Safety and efficacy of inebilizumab for the treatment of neuromyelitis optica spectrum disorder: end-of-study results from the open-label period of the N-MOmentum trial.

BACKGROUND: Inebilizumab, an anti-CD19 B-cell-depleting antibody, demonstrated safety and efficacy in neuromyelitis optica spectrum disorder in the randomised controlled period of the N-MOmentum trial. Here, end-of-study data, including the randomised controlled period and open-label extension period, are reported. METHODS: In the double-blind, randomised, placebo-controlled, phase 2/3 N-MOmentum trial, adults aged 18 years and older with an neuromyelitis optica spectrum disorder diagnosis, Expanded Disability Status Scale score of 8·0 or less, and history of either at least one acute inflammatory attack requiring rescue therapy in the past year or two attacks requiring rescue therapy in the past 2 years, were recruited from 81 outpatient specialty clinics or hospitals in 24 countries. Eligible participants were randomly assigned (3:1), using a central interactive voice system or interactive web response system, and a permuted block randomisation scheme (block size of 4), to receive intravenous inebilizumab (300 mg) or identical placebo on days 1 and 15 of the randomised period, which lasted up to 197 days. Participants and all study staff were masked to treatment assignment. The primary endpoint of the randomised period of the trial was time to onset of adjudicated neuromyelitis optica spectrum disorder attack on or before day 197. Participants in the randomised controlled period who had an adjudicated attack, completed 197 days in the study, or were in the randomised controlled period when enrolment stopped, could voluntarily enter the open-label period. In the open-label period, participants either initiated inebilizumab if assigned placebo (receiving 300 mg on days 1 and 15 of the open-label period) or continued treatment if assigned inebilizumab (receiving 300 mg on day 1 and placebo on day 15, to maintain B-cell depletion and masking of the randomised controlled period). All participants subsequently received inebilizumab 300 mg every 6 months for a minimum of 2 years. The end-of-study analysis endpoints were time to adjudicated attack and annualised attack rate (assessed in all participants who received inebilizumab at any point during the randomised controlled period or open-label period [any inebilizumab population] and the aquaporin-4 [AQP4]-IgG seropositive subgroup [any inebilizumab-AQP4-IgG seropositive population]) and safety outcomes (in all participants who were exposed to inebilizumab, analysed as-treated). This study is registered with ClinicalTrials.gov, NCT02200770, and is now complete. FINDINGS: Between Jan 6, 2015, and Sept 24, 2018, 467 individuals were screened, 231 were randomly assigned, and 230 received at least one dose of inebilizumab (n=174) or placebo (n=56). Between May 19, 2015, and Nov 8, 2018, 165 (95%) of 174 participants in the inebilizumab group and 51 (91%) of 56 in the placebo group entered the open-label period (mean age 42·9 years [SD 12·4], 197 [91%] of 216 were female, 19 [9%] were male, 115 [53%] were White, 45 [21%] were Asian, 19 [9%] were American Indian or Alaskan Native, and 19 [9%] were Black or African American). As of data cutoff for this end of study analysis (Dec 18, 2020; median exposure 1178 days [IQR 856-1538], total exposure of 730 person-years) 225 participants formed the any inebilizumab population, and 208 (92%) participants were AQP4-IgG seropositive. Overall, 63 adjudicated neuromyelitis optica spectrum disorder attacks occurred in 47 (21%) of 225 treated participants (60 attacks occurred in 44 [21%] of 208 in the AQP4-IgG seropositive subgroup); 40 (63%) of 63 attacks occurred in 34 (15%) of 225 treated participants during the first year of treatment. Of individuals who had an adjudicated attack while receiving inebilizumab, 36 (77%) of 47 were subsequently attack-free at the end of 4 years. Annualised attack rates decreased year-on-year, with end-of-study adjusted annualised attack rates being similar in the any inebilizumab-AQP4-IgG seropositive subgroup (0·097 [95% CI 0·070-0·14]) and any inebilizumab populations (0·092 [0·067-0·13]). Overall, 208 (92%) of 225 participants who received any inebilizumab had at least one treatment-emergent adverse event, the most frequent of which were urinary tract infection (59 [26%]), nasopharyngitis (47 [21%]), and arthralgia (39 [17%]). Infection rates did not increase over 4 years. Three (1%) of 225 participants in the any inebilizumab population died during the open-label period (one each due to a CNS event of unknown cause and pneumonia, respiratory insufficiency resulting from an neuromyelitis optica spectrum disorder attack and viral pneumonia related to COVID-19), all of which were deemed to be unrelated to treatment. INTERPRETATION: Data from the end-of-study analysis of the N-MOmentum trial showed continued and sustained clinical benefits of long-term inebilizumab treatment in individuals with neuromyelitis optica spectrum disorder, which supports the role of inebilizumab as a CD19+ B-cell-depleting therapy in neuromyelitis optica spectrum disorder. FUNDING: MedImmune and Viela Bio/Horizon Therapeutics, now part of Amgen.

