The interplay of inflammation and remyelination: rethinking MS treatment with a focus on oligodendrocyte progenitor cells.

BACKGROUND: Multiple sclerosis (MS) therapeutic goals have traditionally been dichotomized into two distinct avenues: immune-modulatory-centric interventions and pro-regenerative strategies. Oligodendrocyte progenitor cells (OPCs) were regarded for many years solely in concern to their potential to generate oligodendrocytes and myelin in the central nervous system (CNS). However, accumulating data elucidate the multifaceted roles of OPCs, including their immunomodulatory functions, positioning them as cardinal constituents of the CNS's immune landscape. MAIN BODY: In this review, we will discuss how the two therapeutic approaches converge. We present a model by which (1) an inflammation is required for the appropriate pro-myelinating immune function of OPCs in the chronically inflamed CNS, and (2) the immune function of OPCs is crucial for their ability to differentiate and promote remyelination. This model highlights the reciprocal interactions between OPCs' pro-myelinating and immune-modulating functions. Additionally, we review the specific effects of anti- and pro-inflammatory interventions on OPCs, suggesting that immunosuppression adversely affects OPCs' differentiation and immune functions. CONCLUSION: We suggest a multi-systemic therapeutic approach, which necessitates not a unidimensional focus but a harmonious balance between OPCs' pro-myelinating and immune-modulatory functions.

The effect of COVID-19 vaccination on multiple sclerosis activity as reflected by MRI.

INTRODUCTION: Examining the safety of theBNT162b2 mRNA vaccine in multiple sclerosis (MS) patients remains inconclusive, particularly regarding the potential for disease exacerbations. This study aims to assess the effects of BNT162b2 COVID-19 vaccination on disease activity in MS patients through sequential MRI imaging. METHODS: A retrospective study of 84 MS patients from five Israeli hospitals was conducted. MS lesion load was determined from three brain MRI scans, one postvaccination and two prevaccination scans. A post hoc analysis compared subgroups featuring vaccinated and unvaccinated patients respectively, with early onset MS. RESULTS: The cohort included 70 women with early onset (mean age 16.4 ± 0.8 years) and adult onset (mean age 34.9 ± 1.1 years) MS. Among the early onset group, vaccinated patients showed an increased risk of new lesions (p = .00026), while there was no increased risk among adult-onset patients. Additionally, a comparison between early onset vaccinated and nonvaccinated groups revealed a higher risk of increased lesions in the vaccinated group (p = .024). DISCUSSION: Overall, the study suggests that the BNT162b2 vaccine is generally safe in MS patients, with no association found between vaccination and new lesions in most patients. However, close MRI follow-up is recommended for early-onset MS cases to monitor lesion development.

A protective effect of lower MHC-II expression in MOGAD.

Myelin oligodendrocyte glycoprotein-antibody-associated disease (MOGAD) is a demyelinating central nervous system disorder. We aimed to uncover immune pathways altered in MOGAD to predict disease progression. Using nanostring nCounter technology, we analyzed immune gene expression in PBMCs from MOGAD patients and compare it with healthy controls (HCs). We found 35 genes that distinguished MOGAD patients and HCs. We then validated those results in a larger cohort including MS and NMOSD patients. Expressions of HLA-DRA was significantly lower in MOGAD patients. This reduction in HLA-DRA, correlated with a monophasic disease course and greater brain volume, enhancing our ability to predict MOGAD progression.

Assessing the applicability of the 2023 international MOGAD panel criteria in real-world clinical settings.

