Background: Currently siponimod, an oral selective S1PR1,5 modulator, is indicated for the treatment of adult patients with active SPMS. Data from the phase 3 study showed a significant effect of the active drug compared with placebo on reduction of disability progression. The visual system is an important model to evaluate the pathophysiology of MS and in the last years it is used as a model for studying outcomes in clinical trials evaluating novel neuroprotective drugs in MS. Visual system can be studied using several technologies as Optical coherence tomography (OCT), Visual evoked potentials (VEPs) and Trans bulbar B-mode sonography (TBS).
Objective: To evaluate the effects of siponimod on neurodegeneration and remyelination in progressive MS patients using OCT, PEV and TBS-derived metrics
Methods: 50 patients with active SPMS taking Siponimod in routine clinical practice will be enrolled in this single-center, pilot study. The primary outcome was the change in RNFL thickness from baseline to 12 months to evaluate the possible role as neuroprotective agent of Siponimod. Secondary outcome will be change in P100 latency on full-field visual evoked potential from baseline to 12 months. Moreover, the role of Trans bulbar B-mode sonography as measure of neurodegeneration in MS will be evaluated.
Conclusion: In EXPAND TRIAL Siponimod have demonstrated a relative risk reduction of 21% for confirmed disability progression (CDP) at 3 and 6 months in patients with active secondary progressive (SP) MS compared with placebo. Siponimod could slow down disease progression via routes beyond an anti-inflammatory effect. None have demostrated if the the disability progression reduction is related to a neuroprotective or remyelinating role of Siponimod. The study of visual system using OCT, PEV and TBS might represent innovative, non invasive and cost- effective technologies to analyze neurodegeneration in MS
Multiple sclerosis (MS) is an inflammatory, chronic, demyelinating disease of the CNS. In MS drugs are currently approved in relapsing remitting multiple sclerosis or active progressive multiple sclerosis. No treatment is able to halt the progressive phase of MS, characterized by ongoing demyelination and neurodegeneration despite reduced inflammatory relapses. An unmet need in MS treatment is the development of strategies to remyelinate. Remyelination could restore some degree of lost neurological function.Siponimod is a sphingosine-1-phosphate (S1P) R1/R5 dual agonist: S1PR1 modulation plays a key role in lymphocyte migration and S1PR5 is expressed on oligodendrocytes where it plays a role in myelination.
Siponimod could have different mechanism beyond the reduction of lymphocyte egress from lymphoid tissue; hypothesized mechanisms are prevention of synaptic neurodegeneration and promotion of remyelination due to its ability to cross the blood¿brain barrier and potentially act directly within the brain. Siponimod demonstrated neuroprotective effects in the central nervous system in a model of EAE in mice . In addition a mouse model of brain inflammation reported that siponimod can prevent loss of GABAergic interneurons, which is thought to contribute to neurodegeneration. Basing on this considerations, we therefore propose to evaluate the effectiveness of Siponimod to reduce neurodegeneration and to improve remyelination in MS.
Primary outcome will be to evaluate Siponimod effectiveness to contrast neurodegeneration in MS Patients. As Primary outcome measure will use OCT to evaluate modification in RNFL thickness .
In addition as secondary measure we will use VEP to evaluate the remyelinating role of Siponimod.
The visual system is an important model to evaluate the pathophysiology of multiple sclerosis (MS) and In the last years it is use as a model for studying outcomes in clinical trials evaluating novel neuroprotective drugs in MS.
Visual evoked potentials (VEPs) provide a functional assessment of ON course. Abnormal VEPs with increased latency have been frequently identified in the clinically unaffected eye of optic neuritis and studies have demonstrated that latency delays can be found in patients with MS with no history of optic neuritis. If we consider remyelination as the primary reason for partial recovery of the VEP latency, VEPs may be considered the outcome of choice in clinical trials assessing remyelinating agents.
Optical coherence tomography (OCT) uses coherent light to provide a highly detailed two-dimensional image of the retina. OCT measures the thickness of the RNFL, which contains non-myelinated axons, as well as the ganglion cell layer (GCL) and inner plexiform layer (IPL) which contain primary neurons. it is an ideal means to study neuronal degeneration and regeneration in MS.
Optic nerve diameter (OND) and optic nerve sheath diameter (ONSD) and OND/ONSD ratio are lower among MS patients compared to healthy controls.Trans bulbar B-mode sonography (TBS) is a non invasive and cost- effective method which easily measures the OND and ONSD and can be useful in detection of optic nerve damage and could be applied for MS diagnosis and progression assessment. In May 2020 Leila Raeesmohammadi et al. Conducted a comparative study of 60 MS patients matched with healthy controls and was found several differences in ONSD that can only be explained with reference to a chronic depletion of axons in MS