Prospective study validating a multidimensional treatment decision score predicting the 24-month outcome in untreated patients with clinically isolated syndrome and early relapsing-remitting multiple sclerosis, the ProVal-MS study.

INTRODUCTION: In Multiple Sclerosis (MS), patients´ characteristics and (bio)markers that reliably predict the individual disease prognosis at disease onset are lacking. Cohort studies allow a close follow-up of MS histories and a thorough phenotyping of patients. Therefore, a multicenter cohort study was initiated to implement a wide spectrum of data and (bio)markers in newly diagnosed patients. METHODS: ProVal-MS (Prospective study to validate a multidimensional decision score that predicts treatment outcome at 24 months in untreated patients with clinically isolated syndrome or early Relapsing-Remitting-MS) is a prospective cohort study in patients with clinically isolated syndrome (CIS) or Relapsing-Remitting (RR)-MS (McDonald 2017 criteria), diagnosed within the last two years, conducted at five academic centers in Southern Germany. The collection of clinical, laboratory, imaging, and paraclinical data as well as biosamples is harmonized across centers. The primary goal is to validate (discrimination and calibration) the previously published DIFUTURE MS-Treatment Decision score (MS-TDS). The score supports clinical decision-making regarding the options of early (within 6 months after study baseline) platform medication (Interferon beta, glatiramer acetate, dimethyl/diroximel fumarate, teriflunomide), or no immediate treatment (> 6 months after baseline) of patients with early RR-MS and CIS by predicting the probability of new or enlarging lesions in cerebral magnetic resonance images (MRIs) between 6 and 24 months. Further objectives are refining the MS-TDS score and providing data to identify new markers reflecting disease course and severity. The project also provides a technical evaluation of the ProVal-MS cohort within the IT-infrastructure of the DIFUTURE consortium (Data Integration for Future Medicine) and assesses the efficacy of the data sharing techniques developed. PERSPECTIVE: Clinical cohorts provide the infrastructure to discover and to validate relevant disease-specific findings. A successful validation of the MS-TDS will add a new clinical decision tool to the armamentarium of practicing MS neurologists from which newly diagnosed MS patients may take advantage. Trial registration ProVal-MS has been registered in the German Clinical Trials Register, `Deutsches Register Klinischer Studien` (DRKS)-ID: DRKS00014034, date of registration: 21 December 2018; https://drks.de/search/en/trial/DRKS00014034.

Immediate and sustained terminal complement inhibition with ravulizumab in patients with anti-aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder.

Objective: To assess the pharmacokinetics and pharmacodynamics of the long-acting terminal complement 5 (C5) inhibitor ravulizumab in adults with anti-aquaporin-4 antibody-positive (AQP4+) neuromyelitis optica spectrum disorder (NMOSD) in the phase 3, open-label CHAMPION-NMOSD trial (NCT04201262). Methods: Patients aged 18 years or older received a weight-based intravenous loading dose of ravulizumab (2,400-3,000 mg) on day 1, followed by weight-based maintenance doses (3,000-3,600 mg) on day 15 and once every 8 weeks thereafter. Pharmacokinetic assessments were maximum observed concentration (Cmax, assessed at the end of the infusion) and concentration at the end of the dosing interval (Ctrough, assessed before dosing) for ravulizumab. Pharmacodynamic assessment was time-matched observed free C5 concentration in serum up to 50 weeks. Results: The pharmacokinetic/pharmacodynamic analysis included 58 patients treated with ravulizumab. Serum ravulizumab concentrations at or above the therapeutic threshold (175 µg/mL) were achieved in all patients after administration of the first dose and maintained for 50 weeks. At week 50, the mean (standard deviation) Cmax (n = 51) and Ctrough (n = 52) were 1,887.6 (411.38) and 764.4 (217.68) µg/mL, respectively. Immediate and complete terminal complement inhibition (free C5 serum concentrations < 0.5 µg/mL) was achieved by the end of the first ravulizumab infusion and sustained throughout the treatment period. No treatment-emergent antibodies to ravulizumab were observed. No impact on ravulizumab pharmacokinetics was seen for age, sex, race, hematocrit, hemoglobin, markers of renal and liver impairment, or medications commonly used by patients with NMOSD. Body weight and BMI were significant covariates of ravulizumab pharmacokinetics. Conclusions: Serum ravulizumab concentrations were maintained above the therapeutic threshold in all patients through 50 weeks of treatment. Ravulizumab achieved immediate and complete terminal complement inhibition that was sustained throughout the treatment period in adults with AQP4+ NMOSD.

