Natalizumab for Multiple Sclerosis: A Case in Point for the Impact of Translational Neuroimmunology

Shirani, Afsaneh; Stüve, Olaf

doi:10.4049/jimmunol.1601358

Cited by 23 publications

(21 citation statements)

References 60 publications

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“…In our longitudinal observational study, we systematically collected real world lab data including specific immune cell subsets and routine laboratory parameters in NAT treated patients during long-term NAT treatment. Upon NAT treated patients, there are a huge amount of reports available discussing long period outcome and clinical parameters including relapse rate, MRI-activity, and disease progression presenting long-term efficacy (28–30), whereas analyses of immune cell subsets and standard lab analyses are restricted only up to 24–48 months follow up (15, 23, 24). Compared to previous studies, we analyzed a representative large number of patients for a treatment period up to 6 years.…”

Section: Discussionmentioning

confidence: 99%

Real-World Lab Data in Natalizumab Treated Multiple Sclerosis Patients Up to 6 Years Long-Term Follow Up

et al. 2018

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Natalizumab inhibits the transmigration of immune cells across the blood-brain barrier thus inhibiting inflammation in the central nervous system. Generally, this blockade at the blood-brain barrier has significant influence on the circulating lymphocytes. Up to date, only short-term data on peripheral blood parameters are available which are mostly from controlled clinical trials and not from real-world experience. Real-world lab data of 120 patients diagnosed with highly active disease course of relapsing-remitting multiple sclerosis (RRMS) were analyzed during natalizumab treatment. Patient sampling was performed by consecutive recruitment in the Multiple Sclerosis Center Dresden. Lab testing was performed before and at every third infusion up to 72 months follow-up. After first natalizumab infusion, absolute numbers of all major lymphocyte populations including CD4+ T-cells, CD8+ T-cells, CD19+ B-cells, and NK-cells significantly increased and remained stable during the whole observation period of 72 months. Upon lymphocyte subsets, CD19+ B-cells presented a disproportionate increase up to levels higher than normal level in most of the treated patients. Neutralizing antibodies to natalizumab abrogated the described changes. Intra-individual variation of lymphocytes and its subsets remained in a narrow range for the whole treatment period. CD4/CD8 ratio did not change compared to baseline measurement up to 6 years of natalizumab treatment. Monocytes, eosinophils, and basophils, but not neutrophils persistently increased during natalizumab treatment. Hematological parameters including erythrocyte, platelet count, hemoglobin, and hematocrit remained unchanged compared to baseline. Interestingly, immature precursor cells including erythroblasts were detectable in 36,8% of the treated patients during natalizumab therapy, but not in the pretreatment period. Asymptomatic elevations of liver enzymes were rare, mostly only transient and lower than 3x upper normal limit. Kidney function parameters remained stable within physiological ranges in most patients. CRP levels >20 mg/dl were recognized only in 10 patients during natalizumab therapy and were mostly linked to respiratory tract infections. In our present analysis, we report persistent, but stable increases of peripheral immune cell subtypes in natalizumab treated patients. Additional serological analyses confirm excellent tolerability and safety even 6 years after natalizumab initiation in post-marketing experience.

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Section: Discussionmentioning

confidence: 99%

Real-World Lab Data in Natalizumab Treated Multiple Sclerosis Patients Up to 6 Years Long-Term Follow Up

et al. 2018

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“…Following additional research and analyses of risks and benefits it was remarketed as monotherapy for highly active RRMS with the recommendation for monitoring for new cases of PML. 4 , 7 Based on data from 2009 to 2018 the risk of PML has leveled-off in mid-2016, and stabilized thereon at at 4.14-4.18/1,000. 8 , 9 The presence of anti-JCV antibodies in serum, long (>2 years) natalizumab therapy duration, and prior receipt of immunosuppressants have been identified as risk factors of PML occurrence.…”

Section: Introductionmentioning

confidence: 99%

Patient and treatment characteristics and safety outcomes of patients with relapsing-remitting multiple sclerosis treated with natalizumab in Greece: Results from the multicenter, 5-year prospective observational study ‘TOPICS greece’

