Effect Of Natalizumab Research Articles

Effects of natalizumab on oligoclonal bands in the cerebrospinal fluid of patients with multiple sclerosis: a systematic review and meta-analysis.

Oligoclonal bands (OCBs) in cerebrospinal fluid (CSF) are utilized for diagnosing multiple sclerosis (MS), as they are found in 95% of patients. Additionally, OCBs are linked to disease prognosis. The primary contributors to OCB production are long-lived plasma cells. This study aims to quantify the impact of natalizumab (NTZ) on OCB levels in the CSF of MS patients. A systematic search on MEDLINE, SCOPUS and Web of Science for English-written and peer-reviewed longitudinal studies on adults was performed. Methodological quality was assessed with the Newcastle-Ottawa Scale. Proportional meta-analysis was performed in R using a generalized linear mixed-effects model. We investigated heterogeneity with influence diagnostics, sensitivity analysis and meta-regression. Eight eligible studies of adequate quality with a total sample of 326 relapsing-remitting MS patients were included. A summary rate of 14.07% [95% CI, 4.48%-36.36%] for complete loss of OCBs and 42.02% [95% CI, 15.23%-74.51%] for reduction in OCB number or intensity was observed, both with considerable heterogeneity. Pooled estimates dropped (11% [95% CI, 0.04%-0.29%] and 34% [95% CI, 0.11%-0.68%] respectively) after the identification of an influential study. Multivariable meta-regression identified IgG index as a factor contributing to heterogeneity (adj. p = 0.0279), regarding reduction of OCB number or intensity. In conclusion, our systematic review and meta-analysis showed that NTZ can lead to reduction of intrathecal OCBs in MS patients, indicating a possible effect of NTZ on memory plasma cells, which are the main source of OCBs in MS.

Effect of Natalizumab on sNfL and sGFAP Levels in Multiple Sclerosis Patients.

Natalizumab is a highly effective therapy for multiple sclerosis (MS). The aim of this study was to evaluate serum neurofilament light chain (sNfL) and serum glial fibrillary acidic protein (sGFAP) in patients with relapsing-remitting MS treated with Natalizumab. sNfL and sGFAP were analyzed at baseline, 6 and 12 months post treatment using the single-molecule array (SiMoA) technique. We recruited matched healthy controls for comparison. The study included 54 patients, with a median age of 33 years (Interquartile range (IQR), 29-41), with 32 women (60%) and 76 healthy controls. A decrease in sNfL was observed at 6 (67%, p = 0.005) and 12 (72%, p < 0.0001) months compared to baseline. After two years, six patients experienced evidence of disease activity (EDA-3). The remaining ones had no evidence of disease activity (NEDA-3). NEDA-3 presented a remarkable reduction in sNfL (p < 0.0001) and sGFAP (p = 0.01) after 6 months of treatment that continued to be observed after 12 months compared to baseline. EDA-3 only reached a significant decrease in sNfL after 12 months; there were no significant changes in sGFAP values. Natalizumab leads to a decrease in sNfL, which is higher and occurs earlier in NEDA-3 patients. Patients also showed a significant reduction in sGFAP levels, which was not observed in the EDA-3 group.

A comparison of natalizumab's effects on SDMT between pediatric-onset and adult-onset multiple sclerosis patients.

Pediatric-onset multiple sclerosis (POMS) patients often exhibit a wide range of cognitive deficits. Therefore, therapeutic approaches should aim not only to prevent cognitive decline but also to promote cognitive improvement. This study aimed to explore the effects of natalizumab (NTZ) on cognitive function, as measured by the Symbol Digit Modalities Test (SDMT), in both POMS and adult-onset multiple sclerosis (AOMS) patients. A total of 63 patients (34 AOMS and 29 POMS) were enrolled in this retrospective, single-center study. Patients were clinically and radiologically assessed every 6 months, and they completed the SDMT at baseline and after at least 24 months of follow-up. SDMT values were reported as corrected values (cSDMT) and z-scores (zSDMT). Annualized cSDMT and zSDMT scores were calculated by dividing the change in scores by the length of the follow-up period (expressed in years). Both POMS and AOMS groups showed improvement in annualized cSDMT and zSDMT scores, but the improvement was significantly greater in the POMS group compared to the AOMS group (+3.85 ± 4.32 vs. +1.76 ± 2.80, p = 0.010 for cSDMT; 0.41 ± 0.40 vs. 0.25 ± 0.34, p = 0.026 for zSDMT). After re-baselining at 6 months, 93% of POMS patients (27 patients) and 85.3% of AOMS patients (29 patients, p = 0.84) achieved NEDA-3 (no evidence of disease activity). The NEDA-3 status, along with clinical and demographic parameters at baseline, did not account for the observed SDMT improvement. The favorable clinical, radiological, and neuropsychological outcomes observed in this study support the use of natalizumab as a viable treatment option in POMS.

