Pharmacogenomics of clinical response to Natalizumab in multiple sclerosis: a genome-wide multi-centric association study.

BACKGROUND: Inter-individual differences in treatment response are marked in multiple sclerosis (MS). This is true for Natalizumab (NTZ), to which a subset of patients displays sub-optimal treatment response. We conducted a multi-centric genome-wide association study (GWAS), with additional pathway and network analysis to identify genetic predictors of response to NTZ. METHODS: MS patients from three different centers were included. Response to NTZ was dichotomized, nominating responders (R) relapse-free patients and non-responders (NR) all the others, over a follow-up of 4 years. Association analysis on ~ 4.7 M imputed autosomal common single-nucleotide polymorphisms (SNPs) was performed fitting logistic regression models, adjusted for baseline covariates, followed by meta-analysis at SNP and gene level. Finally, these signals were projected onto STRING interactome, to elicit modules and hub genes linked to response. RESULTS: Overall, 1834 patients were included: 119 from Italy (R = 94, NR = 25), 81 from Germany (R = 61, NR = 20), and 1634 from Sweden (R = 1349, NR = 285). The top-associated variant was rs11132400T (p = 1.33 × 10-6, OR = 0.58), affecting expression of several genes in the locus, like KLKB1. The interactome analysis implicated a module of 135 genes, with over-representation of terms like canonical WNT signaling pathway (padjust = 7.08 × 10-6). Response-associated genes like GRB2 and LRP6, already implicated in MS pathogenesis, were topologically prioritized within the module. CONCLUSION: This GWAS, the largest pharmacogenomic study of response to NTZ, suggested MS-implicated genes and Wnt/ß-catenin signaling pathway, an essential component for blood-brain barrier formation and maintenance, to be related to treatment response.

Enhanced and cross-reactive in vitro memory B cell response against Epstein-Barr virus nuclear antigen 1 in multiple sclerosis.

Multiple sclerosis (MS) is a prototypical autoimmune disease of the central nervous system (CNS). In addition to CD4+ T cells, memory B cells are now recognized as a critical cell type in the disease. This is underlined by the fact that the best-characterized environmental risk factor for MS is the Epstein-Barr virus (EBV), which can infect and persist in memory B cells throughout life. Several studies have identified changes in anti-EBV immunity in patients with MS. Examples include elevated titers of anti-EBV nuclear antigen 1 (EBNA1) antibodies, interactions of these with the MS-associated HLA-DR15 haplotype, and molecular mimicry with MS autoantigens like myelin basic protein (MBP), anoctamin-2 (ANO2), glial cell adhesion molecule (GlialCAM), and alpha-crystallin B (CRYAB). In this study, we employ a simple in vitro assay to examine the memory B cell antibody repertoire in MS patients and healthy controls. We replicate previous serological data from MS patients demonstrating an increased secretion of anti-EBNA1380-641 IgG in cell culture supernatants, as well as a positive correlation of these levels with autoantibodies against GlialCAM262-416 and ANO21-275. For EBNA1380-641 and ANO21-275, we provide additional evidence suggesting antibody cross-reactivity between the two targets. Further, we show that two efficacious MS treatments - natalizumab (NAT) and autologous hematopoietic stem cell transplantation (aHSCT) - are associated with distinct changes in the EBNA1-directed B cell response and that these alterations can be attributed to the unique mechanisms of action of these therapies. Using an in vitro system, our study confirms MS-associated changes in the anti-EBNA1 memory B cell response, EBNA1380-641 antibody cross-reactivity with ANO21-275, and reveals treatment-associated changes in the immunoglobulin repertoire in MS.

Comparative efficacy of subcutaneous versus intravenous natalizumab on annualized relapse rate: A post-hoc analysis of the REFINE study.

