Natalizumab-treated Patients Research Articles

Switching natalizumab to fingolimod within 6 weeks reduces recurrence of disease activity in MS patients

Background: Natalizumab is an effective treatment in relapsing-remitting multiple sclerosis (MS). Mainly because of the risk of progressive multifocal leukoencephalopathy (PML), a substantial proportion of John Cunningham (JC) virus–positive patients switch to fingolimod. Previous reports show a clear benefit when the duration of a washout (WO) period of natalizumab is 0–3 months in comparison to longer WO periods. However, there is no consensus regarding the optimal duration of a WO period under 3 months. Objective: We compared MS disease activity after different WO periods. In addition, we investigated several factors that possibly influence recurrence of disease activity, including serum natalizumab concentration and lymphocyte counts. Methods: From a prospective observational cohort study of natalizumab-treated patients, we selected 52 patients who switched to fingolimod. We divided the patients in three groups (<6 weeks, 6–8 weeks, >8 weeks WO). Serum natalizumab concentration and lymphocyte count were assessed during and after natalizumab treatment. Results: Patients with a WO period of >8 weeks had a significant higher recurrence of disease activity (odds ratio, 6.8; 95% confidence interval, 1.4–32.8) compared to patients with a WO period of <6 weeks. Serum natalizumab concentration and lymphocyte count did not predict recurrence of disease activity. Interpretation: A short WO period decreases the risk of recurrence of disease activity. The possible impact of a short WO period on the risk of carry-over PML in JC virus–positive patients remains uncertain.

Multiplex array analysis of circulating cytokines and chemokines in natalizumab-treated patients with multiple sclerosis

Natalizumab greatly reduces inflammatory relapses in multiple sclerosis (MS) by blocking the integrin-mediated leukocyte traffic to the brain, but less is known about its effects on the systemic immunity. We measured 48 cytokines/chemokines in sera from 19 natalizumab-treated MS patients. Serum concentrations of both anti-(IL-10, IL1ra) and pro-inflammatory (IL7, IL16) molecules decreased after 21-month treatment, without associations to unbalanced Th2/Th1cytokine ratios, clinical responses, and blood/urine replication of polyomavirus JC (JCPyV). No patient developed the JCPyV-related progressive multifocal leukoencephalopathy (PML), the major risk factor of natalizumab therapy. Our data suggest that natalizumab has marginal impact on the systemic immunity.

The use of natalizumab for multiple sclerosis.

Natalizumab is a monoclonal antibody that acts as an α4 integrin antagonist to prevent leukocyte trafficking into the central nervous system. It is US Food and Drug Administration (FDA) approved for the treatment of relapsing–remitting multiple sclerosis (RRMS). Natalizumab demonstrated high efficacy in Phase III trials by reducing the annualized relapse rate, preventing multiple sclerosis (MS) lesion accumulation on magnetic resonance imaging, and decreasing the probability of sustained progression of disability. The leading safety concern with natalizumab is its association with progressive multifocal leukoencephalopathy (PML), a rare brain infection typically seen only in severely immunocompromised patients caused by reactivation of the John Cunningham virus (JCV). Careful analysis of risk factors for PML in natalizumab-treated MS patients, specifi-cally the presence of anti-JCV antibodies, has led to risk mitigation strategies to improve safety. Additional biomarkers are under investigation to further aid risk stratification. Natalizumab’s high efficacy and favorable tolerability profile have led to a broad use by MS physicians, as both first-and second-line treatments. This review discusses the natalizumab efficacy, safety, and tolerability and finishes with pragmatic considerations regarding its use in clinical practice.