INTRODUCTION: Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is a recently identified demyelinating disorder with a diverse clinical spectrum. Diagnosing MOGAD traditionally relies on clinical judgment, highlighting the necessity for precise diagnostic criteria. Banwell et al. proposed criteria, aiming to refine the diagnostic spectrum. This study evaluates these criteria in a real-life cohort, comparing their performance with clinical judgment and describe the cohort of MOGAD patients. METHODS: This retrospective study, conducted at Hadassah Medical Center, included 88 patients with MOG-IgG antibodies. Patients with a positive or borderline MOG-IgG antibodies by cell-based assay were included. Demographics, clinical and MRI data were recorded. Cases were divided into definite MOGAD and Non-MOGAD groups as determined by the treating physician. We assessed the sensitivity and specificity of the new criteria in comparison to treating physicians' evaluations. Additionally, we examined clinical differences between the MOGAD and Non-MOGAD groups. RESULTS: We observed a strong concordance (98%) between the new MOGAD criteria and treating physicians' diagnoses. Clinical disparities between MOGAD and Non-MOGAD groups included lower EDSS scores, normal MRI scans, preserved brain volume, negative OCB results, and distinct relapse patterns. Also, compared to relapsing patients, monophasic MOGAD patients have greater brain volume and a lower age at onset. CONCLUSION: The study demonstrates robust accuracy of new MOGAD criteria, emphasizing their potential to enhance diagnostic precision. Treatment response integration into the MOGAD diagnosis is crucial, as it could aid in distinguishing MOGAD from other demyelinating disorders. Distinct clinical profiles highlight the importance of informed decisions in managing MOGAD and similar disorders.

Real-World experience with efgartigimod in patients with myasthenia gravis.

Recommendations for the treatment of myasthenia gravis (MG) have been difficult to develop because of limited evidence from large randomized controlled trials. New drugs and treatment approaches have recently been shown to be effective in phase 3 studies in seropositive generalized (g) MG. One such drug is efgartigimod, a human-Fc-fragment of IgG1, with a high affinity for the endosomal FcRn. We conducted a multicenter study to evaluate the real-world clinical and safety effects of efgartigimod in 22 gMG patients. We evaluated the strategies for the timing of re-treatment with it. The participants received a total of 59 efgartigimod -treatment cycles. The median number of cycles was 2 (range 1-6). Twenty patients (86.3%) improved by at least 2 MG-ADL points after the first treatment cycle. The median MG-ADL score at baseline was 6.5 (range: 3-17) and 2.5 (range: 0-9) post-treatment (p < 0.001). A consistent improvement of at least 2 points in the MG-ADL score after each cycle occurs in 18 patients. The effect duration of the treatment was usually between 4 and 12 weeks. Two major clinical patterns of treatment response were found. Treatment with efgartigimod was also associated with significant reductions of prednisone doses Overall, the treatment was safe and associated with only minor adverse events. The single fatality was apparently due tosevere respiratory failure. We found that efgartigimod is clinically effective, may be used as a steroid sparing agent and is generally safe for gMG patients. We recommend a personalized preventive treatment approach until clinical stabilization, followed by discontinuation and periodic evaluations.

Altered immune co-inhibitory receptor expression and correlation of LAG-3 expression to disease severity in NMOSD.

Co-inhibitory receptors (CIR)s regulate T cell-mediated immune responses and growing evidence links co-inhibitory receptors to the progression of neuroimmunological diseases. We studied the expression levels of CIRs: TIM-3, TIGIT, PD-1 and LAG-3 in the peripheral blood mononuclear cells (PBMCs) of 30 patients with Neuromyelitis optica spectrum disorder (NMOSD), 11 Multiple sclerosis (MS) patients and 31 Healthy controls (HC). We found that the mRNA expression levels of TIM-3 were significantly increased in NMOSD compared with HC, and increased LAG-3 surface protein expression was also observed on T-cells of NMOSD patients. Moreover, we observed a negative correlation between LAG-3 expression and disease severity in NMOSD. Our findings suggest a protective effect of LAG-3 in the setting of NMOSD, and that the differential expression of CIRs observed in this study may play a role in the pathological process of NMOSD.

Validation of the 2023 international diagnostic criteria for MOGAD in a pediatric cohort.