BACKGROUND: The non-inferiority of the efficacy of subcutaneous (SC) vs intravenous (IV) administration of natalizumab (NTZ) once every 4 weeks in relapsing-remitting multiple sclerosis (RRMS) was recently demonstrated on the primary outcome of the REFINE study, i.e. MRI "combined unique active lesions number" (CUAL). To provide further evidence on the comparative efficacy of the two NTZ formulations, the effect of NTZ-SC vs NTZ-IV on annualized relapse rate (ARR) was investigated re-analysing the REFINE dataset. METHODS: Post-hoc analysis of the REFINE study dataset aimed at exploring the non-inferiority of the efficacy of NTZ-SC vs NTZ-IV on ARR, i.e. the main secondary outcome of the REFINE study. Robustness of the non-inferiority analysis on CUAL with respect to the presence of cases from the SC arm who received a rescue treatment, including NTZ-IV, was also assessed by sensitivity analyses. Three non-inferiority margins were selected, corresponding to 25 %, 33 %, and 50 % fractions of the effect size of NTZ-IV vs placebo observed in the AFFIRM study on ARR (i.e. 0.125, 0.170, and 0.250). RESULTS: Ninety-nine RRMS patients were included. The mean difference in the effect of NTZ-SC vs NTZ-IV on ARR was close to 0. The lower bound of the 95 % confidence interval (worst case scenario) was -0.119, corresponding to 25 % (p = 0.025) of the effect of NTZ-IV vs placebo on ARR. Sensitivity analyses confirmed the results of the primary non-inferiority analysis on the outcome CUAL. CONCLUSIONS: NTZ-SC resulted not inferior to NTZ-IV on ARR for all the non-inferiority margins. The non-inferiority analysis of the efficacy of NTZ-SC vs NTZ-IV on CUAL was demonstrated to be robust with respect to rescued patients.

[Old and New Biologics and Small Molecules in Inflammatory Bowel Disease: Anti Integrins].

Recently, novel biologics or small molecular drugs have been introduced for overcoming the unmet needs associated with anti-tumor necrosis factor α agents for inflammtory bowel disease (IBD) treatment. Among these novel drugs, anti integrin agents block leukocyte trafficking to the intestine by blocking the interaction between integrin and cell adhesion molecules. Vedolizumab (anti-α4ß7) is most widely used anti-integrin approved in both ulcerative colitis and Crohn's disease .It has been shown to be effective in both induction and maintenance therapy with a favorable safety profile due to gut selectivity. Several models incorporating clinical, genetic, immune and gut microbial markers to predict response to vedolizumab in IBD have been developed. Etrolizumab (anti-ß7) blocks leukocyte trafficking via α4ß7 and cell adhesion via αEß7 integrins. In addition, the introduction of subcutaneous vedolizumab showed similar efficacy and safety with improved patients' convenience. Other investigational anti-integrin therapies include abrilumab (anti-α4ß7 IgG2), PN-943 (orally administered and gut-restricted α4ß7 antagonist peptide), AJM300 (orally active small molecule inhibitor of α4), and ontamalimab (anti-MAdCAM-1 IgG).

Subcutaneous administration of natalizumab can lead to lower drug concentrations compared to intravenous administration.

BACKGROUND: Several studies reported lower drug concentrations with subcutaneous natalizumab compared to intravenous natalizumab. With the emergence of extended interval dosing, gaining more insight into lower concentrations after subcutaneous administration is essential. METHODS: We compared serum trough concentrations between subcutaneous and intravenous administration within a matched cohort (n = 50). RESULTS: Subcutaneous administration (n = 25) was associated with lower concentrations compared to intravenous administration (n = 25) (log-B=-0.28, p = 0.01). In an exploratory group of 11 patients receiving extended interval dosing of subcutaneous natalizumab, the median trough concentration was even lower. CONCLUSION: Subcutaneous natalizumab can lead to lower drug concentrations, potentially limiting extended interval dosing.

[Experience in the management of pregnant patients with highly active multiple sclerosis in the Moscow region]. / Opyt vedeniya beremennykh patsientok s vysokoaktivnym rasseyannym sklerozom v Moskovskoi oblasti.

OBJECTIVE: To evaluate the effect of discontinuation or prolongation of DMT on the activity of the disease during pregnancy and in the postpartum period in patients with aggressive MS from the Moscow region. MATERIAL AND METHODS: The study included female patients with an aggressive course of MS receiving DMT at the time of pregnancy. The patients were followed-up for the period 2016 to February 2024. RESULTS: There were 17 cases of pregnancy during natalizumab (NZ) therapy; discontinuation of therapy in the first trimester of pregnancy provoked a resumption of disease activity in half of the patients. There were no exacerbations in patients whose therapy was prolonged until the 34th week of pregnancy. In 5 patients receiving fingolimod (FGL), therapy was discontinued upon the establishment of pregnancy, which caused the resumption of disease activity in three out of 5 cases. In 3 patients receiving anti-B-cell therapy, pregnancy occurred within a few months after the next infusion, there were no exacerbations during pregnancy. CONCLUSION: The cancellation of NS therapy in the early stages of pregnancy in most cases leads to the resumption of disease activity during pregnancy. Exacerbations in the postpartum period also correlated with early discontinuation of therapy and with a long period before the restart of infusions. Prolongation of infusions to 30-34 weeks of pregnancy contributed to stabilization of the condition throughout the perinatal period. Discontinuation of FGL therapy at the onset of pregnancy increased the risk of repeated relapses of the disease, up to the development of inflammatory immune restoration syndrome during pregnancy and contributed to the increase in disability in the postpartum period.

