Real-world experience of teriflunomide in relapsing multiple sclerosis: paramagnetic rim lesions may play a role.

Objectives: The aims of this study were to report the effectiveness and safety of teriflunomide in Chinese patients with relapsing-remitting multiple sclerosis (RRMS) and to explore the association of paramagnetic rim lesion (PRL) burden with patient outcome in the context of teriflunomide treatment and the impact of teriflunomide on PRL burden. Methods: This is a prospective observational study. A total of 100 RRMS patients treated with teriflunomide ≥3 months were included in analyzing drug persistence and safety. Among them, 96 patients treated ≥6 months were included in assessing drug effectiveness in aspects of no evidence of disease activity (NEDA) 3. The number and total volume of PRL were calculated in 76 patients with baseline susceptibility-weighted imaging (SWI), and their association with NEDA3 failure during teriflunomide treatment was investigated. Results: Over a treatment period of 19.7 (3.1-51.7) months, teriflunomide reduced annualized relapse rate (ARR) from 1.1 ± 0.8 to 0.3 ± 0.5, and Expanded Disability Status Scale (EDSS) scores remained stable. At month 24, the NEDA3% and drug persistence rate were 43.8% and 65.1%, respectively. In patients with a baseline SWI, 81.6% had at least 1 PRL, and 42.1% had ≥4 PRLs. The total volume of PRL per patient was 0.3 (0.0-11.5) mL, accounting for 2.3% (0.0%-49.0%) of the total T2 lesion volume. Baseline PRL number ≥ 4 (OR = 4.24, p = 0.009), younger onset age (OR = 0.94, p = 0.039), and frequent relapses in initial 2 years of disease (OR = 13.40, p = 0.026) were associated with NEDA3 failure. The PRL number and volume were not reduced (p = 0.343 and 0.051) after teriflunomide treatment for more than 24 months. No new safety concerns were identified in this study. Conclusion: Teriflunomide is effective in reducing ARR in Chinese patients with RRMS. Patients with less PRL burden, less frequent relapses, and relatively older age are likely to benefit more from teriflunomide, indicating that PRL might be a valuable measurement to inform clinical treatment decision.

Causal associations between prodromal infection and neuromyelitis optica spectrum disorder: A Mendelian randomization study.

BACKGROUND AND PURPOSE: Prodromal infections are associated with neuromyelitis optica spectrum disorder (NMOSD), but it remains unclear which type of infection has a causal association with NMOSD. We aimed to explore the causal associations between four herpesvirus infections (chickenpox, cold sores, mononucleosis and shingles) and NMOSD, as well as between other types of infections and NMOSD. METHODS: For data on infections, we used the genome-wide association study (GWAS) summary statistics from the 23andMe cohort. For outcomes, we used the GWAS data of participants of European ancestry, including 215 NMOSD patients (132 anti-aquaporin-4 antibody [AQP4-ab]-positive patients and 83 AQP4-ab-negative patients) and 1244 normal controls. Single-nucleotide polymorphism (SNP) identification and two-sample Mendelian randomization (MR) analyses were then performed. RESULTS: In the 23andMe cohort, we identified one SNP for chickenpox (rs9266089 in HLA-B gene), one SNP for cold scores (rs885950 in the POU5F1 gene), one SNP for mononucleosis (rs2596465 in the HCP5 gene), and three SNPs for shingles (rs2523591 in the HLA-B gene; rs7047299 in the IFNA21 gene; rs9260809 in the MICD gene). The association between cold sores and AQP4-ab-positive NMOSD reached statistical significance (odds ratio [OR] 745.318; 95% confidence interval [CI] 22.176, 25,049.53 [p < 0.001, Q < 0.001]). The association between shingles and AQP4-ab-positive NMOSD was also statistically significant (OR 21.073; 95% CI 4.271, 103.974 [p < 0.001, Q < 0.001]). No significant association was observed between other infections and AQP4-ab-positive or AQP4-ab-negative NMOSD. CONCLUSION: These findings suggest there are positive associations between cold sores and shingles and AQP4-ab-positive NMOSD, indicating there may be causal links between herpes simplex virus and varicella-zoster virus infection and AQP4-ab-positive NMOSD.

The immune imbalance between follicular regulatory and helper T cells in myelin oligodendrocyte glycoprotein IgG-associated disease.

Myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD) is a newly defined inflammatory demyelinating disease of the central nervous system. Currently, no immuno-modulatory treatment has been approved for MOGAD. We explored the function of follicular regularoty T (Tfr) and follicular helper T (Tfh) cells in patients with MOGAD. The number of circulating Tfr and Tfh cells and their expression of functional markers were accessed by flow cytometry. Circulating Tfr, Tfh, and B cells were further sorted and co-cultured in vitro to examine the influence of Tfr on Tfh-mediated B cell differentiation. In patients with MOGAD, the percentage of circulating PD-1hi Tfh cells elevated while the frequency of circulating activated Tfr cells decreased significantly. The Tfh/Tfr ratios positively correlated with the percentage of plasmblasts. In vitro, Tfh cells from patients with MOGAD exhibited a stronger capacity to promote the differentiation of plasmablasts through producing interleukin (IL)-21 than non-Tfh cells from patients, whereas Tfr cells suppressed this Tfh-mediated plasmablasts expansion, to a similar extent of IL-1 receptor antagonist (IL-1Ra). In conclusion, we revealed an immune imbalance of Tfr and Tfh cells in MOGAD. Tfr and IL-1Ra could be potential therapeutic targets in MOGAD.

