ABSTRACT Objective To describe the use of central stimulants and amantadine for fatigue in MS and evaluate a potential association with reduced work loss in people with MS. Methods We conducted a nationwide, matched, register‐based cohort study in Sweden (2006 to 2023) using national registers with prospective data collection. We included individuals with MS, identified via the Swedish MS register or ≥ 3 MS diagnoses in the National Patient Register, who initiated treatment with modafinil, amantadine, or central stimulants for ADHD (ADHD‐Drugs), along with untreated individuals matched on modafinil start date, age, sex, time since MS diagnosis, and prior‐year work loss. The main outcome was monthly work loss, defined as the sum of net days on sick leave, disability pension, and activity compensation. Results We identified 2162 new modafinil users, 462 amantadine, 424 ADHD drugs, and 9762 untreated. All cohorts showed increasing work loss before index, followed by no change in work loss over the subsequent 24 months. Modafinil users had a significantly greater attenuation, but with low effect size, of the increasing trajectory of average monthly work loss than untreated (−0.17 days; 95% CI: −0.22, −0.12), with no significant differences between modafinil and other treated groups. Modafinil was the most prescribed treatment, with 1‐year prevalence of 8.5% in 2006 and 7% in 2023. Interpretation A potential minor treatment benefit is suggested by the statistically significant, small attenuation of worsening work loss following fatigue treatment initiation compared with untreated people with MS. No differences in treatment benefit were observed across fatigue treatments.

Background We analysed the COMparison Between All immunoTherapies for Multiple Sclerosis (NCT03193866), a Swedish nationwide observational study in relapsing-remitting multiple sclerosis (RRMS), to identify trajectories of fatigue and their association with physical disability following start of disease-modifying therapy (DMT).Methods Using a group-modelling approach, we assessed trajectories of fatigue with the Fatigue Scale for Motor and Cognitive Functions and physical disability with Expanded Disability Status Scale among 1587 and 1818 individuals who initiated a first DMT and had a first DMT switch, respectively, followed during 2011-2022. We investigated predictors of fatigue trajectories using group membership as a multinomial outcome and calculated conditional probabilities linking membership across the trajectories.Results We identified five trajectories of fatigue in participants who initiated their first DMT: no fatigue (mean starting values=23.7; 18.2% of population), low (35.5; 23.9%), mild (49.0; 21.6%), moderate (61.3; 20.1%) and severe (78.7; 16.1%). While no, low, mild and severe fatigue trajectories remained stable, the moderate trajectory increased to severe fatigue. Similarly, we identified six fatigue trajectories among participants who did a DMT switch, all indicating stable values over time. Women initiating a first DMT were more likely than men to display a severe fatigue trajectory, relative to the no fatigue one. There was a strong association between fatigue and physical disability trajectories.Conclusions In this cohort of people with actively treated RRMS, self-reported fatigue remained stable or increased over the years following DMT start. There was a strong association between fatigue and disability after DMT start.

OBJECTIVE:To assess comparative effectiveness, safety, and tolerability of off-label rituximab, compared with frequently used therapies approved for multiple sclerosis (MS). METHODS:A Swedish cohort study of persons with relapsing-remitting MS, age 18 to 75 years at inclusion and with a first therapy start or a first therapy switch between 2011 and 2018. Low-dose rituximab was compared with MS-approved therapies. Primary outcomes were proportions with 12 months confirmed disability worsening and change in MS Impact Scale-29 (MSIS-29) scores, respectively. Secondary endpoints included relapses, therapy discontinuation, and serious adverse events. Analyses used an intention-to-treat approach and were adjusted for demographics, MS features, and health characteristics. RESULTS:We included 2,449 participants as first therapy start and 2,463 as first therapy switch. Proportions with disability worsening at 3 years were 9.1% for rituximab as first therapy and 5.1% after therapy switch, with no differences to MS-approved comparators. Worsening on rituximab was mostly independent of relapses. MSIS-29 with rituximab at 3 years improved by 1.3/8.4 points (physical/psychological) for first disease-modifying therapy (DMT) and 0.4/3.6 for DMT switch, and was mostly similar across therapies. Rituximab had lower relapse rates and higher therapy persistence in both groups. The rate of hospital-treated infections was higher with rituximab after a therapy switch, but not as a first therapy. INTERPRETATION:This population-based real-world cohort study found low rates of disability progression, mostly independent of relapses, and without significant differences between rituximab and MS-approved comparators. Rituximab led to lower rates of inflammatory activity and higher treatment persistence, but was associated with an increased rate of serious infections. ANN NEUROL 2024;96:678-693.

