A comprehensive systematic review of Ibudilast as a neuroprotective therapy for progressive multiple sclerosis.

BACKGROUND: Ibudilast, a phosphodiesterase inhibitor, has shown promise potential in Multiple sclerosis (MS) therapy. OBJECTIVES: This systematic review synthesizes evidence from clinical trials to assess the neuroprotective effects of ibudilast in progressive MS, focusing on brain atrophy, disability progression, and safety outcomes. METHODS: Following PRISMA 2020 guidelines, a systematic search of PubMed, Embase, Web of Science, and Scopus (1995-2025) for randomized controlled trials and prospective studies was conducted. Thirteen studies met inclusion criteria, including the phase 2 SPRINT-MS trial (n = 255). Outcomes included neuroimaging metrics (brain atrophy, lesion activity), disability progression (Expanded Disability Status Scale [EDSS]), and safety. Risk of bias was assessed using Cochrane RoB 2.0 and ROBINS-I tools. RESULTS: Ibudilast significantly slowed whole-brain atrophy by 48 % versus placebo (p = 0.04), with pronounced effects in primary progressive MS (PPMS; p < 0.01). Gray matter atrophy was reduced by 35 % (p = 0.038), and thalamic integrity was preserved (p = 0.03). Retinal neurodegeneration was attenuated in PPMS (79 % reduction, p = 0.003). Chronic active lesion volume decreased by 23 % (p = 0.003), suggesting suppression of compartmentalized inflammation. No significant impact on EDSS progression or serum neurofilament light chain levels was observed. CONCLUSIONS: Ibudilast demonstrates robust neuroprotection in progressive MS, particularly PPMS, with benefits on brain and retinal atrophy and chronic lesion activity.