Update on the diagnosis and treatment of neuromyelitis optica spectrum disorders (NMOSD) - revised recommendations of the Neuromyelitis Optica Study Group (NEMOS). Part II: Attack therapy and long-term management.

This manuscript presents practical recommendations for managing acute attacks and implementing preventive immunotherapies for neuromyelitis optica spectrum disorders (NMOSD), a rare autoimmune disease that causes severe inflammation in the central nervous system (CNS), primarily affecting the optic nerves, spinal cord, and brainstem. The pillars of NMOSD therapy are attack treatment and attack prevention to minimize the accrual of neurological disability. Aquaporin-4 immunoglobulin G antibodies (AQP4-IgG) are a diagnostic marker of the disease and play a significant role in its pathogenicity. Recent advances in understanding NMOSD have led to the development of new therapies and the completion of randomized controlled trials. Four preventive immunotherapies have now been approved for AQP4-IgG-positive NMOSD in many regions of the world: eculizumab, ravulizumab - most recently-, inebilizumab, and satralizumab. These new drugs may potentially substitute rituximab and classical immunosuppressive therapies, which were as yet the mainstay of treatment for both, AQP4-IgG-positive and -negative NMOSD. Here, the Neuromyelitis Optica Study Group (NEMOS) provides an overview of the current state of knowledge on NMOSD treatments and offers statements and practical recommendations on the therapy management and use of all available immunotherapies for this disease. Unmet needs and AQP4-IgG-negative NMOSD are also discussed. The recommendations were developed using a Delphi-based consensus method among the core author group and at expert discussions at NEMOS meetings.

LST-AI: a Deep Learning Ensemble for Accurate MS Lesion Segmentation.

Automated segmentation of brain white matter lesions is crucial for both clinical assessment and scientific research in multiple sclerosis (MS). Over a decade ago, we introduced a lesion segmentation tool, LST, engineered with a lesion growth algorithm (LST-LGA). While recent lesion segmentation approaches have leveraged artificial intelligence (AI), they often remain proprietary and difficult to adopt. Here, we present LST-AI, an advanced deep learning-based extension of LST that consists of an ensemble of three 3D-UNets. LST-AI specifically addresses the imbalance between white matter (WM) lesions and non-lesioned WM. It employs a composite loss function incorporating binary cross-entropy and Tversky loss to improve segmentation of the highly heterogeneous MS lesions. We train the network ensemble on 491 MS pairs of T1w and FLAIR images, collected in-house from a 3T MRI scanner, and expert neuroradiologists manually segmented the utilized lesion maps for training. LST-AI additionally includes a lesion location annotation tool, labeling lesion location according to the 2017 McDonald criteria (periventricular, infratentorial, juxtacortical, subcortical). We conduct evaluations on 270 test cases -comprising both in-house (n=167) and publicly available data (n=103)-using the Anima segmentation validation tools and compare LST-AI with several publicly available lesion segmentation models. Our empirical analysis shows that LST-AI achieves superior performance compared to existing methods. Its Dice and F1 scores exceeded 0.5, outperforming LST-LGA, LST-LPA, SAMSEG, and the popular nnUNet framework, which all scored below 0.45. Notably, LST-AI demonstrated exceptional performance on the MSSEG-1 challenge dataset, an international WM lesion segmentation challenge, with a Dice score of 0.65 and an F1 score of 0.63-surpassing all other competing models at the time of the challenge. With increasing lesion volume, the lesion detection rate rapidly increased with a detection rate of >75% for lesions larger than 60mm3. Given its higher segmentation performance, we recommend that research groups currently using LST-LGA transition to LST-AI. To facilitate broad adoption, we are releasing LST-AI as an open-source model, available as a command-line tool, dockerized container, or Python script, enabling diverse applications across multiple platforms.

Association of retinal vessel pathology and brain atrophy in relapsing-remitting multiple sclerosis.