Clinical feature and disease outcome in patients with myelin oligodendrocyte glycoprotein antibody-associated disorder: a Chinese study.

BACKGROUND: To identify factors associated with relapse risk and disability in myelin oligodendrocyte glycoprotein antibody-associated disorder (MOGAD). METHOD: Between 2016 and 2021, 186 patients with MOGAD were included in the study. Factors associated with a relapsing course, annualised relapse rate (ARR), recurrent relapses under different maintenance treatments and unfavourable disability outcome were analysed. RESULTS: MOGAD affects women (53.8%) slightly more often than men. After a median disease duration of 51.0 months, 60.2% (112/186) relapsed, with an overall ARR of 0.5. The ARR (0.6 vs 0.4, p=0.049), median Expanded Disability Status Scale (EDSS) score (1 (range 0-9.5) vs 1 (range 0-3.5), p=0.005) and Visual Functional System Score (VFSS) (0 (range 0-6) vs 0 (range 0-3), p=0.023) at last visit were higher in adults than in children, and time to first relapse was shorter in adults than in children (4.1 (range 1.0-111.0) vs 12.2 (range 1.3-266.8) months, p=0.001). Myelin oligodendrocyte glycoprotein antibody (MOG-ab) persistence over 1 year was associated with a relapsing course (OR 7.41, 95% CI 2.46 to 22.33, p=0.000), while timely maintenance therapy was associated with a lower ARR (p=0.008). More than four attacks (OR 4.86, 95% CI 1.65 to 14.28, p=0.004) and poor recovery from the first attack (OR 75.28, 95% CI 14.45 to 392.05, p=0.000) were associated with an unfavourable outcome (EDSS score ≥2 including VFSS ≥2). CONCLUSIONS: The results underscored the importance of timely maintenance treatment to prevent further relapses, especially in adult patients with persistently positive MOG-ab and unsatisfactory recovery from the onset attack.

Baseline retinal nerve fiber layer thickness as a predictor of multiple sclerosis progression: New insights from the FREEDOMS II study.

BACKGROUND AND PURPOSE: The aim was to evaluate the potential of retinal nerve fiber layer thickness (RNFLT) measured with optical coherence tomography in predicting disease progression in relapsing-remitting multiple sclerosis (RRMS). METHODS: Analyses were conducted post hoc of this 24-month, phase III, double-blind study, in which RRMS patients were randomized (1:1:1) to once daily oral fingolimod 0.5 mg, 1.25 mg or placebo. The key outcomes were the association between baseline RNFLT and baseline clinical characteristics and clinical/imaging outcomes up to 24 months. Change of RNFLT with fingolimod versus placebo within 24 months and time to retinal nerve fiber layer (RNFL) thinning were evaluated. RESULTS: Altogether 885 patients were included. At baseline, lower RNFLT was correlated with higher Expanded Disability Status Scale score (r = -1.085, p = 0.018), lower brain volume (r = 0.025, p = 0.006) and deep gray matter volume (r = 0.731, p < 0.0001), worse visual acuity (r = -19.846, p < 0.0001) and longer duration since diagnosis (r = -0.258, p = 0.018). At month 12, low baseline RNFLT (<86 µm) versus high baseline RNFLT (≥99 µm) was associated with a greater brain volume loss (percentage change -0.605% vs. -0.315%, p = 0.035) in patients without optic neuritis history. At month 24, low baseline RNFLT versus high baseline RNFLT was associated with a higher number of new or newly enlarged T2 lesions (mean number 4.0 vs. 2.8, p = 0.014) and a higher risk of subsequent RNFL thinning (hazard ratio 2.55; 95% confidence interval 1.84-3.53; p < 0.001). The atrophy of the RNFL in the inferior quadrant was alleviated with fingolimod 0.5 mg versus placebo at month 24 (Δ(least squares mean) = 1.8, p = 0.047). CONCLUSION: Retinal nerve fiber layer thickness could predict disease progression in RRMS. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT00355134, https://clinicaltrials.gov/ct2/show/NCT00355134.

Directed evolution of the fusion enzyme for improving astaxanthin biosynthesis in Saccharomyces cerevisiae.

