Natalizumab (NTZ) effectively suppresses clinical and radiologic disease activity in paediatric patients with multiple sclerosis (MS), however, it is unclear whether serum neurofilament light chain (sNfL), a biomarker of neuronal injury, normalizes. To evaluate sNfL response to NTZ in the paediatric setting. sNfL was measured (single-molecule array) in 66 paediatric patients on NTZ for highly active MS in a single-centre between 2007 and 2023. sNfL levels were converted to age-adjusted z-scores for longitudinal assessment. sNfL declined significantly on NTZ, however, not all patients achieved normalized levels. Percentage of patients with sNfL < 90th percentile of healthy aged-matched individuals increased from 6.8% initially to 50%, 65% and 75% within 12, 24 and 36 treatment-months, respectively. Higher on-treatment levels were associated with higher baseline levels (B = 0.791, p < 0.001) and John Cunningham virus (JCV) seropositivity (B = 0.286, p < 0.001). sNfL > 97th percentile at 12 treatment-months indicated greater likelihood of disease activity in following year. NTZ treatment resulted in a significant reduction in sNfL levels, correlating with its clinical efficacy in paediatric MS. However, higher baseline sNfL concentrations were associated with a prolonged time to normalization. In addition, JCV seropositivity was linked to elevated NfL levels during treatment.

Integrin alpha 4 inhibition prolongs the survival of NSG mice engrafted with CD19-negative post-CART19 relapsed B-ALL.

NG2-ITGA4 axis regulates Rho GTPases and leukemic aggressiveness in KMT2A-r B-ALL and is targetable with natalizumab.

Real-world cost of disease-modifying treatments administered by intravenous infusion in relapsing-remitting multiple sclerosis patients from Argentina.

Risk of postpartum disease activity with subcutaneous versus intravenous Natalizumab in pregnant women with multiple sclerosis.

Clinical, biological and radiological data that may help in predicting and managing the Progression Independent of Relapse and MRI Activity (PIRMA) in multiple sclerosis (MS). We designed a retrospective, longitudinal study to identify prognostic factors of PIRMA in natalizumab (NTZ) treated patients with MS (pwMS). Clinical and radiological data from pwMS starting NTZ in the period July 2007 to February 2017 were retrospectively collected. 238 patients (age of 29.1 ± 8.5 years) were followed up for 5.5 ± 4.3 years. PIRMA was observed in 70 patients (29.4%). PIRMA was predicted by both EDSS (Cox regression analysis: H.R.= 1.7, p < 0.0001) and disease duration at NTZ first administration (H.R.= 1.0, p = 0.025). Combining disease duration (138 months) and EDSS (4.0) cut-offs, pwMS with lower and disease duration had lower probability of PIRMA compared to patients with 1 risk factor (disease duration ≥138 months or EDSS ≥ 4, H.R. 5.321, 95%IC 2.943 - 9.622, p < 0.0001) or 2 risk factors (H.R. 6.100, 95%IC 2.100 - 17.730, p < 0.0001). To evaluate the effect of age on PIRMA, we focused the analysis on patients that reached at least the age of 45 during the follow-up (age at follow-up end: 51.8 ± 5.7; range: 45-75). Higher baseline EDSS was independently associated with an increased risk of PIRMA (HR 1.65, 95% CI 1.24-2.24, p = 0.0005). Conversely, older age at natalizumab initiation was associated with a lower risk of PIRMA (HR 0.87 per year, 95% CI 0.81-0.95, p = 0.0007). PIRMA was identified as the main driver of disability progression in RRMS treated with NTZ and is predicted by disease duration and EDSS at therapy initiation.

