the past decade, autologous hematopoietic stem cell transplantation (AHSCT) has emerged as a treatment for relapsing-remitting multiple sclerosis (RRMS). How this procedure affects biomarkers of B- and T-cell activation is currently unknown. The objective of this study was to investigate CXCL13 and sCD27 concentrations in CSF before and after AHSCT. METHODS: This prospective cohort study was conducted at a specialized MS clinic in a university hospital. Patients with a diagnosis of RRMS, treated with AHSCT between January 1, 2011, and December 31, 2018, were evaluated for participation. Patients were included if CSF samples from baseline plus at least 1 follow-up were available on June 30, 2020. A control group of volunteers without neurologic disease was included as a reference. CSF concentrations of CXCL13 and sCD27 were measured with ELISA. RESULTS: The study comprised 29 women and 16 men with RRMS, aged 19-46 years at baseline, and 15 women and 17 men, aged 18-48 years, in the control group. At baseline, patients had higher CXCL13 and sCD27 concentrations than controls, with a median (IQR) of 4 (4-19) vs 4 (4-4) pg/mL (p < 0.0001) for CXCL13 and 352 (118-530) vs 63 (63-63) pg/mL (p < 0.0001) for sCD27. After AHSCT, the CSF concentrations of CXCL13 were considerably lower at the first follow-up at 1 year than at baseline, with a median (IQR) of 4 (4-4) vs 4 (4-19) pg/mL (p < 0.0001), and then stable throughout follow-up. The CSF concentrations of sCD27 were also lower at 1 year than at baseline, with a median (IQR) of 143 (63-269) vs 354 (114-536) pg/mL (p < 0.0001). Thereafter, sCD27 concentrations continued to decrease and were lower at 2 years than at 1 year, with a median (IQR) of 120 (63-231) vs 183 (63-290) pg/mL (p = 0.017). DISCUSSION: After AHSCT for RRMS, CSF concentrations of CXCL13 were rapidly normalized, whereas sCD27 decreased gradually over the course of 2 years. Thereafter, the concentrations remained stable throughout follow-up, indicating that AHSCT induced long-lasting biological changes.

The importance of the patient's perspective in decision-making in multiple sclerosis: Results of the OwnMS patient perspectives study.

BACKGROUND: Research is needed to identify the unmet disease education and communication needs of people with multiple sclerosis (PwMS) to support informed decision-making, enable self-management and maintain independence for PwMS for as long as possible. METHODS: An Expert Steering Group co-developed two studies for PwMS aged 18 years and over: a qualitative, online, patient community activity and a quantitative anonymised online survey. The quantitative survey was conducted in the UK from 12 September 2019 to 18 November 2019 amongst PwMS recruited via the Multiple Sclerosis (MS) Trust newsletter and their closed Facebook group. Questions explored the goals, desires, and knowledge gaps of PwMS. Self-reported data from people with relapsing-remitting multiple sclerosis (RRMS) were collated and reviewed, and discussed by the Steering Group. This paper presents descriptive statistics of the quantitative survey findings. RESULTS: The sample consisted of 117 participants with RRMS. Most respondents (73%) had personal goals related to lifestyle and many (69%) were concerned about maintaining independence. More than half of respondents were worried about planning for the future in relation to income (56%), housing (40%) and most respondents also indicated MS had a negative impact on their lives, including their work life (73%) and social life (69%). Limited occupational support was forthcoming (17% were not provided with any support and only 27% report their work environment being adjusted to suit their needs). The ability to plan for the future and to understand the course of MS were highlighted as key priorities by respondents. A positive trend was observed between those who felt able to plan for the future and their knowledge of MS progression. The proportion of patients who report knowing a 'great deal' about MS prognosis and disability progression was low (16% and 9%, respectively), suggesting an increased role for clinical teams to provide information and education for PwMS. Communication between respondents and their clinical teams highlighted the role of specialist nurses for PwMS to provide holistic, informative support and demonstrated the level of comfort that PwMS have in discussing less clinical topics with these providers. CONCLUSION: This UK nationwide survey highlighted some of the unmet needs in disease education and communication in a subgroup of UK patients with RRMS, which can impact quality of life. Discussing goals and planning alongside prognosis and disability progression with MS care teams may enable people with RRMS not only to make informed treatment decisions, but also to self-manage and plan for the future, factors which are important to maintain independence.

