Systematization of studies included in this review demonstrates the effect of pharmacological and non-pharmacological therapies on MS.
| Study | Type of study | Population | Objective | Results |
|---|---|---|---|---|
| Gold et al. [58], 2018 | Phase IIa | 20 adults aged between 18 and 55 years old; with active RRMS (McDonald criteria 2010) and EDSS not exceeding 6.0 | To assess whether raltegravir can reduce the inflammatory activity of RRMS, as measured by active lesions in the brain detected by gadolinium-enhanced MRI. | Raltegravir did not reduce the number of active brain lesions compared to the pre-treatment period. There were no significant improvements in markers of inflammation, disability, and quality of life. |
| Soiza et al. [59], 2018 | Substudy of phase III trials (OPERA I and II) | 103 adults aged between 18 and 55 years: 59 patients with RRMS (McDonald criteria 2010) and EDSS: 0.0–5.5 and 44 healthy individuals | Compare brain volume loss in patients with RRMS treated with ocrelizumab with volume loss in healthy individuals. Assess whether suppression of inflammation with ocrelizumab reduces the rate of neurodegeneration to levels similar to those seen in normal aging. | Patients treated with ocrelizumab had brain volume loss rates similar to those of healthy controls. Patients treated with IFN-β-1a had higher rates of loss. The thalamus was the region with the greatest loss in both healthy individuals and patients. |
| Zurmati and Khan [55], 2023 | Phase IIb | 130 patients aged between 18 and 55 years old, with RRMS or SPMS (McDonald criteria 2017) and EDSS ≤ 5.5 | To determine the dose-response relationship between tolebrutinib and the reduction of new active brain lesions in patients with RRMS and SPMS. | Tolebrutinib significantly reduced inflammation in patients with RRMS. The 60 mg dose showed the best results. |
| Hartung et al. [60], 2022 | Phase IIb and extension | 270 patients aged between 18 and 55 years old; with RRMS (McDonald criteria 2010) and EDSS < 6.0 | Evaluate whether temelimab is effective and safe for treating patients with RRMS. | Temelimab had no effect on reducing acute inflammation, but showed radiological signs of possible antineurodegenerative effects, supporting its development for MS. |
| Kolind et al. [61], 2022 | Substudy of the phase III trial (OPERA II) | 78 participants: 29 patients treated with ocrelizumab, 26 patients treated with IFN-β-1a, and 23 healthy individuals | To evaluate the myelin water fraction in patients with RRMS treated with IFN-β-1a and those treated with ocrelizumab for 2 years (double-blind period), followed by an open-label extension of years of treatment with ocrelizumab. | Ocrelizumab prevents demyelination in white matter and chronic lesions when compared to IFN-β-1a. Some areas of the brain have shown that ocrelizumab can create a more favorable environment for remyelination in damaged tissue. |
| Abdelhak et al. [62], 2022 | Samples from the ReBUILD trial (phase II) | 50 patients with stable RRMS, in which only samples from 34 patients (24 women and 9 men) were analyzed | To assess whether treatment with clemastine fumarate (an antihistamine with remyelinating potential) reduces blood levels of NfL in patients with RRMS without disease progression. | Treatment with clemastine fumarate was associated with a reduction in blood NfL levels, suggesting neuroprotective effects through therapeutic remyelination. |
| Talbot et al. [63], 2022 | Exploratory analysis of data collected from a phase II trial | 120 participants aged between 18 and 65 years: 59 patients with PPMS (24 women and 35 men), 40 patients with RRMS according to the 2017 McDonald criteria (30 women and 10 men) and 21 healthy individuals (11 women and 10 men) | To study the relationship between inflammatory biomarkers in CSF and tissue damage in PPMS. | There is inflammation in the CNS, but this does not appear to be the main cause of brain damage. This may explain why therapies that target inflammation have less significant effects on this form of the disease. Associations with biomarkers of neuroaxonal damage and demyelination were weak, and there were no associations with MRI metrics. |
| Sy et al. [64], 2023 | Open-label, mechanistic phase clinical trial with dose escalation | 34 patients aged between 18 and 75 years old, with RRMS, SPMS or PPMS and taking glatiramer acetate for at least 3 months | To evaluate the effects of N-acetylglucosamine in patients with MS, specifically whether it has the ability to reduce markers of inflammation and neurodegeneration and its safety, as well as possible benefits in neurological function. | Oral N-acetylglucosamine reduced markers of inflammation and neurodegeneration in patients with MS, despite simultaneous immunomodulation by glatiramer acetate. |
| Newsome et al. [65], 2023 | Phase Ib | 20 adults (11 women and 9 men) aged between 18 and 58 years with RRMS (12 adults) or PPMS (8 adults) (McDonald criteria 2010) and EDSS: 3.0–7.5 | To evaluate the safety and tolerability of liothyronine in increasing doses in patients with MS, and whether there is evidence that it may promote remyelination. | Liothyronine showed an acceptable safety profile in patients with MS. These data support the conduct of trials to investigate whether the drug promotes remyelination and improvement in clinical status. |
| Genchi et al. [66], 2023 | Phase I | 12 patients (8 women and 4 men) aged between 18 and 55 years, with SPMS (5 patients) or PPMS (7 patients); EDSS ≥ 6.5 and disease duration: 2–20 years | To evaluate the feasibility, safety, and tolerability of intracranial transplantation of human fetal neural precursor cells in patients with PMS. | It showed that neural precursor cell therapy is feasible, safe, and tolerable. |
| Louapre et al. [67], 2023 | Phase II | 30 patients (16 women and 14 men) aged between 18 and 65 with RRMS and EDSS:0–6. 14 patients underwent treatment with IL-2, and 16 patients underwent placebo treatment | To evaluate whether low-dose IL-2 could activate and expand regulatory T cells in patients with MS and be beneficial in controlling disease activity. | The effect of low-dose IL-2 on regulatory T cells in patients with MS was delayed. However, the findings of this study and the fact that regulatory T cells promote remyelination in MS models support the conduct of larger studies with higher doses and new administration regimens. |
| Nezhad et al. [68], 2024 | Randomized, controlled, longitudinal clinical trial | 24 women aged between 18 and 45 years old, with MS, EDSS ≤ 4.0 and no regular physical activity in the last 6 months | To evaluate the effects of resistance training on serum levels of BBB permeability indices (MMP-2, MMP-9, TIMP-1, TIMP-2, S100B) and cognitive performance in women with MS. | Moderate-intensity resistance exercises can modify biomarkers of BBB pathology in MS, although the role of S100B, MMP-9, TIMP-1, and the MMP-9/TIMP-1 ratio in MS remains unknown. |
| Nakamura et al. [69], 2024 | Phase II | 195 participants (112 women and 83 men) with PPMS (107 patients) or SPMS (88 patients) with at least 4 analyzable MRIs: 97 patients underwent treatment with ibudilast and 98 underwent placebo treatment | To evaluate whether treatment with ibudilast can reduce the progression of slow-growing brain lesions in patients with MS over 96 weeks. | Ibudilast reduced the activity of chronic active lesions in MS and had an effect on compartmentalized inflammation, demonstrating its neuroprotective potential. |
BBB: blood-brain barrier; CSF: cerebrospinal fluid; EDSS: expanded disability status scale; IFN: interferon; MMP: matrix metalloproteinases; MRI: magnetic resonance imaging; MS: multiple sclerosis; NfL: neurofilament light chain; PMS: progressive MS; PPMS: primary PMS; RRMS: relapsing-remitting MS; SPMS: secondary PMS; TIMP: tissue inhibitors of MMP; CNS: central nervous system; IL: interleukin.