JC virus (JCV) reactivation causing progressive multifocal leukoencephalopathy (PML) is a complication in patients with multiple sclerosis (MS) treated with disease-modifying therapies (DMTs). Although natalizumab (NTZ) is most frequently involved, PML also occurs less commonly with sphingosine-1-phosphate receptor modulators (S1P-RM), dimethyl fumarate (DMF), and ocrelizumab. This study aimed to identify factors predicting worse outcomes, focusing on the influence of PML-immune reconstitution inflammatory syndrome (PML-IRIS), plasma exchange (PlEx), corticosteroids, and DMT reintroduction. This retrospective multicenter cohort study analyzed patients with MS who had JCV-associated pathology (PML or granule cell neuronopathy) from 42 centers (2009-2022). The primary outcome was disability at 12 months, measured by the modified Rankin Scale (mRS). Multivariable analyses identified predictors of poor outcomes, PML-IRIS development, and recurrent MS activity. Of 96 identified patients, 94 were analyzed. Most cases occurred under NTZ (77%), followed by S1P-RM (22%) and DMF (1%). Twelve-month survival was 91.5%, with a median mRS of 3 [IQR: 2-4]. Multivariable analysis showed that higher pre-PML disability (OR: 1.95 [95% CI 1.46-2.60], p < 0.001), elevated CSF JCV viral load (OR: 2.45 [95% CI 1.55-3.87], p < 0.001), and symptomatic presentation at onset (OR: 3.93 [95% CI 1.23-12.55], p = 0.021) were associated with worse outcomes. Conversely, PML-IRIS was associated with better outcomes (OR: 0.28 [95% CI 0.09-0.86], p = 0.025). PlEx and corticosteroid use had no negative effect. This study provides valuable insights into the management of iatrogenic PML in patients with MS. The findings may guide clinicians in making informed decisions, particularly regarding the use of PlEx, corticosteroids, and the management of PML-IRIS.

Pediatric-onset multiple sclerosis (POMS) is the onset of MS before the age of 18 and accounts for 3%-5% of all multiple sclerosis (MS) cases. Natalizumab (NTZ) is among the higher-efficacy disease-modifying treatments (HETs) in MS and is increasingly used for POMS. In this systematic review and meta-analysis, we aimed to discuss the debate on the efficacy and safety of natalizumab use in POMS, providing quantitative results on relapse rate, disability progression, adverse events (AEs), and JC virus seropositivity. The primary endpoint for meta-analysis was the mean difference (MD) in annualized relapse rate (ARR) after natalizumab compared to before treatment. Secondary outcomes were the MD of Expanded Disability Status Scale (EDSS) and the proportion of POMS patients experiencing AEs and JC virus seropositivity after natalizumab treatment. We performed a comprehensive search of PubMed, Embase, Web of Science, and Scopus between January 1, 1991 and May 1, 2025. In this systematic review, 18 non-randomized interventional studies including 922 patients with POMS were included. Natalizumab therapy was associated with a mean reduction in ARR of -1.962 relapses per patient-year from baseline (95% confidence interval (CI): -2.449 to -1.475; p < 0.001). The drug was also associated with a statistically significant improvement in disability, with a mean change in EDSS of -0.807 from baseline (95% CI: -1.078 to -0.536; p < 0.001). After treatment, 18% of patients experienced AEs (95% CI: 0.11-0.25), and JC virus seropositivity was observed in 12% (95% CI: 0.07-0.17). No case of progressive multifocal leukoencephalopathy was reported among the 922 natalizumab-treated patients. Natalizumab may represent a viable therapeutic option for POMS patients exhibiting highly active disease or serves as an effective alternative in those with inadequate response to initial treatment. The safety profile remains acceptable, with most AEs being manageable. PROSPERO (CRD42024583911). This study follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses reporting guidelines.

Cerebrospinal fluid (CSF) kappa free light chains (KFLC) is a sensitive marker of intrathecal immunoglobulin synthesis and is incorporated into the 2024 McDonald criteria for multiple sclerosis (MS). How disease-modifying therapies (DMTs) influence KFLC dynamics and their association with treatment response remains unclear. To determine whether intrathecal KFLC synthesis changes during DMT and whether these changes are associated with clinical outcomes. Patients with treatment-naïve relapsing-remitting MS were prospectively enrolled at the Sahlgrenska MS Center (Gothenburg, Sweden). Paired CSF and serum samples were collected at baseline and after 12 months of treatment with dimethyl fumarate (DMF) or natalizumab (NTZ). KFLC index was calculated as [(CSF KFLC/serum KFLC)/(CSF albumin/serum albumin)]. Treatment response was assessed using no evidence of disease activity-3 (NEDA-3) and progression independent of relapse and MRI activity (PIRMA+). Forty-eight patients were included (DMF n = 26, NTZ n = 22). NTZ reduced KFLC index from a median 117.4 (63.6-171.9) at baseline to 78.8 (39.4-104.0) at 12 months (adjusted p = 0.003), corresponding to a median decline of -51.0 (IQR -82.1 to -24.7), whereas DMF produced no meaningful change. In NTZ-treated patients maintaining NEDA-3 or without PIRMA+, KFLC index declined markedly (both p < 0.01). Change in KFLC index predicted outcomes, yielding an AUC of 1.0 for NEDA-3 and 0.79 for non-PIRMA+. Natalizumab appears to reduce intrathecal KFLC synthesis, and a decline in KFLC index may reflect effective suppression of CNS humoral immunity. ΔKFLC index could serve as a sensitive biomarker of treatment response and disease stability in MS.

