Expanded Disability Status Scale Improvement Research Articles

Effectiveness of autologous haematopoietic stem cell transplantation versus natalizumab in progressive multiple sclerosis

BackgroundNatalizumab was not shown to modify disability in progressive multiple sclerosis (MS). This matched observational study compared the effectiveness of autologous haematopoietic stem cell transplantation (AHSCT) with natalizumab in progressive...

Progression independent of relapse activity in relapsing multiple sclerosis: impact and relationship with secondary progression

ObjectivesWe investigated the occurrence and relative contribution of relapse-associated worsening (RAW) and progression independent of relapse activity (PIRA) to confirmed disability accrual (CDA) and transition to secondary progression (SP) in relapsing multiple sclerosis (MS).MethodsRelapsing-onset MS patients with follow-up > / = 5 years (16,130) were extracted from the Italian MS Registry. CDA was a 6-month confirmed increase in Expanded Disability Status Scale (EDSS) score. Sustained disability accumulation (SDA) was a CDA with no EDSS improvement in all subsequent visits. Predictors of PIRA and RAW and the association between final EDSS score and type of CDA were assessed using logistic multivariable regression and multivariable ordinal regression models, respectively.ResultsOver 11.8 ± 5.4 years, 16,731 CDA events occurred in 8998 (55.8%) patients. PIRA (12,175) accounted for 72.3% of CDA. SDA occurred in 8912 (73.2%) PIRA and 2583 (56.7%) RAW (p < 0.001). 4453 (27.6%) patients transitioned to SPMS, 4010 (73.2%) out of 5476 patients with sustained PIRA and 443 (24.8%) out of 1790 patients with non-sustained PIRA. In the multivariable ordinal regression analysis, higher final EDSS score was associated with PIRA (estimated coefficient 0.349, 95% CI 0.120–0.577, p = 0.003).DiscussionIn this real-world relapsing-onset MS cohort, PIRA was the main driver of disability accumulation and was associated with higher disability in the long term. Sustained PIRA was linked to transition to SP and could represent a more accurate PIRA definition and a criterion to mark the putative onset of the progressive phase.

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.

Sex differences in multiple sclerosis relapse presentation and outcome: a retrospective, monocentric study of 134 relapse events.

Reporting of sex-specific analyses in multiple sclerosis (MS) is sparse. Disability accrual results from relapses (relapse-associated worsening) and independent thereof (progression independent of relapses). A population of MS patients during relapse treated per standard of care was analyzed for sex differences and short-term relapse outcome (3-6 months) as measured by Expanded Disability Status Scale (EDSS) change. Single-center retrospective study. We analyzed 134 MS relapses between March 2016 and August 2020. All events required relapse treatment (steroids and/or plasma exchange). Demographic, disease, and paraclinical characteristics [cerebrospinal fluid (CSF) and magnetic resonance imaging (MRI)] were displayed separated by sex. Multivariable linear regression was run to identify factors associated with short-term EDSS change. Mean age at relapse was 38.4 years (95% confidence interval: 36.3-40.4) with a proportion of 71.6% women in our cohort. Smoking was more than twice as prevalent in men (65.8%) than women (32.3%). In- and after-relapse EDSSs were higher in men [men: 3.3 (2.8-3.9), women: 2.7 (2.4-3.0); men: 3.0 (1.3-3.6); women: 1.8 (1.5-2.1)] despite similar relapse intervention. Paraclinical parameters revealed no sex differences. Our primary model identified female sex, younger age, and higher EDSS at relapse to be associated with EDSS improvement. A higher immunoglobulin G (IgG) quotient (CSF/serum) was associated with poorer short-term outcome [mean days between first relapse treatment and last EDSS assessment 130.2 (79.3-181.0)]. Sex and gender differences are important in outcome analyses of MS relapses. Effective treatment regimens need to respect putative markers for a worse outcome to modify long-term prognosis such as clinical and demographic variables, complemented by intrathecal IgG synthesis. Prospective trials should be designed to address these differences and confirm our results.

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.

