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Patients with multiple sclerosis (MS) who are treated with fingolimod have an increased proportion of transitional B cells in the circulation, but the underlying mechanism is not known. We hypothesized that B cell-activating factor of the tumor necrosis factor family (BAFF) is involved in the process. Compared with healthy controls and untreated MS patients, fingolimod-treated MS patients had significantly higher serum concentrations of BAFF, which positively correlated with the proportions and the absolute numbers of transitional B cells in blood. Despite the elevated concentrations of BAFF in fingolimod-treated MS patients, serum levels of soluble transmembrane activator and calcium-modulating cyclophilin ligand interactor, and B cell maturation antigen were not elevated. Our results show that fingolimod induces BAFF in the circulation and expands transitional B cells, but does not activate memory B cells or plasma cells in MS, which is favorable for the treatment of this disease.

Fingolimod is a sphingosine-1-phosphate receptor agonist used to inhibit the inflammatory activity of multiple sclerosis (MS), and has been shown to suppress osteoporosis in mouse models. In this study, levels of bone turnover markers were quantified in serum and urine samples from MS patients treated with fingolimod. Compared with untreated MS patients and healthy controls, fingolimod-treated MS patients had a significantly lower level of the bone resorption marker type I collagen cross-linked N-telopeptide in urine. This finding was prominent in female but was not seen in male subjects. Our results suggest that fingolimod may have a beneficial effect on bone mass loss in female MS patients.

Summary Background In a previous phase 3 study in patients with amyotrophic lateral sclerosis (ALS), edaravone did not show a significant difference in the Revised ALS Functional Rating Scale (ALSFRS-R) score compared with placebo. Post-hoc analysis of these data revealed that patients in an early stage with definite or probable diagnosis of ALS, defined by the revised El Escorial criteria, who met a select set of inclusion criteria showed a greater magnitude of effect than did the full study population. We aimed to substantiate this post-hoc result and assess safety and efficacy of edaravone in a phase 3 trial that focused on patients with early stage ALS who met the post-hoc analysis inclusion criteria. Methods In this phase 3, randomised, double-blind, parallel-group study, patients aged 20–75 years with ALS of grade 1 or 2 in the Japan ALS Severity Classification, scores of at least 2 points on all 12 items of ALSFRS-R, forced vital capacity of 80% or more, definite or probable ALS according to the revised El Escorial criteria, and disease duration of 2 years or less were recruited from 31 hospitals in Japan. Eligible patients also had a decrease of 1–4 points in the ALSFRS-R score during a 12-week observation period before randomisation. Patients meeting all criteria were then randomly assigned 1:1 to receive 60 mg intravenous edaravone or intravenous saline placebo for 6 cycles (4 weeks per cycle with 2 weeks on, 2 weeks off) for a total treatment duration of 24 weeks. In cycle 1, the study drug or placebo was administered once per day for 14 days within a 14 day period, followed by the drug-free period. In cycle 2 and thereafter, the study drug or placebo was administered for 10 days within a 14 day period, followed by a 2 week drug-free period. Participants and investigators, including those assessing outcomes, were masked to treatment allocation. The primary efficacy outcome was the change in ALSFRS-R score from the baseline to 24 weeks (or at discontinuation if this was after the third cycle) after randomisation. The primary outcome was assessed in all patients who had received at least one treatment infusion, had at least one assessment post-baseline, and reached the end of cycle 3. For patients with missing values at the end of cycle 6, data were imputed by the last observation carried forward (LOCF) method, provided the patients had completed at least cycle 3. Safety was assessed in all patients who had received at least one treatment infusion and had at least one assessment post-baseline. This trial is registered with ClinicalTrials.gov, NCT01492686. Findings Between Nov 28, 2011, and Sept 3, 2014, we screened 213 patients, and enrolled 192 as potential participants. Of these, 137 patients completed the observation period: 69 were randomly assigned to receive edaravone, and 68 were randomly assigned to receive placebo. 68 patients taking edaravone and 66 taking placebo were included in the primary efficacy analysis. For the primary outcome, the change in ALSFRS-R score was −5·01 (SE 0·64) in the edavarone group and −7·50 (0·66) in the placebo group. The least-squares mean difference between groups was 2·49 (SE 0·76, 95% CI 0·99–3·98; p=0·0013) in favour of edaravone. Treatment-emergent adverse events were reported in 58 (84%) patients receiving edaravone and 57 (84%) patients receiving placebo. 11 (16%) patients taking edaravone and 16 (24%) taking placebo had serious adverse events, and one (1%) patient receiving edaravone and four (6%) patients receiving placebo had adverse events (one dysphagia in edaravone group and one dyspnoea, two respiratory disorder, and one rash in the placebo group) that led to withdrawal. Interpretation Edaravone showed efficacy in a small subset of people with ALS who met criteria identified in post-hoc analysis of a previous phase 3 study, showing a significantly smaller decline of ALSFRS-R score compared with placebo. There is no indication that edaravone might be effective in a wider population of patients with ALS who do not meet the criteria. Funding Mitsubishi Tanabe Pharma Corporation.

