B cells orchestrate tolerance to the neuromyelitis optica autoantigen AQP4.

Neuromyelitis optica is a paradigmatic autoimmune disease of the central nervous system, in which the water-channel protein AQP4 is the target antigen1. The immunopathology in neuromyelitis optica is largely driven by autoantibodies to AQP42. However, the T cell response that is required for the generation of these anti-AQP4 antibodies is not well understood. Here we show that B cells endogenously express AQP4 in response to activation with anti-CD40 and IL-21 and are able to present their endogenous AQP4 to T cells with an AQP4-specific T cell receptor (TCR). A population of thymic B cells emulates a CD40-stimulated B cell transcriptome, including AQP4 (in mice and humans), and efficiently purges the thymic TCR repertoire of AQP4-reactive clones. Genetic ablation of Aqp4 in B cells rescues AQP4-specific TCRs despite sufficient expression of AQP4 in medullary thymic epithelial cells, and B-cell-conditional AQP4-deficient mice are fully competent to raise AQP4-specific antibodies in productive germinal-centre responses. Thus, the negative selection of AQP4-specific thymocytes is dependent on the expression and presentation of AQP4 by thymic B cells. As AQP4 is expressed in B cells in a CD40-dependent (but not AIRE-dependent) manner, we propose that thymic B cells might tolerize against a group of germinal-centre-associated antigens, including disease-relevant autoantigens such as AQP4.

T cell deletional tolerance restricts AQP4 but not MOG CNS autoimmunity.

Aquaporin-4 (AQP4)-specific Th17 cells are thought to have a central role in neuromyelitis optica (NMO) pathogenesis. When modeling NMO, only AQP4-reactive Th17 cells from AQP4-deficient (AQP4-/-), but not wild-type (WT) mice, caused CNS autoimmunity in recipient WT mice, indicating that a tightly regulated mechanism normally ensures tolerance to AQP4. Here, we found that pathogenic AQP4 T cell epitopes bind MHC II with exceptionally high affinity. Examination of T cell receptor (TCR) α/ß usage revealed that AQP4-specific T cells from AQP4-/- mice employed a distinct TCR repertoire and exhibited clonal expansion. Selective thymic AQP4 deficiency did not fully restore AQP4-reactive T cells, demonstrating that thymic negative selection alone did not account for AQP4-specific tolerance in WT mice. Indeed, AQP4-specific Th17 cells caused paralysis in recipient WT or B cell-deficient mice, which was followed by complete recovery that was associated with apoptosis of donor T cells. However, donor AQP4-reactive T cells survived and caused persistent paralysis in recipient mice deficient in both T and B cells or mice lacking T cells only. Thus, AQP4 CNS autoimmunity was limited by T cell-dependent deletion of AQP4-reactive T cells. In contrast, myelin oligodendrocyte glycoprotein (MOG)-specific T cells survived and caused sustained disease in WT mice. These findings underscore the importance of peripheral T cell deletional tolerance to AQP4, which may be relevant to understanding the balance of AQP4-reactive T cells in health and in NMO. T cell tolerance to AQP4, expressed in multiple tissues, is distinct from tolerance to MOG, an autoantigen restricted in its expression.

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.

Interferon-γ controls aquaporin 4-specific Th17 and B cells in neuromyelitis optica spectrum disorder.

Neuromyelitis optica spectrum disorder (NMOSD) is a CNS autoimmune inflammatory disease mediated by T helper 17 (Th17) and antibody responses to the water channel protein, aquaporin 4 (AQP4), and associated with astrocytopathy, demyelination and axonal loss. Knowledge about disease pathogenesis is limited and the search for new therapies impeded by the absence of a reliable animal model. In our work, we determined that NMOSD is characterized by decreased IFN-γ receptor signalling and that IFN-γ depletion in AQP4201-220-immunized C57BL/6 mice results in severe clinical disease resembling human NMOSD. Pathologically, the disease causes autoimmune astrocytic and CNS injury secondary to cellular and humoral inflammation. Immunologically, the absence of IFN-γ allows for increased expression of IL-6 in B cells and activation of Th17 cells, and generation of a robust autoimmune inflammatory response. Consistent with NMOSD, the experimental disease is exacerbated by administration of IFN-ß, whereas repletion of IFN-γ, as well as therapeutic targeting of IL-17A, IL-6R and B cells, ameliorates it. We also demonstrate that immune tolerization with AQP4201-220-coupled poly(lactic-co-glycolic acid) nanoparticles could both prevent and effectively treat the disease. Our findings enhance the understanding of NMOSD pathogenesis and provide a platform for the development of immune tolerance-based therapies, avoiding the limitations of the current immunosuppressive therapies.