BACKGROUND:We analysed the COMparison Between All immunoTherapies for Multiple Sclerosis (NCT03193866), a Swedish nationwide observational study in relapsing-remitting multiple sclerosis (RRMS), to identify trajectories of processing speed and physical disability after disease-modulating therapy (DMT) start. METHODS:Using a group-modelling approach, we assessed trajectories of processing speed with oral Symbol Digit Modalities Test (SDMT) and physical disability with Expanded Disability Status Scale, from first DMT start among 1645 patients with RRMS followed during 2011-2022. We investigated predictors of trajectories using group membership as a multinomial outcome and calculated conditional probabilities linking membership across the trajectories. RESULTS:We identified 5 stable trajectories of processing speed: low SDMT scores (mean starting values=29.9; 5.4% of population), low/medium (44.3; 25.3%), medium (52.6; 37.9%), medium/high (63.1; 25.8%) and high (72.4; 5.6%). We identified 3 physical disability trajectories: no disability/stable (0.8; 26.8%), minimal disability/stable (1.6; 58.1%) and moderate disability (3.2; 15.1%), which increased to severe disability. Older patients starting interferons were more likely than younger patients starting rituximab to be on low processing speed trajectories. Older patients starting teriflunomide, with more than one comorbidity, and a history of pain treatment were more likely to belong to the moderate/severe physical disability trajectory, relative to the no disability one. There was a strong association between processing speed and physical disability trajectories. CONCLUSIONS:In this cohort of actively treated RRMS, patients' processing speed remained stable over the years following DMT start, whereas patients with moderate physical disability deteriorated in physical function. Nevertheless, there was a strong link between processing speed and disability after DMT start.

PCORI identified multiple sclerosis (MS) as an important research topic.People with MS, clinicians, and others wanted to learn how different treatment strategies, aimed at changing specific symptoms or the overall course of MS, affect patients' symptoms and quality of life.To address this issue, PCORI launched an initiative in 2015 on Treatment of Multiple Sclerosis.The initiative funded this research project and others.

Background: There is a paucity of information on maternal multiple sclerosis (MS) and risk of adverse pregnancy and perinatal outcomes. Objective: The aim of this study was to determine the association between MS and risks of adverse pregnancy and perinatal outcomes in women with MS. In women with MS, the influence of exposure to disease-modifying therapy (DMT) was also investigated. Methods: Population-based retrospective cohort study on singleton births to mothers with MS and matched MS-free mothers from the general population in Sweden between 2006 and 2020. Women with MS were identified through Swedish health care registries, with MS onset before child's birth. Results: Of 29,568 births included, 3418 births were to 2310 mothers with MS. Compared with MS-free controls, maternal MS was associated with increased risks of elective caesarean sections, instrumental delivery, maternal infection and antepartum haemorrhage/ placental abruption. Compared with offspring of MS-free women, neonates of mothers with MS were at increased risks of medically indicated preterm birth and being born small for gestational age. DMT exposure was not associated with increased risks of malformations. Conclusions: While maternal MS was associated with a small increased risk of few adverse pregnancy and neonatal outcomes, DMT exposure close to pregnancy was not associated with major adverse outcomes.

