Acute Relapses Of Multiple Sclerosis Research Articles

Disruption of IFNγ, GZMB, PRF1, or LYST Results in Reduced Suppressive Function in Human CD8+ T Cells.

An imbalance between proinflammatory and regulatory processes underlies autoimmune disease pathogenesis. We have shown that acute relapses of multiple sclerosis are characterized by a deficit in the immune suppressive ability of CD8+ T cells. These cells play an important immune regulatory role, mediated in part through cytotoxicity (perforin [PRF]/granzyme [GZM]) and IFNγ secretion. In this study, we further investigated the importance of IFNγ-, GZMB-, PRF1-, and LYST-associated pathways in CD8+ T cell-mediated suppression. Using the CRISPR-Cas9 ribonucleoprotein transfection system, we first optimized efficient gene knockout while maintaining high viability in primary bulk human CD8+ T cells. Knockout was confirmed through quantitative real-time PCR assays in all cases, combined with flow cytometry where appropriate, as well as confirmation of insertions and/or deletions at genomic target sites. We observed that the knockout of IFNγ, GZMB, PRF1, or LYST, but not the knockout of IL4 or IL5, resulted in significantly diminished invitro suppressive ability in these cells. Collectively, these results reveal a pivotal role for these pathways in CD8+ T cell-mediated immune suppression and provide important insights into the biology of human CD8+ T cell-mediated suppression that could be targeted for immunotherapeutic intervention.

Cytoprotective E-WE thrombin reduces disease severity in a murine model of relapsing-remitting multiple sclerosis.

The blood-brain barrier is composed of microvascular endothelial cells, immune cells, and astrocytes that work in concert with the coagulation cascade to control inflammation and immune cell infiltration into the central nervous system. Endothelial cell dysfunction leading to increased permeability and compromised barrier function are hallmarks of neuroinflammatory and autoimmune disorders, including multiple sclerosis (MS). Therapeutic strategies that improve or protect endothelial barrier function may be beneficial in the treatment or prevention of neuroinflammatory diseases. We therefore tested the hypothesis that biasing thrombin toward anticoagulant and cytoprotective activities would provide equivalent or even additive benefit compared with standard-of-care therapeutic strategies, including corticosteroids. In a mouse model of relapsing-remitting MS, treatment with the thrombin mutant, E-WE thrombin, an engineered thrombin mutant with cytoprotective activities that is biased toward anticoagulant and cytoprotective activity, reduced neuroinflammation and extracellular fibrin formation in SJL mice inoculated with proteolipid protein (PLP) peptide. When administered at the onset of detectable disease, E-WE thrombin significantly improved the disease severity of the initial attack as well as the relapse and delayed the onset of relapse to a similar extent as observed with methylprednisolone. Both methylprednisolone and E-WE thrombin reduced demyelination and immune cell recruitment. These results provide rationale for considering engineered forms of thrombin biased toward anticoagulant and cytoprotective activity as a therapeutic strategy and perhaps an effective alternative to high-dose methylprednisolone for the management of acute relapsing MS attacks.NEW & NOTEWORTHY There are limited treatment options for mitigating acute relapsing attacks for patients with multiple sclerosis. We tested the hypothesis that harnessing the cytoprotective activity of the blood coagulation enzyme, thrombin, would provide benefit and protection against relapsing disease in a mouse model of MS. Our results provide rationale for considering engineered forms of thrombin biased toward cytoprotective activity as a therapeutic strategy and perhaps an alternative to steroids for the management of relapsing MS attacks.

The Impact of Relapses on Pain and Quality of Life in Patients with Multiple Sclerosis Treated with Corticosteroids.

We assessed the prevalence and risks associated with pain during and after a multiple sclerosis (MS) relapse, and the impact of pain on quality of life (QoL), in MS patients. 117 patients suffering an acute MS relapse were evaluated with clinician- and patient-reported outcomes, including the expanded disability status scale (EDSS), Multiple Sclerosis Impact Scale (MSIS-29), and MS Walking scale-12 (MSWS-12). Relapse-related pain was assessed via the short-form 36 (SF-36) questionnaire upon first visit (relapse onset) and at 6 weeks after treatment with intravenous methylprednisolone (follow-up visit). Pain was present in 80% of patients at relapse onset. Patients with pain were more impaired physically (higher mean scores on MSIS-29phys and MSWS-12 and lower mean scores on SF-36 role physical, physical, and vitality scales) at relapse and six weeks after. In total, 74% of patients with MS relapse reported a poorer QoL due to pain. A lower psychological well-being was correlated with greater pain (MSIS29psy score). An increased number of prior relapses was a predictor of more pain at relapse onset. Pain was common at the time of MS relapse and improved, but was still significant, six weeks after treatment with corticosteroids. Further studies are required to better understand relapse-related pain.