The majority of natalizumab-treated MS patients have high natalizumab concentrations at time of re-dosing

Background: Natalizumab is efficacious in the treatment of relapsing-remitting multiple sclerosis. All patients receive the same treatment regimen of 300 mg every 4 weeks, despite differences in pharmacokinetics between individual patients. Objective: To give neurologists insight into natalizumab concentrations at time of re-dosing, we investigated longitudinal natalizumab concentrations in 80 patients in relation to disease activity, with possible influencing factors. Methods: In a prospective observational cohort study, natalizumab trough serum concentrations were measured in 80 patients. Data on demographics, duration of treatment, Expanded Disability Status Scale, clinical exacerbations, brain magnetic resonance imaging (MRI), and body weight were collected. Results: We measured high (≥10 µg/mL) natalizumab trough concentrations in 94% of patients. Intra-individual concentrations were stable. The spread in concentrations was substantial and did not correlate with disease activity. We found a negative association between natalizumab concentration and body weight (β = −0.30, p = 0.010). Interpretation: The majority of patients showed high natalizumab serum concentrations at time of re-dosing. Alternative treatment regimens could lead to more efficient use of natalizumab, but caution is warranted regarding the possibility of recurrence of disease activity. Prospective clinical trials are needed to establish the safety of extended dose intervals in natalizumab treatment.

The frequency of occurrence of atypical lymphocytes in peripheral blood smears of natalizumab-treated patients with multiple sclerosis.

Aside from the extensive published data on immunophenotypic lymphocyte subsets in natalizumab-treated patients with multiple sclerosis (MS), an impact of natalizumab on lymphocyte morphology has rarely been studied. As patients treated with immunomodulating or immunosuppressive drugs are at risk for infectious disorders such as viral infections, knowledge of drug-derived changes in lymphocyte morphology may be beneficial in the diagnostic work-up in such clinical situations. This study aimed to determine the frequency of occurrence of atypical lymphocytes and defined subtypes of variant lymphocytes in natalizumab-treated patients with MS. We compared eight defined morphological lymphocyte subtypes in peripheral blood smears between 14 natalizumab-treated, 13 interferon-treated and 10 untreated subjects with relapse-remitting MS. Atypical lymphocytes were significantly enhanced in natalizumab-treated patients compared to the interferon and control group (P<.0001). Binucleated lymphocytes were restricted to the natalizumab group (P=.0058, P=.018), and plasmacytoid lymphocytes were more frequently found in the natalizumab group (P<.0001). Our data indicate that natalizumab enhances the fraction of atypical lymphocytes, and thereby especially the binucleated and plasmacytoid lymphocytes. Knowledge of these natalizumab-associated changes in lymphocyte morphology may be relevant in clinical routine, to avoid unnecessary diagnostic procedures or even a discontinuation of natalizumab treatment.

Is the risk of progressive multifocal leukoencephalopathy the real reason for natalizumab discontinuation in patients with multiple sclerosis?

BackgroundProgressive multifocal leukoencephalopathy (PML) is one of the major risks of natalizumab therapy. Despite introduction of the currently employed PML risk stratification algorithm, the incidence of natalizumab-associated PML cases is not decreasing.ObjectivesWe addressed the following questions: How do natalizumab-treated multiple sclerosis patients and their treating physicians assess and deal with PML risk? Is PML risk the real reason for natalizumab discontinuation?Methods699 natalizumab-treated multiple sclerosis patients and 99 physicians were included in this prospective observational study. Questionnaires were completed at 5 different time points. Patients were stratified into 5 subgroups according to the presence of PML risk factors (prior immunosuppression, anti-JCV antibody status, treatment duration). Patients with prior immunosuppression (n = 30, treated by n = 7 physicians) were excluded from analyses, because patient numbers were too small. Patients’ anti-JCV antibody index was not considered because data recruitment ended in 2014. Using Bayesian network and regression analysis, we examined the relationship between different patient- and physician-related factors and patients’ discontinuation of natalizumab.ResultsPatients of all subgroups and physicians assessed the PML risk as low. Overall patient adherence to natalizumab was high (87%). Only 13% of patients discontinued therapy. Natalizumab treatment cessation was associated with different patient- and physician-related factors (physicians’ assessment of general PML risk, number of treated patients per year, natalizumab treatment duration, relapses during the course of study) upon which only physicians’ judgment on treatment continuation, patients’ perception of personal PML risk, and JCV seroconversion showed significant relationships.ConclusionAccording to the currently employed risk stratification algorithm, the objective PML risk probably doesn’t play a dominant role in a patients’ decision to continue or stop natalizumab treatment. The decision-making process is rather guided by subjective views and experiences of patients and treating neurologists. Treating physicians should consider this discrepancy in their advice to improve the risk-benefit-ratio for the individual patient.

