Natalizumab therapy for multiple sclerosis.
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ABSTRACT:
SUBMITTER: Chataway J
PROVIDER: S-EPMC3557363 | biostudies-literature | 2013 Jan
REPOSITORIES: biostudies-literature
Publications
Natalizumab therapy for multiple sclerosis.
Chataway Jeremy J Miller David H DH
Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics 20130101 1
The treatment of relapsing remitting multiple sclerosis has witnessed major progress since the first effective disease modifying treatment, ß-interferon, became available in 1993. One of the most remarkable new treatments has been natalizumab. This review describes the evolution of this humanized anti-α4ß1 monoclonal antibody, from preclinical experimental research through proof-of-concept (phase 1/2) and pivotal (phase 3) clinical trials to the now extensive experience of its use in clinical pr ...[more]
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Project description:Natalizumab (Nat) is a humanized monoclonal antibody used for the treatment of relapsing multiple sclerosis (MS). Nat inhibits lymphocyte migration via the blood brain barrier (BBB) by blockage of an integrin adhesion molecule, very late antigen 4. During the phase III clinical trials, it was shown that Nat reduces disease activity and prevents disability progression. In addition, several smaller studies indicate a positive influence of Nat on cognition, depression, fatigue, and quality of life (Qol). Therapeutic efficacy has to be weighed against the risk of developing potentially fatal progressive multifocal leukoencephalopathy (PML), an opportunistic infection by JC-virus (JCV) with an incidence of 3.4/1000 (95% CI 3.08-3.74) in Nat treated MS patients. In this review article, we will review data on the presumed mechanism of Nat action, clinical and paraclinical efficacy parameters, and adverse drug reactions with a special focus on PML.
| S-EPMC4011812 | biostudies-other
Project description:OBJECTIVE: To evaluate the frequency of JC polyomavirus (JCPyV) infection and anti-JCPyV antibodies in patients with multiple sclerosis under natalizumab therapy. METHODS: Presence of anti-JCPyV antibodies and JCPyV DNA was analyzed in 39 patients with relapsing-remitting multiple sclerosis undergoing natalizumab therapy. Anti-JCPyV antibodies were evaluated in serum by a 2-step virus-like particle-based ELISA assay (Stratify), and JCPyV DNA was evaluated in peripheral blood mononuclear cells, plasma, and urine by quantitative PCR. The anti-JCPyV antibodies were evaluated in serum samples collected at the same time or later than those collected for DNA analysis. RESULTS: JCPyV DNA was detected in 59% of patients, and anti-JCPyV antibodies were present in 67%. JCPyV DNA occurred more often in blood than in urine. Anti-JCPyV antibodies were observed in 70% of the JCPyV-infected patients, and JCPyV DNA was detected in 50% of the patients without anti-JCPyV antibodies. When JCPyV DNA was investigated in blood and urine the frequency of infection was higher than previously described. CONCLUSION: Under these experimental conditions, with respect to the observed frequency of JCPyV infection, the sensitivity of the anti-JCPyV antibody assay was lower than expected.
| S-EPMC4299884 | biostudies-other
Project description:We present two natalizumab-treated multiple sclerosis patients who developed glioblastoma multiforme (GBM) with variable outcomes. One patient had an isocitrate dehydrogenase (IDH)-wildtype GBM with aggressive behavior, who declined treatment and died 13 weeks after symptoms onset. The other patient underwent resection of an IDH-mutant secondary GBM that arose from a previously diagnosed grade II astrocytoma. He is still alive 5 years after the diagnosis of GBM. JC virus was not detected in either case. Whether natalizumab played a role in the development of GBM in those patients deserves further investigation.