Elevated serum levels of bone morphogenetic protein-9 are associated with better outcome in AQP4-IgG seropositive NMOSD

Lymphatic drainage in the central nervous system is regulated by meningeal lymphatic vasculature, and recurrent neuroinflammation alters lymphatic vessel remodeling. Patients with aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder (AQP4 + NMOSD) were reported to demonstrate worse outcomes compared with patients with anti-myelin oligodendrocyte glycoprotein-associated disorders (MOGAD). This study aimed to investigate the serum cytokines relevant to vascular remodeling after attacks and their prognostic role in patients with AQP4 + NMOSD. This study measured the serum levels of 12 cytokines relevant to vascular remodeling, including bone morphogenetic protein-9 (BMP-9) and leptin, in 20 patients with AQP4 + NMOSD and 17 healthy controls (HCs). Disease controls included 18 patients with MOGAD. Serum and cerebrospinal fluid interleukin-6 levels were also measured. Clinical severity was evaluated with Kurtzke’s Expanded Disability Status Scale (EDSS). Compared with HCs, patients with AQP4 + NMOSD showed higher BMP-9 (median; 127 vs. 80.7 pg/mL; P = 0.0499) and leptin levels (median; 16,081 vs. 6770 pg/mL; P = 0.0224), but not those with MOGAD. Better improvement in EDSS at 6 months was associated with baseline BMP-9 levels in patients with AQP4 + NMOSD (Spearman’s rho = − 0.47; P = 0.037). Serum BMP-9 is upregulated at relapse and may contribute to vascular remodeling in AQP4 + NMOSD. Serum BMP-9 levels could predict clinical recovery 6 months after the attack.

Variability of the response to immunotherapy among subgroups of patients with multiple sclerosis.

This study assessed the effect of patient characteristics on the response to disease-modifying therapy (DMT) in multiple sclerosis (MS). We extracted data from 61,810 patients from 135 centers across 35 countries from the MSBase registry. The selection criteria were: clinically isolated syndrome or definite MS, follow-up ≥ 1year, and Expanded Disability Status Scale (EDSS) score ≥ 3, with ≥1 score recorded per year. Marginal structural models with interaction terms were used to compare the hazards of 12-month confirmed worsening and improvement of disability, and the incidence of relapses between treated and untreated patients stratified by their characteristics. Among 24,344 patients with relapsing MS, those on DMTs experienced 48% reduction in relapse incidence (hazard ratio [HR]=0.52, 95% confidence interval [CI]=0.45-0.60), 46% lower risk of disability worsening (HR=0.54, 95% CI=0.41-0.71), and 32% greater chance of disability improvement (HR=1.32, 95% CI=1.09-1.59). The effect of DMTs on EDSS worsening and improvement and the risk of relapses was attenuated with more severe disability. The magnitude of the effect of DMT on suppressing relapses declined with higher prior relapse rate and prior cerebral magnetic resonance imaging activity. We did not find any evidence for the effect of age on the effectiveness of DMT. After inclusion of 1985 participants with progressive MS, the effect of DMT on disability mostly depended on MS phenotype, whereas its effect on relapses was driven mainly by prior relapse activity. DMT is generally most effective among patients with lower disability and in relapsing MS phenotypes. There is no evidence of attenuation of the effect of DMT with age.

Therapeutic efficacy and safety of plasmapheresis in elderly patients with neuromyelitis optica spectrum disorder: a single-center observational study

Neuromyelitis optica spectrum disorder (NMOSD) is a devastating autoimmune disorder with cycles of escalating relapse. Rates of diagnosis in the elderly are increasing. Therapeutic decision-making is more challenging in elderly patients due to multiple comorbidities and high risk of drug-induced side effects. This retrospective study assessed the efficacy and safety of standard plasma exchange (PLEX) treatment in an elderly population with NMOSD. Seventy-six patients with NMOSD who received PLEX were apportioned to two groups as either elderly (⩾60 years, n = 26) or young (<60 years) at the time of the first procedure. Therapeutic response was judged according to functional recovery at 6 months, as reflected by Expanded Disability Status Scale (EDSS) and visual outcome scale (VOS) scores. The mean age of the 26 elderly patients was 67.7 ± 7.9 years (range 60-87 years); the population was predominantly female (88.5%). PLEX sessions were generally well tolerated among the elderly. Compared with the young patients, the elderly had significantly more comorbidities and concomitant medications. Twenty-four (96.0%) elderly patients showed functional improvement at 6 months after PLEX, of which 15 (60.0%) experienced moderate-to-marked improvement. Six months after the initial PLEX treatment, the patients overall experienced a significant improvement in EDSS and VOS scores. Logistic regression showed that severe optic neuritis attack was a significant independent prognostic factor associated with poor PLEX response. The groups were comparable regarding overall or serious adverse events. The rate of transient hypotension was significantly higher in the elderly compared with the young. PLEX is an effective and safe therapy for elderly patients with NMOSD and should be considered a treatment option during NMOSD attacks. In the elderly, preventive measures against hypotension are recommended before PLEX.

