Background and purpose
Using the treatment goal of “no evidence of disease activity” (NEDA) incorporating magnetic resonance imaging (MRI) re‐baselining, we aimed to assess the efficacy of ...ocrelizumab in patients with relapsing‐remitting multiple sclerosis with a prior suboptimal response, defined by MRI or relapse criteria, to one or two disease‐modifying therapies (DMTs).
Methods
CASTING was a prospective, international, multicenter, single‐arm, open‐label phase 3 trial (NCT02861014). Patients (Expanded Disability Status Scale EDSS score ≤ 4.0, with discontinued prior DMT of ≥6 months duration due to suboptimal disease control) received intravenous ocrelizumab 600 mg every 24 weeks for 96 weeks. The primary endpoint was NEDA (defined as absence of relapses, disability progression, and inflammatory MRI measures, with prespecified MRI re‐baselining at Week 8) over 96 weeks.
Results
A total of 680 patients were enrolled, 167 (24.6%) based on MRI activity only. At Week 96, 74.8% (95% confidence interval CI 71.3–78.0, n/N = 492/658) of patients had NEDA. NEDA was highest among patients enrolled due to MRI activity alone (80.6% 95% CI 68.6–89.6, n/N = 50/62) versus those enrolled for relapse (75.1% 95% CI 69.0–80.6, n/N = 172/229) or for relapse with MRI (70.5% 95% CI 60.0–79.0, n/N = 74/105). NEDA across subgroups was highest in patients with a baseline EDSS score <2.5 (77.2% 95% CI 72.8–81.2, n/N = 315/408). NEDA was higher in patients receiving one prior DMT (77.6% 95% CI 73.2–81.6, n/N = 312/402) versus two prior DMTs (70.3% 95% CI 64.3–75.8, n/N = 180/256).
Conclusions
In patients switching therapy due to suboptimal disease control, treatment with ocrelizumab led to an overall high NEDA rate across a wide range of disease‐related and demographic subgroups, regardless of prior treatment background, with no new safety signals detected.
Data from the phase IIIb CASTING trial in patients with relapsing‐remitting multiple sclerosis with a suboptimal response to one or two prior DMTs shows that switching to ocrelizumab led to a high proportion of patients with no evidence of disease activity (NEDA; defined as absence of relapses, disability progression, and inflammatory MRI measures, with prespecified magnetic resonance imaging re‐baselining at Week 8) at the end of the 96‐week treatment period.
In autoimmunity, FOXP3+ Tregs skew toward a proinflammatory, nonsuppressive phenotype and are, therefore, unable to control the exaggerated autoimmune response. This largely affects the success of ...autologous Treg therapy, which is currently under investigation for autoimmune diseases, including multiple sclerosis (MS). There is a need to ensure in vivo Treg stability before successful application of Treg therapy. Using genetic fate-mapping mice, we demonstrate that inflammatory, cytokine-expressing exFOXP3 T cells accumulate in the CNS during experimental autoimmune encephalomyelitis. In a human in vitro model, we discovered that interaction with inflamed blood-brain barrier endothelial cells (BBB-ECs) induces loss of function by Tregs. Transcriptome and cytokine analysis revealed that in vitro migrated Tregs have disrupted regenerative potential and a proinflammatory Th1/17 signature, and they upregulate the mTORC1 signaling pathway. In vitro treatment of migrated human Tregs with the clinically approved mTORC1 inhibitor rapamycin restored suppression. Finally, flow cytometric analysis indicated an enrichment of inflammatory, less-suppressive CD49d+ Tregs in the cerebrospinal fluid of people with MS. In summary, interaction with BBB-ECs is sufficient to affect Treg function, and transmigration triggers an additive proinflammatory phenotype switch. These insights help improve the efficacy of autologous Treg therapy of MS.
The long term effects of fingolimod, an oral treatment for relapsing-remitting (RR) multiple sclerosis (MS), on blood circulating B and T cell subtypes in MS patients are not completely understood. ...This study describes for the first time the longitudinal effects of fingolimod treatment on B and T cell subtypes. Furthermore, expression of surface molecules involved in antigen presentation and costimulation during fingolimod treatment are assessed in MS patients in a 12 month follow-up study.
Using flow cytometry, B and T cell subtypes, and their expression of antigen presentation, costimulation and migration markers were measured during a 12 month follow-up in the peripheral blood of MS patients. Data of fingolimod-treated MS patients (n = 49) were compared to those from treatment-naive (n = 47) and interferon-treated (n = 27) MS patients.
In the B cell population, we observed a decrease in the proportion of non class-switched and class-switched memory B cells (p<0.001), both implicated in MS pathogenesis, while the proportion of naive B cells was increased during fingolimod treatment in the peripheral blood (PB) of MS patients (p<0.05). The remaining T cell population, in contrast, showed elevated proportions of memory conventional and regulatory T cells (p<0.01) and declined proportions of naive conventional and regulatory cells (p<0.05). These naive T cell subtypes are main drivers of MS pathogenesis. B cell expression of CD80 and CD86 and programmed death (PD) -1 expression on circulating follicular helper T cells was increased during fingolimod follow-up (p<0.05) pointing to a potentially compensatory mechanism of the remaining circulating lymphocyte subtypes that could provide additional help during normal immune responses.
