Risk of disease relapse following COVID-19 vaccination in patients with AQP4-IgG-positive NMOSD and MOGAD.

Post-vaccination disease relapses have been reported in patients with MOGAD and AQP4-IgG+NMOSD. In this retrospective multicenter Italian study we assessed the frequency of relapses after SARS-CoV-2 vaccination. We included 56 cases: MOGAD, 30; AQP4-IgG+NMOSD, 26. Vaccines received were BNT162b2-Pfizer-BioNTech in 42 patients and mRNA-1273-Moderna in 14 patients. Six patients had a history of SARS-CoV-2 infection; two of them experienced a post-infection disease relapse (MOGAD). The frequency of relapses within one month of SARS-CoV-2 vaccination was 4% (1/26) in the AQP4-IgG+NMOSD group and 0% in the MOGAD group. In these patients the potential benefits of vaccination overcome the risk of relapses.

Pregnancy and antibody-mediated CNS disorders: What do we know and what should we know?

Antibody-mediated central nervous system (CNS) disorders including those associated with aquaporin-4 or myelin oligodendrocyte glycoprotein IgG and autoimmune encephalitis often affect women of childbearing age. Pathogenic antibodies of these diseases can potentially alter reproductive functions and influence fetal development. Hormonal changes occurring during pregnancy may modify the course of autoimmune diseases by influencing relapse risk, attack severity, and affect the delivery and postpartum period. Moreover, balancing treatment related safety issues with the risk of potentially disabling relapses during pregnancy and breastfeeding are major challenges. Intentional prenatal, gestational, and post-partum counseling is paramount to address these issues and mitigate these risks. Fortunately, new insights on risk factors for adverse pregnancy outcomes and possible preventive strategies are emerging. This review aims to summarize the interplay between antibody-mediated CNS disorders and pregnancy during the prenatal, gestational, and postpartum periods, highlight current treatment recommendations, and discuss future areas of research.

Ocrelizumab for the Treatment of Multiple Sclerosis: Safety, Efficacy, and Pharmacology.

The success of selective B-cells depleting therapies, as the anti-CD20 antibodies, in patients with multiple sclerosis (MS) has confirmed that B-cells are critical in the immune pathogenesis of the disease. Ocrelizumab, a humanized monoclonal antibody that selectively targets CD20+ B-cells, profoundly suppresses acute inflammatory disease activity, representing a highly effective therapy for relapsing-remitting multiple sclerosis (RRMS). It is also the first proven therapy able to slow disability progression in primary progressive multiple sclerosis (PPMS), particularly in patients with signs of acute radiological activity before being enrolled. Effectiveness has widely been demonstrated in randomized clinical trials (RCTs), and recently confirmed in open-label extension trials. Here, we review the role of B-cells in MS, the mechanism of action of ocrelizumab, its pharmacokinetics and pharmacodynamics, and the clinical data supporting its use, as well as safety data. We focus on issues related to the maintenance of immunocompetence, essential to ensure an immune response to either a primary infection or a vaccination. Lastly, we discuss about the possible role of ocrelizumab as an exit strategy from natalizumab-treated patients at risk of developing multifocal progressive leukoencephalopathy. In view of using ocrelizumab chronically, collecting long-term safety data and finding strategies to minimize adverse events will be extremely relevant.

Switching to ocrelizumab in RRMS patients at risk of PML previously treated with extended interval dosing of natalizumab.

Discontinuation of natalizumab in patients with relapsing-remitting multiple sclerosis (RRMS) at risk of progressive multifocal leukoencephalopathy (PML) is associated with disease reactivation. Forty-two RRMS patients, who switched from an extended interval dose (EID) of natalizumab to ocrelizumab, underwent magnetic resonance imaging (MRI) and clinical monitoring during washout and after ocrelizumab starting. During the first 3 months, disease reactivation was observed in five (12%) patients; 6 months after ocrelizumab starting, no further relapses were recorded, and Expanded Disability Status Scale (EDSS) remained stable in 38 (90%) patients. In conclusion, ocrelizumab could be considered a choice to mitigate the risk of disease reactivation in patients previously treated with natalizumab-EID.

Early use of low dose tocilizumab in patients with COVID-19: A retrospective cohort study with a complete follow-up.