Long-term potentiation-like plasticity is retained during relapse in patients with Multiple Sclerosis

ObjectiveTo investigate the degree of synaptic plasticity in Multiple Sclerosis (MS) patients during acute relapses compared to stable MS patients and healthy controls (HCs) and to analyze its functional relevance. MethodsFacilitatory quadripulse stimulation (QPS) was applied to the primary motor cortex in 18 acute relapsing and 18 stable MS patients, as well as 18 HCs. The degree of synaptic plasticity was measured by the change in motor evoked potential amplitude following QPS. Symptom recovery was assessed three months after relapse. ResultsSynaptic plasticity was induced in all groups. The degree of induced plasticity did not differ between acute relapsing patients, HCs, and stable MS patients. Plasticity was significantly higher in relapsing patients with motor disability compared to relapsing patients without motor disability. In most patients (n = 9, 50%) symptoms had at least partially recovered three months after the relapse, impeding meaningful analysis of the functional relevance of baseline synaptic plasticity. ConclusionsQPS-induced synaptic plasticity is retained during acute MS relapses. Subgroup analyses suggest that stabilizing metaplastic mechanisms may be more important to prevent motor disability but its functional relevance needs to be verified in larger, longitudinal studies. SignificanceNew insights into synaptic plasticity during MS relapses are provided.

Neuroimmune, clinical and treatment challenges in multiple sclerosis-related psychoses

In recent years, epidemiological and genetic studies have shown an association between autoimmune diseases and psychosis. The question arises whether patients with schizophrenia are more likely to develop multiple sclerosis (MS) later in life. It is well known that the immune system plays an important role in the etiopathogenesis of both disorders. Immune disturbances may be similar or very different in terms of different types of immune responses, disturbed myelination, and/or immunogenetic predispositions. A psychotic symptom may be a consequence of the MS diagnosis itself or a separate entity. In this review article, we discussed the timing of onset of psychotic symptoms and MS and whether the use of corticosteroids as therapy for acute relapses in MS is unfairly neglected in patients with psychiatric comorbidities. In addition, we discussed that the anti-inflammatory potential of antipsychotics could be useful and should be considered, especially in the treatment of psychosis that coexists with MS. Autoimmune disorders could precipitate psychotic symptoms, and in this context, autoimmune psychosis must be considered as a persistent symptomatology that requires continuous and specific treatment.

Natalizumab Promotes Activation of Peripheral Monocytes in Patients With Multiple Sclerosis.

Natalizumab (NTZ), a monoclonal antibody against very late antigen-4 (VLA-4), is one of the most efficient therapies to prevent acute relapses in multiple sclerosis (MS). VLA-4 is the key adhesion molecule for peripheral immune cells, especially lymphocytes to enter the CNS. While its blockade thus virtually abrogates CNS infiltration of these cells, long-term exposure to natalizumab may also affect immune cell function. In this study, we report that in patients with MS, NTZ treatment is associated with an enhanced activation status of peripheral monocytes. Expression of 2 independent activation markers, CD69 and CD150, was significantly higher on blood monocytes from NTZ-treated patients when compared with those from matched untreated patients with MS, while other properties such as cytokine production remained unchanged. These findings consolidate the concept that peripheral immune cells remain fully competent on NTZ treatment, an excellent asset rare among MS treatments. However, they also suggest that NTZ may exert nondesirable effects on the progressive aspect of MS, where myeloid cells and their chronic activation are attributed a prominent pathophysiologic role.

Osteopontin Is Associated with Multiple Sclerosis Relapses.

