Analysis of Evusheld safety and efficacy in multiple sclerosis patients.

BACKGROUND: In December 2021, the U.S. Food and Drug Administration issued emergency use authorization for the combination monoclonal antibodies tixagevimab and cilgavimab (Evusheld - AstraZeneca) for COVID-19 pre-exposure prophylaxis. While COVID-19 vaccination is recommended for multiple sclerosis (MS) patients, there is concern for insufficient antibody response in patients receiving B-cell depleting therapies. The literature is sparse regarding the safety and efficacy of Evusheld use in MS patients. OBJECTIVE: We sought to investigate the administration, safety, and efficacy of Evusheld in MS patients. METHODS: Participants were consecutively recruited from the UCSD MS Center from July 2022 to October 2022. We conducted both a review of medical records and a prospective cohort study. Inclusion criteria included prior diagnosis of MS and eligibility for Evusheld injection due to use of B-cell depleting disease modifying therapy (DMT). All eligible patients were evaluated to determine uptake of Evusheld use. Participant surveys were distributed to Evusheld recipients that evaluated for potential Evusheld side effects and COVID-19 vaccination and infection history. The proportion of COVID-19 infections among participants with or without Evusheld use were compared using Fisher's exact test, and a negative binomial regression analysis was used to evaluate risk for COVID-19 infection after Evusheld administration. RESULTS: A review of medical records showed that 79 MS patients were offered Evusheld by their clinicians during the recruitment period; 48 patients ultimately received the injection. Forty-two participants consented to the prospective cross-sectional study (mean age 46.4 years, 71.8 % female), of which 33 individuals received Evusheld. All participants received at least one COVID-19 vaccination dose, with 92.3 % receiving the initial series and at least one booster dose. One-third (30.8 %) of participants had a previous COVID-19 infection. DMTs included ocrelizumab, rituximab, and ofatumumab. Of the 33 participants who received Evusheld, 10 (30.3 %) reported experiencing at least one side effect. Injection site reactions included pain (most common), itchiness, and redness. General side effects included fatigue (most common), headache, muscle pain, and weakness. Of the 33 participants who received Evusheld, seven participants (21.2 %) tested positive for COVID-19 within 6 months of Evusheld injection. In an unadjusted binomial regression analysis, Evusheld administration was associated with a reduction in COVID-19 infection risk (OR 0.22, 95 % CI 0.05 - 1.02, p = 0.05). After adjusting for age and sex, Evusheld administration was still associated with a lower COVID-19 infection risk though it did not achieve nominal significance (OR 0.21, 95 % CI 0.04 - 1.09, p = 0.06). Of the 9 participants who were offered but did not receive Evusheld, five (55.6 %) tested positive for COVID-19 (p = 0.04 with Pearson's chi square test and p = 0.09 on Fisher's exact test). CONCLUSIONS: Our medical records data demonstrated that only 61 % of MS patients offered Evusheld received the injection. Evusheld seems to be largely well-tolerated. No serious adverse effects were reported. The use of Evusheld was associated with fewer COVID-19 infections, but this did not reach nominal statistical significance in the modest sample size. The lessons learned from the initial Evusheld experience may be applied to future interventions directed at infection prevention in MS patients on immunomodulatory therapies.

Survival Analysis of Immunotherapy Effects on Relapse Rate in Pediatric and Adult Autoimmune Encephalitis.

