Post-Partum Clinical and Patient-Reported Outcome Changes in Mothers with Multiple Sclerosis: Findings from the NAPPREMS Study.

Background and Objective: Pregnancy in mothers with multiple sclerosis (MS) commonly results in significant changes in disease activity and changes in clinical care, including the discontinuation of disease modifying therapy (DMT). This study aimed at understanding the clinical and patient-reported outcomes (PROs) before, during and 1-year after delivery. Materials and Methods: A total of 30 pregnant mothers with MS were recruited as part of the study. Clinical (relapse activity and disability changes), PRO information and MRI outcomes were collected on four separate visits: one baseline visit-0-30 days post-delivery; and 3 follow-up visits at week 24, week 36 and week 52 from the baseline. PRO was assessed using a validated questionnaire called the Fatigue Scale for Motor and Cognitive Function (FSMC). The MRI scans were analyzed, and the count of new T2 lesions and/or contrast-enhancing lesions was determined. Results: The average time between delivery and the start of DMT was 142.5 days. Relapse activity before the pregnancy was numerically linked with the activity during the pregnancy, where up to 57.1% of the activity during pregnancy occurred in pwMS with previously active disease before conception (statistically trending with p = 0.073). The relapse activity after the pregnancy occurred twice as often in pwMS whose MS was clinically active before conception. All five pwMS who experienced a relapse prior to the pregnancy experienced worsening in their physical PRO domain. Conclusions: Pre-pregnancy activity is crucial in the screening of mothers with MS at risk for post-partum relapses, worsening of clinical disability and/or PRO measures. A post-partum MS period may benefit from the routine PRO utilization and screening for its worsening. The inflammatory activity during pregnancy was not associated with short-term disease progression.

Cognitive function in severe progressive multiple sclerosis.

Cognitive impairment is common in multiple sclerosis and negatively impacts quality of life. Cognitive status has yet to be described in people with severe progressive multiple sclerosis, in whom conventional neuropsychological testing is exceptionally difficult. The objective for the study was to characterize cognitive performance in severe progressive multiple sclerosis and compare them with age-, sex- and disease duration-matched less disabled people with multiple sclerosis using a specifically developed auditory, non-motor test of attention/cognitive processing speed-Auditory Test of Processing Speed. Also, we aimed to determine the relationship between cognitive performance and MRI-based outcomes in these matched cohorts. The Comprehensive Assessment of Severely Affected Multiple Sclerosis study was carried out at the University at Buffalo and the Boston Home, a skilled nursing facility in Dorchester, MA. Inclusion criteria were age 30-80 years and expanded disability status scale 3.0-6.5 for community-dwelling and 7.0-9.5 for skilled nursing facility people with multiple sclerosis. The cognitive assessment was performed using the Brief International Cognitive Assessment for Multiple Sclerosis consisting of Symbol Digit Modalities Test, Brief Visuospatial Memory Test-Revised, California Verbal Learning Test-2nd edition along with Auditory Test of Processing Speed, Paced Auditory Serial Addition Test-3 second and Controlled Oral Word Association Test. MRI scans were retrospectively collected and analysed for lesion and volumetric brain measurements. The rate of completion and performance of the cognitive tests was compared between the groups, and the relationship with MRI measures was determined using sex, age and years of education-adjusted linear regression models. Significantly greater percentage of the severe multiple sclerosis group completed Auditory Test of Processing Speed when compared with the current gold standard of Symbol Digit Modalities Test (93.2% versus 65.9%). Severe progressive multiple sclerosis had worse cognitive performance in all cognitive domains with greatest differences for cognitive processing speed (Symbol Digit Modalities Test > Paced Auditory Serial Addition Test-3 second > Auditory Test of Processing Speed, Cohen's d < 2.13, P < 0.001), learning and memory (Cohen's d < 1.1, P < 0.001) and language (Controlled Oral Word Association Test with Cohen's d = 0.97, P < 0.001). Multiple cognitive domains were significantly associated with lower thalamic (standardized ß < 0.419, P < 0.006) and cortical (standardized ß < 0.26, P < 0.031) volumes. Specially designed (auditory) cognitive processing speed tests may provide more sensitive screening of cognitive function in severe progressive multiple sclerosis. The cognitive profile of severe multiple sclerosis is proportional to their physical outcomes and best explained by decreased grey matter volume.