Osteopontin, an extracellular matrix protein involved in bone remodeling, tissue repair and inflammation, has previously been associated with increased inflammation and neurodegeneration in multiple sclerosis (MS), promoting a worse disease course. Osteopontin is also likely involved in acute MS relapses. In 47 patients with relapsing-remitting MS, we explored the correlation between the time elapsed between the last clinical relapse and lumbar puncture, and the cerebrospinal fluid (CSF) levels of osteopontin and a group of inflammatory cytokines and adipokines such as resistin, plasminogen activator inhibitor-1, osteoprotegerin, interleukin (IL)-1β, IL-2, IL-6 and IL-1 receptor antagonist (IL-1ra). We also analyzed the correlations between CSF levels of osteopontin and the other CSF molecules considered. Osteopontin CSF concentrations were higher in patients with a shorter time interval between the last clinical relapse and CSF withdrawal. In addition, CSF levels of osteopontin were positively correlated with the proinflammatory cytokines IL-2 and IL-6 and negatively correlated with the anti-inflammatory molecule IL-1ra. Our results further suggest the role of osteopontin in acute MS relapses showing that, in proximity to relapses, osteopontin expression in CSF may be increased along with other proinflammatory mediators and correlated with decreased concentrations of anti-inflammatory molecules.

Saudi Consensus Recommendations on the Management of Multiple Sclerosis: Disease-Modifying Therapies and Management of Relapses

For the past 10 years, disease-modifying therapy (DMT) options for multiple sclerosis (MS) have grown remarkably where DMTs have been shown to reduce the risk of MS relapses. MS patients are advised to begin treatment with a DMT shortly after diagnosis to limit the possibility of disease progression over time. While patients with radiologically isolated syndrome do not require pharmacologic treatment, high-risk patients with clinically isolated syndrome are advised to start DMTs. This article provides evidence-based recommendations for DMT use in MS management, helping healthcare practitioners advise patients on treatment decisions. We aim to provide recommendations for the management of acute MS relapses. The recommendations herein were developed following the gathering of a panel of experts after evaluating international guidelines, and the latest evidence was collected through a comprehensive literature review.

T Lymphocyte Serotonin 5-HT7 Receptor Is Dysregulated in Natalizumab-Treated Multiple Sclerosis Patients.

Serotonin (5-HT) is known as a potent immune cell modulator in autoimmune diseases and should be protective in the pathogenesis of multiple sclerosis (MS). Nevertheless, there is limited knowledge about receptors involved in 5-HT effects as well as induced mechanisms. Among 5-HT receptors, the 5-HT7 receptor is able to activate naïve T cells and influence the inflammatory response; however, its involvement in the disease has never been studied so far. In this study, we collected blood sample from three groups: acute relapsing MS patients (ARMS), natalizumab-treated MS patients (NTZ), and control subjects. We investigated the 5-HT7 expression on circulating lymphocytes and evaluated the effects of its activation on cytokine production with peripheral blood mononuclear cell (PBMC) cultures. We found a significant increase in the 5-HT7 surface expression on T lymphocytes and on the different CD4+ T cell subsets exclusively in NTZ-treated patients. We also showed that the selective agonist 5-carboxamidotryptamine (5-CT)-induced 5-HT7R activation significantly promotes the production of IL-10, a potent immunosuppressive cytokine in PBMCs. This study provides for the first time a dysregulation of 5-HT7 expression in NTZ-MS patients and its ability to promote IL-10 release, suggesting its protective role. These findings strengthen the evidence that 5-HT7 may play a role in the immuno-protective mechanisms of NTZ in MS disease and could be considered as an interesting therapeutic target in MS.

An interactive web-based programme on relapse management for people with multiple sclerosis (POWER@MS2) - development, feasibility, and pilot testing of a complex intervention.

IntroductionDespite the lack of high-quality evidence regarding its long-term effectiveness, intravenous corticosteroid therapy is recommended as the standard treatment of acute multiple sclerosis relapses in Germany. High financial expenses and the equivalent effectiveness of oral corticosteroid therapy contrast with this trend. There is an urgent need to provide patients with evidence-based and comprehensible information on relapse management and to actively involve patients in relapse treatment decisions. Web-based decision support on relapse management could be an effective measure to empower people with multiple sclerosis making informed treatment decisions.ObjectivesTo develop a web-based programme on relapse management for people with multiple sclerosis and evaluate the feasibility and acceptability of the intervention.MethodsThe study followed the first two phases of the UK Medical Research Council Framework for complex interventions. The first phase involved the development of an interactive web-based programme on relapse management. The second phase focused on the feasibility and pilot testing of the programme with people with multiple sclerosis and experts with a professional background in multiple sclerosis. Data was obtained using questionnaires with closed- and open-ended questions as well as qualitative semi-structured telephone interviews. Quantitative data was analyzed descriptively, whereas qualitative data was clustered by topic.ResultsFeasibility of the intervention programme was tested with 10 people with multiple sclerosis and 10 experts. Feasibility testing indicated good practicability and acceptance of the content. After revision, the programme was piloted with seven people with multiple sclerosis and three experts. The results showed good acceptance in both groups. Based on the feedback, a final revision was performed.ConclusionFeasibility and pilot testing indicated good user-friendliness, acceptance, and practicability of the programme. The programme is currently evaluated in a randomized controlled trial (Registration Number on ClinicalTrials.gov: NCT04233970). It is expected that the programme will have a positive impact on patients' relapse management and strengthen their autonomy and participation.