Attack adjudication in neuromyelitis optica spectrum disorder: Substantiation of criteria by magnetic resonance imaging and biomarkers in N-MOmentum.

BACKGROUND: The N-MOmentum trial investigated safety and efficacy of inebilizumab in participants with neuromyelitis optica spectrum disorder (NMOSD). OBJECTIVE: Evaluate the attack identification process and adjudication committee (AC) performance in N-MOmentum. METHODS: Adults (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. RESULTS: A 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. CONCLUSION: AC adjudication of NMOSD attacks according to predefined criteria appears robust. MRI lesion correlates and sGFAP elevations were found in most adjudicated attacks.

Alterations in Aquaporin-4-IgG Serostatus in 986 Patients: A Laboratory-Based Longitudinal Analysis.

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.

Cerebral enhancement in MOG antibody-associated disease.

INTRODUCTION: Limited data exist on brain MRI enhancement in myelin-oligodendrocyte-glycoprotein (MOG) antibody-associated disease (MOGAD) and differences from aquaporin-4-IgG-positive-neuromyelitis-optica-spectrum-disorder (AQP4+NMOSD), and multiple sclerosis (MS). METHODS: In this retrospective observational study, we identified 122 Mayo Clinic MOGAD patients (1 January 1996-1 July 2020) with cerebral attacks. We explored enhancement patterns using a discovery set (n=41). We assessed enhancement frequency and Expanded Disability Status Scale scores at nadir and follow-up in the remainder (n=81). Two raters assessed T1-weighted-postgadolinium MRIs (1.5T/3T) for enhancement patterns in MOGAD, AQP4+NMOSD (n=14) and MS (n=26). Inter-rater agreement was assessed. Leptomeningeal enhancement clinical correlates were analysed. RESULTS: Enhancement occurred in 59/81 (73%) MOGAD cerebral attacks but did not influence outcome. Enhancement was often patchy/heterogeneous in MOGAD (33/59 (56%)), AQP4+NMOSD (9/14 (64%); p=0.57) and MS (16/26 (62%); p=0.63). Leptomeningeal enhancement favoured MOGAD (27/59 (46%)) over AQP4+NMOSD (1/14 (7%); p=0.01) and MS (1/26 (4%); p<0.001) with headache, fever and seizures frequent clinical correlates. Ring enhancement favoured MS (8/26 (31%); p=0.006) over MOGAD (4/59 (7%)). Linear ependymal enhancement was unique to AQP4+NMOSD (2/14 (14%)) and persistent enhancement (>3 months) was rare (0%-8%) across all groups. Inter-rater agreement for enhancement patterns was moderate. CONCLUSIONS: Enhancement is common with MOGAD cerebral attacks and often has a non-specific patchy appearance and rarely persists beyond 3 months. Leptomeningeal enhancement favours MOGAD over AQP4+NMOSD and MS.

Serum neurofilament light chain levels at attack predict post-attack disability worsening and are mitigated by inebilizumab: analysis of four potential biomarkers in neuromyelitis optica spectrum disorder.