Recognition of viral and self-antigens by TH1 and TH1/TH17 central memory cells in patients with multiple sclerosis reveals distinct roles in immune surveillance and relapses

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) that is caused by autoreactive T cells and associated with viral infections. However, the phenotype of pathogenic T cells in peripheral blood remains to be defined, and how viruses promote MS is debated. We aimed to identify and characterize potentially pathogenic autoreactive T cells, as well as protective antiviral T cells, in patients with MS. We analyzed CD4+ helper T-cell subsets from peripheral blood or cerebrospinal fluid for cytokine production, gene expression, plasticity, homing potentials, and their reactivity to self-antigens and viral antigens in healthy subjects and patients with MS. Moreover, we monitored their frequencies in untreated and fingolimod- or natalizumab-treated patients with MS. TH1/TH17 central memory (TH1/TH17CM) cells were selectively increased in peripheral blood of patients with relapsing-remitting MS with a high disease score. TH1/TH17CM cells were closely related to conventional TH17cells but had more pathogenic features. In particular, they could shuttle between lymph nodes and the CNS and produced encephalitogenic cytokines. The cerebrospinal fluid of patients with active MS was enriched for CXCL10 and contained mainly CXCR3-expressing TH1 and TH1/TH17 subsets. However, while TH1 cells responded consistently to viruses, TH1/TH17CM cells reacted strongly with John Cunningham virus in healthy subjects but responded instead to myelin-derived self-antigens in patients with MS. Fingolimod and natalizumab therapies efficiently targeted autoreactive TH1/TH17CM cells but also blocked virus-specific TH1 cells. We propose that autoreactive TH1/TH17CM cells expand in patients with MS and promote relapses after bystander recruitment to the CNS, whereas TH1 cells performimmune surveillance. Thus the selective targeting of TH1/TH17cells could inhibit relapses without causing JohnCunningham virus-dependent progressive multifocal encephalomyelitis.

Maraviroc as possible treatment for PML-IRIS in natalizumab-treated patients with MS.

Maraviroc as possible treatment for PML-IRIS in natalizumab-treated patients with MS.

Health care resource utilization before and after natalizumab initiation among patients with multiple sclerosis in Germany.

BackgroundMultiple sclerosis (MS), a progressive neurodegenerative disease, greatly impacts the quality of life and economic status of people affected by this disease. In Germany, the total annual cost of MS is estimated at €40,000 per person with MS. Natalizumab has shown to slow MS disease progression, reduce relapses, and improve the quality of life of people with MS.ObjectiveTo evaluate MS-related and all-cause health care resource utilization and costs among German MS patients during the 12 months before and after initiation of natalizumab in a real-world setting.MethodsThe current analysis was conducted using the Health Risk Institute research database. Identified patients were aged ≥18 years with ≥1 diagnosis of MS and had initiated natalizumab therapy (index), with 12-month pre– and post–index-period data. Patients were stratified by prior disease-modifying therapy (DMT) usage or no DMT usage in the pre-index period. Outcome measures included corticosteroid use and number of sick/disability days, inpatient stays, and outpatient visits. Health care costs were calculated separately for pre- and post-index periods on a per-patient basis and adjusted for inflation.ResultsIn a final sample of 193 natalizumab-treated patients, per-patient MS-related corticosteroid use was reduced by 62.3%, MS-related sick days by 27.6%, and inpatient costs by 78.3% from the pre- to post-index period. Furthermore, the proportion of patients with MS-related hospitalizations decreased from 49.7% to 14.0% (P<0.001); this reduction was seen for patients with and without prior DMT use.ConclusionsIn a real-world setting in Germany, initiation of natalizumab treatment in people with MS significantly reduced MS-related hospitalizations, corticosteroid use, sick days, and associated costs.

Study of the anti-JCV antibody levels in a Spanish multiple sclerosis cohort.