Background: Optical coherence tomography angiography (OCTA) allows non-invasive assessment of retinal vessel structures. Thinning and loss of retinal vessels is evident in eyes of patients with multiple sclerosis (MS) and might be associated with a proinflammatory disease phenotype and worse prognosis. We investigated whether changes of the retinal vasculature are linked to brain atrophy and disability in MS. Material and methods: This study includes one longitudinal observational cohort (n=79) of patients with relapsing-remitting MS. Patients underwent annual assessment of the expanded disability status scale (EDSS), timed 25-foot walk, symbol digit modalities test (SDMT), retinal optical coherence tomography (OCT), OCTA, and brain MRI during a follow-up duration of at least 20 months. We investigated intra-individual associations between changes in the retinal architecture, vasculature, brain atrophy and disability. Eyes with a history of optic neuritis (ON) were excluded. Results: We included 79 patients with a median disease duration of 12 (interquartile range 2 - 49) months and a median EDSS of 1.0 (0 - 2.0). Longitudinal retinal axonal and ganglion cell loss were linked to grey matter atrophy, cortical atrophy, and volume loss of the putamen. We observed an association between vessel loss of the superficial vascular complex (SVC) and both grey and white matter atrophy. Both observations were independent of retinal ganglion cell loss. Moreover, patients with worsening of the EDSS and SDMT revealed a pronounced longitudinal rarefication of the SVC and the deep vascular complex. Discussion: ON-independent narrowing of the retinal vasculature might be linked to brain atrophy and disability in MS. Our findings suggest that retinal OCTA might be a new tool for monitoring neurodegeneration during MS.

Time to Disability Milestones and Annualized Relapse Rates in NMOSD and MOGAD.

OBJECTIVE: To investigate accumulation of disability in neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein-antibody-associated disease (MOGAD) in a changing treatment landscape. We aimed to identify risk factors for the development of disability milestones in relation to disease duration, number of attacks, and age. METHODS: We analyzed data from individuals with NMOSD and MOGAD from the German Neuromyelitis Optica Study Group registry. Applying survival analyses, we estimated risk factors and computed time to disability milestones as defined by the Expanded Disability Status Score (EDSS). RESULTS: We included 483 patients: 298 AQP4-IgG+ NMOSD, 52 AQP4-IgG- /MOG-IgG- NMOSD patients, and 133 patients with MOGAD. Despite comparable annualized attack rates, disability milestones occurred earlier and after less attacks in NMOSD patients than MOGAD patients (median time to EDSS 3: AQP4-IgG+ NMOSD 7.7 (95% CI 6.6-9.6) years, AQP4-IgG- /MOG-IgG- NMOSD 8.7) years, MOGAD 14.1 (95% CI 10.4-27.6) years; EDSS 4: 11.9 (95% CI 9.7-14.7), 11.6 (95% lower CI 7.6) and 20.4 (95% lower CI 14.1) years; EDSS 6: 20.1 (95% CI 16.5-32.1), 20.7 (95% lower CI 11.6), and 37.3 (95% lower CI 29.4) years; and EDSS 7: 34.2 (95% lower CI 31.1) for AQP4-IgG+ NMOSD). Higher age at onset increased the risk for all disability milestones, while risk of disability decreased over time. INTERPRETATION: AQP4-IgG+ NMOSD, AQP4-IgG- /MOG-IgG- NMOSD, and MOGAD patients show distinctive relapse-associated disability progression, with MOGAD having a less severe disease course. Investigator-initiated research has led to increasing awareness and improved treatment strategies appearing to ameliorate disease outcomes for NMOSD and MOGAD. ANN NEUROL 2024.

Benefits of a mosaic approach for assessing cortical atrophy in individual multiple sclerosis patients.