Soluble TREM2 triggers microglial dysfunction in neuromyelitis optica spectrum disorders.

Microglia-mediated neuroinflammation contributes to acute demyelination in neuromyelitis optica spectrum disorders (NMOSD). Soluble triggering receptor expressed on myeloid cells 2 (sTREM2) in the CSF has been associated with microglial activation in several neurodegenerative diseases. However, the basis for this immune-mediated attack and the pathophysiological role of sTREM2 in NMOSD remain to be elucidated. Here, we performed Mendelian randomization analysis and identified a genetic association between increased CSF sTREM2 and NMOSD risk. CSF sTREM2 was elevated in patients with NMOSD and was positively correlated with neural injury and other neuroinflammation markers. Single-cell RNA sequencing of human macrophage/microglia-like cells in CSF, a proxy for microglia, showed that increased CSF sTREM2 was positively associated with microglial dysfunction in patients with NMOSD. Furthermore, we demonstrated that sTREM2 is a reliable biomarker of microglial activation in a mouse model of NMOSD. Using unbiased transcriptomic and lipidomic screens, we identified that excessive activation, overwhelmed phagocytosis of myelin debris, suppressed lipid metabolism and enhanced glycolysis underlie sTREM2-mediated microglial dysfunction, possibly through the nuclear factor kappa B (NF-κB) signalling pathway. These molecular and cellular findings provide a mechanistic explanation for the genetic association between CSF sTREM2 and NMOSD risk and indicate that sTREM2 could be a potential biomarker of NMOSD progression and a therapeutic target for microglia-mediated neuroinflammation.

Rituximab abrogates aquaporin-4-specific germinal center activity in patients with neuromyelitis optica spectrum disorders.

Neuromyelitis optica spectrum disorders (NMOSDs) are caused by immunoglobulin G (IgG) autoantibodies directed against the water channel aquaporin-4 (AQP4). In NMOSDs, discrete clinical relapses lead to disability and are robustly prevented by the anti-CD20 therapeutic rituximab; however, its mechanism of action in autoantibody-mediated disorders remains poorly understood. We hypothesized that AQP4-IgG production in germinal centers (GCs) was a core feature of NMOSDs and could be terminated by rituximab. To investigate this directly, deep cervical lymph node (dCLN) aspirates (n = 36) and blood (n = 406) were studied in a total of 63 NMOSD patients. Clinical relapses were associated with AQP4-IgM generation or shifts in AQP4-IgG subclasses (odds ratio = 6.0; range of 3.3 to 10.8; P < 0.0001), features consistent with GC activity. From seven dCLN aspirates of patients not administered rituximab, AQP4-IgGs were detected alongside specific intranodal synthesis of AQP4-IgG. AQP4-reactive B cells were isolated from unmutated naive and mutated memory populations in both blood and dCLNs. After rituximab administration, fewer clinical relapses (annual relapse rate of 0.79 to 0; P < 0.001) were accompanied by marked reductions in both AQP4-IgG (fourfold; P = 0.004) and intranodal B cells (430-fold; P < 0.0001) from 11 dCLNs. Our findings implicate ongoing GC activity as a rituximab-sensitive driver of AQP4 antibody production. They may explain rituximab's clinical efficacy in several autoantibody-mediated diseases and highlight the potential value of direct GC measurements across autoimmune conditions.

AQP4-DARPin1: A Chimeric Antigen Based on Scaffold Protein DARPin for Efficient Detection of AQP4-IgG in NMOSD.

