Clinical risk stratification: Development and validation of the DAAE score, a tool for estimating patient risk of transition to secondary progressive multiple sclerosis.

BACKGROUND: Because secondary progressive multiple sclerosis (SPMS) is associated with worse prognosis, early predictive tools are needed. We aimed to use systematic literature review and advanced methods to create and validate a clinical tool for estimating individual patient risk of transition to SPMS over five years. METHODS: Data from the Jacobs Multiple Sclerosis Center (JMSC) and the Multiple Sclerosis Center Amsterdam (MSCA) was collected between 1994 and 2022. Participants were relapsing-remitting adult patients at initial evaluation. We created the tool in four stages: (1) identification of candidate predictors from systematic literature review, (2) ordinal cutoff determination, (3) feature selection, (4) feature weighting. RESULTS: Patients in the development/internal-validation/external-validation datasets respectively (n = 787/n = 522/n = 877) had a median age of 44.1/42.4/36.6 and disease duration of 7.7/6.2/4.4 years. From these, 12.6 %/10.2 %/15.4 % converted to SPMS (median=4.9/5.2/5.0 years). The DAAE Score was named from included predictors: Disease duration, Age at disease onset, Age, EDSS. It ranges from 0 to 12 points, with risk groups of very-low=0-2, low=3-7, medium=8-9, and high≥10. Risk of transition to SPMS increased proportionally across these groups in development (2.7 %/7.4 %/18.8 %/40.2 %), internal-validation (2.9 %/6.8 %/26.8 %/36.5 %), and external-validation (7.5 %/9.6 %/22.4 %/37.5 %). CONCLUSION: The DAAE Score estimates individual patient risk of transition to SPMS consistently across datasets internationally using clinically-accessible data. With further validation, this tool could be used for clinical risk estimation.

Digital outcome measures are associated with brain atrophy in patients with multiple sclerosis.

BACKGROUND: Digital monitoring of people with multiple sclerosis (PwMS) using smartphone-based monitoring tools is a promising method to assess disease activity and progression. OBJECTIVE: To study cross-sectional and longitudinal associations between active and passive digital monitoring parameters and MRI volume measures in PwMS. METHODS: In this prospective study, 92 PwMS were included. Clinical tests [Expanded Disability Status Scale (EDSS), Timed 25 Foot Walk test (T25FW), 9-Hole Peg Test (NHPT), and Symbol Digit Modalities Test (SDMT)] and structural MRI scans were performed at baseline (M0) and 12-month follow-up (M12). Active monitoring included the smartphone-based Symbol Digit Modalities Test (sSDMT) and 2 Minute Walk Test (s2MWT), while passive monitoring was based on smartphone keystroke dynamics (KD). Linear regression analyses were used to determine cross-sectional and longitudinal relations between digital and clinical outcomes and brain volumes, with age, disease duration and sex as covariates. RESULTS: In PwMS, both sSDMT and SDMT were associated with thalamic volumes and lesion volumes. KD were related to brain, ventricular, thalamic and lesion volumes. No relations were found between s2MWT and MRI volumes. NHPT scores were associated with lesion volumes only, while EDSS and T25FW were not related to MRI. No longitudinal associations were found for any of the outcome measures between M0 and M12. CONCLUSION: Our results show clear cross-sectional correlations between digital biomarkers and brain volumes in PwMS, which were not all present for conventional clinical outcomes, supporting the potential added value of digital monitoring tools.

Evaluation of machine learning-based classification of clinical impairment and prediction of clinical worsening in multiple sclerosis.

