Baseline Expanded Disability Status Scale Research Articles

Efficacy of intrathecal mesenchymal stem cell-neural progenitor therapy in progressive MS: results from a phase II, randomized, placebo-controlled clinical trial

BackgroundMesenchymal stem cell-neural progenitors (MSC-NPs) are a bone marrow mesenchymal stem cell (MSC)-derived ex vivo manipulated cell product with therapeutic potential in multiple sclerosis (MS). The objective of this study was to determine efficacy of intrathecal (IT) MSC-NP treatment in patients with progressive MS.MethodsThe study is a phase II randomized, double-blind, placebo-controlled clinical trial with a compassionate crossover design conducted at a single site. Subjects were stratified according to baseline Expanded Disability Status Scale (EDSS) (3.0-6.5) and disease subtype (secondary or primary progressive MS) and randomized into either treatment or placebo group to receive six IT injections of autologous MSC-NPs or saline every two months. The primary outcome was EDSS Plus, defined by improvement in EDSS, timed 25-foot walk (T25FW) or nine-hole peg test. Secondary outcomes included the individual components of EDSS Plus, the six-minute walk test (6MWT), urodynamics testing, and brain atrophy measurement.ResultsSubjects were randomized into MSC-NP (n = 27) or saline (n = 27) groups. There was no difference in EDSS Plus improvement between the MSC-NP (33%) and saline (37%) groups. Exploratory subgroup analysis demonstrated that in subjects who require assistance for ambulation (EDSS 6.0-6.5) there was a significantly higher percentage of improvement in T25FW and 6MWT in the MSC-NP group (3.7% ± 23.1% and − 9.2% ± 18.2%) compared to the saline group (-54.4% ± 70.5% and − 32.1% ± 30.0%), (p = 0.030 and p = 0.036, respectively). IT-MSC-NP treatment was also associated with improved bladder function and reduced rate of grey matter atrophy on brain MRI. Biomarker analysis demonstrated increased MMP9 and decreased CCL2 levels in the cerebrospinal fluid following treatment.ConclusionResults from exploratory outcomes suggest that IT-MSC-NP treatment may be associated with a therapeutic response in a subgroup of MS patients.Trial RegistrationClinicalTrials.gov NCT03355365, registered November 14, 2017, https://clinicaltrials.gov/study/NCT03355365?term=NCT03355365&rank=1.

Alemtuzumab treatment for multiple sclerosis in Austria: An observational long-term outcome study.

Observational real-world study to analyze the clinical effects of alemtuzumab (ALEM) and subsequent disease-modifying therapy (DMT) usage in multiple sclerosis (MS). Data retrieved from the Austrian MS treatment registry (AMSTR) included baseline (BL) characteristics (at ALEM start), annualized relapse rate (ARR), 6-month confirmed progression independent of relapse activity (PIRA; ≥ 0.5-point Expanded Disability Status Scale (EDSS) score increase), 6-month confirmed disability improvement (CDI; ≥ 0.5-point EDSS decrease), and safety outcomes until initiation of a subsequent DMT. The EDSS was re-baselined at 30 days from ALEM start (BL EDSS). Eighty-seven ALEM-treated patients (median age: 32 years, 72% female, 14% treatment-naïve) were followed for a median of 55 (interquartile range 31-68) months. We found significant reductions in the ARR from 1.16 before ALEM to 0.15 throughout Years 1-9 (p < 0.001). Subsequent DMTs were initiated in 19 patients (22%, 74% anti-CD20 monoclonal antibodies). At Year 5 (n = 53), more patients achieved CDI (58%, 95% confidence interval (CI) 45%-71%) than had experienced PIRA (14%, CI 7.5%-24%), and 58% remained relapse-free. Shorter MS duration (p < 0.001, hazard ratio (HR) 0.86 (CI 0.80-0.93)) and no previous high-efficacy treatment (p < 0.001, HR 5.16 (CI 2.66-10.0)) were the best predictors of CDI, while PIRA was associated with a higher number of previous DMTs (p = 0.04, HR 3.06, CI 1.05-8.89). We found no new safety signals. ALEM had long-lasting beneficial effects on the ARR and disability improvement, especially when initiated early in the course of the disease. Only a subset of patients received subsequent DMTs.

Comparative effectiveness of dimethyl fumarate versus non-specific immunosuppressants: Real-world evidence from MSBase.