BACKGROUND:Fatigue is a debilitating symptom of multiple sclerosis (MS), but its relation to sociodemographic and disease-related characteristics has not been investigated in larger studies. The objectives of this study were to evaluate predictors of self-reported fatigue in a Swedish nationwide register-based MS cohort. METHODS:Using a repeated cross-sectional design, we included 2,165 persons with relapsing- remitting and secondary progressive MS with one or multiple Fatigue Scale for Motor and Cognitive Functions (FSMC) scores, which was modelled using multivariable linear regressions for multiple predictors. RESULTS:Only associations to expanded disability status scale (EDSS) and Symbol Digit Modalities Test (SDMT) were considered clinically meaningful among MS-associated characteristics in our main model; compared to mild disability (EDSS 0-2.5), those with severe disability (EDSS ≥6) scored 17.6 (95% CI 13.1-22.2) FSMC points higher, while the difference was 10.7 (95% CI 8.0-13.4) points for the highest and lowest quartiles of SDMT. Differences between highest and lowest quartiles of health-related quality of life (HRQoL) instruments were even greater and considered clinically meaningful; EuroQoL Visual Analogue Scale (EQ-VAS) 31.9 (95% CI 29.9-33.8), Multiple Sclerosis Impact Scale (MSIS-29) psychological component 35.6 (95% CI 33.8-37.4) and MSIS-29 physical component 45.5 (95% CI 43.7-47.4). CONCLUSION:Higher self-reported fatigue is associated with higher disability level and worse cognitive processing speed, while associations to other MS-associated characteristics including MS type, line of disease modifying therapy (DMT), MS duration, relapse and new cerebral lesions are weak. Furthermore, we found a strong correlation between high fatigue rating and lower ratings on health-related quality of life instruments.

Abstract Objective To estimate risks for all‐cause mortality and for severe COVID‐19 in multiple sclerosis patients and across relapsing–remitting multiple sclerosis patients exposed to disease‐modifying therapies. Methods We conducted a Swedish nationwide population‐based multi‐register linkage cohort study and followed all multiple sclerosis patients (n = 17,692 in March 2020), individually age‐, sex‐, and region‐matched to five population‐based controls (n = 86,176 in March 2020) during March 2020–June 2021. We compared annual all‐cause mortality within and across cohorts, and assessed incidence rates and relative risks for hospitalization, intensive care admission, and death due to COVID‐19 in relation to disease‐modifying therapy use, using Cox regression. Results Absolute all‐cause mortality among multiple sclerosis patients was higher from March to December 2020 than in previous years, but relative risks versus the population‐based controls were similar to preceding years. Incidence rates of hospitalization, intensive care admission, and death due to COVID‐19 remained in line with those for all‐cause hospitalization, intensive care admission, and mortality. Among relapsing–remitting patients on rituximab, trends for differences in risk of hospitalization due to COVID‐19 remained in the demographics‐, socioeconomic status‐, comorbidity‐, and multiple sclerosis severity‐adjusted model. Interpretation Risks of severe COVID‐19‐related outcomes were increased among multiple sclerosis patients as a whole compared to population controls, but risk increases were also seen for non‐COVID‐19 hospitalization, intensive care admission, and mortality, and did not significantly differ during the pandemic compared to pre‐pandemic years. The risk conveyed by disease‐modifying therapies was smaller than previously assumed, likely as a consequence of the possibility to better control for confounders.

