Summary Background B lymphocytes are implicated in the pathogenesis of multiple sclerosis. We aimed to assess efficacy and safety of two dose regimens of the humanised anti-CD20 monoclonal antibody ...ocrelizumab in patients with relapsing-remitting multiple sclerosis. Methods We did a multicentre, randomised, parallel, double-blind, placebo-controlled study involving 79 centres in 20 countries. Patients aged 18–55 years with relapsing-remitting multiple sclerosis were randomly assigned (1:1:1:1) via an interactive voice response system to receive either placebo, low-dose (600 mg) or high-dose (2000 mg) ocrelizumab in two doses on days 1 and 15, or intramuscular interferon beta-1a (30 μg) once a week. The randomisation list was not disclosed to the study centres, monitors, project statisticians or to the project team at Roche. All groups were double blinded to group assignment, except the interferon beta-1a group who were rater masked. At week 24, patients in the initial placebo, 600 mg ocrelizumab, and interferon beta-1a groups received ocrelizumab 600 mg; the 2000 mg group received 1000 mg. Our primary endpoint was the total number of gadolinium-enhancing lesions (GEL) and T1-weighted MRI at weeks 12, 16, 20, and 24. Analyses were done on an intention-to-treat basis. This trial is registered with ClinicalTrials.gov , number NCT00676715. Findings 218 (99%) of the 220 randomised patients received at least one dose of ocrelizumab, 204 (93%) completed 24 weeks of the study and 196 (89%) completed 48 weeks. In the intention-to-treat population of 218 patients, at week 24, the number of gadolinium-enhancing lesions was 89% (95% CI 68–97; p<0·0001) lower in the 600 mg ocrelizumab group than in the placebo group, and 96% (89–99; p<0·0001) lower in the 2000 mg group. In exploratory analyses, both 600 mg and 2000 mg ocrelizumab groups were better than interferon beta-1a for GEL reduction. We noted serious adverse events in two of 54 (4%; 95% CI 3·0–4·4) patients in the placebo group, one of 55 (2%; 1·3–2·3) in the 600 mg ocrelizumab group, three of 55 (5%; 4·6–6·3) in the 2000 mg group, and two of 54 (4%; 3·0–4·4) in the interferon beta-1a group. Interpretation The similarly pronounced effects of B-cell depletion with both ocrelizumab doses on MRI and relapse-related outcomes support a role for B-cells in disease pathogenesis and warrant further assessment in large, long-term trials. Funding F Hoffmann-La Roche Ltd, Biogen Idec Inc.
Summary The clinical features, diagnostic challenges, neuroimaging appearance, therapeutic options, and pathobiological research progress in childhood—and adolescent—onset multiple sclerosis have ...been informed by many new insights in the past 7 years. National programmes in several countries, collaborative research efforts, and an established international paediatric multiple sclerosis study group have contributed to revised clinical diagnostic definitions, identified clinical features of multiple sclerosis that differ by age of onset, and made recommendations regarding the treatment of paediatric multiple sclerosis. The relative risks conveyed by genetic and environmental factors to paediatric multiple sclerosis have been the subject of several large cohort studies. MRI features have been characterised in terms of qualitative descriptions of lesion distribution and applicability of MRI aspects to multiple sclerosis diagnostic criteria, and quantitative studies have assessed total lesion burden and the effect of the disease on global and regional brain volume. Humoral-based and cell-based assays have identified antibodies against myelin, potassium-channel proteins, and T-cell profiles that support an adult-like T-cell repertoire and cellular reactivity against myelin in paediatric patients with multiple sclerosis. Finally, the safety and efficacy of standard first-line therapies in paediatric multiple sclerosis populations are now appreciated in more detail, and consensus views on the future conduct and feasibility of phase 3 trials for new drugs have been proposed.
