BackgroundThis study investigates the pathogenic contributions of aquaporin-4 (AQP4)-specific follicular helper T (Tfh) and T helper 17 (Th17) cells in neuromyelitis optica spectrum disorder (NMOSD), utilizing newly established murine models based on adoptive transfer of antigen-specific T-cell populations.MethodsAQP4-knockout mice were immunized with the AQP4-derived peptide to generate AQP4-reactive Tfh and Th17 cells. These cells were subsequently isolated and adoptively transferred into wild-type recipient mice. At disease peak—defined by consistent neurological deficits—spinal cord and brain tissues were harvested for histopathological analysis, as well as immunohistochemistry. Central nervous system immune cell infiltration was quantified via flow cytometry. Total RNA was extracted from spinal cord tissue for bulk RNA sequencing; differentially expressed genes were validated using quantitative real-time PCR.ResultsRecipient mice that received AQP4-reactive Tfh or Th17 cells developed progressive hind-limb weakness, with Th17-transferred mice exhibiting significantly more severe clinical scores. Histopathological analyses revealed robust perivascular inflammation, parenchymal immune infiltration, and focal demyelination. Immunohistochemical quantification demonstrated significantly increased the optical density of CD3, B220, GFAP, IBA1, and CXCL9, alongside markedly decreased MBP expression. Flow cytometric profiling confirmed substantial infiltration of leukocytes and activated microglia/macrophages into the central nervous system (CNS). Transcriptomic analysis identified CXCL9 as one of the most upregulated chemokines in the spinal cord; its astrocytic origin was further corroborated by confocal immunofluorescence co-localization with GFAP.ConclusionOur findings establish that AQP4-specific Tfh and Th17 cells are sufficient to drive key neuropathological features of NMOSD—including microglial reactivity, leukocyte recruitment, neuroinflammation, and demyelination—in vivo. The pronounced upregulation and astrocyte-derived expression of CXCL9 suggest its involvement in orchestrating CNS inflammation and position it as a potential contributor for NMOSD.

BACKGROUND:IgG4-related hypertrophic pachymeningitis (IgG4-RHP) is a rare immune-mediated fibroinflammatory disorder. Some patients show concurrent serum anti-neutrophil cytoplasmic antibody (ANCA) positivity, which may create diagnostic uncertainty with ANCA-associated vasculitis. We aimed to compare the clinical features of IgG4-RHP patients with and without serum ANCA positivity. METHODS:We retrospectively collected pathologically confirmed IgG4-RHP cases from Huashan Hospital between January 2020 and April 2026. We also searched PubMed and Chinese core journals for biopsy-confirmed IgG4-RHP cases published between January 2014 and April 2026. Patients were divided into ANCA-positive and ANCA-negative groups for comparative analysis. For ANCA-positive cases, we additionally reviewed ANCA pattern/specificity and performed a criteria-informed descriptive phenotypic assessment. RESULTS:A total of 67 patients with pathologically confirmed IgG4-RHP were included, including 4 patients from our center and 63 from the literature. Thirteen patients (19.4%) were serum ANCA-positive. Compared with ANCA-negative patients, ANCA-positive patients were more likely to present with headache (100.0% vs. 60.8%, p = 0.02) and diffuse dural thickening on MRI (100.0% vs. 51.0%, p = 0.001). Among the 13 ANCA-positive cases, 8 were descriptively considered more suggestive of an MPA-like phenotype and 5 of a GPA-like phenotype, while no case showed convincing EGPA-like features. No significant differences were observed in age at onset, sex, cranial nerve involvement, extracranial organ involvement, laboratory findings, or treatment patterns. CONCLUSIONS:Serum ANCA positivity does not exclude the diagnosis of IgG4-RHP. ANCA-positive IgG4-RHP may represent a distinct clinicoradiological phenotype characterized by more frequent headache and diffuse dural involvement. Histopathological confirmation remains crucial for diagnosis.

