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;95:720-732.

Intravenous immunoglobulin treatment for acute attacks in myelin oligodendrocyte glycoprotein antibody disease.

BACKGROUND: The potential therapeutic benefit of intravenous immunoglobulins (IVIGs) for acute attacks of myelin oligodendrocyte glycoprotein antibody disease (MOGAD) is unknown. OBJECTIVE: The objective was to describe the outcomes of IVIG treatment for acute MOGAD attacks. METHODS: A retrospective observational study involving seven tertiary neuroimmunology centers. Data collection included patients' demographics, Expanded Disability Status Scale (EDSS), and visual acuity (VA) before the attack, at the nadir of the attack before IVIG treatment, and at follow-up visits ⩾3 months after treatment. RESULTS: Thirty-nine patients were included, of which 21 (53.8%) were female. The median age was 23 years (range 5-74 years), and the median disease duration was 4 months (range 0-93 months). The most common type of attack treated with IVIG was isolated optic neuritis (ON) (unilateral n = 14, bilateral n = 5, associated with transverse myelitis (TM), n = 1), followed by acute disseminated encephalomyelitis (ADEM) (n = 8), multifocal (n = 7), TM (n = 3), brainstem (n = 1), and other encephalitis (n = 1). A significant improvement in both the EDSS and VA measures was observed at follow-up compared to the time of IVIG treatment initiation (p < 0.0001 for both outcome measures). CONCLUSION: IVIG may be an effective treatment option for acute MOGAD attacks. Further prospective studies are warranted to validate our results.

Cognition in patients with neuromyelitis optica spectrum disorders: A prospective multicentre study of 217 patients (CogniNMO-Study).

BACKGROUND: There is limited and inconsistent information on the prevalence of cognitive impairment in neuromyelitis optica spectrum disorders (NMOSD). OBJECTIVE: To assess cognitive performance and changes over time in NMOSD. METHODS: This study included data from 217 aquaporin-4-IgG-seropositive (80%) and double-seronegative NMOSD patients. Cognitive functions measured by Symbol Digit Modalities Test (SDMT), Paced Auditory Serial-Addition Task (PASAT), and/or Multiple Sclerosis Inventory Cognition (MuSIC) were standardized against normative data (N = 157). Intraindividual cognitive performance at 1- and 2-year follow-up was analyzed. Cognitive test scores were correlated with demographic and clinical variables and assessed with a multiple linear regression model. RESULTS: NMOSD patients were impaired in SDMT (p = 0.007), MuSIC semantic fluency (p < 0.001), and MuSIC congruent speed (p < 0.001). No significant cognitive deterioration was found at follow-up. SDMT scores were related to motor and visual disability (pBon < 0.05). No differences were found between aquaporin-4-IgG-seropositive and double-seronegative NMOSD. CONCLUSIONS: A subset of NMOSD patients shows impairment in visual processing speed and in semantic fluency regardless of serostatus, without noticeable changes during a 2-year observation period. Neuropsychological measurements should be adapted to physical and visual disabilities.

[Autoimmune encephalitis-An update]. / Autoimmunenzephalitis ­ ein Update.

Detection of autoantibodies against neurons and glia cells has brought about the early and specific diagnosis of autoimmune encephalitis in patients with variable neurological and psychiatric symptoms. Growing knowledge not only resulted in profound changes in treatment algorithms including immunotherapy but also in the understanding of disease mechanisms and etiological factors. The still increasing numbers of new autoantibodies calls for continuous updates on the state of the art in antibody diagnostics, frequencies of associated tumors and the clinical spectrum linked to each antibody, which can range from mood changes, cognitive impairment and epileptic seizures to abnormal movements, autonomic dysfunction and impaired levels of consciousness. This article summarizes the recent developments in the predominant clinical presentations of autoimmune encephalitis patients in imaging and cerebrospinal fluid diagnostics and also in prognostic markers, in the establishment of innovative immunotherapies, in the use of diagnostic pathways even before the results of the antibody tests are available and the understanding of the autoimmune etiology.