The accumulation of the intermediate zeaxanthin and canthaxanthin in the astaxanthin biosynthesis pathway catalyzed by ß-carotene hydroxylase (crtZ) and ß-carotene ketolase (crtW) decreases the content of the astaxanthin. Here, we exploited directed evolution of the fusion of crtZ and crtW for improving astaxanthin biosynthesis in Saccharomyces cerevisiae. The results demonstrated that the fusion enzyme of crtZ-crtW with 2 X GGGGS peptides linker can effectively reduce the accumulation of intermediates and improves the content of astaxanthin. Compared with the control strain, the fusion enzyme of ketase and hydroxylase reduced zeaxanthin and canthaxanthin by 7 and 14 times and increased astaxanthin by 1.6 times, respectively. Moreover, 9 variant fusion mutants with improved astaxanthin production were generated through directed evolution. Combining these dominant mutants generated a variant, L95S + I206L, which increased the astaxanthin content of 3.8 times than the control strain. The AlphaFold2 assisted structural analysis indicated that these two mutations alter the interaction between the substrate and the enzymes pocket. Our research provided an efficient idea to reduce the accumulation of the intermediate products in complex biosynthesis pathway.

Analysis of Pregnancy-Related Attacks in Neuromyelitis Optica Spectrum Disorder: A Systematic Review and Meta-Analysis.

Importance: Risk of relapse may be increased in the postpartum period of neuromyelitis optica spectrum disorder (NMOSD). Information regarding factors associated with pregnancy-related attacks is still lacking. Objectives: To identify factors associated with pregnancy-related NMOSD attacks, investigate the integrated annualized relapse rate (ARR) and Expanded Disability Status Scale (EDSS) score in each phase of pregnancy, and summarize pregnancy outcomes and complications in patients with NMOSD. Data Sources: An electronic search was performed in the MEDLINE, PubMed in-process and non-MEDLINE, EMBASE, Web of Science, and Cochrane databases using the OvidSP search platform, updated through December 30, 2021. Study Selection: All published and unpublished studies in English were considered, covering all patients with NMOSD with an informative pregnancy. Data Extraction and Synthesis: Two independent reviewers extracted the published data with a standardized procedure following MOOSE and PRISMA guidelines. The end points were calculated with the DerSimonian and Laird inverse variance (for random effects) method. Main Outcomes and Measures: The primary outcome was the rate of pregnancies with pregnancy-related NMOSD attacks, measured by risk ratios (RRs). The mean differences (MDs) in ARR and EDSS scores between each phase of pregnancy, pregnancy outcomes, and complications were defined as the secondary outcomes. Results: A total of 15 studies were analyzed, including 443 patients with NMOSD with 639 informative pregnancies. Patients receiving immunosuppressive treatment during pregnancy (RR, 0.43; 95% CI, 0.32-0.57; P < .001) and with older age at conception (RR, 0.67; 95% CI, 0.47-0.95; P = .02) had lower rates of pregnancy with pregnancy-related attacks. The increase in the ARR was highest in the first trimester after delivery compared with before pregnancy (MD, 1.28; 95% CI, 0.94-1.62; P < .001). The EDSS scores increased significantly both during pregnancy (MD, 0.44; 95% CI, 0.20-0.69; P < .001) and in the postpartum period (MD, 0.88; 95% CI, 0.51-1.26; P < .001) compared with before pregnancy. Conclusions and Relevance: This systematic review and meta-analysis found that receiving immunosuppressive treatment during pregnancy and older age at conception were associated with reduced risk of pregnancy-related NMOSD attacks, which mostly occurred in the first trimester of the postpartum period, although more high-quality prospective studies are needed.

Deep learning-based relapse prediction of neuromyelitis optica spectrum disorder with anti-aquaporin-4 antibody.

Objective: We previously identified the independent predictors of recurrent relapse in neuromyelitis optica spectrum disorder (NMOSD) with anti-aquaporin-4 antibody (AQP4-ab) and designed a nomogram to estimate the 1- and 2-year relapse-free probability, using the Cox proportional hazard (Cox-PH) model, assuming that the risk of relapse had a linear correlation with clinical variables. However, whether the linear assumption fits real disease tragedy is unknown. We aimed to employ deep learning and machine learning to develop a novel prediction model of relapse in patients with NMOSD and compare the performance with the conventional Cox-PH model. Methods: This retrospective cohort study included patients with NMOSD with AQP4-ab in 10 study centers. In this study, 1,135 treatment episodes from 358 patients in Huashan Hospital were employed as the training set while 213 treatment episodes from 92 patients in nine other research centers as the validation set. We compared five models with added variables of gender, AQP4-ab titer, previous attack under the same therapy, EDSS score at treatment initiation, maintenance therapy, age at treatment initiation, disease duration, the phenotype of the most recent attack, and annualized relapse rate (ARR) of the most recent year by concordance index (C-index): conventional Cox-PH, random survival forest (RSF), LogisticHazard, DeepHit, and DeepSurv. Results: When including all variables, RSF outperformed the C-index in the training set (0.739), followed by DeepHit (0.737), LogisticHazard (0.722), DeepSurv (0.698), and Cox-PH (0.679) models. As for the validation set, the C-index of LogisticHazard outperformed the other models (0.718), followed by DeepHit (0.704), DeepSurv (0.698), RSF (0.685), and Cox-PH (0.651) models. Maintenance therapy was calculated to be the most important variable for relapse prediction. Conclusion: This study confirmed the superiority of deep learning to design a prediction model of relapse in patients with AQP4-ab-positive NMOSD, with the LogisticHazard model showing the best predictive power in validation.