One of the risk factor to develop progressive multifocal leukoencephalopathy (PML) among natalizumab-treated patients is the presence and high levels of anti-JCV antibodies. Our purpose was to test the association of different clinical and demographic variables with the presence and levels of anti-JCV antibodies in a Spanish cohort of patients with multiple sclerosis (MS) during natalizumab treatment. All patients with MS from two hospitals with at least one measure of the anti-JCV antibodies levels (2011-2014) were recruited, among them were two PML cases. Anti-JCV antibody levels were assessed using two-step ELISA. A total of 1061 patients (16·3% natalizumab-treated) participated in this study. The seropositivity rate of anti-JCV antibodies was 58·2%. It increased with age (Pcorrected = 0·00005) and was lower among HLA-DRB1*15:01 carriers (Pcorrected = 0·049). The two patients with PML were HLA-DRB1*15:01 carriers. We had at least three quarterly anti-JCV antibody measurements (index value) from 137 patients, whose levels did not increase during natalizumab treatment. However, 5·8% of these patients had an increase of the index value higher of one point in a maximum of 6 months, something that was more frequently observed (P = 0·054) among patients treated with immunosuppressant prior to natalizumab onset. Old age and HLA-DRB1*15:01 were the factors that influence positively and negatively, respectively, our anti-JCV antibody prevalence, although our both PML cases were HLA-DRB1*15:01carriers. Most of our patients showed a stable anti-JCV antibody index values during natalizumab treatment.

The still under-investigated role of cognitive deficits in PML diagnosis

BackgroundDespite cognitive deficits frequently represent the first clinical manifestations of Progressive Multifocal Leukoencephalopathy (PML) in Natalizumab-treated MS patients, the importance of cognitive deficits in PML diagnosis is still under-investigated. The aim of the current study is to investigate the cognitive deficits at PML diagnosis in a group of Italian patients with PML.MethodsThirty-four PML patients were included in the study. The demographic and clinical data, the lesion load and localization, and the longitudinal clinical course was compared between patients with (n = 13) and without (n = 15) cognitive deficit upon PML suspicion (the remaining six patients were asymptomatic). Clinical presentation of cognitive symptoms was described in detail.ResultAfter symptoms detection, the time to diagnosis resulted to be shorter for patients presenting with cognitive than for patients with non cognitive onset (p = 0.03). Within patients with cognitive onset, six patients were presenting with language and/or reading difficulties (46.15%); five patients with memory difficulties (38.4%); three patients with apraxia (23.1%); two patients with disorientation (15.3%); two patients with neglect (15.3%); one patients with object agnosia (7.7%), one patient with perseveration (7.7%) and one patient with dementia (7.7%). Frontal lesions were less frequent (p = 0.03), whereas temporal lesions were slightly more frequent (p = 0.06) in patients with cognitive deficits. The longitudinal PML course seemed to be more severe in cognitive than in non cognitive patients (F = 2.73, p = 0.03), but differences disappeared (F = 1.24, p = 0.29) when balancing for the incidence of immune reconstitution syndrome and for other treatments for PML (steroids, plasma exchange (PLEX) and other therapies (Mefloquine, Mirtazapine, Maraviroc).ConclusionCognitive deficits at PML onset manifest with symptoms which are absolutely rare in MS. Their appearance in MS patients should strongly suggest PML. Clinicians should be sensitive to the importance of formal neuropsychological evaluation, with particular focus on executive function, which are not easily detected without a formal assessment.

Natalizumab treatment of multiple sclerosis: new insights.

Natalizumab is a monoclonal antibody directed against the α4 chain of the very late activating antigen 4 and α4β7 integrins, present on the leukocytes surface, used as monotherapy for the treatment of relapsing-remitting multiple sclerosis. It substantially reduces relapse rate and the accumulation of disability, but its use is associated with a very adverse event, that is the development of progressive multifocal leukoencephalopathy, a fatal demyelinating disease of the CNS, due to the lytic replication of the human polyomavirus JC. The main focus of the review is to describe the newest insights on natalizumab, its current use in the clinical practice, the natalizumab-treated patients' management and the risk stratification related to the progressive multifocal leukoencephalopathy development.