OBJECTIVE:To evaluate the efficacy and safety of ofatumumab in patients with myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), and compare it with rituximab. METHODS:We conducted a single-center, observational study including 22 MOGAD patients treated with ofatumumab and 21 treated with rituximab. The primary outcome is relapse, while the secondary outcomes are disability status and adverse events. RESULTS:Twenty-two patients received ofatumumab for a median duration of 19.5 months (range 6-41). Among them, 18 patients (81.82%) remained relapse-free during follow-up. Annualized relapse rate (ARR) significantly decreased from 1.30 (95% CI 0.74-2.29) pretreatment to 0.12 (95% CI 0.04-0.35) during ofatumumab therapy (IRR 10.86, 95% CI 3.22-36.70, p < 0.001). Through propensity score matching, 11 patients in the ofatumumab group and 11 patients in the rituximab group were compared. Ofatumumab was observed to be associated with a significantly lower risk of a second attack (HR 0.233, 95% CI 0.061 to 0.893, p = 0.018) compared to rituximab. Adverse events were reported in 54.55% patients (6/11) treated with ofatumumab, most of which were mild and occurred after the initial dose. INTERPRETATION:Ofatumumab was associated with a lower relapse risk compared with rituximab in patients with MOGAD.

Background:This study aimed to compare the proportions of circulating follicular helper T (Tfh) and B cell subsets, as well as serum levels of cytokines and chemokines, between patients with neuromyelitis optica spectrum disorder (NMOSD) who are anti-aquaporin-4 antibody (AQP4-ab)-positive and healthy controls, and to investigate the interaction mechanisms between Tfh and B cells. Methods:AQP4-ab-positive NMOSD patients were enrolled during acute attacks and remission phases, along with age- and sex-matched healthy controls. Flow cytometry was used to assess circulating Tfh and B cell subsets. Purified CD19+ B cells were cultured alone or co-cultured with CD4+CXCR5+ Tfh cells for 6 days, with various interventions applied to evaluate alterations in Tfh or B cell phenotypes. Serum and supernatant levels of interleukin (IL)-6, IL-21, CXCL13, and AQP4-ab were measured. Results:During acute attacks, NMOSD patients exhibited significantly higher proportions of total Tfh, ICOS+ Tfh, activated Tfh17, switched memory B cells, double-negative B cells, plasmablasts, and plasma cells, along with elevated serum levels of IL-6, IL-21, and CXCL13. In contrast, the frequencies of activated Tfh1, naive B cells, and transitional regulatory B cell subsets were significantly reduced. Functional assays revealed that Tfh cells promoted B cell proliferation, differentiation, and AQP4-ab production. Conversely, B cell subsets enhanced Tfh cell proliferation, differentiation, and IL-21 secretion; these effects were attenuated by anti-CD20 and anti-interferon-γ (IFN-γ) monoclonal antibodies, but were augmented by anti-IL-10 monoclonal antibody. Conclusions:Circulating Tfh and B cell subsets are dysregulated in AQP4-ab-positive NMOSD, accompanied by increased levels of IL-6, IL-21, and CXCL13. Reciprocal interactions between Tfh and B cells likely contribute to disease pathogenesis.

Siponimod is a new-generation sphingosine-1-phosphate (S1P) receptor modulator that has demonstrated efficacy and tolerability in patients with secondary progressive multiple sclerosis (SPMS) in pivotal trial. However, real-world data on its use in relapsing-remitting MS (RRMS) remain limited. This study aimed to evaluate the effectiveness and safety of siponimod in RRMS patients in a real-world clinical setting. This was a retrospective, single-center cohort study including RRMS patients treated with siponimod between September 2020 and May 2025. Effectiveness outcomes included annualized relapse rate (ARR), Expanded Disability Status Scale (EDSS), and no evidence of disease activity (NEDA3) status. Cognitive and motor performance were explored in a predefined subgroup using the Symbol Digit Modalities Test (SDMT), 9-Hole Peg Test (9HPT), and Timed 25-Foot Walk (T25FW). Among 77 RRMS patients identified, 68 who received siponimod for more than 6 months were included in the effectiveness analysis, including 52 treatment- naïve and 16 treatment-switched patients. In treatment- naïve patients, mean ARR decreased from 1.08 ± 0.70 to 0.10 ± 0.37 after a median treatment duration of 19.6 months (P < 0.001). Among treatment-switched patients, ARR decreased from 0.70 ± 0.50 to 0.03 ± 0.12 over a median follow-up of 23.7 months (P < 0.001). Median EDSS remained stable in both groups. At the last follow-up, the proportion achieving NEDA3 was comparable between treatment-naïve and switched group (65.4