The description of neuromyelitis optica spectrum disorder: Patient registry in Yangtze River Delta area of China.

OBJECTIVE: To describe the clinical features of neuromyelitis optica spectrum disorder (NMOSD) through patient registry in Yangtze River Delta area of China. METHODS: A total of 502 consecutive patients diagnosed with aquaporin-4 antibody (AQP4-ab)-positive NMOSD were registered between December 2018 to January 2021 in multiple tertiary referral centers within the framework of Yangtze River Delta of China. Their baseline data were reviewed, and follow-up clinical information were collected prospectively. RESULTS: The mean age at onset was 37.3 (range 3-80 years) years and the female-to-male ratio was 8.1:1. The median disease duration was 47 months (interquartile range [IQR] 25-84 months). A total of 1372 attacks of the 502 patients were recorded till the last follow-up, with a median annualized relapse rate of 0.4 (IQR 0.3-0.6). Nearly one-fourth (24.5%, 336/1372) of the attacks had prodromic events, including upper respiratory tract infection (36.3%, 122/336), fever (20.2%, 68/336) and pregnancy-related issues (17.9%, 60/336), etc. Myelitis was the most common attack type throughout the disease course (51.4%, 705/1372), followed by optic neuritis (ON, 43.1%, 592/1372). As for onset phenotype, ON (37.3%, 187/502) prevailed over myelitis (28.3%, 142/502). The median time to first relapse was 12 months (IQR 5-25 months). Patients with brainstem encephalitis at onset were more likely to have other anatomical region involved in subsequent attacks (p < 0.001), compared to other onset type. The median serum AQP4-ab titer measured by cell-based assays was 1:100 (IQR 1:32-1:320, range 1:10-1:10,000). The baseline AQP4-ab titer in cerebrospinal fluid (r = 0.542, p <0.001), overall ARR (r = 0.232, p< 0.001) and the EDSS scores at last follow-up (r = 0.119, p = 0.022) significantly correlated with baseline serum AQP4-ab titer. Antinuclear antibodies (48.4%), thyroid peroxidase antibodies (30.7%), and anti-SSA antibodies (26.2%) represented the most frequent concomitant antibodies, while autoimmune thyroid disorders (13.1%, 66/502) and Sjogren's syndrome (10.8%, 54/502) were the most common accompanying autoimmune diseases. Till the last follow-up, 403 patients received preventive treatments. Azathioprine represented the most common initial treatment, mycophenolate mofetil and rituximab was the most common second and third-line treatment, respectively. The EDSS score at the last follow-up ranged from 0 to 8.5 with a median of 2 (IQR 1-3). CONCLUSIONS: A comprehensive clinical picture of patients with AQP4-ab-positive NMOSD in Yangtze River Delta area of China was presented. More information on disease tragedy and predictive prognostic factors could be generated through long-term observations.

Neuromyelitis Optica Spectrum Disorder With Anti-Aquaporin-4 Antibody: Outcome Prediction Models.

Background: Recognizing the predictors of disease relapses in patients with anti-aquaporin-4 antibody (AQP4-ab)-positive neuromyelitis optica spectrum disorder (NMOSD) is essential for individualized treatment strategy. We aimed to identify the factors that predicted relapses among patients with AQP4-ab-positive NMOSD, develop outcome prediction models, and validate them in a multicenter validation cohort. Methods: Between January 2015 and December 2020, 820 patients with NMOSD were registered at Huashan Hospital. We retrospectively reviewed their medical records, and included 358 AQP4-ab-positive patients with 1135 treatment episodes. Univariate and multivariate analyses were used to explore the predictors of relapse, severe visual or motor disability during follow-up. A model predicting the 1- and 2-year relapse-free probability was developed and validated in an external validation cohort of 92 patients with 213 treatment episodes. Results: Lower serum AQP4-ab titer (< 1:100), higher Expanded Disability Status Scale (EDSS) score at onset (≥ 2.5), and use of intravenous methylprednisolone (IVMP) at the first attack predicted an overall lower annualized relapse rate. Older age (> 48 years), optic neuritis at onset, and higher onset EDSS score (≥ 2.5) significantly increased the risk for blindness, while IVMP at the first attack and maintenance therapy reduced the risk for blindness. Myelitis at onset increased the possibility of motor disability (EDSS ≥ 6.0), severe motor disability or death (EDSS ≥ 8.0), while maintenance therapy reduced these possibilities. Anderson and Gill model identified that the risk factors predicting recurrent relapses under certain treatment status were female gender, high AQP4-ab titer (≥ 1:100), previous attack under same therapy, lower EDSS score at treatment initiation (< 2.5), and no maintenance therapy or oral prednisone lasting less than 6 months. A nomogram using the above factors showed good discrimination and calibration abilities. The concordance indexes in the primary and validation cohort were 0.66 and 0.65, respectively. Conclusion: This study reports the demographic, clinical and therapeutic predictors of relapse, and severe visual or motor disability in NMOSD. Early identification of patients at risk of unfavorable outcomes is of paramount importance to inform treatment decisions.

