Soluble biomarkers to inform on pathophysiological mechanisms and for tailoring therapy in multiple sclerosis

This doctoral thesis explores the use of soluble biomarkers to elucidate pathophysiological mechanisms and inform tailored therapeutic strategies in multiple sclerosis (MS). The work is based on four studies that collectively address key aspects of MS diagnosis and treatment, focusing on B cell depleting therapies and their immunological effects.

Firstly, in Paper I, we investigated the diagnostic accuracy of kappa free light chains (KFLC) compared to oligoclonal bands (OCB) in MS. The findings suggest that KFLC metrics, especially the KFLC intrathecal fraction and CSF KFLC, perform comparably to OCB, offering a potential alternative or complementary biomarker for MS diagnosis.

In Paper II, we compared the effects of ocrelizumab (OCR) and rituximab (RTX) on immunoglobulin levels and safety in MS patients. Results indicate that OCR leads to a more pronounced reduction in immunoglobulin G (IgG) levels and CD19 numbers compared to low-dose RTX, with slightly higher rates of adverse events associated with OCR. Continuing with Paper III, we extended the analysis of RTX's impact on immunoglobulin levels over a longer follow-up period. A modest but significant decline in IgG and immunoglobulin M (IgM) levels was observed, with the decline influenced by factors such as previous treatments, age, and duration of RTX therapy.

Lastly, in Paper IV, we focused on the immunological effects of RTX on T cell subsets. We revealed that RTX selectively reduces specific memory CD4 T cell populations, including Th17 and Th1.17 effector cells, which are implicated in MS inflammatory activity. The study also highlights the role of genetic factors, such as the DRB1*15:01 allele, in modulating T cell responses.

Overall, this thesis underscores the utility of soluble biomarkers, particularly KFLC, in enhancing MS diagnostics. At the same time, IgG and IgM are highlighted to monitor the immunological impact of B cell depleting therapies. The findings contribute to a better understanding of MS pathophysiology and suggest potential avenues for optimising treatment strategies.

List of scientific papers

Shared authorship #

I. Duell F, Evertsson B, Al Nimer F, Sandin Å, Olsson D, Olsson T, Khademi M, Hietala MA, Piehl F, Hansson M. Diagnostic accuracy of intrathecal kappa free light chains compared with OCBs in MS. Neurol Neuroimmunol Neuroinflamm. 2020 Jun 11;7(4):e775. https://doi.org/10.1212/NXI.0000000000000775

II. Evertsson B#, Hoyt T#, Christensen A, Nimer FA, Foley J#, Piehl F#. A comparative study of tolerability and effects on immunoglobulin levels and CD19 cell counts with ocrelizumab vs low dose of rituximab in multiple sclerosis. Mult Scler J Exp Transl Clin. 2020 Oct 12;6(4):2055217320964505. https://doi.org/10.1177/2055217320964505

III. Hallberg S#, Evertsson B#, Lillvall E, Boremalm M, de Flon P, Wang Y, Salzer J, Lycke J, Fink K, Frisell T, Al Nimer F, Svenningsson A. Hypogammaglobulinaemia during rituximab treatment in multiple sclerosis: A Swedish cohort study. Eur J Neurol. 2024 Aug;31(8):e16331. Epub 2024 May 25. https://doi.org/10.1111/ene.16331

IV. Evertsson B, Ruffin N, Theorell J, Huang J, Asplund Högelin K, Khademi K, Piehl F, Nimer FA. B cell depletion has a distinct influence on T cell immunity by decreasing effector memory CD4 Th17 and Th1.17 subsets in multiple sclerosis. [Manuscript]