OBJECTIVE: To validate the recently published diagnostic criteria for Myelin Oligodendrocyte Glycoprotein-antibody associated disease (MOGAD) in real-world cohort of children with acquired demyelinating syndromes. METHODS: Patients <18yrs presenting with demyelinating disease to Pediatric neuroimmunology clinics at two Israeli tertiary centers who had MOG antibodies (MOG-Abs) tested between 01/07/2017 and 15/08/2023 were included. Diagnostic criteria for MOGAD were applied and sensitivity and specificities were calculated. RESULTS: MOG-Abs were detected in 28/63 (44 %). Median age at onset for all patients was 11.4 yrs (range 1.1-17.6 yrs) and 41 (65 %) were female. Of the patients testing negative, ADEM was the most common diagnosis (n = 11) followed by MS (n = 8). No patients without MOG-Abs were diagnosed with MOGAD. All patients with a clinical diagnosis of MOGAD had positive MOG-Abs and fulfilled the 2023 international diagnostic criteria for MOGAD. Sensitivity, specificity, positive predictive value, and negative predictive value were 100 %. We found no difference between younger (<10yrs old) and older (>10 yrs old) children in the number of supportive criteria fulfilled at onset (median 2 vs. 2.5, p = 0.4) The number of supporting features was higher in patients with relapsing (n = 5) vs. monophasic (n = 23) disease course at onset (median 3 vs. 2, p = 0.03) and at final follow-up (median 5 vs. 2, p = 0.004). CONCLUSION: Recent MOGAD diagnostic criteria had excellent performance in this pediatric cohort but did not add to the diagnostic accuracy of the antibody test alone.

Anti- and pro-inflammatory milieu differentially regulate differentiation and immune functions of oligodendrocyte progenitor cells.

Oligodendrocyte progenitor cells (OPCs) were regarded for years solely for their regenerative role; however, their immune-modulatory roles have gained much attention recently, particularly in the context of multiple sclerosis (MS). Despite extensive studies on OPCs, there are limited data elucidating the interactions between their intrinsic regenerative and immune functions, as well as their relationship with the inflamed central nervous system (CNS) environment, a key factor in MS pathology. We examined the effects of pro-inflammatory cytokines, represented by interferon (IFN)-γ and tumour necrosis factor (TNF)-α, as well as anti-inflammatory cytokines, represented by interleukin (IL)-4 and IL-10, on OPC differentiation and immune characteristics. Using primary cultures, enzyme-linked immunosorbent assay and immunofluorescence stainings, we assessed differentiation capacity, phagocytic activity, major histocompatibility complex (MHC)-II expression, and cytokine secretion. We observed that the anti-inflammatory milieu (IL4 and IL10) reduced both OPC differentiation and immune functions. Conversely, exposure to TNF-α led to intact differentiation, increased phagocytic activity, high levels of MHC-II expression, and cytokines secretion. Those effects were attributed to signalling via TNF-receptor-2 and counteracted the detrimental effects of IFN-γ on OPC differentiation. Our findings suggest that a pro-regenerative, permissive inflammatory environment is needed for OPCs to execute both regenerative and immune-modulatory functions.

Thyroid hormone dysfunction in MOGAD and other demyelinating diseases.

BACKGROUND: Thyroid hormones play a critical role in both neuronal and glial cell functions. Multiple sclerosis (MS) has increased co-occurrence with autoimmune thyroid diseases, and recent studies have suggested a potential link between neuromyelitis optica spectrum disorder (NMOSD) and thyroid hormones. However, no previous studies have examined the relationship between thyroid hormones and myelin oligodendrocyte glycoprotein-associated demyelination (MOGAD). METHODS: We investigated the role of thyroid hormones in central nervous system (CNS) autoimmune demyelinating diseases in 26 MOGAD patients, 52 NMOSD patients, 167 patients with MS, and 16 patients with other noninflammatory neurological disorders. Thyroid hormone levels and clinical data (Expanded Disability Status Scale [EDSS]) were analyzed. Volumetric brain information was determined in brain magnetic resonance imaging (MRI) using the MDbrain platform. RESULTS: MOGAD patients had significantly higher levels of free triiodothyronine (FT3) compared to NMOSD patients. No correlation was found between FT3 levels and disease severity or brain volume. Thyroid-stimulating hormone (TSH) levels did not differ significantly between the groups, but in NMOSD patients, higher TSH levels were associated with lower disability scores and increased brain volume. No significant differences in free thyroxine (FT4) levels were observed between the different groups, however, FT4 levels were significantly higher in relapsing versus monophasic MOGAD patients and increased FT4 levels were associated with a higher EDSS and lower brain volume in NMOSD patients. CONCLUSION: Our findings highlight the potential involvement of thyroid hormones specifically in MOGAD patients and other demyelinating CNS disorders. Understanding the role of thyroid hormones in relapsing vs monophasic MOGAD patients and in comparison to other demyelinating disorder could lead to the development of therapeutic interventions. Further studies are needed to explore the precise mechanisms and potential interventions targeting the thyroid axis as a treatment strategy.