Efficacy and safety of azathioprine, mycophenolate mofetil, and reduced dose of rituximab in neuromyelitis optica spectrum disorder.

BACKGROUND AND PURPOSE: Data regarding the efficacy and safety of currently widely available preventive therapies in neuromyelitis optica spectrum disorder (NMOSD) are needed. We compared the efficacy and safety of azathioprine (AZA), mycophenolate mofetil (MMF), and reduced dose of rituximab (RTX) in NMOSD based on a large multicenter retrospective cohort. METHODS: Patients with aquaporin 4 (AQP4) antibody-positive NMOSD with AZA (n = 167), MMF (n = 131), or RTX (n = 55) as initial preventive treatment were included. The main outcome was the occurrence of relapse after the initiation of immunotherapy. Secondary outcomes were annual relapse rate, disability accumulation, drug persistence, and adverse events. RESULTS: The median follow-up time of the 353 patients was 30.3 months. The regimen of RTX was 100 mg on Day 1 and 500 mg on Day 2, followed by 500 mg every 6 months. The proportions of patients with concomitant steroid therapy at baseline were 96.4%, 95.4%, and 76.4% in the AZA, MMF, and RTX groups. Risk of relapse was significantly reduced in patients treated with RTX compared with those treated with AZA (hazard ratio [HR] = 4.40, 95% confidence interval [CI] = 1.41-13.80, p = 0.011) or MMF (HR = 5.20, 95% CI = 1.60-16.86, p = 0.006) after adjusting for potential confounding variables. Drug discontinuations were less likely on RTX than AZA (HR = 2.22, 95% CI = 1.34-3.66, p = 0.002). RTX exhibited lower incidence of adverse events (32.7%) than AZA (62.3%, p < 0.001). CONCLUSIONS: We provide Class III evidence that reduced dose of RTX is superior to AZA and MMF as initial treatment to reduce the risk of relapse and is better tolerated than AZA in Chinese patients with AQP4 antibody-positive NMOSD.

Late onset neuromyelitis optica spectrum disorder with anti-aquaporin 4 and anti-myelin oligodendrocyte glycoprotein antibodies.

BACKGROUND AND PURPOSE: This study aimed to evaluate the clinical characteristics and prognosis of late onset (≥50 years) neuromyelitis optica spectrum disorder (LO-NMOSD), and compare them with those of early onset (<50 years) NMOSD (EO-NMOSD) and NMOSD with various antibody serostatuses. METHODS: From January 2015 to December 2020, 360 anti-aquaporin 4 antibody (AQP4-ab)-positive and 130 anti-myelin oligodendrocyte glycoprotein antibody (MOG-ab)-positive patients presented to the Huashan Hospital, China. We retrospectively reviewed their medical records, including the Expanded Disability Status Scale (EDSS) score at each visit and the annualized relapse rate (ARR). Prognostic outcomes included the time to first relapse, blindness, motor dysfunction, severe motor dysfunction, and death. Correlations between the age at onset, lesion location, and clinical parameters were analyzed. RESULTS: This study included 122 (24.9%) patients with LO-NMOSD, 101 with AQP4-ab and 21 with MOG-ab. Compared with EO-NMOSD patients, those with LO-NMOSD had higher EDSS scores and more frequent disease onset with transverse myelitis, blindness, motor dysfunction, and severe motor dysfunction. Compared with LO-NMOSD patients with MOG-ab, those with AQP4-ab had a worse prognosis. Age at disease onset had a significantly positive correlation with EDSS score at the last follow-up of all NMOSD patients, but a negative correlation with ARR-1 (ARR excluding the first attack, calculated from disease onset to final follow-up) in NMOSD patients with AQP4-ab. CONCLUSIONS: Patients with LO-NMOSD, especially those with AQP4-ab, had a worse prognosis compared with patients with EO-NMOSD. Age at disease onset and antibody serostatus predicted blindness and motor dysfunction.

Serum Neurofilament Light and GFAP Are Associated With Disease Severity in Inflammatory Disorders With Aquaporin-4 or Myelin Oligodendrocyte Glycoprotein Antibodies.