Background: Depression and use of antidepressants are more common among patients with multiple sclerosis (MS) compared to the general population, but the relation of psychiatric comorbidity to use of different disease-modifying therapies (DMTs) is less clear. Objective: To determine whether risk of incident depression or antidepressant use differed across DMTs, and to assess whether depression and antidepressants affected risk of DMT discontinuation and MS relapses. Methods: We prospectively followed for 8 years a register-based nationwide cohort of 3803 relapsing-remitting MS patients. Results: Patients on rituximab had a lower risk of being diagnosed with depression or initiating antidepressants compared with the reference group treated with interferons (hazard ratio (HR) = 0.72, 95% confidence interval (CI) = 0.54–0.96). Patients diagnosed with depression discontinued interferon treatment to a higher extent than patients without depression (HR = 1.51; 95% CI = 1.15–1.98), as did patients on fingolimod initiating an antidepressant compared to patients who did not initiate an antidepressant (HR = 1.47; 95% CI = 1.04–2.08). Conclusions: Our results indicate that the choice of DMT is associated with subsequent risk of depression in MS, but further studies are needed to establish whether there is a causal link. Overall, depression and use of antidepressants displayed limited associations with DMT discontinuation and MS relapse.

BACKGROUND:It remains unclear whether and to what extent health behaviours may prolong survival and compress the period of survival with disability. OBJECTIVE:To identify modifiable health behaviours that are associated with later disability onset and longer disability-free survival. DESIGN:This population-based cohort study used data from the Swedish National Study on Ageing and Care in Kungsholmen (SNAC-K) ranging between 2001 and 2016. SETTING AND SUBJECTS:A total of 3,041 disability-free adults aged ≥60 years were followed up to 15 years. METHODS:Data on health behaviours were collected at baseline. Information on limitations in activities of daily living was obtained at baseline and during the follow-up. Laplace regression was used to model the median age at death and disability occurrence as a function of health behaviours. RESULTS:Never smoking, moderate alcohol drinking, rich social network and high leisure activity were individually related to longer survival by 1-3 years. Participants with high leisure activity lived 1.6 years (95% CI: 0.9-2.3) more without a disability. After combining lifestyle factors, social network, and leisure activities into a 4-level 'health behaviour profile', people with the healthiest behaviour profile lived 2.8 years (95% CI: 1.3-4.2) longer, had disability 3.5 years (95% CI: 1.7-5.3) later and lived 0.7 years (95% CI, 0.4-1.1) more without a disability compared to those with the least healthy behaviours profile. CONCLUSIONS:These findings suggest that health behaviours could prolong the lifespan, and leisure activities may further compress years lived with disability among older adults.

This case-control study examines the risk of severe COVID-19 infection in individuals with multiple sclerosis who were receiving rituximab.

Background : Descriptive data report a very low rate of postoperative nausea and vomiting (PONV) following spinal anaesthesia in children. In an attempt to corroborate this observation, we designed a prospective randomized study to compare spinal anaesthesia with intravenous propofol sedation (SA) ( n =21) to inhalational sevoflurane anaesthesia (IA) ( n =19) with regard to PONV and postoperative analgesia in children (aged 3–12 years) undergoing ambulatory inguinal surgery. Results : No difference was found concerning the number of patients experiencing PONV in each group (SA 1/21 versus IA 5/19; P =0.085). However, spinal anaesthesia was associated with a reduced number of PONV episodes (1/21) compared with inhalation anaesthesia (8/19) ( P =0.014) and the need for supplemental postoperative analgesia with ketoralac was significantly lower in the SA group (3/21) compared to the IA group (14/19) ( P < 0.001). Despite these benefits of spinal anaesthesia compared with inhalational anaesthesia, spinal anaesthesia did not decrease the time to discharge from the ambulatory surgery unit [SA 161 (SD 51) min, IA 164 (SD 41) min; P =NS] and the overall PONV experience was rated as ‘no problem’ by all patients, except one, regardless of anaesthetic protocol used. Conclusions : Despite the reduced number of emetic episodes and the better immediate postoperative analgesia associated with spinal anaesthesia, no difference could be identified between the two different anaesthetic protocols regarding time to discharge or overall patient satisfaction. Thus, despite minor advantages associated with spinal anaesthesia with propofol sedation, both anaesthetic regimen appear equally suitable for use in the paediatric outpatient setting.