Single-cell analysis of anti-BCMA CAR T cell therapy in patients with central nervous system autoimmunity.

Chimeric antigen receptor (CAR) T cell immunotherapy for the treatment of neurological autoimmune diseases is promising, but CAR T cell kinetics and immune alterations after treatment are poorly understood. Here, we performed single-cell multi-omics sequencing of paired cerebrospinal fluid (CSF) and blood samples from patients with neuromyelitis optica spectrum disorder (NMOSD) treated with anti-B cell maturation antigen (BCMA) CAR T cells. Proliferating cytotoxic-like CD8+ CAR T cell clones were identified as the main effectors in autoimmunity. Anti-BCMA CAR T cells with enhanced features of chemotaxis efficiently crossed the blood-CSF barrier, eliminated plasmablasts and plasma cells in the CSF, and suppressed neuroinflammation. The CD44-expressing early memory phenotype in infusion products was potentially associated with CAR T cell persistence in autoimmunity. Moreover, CAR T cells from patients with NMOSD displayed distinctive features of suppressed cytotoxicity compared with those from hematological malignancies. Thus, we provide mechanistic insights into CAR T cell function in patients with neurological autoimmune disease.

B cell lineage reconstitution underlies CAR-T cell therapeutic efficacy in patients with refractory myasthenia gravis.

B-cell maturation antigen (BCMA), expressed in plasmablasts and plasma cells, could serve as a promising therapeutic target for autoimmune diseases. We reported here chimeric antigen receptor (CAR) T cells targeting BCMA in two patients with highly relapsed and refractory myasthenia gravis (one with AChR-IgG, and one with MuSk-IgG). Both patients exhibited favorable safety profiles and persistent clinical improvements over 18 months. Reconstitution of B-cell lineages with sustained reduced pathogenic autoantibodies might underlie the therapeutic efficacy. To identify the possible mechanisms underlying the therapeutic efficacy of CAR-T cells in these patients, longitudinal single-cell RNA and TCR sequencing was conducted on serial blood samples post infusion as well as their matching infusion products. By tracking the temporal evolution of CAR-T phenotypes, we demonstrated that proliferating cytotoxic-like CD8 clones were the main effectors in autoimmunity, whereas compromised cytotoxic and proliferation signature and profound mitochondrial dysfunction in CD8+ Te cells before infusion and subsequently defect CAR-T cells after manufacture might explain their characteristics in these patients. Our findings may guide future studies to improve CAR T-cell immunotherapy in autoimmune diseases.

Interleukin-6 trans-signaling regulates monocyte chemoattractant protein-1 production in immune-mediated necrotizing myopathy.

OBJECTIVE: Immune-mediated necrotizing myopathy (IMNM) is pathologically characterized by diffuse myofiber necrosis and regeneration, myophagocytosis, and a sparse inflammatory infiltrate. The monocyte chemoattractant protein-1 (MCP-1) is a key chemokine that regulates monocyte/macrophage infiltration into injured tissues. The interleukin-6 (IL-6) signalling in the induction of MCP-1 expression has not been investigated in IMNM. METHODS: MCP-1 expression in muscle specimens was assessed using immunohistochemistry and real-time quantitative polymerase chain reaction (RT-qPCR). Levels of multiple serological cytokines were evaluated using the Meso Scale Discovery electrochemiluminescence system. Flow cytometry, RT-qPCR, enzyme-linked immunosorbent assay, western blot, dual-luciferase reporter assays, and chromatin immunoprecipitation-qPCR were performed to explore the effects of IL-6 signalling on MCP-1 production in human myoblasts. RESULTS: MCP-1 was scattered and was positively expressed within myofibers and a few inflammatory cells in the muscles of patients with IMNM. Sarcoplasmic MCP-1 expression significantly correlated with myonecrosis, myoregeneration, and inflammatory infiltration. Serum MCP-1, IL-6, and the soluble form of the IL-6 receptor (sIL-6R) were elevated in patients with IMNM compared with controls. Serological MCP-1 levels were significantly associated with serum IL-6 expression and clinical disease severity in IMNM patients. The IL-6/sIL-6R complex induced MCP-1 expression via the signal transducer and activator of transcription 3 (STAT3) pathway in human myoblasts. Mechanistically, phospho-STAT3 was enriched in the MCP-1 promoter region and promoted the transcription. CONCLUSION: IL-6 trans-signalling may contribute to the immunopathogenesis of IMNM by augmenting inflammation through regulation of MCP-1 expression in IMNM.