MS patients treated with fingolimod showed a change in PB lymphocyte subtype proportions and expression of functional molecules on T and B cells, suggesting an association with the therapeutic efficacy of fingolimod.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Fatigue and walking difficulties are common impairments and activity limitations in persons with multiple sclerosis (PwMS). Walking fatigability (WF) can be measured by a Distance Walked Index and is ...defined as a decline in walking distance of 10% or more during the six-minute walking test (6MWT). However, the clinical manifestation and perceived symptoms related to fatigability are still not well documented. Forty-nine PwMS Expanded Disability Status Scale (EDSS) ≤6 and 28 healthy controls (HC) performed a 6MWT. The perceived severity of 11 common symptoms was rated on a visual analogue scale of 0-10 before, immediately after, and 10, 20 and 30 minutes after the 6MWT by means of the symptom inventory. Short motor impairment screening tests at baseline together with other descriptive measures were performed. Twenty pwMS were categorized in the WF group and were more disabled (EDSS: 4.16 ± 1.41) than the non-walking fatigability group (n = 29, EDSS: 2.62 ± 1.94). PwMS showed exacerbations of several perceived symptoms in MS, where most symptoms returned to baseline within 10 minutes after the walking test. The WF group showed significantly more muscle weakness and gait impairment, together with balance problems, and experienced an increase in spasticity, pain and dizziness after 6MWT. Our findings showed that perceived severity of symptoms are higher in pwMS presenting WF, and increase temporally after the 6MWT. Future research with quantitative measurement during and after walking is recommended.
Oral immunotherapies have become a standard treatment in relapsing-remitting multiple sclerosis. Direct comparison of their effect on relapse and disability is needed.
We identified all patients with ...relapsing-remitting multiple sclerosis treated with teriflunomide, dimethyl fumarate or fingolimod, with minimum 3-month treatment persistence and disability follow-up in the global MSBase cohort study. Patients were matched using propensity scores. Three pairwise analyses compared annualised relapse rates and hazards of disability accumulation, disability improvement and treatment discontinuation (analysed with negative binomial models and weighted conditional survival models, with pairwise censoring).
The eligible cohorts consisted of 614 (teriflunomide), 782 (dimethyl fumarate) or 2332 (fingolimod) patients, followed over the median of 2.5 years. Annualised relapse rates were lower on fingolimod compared with teriflunomide (0.18 vs 0.24; p=0.05) and dimethyl fumarate (0.20 vs 0.26; p=0.01) and similar on dimethyl fumarate and teriflunomide (0.19 vs 0.22; p=0.55). No differences in disability accumulation (p≥0.59) or improvement (p≥0.14) were found between the therapies. In patients with ≥3-month treatment persistence, subsequent discontinuations were less likely on fingolimod than teriflunomide and dimethyl fumarate (p<0.001). Discontinuation rates on teriflunomide and dimethyl fumarate were similar (p=0.68).
The effect of fingolimod on relapse frequency was superior to teriflunomide and dimethyl fumarate. The effect of the three oral therapies on disability outcomes was similar during the initial 2.5 years on treatment. Persistence on fingolimod was superior to the two comparator drugs.
Background:
The magnetic resonance imaging in multiple sclerosis (MAGNIMS) score combines relapses and magnetic resonance imaging (MRI) lesions to predict disability outcomes in relapsing–remitting ...multiple sclerosis (RRMS) treated with interferon-β.
Objective:
To validate the MAGNIMS score and extend to other disease-modifying therapies (DMTs). To examine the prognostic value of gadolinium contrast-enhancing (Gd+) lesions.
Methods:
This RRMS MSBase cohort study (n = 2293) used a Cox model to examine the prognostic value of relapses, MRI activity and the MAGNIMS score for disability worsening during treatment with interferon-β and three other DMTs.
Results:
Three new T2 lesions (hazard ratio (HR) = 1.60, p = 0.028) or two relapses (HR = 2.24, p = 0.002) on interferon-β (for 12 months) were predictive of disability worsening over 4 years. MAGNIMS score = 2 (1 relapse and ⩾3 T2 lesions or ⩾2 relapses) was associated with a greater risk of disability worsening on interferon-β (HR = 2.0, p = 0.001). In pooled cohort of four DMTs, similar associations were seen (MAGNIMS score = 2: HR = 1.72, p = 0.001). Secondary analyses demonstrated that the addition of Gd+ to the MAGNIMS did not materially improve its prediction of disability worsening.
Conclusion:
We have validated the MAGNIMS score in RRMS and extended its application to three other DMTs: 1 relapse and ⩾3 T2 lesions or ⩾2 relapses predicted worsening of disability. Contrast-enhancing lesions did not substantially improve the prognostic score.
