Search

BackgroundThe N-MOmentum trial investigated safety and efficacy of inebilizumab in participants with neuromyelitis optica spectrum disorder (NMOSD).ObjectiveEvaluate the attack identification process and adjudication committee (AC) performance in N-MOmentum.MethodsAdults (n = 230) with NMOSD and Expanded Disability Status Scale score ⩽8 were randomized (3:1) to inebilizumab 300 mg or placebo. The randomized controlled period was 28 weeks or until adjudicated attack. Attacks were adjudicated according to 18 predefined criteria. Magnetic resonance imaging (MRI) and biomarker (serum glial fibrillary acidic protein [sGFAP]) analyses were performed.ResultsA total of 64 participant-reported neurological events occurred; 51 (80%) were investigator-determined to be attacks. The AC confirmed 43 of the investigator-determined attacks (84%). There was high inter- and intra-AC-member agreement. In 25/64 events (39%) and 14/43 AC-adjudicated attacks (33%), MRI was reviewed during adjudication. Retrospective analysis revealed new domain-specific T1 and T2 MRI lesions in 90% of adjudicated attacks. Increased mean sGFAP concentrations (>2-fold change) from baseline were observed in 56% of adjudicated attacks versus 14% of investigator-determined attacks rejected by the AC and 31% of participant-reported events determined not to be attacks.ConclusionAC adjudication of NMOSD attacks according to predefined criteria appears robust. MRI lesion correlates and sGFAP elevations were found in most adjudicated attacks.

ObjectiveBlood tests to monitor disease activity, attack severity, or treatment impact in neuromyelitis optica spectrum disorder (NMOSD) have not been developed. This study investigated the relationship between serum glial fibrillary acidic protein (sGFAP) concentration and NMOSD activity and assessed the impact of inebilizumab treatment.MethodsN-MOmentum was a prospective, multicenter, double-blind, placebo-controlled, randomized clinical trial in adults with NMOSD. sGFAP levels were measured by single-molecule arrays (SIMOA) in 1,260 serial and attack-related samples from 215 N-MOmentum participants (92% aquaporin 4-immunoglobulin G-seropositive) and in control samples (from healthy donors and patients with relapsing-remitting multiple sclerosis).ResultsAt baseline, 62 participants (29%) exhibited high sGFAP concentrations (≥170 pg/ml; ≥2 standard deviations above healthy donor mean concentration) and were more likely to experience an adjudicated attack than participants with lower baseline concentrations (hazard ratio [95% confidence interval], 3.09 [1.6-6.1], p = 0.001). Median (interquartile range [IQR]) concentrations increased within 1 week of an attack (baseline: 168.4, IQR = 128.9-449.7 pg/ml; attack: 2,160.1, IQR = 302.7-9,455.0 pg/ml, p = 0.0015) and correlated with attack severity (median fold change from baseline [FC], minor attacks: 1.06, IQR = 0.9-7.4; major attacks: 34.32, IQR = 8.7-107.5, p = 0.023). This attack-related increase in sGFAP occurred primarily in placebo-treated participants (FC: 20.2, IQR = 4.4-98.3, p = 0.001) and was not observed in inebilizumab-treated participants (FC: 1.1, IQR = 0.8-24.6, p > 0.05). Five participants (28%) with elevated baseline sGFAP reported neurological symptoms leading to nonadjudicated attack assessments.InterpretationSerum GFAP may serve as a biomarker of NMOSD activity, attack risk, and treatment effects. ANN NEUROL 2021;89:895-910.