Impaired response of blood neutrophils to cell-death stimulus differentiates AQP4-IgG-seropositive NMOSD from MOGAD.

BACKGROUND: In neuromyelitis optica spectrum disorders (NMOSD) and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), neutrophils are found in CNS lesions. We previously demonstrated that NMOSD neutrophils show functional deficiencies. Thus, we hypothesized that neutrophil accumulation in the CNS may be facilitated by impairments affecting mechanisms of neutrophil death. OBJECTIVE: To evaluate cell death in blood neutrophils from aquaporin-4 (AQP4)-IgG-seropositive NMOSD and MOGAD patients as well as matched healthy controls (HC) using in vitro assays. METHODS: Twenty-eight AQP4 + NMOSD and 19 MOGAD patients in stable disease phase as well as 45 age- and sex-matched HC were prospectively recruited. To induce cell death, isolated neutrophils were cultured with/without phorbol 12-myristate 13-acetate (PMA). Spontaneous and PMA-induced NETosis and apoptosis were analyzed using 7-AAD and annexin-V by flow cytometry. Caspase-3 was assessed by western blot. Myeloperoxidase-DNA complexes (MPO-DNA), MPO and elastase were evaluated by ELISA, and cell-free DNA (cfDNA) by a fluorescence-based assay. Reactive oxygen species (ROS) were evaluated by a dihydrorhodamine 123-based cytometric assay. Serum GM-CSF, IL-6, IL-8, IL-15, TNF-ɑ and IL-10 were evaluated by multiplex assays, and neurofilament light chain (NfL) by single-molecule array assay. RESULTS: In response to PMA, neutrophils from AQP4 + NMOSD but not from MOGAD patients showed an increased survival, and subsequent reduced cell death (29.6% annexin V+ 7-AAD+) when compared to HC (44.7%, p = 0.0006). However, AQP4 + NMOSD also showed a mild increase in annexin V+ 7-AAD- early apoptotic neutrophils (24.5%) compared to HC (20.8%, p = 0.048). PMA-induced reduction of caspase-3 activation was more pronounced in HC (p = 0.020) than in AQP4 + NMOSD neutrophils (p = 0.052). No differences were observed in neutrophil-derived MPO-DNA or serum levels of MPO, elastase, IL-6, IL-8 and TNF-ɑ. IL-15 levels were increased in both groups of patients. In AQP4 + NMOSD, an increase in cfDNA, GM-CSF and IL-10 was found in serum. A positive correlation among cfDNA and NfL was found in AQP4 + NMOSD. CONCLUSIONS: AQP4 + NMOSD neutrophils showed an increased survival capacity in response to PMA when compared to matched HC neutrophils. Although the data indicate that the apoptotic but not the NETotic response is altered in these neutrophils, additional evaluations are required to validate this observation.

Impaired motion perception is associated with functional and structural visual pathway damage in multiple sclerosis and neuromyelitis optica spectrum disorders.

BACKGROUND: Decreased motion perception has been suggested as a marker for visual pathway demyelination in optic neuritis (ON) and/or multiple sclerosis (MS). OBJECTIVES: To examine the influence of neuro-axonal damage on motion perception in MS and neuromyelitis optica spectrum disorders (NMOSD). METHODS: We analysed motion perception with numbers-from-motion (NFM), visual acuity, (multifocal (mf)) VEP, optical coherence tomography in patients with MS (n = 38, confirmatory cohort n = 43), NMOSD (n = 13) and healthy controls (n = 33). RESULTS: NFM was lower compared with controls in MS (B = -12.37, p < 0.001) and NMOSD (B = -34.5, p < 0.001). NFM was lower in ON than in non-ON eyes (B = -30.95, p = 0.041) in NMOSD, but not MS. In MS and NMOSD, lower NFM was associated with worse visual acuity (B = -139.4, p < 0.001/B = -77.2, p < 0.001) and low contrast letter acuity (B = 0.99, p = 0.002/B = 1.6, p < 0.001), thinner peripapillary retinal nerve fibre layer (B = 1.0, p < 0.001/ B = 0.92, p = 0.016) and ganglion cell/inner plexiform layer (B = 64.8, p < 0.001/B = 79.5, p = 0.006), but not with VEP P100 latencies. In the confirmatory MS cohort, lower NFM was associated with thinner retinal nerve fibre layer (B = 1.351, p < 0.001) and increased mfVEP P100 latencies (B = -1.159, p < 0.001). CONCLUSIONS: Structural neuro-axonal visual pathway damage is an important driver of motion perception impairment in MS and NMOSD.