Dynamic disability measures decrease the clinico-radiological gap in people with severely affected multiple sclerosis.

BACKGROUND: Expanded Disability Status Scale (EDSS) is limited when utilized in highly disabled people with multiple sclerosis (pwMS). OBJETIVE: To explore the relationship between disability measures and MRI outcomes in severely-affected pwMS. METHODS: PwMS recruited from The Boston Home (TBH), a specialized residential facility for severly-affected pwMS and University at Buffalo (UB) MS Center were assessed using EDSS, MS Severity Scale, age-related MSS, Scripps Neurological Rating Scale (SNRS) and Combinatorial Weight-Adjusted Disability Score (CombiWISE). In all scores except SNRS, higher score indicates greater disability. MRI measures of T1, T2-lesion volume (LV), whole brain, gray matter, medulla oblongata and thalamic volumes (WBV, GMV, MOV, TV) and thalamic dysconnectivity were obtained. RESULTS: Greatest disability differences between the TBH and UB pwMS were in SNRS (24.4 vs 71.9, p < 0.001, Cohen's d = 4.05) and CombiWISE (82.3 vs. 38.9, p < 0.001, Cohen's d = 4.02). In combined analysis of all pwMS, worse SNRS scores were correlated with worse MRI pathology in 8 out of 9 outcomes. EDSS only with 3 measures (GMV, MOV and TV). In severely-affected pwMS, SNRS was associated with T1-LV, T2-LV and WBV (not surviving false discovery rate (FDR) correction for multiple comparisons) whereas EDSS did not. CONCLUSION: Granular and dynamic disability measures may bridge the clinico-radiologcal gap present in severely affected pwMS.

Tixagevimab and Cilgavimab (Evusheld™) Prophylaxis Prevents Breakthrough COVID-19 Infections in Immunosuppressed Population: 6-Month Prospective Study.

BACKGROUND: Persons with neuroinflammatory diseases (pwNID) treated with potent immunosuppressives are at risk of severe COVID-19 outcomes and reduced vaccine seroconversion. We aimed at determining the real-world efficacy of tixagevimab and cilgavimab (Evusheld™) in immunosuppressed pwNID in preventing breakthrough COVID-19 infections. METHODS: 31 immunosuppressed pwNID were followed for 6 months after administration of tixagevimab and cilgavimab as a prophylactic COVID-19 medication (January 2022-July 2022). Only pwNID treated with anti-CD20 monoclonal antibodies and sphingosine-1-phosphate modulators were considered eligible for the study. A control group of 126 immunosuppressed pwNID (38 seropositive and 88 seronegative after SARS-CoV-2 vaccination) were included. Breakthrough COVID-19 infections rate and their severity was determined over the follow-up. RESULTS: The pwNID treated with tixagevimab and cilgavimab had more comorbidities when compared with the total and seronegative pwNID control group (54.8% vs. 30.2% vs. 27.3%, p = 0.02 and p = 0.005, respectively). After a 6-month follow-up, significantly lower numbers of pwNID treated with tixagevimab and cilgavimab had breakthrough COVID-19 when compared with the control pwNID group (6.5% vs. 34.1%, p = 0.002) and seronegative control pwNID group (6.5% vs. 38.6%, p < 0.001). All COVID-19 infections in Evusheld-treated pwNID were mild, whereas 9/43 COVID-19 infections in the control group were moderate/severe. No side effects to tixagevimab and cilgavimab were recorded. CONCLUSION: In pwNID treated with immunosuppressive therapies, tixagevimab and cilgavimab (Evusheld™) significantly reduced the numbers and severity of breakthrough COVID-19 infections during the Omicron (BA.2-BA.5 variants) wave.

Multiple Sclerosis in Children: Differential Diagnosis, Prognosis, and Disease-Modifying Treatment.