OBJECTIVE: Cortical gray matter (GM) atrophy plays a central role in multiple sclerosis (MS) pathology. However, it is not commonly assessed in clinical routine partly because a number of methodological problems hamper the development of a robust biomarker to quantify GM atrophy. In previous work, we have demonstrated the clinical utility of the "mosaic approach" (MAP) to assess individual GM atrophy in the motor neuron disease spectrum and frontotemporal dementia. In this study, we investigated the clinical utility of MAP in MS, comparing this novel biomarker to existing methods for computing GM atrophy in single patients. We contrasted the strategies based on correlations with established biomarkers reflecting MS disease burden. METHODS: We analyzed T1-weighted MPRAGE magnetic resonance imaging data from 465 relapsing-remitting MS patients and 89 healthy controls. We inspected how variations of existing strategies to estimate individual GM atrophy ("standard approaches") as well as variations of MAP (i.e., different parcellation schemes) impact downstream analysis results, both on a group and an individual level. We interpreted individual cortical disease burden as single metric reflecting the fraction of significantly atrophic data points with respect to the control group. In addition, we evaluated the correlations to lesion volume (LV) and Expanded Disability Status Scale (EDSS). RESULTS: We found that the MAP method yielded highest correlations with both LV and EDSS as compared to all other strategies. Although the parcellation resolution played a minor role in terms of absolute correlations with clinical variables, higher resolutions provided more clearly defined statistical brain maps which may facilitate clinical interpretability. CONCLUSION: This study provides evidence that MAP yields high potential for a clinically relevant biomarker in MS, outperforming existing methods to compute cortical disease burden in single patients. Of note, MAP outputs brain maps illustrating individual cortical disease burden which can be directly interpreted in daily clinical routine.

Autologous haematopoietic stem cell transplantation for multiple sclerosis: a position paper and registry outline.

Background: While substantial progress has been made in the development of disease-modifying medications for multiple sclerosis (MS), a high percentage of treated patients still show progression and persistent inflammatory activity. Autologous haematopoietic stem cell transplantation (AHSCT) aims at eliminating a pathogenic immune repertoire through intense short-term immunosuppression that enables subsequent regeneration of a new and healthy immune system to re-establish immune tolerance for a long period of time. A number of mostly open-label, uncontrolled studies conducted over the past 20 years collected about 4000 cases. They uniformly reported high efficacy of AHSCT in controlling MS inflammatory disease activity, more markedly beneficial in relapsing-remitting MS. Immunological studies provided evidence for qualitative immune resetting following AHSCT. These data and improved safety profiles of transplantation procedures spurred interest in using AHSCT as a treatment option for MS. Objective: To develop expert consensus recommendations on AHSCT in Germany and outline a registry study project. Methods: An open call among MS neurologists as well as among experts in stem cell transplantation in Germany started in December 2021 to join a series of virtual meetings. Results: We provide a consensus-based opinion paper authored by 25 experts on the up-to-date optimal use of AHSCT in managing MS based on the Swiss criteria. Current data indicate that patients who are most likely to benefit from AHSCT have relapsing-remitting MS and are young, ambulatory and have high disease activity. Treatment data with AHSCT will be collected within the German REgistry Cohort of autologous haematopoietic stem CeLl trAnsplantation In MS (RECLAIM). Conclusion: Further clinical trials, including registry-based analyses, are urgently needed to better define the patient characteristics, efficacy and safety profile of AHSCT compared with other high-efficacy therapies and to optimally position it as a treatment option in different MS disease stages.

Autologous haematopoietic stem cell transplantation for multiple sclerosis Substantial progress has been made in the development of disease-modifying medications for multiple sclerosis (MS) during the last 20 years. However, in a relevant percentage of patients, the disease cannot completely be contained. Autologous haematopoietic stem cell transplantation (AHSCT) enables rebuilding of a new and healthy immune system and to potentially stop the autoimmune disease process for a long time. A number of studies documenting 4000 cases cumulatively over the past 20 years reported high efficacy of AHSCT in controlling MS inflammatory disease activity. These data and improved safety profiles of the treatment procedures spurred interest in using AHSCT as a treatment option for MS. An open call among MS neurologists as well as among experts in stem cell transplantation in Germany started in December 2021 to join a series of video calls to develop recommendations and outline a registry study project. We provide a consensus-based opinion paper authored by 25 experts on the up-to-date optimal use of AHSCT in managing MS. Current data indicate that patients are most likely to benefit from AHSCT if they are young, ambulatory, with high disease activity, that is, relapses or new magnetic resonance imaging (MRI) lesions. Treatment data with AHSCT will be collected within the German REgistry Cohort of autoLogous haematopoietic stem cell transplantation MS (RECLAIM). Further clinical trials including registry-based analyses and systematic follow-up are urgently needed to better define the optimal patient characteristics as well as the efficacy and safety profile of AHSCT compared with other high-efficacy therapies. These will help to position AHSCT as a treatment option in different MS disease stages.

The role of intrathecal free light chains kappa for the detection of autoimmune encephalitis in subacute onset neuropsychiatric syndromes.