Objective: To evaluate the potential of serum neurofilament light (sNfL) and serum glial fibrillary acidic protein (sGFAP) as disease biomarkers in neuromyelitis optica spectrum disorder (NMOSD) with aquaporin-4 antibody (AQP4-ab) or myelin oligodendrocyte glycoprotein-antibody-associated disease (MOGAD). Methods: Patients with AQP4-ab-positive NMOSD (n = 51), MOGAD (n = 42), and relapsing-remitting multiple sclerosis (RRMS) (n = 31 for sNfL and n = 22 for sGFAP testing), as well as healthy controls (HCs) (n = 28), were enrolled prospectively. We assessed sNfL and sGFAP levels using ultrasensitive single-molecule array assays. Correlations of sNfL and sGFAP levels with clinical parameters were further examined in AQP4-ab-positive NMOSD and MOGAD patients. Results: sNfL levels were significantly higher in patients with AQP4-ab-positive NMOSD (median 17.6 pg/mL), MOGAD (27.2 pg/mL), and RRMS (24.5 pg/mL) than in HCs (7.4 pg/mL, all p < 0.001). sGFAP levels were remarkably increased in patients with AQP4-ab-positive NMOSD (274.1 pg/mL) and MOGAD (136.7 pg/mL) than in HCs (61.4 pg/mL, both p < 0.001). Besides, sGFAP levels were also significantly higher in patients with AQP4-ab-positive NMOSD compared to those in RRMS patients (66.5 pg/mL, p < 0.001). The sGFAP/sNfL ratio exhibited good discrimination among the three disease groups. sNfL levels increased during relapse in patients with MOGAD (p = 0.049) and RRMS (p < 0.001), while sGFAP levels increased during relapse in all three of the disease groups (all p < 0.05). Both sNfL and sGFAP concentrations correlated positively with Expanded Disability Status Scale scores in AQP4-ab-positive NMOSD (ß = 1.88, p = 0.018 and ß = 2.04, p = 0.032) and MOGAD patients (ß = 1.98, p = 0.013 and ß = 1.52, p = 0.008). Conclusion: sNfL and sGFAP levels are associated with disease severity in AQP4-ab-positive NMOSD and MOGAD patients, and the sGFAP/sNfL ratio may reflect distinct disease pathogenesis.

The Alteration of Circulating Lymphocyte Subsets During Tacrolimus Therapy in Neuromyelitis Optica Spectrum Disorder and Its Correlation With Clinical Outcomes.

OBJECTIVES: We aimed to explore the alteration of circulating lymphocyte subsets before and after tacrolimus (TAC) therapy in neuromyelitis optica spectrum disorder (NMOSD) and its correlation with clinical outcomes. METHODS: Anti-aquaporin-4 antibody (AQP4-ab)-positive patients with NMOSD treated with TAC were followed and clinically evaluated at 0, 3, 6, and 12 months after initiation of TAC. Flow cytometry was employed to detect the proportion of various whole blood lymphocyte subsets at every time point. Correlation analysis was further performed to explore the association between annualized relapse rate (ARR), the Expanded Disability Status Scale (EDSS) score, and the proportion of circulating lymphocyte subsets before and after TAC therapy. RESULTS: A total of 13 eligible patients with NMOSD were included. The proportion of CD19+CD24hiCD38hi/CD19+ and CD19+CD5+CD1dhi/CD19+ lymphocyte subsets increased significantly after TAC therapy (p = 0.010 and p < 0.001). The proportion of CD19+BAFFR+, CD19+IFN-γ+, and CD19+IL-10+ subsets decreased significantly after TAC therapy (p = 0.015, 0.018, and 0.042, respectively). There was a negative correlation between CD4+CD25hi subset and EDSS score (p = 0.016, r = -0.652). CONCLUSION: Possibly through increasing regulatory B and suppressing BAFFR+ B and interferon (IFN)-γ+ B subsets, TAC could decrease relapse. EDSS score may be correlated with some lymphocyte subsets after TAC therapy.

Low-dose tacrolimus in treating neuromyelitis optica spectrum disorder.

BACKGROUND: The value of tacrolimus (TAC) in neuromyelitis optica spectrum disorder (NMOSD) has not been fully demonstrated. In this study, we aimed to explore the effectiveness and safety of low-dose TAC in treating NMOSD. METHODS: Patients with NMOSD taking low-dose TAC were retrospectively collected. We compared the annualized relapse rate (ARR) before and after the initiation of TAC. Cox proportional hazards model was used to identify the risk factors of relapse during TAC treatment with their hazard ratio (HR). The effectiveness and safety of TAC were also compared with a group of patients on mycophenolate mofetil (MMF). RESULTS: A total of 42 NMOSD patients taking TAC were included, with the administered dose of 1-3mg/d. The ARR (1, 0-3) after the initiation of TAC decreased significantly compared to those before TAC treatment (0, 0-2, p < 0.001). The most common adverse events (AEs) observed included alopecia (23.8%), tremor (16.7%) and elevated blood glucose (11.9%). Multivariate Cox proportional hazards model exhibited that patients with higher baseline ARR (HR: 1.77, 0.76-4.16) and Expanded Disability Status Scale (EDSS) score (HR: 1.79, 1.20-2.68) were at a higher risk for relapse during TAC treatment (p = 0.188 and 0.004, respectively). We did not observe significant difference between TAC-treated and MMF-treated patients regarding the risk of relapse (p = 0.323). CONCLUSION: Low-dose TAC was an effective and tolerable choice in treating NMOSD.

