Cladribine tablets after treatment with natalizumab (CLADRINA) - rationale and design.

Background: Individual disease modifying therapies approved for multiple sclerosis (MS) have limited effectiveness and potentially serious side effects, especially when administered over long periods. Sequential combination therapy is a plausible alternative approach. Natalizumab is a monoclonal therapeutic antibody that reduces leukocyte access to the central nervous system that is associated with an increased risk of progressive multifocal leukoencephalopathy and disease reactivation after its discontinuation.

Side effects that occurred early in people with multiple sclerosis during the first year of treatment with cladribine tablets: a plain language summary.

People with multiple sclerosis (also shortened to MS) may have difficulties staying on treatment due to side effects. Cladribine tablets, approved for treating relapsing forms of MS, are given by mouth for four short periods over two years. The benefit of convenient dosing may be lost if side effects prevent people with MS from finishing their treatment.

Treatment-emergent adverse events occurring early in the treatment course of cladribine tablets in two phase 3 trials in multiple sclerosis.

Background: Treatment-emergent adverse events (TEAEs) that occur close to treatment initiation may negatively affect overall tolerability and adherence. It is important to develop a clear understanding of potential early TEAEs after initiating treatment with cladribine tablets.

Objective: To identify TEAEs that begin early in the course of treatment in patients enrolled in CLARITY and ORACLE-MS studies.

The implications of suboptimal year-1 outcomes with disease-modifying therapy in employees with multiple sclerosis.

Aim: Multiple sclerosis (MS) poses a substantial employer burden in medically related absenteeism and disability costs due to the chronic and debilitating nature of the disease. Although previous studies have evaluated relapse, nonadherence, discontinuation, and switching individually, little is known about their overall collective prevalence and implications in employees with MS treated with disease-modifying therapies (DMTs). This study evaluated the proportion of employees with MS with suboptimal DMT year-1 outcomes and to quantify the clinical and economic burden of suboptimal year-1 outcomes from a US employer perspective.

Early MRI outcomes in participants with a first clinical demyelinating event at risk of multiple sclerosis in the ORACLE-MS study.

Background: In the Phase 3, 96-week ORACLE-MS study, cladribine tablets 10 mg (3.5 or 5.25 mg/kg cumulative dosage over two years) significantly reduced lesions associated with multiple sclerosis versus placebo in participants following a first clinical demyelinating event (FCDE).

CLICK-MS and MASTER-2 Phase IV trial design: cladribine tablets in suboptimally controlled relapsing multiple sclerosis.

Cladribine tablets 10 mg (3.5 mg/kg cumulative dose over 2 years) are approved for the treatment of relapsing forms of multiple sclerosis (MS), including relapsing-remitting MS and active secondary progressive MS. However, real-world data on cladribine tablets are limited.

Accelerated axon loss in MOG35-55 experimental autoimmune encephalomyelitis (EAE) in myelin-associated glycoprotein-deficient (MAGKO) mice.

Myelin-associated glycoprotein (MAG) expressed by oligodendrocytes promotes the stability of axons but also impedes neural repair by inhibiting axon extension through lesioned white matter. We previously reported exacerbated axon losses in MAGKO as compared to wild type mice, 30days into experimental autoimmune encephalitis (EAE). Here, we report the time course of axon losses in EAE and show this occurs as early as 7days post-immunization, confirming MAG is protective against immune-mediated axon transection events.

Aging enhances classical activation but mitigates alternative activation in the central nervous system.

The roles of microglia and macrophages during neuroinflammation and neurodegenerative diseases remain controversial. To date, at least 2 activations states have been suggested, consisting of a classical response (M1) and the alternative response (M2). Identifying selective biomarkers of microglia that representative their functional activation states may help elucidate disease course and enable a better understanding of repair mechanisms.

Kv1.3 deletion biases T cells toward an immunoregulatory phenotype and renders mice resistant to autoimmune encephalomyelitis.

Increasing evidence suggests ion channels have critical functions in the differentiation and plasticity of T cells. Kv1.3, a voltage-gated K(+) channel, is a functional marker and a pharmacological target for activated effector memory T cells.

Chronological age impacts immunotherapy and monocyte uptake independent of amyloid load.

One vexing issue in biomedical research is the failure of many therapies to translate from success in animal models to effective treatment of human disease. One significant difference between the animal models and the human disease is the age of the subject. Cancer, stroke and Alzheimer's occur mainly in humans beyond the 75% mean survival age, while most mouse models use juvenile or young adult animals.

Cutting edge: The transcription factor Kruppel-like factor 4 regulates the differentiation of Th17 cells independently of RORγt.

Th17 cells play a significant role in inflammatory and autoimmune responses. Although a number of molecular pathways that contribute to the lineage differentiation of T cells have been discovered, the mechanisms by which lineage commitment occurs are not fully understood. Transcription factors play a key role in driving T cells toward specific lineages.

Trafficking CD11b-positive blood cells deliver therapeutic genes to the brain of amyloid-depositing transgenic mice.

A major question for gene therapy in brain concerns methods to administer therapeutic genes in a uniform manner over major portions of the brain. A second question in neuroimmunology concerns the extent to which monocytes migrate to the CNS in degenerative disorders. Here we show that CD11b+ cells (largely monocytes) isolated from the bone marrow of GFP (green fluorescent protein)-expressing donors spontaneously home to compacted amyloid plaques in the brain.

Aging analysis reveals slowed tau turnover and enhanced stress response in a mouse model of tauopathy.

We have extensively analyzed the biochemical and histochemical profiles of the tau protein from the rTg4510 transgenic mouse model in which the animals uniquely develop forebrain tau pathologies similar to those found in human tauopathies. Levels of several soluble phosphorylated tau species were highest at 1 month relative to later time points, suggesting that certain tau hyperphosphorylation events were insufficient to drive tangle formation in young mice. Despite a robust, pre-tangle-like accumulation of phospho-tau in 1-month-old mice, this material was cleared by 3 months, indicating that the young mouse brain either fails to facilitate tau insolubility or possesses an enhanced ability to clear tau relative to the adult.