Immunoadsorption versus double-dose methylprednisolone in refractory multiple sclerosis relapses

ObjectiveIntravenous methylprednisolone is the standard treatment for a multiple sclerosis relapse; however, this fails to improve symptoms in up to one quarter of patients. Immunoadsorption is an accepted treatment for refractory relapses, but prospective comparator-controlled studies are missing.MethodsIn this observational study, patients with steroid-refractory acute multiple sclerosis relapses receiving either six courses of tryptophan-immunoadsorption or double-dose methylprednisolone therapy were analysed. Outcomes were evaluated at discharge and three months later. Immune profiling of blood lymphocytes and proteomic analysis were performed by multi-parameter flow cytometry and Olink analysis, respectively (NCT04450030).Results42 patients were enrolled (methylprednisolone: 26 patients; immunoadsorption: 16 patients). For determination of the primary outcome, treatment response was stratified according to relative function system score changes (“full/best” vs. “average” vs. “worse/none”). Upon discharge, the adjusted odds ratio for any treatment response (“full/best” + ”average” vs. “worse/none”) was 10.697 favouring immunoadsorption (p = 0.005 compared to methylprednisolone). At follow-up, the adjusted odds ratio for the best treatment response (“full/best” vs. “average” + ”worse/none”) was 103.236 favouring IA patients (p = 0.001 compared to methylprednisolone). Similar results were observed regarding evoked potentials and quality of life outcomes, as well as serum neurofilament light-chain levels. Flow cytometry revealed a profound reduction of B cell subsets following immunoadsorption, which was closely correlated to clinical outcomes, whereas methylprednisolone had a minimal effect on B cell populations. Immunoadsorption treatment skewed the blood cytokine network, reduced levels of B cell-related cytokines and reduced immunoglobulin levels as well as levels of certain coagulation factors.InterpretationImmunoadsorption demonstrated favourable outcomes compared to double-dose methylprednisolone. Outcome differences were significant at discharge and follow-up. Further analyses identified modulation of B cell function as a potential mechanism of action for immunoadsorption, as reduction of B cell subsets correlated with clinical improvement.

Acute relapse of Multiple Sclerosis (MS) in an adolescent patient after Tuberculin skin test (TST): a case report

Activation of MS as a result of bacterial and viral infections is proposed by various studies. However, immune responses initiated by a bacterial antigen can rarely lead to the activation or occurrence of MS. Hereby, we report a unique case of Multiple Sclerosis (MS) relapse following a Tuberculin skin test (TST). After one year of MS remission, a 13-years old female, presented with symptoms supporting tuberculosis (TB), although TST denied TB infection. Two weeks later, the patient returned with symptoms indicating MS relapse, confirmed by magnetic resonance imaging (MRI). A series of immune system interactions, starting with the activation of Toll-like receptors (TLRs) by Mycobacterial components, may expose the central nervous system (CNS) to autoimmune reactions. TST-induced type IV hypersensitivity can be another parallel mechanism in light of MS being a CD4 T-cell mediated disease. This case report highlights the importance of environmental factors such as bacterial agents in the pathophysiology of MS.