Neuromyelitis optica spectrum disorder (NMOSD) is an uncommon inflammatory disease of the central nervous system, manifesting clinically as optic neuritis, myelitis, and certain brain and brainstem syndromes. Cases clinically diagnosed as NMOSD may include aquaporin 4 (AQP4)-antibody-seropositive autoimmune astrocytopathic disease, myelin oligodendrocyte glycoprotein (MOG)-antibody-seropositive inflammatory demyelinating disease, and double-seronegative disease. AQP4-antibody disease has a high female-to-male ratio (up to 9:1), and its mean age at onset of ~40 years is later than that seen in multiple sclerosis. For MOG-antibody disease, its gender ratio is closer to 1:1, and it is more common in children than in adults. Its clinical phenotypes differ but overlap with those of AQP4-antibody disease and include acute disseminated encephalomyelitis, brainstem and cerebral cortical encephalitis, as well as optic neuritis and myelitis. Double-seronegative disease requires further research and clarification. Population-based studies over the past two decades report the prevalence and incidence of NMOSD in different populations worldwide. One relevant finding is the varying prevalence observed in different racial groups. Consistently, the prevalence of NMOSD among Whites is ~1/100,000 population, with an annual incidence of

BackgroundDebate exists about whether neuromyelitis optica spectrum disorder seronegative disease represents the same immune-mediated attack on astrocytic aquaporin-4 as in seropositive disease.ObjectiveWe investigated whether response to common treatments for neuromyelitis optica spectrum disorder differed by serostatus, as assessed by change in annualized relapse rate.MethodsWe performed a multicenter retrospective analysis of 245 patients with neuromyelitis optica spectrum disorder who were treated with either rituximab or mycophenolate mofetil as their first-line immunosuppressive treatment for disease prevention. Patients were followed for a minimum of 6 months following treatment initiation.ResultsIn those started on rituximab, the pre-treatment annualized relapse rates for seropositive and seronegative patients were 1.81 and 1.93, respectively. On-treatment annualized relapse rates significantly declined to 0.32 (seropositive; p

BackgroundRelapses of multiple sclerosis decrease during pregnancy, when the hormone estriol is increased. Estriol treatment is anti-inflammatory and neuroprotective in preclinical studies. In a small single-arm study of people with multiple sclerosis estriol reduced gadolinium-enhancing lesions and was favourably immunomodulatory. We assessed whether estriol treatment reduces multiple sclerosis relapses in women.MethodsWe did a randomised, double-blind, placebo-controlled phase 2 trial at 16 academic neurology centres in the USA, between June 28, 2007, and Jan 9, 2014. Women aged 18-50 years with relapsing-remitting multiple sclerosis were randomly assigned (1:1) with a random permuted block design to either daily oral estriol (8 mg) or placebo, each in combination with injectable glatiramer acetate 20 mg daily. Patients and all study personnel, except for pharmacists and statisticians, were masked to treatment assignment. The primary endpoint was annualised relapse rate after 24 months, with a significance level of p=0.10. Relapses were confirmed by an increase in Expanded Disability Status Scale score assessed by an independent physician. Analysis was by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00451204.FindingsWe enrolled 164 patients: 83 were allocated to the estriol group and 81 were allocated to the placebo group. The annualised confirmed relapse rate was 0.25 relapses per year (95% CI 0.17-0.37) in the estriol group versus 0.37 relapses per year (0.25-0.53) in the placebo group (adjusted rate ratio 0.63, 95% CI 0.37-1.05; p=0.077). The proportion of patients with serious adverse events did not differ substantially between the estriol group and the placebo group (eight [10%] of 82 patients vs ten [13%] of 76 patients). Irregular menses were more common in the estriol group than in the placebo group (19 [23%] vs three [4%], p=0.0005), but vaginal infections were less common (one [1%] vs eight [11%], p=0.0117). There were no differences in breast fibrocystic disease, uterine fibroids, or endometrial lining thickness as assessed by clinical examination, mammogram, uterine ultrasound, or endometrial lining biopsy.InterpretationEstriol plus glatiramer acetate met our criteria for reducing relapse rates, and treatment was well tolerated over 24 months. These results warrant further investigation in a phase 3 trial.FundingNational Institutes of Health, National Multiple Sclerosis Society, Conrad N Hilton Foundation, Jack H Skirball Foundation, Sherak Family Foundation, and the California Community Foundation.