Effectiveness of acupuncture for fatigue in patients with relapsing-remitting multiple sclerosis: a randomized controlled trial.

BACKGROUND: Fatigue is experienced by more than 65% of individuals with multiple sclerosis (MS). Some studies have supported the effectiveness of acupuncture in improving the symptoms of MS. OBJECTIVE: The present research was intended to investigate the effectiveness of acupuncture plus amantadine compared with amantadine alone on fatigue in patients with relapsing-remitting MS (RRMS) in the remission stage of the disease. METHODS: In this randomized controlled trial, 60 participants with RRMS suffering from fatigue were recruited and randomized equally to acupuncture (n = 30) and control (n = 30) groups. The acupuncture group received treatment 2 to 3 times per week for 10 sessions over 4 weeks. Both the acupuncture and control groups received amantadine 100 mg daily and routine treatment with immuno-modulators. The primary outcome was the fatigue severity scale (FSS) score, which was evaluated at baseline, and after 2 and 4 weeks. The secondary outcome was the Multiple Sclerosis Quality of Life 54 (MSQOL-54) questionnaire score, measured at baseline and the end of the 4-week treatment period. RESULTS: The severity of fatigue was reduced in both groups. However, after 4 weeks of treatment, the reduction of fatigue in the acupuncture group was more significant than in the control group (P < 0.01, mean difference (MD) = -1.14, 95% confidence interval (CI): -1.83 to -0.45). Quality of life, including mental and physical status, was significantly improved in the acupuncture group compared with the control group (P < 0.05, MD = 9.09, 95% CI: 0.46 to 17.73). No adverse events occurred in any of the participants. CONCLUSIONS: Acupuncture combined with amantadine and routine care compared with amantadine and routine care alone appears to be an effective short-term treatment for reducing fatigue and enhancing quality of life, including physical function and mental status, in patients with RRMS.

Hematopoietic Stem Cell Transplantation in People With Active Secondary Progressive Multiple Sclerosis.

BACKGROUND AND OBJECTIVES: Uncontrolled evidence suggests that autologous hematopoietic stem cell transplantation (AHSCT) can be effective in people with active secondary progressive multiple sclerosis (SPMS). In this study, we compared the effect of AHSCT with that of other anti-inflammatory disease-modifying therapies (DMTs) on long-term disability worsening in active SPMS. METHODS: We collected data from the Italian Bone Marrow Transplantation Study Group and the Italian Multiple Sclerosis Register. Patients were considered eligible if treatment had been started after the diagnosis of SPMS. Disability worsening was assessed by the cumulative proportion of patients with a 6-month confirmed disability progression (CDP) according to the Expanded Disability Status Scale (EDSS) score. Key secondary endpoints were the EDSS time trend after treatment start and the prevalence of disability improvement over time. Time to first CDP was assessed by means of proportional hazard Cox regression models. A linear mixed model with a time × treatment group interaction was used to assess the longitudinal EDSS time trends. Prevalence of improvement was estimated using a modified Kaplan-Meier estimator and compared between groups by bootstrapping the area under the curve. RESULTS: Seventy-nine AHSCT-treated patients and 1975 patients treated with other DMTs (beta interferons, azathioprine, glatiramer-acetate, mitoxantrone, fingolimod, natalizumab, methotrexate, teriflunomide, cyclophosphamide, dimethyl fumarate, and alemtuzumab) were matched to reduce treatment selection bias using propensity score and overlap weighting approaches. Time to first CDP was significantly longer in transplanted patients (hazard ratio [HR] = 0.50; 95% CI = 0.31-0.81; p = 0.005), with 61.7% of transplanted patients free from CPD at 5 years. Accordingly, EDSS time trend over 10 years was higher in patients treated with other DMTs than in AHSCT-treated patients (+0.157 EDSS points per year compared with -0.013 EDSS points per year; interaction p < 0.001). Patients who underwent AHSCT were more likely to experience a sustained disability improvement: 34.7% of patients maintained an improvement (a lower EDSS than baseline) 3 years after transplant vs 4.6% of patients treated by other DMTs (p < 0.001). DISCUSSION: The use of AHSCT in people with active SPMS is associated with a slowing of disability progression and a higher likelihood of disability improvement compared with standard immunotherapy. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that autologous hematopoietic stem cell transplants prolonged the time to CDP compared with other DMTs.