Pediatric-onset Multiple Sclerosis treatment: a multicentre observational study comparing natalizumab with fingolimod.

BACKGROUND: Pediatric-onset Multiple Sclerosis (POMS) patients show more inflammatory disease compared with adult-onset MS. However, highly effective treatments are limited with only fingolimod being approved in Italy and natalizumab prescribed as off-label treatment. OBJECTIVES: to compare the efficacy of natalizumab versus fingolimod in POMS. METHODS: This is an observational longitudinal multicentre study including natalizumab- and fingolimod-treated POMS patients (N-POMS and F-POMS, respectively). We collected Annual Relapse Rate (ARR), Expanded Disability Status Scale (EDSS), Symbol Digit Modality Test (SDMT), and MRI activity at baseline (T0), 12-18 months (T1), and last available observation (T2). RESULTS: We enrolled 57 N-POMS and 27 F-POMS patients from six Italian MS Centres. At T0, N-POMS patients showed higher ARR (p = 0.03), higher EDSS (p = 0.003) and lower SDMT (p = 0.04) at baseline compared with F-POMS. Between T0 and T1 ARR improved for both N-POMS and F-POMS (p < 0.001), while EDSS (p < 0.001) and SDMT (p = 0.03) improved only for N-POMS. At T2 (66.1 ± 55.4 months) we collected data from 42 out of 57 N-POMS patients showing no further ARR decrease. CONCLUSION: Both natalizumab and fingolimod showed high and sustained efficacy in controlling relapses and natalizumab also associated to a disability decrease in POMS. This latter effect might be partly mediated by the high inflammatory activity at baseline in N-POMS.

Literature review and meta-analysis of natalizumab therapy for the treatment of highly active relapsing remitting multiple sclerosis in the 'suboptimal therapy' patient population.

BACKGROUND: Highly active (HA) relapsing remitting multiple sclerosis (RRMS) is associated with frequent relapses and high burden of disease/disability. Natalizumab is licensed for HA RRMS, including rapidly evolving severe (RES) (≥2 relapses in previous year) and sub-optimally treated (SOT) (≥1 relapse in previous year despite treatment) populations. However, there is limited RCT evidence in the SOT subpopulation. OBJECTIVE: To review the non-RCT evidence for natalizumab in SOT HA RRMS. METHODS: Databases were searched to January 2023 for non-randomised studies of natalizumab in HA RRMS. Studies in patients with ≥1 relapse during previous treatment were eligible for inclusion. Meta-analyses were conducted to compare natalizumab with platform and higher efficacy disease-modifying therapies, with sensitivity analysis restricted to studies of low risk of bias. RESULTS: Included comparative studies (n = 16) showed natalizumab had lower relapse rates, disease activity and MRI (radiological) outcomes compared with platform and higher efficacy therapy. Case series (n = 11) showed natalizumab was associated with high rates of freedom from relapse and clinical/radiological disease activity and reductions in annualised relapse rate and disability progression. CONCLUSIONS: Literature reviewed indicates that natalizumab is more effective than other included treatments for SOT patients. Findings were consistent with studies in the broad HA RRMS population, suggesting that natalizumab may have similar efficacy for SOT and RES HA RRMS.

Frequent detection of IFN-gamma -producing memory effector and effector T cells in patients with progressive multifocal leukoencephalopathy.