Myelitis in inflammatory disorders associated with myelin oligodendrocyte glycoprotein antibody and aquaporin-4 antibody: A comparative study in Chinese Han patients.

BACKGROUND AND PURPOSE: Myelitis is an important clinical component of myelin oligodendrocyte glycoprotein antibody (MOG-ab)-associated disease (MOGAD) and aquaporin-4 antibody (AQP4-ab)-positive neuromyelitis optica spectrum disorder (NMOSD). The aim of this work was to evaluate the differentiating features of myelitis between the two diseases. METHODS: Myelitis-related clinical and radiologic data from 130 patients with MOGAD and 125 patients with AQP4-ab-positive NMOSD were retrospectively reviewed and compared. A scoring model was established to differentiate MOG-ab-associated myelitis from AQP4-ab-associated myelitis. RESULTS: Overall, 29.2% (38/130) of patients with MOGAD and 66.4% (83/125) of patients with AQP4-ab-positive NMOSD had ever experienced myelitis. Compared with those with NMOSD, patients with MOGAD exhibited a lower frequency of myelitis, either during the first episode (p < 0.0001) or throughout the disease duration (p < 0.0001). Compared with AQP4-ab-associated myelitis, MOG-ab-associated myelitis manifested a higher male-to-female ratio (p < 0.0001), younger age at disease onset (p = 0.0004), more prodromic influenza-like symptoms (p = 0.030), more prodromic fever (p = 0.0003), more bowel and bladder dysfunction (p = 0.011), less painful tonic spasms (p < 0.0001), and lower Expanded Disability Status Scale scores after treatment (p < 0.0001). On magnetic resonance imaging, lower spinal cord lesions (p = 0.023), short-segment lesions (p = 0.021), conus involvement (p = 0.0001), and H sign (p < 0.0001) were more common in MOG-ab-associated myelitis. A scoring model with a cutoff value of 4 differentiated MOG-ab-associated myelitis from AQP4-ab-associated myelitis with a sensitivity of 87.9% and a specificity of 90.1%. CONCLUSIONS: Myelitis was less commonly observed in MOGAD and exhibited distinct features compared to those of AQP4-ab-positive NMOSD.

Neuromyelitis optica spectrum disorder in China: Quality of life and medical care experience.

BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) is considered to be the most common subset of CNS inflammatory demyelinating diseases in China. We aimed to systematically evaluate the impact of NMOSD on Chinese patients' quality of life (QoL), medical care experience, family wellness and social life. METHODS: A cross-sectional survey was performed involving 210 mostly AQP4-IgG-positive NMOSD patients from 25 provinces across China. An established survey instrument specific for NMOSD developed by The Guthy-Jackson Charitable Foundation and the Multiple Sclerosis Quality of Life-54 scale were implemented. Pearson or Spearman Correlation analysis was performed to define the significant determinants of QoL. RESULTS: More than 70% of the participants carried an initial diagnosis other than NMOSD, most of the patients were initially diagnosed with idiopathic optic neuritis (43.6%), multiple sclerosis (19.5%), gastrointestinal disorders (11.0%) and depression (10.0%). The average time elapsed between the first symptoms and accurate NMOSD diagnosis was 2.4 ± 4.9 years. Sixty-one percent of the participants reported NMOSD imposing a great negative impact on their life quality. NMOSD worsened both physical and emotional health (Short Form-36 physical health score: 37.9 ± 43.7, emotional health score: 44.8 ± 44.3). Visual impairment, pain, and bowel and bladder dysfunction were the greatest negative physical determinants of overall QoL. Worsened physical health was associated with diminished emotional health (r = 0.71, p < 0.001), and also with an interference in the ability to work (r = 0.41, p < 0.001). Only a small portion (3.3%) of the patients exhibited psychological resilience (with poor physical health but very robust emotional health). NMOSD significantly influenced the decision to have children in the study cohort, especially in the younger generation (r = -0.476, p < 0.001). Non-specific oral immunosuppressants were the most common preventive treatments, and only 13.9% received rituximab treatment. More than half (55.7%) of the patients reported dissatisfaction with current treatment options. A large proportion (88.1%) of the participants reported health insurance insufficient to pay all disease-related costs. Both concerns about treatment and about financial burden contributed to diminished QoL. CONCLUSIONS: This investigation yields novel insights into the physical, emotional, and socioeconomic impact of NMOSD on Chinese patients, which may afford potentially modifiable aspects of personal or clinical care to improve the patients' QoL, as well as serve as baseline data to reflect how future standard treatments will change patients' life quality.