BACKGROUND: Robust predictive models of clinical impairment and worsening in multiple sclerosis (MS) are needed to identify patients at risk and optimize treatment strategies. OBJECTIVE: To evaluate whether machine learning (ML) methods can classify clinical impairment and predict worsening in people with MS (pwMS) and, if so, which combination of clinical and magnetic resonance imaging (MRI) features and ML algorithm is optimal. METHODS: We used baseline clinical and structural MRI data from two MS cohorts (Berlin: n = 125, Amsterdam: n = 330) to evaluate the capability of five ML models in classifying clinical impairment at baseline and predicting future clinical worsening over a follow-up of 2 and 5 years. Clinical worsening was defined by increases in the Expanded Disability Status Scale (EDSS), Timed 25-Foot Walk Test (T25FW), 9-Hole Peg Test (9HPT), or Symbol Digit Modalities Test (SDMT). Different combinations of clinical and volumetric MRI measures were systematically assessed in predicting clinical outcomes. ML models were evaluated using Monte Carlo cross-validation, area under the curve (AUC), and permutation testing to assess significance. RESULTS: The ML models significantly determined clinical impairment at baseline for the Amsterdam cohort, but did not reach significance for predicting clinical worsening over a follow-up of 2 and 5 years. High disability (EDSS ≥ 4) was best determined by a support vector machine (SVM) classifier using clinical and global MRI volumes (AUC = 0.83 ± 0.07, p = 0.015). Impaired cognition (SDMT Z-score ≤ -1.5) was best determined by a SVM using regional MRI volumes (thalamus, ventricles, lesions, and hippocampus), reaching an AUC of 0.73 ± 0.04 (p = 0.008). CONCLUSION: ML models could aid in classifying pwMS with clinical impairment and identify relevant biomarkers, but prediction of clinical worsening is an unmet need.

[Treatment of multiple sclerosis]. / Behandelmogelijkheden bij multiple sclerose.

Multiple sclerosis is a chronic inflammatory disease of the central nervous system, caused by an autoimmune reaction. Treatment options have largely increased over the years. In this article, we present two clinical cases. Patient A has a classic relapsing remitting course of multiple sclerosis with satisfactory effect on second line therapy. Patient B had a stable disease course until a new relapse occurred after the initiation of TNF-alpha blocking therapy because of Crohn's disease. The co-occurrence of multiple auto-immune diseases creates challenges, but also opportunities in choosing the right treatment strategy.

Mono-allelic KCNB2 variants lead to a neurodevelopmental syndrome caused by altered channel inactivation.

Ion channels mediate voltage fluxes or action potentials that are central to the functioning of excitable cells such as neurons. The KCNB family of voltage-gated potassium channels (Kv) consists of two members (KCNB1 and KCNB2) encoded by KCNB1 and KCNB2, respectively. These channels are major contributors to delayed rectifier potassium currents arising from the neuronal soma which modulate overall excitability of neurons. In this study, we identified several mono-allelic pathogenic missense variants in KCNB2, in individuals with a neurodevelopmental syndrome with epilepsy and autism in some individuals. Recurrent dysmorphisms included a broad forehead, synophrys, and digital anomalies. Additionally, we selected three variants where genetic transmission has not been assessed, from two epilepsy studies, for inclusion in our experiments. We characterized channel properties of these variants by expressing them in oocytes of Xenopus laevis and conducting cut-open oocyte voltage clamp electrophysiology. Our datasets indicate no significant change in absolute conductance and conductance-voltage relationships of most disease variants as compared to wild type (WT), when expressed either alone or co-expressed with WT-KCNB2. However, variants c.1141A>G (p.Thr381Ala) and c.641C>T (p.Thr214Met) show complete abrogation of currents when expressed alone with the former exhibiting a left shift in activation midpoint when expressed alone or with WT-KCNB2. The variants we studied, nevertheless, show collective features of increased inactivation shifted to hyperpolarized potentials. We suggest that the effects of the variants on channel inactivation result in hyper-excitability of neurons, which contributes to disease manifestations.

Rapid diagnostic of multidrug-resistant sepsis pathogens directly from blood culture bottles using MALDI-TOF and the EUCAST RAST.