Comparison of Effectiveness of Leflunomide against High Dose Methyl-Prednisolone in Multiple Sclerosis

Background: Leflunomide is a disease-modifying, anti-rheumatic drug, whose active metabolite Teriflu-nomide is licensed drug therapy for reducing progression in Multiple sclerosis. Intravenous high dose Methyl-Prednisolone is an established treatment for acute relapses of multiple sclerosis that escalates reco-very. Intravenous methyl-prednisone also being used anecdotally for the prevention of relapses. Methods: Each patient after enrollment in the study received treatment for 1 year. A total of 30 patients, 15 patients in each group were taken. Patients fulfilling inclusion criteria and giving written informed con-sent were randomly divided into 2 groups (Group A and Group B) using a computer-generated random numbers table. Group A patients received Leflunomide 20mg with a loading dose of 3 tablets for 3 days and then once daily for one year. And group B patients received high-dose intravenous Methyl Prednisolone 1g monthly for a period of one year. Results: Methyl Prednisolone group, 5 (33.3%) had only 1(%) relapse and 10 (66.7%) cases had no relapse. In contrast, Leflunomide group, no relapse was recorded. The frequency of relapse was consequently statistically higher in Methyl Prednisolone group, p-value < 0.05. In respect of, a number of lesions on MRI; Methyl Prednisolone group demonstrated no change in 4 (26.67%) cases and 11 (73.33%) cases had lesions increased from baseline. Whereas, in the Leflunomide group the number of lesions significantly decreased (p-value < 0.05). Significant improvement in Expanded disability status was observed leflunomide group (p-value < 0.05). Conclusion: Leflunomide was more effective in preventing relapses and in decreasing disease activity on MRI, as compared with high dose monthly Methyl-prednisone in patients with Multiple Sclerosis.

Cognition in acute relapses: A psychometric evaluation and its correlation with event-related potential, P300 in multiple sclerosis

Objective During acute relapses of multiple sclerosis (MS), physical symptoms attract utmost care. However, cognitive impairment may constitute an substantial part of a new relapse. In this study, we evaluated the cognitive status of MS patients during acute relapses. Materials and methods We enrolled 35 definite MS patients and 21 healthy subjects. Neuropsychometric tests and the event-related potential, P300 were administered to the MS patients before corticosteroid treatment, and 3 months later. The control subjects were tested only once. Results The differences between the scores of the Timed 25-Foot Walk test, the Brief Repeatable Battery subtests (10/36 SPART, SDMT, SRT, SRT-LTM) in the relapse and remission phases were statistically significant (p = .005, p = .007, p = .05, p = .029, p = .001, respectively). The latencies of P300 waves during the relapses were significantly prolonged than the ones in the remission and the controls’ (p = .004, p < .001, respectively). Conclusions In this study, we observed a significant involvement of visual-spatial perception, remote memory, and recall, as well as P300 latencies in acute relapses. The inclusion of cognitive assessment during a relapse can provide accurate information on cognitive status for future treatment modalities.

Electroconvulsive Therapy in Multiple Sclerosis: A Review of Current Evidence.

To review the published literature over the last 5 years on the use of electroconvulsive therapy (ECT) in multiple sclerosis (MS), focusing on efficacy, safety, and tolerability. MS commonly has neuropsychiatric comorbidity. ECT is used in MS for severe and life-threatening forms of mental illness when other treatment options have failed or when a rapid response is required. English-language literature published in the last 5 years (January 2015-June 2, 2020) was searched using the terms: ECT, electroconvulsive therapy, shock therapy, electroshock therapy, electroconvulsive therapies, multiple sclerosis, chronic progressive multiple sclerosis, acute relapsing multiple sclerosis, and multiple sclerosis, relapsing and remitting. KnowledgeShare, a National Health Service library application providing updates on evidence-based practice, was used along with EMBASE, PsycInfo, MEDLINE, PubMed, the TRIP database (which offers a complete and updated list of evidence-based online resources), HDAS (Healthcare Databases Advanced Search), CRDWeb (Centre for Reviews and Dissemination), and the Cochrane Library. Reference lists of articles identified in the search were also reviewed. Our initial search revealed 30 articles of potential relevance. However, after individually evaluating these articles, only 6 case studies and 1 review article detailing the use of ECT in MS were included. The studies were analyzed by both authors to obtain clinical information relevant to meeting the objectives of the review. The efficacy and safety in using ECT for MS is derived only from case series and case reports. There were no controlled trials or systematic reviews, and the evidence collated was of low quality. The consensus is that ECT is an effective treatment for specific mental disorders in MS including catatonia. We have used ECT successfully in our clinic for patients with MS. However, there are concerns about the potential effects of ECT on neurologic and cognitive function. There are also possible risks with using anesthetic agents and particularly neuromuscular blockers.