Prevalence of disability improvement in relapsing-remitting multiple sclerosis patients treated with cladribine tablets.

The aim was to show the application of the prevalence estimator of Expanded Disability Status Scale (EDSS) improvement over time in patients treated with cladribine tablets in the phase III CLARITY/CLARITY extension trials. Relapsing-remitting multiple sclerosis patients who entered the CLARITY extension study were evaluated. Patients originally randomized in CLARITY to cladribine tablets 3.5mg/kg and placebo in CLARITY extension (early cladribine [EC]) were compared to patients originally randomized to placebo and then assigned to cladribine tablets 3.5mg/kg (delayed cladribine [DC]). The EC group was compared to the DC group on the prevalence of EDSS improvement over time and on the cumulative incidence of EDSS improvement. Prevalence of improvement was assessed by a new approach based on the difference of Kaplan-Meier estimators, whilst the incidence of improvement was assessed by standard Kaplan-Meier curves. A total of 98 patients in the EC group and 244 patients in the DC group were compared. Patients in the EC group showed a significantly higher (p=0.011) prevalence of improvement at year 2 (EC 21.3%, 95% confidence interval [CI] 13.6-29.3; DC 8.9%, 95% CI 5.5-12.8) and at year 5 (EC 15.7%, 95% CI 8.2-23.7; DC 8.3%, 95% CI 4.5-12.4). The cumulative incidence of improvement was also significantly different (hazard ratio1.82, 95% CI 1.13-2.94, p=0.013). Assessment of the prevalence of EDSS improvement is an alternative outcome to assess if a treatment induces and maintains an improvement over the long term. This estimator was found to be more powerful than the cumulative incidence of improvement to detect a treatment effect of cladribine versus placebo over 5years.

Meta-analysis of effectiveness of steroid-sparing attack prevention in MOG-IgG-associated disorder

ObjectiveTo estimate the efficacy of the commonly used long-term immunotherapies in myelin oligodendrocyte glycoprotein IgG associated disorder (MOGAD) MethodA comprehensive search of the databases including PubMed/MEDLINE, EMBASE, and Cochrane database was performed for all studies that assessed the efficacy of azathioprine (AZA), mycophenolate mofetil (MMF), rituximab (RTX), and maintenance intravenous immunoglobulin (mIVIG) in MOGAD. The random-effect model is used to estimate the standard mean difference (SMD) of annualized relapse rate (ARR) and expanded disability status scale (EDSS), mean ARR, probabilities of relapse and worsening EDSS during treatment. ResultsThe initial search identified 714 articles, and 21 satisfied eligibility criteria. All immunotherapies significantly reduced ARR in both pediatric and adult populations. Relapse probabilities and pooled mean ARR (SE: standard error) during therapies were as follow: AZA 53.1% [95%CI 37.4% to 68.2%; ARR 0.291 (0.134)], MMF 38.5% [95%CI 19.4% to 62.0%; ARR 0.836 (0.176)], RTX 48.9% [95%CI 37.8% to 60.2%; ARR 0.629(0.162)], and mIVIG 25.3% [95%CI 14.0% to 41.3%; ARR 0.081 (0.058)]. Only RTX significantly improved EDSS, SMD -0.499 (95%CI -0.996 to -0.003). The proportion of worsening EDSS with immunotherapies were 20.7% (95%CI 8.8% to 41.6%), 8.1% (95%CI 1.1% to 41.2%), and 10.8% (95%CI 3.8% to 26.8%) for AZA, MMF, and RTX, respectively. ConclusionThese commonly used immunotherapies significantly reduced ARR in MOGAD. Only RTX had a significant benefit in EDSS improvement. However, a substantial portion of patients continued to relapse with treatment. Randomized controlled studies are needed to verify these findings and perform head-to-head comparisons among these treatment options.

The Effectiveness of Statins as Potential Therapy for Multiple Sclerosis: A Systematic Review of Randomized Controlled trials.