A comparison of natalizumab and ocrelizumab on disease progression in multiple sclerosis.

No direct comparisons of the effect of natalizumab and ocrelizumab on progression independent of relapse activity (PIRA) and relapse-associated worsening (RAW) events are currently available. We aimed to compare the risk of achieving first 6 months confirmed PIRA and RAW events and irreversible Expanded Disability Status Scale (EDSS) 4.0 and 6.0 in a cohort of naïve patients treated with natalizumab or ocrelizumab from the Italian Multiple Sclerosis Register. Patients with a first visit within 1 year from onset, treated with natalizumab or ocrelizumab, and ≥3 visits were extracted. Pairwise propensity score-matched analyses were performed. Risk of reaching the first PIRA, RAW, and EDSS 4.0 and 6.0 events were estimated using multivariable Cox proportional hazards models. Kaplan-Meier curves were used to show cumulative probabilities of reaching outcomes. In total, 770 subjects were included (natalizumab = 568; ocrelizumab = 212) and the propensity score-matching retrieved 195 pairs. No RAW events were found in natalizumab group and only 1 was reported in ocrelizumab group. A first PIRA event was reached by 23 natalizumab and 25 ocrelizumab exposed patients; 7 natalizumab- and 10 ocrelizumab-treated patients obtained an irreversible EDSS 4.0, while 13 natalizumab- and 15 ocrelizumab-treated patients reached an irreversible EDSS 6.0. No differences between the two groups were found in the risk (HR, 95%CI) of reaching a first PIRA (1.04, 0.59-1.84; p = 0.88) event, an irreversible EDSS 4.0 (1.23, 0.57-2.66; p = 0.60) and 6.0 (0.93, 0.32-2.68; p = 0.89). Both medications strongly suppress RAW events and, in the short term, the risk of achieving PIRA events, EDSS 4.0 and 6.0 milestones is not significantly different.

Hyper-reflective foci changes in RRMS under natalizumab therapy.

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. To analyze HRF in patients treated with Natalizumab (NTZ), a high efficacy therapy for MS. 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. 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. 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.

Long-term neuroprotective effects of natalizumab and fingolimod in multiple sclerosis: Evidence from real-world clinical data

BackgroundThe long-term effect of high efficacy disease modifying therapy (DMT) on neurodegeneration in people with multiple sclerosis (pwMS) is largely unknown. The aim of this study was to evaluate the long-term effect of natalizumab (NTZ) or fingolimod (FTY) therapy on the evolution of brain atrophy compared to moderate efficacy DMT in a real-world clinical setting. MethodsA total of 438 pwMS with 2,439 MRI exams during treatment were analyzed: 252 pwMS treated with moderate efficacy DMT, 130 with NTZ and 56 with FTY. Evolution of brain atrophy was analyzed over an average follow-up of 6.6 years after treatment initiation. Brain segmentation was performed on clinical 3D-FLAIRs using SynthSeg and regional brain volume changes over time were compared between the treatment groups. ResultsTotal brain, white matter and deep gray matter atrophy rates did not differ between moderate efficacy DMTs, NTZ and FTY. Annualized ventricle growth rates were lower in pwMS treated with NTZ (1.1 %/year) compared with moderate efficacy DMT (2.4 %/year, p < 0.001) and similar to FTY (2.0 %/year, p = 0.051). Cortical atrophy rates were lower in NTZ (-0.08 %/year) compared with moderate efficacy DMT (-0.16 %/year, p = 0.048). ConclusionIn a real-world clinical setting, pwMS treated with NTZ had slower ventricular expansion and cortical atrophy compared to those treated with moderate efficacy DMT.