Introduction: Progressive Multifocal Leukoencephalopathy (PML) is a rare and deadly demyelinating disease caused by JC virus (JCV) replication in the central nervous system. PML occurs exclusively in patients with severe underlying immune deficiencies, including AIDS and hematological malignancies. PML has also emerged as a significant threat to patients on potent new immunosuppressive biologics, including natalizumab in multiple sclerosis. Methods: Here, we developed an IFN-γ release assay (IGRA) that mainly detects JCV-specific effector memory T cells and effectors T cells in the blood. Results: This assay was frequently positive in patients with active PML (with a positive JCV PCR in CSF) of various underlying immunosuppression causes (84% sensitivity). Only 3% of healthy donors had a positive response (97% specificity). The frequency of positivity also increased in multiple sclerosis patients according to the time on natalizumab (up to 36% in patients treated for more than 48 months, who are considered at a higher risk of PML). Discussion: The results show this assay's frequent or increased positivity in patients with PML or an increased risk of PML, respectively. The assay may help to stratify the risk of PML.

Patient Preference for Subcutaneous Versus Intravenous Administration with Every-6-Week Natalizumab (Tysabri®) Dosing: NOVA Phase IIIb Extension Study (Part 2).

INTRODUCTION: Following NOVA (part 1) and the approval of the subcutaneous (SC) route of administration of natalizumab by the European Medicines Agency, an extension phase of the NOVA phase IIIb study (part 2) was initiated to collect patient preference data for SC versus intravenous (IV) dosing in patients receiving every-6-week (Q6W) dosing of natalizumab. This study was performed to evaluate patient preference for SC versus IV natalizumab administration and explore the efficacy, safety, and pharmacology characteristics of both routes of administration. METHODS: In part 2, participants received natalizumab (Tysabri®) 300 mg via IV infusion Q6W for 36 weeks and then were randomized to 48 weeks of crossover treatment (24 weeks SC Q6W and 24 weeks IV Q6W, or vice versa). The primary endpoint was the proportion of participants who indicated a preference for natalizumab SC administration on the Patient Preference Questionnaire. RESULTS: A total of 153 participants were randomized in NOVA part 2. Of 123 with patient preference data, 108 (87.8%) preferred the SC route of administration for natalizumab over the IV route; 102 (82.9%) specified "requires less time in the clinic" as the reason for the SC preference. CONCLUSION: In NOVA (part 2), most participants on Q6W dosing of natalizumab preferred SC administration versus IV administration. CLINICALTRIALS: GOV: NCT03689972. INFOGRAPHIC.

Post-Partum Clinical and Patient-Reported Outcome Changes in Mothers with Multiple Sclerosis: Findings from the NAPPREMS Study.

Background and Objective: Pregnancy in mothers with multiple sclerosis (MS) commonly results in significant changes in disease activity and changes in clinical care, including the discontinuation of disease modifying therapy (DMT). This study aimed at understanding the clinical and patient-reported outcomes (PROs) before, during and 1-year after delivery. Materials and Methods: A total of 30 pregnant mothers with MS were recruited as part of the study. Clinical (relapse activity and disability changes), PRO information and MRI outcomes were collected on four separate visits: one baseline visit-0-30 days post-delivery; and 3 follow-up visits at week 24, week 36 and week 52 from the baseline. PRO was assessed using a validated questionnaire called the Fatigue Scale for Motor and Cognitive Function (FSMC). The MRI scans were analyzed, and the count of new T2 lesions and/or contrast-enhancing lesions was determined. Results: The average time between delivery and the start of DMT was 142.5 days. Relapse activity before the pregnancy was numerically linked with the activity during the pregnancy, where up to 57.1% of the activity during pregnancy occurred in pwMS with previously active disease before conception (statistically trending with p = 0.073). The relapse activity after the pregnancy occurred twice as often in pwMS whose MS was clinically active before conception. All five pwMS who experienced a relapse prior to the pregnancy experienced worsening in their physical PRO domain. Conclusions: Pre-pregnancy activity is crucial in the screening of mothers with MS at risk for post-partum relapses, worsening of clinical disability and/or PRO measures. A post-partum MS period may benefit from the routine PRO utilization and screening for its worsening. The inflammatory activity during pregnancy was not associated with short-term disease progression.

Safety and effectiveness of disease-modifying therapies after switching from natalizumab.

