Ocrelizumab exposure in relapsing–remitting multiple sclerosis: 10-year analysis of the phase 2 randomized clinical trial and its extension

Disease-modifying therapies; Multiple sclerosis; OcrelizumabTerapias modificadoras de la enfermedad; Esclerosis múltiple; OcrelizumabTeràpies modificadores de la malaltia; Esclerosi múltiple; OcrelizumabOpen-label extension (OLE) studies help inform long-term safety and efficacy of disease-modifying therapies in multiple sclerosis (MS). We report exploratory analyses from a phase 2 trial on the longest follow-up to date of ocrelizumab-treated patients with relapsing–remitting MS (RRMS). The primary treatment period (PTP) comprised four 24-week treatment cycles; participants were randomized to double-blind ocrelizumab (2000 mg or 600 mg), placebo, or interferon β-1a (open label) for one cycle, then dose-blinded ocrelizumab 1000 mg or 600 mg for the remaining cycles. The PTP was followed by consecutive assessed and unassessed treatment-free periods (TFPs) and then the OLE (ocrelizumab 600 mg every 24 weeks). Safety and efficacy were prospectively assessed. Of 220 participants randomized, 183 (84%) completed the PTP. After the TFP, 103 entered OLE (median OLE ocrelizumab exposure 6.5 years). Most common adverse events across all periods were infusion-related reactions. MRI activity, annualized relapse rate, and confirmed disability progression (CDP) rates remained low throughout. During the assessed TFP, there was a trend toward less and later B-cell repletion, and later CDP, for patients randomized to ocrelizumab; MRI activity was observed in 16.3% of patients, the earliest 24 weeks after the last ocrelizumab dose. This is the longest follow-up of ocrelizumab-treated patients with RRMS, with no new safety signals emerging during an observation period from 2008 to 2020. Results reinforce the sustained efficacy of long-term ocrelizumab. Reduced disease activity was maintained following interruption of 6-month dosing cycles, with no evidence of rebound.This research was funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland. Editorial assistance for this article was provided by Nicholas Fitch and Martha Hoque of Articulate Science, UK, and funded by F. Hoffmann-La Roche Ltd. The authors had full editorial control of the manuscript and provided their final approval of all content

The effect of arm training on thermoregulatory responses and calf volume during upper body exercise

The final publication is available at Springer via https://doi.org/10.1007/s00421-014-2842-9.PURPOSE: The smaller muscle mass of the upper body compared to the lower body may elicit a smaller thermoregulatory stimulus during exercise and thus produce novel training-induced thermoregulatory adaptations. Therefore, the principal aim of the study was to examine the effect of arm training on thermoregulatory responses during submaximal exercise. METHODS: Thirteen healthy male participants (Mean ± SD age 27.8 ± 5.0 years, body mass 74.8 ± 9.5 kg) took part in 8 weeks of arm crank ergometry training. Thermoregulatory and calf blood flow responses were measured during 30 min of arm cranking at 60% peak power (W peak) pre-, and post-training and post-training at the same absolute intensity as pre-training. Core temperature and skin temperatures were measured, along with heat flow at the calf, thigh, upper arm and chest. Calf blood flow using venous occlusion plethysmography was performed pre- and post-exercise and calf volume was determined during exercise. RESULTS: The upper body training reduced aural temperature (0.1 ± 0.3 °C) and heat storage (0.3 ± 0.2 J g(-1)) at a given power output as a result of increased whole body sweating and heat flow. Arm crank training produced a smaller change in calf volume post-training at the same absolute exercise intensity (-1.2 ± 0.8% compared to -2.2 ± 0.9% pre-training; P < 0.05) suggesting reduced leg vasoconstriction. CONCLUSION: Training improved the main markers of aerobic fitness. However, the results of this study suggest arm crank training additionally elicits physiological responses specific to the lower body which may aid thermoregulation.Peer reviewedFinal Accepted Versio

Oxygen uptake kinetics in trained adolescent females

Little evidence exists with regard to the effect that exercise training has upon oxygen uptake kinetics in adolescent females. PURPOSE: The aim of the study was to compare [Formula: see text] and muscle deoxygenation kinetics in a group of trained (Tr) and untrained (Utr) female adolescents. METHOD: Twelve trained (6.4 ± 0.9 years training, 10.3 ± 1.4 months per year training, 5.2 ± 2.0 h per week) adolescent female soccer players (age 14.6 ± 0.7 years) were compared to a group (n = 8) of recreationally active adolescent girls (age 15.1 ± 0.6 years) of similar maturity status. Subjects underwent two, 6-min exercise transitions at a workload equivalent to 80 % of lactate threshold from a 3-min baseline of 10 W. All subjects had a passive rest period of 1 h between each square-wave transition. Breath-by-breath oxygen uptake and muscle deoxygenation were measured throughout and were modelled via a mono-exponential decay with a delay relative to the start of exercise. RESULT: Peak [Formula: see text] was significantly (p < 0.05) greater in the Tr compared to the Utr (Tr: 43.2 ± 3.2 mL kg(-1 )min(-1) vs. Utr: 34.6 ± 4.0 mL kg(-1 )min(-1)). The [Formula: see text] time constant was significantly (p < 0.05) faster in the Tr compared to the Utr (Tr: 26.3 ± 6.9 s vs. Utr: 35.1 ± 11.5 s). There was no inter-group difference in the time constant for muscle deoxygenation kinetics (Tr: 8.5 ± 3.0 s vs. Utr: 12.4 ± 8.3 s); a large effect size, however, was demonstrated (-0.804). CONCLUSION: Exercise training and/or genetic self-selection results in faster kinetics in trained adolescent females. The faster [Formula: see text] kinetics seen in the trained group may result from enhanced muscle oxygen utilisation

