Background. Cladribine is a deoxyadenosine analogue that can penetrate the blood-brain barrier. It is used to treat multiple sclerosis. 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. Objectives. 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 twelve months later. Results. The CLADRIPLAS study found no evidence of a difference in the odds of a positive cerebrospinal fluid oligoclonal band (cOCB) 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 to memory B cells at physiological concentrations. This was consistent with the loss of intracellular deoxycytidine kinase during antibody-secreting cell differentiation. Discussion. CLADRIPLAS indicates that cOCB 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.

K. Allen-Philbey reports no disclosures relevant to the manuscript. S. Stephenson reports no disclosures relevant to the manuscript. G. Doody has received honoraria from Takeda and has grant support from CSL and UCB. A. MacDougall reports no disclosures relevant to the manuscript. M. Aboulwafaali reports no disclosures relevant to the manuscript. F. Ammoscato reports no disclosures relevant to the manuscript. M. Andrews reports no disclosures relevant to the manuscript. S. Gnanapavan has received honoraria from Biogen Idec, Sanofi Genzyme, Janssen Cilag, Merck, Neurodiem, Novartis, Roche, and Teva and grant support from ECTRIMS, Genzyme, Merck, National MS Society, Takeda, UK MS Society, NIHR and NHSx. G. Giovannoni has received honoraria and meeting support from AbbVie Biotherapeutics, Biogen, Canbex, Ironwood, Novartis, Merck, Merck Serono, Roche, Sanofi Genzyme, Synthon, Teva, and Vertex. He also serves as chief editor for Multiple Sclerosis and Related Disorders. S. Grigoriadou reports no disclosures relevant to the manuscript. A. Hickey reports no disclosures relevant to the manuscript. D. Holden reports no disclosures relevant to the manuscript. H. Lock reports no disclosures relevant to the manuscript. M. Papachatzaki reports no disclosures relevant to the manuscript. I. Redha reports no disclosures relevant to the manuscript. D. Baker has received compensation from InMuneBio, Lundbeck, Merck, Novartis, Rock, and Teva. R. Tooze has served in an advisory role for Medicxi Venures and received research support from UCB. K. Schmierer has received research support from Biogen, Merck KGaA, and Novartis, speaking honoraria from, and/or served in an advisory role for, Biogen, EMD Serono, Merck KGaA, Novartis, Roche, Sanofi-Genzyme, and TG Therapeutics; and remuneration for teaching activities from AcadeMe and Medscape.

CLADRIPLAS was supported by MS Society grant #69.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

CLADRIPLAS was approved by the North of Scotland Research Ethics Committee 1 (Integrated Research Application System ID: 240360). The Leeds East Research Ethics Committee approved the in vitro studies of the effect of cladribine on the different stages of B cell differentiation (Ref: 07/Q1206/47).

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Data and supplementary materials are available on request.