BackgroundAutoimmune glial fibrillary acidic protein astrocytopathy (GFAP-A) is an inflammatory disorder of the central nervous system. The clinical implications of Epstein–Barr virus (EBV) sequences detected in cerebrospinal fluid (CSF) by metagenomic next-generation sequencing (mNGS) remain uncertain.MethodsThis multicenter retrospective cohort study enrolled 60 patients with GFAP-A screened from electronic medical records of two hospitals (Jan 2019–Dec 2025). Patients were stratified into CSF EBV-positive (n = 10) and CSF EBV-negative (n = 50) groups based on CSF mNGS results. Demographic characteristics, clinical manifestations, laboratory findings, MRI features, treatment, and outcomes were compared. Bonferroni correction was applied to three clinically prioritized endpoints (CSF white blood cell count, altered consciousness, CSF chloride) selected based on prior GFAP-A literature to limit multiplicity bias; the corrected two-sided significance threshold was set at α = 0.05/3 ≈ 0.0167. An exploratory Firth penalized multivariable logistic regression model fitted via R (v4.3.1, logistf package) was used to examine the adjusted associations between CSF mNGS-detectable EBV sequences and acute altered consciousness, adjusting for age and sex to mitigate small-sample bias. All other unadjusted baseline comparisons were considered exploratory and were not adjusted for multiplicity. Spearman’s rank correlation was used to assess the relationships of raw EBV mNGS read counts with peak pretreatment modified Rankin Scale (mRS) score and CSF WBC count among EBV-positive patients.ResultsCSF WBC count was higher in the CSF EBV-positive group than in the CSF EBV-negative group [median, 120 (interquartile range, 105–220) vs. 33 (16–97) × 10⁶/L; raw p = 0.004; Bonferroni-adjusted p = 0.012]. Altered consciousness was more frequent in the EBV-positive group (80.0% vs. 42.0%; crude odds ratio [OR] = 5.52, 95% confidence interval [CI] 1.06–28.71; raw p = 0.039), and CSF chloride was numerically lower [111.50 (104.00–117.00) vs. 115.70 (113.00–120.00) mmol/L; raw p = 0.048]; however, neither comparison met the Bonferroni-corrected criterion (adjusted p = 0.117 and 0.144, respectively). Firth penalized multivariable logistic regression fitted in R was adjusted for age and sex. CSF EBV positivity exhibited a non-significant trend toward higher odds of acute altered consciousness (OR = 4.10, 95% CI: 0.94–24.84, p = 0.060). The extremely wide confidence interval indicated high estimation uncertainty limited by the small EBV-positive subgroup (n = 10). Female sex was associated with lower estimated odds of altered consciousness (OR = 0.17, 95% CI: 0.04–0.58, p = 0.004), while age showed no independent association (OR = 0.98, 95% CI: 0.95–1.02, p = 0.312). No statistically detectable between-group differences were observed in GFAP-IgG characteristics, MRI findings, relapse, or functional outcomes. Among the 10 EBV-positive patients, raw EBV read counts were not statistically correlated with peak pretreatment mRS score (rs = 0.118, p = 0.745) or CSF WBC count (rs = −0.073, p = 0.841).ConclusionCSF WBC count was the only clinically prioritized comparison that remained statistically significant after Bonferroni correction, suggesting greater CSF pleocytosis and possibly increased intrathecal inflammatory activity in GFAP-A patients with mNGS-detectable CSF EBV. Differences in altered consciousness and CSF chloride remained inconclusive after multiplicity adjustment. Within the EBV-positive subgroup, raw EBV sequencing reads showed no correlation with inflammatory or disability measures. Current findings do not establish CSF EBV positivity as an independent pathogenic or prognostic biomarker for GFAP-A, and the biological origin of the detected EBV sequences remains uncertain.