The association between human endogenous retroviruses and multiple sclerosis: a systematic review and meta-analysis

Background: The interaction between genetic and environmental factors is crucial to multiple sclerosis (MS) pathogenesis. Human Endogenous Retroviruses (HERVs) are endogenous viral elements of the human genome whose expression is associated with MS. Objective: To perform a systematic review and meta-analysis and to assess qualitative and quantitative evidence on the expression of HERV families in MS patients. Methods: Medline, Embase and the Cochrane Library were searched for published studies on the association of HERVs and MS. Meta-analysis was performed on the HERV-W family. Odds Ratio (OR) and 95% confidence interval (CI) were calculated for association. Results: 43 reports were extracted (25 related to HERV-W, 13 to HERV-H, 9 to HERV-K, 5 to HRES-1 and 1 to HER-15 family). The analysis showed an association between expression of all HERV families and MS. For HERV-W, adequate data was available for meta-analysis. Results from meta-analyses of HERV-W were OR = 22.66 (95%CI 6.32 to 81.20) from 4 studies investigating MSRV/HERV-W(MS-associated retrovirus) envelope mRNA in peripheral blood mononuclear cells, OR = 44.11 (95%CI 12.95 to 150.30) from 6 studies of MSRV/ HERV-W polymerase mRNA in serum/plasma and OR = 6.00 (95%CI 3.35 to 10.74) from 4 studies of MSRV/HERV-W polymerase mRNA in CSF

Serial anti–myelin oligodendrocyte glycoprotein antibody analyses and outcomes in children with demyelinating syndromes

Importance Identifying the course of demyelinating disease associated with myelin oligodendrocyte glycoprotein (MOG) autoantibodies is critical to guide appropriate treatment choices. Objective To characterize serial anti-MOG antibody serologies and clinical and imaging features at presentation and during follow-up in an inception cohort of prospectively monitored children with acquired demyelination. Design, Setting, and Participants In this prospective cohort study, study participants were recruited from July 2004 to February 2017 through the multicenter Canadian Pediatric Demyelinating Disease Study. Inclusion criteria included (1) incident central nervous system demyelination, (2) at least 1 serum sample obtained within 45 days from onset, and (3) complete clinical information. Of 430 participants with acquired demyelinating syndrome recruited, 274 were included in analyses. Of 156 excluded participants, 154 were excluded owing to missing baseline samples and 2 owing to incomplete clinical information. Data were analyzed from May to October 2018. Main Outcomes and Measures Presence of anti-MOG antibodies was blindly assessed in serial samples collected over a median of 4 years. Clinical, magnetic resonance imaging, and cerebrospinal fluid features were characterized at presentation, and subsequent disease course was assessed by development of new brain magnetic resonance imaging lesions, total lesion volume at last evaluation, annualized relapse rates, Expanded Disability Status Scale score and visual functional score at 4 years, and any disease-modifying treatment exposure. Results Of the 274 included participants, 140 (51.1%) were female, and the median (interquartile range) age of all participants was 10.8 (6.2-13.9) years. One-third of children were positive for anti-MOG antibodies at the time of incident demyelination. Clinical presentations included a combination of optic neuritis, transverse myelitis, and acute disseminated encephalomyelitis for 81 of 84 anti-MOG antibody–positive children (96%). Brain lesions were present in 51 of 76 anti-MOG antibody–positive participants (67%), but magnetic resonance imaging characteristics differed with age at presentation. Complete resolution of baseline lesions was observed in 26 of 49 anti-MOG antibody–positive participants (53%). On serial serum analysis, 38 of 67 participants (57%) who were seropositive at onset became seronegative (median time to conversion, 1 year). Among all participants who were positive for anti-MOG antibodies at presentation, clinical relapses occurred in 9 of 24 children (38%) who remained persistently seropositive and in 5 of 38 children (13%) who converted to seronegative status. Conclusions and Relevance Myelin oligodendrocyte glycoprotein antibodies are common in children with acquired demyelinating syndrome and are transient in approximatively half of cases. Even when persistently positive, most anti-MOG antibody–positive children experience a monophasic disease. The presence of anti-MOG antibodies at the time of incident demyelination should not immediately prompt the initiation of long-term immunomodulatory therapy