The effect of self-acupressure on quality of life, physical and cognitive function in relapsing remitting multiple sclerosis patients: A randomized controlled study.

OBJECTIVE: This study was conducted to evaluate the effectiveness of self-acupressure on quality of life, physical and cognitive functions in individuals with Relapsing-Remitting Multiple Sclerosis (RRMS). METHODS: In our randomized controlled study; participants in the study group were asked to perform self-acupressure on 6 points. They were asked to perform a total of 16 sessions, 2 days a week, for an average of 27 min each session in the morning and evening. No intervention was made in the control group during the study. Data were collected using Descriptive Information Form, Multiple Sclerosis Functional Composite Test (MSFC), and Multiple Sclerosis Quality of Life 54 Scale (MSQL-54). RESULTS: Thirty-one individuals with RRMS in each group, 25 women in the study group and 21 women in the control group, were included in the study. After the self-acupressure application, a positive and significant difference was detected in all MSFC sub-parameters (9-Hole Peg Test, Timed 25-foot Walk Test, Paced Auditory Serial Addition Test) values of the study group compared to the control group. In addition, after self-acupressure application, the study group was found to have statistically significantly higher scores in both the combined physical health and composite mental health sub-parameters of MSQOL-54 compared to the control group (p < 0.05). CONCLUSION: We found that self-acupressure was effective in improving physical function, cognitive function and quality of life in RRMS patients. Additionally, self-acupressure is a feasible, accessible and inexpensive method in the disease management of multiple sclerosis, which needs to be treated or supported continuously.

Progression of Relapsing-Remitting Multiple Sclerosis despite the new era of treatments / Progressão da Esclerose Múltipla Remitente-Recorrente apesar da nova era de medicamentos / Progresión de la esclerosis múltiple recurrente-remitente a pesar de la nueva era de las drogas

Objective. The present study aims to evaluate the conditions associated with the progression of Multiple Sclerosis (MS) and patients' dysfunctions. Methods. We perform aretrospective longitudinal analytical observational study in 46 patients with MS from a polyclinic in Rio de Janeiro, Brazil. We used the Expanded Disability Status Scale (EDSS) to rank the pa-tients according to their disability and establish a correlation with risk factors, treatment, and time of disease. Results. Of 46 patients, 69.6% were female, and 67.4% were white. Patients with fewer functional systems affected at the beginning of the disease had a longer time for disease progression, according to EDSS. Low-efficacy drugs led to a high rate of discon-tinuation of the treatment. Patients who used a continuous treatment took longer to reach higher EDSS values than those who discontinued treatment. Conclusion. Despite the control of MS with high-effective drugs, there is still some disability for the patient. The factors that influenced the progression of the disability were: multiple symptoms at the beginning of the disease, more than 30 years old at the beginning of the MS, delay in diagnosis and initiation of treatment, among others. (AU)

Objetivo. O presente estudo tem como objetivo avaliar as condições associadas à progressão de doença e disfunções dos pacientes com Esclerose Múltipla (EM). Métodos. Estudo observacional analítico longitudinal retrospectivo com 46 pacientes com EM de uma policlínica do Rio de Janeiro, Brasil. Foi utilizada a Escala de Incapacidade Funcional Expan-dida (EDSS) para classificar os pacientes de acordo com a incapacidade e estabelecer correlação com fatores de risco, tratamento e tempo de doença. Resultados. Dos 46 pacientes, 69,6% eram do sexo feminino e 67,4% eram brancos. Pacientes com menos sistemas funcionais afetados no início da EM levaram maior tempo para progressão da doença. Medicamentos de baixa eficácia foram associados a uma alta taxa de descontinuação do tratamento. Pacientes em trata-mento contínuo levaram maior tempo para atingir valores mais altos de EDSS comparado com pacientes que descon-tinuaram o tratamento. Conclusão. Apesar do controle da EM com medicamentos de alta eficácia, os pacientes ainda apresentam alguma incapacidade. Os fatores que influenciaram a progressão da incapacidade foram: múltiplos sintomas no início da doença, mais de 30 anos no início da EM, atraso no diagnóstico e início do tratamento, entre outros. (AU)