Personalized treatment is highly desirable in multiple sclerosis (MS). We believe that multidisciplinary measurements including clinical, functional and patient-reported outcome measures in ...combination with extensive patient profiling can enhance personalized treatment and rehabilitation strategies. We elaborate on four reasons behind this statement: (1) MS disease activity and progression are complex and multidimensional concepts in nature and thereby defy a one-size-fits-all description, (2) functioning, progression, treatment, and rehabilitation effects are interdependent and should be investigated together, (3) personalized healthcare is based on the dynamics of system biology and on technology that confirms a patient’s fundamental biology and (4) inclusion of patient-reported outcome measures can facilitate patient-relevant healthcare. We discuss currently available multidisciplinary MS data initiatives and introduce joint actions to further increase the overall success. With this topical review, we hope to drive the MS community to invest in expanding towards more multidisciplinary and longitudinal data collection.
Multiple sclerosis (MS) is a chronic autoimmune neurological disease that typically affects young adults, causing irreversible physical disability and cognitive impairment. Alemtuzumab, administered ...intravenously as 2 initial courses of 12 mg/day (5 consecutive days at baseline, and 3 consecutive days 12 months later), resulted in significantly greater improvements in clinical and MRI outcomes vs. subcutaneous interferon beta-1a over 2 years in patients with active relapsing-remitting MS (RRMS) who were either treatment-naive (CARE-MS I; NCT00530348) or had an inadequate response to prior therapy (CARE-MS II; NCT00548405). Efficacy with alemtuzumab was maintained over 7 years in subsequent extension studies (NCT00930553; NCT02255656), in the absence of continuous treatment and with a consistent safety profile. There is an increased incidence of autoimmune events in patients treated with alemtuzumab (mainly thyroid events, but also immune thrombocytopenia and nephropathy), which imparts a need for mandatory safety monitoring for 4 years following the last treatment. The risk management strategy for alemtuzumab-treated patients includes laboratory monitoring and a comprehensive patient education and support program that enables early detection and effective management of autoimmune events, yielding optimal outcomes for MS patients. Here we provide an overview of tools and techniques that have been implemented in real-world clinical settings to reduce the burden of monitoring for both patients and healthcare providers, including customized educational materials, the use of social media, and interactive online databases for managing healthcare data. Many practices are also enhancing patient outreach efforts through coordination with specialized nursing services and ancillary caregivers. The best practice recommendations for safety monitoring described in this article, based on experiences in real-world clinical settings, may enable early detection and management of autoimmune events, and help with implementation of monitoring requirements while maximizing the benefits of alemtuzumab treatment for MS patients.
•The effect of anodal tDCS on corticospinal excitability was evaluated in MS-patients.•A single session of 20min anodal tDCS was applied to the M1 contralateral to the most impaired hand.•TMS ...recruitment curves were measured to evaluate changes in corticospinal excitability.•After anodal tDCS the area under the recruitment curves increased significantly and a significant higher plateau was reached.•Our results showed that anodal tDCS over M1 has the ability to increase CS output and projection strength in MS-patients.
The application of anodal transcranial direct current stimulation (atDCS) to the human brain has been shown to elicit corticospinal (CS) excitability changes. This study evaluated the effect of a single session of atDCS on CS excitability in patients with multiple sclerosis (MS). atDCS and sham tDCS (stDCS) were applied to the primary motor cortex (M1) contralateral to the more severely impaired hand for 20min in a double-blinded crossover design. Changes in CS excitability were assessed using transcranial magnetic stimulation (TMS). The area under the recruitment curves increased significantly after application of atDCS (+56.58%, p=0.023) but not after stDCS. A sigmoidal curve-analysis revealed a higher plateau of the curve after atDCS (+22.2%, p<0.001). Our results showed that atDCS over M1 has the ability to increase CS output and projection strength in MS-patients, suggesting that atDCS can be considered during neural rehabilitation to facilitate motor recovery in MS.
Background and aims:
Alemtuzumab is a humanized monoclonal antibody that depletes CD52-bearing B and T lymphocytes. Clinical trials defined that systemic administration of alemtuzumab reduces disease ...severity in the relapsing–remitting phase of multiple sclerosis (MS). However, its efficacy in progressive MS patients is limited, which may reflect the inability of alemtuzumab to cross the reconstituted BBB in these patients. Objective: to study whether central nervous system (CNS) delivery of anti-CD52 antibodies reduces disease severity and the neuroinflammatory burden in the experimental autoimmune encephalomyelitis (EAE) model.
Methods:
Anti-CD52 antibodies were administered intrathecally during the acute and chronic phases of EAE. Flow cytometry and immunohistochemistry were utilized to define immunological and pathological parameters.
Results:
We show that subcutaneously administrated anti-CD52 antibodies completely abolish EAE disease severity. CNS delivery of anti-CD52 antibodies during both the acute and chronic phases of EAE moderately reduces disease severity and the neuroinflammatory burden. Our findings further suggest that CNS delivery of anti-CD52 antibodies impacts both the peripheral and CNS immune cell compartments in the EAE model but not in healthy mice.
Conclusion:
Collectively, our findings highlight the therapeutic potential of CNS delivery of alemtuzumab for the treatment of progressive as well as early MS.
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