Intrathecal synthesis of free light chains kappa (FLCK) is increasingly recognized as a marker of inflammatory CNS pathologies. Here, we tested the performance of FLCK in differentiating autoimmune encephalitis (AIE) from non-inflammatory etiologies in subacute onset neuropsychiatric syndromes. Patients undergoing diagnostic work-up for suspected autoimmune encephalitis at our department between 2015 and 2020 were retrospectively assessed for definitive diagnosis, available CSF and blood samples, as well as complete clinical records. Intrathecal FLCK was measured along with established CSF markers of CNS inflammation. The study cohort consisted of 19 patients with antibody-mediated AIE (AIE+), 18 patients with suspected AIE but without detectable autoantibodies (AIE-), 10 patients with infectious (viral) encephalitis (INE), and 15 patients with degenerative encephalopathies (DGE). 25 age- and sex-matched patients with non-inflammatory neurological diseases (NIND) were used as a control group. All AIE+ patients exhibited intrathecal synthesis of FLCK compared to only 39% of AIE- patients and 81% of patients in the INE group. No intrathecal synthesis of FLCK was found in DGE and NIND patients. While intrathecal FLCK was equally specific for an inflammatory etiology as oligoclonal bands (OCB) in the cerebrospinal fluid (CSF), the sensitivity of intrathecal FLCK for any inflammatory intrathecal process was higher than that of OCB (83% vs. 38%). Intrathecal FLCK synthesis was found to discriminate AIE+ from non-inflammatory encephalopathies and AIE- when the CSF cell count was normal [receiver operating characteristic (ROC) analysis area under the curve (AUC): 0.867, p = 0.002], while it failed to differentiate between AIE+ and INE in the presence of CSF pleocytosis (AUC: 0.561, p = 0.607). In conclusion, in the absence of CSF pleocytosis, intrathecal FLCK discriminated AIE+ from competing diagnoses in our cohort of subacute onset neuropsychiatric syndromes. In addition to established markers of CSF inflammation, intrathecal FLCK might support clinical decision-making and contribute to selecting patients for (repeated) antibody testing.

Factors associated with depressive mood at the onset of multiple sclerosis - an analysis of 781 patients of the German NationMS cohort.

Background: Depression has a major impact on the disease burden of multiple sclerosis (MS). Analyses of overlapping MS and depression risk factors [smoking, vitamin D (25-OH-VD) and Epstein-Barr virus (EBV) infection] and sex, age, disease characteristics and neuroimaging features associated with depressive symptoms in early MS are scarce. Objectives: To assess an association of MS risk factors with depressive symptoms within the German NationMS cohort. Design: Cross-sectional analysis within a multicenter observational study. Methods: Baseline data of n = 781 adults with newly diagnosed clinically isolated syndrome or relapsing-remitting MS qualified for analysis. Global and region-specific magnetic resonance imaging (MRI)-volumetry parameters were available for n = 327 patients. Association of demographic factors, MS characteristics and risk factors [sex, age, smoking, disease course, presence of current relapse, expanded disability status scale (EDSS) score, fatigue (fatigue scale motor cognition), 25-OH-VD serum concentration, EBV nuclear antigen-1 IgG (EBNA1-IgG) serum levels] and depressive symptoms (Beck Depression Inventory-II, BDI-II) was tested as a primary outcome by multivariable linear regression. Non-parametric correlation and group comparison were performed for associations of MRI parameters and depressive symptoms. Results: Mean age was 34.3 years (95% confidence interval: 33.6-35.0). The female-to-male ratio was 2.3:1. At least minimal depressive symptoms (BDI-II > 8) were present in n = 256 (32.8%), 25-OH-VD deficiency (<20 ng/ml) in n = 398 (51.0%), n = 246 (31.5%) participants were smokers. Presence of current relapse [coefficient (c) = 1.48, p = 0.016], more severe fatigue (c = 0.26, p < 0.0001), lower 25-OH-VD (c = -0.03, p = 0.034) and smoking (c = 0.35, p = 0.008) were associated with higher BDI-II scores. Sex, age, disease course, EDSS, month of visit, EBNA1-IgG levels and brain volumes at baseline were not. Conclusion: Depressive symptoms need to be assessed in early MS. Patients during relapse seem especially vulnerable to depressive symptoms. Contributing factors such as fatigue, vitamin D deficiency and smoking, could specifically be targeted in future interventions and should be investigated in prospective studies.