AQP4-IgG is an autoantibody associated with neuromyelitis optica spectroscopic disorder (NMOSD), a central nervous system inflammatory disease that requires early diagnosis and treatment. We designed two fusion proteins, AQP4-DARPin1 and AQP4-DARPin2, comprising the complete antigenic epitopes of aquaporin-4 (AQP4) and the constant region of the scaffold protein DARPin. These fusion proteins were expressed and purified from Escherichia coli and coated on microplates to develop an efficient method for detecting AQP4-IgG. Molecular dynamics simulation revealed that the fusion of AQP4 extracellular epitopes with DARPin did not alter the main structure of DARPin. The purified AQP4-DARPins bound recombinant antibody rAb-53 (AQP4-IgG) with affinities of 135 and 285 nM, respectively. Enzyme-linked immunosorbent assay (ELISA) and immunoprecipitation demonstrated that AQP4-DARPin1 specifically recognized AQP4-IgG in the NMOSD patient serum. AQP4-DARPin1 as a coated antigen showed higher ELISA signal and end point dilution ratio than full-length AQP4. Our AQP4-DARPin1-coated AQP4-IgG ELISA had 100% specificity and 90% sensitivity. These results indicate that AQP4-DARPin1, compared to existing detection strategies that use full-length or extracellular loop peptides of AQP4, provides a new and more effective approach to the ELISA detection of NMOSD.

Renal dysfunction in AQP4 NMOSD and MS; a potential predictor of relapse and prognosis.

OBJECTIVE: This study aimed to explore the association between kidney function and the risk of relapse as well as prognosis in patients with aquaporin-4 (AQP4)-immunoglobulin G (IgG)-seropositive neuromyelitis optica spectrum disorder (NMOSD). METHODS: We focused on patients experiencing their first onset of AQP4-IgG-seropositive NMOSD. Data on demographics, disease characteristics, and kidney function were collected, with the primary assessment utilizing the estimated glomerular filtration rate (eGFR). Associations between eGFR and relapse risk were examined using multivariate Cox proportional hazards regression models. Additionally, logistic regression models were employed to evaluate the impact of eGFR on clinical prognosis. RESULTS: Our analysis revealed glomerular hyperfiltration and impaired urine concentrating ability in patients with AQP4-IgG-seropositive NMOSD. Multivariate Cox proportional hazards regression demonstrated a positive correlation between eGFR and the risk of relapse. Logistic regression analysis further identified higher eGFR as an independent predictor of disease relapse and prognosis in AQP4-IgG-seropositive NMOSD patients. CONCLUSIONS: The eGFR of patients with AQP4-IgG-seropositive NMOSD emerges as a potential diagnostic biomarker for this condition, indicating its significance in predicting both relapse risk and clinical prognosis.

Comparative analysis of glymphatic system alterations in multiple sclerosis and neuromyelitis optica spectrum disorder using MRI indices from diffusion tensor imaging.

OBJECTIVE: The glymphatic system is a glial-based perivascular network that promotes brain metabolic waste clearance. Glymphatic system dysfunction has been observed in both multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD), indicating the role of neuroinflammation in the glymphatic system. However, little is known about how the two diseases differently affect the human glymphatic system. The present study aims to evaluate the diffusion MRI-based measures of the glymphatic system by contrasting MS and NMOSD. METHODS: This prospective study included 63 patients with NMOSD (n = 21) and MS (n = 42) who underwent DTI. The fractional volume of extracellular-free water (FW) and an index of diffusion tensor imaging (DTI) along the perivascular space (DTI-ALPS) were used as indirect indicators of water diffusivity in the interstitial extracellular and perivenous spaces of white matter, respectively. Age and EDSS scores were adjusted. RESULTS: Using Bayesian hypothesis testing, we show that the present data substantially favor the null model of no differences between MS and NMOSD for the diffusion MRI-based measures of the glymphatic system. The inclusion Bayes factor (BF10) of model-averaged probabilities of the group (MS, NMOSD) was 0.280 for FW and 0.236 for the ALPS index. CONCLUSION: Together, these findings suggest that glymphatic alteration associated with MS and NMOSD might be similar and common as an eventual result, albeit the disease etiologies differ. PRACTITIONER POINTS: Previous literature indicates important glymphatic system alteration in MS and NMOSD. We explore the difference between MS and NMOSD using diffusion MRI-based measures of the glymphatic system. We show support for the null hypothesis of no difference between MS and NMOSD. This suggests that glymphatic alteration associated with MS and NMOSD might be similar and common etiology.