OBJECTIVE: To investigate relationships between serum neurofilament light chain (sNfL), ubiquitin C-terminal hydrolase L1 (sUCHL1), tau (sTau) and glial fibrillary acidic protein (sGFAP) levels and disease activity/disability in neuromyelitis optica spectrum disorder (NMOSD), and the effects of inebilizumab on these biomarkers in N-MOmentum. METHODS: N-MOmentum randomised participants to receive inebilizumab or placebo with a randomised controlled period (RCP) of 28 weeks and an open-label follow-up period of ≥2 years. The sNfL, sUCHL1, sTau and sGFAP were measured using single-molecule arrays in 1260 scheduled and attack-related samples from N-MOmentum participants (immunoglobulin G (IgG) autoantibodies to aquaporin-4-positive, myelin oligodendrocyte glycoprotein-IgG-positive or double autoantibody-negative) and two control groups (healthy donors and patients with relapsing-remitting multiple sclerosis). RESULTS: The concentration of all four biomarkers increased during NMOSD attacks. At attack, sNfL had the strongest correlation with disability worsening during attacks (Spearman R2=0.40; p=0.01) and prediction of disability worsening after attacks (sNfL cut-off 32 pg/mL; area under the curve 0.71 (95% CI 0.51 to 0.89); p=0.02), but only sGFAP predicted upcoming attacks. At RCP end, fewer inebilizumab-treated than placebo-treated participants had sNfL>16 pg/mL (22% vs 45%; OR 0.36 (95% CI 0.17 to 0.76); p=0.004). CONCLUSIONS: Compared with sGFAP, sTau and sUCHL1, sNfL at attack was the strongest predictor of disability worsening at attack and follow-up, suggesting a role for identifying participants with NMOSD at risk of limited post-relapse recovery. Treatment with inebilizumab was associated with lower levels of sGFAP and sNfL than placebo. TRIAL REGISTRATION NUMBER: NCT02200770.

A single relapse induces worsening of disability and health-related quality of life in patients with neuromyelitis optica spectrum disorder.

Background: Cumulative damage from multiple relapses in neuromyelitis optica spectrum disorder (NMOSD) is associated with poor health-related quality of life (HRQoL) and long-term disability in patients positive for anti-aquaporin 4 antibodies (AQP4+). This study assessed the effect of an individual relapse on HRQoL and disability outcomes in AQP4+ NMOSD. Methods: Post hoc analyses of data pooled from the PREVENT study and its open-label extension, which evaluated the efficacy and safety of eculizumab in AQP4+ NMOSD, examined the effect of a single relapse on 3 disability and 4 HRQoL outcome measures. Assuming the effect of 1 relapse extends to multiple relapses, an extrapolation was done to assess the effect of 2 relapses on these outcomes. Results: In 27 patients (placebo: n = 20; eculizumab: n = 7) experiencing an independently adjudicated relapse, 1 relapse led to significantly worse disability (modified Rankin Scale and Expanded Disability Status Scale [EDSS]) and HRQoL (36-item Short-Form Health Survey mental and physical component summaries; European Quality of Life 5-Dimension questionnaire 3-Level visual analogue scale and utility index) scores. In 4 of 7 outcomes, clinically meaningful worsening was more likely for relapsing versus non-relapsing patients (n = 116). Extrapolating the effect of 2 relapses predicted that clinically meaningful worsening was more likely in 6 out of 7 outcomes, including EDSS, for patients experiencing multiple relapses versus patients experiencing no relapses. Conclusion: Findings from these clinical trial data demonstrate that a single NMOSD relapse can worsen disability and HRQoL, underscoring the role of relapse prevention in improving long-term outcomes in patients with AQP4+ NMOSD.

Characterization of Disease Severity and Stability in NMOSD: A Global Clinical Record Review with Patient Interviews.

INTRODUCTION: We sought insights into the classification of and factors associated with relapse severity and disease stability in neuromyelitis optica spectrum disorder (NMOSD) clinical practice worldwide. METHODS: Neurologists recruited from six countries (the USA, Germany, Italy, Brazil, South Korea, and China) participated in a 30-60 minute online survey and submitted two to four clinical records for aquaporin-4-immunoglobulin G (AQP4-IgG)-seropositive adults with NMOSD, which included patient demographics, diagnosis, maintenance treatment history, relapse occurrence, and severity. Separately, patients with NMOSD receiving maintenance therapy were interviewed over the telephone about their treatment journey, as well as perceptions of relapse severity and disease stability, and their potential influence on treatment decisions. RESULTS: Clinical records for 1185 patients with AQP4-IgG-seropositive NMOSD were provided by 389 neurologists (July-August 2020); 33 patients were interviewed (October-November 2020). There was no clear consensus on how relapse severity was defined in clinical practice, with geographical variations in relapse classification also found. Neurologists tended to rely on clinical assessments when determining severity, viewing each relapse in isolation, whereas patients had a more subjective view based on the changes in their daily lives and comparisons with prior relapses. Similarly, there was a disconnect in the definition of disease stability: the complete absence of relapses was more important for patients than for neurologists. CONCLUSION: A clear consensus on how to assess relapse severity and disease stability is needed to ensure that patients receive appropriate and timely treatment. In the future, clinical measures should be combined with patient-focused assessments.