INTRODUCTION: One strategy to mitigate progressive multifocal leukoencephalopathy (PML) risk is to switch to other highly effective disease-modifying therapies (DMTs). However, the optimal switch DMT following natalizumab (NTZ) discontinuation is yet to be determined. OBJECTIVE: The objective of the study is to determine the most effective and tolerable DMTs to switch to following NTZ discontinuation due to John Cunningham virus (JCV) antibody positivity. METHODS: This is a multicenter observational cohort study that included all stable relapsing-remitting multiple sclerosis (MS) patients who were treated with NTZ for at least 6 months before switching therapy due to JCV antibody positivity. RESULTS: Of 321 patients, 255 switched from NTZ to rituximab/ocrelizumab, 52 to fingolimod, and 14 to alemtuzumab, with higher annualized relapse rate (ARR) in fingolimod switchers (0.193) compared with rituximab/ocrelizumab or alemtuzumab (0.028 and 0.032, respectively). Fingolimod switchers also had increased disability progression (p = 0.014) and a higher proportion developed magnetic resonance imaging (MRI) lesions compared with rituximab/ocrelizumab (62.9% vs. 13.0%, p < 0.001, and 66.6% vs. 24.0%, p < 0.001, respectively). Mean drug survival favored rituximab/ocrelizumab or alemtuzumab over fingolimod (p < 0.001). CONCLUSION: Our study shows superior effectiveness of rituximab/ocrelizumab and alemtuzumab compared with fingolimod in stable patients switching from NTZ due to JC virus antibody positivity.

Hyper-reflective foci changes in RRMS under natalizumab therapy.

Introduction: Microglia (MG) is suggested to play an immunopathological role of in Multiple Sclerosis (MS). Since hyper-reflective foci (HRF) might mark MG activation, in vivo analysis by Optic Coherence Tomography (OCT) in MS patients under disease modifying therapies may help to clarify MS immunopathology as well as drug's mechanism of intrathecal action. Objective: To analyze HRF in patients treated with Natalizumab (NTZ), a high efficacy therapy for MS. Materials and methods: The effect of NTZ on the retina of 36 Relapsing-Remitting MS patients was investigated in a prospective, single-center study. OCT was performed immediately before the first infusion and then between infusion 3 and 4, infusion 6 and 7, infusion 11 and 13. Peripapillary and macular scans were acquired, evaluating peripapillary RNFL thickness, macular volumes (vertical scans), and HRF count (horizontal scan) in Ganglion Cell Layer (GCL), Inner Plexiform Layer (IPL) and Inner Nuclear Layer (INL). Clinical examination was performed every six months. Results: HRF count significantly increased under NTZ therapy (p<0.001) in both GCL (18.85 ± 6.93 at baseline, 28.24 ± 9.55 after 12 months) and IPL (25.73 ± 7.03 at baseline, 33.21 ± 8.50 after 12 months) but remained stable in INL (33.65 ± 7.76 at baseline, 36.06 ± 6.86 after 12 months, p=0.87), while no relevant modification of pRNFL and macular volumes were observed during the study. EDSS remained stable and no clinical relapse was observed between month 6 and 12. Conclusion: In RRMS NTZ affects HRF count in GCL and IPL, but not in INL, suggesting that NTZ does not impact on some aspects of MS immunopathology.

Insight into motor fatigue mechanisms in natalizumab treated multiple sclerosis patients with wearing off.

Motor fatigue in Multiple Sclerosis (MS) is due to reduced motor cortex (M1) output and altered sensorimotor network (SMN) modulation. Natalizumab, a disease-modifying therapy, reduces neuroinflammation and improves fatigue. However, some patients treated with natalizumab experience fatigue recurrence ('wearing-off') before subsequent infusions. Wearing-off provides a valuable window into MS-related motor fatigue mechanisms in a controlled, clinically stable, setting. This study investigates whether wearing-off is associated with worsening motor fatigue and its neurophysiological mechanisms and assesses natalizumab's effect on MS-related fatigue. Forty-five relapsing-remitting MS patients with wearing-off symptoms were evaluated pre- and post-natalizumab infusion. Assessments included evaluating disability levels, depressive symptoms, and the impact of fatigue symptoms on cognitive, physical, and psychosocial functioning. The motor fatigue index was computed through the number of blocks completed during a fatiguing task and peripheral, central, and supraspinal fatigue (M1 output) were evaluated by measuring the superimposed twitches evoked by peripheral nerve and transcranial magnetic stimulation of M1. Transcranial magnetic stimulation-electroencephalography assessed M1 effective connectivity by measuring TMS-evoked potentials (TEPs) within the SMN before- and after the task. We found that wearing-off was associated with increased motor fatigue index, increased central and supraspinal fatigue, and diminished task-related modulation of TEPs compared to post-natalizumab infusion. Wearing-off was also associated with worsened fatigue impact and depression symptom scores. We conclude that the wearing-off phenomenon is associated with worsening motor fatigue due to altered M1 output and modulation of the SMN. Motor fatigue in MS may reflect reversible, inflammation-related changes in the SMN that natalizumab can modulate. Our findings apply primarily to MS patients receiving natalizumab, emphasizing the need for further research on other treatments with wearing-off.

