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.

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.

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.

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.

Dual positivity for anti-MOG and oligoclonal bands: Unveiling unique clinical profiles and implications.

BACKGROUND: Distinguishing between MOG-associated disease (MOGAD) and multiple sclerosis (MS) presents a considerable challenge, as there are instances of overlapping clinical presentations. This complexity is further magnified in cases where patients concurrently exhibit both anti-myelin oligodendrocyte glycoprotein (anti-MOG) positivity and detectable oligoclonal bands (OCBs) This retrospective study investigates the clinical and imaging attributes of dual-positive patients, those with both anti-MOG positivity and OCBs, The study aims to show potential areas of overlap between multiple sclerosis (MS) and MOGAD. METHODS: Utilizing data gathered from three medical centers, we evaluated a cohort of 45 patients, stratifying them into two groups: those exclusively positive for anti-MOG antibodies and those displaying dual positivity. Our analysis encompassed a wide range of clinical and imaging parameters. The statistical techniques employed comprised Fisher's Exact Test along with Benjamini-Hochberg correction to ensure robustness of the findings. RESULTS: The study involved 45 patients with anti-MOG antibodies; 30 exhibited isolated anti-MOG positivity without OCBs, while 15 were dual-positive. The first group's average age was 10±7 years, compared to 28±17 years in the double-positive group (p = 0.001). CSF analysis showed no significant differences in pleocytosis, protein levels, or opening pressure between the groups. In the exclusive anti-MOG positivity cohort, 9 out of 15 patients received IVIG treatment; a larger subgroup with dual positivity chose anti-CD20 treatment. Notably, papilledema incidence was higher in the single-positive group (p = 0.014). Optic nerve enhancement (p = 0.0038) and nerve thickening (p = 0.0017) were markedly elevated in the single-positive population, with a trend towards pre-chiasmatic lesions (p = 0.06). Double-positive cases exhibited more polyfocal presentation (p = 0.013) and higher attacks per case (p = 0.002, HR=10.2, 95 % CI: 2.19 to 49.23). The double-positive group had more brain lesions (p = 0.0063) but no significant distinctions in other aspects. CONCLUSION: The results emphasize the challenges inherent in differentiating between MS and a more MOGAD. While the data suggest two plausible scenarios-either falling within the spectrum of MS or representing an intensified MOGAD-we recognize the need for stronger evidence to definitively classify these instances. This study underscores the imperative for thorough investigations to ascertain whether these cases align with the MS spectrum or denote an inflammatory variant of MOGAD.

Oligodendrocyte progenitor cells differentiation induction with MAPK/ERK inhibitor fails to support repair processes in the chronically demyelinated CNS.

Remyelination failure is considered a major obstacle in treating chronic-progressive multiple sclerosis (MS). Studies have shown blockage in the differentiation of resident oligodendrocyte progenitor cells (OPC) into myelin-forming cells, suggesting that pushing OPC into a differentiation program might be sufficient to overcome remyelination failure. Others stressed the need for a permissive environment to allow proper activation, migration, and differentiation of OPC. PD0325901, a MAPK/ERK inhibitor, was previously shown to induce OPC differentiation, non-specific immunosuppression, and a significant therapeutic effect in acute demyelinating MS models. We examined PD0325901 effects in the chronically inflamed central nervous system. Treatment with PD0325901 induced OPC differentiation into mature oligodendrocytes with high morphological complexity. However, treatment of Biozzi mice with chronic-progressive experimental autoimmune encephalomyelitis with PD0325901 showed no clinical improvement in comparison to the control group, no reduction in demyelination, nor induction of OPC migration into foci of demyelination. PD0325901 induced a direct general immunosuppressive effect on various cell populations, leading to a diminished phagocytic capability of microglia and less activation of lymph-node cells. It also significantly impaired the immune-modulatory functions of OPC. Our findings suggest OPC regenerative function depends on a permissive environment, which may include pro-regenerative inflammatory elements. Furthermore, they indicate that maintaining a delicate balance between the pro-myelinating and immune functions of OPC is of importance. Thus, the highly complex mission of creating a pro-regenerative environment depends upon an appropriate immune response controlled in time, place, and intensity. We suggest the need to employ a multi-systematic therapeutic approach, which cannot be achieved through a single molecule-based therapy.

Practical recommendations on treatment of multiple sclerosis with Cladribine: an Israeli Experts Group Viewpoint.

Cladribine tablets (Mavenclad®) were approved by the European Union in 2017 as high-efficacy therapy for highly active relapsing-remitting multiple sclerosis. In Israel, Mavenclad® was approved in 2018. Real-life experience has confirmed the efficacy of cladribine tablets over at least 4 years from the initial course. During the last years, several questions were raised concerning the management of people with MS who show disease activity during years 3 and 4 post-cladribine initiation and what treatment decisions are needed beyond year 4. A few expert boards have tried to provide insight based on research data and to suggest recommendations on the therapeutic dilemmas and treatment decisions with cladribine. However, there is currently no widely accepted consensus about these issues. The vast clinical experience gained in Israel in the past 5 years in several MS centers across the country allows for a broad perspective of the outcomes with long-term cladribine use. This article summarizes previously published recent recommendations and describes the insights of Israeli neurology key opinion leaders that convened for an advisory board meeting on January 29th, 2023, with the aim of reaching a consensus regarding cladribine long-term treatment and follow-up.

