To assess the 1-year efficacy and safety of a regimen of tocilizumab plus methotrexate or placebo, which was augmented by a treat-to-target strategy from week 24.
ACT-RAY was a double-blind, 3-year ...trial. Adults with active rheumatoid arthritis despite methotrexate were randomised to add tocilizumab to ongoing methotrexate (add-on strategy) or to switch to tocilizumab plus placebo (switch strategy). Tocilizumab 8 mg/kg was administered every 4 weeks. Conventional open-label disease-modifying antirheumatic drugs (DMARDs) other than methotrexate were added at week 24 or later in patients with DAS28>3.2.
556 patients were randomised; 85% completed 52 weeks. The proportion of patients receiving open-label DMARDs was comparable in the add-on (29%) and switch (33%) arms. Overall, week 24 results were maintained or further improved at week 52 in both arms. Some endpoints favoured the add-on strategy. Mean changes in Genant-modified Sharp scores were small; more add-on (92.8%) than switch patients (86.1%) had no radiographic progression. At week 52, comparable numbers of patients had antidrug antibodies (ADAs; 1.5% and 2.2% of add-on and switch patients, respectively) and neutralising ADAs (0.7% and 1.8%). Rates of serious adverse events and serious infections per 100 patient-year (PY) were 11.3 and 4.5 in add-on and 16.8 and 5.5 in switch patients. In patients with normal baseline values, alanine aminotransferase elevations >3× upper limit of normal were observed in 11% of add-on and 3% of switch patients.
Despite a trend favouring the add-on strategy, these data suggest that both tocilizumab add-on and switch strategies led to meaningful clinical and radiographic responses.
Background:
In multiple sclerosis (MS), thalamic integrity is affected directly by demyelination and neuronal loss, and indirectly by gray/white matter lesions outside the thalamus, altering thalamic ...neuronal projections.
Objective:
To assess the efficacy of ocrelizumab compared with interferon beta-1a (IFNβ1a)/placebo on thalamic volume loss and the effect of switching to ocrelizumab on volume change in the Phase III trials in relapsing MS (RMS, OPERA I/II; NCT01247324/NCT01412333) and in primary progressive MS (PPMS, ORATORIO; NCT01194570).
Methods:
Thalamic volume change was computed using paired Jacobian integration and analyzed using an adjusted mixed-effects repeated measurement model.
Results:
Over the double-blind period, ocrelizumab treatment significantly reduced thalamic volume loss with the largest effect size (Cohen’s d: RMS: 0.561 at week 96; PPMS: 0.427 at week 120) compared with whole brain, cortical gray matter, and white matter volume loss. At the end of up to 7 years of follow-up, patients initially randomized to ocrelizumab still showed less thalamic volume loss than those switching from IFNβ1a (p < 0.001) or placebo (p < 0.001).
Conclusion:
Ocrelizumab effectively reduced thalamic volume loss compared with IFNβ1a/placebo. Early treatment effects on thalamic tissue preservation persisted over time. Thalamic volume loss could be a potential sensitive marker of persisting tissue damage.
Floodlight Open was a global, open-access, digital-only study designed to understand the drivers and barriers in deployment and use of a smartphone app in a naturalistic setting and broad study ...population of people with and without multiple sclerosis (MS). The study utilised the Floodlight Open app: a 'bring-your-own-device' solution that remotely measures a user's mood, cognition, hand motor function, and gait and postural stability via smartphone sensor-based tests requiring active user input ('active tests'). Levels of mobility of study participants ('life-space measurement') were passively measured. Study data from these tests were made available via an open-access platform. Data from 1350 participants with self-declared MS and 1133 participants with self-declared non-MS from 17 countries across four continents were included in this report. Overall, MS participants provided active test data for a mean duration of 5.6 weeks or a mean duration of 19 non-consecutive days. This duration increased among MS participants who persisted beyond the first week to a mean of 10.3 weeks or 36.5 non-consecutive days. Passively collected life-space measurement data were generated by MS participants for a mean duration of 9.8 weeks or 50.6 non-consecutive days. This duration increased to 16.3 weeks/85.1 non-consecutive days among MS participants who persisted beyond the first week. Older age, self-declared MS disease status, and clinical supervision as part of concomitant clinical research were all significantly associated with higher persistence of the use of the Floodlight Open app. MS participants performed significantly worse than non-MS participants on four out of seven active tests. The findings from this multinational study inform future research to improve the dynamics of persistence of use of digital monitoring tools and further highlight challenges and opportunities in applying them to support MS clinical care.
