Spinal cord size as promising biomarker of disability outcomes after hematopoietic stem cell transplantation in multiple sclerosis.

BACKGROUND: Biomarkers predictive of disability outcomes in individual multiple sclerosis (MS) patients undergoing autologous haematopoietic stem cell transplantation (AHSCT) are currently lacking. As correlations between spinal cord atrophy and clinical disability in MS were previously described, in this study spinal cord size was investigated in MS patients treated with AHSCT, exploring whether baseline spinal cord volume may predict disability progression after AHSCT. METHODS: relapsing-remitting (RR-) and secondary-progressive (SP-) MS patients treated with AHSCT (BEAM/ATG regimen) at a single academic centre in Florence, who performed at least two standardized brain magnetic resonance imaging (MRIs) scans (acquired between one-year pre-AHSCT to 5 years after AHSCT) were included. Cervical spinal cord atrophy was estimated as upper cervical spinal cord cross-sectional area (SCCSA). Brain volume loss (BVL) was analysed at the same timepoints. RESULTS: Eleven (8 RR-; 3 SP-) MS patients were included. Over a median follow-up of 66 (range 37 - 100) months, no relapses nor brain MRI activity were observed; disability progressed in 2 cases (both SP-MS). Baseline SCCSA was associated with EDSS change between pre- and one-year post-AHSCT. Compared to patients who stabilized, patients who progressed after AHSCT tended to have lower SCCSA at C4 level at baseline and year 1 after AHSCT. Longitudinal changes in SCCSA or BVL did not correlate with EDSS change. CONCLUSIONS: Baseline pre-AHSCT SCCSA, but not its longitudinal changes nor BVL, predicted EDSS change within the two years following AHSCT. SCCSA may represent a biomarker of treatment response and a promising screening tool for assessing patient eligibility for high-impact treatments such as AHSCT.

Socioeconomic status and quality of multiple sclerosis care in Sweden.

In Sweden's universal healthcare system, it is unknown whether people of higher socioeconomic status receive higher quality multiple sclerosis (MS) care. Using linked clinical and administrative data, we investigated the quality of care received by 4426 adults aged 23-60 with relapsing-remitting MS. In adjusted analyses, we demonstrated that higher premorbid educational attainment is associated with 4-12 % more frequent neurologist visits and MRI scans in the first four years post diagnosis, while higher premorbid income was associated with faster diagnosis-to-treatment times by 34-64 days. Neither education nor income were associated with time to diagnosis. This suggests that the more favourable MS outcomes observed for people of higher socioeconomic status may in part be related to higher quality care.

Neurological efficacy and safety of mesenchymal stem cells (MSCs) therapy in people with multiple sclerosis (pwMS): An updated systematic review and meta-analysis.

BACKGROUND: Current therapeutic strategies for multiple sclerosis (MS) aim to suppress the immune response and reduce relapse rates. As alternative treatments, mesenchymal stem cells (MSCs) are being explored. MSCs show promise in repairing nerve tissue and reducing autoimmune responses in people with MS (pwMS). OBJECTIVE: This review delves into the literature on the efficacy and safety of MSC therapy for pwMS. METHODS: A comprehensive search strategy was employed to identify relevant articles from five databases until January 2024. The inclusion criteria encompassed interventional studies. Efficacy and safety data concerning MSC therapy in relapsing-remitting MS (RRMS), secondary progressive MS (SPMS), and primary progressive MS (PPMS) groups were extracted and analyzed. RESULTS: A comprehensive analysis encompassing 30 studies revealed that individuals who underwent intrathecal (IT) protocol-based transplantation of MSCs experienced a noteworthy improvement in their expanded disability status scale (EDSS) compared to the placebo group. Weighted mean difference (WMD) was -0.28; 95 % CI -0.53 to -0.03, I2 = 0 %, p-value = 0.028); however, the intravenous (IV) group did not show significant changes in EDSS scores. The annualized relapse rate (ARR) did not significantly decrease among pwMS (WMD = -0.34; 95 % CI -1.05 to 0.38, I2 = 98 %, p-value = 0.357). Favorable results were observed in magnetic resonance imaging (MRI), with only 19.11 % of pwMS showing contrast-enhanced lesions (CEL) in the short term and no long-term MRI activity. The most common complications in both short-term and long-term follow-ups were infection, back pain, and gastrointestinal symptoms. CONCLUSIONS: The study highlights the safety potential of MSC therapy for pwMS. While MRI-based neural regeneration shows significant treatment potential, the effectiveness of MSC therapy remains uncertain due to study limitations and ineffective outcome measures. Further research is needed to establish efficacy and optimize evaluation methods for MSC therapy on pwMS.

Serum neurofilament light chain and glial fibrillary acidic protein for predicting response to apheresis in steroid-refractory multiple sclerosis relapses.