Berlin Registry of Neuroimmunological entities (BERLimmun): protocol of a prospective observational study.

BACKGROUND: Large-scale disease overarching longitudinal data are rare in the field of neuroimmunology. However, such data could aid early disease stratification, understanding disease etiology and ultimately improve treatment decisions. The Berlin Registry of Neuroimmunological Entities (BERLimmun) is a longitudinal prospective observational study, which aims to identify diagnostic, disease activity and prognostic markers and to elucidate the underlying pathobiology of neuroimmunological diseases. METHODS: BERLimmun is a single-center prospective observational study of planned 650 patients with neuroimmunological disease entity (e.g. but not confined to: multiple sclerosis, isolated syndromes, neuromyelitis optica spectrum disorders) and 85 healthy participants with 15 years of follow-up. The protocol comprises annual in-person visits with multimodal standardized assessments of medical history, rater-based disability staging, patient-report of lifestyle, diet, general health and disease specific symptoms, tests of motor, cognitive and visual functions, structural imaging of the neuroaxis and retina and extensive sampling of biological specimen. DISCUSSION: The BERLimmun database allows to investigate multiple key aspects of neuroimmunological diseases, such as immunological differences between diagnoses or compared to healthy participants, interrelations between findings of functional impairment and structural change, trajectories of change for different biomarkers over time and, importantly, to study determinants of the long-term disease course. BERLimmun opens an opportunity to a better understanding and distinction of neuroimmunological diseases.

Serum GFAP and NfL as disease severity and prognostic biomarkers in patients with aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder.

BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) is a frequently disabling neuroinflammatory syndrome with a relapsing course. Blood-based disease severity and prognostic biomarkers for NMOSD are a yet unmet clinical need. Here, we evaluated serum glial fibrillary acidic protein (sGFAP) and neurofilament light (sNfL) as disease severity and prognostic biomarkers in patients with aquaporin-4 immunoglobulin (Ig)G positive (AQP4-IgG+) NMOSD. METHODS: sGFAP and sNfL were determined by single-molecule array technology in a prospective cohort of 33 AQP4-IgG+ patients with NMOSD, 32 of which were in clinical remission at study baseline. Sixteen myelin oligodendrocyte glycoprotein IgG-positive (MOG-IgG+) patients and 38 healthy persons were included as controls. Attacks were recorded in all AQP4-IgG+ patients over a median observation period of 4.25 years. RESULTS: In patients with AQP4-IgG+ NMOSD, median sGFAP (109.2 pg/ml) was non-significantly higher than in MOG-IgG+ patients (81.1 pg/ml; p = 0.83) and healthy controls (67.7 pg/ml; p = 0.07); sNfL did not substantially differ between groups. Yet, in AQP4-IgG+, but not MOG-IgG+ patients, higher sGFAP was associated with worse clinical disability scores, including the Expanded Disability Status Scale (EDSS, standardized effect size = 1.30, p = 0.007) and Multiple Sclerosis Functional Composite (MSFC, standardized effect size = - 1.28, p = 0.01). While in AQP4-IgG+, but not MOG-IgG+ patients, baseline sGFAP and sNfL were positively associated (standardized effect size = 2.24, p = 0.001), higher sNfL was only non-significantly associated with worse EDSS (standardized effect size = 1.09, p = 0.15) and MSFC (standardized effect size = - 1.75, p = 0.06) in patients with AQP4-IgG+ NMOSD. Patients with AQP4-IgG+ NMOSD with sGFAP > 90 pg/ml at baseline had a shorter time to a future attack than those with sGFAP ≤ 90 pg/ml (adjusted hazard ratio [95% confidence interval] = 11.6 [1.3-105.6], p = 0.03). In contrast, baseline sNfL levels above the 75th age adjusted percentile were not associated with a shorter time to a future attack in patients with AQP4-IgG+ NMOSD. CONCLUSION: These findings suggest a potential role for sGFAP as biomarker for disease severity and future disease activity in patients with AQP4-IgG+ NMOSD in phases of clinical remission.

