Multiple Sclerosis, Dimethyl Fumarate, and Genetic Variation

Multiple sclerosis (MS) is a complex immune-mediated disease characterized by the immune system attacking the central nervous system (CNS), leading to demyelination and neurodegeneration. The disease manifests in various forms, with relapsing-remitting MS (RRMS) being the most common. Treatment strategies have evolved over the years, with disease-modifying therapies (DMTs) playing a pivotal role in managing the disease course. Dimethyl fumarate (DMF) is one such oral DMT approved for RRMS, known for its immunomodulatory and neuroprotective properties.

Mechanism of Action of Dimethyl Fumarate
DMF exerts its therapeutic effects primarily through the activation of the nuclear factor erythroid 2–related factor 2 (Nrf2) pathway. This activation leads to the upregulation of antioxidant response elements, enhancing the cellular defense against oxidative stress. Additionally, DMF inhibits the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway, reducing the expression of pro-inflammatory cytokines. These combined actions result in decreased inflammation and protection against neuronal damage in the CNS.

Clinical Efficacy of DMF
Clinical trials have demonstrated the efficacy of DMF in reducing relapse rates and delaying disability progression in RRMS patients. The DEFINE and CONFIRM studies showed that DMF significantly reduced the annualized relapse rate and the risk of disability progression compared to placebo. Moreover, MRI analyses indicated a reduction in the number and size of lesions in patients treated with DMF.

Adverse Effects and Lymphopenia
While DMF is generally well-tolerated, some patients experience adverse effects, the most notable being lymphopenia—a reduction in lymphocyte counts. Severe lymphopenia can increase the risk of opportunistic infections, including progressive multifocal leukoencephalopathy (PML). Regular monitoring of lymphocyte counts is recommended during DMF therapy to mitigate these risks.

Genetic Variations Influencing DMF Response
Polygenic Risk and Lymphopenia
Emerging research has identified common genetic variations that contribute to a polygenic risk model for DMF-induced lymphopenia. These findings highlight the role of pharmacogenomics in predicting adverse effects and guiding individualized treatment strategies in MS.

NOX3 Gene Variant
A study conducted by researchers at Karolinska Institutet uncovered a single nucleotide polymorphism (SNP) in the NOX3 gene associated with an enhanced therapeutic response to DMF. This variant increases monocytic production of reactive oxygen species (ROS), which is thought to enhance the drug’s immunomodulatory effects. Patients carrying this SNP showed improved clinical outcomes.

Transcriptomic Differences in Responders vs. Non-Responders
Transcriptomic analyses have further elucidated the molecular basis of differential DMF responses. Responders to DMF treatment exhibit distinct gene expression profiles compared to non-responders, including:
Downregulation of pro-inflammatory chemokines and cytokines:
CXCL10, CCR6, CXCR6, CCR9

Altered expression of T-cell and immune regulation genes:
CD8A, IL2RG, LAG3

Modulation of genes involved in the NF-κB signaling pathway
These gene expression differences suggest an immunological reprogramming effect of DMF in responders, potentially serving as predictive biomarkers for clinical response.

Future Directions

The integration of pharmacogenomic and transcriptomic data into clinical practice holds great promise for the personalized treatment of MS. By identifying genetic markers and immune signatures predictive of therapeutic response and side effect susceptibility, clinicians can tailor DMF therapy to each patient's unique genetic makeup. Further validation in larger cohorts is essential to translate these findings into routine clinical practice.

Disclaimer: This blog post is based on the provided research article and is intended for informational purposes only. It is not intended to provide medical advice. Please consult with a healthcare professional for any health concerns.

References:
Linker, R. A., & Haghikia, A. (2016). Dimethyl fumarate in multiple sclerosis: latest developments, evidence and place in therapy. Therapeutic advances in chronic disease, 7(4), 198-207. Fox, R. J., Miller, D. H., Phillips, J. T., Hutchinson, M., Havrdova, E., Kita, M., Yang, M., Raghupathi, K., Novas, M., Sweetser, M. T., Viglietta, V., Dawson, K. T., & CONFIRM Study Investigators (2012). Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis. The New England journal of medicine, 367(12), 1087–1097. https://doi.org/10.1056/NEJMoa1206328 Manouchehrinia, A., Kingwell, E., Carruthers, R., Marrie, R. A., Rotstein, D. L., Evans, C., ... & Kowalec, K. (2024, September). Common genetic variation and polygenicity associated with dimethyl fumarate-induced lymphopenia in multiple sclerosis. In MULTIPLE SCLEROSIS JOURNAL (Vol. 30, No. 3, pp. 608-609). 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND: SAGE PUBLICATIONS LTD. Carlström K, et al. Unexpected effect of MS drug. Karolinska Institutet. news.ki.se
Sánchez-Sanz, A., García-Martín, S., Sabín-Muñoz, J., Moreno-Torres, I., Elvira, V., Al-Shahrour, F., García-Grande, A., Ramil, E., Rodríguez-De la Fuente, O., Brea-Álvarez, B., García-Hernández, R., García-Merino, A., & Sánchez-López, A. J. (2023). Dimethyl fumarate-related immune and transcriptional signature is associated with clinical response in multiple sclerosis-treated patients. Frontiers in immunology, 14, 1209923. https://doi.org/10.3389/fimmu.2023.1209923