| S-EPMC5497532 | biostudies-other
Project description:The objective of this study was to investigate confirmed progression independent of relapse activity in relapsing-remitting multiple sclerosis patients under long-term natalizumab treatment. We performed a retrospective, cross-sectional study of clinical data captured between 1994 and 2019 at two German multiple sclerosis tertiary referral centres. Data files of all relapsing-remitting multiple sclerosis patients treated with natalizumab for ≥24 months were analysed. Confirmed progression independent of relapse activity was defined as ≥12 week confirmed disability progression on a roving Expanded Disability Status Scale reference score by 1 point in patients with an Expanded Disability Status Scale score ≤3 or 0.5 in patients with an Expanded Disability Status Scale score ≥3.5 in the absence of a relapse. Cox proportional hazard models were used to analyse the probability of developing confirmed progression independent of relapse activity depending on both disease and natalizumab treatment duration. Among the 184 patients identified, 44 (24%) developed confirmed progression independent of relapse activity under natalizumab irrespective of the Expanded Disability Status Scale score at natalizumab onset. Time to confirmed progression independent of relapse activity was not affected by Expanded Disability Status Scale at natalizumab onset (categorized by Expanded Disability Status Scale score ≤3.5 versus >3.5) nor by duration of disease nor by duration of therapy. Confirmed progression independent of relapse activity occurred earlier in the disease course in patients with an earlier natalizumab therapy onset with regard to disease duration. A stepwise forward regression analysis revealed disease duration as the main factor for confirmed progression independent of relapse activity development (P = 0.005). Taken together, confirmed progression independent of relapse activity occurs in a substantial proportion of patients on long-term natalizumab treatment and independent of Expanded Disability Status Scale score at natalizumab onset. Our findings suggest that patients who are initiated on natalizumab early during disease course, usually in order to treat an aggressive clinical phenotype, have a higher risk of early confirmed progression independent of relapse activity.
| S-EPMC8573181 | biostudies-literature
Project description:Natalizumab, a recombinant humanized monoclonal antibody directed against the α4 subunit of the integrins α4ß1 and α4ß7, has been approved for the treatment of active relapsing-remitting MS. Although natalizumab is a highly beneficial drug that effectively reduces the risk of sustained disability progression and the rate of clinical relapses, some patients do not respond to it, and some are at higher risk of developing progressive multifocal leukoencephalopathy (PML). The histopathological effects after natalizumab therapy are still unknown. We, therefore, performed a detailed histological characterization of the CNS inflammatory cell infiltrate of 24 brain specimens from natalizumab treated patients, consisting of 20 biopsies and 4 autopsies and 21 MS controls. To complement the analysis, immune cells in blood and cerebrospinal fluid (CSF) of 30 natalizumab-treated patients and 42 MS controls were quantified by flow cytometry. Inflammatory infiltrates within lesions were mainly composed of T cells and macrophages, some B cells, plasma cells, and dendritic cells. There was no significant difference in the numbers of T cells or macrophages and microglial cells in lesions of natalizumab-treated patients as compared to controls. A shift towards cytotoxic T cells of a memory phenotype was observed in the CSF. Plasma cells were significantly increased in active demyelinating lesions of natalizumab-treated patients, but no correlation to clinical disability was observed. Dendritic cells within lesions were found to be reduced with longer ongoing therapy duration. Our findings suggest that natalizumab does not completely prevent immune cells from entering the CNS and is associated with an accumulation of plasma cells, the pathogenic and clinical significance of which is not known. As B cells are considered to serve as a reservoir of the JC virus, the observed plasma cell accumulation and reduction in dendritic cells in the CNS of natalizumab-treated patients may potentially play a role in PML development.