The use of non-specific immunosuppressants (NSIS) to treat multiple sclerosis (MS) remains prevalent in certain geographies despite safety concerns, likely due to resource limitations. To use MSBase registry data to compare real-world outcomes in adults with relapsing-remitting MS (RRMS) treated with dimethyl fumarate (DMF) or NSIS (azathioprine, cyclosporine, cyclophosphamide, methotrexate, mitoxantrone or mycophenolate mofetil) between January 1, 2014 and April 1, 2022. Treatment outcomes were compared using inverse probability of treatment weighting (IPTW) Cox regression. Outcomes were annualized relapse rates (ARRs), time to discontinuation, time to first relapse (TTFR) and time to 24-week confirmed disability progression (CDP) or 24-week confirmed disability improvement (CDI; in patients with baseline Expanded Disability Status Scale [EDSS] score ≥2). After IPTW, ARR was similar for DMF (0.13) and NSIS (0.16; p = 0.29). There was no difference in TTFR between cohorts (hazard ratio [HR]: 0.98; p = 0.84). The DMF cohort experienced longer times to discontinuation (HR: 0.75; p = 0.001) and CDP (HR: 0.53; p = 0.001), and shorter time to CDI (HR: 1.99; p < 0.008), versus the NSIS cohort. This analysis supports the use of DMF to treat patients with relapsing forms of MS, and may have implications for MS practices in countries where NSIS are commonly used to treat RRMS.

Comparing ocrelizumab to interferon/glatiramer acetate in people with multiple sclerosis over age 60

BackgroundOngoing controversy exists regarding optimal management of disease modifying therapy (DMT) in older people with multiple sclerosis (pwMS). There is concern that the lower relapse rate, combined with a higher...

Complement Activation Is Associated With Disease Severity in Multiple Sclerosis.

Histopathologic studies have identified immunoglobulin (Ig) deposition and complement activation as contributors of CNS tissue damage in multiple sclerosis (MS). Intrathecal IgM synthesis is associated with higher MS disease activity and severity, and IgM is the strongest complement-activating immunoglobulin. In this study, we investigated whether complement components (CCs) and complement activation products (CAPs) are increased in persons with MS, especially in those with an intrathecal IgM synthesis, and whether they are associated with disease severity and progression. CC and CAP levels were quantified in plasma and CSF of 112 patients with clinically isolated syndrome (CIS), 127 patients with MS (90 relapsing-remitting, 14 primary progressive, and 23 secondary progressive), 31 inflammatory neurologic disease, and 44 symptomatic controls from the Basel CSF databank study. Patients with CIS/MS were followed in the Swiss MS cohort study (median 6.3 years). Levels of CC/CAP between diagnosis groups were compared; in CIS/MS, associations of CC/CAP levels with intrathecal Ig synthesis, baseline Expanded Disability Status Scale (EDSS) scores, MS Severity Score (MSSS), and neurofilament light chain (NfL) levels were investigated by linear regression, adjusted for age, sex, and albumin quotient. CSF (but not plasma) levels of C3a, C4a, Ba, and Bb were increased in patients with CIS/MS, being most pronounced in those with an additional intrathecal IgM production. In CIS, doubling of C3a and C4a in CSF was associated with 0.31 (CI 0.06-0.56; p = 0.016) and 0.32 (0.02-0.62; p = 0.041) increased EDSS scores at lumbar puncture. Similarly, doubling of C3a and Ba in CIS/MS was associated with 0.61 (0.19-1.03; p < 0.01) and 0.74 (0.18-1.31; p = 0.016) increased future MSSS. In CIS/MS, CSF levels of C3a, C4a, Ba, and Bb were associated with increased CSF NfL levels, e.g., doubling of C3a was associated with an increase of 58% (Est. 1.58; CI 1.37-1.81; p < 0.0001). CNS-compartmentalized activation of the classical and alternative pathways of complement is increased in CIS/MS and associated with the presence of an intrathecal IgM production. Increased complement activation within the CSF correlates with EDSS, future MSSS, and NfL levels, supporting the concept that complement activation contributes to MS pathology and disease progression. Complement inhibition should be explored as therapeutic target to attenuate disease severity and progression in MS.

CSF levels of Chitinase3like1 correlate with early response to cladribine in multiple sclerosis.

