Effects of cladribine on intrathecal and peripheral B and plasma cells.

Abstract

Introduction: Cladribine is a deoxyadenosine analogue that can penetrate the blood-brain barrier. It is used to treat multiple sclerosis (MS). However, the mechanistic understanding of the effect of this highly effective therapy on B cells and plasma cells in the central nervous system compartment is limited. The CLADRIPLAS study examined the effect of cladribine on peripheral and intrathecal B and plasma cell biology in people with MS.

Methods: Thirty-eight people with progressive MS ineligible for- or rejecting-treatment with licenced therapies were recruited and supplied a baseline lumbar puncture. Those exhibiting gadolinium-enhancing or new/enlarging T2 magnetic resonance imaging lesions and/or elevated neurofilament levels were offered subcutaneous cladribine (Litak®). Seven people were eligible; one person died before treatment, and only five completed the first year of treatment. Twenty-two ineligible people were willing to provide a repeat lumbar puncture 12 months later.

Results: The CLADRIPLAS study found no evidence of a difference in the odds of a positive cerebrospinal fluid oligoclonal band result between the cladribine-treated and untreated group. This is probably explained by microarray and in vitro studies, which demonstrated that plasmablasts and notably long-lived plasma cells are relatively resistant to the cytotoxic effect of cladribine compared with memory B cells at physiological concentrations. This was consistent with the loss of intracellular deoxycytidine kinase during antibody-secreting cell differentiation.

Conclusion: CLADRIPLAS indicates that cerebrospinal fluid oligoclonal bands are not rapidly eliminated in most people with MS. This may be explained by the relative lack of direct cytotoxic action of cladribine on long-lived plasma cells.