Discontinuation of First-Line Disease-Modifying Therapy in Patients With Stable Multiple Sclerosis: The DOT-MS Randomized Clinical Trial.

Importance: Increasing numbers of people with multiple sclerosis (MS) use disease-modifying therapy (DMT). Long-term stable disease while taking such medications provides a rationale for considering DMT discontinuation given patient burden, costs, and potential adverse effects of immunomodulating therapy.

Objective: To investigate whether first-line DMT can be safely discontinued in patients with long-term stable MS.

Serum neurofilament light and glial fibrillary acidic protein levels are not associated with wearing-off symptoms in natalizumab-treated multiple sclerosis patients.

Background: Biomarkers of neuronal and axonal damage (serum neurofilament light (sNfL) and serum glial fibrillary acidic protein (sGFAP)) may provide insight into the aetiology of natalizumab wearing-off symptoms (WoSs).

Objectives: We investigated the longitudinal association between and predictive value of sNfL and sGFAP and the occurrence of WoS in MS patients treated with natalizumab.

Methods: We performed longitudinal measurements of sNfL and sGFAP in NEXT-MS trial participants who completed a questionnaire about WoS.

Prospective trial of natalizumab personalised extended interval dosing by therapeutic drug monitoring in relapsing-remitting multiple sclerosis (NEXT-MS).

Background: Extended interval dosing (EID) of natalizumab is a promising strategy to optimise treatment in multiple sclerosis (MS). Personalised EID by therapeutic drug monitoring can enable further extension of treatment intervals.

Methods: The NEXT-MS trial is an investigator-initiated prospective phase IV non-randomised study.

The fat embolism syndrome as a cause of paraplegia.

The fat embolism syndrome is a well-known complication in trauma patients. We describe a rare case of traumatic fat embolism that leads to paraplegia. A 19-year-old male motorcycle accident victim was presented to our hospital.

Natalizumab-associated progressive multifocal leukoencephalopathy is not preceded by elevated drug concentrations.

Background: In recent years, a small but increasing number of neurologists choose to extend dose intervals of natalizumab with the aim of reducing the risk of progressive multifocal leukoencephalopathy (PML). This idea is based on the hypothesis that high drug concentrations increase the risk of PML.

Objective: We investigated the relation between longitudinal natalizumab concentrations in patients who developed PML and patients who did not develop PML.

MRI criteria differentiating asymptomatic PML from new MS lesions during natalizumab pharmacovigilance.

Objective: Differentiation between progressive multifocal leukoencephalopathy (PML) and new multiple sclerosis (MS) lesions on brain MRI during natalizumab pharmacovigilance in the absence of clinical signs and symptoms is challenging but is of substantial clinical relevance. We aim to define MRI characteristics that can aid in this differentiation.

Methods: Reference and follow-up brain MRIs of natalizumab-treated patients with MS with asymptomatic PML (n=21), or asymptomatic new MS lesions (n=20) were evaluated with respect to characteristics of newly detected lesions by four blinded raters.

Diagnostic performance of brain MRI in pharmacovigilance of natalizumab-treated MS patients.

Background: In natalizumab-treated multiple sclerosis (MS) patients, magnetic resonance imaging (MRI) is considered as a sensitive tool in detecting both MS disease activity and progressive multifocal leukoencephalopathy (PML).

Objective: To investigate the performance of neuroradiologists using brain MRI in detecting new MS lesions and asymptomatic PML lesions and in differentiating between MS and PML lesions in natalizumab-treated MS patients. The secondary aim was to investigate interrater variability.

MRI characteristics of early PML-IRIS after natalizumab treatment in patients with MS.

Objective: The early detection of MRI findings suggestive of immune reconstitution inflammatory syndrome (IRIS) in natalizumab-associated progressive multifocal leukoencephalopathy (PML) is of crucial clinical relevance in terms of treatment decision-making and clinical outcome. The aim of this study was to investigate the earliest imaging characteristics of PML-IRIS manifestation in natalizumab-treated patients with multiple sclerosis and describe an imaging pattern that might aid in the early and specific diagnosis.

Methods: This was a retrospective study assessing brain MRI of 26 patients with natalizumab-associated PML presenting with lesions suggestive of PML-IRIS during follow-up.

Longitudinal JCV serology in multiple sclerosis patients preceding natalizumab-associated progressive multifocal leukoencephalopathy.

The presence of anti-John Cunningham Virus (JCV) antibodies is a risk factor for the development of progressive multifocal leukoencephalopathy (PML) in MS patients treated with natalizumab. It has been suggested that an increase in serum anti-JCV antibody index precedes the development of PML. We here describe extensive longitudinal serum anti-JCV antibody indexes of four MS patients who developed PML.

