Abstract
We previously demonstrated that patients with multiple sclerosis (MS) of high serum Sema4A levels are resistant to IFN-β therapy. To further elucidate the role of serum Sema4A as a biomarker for therapeutic stratification in MS patients, it is important to clarify the efficacy of other disease-modifying drugs (DMD) in those with high serum Sema4A levels. Thus, in this study we investigated whether fingolimod has beneficial effects on MS patients with high Sema4A levels. We retrospectively analyzed annualized relapse rate (ARR) and Expanded Disability Status Scale (EDSS) change in 56 relapsing—remitting multiple sclerosis (RRMS) patients who had been treated with fingolimod, including those who switched from IFN-β therapy. The levels of Sema4A in the sera were measured by sandwich ELISA. The implications of Sema4A on the efficacy of fingolimod were investigated by administering recombinant Sema4A-Fc and fingolimod to mice with experimental autoimmune encephalomyelitis (EAE). Retrospective analysis of MS cohort (17 high Sema4A and 39 low Sema4A) demonstrated the effectiveness of fingolimod in those with high serum Sema4A levels, showing reduction of ARR (from 1.21 to 0.12) and EDSS progression (from 0.50 to 0.04). Consistent with this observation, improvement in the disease severity of EAE mice receiving recombinant Sema4A-Fc was also observed after fingolimod treatment. These data suggest that fingolimod could serve as a candidate DMD for managing the disease activity of MS patients with high Sema4A levels.
Highlights
Multiple Sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) [1]
We previously demonstrated that Sema4A is increased in the sera of patients with MS, and those with high serum Sema4A levels do not respond to IFNβ therapy [6]
To investigate the clinical relevance of the distinct modes of action of fingolimod and IFN-β therapies in MS patients with various Sema4A levels, we first examined the correlation of serum Sema4A levels and fingolimod efficacy among the patients recruited in our study
Summary
Multiple Sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) [1]. In addition to IFN-β and glatiramer acetate (GA), a variety of disease-modifying drugs (DMDs) including fingolimod have been recently developed and applied in MS treatment [2]. We previously demonstrated that Sema4A is increased in the sera of patients with MS, and those with high serum Sema4A levels do not respond to IFNβ therapy [6]. Consistent with these clinical observations, we showed IFN-β non-responsiveness in experimental autoimmune encephalomyelitis (EAE) mice with high serum Sema4A state [7]. It is important to address whether fingolimod has beneficial effects in patients with high serum Sema4A levels, representing non-responders to first-line IFN-β therapy
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