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.

MOG and AQP4 Antibodies among Children with Multiple Sclerosis and Controls.

OBJECTIVE: The purpose of this study was to determine the frequency of myelin oligodendrocyte glycoprotein (MOG)-IgG and aquaporin-4 (AQP4)-IgG among patients with pediatric-onset multiple sclerosis (POMS) and healthy controls, to determine whether seropositive cases fulfilled their respective diagnostic criteria, to compare characteristics and outcomes in children with POMS versus MOG-IgG-associated disease (MOGAD), and identify clinical features associated with final diagnosis. METHODS: Patients with POMS and healthy controls were enrolled at 14 US sites through a prospective case-control study on POMS risk factors. Serum AQP4-IgG and MOG-IgG were assessed using live cell-based assays. RESULTS: AQP4-IgG was negative among all 1,196 participants, 493 with POMS and 703 healthy controls. MOG-IgG was positive in 30 of 493 cases (6%) and zero controls. Twenty-five of 30 patients positive with MOG-IgG (83%) had MOGAD, whereas 5 of 30 (17%) maintained a diagnosis of multiple sclerosis (MS) on re-review of records. MOGAD cases were more commonly in female patients (21/25 [84%] vs 301/468 [64%]; p = 0.044), younger age (mean = 8.2 ± 4.2 vs 14.7 ± 2.6 years; p < 0.001), more commonly had initial optic nerve symptoms (16/25 [64%] vs 129/391 [33%]; p = 0.002), or acute disseminated encephalomyelitis (ADEM; 8/25 [32%] vs 9/468 [2%]; p < 0.001), and less commonly had initial spinal cord symptoms (3/20 [15%] vs 194/381 [51%]; p = 0.002), serum Epstein-Barr virus (EBV) positivity (11/25 [44%] vs 445/468 [95%]; p < 0.001), or cerebrospinal fluid oligoclonal bands (5/25 [20%] vs 243/352 [69%]; p < 0.001). INTERPRETATION: MOG-IgG and AQP4-IgG were not identified among healthy controls confirming their high specificity for pediatric central nervous system (CNS) demyelinating disease. Five percent of those with prior POMS diagnoses ultimately had MOGAD; and none had AQP4-IgG positivity. Clinical features associated with a final diagnosis of MOGAD in those with suspected MS included initial ADEM phenotype, younger age at disease onset, and lack of EBV exposure. ANN NEUROL 2023;93:271-284.

Aquaporin-4 Antibody Dynamics and Relapse Risk in Seropositive Neuromyelitis Optica Spectrum Disorder Treated with Immunosuppressants.

OBJECTIVE: To investigate aquaporin-4 antibody (AQP4-IgG) dynamics and relapse risk in patients with seropositive neuromyelitis optica spectrum disorder treated with immunosuppressants. METHODS: This observational cohort study with prospectively collected data included 400 neuromyelitis optica spectrum disorder patients seropositive for AQP4-IgG and treated with immunosuppressants. Serum AQP4-IgG was detected by fixed cell-based assay every 6 months. RESULTS: After treatment with immunosuppressants, 128 patients became AQP4-IgG seronegative. The median time to become seronegative for 400 patients was 76.4 months (61.4 months, NA). Among those patients with negative change of AQP4-IgG, the mean annualized relapse rate significantly decreased after patients became seronegative (0.20 vs 0.77, p < 0.001), and a positive correlation was observed between time to become seronegative and relapse (OR 1.018, 95% CI 1.001-1.035, p < 0.05). Independent risk factors for AQP4-IgG becoming seronegative were older age at onset, initiation of immunosuppressants at onset, and shorter disease duration before maintenance therapy. Independent risk factors for relapse included younger age (≤46.4 years) at onset, poly-system involvement in the first attack, and unchanged or increased AQP4-IgG titer. The relapse risk was not associated with sex, combination with connective tissue disease, seropositivity for systemic autoimmune antibodies, or incomplete recovery from the first attack. INTERPRETATION: Patients with younger age at onset, poly-system involvement in the first attack, and unchanged or increased titer of AQP4-IgG are most likely to experience relapse under treatment with immunosuppressants. Time to AQP4-IgG becoming seronegative and change of AQP4-IgG titer may become the surrogate efficacy biomarkers in clinical trials. ANN NEUROL 2023;93:1069-1081.

