Cladribine tablets in the new multiple sclerosis era

Abstract

Multiple sclerosis (MS) is an autoimmune condition characterized by inflammatory demyelination that leads to irreversible neurological damage within the central nervous system (CNS). This review examines the therapeutic potential and clinical efficacy of cladribine tablets (CladT) for treating MS, focusing on the immune reconstitution mechanism and CNS effects. CladT represents a notable advance among disease-modifying therapies for MS due to its selective targeting of lymphocytes, resulting in sustained yet reversible immune modulation. This action leads to a substantial reduction in memory B cells while preserving the innate immune system and maintaining immunoglobulin levels, thereby mitigating the risks of secondary autoimmunity and infection. Cladribine appears to penetrate the blood-brain barrier, as indicated by cerebrospinal fluid (CSF) studies from parenteral cladribine use. In MS, CladT is associated with reductions in CSF immunological markers, such as oligoclonal bands and neurofilament light chain levels; it also mitigates acute and chronic inflammation, as evidenced, respectively, by consistent reductions in unique active lesions, and significant decrease in slowly expanding lesions in patients with predominant grey matter damage. These findings underscore the potential of CladT in reducing disability accumulation and improving long-term clinical outcomes in patients with highly active disease. By synthesizing data from clinical trials and real-world studies, this review underscores the effectiveness of CladT in reducing relapse rates, disability progression and magnetic resonance imaging-detected disease activity and emphasizes the importance of early high-efficacy treatment for optimizing long-term outcomes. Furthermore, emerging biomarkers are discussed as potential tools for predicting individual responses to therapy, thereby enabling more personalized treatment strategies. This review also provides valuable insights into the positive impact of CladT on quality of life measures, long-term outcomes and safety profile, all of which support the use of CladT in the evolving landscape of MS management.

Keywords: B cells; T cells; cladribine tablets; disease-modifying therapy; multiple sclerosis.

Figure 1.

The dynamics of immune cell populations across different phases during CladT treatment: reduction phase, repopulation phase and reconstitution phase. The adaptive and innate immune cells are depicted, highlighting changes in B cells (blue), T cells (green), neutrophils (lilac) and monocytes (light purple). The left side outlines the transitions in immune cell populations, indicating a decrease in memory B cells and T cell subsets, followed by an increase in regulatory, transitional and naïve B cells. The right-side details cytokine-producing cells, differentiating between pro-inflammatory and anti-inflammatory responses. The diagram shows a decrease in IL-6+ and GM-CSF+ CD4+ and CD8+ T cells, while memory IL-10+ B cells and IL-4+ CD4+ and CD8+ T cells increase, indicating a shift towards an anti-inflammatory phenotype. CladT, cladribine tablets; GM-CSF, granulocyte-macrophage colony-stimulating factor; IL-6, interleukin-6.

Figure 2.

The central effects of CladT. (a) Reduction of OCB in the CSF of patients with MS treated with CladT (clad). (b) Reduction of NfL levels in CSF samples collected pre- and post-treatment. (c) Reduction of protein levels of CXCL13 in the CSF and the transcripts of the CXCL13 receptor (CXCR5) in peripheral blood. (d) The role of CladT in preventing further brain atrophy is associated with a reduction in cumulative SELs and CUA lesions in patients with MS with grey matter damage. CladT, cladribine tablets; CSF, cerebrospinal fluid; CUA, combined unique active; MS, multiple sclerosis; NfL, neurofilament light chain; OCB, oligoclonal bands; SEL, slowly expanding lesion.

Figure 3.

Peripheral and central combined effects of CladT on clinical outcomes. The distinct yet interconnected peripheral and central effects of CladT on clinical outcomes in patients. The left circle represents peripheral effects, highlighting the involvement of B cells (blue) and T cells (green). The right circle depicts central effects related to neuroinflammation and neuroprotection. The central area showcases key clinical and radiological outcomes, including early onset of action measured by conventional MRI parameters (reduction in T1 Gd+, CUA and active T2 lesions); reduction in relapse-free rates; impact on disability accumulation in terms of EDSS score, HRQoL, SDMT, c-PIRA. These findings underscore the multifaceted role of CladT in improving patient outcomes through both peripheral and central mechanisms. 6mCDP, 6 months confirmed disability progression; 9-HPT, 9-Hole Peg Test; CladT, cladribine tablets; c-PIRA, combined progression independent of relapse activity; CUA, combined unique active lesions; EDSS; Expanded Disability Status Scale; Gd+, gadolinium positive; HRQoL, Health-Related Quality of Life; MRI, magnetic resonance imaging; SDMT, Symbol Digit Modalities Test; T25FW, Timed 25-Foot-Walk.