Single-cell analysis of refractory anti-SRP necrotizing myopathy treated with anti-BCMA CAR-T cell therapy.

Immune-mediated necrotizing myopathy (IMNM) is an autoimmune disorder associated with the presence of autoantibodies, characterized by severe clinical presentation with rapidly progressive muscular weakness and elevated levels of creatine kinase, while traditional pharmacological approaches possess varying and often limited effects. Considering the pathogenic role of autoantibodies, chimeric antigen receptor (CAR)-T cells targeting B cell maturation antigen (BCMA) have emerged as a promising therapeutic strategy. We reported here a patient with anti-signal recognition particle IMNM refractory to multiple available therapies, who was treated with BCMA-targeting CAR-T cells, exhibited favorable safety profiles, sustained reduction in pathogenic autoantibodies, and persistent clinical improvements over 18 mo. Longitudinal single-cell RNA, B cell receptor, T cell receptor sequencing analysis presented the normalization of immune microenvironment after CAR-T cell infusion, including reconstitution of B cell lineages, replacement of T cell subclusters, and suppression of overactivated immune cells. Analysis on characteristics of CAR-T cells in IMNM demonstrated a more active expansion of CD8+ CAR-T cells, with a dynamic phenotype shifting pattern similar in CD4+ and CD8+ CAR-T cells. A comparison of CD8+ CAR-T cells in patients with IMNM and those with malignancies collected at different timepoints revealed a more NK-like phenotype with enhanced tendency of cell death and neuroinflammation and inhibited proliferating ability of CD8+ CAR-T cells in IMNM while neuroinflammation might be the distinct characteristics. Further studies are warranted to define the molecular features of CAR-T cells in autoimmunity and to seek higher efficiency and longer persistence of CAR-T cells in treating autoimmune disorders.

The diagnostic value of serum YKL-40 for myocardial involvement in immune-mediated necrotising myopathy.

OBJECTIVES: This study aimed to determine the diagnostic value of YKL-40 for myocardial involvement in immune-mediated necrotising myopathy (IMNM). METHODS: We retrospectively analysed the data of patients with IMNM admitted to the Neurology Department at Tongji Hospital between April 2013 and August 2022. Clinical data including patients' demographics, clinical characteristics (disease duration, muscle strength, atrophy, rash, dysphagia, dyspnoea, and myalgia) and laboratory test results were collected from the electronic medical record system. Serum YKL-40 levels were measured using an enzyme-linked immunosorbent assay. A receiver operating characteristic (ROC) curve was drawn, and the area under the ROC curve was calculated to evaluate the diagnostic value of YKL-40 for cardiac involvement in IMNM. RESULTS: 29 patients with IMNM and15 sex and age-matched volunteers without history of heart diseases were recruited for the study. Compared with the healthy controls, serum YKL-40 levels were notably up-regulated [96.3 (55.5 120.6) pg/ml versus 19.6 (13.8 20.9) pg/ml; p=0.000] in patients with IMNM. We compared 14 patients with IMNM with cardiac abnormalities and 15 patients with IMNM without cardiac abnormalities. The most important finding was that serum YKL-40 levels were higher in the patients with IMNM with cardiac involvement based on cardiac magnetic resonance (CMR) examination [119.2 (88.4 185.69) pm/ml versus 72.5 (35.7 98) pm/ml; p=0.002]. YKL-40 had a specificity and sensitivity of 86.7% and 71.4% respectively, at a cut-off value of 105.46 pg/ml for predicting myocardial injury in patients with IMNM. CONCLUSIONS: YKL-40 could be a promising non-invasive biomarker for diagnosing myocardial involvement in IMNM. However, larger prospective study is warranted.