Narcolepsy type 1 (NT1) is a disorder with well‐established markers and a suspected autoimmune aetiology. Conversely, the narcoleptic borderland (NBL) disorders, including narcolepsy type 2, ...idiopathic hypersomnia, insufficient sleep syndrome and hypersomnia associated with a psychiatric disorder, lack well‐defined markers and remain controversial in terms of aetiology, diagnosis and management. The Swiss Primary Hypersomnolence and Narcolepsy Cohort Study (SPHYNCS) is a comprehensive multicentre cohort study, which will investigate the clinical picture, pathophysiology and long‐term course of NT1 and the NBL. The primary aim is to validate new and reappraise well‐known markers for the characterization of the NBL, facilitating the diagnostic process. Seven Swiss sleep centres, belonging to the Swiss Narcolepsy Network (SNaNe), joined the study and will prospectively enrol over 500 patients with recent onset of excessive daytime sleepiness (EDS), hypersomnia or a suspected central disorder of hypersomnolence (CDH) during a 3‐year recruitment phase. Healthy controls and patients with EDS due to severe sleep‐disordered breathing, improving after therapy, will represent two control groups of over 50 patients each. Clinical and electrophysiological (polysomnography, multiple sleep latency test, maintenance of wakefulness test) information, and information on psychomotor vigilance and a sustained attention to response task, actigraphy and wearable devices (long‐term monitoring), and responses to questionnaires will be collected at baseline and after 6, 12, 24 and 36 months. Potential disease markers will be searched for in blood, cerebrospinal fluid and stool. Analyses will include quantitative hypocretin measurements, proteomics/peptidomics, and immunological, genetic and microbiota studies. SPHYNCS will increase our understanding of CDH and the relationship between NT1 and the NBL. The identification of new disease markers is expected to lead to better and earlier diagnosis, better prognosis and personalized management of CDH.
Summary
Objective
To investigate effects of interictal epileptic activity (IEA) and antiepileptic drugs (AEDs) on reactivity and aspects of the fitness to drive for epilepsy patients.
Methods
...Forty‐six adult patients with demonstration of focal or generalized bursts of IEA in electroencephalography (EEG) readings within 1 year prior to inclusion irrespective of medication performed a car driving computer test or a single light flash test (39 patients performed both). Reaction times (RTs), virtual crashes, or lapses (RT ≥ 1 s in the car or flash test) were measured in an IEA burst–triggered fashion during IEA and compared with RT‐measurements during unremarkable EEG findings in the same session.
Results
IEA prolonged RTs both in the flash and car test (p < 0.001) in individual patients up to 200 ms. Generalized IEA with spike/waves (s/w) had the largest effect on RT prolongation (p < 0.001, both tests), whereas mean RT during normal EEG, age, gender, and number of AEDs had no effect. The car test was better than the flash test in detecting RT prolongations (p = 0.030). IEA increased crashes/lapses >26% in sessions with generalized IEA with s/w. The frequency of IEA‐associated RT >1 s exceeded predictions (p < 0.001) based on simple RT shift, suggesting functional impairment beyond progressive RT prolongation by IEA. The number of AEDs correlated with prolonged RTs during normal EEG (p < 0.021) but not with IEA‐associated RT prolongation or crashes/lapses.
Significance
IEA prolonged RTs to varying extents, dependent on IEA type. IEA‐associated RTs >1 s were more frequent than predicted, suggesting beginning cerebral decompensation of visual stimulus processing. AEDs somewhat reduced psychomotor speed, but it was mainly the IEA that contributed to an excess of virtual accidents.
•2-Year change in MS myelin water fraction favored ocrelizumab over interferon.•Matched healthy controls showed no change in myelin water fraction over 2 years.•Ocrelizumab appears to protect against ...demyelination in MS white matter and lesions.
Myelin water imaging is a magnetic resonance imaging (MRI) technique that quantifies myelin damage and repair in multiple sclerosis (MS) via the myelin water fraction (MWF).
In this substudy of a phase 3 therapeutic trial, OPERA II, MWF was assessed in relapsing MS participants assigned to interferon beta-1a (IFNb-1a) or ocrelizumab (OCR) during a two-year double-blind period (DBP) followed by a two-year open label extension (OLE) with ocrelizumab treatment.