Efficacy, safety, and pharmacokinetics of natalizumab in Japanese multiple sclerosis patients: A double-blind, randomized controlled trial and open-label pharmacokinetic study

BackgroundNatalizumab, an anti-α4 integrin monoclonal antibody, has demonstrated efficacy in phase 2 and 3 studies of predominantly Caucasian patients with relapsing-remitting multiple sclerosis (RRMS). ObjectiveTo evaluate the efficacy, safety, pharmacokinetics (PK), and pharmacodynamics (PD) of natalizumab in Japanese RRMS patients. MethodsThis multicenter, phase 2 study included an open-label PK/PD study in 12 patients (part A) and a double-blind, placebo-controlled, randomized (computer-generated sequence) study in 94 patients (part B). For part B, patients received intravenous natalizumab 300mg (n=47) or placebo (n=47) every 4 weeks. The primary efficacy endpoint was the rate of development of new active lesions (gadolinium-enhancing or new/enlarging T2 lesions) over 24 weeks. Clinical relapses and safety were also assessed. ResultsNew active lesions developed at a significantly lower mean rate in natalizumab-treated patients (0.06 lesions/24 weeks) than in placebo-treated patients (0.35 lesions/24 weeks) (p<0.001). The annualized relapse rate was 0.53 for natalizumab and 1.73 for placebo (p<0.001). Twice as many natalizumab-treated patients (79%) as placebo-treated patients (38%) were relapse-free (p<0.001). The safety, PK, and PD profiles of natalizumab in this study were consistent with data in Caucasian RRMS patients. ConclusionsIn Japanese RRMS patients, natalizumab treatment every 4 weeks for 24 weeks was well tolerated and reduced the development of new brain lesions and relapses (Funded by Biogen; ClinicalTrials.gov identifier: NCT01440101).

JC polyomavirus expression and bell-shaped regulation of its SF2/ASF suppressor during the follow-up of multiple sclerosis patients treated with natalizumab.

Natalizumab is effective against multiple sclerosis (MS), but is associated with progressive multifocal leukoencephalopathy (PML), fatal disease caused by the JCV polyomavirus. The SF2/ASF (splicing factor2/alternative splicing factor) inhibits JCV in glial cells. We wondered about SF2/ASF modulation in the blood of natalizumab-treated patients and if this could influence JCV reactivation. Therefore, we performed a longitudinal study of MS patients under natalizumab, in comparison to patients under fingolimod and to healthy blood donors. Blood samples were collected at time intervals. The expression of SF2/ASF and the presence and expression of JCV in PBMC were analyzed. A bell-shaped regulation of SF2/ASF was observed in patients treated with natalizumab, increased in the first year of therapy, and reduced in the second one, while slightly changed, if any, in patients under fingolimod. Notably, SF2/ASF was up-regulated, during the first year, only in JCV DNA-positive patients, or with high anti-JCV antibody response; the expression of the JCV T-Ag protein in circulating B cells was inversely related to SF2/ASF protein expression. The SF2/ASF reduction, parallel to JCV activation, during the second year of therapy with natalizumab, but not with fingolimod, may help explain the increased risk of PML after the second year of treatment with natalizumab, but not with fingolimod. We propose that SF2/ASF has a protective role against JCV reactivation in MS patients. This study suggests new markers of disease behavior and, possibly, help in re-evaluations of therapy protocols.

Occurrence of Anti-Drug Antibodies against Interferon-Beta and Natalizumab in Multiple Sclerosis: A Collaborative Cohort Analysis.

Immunogenicity of biopharmaceutical products in multiple sclerosis is a frequent side effect which has a multifactorial etiology. Here we study associations between anti-drug antibody (ADA) occurrence and demographic and clinical factors. Retrospective data from routine ADA test laboratories in Sweden, Denmark, Austria and Germany (Dusseldorf group) and from one research study in Germany (Munich group) were gathered to build a collaborative multi-cohort dataset within the framework of the ABIRISK project. A subset of 5638 interferon-beta (IFNβ)-treated and 3440 natalizumab-treated patients having data on at least the first two years of treatment were eligible for interval-censored time-to-event analysis. In multivariate Cox regression, IFNβ-1a subcutaneous and IFNβ-1b subcutaneous treated patients were at higher risk of ADA occurrence compared to IFNβ-1a intramuscular-treated patients (pooled HR = 6.4, 95% CI 4.9–8.4 and pooled HR = 8.7, 95% CI 6.6–11.4 respectively). Patients older than 50 years at start of IFNβ therapy developed ADA more frequently than adult patients younger than 30 (pooled HR = 1.8, 95% CI 1.4–2.3). Men developed ADA more frequently than women (pooled HR = 1.3, 95% CI 1.1–1.6). Interestingly we observed that in Sweden and Germany, patients who started IFNβ in April were at higher risk of developing ADA (HR = 1.6, 95% CI 1.1–2.4 and HR = 2.4, 95% CI 1.5–3.9 respectively). This result is not confirmed in the other cohorts and warrants further investigations. Concerning natalizumab, patients older than 45 years had a higher ADA rate (pooled HR = 1.4, 95% CI 1.0–1.8) and women developed ADA more frequently than men (pooled HR = 1.4, 95% CI 1.0–2.0). We confirmed previously reported differences in immunogenicity of the different types of IFNβ. Differences in ADA occurrence by sex and age are reported here for the first time. These findings should be further investigated taking into account other exposures and biomarkers.