Evidence of the effectiveness of statins, the lipid-lowering agents in retarding the progression of Multiple Sclerosis (MS), a disabling neurological disease with autoimmune etiology, have been highlighted in animal studies and observational studies. The proposed immune-modulatory actions and neuroprotective effects of statins make them a promising treatment option for MS that needs to be explored further. In this systematic review, we aim to investigate the role of different statins as monotherapy or in combination with the established MS medications in improving the clinical and radiological course of MS variants, including optic neuritis, using randomized controlled trials (RCTs). We systematically searched PubMed, PubMed Central (PMC), MEDLINE, Cochrane library, and Scopus databases using regular keywords and medical subject headings terms. Randomized controlled trials of any statin used in any variants of MS, including studies on statins used in optic neuritis published up to April 2021, were included in the review. Data on the effects on the relapse rate, the Expanded Disability Status Scale (EDSS) alterations, and the changes in Magnetic Resonance Imaging (MRI) lesions were collected from the included studies.Seven studies with a total of 831 patients and an average duration of follow-up of six to 36 months were included in our review. Five trials were of statins add-on to interferon therapy in relapsing-remitting multiple sclerosis (RRMS), of which four studies were assessed to be of good quality while the remaining study featured a high risk of bias. One trial of simvastatin monotherapy in Secondary Progressive Multiple Sclerosis (SPMS) was included, which was assessed to be of good methodological quality with low risk of bias and adequate patient number. A trial of simvastatin monotherapy on patients with optic neuritis was included, which was evaluated as a good quality study. Still, it had a low number of participants and a short duration of follow-up.We used the changes in disease relapse rate and EDSS as primary outcome variables and the MRI lesions changes as a secondary outcome variable. Studies in RRMS showed no significant effects on primary and secondary outcomes. The study on SPMS featured a significant improvement in EDSS in simvastatin-treated patients with no effect on relapse rate or MRI changes. Simvastatin use in optic neuritis enhances clinical visual outcomes with no significant effect on MRI changes or the rate of progression to definite MS.In contrast to animal studies and observational studies, randomized controlled trials do not replicate the positive effects of statins used as monotherapy or combined with interferon beta in patients with RRMS and optic neuritis in relapse rate EDSS or MRI changes. However, trials of statins on SPMS showed a promising effect on disability progression (EDSS score), which might support the proposed immune-modulatory and neuroprotective role of statins and serve as a baseline for further RCTs applying statins as monotherapy or combination with other established MS therapies.

Safety and efficacy of MD1003 (high-dose biotin) in patients with progressive multiple sclerosis (SPI2): a randomised, double-blind, placebo-controlled, phase 3 trial

There is an unmet need to develop therapeutic interventions directed at the neurodegeneration that underlies progression in multiple sclerosis. High-dose, pharmaceutical-grade biotin (MD1003) might enhance neuronal and oligodendrocyte energetics, resulting in improved cell function, repair, or survival. The MS-SPI randomised, double-blind, placebo-controlled study found that MD1003 improved disability outcomes over 12 months in patients with progressive multiple sclerosis. The SPI2 study was designed to assess the safety and efficacy of MD1003 in progressive forms of multiple sclerosis in a larger, more representative patient cohort. SPI2 was a randomised, double-blind, parallel-group, placebo-controlled trial done at 90 academic and community multiple sclerosis clinics across 13 countries. Patients were aged 18-65 years, had a diagnosis of primary or secondary progressive multiple sclerosis fulfilling the revised International Panel criteria and Lublin criteria, a Kurtzke pyramidal functional subscore of at least 2 (defined as minimal disability), an expanded disability status scale (EDSS) score of 3·5-6·5, a timed 25-foot walk (TW25) of less than 40 s, evidence of clinical disability progression, and no relapses in the 2 years before enrolment. Concomitant disease-modifying therapies were allowed. Patients were randomly assigned (1:1) by an independent statistician using an interactive web response system, with stratification by study site and disease history, to receive MD1003 (oral biotin 100 mg three times daily) or placebo. Participants, investigators, and assessors were masked to treatment assignment. The primary endpoint was a composite of the proportion of participants with confirmed improvement in EDSS or TW25 at month 12, confirmed at month 15, versus baseline. The primary endpoint was assessed in the intention-to-treat analysis set, after all participants completed the month 15 visit. Safety analyses included all participants who received at least one dose of MD1003. This trial is registered with ClinicalTrials.gov (NCT02936037) and the EudraCT database (2016-000700-29). From Feb 22, 2017, to June 8, 2018, 642 participants were randomly assigned MD1003 (n=326) or placebo (n=316). The double-blind, placebo-controlled phase of the study ended when the primary endpoint for the last-entered participant was assessed on Nov 15, 2019. The mean time in the placebo-controlled phase was 20·1 months (SD 5·3; range 15-27). For the primary outcome, 39 (12%) of 326 patients in the MD1003 group compared with 29 (9%) of 316 in the placebo group improved at month 12, with confirmation at month 15 (odds ratio 1·35 [95% CI 0·81-2·26]). Treatment-emergent adverse events occurred in 277 (84%) of 331 participants in the MD1003 group and in 264 (85%) of 311 in the placebo group. 87 (26%) of 331 participants in the MD1003 group and 82 (26%) of 311 participants in the placebo group had at least one serious treatment-emergent adverse event. One (<1%) person died in the MD1003 group and there were no deaths in the placebo group. Despite use of mitigation strategies, MD1003 led to inaccurate laboratory results for tests using biotinylated antibodies. This study showed that MD1003 did not significantly improve disability or walking speed in patients with progressive multiple sclerosis and thus, in addition to the potential of MD1003 for deleterious health consequences from interference of laboratory tests, MD1003 cannot be recommended for treatment of progressive multiple sclerosis. MedDay Pharmaceuticals.