Summary Background Modulation of sphingosine 1-phosphate (S1P) receptors in a non-selective manner decreases disease activity in patients with multiple sclerosis but has potential safety concerns. We ...assessed the safety and efficacy of the oral selective S1P receptor modulator ozanimod in patients with relapsing multiple sclerosis. Methods RADIANCE is a combined phase 2/3 trial. Patients with relapsing multiple sclerosis were recruited from 55 academic and private multiple sclerosis clinics in 13 countries across Europe and the USA. Eligible participants were aged 18–55 years, had an Expanded Disability Status Scale (EDSS) score of 0–5·0, and had either one or more relapses in the previous 12 months, or one or more relapses in the past 24 months and one or more gadolinium-enhancing lesions on MRI in the previous 12 months before screening. Participants were assigned by a computer-generated randomisation sequence in a 1:1:1 ratio to ozanimod (0·5 mg or 1 mg) or matching placebo once daily for 24 weeks by an independent, unmasked, statistical team. Trial participants, study site personnel, MRI assessors, steering committee members, and the study statistician were masked to treatment assignment. To attenuate first-dose cardiac effects, ozanimod was up-titrated from 0·25 mg to 0·5 mg or 1 mg over 8 days. The primary endpoint was the cumulative number of total gadolinium-enhancing MRI lesions measured by an independent MRI analysis centre at weeks 12–24 after treatment initiation. Analysis was by intention to treat. Here, we report results from the 24-week phase 2 trial. This trial is registered with ClinicalTrials.gov , number NCT01628393 . The 2-year phase 3 trial is ongoing. Findings The first patient was randomised on Oct 18, 2012, and the final visit of the last randomised patient was on May 11, 2014. The intention-to-treat and safety population consisted of 258 participants, 88 were assigned placebo, 87 ozanimod 0·5 mg, and 83 ozanimod 1 mg; 252 (98%) patients completed the assigned treatment. The mean cumulative number of gadolinium-enhancing lesions at weeks 12–24 was 11·1 (SD 29·9) with placebo compared with 1·5 (3·7) with ozanimod 0·5 mg (odds ratio 0·16, 95% CI 0·08–0·30; p<0·0001) and 1·5 (3·4) with ozanimod 1 mg (odds ratio 0·11, 95% CI 0·06–0·21; p<0·0001). Three serious adverse events unrelated to treatment were reported in patients assigned ozanimod 0·5 mg: optic neuritis, somatoform autonomic dysfunction, and cervical squamous metaplasia (HPV-related). No serious infectious or cardiac adverse events were reported, and no cases of macular oedema arose. The most common adverse events in the ozanimod 0·5 mg and 1 mg groups compared with placebo were nasopharyngitis (11 and five vs 12), headache (five and three vs eight), and urinary-tract infections (six and two vs two). The maximum reduction in mean heart rate by Holter monitoring during the first 6 h in ozanimod-treated participants was less than 2 beats per min (bpm) compared with baseline, with no patient having a minimum hourly heart rate less than 45 bpm. Electrocardiograms and 24-h Holter monitoring showed no increased incidence of atrioventricular block or sinus pause with ozanimod. Interpretation Ozanimod significantly reduced MRI lesion activity in participants with relapsing multiple sclerosis, with a favourable safety profile over a period of 24 weeks. These findings warrant phase 3 trials, which are ongoing. Funding Receptos, Inc.
Summary The onset of multiple sclerosis (MS) in childhood poses diagnostic and therapeutic challenges, particularly if the symptoms of the first demyelinating event resemble acute disseminated ...encephalomyelitis (ADEM). MRI is an invaluable diagnostic tool but it lacks the specificity to distinguish ADEM from the first attack of MS. Advanced MRI techniques might have the required specificity to reveal whether the loss of integrity in non-lesional tissue occurs as a fundamental feature of MS. Although the onset of MS in childhood typically predicts a favourable short-term prognosis, some children are severely disabled, either physically or cognitively, and more than 50% are predicted to enter the secondary-progressive phase of the disease by the age of 30 years. Immunomodulatory therapies for MS and their safe application in children can improve long-term prognosis. Genetic and environmental factors, such as viral infection, might be uniquely amenable to study in paediatric patients with MS. Understanding the immunological consequences of these putative exposures will shed light on the early pathological changes in MS.