Astrocyte-Derived Exosomes Contribute to Pathologies of Neuromyelitis Optica Spectrum Disorder in Rodent Model.

OBJECTIVE: Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory demyelinating disease that leads to severe disability. A large proportion of NMOSD patients are seropositive for aquaporin-4 autoantibodies (AQP4-IgG, named as NMO-IgG) targeting AQP4, which is selectively expressed on astrocytes in the central nervous system. This study tests the hypothesis that in response to NMO-IgG, the pathogenic astrocyte-derived exosomes are released and injure the neighboring cells. METHODS: IgG purified from serum of either NMOSD patients or healthy controls was used to generate astrocyte-derived exosomes (AST-ExosNMO vs AST-ExosCON ) in cultured rat astrocytes. The exosomes were respectively delivered to cultured rat oligodendrocytes in vitro, tissue culture of rat optic nerve ex vivo, and rat optic nerve in vivo to evaluate the pathogenic roles of AST-ExosNMO . The microRNA (miRNA) sequencing of AST-Exos and verification were performed to identify the key pathogenic miRNA. The custom-designed adeno-associated virus (AAV) antagonizing the key miRNA was evaluated for its therapeutic effects in vivo. Moreover, the serum levels of the key exosomal miRNA were measured between NMOSD patients and healthy controls. RESULTS: AST-ExosNMO led to notable demyelination in both cultured oligodendrocytes and optic nerve tissue. Exosomal miR-129-2-3p was identified as the key miRNA mediating the demyelinating pathogenesis via downstream target gene SMAD3. AAV antagonizing miR-129-2-3p protected against demyelination in an NMOSD rodent model. The serum exosomal miR-129-2-3p level was significantly elevated in NMOSD patients and correlated with disease severity. INTERPRETATION: Astrocytes targeted by NMO-IgG release pathogenic exosomes that could potentially be used as therapeutic targets or disease monitoring biomarkers in NMOSD. ANN NEUROL 2023;94:163-181.

Stage-dependent immunity orchestrates AQP4 antibody-guided NMOSD pathology: a role for netting neutrophils with resident memory T cells in situ.

Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune disease of the CNS characterized by the production of disease-specific autoantibodies against aquaporin-4 (AQP4) water channels. Animal model studies suggest that anti-AQP4 antibodies cause a loss of AQP4-expressing astrocytes, primarily via complement-dependent cytotoxicity. Nonetheless, several aspects of the disease remain unclear, including: how anti-AQP4 antibodies cross the blood-brain barrier from the periphery to the CNS; how NMOSD expands into longitudinally extensive transverse myelitis or optic neuritis; how multiphasic courses occur; and how to prevent attacks without depleting circulating anti-AQP4 antibodies, especially when employing B-cell-depleting therapies. To address these knowledge gaps, we conducted a comprehensive 'stage-dependent' investigation of immune cell elements in situ in human NMOSD lesions, based on neuropathological techniques for autopsied/biopsied CNS materials. The present study provided three major findings. First, activated or netting neutrophils and melanoma cell adhesion molecule-positive (MCAM+) helper T (TH) 17/cytotoxic T (TC) 17 cells are prominent, and the numbers of these correlate with the size of NMOSD lesions in the initial or early-active stages. Second, forkhead box P3-positive (FOXP3+) regulatory T (Treg) cells are recruited to NMOSD lesions during the initial, early-active or late-active stages, suggesting rapid suppression of proinflammatory autoimmune events in the active stages of NMOSD. Third, compartmentalized resident memory immune cells, including CD103+ tissue-resident memory T (TRM) cells with long-lasting inflammatory potential, are detected under "standby" conditions in all stages. Furthermore, CD103+ TRM cells express high levels of granzyme B/perforin-1 in the initial or early-active stages of NMOSD in situ. We infer that stage-dependent compartmentalized immune traits orchestrate the pathology of anti-AQP4 antibody-guided NMOSD in situ. Our work further suggests that targeting activated/netting neutrophils, MCAM+ TH17/TC17 cells, and CD103+ TRM cells, as well as promoting the expansion of FOXP3+ Treg cells, may be effective in treating and preventing relapses of NMOSD.

