Cognitive changes in MS – what can teriflunomide do?
In Phase III clinical trials, teriflunomide demonstrated its ability to slow down brain tissue atrophy in patients with relapsing-remitting multiple sclerosis (RRMS). What impact did the treatment have on the cognitive state of these patients?
Introduction
Cognitive impairment affects 40–65% of patients with MS. One of the underlying causes may be the acceleration of total brain volume loss (BVL), which is generally present from the early stages of the disease. In a post hoc analysis of the TEMSO study, the beneficial effect of teriflunomide on reducing the rate of BVL was previously demonstrated. The question remains about its real impact on cognitive abilities.
Teriflunomide is an immunomodulatory agent with anti-inflammatory effects that selectively and reversibly inhibits the mitochondrial enzyme dihydroorotate dehydrogenase (DHO-DH), functionally related to the respiratory chain. Inhibition of DHO-DH generally reduces the proliferation of rapidly dividing cells dependent on de novo pyrimidine synthesis. The exact mechanism of teriflunomide's therapeutic effect in MS is not known but is based on reducing the number of lymphocytes.
Methodology of the analysis
The authors of the recently published work analyzed the results of the TEMSO study and its extension. Specifically, they examined data from 709 patients taking teriflunomide at a dose of 14 mg daily. These patients were divided into three groups based on BVL over 2 years (group with the smallest BVL: ≤ 0.52%; group with medium BVL: 0.52–2.18%; group with the largest BVL: > 2.18%). Cognitive changes in MS patients were measured using the Paced Auditory Serial Addition Test (PASAT-3).
The PASAT measures the speed of processing auditory stimuli, flexibility, and calculation ability. It was originally developed in 1977 to monitor the cognitive state of patients after head trauma. In 1989, Stephen M. Rao adjusted the speed of stimuli for MS patients, and this test has since been widely used in clinical studies. It consists of a series of 60 numbers played at intervals of 3 (PASAT-3) or 2 (PASAT-2) seconds. The patient is tasked with adding the last stated number to the previous number in the series. The resulting score is the number of correct answers (with a maximum of 60 points).
Results
Over 2 years, patients taking 14 mg of teriflunomide daily showed a significant improvement in the PASAT-3 Z-score compared to participants taking a placebo. During the 3-year extension of the clinical study, the improvement in the groups with the smallest and medium BVL was significantly greater than in the group with the largest BVL. Mediation analysis confirmed that 44% of teriflunomide's effect on cognitive abilities is due to its effects on BVL.
Conclusion
In the presented analysis, teriflunomide positively influenced the cognitive abilities of MS patients. The exact mechanism underlying this therapeutic effect is not fully understood. However, according to this analysis, approximately 44% of teriflunomide's effect on cognitive abilities can be explained by its beneficial effect on the rate of total brain volume loss.
(dos)
Sources:
1. Sprenger T., Kappos L., Sormani M. P. et al. Effects of teriflunomide treatment on cognitive performance and brain volume in patients with relapsing multiple sclerosis: post hoc analysis of the TEMSO core and extension studies. Mult Scler 2022 Apr 29: 13524585221089534, doi: 10.1177/13524585221089534.
2. SPC Aubagio. Available at: www.ema.europa.eu/en/documents/product-information/aubagio-epar-product-information_cs.pdf
Did you like this article? Would you like to comment on it? Write to us. We are interested in your opinion. We will not publish it, but we will gladly answer you.