Neuromyelitis optica (NMO) is an inflammatory CNS syndrome distinct from multiple sclerosis (MS) that is associated with serum aquaporin-4 immunoglobulin G antibodies (AQP4-IgG). Prior NMO diagnostic criteria required optic nerve and spinal cord involvement but more restricted or more extensive CNS involvement may occur. The International Panel for NMO Diagnosis (IPND) was convened to develop revised diagnostic criteria using systematic literature reviews and electronic surveys to facilitate consensus. The new nomenclature defines the unifying term NMO spectrum disorders (NMOSD), which is stratified further by serologic testing (NMOSD with or without AQP4-IgG). The core clinical characteristics required for patients with NMOSD with AQP4-IgG include clinical syndromes or MRI findings related to optic nerve, spinal cord, area postrema, other brainstem, diencephalic, or cerebral presentations. More stringent clinical criteria, with additional neuroimaging findings, are required for diagnosis of NMOSD without AQP4-IgG or when serologic testing is unavailable. The IPND also proposed validation strategies and achieved consensus on pediatric NMOSD diagnosis and the concepts of monophasic NMOSD and opticospinal MS.

Current management of neuromyelitis optica (NMO) is noncurative and only partially effective. Immunosuppressive or immunomodulatory agents are the mainstays of maintenance treatment. Safer, better-tolerated, and proven effective treatments are needed. The perceived rarity of NMO has impeded clinical trials for this disease. However, a diagnostic biomarker and recognition of a wider spectrum of NMO presentations has expanded the patient population from which study candidates might be recruited. Emerging insights into the pathogenesis of NMO have provided rationale for exploring new therapeutic targets. Academic, pharmaceutical, and regulatory communities are increasingly interested in meeting the unmet needs of patients with NMO. Clinical trials powered to yield unambiguous outcomes and designed to facilitate rapid evaluation of an expanding pipeline of experimental agents are needed. NMO-related disability occurs incrementally as a result of attacks; thus, limiting attack frequency and severity are critical treatment goals. Yet, the severity of NMO and perception that currently available agents are effective pose challenges to study design. We propose strategies for NMO clinical trials to evaluate agents targeting recovery from acute attacks and prevention of relapses, the 2 primary goals of NMO treatment. Aligning the interests of all stakeholders is an essential step to this end.

Objective: This study was undertaken to investigate factors associated with aquaporin‐4 (AQP4)‐IgG serostatus change using a large serological database. Methods: This retrospective study utilizes Mayo Clinic Neuroimmunology Laboratory data from 2007 to 2021. We included all patients with ≥2 AQP4‐IgG tests (by cell‐based assay). The frequency and clinical factors associated with serostatus change were evaluated. Multivariable logistic regression analysis examined whether age, sex, or initial titer was associated with serostatus change. Results: There were 933 patients who had ≥2 AQP4‐IgG tests with an initial positive result. Of those, 830 (89%) remained seropositive and 103 (11%) seroreverted to negative. Median interval to seroreversion was 1.2 years (interquartile range [IQR] = 0.4–3.5). Of those with sustained seropositivity, titers were stable in 92%. Seroreversion was associated with age ≤ 20 years (odds ratio [OR] = 2.25; 95% confidence interval [CI] = 1.09–4.63; p = 0.028) and low initial titer of ≤1:100 (OR = 11.44, 95% CI = 3.17–41.26, p < 0.001), and 5 had clinical attacks despite seroreversion. Among 62 retested after seroreversion, 50% returned to seropositive (median = 224 days, IQR = 160–371). An initial negative AQP4‐IgG test occurred in 9,308 patients. Of those, 99% remained seronegative and 53 (0.3%) seroconverted at a median interval of 0.76 years (IQR = 0.37–1.68). Interpretation: AQP4‐IgG seropositivity usually persists over time with little change in titer. Seroreversion to negative is uncommon (11%) and associated with lower titers and younger age. Seroreversion was often transient, and attacks occasionally occurred despite prior seroreversion, suggesting it may not reliably reflect disease activity. Seroconversion to positive is rare (<1%), limiting the utility of repeat testing in seronegative patients unless clinical suspicion is high. ANN NEUROL 2023;94:727–735 [ABSTRACT FROM AUTHOR]