Anti-BCMA CAR T-cell therapy CT103A in relapsed or refractory AQP4-IgG seropositive neuromyelitis optica spectrum disorders: phase 1 trial interim results.

Chimeric antigen receptor (CAR) T-cell therapy that targets B-cell maturation antigen (BCMA) have great potentials in autoimmune diseases and could be novel therapeutics for relapsed/refractory neuromyelitis optica spectrum disorder (NMOSD). To evaluate the safety and efficacy of the CT103A, a self-developed BCMA-targeting CAR construct against BCMA, in patients with AQP4-IgG seropositive NMOSD, an ongoing, investigator-initiated, open-label, single-arm, phase 1 clinical trial is conducted at our center. In total, 12 patients were administered with a CAR-BCMA infusion. Ten of the 12 patients dosed were women (83.3%), with a median age of 49.5 years (range, 30-67). were The most common events of grade 3 or higher were hematologic toxic effects. Seven patients (58%) developed infections, but no grade 4 infections occurred. Cytokine release syndrome was reported in all patients with only events of grade 1 or 2 observed. During the follow-up of a median 5.5 months, 11 patients had no relapse; all patients generally reported improvement in disabilities and quality-of-life outcomes; 11 patients' AQP-4 antibodies in serum showed a downward trend by the cutoff date. CAR T-cell expansion was associated with responses, and persisted more than 6 months post-infusion in 17% of the patients. In summary, CAR T-cell therapy shows a manageable safety profile and therapeutic potentials for patients with relapsed/refractory AQP4-IgG seropositive NMOSD. Another expansion phase is currently underway to determine the safety and efficacy of CAR T-BCMA infusion in patients with other neuro-inflammatory diseases.

Anti-SRP immune-mediated necrotizing myopathy: A critical review of current concepts.

Purpose of review: This review aims to describe clinical and histological features, treatment, and prognosis in patients with anti-signal recognition particle (SRP) autoantibodies positive immune-mediated necrotizing myopathy (SRP-IMNM) based on previous findings. Previous findings: Anti-SRP autoantibodies are specific in IMNM. Humoral autoimmune and inflammatory responses are the main autoimmune characteristics of SRP-IMNM. SRP-IMNM is clinically characterized by acute or subacute, moderately severe, symmetrical proximal weakness. Younger patients with SRP-IMNM tend to have more severe clinical symptoms. Patients with SRP-IMNM may be vulnerable to cardiac involvement, which ought to be regularly monitored and cardiac magnetic resonance imaging is the recommended detection method. The pathological features of SRP-IMNM are patchy or diffuse myonecrosis and myoregeneration accompanied by a paucity of inflammatory infiltrates. Endoplasmic reticulum stress-induced autophagy pathway and necroptosis are activated in skeletal muscle of SRP-IMNM. Treatment of refractory SRP-IMNM encounters resistance and warrants further investigation. Summary: Anti-SRP autoantibodies define a unique population of IMNM patients. The immune and non-immune pathophysiological mechanisms are involved in SRP-IMNM.

Endoplasmic Reticulum Stress Is Involved in Muscular Pathogenesis in Idiopathic Inflammatory Myopathies.