Background:Inebilizumab was included in China's national reimbursement drug list in 2023, enhancing its accessibility. However, there is a paucity of real-world data evaluating its performance in Chinese patients with aquaporin-4 immunoglobulin G-seropositive neuromyelitis optica spectrum disorder (AQP4-IgG+ NMOSD). This prospective study therefore sought to assess the treatment outcomes and identify predictive factors for relapse and severe pneumonia in Chinese patients treated with Inebilizumab. Methods:This study enrolled AQP4-IgG+ NMOSD patients receiving ≥1 dose of inebilizumab from March 2023 to June 2025. The primary outcome was time to first relapse. Secondary outcomes included annualized relapse rate (ARR), Expanded Disability Status Scale (EDSS) score, drug retention rates, and adverse events (AEs). Multivariate regression analyses were conducted to identify predictors of relapse and severe pneumonia. Results:Among 136 patients (91.9% female; mean age 40.3 years; median treatment duration 13.8 months), the 12-month relapse-free rate was 88.1% (95% confidence interval [CI] =82.1-94.5%). Thirteen patients experienced 14 relapses, with 7 occurring within the first 6 months. The median time to first relapse was 5.2 months (range, 0.3-11.8). Risk factors for relapse within 12 months included: age at onset ≤ 20 years (hazard ratio [HR] 8.17, 95% CI = 1.96-34.03, p=0.004), disease duration >5 years (HR 8.06, 95% CI = 1.72-37.83, p=0.008), and pre-treatment relapses (HR 3.04, 95% CI = 1.32-6.98, p=0.009). The annualized relapse rate (ARR) significantly decreased (1.496 vs 0.117, p<0.001). The median EDSS score decreased (from 2.5 to 2.0, p = 0.002) in patients who started inebilizumab during the remission phase. The 12-month drug retention rate was 88.9% (95% CI 82.8-95.5%). Seven patients developed severe pneumonia, significantly associated with baseline EDSS ≥6.5 (odds ratio [OR] 25.4, 95% CI = 2.12-334, p=0.013) and IgG <6 g/L (OR 14.2, 95% CI = 1.79-136, p=0.007). Conclusion:This study confirms the real-world effectiveness of inebilizumab in Chinese NMOSD patients but identifies distinct clinical profiles for relapse and infection risk. Patients with early-onset, long-standing, or highly active disease are at greater risk of breakthrough relapses, whereas those with high disability and hypogammaglobulinemia require vigilance for severe pneumonia. These findings advocate for a risk-stratified management approach to optimize treatment outcomes.

Abstract Background: Disease-modifying therapies have been approved for the treatment of relapsing multiple sclerosis (RMS). The present study aims to examine the safety of teriflunomide in Chinese patients with RMS. Methods: This non-randomized, multi-center, 24-week, prospective study enrolled RMS patients with variant (c.421C>A) or wild type ABCG2 who received once-daily oral teriflunomide 14 mg. The primary endpoint was the relationship between ABCG2 polymorphisms and teriflunomide exposure over 24 weeks. Safety was assessed over the 24-week treatment with teriflunomide. Results: Eighty-two patients were assigned to variant (n = 42) and wild type groups (n = 40), respectively. Geometric mean and geometric standard deviation (SD) of pre-dose concentration (variant, 54.9 [38.0] μg/mL; wild type, 49.1 [32.0] μg/mL) and area under plasma concentration-time curve over a dosing interval (AUCtau) (variant, 1731.3 [769.0] μg∙h/mL; wild type, 1564.5 [1053.0] μg∙h/mL) values at steady state were approximately similar between the two groups. Safety profile was similar and well tolerated across variant and wild type groups in terms of rates of treatment emergent adverse events (TEAE), treatment-related TEAE, grade ≥3 TEAE, and serious adverse events (AEs). No new specific safety concerns or deaths were reported in the study. Conclusion: ABCG2 polymorphisms did not affect the steady-state exposure of teriflunomide, suggesting a similar efficacy and safety profile between variant and wild type RMS patients. Registration: NCT04410965, https://clinicaltrials.gov.

To evaluate the relationship between aquaporin-4 immunoglobulin G (AQP4-IgG) titer dynamics and relapse in neuromyelitis optica spectrum disorder (NMOSD), compare AQP4-IgG dynamics across different maintenance therapy strategies, and identify factors associated with AQP4-IgG titer seroreversion to negativity. Altogether 171 patients with ≥ 2 serum AQP4-IgG tests by fixed cell-based assay 30 days apart and at least once positive were included. Their clinical and treatment data were reviewed. Among the 171 NMOSD patients with a median disease duration of 81.3 months, 44 (25.7

