Impact of rituximab treatment regime on time to relapse in aquaporin-4 antibody positive neuromyelitis optica spectrum disorder.

BACKGROUND: Aquaporin-4 (AQP4) antibody associated neuromyelitis optica (NMOSD) requires long-term immunosuppression. Rituximab is increasingly used worldwide, however the optimal regime is not established. METHODS: We retrospectively examined different rituximab regimens in AQP4-NMOSD. Standard monotherapy (SM; 6 monthly infusions), SM plus oral steroids (SM+S), extended interval dosing (EID; guided by CD19 repopulation) and EID with oral steroids (EID+S) were compared. The primary outcome was time to first clinical relapse. Potential confounders including age, gender, number of previous relapses, and onset phenotype were included. RESULTS: 77 patients were included: 67 females, median onset age 35.6, median DSS at rituximab initiation 5.0. 39 were on SM+S, 20 SM, 6 EID, and 12 EID+S. 25/77 patients relapsed during a median follow-up of 44.0 months. No significant difference in time to first relapse was observed between any rituximab regimen. Pooled analyses to compare regimens that use standard monotherapy (SM and SM+S) against those that use extended interval dosing (EID and EID+S) showed no significant difference. Pooled analysis of regimens using steroids with those not using steroids also showed no significant difference. Adjusted Cox proportional hazard model revealed no significant difference between rituximab regimens or influence of demographic factors. 9 significant adverse events were recorded, 5 in the SM group and 4 in SM+S. CONCLUSIONS: This study provides some basis for further exploring EID as a viable option for long term treatment of AQP4-NMOSD. This may improve patient experience and consolidate use of hospital resources.

Predictors of azathioprine and mycophenolate mofetil response in patients with neuromyelitis optica spectrum disorder: A cohort study.

BACKGROUND: Relapse rates of 47 % have been reported in patients with neuromyelitis optica (NMOSD) using Azathioprine (AZA) and mycophenolate mofetil (MMF). Prediction of non-responders could help determine which patients are most likely to benefit from newer monoclonal antibody treatments from the outset. OBJECTIVES: To identify predictors of AZA and MMF treatment response in NMOSD. METHODS: Multicenter cohort study of NMOSD patients from Brazil and the United Kingdom, treated with AZA and MMF. An unsatisfactory response was defined as one severe or two non-severe attacks in a year. Cox regression was used to identify predictive factors of unsatisfactory response to AZA and MMF. RESULTS: 103 NMOSD patients, mean age 38 years, 83% female, and 65% of Black ethnic group were included. An unsatisfactory IS response was observed in 42% of patients over 2.5 years (IQR 1.0-8.8) years. A severe preceding attack was more common in non-responders (31.1% x 76.7%, p = <0.001). In multivariable analysis, severe attack (RR 3.13; 95 % CI 1.37-7.18, p = 0.007) or higher annualized relapse rate (RR 4.84; 95 % CI 2.01-11.65, p = < 0.001) predicted an unsatisfactory response. Interestingly, Black NMOSD patients had a lower risk of poor response (RR 0.39, 95 % CI 0.17-0.85, p = 0.019). CONCLUSION: Severe attack and a higher annualized relapse rate before AZA or MMF initiation were associated with an unsatisfactory IS response. In patients with these characteristics, treatment with higher-efficacy drugs should be considered from the outset.

The absence of antibodies in longitudinally extensive transverse myelitis may predict a more favourable prognosis.