Summary Background The full spectrum of clinical manifestations and outcome, and the potential importance of regional or demographic features or viral triggers in paediatric multiple sclerosis (MS), ...has yet to be fully characterised. Our aim was to determine some of these characteristics in children with MS. Methods 137 children with MS and 96 control participants matched by age and geographical region were recruited in a multinational study. They underwent structured clinical-demographic interviews, review of academic performance, physical examination, disability assessment (MS patients only), and standardised assays for IgG antibodies directed against Epstein-Barr virus, cytomegalovirus, parvovirus B19, varicella zoster virus, and herpes simplex virus. Findings MS was relapsing-remitting at diagnosis in 136 (99%) children. The first MS attack resembled acute disseminated encephalomyelitis (ADEM) in 22 (16%) of the children, most under 10 years old (mean age 7·4 SD 4·2 years). Children with ADEM-like presentations were significantly younger than were children with polyfocal (11·2 4·5 years; p<0·0001) or monofocal (12·0 3·8 years; p=0·0005) presentations. Permanent physical disability (EDSS≥4·0) developed within 5 years in 15 (13%) of the 120 children for whom EDSS score was available. 23 (17%) had impaired academic performance, which was associated with increasing disease duration (p=0·02). Over 108 (86%) of the children with MS, irrespective of geographical residence, were seropositive for remote EBV infection, compared with only 61 (64%) of matched controls (p=0·025, adjusted for multiple comparisons). Children with MS did not differ from controls in seroprevalence of the other childhood viruses studied, nor with respect to month of birth, sibling number, sibling rank, or exposure to young siblings. Interpretation Paediatric MS is a relapsing-remitting disease, with presenting features that vary by age at onset. MS in children might be associated with exposure to EBV, suggesting a possible role for EBV in MS pathobiology.
Summary Background Multiple sclerosis (MS) diagnostic criteria incorporate MRI features that can be used to predict later diagnosis of MS in adults with acute CNS demyelination. To identify MRI ...predictors of a subsequent MS diagnosis in a paediatric population, we created a standardised scoring method and applied it to MRI scans from a national prospective incidence cohort of children with CNS demyelination. Methods Clinical and MRI examinations were done at the onset of acute CNS demyelination and every 3 months in the first year after that, and at the time of a second demyelinating attack. MS was diagnosed on the basis of clinical or MRI evidence of relapsing disease. Baseline MRI scans were assessed for the presence of 14 binary response parameters. Parameters were assessed with a multiple tetrachoric correlation matrix. Univariate analyses and multivariable Cox proportional hazards models were used to identify predictors of MS. Findings Between Sept 1, 2004, and June 30, 2010, 332 children and adolescents were assessed for eligibility. 1139 scans were available from 284 eligible participants who had been followed up for 3·9 (SD 1·7) years. 57 (20%) were diagnosed with MS after a median of 188 (IQR 144–337) days. Seven of 14 binary response parameters were retained. The presence of either one or more T1-weighted hypointense lesions (hazard ratio 20·6, 95% CI 5·46–78·0) or one or more periventricular lesions (3·34, 1·27–8·83) was associated with an increased likelihood of MS diagnosis (sensitivity 84%, specificity 93%, positive predictive value 76%, negative predictive value 96%). Risk for MS diagnosis was highest when both parameters were present (34·27, 16·69–70·38). Although the presence of contrast enhancement, cerebral white matter, intracallosal, and brainstem lesions was associated with MS in the univariate analyses, these parameters were not retained in the multivariable models. Interpretation Specific MRI parameters can be used to predict diagnosis of MS in children with incident demyelination of the CNS. The ability to promptly identify children with MS will enhance timely access to care and will be important for future clinical trials in paediatric MS. Funding Canadian Multiple Sclerosis Scientific Research Foundation.
