Naoto Fujiki

Suppressed pro-inflammatory properties of circulating B cells in patients with multiple sclerosis treated with fingolimod, based on altered proportions of B-cell subpopulations.

The chief therapeutic mechanism of fingolimod in multiple sclerosis (MS) is considered to be sequestration of pathogenic lymphocytes into secondary lymphoid tissues. B cells have recently been recognized as important immune regulators in MS. In this study, the effects of fingolimod on B cells in MS patients were analyzed. MS patients treated with fingolimod (MS-F) had a significantly lower number of B cells in the circulation. The remaining B cells in the blood of MS-F had a reduced proportion of memory B cells and an increased proportion of naïve B cells, expressed lower levels of the costimulatory molecule CD80, and produced less tumor necrosis factor-α and more interleukin-10. These observations in MS-F were based on an increased proportion of the transitional B-cell subpopulation within the naïve B-cell compartment. The observed findings in B cells of MS-F might be related to the therapeutic effect of this drug in MS.

MR imaging of spinal cord in Devic disease.

A 20-year-old man with typical features of Devic disease was studied with magnetic resonance (MR) demonstrating sequential changes of the spinal cord from swelling to atrophy. A good correlation between neurological findings and MR imaging was documented.

Five-year follow-up with low-dose tacrolimus in patients with myasthenia gravis

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.

Clinical characterization and successful treatment of 6 patients with Churg-Strauss syndrome-associated neuropathy

OBJECTIVE To confirm the reported findings and clarify unknown clinical features of Churg-Strauss syndrome (CSS)-associated neuropathy and design appropriate treatment. PATIENTS AND METHODS We assessed the clinical features of 6 patients with CSS-associated neuropathy. RESULTS Mononeuritis multiplex was present in 4 cases and polyneuropathy in the remaining cases. Both groups progressed to sensori-motor polyneuropathy in an acute or subacute course. All cases showed bronchial asthma and eosinophilia. Two cases with serum antineutrophil cytoplasmic antibodies to myeloperoxidase (MPO-ANCA) had an acute clinical course and severe symptoms. Nerve conduction studies (NCS) of these 2 cases revealed conduction blocks at the initial stage, although NCS finally indicated sensori-motor axonopathy at the involved extremities. For treatment, high-dose corticosteroid therapy for 4 cases, and cyclophosphamide combined with corticosteroids for 1 case, were effective. For the remaining case, intravenous immunoglobulin (IVIg) at the chronic phase resulted in a slow improvement of neuropathy in the symptomatic aspect. There was no relapse of neuropathy with low-dose corticosteroid treatment for 14-24 months after the initial treatment, except 1 case. There was also no relapse in the other case that was treated with moderate-dose steroids. CONCLUSION Our study showed that CSS-associated neuropathy is a treatable disorder and that the first choice therapy is high-dose corticosteroid. In cases where corticosteroids are ineffective or for severe cases, immunosuppressive therapy (cyclophosphamide) with steroids should be considered, and IVIg might be a treatment option.

Focal (segmental) dyshidrosis in syringomyelia

The features or mechanisms of dyshidrosis have not been sufficiently clarified. Neither has the difference between hyperhidrosis and hypohidrosis. To clarify the features and mechanisms of dyshidrosis (hyperhidrosis and hypohidrosis) in syringomyelia, the clinical features focusing on hidrosis of 30 patients with syringomyelia and Chiari malformation located from a syringomyelia database were prospectively analysed. The patients were classified into three groups: eight patients (26.7%) had segmental hypohidrosis, 10 (33.3%) had segmental hyperhidrosis, and 12 (40.0%) had normohidrosis. We found that the Karnofsky functional status for the hyperhydrosis and normohidrosis groups were significantly higher than for the hypohidrosis group (p=0.0012), with no significant differences between the hyperhidrosis and normohidrosis groups. The duration from the onset of syringomyelia to the current dyshidrosis was significantly longer in the hypohidrosis group than in the hyperhidrosis group (p=0.0027). A significant correlation was identified between the duration from the onset of syringomyelia to the time at study and the performance score (r=−0.599, p=0.0003). The results substantiate previous hypotheses that in its early stage syringomyelia causes segmental hyperactivity of the sympathetic preganglionic neurons, and hyperactivity of these gradually subsides as tissue damage progresses. Focal hyperhidrosis may be regarded as a hallmark of a relatively intact spinal cord, as well as normohidrosis.

Suppression of IL-10 production by calcitriol in patients with multiple sclerosis

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.

Association of serum vitamin D levels in Japanese patients with multiple sclerosis

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.

Fingolimod induces BAFF and expands circulating transitional B cells without activating memory B cells and plasma cells in multiple sclerosis

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.

CD5-positive B cell subsets in secondary progressive multiple sclerosis

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.

Neuro‐Behçet Disease and Magnetic Resonance Imaging

Abstract: A case of neuro‐Behçet disease presenting the signs and symptoms of brain stem involvement was diagnosed with magnetic resonance imaging (MRI), while a CTscan failed to show any abnormalities.