Cladribine has been introduced as a high-efficacy drug for treating relapsing-remitting multiple sclerosis (RRMS). Initial cohort studies showed early disease activity in the first year after drug initiation. Biomarkers that can predict early disease activity are needed. To estimate cerebrospinal fluid (CSF) markers of clinical and radiological responses after initiation of cladribine. Forty-two RRMS patients (30F/12M) treated with cladribine were included in a longitudinal prospective study. All patients underwent a CSF examination at treatment initiation, clinical follow-up including Expanded Disability Status Scale (EDSS) assessment, and a 3T MRI scan after 6,12 and 24 months, including the evaluation of white matter (WM) and cortical lesions (CLs). CSF levels of 67 inflammatory markers were assessed with immune-assay multiplex techniques. The 'no evidence of disease activity' (NEDA-3) status was assessed after two years and defined by no relapses, no disability worsening measured by EDSS and no MRI activity, including CLs. Three patients were lost at follow-up. At the end of follow-up, 19 (48%) patients remained free from disease activity. IFNgamma, Chitinase3like1, IL32, Osteopontin, IL12(p40), IL34, IL28A, sTNFR2, IL20 and CCL2 showed the best association with disease activity. When added in a multivariate regression model including age, sex, and baseline EDSS, Chitinase 3 like1 (p = 0.049) significantly increased in those patients with disease activity. Finally, ROC analysis with Chitinase3like1 added to a model with EDSS, sex, age previous relapses, WM lesion number, CLs, number of Gad enhancing lesions and spinal cord lesions provided an AUC of 0.76 (95%CI 0.60-0.91). CSF Chitinase 3 like1 might provide prognostic information for predicting disease activity in the first years after initiation of cladribine. The drug's effect on chronic macrophage and microglia activation deserves further evaluation.

Assessing the duration of EDSS improvement after a therapy start: A novel approach applied to the long-term extension of the PRISMS study.

In a chronic and progressive disease such as multiple sclerosis (MS), the improvement on Expanded Disability Status Scale (EDSS) can be a transient event. Therefore, estimating the prevalence of disability improvement over time, accounting both for improvement incidence and duration, is of interest. The aim of this study was to show the application of a simple estimator for the proportion of patients with sustained improvement over time using data from the long-term extension of the PRISMS trial. A total of 534 relapsing-remitting MS (RRMS) patients from the PRISMS trial were included. Patients with a baseline EDSS of 0 were excluded. Patients were randomized to placebo (n=178), subcutaneous interferon beta-1a (sc IFN β-1a) 22µg (n=181) or sc IFN β-1a 44µg (n=175). At Year 2, patients receiving placebo were re-randomized to sc IFN β-1a 22µg or 44µg (delayed sc IFN β-1a) while patients receiving sc IFN β-1a 22µg or 44µg continued their initial regimen. Patients were followed up for over 7 years post-randomization. Disability improvement was defined as a 1-point decrease in EDSS from baseline confirmed at 6 months. Prevalence of improvement was estimated as difference of Kaplan-Meier (KM) estimators while the cumulative incidence of improvement was calculated using the standard KM curves. No significant differences in cumulative incidence of EDSS improvement at 3 years between delayed sc IFN β-1a (20.3%) and sc IFN β-1a 22µg (20.8%; p=0.49) or 44µg (21.3%; p=0.33). When taking duration of improvement into account, the proportion of patients showing an improved condition after 3 years was 10.1% with delayed sc IFN β-1a, 11.3% with sc IFN β-1a 22µg (p=0.17) and 15.4% with sc IFN β-1a 44µg (p=0.037) that was substantially maintained over the long term. With the use of this new statistical methodology, it is possible to estimate the time to improvement as well as the duration of improvement, information that is better suited to describing a non-final outcome like disability improvement. In this case, early sc IFN β-1a 44µg initiation had a greater proportion of patients with a sustained disability improvement over a long period of follow-up as compared to patients who had initially been randomized to placebo. In contrast, no significant differences on the cumulative incidence of improvement were observed.

Effectiveness and Safety of Teriflunomide in Relapsing-Remitting Multiple Sclerosis and Improvements in Quality of Life: Results from the Real-World TERICARE Study.