Emerging drugs for the treatment of neuromyelitis optica.

INTRODUCTION: Evidence-based treatment options for neuromyelitis optica spectrum disorders (NMOSD) patients are beginning to enter the market. Where previously, there was only the exclusive use of empiric and off-label immunosuppressants in this rare and devastating central nervous system autoimmune disease. AREAS COVERED: In accordance to expanding pathogenetic insights, drugs in phase II and III clinical trials are presented in the context of the current treatment situation for acute attacks and immunopreventative strategies in NMOSD. Some such drugs are the 2019-approved complement inhibitor eculizumab, other compounds in late development include its modified successor ravulizumab, IL-6 receptor antibody satralizumab, CD19 targeting antibody inebilizumab and the TACI-Fc fusion protein telitacicept. EXPERT OPINION: Moving from broad immunosuppression to tailored treatment strategies, the prospects for efficient NMOSD therapy are positive. For the first time in this disease, class I treatment evidence is available, but long-term data will be necessary to confirm the overall promising study results of the compounds close to approval. While drug development still centers around AQP4 antibody seropositive patients, current and future research requires consideration of possible diverging treatment demands for the smaller group of seronegative patients and patients with presence of MOG antibodies.

Effects of the COVID-19 Pandemic on Patients With NMO Spectrum Disorders and MOG-Antibody-Associated Diseases: COPANMO(G)-Study.

BACKGROUND AND OBJECTIVES: To evaluate the effects of the coronavirus disease 2019 (COVID-19) pandemic on the life of patients with neuromyelitis optica spectrum disorders (NMOSD) and myelin oligodendrocyte glycoprotein antibody-associated diseases (MOGAD). METHODS: This multicenter, cross-sectional study included data of 187 patients recruited from 19 different German and Austrian Neuromyelitis Optica Study Group (NEMOS) centers between July 2021 and March 2022. The effects of the pandemic on immunotherapeutic treatment and access to care, the possible severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, and the potential effect of vaccination against SARS-CoV-2 on disease incidence and relapse risk were assessed using a patient questionnaire. Health-related quality of life (HRQoL) was measured with the EuroQoL Group 5-Dimension 5-Level Scale (EQ-5D-5L). Demographic and clinical characteristics were retrieved from the NEMOS database. RESULTS: One hundred eighty-seven patients (75% women; median age 47 [range 21-86] years; median disease duration 5.5 [range 0-67] years; median Expanded Disability Status Scale 2.0 [range 0-8.0]; 51% aquaporin-4 immunoglobulin G (AQP4-IgG)-positive, 36% myelin oligodendrocyte glycoprotein (MOG)-IgG-positive 13% double-seronegative) were analyzed. Most patients maintained excellent access to healthcare services throughout the pandemic. Immunotherapy was not changed in 88% of patients. Ninety-one percent of all patients were satisfied with medical care during the pandemic. Nearly two-thirds (64%) of patients rated their risk of infection with SARS-CoV-2 as low or moderate. Among this study sample, 23 patients (12%) knowingly acquired an infection with SARS-CoV-2 and predominantly had a nonsevere course of illness (n = 22/23, 96%). The SARS-CoV-2 vaccination rate was 89%, with 4 cases of confirmed attack or first manifestation of NMOSD/MOGAD occurring in temporal association with the vaccination (range 2-9 days). The reported HRQoL did not decline compared with a prepandemic assessment (mean EQ-5D-5L index value 0.76, 95% bootstrap confidence interval [CI] 0.72-0.80; mean EQ-VAS 66.5, 95% bootstrap CI 63.5-69.3). DISCUSSION: This study demonstrates that, overall, patients with NMOSD/MOGAD affiliated with specialized centers received ongoing medical care during the pandemic. Patients' satisfaction with medical care and HRQoL did not decrease.