Brain MRI activity during the year before pregnancy can predict long-term clinical worsening in patients with Multiple Sclerosis.

BACKGROUND: Pregnancy has been observed to reduce the frequency of relapses in Multiple Sclerosis (MS) patients, but the relapse risk tends to increase during the early post-partum period. Increased pre- and post-partum disease activity may predict a poor long-term prognosis. This study aimed to evaluate the correlation between magnetic resonance imaging (MRI) activity during the year before pregnancy and long-term clinically meaningful worsening in Expanded Disability Status Scale (EDSS). METHODS: This observational, retrospective, case-control study included 141 pregnancies in 99 females with MS. Statistical analyses were used to evaluate the correlation between MRI activity during the year pre-pregnancy and post-partum clinical worsening during a 5-year follow-up. Clustered logistic regression was used to investigate the predictors of 5-year clinically meaningful worsening in EDSS (lt-EDSS). RESULTS: We found a significant correlation between an active MRI pre-pregnancy and lt-EDSS (p = 0.0006). EDSS pre-pregnancy and lt-EDSS were also significantly correlated (p = 0.043). Using a multivariate model, we predicted which females would not experience long-term clinical deterioration by a stable MRI pre-pregnancy (92.7% specificity; p = 0.004). CONCLUSIONS: An active MRI pre-conception is a strong predictor of lt-EDSS and a higher annual relapse rate during the follow-up period, regardless of whether the female had clinical evidence of disease activity prior to conception and delivery. Optimizing disease control and achieving imaging stability prior to conception may reduce the risk of long-term clinical deterioration.

International Delphi Consensus on the Management of AQP4-IgG+ NMOSD: Recommendations for Eculizumab, Inebilizumab, and Satralizumab.

BACKGROUND AND OBJECTIVES: Neuromyelitis optica spectrum disorder (NMOSD) is a rare debilitating autoimmune disease of the CNS. Three monoclonal antibodies were recently approved as maintenance therapies for aquaporin-4 immunoglobulin G (AQP4-IgG)-seropositive NMOSD (eculizumab, inebilizumab, and satralizumab), prompting the need to consider best practice therapeutic decision-making for this indication. Our objective was to develop validated statements for the management of AQP4-IgG-seropositive NMOSD, through an evidence-based Delphi consensus process, with a focus on recommendations for eculizumab, inebilizumab, and satralizumab. METHODS: We recruited an international panel of clinical experts in NMOSD and asked them to complete a questionnaire on NMOSD management. Panel members received a summary of evidence identified through a targeted literature review and provided free-text responses to the questionnaire based on both the data provided and their clinical experience. Responses were used to generate draft statements on NMOSD-related themes. Statements were voted on over a maximum of 3 rounds; participation in at least 1 of the first 2 rounds was mandatory. Panel members anonymously provided their level of agreement (6-point Likert scale) on each statement. Statements that failed to reach a predefined consensus threshold (≥67%) were revised based on feedback and then voted on in the next round. Final statements were those that met the consensus threshold (≥67%). RESULTS: The Delphi panel comprised 24 experts, who completed the Delphi process in November 2021 after 2 voting rounds. In round 1, 23/25 statements reached consensus and were accepted as final. The 2 statements that failed to reach consensus were revised. In round 2, both revised statements reached consensus. Twenty-five statements were agreed in total: 11 on initiation of or switching between eculizumab, inebilizumab, and satralizumab; 3 on monotherapy/combination therapy; 7 on safety and patient population considerations; 3 on biomarkers/patient-reported outcomes; and 1 on research gaps. DISCUSSION: An established consensus method was used to develop statements relevant to the management of AQP4-IgG-seropositive NMOSD. These international statements will be valuable for informing individualized therapeutic decision-making and could form the basis for standardized practice guidelines.

Pearls & Oy-sters: Reversible Postpartum Pseudocoma State Associated With Magnesium Therapy: A Report of 2 Cases.

Magnesium (Mg) competes with calcium in normal synaptic transmission, inhibiting neurotransmitter release. As a drug, it is usually given as a treatment for eclampsia and preeclampsia. Two eclamptic pregnant women treated with Mg developed a pseudocoma state immediately after emergency Caesarian section. The clinical presentation was flaccid quadriparesis, areflexia, absent respiratory effort and vestibular-ocular reflexes, but with preserved pupillary responses. Decremental responses on repetitive nerve stimulation were found in both women. Recovery was obtained after cessation of Mg. The persistence of pupillary reflexes in the absence of reflexes involving striated muscles was an important clinical clue, indicating neuromuscular junction dysfunction.

