Henrik Boye Jensen

Background: Ocrelizumab and natalizumab are highly effective disease‐modifying treatments for relapsing–remitting multiple sclerosis (RRMS). Direct comparison of effectiveness is crucial for optimizing treatment decisions and improving patient outcomes. The aim was to compare any difference in effectiveness of ocrelizumab and natalizumab on disease activity and progression in RRMS. Methods: This was a national multicenter comparative effectiveness research study using data from the nationwide population‐based registry of MS cases in Denmark. Patients were included from January 2018 to April 2023 with a history of RRMS treated with ocrelizumab or natalizumab. Inverse probability of treatment weighting based on propensity scores was applied. Main outcomes were the comparison of annualized relapse rate (ARR), time to first progression independent of relapse activity (PIRA), and time to first occurrence of new/enlarging T2 or contrast‐enhancing lesions on cerebral MRI scans. Results: We found no statistically significant differences in the ARR between ocrelizumab‐treated ( n = 542) and natalizumab‐treated ( n = 384) patients (mean [95% CI] ARR of 0.071 [0.057–0.088] and 0.071 [0.054–0.092], respectively) and in the ARR ratio (0.996, 95% CI [0.687–1.444], p = 0.983). Similarly, we did not find differences between the two groups in terms of time to first PIRA (HR, 1.34; 95% CI, 0.88–2.02; p = 0.17) and time to first inflammatory activity in MRI scans (HR, 1.04; 95% CI, 0.74–1.25; p = 0.78). Conclusions: The study could not demonstrate a difference in effectiveness of ocrelizumab and natalizumab treatment in this nationwide population‐based registry study in risk of relapses, disability progression, and MRI activity.

Background: This systematic review assessed the current literature regarding the analgesic treatment of central neuropathic pain (CNP) in central nervous system (CNS) conditions, such as spinal cord injuries, multiple sclerosis, post-stroke disorders, and Parkinson’s disease. The aim of this systematic review was to compare the current algorithmic treatment of CNP, which generally does not discriminate among underlying conditions, with RCTs investigating algorithm-recommended and non-algorithm-recommended drugs for differing underlying conditions. Methods: The PubMed and EMBASE databases were used to identify relevant randomized control trials (RCTs). MeSH terms and EmTree terms were searched as well as free text words in the title/abstract of the studies. A risk of bias tool was used to assess all included studies. Results: A total of 903 RCTs were identified from the initial search. Thirty-eight RCTs published between January 2002 and November 2024 fulfilled all the inclusion criteria and none of the exclusion criteria. The review investigated progressive and stable neurological diseases and conditions with associated CNP. Conclusions: From the majority of the included studies, the current recommended treatment algorithm seems to be effective and safe; however, the underlying condition seems to influence how the patient responds to tier-appropriate medication.

Currently, there are limited therapeutic options for patients with non-active secondary progressive multiple sclerosis. Therefore, real-world studies have investigated differences between patients with relapsing-remitting multiple sclerosis, non-active secondary progressive multiple sclerosis and active secondary progressive multiple sclerosis. Here, we explore patterns and predictors of transitioning between these phenotypes. We performed a cohort study using data from The Danish Multiple Sclerosis Registry. We included patients with a relapsing-remitting phenotype, registered changes to secondary progressive multiple sclerosis and subsequent transitions between relapsing and non-relapsing secondary progressive multiple sclerosis, which was defined by the presence of relapses in the previous 2 years. We analysed predictors of transitioning from relapsing-remitting multiple sclerosis to relapsing and non-relapsing secondary progressive multiple sclerosis, as well as between the secondary progressive states using a multi-state Markov model. We included 4413 patients with relapsing-remitting multiple sclerosis. Within a median follow-up of 16.2 years, 962 were diagnosed with secondary progressive multiple sclerosis by their treating physician. Of these, we classified 729 as non-relapsing and 233 as relapsing secondary progressive multiple sclerosis. The risk of transitioning from relapsing-remitting to non-relapsing secondary progressive multiple sclerosis included older age (hazard ratio per increase of 1 year in age: 1.044, 95% confidence interval: 1.035–1.053), male sex (hazard ratio for female: 0.735, 95% confidence interval: 0.619–0.874), fewer relapses (hazard ratio per each additional relapse: 0.863, 95% confidence interval: 0.823–0.906), higher expanded disability status scale (hazard ratio per each additional point: 1.522, 95% confidence interval: 1.458–1.590) and longer time on disease-modifying therapies (hazard ratio per increase of 1 year in treatment, high-efficacy disease-modifying therapy: 1.095, 95% confidence interval: 1.051–1.141; hazard ratio, moderate-efficacy disease-modifying therapy: 1.073, 95% confidence interval: 1.051–1.095). We did not find significant predictors associated with the transition from relapsing secondary progressive multiple sclerosis to non-relapsing secondary progressive multiple sclerosis, whereas older age (hazard ratio per increase of 1 year in age: 0.956, 95% confidence interval: 0.942–0.971) prevented the transition from non-relapsing secondary progressive multiple sclerosis to relapsing secondary progressive multiple sclerosis. Our study suggests that transitioning from relapsing-remitting multiple sclerosis to non-relapsing secondary progressive multiple sclerosis depends on well-known factors affecting diagnosing secondary progressive multiple sclerosis. Further transitions between non-relapsing and relapsing secondary progressive multiple sclerosis are only affected by age. These findings add to the knowledge of non-active secondary progressive multiple sclerosis, a patient group with unmet needs in terms of therapies.

