Suboptimal dose of approved disease modifying therapies in management of patients with multiple sclerosis: A...

Multiple sclerosis (MS) is the most common immune-mediated neurodegenerative disorder of the central nervous system (CNS). Suboptimal dosing of disease-modifying treatment (DMT) has emerged as an issue of interest in recent years. Herein, we investigated the clinical efficacy and safety issues of approved DMTs for patients with relapse-remitting MS (RRMS).

This systematic review was prepared according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA). Electronic databases of PubMed, Embase, Scopus, and Web of Science were systematically searched from inception to 27 July 2025. Relevant studies on the clinical efficacy and safety of suboptimal dosages of approved DMTs were considered for data synthesis.

Out of 11,568 records, 34studies met the inclusion criteria. A total of 527 patients on standard dose compared to 502 patients on the suboptimal dose of interferon-ß,558 patients on standard dose compared to 576 patients on the suboptimal dose of fingolimod, 145 patients on standard dose compared to 139 patients on suboptimal dose of ponesimod, 4944 patients on standard dose compared to 3689 patients on suboptimal dose of natalizumab, and 947 patients on standard dose compared to 836 patients on suboptimal dose of ocrelizumab were evaluated. Main reasons for choosing a suboptimal strategy included the reduction of potential adverse events associated with the DMTs, such as injection reaction for interferon-ß, lymphopenia and elevated enzyme levels for fingolimod, progressive multifocal leukoencephalopathy risk for natalizumab, and an increased risk of infection and hypogammaglobulinemia for ocrelizumab. The primary suboptimal dosing strategies included reducing the dose and extending the dosing interval (EID) for interferon-ß, non-daily dosing for fingolimod, and EID for natalizumab and ocrelizumab. While the suboptimal dosing strategy successfully reduced adverse events, the results were equivocal in terms of efficacy, with most evidence showing similar efficacy of the EID every six weeks of natalizumab and EID (6 months + ≥ 4 weeks) of ocrelizumab compared with the standard dose.

Suboptimal dosing of DMTs in MS is a growing treatment strategy to enhance patient adherence and reduce adverse events. Future prospective studies are necessary to establish the safety and efficacy of suboptimal dosing protocols for different classes of DMTs in MS management.