IL-12-Induced Immune Suppressive Deficit During CD8+ T-Cell Differentiation

Autoimmune diseases are characterized by regulatory deficit in both the CD4+ and CD8+ T-cell compartments. We have shown that CD8+ T-cells associated with acute relapse of multiple sclerosis are significantly deficient in their immune suppressive ability. We hypothesized that distinct CD8+ cytotoxic T-cell (Tc) lineages, determined by cytokine milieu during naïve T-cell differentiation, may harbor differential ability to suppress effector CD4+ T-cells. We differentiated purified human naïve CD8+ T-cells in vitro toward Tc0 (media control), Tc1 and Tc17 lineages. Using in vitro flow cytometric suppression assays, we observed that Tc0 and Tc17 cells had similar suppressive ability. In contrast, Tc1 cells showed significant loss of suppressive ability against ex vivo CD4+ T-cells and in vitro-differentiated Th0, Th1 and Th17 cells. Of note, Tc1 cells were also suboptimal in suppressing CD4-induced acute xenogeneic graft versus host disease (xGVHD) in vivo. Tc subtypes derived under various cytokine combinations revealed that IL-12-containing conditions resulted in less suppressive cells exhibiting dysregulated cytotoxic degranulation. RNA sequencing transcriptome analyses indicated differential regulation of inflammatory genes and enrichment in GM-CSF-associated pathways. These studies provide insights into the role of T-cell differentiation in CD8 suppressive biology and may reveal therapeutically targetable pathways to reverse suppressive deficit during immune-mediated disease.

Inflammatory activity following motor progression due to critical CNS demyelinating lesions

Background: New inflammatory activity is of unclear frequency and clinical significance in progressive multiple sclerosis (MS); it is uncertain in patient cohorts with motor progression due to critical demyelinating lesions. Objectives: The aim of this study is to determine the likelihood of central nervous system (CNS) inflammatory activity, assessed by new clinical relapses or active magnetic resonance imaging (MRI) lesions, following onset of motor progression due to critical demyelinating lesions. Methods: Patients with progressive upper motor neuron impairment for ⩾1 year attributable to critical demyelinating lesions with single CNS lesion (progressive solitary sclerosis (PSS)), 2 to 5 total CNS demyelinating lesions (progressive “pauci-sclerosis” (PPS)), or >5 CNS demyelinating lesions and progressive exclusively unilateral monoparesis or hemiparesis (PUHMS) were identified. Clinical data were reviewed for acute MS relapses, and subsequent MRI was reviewed for active T1-gadolinium-enhancing or T2-demyelinating lesions. Results: None of the 91 patients (22 PSS, 40 PPS, 29 PUHMS) identified experienced clinical relapses over a median clinical follow-up of 93 months (range: 12–518 months). Nine patients (10%) developed active lesions over median 84 months radiologic follow-up (range: 12–518 months). Active lesions occurred in 24% PUHMS, 5% PSS, and 3% PPS cohorts. Conclusion: New inflammatory activity, defined by active lesions and clinical relapses following motor progression in patients with critical demyelinating lesions, is low. Disease-modifying therapies that reduce demyelinating relapses and active MRI lesions are of uncertain benefit in these cohorts.

Inner nuclear layer and olfactory threshold are interlinked and reflect inflammatory activity in multiple sclerosis.

BackgroundRetinal inner nuclear layer (INL) and olfactory threshold (OT) are associated with inflammatory activity in multiple sclerosis (MS).ObjectiveThe study aims to investigate (a) whether there is an association of INL and OT in MS and (b) if changes in INL and OT follow a time pattern in relation to MS relapse.MethodsWe assessed INL by optical coherence tomography and OT by Sniffin’ Sticks in three different cohorts: a cross-sectional MS cohort (n = 260), a longitudinal, 3-year cohort of MS (n = 141) and healthy controls (n = 30), and a longitudinal, 24-weeks cohort with acute MS relapse (n = 28) and stable MS controls (n = 27).ResultsCross-sectionally, INL and OT were strongly correlated with number but not localization of relapse in the previous 12 months and INL correlated with OT. Longitudinally, INL was thicker and OT score was lower short term in times of relapse activity, but not long term and independent of relapse localization. In acute MS relapse, INL and OT were altered compared with stable MS, again, independent of relapse localization resolving over 12–24 weeks with faster approximation to stable MS after escalation of disease-modifying treatment.ConclusionsINL and OT are interlinked markers of short-term inflammatory activity, following a nearly congruent time pattern and independent of relapse localization, possibly reflecting a proinflammatory state within the central nervous system.