Teriflunomide is a once-daily oral immunomodulator approved for relapsing forms of multiple sclerosis (MS) or relapsing-remitting multiple sclerosis (RRMS; depending on the local label), based on extensive evidence from clinical trials and a real-world setting on efficacy, tolerability and patient-reported benefits. The TERICARE study assessed the impact of teriflunomide treatment over 2years on health-related quality of life (HRQoL) and some of the most common and disabling symptoms of MS, such as fatigue and depression. This prospective observational study in Spain included RRMS patients treated with teriflunomide for ≤ 4weeks. The following patient-reported outcomes (PROs) were collected at baseline and every 6months for 2years: the 29-item Multiple Sclerosis Impact Scale version 2 (MSIS-29), the 21-item Modified Fatigue Impact Scale (MFIS-21), the Beck Depression Inventory (BDI-II), the Short Form (SF)-Qualiveen and theTreatment Satisfaction Questionnaire for Medication v1.4 (TSQM). Annualised relapse rate (ARR), disability progression according to the Expanded Disability Status Scale (EDSS), and no evidence of disease activity (NEDA-3) were also assessed. A total of 325 patients were analysed. Patients had a mean (SD) age of 43.2years (10.4), a mean baseline EDSS score of 1.75 (1.5), a mean number of relapses in the past 2years of 1.5 (0.7), and 64% had received prior disease-modifying therapy (DMT). Patients showed significant improvements in the psychological domain of MSIS-29 from 35.9 (26.6) at baseline to 29.4 (25.5) at 18months (p = 0.004) and 29.0 (24.6) at 24months (p = 0.002). Levels of fatigue and depression were also reduced. After 2years of treatment with teriflunomide, ARR was reduced to 0.17 (95% CI 0.14-0.21) from the baseline of 0.42 (95% CI 0.38-0.48), representing a 60.1% reduction. Mean EDSS scores remained stable during the study, and 79.9% of patients showed no disability progression. 54.7% of patients achieved NEDA-3 in the first 12months, which increased to 61.4% during months 12-24. Patients reported increased satisfaction with treatment over the course of the study, regardless of whether they were DMT naive or not. Teriflunomide improves psychological aspects of HRQoL and maintains low levels of fatigue and depression. Treatment with teriflunomide over 2years is effective in reducing ARR and disability progression.

Comparative analysis of dimethyl fumarate and teriflunomide in relapsing-remitting multiple sclerosis.

In relapsing-remitting multiple sclerosis (RRMS), analyses from observational studies comparing dimethyl fumarate (DMF) and teriflunomide showed conflicting results. We aimed to compare the effectiveness of DMF and teriflunomide in a real-world setting, where both drugs are licensed as first-line therapies for RRMS. We included all patients who initiated DMF or teriflunomide between 2013 and 2022, listed in the Swiss National Treatment Registry. Coarsened exact matching was applied using age, gender, disease duration, baseline Expanded Disability Status Scale (EDSS) score, time since last relapse, and relapse rate in the previous year as matching variables. Time to relapse and time to 12-month confirmed EDSS worsening were compared using Cox proportional hazard models. In total, 2028 patients were included in this study, of whom 1498 were matched (DMF: n = 1090, 69.6% female, mean age 45.1 years, median EDSS score 2.0; teriflunomide: n = 408, 68.9% female, mean age 45.1 years, median EDSS score 2.0). Time to relapse and time to EDSS worsening was longer in the DMF than the teriflunomide group (hazard ratio 0.734, p = 0.026 and hazard ratio 0.576, p = 0.003, respectively). Analysis of real-world data showed that DMF treatment was associated with more favorable outcomes than teriflunomide treatment.

Functional Disability and Brain MRI Volumetry Results among Multiple Sclerosis Patients during 5-Year Follow-Up.