Altered lymphocyte profiles and herpes zoster infections in patients with multiple sclerosis on natalizumab.

Cases of herpes zoster (HZ) in patients with MS on natalizumab (NTZ) have been documented. In this study, we assessed lymphocyte subsets in NTZ-treated patients with HZ compared to matched controls without HZ. Twenty unvaccinated patients developed HZ while on NTZ for an incidence rate of 12.3 per 1000 patient-years. These patients had lower CD8+% and higher CD4+:CD8+ ratios (p ⩽ 0.01) than non-HZ matched controls. Two patients with relapsing-remitting MS developed HZ twice while on NTZ. These findings underscore the importance of pre-NTZ HZ vaccination due to potential HZ risk.

A multi-centre longitudinal study analysing multiple sclerosis disease-modifying therapy prescribing patterns during the COVID-19 pandemic.

BACKGROUND: The COVID-19 pandemic raised concern amongst clinicians that disease-modifying therapies (DMT), particularly anti-CD20 monoclonal antibodies (mAb) and fingolimod, could worsen COVID-19 in people with multiple sclerosis (pwMS). This study aimed to examine DMT prescribing trends pre- and post-pandemic onset. METHODS: A multi-centre longitudinal study with 8,771 participants from MSBase was conducted. Two time periods were defined: pre-pandemic (March 11 2018-March 10 2020) and post-pandemic onset (March 11 2020-11 March 2022). The association between time and prescribing trends was analysed using multivariable mixed-effects logistic regression. DMT initiation refers to first initiation of any DMT, whilst DMT switches indicate changing regimen within 6 months of last use. RESULTS: Post-pandemic onset, there was a significant increase in DMT initiation/switching to natalizumab and cladribine [(Natalizumab-initiation: OR 1.72, 95% CI 1.39-2.13; switching: OR 1.66, 95% CI 1.40-1.98), (Cladribine-initiation: OR 1.43, 95% CI 1.09-1.87; switching: OR 1.67, 95% CI 1.41-1.98)]. Anti-CD20mAb initiation/switching decreased in the year of the pandemic, but recovered in the second year, such that overall odds increased slightly post-pandemic (initiation: OR 1.26, 95% CI 1.06-1.49; Switching: OR 1.15, 95% CI 1.02-1.29. Initiation/switching of fingolimod, interferon-beta, and alemtuzumab significantly decreased [(Fingolimod-initiation: OR 0.55, 95% CI 0.41-0.73; switching: OR 0.49, 95% CI 0.41-0.58), (Interferon-gamma-initiation: OR 0.48, 95% CI 0.41-0.57; switching: OR 0.78, 95% CI 0.62-0.99), (Alemtuzumab-initiation: OR 0.27, 95% CI 0.15-0.48; switching: OR 0.27, 95% CI 0.17-0.44)]. CONCLUSIONS: Post-pandemic onset, clinicians preferentially prescribed natalizumab and cladribine over anti-CD20 mAbs and fingolimod, likely to preserve efficacy but reduce perceived immunosuppressive risks. This could have implications for disease progression in pwMS. Our findings highlight the significance of equitable DMT access globally, and the importance of evidence-based decision-making in global health challenges.

Spontaneous human CD8 T cell and autoimmune encephalomyelitis-induced CD4/CD8 T cell lesions in the brain and spinal cord of HLA-DRB1*15-positive multiple sclerosis humanized immune system mice.