Natalizumab reduces loss of gray matter and thalamic volume in patients with relapsing-remitting multiple sclerosis: A post hoc analysis from the randomized, placebo-controlled AFFIRM trial

Background: Loss of brain gray matter fractional volume predicts multiple sclerosis (MS) progression and is associated with worsening physical and cognitive symptoms. Within deep gray matter, thalamic damage is evident in early stages of MS and correlates with physical and cognitive impairment. Natalizumab is a highly effective treatment that reduces disease progression and the number of inflammatory lesions in patients with relapsing-remitting MS (RRMS). Objective: To evaluate the effect of natalizumab on gray matter and thalamic atrophy. Methods: A combination of deep learning–based image segmentation and data augmentation was applied to MRI data from the AFFIRM trial. Results: This post hoc analysis identified a reduction of 64.3% (p = 0.0044) and 64.3% (p = 0.0030) in mean percentage gray matter volume loss from baseline at treatment years 1 and 2, respectively, in patients treated with natalizumab versus placebo. The reduction in thalamic fraction volume loss from baseline with natalizumab versus placebo was 57.0% at year 2 (p < 0.0001) and 41.2% at year 1 (p = 0.0147). Similar findings resulted from analyses of absolute gray matter and thalamic fraction volume loss. Conclusion: These analyses represent the first placebo-controlled evidence supporting a role for natalizumab treatment in mitigating gray matter and thalamic fraction atrophy among patients with RRMS. ClinicalTrials.gov identifier: NCT00027300 URL: https://clinicaltrials.gov/ct2/show/NCT00027300

Effectiveness of multiple disease-modifying therapies in relapsing-remitting multiple sclerosis: causal inference to emulate a multiarm randomised trial

BackgroundSimultaneous comparisons of multiple disease-modifying therapies for relapsing-remitting multiple sclerosis (RRMS) over an extended follow-up are lacking. Here we emulate a randomised trial simultaneously comparing the effectiveness of six commonly...

Natalizumab Treatment of Relapsing Remitting Multiple Sclerosis Has No Long-Term Effects on the Proportion of Circulating Regulatory T Cells.

Natalizumab (NTZ), a monoclonal antibody against the integrin α4β1 (VLA-4) found on activated T cells and B cells, blocks the interaction of this integrin with adhesion molecules of central nervous system (CNS) endothelial cells and lymphocyte migration through the blood-brain barrier, effectively preventing new lesion formation and relapses in multiple sclerosis (MS). Whether NTZ treatment has additional effects on the peripheral immune system cells, and how its actions compare with other MS disease-modifying treatments, have not been extensively investigated. In particular, its effect on the proportions of circulating regulatory T cells (Treg) is unclear. In this study, we investigated the effect of NTZ treatment in 12 patients with relapsing MS, at 6 and 12months after the start of treatment. We evaluated the proportions of regulatory T cells (Treg), defined by flow cytometry as CD4+CD25++FoxP3+cells and CD4+CD25++CD127- cells at these intervals. As an exploratory study, we also investigated the NTZ effects on the proportions of bulk T and B lymphocyte populations, and of those expressing novel the markers CD195 (CCR5), CD196 (CCR6), or CD161 (KLRB1), which are involved in MS pathogenesis but have been studied less in the context of MS treatment. The effects of NTZ were compared to those obtained with 11 patients under interferon-beta-1a (IFN-β1a) treatment, and against 9 healthy volunteers. We observed a transient increment in the proportion of Treg cells at 6months, which was not sustained at 12months. We observed a reduction in the proportion of T cells expressing CD195 (CCR5) and CD161 (KLRB1) subsets of T cells. We conclude that NTZ does not have an effect on the proportion of Treg cells over 1year, but it may affect the expression of molecules important for some aspects MS pathogenesis, in a manner that is not shared with IFN-β1a.

Assessing the utility of magnetic resonance imaging-based "SuStaIn" disease subtyping for precision medicine in relapsing-remitting and secondary progressive multiple sclerosis.