Long-term disability progression in aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder: a retrospective analysis of 101 patients.

BACKGROUND: Anti-aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder (AQP4Ab+NMOSD) is an inflammatory disorder of the central nervous system with relapse-dependent progression. Few studies have reported the effects of prednisolone and biologics on disability progression in AQP4Ab+NMOSD, although it is established that they prevent clinical relapses. This retrospective study investigated long-term disability progression and the effects of therapeutic interventions on disability progression in AQP4Ab+NMOSD. METHODS: This study included a total of 101 patients with AQP4Ab+NMOSD. Disease progression was investigated in the following two cohorts: (1) duration from disease onset to Expanded Disability Status Scale (EDSS) 3.0 in patients who did or did not receive oral prednisolone or biologics before reaching EDSS 3.0 and (2) duration from disease onset to EDSS 6.0 in patients who did or did not receive oral prednisolone or biologics before reaching EDSS 6.0. RESULTS: Approximately half of the untreated patients reached EDSS 3.0 and 6.0 at 10 and 46 months after disease onset, respectively. In addition, 88% and 71% of the untreated patients reached EDSS 3.0 and 6.0 within 10 years after disease onset, respectively. Disability progression, clinical relapses and attack severity were suppressed by prednisolone and biologics. CONCLUSIONS: AQP4Ab+NMOSD is a severely disabling disease. Treatment interventions using prednisolone and biologics are useful in suppressing disability progression in AQP4Ab+NMOSD.

An aggressive form of MOGAD treated with aHSCT: A case report.

BACKGROUND: Although myelin-oligodendrocyte-glycoprotein (MOG)-antibody-associated disease (MOGAD) has been considered a more favorable demyelinating central nervous system disorder, recent data evidence that some patients might experience severe relapses and high disability. Actual treatment-options are acquired mostly from anti-aquaporin-4-antibody-positive neuromyelitis optica spectrum disorder and rely on clinical experience. Therefore, treatment of aggressive forms of MOGAD can be challenging. OBJECTIVES AND METHODS: To describe a patient with an aggressive MOGAD treated with autologous hematopoietic stem cell transplantation (aHSCT). RESULTS: A 56-year-old man was diagnosed with MOGAD in 2017 because of right optic-neuritis and anti-MOG-antibody positivity. In the following 2 years, he experienced two optic neuritis with good recovery after high-dose steroid. At the end of 2019, he presented sensory and motor impairment at lower limbs with evidence of several spinal, longitudinally extended, tumefactive inflammatory lesions. Despite sequential treatment with rituximab and tocilizumab alongside high-dose steroid, intravenous immunoglobulins and plasma-exchange, he experienced several clinical relapses and exhibited persistent magnetic resonance activity. He was finally addressed to intense immunosuppression with myeloablative conditioning regimen followed by autologous hematopoietic stem cell transplantation (aHSCT). After 2 years follow-up, he is free from disease-activity. CONCLUSIONS: In a patient affected by aggressive, treatment-refractory MOGAD, aHSCT resulted as safe and was able to suppress disease-activity for over 2 years.

Rituximab and pregnancy: Late-onset neutropenia in a 2-month infant whose mother received rituximab 2 weeks prior to childbirth.

Late-onset neutropenia (LON) is a rare adverse event that has not been reported from in utero exposure. We describe a case of LON in an infant, whose mother had neuromyelitis optica and received rituximab in the third trimester due to re-emergence of CD19 B cells. The newborn was born without complications but 2 months later was found to have grade IV neutropenia. No etiology was identified. Neutropenia self-resolved within 1 week. This case emphasizes an unmet need for developing guidelines and protocols to manage in utero rituximab exposure.

Increased levels of circulating soluble CD226 in multiple sclerosis.