Vitamin D supplementation reduces relapse rate in relapsing-remitting multiple sclerosis patients treated with natalizumab

BackgroundVitamin D insufficiency is common among multiple sclerosis patients, and hypovitaminosis D has been associated with multiple sclerosis (MS) risk and disease activity. ObjectiveTo investigate how recommendations on vitamin D3 supplements affect 25-hydroxyvitamin D (25(OH)D) levels in patients with relapsing-remitting MS (RRMS) and to examine the clinical effects associated with changes in 25(OH)D levels. MethodsIn this prospective cohort study, baseline blood samples were collected from 170 natalizumab-treated RRMS patients during winter 2009–2010 and were repeated the following winter. Vitamin D supplements were recommended according to standard clinical practice in our clinic to patients with serum 25(OH)D<50nmol/l at baseline. Information was obtained on annualized relapse-rate (ARR) the year prior to baseline and the following year. ResultsWe found that recommending vitamin D supplements in patients with vitamin D insufficiency was associated with a significant increase in serum 25(OH)D concentrations (p=5.1×10−10), which was significantly related with decreases in ARR; for each nmol/l increase in Δ25(OH)D a −0.014 (95% CI −0.026 to −0.003) decrease in ΔARR was observed, p=0.02. ConclusionCorrection of hypovitaminosis D in clinical practice by recommending oral D3 supplements resulted in increases in 25(OH)D levels in serum, which were associated with decreases in ARR in RRMS.

Natalizumab treatment leads to an increase in circulating CXCR3-expressing B cells.

Objective:To study the effects of natalizumab treatment on subgroups of circulating peripheral blood B cell populations.Methods:We studied the proportions and absolute numbers of CD19+CD20+, CD10+, and CD5+ B cell populations, and determined very late activation antigen-4 and chemokine receptor CXCR3, CCR5, and CCR6 expression on B cells in the peripheral blood of 14 natalizumab-treated patients with relapsing-remitting multiple sclerosis. Five blood samples per patient were obtained longitudinally before and during the first year of treatment. Blood samples were analyzed by 6-color flow cytometry.Results:Proportions of B cells and CD10+ pre–B cells were significantly increased, and very late activation antigen-4 expression on the B cell surface was significantly decreased already after 1 week of natalizumab treatment. Natalizumab-induced sustained increase in the proportion and absolute number of CXCR3-expressing B cells was statistically significant after 1 month of treatment. There were no changes in the proportions of CCR5- or CCR6-expressing B cells.Conclusions:The rapid and persistent increase in circulating CXCR3-expressing B cells in response to natalizumab treatment possibly reflects the relevance of this chemokine receptor in controlling migration of B cells into the CNS in humans in vivo.

Decreased soluble IFN-β receptor (sIFNAR2) in multiple sclerosis patients: A potential serum diagnostic biomarker

