The Effect of High Effective Treatments on Unconventional Clinical and Para-clinical Parameters in Patients with Multiple Sclerosis

Background: Multiple sclerosis (MS) is a chronic, immune-mediated disease of the central nervous system (CNS), characterized by demyelination, axonal damage, and neurodegeneration. MS is one of the leading causes of non-traumatic neurological disability in young adults, with a significant social and economic burden. Manifestations of the disease are highly heterogeneous, and depend mostly on the area where damage occurs, which arises from the inflammation. Among the most common sites of damage is the optic nerve. Damage to the optic nerve can trigger several alterations within the retinal layers such as reduction of thickness, volume and the formation of hyperreflective foci (HRF). These alterations are linked to both clinical disability and a higher disease load, like the presence of brain lesions, which are determined by the disease progression. In recent years, there has been a growing interest in comprehending more profoundly the significance and behavior of the alterations detected in the retinal layers and their possible implication on the disease progression. Objective: This study focuses on evaluating the effect of Ofatumumab and sphingosine-1-phosphate receptor (S1PR) modulators, on retinal layers thickness and volume in patients with relapsing-remitting MS (RRMS). Furthermore, this study also aimed to better understand the behavior of HRF, and to monitor the impact that the treatments had on their count. Materials and methods: To this prospective single-center longitudinal study 25 patients diagnosed with RRMS were recruited. The patients were divided into two treatment cohorts: 14 patients were treated with Ofatumumab, and 11 patients underwent a therapy with S1PR modulators (Siponimod, Ozanimod, or Ponesimod). Each patient underwent optical coherence tomography (OCT) imaging at baseline (T0) and approximately six months later (T1). OCT scans were utilized to measure changes in the sectors of the peripapillary retinal nerve fiber layer (pRNFL) thickness, in macular layers volumes, as well as the HRF count in various inner-retinal layers. we compared the changes in thicknesses, volumes and HRF count in the various retinal layers between the two cohorts and across the six-month period. Results: The S1PR modulators cohort exhibited a significant reduction in the nasal inferior sector of pRNFL, as well as a decrease in total volume of the macular ganglion cell layer (GCL) and thinning of the GCL outer ring thickness. On the other hand, the Ofatumumab cohort did not show any significant changes in the parameters examined during the study period. Additionally, the S1PR modulators cohort demonstrated a significant decrease in HRF count in the intermediate capillary plexus (and area situated between INL and IPL). Finally, the comparison between the two treatment cohorts yielded a significant difference in the change of the total volume of GCL and the GCL outer ring thickness, where both parameters were decreased significantly more during the 6 months study duration in the S1PR modulators cohort. Conclusions: This study found that Ofatumumab was able to maintain stable peripapillary RNFL thickness and retinal layer volumes, likely due to its anti-inflammatory properties. In contrast, S1PR modulators were linked to reductions in thickness and volume, particularly in the GCL, which may indicate pseudo-atrophy or disease progression. Ofatumumab was more effective in preserving GCL outer ring thickness and total volume compared to S1PR modulators. Additionally, the reduction in HRF count in the ICP observed with S1PR modulators cohort further supports the theory of a microglial origin for HRF and its connection to the blood-retina barrier (BRB).