Evaluation of no evidence of progression or active disease (NEPAD) in patients with primary progressive multiple sclerosis in the ORATORIO trial

Wolinsky, Jerry S.; Montalbán, Xavier; Hauser, Stephen L.; Giovannoni, Gavin; Vermersch, Patrick; Bernasconi, Corrado; Deol‐Bhullar, Gurpreet; Garren, Hideki; Chin, Peter; Belachew, Shibeshih; Kappos, L

doi:10.1002/ana.25313

Cited by 42 publications

(19 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Recent advances in the treatment of progressive forms of MS emphasized the importance of reliable and comprehensive measures of disease progression, as EDSS has limited ability to reliably capture change in functioning in a range of domains . Therefore, a composite measure including upper limb function, ambulation speed as well as EDSS was developed to measure disability progression . The results of the present study have shown that an EP score >13 which uses VEMPs and tSSEPs increases the likelihood for progression measured with this composite measure.…”

Section: Discussionmentioning

confidence: 86%

“…Additionally, T25FW and 9HPT were performed on the baseline visit and after 2 years of follow‐up. For better insight into disease progression, a composite measure consisting of EDSS, T25FW and 9HPT was used to evaluate evidence of progression . The evidence for progression was defined as the presence of SAD measured by the EDSS as described above, or evidence of ≥20% progression on hand/arm function as measured by the 9HPT, and/or evidence of ≥20% progression on ambulation as measured by the T25FW.…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Evoked potentials can predict future disability in people with clinically isolated syndrome

Crnošija

Gabelić

Barun

et al. 2019

Euro J of Neurology

View full text Add to dashboard Cite

Background and purpose The aim was to evaluate whether the addition of evoked potentials (EPs) which evaluate brainstem function to the EP score improves its ability to predict disease progression in people with clinically isolated syndrome (pwCIS). Methods For 94 pwCIS, data on disease activity and progression after 2.9 (1.4–4.1) years of follow‐up were available. Baseline characteristics included magnetic resonance imaging (MRI) parameters, visual EPs, auditory EPs, somatosensory EPs of the median and tibial nerves, vestibular evoked myogenic potentials and tongue somatosensory EPs. Results A multivariable regression model including age, sex, total number of T2 lesions on baseline MRI and EP score >13 showed that the total number of T2 lesions on baseline MRI and EP score >13 increase the likelihood for sustained accumulation of disability (SAD). After controlling for age, sex and the total number of T2 lesions on baseline MRI, the hazard of SAD for participants with EP score >13 is 4.093 times that of participants with EP score ≤13. EP score >13 also increases the likelihood for progression measured with a composite measure of progression which uses the Expanded Disability Status Scale, the nine‐hole peg test and the timed 25‐ft walk (exp(B) = 5.577, 95% confidence interval 1.520–20.468, P = 0.01). Conclusion The addition of EPs that evaluate brainstem function to the EP score enables prediction of the progression of disability in pwCIS.

show abstract

Section: Discussionmentioning

confidence: 86%

Section: Methodsmentioning

confidence: 99%

Evoked potentials can predict future disability in people with clinically isolated syndrome

Crnošija

Gabelić

Barun

et al. 2019

Euro J of Neurology

View full text Add to dashboard Cite

show abstract

“…Although the effect of ocrelizumab in PPMS was only modest, it was sustained, and patients in the extension study initiating ocrelizumab between 3-5 years earlier had significant and sustained reductions in disability progression compared with patients switching from placebo after 144-240 weeks (45). In post-hoc analyses, ocrelizumab increased 3-fold the proportion of PPMS patients achieving a novel combined measure of NEPAD (no evidence of progression or active disease), defined by the absence of both progression and inflammatory disease activity, which may represent a measure of disease control that is sensitive and meaningful in patients with PPMS (46). Ocrelizumab also reduced the progression of upper limb disability in more disabled or older patients, a finding that set the stage for a larger ORATORIO-HAND study, which is intended to further investigate the efficacy of ocrelizumab in improving upper limb function (47).…”