A Genetic Risk Variant for Multiple Sclerosis Severity is Associated with Brain Atrophy.

The minor allele of the genetic variant rs10191329 in the DYSF-ZNF638 locus is associated with unfavorable long-term clinical outcomes in multiple sclerosis patients. We investigated if rs10191329 is associated with brain atrophy measured by magnetic resonance imaging in a discovery cohort of 748 and a replication cohort of 360 people with relapsing multiple sclerosis. We observed an association with 28% more brain atrophy per rs10191329*A allele. Our results encourage stratification for rs10191329 in clinical trials. Unraveling the underlying mechanisms may enhance our understanding of pathophysiology and identify treatment targets. ANN NEUROL 2023;94:1080-1085.

Prognostic value of spinal cord lesion measures in early relapsing-remitting multiple sclerosis.

BACKGROUND: Spinal cord (SC) lesions have been associated with unfavourable clinical outcomes in multiple sclerosis (MS). However, the relation of whole SC lesion number (SCLN) and volume (SCLV) to the future occurrence and type of confirmed disability accumulation (CDA) remains largely unexplored. METHODS: In this monocentric retrospective study, SC lesions were manually delineated. Inclusion criteria were: age between 18 and 60 years, relapsing-remitting MS, disease duration under 2 years and clinical follow-up of 5 years. The first CDA event after baseline, determined by a sustained increase in the Expanded Disability Status Scale over 6 months, was classified as either progression independent of relapse activity (PIRA) or relapse-associated worsening (RAW). SCLN and SCLV were compared between different (sub)groups to assess their prospective value. RESULTS: 204 patients were included, 148 of which had at least one SC lesion and 59 experienced CDA. Patients without any SC lesions experienced significantly less CDA (OR 5.8, 95% CI 2.1 to 19.8). SCLN and SCLV were closely correlated (rs=0.91, p<0.001) and were both significantly associated with CDA on follow-up (p<0.001). Subgroup analyses confirmed this association for patients with PIRA on CDA (34 events, p<0.001 for both SC lesion measures) but not for RAW (25 events, p=0.077 and p=0.22). CONCLUSION: Patients without any SC lesions are notably less likely to experience CDA. Both the number and volume of SC lesions on MRI are associated with future accumulation of disability largely independent of relapses.

Update on the diagnosis and treatment of neuromyelits optica spectrum disorders (NMOSD) - revised recommendations of the Neuromyelitis Optica Study Group (NEMOS). Part I: Diagnosis and differential diagnosis.

The term 'neuromyelitis optica spectrum disorders' (NMOSD) is used as an umbrella term that refers to aquaporin-4 immunoglobulin G (AQP4-IgG)-positive neuromyelitis optica (NMO) and its formes frustes and to a number of closely related clinical syndromes without AQP4-IgG. NMOSD were originally considered subvariants of multiple sclerosis (MS) but are now widely recognized as disorders in their own right that are distinct from MS with regard to immunopathogenesis, clinical presentation, optimum treatment, and prognosis. In part 1 of this two-part article series, which ties in with our 2014 recommendations, the neuromyelitis optica study group (NEMOS) gives updated recommendations on the diagnosis and differential diagnosis of NMOSD. A key focus is on differentiating NMOSD from MS and from myelin oligodendrocyte glycoprotein antibody-associated encephalomyelitis (MOG-EM; also termed MOG antibody-associated disease, MOGAD), which shares significant similarity with NMOSD with regard to clinical and, partly, radiological presentation, but is a pathogenetically distinct disease. In part 2, we provide updated recommendations on the treatment of NMOSD, covering all newly approved drugs as well as established treatment options.

The impact of disease-modifying therapies on immunoglobulin blood levels in patients with multiple sclerosis: a retrospective cross-sectional study.