Background: This systematic review searched to identify a potential biomarker in serum/plasma or cerebrospinal fluid (CSF) to differentiate between relapsing-remitting multiple sclerosis (RRMS) and secondary progressive multiple sclerosis (SPMS). There is currently no definitive method for determining whether a patient is in the RRMS course or has converted to the SPMS course. A biomarker could therefore aid the clinician to make this diagnosis. The aim of this study is to assess if there are biomarkers or combinations of biomarkers in serum/plasma or CSF that can detect secondary progression in multiple sclerosis at an early stage. Methods: The PubMed and EMBASE databases were searched to identify relevant studies. Both MeSH terms and text words in the title/abstract were used in both search strategies. The method included forward and backward citation searches. A risk of bias tool was used to assess all the studies that were included. Results: A total of 7581 articles were identified from the initial search. Additionally, 3386 articles were added after the citation search. Of these, 39 articles fulfilled the inclusion criteria and none of the exclusion criteria. The review investigated 28 different biomarkers in CSF and serum/plasma. Discussion: Of the 28 different biomarkers, six biomarkers appeared to be the most promising: neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), Galectin-9, YKL-40/CHI3L1, osteopontin, and MCP-1. This review provides new insights into potential directions for future studies to investigate biomarkers as a diagnostic tool for SPMS.

Peripheral cytokine levels may serve as biomarkers for treatment response and disease monitoring in patients with multiple sclerosis (pwMS). The objectives were to assess changes in plasma biomarkers in PwMS after 14 days of fampridine treatment and to explore correlations between changes in performance measures and plasma biomarkers. We included 27 PwMS, 14 women and 13 men, aged 52.0 ± 11.6 years, with a disease duration of 17 ± 8.5 years, and an Expanded Disability Status Scale of 6 [IQR 5.0/6.5]. Gait and hand function were assessed using performance tests completed prior to fampridine and after 14 days of treatment. Venous blood was obtained, and chemiluminescence analysis conducted to assess plasma cytokines and neurodegenerative markers. All performance measures demonstrated improvements. Biomarkers showed decreased tumor necrosis factor (TNF) receptor-2 levels. Associations were found between change scores in (i) Six Spot Step Test and Interleukin (IL)-2, IL-8, and IL-17 levels; (ii) timed 25-foot walk and interferon-γ, IL-2, IL-8, TNF-α, and neurofilament light levels, and (iii) 12-Item Multiple Sclerosis Walking Scale and IL-17 levels. The associations may reflect increased MS-related inflammatory activity rather than a fampridine-induced response or that a higher level of inflammation induces a better response to fampridine.