In this study, rapid diagnostic of multidrug-resistant (MDR) sepsis pathogens, directly from positive blood culture (BC) bottles, was evaluated by combining MALDI-TOF and the EUCAST Rapid Antimicrobial Susceptibility Testing (RAST). Carbapenemase production in Escherichia coli and Klebsiella pneumoniae isolates was also evaluated by RAST. From 171 positive BC bottles analyzed, 79 (46 %) MDR species, including E. coli (4/34, 12 %), K. pneumoniae (33/48, 69 %), Pseudomonas aeruginosa (12/12, 100 %), Acinetobacter baumannii (15/15, 100 %), and Staphylococcus aureus (14/37, 38 %) displaying resistance to beta-lactams, fluoroquinolones, aminoglycosides, and/or trimethoprim/sulphamethoxazole, were identified. In this regard, turnaround time of direct MALDI-TOF identification and RAST was < 7 h, which was significantly (p< 0.05) lower than our routine method. Carbapenemase detection by RAST displayed 100% sensitivity and 88.7 % specificity at 8 h. This protocol could offer advantages for the treatment and clinical outcomes of septic patients, improving the rapid diagnostic of sepsis by MDR pathogens.

Improved Clinical Staging System for Localized Pancreatic Cancer Using the ABC Factors: A TAPS Consortium Study.

PURPOSE: Previous studies suggest that besides anatomy (A: resectable, borderline resectable [BR], or locally advanced [LA]) also biologic (B: carbohydrate antigen 19-9 [CA 19-9]) and conditional (C: performance status) factors should be considered when staging patients with localized pancreatic ductal adenocarcinoma (PDAC). The prognostic value of the combined ABC factors has not been quantitatively validated. METHODS: In this retrospective cohort study, we evaluated patients with localized PDAC treated with initial (modified) fluorouracil with leucovorin, irinotecan, and oxaliplatin ([m]FOLFIRINOX) at five high-volume pancreatic cancer centers in the United States and the Netherlands (2012-2019). Multivariable Cox proportional hazards analysis was used to investigate the impact of the ABC factors for overall survival (OS). RESULTS: Overall, 1,835 patients with localized PDAC were included. Tumor stage at diagnosis was potentially resectable in 346 (18.9%), BR in 531 (28.9%), and LA in 958 (52.2%) patients. The baseline CA 19-9 was >500 U/mL in 559 patients (32.5%). Performance status was ≥1 in 1,110 patients (60.7%). Independent poor prognostic factors for OS were BR disease (hazard ratio [HR], 1.26 [95% CI, 1.06 to 1.50]), LA disease (HR, 1.71 [95% CI, 1.45 to 2.02]), CA 19-9 >500 U/mL (HR, 1.36 [95% CI, 1.21 to 1.52]), and WHO performance status ≥1 (HR, 1.31 [95% CI, 1.16 to 1.47]). Patients were assigned 1 point for each poor ABC factor and 2 points for LA disease. The median OS for patients with score 0-4 was 49.7, 29.9, 22.0, 19.1, and 14.9 months with corresponding 5-year OS rates of 47.0%, 28.9%, 19.2%, 9.3%, and 4.8%, respectively. CONCLUSION: The ABC factors of tumor anatomy, CA 19-9, and performance status at diagnosis were independent prognostic factors for OS in patients with localized PDAC treated with initial (m)FOLFIRINOX. Staging of patients with localized PDAC at diagnosis should be based on anatomy, CA 19-9, and performance status.

The role of CD56bright NK cells in neurodegenerative disorders.

Emerging evidence suggests a potential role for natural killer (NK) cells in neurodegenerative diseases, such as multiple sclerosis, Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. However, the precise function of NK cells in these diseases remains ambiguous. The existence of two NK cell subsets, CD56bright and CD56dim NK cells, complicates the understanding of the contribution of NK cells in neurodegeneration as their functions within the context of neurodegenerative diseases may differ significantly. CD56bright NK cells are potent cytokine secretors and are considered more immunoregulatory and less terminally differentiated than their mostly cytotoxic CD56dim counterparts. Hence, this review focusses on NK cells, specifically on CD56bright NK cells, and their role in neurodegenerative diseases. Moreover, it explores the mechanisms underlying their ability to enter the central nervous system. By consolidating current knowledge, we aim to provide a comprehensive overview on the role of CD56bright NK cells in neurodegenerative diseases. Elucidating their impact on neurodegeneration may have implications for future therapeutic interventions, potentially ameliorating disease pathogenesis.