BACKGROUND: Isolated first episodes of longitudinally extensive transverse myelitis (LETM) have typically been associated with neuromyelitis optica spectrum disorder (NMOSD) or myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). However, in some cases, serological testing and screening for other aetiologies are negative, a condition referred to as double seronegative longitudinally extensive transverse myelitis (dsLETM). OBJECTIVE: The objective of this study was to evaluate comparative outcomes of dsLETM, MOGAD-LETM and NMOSD-LETM. METHODS: Cohort study of LETM cases seen in the UK NMOSD Highly Specialised Service between January 2008 and March 2022. RESULTS: LETM = 87 cases were identified (median onset age = 46 years (15-85); median follow-up = 46 months (1-144); 47% NMOSD-LETM = 41 (aquaporin-4 antibodies (AQP4-IgG) positive = 36), 20% MOGAD-LETM = 17 and 33% dsLETM = 29). Despite similar Expanded Disability Status Scale (EDSS) at nadir, last EDSS was higher in AQP4-IgG and seronegative NMOSD-LETM (sNMOSD) (p = 0.006). Relapses were less common in dsLETM compared to AQP4-IgG NMOSD-LETM and sNMOSD-LETM (19% vs 60% vs 100%; p = 0.001). Poor prognosis could be predicted by AQP4-IgG (odds ratio (OR) = 38.86 (95% confidence interval (CI) = 1.36-1112.86); p = 0.03) and EDSS 3 months after onset (OR = 65.85 (95% CI = 3.65-1188.60); p = 0.005). CONCLUSION: dsLETM remains clinically challenging and difficult to classify with existing nosological terminology. Despite a similar EDSS at nadir, patients with dsLETM relapsed less and had a better long-term prognosis than NMOSD-LETM.

Timing of MOG-IgG Testing Is Key to 2023 MOGAD Diagnostic Criteria.

BACKGROUND AND OBJECTIVES: Myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD) is a recently identified autoimmune demyelinating disorder of the CNS affecting both adults and children. Diagnostic criteria for MOGAD have recently been published. We aimed to validate the 2023 MOGAD diagnostic criteria in a real-world cohort of patients with atypical CNS inflammation. METHODS: All patients referred to the National neuromyelitis optica spectrum disorder (NMOSD) specialized service at The Walton Center NHS Foundation Trust between 2012 and 2023 with an atypical demyelinating syndrome were evaluated. We systematically applied the 2023 MOGAD diagnostic criteria and previous 2018 International Diagnostic Recommendations for MOG encephalomyelitis to our retrospective cohort. RESULTS: 474 patients were screened and 66 were excluded for lack of clinical information. Preexisting diagnoses within our cohort included the following: MOGAD, n = 127; AQP4-IgG NMOSD, n = 125; seronegative NMOSD, n = 33; multiple sclerosis (MS), n = 10; and other diagnoses, n = 113. Of patients with preexisting MOGAD, 97% (123/127) fulfilled the 2023 MOGAD diagnostic criteria. Three patients with a low-positive MOG-IgG did not meet supportive features though 2/3 had insufficient investigations. Alternative diagnoses could not be excluded in 1 patient with MS-MOGAD overlap. No patients with a non-MOGAD diagnosis were found to fulfill the 2023 diagnostic criteria. The sensitivity and specificity of the 2023 MOGAD diagnostic criteria were 97% and 100% with no false positives, improving on 2018 International Diagnostic Recommendations for MOG encephalomyelitis. Low-positive MOG-IgG results were more often associated with a longer time from disease onset to sampling (p < 0.001). In addition, in patients with a MOG-IgG1 test within 6 months of clinical onset, approximately 25% can become low positive by 6 months. Of patients with preexisting MOGAD, 9% (12/127) had insufficient investigations and examinations to fully evaluate additional supportive features. However, in those who were completely evaluated, supportive features were fulfilled in 97% (111/115). DISCUSSION: The 2023 MOGAD diagnostic criteria were highly sensitive and specific and closely align with historically established cases of MOGAD. However, because additional supportive features are stipulated for patients with a low-positive MOG-IgG result, missed diagnoses may occur due to delayed testing or insufficient investigations.

Risks and outcomes of pregnancy in neuromyelitis optica spectrum disorder: A comprehensive review.

Neuromyelitis optica spectrum disorder (NMOSD) is a rare central nervous system autoimmune disease. Aquaporin-4 antibody (AQP4-IgG) is present in over 75% of cases and criteria also exist for the diagnosis of seronegative NMOSD. AQP4-IgG NMOSD has a strong female predominance (9:1 ratio), with a median onset age of 40 years. Pregnancy in those with NMOSD is therefore an important topic. Fecundity in NMOSD is likely impaired, and for females who conceive, obstetric complications including miscarriages and pre-eclampsia are significantly higher in NMOSD compared to the general population and in related conditions such as multiple sclerosis (MS). In contrast to MS, NMOSD disease activity does not subside during pregnancy. Also, relapse risk substantially rises above pre-pregnancy rates in the early postpartum period. In view of the evolving landscape of NMOSD, we provide a contemporary update of the impacts of pregnancy in NMOSD.