Aggressive multiple sclerosis: a single-centre, real-world treatment experience with autologous haematopoietic stem cell transplantation and alemtuzumab.

The best therapeutic approach for aggressive relapsing-remitting multiple sclerosis remains unknown. The objective was to compare the efficacy and safety of autologous haematopoietic stem cell transplantation (aHSCT) and alemtuzumab in aggressive relapsing-remitting multiple sclerosis. The time to first relapse, time to confirmed disability worsening, time to first evidence of magnetic resonance imaging (MRI) activity and time to first evidence of disease activity were compared between the two treatment groups. Secondary outcomes included the 12, 24 and 36month annualized relapse rate (ARR) and the 6-month confirmed Expanded Disability Status Scale (EDSS) changes at months 12 and 24. Fifty-seven patients treated with aHSCT (n=25) or alemtuzumab (n=32) were included. At baseline, aHSCT patients had a higher EDSS (median score 6 vs. 3; P<0.001), higher ARR (mean ARR 3.2 vs. 1.7; P=0.001) and a higher number of baseline T1 gadolinium-enhancing lesions on MRI (mean number 15.5 vs. 1.6; P<0.001). NEDA-3 (no evidence of disease activity) status was more frequently achieved in aHSCT-treated patients than in alemtuzumab-treated patients [75% vs. 56% of patients at the end of the observation period; hazard ratio (HR)0.27, 95% confidence interval (CI) 0.08-0.84; P=0.023]. aHSCT significantly reduced the risk of relapse (relapse-free survival 84% vs. 69%; HR 0.13, 95% CI 0.02-0.63; P=0.012) and MRI activity (MRI-activity-free survival 85% vs. 59%; HR0.13, 95% CI 0.03-0.59; P=0.009). The ARR at 36months was significantly lower in the aHSCT group (0.05 vs. 0.35, P=0.02). A significant effect of aHSCT in promoting EDSS improvement compared with alemtuzumab was noted (P=0.035). Alemtuzumab and aHSCT are effective treatment choices for aggressive multiple sclerosis. aHSCT seems to be superior to alemtuzumab in inducing complete disease control and in promoting short-term disability improvement.

Beneficial effects of intravenous immunoglobulin as an add-on therapy to azathioprine for NMO-IgG-seropositive neuromyelitis optica spectrum disorders