The association between weight during early life and multiple sclerosis onset in a nationwide Dutch birth year cohort.

BACKGROUND: The relationship between being overweight during early life and disease course in multiple sclerosis (MS) is unresolved. We investigated the association between being overweight or obese during early life (childhood and adolescence) and MS case status, age of first symptom onset and onset type in people with MS (pwMS) of the same birth year. METHODS: We enrolled 363 PwMS and 125 healthy controls (HC) from Project Y, a Dutch population-based cross-sectional cohort study including all PwMS born in 1966 and age and sex-matched HC. The associations between weight during childhood and adolescence (non-overweight vs. overweight or obese) and MS, age at symptom onset and onset type (relapsing vs. progressive) were assessed using logistic and linear regressions. In addition, sex-separated associations were explored. RESULTS: Being overweight or obese during childhood (OR = 2.82, 95% CI 1.17-6.80) and adolescence (OR = 2.45, 95% CI 1.13-5.34) was associated with developing MS. Furthermore, being overweight or obese during adolescence was associated with a younger age of onset (ß = -0.11, p = 0.041). Of all 47 patients with a primary progressive (PP) onset type, only one patient (2.1%) was overweight or obese during childhood, whereas 45 patients with a relapsing remitting (RR) onset (14.3%) were overweight or obese during childhood (PP vs. RR p = 0.017; PP vs. HC p = 0.676; RR vs. HC, p = 0.015). However, using logistic regression analysis we did not find evidence of a significant association. CONCLUSION: In a nationwide population-based birth year cohort, being overweight or obese during childhood or adolescence is associated with MS prevalence and an earlier age of onset, but does not seem to associate with the type of onset.

The role of diet in multiple sclerosis onset and course: results from a nationwide retrospective birth-year cohort.

OBJECTIVE: To examine (1) the association between childhood diet and developing MS, age of onset and onset type and (2) the association between diet at age 50 and disability and MRI volumes in people with MS (PwMS). METHODS: The study enrolled 361 PwMS born in 1966 and 125 age- and sex-matched healthy controls (HCs). Information on individual dietary components (fruit, vegetables, red meat, oily fish, whole-grain bread and candy, snacks and fast food) and MS risk factors at the age of 10 and 50 years were collected using questionnaires. Overall diet quality score was calculated for each participant. Multivariable regression analyses were used to evaluate the association between diet at childhood and developing MS, age of onset and onset type and to evaluate diet at age 50, disability and MRI outcomes. RESULTS: Poorer overall diet quality and individual dietary components during childhood (less whole-grain bread, more candy, snacks and fast food and oily fish) were associated with developing MS and onset type (all p < 0.05), but not with the age of onset. Fruit consumption at age 50 was associated with lower disability (Q3 vs. Q1: -0.51; 95% CI: -0.89 to -0.13). Furthermore, several individual dietary components at age 50 were associated with MRI volumetric measures. Higher-diet quality at age 50 was only associated with lower lesion volumes in PwMS (Q2 vs. Q1: -0.3 mL; 95% CI: -0.5 to -0.02). INTERPRETATION: We demonstrate significant associations between dietary factors in childhood and developing MS, age of onset and onset type and between dietary factors at age 50 and disability and MRI-derived volumes.

Association of Arachidonic Acid-Derived Lipid Mediators With Disease Severity in Patients With Relapsing and Progressive Multiple Sclerosis.