A comprehensive review of the advances in neuromyelitis optica spectrum disorder.

Neuromyelitis optica spectrum disorder (NMOSD) is a rare relapsing neuroinflammatory autoimmune astrocytopathy, with a predilection for the optic nerves and spinal cord. Most cases are characterised by aquaporin-4-antibody positivity and have a relapsing disease course, which is associated with accrual of disability. Although the prognosis in NMOSD has improved markedly over the past few years owing to advances in diagnosis and therapeutics, it remains a severe disease. In this article, we review the evolution of our understanding of NMOSD, its pathogenesis, clinical features, disease course, treatment options and associated symptoms. We also address the gaps in knowledge and areas for future research focus.

Do we still need OCBs in MS diagnosis and how many?

BACKGROUND: CSF-specific oligoclonal bands (CSF-OCBs) can be used for dissemination in time (DIT) in the 2017 multiple sclerosis (MS) diagnostic criteria. A cut-off of ≥2 CSF-OCBs was recommended but studies have suggested ≥3 CSF-OCBs may be superior. OBJECTIVES: To assess utility of ≥2 and ≥3 CSF-OCBs as a cut-off for MS diagnosis. METHODS: Paired serum and CSF-OCBs sent to the Walton Centre, UK between July 2018 and June 2020 were included. CSF-OCBs were assessed using isoelectric focussing and reviewed by two blinded raters. Case records were reviewed. RESULTS: Of 1334 paired serum and CSF-OCB requests, 945 cases had sufficient clinical information. More than 1 CSF-OCB was detected in 268/945(28%) cases. Of these, 252 had ≥2 and 230 had ≥3 CSF-OCBs. The sensitivity and specificity for MS with ≥2 and ≥3 CSF-OCBs were 91.7%, 91.2%, 90.2% and 93.8% respectively. Only 3/22 patients with 2 CSF-OCBs had MS. In 25% of patients, CSF-OCBs reduced time to MS diagnosis (median 437.5 days (28-1332)). CONCLUSION: Although cut-offs of ≥2 or ≥3 CSF-OCBs performed similarly well, 2 CSF-OCBs were frequently seen with non-inflammatory pathology. Use of ≥3 CSF-OCBs for MS diagnosis should be considered. CSF analysis reduced time to MS diagnosis by approximately 14 months.

IgG1-3 MuSK Antibodies Inhibit AChR Cluster Formation, Restored by SHP2 Inhibitor, Despite Normal MuSK, DOK7, or AChR Subunit Phosphorylation.

BACKGROUND AND OBJECTIVES: Up to 50% of patients with myasthenia gravis (MG) without acetylcholine receptor antibodies (AChR-Abs) have antibodies to muscle-specific kinase (MuSK). Most MuSK antibodies (MuSK-Abs) are IgG4 and inhibit agrin-induced MuSK phosphorylation, leading to impaired clustering of AChRs at the developing or mature neuromuscular junction. However, IgG1-3 MuSK-Abs also exist in MuSK-MG patients, and their potential mechanisms have not been explored fully. METHODS: C2C12 myotubes were exposed to MuSK-MG plasma IgG1-3 or IgG4, with or without purified agrin. MuSK, Downstream of Kinase 7 (DOK7), and ßAChR were immunoprecipitated and their phosphorylation levels identified by immunoblotting. Agrin and agrin-independent AChR clusters were measured by immunofluorescence and AChR numbers by binding of 125I-α-bungarotoxin. Transcriptomic analysis was performed on treated myotubes. RESULTS: IgG1-3 MuSK-Abs impaired AChR clustering without inhibiting agrin-induced MuSK phosphorylation. Moreover, the well-established pathway initiated by MuSK through DOK7, resulting in ßAChR phosphorylation, was not impaired by MuSK-IgG1-3 and was agrin-independent. Nevertheless, the AChR clusters did not form, and both the number of AChR microclusters that precede full cluster formation and the myotube surface AChRs were reduced. Transcriptomic analysis did not throw light on the pathways involved. However, the SHP2 inhibitor, NSC-87877, increased the number of microclusters and led to fully formed AChR clusters. DISCUSSION: MuSK-IgG1-3 is pathogenic but seems to act through a noncanonical pathway. Further studies should throw light on the mechanisms involved at the neuromuscular junction.