Pediatric-onset multiple sclerosis (POMS) is a rare neuroinflammatory and neurodegenerative disease that has a significant impact on long-term physical and cognitive patient outcomes. A small percentage of multiple sclerosis (MS) diagnoses occur before the age of 18 years. Before treatment initiation, a careful differential diagnosis and exclusion of other similar acquired demyelinating syndromes such as anti-aquaporin-4-associated neuromyelitis optica spectrum disorder (AQP4-NMOSD) and myelin oligodendrocyte glycoprotein antibody spectrum disorder (MOGSD) is warranted. The recent 2017 changes to the McDonald criteria can successfully predict up to 71% of MS diagnoses and have good specificity of 95% and sensitivity of 71%. Additional measures such as the presence of T1-weighted hypointense lesions and/or contrast-enhancing lesions significantly increase the accuracy of diagnosis. In adults, early use of disease-modifying therapies (DMTs) is instrumental to a better long-term prognosis, including lower rates of relapse and disability worsening, and numerous FDA-approved therapies for adult-onset MS are available. However, unlike their adult counterparts, the development, testing, and regulatory approval of POMS treatments have been significantly slower and hindered by logistic and/or ethical considerations. Currently, only two MS DMTs (fingolimod and teriflunomide) have been tested in large phase III trials and approved by regulatory agencies for use in POMS. First-line therapies not approved by the FDA for use in children (interferon-ß and glatiramer acetate) are also commonly used and result in a significant reduction in inflammatory activity when compared with non-treated POMS patients. An increasing number of POMS patients are now treated with moderate efficacy therapies such as dimethyl fumarate and high-efficacy therapies such as natalizumab, anti-CD20 monoclonal antibodies, anti-CD52 monoclonal antibodies, and/or autologous hematopoietic stem cell transplantation. These high-efficacy DMTs generally provide additional reduction in inflammatory activity when compared with the first-line medications (up to 62% of relapse-rate reduction). Therefore, a number of phase II and III trials are currently investigating their efficacy and safety in POMS patients. In this review, we discuss potential changes in the regulatory approval process for POMS patients that are recommended for DMTs already approved for the adult MS population, including smaller sample size for pharmacokinetic/pharmacodynamic studies, MRI-centered primary outcomes, and/or inclusion of teenagers in the adult trials.

A prospective study to validate the expanded timed get-up-and-go in a population with multiple sclerosis.

Background: Timed 25-foot walk (T25FW) test serves as gold standard in care of persons with multiple sclerosis (PwMS) and as walking measure of regulatory trials. Objective: To validate and determine the clinical utility of Expanded Timed Get-Up and Go (ETGUG) as a disability measure in MS. Methods: ETGUG intra-rater and inter-rater reproducibility was determined in 65 PwMS that were examined twice in two centres over 1-week. Values below the 5th and above the 95th percentile were considered minimally detectable change. A longitudinal cohort (32.4 months) of 145 PwMS from New York State MS Consortium (NYSMSC) was used for clinical validation as a predictor of disability worsening measured by Expanded Disability Status Scale (EDSS). Results: ETGUG and T25FW had noteworthy intra-rater and inter-rater reproducibility (Cronbach coefficient>0.949). One-week ETGUG difference ranged from 15.07% to -14.84% (5th and 95th percentile). Over the NYSMSC follow-up, PwMS had significant slowing in walking as measured by ETGUG (20.8 to 25.9s, p = 0.009) but not by T25FW. 15% ETGUG worsening had similar ability to predict EDSS worsening when compared to 20% T25FW worsening (AUC 0.596 vs. 0.552). Conclusion: Over 32-month follow-up, PwMS experience slowing in ETGUG walking time but not in T25FW. Although the scoring may be more challenging, ETGUG could be more sensitive to change and provide more comprehensive measure of lower extremity performance and ambulation in PwMS.

COVID-19 Vaccination in Multiple Sclerosis and Inflammatory Diseases: Effects from Disease-Modifying Therapy, Long-Term Seroprevalence and Breakthrough Infections.