Abstract The present study examined the differences in the lower extremity gait kinematic profile of patients recovering from ankle fracture compared with healthy controls. In addition, we inquired ...whether the profile would differ among fracture severity groups. A total of 48 patients participated in the present prospective, case-control study. The gait of 24 patients recovering from an ankle fracture injury and 24 healthy matched controls was examined using an inertial measurement unit sensor system. The following gait parameters were evaluated: knee range of motion (ROM) during the swing phase, maximum knee flexion angle during stance, thigh and calf ROM, and stride duration. Statistically significant differences were found between the ankle fracture group and the control group for all parameters. The patients with ankle fracture had a lower knee ROM during swing phase compared with the control group (mean ± standard deviation 43.0° ± 15.5° compared with 66.7° ± 5.1°, respectively; p < .001). The maximum knee flexion angle during stance was lower in the patients with ankle fracture than in the control group (mean ± standard deviation 10.5° ± 6.1° compared with 21.2° ± 4.5°, respectively; p < .001). Patients with ankle fracture also had lower gait cycle thigh and calf ROM angles ( p < .001) and a longer stride duration ( p < .001) compared with the control group. No statistically significant differences were found among the severity groups. These results suggest that the gait kinematic characteristics vary between healthy people and patients recovering from an ankle fracture injury during the short-term period after injury.
Objective To determine the biopsychosocial correlates of general, physical, and mental fatigue in patients with postpoliomyelitis syndrome (PPS) by assessing the additional contribution of ...potentially modifiable factors after accounting for important nonmodifiable disease-related factors. It was hypothesized that disease-related, behavioral, and psychosocial factors would contribute in different ways to general, physical, and mental fatigue in PPS and that a portion of fatigue would be determined by potentially modifiable factors. Design Cross-sectional study. Setting A tertiary university-affiliated hospital post-polio clinic. Patients Fifty-two ambulatory patients with PPS who were not severely depressed were included. Assessment of Risk Factors Potential correlates for fatigue included disease-related factors (acute polio weakness, time since acute polio, PPS duration, muscle strength, pain, forced vital capacity, maximum inspiratory pressure, maximum expiratory pressure, body mass index, disability, fibromyalgia), behavioral factors (physical activity, sleep quality), and psychosocial factors (depression, stress, self-efficacy). Main Outcome Measurements Fatigue was assessed with the Multidimensional Fatigue Inventory (MFI; assesses fatigue on 5 subscales) and the Fatigue Severity Scale (FSS). Results Multivariate models were computed for MFI General, Physical, and Mental Fatigue. Age-adjusted multivariate models with nonmodifiable factors included the following predictors of (1) MFI General Fatigue: maximum inspiratory pressure, fibromyalgia, muscle strength; (2) MFI Physical Fatigue: maximum expiratory pressure, muscle strength, age, time since acute polio; and (3) MFI Mental Fatigue: none. The following potentially modifiable predictors made an additional contribution to the models: (1) MFI General Fatigue: stress, depression; (2) MFI Physical Fatigue: physical activity, pain; and (3) MFI Mental Fatigue: stress. Conclusions PPS fatigue is multidimensional. Different types of fatigue are determined by different variables. Potentially modifiable factors account for a portion of fatigue in PPS.
Summary Background Strong immunosuppression, including chemotherapy and immune-depleting antibodies followed by autologous haemopoietic stem-cell transplantation (aHSCT), has been used to treat ...patients with multiple sclerosis, improving control of relapsing disease. We addressed whether near-complete immunoablation followed by immune cell depleted aHSCT would result in long-term control of multiple sclerosis. Methods We did this phase 2 single-arm trial at three hospitals in Canada. We enrolled patients with multiple sclerosis, aged 18–50 years with poor prognosis, ongoing disease activity, and an Expanded Disability Status Scale of 3·0–6·0. Autologous CD34 selected haemopoietic stem-cell grafts were collected after mobilisation with cyclophosphamide and filgrastim. Immunoablation with busulfan, cyclophosphamide, and rabbit anti-thymocyte globulin was followed by aHSCT. The primary outcome was multiple sclerosis activity-free survival (events were clinical relapse, appearance of a new or Gd-enhancing lesion on MRI, and sustained progression of Expanded Disability Status Scale score). This study was registered at ClinicalTrials.gov , NCT01099930. Findings Between diagnosis and aHSCT, 24 patients had 167 clinical relapses over 140 patient-years with 188 Gd-enhancing lesions on 48 pre-aHSCT MRI scans. Median follow-up was 6·7 years (range 3·9–12·7). The primary outcome, multiple sclerosis activity-free survival at 3 years after transplantation was 69·6% (95% CI 46·6–84·2). With up to 13 years of follow-up after aHSCT, no relapses occurred and no Gd enhancing lesions or new T2 lesions were seen on 314 MRI sequential scans. The rate of brain atrophy decreased to that expected for healthy controls. One of 24 patients died of transplantation-related complications. 35% of patients had a sustained improvement in their Expanded Disability Status Scale score. Interpretation We describe the first treatment to fully halt all detectable CNS inflammatory activity in patients with multiple sclerosis for a prolonged period in the absence of any ongoing disease-modifying drugs. Furthermore, many of the patients had substantial recovery of neurological function despite their disease's aggressive nature. Funding Multiple Sclerosis Scientific Research Foundation.