Karanasios

Karachalios²,

Gourgioti³

et al. 2021

Multiple Sclerosis Journal - Experimental, Translational and Cl

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Background Natalizumab is a highly efficacious treatment for relapsing-remitting multiple sclerosis (RRMS). Objective To assess the real-world long-term safety of natalizumab in RRMS. Methods This multicenter, 5-year prospective observational study, included adults with RRMS newly initiated on natalizumab as per the approved product label in the routine care in Greece. Safety was evaluated by collecting serious adverse events (SAEs) following study enrollment. Results Between 19-Apr-2012 and 18-Dec-2014, 304 eligible patients (median age at natalizumab initiation: 38.0 years; median disease duration: 6.2 years) were enrolled by 20 hospital-based neurologists. Over a median treatment duration period of 58.7 months, 50.7% of the patients discontinued natalizumab, mainly due to anti-JCV antibody detection (59.1%). The adverse event treatment discontinuation rate was 5.2%. The SAE incidence rate during the safety data collection period (median: 48.7 months) was 4.6%. The most common SAEs were infections (1.0%), including 2 cases (0.7%) of progressive multifocal leukoencephalopathy (PML), and no other opportunistic infections. PML diagnoses occurred 6.2-6.7 years after natalizumab initiation, and approximately 2 years after first detection of anti-JCV antibody for both patients. The incidence rate of malignancies was 0.7%. Conclusion In real-world settings in Greece, natalizumab displayed an acceptable safety profile, with no new safety signals emerging.

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“…The distinct DMTs achieve their effect by a number of different mechanisms, including dampening the immune response with for example interferon [1] or shifting the focus of the immune response by glatiramer acetate [2]. Alternatively, immune cells can be sequestered within lymphoid structures using siponimod or fingolimod [3,4] or drugs such as natalizumab can otherwise hinder extravasation from the blood into the central nervous system (CNS) [5]. Furthermore, there are several more or less specific therapeutic strategies that focus on the removal of immune cells or selected subsets of immune cells.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Bruton´s tyrosine kinase as a novel therapeutic approach in multiple sclerosis

Torke

Weber

2020

Expert Opinion on Investigational Drugs

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Introduction: B cells have increasingly come under the spotlight as mediators of inflammatory central nervous system (CNS) demyelinating diseases such as multiple sclerosis (MS). B cell depletion via the targeting of the surface molecule CD20 has proven to be highly effective; however, continuous absence of an integral component of the immune system may cause safety concerns over time. Declining humoral competence and potential immune system impairments are key issues, and moreover, unselective removal of B cells reduces immune system control functions which should preferably be maintained in inflammatory CNS disease. Areas covered: This paper illuminates the novel approach of specific interference with B cell signaling by targeting Bruton´s tyrosine kinase (BTK). We discuss the role of BTK within the B cell receptor (BCR) signaling cascade and BTK inhibition as a promising strategy to control inflammatory CNS disease which crucially excludes immune-cell depletion. We searched PubMed or clinicaltrials.gov for the terms 'BTK inhibition' or 'Bruton´s Tyrosine Kinase' or 'anti-CD20ʹ and 'Multiple Sclerosis' Expert opinion: BTK inhibition has shown effectiveness in preclinical models of CNS disease and MS clinical trials. Further studies are necessary to differentiate this approach from B cell depletion and to position it in the armamentarium of therapeutics.

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Natalizumab for Multiple Sclerosis: A Case in Point for the Impact of Translational Neuroimmunology

Cited by 23 publications

References 60 publications

Real-World Lab Data in Natalizumab Treated Multiple Sclerosis Patients Up to 6 Years Long-Term Follow Up

Real-World Lab Data in Natalizumab Treated Multiple Sclerosis Patients Up to 6 Years Long-Term Follow Up

Patient and treatment characteristics and safety outcomes of patients with relapsing-remitting multiple sclerosis treated with natalizumab in Greece: Results from the multicenter, 5-year prospective observational study ‘TOPICS greece’

Inhibition of Bruton´s tyrosine kinase as a novel therapeutic approach in multiple sclerosis

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