BACKGROUND: The glycoprotein CD226 plays a key role in regulating immune cell function. Soluble CD226 (sCD226) is increased in sera of patients with several chronic inflammatory diseases but its levels in neuroinflammatory diseases such as multiple sclerosis (MS) are unknown. OBJECTIVE: To investigate the presence and functional implications of sCD226 in persons with multiple sclerosis (pwMS) and other neurological diseases. METHODS: The mechanisms of sCD226 production were first investigated by analyzing CD226 surface expression levels and supernatants of CD3/CD226-coactivated T cells. The role of sCD226 on dendritic cell maturation was evaluated. The concentration of sCD226 in the sera from healthy donors (HD), pwMS, neuromyelitis optica (NMO), and Alzheimer's disease (AD) was measured. RESULTS: CD3/CD226-costimulation induced CD226 shedding. Addition of sCD226 to dendritic cells during their maturation led to an increased production of the pro-inflammatory cytokine interleukin (IL)-23. We observed a significant increase in sCD226 in sera from pwMS and NMO compared to HD and AD. In MS, levels were increased in both relapsing-remitting multiple sclerosis (RRMS) and secondary-progressive multiple sclerosis (SPMS) compared to clinically isolated syndrome (CIS). CONCLUSION: Our data suggest that T-cell activation leads to release of sCD226 that could promote inflammation and raises the possibility of using sCD226 as a biomarker for neuroinflammation.

Risk of depression and anxiety in multiple sclerosis and neuromyelitis optica spectrum disorder: A nationwide cohort study in South Korea.

BACKGROUND: We investigated the risks of depression/anxiety in patients with multiple sclerosis (pwMS) or patients with neuromyelitis optica spectrum disorder (pwNMOSD). OBJECTIVES: MS/NMOSD cohorts were collected from Korean National Health Insurance Service, using the International Classification of Diseases-10th and information on Rare Intractable Disease program. Patients who were younger than 20 years, had a previous depression/anxiety, or died in the index year were excluded. METHODS: Hazard ratios (HRs) of depression/anxiety in pwMS and pwNMOSD from controls matched 1:5 for age, sex, hypertension, diabetes, and dyslipidemia were calculated using Cox regressions with a 1-year lag period and estimated over time. RESULTS: During a mean follow-up of 4.1 years, adjusted hazard ratios (aHR) for depression were 3.25 (95% confidence interval (CI) = 2.59-4.07) in MS and 2.17 (1.70-2.76) in NMOSD, and aHRs for anxiety were 1.83 (1.49-2.23) in MS and 1.56 (1.26-1.91) in NMOSD. The risks of anxiety/depression did not differ between MS and NMOSD and were highest in the second year after diagnosis of MS/NMOSD. The relative risk of depression was higher in younger pwMS/pwNMOSD, and the relative risk of anxiety was higher in pwMS who was male, had low income, or lived in a non-urban area. CONCLUSION: The risk of depression and anxiety was increased in pwMS/pwNMOSD.

Deciphering prognostic indicators in AQP4-IgG-seropositive neuromyelitis optica spectrum disorder: An integrative review of demographic and laboratory factors.

BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) is a group of inflammatory diseases affecting the central nervous system, characterized by optic neuritis and myelitis. The complex nature of NMOSD and varied patient response necessitates personalized treatment and efficient patient stratification strategies. OBJECTIVE: To provide a comprehensive review of recent advances in clinical and biomarker research related to aquaporin-4 (AQP4)-immunoglobulin G (IgG)-seropositive NMOSD prognosis and identify key areas for future research. METHODS: A comprehensive review and synthesis of recent literature were conducted, focusing on demographic factors and laboratory investigations. RESULTS: Demographic factors, such as age, ethnicity, and sex, influence NMOSD prognosis. Key biomarkers for NMOSD prognosis include homocysteine, antinuclear antibodies, neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, thyroid hormone levels, neurofilament light chain levels, and serum glial fibrillary acidic protein might also predict NMOSD attack prognosis. CONCLUSION: Further investigation is required to understand sex-related disparities and biomarker inconsistencies. Identification and understanding of these factors can aid in the development of personalized therapeutic strategies, thereby improving outcomes for NMOSD patients. Future studies should focus on unifying research design for consistent results.