Background: To determine the effect of disease-modifying therapies (DMT) on humoral postvaccine seroconversion, long-term humoral response, and breakthrough COVID-19 infections in persons with multiple sclerosis (PwMS) and other neuroinflammatory disorders. Methods: A total of 757 PwMS and other neuroinflammatory disorders were recruited in two MS centers and vaccinated with one of the FDA-approved vaccines (BNT162b2, mRNA-1273, Ad26.COV2.S). The primary outcomes are the rate of humoral postvaccine seroconversion and anti-severe acute respiratory syndrome coronavirus 2 (anti-SARS-CoV-2) immunoglobulin G (IgG) differences between patients on different DMTs. Secondary measures include breakthrough infections and humoral response after six months. Other outcomes include differences in vaccine response between SARS-CoV-2 vaccines and the effects of age and comorbidities on the vaccine response. Results: A total of 465 (68.4%) PwMS and 55 (74.3%) patients with neuroinflammatory diseases were seropositive at 4−12 weeks after vaccination. A significant difference in seroconversion based on the DMT used at the time of vaccination (p < 0.001) was observed, with the lowest rates seen in patients treated with anti-CD20 antibodies (23.2%) and sphingosine-1-phosphate modulators (S1P) (30.8%). In seropositive patients, there was a significant decrease in anti-SARS IgG from mean 20.0 to 4.7 at six months (p = 0.004). Thirty-nine patients had breakthrough infection, but only two seronegative patients required hospitalization. mRNA vaccines resulted in significantly greater seroconversion compared to Ad26.COV2.S (p < 0.001). Older age and presence of cardiovascular comorbidities were associated with lower anti-SARS IgG (p = 0.021 and p = 0.003, respectively) Conclusions: PwMS and neuroinflammatory disorders treated with anti-CD20 and S1P medications have lower humoral response after anti-SARS-CoV-2 vaccination, even after booster dose. Waning of the humoral response puts vaccinated PwMS at a greater risk of COVID-19 breakthrough.

Considering patient age when treating multiple sclerosis across the adult lifespan.

Introduction: The successful development of anti-inflammatory disease-modifying treatments (DMT) significantly improved disease outcomes and longevity of persons with multiple sclerosis (pwMS). However, the shift toward an elderly MS population has resulted with new concerns regarding DMT efficacy and safety.Areas covered: This review summarizes the evidence of an age-based decrease in the efficacy of MS DMTs and increase in pharmacovigilance concerns. The age effects on pathophysiological MS processes, immunosenescence and its relevance to DMT selection or discontinuation are also reviewed. Lastly, the authors discuss the influence of age-associated comorbidities on DMT initiation and drug-induced events.Expert opinion: There is an age discrepancy between pwMS included in regulatory drug trials and an aging real-world MS population. Most trials demonstrate significantly diminished anti-inflammatory efficacy in patients older than 40 years old. Older age is associated with a greater risk for adverse events including serious infections. Age-associated comorbidities influence the risk-benefit analysis and sometimes cause patients to discontinue DMTs. Instead of chronological age cutoffs, therefore, studies should aim at promoting biologically-based age biomarkers.

Dimethyl Fumarate in the Treatment of Relapsing-Remitting Multiple Sclerosis: Patient Reported Outcomes and Perspectives.

Dimethyl fumarate (DMF) is a commonly prescribed oral medication for the treatment of relapsing forms of multiple sclerosis (MS) with a wide range of hypothesized downstream mechanisms of action. Randomized clinical trials have established its clinical efficacy by using standard objective clinical measures. However, MS is a chronic disease that, apart from physical ailments, can affect an individual's mood, psychosocial status, and quality of life which cannot be captured by using only objective assessment tools. Given the challenge of determining the efficacy of the treatment in a real-world clinical setting, the use of patient-reported outcomes (PROs) may help us to better address these aspects of patient care and establish a more patient-centered approach to MS care. To date, a review of PubMed identified six studies which reported on PROs in patients who are taking DMF. In total, twelve different kinds of PRO measures were utilized and 6359 patients provided at least one form of PRO in these studies. Upon review of these studies, we were able to conclude that people with MS had decreased quality of life compared to the healthy population in the US. MS patients on DMF, however, had better health-related quality of life assessment scores compared to those using a placebo. Previous studies also suggested that DMF decreased work productivity impairment scores after one year of use compared to baseline. DMF was associated with less impairment in fatigue and depression scales along with improved treatment quality assessment and adherence scores. This review will present a brief synopsis of the published literature and will provide indications for future directions with respect to PROs and DMF in people with MS.