Do Early Relapses Predict the Risk of Long-Term Relapsing Disease in an Adult and Paediatric Cohort with MOGAD?

OBJECTIVE: Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) can be monophasic or relapsing, with early relapse being a feature. However, the relevance of early relapse on longer-term relapse risk is unknown. Here, we investigate whether early relapses increase longer-term relapse risk in patients with MOGAD. METHODS: A retrospective analysis of 289 adult- and pediatric-onset patients with MOGAD followed for at least 2 years in 6 specialized referral centers. "Early relapses" were defined as attacks within the first 12 months from onset, with "very early relapses" defined within 30 to 90 days from onset and "delayed early relapses" defined within 90 to 365 days. "Long-term relapses" were defined as relapses beyond 12 months. Cox regression modeling and Kaplan-Meier survival analysis were used to estimate the long-term relapse risk and rate. RESULTS: Sixty-seven patients (23.2%) had early relapses with a median number of 1 event. Univariate analysis revealed an elevated risk for long-term relapses if any "early relapses" were present (hazard ratio [HR] = 2.11, p < 0.001), whether occurring during the first 3 months (HR = 2.70, p < 0.001) or the remaining 9 months (HR = 1.88, p = 0.001), with similar results yielded in the multivariate analysis. In children with onset below aged 12 years, only delayed early relapses were associated with an increased risk of long-term relapses (HR = 2.64, p = 0.026). INTERPRETATION: The presence of very early relapses and delayed early relapses within 12 months of onset in patients with MOGAD increases the risk of long-term relapsing disease, whereas a relapse within 90 days appears not to indicate a chronic inflammatory process in young pediatric-onset disease. ANN NEUROL 2023;94:508-517.

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

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

International Delphi Consensus on the Management of AQP4-IgG+ NMOSD: Recommendations for Eculizumab, Inebilizumab, and Satralizumab.

BACKGROUND AND OBJECTIVES: Neuromyelitis optica spectrum disorder (NMOSD) is a rare debilitating autoimmune disease of the CNS. Three monoclonal antibodies were recently approved as maintenance therapies for aquaporin-4 immunoglobulin G (AQP4-IgG)-seropositive NMOSD (eculizumab, inebilizumab, and satralizumab), prompting the need to consider best practice therapeutic decision-making for this indication. Our objective was to develop validated statements for the management of AQP4-IgG-seropositive NMOSD, through an evidence-based Delphi consensus process, with a focus on recommendations for eculizumab, inebilizumab, and satralizumab. METHODS: We recruited an international panel of clinical experts in NMOSD and asked them to complete a questionnaire on NMOSD management. Panel members received a summary of evidence identified through a targeted literature review and provided free-text responses to the questionnaire based on both the data provided and their clinical experience. Responses were used to generate draft statements on NMOSD-related themes. Statements were voted on over a maximum of 3 rounds; participation in at least 1 of the first 2 rounds was mandatory. Panel members anonymously provided their level of agreement (6-point Likert scale) on each statement. Statements that failed to reach a predefined consensus threshold (≥67%) were revised based on feedback and then voted on in the next round. Final statements were those that met the consensus threshold (≥67%). RESULTS: The Delphi panel comprised 24 experts, who completed the Delphi process in November 2021 after 2 voting rounds. In round 1, 23/25 statements reached consensus and were accepted as final. The 2 statements that failed to reach consensus were revised. In round 2, both revised statements reached consensus. Twenty-five statements were agreed in total: 11 on initiation of or switching between eculizumab, inebilizumab, and satralizumab; 3 on monotherapy/combination therapy; 7 on safety and patient population considerations; 3 on biomarkers/patient-reported outcomes; and 1 on research gaps. DISCUSSION: An established consensus method was used to develop statements relevant to the management of AQP4-IgG-seropositive NMOSD. These international statements will be valuable for informing individualized therapeutic decision-making and could form the basis for standardized practice guidelines.