Autoimmune diseases of the central nervous system (CNS) such as multiple sclerosis (MS) are only partially represented in current experimental models and the development of humanized immune mice is crucial for better understanding of immunopathogenesis and testing of therapeutics. We describe a humanized mouse model with several key features of MS. Severely immunodeficient B2m-NOG mice were transplanted with peripheral blood mononuclear cells (PBMCs) from HLA-DRB1-typed MS and healthy (HI) donors and showed rapid engraftment by human T and B lymphocytes. Mice receiving cells from MS patients with recent/ongoing Epstein-Barr virus reactivation showed high B cell engraftment capacity. Both HLA-DRB1*15 (DR15) MS and DR15 HI mice, not HLA-DRB1*13 MS mice, developed human T cell infiltration of CNS borders and parenchyma. DR15 MS mice uniquely developed inflammatory lesions in brain and spinal cord gray matter, with spontaneous, hCD8 T cell lesions, and mixed hCD8/hCD4 T cell lesions in EAE immunized mice, with variation in localization and severity between different patient donors. Main limitations of this model for further development are poor monocyte engraftment and lack of demyelination, lymph node organization, and IgG responses. These results show that PBMC humanized mice represent promising research tools for investigating MS immunopathology in a patient-specific approach.

Influence of personalized extended interval dosing on the natalizumab wearing-off effect - a sub-study of the NEXT-MS trial.

BACKGROUND AND OBJECTIVES: Wearing-off symptoms during natalizumab treatment in multiple sclerosis are characterized by an increase of MS-related symptoms prior to natalizumab administration. The influence of extended interval dosing (EID) on wearing-off symptoms are important to consider, as this might cause hesitancy in initiating or continuing EID. METHODS: Participants of the NEXT-MS trial, in which treatment intervals are adjusted based on drug concentrations, were divided into two groups: an extended group containing participants with at least one week of additional interval extension, and a group with a fixed interval during the trial (range 4-7 weeks). Changes in the occurrence, frequency, onset, and severity of wearing-off symptoms were evaluated. RESULTS: 255 participants were included (extended group n = 171, fixed group n = 84). The odds on occurrence of wearing-off symptoms in the extended group did not increase after extending the treatment interval. Additional analyses for frequency, onset, and severity of wearing-off symptoms showed no changes over time. Mean decrease in natalizumab drug concentration did not influence the frequency of wearing-off symptoms. DISCUSSION: Wearing-off symptoms were not reinforced by further extending the natalizumab interval. Wearing-off symptoms might increase in a minority of patients after EID, although our data support the view that wearing-off symptoms appear to be unrelated to the decrease in natalizumab trough drug concentrations.

Old and New Strategies in the Treatment of Pediatric Multiple Sclerosis: A Personal View for a New Treatment Approach.

Up to 10 years ago the most common approach to the treatment of pediatric MS (ped-MS) was to start with IFNB or GA (so-called first-line therapies or moderate-efficacy disease-modifying therapies [ME-DMTs]) and to switch to more aggressive treatments (or high-efficacy disease-modifying therapies [HE-DMTs]) in non-responder patients. The use of HE-DMTs as first choice was recommended in selected cases with an active, aggressive form of MS. Indications for the treatment of ped-MS were essentially derived from data of observational studies. Recently, results of three randomized clinical trials have been published as well as data from many observational studies evaluating the effect of new and more active DMTs, with clear evidence that HE-DMTs are more effective than ME-DMTs. Therefore, the paradigm of treatment for patients with MS onset before 18 years of age should be changed, offering treatment with HE-DMTs as first option, because of their superior effectiveness to prevent relapses and disease progression. HE-DMTs present an overall reassuring safety profile and obtain better adherence to treatment.

Neuroaxonal damage in natalizumab-treated MS patients: The role of JCV antibody titres.

BACKGROUND: While John Cunningham virus (JCV) is known to cause neuronal damage in progressive multifocal leukoencephalopathy (PML) among natalizumab-treated MS patients, its association with axonal loss in non-PML conditions remains unclear. METHODS: In a cohort of 128 natalizumab-treated MS patients, serum neurofilament (sNfL) levels and JCV antibody titres were measured. RESULTS: Among 128 patients (mean age = 38.4 years, 71.9% female), 51 (40%) were JCV positive. NfL levels increased by 15.3% for JCV index <0.7 (95% confidence interval [CI] = 0.963-1.381), by 18.6% for index 0.7-1.5 (95% CI = 1.009-1.394) and by 21.1% for index >1.5 (95% CI = 1.040-1.409) compared to JCV negative patients. CONCLUSION: These findings indicate a potential link between JCV burden and neuroaxonal degeneration in natalizumab-treated MS patients.