BACKGROUND AND OBJECTIVES: Excessive activation of certain lipid mediator (LM) pathways plays a role in the complex pathogenesis of multiple sclerosis (MS). However, the relationship between bioactive LMs and different aspects of CNS-related pathophysiologic processes remains largely unknown. Therefore, in this study, we assessed the association of bioactive LMs belonging to the ω-3/ω-6 lipid classes with clinical and biochemical (serum neurofilament light [sNfL] and serum glial fibrillary acidic protein [sGFAP]) parameters and MRI-based brain volumes in patients with MS (PwMS) and healthy controls (HCs). METHODS: A targeted high-performance liquid chromatography-tandem mass spectrometry approach was used on plasma samples of PwMS and HCs of the Project Y cohort, a cross-sectional population-based cohort that contains PwMS all born in 1966 in the Netherlands and age-matched HCs. LMs were compared between PwMS and HCs and were correlated with levels of sNfL, sGFAP, disability (Expanded Disability Status Scale [EDSS]), and brain volumes. Finally, significant correlates were included in a backward multivariate regression model to identify which LMs best related to disability. RESULTS: The study sample consisted of 170 patients with relapsing remitting MS (RRMS), 115 patients with progressive MS (PMS), and 125 HCs. LM profiles of patients with PMS significantly differed from those of patients with RRMS and HCs, particularly patients with PMS showed elevated levels of several arachidonic acid (AA) derivatives. In particular, 15-hydroxyeicosatetraenoic acid (HETE) (r = 0.24, p < 0.001) correlated (average r = 0.2, p < 0.05) with clinical and biochemical parameters such as EDSS and sNfL. In addition, higher 15-HETE levels were related to lower total brain (r = -0.24, p = 0.04) and deep gray matter volumes (r = -0.27, p = 0.02) in patients with PMS and higher lesion volume (r = 0.15, p = 0.03) in all PwMS. DISCUSSION: In PwMS of the same birth year, we show that ω-3 and ω-6 LMs are associated with disability, biochemical parameters (sNfL, GFAP), and MRI measures. Furthermore, our findings indicate that, particularly, in patients with PMS, elevated levels of specific products of the AA pathway, such as 15-HETE, associate with neurodegenerative processes. Our findings highlight the potential relevance of ω-6 LMs in the pathogenesis of MS.

Longitudinal Changes in Cognitive Test Scores in Patients With Relapsing-Remitting Multiple Sclerosis: An Analysis of the DECIDE Dataset.

BACKGROUND AND OBJECTIVES: Cognitive impairment is a common and impactful symptom of relapsing-remitting multiple sclerosis (RRMS). Cognitive outcome measures are often used in cross-sectional studies, but their performance as longitudinal outcome measures in clinical trials is not widely researched. In this study, we used data from a large clinical trial to describe change on the Symbol Digit Modalities Test (SDMT) and the Paced Auditory Serial Addition Test (PASAT) over up to 144 weeks of follow-up. METHODS: We used the data set from DECIDE (clinicaltrials.gov identifier NCT01064401), a large randomized controlled RRMS trial to describe change on the SDMT and PASAT over 144 weeks of follow-up. We compared change on these cognitive outcomes with change on the timed 25-foot walk (T25FW), a well-established physical outcome measure. We investigated several definitions for clinically meaningful change: any change, 4-point change, 8-point change, and 20% change for the SDMT, any change, 4-point change, and 20% change for the PASAT, and 20% change for the T25FW. RESULTS: DECIDE included 1,814 trial participants. SDMT and PASAT scores steadily improved throughout follow-up: the SDMT from a mean 48.2 (SD, 16.1) points at baseline to 52.6 (SD 15.2) at 144 weeks and the PASAT from 47.0 (SD 11.3) at baseline to 50.0 (SD 10.8) at 144 weeks. This improvement in scores is most likely due to a practice effect. Throughout the trial, participants were more likely to experience improvement than worsening of their SDMT and PASAT performance, whereas the number of worsening events on the T25FW steadily increased. Changing the definition of clinically meaningful change for the SDMT and PASAT or using a 6-month confirmation changed the overall number of worsening or improvement events but did not affect the overall behavior of these measures. DISCUSSION: Our findings suggest that the SDMT and PASAT scores do not accurately reflect the steady cognitive decline that people with RRMS experience. Both outcomes show postbaseline increases in scores, which complicates the interpretation of these outcome measures in clinical trials. More research into the size of these changes is needed before recommending a general threshold for clinically meaningful longitudinal change.