Diagnostic value of intereye difference metrics for optic neuritis in aquaporin-4 antibody seropositive neuromyelitis optica spectrum disorders.

BACKGROUND: The novel optic neuritis (ON) diagnostic criteria include intereye differences (IED) of optical coherence tomography (OCT) parameters. IED has proven valuable for ON diagnosis in multiple sclerosis but has not been evaluated in aquaporin-4 antibody seropositive neuromyelitis optica spectrum disorders (AQP4+NMOSD). We evaluated the diagnostic accuracy of intereye absolute (IEAD) and percentage difference (IEPD) in AQP4+NMOSD after unilateral ON >6 months before OCT as compared with healthy controls (HC). METHODS: Twenty-eight AQP4+NMOSD after unilateral ON (NMOSD-ON), 62 HC and 45 AQP4+NMOSD without ON history (NMOSD-NON) were recruited by 13 centres as part of the international Collaborative Retrospective Study on retinal OCT in Neuromyelitis Optica study. Mean thickness of peripapillary retinal nerve fibre layer (pRNFL) and macular ganglion cell and inner plexiform layer (GCIPL) were quantified by Spectralis spectral domain OCT. Threshold values of the ON diagnostic criteria (pRNFL: IEAD 5 µm, IEPD 5%; GCIPL: IEAD: 4 µm, IEPD: 4%) were evaluated using receiver operating characteristics and area under the curve (AUC) metrics. RESULTS: The discriminative power was high for NMOSD-ON versus HC for IEAD (pRNFL: AUC 0.95, specificity 82%, sensitivity 86%; GCIPL: AUC 0.93, specificity 98%, sensitivity 75%) and IEPD (pRNFL: AUC 0.96, specificity 87%, sensitivity 89%; GCIPL: AUC 0.94, specificity 96%, sensitivity 82%). The discriminative power was high/moderate for NMOSD-ON versus NMOSD-NON for IEAD (pRNFL: AUC 0.92, specificity 77%, sensitivity 86%; GCIP: AUC 0.87, specificity 85%, sensitivity 75%) and for IEPD (pRNFL: AUC 0.94, specificity 82%, sensitivity 89%; GCIP: AUC 0.88, specificity 82%, sensitivity 82%). CONCLUSIONS: Results support the validation of the IED metrics as OCT parameters of the novel diagnostic ON criteria in AQP4+NMOSD.

Visual Outcomes Following Plasma Exchange for Optic Neuritis: An International Multicenter Retrospective Analysis of 395 Optic Neuritis Attacks.

PURPOSE: To evaluate the effectiveness of plasma exchange (PLEX) for optic neuritis (ON). METHODS: We conducted an international multicenter retrospective study evaluating the outcomes of ON following PLEX. Outcomes were compared to raw data from the Optic Neuritis Treatment Trial (ONTT) using a matched subset. RESULTS: A total of 395 ON attack treated with PLEX from 317 patients were evaluated. The median age was 37 years (range 9-75), and 71% were female. Causes of ON included multiple sclerosis (108), myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) (92), aquaporin-4-IgG-positive neuromyelitis optica spectrum disorder (AQP4+NMOSD) (75), seronegative-NMOSD (34), idiopathic (83), and other (3). Median time from onset of vision loss to PLEX was 2.6 weeks (interquartile range [IQR], 1.4-4.0). Median visual acuity (VA) at the time of PLEX was count fingers (IQR, 20/200-hand motion), and median final VA was 20/25 (IQR, 20/20-20/60) with no differences among etiologies except MOGAD-ON, which had better outcomes. In 81 (20.5%) ON attacks, the final VA was 20/200 or worse. Patients with poor outcomes were older (P = .002), had worse VA at the time of PLEX (P < .001), and longer delay to PLEX (P < .001). In comparison with the ONTT subset with severe corticosteroid-unresponsive ON, a final VA of worse than 20/40 occurred in 6 of 50 (12%) PLEX-treated ON vs 7 of 19 (37%) from the ONTT treated with intravenous methylprednisolone without PLEX (P = .04). CONCLUSION: Most ON attacks improved with PLEX, and outcomes were better than attacks with similar severity in the ONTT. The presence of severe vision loss at nadir, older age, and longer delay to PLEX predicted a worse outcome whereas MOGAD-ON had a more favorable prognosis. NOTE: Publication of this article is sponsored by the American Ophthalmological Society.