Structure-function correlates of vision loss in neuromyelitis optica spectrum disorders.

Optic neuritis (ON) in neuromyelitis optica spectrum disorders (NMOSD) regularly leads to more profound vision loss compared to multiple sclerosis (MS) and myelin-oligodendrocyte-glycoprotein-antibody associated disease (MOGAD). Here we investigate ON-related vision loss in NMOSD compared to MS and MOGAD in order to identify neuroaxonal and retinal contributors to visual dysfunction. In this retrospective study we included patients with aquaporin-4-antibody seropositive NMOSD (n = 28), MOGAD (n = 14), MS (n = 29) and controls (n = 14). We assessed optic nerve damage and fovea morphometry by optical coherence tomography. Visual function was assessed as high (HCVA) and low contrast visual acuity (LCVA), and visual fields' mean deviation (MD). In all diseases, lower visual function was associated with peripapillary retinal nerve fiber layer (pRNFL) and ganglion cell and inner plexiform layer (GCIP) thinning following a broken stick model, with pRNFL and GCIP cutoff point at ca. 60 µm. HCVA loss per µm pRNFL and GCIP thinning was stronger in NMOSD compared with MOGAD. Foveal inner rim volume contributed to MD and LCVA in NMOSD eyes, only. Together these data supports that visual dysfunction in NMOSD is associated with neuroaxonal damage beyond the effect seen in MS and MOGAD. A primary retinopathy, respectively Müller cell pathology, may contribute to this effect.

Serum glial fibrillary acidic protein correlates with retinal structural damage in aquaporin-4 antibody positive neuromyelitis optica spectrum disorder.

BACKGROUND: Aquaporin-4 immunoglobulin-G positive (AQP4-IgG+) neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune astrocytopathy associated with optic neuritis (ON). Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is an oligodendrocytopathy with a similar phenotype. Serum glial fibrillary acidic protein (sGFAP), an astrocyte-derived protein, is associated with disease severity in AQP4-IgG+ NMOSD. Serum neurofilament light (sNfL) indicates neuroaxonal damage. The objective was to investigate the association of sGFAP and sNfL with subclinical afferent visual system damage in clinically stable AQP4-IgG+ NMOSD and MOGAD patients. METHODS: In this cross-sectional study, clinically stable patients with AQP4-IgG+ NMOSD (N = 33) and MOGAD (N = 16), as diseased controls, underwent sGFAP and sNfL measurements by single molecule array, retinal optical coherence tomography and visually evoked potentials. RESULTS: Higher sGFAP concentrations were associated with thinner ganglion cell-inner plexiform layer (ß (95% confidence interval (CI)) = -0.75 (-1.23 to -0.27), p = 0.007) and shallower fovea (average pit depth: ß (95%CI) = -0.59 (-0.63 to -0.55), p = 0.020) in NMOSD non-ON eyes. Participants with pathological P100 latency had higher sGFAP (median [interquartile range]: 131.32 [81.10-179.34] vs. 89.50 [53.46-121.91] pg/ml, p = 0.024). In MOGAD, sGFAP was not associated with retinal structural or visual functional measures. CONCLUSIONS: The association of sGFAP with structural and functional markers of afferent visual system damage in absence of ON suggests that sGFAP may be a sensitive biomarker for chronic disease severity in clinically stable AQP4-IgG+ NMOSD.