Patient stratification and individualized treatment decisions based on multiple sclerosis (MS) clinical phenotypes are arbitrary. Subtype and Staging Inference (SuStaIn), a published machine learning algorithm, was developed to identify data-driven disease subtypes with distinct temporal progression patterns using brain magnetic resonance imaging; its clinical utility has not been assessed. The objective of this study was to explore the prognostic capability of SuStaIn subtyping and whether it is a useful personalized predictor of treatment effects of natalizumab and dimethyl fumarate. Subtypes were available from the trained SuStaIn model for 3 phase 3 clinical trials in relapsing-remitting and secondary progressive MS. Regression models were used to determine whether baseline SuStaIn subtypes could predict on-study clinical and radiological disease activity and progression. Differences in treatment responses relative to placebo between subtypes were determined using interaction terms between treatment and subtype. Natalizumab and dimethyl fumarate reduced inflammatory disease activity in all SuStaIn subtypes (all p < 0.001). SuStaIn MS subtyping alone did not discriminate responder heterogeneity based on new lesion formation and disease progression (p > 0.05 across subtypes). SuStaIn subtypes correlated with disease severity and functional impairment at baseline but were not predictive of disability progression and could not discriminate treatment response heterogeneity.

Long-term effects of natalizumab on MRI activity and clinical outcomes in Japanese patients with relapsing-remitting multiple sclerosis

BackgroundRelapsing-remitting multiple sclerosis (RRMS) is the most common phenotype of multiple sclerosis (MS), and its active stage is characterized by active T2 lesions with or without gadolinium (Gd) enhancement on magnetic resonance imaging (MRI). Natalizumab is indicated as monotherapy in adults with active RRMS in Japan. The main objective of this study was to investigate the long-term effect of natalizumab on disease progression in Japanese patients with RRMS using MRI data.MethodsThis retrospective, chart review study was conducted at a single center in Japan. The main study outcome was the yearly proportion of patients with active T2-weighted image lesions detected with or without Gd enhancement on brain MRI (incidence rate) after treatment initiation for up to 5 years. Additional endpoints included annual relapse rate (ARR) and expanded disability status scale (EDSS) score.ResultsThis study included data from 85 patients with RRMS who had received natalizumab for ≥ 1 year; of these, 65 (76.5%) were female and the mean ± standard deviation (SD) age at baseline was 37.5 ± 10.0 years. The incidence rate of active T2 lesions was 52.9% (45/85) in the year prior to natalizumab treatment (Year − 1), which decreased to 2.4% and 1.6% in Year 0.5–1.5 and Year 1.5–2.5, respectively. No active T2 lesions were detected in Year 2.5–5.5 in patients who continued natalizumab treatment. EDSS score was stable, improved, and worsened in 61.8%, 26.3%, and 11.8% of patients, respectively. The median (range) EDSS score was 2.0 (0.0–7.0) at baseline (n = 85) and remained within a similar range (median score between 1.0 and 2.25 during Years 1–5). ARR decreased from 1.12 relapses per year at baseline to 0.12 relapses per year during Year 1 and remained below 0.15 relapses per year up to Year 5.ConclusionThe results of this first long-term study evaluating the effect of natalizumab on MRI activity and clinical outcomes in Japanese patients with RRMS suggest that natalizumab markedly reduced disease activity and maintained effectiveness over several years.

Improvements in Cognitive Processing Speed, Disability, and Patient-Reported Outcomes in Patients with Early Relapsing-Remitting Multiple Sclerosis Treated with Natalizumab: Results of a 4-year, Real-World, Open-Label Study.