Understanding Treatment Decisions in Neuromyelitis Optica Spectrum Disorder: A Global Clinical Record Review with Patient Interviews.

INTRODUCTION: We sought insights into neuromyelitis optica spectrum disorder (NMOSD) treatment practices worldwide. METHODS: Neurologists from the USA, Germany, Italy, Brazil, South Korea, and China completed an online survey, contributing clinical records for aquaporin-4 (AQP4) immunoglobulin G (IgG)-seropositive adults with NMOSD, which included patient demographics, diagnosis, maintenance treatment history, relapse occurrence, and severity. Interviewed patients receiving NMOSD maintenance therapy provided information about their diagnosis, treatment, perceptions about relapse severity or disease stability, and treatment switches. RESULTS: A total of 389 neurologists submitted clinical records for 1185 patients with AQP4-IgG-seropositive NMOSD; 33 patients with NMOSD were interviewed. Approximately 25% (228/910) of patients from the clinical record review (CRR) were initially misdiagnosed; 24% (8/33) of patients interviewed reported formal misdiagnosis. Misdiagnosis was associated with treatment delay and more relapses compared with correct diagnosis (mean 3.3 vs 2.8). Maintenance therapy was not initiated within 2 months for 47% (221/472) of patients from the CRR and 24% (8/33) of interviewed patients. Oral corticosteroids/immunosuppressive therapies were typically the first maintenance treatment initiated, except for the USA, where monoclonal antibodies were equally likely to be prescribed. Relapse severity influenced the decision to initiate/change therapy and use monoclonal antibodies. Of interviewed patients, 76% (25/33) did not recall having a choice of treatment and many did not know the rationale for treatment choice. CONCLUSION: Misdiagnosis of NMOSD appears to be common and is associated with a delay in initiation of maintenance therapy, with decisions influenced by relapse severity. Further real-world studies assessing relapse severity in treatment initiation/switch are required to revise NMOSD treatment recommendations.

Is Intravenous Immunoglobulin Effective in Reducing the Risk of Mortality and Morbidity in Neuroinvasive West Nile Virus Infection?: A Critically Appraised Topic.

BACKGROUND: The clinical benefit of intravenous immunoglobulin (IVIG) in adult individuals with neuroinvasive West Nile virus (niWNV) infection is not well substantiated. We sought to critically assess current evidence regarding the efficacy of IVIG in treating patients with niWNV. METHODS: The objective was addressed through the development of a critically appraised topic that included a clinical scenario, structured question, literature search strategy, critical appraisal, assessment of results, evidence summary, commentary, and bottom-line conclusions. Participants included consultant and resident neurologists, a medical librarian, clinical epidemiologists, and a content expert in the field of neuro-infectious diseases. RESULTS: The appraised study enrolled 62 participants with suspected niWNV, randomized into 3 different arms [37 participants in the Omr-IgG-am group, 12 in the Polygam group, and 13 in the normal saline (NS) group]. Omr-IgG-am and Polygam are different formulations of IVIG. IVIG safety, measured as rates of serious adverse events, was the primary study outcome while IVIG efficacy, measured as rates of unfavorable outcomes, was a secondary endpoint. The estimated rates of SAE were statistically similar in all groups (51.4% Omr-IgG-am, 58.3% Polygam, and 23.1% NS groups). Unfavorable outcomes also occurred at a similar rate between all the groups (51.5% Omr-IgG-am, 54.5% Polygam, and 27.3% NS). CONCLUSIONS: The appraised trial showed that Omr-IgG-am and Polygam are as safe as NS. Data on efficacy from this trial were limited by a small sample size. Phase III clinical trials on IVIG efficacy in NiWNV infection are needed.