MWF in normal appearing white matter (NAWM), including both whole brain NAWM and 5 white matter structures, and chronic lesions, was assessed in 29 OCR and 26 IFNb-1a treated participants at weeks 0, 24, 48 and 96 (DBP), and weeks 144 and 192 (OLE), and in white matter for 23 healthy control participants at weeks 0, 48 and 96.
Linear mixed-effects models of data from baseline to week 96 showed a difference in the change in MWF over time favouring ocrelizumab in all NAWM regions. At week 192, lesion MWF was lower for participants originally randomised to IFNb-1a compared to those originally randomised to OCR. Controls showed no change in MWF over 96 weeks in any region.
Ocrelizumab appears to protect against demyelination in MS NAWM and chronic lesions and may allow for a more permissive micro environment for remyelination to occur in focal and diffusely damaged tissue.
To evaluate signal intensity of the inner ear using 3D-CISS imaging and correlated signal characteristics in patients with vestibular schwannoma to neuro-otological symptoms.
Sixty patients with ...unilateral vestibular schwannoma were retrospectively reviewed. All patients had had initial and follow-up magnetic resonance imaging (MRI). Individual treatment strategies consisted of “wait-and-watch”, surgical tumour resection, stereotactic radiosurgery or both surgery and stereotactic radiosurgery. For all patients a complete baseline and treatment course neuro-otological examination was re-studied.
On initial MRI, 3D-CISS sequence signal loss of the membranous labyrinth was present in 20 patients (33.3%); signal loss of cochlea in 20 (33.3%) and coincident signal loss of sacculus/utriculus in 17 (85%) of them. Sequential analysis of follow-up MRI series demonstrated slightly increased labyrinthine signal degradation, independently of the chosen therapy. Correlation of initial MRI results with initial neuro-otological symptoms showed significance only for cochlear obstruction versus vertigo (p=0.0397) and sacculus/utriculus obstruction versus vertigo (p=0.0336). No other statistically significant relationships were noted.
3D-constructive interference into steady state (3D-CISS) is appropriate for observing inner ear signal loss in patients with vestibular schwannoma. However, except for vertigo, no significant correlation was noted between initial neuro-otological symptomatology and signal loss of the inner ear.
Background
Chronic subdural hematoma (cSDH) is a disease affecting mainly elderly individuals. The reported incidence ranges from 2.0/100,000 to 58 per 100,000 person-years when only considering ...patients who are over 70 years old, with an overall incidence of 8.2–14.0 per 100,000 persons. Due to an estimated doubling of the population above 65 years old between 2000 and 2030, cSDH will become an even more significant concern. To gain an overview of cSDH hospital admission rates, treatment, and outcome, we performed this multicenter national cohort study of patients requiring surgical treatment of cSDH.
Methods
A multicenter cohort study included patients treated in 2013 in a Swiss center accredited for residency. Demographics, medical history, symptoms, and medication were recorded. Imaging at admission was evaluated, and therapy was divided into burr hole craniostomy (BHC), twist drill craniostomy (TDC), and craniotomy. Patients' outcomes were dichotomized into good (mRS, 0–3) and poor (mRS, 4–6) outcomes. A two-sided
t
-test for unpaired variables was performed, while a chi-square test was performed for categorical variables, and a
p
-value of <0.05 was considered to be statistically significant.
Results
A total of 663 patients were included. The median age was 76 years, and the overall incidence rate was 8.2/100,000. With age, the incidence rate increased to 64.2/100,000 in patients aged 80–89 years. The most prevalent symptoms were gait disturbance in 362 (58.6%) of patients, headache in 286 (46.4%), and focal neurological deficits in 252 (40.7%). CSDH distribution was unilateral in 478 (72.1%) patients, while 185 presented a bilateral hematoma with no difference in the outcome. BHC was the most performed procedure for 758 (97.3%) evacuations. CSDH recurrence was noted in 104 patients (20.1%). A good outcome was seen in almost 81% of patients. Factors associated with poor outcomes were age, GCS and mRS on admission, and the occurrence of multiple deficits present at the diagnosis of the cSDH.