BACKGROUND:Neuronal intranuclear inclusion disease (NIID) is a progressive neurodegenerative disorder characterized by eosinophilic intranuclear inclusions in neurons and multiple visceral organs, leading to heterogeneous clinical manifestations. This case report presents two rare NIID patients with recurrent encephalitis-like episodes, periodic prolonged hospitalizations, mimicking mitochondrial encephalomyopathies. CASE PRESENTATION:The first patient was a 63-year-old man with a history of migraines, who experienced two episodes of acute fever, headache, motor aphasia, behavioral abnormalities, seizures, and stroke-like symptoms over a period of four years. Brain MRI revealed swelling in the temporo-occipital lobe. Cerebrospinal fluid analysis demonstrated elevated protein levels, while tests for autoimmune encephalitis antibodies and mitochondrial gene mutations were negative. The second patient was a 38-year-old man with a family history of consanguinity, who presented with recurrent episodes of fever, limb weakness, aphasia, and psychiatric disturbances, occurring numerous times over five years. A recent MRI showed swelling in the left temporo-occipital lobe, dot-like high signals in the right frontal-parietal-temporal lobe, and filamentous high signals at the corticomedullary junction. Genetic testing revealed 93 and 101 GGC repeats, respectively, in the 5' untranslated region (5' UTR) of the NOTCH2NLC gene, indicating abnormal expansion and confirming the diagnosis of NIID. CONCLUSIONS:This report underscores the importance of recognizing NIID in patients with recurrent encephalitis-like presentations and highlights the diagnostic utility of genetic testing in distinguishing it from conditions like mitochondrial encephalopathies.

Peripapillary retinal nerve fiber layer (pRNFL) thinning, detected by optical coherence tomography (OCT), is an early marker of neuroaxonal injury in multiple sclerosis (MS). Its prognostic value for long-term outcomes and responsiveness to disease-modifying therapies (DMTs) remains insufficiently explored, particularly in Asian populations. This study aimed to identify clinical and radiological correlates of pRNFL thickness, evaluate whether pRNFL thinning predicts disability and cognitive decline, and examine the effects of DMTs on retinal neurodegeneration in Chinese MS patients. We analyzed 354 Chinese MS patients who underwent OCT, neurological assessments, and brain MRI. Multivariate regression identified determinants of baseline pRNFL thickness. Among 159 patients with follow-up longer than 12 months, logistic regression was used to assess whether baseline pRNFL thickness and annualized pRNFL thinning predicted disability or cognitive decline. Linear mixed-effects models were applied to evaluate longitudinal effects of DMT classes on pRNFL thinning. Median pRNFL thickness was 105.0 μm (range: 65.0–136.5). Thinner pRNFL was associated with longer disease duration (p < 0.001), optic neuritis (p = 0.019), longer 9-Hole Peg Test completion time (p = 0.025), and increased paramagnetic rim lesions (p = 0.002). Baseline pRNFL thickness did not predict EDSS progression or Symbol Digit Modalities Test (SDMT) decline. In contrast, faster annualized pRNFL thinning predicted SDMT worsening (OR = 1.29, p = 0.018), alongside fewer years of education (OR = 0.84, p = 0.033) and a secondary progressive MS phenotype (OR = 7.67, p = 0.006). No significant differences in pRNFL preservation were observed among DMT classes. pRNFL thinning reflects disease severity and predicts cognitive decline in MS. Current DMTs provide limited retinal neuroprotection. These findings support the routine OCT-derived pRNFL monitoring and highlight the need for neuroprotective strategies in MS.

BACKGROUND:Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) frequently follows a relapsing course, necessitating early identification of patients at high risk of relapse to guide management strategies. Until recently, no validated risk assessment tool was available. The MOGAD Relapse (MOG-AR) score, developed within a Chinese cohort, stratifies post-attack relapse risk using various clinical factors. Our study aimed to externally validate the MOG-AR score in an independent Chinese MOGAD cohort. METHODS:We conducted a retrospective analysis of 157 MOGAD patients from a tertiary center in South China, spanning June 2015 to May 2023. Clinical data were collected, and each patient's MOG-AR score was calculated based on five predictors: onset age, sex, attack phenotype, immunosuppressive therapy, and oral corticosteroid duration. Model performance was evaluated using Harrell's C-index for discrimination, calibration plots for calibration, and Kaplan-Meier analysis for comparing risk between MOG-AR score groups. RESULTS:The cohort's median onset age was 27 years, with 51.6 % female and 78.3 % adults. Optic neuritis was the most common initial presentation (40.8 %), followed by transverse myelitis (14.0 %). During a median disease duration of 46 months, 87 patients (55.4 %) experienced at least one relapse. The MOG-AR score demonstrated a C-index of 0.72 (95 % confidence interval 0.63-0.81) and showed favorable alignment with calibration curves. Kaplan-Meier survival curves stratified by MOG-AR grade exhibited clear separation (log-rank p < 0.001). CONCLUSION:The MOG-AR score was successfully externally validated in our MOGAD cohort, demonstrating strong discrimination and calibration in predicting post-attack relapses. Patients with higher MOG-AR scores exhibited significantly elevated relapse risks and shorter time to relapse.