Background: Although disease-modifying therapies (DMTs) in multiple sclerosis (MS) are known to target the immune system, mechanisms of action, efficacy, safety, and tolerability profiles differ. The long-term impact of DMTs on the immune system and its relation to infectious complications is still poorly understood. Objectives: To analyze the effect of DMTs on serum immunoglobulin (Ig) levels under consideration of patient demographics and therapy duration. Design: We included 483 patients on DMTs, 69 patients without DMTs, and 51 controls in this retrospective cross-sectional study. Methods: IgG, IgM, and IgG subclass 1-4 levels of patients with MS under treatment with DMTs were compared with treatment naive MS patients and controls by multivariate linear regression. Further, Ig levels stratified by DMTs were analyzed regarding therapy duration. Results: MS patients treated with fingolimod (FG), natalizumab, and B-cell depleting therapies (BCDT) demonstrated significantly lower IgG and IgM levels than healthy controls after a median treatment of 37, 31, and 23 months, respectively (p < 0.05). Treatment with dimethyl fumarate (DMF) and teriflunomide was associated with lower IgG, but not IgM levels. DMF and BCDT were also associated with lower IgG1 levels, while FG led to a reduction of IgG2. Treatment with interferon-beta (IFN) and glatiramer acetate (GA) had no impact on Ig levels. Analysis of subgroups by linear regression also showed a time-dependent decrease of Igs levels in patients treated with BCDT with a median annual reduction of IgG of 3.2% and IgM of 6.2%. Conclusion: Treatment with DMTs, except GA and IFN, was associated with a decrease in Ig levels. DMTs differed in the extent of decreasing Ig levels but also in their differential effects on Ig subclasses. Monitoring of Ig levels should be considered in patients on long-term treatment with DMTs, particularly those on BCDT, to identify patients at risk of low immunoglobulin levels.

A single relapse induces worsening of disability and health-related quality of life in patients with neuromyelitis optica spectrum disorder.

Background: Cumulative damage from multiple relapses in neuromyelitis optica spectrum disorder (NMOSD) is associated with poor health-related quality of life (HRQoL) and long-term disability in patients positive for anti-aquaporin 4 antibodies (AQP4+). This study assessed the effect of an individual relapse on HRQoL and disability outcomes in AQP4+ NMOSD. Methods: Post hoc analyses of data pooled from the PREVENT study and its open-label extension, which evaluated the efficacy and safety of eculizumab in AQP4+ NMOSD, examined the effect of a single relapse on 3 disability and 4 HRQoL outcome measures. Assuming the effect of 1 relapse extends to multiple relapses, an extrapolation was done to assess the effect of 2 relapses on these outcomes. Results: In 27 patients (placebo: n = 20; eculizumab: n = 7) experiencing an independently adjudicated relapse, 1 relapse led to significantly worse disability (modified Rankin Scale and Expanded Disability Status Scale [EDSS]) and HRQoL (36-item Short-Form Health Survey mental and physical component summaries; European Quality of Life 5-Dimension questionnaire 3-Level visual analogue scale and utility index) scores. In 4 of 7 outcomes, clinically meaningful worsening was more likely for relapsing versus non-relapsing patients (n = 116). Extrapolating the effect of 2 relapses predicted that clinically meaningful worsening was more likely in 6 out of 7 outcomes, including EDSS, for patients experiencing multiple relapses versus patients experiencing no relapses. Conclusion: Findings from these clinical trial data demonstrate that a single NMOSD relapse can worsen disability and HRQoL, underscoring the role of relapse prevention in improving long-term outcomes in patients with AQP4+ NMOSD.

CNS demyelinating events in primary Sjögren's syndrome: A single-center case series on the clinical phenotype.

Objective: The study aimed to assess the prevalence, clinical characteristics, and therapeutic outcomes of the central nervous system (CNS) demyelinating disease in a large cohort of primary Sjögren's syndrome (pSS). Methods: This is an explorative cross-sectional study of patients with pSS seen in the departments of rheumatology, otorhinolaryngology, or neurology of a tertiary university center between January 2015 and September 2021. Results: In a cohort of 194 pSS patients, 22 patients had a CNS manifestation. In this CNS group, 19 patients had a lesion pattern suggestive of demyelination. While there were no obvious differences in the patients' epidemiological disposition or rate of other extraglandular manifestations, the CNS group differed from the remaining patients with pSS by having less glandular manifestations but a higher seroprevalence for anti-SSA/Ro antibodies. Notably, patients with CNS manifestations were often diagnosed with multiple sclerosis (MS) and treated as such, although age and disease course were atypical of MS. Many first-line MS agents were ineffective in these "MS look-alikes"; however, the disease course was benign with B-cell-depleting agents. Conclusion: Neurological symptoms of pSS are common and clinically manifest mainly as myelitis or optic neuritis. Notably, in the CNS, the pSS phenotype can overlap with MS. The prevailing disease is crucial since it has a major impact on the long-term clinical outcome and the choice of disease-modifying agents. Although our observations neither confirm pSS as a more appropriate diagnosis nor rule out simple comorbidity, physicians should consider pSS in the extended diagnostic workup of CNS autoimmune diseases.