Choroid Plexus Volume in Multiple Sclerosis vs Neuromyelitis Optica Spectrum Disorder: A Retrospective, Cross-sectional Analysis.

BACKGROUND AND OBJECTIVES: The choroid plexus has been shown to play a crucial role in CNS inflammation. Previous studies found larger choroid plexus in multiple sclerosis (MS) compared with healthy controls. However, it is not clear whether the choroid plexus is similarly involved in MS and in neuromyelitis optica spectrum disorder (NMOSD). Thus, the aim of this study was to compare the choroid plexus volume in MS and NMOSD. METHODS: In this retrospective, cross-sectional study, patients were included by convenience sampling from 4 international MS centers. The choroid plexus of the lateral ventricles was segmented fully automatically on T1-weighted MRI sequences using a deep learning algorithm (Multi-Dimensional Gated Recurrent Units). Uni- and multivariable linear models were applied to investigate associations between the choroid plexus volume, clinically meaningful disease characteristics, and MRI parameters. RESULTS: We studied 180 patients with MS and 98 patients with NMOSD. In total, 94 healthy individuals and 47 patients with migraine served as controls. The choroid plexus volume was larger in MS (median 1,690 µL, interquartile range [IQR] 648 µL) than in NMOSD (median 1,403 µL, IQR 510 µL), healthy individuals (median 1,533 µL, IQR 570 µL), and patients with migraine (median 1,404 µL, IQR 524 µL; all p < 0.001), whereas there was no difference between NMOSD, migraine, and healthy controls. This was also true when adjusted for age, sex, and the intracranial volume. In contrast to NMOSD, the choroid plexus volume in MS was associated with the number of T2-weighted lesions in a linear model adjusted for age, sex, total intracranial volume, disease duration, relapses in the year before MRI, disease course, Expanded Disability Status Scale score, disease-modifying treatment, and treatment duration (beta 4.4; 95% CI 0.78-8.1; p = 0.018). DISCUSSION: This study supports an involvement of the choroid plexus in MS in contrast to NMOSD and provides clues to better understand the respective pathogenesis.

Costs and Health-Related Quality of Life in Patients With NMO Spectrum Disorders and MOG-Antibody-Associated Disease: CHANCENMO Study.

BACKGROUND AND OBJECTIVES: To evaluate costs and health-related quality of life (HRQoL) of neuromyelitis optica spectrum disorders (NMOSD) and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). METHODS: In this multicenter cross-sectional study, data on consumption of medical and nonmedical resources and work ability were assessed via patient questionnaires. Costs were analyzed in Euros for 2018 from the societal perspective. HRQoL was captured by the EuroQoL Group 5 Dimension 5 Level Scale (EQ-5D-5L) questionnaire. Clinical data were retrieved from the Neuromyelitis Optica Study Group (NEMOS) database. RESULTS: Two hundred twelve patients (80% women, median age 50 [19-83] years, median disease duration 7 [0-43] years, median Expanded Disability Status Scale [EDSS] score 3.5 [0-8.5], 66% aquaporin-4 immunoglobulin G [IgG] positive, 22% MOG IgG positive, 12% double seronegative) were analyzed. The mean total annual per capita cost of illness accounted for €59,574 (95% CI 51,225-68,293 or US dollars [USD] 70,297, 95% CI 60,445-80,586), and the mean index value of the EQ-5D-5L was 0.693 (95% CI 0.65-0.73). The most important cost drivers were informal care costs (28% of total costs), indirect costs (23%), and drugs (16%), especially immunotherapeutics. Costs showed a positive correlation with disease severity (ρ = 0.56, 95% CI 0.45-0.65); in the EDSS score 6.5 to 8.5 subgroup, the mean annual costs were €129,687 (95% CI 101,946-160,336 or USD 153,031, 95% CI 120,296-189,196). The HRQoL revealed a negative correlation to disease severity (ρ = -0.69, 95% CI -0.76 to -0.61); in the EDSS score 6.5 to 8.5 subgroup, the EQ-5D-5L mean index value was 0.195 (95% CI 0.13-0.28). Neither antibody status nor disease duration influenced the total annual costs or HRQoL. DISCUSSION: These German data from the era without approved preventive immunotherapies show enormous effects of the diseases on costs and quality of life. An early and cost-effective therapy should be provided to prevent long-term disability and to preserve quality of life.