BACKGROUND: Pneumonia with severe respiratory failure represents the principal cause of death in COVID-19, where hyper-inflammation plays an important role in lung damage. An effective treatment aiming at reducing the inflammation without preventing virus clearance is thus urgently needed. Tocilizumab, an anti-soluble IL-6 receptor monoclonal antibody, has been proposed for treatment of patients with COVID-19. METHODS: A retrospective cohort study at the Montichiari Hospital, Brescia, Italy, was conducted. We included consecutive patients with COVID-19 related pneumonia at the early stage of respiratory failure, all treated with a standard protocol (hydroxychloroquine 400 mg daily, lopinavir 800 mg plus ritonavir 200 mg per day). We compared survival rate and clinical status in a cohort of patients who received additional treatment with tocilizumab once (either 400 mg intravenous or 324 mg subcutaneous) with a retrospective cohort of patients who did not receive tocilizumab (referred to as the standard treatment group). All outcomes were assessed at the end of the follow-up, that correspond to death or complete recovery and discharge from the hospital. FINDINGS: 158 patients were included, 90 of which received tocilizumab. 34 out of 68 (50%) patients in the standard treatment group and 7 out of 90 (7.7%) in the tocilizumab group died. Tocilizumab significantly improved survival compared to standard care (multivariate HR: 0.057; 95% C.I = 0.017- 0.187, p < 0.001). No differences between the two administration routes of tocilizumab were observed. No tocilizumab-related infections and/or side effects were observed. INTERPRETATION: Early treatment with tocilizumab could be helpful to prevent excessive hyper-inflammation and death in COVID-19 related pneumonia. Low dose administration of tocilizumab is not associated with adverse events. FUNDING: none.

Diagnostic features of initial demyelinating events associated with serum MOG-IgG.

BACKGROUND: Myelin oligodendrocyte glycoprotein (MOG)-IgG associated disorders are increasingly recognized as a distinct disease entity. However, diagnostic sensitivity and specificity of serum MOG-IgG as well as recommendations for testing are still debated. MATERIALS AND METHODS: Between October 2015 and July 2017 we tested serum MOG-IgG in 91 adult patients (49 females) with a demyelinating event (DE) not fulfilling 2010 McDonald criteria for MS at sampling, negative for neuromyelitis optica (NMO)-IgG and followed-up for at least 12 months. We assessed the sensitivity and specificity of a live-cell MOG-IgG assay for each final diagnosis at last follow-up, for the 2018 international recommendations for MOG-IgG testing, and for other combinations of clinical and laboratory characteristics. RESULTS: Clinical presentations included acute myelitis (n = 48), optic neuritis (n = 36), multifocal encephalomyelitis (n = 4), and brainstem syndrome (n = 3). Twenty-four patients were MOG-IgG positive. Sensitivity and specificity of MOG-IgG test applied to the 2018 international recommendations were 28.4% and 86.7%, while they were 42.1% and 88.6% when applied to DE of unclear aetiology as defined above with two or more among: 1_no periventricular and juxtacortical MS-like lesions on brain MRI; 2_longitudinally extensive MRI optic nerve lesion; 3_no CSF-restricted oligoclonal bands; 4_CSF protein > 50 mg/dl. CONCLUSIONS: Simplified requirements compared to those currently proposed for MOG-IgG testing could facilitate the applicability of the assay in the diagnosis of adults with DEs of unclear aetiology.

Induction Versus Escalation in Multiple Sclerosis: A 10-Year Real World Study.

In this independent, multicenter, post-marketing study, we directly compare induction immunosuppression versus escalation strategies on the risk of reaching the disability milestone of Expanded Disability Status Scale (EDSS) ≥ 6.0 over 10 years in previously untreated patients with relapsing-remitting multiple sclerosis. We collected data of patients who started interferon beta (escalation) versus mitoxantrone or cyclophosphamide (induction) as initial treatment. Main eligibility criteria included an EDSS score ≤ 4.0 at treatment start and either ≥ 2 relapses or 1 disabling relapse with evidence of ≥ 1 gadolinium-enhancing lesion at magnetic resonance imaging scan in the pre-treatment year. Since patients were not randomized to treatment group, we performed a propensity score (PS)-based matching procedure to select individuals with homogeneous baseline characteristics. Comparisons were then conducted using Cox models stratified by matched pairs. Overall, 75 and 738 patients started with induction and escalation, respectively. Patients in the induction group were older and more disabled than those in the escalation group (p < 0.05). The PS-matching procedure retained 75 patients per group. In the re-sampled population, a lower proportion of patients reached the outcome after induction (21/75, 28.0%) than escalation (29/75, 38.7%) (hazard ratio = 0.48; p = 0.024). Considering the whole sample, serious adverse events occurred more frequently after induction (8/75, 10.7%) than escalation (18/738, 2.4%) (odds ratio = 3.36, p = 0.015). These findings suggest that, in patients with poor prognostic factors, induction was more effective than escalation in reducing the risk of reaching the disability milestone, albeit with a worse safety profile. Future studies are warranted to explore if newer induction agents may provide a more advantageous long-lasting risk:benefit profile.

From high- to low-frequency administered interferon-beta for multiple sclerosis: a multicenter study.