Conclusion
As the first multicenter national cohort-based study analyzing the disease burden of cSDH, our study reveals that the hospital admission rate of cSDH was 8.2/100,000, while with age, it rose to 64.2/100,000. A good outcome was seen in 81% of patients, who maintained the same quality of life as before the surgery. However, the mortality rate was 4%.
Objective
To validate the smartphone sensor‐based Draw a Shape Test – a part of the Floodlight Proof‐of‐Concept app for remotely assessing multiple sclerosis‐related upper extremity impairment by ...tracing six different shapes.
Methods
People with multiple sclerosis, classified functionally normal/abnormal via their Nine‐Hole Peg Test time, and healthy controls participated in a 24‐week, nonrandomized study. Spatial (trace accuracy), temporal (mean and variability in linear, angular, and radial drawing velocities, and dwell time ratio), and spatiotemporal features (trace celerity) were cross‐sectionally analyzed for correlation with standard clinical and brain magnetic resonance imaging (normalized brain volume and total lesion volume) disease burden measures, and for capacity to differentiate people with multiple sclerosis from healthy controls.
Results
Data from 69 people with multiple sclerosis and 18 healthy controls were analyzed. Trace accuracy (all shapes), linear velocity variability (circle, figure‐of‐8, spiral shapes), and radial velocity variability (spiral shape) had a mostly fair/moderate‐to‐good correlation (|r| = 0.14–0.66) with all disease burden measures. Trace celerity also had mostly fair/moderate‐to‐good correlation (|r| = 0.18–0.41) with Nine‐Hole Peg Test performance, cerebellar functional system score, and brain magnetic resonance imaging. Furthermore, partial correlation analysis related these results to motor impairment. People with multiple sclerosis showed greater drawing velocity variability, though slower mean velocity, than healthy controls. Linear velocity (spiral shape) and angular velocity (circle shape) potentially differentiate functionally normal people with multiple sclerosis from healthy controls.
Interpretation
The Draw a Shape Test objectively assesses upper extremity impairment and correlates with all disease burden measures, thus aiding multiple sclerosis‐related upper extremity impairment characterization.
Background
The development of touchscreen-based assessments of upper extremity function could benefit people with multiple sclerosis (MS) by allowing convenient, quantitative assessment of their ...condition. The Pinching Test forms a part of the Floodlight smartphone app (F. Hoffmann-La Roche Ltd, Basel, Switzerland) for people with MS and was designed to capture upper extremity function.
Objective
This study aimed to evaluate the Pinching Test as a tool for remotely assessing upper extremity function in people with MS.
Methods
Using data from the 24-week, prospective feasibility study investigating the Floodlight Proof-of-Concept app for remotely assessing MS, we examined 13 pinching, 11 inertial measurement unit (IMU)–based, and 13 fatigability features of the Pinching Test. We assessed the test-retest reliability using intraclass correlation coefficients second model, first type; ICC(2,1), age- and sex-adjusted cross-sectional Spearman rank correlation, and known-groups validity (data aggregation: median all features, SD fatigability features).
Results
We evaluated data from 67 people with MS (mean Expanded Disability Status Scale EDSS: 2.4 SD 1.4) and 18 healthy controls. In this cohort of early MS, pinching features were reliable ICC(2,1)=0.54-0.81; correlated with standard clinical assessments, including the Nine-Hole Peg Test (9HPT) (|r|=0.26-0.54; 10/13 features), EDSS (|r|=0.25-0.36; 7/13 features), and the arm items of the 29-item Multiple Sclerosis Impact Scale (MSIS-29) (|r|=0.31-0.52; 7/13 features); and differentiated people with MS-Normal from people with MS-Abnormal (area under the curve: 0.68-0.78; 8/13 features). IMU-based features showed similar test-retest reliability ICC(2,1)=0.47-0.84 but showed little correlations with standard clinical assessments. In contrast, fatigability features (SD aggregation) correlated with 9HPT time (|r|=0.26-0.61; 10/13 features), EDSS (|r|=0.26-0.41; 8/13 features), and MSIS-29 arm items (|r|=0.32-0.46; 7/13 features).
Conclusions
The Pinching Test provides a remote, objective, and granular assessment of upper extremity function in people with MS that can potentially complement standard clinical evaluation. Future studies will validate it in more advanced MS.
Trial Registration
ClinicalTrials.gov NCT02952911; https://clinicaltrials.gov/study/NCT02952911
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