Exploring the association of disease-modifying therapies for multiple sclerosis and BTK inhibitors with epilepsy

Afsaneh Shirani; Nil Saez-Calveras; Jack P Antel; Moein Yaqubi; Wayne Moore; Amy L Brewster; Olaf Stuve

doi:10.1177/17562864241276204

Exploring the association of disease-modifying therapies for multiple sclerosis and BTK inhibitors with epilepsy

Ther Adv Neurol Disord. 2024 Sep 21:17:17562864241276204. doi: 10.1177/17562864241276204. eCollection 2024.

Authors

Afsaneh Shirani¹, Nil Saez-Calveras^{2

3}, Jack P Antel⁴, Moein Yaqubi⁵, Wayne Moore⁶, Amy L Brewster⁷, Olaf Stuve^{8

9

10}

Affiliations

¹ Department of Neurological Sciences, University of Nebraska Medical Center, Omaha, NE, USA.
² Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
³ Parkland Memorial Hospital, Dallas, TX, USA.
⁴ Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC, Canada.
⁵ Department of Neuroscience, Montreal Neurological Institute, McGill University, Montreal, QC, Canada.
⁶ Department of Pathology and Laboratory Medicine, and International Collaboration on Repair Discoveries (ICORD), University of British Columbia, Vancouver, BC, Canada.
⁷ Department of Biological Sciences, Southern Methodist University, Dallas, TX, USA.
⁸ Department of Neurology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9096, USA.
⁹ Neurology Section, VA North Texas Health Care System, Dallas, TX, USA.
¹⁰ Peter O'Donnell Jr. Brain Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.

Abstract

Background: Multiple lines of evidence suggest a role of inflammation in epilepsy. Seizure incidence in patients with multiple sclerosis (MS) is twofold to threefold higher than the age-matched general population.

Objectives: To explore the association of MS disease-modifying therapies (DMTs) and FDA-approved Bruton tyrosine kinase inhibitors (for lymphocytic malignancies) with the occurrence of epilepsy using the US Food and Drug Administration Adverse Event Reporting System (FAERS) database.

Design: Secondary analysis of the FAERS database.

Methods: We conducted a disproportionality analysis of FAERS between 2003-Q4 and 2023-Q3. MS DMTs and the Bruton tyrosine kinase inhibitor, ibrutinib, were included in the analysis. An inverse association was defined by a 95% confidence interval (CI) upper limit of reporting odds ratio (ROR) <1.

Results: We found an inverse association of ibrutinib, ocrelizumab, ofatumumab, rituximab, and teriflunomide with epilepsy. The strongest inverse association was seen with ibrutinib (ROR: 0.338; 95% CI: 0.218-0.524).

Conclusion: Our findings suggest the possibility of considering these medications for repurposing opportunities in epilepsy and support a potential pathogenic role of leukocyte subsets in seizure perpetuation.

Keywords: BTK inhibitors; FAERS database; disease-modifying therapies; epilepsy; multiple sclerosis.

Plain language summary

How multiple sclerosis treatments and Bruton tyrosine kinase inhibitors may be linked to epilepsy The research presented in this manuscript attempts to elucidate the potential relationship between inflammation and epilepsy. Multiple sclerosis (MS) is the most common inflammatory disorder of the brain and spinal cord in humans. There are over 20 FDA-approved disease-modifying therapies (DMTs) for MS. Other anti-inflammatory agents called Bruton tyrosine kinase (BTK) inhibitors are in clinical development. We show that the use of some DMTs and a BTK inhibitor appear to be associated with a lower chance of epilepsy.