Satralizumab in the treatment of neuromyelitis optica spectrum disorder.

Neuromyelitis optica spectrum disorder (NMOSD) is a rare and debilitating autoimmune astrocytopathy with a predominantly relapsing disease course. Satralizumab, a humanized monoclonal antibody, was designed to treat NMOSD by targeting the IL-6 receptor. Satralizumab builds on positive experiences of off-label use tocilizumab in recent years. Before 2019, no medications were approved for the treatment of NMOSD. In 2020, satralizumab became the third compound to enter the US market, adding to the complement inhibitor eculizumab and the CD19 inhibitor inebilizumab. Here, we review the two randomized, double-blind, Phase III trials that investigated the subcutaneous administration of satralizumab as add-on treatment and monotherapy. Both studies revealed positive effects concerning the reduction of relapse risk for AQP4 seropositive NMOSD patients and generally good tolerability.

Anti-aquaporin 4 IgG Is Not Associated With Any Clinical Disease Characteristics in Neuromyelitis Optica Spectrum Disorder.

Background: Neuromyelitis optica spectrum disorder (NMOSD) is a clinically defined, inflammatory central nervous system (CNS) disease of unknown cause, associated with humoral autoimmune findings such as anti-aquaporin 4 (AQP4)-IgG. Recent clinical trials showed a benefit of anti-B cell and anti-complement-antibodies in NMOSD, suggesting relevance of anti-AQP4-IgG in disease pathogenesis. Objective: AQP4-IgG in NMOSD is clearly defined, yet up to 40% of the patients are negative for AQP4-IgG. This may indicate that AQP4-IgG is not disease-driving in NMOSD or defines a distinct patient endotype. Methods: We established a biobank of 63 clinically well-characterized NMOSD patients with an extensive annotation of 351 symptoms, patient characteristics, laboratory results and clinical scores. We used phylogenetic clustering, heatmaps, principal component and longitudinal causal interference analyses to test for the relevance of anti-AQP4-IgG. Results: Anti-AQP4-IgG was undetectable in 29 (46%) of the 63 NMOSD patients. Within anti-AQP4-IgG-positive patients, anti-AQP4-IgG titers did not correlate with clinical disease activity. Comparing anti-AQP4-IgG-positive vs. -negative patients did not delineate any clinically defined subgroup. However, anti-AQP4-IgG positive patients had a significantly (p = 0.022) higher rate of additional autoimmune diagnoses. Conclusion: Our results challenge the assumption that anti-AQP4-IgG alone plays a disease-driving role in NMOSD. Anti-AQP4-IgG might represent an epiphenomenon associated with NMOSD, may represent one of several immune mechanisms that collectively contribute to the pathogenesis of this disease or indeed, anti-AQP4-IgG might be the relevant factor in only a subgroup of patients.

SIGLEC1 (CD169): a marker of active neuroinflammation in the brain but not in the blood of multiple sclerosis patients.