Acute Inflammatory Diseases of the Central Nervous System After SARS-CoV-2 Vaccination.

BACKGROUND AND OBJECTIVES: Acute inflammatory CNS diseases include neuromyelitis optica spectrum disorders (NMOSDs) and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). Both MOGAD and acute disseminated encephalomyelitis (ADEM) have been reported after vaccination. Consequently, the mass SARS-CoV-2 vaccination program could result in increased rates of these conditions. We described the features of patients presenting with new acute CNS demyelination resembling NMOSDs or MOGAD within 8 weeks of SARS-CoV-2 vaccination. METHODS: The study included a prospective case series of patients referred to highly specialized NMOSD services in the UK from the introduction of SARS-CoV-2 vaccination program up to May 2022. Twenty-five patients presented with new optic neuritis (ON) and/or transverse myelitis (TM) ± other CNS inflammation within 8 weeks of vaccination with either AstraZeneca (ChAdOx1S) or Pfizer (BNT162b2) vaccines. Their clinical records and paraclinical investigations including MRI scans were reviewed. Serologic testing for antibodies to myelin oligodendrocyte glycoprotein (MOG) and aquaporin 4 (AQP4) was performed using live cell-based assays. Patients' outcomes were graded good, moderate, or poor based on the last clinical assessment. RESULTS: Of 25 patients identified (median age 38 years, 14 female), 12 (48%) had MOG antibodies (MOGIgG+), 2 (8%) had aquaporin 4 antibodies (AQP4IgG+), and 11 (44%) had neither. Twelve of 14 (86%) antibody-positive patients received the ChAdOx1S vaccine. MOGIgG+ patients presented most commonly with TM (10/12, 83%), frequently in combination with ADEM-like brain/brainstem lesions (6/12, 50%). Transverse myelitis was longitudinally extensive in 7 of the 10 patients. A peak in new MOGAD cases in Spring 2021 was attributable to postvaccine cases. Both AQP4IgG+ patients presented with brain lesions and TM. Four of 6 (67%) seronegative ChAdOx1S recipients experienced longitudinally extensive TM (LETM) compared with 1 of 5 (20%) of the BNT162b2 group, and facial nerve inflammation was reported only in ChAdOx1S recipients (2/5, 40%). Guillain-Barre syndrome was confirmed in 1 seronegative ChAdOx1S recipient and suspected in another. DISCUSSION: ChAdOx1S was associated with 12/14 antibody-positive cases, the majority MOGAD. MOGAD patients presented atypically, only 2 with isolated ON (1 after BNT162b2 vaccine) but with frequent ADEM-like brain lesions and LETM. Within the seronegative group, phenotypic differences were observed between ChAdOx1S and BNT162b2 recipients. These observations might support a causative role of the ChAdOx1S vaccine in inflammatory CNS disease and particularly MOGAD. Further study of this cohort could provide insights into vaccine-associated immunopathology.

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

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

Progressive myelin oligodendrocyte glycoprotein-associated demyelination mimicking leukodystrophy.

BACKGROUND: Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) may be associated with relapsing disease, but clinical progression independent of relapse activity is rare. OBJECTIVES: To report progressive disease in a patient with MOGAD. METHODS: A single retrospective case report. RESULTS: At 4 years of age, the patient had a single episode of acute disseminated encephalomyelitis. She remained well until age 17 years but over the next 9 years developed progressive spastic quadriparesis, cognitive and bulbar dysfunction. Brain imaging showed a leukodystrophy-like pattern of white matter abnormality with contrast enhancement at different time points. Myelin oligodendrocyte glycoprotein (MOG)-IgG was repeatedly positive by live cell-based assay. CONCLUSION: Secondary progression may be a rare presentation of MOG-IgG-associated disease.

