Peripheral oedema as an adverse effect of treatment of secondary progressive multiple sclerosis with siponimod: A case series.

Siponimod is a sphingosine 1-phosphate receptor (S1P) modulator used to treat secondary progressive multiple sclerosis (SPMS). We report 3 SPMS patients treated with siponimod who developed new or worsening peripheral oedema soon after commencing treatment. In one case, peripheral oedema resulted in immobility. Siponimod-related peripheral oedema deserves wider recognition due to the potential for morbidity and over-investigation. Clinicians should assess for pre-existing oedema and coexisting conditions that may predispose to developing peripheral oedema prior to commencing siponimod.

Ocrelizumab Extended Interval Dosing in Primary Progressive Multiple Sclerosis: An Italian Experience.

BACKGROUND: The intervals between two courses of anti CD20 therapies in the COVID19 pandemic era provided the opportunity to individually delay therapy, known as extended interval dosing (EID). METHODS: We collect real-world data on patients with primary progressive MS (PPMS) treated with Ocrelizumab (OCR) during the COVID'19 pandemic. The observation period in which the standard interval dosing (SID) or EID occurred (always a maintenance cycle, 600 mg) was from January 2020 to June 2021. All patients had two infusions during the observation period. Our first aim was to compare confirmed disability progression (CDP) between SID and EID patients. RESULTS: From a total cohort of 410 patients treated with OCR, 96 patients fulfilled the inclusion criteria. All patients received two infusions during the index window, 71 received only SID infusions whilst 25 received at least one EID infusion throughout the entire follow-up. During the entire available follow-up (median 10 months, IQR 7-11), CDP was recorded in 5 patients (3/71, 4.2% SID and 2/25, 8% EID, V-Cramer = 0.141, p-value = 0.167). EID regimen did not influence the risk of CDP during the investigated follow up. CONCLUSION: In our multicentre real-world cohort, the EID regimen in PPMS patients did not result in increased CDP during the available follow-up.

The Benefits and Risks of Switching from Fingolimod to Siponimod for the Treatment of Relapsing-Remitting and Secondary Progressive Multiple Sclerosis.

Multiple sclerosis (MS) is a chronic neurodegenerative disease that affects the central nervous system (CNS). Currently, MS treatment is limited to several Food and Drug Administration (FDA)- and European Medicines Agency (EMA)-approved medications that slow disease progression by immunomodulatory action. Fingolimod and siponimod have similar mechanisms of action, and consequently, their therapeutic effects may be comparable. However, while fingolimod is mainly used for relapsing-remitting MS (RRMS), siponimod, according to EMA label, is recommended for active secondary progressive MS (SPMS). Clinicians and scientists are analysing whether patients can switch from fingolimod to siponimod and identifying the advantages or disadvantages of such a switch from a therapeutic point of view. In this review, we aim to discuss the therapeutic effects of these two drugs and the advantages/disadvantages of switching treatment from fingolimod to siponimod in patients with the most common forms of MS, RRMS and SPMS.

Modeling compartmentalized chronic immune-mediated demyelinating CNS disease in the Biozzi ABH mouse.

We explored whether experimental autoimmune encephalomyelitis (EAE) in Biozzi mice recapitulates temporal dynamics of tissue injury, immune-pathogenesis and CNS compartmentalization occurring in progressive multiple sclerosis (MS). Chronic EAE exhibited relapsing and progressing disease, partial closure of BBB, reduced tissue inflammatory activity, and development of meningeal ectopic lymphoid tissue, directly opposing (potentially driving) spinal subpial demyelinated plaques. A T cell predominant disease during relapses transformed into a B cell predominant disease in late chronic EAE, with high serum anti-MOG reactivity. Thus, late chronic Biozzi EAE recapitulates essential features of progressive MS, and is suitable for developing disease modifying and regenerative therapies.

iPS-derived neural progenitor cells from PPMS patients reveal defect in myelin injury response.

Primary progressive multiple sclerosis (PPMS) is a chronic demyelinating disease of the central nervous system (CNS) currently lacking any effective treatment. Promoting endogenous brain repair offers a potential strategy to halt and possibly restore neurologic function in PPMS. To understand how the microenvironment within white matter lesions plays a role in repair we have focused on neural progenitor cells (NPCs) since these are found in lesions in PPMS and have been found to influence oligodendrocyte progenitor cell maturation (OPCs). To better understand the cellular nature of NPCs in PPMS we developed iPS cells from blood samples of PPMS patients and age matched non-disease spouse or blood relative controls. Using these iPS cell lines we determined that the NPCs from PPMS cases provided no neuroprotection against active CNS demyelination compared to NPCs from control iPS lines which were capable of completely preventing injury. Conditioned media (CM) from PPMS NPCs provides no protection to OPCs and prevents maturation of OPCs into oligodendrocytes in vitro. We also found that CM from PPMS iPS NPCs elicited patient-specific differences in the response to compounds that should foster oligodendrocyte (OL) maturation. Together, these data establish a new model for understanding the nature of myelination defects in PPMS which may lead to novel targeted approaches for preventing demyelination in these patients.