Summary Background Patients with multiple sclerosis, a chronic inflammatory demyelinating disease of the central nervous system with autoimmune pathogenesis, have shown partial response to a number ...of immunomodulating treatments, but the search for more effective, safe, and convenient therapeutic options continues. Amiselimod is an oral selective modulator of sphingosine 1-phosphate 1 (S1P1 ) receptor, which is being developed for the treatment of various autoimmune-mediated diseases. We assessed the safety and efficacy of amiselimod in patients with relapsing– remitting multiple sclerosis. Methods In this double-blind phase 2 trial, patients aged 18–60 years with active relapsing–remitting multiple sclerosis from 84 centres in Europe and Canada were randomly assigned (1:1:1:1) with an interactive web-response system to receive once daily oral amiselimod 0·1 mg, 0·2 mg, 0·4 mg, or placebo for 24 weeks. All study personnel, site personnel, investigators, and patients were masked to the treatment assignment during the study. The primary endpoint was the total number of gadolinium-enhanced T1-weighted lesions on monthly brain MRI scans from weeks 8 to 24. Analysis was done on the predefined evaluable population (all randomised patients who did not have any major protocol deviations, completed 24 weeks of treatment as planned, and had at least three valid post-dose MRI scans). This trial is registered with ClinicalTrials.gov , number NCT01742052. Findings Between Jan 31, 2013, and Dec 24, 2013, 536 patients were screened and 415 patients randomly assigned to amiselimod 0·1 mg (n=105), 0·2 mg (n=103), 0·4 mg (n=104), or placebo (n=103). The median total number of gadolinium-enhanced T1-weighted lesions from weeks 8 to 24 did not differ between the amiselimod 0·1 mg and placebo groups (median 1·6 lesions range 0–132 in the placebo group vs 2·0 0–105 in the 0·1 mg group median difference 0·0, 95% CI −1·0 to 0·0, p=0·7517), but was significantly lower in the two higher amiselimod dose groups than in the placebo group (0·0 lesions range 0–35 in the 0·2 mg group median difference vs placebo −1·0, 95% CI −1·0 to 0·0, p=0·0021 and 0·0 range 0–30 in the 0·4 mg group –1·0, −1·2 to 0·0, p=0·0003). The estimated incident rate ratio compared with placebo was dose-dependently decreased with amiselimod (0·1 mg 0·53 95% CI 0·33–0·85; p=0·0079, 0·2 mg 0·39 95% CI 0·24–0·63; p=0·0001, and 0·4 mg 0·23 95% CI 0·14–0·38; p<0·0001). The incidence of treatment-emergent adverse events, including infections and cardiac disorders, were similar in the amiselimod treatment groups (59 56% of 105 patients in the 0·1 mg group, 69 67% of 103 in the 0·2 mg group, and 58 56% of 104 in the 0·4 mg group) to the incidence in the placebo group (66 64% of 103 patients); the most common treatment-emergent adverse events were headache (ten 10%, ten 10%, and ten 10% vs four 4%) and nasopharyngitis (nine 9%, seven 7%, ten 10% vs eight 8%). No serious treatment-emergent adverse event was reported for more than one patient in any group and no clinically significant heart rate reduction was observed at any amiselimod dose. Interpretation Amiselimod 0·2 mg and 0·4 mg significantly reduced the total number of gadolinium-enhanced T1-weighted lesions. The safety and efficacy profiles of amiselimod suggest that this S1P1 receptor modulator is a new potential treatment in multiple sclerosis and potentially other immune-mediated inflammatory diseases and deserves further investigation. Funding Mitsubishi Tanabe Pharma Corporation.
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