BackgroundThe efficacy of intravenous immunoglobulin (IVIG) in neuromyelitis optica spectrum disorders (NMOSD) has rarely been investigated, despite it being a conceivable therapeutic strategy based on its mode of action. We aimed to evaluate the efficacy of IVIG as an add-on therapy to azathioprine in the prevention of NMOSD relapse. MethodsWe retrospectively reviewed the medical records of NMO-IgG-positive NMOSD patients treated with IVIG infusions (0.4 g/kg/day) every one to three months as a part of combination therapy with azathioprine for more than six months. Treatment efficacy and safety were assessed based on the changes in the pre-IVIG and post-IVIG treatment annualized relapse rates (ARR), and on the proportion of relapse-free and progression-free patients and adverse events. ResultsThis study was performed on 20 patients (19 women; median age 52 years). After add-on therapy with IVIG, 19 patients (95%) showed a significant reduction in the median ARR from 1.1 [interquartile range, 0.6‒1.4] to 0.3 [interquartile range, 0‒0.6] (p < 0.001). Seven patients (35%) were relapse-free during 43.5 months (median) of treatment. The median Expanded Disability Status Scale (EDSS) score remained stable at 4.0. In addition, 80% of the patients showed no disability progression, and 25% of the patients experienced an improvement in EDSS. The median NMO-IgG titer decreased from 1:480 (n = 19) to 1:120 (n = 13) after treatment (p = 0.006) and was found to be negative in three patients. Six patients (30%) stopped IVIG due to relapses after 27.5 months (median; interquartile range, 15.3‒43.3) of IVIG initiation. There were no severe side effects that led to discontinuation of IVIG. ConclusionIVIG as add-on therapy may be associated with beneficial effects in preventing relapse and disability progression in NMO-IgG-positive NMOSD patients who have breakthrough disease activity despite immunosuppressive treatment with azathioprine. Further randomized controlled trials are necessary to validate the efficacy of IVIG in NMOSD.

Long term effect of delayed treatment on disability in patients with paediatric onset multiple sclerosis: A prospective Danish cohort study

BackgroundA consensus of early treatment with disease-modifying therapies (DMT) in multiple sclerosis (MS) has been reached based on several observational and experimental studies in adults. However, paediatric onset (PO)MS appears phenotypically different from adult onset MS, characterized by increased relapse rate and pronounced radiological activity on MRI. The objective of this study was to investigate the long-term consequences of delayed treatment start in POMS on disability in a real-world, population-based setting. MethodsBased on prospectively collected data from The Danish Multiple Sclerosis Registry, we defined a cohort of MS patients with onset before the age of 18 years, who were born in 1980 or later, and started treatment with a DMT between 1998 and 2018. The POMS cohort was stratified according to treatment start within 2 years of onset (N = 140) or later (N = 151). Annualised relapse rate in each study group was compared using a negative binomial regression; and Cox proportional hazard model was used to estimate hazard ratios (HR) of time to sustained Expanded Disability Status Scale (EDSS) score 4, 6-month confirmed EDSS worsening and 6-month confirmed EDSS improvement, respectively, according to disease duration. ResultsThe POMS cohort had a total median follow-up time of 7.7 years (interquartile range 4.6–11.6). There was no association between risk of relapses in patients with delayed treatment start compared to earlier treatment start. Patients starting on a DMT later than 2 years after onset had a 2.52-fold increased risk of reaching sustained EDSS 4 compared to those starting within 2 years of onset (HR=2.52, 95% confidence interval (CI)=1.01–6.34). For every year increment from onset to start of first DMT, the risk of reaching sustained EDSS 4 increased by 17% (HR=1.17, 95% CI=1.05–1.30). In line with this, the risk of reaching confirmed EDSS worsening was increased by 44% compared to those starting earlier, although not statistically significant (HR=1.44, 95% CI=0.95–2.19). Starting on a DMT later was associated with 61% decreased chance of confirmed EDSS improvement compared to those starting earlier (HR=0.39, 95% CI=0.26–0.59). For every year increment from onset to starting DMT, the risk of confirmed EDSS improvement decreased by 10% (HR=0.90, 95% CI=0.84–0.96). ConclusionsDelayed treatment start in this POMS cohort was associated with shorter time to reach sustained EDSS 4 and confirmed EDSS worsening, and decreased chance of reaching confirmed EDSS improvement, and thus support early treatment start in POMS patients.

Therapeutic Plasma Exchange in Neuromyelitis Optica Spectrum Disorders and Related Disorders in Resource-Limited Settings: Outcomes in a Multiethnic Single-Center Population.