Objective Vitamin D levels are one of the most likely environmental factors related to the development of multiple sclerosis (MS). As vitamin D levels differ between ethnicities, the associated risk of MS also differs. We aimed to determine the associations of serum vitamin D levels in Japanese patients with MS. Methods Serum levels of 25-hydroxyvitamin D (25[OH]D), 1,25-dihydroxyvitamin D (1,25[OH]2D), and vitamin D-binding protein (DBP) were measured in 29 patients with relapsing-remitting (RR) and secondary-progressive (SP) MS, and in 34 healthy controls. Results The serum levels of 25(OH)D in SPMS patients were significantly decreased compared with those of controls and RRMS patients at remitting phase (7.9 ± 7.2 nM vs 24.2 ± 14.2 nM vs 22.5 ± 13.2 nM, respectively; P

Previous studies have demonstrated that CD5 + B cells produce more interleukin (IL)-10 than CD5 − B cells and that CD5 + B cells confer significant protection against experimental autoimmune encephalomyelitis (EAE). The objective of the present study was to determine whether CD5-positive B cell populations are associated with secondary progressive multiple sclerosis (SPMS) and to explore which subsets on CD5 + B cells are associated with SPMS. A total of 26 patients with SPMS, of whom 11 were treated with IFNβ (IFN-SPMS) and 15 were not treated (non-IFN-SPMS), and 19 healthy control (HC) subjects were included in the study. Expression levels of CD11a, CD23, CD25, CD38, CD49d, CD80, CD86, CD138, CCR5, and CXCR5 on CD5 + B cells in blood samples were examined by flow cytometry. The percentage of CD5 + B cells in the SPMS group was significantly lower than in the HC group. Within the subsets of CD5 + B cells, the expression of CD11a in the non-IFN-SPMS group was significantly decreased compared to the HC subjects. Patients with SPMS showed lower CCR5, CD25, and CD138 positivity on CD5 + B cells than HC subjects. Our results indicate that CD5 + B cell subsets might be associated with pathogenesis of SPMS.

Myasthenia gravis (MG) is an antibody-mediated autoimmune disease of the neuromuscular junction, and prednisolone (PSL) and immunosuppressive drugs are available for treatment. Tacrolimus, a macrolide that suppresses the immune system, is used as a second-line treatment for MG. There have been several reports of the effects of tacrolimus over a few years of follow-up. Here, we report data from 9 patients with steroid-dependent generalized MG treated with low-dose tacrolimus (2-3 mg/day) for 5 years. Following treatment with tacrolimus, mean MG-activities of daily living score improved from 4.6 at baseline to 3.3 at 5 years after initiation of treatment. Mean dose of PSL could also be reduced, from 24.0 mg/day at baseline to 10.2 mg/day at 5 years, although there were no cases of total withdrawal of PSL. By contrast, 5 of the 9 patients experienced exacerbation of symptoms and transient increases in PSL dose during the 5-year period. Tacrolimus is an important option for treatment of MG; however, careful management is needed for long-term treatment with this drug.

We investigated whether calcitriol (1,25-dihydroxyvitamin D) differentially modulates cytokine production by peripheral blood mononuclear cells from multiple sclerosis (MS) patients compared with that from healthy controls. In response to phytohemagglutinin (PHA) or lipopolysaccharide (LPS), cytokine level in a calcitriol-added sample was normalized to that in a calcitriol-absent sample, and this relative unit was compared. The relative unit of IL-12/23(p40) in LPS-stimulation was higher in MS patients. Moreover, the relative unit of IL-10 in PHA-stimulation was lower in MS patients, and negatively correlated with the Expanded Disability Status Scale. The anti-inflammatory response to vitamin D may be reduced in MS.

Neck extensor muscle weakness and the dropped head sign are associated with various neuromuscular disorders. However, these symptoms are comparatively rare in myasthenia gravis (MG). We report a MG case that presented with dropped head sign as the main symptom. A 55-year-old man developed subacute weakness of the neck extensor muscle and presented with dropped head. We established a diagnosis of MG based on the results of an edrophonium test and a voluntary single fiber electromyogram (vSFEMG), and a high serum antiacetylcholine receptor antibody level. This patient was treated with pyridostigmine and his neurological symptoms improved. There are reported cases of dropped head sign as the first symptom of MG, however, in those cases, other muscles showed weakness during the first few months after onset. In the present case, throughout the clinical course no other symptoms outside of dropped head sign were seen.

An autopsy case of HIV encephalomyelopathy in a homosexual patient who initially presented with signs of myelopathy, such as urinary incontinence and spasticity of both legs, is reported. The pathological examination disclosed typical HIV encephalopathy with macrophages and multinucleated giant cells (MGC) in the cerebral white matter and loss of neurons of the cerebral cortex. The MGC contained HIV-1 p24 antigen. The thoracic spinal cord was markedly atrophied with degeneration of both lateral tracts, and histologically characterized by gliosis and perivascular accumulation of macrophages. Vacuolar changes and HIV-1 p24-containing cells were not observed in the spinal cord. The present case indicates that myelopathy can occur as an initial sign in AIDS patients, even though its pathomechanism remains to be elucidated.

Anti-aquaporin-4 (AQP4) antibody is highly specific for neuromyelitis optica (NMO) and NMO spectrum disorder. Brainstem lesions sometimes show involvement in NMO and NMO spectrum disorder, and onset is usually diagnosed in young or middle-aged adults. Here, we report the case of an 87-year-old woman with recurrent brainstem lesions and subsequent severe longitudinally extensive cervical cord lesions who was found to be positive for anti-AQP4 antibody. In patients with recurrent brainstem lesions, even in the elderly and those with symptoms mimicking infarction, NMO spectrum disorder should be considered as a differential diagnosis.