Approximately half of patients with relapsing-remitting multiple sclerosis treated with natalizumab (NTZ) report transient symptom worsening - particularly fatigue - toward the end of the dosing interval. This phenomenon, commonly referred to as the wearing-off effect (WOE), has been hypothesized to result from a decrease in α4-integrin receptor saturation on circulating leucocytes. However, existing evidence is inconsistent, considering either small samples studied or conflicting results derived from previous studies. Our study aimed to investigate the association between α4-integrin receptor saturation and the WOE in a large prospective cohort of NTZ treated patients. We conducted a prospective observational study collecting demographic and clinical data, including WOE assessment via a structured questionnaire, treatment interval data, and α4-integrin receptor saturation levels across T-lymphocyte subset. Among 117 participants, 57.3 % reported experiencing WOE. WOE was significantly associated with higher disability (EDSS score) and longer NTZ treatment duration. However, no significant correlation was found between WOE and α4-integrin receptor saturation in any T-lymphocyte subset. Our findings suggest that WOE is not related to reduced α4-integrin receptor saturation and thus does not reflect diminished pharmacodynamic efficacy of NTZ. These results provide reassurance regarding the continued therapeutic effect of NTZ in patients experiencing WOE.

Influence of FCGR2A (rs1801274) and FCGR3A (rs396991) polymorphisms on natalizumab response on multiple sclerosis.

BackgroundIn January 2024, all people with multiple sclerosis (pwMS) treated with natalizumab (NTZ) at Oslo University Hospital were switched from originator to biosimilar NTZ. We prospectively evaluated disease activity, safety, serum drug levels, immunogenicity and biomarkers.MethodsThis observational study included 39 pwMS switching to biosimilar NTZ. Clinical relapses, MRI activity and side effects were recorded. NTZ levels and anti-drug antibodies (ADAb) by in-house assays; anti-John Cunningham virus (JCV) antibodies by Stratify (Biogen) and Immunowell (Sandoz) platforms; leucocytes and serum levels of neurofilament light chain (NfL) and glial fibrillar acidic protein (GFAP) were measured by Mesoscale platform.ResultsEleven pwMS (28%) reported new side effects, most commonly fatigue, headache and muscle pain. Mean NTZ levels were 15.1 mg/L before and 14.9 mg/L after switching (difference –0.3, 95% CI –1.4 to 0.8). ADAb was detected in one pwMS, unchanged after switch. The proportion of JCV-positive cases increased from 13% (Stratify) to 52% (Immunowell), leading four pwMS to discontinue NTZ. Leukocytes were stable after switch. Median NfL remained stable (45.3 vs 44.0 pg/mL; median difference –1.3, 95% CI –6.0 to 3.5), whereas GFAP decreased (23.0 vs 20.5 pg/mL; difference –2.5, 95% CI –4.7 to –0.3).ConclusionsSwitching from originator to biosimilar NTZ was associated with stable disease activity. Drug levels, ADAb, leukocytes and NfL remained similar before and after switching, and GFAP decreased, of uncertain relevance. The marked rise in JCV-positivity on the Immunowell assay underscores the need for harmonisation of anti-JCV antibody testing.

Natalizumab (NTZ) is a high-efficacy therapy for relapsing-remitting multiple sclerosis (RRMS) that blocks peripheral immune cell migration into the central nervous system. While short-term NTZ treatment reduces cerebrospinal fluid (CSF) inflammation, the extent of residual intrathecal inflammation after long-term NTZ treatment and its association with oligoclonal band (OCB) status remains unclear. In this study, we examined associations between NTZ treatment duration, OCB status and CSF inflammatory and tissue biomarkers as well as presence of residual intrathecal inflammation after more than five years of NTZ treatment. In this cross-sectional observational study, fifteen inflammatory and tissue biomarkers were reliably measured in CSF using validated immunoassays or extracted from clinical records of 88 NTZ-treated RRMS and 104 untreated RRMS patients as well as 94 controls. Compared to untreated RRMS patients, most CSF biomarkers were significantly lower in NTZ-treated and controls (Bonferroni-adjusted p (adj-p) < 0.05). However, soluble B cell maturation antigen (sBCMA), soluble CD27 (sCD27), chitotriosidase-1 (CHIT1), IgG index and interleukin-10 (IL-10) were higher in NTZ-treated compared to controls (adj-p < 0.05). NTZ treatment duration was inversely associated with sCD27 levels, and a positive OCB status was associated with higher sCD27 and IgG index (adj-p < 0.05). In patients treated with NTZ for more than five years (n = 41), levels of sCD27, IgG index and sBCMA were higher in OCB-positive patients (adj-p < 0.05), but not in OCB-negative, compared to age-matched controls. Natalizumab treatment reduces CSF inflammation biomarkers, but after more than five years of treatment levels of sCD27, sBCMA and IgG index remain significantly above control levels in OCB-positive NTZ-treated patients. This indicates residual intrathecal adaptive immune activation in OCB-positive NTZ-treated RRMS patients, suggesting that compartmentalized adaptive inflammation in RRMS is incompletely suppressed by NTZ.