Section: Ms Therapies Targeting B Cellsmentioning

confidence: 99%

Therapies for multiple sclerosis targeting B cells

Milo

2019

Croat Med J

View full text Add to dashboard Cite

Increasing evidence suggests that B cells contribute both to the regulation of normal autoimmunity and to the pathogenesis of immune mediated diseases, including multiple sclerosis (MS). B cells in MS are skewed toward a pro-inflammatory profile, and contribute to MS pathogenesis by antibody production, antigen presentation, T cells stimulation and activation, driving autoproliferation of brain-homing autoreactive CD4+ T cells, production of pro-inflammatory cytokines, and formation of ectopic meningeal germinal centers that drive cortical pathology and contribute to neurological disability. The recent interest in the key role of B cells in MS has been evoked by the profound anti-inflammatory effects of rituximab, a chimeric monoclonal antibody (mAb) targeting the B cell surface marker CD20, observed in relapsing-remitting MS. This has been reaffirmed by clinical trials with less immunogenic and more potent B cell-depleting mAbs targeting CD20 – ocrelizumab, ofatumumab and ublituximab. Ocrelizumab is also the first disease-modifying drug that has shown efficacy in primary-progressive MS, and is currently approved for both indications. Another promising approach is the inhibition of Bruton's tyrosine kinase, a key enzyme that mediates B cell activation and survival, by agents such as evobrutinib. On the other hand, targeting B cell cytokines with the fusion protein atacicept increased MS activity, highlighting the complex and not fully understood role of B cells and humoral immunity in MS. Finally, all other approved therapies for MS, some of which have been designed to target T cells, have some effects on the frequency, phenotype, or homing of B cells, which may contribute to their therapeutic activity.

show abstract

“…In the phase 3 RCT in PPMS (ORATORIO), we considered only the placebo arm for the longitudinal analysis because the time-to-event analysis was modified by the experimental drug 13 . Since the number of 24-week confirmed EDSS progression events per MS subtype in the placebo group was too small (<23 events per subtype on average) to provide statistically reliable results, we defined an event as ≥20% increase in the averaged 9 Hole-Peg Test time between two hands, following Wolinsky et al's recommendation 32 .…”

Section: ) Testing Sustain On the External Unseen Datasetmentioning

confidence: 99%

Defining multiple sclerosis subtypes using machine learning

Eshaghi

Young

Wijertane

et al. 2019

Preprint

View full text Add to dashboard Cite

Multiple sclerosis (MS) is subdivided into four phenotypes on the basis of medical history and clinical symptoms. These phenotypes are defined retrospectively and lack clear pathobiological underpinning. Since Magnetic Resonance Imaging (MRI) better reflects disease pathology than clinical symptoms, we aimed to explore MRI-driven subtypes of MS based on pathological changes visible on MRI using unsupervised machine learning. In separate train and external validation sets we looked at a total of 21,170 patient-years of data from 15 randomised controlled trials and three observational cohorts to explore MRI-driven subtypes and test whether these subtypes had differential clinical outcomes. We processed MRI data to obtain measures of brain volumes, lesion volumes, and normal appearing white matter T1/T2. We identified three MRI-driven subtypes who were similar in how they accumulated MRI abnormality. Based on the earliest abnormalities suggested by our model they were called: cortex-led, normal appearing white matter-led, and lesion-led subtypes. In the external validation datasets, the lesion-led subtype showed a faster disability progression and higher disease activity than the cortex-led subtype. In all datasets, MRI-driven subtypes were associated with disability progression (βSubtype=0.04, p=0.02; βStage=-0.06, p<0.001), whilst clinical phenotypes and baseline disability were not. Only the lesion-led subtype showed a significant treatment response in three progressive multiple sclerosis randomised controlled trials (-66%, p=0.009) and in three relapsing remitting multiple sclerosis trials (-89%, p=0.04). Our results show that MRI-driven subtyping using machine learning can prospectively enrich clinical trials with patients who are most likely to respond to treatments.

show abstract

Evaluation of no evidence of progression or active disease (NEPAD) in patients with primary progressive multiple sclerosis in the ORATORIO trial

Cited by 42 publications

References 25 publications

Evoked potentials can predict future disability in people with clinically isolated syndrome

Evoked potentials can predict future disability in people with clinically isolated syndrome

Therapies for multiple sclerosis targeting B cells

Defining multiple sclerosis subtypes using machine learning

Contact Info

Product

Resources

About