Aligning payer and provider strategies with the latest evidence to optimize clinical outcomes for patients with neuromyelitis optica spectrum disorder.

BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) is a rare autoimmune disorder affecting the central nervous system that is associated with significant morbidity and mortality. Early diagnosis and treatment are essential to minimize long-term disability. Recent advances in the understanding of the pathophysiology of NMOSD have led to multiple new therapies, but significant care and knowledge gaps persist. OBJECTIVES: To summarize current knowledge about the burden of disease and diagnosis and treatment of NMOSD in order to support managed care professionals and health care providers in making collaborative, evidence-based decisions to optimize outcomes among patients with NMOSD. In addition, this review also presents findings of a patient survey that provides insight into real-world experiences of those living with NMOSD. SUMMARY: Diagnosis of NMOSD is based on detection of immunoglobulin G antibodies to the water channel protein aquaporin-4 (AQP4-IgG) in the context of compatible clinical and magnetic resonance imaging features. Patients who are AQP4-IgG seronegative and/or who are positive for myelin oligodendrocyte glycoprotein antibodies may also satisfy criteria for NMOSD. The rarity of the condition combined with the significant overlap in clinical features with other autoimmune diseases affecting the central nervous system, most notably multiple sclerosis, can delay accurate diagnosis, which in turn can delay appropriate treatment, leading to the accumulation of long-term disability. Accumulating disability associated with NMOSD has a substantial negative impact on quality of life. The disease typically evolves as relapsing (ie, repeated) acute attacks. Treatment consists of management of acute attacks, prevention of subsequent attacks, and management of acute and chronic symptoms. The armamentarium of therapies to prevent attacks consists of several monoclonal antibodies (mAbs) approved to treat AQP4-IgG-seropositive disease and several off-label therapies used for patients with either seropositive or seronegative disease. There is limited evidence to guide treatment decision-making, including which therapies to use first line, when to switch, and when to use monotherapy vs combination therapy. In addition, therapies with the greatest demonstrated safety and efficacy in NMOSD are costly and may not be accessible to all patients. Moreover, the results of the patient survey revealed significant clinical and financial burdens to patients with NMOSD including frequent attacks, delays in therapy initiation, need for urgent care and repeat hospitalizations, new and worsening symptoms, accumulating disability, and difficulties affording care. As such, key stakeholders must weigh them against the substantial economic costs of untreated or suboptimal treatment of disease. DISCLOSURES: Dr Wingerchuk has served on the advisory board or panel for Alexion, Biogen, Genentech, Horizon, Mitsubishi Tanabe, Novartis, Roche, UCB, and Viela Bio and has received grants of research support from Alexion. Dr Weinshenker has served as a consultant or on the advisory board or panel for Alexion, Genentech, Horizon, Mitsubishi Tanabe, Roche, UCB, and Viela Bio, served on the speakers bureau or other promotional education for Genentech and Roche, and has received royalties from RSR Ltd.

In Patients With Melanoma Brain Metastases, Is Combination Immune Checkpoint Inhibition a Safe and Effective First-Line Treatment? A Critically Appraised Topic.

BACKGROUND: Combined PD-1/PD-L1 and CTLA-4 immune checkpoint inhibition for the has been shown to produce superior results in the treatment of malignant melanoma when compared to monotherapy. However, patients with intracranial disease were excluded from these studies given their poor prognosis. OBJECTIVE: The objective of this study was to critically assess current evidence supporting the co-administration of PD-1/PD-L1 and CTLA-4 inhibitors in the treatment of melanoma brain metastases. METHODS: The objective was addressed through the development of a critically appraised topic that included a clinical scenario, structured question, literature search strategy, critical appraisal, assessment of results, evidence summary, commentary, and bottom-line conclusions. Participants included consultant and resident neurologists, a medical librarian, clinical epidemiologists, and a content expert in the field of neuro-oncology. RESULTS: A recent, open-label, non-comparative randomized phase II trial was selected for critical appraisal. This trial evaluated the efficacy and safety of nivolumab alone or in combination with ipilimumab in 79 adult patients with untreated, asymptomatic melanoma brain metastases. The rates of the primary outcome (intracranial response at ≥12 wk) in the primary endpoint cohort were 46% for cohort A (combination therapy) and 20% for cohort B (nivolumab monotherapy). No treatment related deaths were observed in the study. Grade 4 adverse events occurred in 9% of patients in cohort A and none in cohort B. CONCLUSIONS: Co-administration of ipilimumab and nivolumab as first-line therapy is effective in the treatment of asymptomatic melanoma brain metastases, with an acceptable safety profile.