We aimed to evaluate SIGLEC1 (CD169) as a biomarker in multiple sclerosis (MS) and Neuromyelitis optica spectrum disorder (NMOSD) and to evaluate the presence of SIGLEC1+ myeloid cells in demyelinating diseases. We performed flow cytometry-based measurements of SIGLEC1 expression on monocytes in 86 MS patients, 41 NMOSD patients and 31 healthy controls. Additionally, we histologically evaluated the presence of SIGLEC1+ myeloid cells in acute and chronic MS brain lesions as well as other neurological diseases. We found elevated SIGLEC1 expression in 16/86 (18.6%) MS patients and 4/41 (9.8%) NMOSD patients. Almost all MS patients with high SIGLEC1 levels received exogenous interferon beta as an immunomodulatory treatment and only a small fraction of MS patients without interferon treatment had increased SIGLEC1 expression. In our cohort, SIGLEC1 expression on monocytes was-apart from those patients receiving interferon treatment-not significantly increased in patients with MS and NMOSD, nor were levels associated with more severe disease. SIGLEC1+ myeloid cells were abundantly present in active MS lesions as well as in a range of acute infectious and malignant diseases of the central nervous system, but not chronic MS lesions. The presence of SIGLEC1+ myeloid cells in brain lesions could be used to investigate the activity in an inflammatory CNS lesion.

AQP4-IgG autoimmunity in Japan and Germany: Differences in clinical profiles and prognosis in seropositive neuromyelitis optica spectrum disorders.

BACKGROUND: Clinical outcomes in neuromyelitis optica spectrum disorders (NMOSD) vary across different regions. OBJECTIVE: To describe clinical profiles in Japanese and German NMOSD patients. METHODS: Medical records of aquaporin-4-immunoglobulin G (AQP4-IgG) positive NMOSD patients from Japan (n = 54) and Germany (n = 38) were retrospectively analyzed. RESULTS: The disability status was similar between both cohorts, although Japanese patients had a longer disease duration (13.3 ± 11.1 vs. 8.1 ± 6.9 years, p = 0.018) but similar relapse rates. Optic neuritis and myelitis were the most frequent attacks in both cohorts. Brain attacks occurred more frequently in Japanese patients (40.7% vs. 15.8%, p = 0.020). The time from disease onset (median [interquartile range] 2.3 [0.3-10.1] vs. 0.6 [0.2-1.9] years, p = 0.009) and the number of attacks (2.5 [1-7] vs. 2 [1-3], p = 0.047) until start of the first immunotherapy were higher in the Japanese cohort. Rituximab was the most common drug in the German cohort (52.6%) and not given in the Japanese cohort (p < 0.001), where oral prednisolone was the most common drug (92.6% vs. 15.8%, p < 0.001). The frequency of autoimmune comorbidities was higher in the German cohort (39.5% vs. 18.5%, p = 0.047). CONCLUSION: Compared with Japanese NMOSD patients, German patients presented with similar disability despite shorter disease duration and earlier and more frequent immunosuppressive therapy.

Current and emerging biologics for the treatment of neuromyelitis optica spectrum disorders.

INTRODUCTION: Treatment options for patients suffering from neuromyelitis optica spectrum disorders (NMOSD) so far have relied on off-label and empiric drugs. The first drug for the therapy of anti-aquaporin-4 (AQP4) antibody-seropositive NMOSD patients has been approved in 2019: the C5 complement inhibitor eculizumab. The interleukin-6 receptor inhibitor satralizumab and anti-CD19 antibody inebilizumab have published positive phase III trial results and await approval in the near future. AREAS COVERED: We sum up current treatment options and portray in detail the new developments in NMOSD drugs focusing on phase III clinical trials, followed by an overview of emerging drugs in less advanced clinical trial stages. EXPERT OPINION: Eculizumab's approval by the competent authorities marks a milestone in NMOSD treatment. Satralizumab and inebilizumab will most likely follow in approval given their presented results in efficacy and safety. All three drugs have shown efficacy in reducing relapse rates in NMOSD patients with anti-AQP4 antibodies. Although we will have even more evidence-based therapy options in the future, empirically used medications will keep their importance for now. The potential effect of new medications in AQP4 antibody-seronegative NMOSD and patients with an NMOSD phenotype and antibodies to myelin oligodendrocyte glycoprotein remains to be determined.