Background and Objectives: We aimed to determine the link between brain volumetry results and functional disability calculated using the Expanded Disability Status Scale (EDSS) among multiple sclerosis (MS) patients in relation to the provided treatment (disease-modifying therapies (DMTs)) during a 5-year follow-up period. Materials and Methods: A retrospective cohort study was performed enrolling 66 consecutive patients with a confirmed diagnosis of MS, predominantly females (62% (n = 41)). Relapsing-remitting (RR) MS was noted in 92% (n = 61) of patients, with the rest being patients with secondary progressive (SP) MS. The mean age was 43.3 years (SD 8.3 years). All patients were evaluated clinically using the EDSS and "FreeSurfer© 7.2.0" radiologically during a 5-year follow-up. Results: A significant increase in patient functional disability was noted, calculated using the EDSS during a 5-year follow-up. The baseline EDSS ranged between 1 and 6 with a median of 1.5 (IQR 1.5-2.0), and after 5 years, the EDSS was between 1 and 7, with a median EDSS of 3.0 (IQR 2.4-3.6). Compared with RRMS patients, SPMS patients demonstrated a significant increase in EDSS score during a 5-year period, with a median EDSS of 2.5 in RRMS patients (IQR 2.0-3.3) and 7.0 (IQR 5.0-7.0) among SPMS patients. Significantly lower brain volumetry results in different brain areas were found, including cortical, total grey and white matter, p < 0.05. Statistically significant differences were observed between baseline volumetry results of the hippocampus and the middle anterior part of the corpus callosum and their volumetry results after 5 years, p < 0.001. In this study population, the thalamus did not demonstrate significant changes in volumetry results during follow-up, p > 0.05. The provided treatment (DMTs) did not demonstrate a significant impact on the brain MRI volumetry results during a 5-year follow-up, p > 0.05. Conclusions: Brain MRI volumetry seriously impacts the early detection of brain atrophic changes. In this study, significant relationship between brain magnetic resonance volumetry results and disability progression among MS patients with no important impact of the provided treatment was described. Brain MRI volumetry may aid in the identification of early disease progression among MS patients, as well as enrich the clinical evaluation of MS patients in clinical patient care.

Early depressive symptoms and disability accrual in Multiple Sclerosis: a UK MS Register study

Understanding the associations and potential drivers of long-term disability in Multiple Sclerosis (MS) is of clinical and prognostic value. Previous data have suggested a link between depression and disability accrual in MS. We aimed to determine whether depression in early MS predicts subsequent accrual of disability. Using data from the UK MS Register, we identified individuals with and without symptoms of depression and anxiety close to disease onset. We used Cox proportional hazards regression to evaluate whether early depressive or anxiety symptoms predict subsequent physical disability worsening, measured using the Expanded Disability Status Scale (EDSS). We analysed data from 862 people with MS of whom 134 (15.5%) reached an EDSS of ≥ 6.0. Early depressive symptoms were associated with an increased risk of reaching an EDSS of 6.0 (HR 2.42, 95% CI 1.49–3.95, p < 0.001), however this effect dissipated when adjusting for baseline EDSS (HR 1.40, 95% CI 0.84–2.32, p = 0.2). These data suggest that early depressive symptoms in MS are associated with subsequent disability accrual, but are likely the result of disability rather than its cause.

Delayed Signs of Early Disability Progression After 8.5 Years of Ocrelizumab Treatment in Patients With Relapsing Multiple Sclerosis (S46.003)

Delayed Signs of Early Disability Progression After 8.5 Years of Ocrelizumab Treatment in Patients With Relapsing Multiple Sclerosis (S46.003)

Ocrelizumab and Cladribine had similar EDSS stability and safety profile in patients with highly active multiple sclerosis (P8-3.011)

<h3>Objective:</h3> To study change of disability in patients with highly-active relapsing remitting multiple sclerosis (RRMS) treated with cladribine or ocrelizumab. <h3>Background:</h3> Highly active MS patients have a higher risk of early progression. <h3>Design/Methods:</h3> This is prospective study including RRMS who were treated with cladribine or ocrelizumab and have one year follow up. Expanded disability status scale (EDSS) at initiation of treatment and at the end of observational period were reported. Confirmed disability progression (CDP) on EDSS defined as increase on the EDSS of at least 1.5 points for baseline EDSS of 0, an increase on the EDSS of at least 1 point for baseline EDSS between 1 and 5, or an increase of at least 0.5 point for a baseline EDSS at least 5.5. Improved disability was defined as any decrease in EDSS score 1 or more if baseline EDSS was 1–4.5 or 0.5 or more if EDSS was 5.0 or more. <h3>Results:</h3> Among 200 patients with highly-active MS, 72 patients received cladribine tablets and 128 received ocrelizumab infusions. Most of this cohort are females 139 (69.5%) with mean age 34.62 ±9.80 and mean disease duration 7.30 ±5.97. EDSS was stable among most of patients who received cladribine 56 (77.8%) and those who received ocrelizumab 105 (82%); P&lt;0.466.CPD was similar among patients under cladribine 5(6.9%) and those under ocrelizumab 9 (7%) ; P&lt;0.983. Improvement of disability was higher among cladribine group 11 (15.3%) compared to ocrelizumab group 14 (10.9%); P&lt;0.466. The mean EDSS score before cladribine was 1.63±1.30, whereas the mean EDSS before Ocrevus was 1.80±1.31. EDSS score remained stable under both cladribine 1.56±1.40 and under ocrelizumab 1.78±1.24. Patients reported mild adverse events in similar ratios under both cladribine and ocrelizumab (19.4%, 18% respectively, p&gt;0.850). <h3>Conclusions:</h3> Both cladribine and ocrelizumab resulted similar in terms of EDSS stability and safety profile. <b>Disclosure:</b> Dr. Alshawaf has nothing to disclose. Dr. Ahmed has nothing to disclose. Dr. Al-Hashel has nothing to disclose. Dr. Alroughani has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen, Bayer, Novartis, Merck, Roche, Sanofi. Dr. Alroughani has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Bayer, Biogen, Novartis, Merck, Roche, Sanofi.