OBJECTIVES: To investigate whether clinical and magnetic resonance imaging (MRI) outcomes of patients with multiple sclerosis (MS) who required a reduction of administration frequency of interferon-beta (IFNB) were similar to those of patients who did not. METHODS: We identified three subgroups of patients under treatment for 24 months with subcutaneous (sc) high-frequency IFNB-1a or -1b: those continuing to receive IFNB according to the drug label (recommended frequency group), those reducing the administration frequency of sc IFNB-1a or -1b (reduced frequency group), and those switched to once weekly intramuscular (im) IFNB (switched group). All patients were followed for further 24 months. The occurrence of relapse, MRI activity and disability worsening were considered as outcome measures. RESULTS: We identified 308 patients, 201 in the recommended frequency group, 70 in the reduced frequency group, and 37 in the switched group. Patients in the reduced frequency group had increased risk for relapses (HR = 1.95, p < 0.001) and MRI activity (HR = 1.41, p < 0.001), while patients in the switched group had increased risk for relapses (HR = 1.67, p = 0.012), but not for MRI activity (HR = 1.26, p = 0.08) than those in the recommended frequency group. Predictors for disease activity re-start after the reduction of IFNB administration frequency were younger age, higher pre-IFNB relapse rate, and reducing sc IFNB frequency to twice weekly rather than switching to im IFNB-1a once weekly. CONCLUSION: Our findings discourage the reduction of sc IFNB administration frequency, especially in younger patients with a higher pre-IFNB relapse rate. However, switching to im IFNB-1a may be considered in some selected cases.

Interferon beta failure predicted by EMA criteria or isolated MRI activity in multiple sclerosis.

OBJECTIVE: The objective of this paper is to investigate four-year outcomes of interferon beta (IFNB)-treated patients with multiple sclerosis (MS) according to their clinical or magnetic resonance imaging (MRI) activity status at first year of treatment. METHODS: A total of 370 patients with MS duration ≤5 years before IFNB start were followed-up for four years. The optimal threshold for one-year MRI activity that more accurately predicted subsequent relapses or disability worsening was identified. The risk of relapses and disability worsening after the first year was then estimated by propensity score (PS)-adjusted analyses in patients fulfilling European Medicines Agency (EMA) criteria for second-line escalation and in those with isolated MRI activity. RESULTS: A total of 192 (51.9%) patients relapsed, and 66 (17.8%) worsened in disability from year 1 to 4 of follow-up. The more accurate threshold for one-year MRI activity was the occurrence of ≥1 enhancing or ≥2 new T2-lesions. An increased risk of relapses and disability worsening was found in either patients fulfilling EMA criteria (hazard ratio (HR) = 3.69, and HR = 6.02) and in those experiencing isolated MRI activity (HR = 3.15, and HR = 5.31) at first year of treatment, when compared with stable patients (all p values <0.001). CONCLUSION: The four-year outcomes of patients with isolated MRI activity did not differ from those fulfilling EMA criteria at first year of IFNB treatment.

Balance deficit with opened or closed eyes reveals involvement of different structures of the central nervous system in multiple sclerosis.

OBJECTIVE: To evaluate whether balance deficit in patients with multiple sclerosis (MS), as assessed with eyes opened (EO) and closed (EC), is associated with damage of different structures of the central nervous system (CNS). METHODS: Fifty patients with MS and 20 healthy controls (HCs) underwent static posturography to calculate the body's center of pressure displacement (COP path) with EO and EC. They were scanned using a 3.0T magnet to obtain PD/T2 and 3D-T1-weighted images of the brain and spinal cord. We determined the mid-sagittal cerebellum area (MSCA) and upper cervical cord cross-sectional area (UCCA). We also measured the patients' lesion volumes (T2-LVs) on the whole brain and at different infratentorial levels. RESULTS: MS patients had wider COP paths with both EO and EC (p < 0.001), and lower values in both MSCA (p = 0.01) and UCCA (p = 0.008) than HCs. The COP path with EO was associated with MSCA (Beta = -0.58; p = 0.004) and T2-LV on middle cerebellar peduncles (Beta = 0.59; p = 0.002). The COP path with EC was associated with UCCA (Beta= -22.74; p = 0.003) and brainstem T2-LV (Beta = 0.52; p = 0.01). CONCLUSIONS: Balance deficit in MS was related to atrophy of both the cerebellum and spinal cord, but the extent of COP path under the two different conditions (EO or EC) implied different patterns of damage in the CNS.

Advances in the treatment of relapsing-remitting multiple sclerosis - critical appraisal of fingolimod.

Multiple sclerosis (MS) is a chronic inflammatory disorder of the central nervous system, traditionally considered to be an autoimmune, demyelinating disease. Based on this understanding, initial therapeutic strategies were directed at immune modulation and inflammation control. At present, there are five licensed first-line disease-modifying drugs for MS in Europe, and two second-line treatments. Currently available MS therapies have shown significant efficacy throughout many trials, but they produce different side effects. Despite disease-modifying drugs being well known and safe, they require regular and frequent parenteral administration and are associated with limited long-term treatment adherence. Therefore, the development of new therapeutic strategies is warranted. Several oral compounds are in late stages of development for treating MS. fingolimod is an oral sphingosine-1-phosphate receptor modulator that has demonstrated superior efficacy compared with placebo and interferon ß-1a in phase III studies. It has already been approved in the treatment of MS. This review focuses on advances in current and novel oral treatment approaches in MS. We summarily review the oral compounds in this study, focusing on the recent development, approval, and the clinical experience with fingolimod.