Frequency of Asymptomatic Optic Nerve Enhancement in a Large Retrospective Cohort of Patients With Aquaporin-4+ NMOSD.

BACKGROUND AND OBJECTIVES: Asymptomatic or persistent optic nerve enhancement in aquaporin-4 (AQP4)-immunoglobulin G (IgG)-positive neuromyelitis optica spectrum disorder (NMOSD) is thought to be rare. Improved understanding may have important implications for assessment of treatment efficacy in clinical trials and in clinical practice. Our objective was to characterize NMOSD interattack optic nerve enhancement. METHODS: This was a retrospective cohort study performed between 2000 and 2019 (median follow-up 5.5 [range 1-35] years) of patients with AQP4-IgG-positive optic neuritis (ON) evaluated at Mayo Clinic. MRI orbits were reviewed by a neuroradiologist, neuro-ophthalmologist, and neuroimmunologist blinded to the clinical history. Interattack optic nerve enhancement (>30 days after attack) was measured. The correlation between interattack enhancement and Snellen visual acuity (VA), converted to logarithm of the minimum angle of resolution (logMAR), at attack and at follow-up were assessed. RESULTS: A total of 198 MRI scans in 100 patients with AQP4-IgG+ NMOSD were identified, with 107 interattack MRIs from 78 unique patients reviewed. Seven scans were performed before any ON (median 61 days before attack [range 21-271 days]) and 100 after ON (median 400 days after attack [33-4,623 days]). Optic nerve enhancement was present on 18/107 (16.8%) interattack scans (median 192.5 days from attack [33-2,943]) of patients with preceding ON. On 15 scans, enhancement occurred at the site of prior attacks; the lesion location was unchanged, but the lesion length was shorter. Two scans (1.8%) demonstrated new asymptomatic lesions (prior scan demonstrated no enhancement). In a third patient with subjective blurry vision, MRI showed enhancement preceding detectable eye abnormalities on examination noted 15 days later. There was no difference in VA at preceding attack nadir (logMAR VA 1.7 vs 2.1; p = 0.79) or long-term VA (logMAR VA 0.4 vs 0.2, p = 0.56) between those with and without interattack optic nerve enhancement. DISCUSSION: Asymptomatic optic nerve enhancement occurred in 17% of patients with NMOSD predominantly at the site of prior ON attacks and may represent intermittent blood-brain barrier breakdown or subclinical ON. New asymptomatic enhancement was seen only in 2% of patients. Therapeutic clinical trials for NMOSD require blinded relapse adjudication when assessing treatment efficacy, and it is important to recognize that asymptomatic optic nerve enhancement can occur in patients with ON.

AQP4-IgG-seronegative patient outcomes in the N-MOmentum trial of inebilizumab in neuromyelitis optica spectrum disorder.