Objectives Fatigue and walking impairment are disabling symptoms of multiple sclerosis (MS). We investigated the effects of progressive aerobic exercise (PAE) on fatigue, walking, cardiorespiratory fitness (VO₂max), and quality of life in people with MS (pwMS). Materials & Methods Randomized controlled trial (1:1 ratio, stratified by sex) with a 24-week crossover follow-up and intention-to-treat analysis. Allocation to an exercise (24 weeks of PAE followed by self-guided physical activity) and a waitlist (24 weeks of habitual lifestyle followed by PAE) group. PAE comprised two supervised sessions per week; 30–60 min, 65–95% of maximum heart rate. Fatigue impact (Modified Fatigue Impact Scale; MFIS) and severity (Fatigue Severity Scale; FSS), walking ability (12-item MS Walking Scale; MSWS-12) and capacity (Six-Minute Walk Test; 6MWT, Six Spot Step Test; SSST), quality of life (Short Form 36 health survey; SF-36), and VO₂max were measured at baseline, 24 weeks, and 48 weeks. Results Eighty-six pwMS were enrolled. Following PAE between-group differences showed reductions in MFIS_total (−5.3 [95% CI: −10.9;0.4], point estimate >clinical relevance), MFIS_physical subscore (−2.8 [−5.6;-0.1]), and MFIS_psychosocial subscore (−0.9 [−1.6;-0.2]), and an increase in VO₂max (+3.5 ml O₂/min/kg [2.0;5.1]). MSWS-12 (−5.9 [−11.9; 0.2]) and 6MWT (+14 m [−5;33]) differences suggested potential small walking improvements. No changes observed in FSS, SSST, or SF-36. Conclusions In a representative sample of pwMS, PAE induced a clinically relevant reduction in fatigue impact, whereas small and no effects were seen for walking and quality of life, respectively. The results need confirmation in a future trial due to the study limitations.

Objective To determine whether 24 weeks of high-intensity progressive aerobic exercise (PAE) affects brain MRI measures in people with multiple sclerosis (MS). Methods We conducted a randomized, controlled, phase 2 trial (with a crossover follow-up) including an exercise group (supervised PAE followed by self-guided physical activity) and a waitlist group (habitual lifestyle followed by supervised PAE). Mildly to severely impaired patients with MS aged 18–65 years were randomized (1:1). The primary outcome was percentage brain volume change (PBVC) after 24 weeks, analyzed using the intention-to-treat principle. Results Eighty-six participants were recruited. PBVC did not change over the intervention period (mean between-group change +0.12%, 95% confidence interval [CI] −0.27 to 0.51, p = 0.55). In contrast, cardiorespiratory fitness (+3.5 mL O₂/min/kg, 2.0 to 5.1, p < 0.01) and annualized relapse rate (0.00, 0.00–0.07 vs +0.45, 0.28 to 0.61, p < 0.01) improved in the exercise group. Conclusion These findings do not support a neuroprotective effect of PAE in terms of total brain atrophy in people with MS and it did not lead to a statistically significant difference in gray matter parenchymal fraction. PAE led to improvements in cardiorespiratory fitness and a lower relapse rate. While these exploratory findings cautiously support PAE as a potential adjunct disease-modifying treatment in MS, further investigations are warranted. Clinicaltrials.gov identifier NCT02661555. Classification of evidence This study provides Level I evidence that 24 weeks of high-intensity PAE did not elicit disease-modifying effects in PBVC in people with MS. Exploratory analyses showed that PAE may reduce relapse rate.

A systematic review of literature was conducted comparing neurophysiological outcomes in persons with multiple sclerosis (PwMS) to healthy controls (HC), with studies of central nervous system (CNS) function comprising motor evoked potentials (MEP) elicited by transcranial magnetic stimulation (TMS), and studies of peripheral nervous system (PNS) function comprising electroneuronography (ENG) outcomes elicited by peripheral nerve stimulation. Studies comparing neuromuscular function, assessed during maximal voluntary contraction (MVC) of muscle, were included if they reported muscle strength along with muscle activation by use of electromyography (EMG) and/or interpolated twitch technique (ITT). Studies of CNS function showed prolonged central motor conduction times, asymmetry of nerve conduction motor pathways and prolonged latencies in PwMS when compared to HC. Resting motor threshold, amplitude and cortical silent periods showed conflicting results. CNS findings generally correlated with disabilites. Studies of PNS function showed near significant prolongation in motor latency of the median nerve, reduced nerve conduction velocities in the tibial and peroneal nerves and decreased compound muscle action potential amplitudes of the tibial nerve in PwMS. ENG findings did not correlate with clinical severity of disabilities. Studies of neuromuscular function showed lower voluntary muscle activation and increased central fatigue in PwMS, whereas EMG showed divergent muscle activation (i.e. EMG amplitude) during MVC. When comparing the existing literature on neurophysiological motor examinations in PwMS and HC consistent and substantial impairments of CNS function were seen in PwMS, whereas impairments of the PNS were less pronounced and inconsistent. In addition, impairments in muscle activation were observed in PwMS.

The authors wish to make the following corrections to this paper