BACKGROUND AND OBJECTIVES: Prior observational studies for autoimmune encephalitis (AE) have mostly focused on outcomes after acute immunotherapies with better outcomes associated with earlier immunotherapy use. However, the impact of long-term immunotherapy and its association with clinical relapse is not well known. METHODS: We conducted a retrospective study of consecutive patients meeting published clinical criteria for AE evaluated at UC San Diego and Rady Children's Hospital from January 2007 to November 2021. Survival analysis and Cox multivariable regression models were used to evaluate relapse risk using rituximab exposure as a time-dependent variable. Pooled and age-stratified analyses were performed. RESULTS: A total of 204 pediatric and 380 adult participants were screened of which 30 pediatric and 75 adult participants were included. The most common antibody subtype in both cohorts was anti-NMDA receptor (76% in pediatric, 34% in adult). Relapses occurred in 31% of pediatric antibody-positive, 40% of adult antibody-positive, and 20% of adult antibody-negative cases. Times to first relapse (TTFR) were 10.6 ± 7.4 months (pediatric antibody-positive), 13.1 ± 24.5 months (adult antibody-positive), and 6.9 ± 3.8 months (adult antibody-negative). Rituximab was the most common second-line immunotherapy used. Combining pediatric and adult data, rituximab use was associated with a 71% lower hazard for time to first relapse (hazard ratio [HR] 0.29, 95% CI 0.09-0.85) and 51% lower hazard for recurring relapses (HR 0.49, 95% CI 0.9-1.26). The HR for TTFR with rituximab use in children was 0.30 (95% CI 0.05-1.69), 0.29 (95% CI 0.07-1.29) in adults, 0.32 in non-NMDA antibody-positive encephalitis (95% CI 0.07-1.39), and 0.42 (95% CI 0.07-2.67) for anti-NMDAR. DISCUSSION: Relapses are common in pediatric and adult patients with AE, although less frequently in anti-NMDARE. Using a rigorous survival model, we demonstrate a substantial benefit of rituximab use for reducing relapse rates in AE, especially for the adult population. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that rituximab is associated with a lower hazard to relapse in patients with AE.

Longitudinal analysis and treatment of neuropsychiatric symptoms in post-acute sequelae of COVID-19.

BACKGROUND: Persistent neuropsychiatric symptoms following acute COVID-19 infection are frequently reported. These include anxiety, depression, difficulty concentrating, fatigue, and insomnia. The longitudinal evolution of this neuropsychiatric burden is poorly understood and clinical guidelines concerning treatment are lacking. OBJECTIVE: We sought to describe the longitudinal evolution of neuropsychiatric symptoms in the post-acute sequelae of COVID-19 (PASC) syndrome and examine symptom treatment at a single center. METHODS: Consecutive participants experiencing persistent neurologic symptoms after acute COVID-19 infection were recruited from October 2020 to July 2022. Data collected included COVID-19 infection history, neurological exam and review of systems, Montreal Cognitive Assessment (MoCA), and self-reported surveys concerning neuropsychiatric symptoms and treatment. Data were collected at baseline and at 1-year follow-up. RESULTS: A total of 106 participants (mean age 48.6, females 67%) were included in the study. At 1-year follow-up, 72.5% of participants reported at least one neuropsychiatric symptom. Over half (52.5%) of participants reported persistent fatigue. At baseline, 38.8% of all participants had met the established MoCA cut-off score of < 26 for mild cognitive impairment; this decreased to 20.0% at 1 year. COVID-19 infection severity was associated with neuro-PASC symptoms (including fatigue and anxiety) at 1 year. Overall, 29% of participants started at least one new medication for COVID-19-associated neuropsychiatric symptoms. Of the participants who started new medications, fatigue was the most common indication (44.8%) followed by insomnia (27.6%). CONCLUSIONS: Neuropsychiatric symptoms related to neuro-PASC improve over time but can persist for over a year post-recovery. Most treatment modalities targeted neuro-PASC fatigue.

Effect of spin labelling on the aggregation kinetics of yeast prion protein Ure2.

Amyloid formation is involved in a wide range of neurodegenerative diseases including Alzheimer's and prion diseases. Structural understanding of the amyloid is critical to delineate the mechanism of aggregation and its pathological spreading. Site-directed spin labelling has emerged as a powerful structural tool in the studies of amyloid structures and provided structural evidence for the parallel in-register ß-sheet structure for a wide range of amyloid proteins. It is generally accepted that spin labelling does not disrupt the structure of the amyloid fibrils, the end product of protein aggregation. The effect on the rate of protein aggregation, however, has not been well characterized. Here, we employed a scanning mutagenesis approach to study the effect of spin labelling on the aggregation rate of 79 spin-labelled variants of the Ure2 prion domain. The aggregation of Ure2 protein is the basis of yeast prion [URE3]. We found that all spin-labelled Ure2 mutants aggregated within the experimental timeframe of 15 to 40 h. Among the 79 spin-labelled positions, only five residue sites (N23, N27, S33, I35 and G42) showed a dramatic delay in the aggregation rate as a result of spin labelling. These positions may be important for fibril nucleation, a rate-limiting step in aggregation. Importantly, spin labelling at most of the sites had a muted effect on Ure2 aggregation kinetics, showing a general tolerance of spin labelling in protein aggregation studies.