Biomarkers of demyelination and axonal damage are decreased after autologous hematopoietic stem cell transplantation for multiple sclerosis.

BACKGROUND: Autologous hematopoietic stem cell transplantation (aHSCT) has seen increased use for relapsing-remitting multiple sclerosis (RRMS) in recent years. It is considered one of the most effective treatments for RRMS and has been associated with improvement in disability and prolonged remission. This suggests that the tissue-injuring disease process may have been altered by aHSCT. To assess whether this hypothesis is correct, we performed a study of three commonly used cerebrospinal fluid biomarkers of tissue damage. METHODS: In this single center study, 63 patients treated with aHSCT at Uppsala University Hospital between January 1st 2012 and January 31st 2019 were screened for participation. A control group consisting of volunteers without neurologic disease were included as a reference. Cerebrospinal fluid concentrations of neurofilament light (NFL), myelin basic protein (MBP) and glial acidic fibrillary protein (GFAp) were determined using ELISA and a multiplex proteomics platform from Meso Scale Discovery. RESULTS: Forty-three patients with a mean age of 31 and a median follow-up time of 3.9 years were included. Their median baseline expanded disability status scale (EDSS) score was 3.5 and the annualized relapse rate in the year preceding aHSCT was 1.6. At baseline the proportion of patients with values above the upper limit of normal was 67% for NFL, 63% for MBP and 16% for GFAp. At 5-year follow-up, the proportion of patients with values above the upper limit of normal was 12% for NFL, 12% for MBP and 25% for GFAp. The mean concentration of NFL decreased from 920 pg/mL at baseline to 270 pg/mL at 5-year follow-up (p < 0.001); MBP decreased from 1500 to 680 pg/mL (p < 0.001); whereas the mean concentration of GFAp was unchanged. CONCLUSION: In a majority of patients, biomarkers of demyelination and axonal damage reached normal values within five years from treatment with aHSCT.

Effect of eight weeks respiratory muscle training on respiratory capacity, functional capacity and quality of life on subjects with mild to moderate relapsing-remitting multiple sclerosis: A single-blinded randomized controlled trial.

BACKGROUND: Multiple Sclerosis (MS) is a chronic inflammatory disease of the nervous system leading to muscle weakness, including the respiratory muscles that cause pulmonary complications, impair functional capacity, increased fatigue, and as a result decreases the quality of life. AIM: The purpose of the present study is to examine the influence of 8 weeks of respiratory muscle training (RMT) on pulmonary function and respiratory muscle strength in MS patients. METHODS: The present study was a single-blind, randomized controlled trial that was conducted on 36 (27 Female, 9 Male) relapsing-remitting MS patients who were definitively diagnosed by a neurologist and randomly were divided into intervention and control groups. Both groups were educated on lifestyle modification with an emphasis on regular physical activity. In addition, the intervention group was prescribed eight weeks of respiratory muscle training with a threshold resistance device, daily, twice a day for three sets of 15 repetitions per set. Maximal expiratory pressure (PImax), maximal expiratory pressure (PEmax), spirometric indices, functional tests (six-minute walk test, timed up and go test), fatigue questionnaire, and questionnaire of quality of life were assessed before and after trials. RESULTS: A total of 36 patients (75% female; mean age 38.00(8.86) years; BMI 26.56(2.64) kg/m2) were included in the study. The strength of inspiratory and expiratory muscles, respiratory function, fatigue, and quality of life were significantly improved in the intervention group (p<0.005). In addition, there was a significant improvement in the rate of fatigue and quality of life in all their dimensions (p<0.005). Only in the six-minute walk test, no significant improvement was seen in the intervention group compared to the control group (p = 0.262). CONCLUSION: Findings could help therapists to provide MS patients with more effective respiratory muscle training protocols to maximize the benefits of rehabilitation.