Immunoglobulin G index as a biomarker of relapse response to corticosteroids during early stages of multiple sclerosis

BackgroundDespite the considerable advances in disease modifying therapy in multiple sclerosis (MS), management of acute MS relapses remains understudied. The response to relapse therapy is heterogenous among patients, and the exact reason behind such response remains elusive. Identification of a reliable biomarker for relapse responsiveness would contribute considerably to optimizing the relapse outcome. Objectivesto explore whether the immunoglobulin G (IgG) index during acute relapse contributes to relapse response to corticosteroid therapy or not. MethodsA prospective study was conducted on 46 MS patients attending MS clinic in relapse with a baseline EDSS≤3 before the relapse. IgG index was measured in all patients before corticosteroids therapy, and their EDSS was re-assessed after 3 months. ResultsThe mean age of the recruited patients was 26.89±4.19 years, with females constituting 71.7% of the sample. IgG index was significantly higher in patients who recovered fully after relapse (1.44) than those who were partially recovered (0.95)(P<0.001), and it was inversely correlated with EDSS increase after the relapse (r=-0.390, P = 0.007). On regression analysis, the OR of IgG index to relapse response was 0.05 (CI: 0.07–0.31, 95%)(P = 0.003). ConclusionsIgG index can be a promising biomarker of relapse response to steroids in early stages of MS.

Safety and efficacy of immunoadsorption versus plasma exchange in steroid-refractory relapse of multiple sclerosis and clinically isolated syndrome: A randomised, parallel-group, controlled trial

SummaryBackgroundPlasma exchange (PE) constitutes the standard therapy for steroid-refractory relapse in multiple sclerosis and clinically isolated syndrome. Immunoadsorption (IA) is an alternative method of apheresis which selectively removes immunoglobulines (Ig) while preserving other plasma proteins. Although IA is regarded as a well-tolerated, low-risk procedure, high-level evidence for its efficacy is lacking. Therefore, we sought to investigate whether IA is superior to PE in patients with acute relapse of multiple sclerosis or clinically isolated syndrome who had insufficiently responded to high-dose intravenous methylprednisolone (MP).MethodsPatients with acute relapse of multiple sclerosis or clinically isolated syndrome and without complete clinical remission of symptoms after at least one cycle of high-dose intravenous MP therapy were enrolled to our randomised, controlled, parallel-group, monocentric trial. Eligible patients were aged at least 12 years and had no clinical or laboratory signs of systemic infection. Eligible patients were randomly assigned (1:1) to receive either IA or PE. Patients in both groups received 5 treatments on 5 consecutive days. In the IA group, the 2.0-fold individual total plasma volume was processed on day 1, and the 2.5-fold on days 2–5. In the PE group, 2 liters of plasma (corresponding to the 0.69 ± 0.12-fold individual total plasma volume) were removed each day and substituted by 5% human albumin solution. Patients were followed up directly after last apheresis as well as 2 and 4 weeks after last treatment. The primary endpoint was change of the Multiple Sclerosis Functional Composite (MSFC) after 4 weeks compared to baseline. Analyses of primary outcome and safety measures were done in all patients who received at least one treatment (intention-to-treat-population). The trial is registered with ClinicalTrials.gov, number NCT02671682.FindingsBetween January 21, 2016, and October 26, 2018, 63 patients were screened for eligibility, and 61 patients were randomly assigned to receive IA (n = 31) or PE (n = 30). All randomised patients were included in the intention-to-treat-analysis. For the primary outcome, the median improvement of MSFC after 4 weeks compared to baseline was 0.385 (IQR 0.200–0.675; p < 0.001) in the IA group and 0.265 (IQR 0.100–0.408; p < 0.001) in the PE group. Improvement in the IA group was significantly larger (p = 0.034) compared to PE. Response rates after 4 weeks were 86.7% in the IA group and 76.7% in the PE group. One deep venous thrombosis occurred in each group.InterpretationBoth IA and PE were safe in patients with steroid-refractory relapse and resulted in significant improvements of the primary outcome MSFC after 4 weeks compared to baseline. IA patients showed significantly larger improvements of MSFC compared to PE patients after 4 weeks. The results indicate a potential superiority of IA compared to PE in treatment of steroid-refractory relapse in multiple sclerosis and clinically isolated syndrome, which has to be confirmed by future studies.FundingFresenius Medical Care Deutschland GmbH, Bad Homburg, Germany