BACKGROUND: The N-MOmentum trial, a double-blind, randomized, placebo-controlled, phase 2/3 study of inebilizumab in neuromyelitis optica spectrum disorder (NMOSD), enrolled participants who were aquaporin-4-immunoglobulin G (AQP4-IgG)-seropositive (AQP4+) or -seronegative (AQP4-). This article reports AQP4- participant outcomes. METHODS: AQP4-IgG serostatus was determined for all screened participants by a central laboratory, using a validated, fluorescence-observation cell-binding assay. Medical histories and screening data for AQP4- participants were assessed independently by an eligibility committee of three clinical experts during screening. Diagnosis of NMOSD was confirmed by majority decision using the 2006 neuromyelitis optica criteria. Myelin oligodendrocyte glycoprotein-immunoglobulin G (MOG-IgG) serology (using a clinically validated, flow cytometry assay) and annualized attack rates (AARs) were evaluated post hoc. Efficacy outcomes were assessed by comparing pre-study and on-study AARs in treated participants. RESULTS: Only 18/50 AQP4- screened participants (36%) were initially considered eligible for randomization; 16 were randomized and received full treatment, 4 to placebo (1 MOG-IgG-seropositive [MOG+]) and 12 to inebilizumab (6 MOG+). The most common reason for failure to pass screening among prospective AQP4- participants was failure to fulfill the 2006 NMO MRI criteria. In inebilizumab-treated AQP4- participants, on-study AARs (95% confidence interval [CI]) calculated from treatment initiation (whether from randomization or when received at the start of the open-label period) to the end of study were lower than pre-study rates: for all AQP4- participants (n = 16), mean (95% CI) AAR was 0.048 (0.02-0.15) versus 1.70 (0.74-2.66), respectively. For the subset of AQP4-/MOG+ participants (n = 7), AAR was 0.043 (0.006-0.302) after treatment versus 1.93 (1.10-3.14) before the study. For the subset of AQP4-/MOG- participants (n = 9), post-treatment AAR was 0.051 (0.013-0.204) versus 1.60 (1.02-2.38). Three attacks occurred during the randomized controlled period in the AQP4- inebilizumab group and were of mild severity; no attacks occurred in the AQP4- placebo group. The low number of participants receiving placebo (n = 4) confounds direct comparison with the inebilizumab group. No attacks were seen in any AQP4- participant after the second infusion of inebilizumab. Inebilizumab was generally well tolerated by AQP4- participants and the adverse event profile observed was similar to that of AQP4+ participants. CONCLUSION: The high rate of rejection of AQP4- participants from enrollment into the study highlights the challenges of implementing the diagnostic criteria of AQP4- NMOSD. An apparent reduction of AAR in participants with AQP4- NMOSD who received inebilizumab warrants further investigation.

In Patients With Functional Movement Disorders, Is Specialized Physical Therapy Effective in Improving Motor Symptoms?: A Critically Appraised Topic.

BACKGROUND: Functional movement disorders (FMD, aka psychogenic movement disorders) are very common and frequently chronic and disabling. Despite this, there is a paucity of evidence-based treatment to manage and alleviate these conditions. Specialized physical therapy (PT), involving sequential motor relearning and redirecting attention, has shown promise as a therapeutic intervention for motor symptoms. METHODS: The objective of this study was to critically assess current evidence regarding specialized PT compared with usual care in improving motor symptoms among patients with FMD. This was addressed through the development of a structured critically appraised topic. This included a clinical scenario with a clinical question, literature search strategy, critical appraisal, results, evidence summary, commentary, and bottom-line conclusions. Participants included consultant and resident neurologists, a medical librarian, and content experts in the fields of physical medicine and rehabilitation, physical and occupational therapy, psychiatry, and psychology. RESULTS: A randomized controlled feasibility trial was identified and selected for critical appraisal. This study randomized 60 patients with FMD to a 5-day specialized outpatient PT program or to general outpatient PT referral, and measured patient-reported and clinician-measured outcomes. At 6 months, 72% of patients in the intervention group had a good outcome compared with 18% of control group patients. Patients in the specialized outpatient PT program had significantly better outcomes in 3 Short-Form 36 (SF36) domains (d=0.46 to 0.79) and multiple other scales of physical and social function as well as clinician-measured outcomes. The intervention resulted in 0.08 additional quality-adjusted life years in a cost-effective manner. CONCLUSIONS: Current evidence suggests that in patients with FMD, specialized PT improves motor symptoms in a clinically significant, sustained, and cost-effective manner. This promising intervention warrants further investigation and replication.

Network Meta-analysis of Food and Drug Administration-approved Treatment Options for Adults with Aquaporin-4 Immunoglobulin G-positive Neuromyelitis Optica Spectrum Disorder.