Neuromyelitis optica spectrum disorder: pregnancy-related attack and predictive risk factors.

OBJECTIVES: To investigate the influence of pregnancy on patients with neuromyelitis optica spectrum disorder (NMOSD) and to identify risk factors that predict pregnancy-related attack. METHODS: From January 2015 to April 2019, 418 female patients with NMOSD were registered at Huashan Hospital. We retrospectively reviewed their medical records and identified 110 patients with 136 informative pregnancies, of whom 83 were aquaporin-4 antibody (AQP4-ab)-positive and 21 were myelin oligodendrocyte glycoprotein-antibody-positive. Pregnancy-related attack was defined as an attack that occurred during pregnancy or within 1 year after delivery/abortion. We compared annualised relapse rate (ARR) during 12 months before pregnancy with that during every trimester of pregnancy and after delivery/abortion. Multivariate analyses were used to explore the independent risk factors involved and a nomogram was generated for the prediction of pregnancy-related attack. Thirty-five female patients from 3 other centres formed an external cohort to validate this nomogram. RESULTS: ARR increased significantly during the first trimester after delivery (p<0.001) or abortion (p=0.019) compared with that before pregnancy. Independent risk factors predicting pregnancy-related attack included age at delivery/abortion (20-26.5, p=0.018; 26.5-33, p=0.001), AQP4-ab titre (≥1:100, p=0.049) and inadequate treatment during pregnancy and postpartum period (p=0.004). The concordance index of nomogram was 0.87 and 0.77 using bootstrap resampling in internal and external validation. CONCLUSIONS: The first trimester post partum is a high-risk period for NMOSD recurrence. Patients with younger age, higher AQP4-ab titre and inadequate treatment are at higher risk for pregnancy-related attack.

The imbalance between regulatory and memory B cells accompanied by an increased number of circulating T-follicular helper cells in MOG-antibody-associated demyelination.

OBJECTIVE: To explore the alteration of T and B lymphocyte subsets proportions in myelin oligodendrocyte glycoprotein (MOG)-antibody-associated demyelination. METHODS: 19 MOG-antibody-positive, 25 AQP4-antibody-positive and 25 double-negative NMOSD patients in the acute phase of the diseases were included in the study, as well as 29 healthy controls. The frequencies of different lymphocyte subsets, including CD19+CD27+ memory B cells, CD19+CD24hiCD38hi, and CD19+CD5+CD1dhi regulatory B cells, IFN-γexpressing B cells, IL-10 expressing B cells and CD4+CXCR5+ICOS+T-follicular helper cells (TFH) were measured via flow cytometry and compared among the four groups. RESULTS: The frequencies of CD19+CD24hiCD38hi, CD19+CD5+CD1dhi regulatory B cells as well as the IL-10 expressing B cells were significantly lower in the MOG-antibody-associated demyelination compared to the healthy controls, whereas the frequencies of CD19+CD27+ memory B cells were significantly higher in the MOG-antibody-positive group. The frequencies of TFH were significantly higher in the MOG-antibody-positive group as compared to the healthy controls. No significant difference was detected in the above mentioned lymphocytic profile between the MOG-antibody-positive and the AQP4-antibody-positive groups. CONCLUSIONS: The immuno-regulatory functions of B cells were significantly impaired whereas TFH cells were markedly increased in the acute phase of MOG-antibody-associated demyelination. Despite having distinct clinical features, MOG-antibody-associated demyelination shared a similar lymphocytic profile with AQP4-antibody-positive NMOSD in the acute relapse phase.

Peripapillary and parafoveal vascular network assessment by optical coherence tomography angiography in aquaporin-4 antibody-positive neuromyelitis optica spectrum disorders.

BACKGROUND/AIMS: Current understanding of the alterations in the retinal vascular network in neuromyelitis optica spectrum disorders (NMOSDs) is limited. We aim to assess the peripapillary and parafoveal vessel density in aquaporin-4 antibody-positive NMOSD patients by optical coherence tomography (OCT) angiography. METHODS: A total of 55 aquaporin-4 antibody-positive NMOSD patients with or without a history of optic neuritis (ON) and 33 healthy controls underwent spectral domain OCT and OCT angiography. Clinical histories, Expanded Disability Status Scale score, visual functional system score (VFSS) and disease duration were collected. RESULTS: Peripapillary and parafoveal vessel density was significantly decreased in NMOSD eyes with or without a history of ON. The decrease in retinal vessel density could occur before ON and retinal nerve fibre layer (RNFL) atrophy. Peripapillary vessel density correlated well with the spectral domain OCT measurements and VFSS in NMOSD eyes with a history of ON. CONCLUSION: Subclinical primary retinal vasculopathy may occur in NMOSD prior to ON and RNFL atrophy. Peripapillary vessel density might be a sensitive predictor of visual outcomes in NMOSD patients with ON.