Clinical outcomes of COVID-19 in patients with multiple sclerosis treated with ocrelizumab in the pre- and post-SARS-CoV-2 vaccination periods: Insights from Israel.

The coronavirus disease 2019 (COVID-19) pandemic caused challenges in the management of patients living with multiple sclerosis (PLwMS). We investigated the occurrence and severity of COVID-19 infection post-vaccination among PLwMS treated with ocrelizumab and enrolled in the Maccabi Health Services (MHS) (n = 289) or followed at the Hadassah Medical Center (HMC) (n = 80) in Israel. Most patients were fully vaccinated (MHS n = 218; HMC n = 76) and confirmed infection post-vaccination was low (3.7% and 2.6%, respectively). MHS: infection was more severe (hospitalization/intensive care unit/death) in non-vaccinated (33.3%) vs vaccinated patients (25%). HMC: one vaccinated patient required hospitalization with COVID-19 vs two unvaccinated patients. These data from two Israel cohorts suggest that occurrence of COVID-19 after mRNA vaccination is low and limited in severity.

Sera of Neuromyelitis Optica Patients Increase BID-Mediated Apoptosis in Astrocytes.

Neuromyelitis optica (NMO) is a rare disease usually presenting with bilateral or unilateral optic neuritis with simultaneous or sequential transverse myelitis. Autoantibodies directed against aquaporin-4 (AQP4-IgG) are found in most patients. They are believed to cross the blood−brain barrier, target astrocytes, activate complement, and eventually lead to astrocyte destruction, demyelination, and axonal damage. However, it is still not clear what the primary pathological event is. We hypothesize that the interaction of AQP4-IgG and astrocytes leads to DNA damage and apoptosis. We studied the effect of sera from seropositive NMO patients and healthy controls (HCs) on astrocytes' immune gene expression and viability. We found that sera from seropositive NMO patients led to higher expression of apoptosis-related genes, including BH3-interacting domain death agonist (BID), which is the most significant differentiating gene (p < 0.0001), and triggered more apoptosis in astrocytes compared to sera from HCs. Furthermore, NMO sera increased DNA damage and led to a higher expression of immunological genes that interact with BID (TLR4 and NOD-1). Our findings suggest that sera of seropositive NMO patients might cause astrocytic DNA damage and apoptosis. It may be one of the mechanisms implicated in the primary pathological event in NMO and provide new avenues for therapeutic intervention.

IL-6 as a marker for NMOSD disease activity.

To date, there are no accepted soluble markers for disease activity and progression of neuromyelitis optica spectrum disorder (NMOSD). We aimed to evaluate longitudinal interleukin (IL)-6 levels in sera of NMOSD patients in correlation with disease activity and brain volume. We analyzed IL-6 serum levels of 26 NMOSD patients during relapse and remission. Significantly increased IL-6 levels were detected in patients with NMOSD during relapse. Furthermore, increased IL-6 levels correlated with relapse severity and brain atrophy. Our findings suggest that IL-6 serum level could serve as a biomarker for disease activity in NMOSD.

Longitudinal humoral response in MS patients treated with cladribine tablets after receiving the second and third doses of SARS-CoV-2 mRNA vaccine.

BACKGROUND: Multiple sclerosis (MS) patients receive immunomodulatory treatments which can influence their ability to maintain vaccine specific serological response overtime. MS patients treated with cladribine tablets developed a positive serology response following two doses of mRNA COVID-19 vaccine. However, there is only limited data regarding the effect of cladribine tablets on long-term humoral response after the second and the third booster. METHODS: Serology response to SARS-CoV-2 was tested in healthy controls (HCs) and MS patients treated with cladribine tablets 6 and 9-12 months after the second dose, and 1 and 3-6 months following the third booster-dose of the BTN162b2 mRNA vaccine. RESULTS: Thirty-five out of 36 MS patients treated with cladribine tablets and 100% (46/46) of HCs had a positive serology response up to 10 months after the second vaccine dose. In addition, all cladribine tablets -treated MS patients (22/22) and HCs (24/24) had a positive robust serology response following the third vaccine with a positive humoral response sustain up to 6 months. One month after the third vaccine dose IgG levels were significantly lower in patients treated with cladribine tablets compared to HCs (15,598+11,313 vs 26,394+11,335, p<0.01). Six-month post second vaccine and 3-6 months post third vaccine there was no difference in IgG levels between the groups (1088.0 ± 1072.0 vs 1153.0 ± 997.1, p = 0.79; 5234+4097 vs 11,198+14,679, p = 0.4). CONCLUSION AND RELEVANCE: MS patients treated with cladribine tablets have sustained positive vaccine specific serology response following the second and third SARS-CoV-2 vaccine dose.