Association of Maintenance Intravenous Immunoglobulin With Prevention of Relapse in Adult Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease.

Importance: Recent studies suggest that maintenance intravenous immunoglobulin (IVIG) may be an effective treatment to prevent relapses in myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD); however, most of these studies had pediatric cohorts, and few studies have evaluated IVIG in adult patients. Objective: To determine the association of maintenance IVIG with the prevention of disease relapse in a large adult cohort of patients with MOGAD. Design, Setting, and Participants: This was a retrospective cohort study conducted from January 1, 2010, to October 31, 2021. Patients were recruited from 14 hospitals in 9 countries and were included in the analysis if they (1) had a history of 1 or more central nervous system demyelinating attacks consistent with MOGAD, (2) had MOG-IgG seropositivity tested by cell-based assay, and (3) were age 18 years or older when starting IVIG treatment. These patients were retrospectively evaluated for a history of maintenance IVIG treatment. Exposures: Maintenance IVIG. Main Outcomes and Measures: Relapse rates while receiving maintenance IVIG compared with before initiation of therapy. Results: Of the 876 adult patients initially identified with MOGAD, 59 (median [range] age, 36 [18-69] years; 33 women [56%]) were treated with maintenance IVIG. IVIG was initiated as first-line immunotherapy in 15 patients (25%) and as second-line therapy in 37 patients (63%) owing to failure of prior immunotherapy and in 7 patients (12%) owing to intolerance to prior immunotherapy. The median (range) annualized relapse rate before IVIG treatment was 1.4 (0-6.1), compared with a median (range) annualized relapse rate while receiving IVIG of 0 (0-3) (t108 = 7.14; P < .001). Twenty patients (34%) had at least 1 relapse while receiving IVIG with a median (range) time to first relapse of 1 (0.03-4.8) years, and 17 patients (29%) were treated with concomitant maintenance immunotherapy. Only 5 of 29 patients (17%) who received 1 g/kg of IVIG every 4 weeks or more experienced disease relapse compared with 15 of 30 patients (50%) treated with lower or less frequent dosing (hazard ratio, 3.31; 95% CI, 1.19-9.09; P = .02). At final follow-up, 52 patients (88%) were still receiving maintenance IVIG with a median (range) duration of 1.7 (0.5-9.9) years of therapy. Seven of 59 patients (12%) discontinued IVIG therapy: 4 (57%) for inefficacy, 2 (29%) for adverse effects, and 1 (14%) for a trial not receiving therapy after a period of disease inactivity. Conclusions and Relevance: Results of this retrospective, multicenter, cohort study of adult patients with MOGAD suggest that maintenance IVIG was associated with a reduction in disease relapse. Less frequent and lower dosing of IVIG may be associated with treatment failure. Future prospective randomized clinical trials are warranted to confirm these findings.

Health utilities and costs for neuromyelitis optica spectrum disorder.

BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) is a rare, neurological disease that places a significant burden on patients, their carers, and healthcare systems. OBJECTIVES: To estimate patient and carer health utilities and costs of NMOSD within the UK setting. METHODS: Patients with NMOSD and their carers, recruited via a regional specialist treatment centre, completed a postal questionnaire that included a resource use measure, the EuroQoL (EQ)-5D-5L, EQ-5D-VAS, Vision and Quality of Life Index (VisQoL), Carer Experience Survey (CES) and the Expanded Disability Status Scale (EDSS). The questionnaire asked about respondents' use of health and community care services, non-medical costs, informal care and work capacity. Data were analysed descriptively. Uncertainties in costs and utilities were assessed using bootstrap analysis. RESULTS: 117 patients and 74 informal carers responded to the survey. Patients' mean EQ-5D-5L and VisQoL health utilities (95% central range) were 0.54 (- 0.29, 1.00) and 0.79 (0.11, 0.99), respectively. EQ-5D-5L utility decreased with increasing EDSS score bandings, from 0.80 (0.75, 0.85) for EDSS ≤ 4.0, to 0.20 (- 0.29, 0.56) for EDSS 8.0 to 9.5. Mean, 3-month total costs were £5623 (£2096, £12,156), but ranged from £562 (£381, £812) to £32,717 (£2888, £98,568) for these EDSS bandings. Carer-reported EQ-5D-5L utility and CES index scores were 0.85 (0.82, 0.89) and 57.67 (52.69, 62.66). Mean, 3-month costs of informal care were £13,150 to £24,560. CONCLUSIONS: NMOSD has significant impacts on health utilities and NHS and carer costs. These data can be used as inputs to cost-effectiveness analyses of new medicines for NMOSD.