Repair what is lost: Neuroprotection through neural stem cells in progressive MS.

Genchi et al.1 report the first phase 1 trial of neural stem cell transplantation in multiple sclerosis showing a reduction in gray matter atrophy. Results give hope for a new era of induced neuroprotection, especially in progressive multiple sclerosis.

Association of volumetric MRI measures and disability in MS patients of the same age: Descriptions from a birth year cohort.

BACKGROUND AND OBJECTIVES: Although MRI-based markers of neuroinflammation have proven crucial for the diagnosis of multiple sclerosis (MS), predicting clinical progression with inflammation remains difficult. Neurodegenerative markers such as brain volume loss show stronger clinical (predictive) correlations, but also harbor age-related variation that must be disentangled from disease duration. In this study we investigated how clinical disability is related to volumetric MRI measures in a cohort of MS patients and healthy controls (HC) of the same age: Project Y. METHODS: This study included 234 MS patients born in 1966 and 112 HC born between 1965 and 1967 in the Netherlands. Disability was quantified using the expanded disability status scale (EDSS), nine hole peg test (9HPT), and timed 25 foot walking test (T25FWT). Volumes were quantified on 3T MRI as normalized whole brain (NBV) and regional gray matter (GM) volumes using the same scanner and MRI protocol: cortical (normalized cortical gray matter volume; NCGMV), deep (NDGMV), thalamic (NThalV), and cerebellar (NCbV) GM volumes. In addition, mean upper cervical cord area (MUCCA), white matter lesion volume (LV), and spinal cord lesions were assessed. These measures were compared between patients and HC, and related to disability measures using linear regression. RESULTS: Mean age of people with MS (PwMS) was 52.8 years (SD 0.9) and median disease duration 15.8 years (IQR 8.7-24.8). All global and regional brain measures were lower in MS patients compared to HC. Univariate regression models showed that NDGMV (ß = -0.20) and MUCCA (ß = -0.38) were most strongly related to the EDSS in all PwMS. After subtype stratification, MUCCA was most strongly related to the EDSS (ß = -0.60) and 9HPT (ß = -0.55) in secondary progressive PwMS. Multivariate regression models demonstrated that in all PwMS, the EDSS was best explained by lower MUCCA, longer disease durations and a progressive disease course (adjusted-R (Sastre-Garriga et al., 2017) = 0.26, p < 0.001). MUCCA was a consistent correlate in separate models of the EDSS for all PwMS, relapsing and progressive onset PwMS. The 9HPT (adjusted-R (Sastre-Garriga et al., 2017) = 0.20, p < 0.001) was best explained by lower MUCCA, higher LV and pack years, while lower limb disability (adjusted-R (Sastre-Garriga et al., 2017) = 0.11, p < 0.001) was best explained by lower MUCCA, progressive onset MS and female sex. DISCUSSION: Our results indicate that in a cohort unbiased by age differences, spinal cord and deep gray matter volumes best related to physical disability. Our results support the use of these measures in clinical practice and trials.

Isolated neurological presentations of mevalonate kinase deficiency.

Mevalonate kinase (MK) deficiency is a rare autosomal recessive metabolic disorder caused by pathogenic variants in the MVK gene with a broad phenotypic spectrum including autoinflammation, developmental delay and ataxia. Typically, neurological symptoms are considered to be part of the severe end of the phenotypical spectrum and are reported to be in addition to the autoinflammatory symptoms. Here, we describe a patient with MK deficiency with severe neurological symptoms but without autoinflammation and we found several similar patients in the literature. Possibly, the non-inflammatory phenotype is related to a specific genotype: the MVK p.(His20Pro)/p.(Ala334Thr) variant. There is probably an underdetection of the neurological MK deficient phenotype without inflammatory symptoms as clinicians may not test for MK deficiency when patients present with only neurological symptoms. In conclusion, although rare, neurological symptoms without hyperinflammation might be more common than expected in MK deficiency. It seems relevant to consider MK deficiency in patients with psychomotor delay and ataxia, even if there are no inflammatory symptoms.