Efficacy and safety of ozanimod in multiple sclerosis: Dose-blinded extension of a randomized phase II study

© The Author(s), 2018. Background: Ozanimod, an oral immunomodulator, selectively targets sphingosine 1-phosphate receptors 1 and 5. Objective: Evaluate efficacy, safety, and tolerability of ozanimod in relapsing multiple sclerosis. Methods: In the RADIANCE Part A phase II study (NCT01628393), participants with relapsing multiple sclerosis were randomized (1:1:1) to once-daily ozanimod hydrochloride (0.5 or 1 mg) or placebo. After 24 weeks, participants could enter a 2-year, dose-blinded extension. Ozanimod-treated participants continued their assigned dose; placebo participants were re-randomized (1:1) to ozanimod hydrochloride 0.5 or 1 mg (equivalent to ozanimod 0.46 and 0.92 mg). Results: A total of 223 (89.6%) of the 249 participants completed the blinded extension. At 2 years of the extension, the percentage of participants who were gadolinium-enhancing lesion-free ranged from 86.5% to 94.6%. Unadjusted annualized relapse rate during the blinded extension (week 24—end of treatment) was 0.32 for ozanimod hydrochloride 0.5 mg → ozanimod hydrochloride 0.5 mg, 0.18 for ozanimod hydrochloride 1 mg → ozanimod hydrochloride 1 mg, 0.30 for placebo → ozanimod hydrochloride 0.5 mg, and 0.18 for placebo → ozanimod hydrochloride 1 mg. No second-degree or higher atrioventricular block or serious opportunistic infection was reported. Conclusion: Ozanimod demonstrated sustained efficacy in participants continuing treatment up to 2 years and reached similar efficacy in participants who switched from placebo; no unexpected safety signals emerged

Treatment of neuromyelitis optica: state-of-the-art and emerging therapies.

Neuromyelitis optica (NMO) is an autoimmune disease of the CNS that is characterized by inflammatory demyelinating lesions in the spinal cord and optic nerve, potentially leading to paralysis and blindness. NMO can usually be distinguished from multiple sclerosis (MS) on the basis of seropositivity for IgG antibodies against the astrocytic water channel aquaporin-4 (AQP4). Differentiation from MS is crucial, because some MS treatments can exacerbate NMO. NMO pathogenesis involves AQP4-IgG antibody binding to astrocytic AQP4, which causes complement-dependent cytotoxicity and secondary inflammation with granulocyte and macrophage infiltration, blood-brain barrier disruption and oligodendrocyte injury. Current NMO treatments include general immunosuppressive agents, B-cell depletion, and plasma exchange. Therapeutic strategies targeting complement proteins, the IL-6 receptor, neutrophils, eosinophils and CD19--all initially developed for other indications--are under clinical evaluation for repurposing for NMO. Therapies in the preclinical phase include AQP4-blocking antibodies and AQP4-IgG enzymatic inactivation. Additional, albeit currently theoretical, treatment options include reduction of AQP4 expression, disruption of AQP4 orthogonal arrays, enhancement of complement inhibitor expression, restoration of the blood-brain barrier, and induction of immune tolerance. Despite the many therapeutic options in NMO, no controlled clinical trials in patients with this condition have been conducted to date

Laboratory predictors of uphill cycling performance in trained cyclists

This study aimed to assess the relationship between an uphill time-trial (TT) performance and both aerobic and anaerobic parameters obtained from laboratory tests. Fifteen cyclists performed a Wingate anaerobic test, a graded exercise test (GXT) and a field-based 20-min TT with 2.7% mean gradient. After a 5-week non-supervised training period, 10 of them performed a second TT for analysis of pacing reproducibility. Stepwise multiple regressions demonstrated that 91% of TT mean power output variation (W kg-1) could be explained by peak oxygen uptake (ml kg-1.min-1) and the respiratory compensation point (W kg-1), with standardised beta coefficients of 0.64 and 0.39, respectively. The agreement between mean power output and power at respiratory compensation point showed a bias ± random error of 16.2 ± 51.8 W or 5.7 ± 19.7%. One-way repeated-measures analysis of variance revealed a significant effect of the time interval (123.1 ± 8.7; 97.8 ± 1.2 and 94.0 ± 7.2% of mean power output, for epochs 0-2, 2-18 and 18-20 min, respectively; P < 0.001), characterising a positive pacing profile. This study indicates that an uphill, 20-min TT-type performance is correlated to aerobic physiological GXT variables and that cyclists adopt reproducible pacing strategies when they are tested 5 weeks apart (coefficients of variation of 6.3; 1 and 4%, for 0-2, 2-18 and 18-20 min, respectively)