STRIVE was a prospective, 4-year, multicenter, observational, open-label, single-arm study of natalizumab treatment in anti-JC virus antibody-negative patients with early relapsing-remitting multiple sclerosis (RRMS). Study objectives examined the effects of natalizumab on cognitive processing speed, confirmed disability improvement (CDI), and patient-reported outcomes (PROs). Clinical and PRO secondary endpoints were assessed annually over 4 years in STRIVE. The Symbol Digit Modalities Test (SDMT) was used as a measure of cognitive processing speed. PROs were assessed using the Multiple Sclerosis Impact Score (MSIS-29) and the Work Productivity and Activity Impairment Questionnaire (WPAI). At all four annual assessments, the proportion of patients in the intent-to-treat (ITT) population (N = 222) who exhibited clinically meaningful improvement in their SDMT score from baseline (i.e., change ≥4 points) ranged from 41.9 to 54.0%. The cumulative probability of CDI at 4 years in patients in the ITT population with a baseline Expanded Disability Status Scale score ≥2 (N = 133) was 43.9%. Statistically significant reductions in the mean change from screening in the MSIS-29 physical and psychological scores, indicating improved quality of life, were observed over all 4 years (P ≤0.0012 for all). A statistically significant decrease from screening in the impact of MS on regular activities, signifying an improvement in this WPAI measure, was also observed over all 4 years of the study. These results further extend our knowledge of the effectiveness, specifically regarding improvements in cognitive processing speed, disability and PROs, of long-term natalizumab treatment in early RRMS patients. GOV: NCT01485003 (5 December 2011).

Superior effects of natalizumab versus other DMTs on patient-reported outcomes in people with multiple sclerosis

BackgroundLittle is known about the comparative effectiveness of multiple sclerosis (MS) disease-modifying therapies (DMTs) on patient-reported outcomes in MS. We compared the effects of natalizumab to other DMTs in relation...

Biomechanical changes in the liver tissue induced by a mouse model of multiple sclerosis (EAE) and the effect of anti-VLA-4 mAb treatment

Experimental autoimmune encephalomyelitis (EAE) is a mouse model of demyelinating diseases, such as multiple sclerosis (MS). MS can be accompanied by autoimmune hepatitis. In this study, nanomechanical, biorheological and histological examinations were carried out by atomic force microscopy (AFM), rheology, and immunofluorescence microscopy to investigate changes in the liver tissue of EAE mice and the effect of natalizumab, a monoclonal antibody against α4-integrin (VLA-4) cell adhesion molecule, used in MS therapy. Liver samples collected from EAE mice in three successive phases of the disease showed inflammatory changes manifested by leukocyte infiltrations and elevated levels of proinflammatory cytokine IL-1β. Liver stiffness and viscoelasticity increased in the onset phase of EAE, decreased in the peak phase and increased again in the chronic phase to reach the highest values. These changes were not associated with inflammation parameters which increased in the peak phase and decreased to the lowest values in the chronic phase. Moreover, anti-VLA treatment, which reduced the inflammation parameters, had an ambiguous effect on stiffness and viscoelasticity: it increased them in the peak phase but decreased in the chronic phase. The observed discrepancies can result from a complex network of interactions between inflammation and fibrosis, as well as between liver cells and the extracellular matrix influencing the biomechanical properties of the liver tissue.

Natalizumab Induces Changes of Cerebrospinal Fluid Measures in Multiple Sclerosis.

Background: There is a lack of knowledge about the evolution of cerebrospinal fluid (CSF) markers in multiple sclerosis (MS) patients undergoing natalizumab treatment. Aim: We aimed to evaluate the effect of natalizumab on basic inflammatory CSF and MRI measures. Methods: Together, 411 patients were screened for eligibility and 93 subjects with ≥2 CSF examinations ≤6 months before and ≥12 months after natalizumab initiation were recruited. The effect of natalizumab on CSF as well as clinical and paraclinical measures was analyzed using adjusted mixed models. Results: Natalizumab induced a decrease in CSF leukocytes (p < 1 × 10−15), CSF protein (p = 0.00007), the albumin quotient (p = 0.007), the IgG quotient (p = 6 × 10−15), the IgM quotient (p = 0.0002), the IgG index (p = 0.0004), the IgM index (p = 0.003) and the number of CSF-restricted oligoclonal bands (OCBs) (p = 0.0005). CSF-restricted OCBs positivity dropped from 94.6% to 86% but 26 patients (28%) had an increased number of OCBs at the follow-up. The baseline to follow-up EDSS and T2-LV were stable; a decrease in the relapse rate was consistent with a decrease in the CSF inflammatory markers and previous knowledge about the effectiveness of natalizumab. The average annualized brain volume loss during the follow-up was −0.50% (IQR = −0.96, −0.16) and was predicted by the baseline IgM index (B = −0.37; p = 0.003). Conclusions: Natalizumab is associated with a reduction of basic CSF inflammatory measures supporting its strong anti-inflammatory properties. The IgM index at the baseline predicted future brain volume loss during the course of natalizumab treatment.