Decrease of natalizumab drug levels after switching from intravenous to subcutaneous administration in patients with multiple sclerosis.

BACKGROUND: Natalizumab is effective in the treatment of multiple sclerosis (MS). In 2021, the European Medicines Agency approved the subcutaneous (SC) variant of natalizumab which can be used instead of intravenous administration. However, the course of drug levels varies between administration routes, and the Food and Drug Administration rejected the request for approval of natalizumab SC for reasons that were not disclosed. Our objective was to evaluate the course of natalizumab trough drug levels in patients who switched from natalizumab intravenous to SC on various treatment intervals. METHODS: The NEXT-MS trial (N=382) investigates personalised treatment of natalizumab, in which infusion intervals are prolonged based on individual natalizumab trough drug levels. In 2021, an amendment was approved allowing participants to switch from intravenous to SC administration with frequent measurements of natalizumab drug levels and antidrug antibodies (ADAs). Results were compared with linear mixed model analyses. RESULTS: Until December 2022, 15 participants switched to SC natalizumab. Natalizumab drug levels with SC administration were on average 55% lower compared with intravenous administration (Exp (estimate) 0.45, 95% CI 0.39 to 0.53, p<0.001), leading to very low trough drug levels in three patients on extended treatment intervals. No natalizumab ADAs were detected during intravenous or SC treatment. None of the participants on natalizumab SC showed evidence of MS disease activity. CONCLUSIONS: Natalizumab trough drug levels can decrease after switching from natalizumab intravenous to SC administration. We advise to monitor trough drug levels in patients with low natalizumab drug levels during intravenous treatment, patients with higher body mass index or patients on extended treatment intervals who switch to SC administration of natalizumab.

Ocrelizumab concentration and antidrug antibodies are associated with B-cell count in multiple sclerosis.

BACKGROUND: The majority of patients with multiple sclerosis on ocrelizumab have B-cell depletion after standard interval dosing of 26 weeks. With B-cell-guided dosing patients receive their next dose when B-cell repopulation occurs. Prediction of B-cell repopulation using ocrelizumab concentrations could aid in personalising treatment regimes. The objectives of this study were to evaluate the association between ocrelizumab drug concentration, antidrug antibodies (ADAs) and CD19 B-cell count, and to define a cut-off ocrelizumab concentration for start of B-cell repopulation (defined by ≥10 CD19+ B cells/µL). METHODS: In this investigator-initiated prospective study, blood samples at various time points during ocrelizumab treatment were collected from a biobank. Serum ocrelizumab concentrations and ADAs were measured with two different assays developed for this study. Data were analysed using linear mixed effect models. An receiver operating characteristic (ROC) curve was used to determine a cut-off ocrelizumab concentration for start of B-cell repopulation (defined by ≥10 cells/µL). RESULTS: A total of 452 blood samples from 72 patients were analysed. Ocrelizumab concentrations were detectable up until 53.3 weeks after last infusion and ranged between <0.0025 and 204 µg/mL after 1-67 weeks. Ocrelizumab concentration was negatively associated with B-cell count, with body mass index identified as effect modifier. We found a cut-off value of 0.06 µg/mL for start of B-cell repopulation of ≥10 cells/µL. Ocrelizumab ADAs were detectable in four patients (5.7%) with corresponding low ocrelizumab concentrations and start of B-cell repopulation. CONCLUSIONS: Serum ocrelizumab concentration was strongly associated with B-cell count. Measurement of ocrelizumab drug concentrations and ADAs could play an important role to further personalise treatment and predict the start of B-cell repopulation.

Neuroaxonal and Glial Markers in Patients of the Same Age With Multiple Sclerosis.