Retrospective cohort study to devise a treatment decision score predicting adverse 24-month radiological activity in early multiple sclerosis.

Background: Multiple sclerosis (MS) is a chronic neuroinflammatory disease affecting about 2.8 million people worldwide. Disease course after the most common diagnoses of relapsing-remitting multiple sclerosis (RRMS) and clinically isolated syndrome (CIS) is highly variable and cannot be reliably predicted. This impairs early personalized treatment decisions. Objectives: The main objective of this study was to algorithmically support clinical decision-making regarding the options of early platform medication or no immediate treatment of patients with early RRMS and CIS. Design: Retrospective monocentric cohort study within the Data Integration for Future Medicine (DIFUTURE) Consortium. Methods: Multiple data sources of routine clinical, imaging and laboratory data derived from a large and deeply characterized cohort of patients with MS were integrated to conduct a retrospective study to create and internally validate a treatment decision score [Multiple Sclerosis Treatment Decision Score (MS-TDS)] through model-based random forests (RFs). The MS-TDS predicts the probability of no new or enlarging lesions in cerebral magnetic resonance images (cMRIs) between 6 and 24 months after the first cMRI. Results: Data from 65 predictors collected for 475 patients between 2008 and 2017 were included. No medication and platform medication were administered to 277 (58.3%) and 198 (41.7%) patients. The MS-TDS predicted individual outcomes with a cross-validated area under the receiver operating characteristics curve (AUROC) of 0.624. The respective RF prediction model provides patient-specific MS-TDS and probabilities of treatment success. The latter may increase by 5-20% for half of the patients if the treatment considered superior by the MS-TDS is used. Conclusion: Routine clinical data from multiple sources can be successfully integrated to build prediction models to support treatment decision-making. In this study, the resulting MS-TDS estimates individualized treatment success probabilities that can identify patients who benefit from early platform medication. External validation of the MS-TDS is required, and a prospective study is currently being conducted. In addition, the clinical relevance of the MS-TDS needs to be established.

Ravulizumab in Aquaporin-4-Positive Neuromyelitis Optica Spectrum Disorder.

OBJECTIVE: CHAMPION-NMOSD (NCT04201262) is a phase 3, open-label, externally controlled interventional study evaluating the efficacy and safety of the terminal complement inhibitor ravulizumab in adult patients with anti-aquaporin-4 antibody-positive (AQP4+) neuromyelitis optica spectrum disorder (NMOSD). Ravulizumab binds the same complement component 5 epitope as the approved therapeutic eculizumab but has a longer half-life, enabling an extended dosing interval (8 vs 2 weeks). METHODS: The availability of eculizumab precluded the use of a concurrent placebo control in CHAMPION-NMOSD; consequently, the placebo group of the eculizumab phase 3 trial PREVENT (n = 47) was used as an external comparator. Patients received weight-based intravenous ravulizumab on day 1 and maintenance doses on day 15, then once every 8 weeks. The primary endpoint was time to first adjudicated on-trial relapse. RESULTS: The primary endpoint was met; no patients taking ravulizumab (n = 58) had an adjudicated relapse (during 84.0 patient-years of treatment) versus 20 patients with adjudicated relapses in the placebo group of PREVENT (during 46.9 patient-years; relapse risk reduction = 98.6%, 95% confidence interval = 89.7%-100.0%, p < 0.0001). Median (range) study period follow-up time was 73.5 (11.0-117.7) weeks for ravulizumab. Most treatment-emergent adverse events were mild/moderate; no deaths were reported. Two patients taking ravulizumab experienced meningococcal infections. Both recovered with no sequelae; one continued ravulizumab treatment. INTERPRETATION: Ravulizumab significantly reduced relapse risk in patients with AQP4+ NMOSD, with a safety profile consistent with those of eculizumab and ravulizumab across all approved indications. ANN NEUROL 2023;93:1053-1068.