Cognitive Processing Speed Predicts Disability Milestones in Multiple Sclerosis (P5-3.014)

Cognitive Processing Speed Predicts Disability Milestones in Multiple Sclerosis (P5-3.014)

Baseline predictors of disability worsening among patients wth a Clinically Isolated Syndrome. (P5-3.015)

Baseline predictors of disability worsening among patients wth a Clinically Isolated Syndrome. (P5-3.015)

Effectiveness of ocrelizumab on clinical and MRI outcome measures in multiple sclerosis across black and white cohorts: A single-center retrospective study.

To examine differences in the therapeutic response to ocrelizumab in multiple sclerosis (MS) patients who self-identified as either White or Black, assessed longitudinally by expanded disability status scale (EDSS) progression and MRI brain volume loss. MS subjects treated with ocrelizumab were retrospectively identified. Clinical data were available for 229 subjects (White 146; Black 83) and MRI data from for 48 subjects (White 31; Black 17). Outcome measures were changes in the EDSS and brain volume over time. EDSS were analyzed as raw scores, ambulatory (EDSS <5.0) vs. ambulatory with assistance (5.5 ≤ EDSS ≤ 6.5) status, and EDSS severity (< 3.0, 3.0-5.0, and > 5.5 ≤ 6.5). General linear mixed model was used for statistical analysis. FreeSurfer was used for volumetric analysis. The Black cohort had overrepresentation of females (78% vs. 62%, p=0.013), lower age (median, 45 (IQR 39-51) vs. 49 (38-58), p=0.08), lower Vitamin D levels (33 (21-45) vs. 40 (29-52), p=0.002), and higher EDSS (4 (2-6) vs. 2.5 (1-6), p=0.019). There was no progression of EDSS scores over the 2-year observation period. The covariates with significant influence on the baseline EDSS scores were older age, race, longer disease duration, prior MS treatment, and lower vitamin D levels. No differences were observed between the racial groups over time in the cortical, thalamic, caudate, putamen, and brainstem gray matter volumes nor in the cortical thickness or total lesion volume. In this real-world clinical and radiological study, ocrelizumab treatment was highly effective in stabilizing clinical and MRI measures of disease progression in Blacks and Whites, despite higher baseline disability in the Black cohort.

Ratio of lymphocyte to monocyte area under the curve as a novel predictive factor for severe infection in multiple sclerosis.