Objectives: Endoplasmic reticulum (ER) stress plays pivotal roles in the regulation of skeletal muscle damage and dysfunction in multiple disease conditions. We postulate the activation of ER stress in idiopathic inflammatory myopathies (IIM). Methods: Thirty-seven patients with immune-mediated necrotizing myopathy (IMNM), 21 patients with dermatomyositis (DM), 6 patients with anti-synthetase syndrome (ASS), and 10 controls were enrolled. The expression of ER stress-induced autophagy pathway was detected using histological sections, Western blot, and real-time quantitative Polymerase Chain Reaction. Results: ER stress-induced autophagy pathway was activated in biopsied muscle of patients with IMNM, DM, and ASS. The ER chaperone protein, glucose-regulated protein 78 (GRP78)/BiP expression in skeletal muscle correlated with autophagy, myofiber atrophy, myonecrosis, myoregeneration, and disease activity in IMNM. Conclusion: ER stress was involved in patients with IIM and correlates with disease activity in IMNM. ER stress response may be responsible for skeletal muscle damage and repair in IIM.

Contribution of relapse-associated worsening to overall disability accrual in patients with relapsing-onset multiple sclerosis: A mediation analysis.

OBJECTIVE: The neurological disability accumulation in patients with relapsing-onset multiple sclerosis (MS) is commonly attributed to relapse-associated worsening (RAW) and progression independent of relapse activity (PIRA). Using a mediation model, this research aimed to investigate and quantify the contributions of RAW and PIRA to the overall disability accrual. METHODS: Clinical data, containing Expanded Disability Status Scale (EDSS) scores, duration, attack number, and demographics, were collected from 121 patients with relapsing-onset MS in China and included in the mediation model. Two phases were defined: an early phase, from the clinical onset to EDSS 3, and a later phase, greater than EDSS 3. RESULTS: Clinical attack number partly mediated the relationship between duration and neurological disability (Duration â†’ Attack â†’ EDSS score) only in the early phase, with the ratio of indirect (RAW) to total effect of 0.414; while this mediator effect became negligible (<10%) in the later phase, with a predominating direct effect (PIRA). Onset age positively correlated with EDSS scores during the early stage, independent of the clinical attack number (the direct effect was significant, but the indirect effect was not), while this association was insignificant later. Besides, compared to females, male patients appeared to relapse less frequently before reaching EDSS 3 but were vulnerable to an accelerated progression after that. CONCLUSIONS: In relapsing-onset MS, PIRA is the major contributor to the irreversible disability accrual throughout the whole disease course, albeit RAW is also partly involved during the early stage. The correlations between the disabled outcome and the onset age or sex vary in different phases.

Immunological predictors for the outcome in patients with antibody-mediated autoimmune encephalitis.

We investigated the immunological outcome predictors in patients with antibody-mediated autoimmune encephalitis. A severe disability on admission, a low lymphocyte count, including T, B, and T + B + NK (TBNK) cells, an elevated neutrophil (%) and neutrophil to lymphocyte ratio (NLR) could predict poor prognoses. The increased neutrophils (%) and NLR with the decreased eosinophil percent and count were sensitive (>0.8) in predicting severe disabilities, while the declined total T cell count, lymphocyte percent and count were specific (>0.9). TBNK cell count had a balanced sensitivity and specificity (both>0.8). Patients with autoimmune encephalitis with poor outcomes are immunologically distinct from those with good recoveries.

Distinct Immunological Features of Inflammatory Demyelinating Diseases of the Central Nervous System.

OBJECTIVE: The immunological features between neuromyelitis optica spectrum disorder (NMOSD), multiple sclerosis (MS), and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), lacked systemic comparisons. Accordingly, we aimed to investigate immunological differences between NMOSD, MS, and MOGAD. METHODS: Patients with MOGAD, MS, and NMOSD who received immunological tests including cytokine profiles and cytometry analysis of the lymphocyte subgroups were retrospectively reviewed and divided into training and validation sets. Discriminatory models based on immunological data were established to identify optimal classifiers using orthogonal partial least square discriminant analysis (OPLS-DA). Constructed models were tested in another independent cohort. RESULTS: OPLS-DA of the immunological data from 50 patients (26 NMOSD, 14 MS, and 10 MOGAD) demonstrated the discriminatory values of a relatively low level of T-lymphocyte subsets, especially the CD4+ T cells, in MOGAD; a decreased NK cell, eosinophil, and lymphocyte level; an elevated neutrophil-to-lymphocyte ratio in NMOSD; and a declined IFN-γ-producing CD4+ T cells/Th with an increased IL-8 concentration in MS. All the models (NMOSD vs. MS, NMOSD vs. MOGAD, and MS vs. MOGAD) exhibited a significant predictive value and accuracy (>85%). CONCLUSIONS: NMOSD, MS, and MOGAD may be different in pathogenesis, and several immunological biomarkers can serve as potential classifiers clinically.