INTRODUCTION: Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune disease defined by attacks on the central nervous system that cause irreversible damage. Recent approval of NMOSD therapies warrants investigations of comparative efficacy to inform treatment decisions. METHODS: A network meta-analysis (NMA) of all U.S. Food and Drug Administration-approved therapies (eculizumab, inebilizumab, and satralizumab) for adults with aquaporin-4 immunoglobulin G-positive (AQP4+) NMOSD was conducted via a systematic literature review (SLR) using data from randomized controlled trials (RCTs). Database searches of MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were executed for the SLR. A fixed-effects proportional hazards Bayesian NMA was used to estimate relative treatment effects based on data extracted from RCTs identified during the SLR (search end date: 11 September 2020). Four unique RCTs (N-MOmentum, PREVENT, SAkuraSky, and SAkuraStar) were identified, and data from 29 publications were extracted for analysis. Network scenarios describing the most comparable patient population groups (such as by treatment settings) were evaluated in our analyses. Relative treatment effects were evaluated based on time-to-first relapse and were expressed as hazard ratios (HRs) with 95% credible intervals (CrIs). RESULTS: In patients treated with a monoclonal antibody only, eculizumab was associated with a lower risk of relapse compared with satralizumab (HR 0.10, 95% CrI 0.01, 0.65) and inebilizumab (HR 0.11, 95% CrI 0.02, 0.68). In patients treated with monoclonal antibody with or without background immunosuppressive therapy (IST), patients treated with eculizumab ± IST were also less likely to relapse than patients treated with satralizumab ± IST (HR 0.24, 95% CrI 0.06, 0.98). CONCLUSION: The NMA results suggest that complement component 5 (C5) inhibition prevents NMOSD relapses more effectively than broader mechanisms of action.

Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune disease characterized by inflammation that damages the brain and spinal cord. Many patients with NMOSD produce antibodies against a protein called aquaporin-4 (AQP4+). In the past two years, three drugs (eculizumab, inebilizumab, and satralizumab) have been approved by the U.S. Food and Drug Administration for the treatment of adults with AQP4+ NMOSD. Comparing the efficacy of these three drugs would help physicians make treatment decisions for their patients. In the absence of clinical trials directly comparing these three drugs, we conducted a Bayesian network meta-analysis in order to allow for simultaneous comparisons of these three drugs and estimate relative treatment effects between any pair of interventions in a connected network. With a Bayesian methodology, it is also possible to estimate the probability of being the best treatment out of all other interventions in a connected network. While all three drugs are safe and shown to prevent relapses in placebo-controlled trials, the results of our analysis suggests that eculizumab was the most efficacious in preventing relapses when compared with inebilizumab or satralizumab. These findings may help to inform physicians and their patients when determining the best treatment option for preventing the occurrence of relapses in adults with AQP4+ NMOSD.

Eculizumab monotherapy for NMOSD: Data from PREVENT and its open-label extension.

During PREVENT (a phase 3, randomized, double-blind, placebo-controlled, time-to-event study) and its open-label extension (interim analysis), 33 adults with aquaporin-4 immunoglobulin G-positive neuromyelitis optica spectrum disorder (AQP4-IgG + NMOSD) received eculizumab monotherapy for a median of 2.8 years (range, 14 weeks-5.2 years). At 192 weeks (~4 years), 96% of these patients were free from adjudicated relapses (Kaplan-Meier analysis; 95% confidence interval, 75.7-99.4). During PREVENT, 95% (20/21) of patients receiving eculizumab monotherapy had no disability worsening. Eculizumab monotherapy provides effective long-term relapse prevention, relieving the chronic immunosuppression burden in patients with AQP4-IgG + NMOSD. ClinicalTrials.gov; PREVENT: NCT01892345; open-label extension: NCT02003144.

Diagnostic value of aquaporin-4-IgG live cell based assay in neuromyelitis optica spectrum disorders.

OBJECTIVE: Determine the utility of aquaporin 4 IgG (AQP4-IgG) testing (live cell-based assay) for Neuromyelitis Optica Spectrum Disorders (NMOSD). METHODS: We included Mayo Clinic patients (1/1/2018-12/31/2019) tested for serum AQP4-IgG by live cell-based flow-cytometric assay. Medical records were reviewed to assess if patients fulfilled 2015 NMOSD criteria. RESULTS: Of 1371 patients tested, 41 were positive (3%) and all fulfilled NMOSD criteria with AQP4-IgG (specificity = 100%). Only 10/1330 testing negative met NMOSD criteria without AQP4-IgG (sensitivity = 80%) and seven of these 10 were MOG-IgG positive. CONCLUSIONS: AQP4-IgG by live cell-based assay was highly specific and without false positives in a high throughput setting.