Individuals with multiple sclerosis (MS) are vulnerable to all types of infection, because MS itself involves immunodeficiency, in addition to involving treatment with immunosuppressants. Simple predictive variables for infection that are easily assessed in daily examinations are warranted. Lymphocyte area under the curve (L_AUC), defined as the sum of serial absolute lymphocyte counts under the lymphocyte count-time curve, has been established as a predictive factor for several infections after allogenic hematopoietic stem cell transplantation. We assessed whether L_AUC could also be a useful factor for predicting severe infection in MS patients. From October 2010 to January 2022, MS patients, diagnosed based on the 2017 McDonald criteria, were retrospectively reviewed. We extracted patients with infection requiring hospitalization (IRH) from medical records and matched with controls in a 1:2 ratio. Variables including clinical severity and laboratory data were compared between the infection group and controls. L_AUC was calculated along with the AUC of total white blood cells (W_AUC), neutrophils (N_AUC), lymphocytes (L_AUC), and monocytes (M_AUC). To correct for different times of blood examination and extract mean values of AUC per time point, we divided the AUC by follow-up duration. For example, in evaluating lymphocyte counts, we defined the ratio of [L_AUC] to [follow-up duration] as [L_AUC/t]. Multivariate regression analysis was conducted to extract predictive factors associated with IRH. Also, discriminative analysis was conducted using candidate variables from multivariate analysis. The total case-control sample included 177 patients of MS with IRH (n=59) and non-IRH (controls) (n=118). Adjusted odds ratios (OR) for the risk of serious infection in patients with MS with higher baseline expanded disability status scale (EDSS) (OR 1.340, 95% confidence interval [CI] 1.070-1.670, p = 0.010) and lower ratio of L_AUC/t to M_AUC/t (OR 0.766, 95%CI 0.591-0.993, p = 0.046) were significant. Notably, the kind of treatment, including glucocorticoids (GCs), disease-modifying drugs (DMDs) and other immunosuppressants agents, and dose of GCs were not significantly associated with serious infection after correlated with EDSS and ratio of L_AUC/t to M_AUC/t. In discriminative analysis, sensitivity was 88.1% (95%CI 76.5-94.7%) and specificity was 35.6% (95%CI 27.1-45.0%), using EDSS ≥ 6.0 or ratio of L_AUC/t to M_AUC/t ≤ 3.699, while sensitivity was 55.9% (95%CI 42.5-68.6%) and specificity was 83.9% (95%CI 75.7-89.8%), using both EDSS ≥ 6.0 and ratio of L_AUC/t to M_AUC/t ≤ 3.699. Our study revealed the impact of the ratio L_AUC/t to M_AUC/t as a novel prognostic factor for IRH. Clinicians should pay more attention to laboratory data such as lymphocyte or monocyte counts itself, directly presenting individual immunodeficiency, rather than the kind of drug to prevent infection as a clinical manifestation.

Serum Glial Fibrillary Acidic Protein Compared With Neurofilament Light Chain as a Biomarker for Disease Progression in Multiple Sclerosis

There is a lack of validated biomarkers for disability progression independent of relapse activity (PIRA) in multiple sclerosis (MS). To determine how serum glial fibrillary acidic protein (sGFAP) and serum neurofilament light chain (sNfL) correlate with features of disease progression vs acute focal inflammation in MS and how they can prognosticate disease progression. Data were acquired in the longitudinal Swiss MS cohort (SMSC; a consortium of tertiary referral hospitals) from January 1, 2012, to October 20, 2022. The SMSC is a prospective, multicenter study performed in 8 centers in Switzerland. For this nested study, participants had to meet the following inclusion criteria: cohort 1, patients with MS and either stable or worsening disability and similar baseline Expanded Disability Status Scale scores with no relapses during the entire follow-up; and cohort 2, all SMSC study patients who had initiated and continued B-cell-depleting treatment (ie, ocrelizumab or rituximab). Patients received standard immunotherapies or were untreated. In cohort 1, sGFAP and sNfL levels were measured longitudinally using Simoa assays. Healthy control samples served as the reference. In cohort 2, sGFAP and sNfL levels were determined cross-sectionally. This study included a total of 355 patients (103 [29.0%] in cohort 1: median [IQR] age, 42.1 [33.2-47.6] years; 73 female patients [70.9%]; and 252 [71.0%] in cohort 2: median [IQR] age, 44.3 [33.3-54.7] years; 156 female patients [61.9%]) and 259 healthy controls with a median [IQR] age of 44.3 [36.3-52.3] years and 177 female individuals (68.3%). sGFAP levels in controls increased as a function of age (1.5% per year; P < .001), were inversely correlated with BMI (-1.1% per BMI unit; P = .01), and were 14.9% higher in women than in men (P = .004). In cohort 1, patients with worsening progressive MS showed 50.9% higher sGFAP levels compared with those with stable MS after additional sNfL adjustment, whereas the 25% increase of sNfL disappeared after additional sGFAP adjustment. Higher sGFAP at baseline was associated with accelerated gray matter brain volume loss (per doubling: 0.24% per year; P < .001) but not white matter loss. sGFAP levels remained unchanged during disease exacerbations vs remission phases. In cohort 2, median (IQR) sGFAP z scores were higher in patients developing future confirmed disability worsening compared with those with stable disability (1.94 [0.36-2.23] vs 0.71 [-0.13 to 1.73]; P = .002); this was not significant for sNfL. However, the combined elevation of z scores of both biomarkers resulted in a 4- to 5-fold increased risk of confirmed disability worsening (hazard ratio [HR], 4.09; 95% CI, 2.04-8.18; P < .001) and PIRA (HR, 4.71; 95% CI, 2.05-9.77; P < .001). Results of this cohort study suggest that sGFAP is a prognostic biomarker for future PIRA and revealed its complementary potential next to sNfL. sGFAP may serve as a useful biomarker for disease progression in MS in individual patient management and drug development.