Regulatory T cells protect against brain damage by alleviating inflammatory response in neuromyelitis optica spectrum disorder.

BACKGROUND AND PURPOSE: Neuromyelitis optica spectrum disorder (NMOSD) is mainly an anti-aquaporin 4 (anti-AQP4) autoantibodies-mediated idiopathic inflammatory demyelinating disease of the central nervous system. Systemic and local inflammatory responses play a key role in the pathophysiology of NMOSD. However, the role of the crucial immunomodulators CD4+CD25+ forkhead box P3+ (Foxp3) regulatory T cells (Tregs) has not been investigated in NMOSD. METHODS: Twenty-five patients with anti-AQP4-postive NMOSD undergoing an attack and 21 healthy controls (HCs) were enrolled. Frequencies of T cell subsets and Tregs in the peripheral blood were assessed by flow cytometry. Additionally, a model of NMOSD using purified immunoglobulin G from anti-AQP4-antibodies-positive patients with NMOSD and human complement injected into brain of female adult C57BL/6J mice was established. Infiltrated Tregs into NMOSD mouse brain lesions were analyzed by flow cytometry, histological sections, and real-time quantitative Polymerase Chain Reaction. Astrocyte loss, demyelination, and inflammatory response were also evaluated in our NMOSD mouse model. Finally, we examined the effects of both depletion and adoptive transfer of Tregs. RESULTS: The percentage of Tregs, especially naïve Tregs, among total T cells in peripheral blood was significantly decreased in NMOSD patients at acute stage when compared to HCs. Within our animal model, the number and proportion of Tregs among CD4+ T cells were increased in the lesion of mice with NMOSD. Depletion of Tregs profoundly enhanced astrocyte loss and demyelination in these mice, while adoptive transfer of Tregs attenuated brain damage. Mechanistically, the absence of Tregs induced more macrophage infiltration, microglial activation, and T cells invasion, and modulated macrophages/microglia toward a classical activation phenotype, releasing more chemokines and pro-inflammatory cytokines. In contrast, Tregs transfer ameliorated immune cell infiltration in NMOSD mice, including macrophages, neutrophils, and T cells, and skewed macrophages and microglia towards an alternative activation phenotype, thereby decreasing the level of chemokines and pro-inflammatory cytokines. CONCLUSION: Tregs may be key immunomodulators ameliorating brain damage via dampening inflammatory response after NMOSD.

Characteristics of immune and inflammatory responses among different age groups of pediatric patients with COVID-19 in China.

