Dimethyl fumarate for treatment of multiple sclerosis : clinical effects and mechanisms

Multiple sclerosis (MS) is a chronic immune-mediated disease of the central nervous system (CNS). Dimethyl fumarate (DMF) is one of the more recent additions to a rapidly expanding treatment repertoire for MS. While DMF has proven beneficial for relapsing-remitting MS (RRMS) patients, its clinical profile in relation to current alternatives as well as its immunological effects are less known. The overarching aim of the thesis was to assess the clinical effects of DMF for MS patients and investigate the underlying immunological mechanisms. Since both DMF and physical exercise is known to elicit an antioxidative response through the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2), we further explored their immunological commonalities.

In Paper I, we showed that treatment discontinuations with DMF were lower than with interferons, the main existing initial drug choice, among newly diagnosed MS patients in Stockholm and Västerbotten Counties. Risks of having persistent disease activity, as shown by relapses and/or magnetic resonance imaging (MRI), were similar to fingolimod and natalizumab; two more recent disease modulatory therapies (DMTs). The main finding of the article, however, was that the comparator treatment, rituximab (Mabthera®; RTX), had a superior clinical effect compared to all other DMTs in terms of both clinical effect and treatment discontinuation. In Paper II, we used Swedish nationwide data to compare DMF to interferons and glatiramer acetate, two common initial DMT choices, and fingolimod, which mainly is used as an escalation treatment. DMF proved more effective and had better drug survival in the first line comparison with interferons and glatiramer acetate but was less well tolerated than fingolimod when used second line. In Paper III, we explored the immunological mechanisms of DMF treatment in humans underlying the clinical effects we observed in Paper I and II. We observed that DMF increased production of reactive oxygen species (ROS) in monocytes and that methylation changes occurred earlier in monocytes than in T cells. In addition, monocyte counts and levels of oxidized fat in blood were higher among treatment responders compared to non-responders, supporting the notion that DMF act by increasing oxidative burst in myeloid cells. In Paper IV, we investigated the effects of aerobic exercise of moderate and high intensity on immune protein markers and kynurenine pathway (KP) metabolites in cerebrospinal fluid (CSF) and plasma of healthy participants. Participants in the high intensity group displayed changes in concentration of several immune markers and KP metabolites in both CSF and plasma, whereas participants in the moderate intensity group displayed few changes, suggesting a dose-response relationship. A separate comparison with DMF treated MS patients revealed few overlapping immune markers despite indications of overlapping mechanisms.

In conclusion, by affecting Nrf2 and oxidative burst, DMF has a unique mode of action among existing DMT options for RRMS, however, with limited overlap to effects mediated by physical exercise. Its clinical effectiveness is superior to traditional DMTs for newly diagnosed patients, but inferior to RTX. As an escalation DMT, it is less well tolerated than existing alternatives.

List of scientific papers

I. Comparative effectiveness of rituximab and other initial treatment choices for multiple sclerosis. Mathias Granqvist, Malin Boremalm, Amyar Poorghobad, Anders Svenningsson, Jonatan Salzer, Thomas Frisell, Fredrik Piehl. JAMA Neurology. 2018 Mar 1;75(3):320-327.
https://doi.org/10.1001/jamaneurol.2017.4011

II. Comparative effectiveness of dimethyl fumarate as the initial and secondary treatment for MS. Mathias Granqvist, Joachim Burman, Martin Gunnarsson, Jan Lycke, Petra Nilsson, Tomas Olsson, Peter Sundström, Anders Svenningsson, Magnus Vrethem, Thomas Frisell, Fredrik Piehl. Multiple Sclerosis Journal. 2019 Aug 8:1352458519866600.
https://doi.org/10.1177/1352458519866600

III. Therapeutic efficacy of dimethyl fumarate in relapsing-remitting multiple sclerosis associates with ROS pathway in monocytes. Karl Carlström, Ewoud Ewing, Mathias Granqvist*, Alexandra Gyllenberg*, Shahin Ainehband, Sara Lind Enoksson, Antonio Checa, Tejaswi Badam, Jesse Huang, David Gomez-Cabrero, Mika Gustafsson, Faiez Al Nimer, Craig Wheelock, Ingrid Kockum, Tomas Olsson, Maja Jagodic, Fredrik Piehl. *These authors contributed equally to this work. Nature Communications. 2019 Jul 12;10(1):3081.
https://doi.org/10.1038/s41467-019-11139-3

IV. Effects from physical exercise on measured soluble immune markers and kynurenine pathway metabolites in the intrathecal and peripheral compartment in healthy subjects. Josef Isung, Mathias Granqvist, Ada Trepci, Jesse Huang, Lilly Schwieler, Marie Kierkegaard, Sophie Erhardt, Jussi Jokinen, Fredrik Piehl. [Manuscript]