We evaluated therapeutic plasma exchange (TPE) efficiency in treatment of a single relapse in steroid-refractory patients with neuromyelitis optica spectrum disorders (NMOSD) in a multi-ethnic resource-limited setting. This was a historical cohort study on the clinical outcomes post-TPE in a multiethnic cohort of 53 steroid-refractory NMOSD patients at a single Malaysian tertiary center. Primary outcomes, assessed both pre- and post-TPE, were Medical Research Council scale of muscle power, Modified Rankin Scale, Expanded Disability Status Scale (EDSS), and visual acuity. Secondary outcomes were ambulatory status and target neurological deficit (TND)-based TPE response. Significant improvements in Medical Research Council, Modified Rankin Scale, EDSS, and visual acuity (P < 0.001) were observed at 1-month post-TPE with further improvement of EDSS at 6 months (EDSSΔ6) post-TPE (P < 0.001). At 6 months post-TPE, 87% of patients has successful TND-based TPE response and 69.8% were ambulating without support. Patients with anti-aquaporin 4 seronegativity (P = 0.004), myelitis and brainstem features at first relapse (P = 0.004), longer cord lesions (P = 0.030), higher pre-TPE EDSS of ≥8 (P = 0.018) and delayed TPE initiation of >14 days (P = 0.047) were significantly associated with improved EDSSΔ6. TND-based TPE response was significant in absence of cord atrophy (P = 0.030). TPE is an effective treatment for steroid-refractory acute relapses of NMOSD in a multiethnic Malaysian population despite its resource-limited setting. The predictive factors of EDSSΔ6 improvement were anti-aquaporin 4 seronegativity, longer cord lesions, and higher pre-TPE EDSS. Absence of cord atrophy was predictive of better TND-based TPE response. Unexpectedly, our study showed that delayed TPE initiation of more than 14 days and up to 60 days may also be beneficial.

Outcomes of natalizumab treatment within 3\u2009years of relapsing-remitting multiple sclerosis diagnosis: a prespecified 2-year interim analysis of STRIVE

BackgroundSTRIVE is a multicenter, observational, open-label, single-arm study of natalizumab in anti–JC virus (JCV) seronegative patients with early relapsing-remitting multiple sclerosis (RRMS). The objective of this prespecified 2-year interim analysis was to determine the effectiveness of natalizumab in establishing and maintaining no evidence of disease activity (NEDA) in early RRMS.MethodsPatients aged 18–65 years had an RRMS diagnosis < 3 years prior to screening, an Expanded Disability Status Scale (EDSS) score ≤ 4.0, and anti-JCV antibody negative status. Magnetic resonance imaging was performed at baseline and yearly thereafter. Cumulative probabilities of 24-week–confirmed EDSS worsening and improvement were evaluated at 2 years. NEDA (no 24-week–confirmed EDSS worsening, no relapses, no gadolinium-enhancing lesions, and no new/newly enlarging T2-hyperintense lesions) was evaluated over 2 years. The Symbol Digit Modalities Test (SDMT) and Multiple Sclerosis Impact Score (MSIS-29) were assessed at baseline and 1 and 2 years. Statistical analysis used summary statistics and frequency distributions.ResultsThe study population (N = 222) had early RRMS, with mean (standard deviation [SD]) time since diagnosis of 1.6 (0.77) years and mean (SD) baseline EDSS score of 2.0 (1.13). NEDA was achieved in 105 of 187 patients (56.1%) during year 1 and 120 of 163 (73.6%) during year 2. Over 2 years, 76 of 171 patients (44.4%) attained overall NEDA. Probabilities of 24-week–confirmed EDSS worsening and improvement were 14.1% and 28.4%, respectively. After 2 years, patients exhibited significant improvements from baseline in SDMT (n = 158; mean [SD]: 4.3 [11.8]; p < 0.001) and MSIS-29 physical (n = 153; mean [SD]: − 3.9 [14.7]; p = 0.001), psychological (n = 152; mean [SD]: − 2.0 [7.9]; p < 0.001), and quality-of-life (n = 153; mean [SD]: − 6.0 [21.3]; p < 0.001) scores.ConclusionsThese results support natalizumab’s effectiveness over 2 years, during which nearly half of early RRMS patients achieved NEDA. During year 2, nearly 75% of patients exhibited NEDA. Over 2 years, patients continued to experience significant cognitive and quality-of-life benefits. These results are limited by the lack of a comparator group to determine the extent of a placebo effect.Trial registrationclinicaltrials.gov, NCT01485003, registered 5 December 2011.