Safety and efficacy with alemtuzumab over 13 years in relapsing-remitting multiple sclerosis: final results from the open-label TOPAZ study.

Alemtuzumab demonstrated superior efficacy versus subcutaneous interferon (IFN) beta-1a in participants with relapsing-remitting multiple sclerosis in the 2-year CARE-MS I and II trials. Efficacy was maintained in the 4-year CARE-MS extension, during which alemtuzumab-treated participants ('alemtuzumab-only') could receive additional courses upon disease activity, and IFN-treated participants switched to alemtuzumab ('IFN-alemtuzumab'). Participants who completed the CARE-MS extension could enroll in the open-label TOPAZ study which assessed safety and efficacy for 5-7 years (11-13 years after alemtuzumab/IFN initiation). Participants received additional alemtuzumab courses as needed. Assessments included adverse events (AEs; primary outcome), annualized relapse rate (ARR), 6-month confirmed disability worsening [CDW; ⩾1.0-point Expanded Disability Status Scale (EDSS) score increase or ⩾1.5 if baseline EDSS = 0], and 6-month confirmed disease improvement [CDI; >1.0-point EDSS decrease (baseline score ⩾2.0)]. 43.5% of alemtuzumab-only participants from CARE-MS II and 54.2% from CARE-MS I received no additional alemtuzumab courses; 30.0% and 20.9%, respectively, received one additional course (the median). Incidences of AEs, including thyroid AEs and infections, declined over time. The safety profile of alemtuzumab was similar for participants who received zero, one, or two additional courses. For CARE-MS II participants, who had inadequate response to previous treatment, ARR remained low during Years 3-13 for the alemtuzumab-only [0.17; 95% confidence interval (CI) 0.15-0.20] and IFN-alemtuzumab (0.14; 0.11-0.17) groups. At Year 11, the proportions of participants who were either free from CDW or who had CDI were higher in the alemtuzumab-only group (58% and 49%, respectively) than in the IFN-alemtuzumab group (51% and 37%). For CARE-MS I participants, who were previously treatment-naïve, clinical outcomes remained improved, and no between-group differences were apparent. Safety risks associated with alemtuzumab treatment declined over time. Clinical benefits were maintained up to 11-13 years, and most participants did not require more than one additional course. NCT00530348; NCT00548405; NCT00930553; NCT02255656.

Biomarkers of demyelination and axonal damage are decreased after autologous hematopoietic stem cell transplantation for multiple sclerosis

BackgroundAutologous hematopoietic stem cell transplantation (aHSCT) has seen increased use for relapsing-remitting multiple sclerosis (RRMS) in recent years. It is considered one of the most effective treatments for RRMS and has been associated with improvement in disability and prolonged remission. This suggests that the tissue-injuring disease process may have been altered by aHSCT. To assess whether this hypothesis is correct, we performed a study of three commonly used cerebrospinal fluid biomarkers of tissue damage. MethodsIn this single center study, 63 patients treated with aHSCT at Uppsala University Hospital between January 1st 2012 and January 31st 2019 were screened for participation. A control group consisting of volunteers without neurologic disease were included as a reference. Cerebrospinal fluid concentrations of neurofilament light (NFL), myelin basic protein (MBP) and glial acidic fibrillary protein (GFAp) were determined using ELISA and a multiplex proteomics platform from Meso Scale Discovery. ResultsForty-three patients with a mean age of 31 and a median follow-up time of 3.9 years were included. Their median baseline expanded disability status scale (EDSS) score was 3.5 and the annualized relapse rate in the year preceding aHSCT was 1.6. At baseline the proportion of patients with values above the upper limit of normal was 67% for NFL, 63% for MBP and 16% for GFAp. At 5-year follow-up, the proportion of patients with values above the upper limit of normal was 12% for NFL, 12% for MBP and 25% for GFAp. The mean concentration of NFL decreased from 920 pg/mL at baseline to 270 pg/mL at 5-year follow-up (p < 0.001); MBP decreased from 1500 to 680 pg/mL (p < 0.001); whereas the mean concentration of GFAp was unchanged. ConclusionIn a majority of patients, biomarkers of demyelination and axonal damage reached normal values within five years from treatment with aHSCT.