Cladribine Tablets Mode of Action, Learning from the Pandemic: A Narrative Review

Multiple sclerosis (MS) is an immune-mediated disease of the central nervous system, characterized by chronic, inflammatory, demyelinating, and neurodegenerative processes. MS management relies on disease-modifying drugs that suppress/modulate the immune system. Cladribine tablets (CladT) have been approved by different health authorities for patients with various forms of relapsing MS. The drug has been demonstrated to deplete CD4+ and CD8+ T-cells, with a higher effect described in the former, and to decrease total CD19+, CD20+, and naive B-cell counts. COVID-19 is expected to become endemic, suggesting its potential infection risk for immuno-compromised patients, including MS patients treated with disease-modifying drugs. We report here the available data on disease-modifying drug-treated-MS patients and COVID-19 infection and vaccination, with a focus on CladT. MS patients treated with CladT are not at higher risk of developing severe COVID-19. While anti-SARS-CoV-2 vaccination is recommended in all MS patients with guidelines addressing vaccination timing according to the different disease-modifying drugs, no vaccination timing restrictions seem to be necessary for cladribine, based on its mechanism of action and available evidence. Published data suggest that CladT treatment does not impact the production of anti-SARS-CoV-2 antibodies after COVID-19 vaccination, possibly due to its relative sparing effect on naïve B-cells and the rapid B-cell reconstitution following treatment. Slightly lower specific T-cell responses are likely not impacting the risk of breakthrough COVID-19. It could be stated that cladribine’s transient effect on innate immune cells likely contributes to maintaining an adequate first line of defense against the SARS-CoV-2 virus

Composite MRI measures and short-term disability in patients with clinically isolated syndrome suggestive of MS

The use of composite magnetic resonance imaging (MRI) measures has been suggested to better explain disability in patients with multiple sclerosis (MS). However, little is known about the utility of composite scores at the earliest stages of the disease

Natalizumab affects T-cell phenotype in multiple sclerosis: implications for JCV reactivation

The anti-CD49d monoclonal antibody natalizumab is currently an effective therapy against the relapsing-remitting form of multiple sclerosis (RRMS). Natalizumab therapeutic efficacy is limited by the reactivation of the John Cunningham polyomavirus (JCV) and development of progressive multifocal leukoencephalopathy (PML). To correlate natalizumab-induced phenotypic modifications of peripheral blood T-lymphocytes with JCV reactivation, JCV-specific antibodies (serum), JCV-DNA (blood and urine), CD49d expression and relative abundance of peripheral blood T-lymphocyte subsets were longitudinally assessed in 26 natalizumab-treated RRMS patients. Statistical analyses were performed using GraphPad Prism and R. Natalizumab treatment reduced CD49d expression on memory and effector subsets of peripheral blood T-lymphocytes. Moreover, accumulation of peripheral blood CD8+ memory and effector cells was observed after 12 and 24 months of treatment. CD4+ and CD8+ T-lymphocyte immune-activation was increased after 24 months of treatment. Higher percentages of CD8+ effectors were observed in subjects with detectable JCV-DNA. Natalizumab reduces CD49d expression on CD8+ T-lymphocyte memory and effector subsets, limiting their migration to the central nervous system and determining their accumulation in peripheral blood. Impairment of central nervous system immune surveillance and reactivation of latent JCV, can explain the increased risk of PML development in natalizumab-treated RRMS subjects

Rituximab suppresses disease activity after natalizumab withdrawal: an exploratory study

Background Natalizumab is highly effective in reducing multiple sclerosis disease activity; however it carries a risk of progressive multifocal leukoencephalopathy, that represents the main reason of drug discontinuation. After natalizumab withdrawal, reactivation of disease is soon observed and, until now, it is not known which treatment strategy should be followed after natalizumab discontinuation. Aim of this study is to evaluate rituximab efficacy in controlling disease activity after natalizumab withdrawal