Effect of natalizumab treatment on the rate of No Evidence of Disease Activity in young adults with multiple sclerosis in relation to pubertal stage

Approximately 40% of young-onset multiple sclerosis (MS) patients experience breakthrough disease, which carries a high risk for long-term disability, and requires using therapies beyond traditional first-line agents. Despite the increasing use of newer disease-modifying treatments (DMTs) in this population, data are not available to guide the need for escalating DMTs and there is a scarcity of data on the effects of natalizumab in children and young adults with active disease. We performed a retrospective analysis of the rate of No Evidence of Disease Activity (NEDA), tolerability, and safety of natalizumab in a multi-center cohort of 36 children and young adults with highly active MS. All patients had active disease and initiated treatment with natalizumab. The primary endpoint was the rate of achieving NEDA-3 status, within two years of natalizumab treatment. To examine a possible effect of age on the outcome of treatment, outcomes were also analyzed by pre-pubertal (n = 13 children aged 9–13 years) and pubertal subgroups (n = 23 young adolescents aged 14–20 years). The NEDA-3 status of the pre-pubertal group was 92% in the first and second year and in the pubertal group - 96% in the first year and 92% in the second year. Natalizumab reduced the number and volume of brain lesions in both pre-pubertal and pubertal groups. Treatment was well-tolerated, only 8 patients (22.2%) had adverse events during the 2-year study period. Our analysis shows that natalizumab is effective and well-tolerated in pre-pubertal and pubertal MS patients.

Role of Natalizumab in Relapsing-Remitting Multiple Sclerosis: A review

Introduction: Multiple sclerosis is a non-traumatic neurological disease caused by an immune-mediated reaction leading to a chronic inflammatory demyelinating disorder of the central nervous system. The treatments for multiple sclerosis are mainly divided into three categories: treatment of exacerbation, slowing disease progression with disease-modifying therapies, and symptomatic therapies. Natalizumab is a monoclonal antibody that works by preventing the adhesion of lymphocytes into the endothelium of the blood-brain barrier, reducing lymphocyte infiltration into the central nervous system. This review aims to study the efficacy and safety of natalizumab in relapsing-remitting multiple sclerosis. Methods: The review was performed using databases like PubMed, Cochrane library, Google scholar from which 48 relevant articles were selected based on the various inclusion criteria. The following keywords were used: “Natalizumab”, “Multiple sclerosis”, “side effects”, “Relapsing-remitting multiple sclerosis”, “progressive multifocal leukoencephalopathy” in different combinations. Results: The literature review suggests that natalizumab reduces the rate of sustained progression of the disease and disability, and was associated with a lower relapse rate in patients with relapsing-remitting multiple sclerosis. However, Progressive multifocal leukoencephalopathy is one of the serious side effects of natalizumab. Conclusion: The literature review suggests that Natalizumab has favorable outcomes in patients with relapsing-remitting multiple sclerosis. Since progressive multifocal leukoencephalopathy is one of the serious side effects of natalizumab, risk stratification should be done.

Effects of Natalizumab Therapy on Intrathecal Immunoglobulin G Production Indicate Targeting of Plasmablasts.