Long-term disease activity and disability progression in relapsing-remitting multiple sclerosis patients on natalizumab

BackgroundNatalizumab is an effective treatment for relapsing-remitting multiple sclerosis (RRMS). Data on clinical and imaging measures predictive of disease activity and progression during treatment is limited. ObjectiveTo determine clinical and imaging predictors of long-term inflammatory disease activity and disability progression in RRMS patients on natalizumab. MethodsPatients (n = 135) were selected from our prospective observational natalizumab cohort and monitored using brain MRI and extensive clinical testing. Progression and improvement on the Expanded Disability Status Scale (EDSS), no evidence of disease activity (NEDA) and no evidence of progression or active disease (NEPAD) status were determined using measurements after the initial phase of inflammation and the early anti-inflammatory impact of natalizumab. ResultsEDSS progression was seen in 43.7% of patients and EDSS improvement in 17.8%. Median follow-up was 4.9 years (IQR 3.6–6.0). Patients with a longer disease duration at natalizumab initiation have a higher hazard for earlier EDSS progression (HR 1.05, CI 1.00–1.09, p = 0.037) and a higher pre-baseline relapse rate predicted a longer NEPAD status (HR 1.70, CI 1.06–2.72, p = 0.028). ConclusionThe results suggest that starting natalizumab early, during active inflammatory disease results in a more favourable outcome. When taking into account early inflammation and the impact of natalizumab on disease activity during the initial treatment phase, a higher than expected proportion of patients showed disability progression.

Predictors of hospital-based multidisciplinary rehabilitation effects in persons with multiple sclerosis: a large-scale, single-centre study.

BackgroundPersons with multiple sclerosis may benefit from hospital-based multidisciplinary rehabilitation.ObjectivesTo investigate the effects of hospital-based multidisciplinary rehabilitation and to identify their potential predictors in a large sample of persons with multiple sclerosis.MethodsFrom the charts of 655 persons with multiple sclerosis consecutively admitted to our unit, disease profiles, modified Barthel index, Expanded Disability Status Scale (EDSS), pain numerical rating score and type of interventions were retrospectively collected. We defined an improvement at discharge as follows: modified Barthel index increase of at least 5 points, EDSS decrease of 1.0 if baseline score was 5.5 or less and of 0.5 if baseline score was greater than 5.5; any numerical rating score decrease.ResultsAfter a median admission period of 36 days, at discharge 65%, 22% and 89% of persons with multiple sclerosis improved for modified Barthel index, EDSS and numerical rating score, respectively. The modified Barthel index improvement was associated with shorter disease duration, lower EDSS at baseline and with access to psychological counselling. EDSS improvement was associated with shorter disease duration, relapsing–remitting course, female gender and longer duration of the admission period.ConclusionsInpatient multidisciplinary rehabilitation was associated with improved autonomy in activities of daily living in a relevant proportion of persons with multiple sclerosis. The effect seems to be more evident in individuals with shorter multiple sclerosis duration and relapsing–remitting disease course.

Real-world data from over 10 years in the TYSABRI® Observational Program: Long-term safety and effectiveness of natalizumab in relapsing-remitting multiple sclerosis patients

Introduction The TYSABRI Observational Program (TOP) began > 10 years ago to inform on long-term safety and effectiveness of natalizumab in relapsing-remitting multiple sclerosis (RRMS) patients in clinical practice. Objectives Report an interim analysis of safety and effectiveness in patients with up to 10 years of natalizumab treatment in TOP, an open-label, multinational, prospective, observational study. Patients and methods Annualised relapse rates (ARRs) for the year prior to starting natalizumab and on natalizumab (and ≤ 84 days post discontinuation) were compared using a repeated Poisson model. Confirmed Expanded Disability Status Scale (EDSS) worsening, and improvement, while on natalizumab were estimated by Kaplan–Meier analysis. Serious adverse events (SAEs) were assessed at clinical visits. Results As of November 2017, TOP included 6149 patients. ARR while on natalizumab was reduced by 89.4% (from 1.99 pre- natalizumab to 0.21 on natalizumab; P Discussion At 10 years, cumulative probabilities of 24-week–confirmed EDSS worsening and improvement were 32.9% and 35.5%, respectively. Overall, 828 of 6149 patients (13.5%) experienced ≥ 1 SAE (most commonly reported by system organ class: infections and infestations, 253 patients [4.1%]). Conclusion This analysis reinforces the consistent effectiveness—particularly when used earlier in the disease and treatment course–and the established safety profile of natalizumab, now assessed over 10 years.