MRI pattern in asymptomatic natalizumab-associated PML.

Objective: To investigate the MRI manifestation pattern of asymptomatic natalizumab-associated progressive multifocal leukoencephalopathy (PML) in patients with multiple sclerosis (MS).

Methods: 18 patients with MS with natalizumab-associated PML lesions on MRI were included. In 6 patients, the PML lesions were identified on MRI prospectively and in 12 patients PML lesions were identified retrospectively.

Diagnosis of asymptomatic natalizumab-associated PML: are we between a rock and a hard place?

The diagnosis of natalizumab-associated progressive multifocal leukoencephalopathy (PML) in multiple sclerosis patients in an asymptomatic stage is crucial since it is associated with better clinical outcome measures. Current diagnostic criteria on PML diagnosis in asymptomatic patients require the detection of JC virus and corresponding imaging findings. Magnetic resonance imaging (MRI) is the most sensitive diagnostic method for these purposes.

The impact of pre-analytical variables on the stability of neurofilament proteins in CSF, determined by a novel validated SinglePlex Luminex assay and ELISA.

Background: Neurofilament (Nf) proteins have been shown to be promising biomarkers for monitoring and predicting disease progression for various neurological diseases. The aim of this study was to evaluate the effects of pre-analytical variables on the concentration of neurofilament heavy (NfH) and neurofilament light (NfL) proteins.

Methods: For NfH an in-house newly-developed and validated SinglePlex Luminex assay was used; ELISA was used to analyze NfL.

Drug interference in immunogenicity assays depends on valency.

Direct comparison of immunogenicity data is hampered by differential drug interference in different assay formats. In this paper we identify a drug-related factor that influences the extent of drug interference. We systematically investigated the influence of drug valency of different antibody-derived biologicals on the drug interference, using mono- and bivalent formats of adalimumab as a model system.

Safety, anxiety and natalizumab continuation in JC virus-seropositive MS patients.

The use of natalizumab in multiple sclerosis has been restricted by the risk of progressive multifocal leukoencephalopathy (PML). JC virus carriership, duration of natalizumab treatment and past immunosuppression are known risk factors. This has allowed for calculated risk assessment for individual patients to be implemented.

Clinical relevance of serum natalizumab concentration and anti-natalizumab antibodies in multiple sclerosis.

Background: Antibodies against natalizumab have been found in 4.5-14.1% of natalizumab-treated multiple sclerosis (MS) patients.

Natalizumab remains detectable in patients with multiple sclerosis long after treatment is stopped.

Natalizumab is frequently used as a treatment for multiple sclerosis (MS). The occurrence of progressive multifocal leukoencephalopathy (PML) in natalizumab-treated patients indicates that its prominent beneficial effects need to be balanced against the risks. Also, cessation of the drug seems to be associated with recurrence of disease activity.

Antibodies against aquaporin-4 in neuromyelitis optica: distinction between recurrent and monophasic patients.

The detection of antibodies against aquaporin-4 (AQP4) has improved the diagnosis of neuromyelitis optica (NMO). We evaluated a recently established cell-based anti-AQP4 assay in 273 patients with inflammatory CNS demyelination. The assay had a specificity of 99% and a sensitivity of 56% to detect all NMO patients and of 74% to detect the recurrent NMO patients, similar to the initial studies reported.

Measurement of serum levels of natalizumab, an immunoglobulin G4 therapeutic monoclonal antibody.

Human immunoglobulin G4 (IgG4) is a poor trigger of effector functions and, therefore, is the preferred subclass for therapeutic monoclonal antibodies that merely aim to block their in vivo targets. An example is natalizumab, a recombinant IgG4 antibody directed against α4-integrin and used for treatment of multiple sclerosis. Efficient treatment requires that the pharmacokinetics of therapeutic monoclonal antibodies can be accurately monitored.

Natalizumab drug holiday in multiple sclerosis: poorly tolerated.

It has been suggested that natalizumab-associated progressive multifocal leukoencephalopathy may be prevented by structured interruptions of treatment. Evidence supporting such a drug holiday is not yet available. Here we present initial observations in 10 multiple sclerosis patients who were stringently monitored up to 6 months after discontinuation of the infusions.

T lymphocytes impair P-glycoprotein function during neuroinflammation.

The ATP-binding cassette (ABC) transporter P-glycoprotein (P-gp; ABCB1) is highly expressed at the blood-brain barrier (BBB). P-gp actively secretes and keeps the central nervous system (CNS) safe from body-born metabolites, but also from drugs and food components, emphasising the importance of its optimal function to maintain brain homeostasis. Here we demonstrate that vascular P-gp expression and function are strongly decreased during neuroinflammation.