ObjectivesTo evaluate the long-term effects of natalizumab (NTZ) on different features of intrathecal immunoglobulin (Ig) synthesis in patients with multiple sclerosis (MS) and to quantify the expression of α4-integrin in stages of B-cell maturation.MethodsWe combined a cross-sectional (49 NTZ-treated MS patients, mean treatment duration 5.1 years, and 47 untreated MS patients) and a longitudinal study (33 patients with MS before and during NTZ, mean treatment duration: 4.8 years), analyzing paired serum and CSF samples for IgG, IgA, and IgM levels, reactivity against selected viruses (measles virus, rubella virus, and varicella zoster virus [MRZ] reaction), and oligoclonal bands (OCBs). Banding patterns before and after therapy were directly compared by isoelectric focusing in 1 patient. In addition, we determined the expression of α4-integrin by FACS analysis on blood-derived B-cell subsets (plasmablasts, memory B cells, and naive B cells) of healthy controls.ResultsIn serum, NTZ decreased IgM and IgG, but not IgA, levels. IgM hypogammaglobulinemia occurred in 28% of NTZ-treated patients. In CSF, NTZ treatment resulted in a strong reduction of intrathecally produced IgG and, to a lesser extent, IgA, whereas IgM indices [(Ig CSF/Serum)/(Albumin CSF/Serum)] remained largely unchanged. Reduction of the IgG index correlated with NTZ treatment duration, as did serum IgM and IgA levels. MRZ reaction was unchanged and OCB persisted. Direct comparison of OCB pattern before and after NTZ revealed the persistence of individual bands. α4-Integrin expression was highest on plasmablasts (CD19+CD38+CD27+).ConclusionOur data indicate that NTZ reduces short-lived plasmablasts in the CNS compartment but has little effect on locally persisting long-lived plasma cells.

Natalizumab induced blood eosinophilia: A retrospective pharmacovigilance cohort study and review of the literature

ObjectiveTo describe frequency of natalizumab related eosinophilia and clinical symptoms of eosinophilic disease in our monocentric cohort. MethodsComparison of clinical characteristics of 115 natalizumab treated and 116 untreated RRMS patients and review of literature. Results38% of natalizumab treated patients had eosinophilia, which occurred significantly more frequently compared to untreated MS patients (3%, p-value<0.001). In symptomatic patients, mean eosinophil counts were significantly higher than in asymptomatic patients and symptoms developed within one year. DiscussionEosinophilia is a side effect of natalizumab and mostly asymptomatic. However, few patients develop within one year after start of natalizumab an eosinophilic disease as severe side effect.

Effects of Fingolimod and Natalizumab on Brain T1-/T2-Weighted and Magnetization Transfer Ratios: a 2-Year Study.

Fingolimod and natalizumab significantly reduce disease activity in relapsing-remitting multiple sclerosis (RRMS) and could promote tissue repair and neuroprotection. The ratio between conventional T1- and T2-weighted sequences(T1w/T2w-ratio) and magnetization transfer ratio (MTR) allow to quantify brain microstructural tissue abnormalities. Here, we compared fingolimod and natalizumab effects on brain T1w/T2w-ratio and MTR in RRMS over 2years of treatment. RRMS patients starting fingolimod (n = 25) or natalizumab (n = 30) underwent 3T brain MRI scans at baseline (T0), month 6 (M6), month 12 (M12), and month 24 (M24). White matter (WM) lesions, normal-appearing (NA) WM, and gray matter (GM) T1w/T2w-ratio and MTR were estimated and compared between groups using linear mixed models. No baseline demographic, clinical, and MRI difference was found between groups. In natalizumab patients, lesion T1w/T2w-ratio and MTR significantly increased at M6 vs. T0 (p ≤ 0.035) and decreased at subsequent timepoints (p ≤ 0.037). In fingolimod patients, lesion T1w/T2w-ratio increased at M12 vs. T0 (p = 0.010), while MTR gradually increased at subsequent timepoints vs. T0 (p ≤ 0.027). Natalizumab stabilized NAWM and GM T1w/T2w-ratio and MTR. In fingolimod patients, NAWM T1w/T2w-ratio and MTR significantly increased at M24 vs. M12 (p ≤ 0.001). A significant GM T1w/T2w-ratio decrease at M6 vs. T0 (p = 0.014) and increase at M24 vs. M6 (p = 0.008) occurred, whereas GM MTR was significantly higher at M24 vs. previous timepoints (p ≤ 0.017) with significant between-group differences (p ≤ 0.034). Natalizumab may promote an early recovery of lesional damage and prevent microstructural damage accumulation in NAWM and GM during the first 2years of treatment. Fingolimod enhances tissue damage recovery being visible after 6months in lesions and after 2years in NAWM and GM.