Factors Associated With Relapse and Treatment of Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease in the United Kingdom.

Importance: Longer-term outcomes and risk factors associated with myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) are not well established. Objective: To investigate longer-term risk of relapse and factors associated with this risk among patients with MOGAD. Design, Setting, and Participants: This large, single-nation, prospective cohort study was conducted among 276 patients with MOGAD at 5 health care centers in the UK. Data from January 1973 to March 2020 were collected from 146 patients at Oxford and its outreach sites, 65 patients at Liverpool, 32 patients at a children's hospital in Birmingham, 22 patients at a children's hospital in London, and 11 patients at Cardiff, Wales. Data were analyzed from April through July 2020. Main Outcomes and Measures: Risk of relapse and annualized relapse rate were evaluated according to different baseline features, including onset age, onset phenotype, and incident vs nonincident group, with the incident group defined as patients diagnosed with antibodies against myelin oligodendrocyte glycoprotein before a second attack. Time to next relapse among patients experiencing relapse was measured and compared between the maintenance therapy subgroup and each first-line treatment group. The no-treatment group was defined as the off-treatment phase among patients who were relapsing, which could occur between any attack or between the last attack and last follow-up. Results: Among 276 patients with MOGAD, 183 patients were identified as being part of the incident group. There were no differences in mean (SD) onset age between total and incident groups (26.4 [17.6] years vs 28.2 [18.1] years), and female patients were predominant in both groups (166 [60.1%] female patients vs 106 [57.9%] female patients). The most common presentation overall was optic neuritis (ON) (119 patients among 275 patients with presentation data [43.3%]), while acute disseminated encephalomyelitis (ADEM), brain, or brainstem onset was predominant among 69 patients aged younger than 12 years (47 patients [68.1%]), including 41 patients with ADEM (59.4%). In the incident group, the 8-year risk of relapse was 36.3% (95% CI, 27.1%-47.5%). ON at onset was associated with increased risk of relapse compared with transverse myelitis at onset (hazard ratio [HR], 2.66; 95% CI, 1.01-6.98; P = .047), but there was no statistically significant difference with adjustment for a follow-on course of corticosteroids. Any TM at onset (ie, alone or in combination with other presentations [ie, ON or ADEM, brain, or brain stem]) was associated with decreased risk of relapse compared with no TM (HR, 0.41; 95% CI, 0.20-0.88; P = .01). Young adult age (ie, ages >18-40 years) was associated with increased risk of relapse compared with older adult age (ie, ages >40 years) (HR, 2.71; 95% CI, 1.18-6.19; P = .02). First-line maintenance therapy was associated with decreased risk of relapse when adjusted for covariates (prednisolone: HR, 0.33; 95% CI, 0.12-0.92; P = .03; prednisolone, nonsteroidal immunosuppressant, or combined: HR, 0.51; 95% CI, 0.28-0.92; P = .03) compared with the no-treatment group. Conclusions and Relevance: The findings of this cohort study suggest that onset age and onset phenotype should be considered when assessing subsequent relapse risk and that among patients experiencing relapse, prednisolone, first-line immunosuppression, or a combination of those treatments may be associated with decreased risk of future relapse by approximately 2-fold. These results may contribute to individualized treatment decisions.