BACKGROUND: Severe cases of coronavirus disease 2019 (COVID-19) among pediatric patients are more common in children less than 1 year of age. Our aim is to address the underlying role of immunity and inflammation conditions among different age groups of pediatric patients. METHODS: We recruited pediatric patients confirmed of moderate COVID-19 symptoms, admitted to Wuhan Children's Hospital from January 28th to April 1st in 2020. Patients were divided into four age groups (≤ 1, 1-6, 7-10, and 11-15 years). Demographic information, clinical characteristics, laboratory results of lymphocyte subsets test, immune and inflammation related markers were all evaluated. RESULTS: Analysis included 217/241 (90.0%) of patients with moderate clinical stage disease. Average recovery time of children more than 6 years old was significantly shorter than of children younger than 6 years (P = 0.001). Reduced neutrophils and increased lymphocytes were significantly most observed among patients under 1 year old (P < 0.01). CD19+ B cells were the only significantly elevated immune cells, especially among patients under 1 year old (cell proportion: n = 12, 30.0%, P < 0.001; cell count: n = 13, 32.5%, P < 0.001). While, low levels of immune related makers, such as immunoglobulin (Ig) G (P < 0.001), IgA (P < 0.001), IgM (P < 0.001) and serum complement C3c (P < 0.001), were also mostly found among patients under 1 year old, together with elevated levels of inflammation related markers, such as tumor necrosis factor γ (P = 0.007), interleukin (IL)-10 (P = 0.011), IL-6 (P = 0.008), lactate dehydrogenase (P < 0.001), and procalcitonin (P = 0.007). CONCLUSION: The higher rate of severe cases and long course of COVID-19 among children under 1 year old may be due to the lower production of antibodies and serum complements of in this age group.

Dynamic Changes in AQP4-IgG Level and Immunological Markers During Protein-A Immunoadsorption Therapy for NMOSD: A Case Report and Literature Review.

The changes in the serum levels of aquaporin-4-IgG (AQP4-IgG), immunoglobulins, and inflammatory mediators in neuromyelitis optica spectrum disorder (NMOSD) cases treated with immunoadsorption have been rarely described in detail. Here we report a 29-year-old steroid-resistant NMOSD female with a severe disability (bilateral blindness and paraplegia) who received protein-A immunoadsorption as a rescue treatment. During the total 5 sessions, the circulating level of AQP4-IgG, immunoglobulins, and complement proteins (C3 and C4) showed a rapid and sawtooth-like decrease, and the serum AQP4-IgG titer declined from 1:320 to below the detectable limit at the end of the 3rd procedure. Of all the antibodies, IgG had the biggest removal rate (>96.1%), followed by IgM (>66.7%) and IgA (53%), while complement C3 and C4 also dropped by 73% and 65%, respectively. The reduced pro-inflammatory cytokines (interleukin-8 and tumor necrosis factor-α) and marked increased lymphocyte (T and B cell) counts were also observed. The improvement of symptoms initiated after the last session, with a low AQP4-IgG titer (1:32) persisting thereafter. Accordingly, protein-A immunoadsorption treatment could be one of the potential rescue therapies for steroid-resistant NMOSD patients with a severe disability.

Case Report: Clinical and Imaging Characteristics of a Patient with Anti-flotillin Autoantibodies: Neuromyelitis Optica or Multiple Sclerosis?

Background: Demyelination diseases are complex puzzles that are not always straightforward to diagnose. Multiple sclerosis and neuromyelitis optica are two that are frequently encountered. Numerous autoantibodies newly discovered in recent years have significantly aided clinical reasoning and diagnosis in differentiating demyelination disorders. Here we report a case of demyelination disease with anti-flotillin autoantibodies positive, which is not common in past references. Case summary: The patient presented with characteristic neuromyelitis optica symptoms and had remission and relapse. But his images exhibited characteristics of both neuromyelitis optica spectrum illness and multiple sclerosis. Conclusion: This is the first case report describing the clinical course and imaging characteristics of demyelination illness associated with anti-flotillin autoantibodies. Although so far it appears to be a subtype of multiple sclerosis, there is still a potential that it is separate from MS and NMOSD.

A Comparison of IgG Index and Oligoclonal Band in the Cerebrospinal Fluid for Differentiating between RRMS and NMOSD.