| S-EPMC8549024 | biostudies-literature
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| S-EPMC3858305 | biostudies-literature
Project description:OBJECTIVE: To compare treatment efficacy and persistence in patients who switched to natalizumab versus those who switched between glatiramer acetate (GA) and interferon-beta (IFN?) after an on-treatment relapse on IFN? or GA using propensity score matched real-world datasets. METHODS: Patients included were registered in MSBase or the TYSABRI Observational Program (TOP), had relapsed on IFN? or GA within 12 months prior to switching to another therapy, and had initiated natalizumab or IFN?/GA treatment ?6 months after discontinuing prior therapy. Covariates were balanced across post switch treatment groups by propensity score matching at treatment initiation. Relapse, persistence, and disability measures were compared between matched treatment arms in the total population (n = 869/group) and in subgroups defined by prior treatment history (IFN? only [n = 578/group], GA only [n = 165/group], or both IFN? and GA [n = 176/group]). RESULTS: Compared to switching between IFN? and GA, switching to natalizumab reduced annualized relapse rate in year one by 65-75%, the risk of first relapse by 53-82% (mean follow-up 1.7-2.2 years) and treatment discontinuation events by 48-65% (all P ? 0.001). In the total population, switching to natalizumab reduced the risk of confirmed disability progression by 26% (P = 0.036) and decreased the total disability burden by 1.54 EDSS-years (P < 0.0001) over the first 24 months post switch. INTERPRETATION: Using large, real-world, propensity-matched datasets we demonstrate that after a relapse on IFN? or GA, switching to natalizumab (rather than between IFN? and GA) led to superior outcomes for patients in all measures assessed. Results were consistent regardless of the prior treatment identity.
| S-EPMC4402083 | biostudies-other
Project description:In women with very active multiple sclerosis (MS), natalizumab can be continued during pregnancy to prevent rebound disease activity. Our aim was to evaluate changes in serum natalizumab trough concentrations during pregnancy. Blood samples of 3 patients were collected before, during, and after pregnancy. Natalizumab trough concentrations gradually decreased during pregnancy. The patient with the lowest trough concentrations during the third trimester was treated with extended interval dosing (EID). After delivery, natalizumab concentrations increased to similar levels as before pregnancy. All patients remained clinically and radiologically stable. MS neurologists should be aware of decreasing natalizumab concentrations during pregnancy, especially in patients with low initial trough concentrations and patients with EID.
| S-EPMC8795211 | biostudies-literature
Project description:There is a lack of knowledge about the evolution of cerebrospinal fluid (CSF) markers in multiple sclerosis (MS) patients undergoing natalizumab treatment. We aimed to evaluate the effect of natalizumab on basic inflammatory CSF and MRI measures. 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. 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). 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.
| S-EPMC8699923 | biostudies-literature
Project description:ObjectiveTo compare 2-year effectiveness and discontinuation of natalizumab (NTZ) versus fingolimod (FTY) and dimethyl fumarate (DMF) in the treatment of multiple sclerosis (MS).MethodsPatients prescribed NTZ, FTY, or DMF at the Rocky Mountain MS Center at University of Colorado were identified. Clinician-reported data were retrospectively collected. Outcomes include a composite effectiveness measure consisting of new T2 lesion, gadolinium-enhancing lesion, and/or clinical relapse, individual effectiveness outcomes and discontinuation over 2 years. Logistic regression was used for data analysis on patients matched by propensity scores and using ATT doubly robust weighting estimator.ResultsA total of 451, 271, and 342 patients were evaluated on NTZ, FTY, and DMF over 2 years, respectively. Patients had a mean age of 39.8 (NTZ), 42.5(FTY), and 45.8 (DMF) years; were predominantly female (76.7% NTZ; 72.0% FTY; 69.6% DMF); and had a mean MS disease duration of 11-12 years for all groups. At ≤24 months, 22.2%, 34.7%, and 33.6% experienced a new T2 lesion, gadolinium-enhancing lesion, and/or clinical relapse on NTZ, FTY, and DMF, respectively. Using ATT doubly robust weighting estimator, FTY versus NTZ and DMF versus NTZ had an odds ratio of 2.00 (95%CI:[1.41-2.85], P < 0.001) and 2.38 [95% CI: 1.68-3.37], P < 0.001) respectively, for experiencing a new T2 lesion, gadolinium enhancing lesion, and/or clinical relapse. At ≤24 months, 32.6%, 34.3%, and 47.1% discontinued NTZ, FTY, and DMF, respectively. The majority of discontinuations were due to becoming JCV positive(12.6%) for NTZ and due to adverse events for both FTY(17%) and DMF(24.0%).InterpretationNTZ appears to be more effective and tolerable than FTY and DMF.
| S-EPMC6389745 | biostudies-literature