BACKGROUND AND OBJECTIVES: The specificity of novel blood biomarkers for multiple sclerosis (MS)-related neurodegeneration is unclear because neurodegeneration also occurs during normal aging. To understand which aspects of neurodegeneration the serum biomarkers neurofilament light (sNfL), serum glial fibrillary acidic protein (sGFAP), and serum contactin-1 (sCNTN1) reflect, we here explore their cross-sectional association with disability outcome measures and MRI volumes in a unique cohort of people with MS (PwMS) of the same age. METHODS: sNfL, sGFAP (both singe-molecule array technology) and sCNTN1 (Luminex) were measured in serum samples of 288 PwMS and 125 healthy controls (HCs) of the Project Y cohort, a population-based cross-sectional study of PwMS born in the Netherlands in 1966 and age-matched HC. RESULTS: sNfL (9.83 pg/mL [interquartile range {IQR}: 7.8-12.0]) and sGFAP (63.7 pg/mL [IQR: 48.5-84.5]) were higher in PwMS compared with HC (sNfL: 8.8 pg/mL [IQR: 7.0-10.5]; sGFAP: 51.7 pg/mL [IQR: 40.1-68.3]) (p < 0.001), whereas contactin-1 (7,461.3 pg/mL [IQR: 5,951.8-9,488.6]) did not significantly differ between PwMS compared with HC (7,891.2 pg/mL [IQR: 6,120.0-10,265.8]) (p = 0.068). sNfL and sGFAP levels were 1.2-fold higher in secondary progressive patients (SPMS) compared with relapsing remitting patients (p = 0.009 and p = 0.043). Stratified by MS subtype, no relations were seen for CNTN1, whereas sNfL and sGFAP correlated with the Expanded Disability Status Scale (ρ = 0.43 and ρ = 0.39), Nine-Hole Peg Test, Timed 25-Foot Walk Test, and Symbol Digit Modalities Test (average ρ = 0.38) only in patients with SPMS. Parallel to these clinical findings, correlations were only found for sNfL and sGFAP with MRI volumes. The strongest correlations were observed between sNfL and thalamic volume (ρ = -0.52) and between sGFAP with deep gray matter volume (ρ = - 0.56) in primary progressive patients. DISCUSSION: In our cohort of patients of the same age, we report consistent correlations of sNfL and sGFAP with a range of metrics, especially in progressive MS, whereas contactin-1 was not related to clinical or MRI measures. This demonstrates the potential of sNfL and sGFAP as complementary biomarkers of neurodegeneration, reflected by disability, in progressive MS.

Adipokines in multiple sclerosis patients are related to clinical and radiological measures.

BACKGROUND: An imbalance of adipokines, hormones secreted by white adipose tissue, is suggested to play a role in the immunopathology of multiple sclerosis (MS). In people with MS (PwMS) of the same age, we aimed to determine whether the adipokines adiponectin, leptin, and resistin are associated with MS disease severity. Furthermore, we aimed to investigate whether these adipokines mediate the association between body mass index (BMI) and MS disease severity. METHODS: Adiponectin, resistin, and leptin were determined in serum using ELISA. 288 PwMS and 125 healthy controls (HC) were included from the Project Y cohort, a population-based cross-sectional study of people with MS born in the Netherlands in 1966, and age and sex-matched HC. Adipokine levels and BMI were related to demographic, clinical and disability measures, and MRI-based brain volumes. RESULTS: Adiponectin levels were 1.2 fold higher in PwMS vs. HC, especially in secondary progressive MS. Furthermore, we found a sex-specific increase in adiponectin levels in primary progressive (PP) male patients compared to male controls. Leptin and resistin levels did not differ between PwMS and HC, however, leptin levels were associated with higher disability (EDSS) and resistin strongly related to brain volumes in progressive patients, especially in several grey matter regions in PPMS. Importantly, correction for BMI did not significantly change the results. CONCLUSION: In PwMS of the same age, we found associations between adipokines (adiponectin, leptin, and resistin) and a range of clinical and radiological metrics. These associations were independent of BMI, indicating distinct mechanisms.