As the oligoclonal band in the cerebrospinal fluid (CSF-OCB) in predicting relapsing-remitting multiple sclerosis (RRMS) is less sensitive in Asian populations than that in westerners, it remains elusive whether the IgG index could serve as an alternative. The purpose of this study was to compare these two methods of differentiating between RRMS and neuromyelitis optica spectrum disorder (NMOSD) in Chinese patients. A total of 171 patients (81 RRMS and 90 NMOSD) were retrospectively recruited, of whom 82 (56 RRMS and 26 NMOSD) received the CSF-OCB testing additionally. When the onset age was ≤38.5 years, IgG index with the threshold of 0.67 had a significant agreement (k = 0.4, p < 0.001) with the diagnosis while CSF-OCB failed to discriminate (k = 0.1, p = 0.578). However, when the onset age was >38.5 years, both IgG index with the threshold of 0.8 and CSF-OCB were moderately consistent with the diagnosis (both k > 0.4, p < 0.05). In total, our optimized algorithm had the sensitivity, specificity, and predictive accuracy of 0.778, slightly outperforming the CSF-OCB model. Accordingly, a combination of the onset age and IgG index could serve as an alternative to CSF-OCB for differentiating between RRMS and NMOSD in Chinese patients.

Predictive Factors of Resistance to High-Dose Steroids Therapy in Acute Attacks of Neuromyelitis Optica Spectrum Disorder.

High-dose steroids, the first-line therapy for acute attacks in neuromyelitis optica spectrum disorder (NMOSD), were ineffective in a proportion of NMOSD attacks. This study aimed to explore possible predictors of high-dose steroid resistance. Demographics and disease characteristics of acute attacks were compared between those who responded to high-dose intravenous methylprednisolone (IVMP) and those resistant to IVMP. In total, 197 attacks in 160 patients were identified in our NMOSD registry. Compared with responders, attacks resistant to high-dose steroids tended to have a higher proportion of previous history of immunosuppressive use (25.5 vs. 15.5%, p = 0.080). Significantly higher levels of proteins in the cerebrospinal fluid (CSF) were found in non-responders than in responders [485.5 (388-656) vs. 387 (291.5-532) mg/L, p = 0.006]. More active lesions were found in the brain stem of non-responders (8 attacks in 55, 14.5%), especially in the pons (7.3%) and medulla (14.5%), as opposed to responders (7 patients in 142, 4.9%). Multivariable logistic regression showed that resistance to high-dose steroid treatment was associated with previous immunosuppressant use [odds ratio (OR), 2.31; 95% confidence interval (CI) 1.002-5.34, p = 0.049], CSF protein level above 450 mg/L (OR 3.42, 95% CI 1.72-6.82, p < 0.001), and active lesions in the brainstem (OR 3.80, 95% CI 1.17-12.32, p = 0.026). In conclusion, NMOSD patients with previous use of immunosuppressants, higher levels of CSF protein, and active lesions in the brainstem are more likely to respond poorly to high-dose IVMP alone during an acute attack.

Efficacy of plasma exchange in acute attacks of neuromyelitis optica spectrum disorders: A systematic review and meta-analysis.

BACKGROUND: Plasma exchange (PE) has usually to be considered as a rescue therapy when intravenous corticosteroids is insufficient in acute attacks of neuromyelitis optica spectrum disorders (NMOSD). The efficacy of PE has not been quantified. This system review and meta-analysis was aimed to evaluate the efficacy of PE therapy in acute attacks of NMOSD. METHODS: Studies evaluating the efficacy of PE in patients with NMOSD were identified from PubMed and Embase. Changes of Expanded Disability Status Scale (EDSS) score between before and after PE therapy, and the rate of response to PE, were defined as the main efficacy outcomes. Meta-regression was performed to identify the sources of heterogeneity. Subgroup meta-analysis were performed based on the interval of initiation PE after attack onset and AQP4-IgG serostatus of patients. RESULTS: Twenty-four studies containing 528 patients with NMOSD were included in this meta-analysis. As a rescue therapy when patients failed to respond to intravenous corticosteroids (PE rescue), PE treatment resulted in a reduction in the mean EDSS score by 1.69 (95% CI: 0.88-2.50), with a response rate of 75%(95%CI: 66%-83%). As a first-line therapy being used alone or simultaneously with intravenous corticosteroids (PE first-line), PE resulted in a reduction in the mean EDSS score by 2.34 (95% CI: 1.69-2.98), with a response rate of 71%(95%CI: 44%-93%). Overall, PE resulted in a reduction in the mean EDSS score by 1.83 (95% CI: 1.19-2.47), with a response rate of 74% (95%CI: 66%-82%). Subgroup analysis suggested that earlier PE initiation and AQP4-IgG seronegative patients seemed to be associated with a superior response to PE therapy. CONCLUSION: Plasma exchange, whether used as rescue or as first-line therapy, is an effective therapeutic method in patients during acute attacks of NMOSD.