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.

Immunotherapy for people with clinically isolated syndrome or relapsing-remitting multiple sclerosis: treatment response by demographic, clinical, and biomarker subgroups (PROMISE)-a systematic review protocol.

BACKGROUND: Multiple sclerosis (MS) is an inflammatory and degenerative disease of the central nervous system with an increasing worldwide prevalence. Since 1993, more than 15 disease-modifying immunotherapies (DMTs) have been licenced and have shown moderate efficacy in clinical trials. Based on the heterogeneity of the disease and the partial effectiveness of therapies, a personalised medicine approach would be valuable taking individual prognosis and suitability of a chosen therapy into account to gain the best possible treatment effect. The primary objective of this review is to assess the differential treatment effects of all approved DMTs in subgroups of adults with clinically isolated syndrome or relapsing forms of MS. We will analyse possible treatment effect modifiers (TEM) defined by baseline demographic characteristics (gender, age), and diagnostic (i.e. MRI measures) and clinical (i.e. relapses, disability level) measures of MS disease activity. METHODS: We will include all published and accessible unpublished primary and secondary analyses of randomised controlled trials (RCTs) with a follow-up of at least 12 months investigating the efficacy of at least one approved DMT, with placebo or other approved DMTs as control intervention(s) in subgroups of trial participants. As the primary outcome, we will address disability as defined by the Expanded Disability Status Scale or multiple sclerosis functional composite scores followed by relapse frequency, quality of life measures, and side effects. MRI data will be analysed as secondary outcomes. MEDLINE, EMBASE, CINAHL, LILACS, CENTRAL and major trial registers will be searched for suitable studies. Titles and abstracts and full texts will be screened by two persons independently using Covidence. The risk of bias will be analysed based on the Cochrane "Risk of Bias 2" tool, and the certainty of evidence will be assessed using GRADE. Treatment effects will be reported as rate ratio or odds ratio. Primary analyses will follow the intention-to-treat principle. Meta-analyses will be carried out using random-effects models. DISCUSSION: Given that individual patient data from clinical studies are often not available, the review will allow to analyse the evidence on TEM in MS immunotherapy and thus support clinical decision making in individual cases. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42021279665 .

Time to first treatment and risk of disability pension in relapsing-remitting multiple sclerosis.

Background Initiation of disease-modifying therapy early in the disease course of relapsing-remitting multiple sclerosis (RRMS) has demonstrated beneficial effects on clinical outcomes, but socioeconomic outcomes remain largely unexplored. Objective To investigate the association between the delay from disease onset to first treatment and the hazard of disability pension. Methods We performed a population-based cohort study with data from the nationwide Danish Multiple Sclerosis Registry and Danish nationwide registries. Patients with a disease onset between 1 January 1996 to 5 April 2016 were followed until disability pension or a competing risk/censoring event. 7859 patients were assessed for eligibility of which 5208 were included in the final cohort. Key inclusion criteria were: a diagnosis of multiple sclerosis, relapsing-remitting phenotype, treatment in history, age 18-65 years and an Expanded Disability Status Scale≤4. Patients were categorised according to time from onset to first treatment: within 1 year (early), between 1 and 4 years (intermediate) and from 4 to 8 years (late). Results Of the 5208 patients, 1922 were early, 2126 were intermediate and 1160 were late. Baseline clinical and socioeconomic variables were well balanced. The hazard of receiving disability pension increased with increasing delay of treatment initiation compared with the early group. Cox regression estimates adjusted for clinical and socioeconomic confounders: intermediate (HR, 1.37; 95% CI, 1.12 to 1.68) and late (HR, 1.97; 95% CI, 1.55 to 2.51). Conclusion Early treatment initiation is associated with a reduced risk of disability pension in patients with RRMS. This finding underlines the importance of early diagnosis and treatment on a patient-centred, socioeconomic disability milestone.