Anti-CD20 therapy in multiple sclerosis : clinical and paraclinical outcomes

Multiple sclerosis is a chronic inflammatory disease of the central nervous system and the most common non-traumatic cause of neurological disability in young adults. Rituximab is a B-cell depleting drug targeting the CD20 epitope on B-cells, which drive inflammation in relapsing-remitting multiple sclerosis by acting as antigen-presenting cells to activate T-cell responses against central nervous system autoantigens. Despite not being formally approved for this disease, rituximab is Sweden´s most common multiple sclerosis disease-modifying treatment. The objective of this thesis was to through observational studies increase the knowledge base for the risk-benefit of rituximab in multiple sclerosis by determining clinical and paraclinical outcomes, in comparison with drugs approved for this disease, in real-world cohorts.

Study I is a multicentre retrospective study of 241 relapsing-remitting multiple sclerosis patients switching from interferon-β or glatiramer acetate to rituximab, natalizumab or fingolimod due to breakthrough disease. Our results indicate a superior efficacy with rituximab and natalizumab compared to fingolimod, a similar tolerability profile between treatments, but a significantly higher overall drug persistence with rituximab. Study II is a single-centre retrospective study of all 808 relapsing-remitting multiple sclerosis patients ever treated with rituximab at Karolinska. Data on reason for therapy stop, new therapies and clinical and radiological outcomes after rituximab termination were recorded. Rituximab was stopped in 92 (11%) cases, with 7 (< 1%) of all patients doing so due to lack of efficacy. Pregnancy plans and adverse events were the most frequent reasons for stopping therapy and disease activity remained low regardless if a new disease-modifying drug was started or not. The cross-sectional Study III surveyed frequency of anti-drug antibodies and their potential impact on efficacy and safety outcomes in 339 rituximab treated multiple sclerosis patients. Presence of anti-drug antibodies was high; 37% and 26% in patients with relapsing-remitting and progressive disease, respectively. High anti-drug antibody titres were associated with incomplete B-cell depletion, but not with reduced clinical effectiveness or tolerability. Study IV is a retrospective study comparing rates of regional atrophy and T1-weighted lesion volume accumulation on magnetic resonance imaging in relapsing-remitting multiple sclerosis patients starting rituximab (n = 15) or interferon-β (n = 67) as initial treatment. The rituximab group had lower rate of T1-weighted lesion volume accumulation, but higher volume loss in some brain regions compared to interferon-β, possibly due to pseudoatrophy.

The results add to a growing body of evidence suggesting equal or better effectiveness and tolerability of rituximab compared to commonly used drugs in relapsing-remitting multiple sclerosis. Furthermore, rituximab interruption is not associated with a rebound effect and anti-drug antibodies, while frequent, do not seemingly impact on therapeutic effect or tolerability. Lastly, rituximab is associated with slower brain lesion volume accumulation compared to a first-line treatment. The finding of a higher rate of regional brain volume loss with rituximab treatment, however, warrants further studies conducted over longer time periods.

List of scientific papers

I. Boremalm M*, Juto A*, Axelsson M, Novakova L, Frisell T, Svenningsson A, Lycke J, Piehl F, Salzer J. Natalizumab, rituximab and fingolimod as escalation therapy in multiple sclerosis. European Journal of Neurology 2019;26(8):1060-7. *These authors contributed equally.
https://doi.org/10.1111/ene.13936

II. Juto A, Fink K, Al Nimer F, Piehl F. Interrupting rituximab treatment in relapsing-remitting multiple sclerosis; no evidence of rebound disease activity. Multiple Sclerosis and Related Disorders. 2020;37:101468.
https://doi.org/10.1016/j.msard.2019.101468

III. Dunn N*, Juto A*, Ryner M, Manouchehrinia A, Piccoli L, Fink K, Piehl F, Fogdell-Hahn A. Rituximab in multiple sclerosis: Frequency and clinical relevance of anti-drug antibodies. Multiple Sclerosis Journal. 2018;24(9):1224-33. *These authors contributed equally.
https://doi.org/10.1177/1352458517720044

IV. Juto A, Ouellette R, Frisell T, Piehl F, Granberg T. Greater T1 lesion volume accumulation rate with interferons compared to rituximab in treatment-naïve relapsing-remitting multiple sclerosis patients. [Manuscript]