Maternal and neonatal outcomes associated with natalizumab exposure during pregnancy in Iranian patients with multiple sclerosis.

Epstein-Barr virus (EBV) may be crucial for development of multiple sclerosis (MS). EBV encodes 44 microRNAs (miRNAs) that are found in exosomes. We investigated EBV miRNAs in cerebrospinal fluid (CSF) exosomes in 50 newly diagnosed people with relapsing-remitting MS (pwRRMS), 24 with clinically isolated syndromes (CIS), 45 symptomatic controls (SC), 15 anti-CD20 antibody-treated 24 natalizumab (NTZ)-treated pwRRMS. miRNAs were measured by quantitative PCR. Plasma anti-EBNA1 antibody and various CSF biomarkers were measured by immunoassays. ebv-miR-BART13-5p and ebv-miR-BART19-3p were reliably measured. ebv-miR-BART19-3p was lower in pwRRMS and correlated with disease severity. In NTZ-treated pwRRMS, ebv-miR-BART19-3p was higher, correlated with treatment duration, and was associated with soluble B-cell maturation antigen, CD27, and zonula occludens-1. No differences were observed in anti-CD20 antibody-treated pwRRMS. These findings may reflect the presence of more exosome recipient cells in pwRRMS, resulting in fewer exosomes as they become internalized in recipient cells along with their EBV miRNA cargo.

To investigate whether the VIAADISC score predicts disease reactivation in relapsing multiple sclerosis (RMS) after de-escalation/discontinuation of disease-modifying-therapy (DMT) METHODS: We included RMS patients who i) received any DMT other than interferon-beta or glatiramer-acetate ≥12 months, ii) de-escalated/discontinued DMT, iii) had MRI before de-escalation/discontinuation, and iv) had ≥12 months of follow-up. VIAADISC score (0-6; age <45/45-54/≥55 = 2/1/0 points, MRI activity = 2 points, duration without clinical disease activity <4/4-8/>8 years = 2/1/0 points) was calculated. The primary endpoint was disease reactivation (relapse and/or disability progression). Of 129 RMS patients included (65.1 % females), 44.2 % had received natalizumab (NTZ), 19.4 % dimethylfumarate (DMF), 17.1 % teriflunomide (TERI), 14.0 % fingolimod (FTY) and 5.4 % rituximab (RTX). At de-escalation/discontinuation, mean age was 44.3 years (12.3), median duration of clinical stability 2.4 years (IQR1.5-3.9) and 93.1 % were without MRI activity, resulting in median VIAADISC score of 3 (IQR 2-4). Over median 6.0 years, disease reactivation reoccurred in 55.0 %, most frequently after NTZ/FTY discontinuation (73.3 %). In Cox regression, risk of disease reactivation was independently predicted by higher VIAADISC scores (HR 1.25 per point [95 % CI 1.03-1.53], p = 0.028) and de-escalation from FTY/NTZ (HR 2.20 [CI 1.18-4.10], p = 0.013). No disease reactivation was observed when DMF/TERI were discontinued with VIAADISC <2. Risk of disease reactivation after discontinuation from DMF/TERI can be stratified with the VIAADISC score and appears to be safe above age 45-55 and with long-lasting stability. However, risk after de-escalation from NTZ/FTY is too high to allow reliable stratification and should be avoided by lateral switch.

Fatigue in natalizumab-treated Multiple Sclerosis patients: How much is wearing-off to blame?