BACKGROUND AND PURPOSE: The predictive value of serum neurofilament light chain (sNfL) and serum glial fibrillary acidic protein (sGFAP) for apheresis outcome in steroid-refractory multiple sclerosis (MS) relapse has not yet been evaluated. METHODS: We used pre- and postapheresis serum samples from 38 participants of the IAPEMS trial (clinicaltrials.gov: NCT02671682), which investigated the use of immunoadsorption versus plasma exchange for the treatment of steroid-refractory MS attacks. Response to apheresis was classified based on improvement on (i) the Expanded Disability Status Scale (EDSS), (ii) the affected functional system scores (FSS) of the EDSS, or (iii) the visual acuity for patients with optic neuritis, 4 weeks postapheresis. sNFL and sGFAP were measured by single molecule arrays. RESULTS: Preprocedural sGFAP levels could discriminate between responders and nonresponders, determined by FSS improvement (p = 0.017). In multivariate logistic regression analysis, younger age (odds ratio [OR] = 0.781, 95% confidence interval [CI] = 0.635-0.962, p = 0.020) and lower sGFAP levels (OR = 0.948, 95% CI = 0.903-0.995, p = 0.031) could predict response to apheresis in the overall cohort. We could observe a trend towards a favourable apheresis outcome with higher sNfL levels (OR = 1.413, 95% CI = 0.965-2.069, p = 0.076). Analysis of the sNfL-to-sGFAP ratio showed an OR of 1.924 (95% CI = 1.073-3.451, p = 0.028) for predicting apheresis response. The ratio showed a better predictive value than the individual parameters. Neither biomarker was affected by the number of steroid cycles preapheresis. CONCLUSIONS: Lower sGFAP levels, a higher sNfL-to-sGFAP ratio, and younger age are associated with a favourable apheresis outcome.

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.

Cost and effectiveness of autologous haematopoietic stem cell transplantation and high-efficacy disease-modifying therapies in relapsing-remitting multiple sclerosis.

BACKGROUND: Autologous haematopoietic stem cell transplantation (AHSCT) is a highly effective one-off treatment for relapsing-remitting multiple sclerosis (RR-MS), potentially representing an optimal front-loading strategy for costs. OBJECTIVE: Exploring cost/effectiveness of AHSCT and high-efficacy disease-modifying treatments (HE-DMTs) in RR-MS, estimating costs at our centre in Italy, where National Health Service (NHS) provides universal health coverage. METHODS: Costs (including drugs, inpatient/outpatient management) for treatment with AHSCT and HE-DMTs were calculated as NHS expenditures over 2- and 5-year periods. Cost-effectiveness for each treatment was estimated as "cost needed to treat" (CNT), i.e. expense to prevent relapses, progression, or disease activity (NEDA) in one patient over n-years, retrieving outcomes from published studies. RESULTS: Costs of AHSCT and HE-DMTs were similar over 2 years, whereas AHSCT was cheaper than most HE-DMTs over 5 years (€46 600 vs €93 800, respectively). When estimating cost-effectiveness of treatments, over 2 years, mean CNT of HE-DMTs for NEDA was twofold that of AHSCT, whereas it was similar for relapses and disability. Differences in CNT were remarkable over 5 years, especially for NEDA, being mean CNT of HE-DMTs €382 800 vs €74 900 for AHSCT. CONCLUSIONS: AHSCT may be highly cost-effective in selected aggressive RR-MS. Besides priceless benefits for treated individuals, cost-savings generated by AHSCT may contribute to improving healthcare assistance at a population level.

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.

Relapsing/remitting multiple sclerosis: A speculative model and its implications for a novel treatment.

The clinical pattern in relapsing/remitting multiple sclerosis may be accounted for if an autoreactive immune response can transition back and forth between inflammatory, pathogenic, and non-inflammatory, non-pathogenic modes. Such 'back-and-forth' immune responses are rare. I speculate how such back-and-forth immune responses may arise. Understanding the nature of these different modes, and what controls their mutual transition, may help in designing strategies to favour the nonpathogenic mode, thus constituting treatment. Antigen dose is known to be critical in determining the class/subclass of primary immune responses. Observations have led us to suggest the level of antigen also similarly influences the class/subclass of on-going immune responses. I propose the relapsing, inflammatory and the remitting modes are respectively sustained by relatively low and high amounts of the responsible autoantigens, as is the case, for example, for Th1 and Th2 responses to foreign antigens. In addition, I propose more self-antigens are released during an inflammatory than during a remitting mode. The decrease in the amount of antigen released, as the response transitions from an inflammatory to a remitting mode, results in time in a decreased level of antigen and so the response again evolves towards the inflammatory mode. The inflammatory mode then leads to an increased release of antigen and so, in time, to remission. This model thus explains the transition between different modes. I outline non-invasive, testable predictions of the hypothesis. If confirmed, it may be ethical to examine whether the non-inflammatory mode can be sustained by administering myelin antigens during the remitting phase.