Background: The soluble isoform of the interferon-β (IFN-β) receptor (sIFNAR2) could modulate the activity of both endogenous and systemically administered IFN-β. Previously, we described lower serum sIFNAR2 levels in untreated multiple sclerosis (MS) than in healthy controls (HCs). Objective: To assess sIFNAR2 levels in a new cohort of MS patients and HCs, as well as in patients with clinically isolated syndrome (CIS) and with other inflammatory neurological disorders (OIND) and to assess its ability as a diagnostic biomarker. Methods: The cross-sectional study included 148 MS (84 treatment naive and 64 treated), 87 CIS, 42 OIND, and 96 HCs. Longitudinal study included 94 MS pretreatment and after 1 year of therapy with IFN-β, glatiramer acetate (GA), or natalizumab. sIFNAR2 serum levels were measured by a quantitative ELISA developed and validated in our laboratory. Results: Naive MS and CIS patients showed significantly lower sIFNAR2 levels than HCs and OIND patients. The sensitivity and specificity to discriminate between MS and OIND, for a sIFNAR2 cutoff value of 122.02 ng/mL, were 70.1%, and 79.4%, respectively. sIFNAR2 increased significantly in IFN-β-treated patients during the first year of therapy in contrast to GA- and natalizumab-treated patients who showed non-significant changes. Conclusion: The results suggest that sIFNAR2 could be a potential diagnostic biomarker for MS.

Soluble serum VCAM-1, whole blood mRNA expression and treatment response in natalizumab-treated multiple sclerosis

BackgroundNatalizumab reduces disease activity in multiple sclerosis (MS). Natalizumab binds to the very late antigen-4 and inhibits vascular cell adhesion molecule-1 (VCAM-1)-mediated transmigration of immune cells across the blood-brain-barrier. This is associated with decreased serum concentrations of soluble (s)VCAM-1 and an altered composition of immune cell-subsets in the blood. ObjectiveWe aimed to examine if sVCAM-1 serum concentrations and whole blood mRNA expression levels of immune activation biomarkers is associated with disease activity in natalizumab-treated MS-patients. MethodssVCAM-1 serum concentrations and whole blood mRNA expression were measured in blood samples from untreated RRMS-patients and from two independent groups of natalizumab-treated patients. ResultssVCAM-1 serum concentrations and whole blood expression of HLX1 and IL1B mRNA were lower, whereas expression of EBI3 mRNA was higher in natalizumab-treated MS-patients. Five genes were differentially expressed in clinically unstable natalizumab-treated MS-patients in the discovery but not in the validation group. ConclusionDecreased serum concentrations of sVCAM-1 and altered whole blood mRNA expression levels of a panel of immunomarkers, associated with natalizumab-treatment, are not sensitive markers of MS disease activity. However, decreased expression of pro-inflammatory HLX1 and IL1B and increased expression of immunoregulatory EBI3 may indicate a less pathogenic immune activation status in natalizumab-treated MS.

Comparative efficacy of fingolimod vs natalizumab: A French multicenter observational study

OBJECTIVE: To compare natalizumab and fingolimod on both clinical and MRI outcomes in patients with relapsing-remitting multiple sclerosis (RRMS) from 27 multiple sclerosis centers participating in the French follow-up cohort Observatoire of Multiple Sclerosis. METHODS: Patients with RRMS included in the study were aged from 18 to 65 years with an Expanded Disability Status Scale score of 0-5.5 and an available brain MRI performed within the year before treatment initiation. The data were collected for 326 patients treated with natalizumab and 303 with fingolimod. The statistical analysis was performed using 2 different methods: logistic regression and propensity scores (inverse probability treatment weighting). RESULTS: The confounder-adjusted proportion of patients with at least one relapse within the first and second year of treatment was lower in natalizumab-treated patients compared to the fingolimod group (21.1% vs 30.4% at first year, p = 0.0092; and 30.9% vs 41.7% at second year, p = 0.0059) and supported the trend observed in nonadjusted analysis (21.2% vs 27.1% at 1 year, p = 0.0775). Such statistically significant associations were also observed for gadolinium (Gd)-enhancing lesions and new T2 lesions at both 1 year (Gd-enhancing lesions: 9.3% vs 29.8%, p \textless 0.0001; new T2 lesions: 10.6% vs 29.6%, p \textless 0.0001) and 2 years (Gd-enhancing lesions: 9.1% vs 22.1%, p = 0.0025; new T2 lesions: 16.9% vs 34.1%, p = 0.0010) post treatment initiation. CONCLUSION: Taken together, these results suggest the superiority of natalizumab over fingolimod to prevent relapses and new T2 and Gd-enhancing lesions at 1 and 2 years. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for patients with RRMS, natalizumab decreases the proportion of patients with at least one relapse within the first year of treatment compared to fingolimod