Some people with multiple sclerosis (PwMS) exhibit reduced serum immunoglobulin (Ig) levels, potentially due to disease-modifying therapies (DMTs), which raises concerns about initiating anti-CD20 therapies. We assessed the frequency of hypogammaglobulinemia in PwMS who previously received non-anti-CD20 DMTs and evaluated short-term Ig level changes after switching to rituximab (RTX) or ocrelizumab (OCR). This retrospective study included PwMS starting RTX or OCR, with or without prior DMT exposure. Patients were grouped as treatment-naïve or receiving fingolimod (FING), natalizumab (NTZ), or moderate-efficacy DMTs (interferons, glatiramer acetate, dimethyl fumarate, or teriflunomide) before the switch. Among 417 included patients, 89 were treatment-naïve, 207 had received FING, 70 NTZ, and 51 moderate-efficacy DMTs. Before switching, hypogammaglobulinemia (IgG level <7 ​g/L) was rare in treatment-naïve and moderate-efficacy DMT groups (2 ​%) but more frequent after FING (29 ​%) and NTZ (14 ​%) treatment. One year after initiating RTX/OCR, IgG level slightly decreased in treatment-naïve patients (p ​< ​0.05), remained stable in NTZ and moderate-efficacy DMT groups, and increased significantly in FING-treated patients (8.0–8.6 ​g/L, p ​< ​0.0001), with a decline in hypogammaglobulinemia prevalence (29 ​%–21.5 ​%). FING exposure was associated with frequent IgG hypogammaglobulinemia, but switching to RTX/OCR was not linked to a short-term decrease in IgG level; instead, it led to a significant increase in level. These findings support that hypogammaglobulinemia should not be an absolute contraindication to switching to RTX/OCR after FING discontinuation given their efficacy in preventing MS reactivation. A secondary de-escalation strategy may be considered based on individual risk profiles and IgG level trajectories.

Ofatumumab (OFA), a fully human anti-CD20 monoclonal antibody, has shown promising efficacy in treating relapsing multiple sclerosis (RMS) by depleting B cells and reducing disease activity. This real-world, prospective, multicenter study evaluated the effectiveness and safety of OFA in treatment-naïve patients and those transitioning from other disease-modifying therapies (DMTs), including natalizumab (NTZ). RRMS patients initiating OFA at seven MS centers in Sicily and treated for at least 12 months were analyzed. Outcomes included annualized relapse rates (ARR), Expanded Disability Status Scale (EDSS), and the percentage of patients free from relapse, MRI activity, and confirmed EDSS worsening (CEW). Of 213 patients, 66 (30.9 ​%) were naïve and 147 (69.1 ​%) were switchers. At 12 months, both groups showed comparable CEW-free (93.9 ​% vs. 93.8 ​%), relapse-free (92.4 ​% vs. 93.2 ​%), and MRI activity-free (84.8 ​% vs. 85.0 ​%) proportions. Within the high-efficacy group, NTZ-switchers showed significantly better MRI outcomes than those switching from other agents, while CEW-free and relapse-free rates remained similar. OFA was well tolerated with no serious adverse events. Predictors of non-response included high baseline MRI activity, disease duration >10 years, and prior NTZ and non-NTZ high-efficacy DMTs. These findings support OFA as a safe and effective option for RRMS across patient subtypes.

Natalizumab (NTZ) is a highly effective multiple sclerosis (MS) treatment but carries a high risk of progressive multifocal leukoencephalopathy in JCV-positive patients. Switching to other therapies is sometimes necessary despite the risk of increasing disease activity, even with other highly effective treatments, such as anti-CD20 therapies. To evaluate anti-CD20 therapies effectiveness after NTZ discontinuation. A retrospective study including MS patients who switched NTZ to anti-CD20 therapies: rituximab (RTX), ocrelizumab (OCR), and ofatumumab (OFA). Demographic, clinical, and safety data were analyzed. We included 59 patients (41 female). Mean disease duration at data collection was 7,88 ± 6,62 years. The main reason for NTZ discontinuation was safety concerns related to JCV seroconversion and serum titer increase (n = 52). RTX patients had significantly longer and more active disease before transition. Comparing annualized relapse rate (ARR) and EDSS before and after switch, RTX significantly reduced ARR (0,65 vs 0,08; p = 0007) but led to a significant EDSS increase (3,65 vs 4,15; p = 0022). No significant changes were observed for OCR and OFA. ARR reduction was greater with RTX than OCR and OFA (p = 0018), though EDSS variation did not differ. Survival analysis showed no difference in time to disease activity between groups. In this cohort, 70 % of disability progression was due to progression independent of relapse activity (PIRA). Anti-CD20 therapies appear to be a safe option after NTZ discontinuation, with no rebound disease and stable EDSS. PIRA was the main driver for disability progression, emphasizing the need to control smoldering disease.