Unilateral cerebral cortical encephalitis with epilepsy: a possible special phenotype of MOG antibody-associated disorders.

Myelin oligodendrocyte glycoprotein (MOG) antibody-related encephalomyelitis is an increasingly recognized entity with heterogeneity in phenotype. Among all clinical phenotypes, encephalitis restricted to cerebral cortex might be most easily ignored and under-estimated type. Here, we described two cases of cerebral cortical encephalitis with MOG seropositivity to facilitate the awareness of the manifestations of the disease. In case 1, the patient presented with headaches and fevers turned out to have elevated CSF cells and cerebral cortical FLAIR hyperintense lesions in brain MRI. He was treated as intracranial infection during his first and second admission and fully resolved when discharged. During the patient's third admission, the patient experienced a seizure, and we found cerebral cortical FLAIR hyperintensity again and MOG antibody was positive in the serum. Therefore, we considered the patient suffered from MOG antibody encephalitis. In case 2, the patient also had headache, fever, and experienced a seizure. MOG antibody was positive in the serum and brain MRI showed cortical hyperintense lesions. Both the patients were young man, response well to corticosteroids and recovered completely. The two cases suggested that encephalitis, especially benign recurrent unilateral cerebral cortical encephalitis with epilepsy, might be a special phenotype of MOG antibody-associated disorders.

The clinical value of the albumin quotient in patients with neuromyelitis optica spectrum disorder.

BACKGROUND: The disruption of the blood-brain barrier (BBB) is common in patients with neuromyelitis optica spectrum disorder (NMOSD), causing pro-inflammatory immune cells to migrate into the central nervous system (CNS) and active demyelinating lesions. Albumin quotient is commonly used as an indicator for BBB permeability or dysfunction, but its potential clinical value in NMOSD treatment has never been explored. The present study investigated the differences in the albumin quotient level among NMOSD patients with different antibodies (AQP4-IgG and MOG-IgG) and the relationship between the albumin quotient and neurological dysfunction. METHODS: We retrospectively collected data from 141 patients with NMOSD (104 with AQP4-IgG and 37 with MOG-IgG) and reviewed their clinical features and albumin quotient levels. RESULTS: The percentage of patients with an abnormal albumin quotient was significantly higher in the MOG-IgG group than in the AQP4-IgG group (48.6% vs 27.9%, P = 0.026); albumin quotient levels in the AQP4-IgG-positive group were similar to those in the MOG-IgG groups (5.65 vs 5.8, P = 0.23). Among those with an abnormal quotient, no differences in the proportions of severe neurological disability across treatment were found between patients with AQP4-IgG and those with MOG-IgG (pre-treatment: AQP4-IgG group vs MOG-IgG group: 58.6% vs 38.9%, P = 0.24; post-treatment: AQP4-IgG group vs MOG-IgG group: 31.0% vs 22.2%, P = 0.74). CONCLUSIONS: The BBB breakdown in NMOSD patients with MOG-IgG may be more common than in those with AQP4-IgG. AQP4-IgG-positive patients and MOG-IgG-positive patients with severe neurological disability tend to exhibit similar disruptions to the BBB.