Prospective Cohort Study

The demyelinating potential of antibodies to myelin oligodendrocyte glycoprotein is related to their ability to fix complement

In order to clarify the relationship between the clinical phenotype and the human leucocyte antigen (HLA) in multiple sclerosis in Asians, 93 Japanese patients with clinically definite multiple sclerosis underwent clinical MRI and HLA-DPB1 gene typing studies. According to a neurological examination, 29 patients were classified as opticospinal multiple sclerosis, 17 as spinal multiple sclerosis and 47 as Western type multiple sclerosis showing the involvement of multiple sites in the CNS including either the cerebrum, cerebellum or brainstem. The opticospinal multiple sclerosis showed a significantly higher age of onset, higher expanded disability status scale scores and higher CSF cell counts and protein content than the Western type multiple sclerosis. On brain and spinal cord MRI, the opticospinal multiple sclerosis showed a significantly lower number of brain lesions, but a higher frequency of gadolinium-enhancement of the optic nerve and a higher frequency of spinal cord atrophy than in Western type multiple sclerosis. The frequency of the HLA-DPB1*0501 allele was found to be significantly greater in opticospinal multiple sclerosis (93%) than in healthy controls (63%, corrected P value = 0.0091 and relative risk = 7.9), but not in Western type multiple sclerosis (66%) or spinal multiple sclerosis (82%). The marked differences in the clinical and MRI findings as well as in the immunogenetic backgrounds between the opticospinal multiple sclerosis and Western-type multiple sclerosis together suggest that HLA-DPB1*0501-associated opticospinal multiple sclerosis is a distinct subtype of multiple sclerosis.

[HLA-DPB1* 0501-associated opticospinal multiple sclerosis: clinical, neuroimaging and immunogenetic studies].

Using the ImmunoChip custom genotyping array, we analyzed 14,498 subjects with multiple sclerosis and 24,091 healthy controls for 161,311 autosomal variants and identified 135 potentially associated regions (P < 1.0 × 10(-4)). In a replication phase, we combined these data with previous genome-wide association study (GWAS) data from an independent 14,802 subjects with multiple sclerosis and 26,703 healthy controls. In these 80,094 individuals of European ancestry, we identified 48 new susceptibility variants (P < 5.0 × 10(-8)), 3 of which we found after conditioning on previously identified variants. Thus, there are now 110 established multiple sclerosis risk variants at 103 discrete loci outside of the major histocompatibility complex. With high-resolution Bayesian fine mapping, we identified five regions where one variant accounted for more than 50% of the posterior probability of association. This study enhances the catalog of multiple sclerosis risk variants and illustrates the value of fine mapping in the resolution of GWAS signals.

Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis

Objective: We sought to compare the seroepidemiology of neuromyelitis optica and its spectrum disorders (NMOSD) across two ethnically divergent populations.
Background: NMO/NMOSD are inflammatory demyelinating diseases (IDD) with a specific biomarker, aquaporin-4-IgG. Prior NMO/NMOSD epidemiological studies are limited by lack of aquaporin-4-IgG seroprevalence assessment, absence of population-based USA studies and under-representation of blacks.
Methods: We performed a population-based comparative study of the incidence (2003-2011) and prevalence (on December 31, 2011) of NMO/NMOSD and aquaporin-4-IgG seroincidence and seroprevalence (sera collected in 80-84[percnt] of IDD) among patients with IDD diagnosis in Olmsted County, USA (82[percnt] white [Caucasian]) and Martinique (90[percnt] black [Afro-Caribbean]). Aquaporin-4-IgG was measured by M1-isoform-fluorescent-activated-cell-sorting assays.
Results: The incidence (7.6 vs 0.8/1,000,000 person-years [p<0.01]) and prevalence (9.9 vs 4.1/100,000[p=0.04]) in Martinique exceeded that in Olmsted County. The AQP4-IgG seroincidence (6.8 vs 0.8/1,000,000 person-years [p=0.01]) and seroprevalence (7.9 vs 3.4/100,000[p=0.09]) was also higher in Martinique than Olmsted County. The ethnicity-specific prevalence was similar in Martinique and Olmsted County: 10.8 and 12.6/100,000 in blacks, and 5.1 and 4.1/100,000 in whites, respectively. NMO/NMOSD represented a higher proportion of IDD in Martinique than Olmsted County (16[percnt] vs 1.4[percnt]; p<0.01). The onset age (median, 35-37 years) and female:male distribution (8-9:1) were similar across both populations; 60[percnt] of prevalent cases were either blind in one eye, dependent on a gait aid or both.
Conclusions: This study reports the highest prevalence of NMO/NMOSD in any population (9.9/100,000 in Martinique), estimates it affects 16,000-17,000 in the USA (higher than previous predictions) and demonstrates it disproportionately affects blacks. Disclosure: Dr. Flanagan has nothing to disclose. Dr. P. Cabre has received personal compensation for activities with Biogen Idec, EMD Serono and Novartis as consultant. Dr. Weinshenker has received personal compensation for activities with Novartis, Biogen Idec, Mitsubishi Pharmaceuticals, MedImmune Pharmaceuticals, Chugai, and Chord as a consultant. Dr. Weinshenker has received royalty payments from RSR Ltd. and Oxford Dr. St. Sauver has nothing to disclose. Dr. Majed has nothing to disclose. Dr. Lennon has received research support from the National Institutes of Health. Dr. Lucchinetti stands to receive royalty payments for commercial assays. Dr. McKeon has received research support from Medimmune. Dr. Wingerchuk has received personal compensation for serving on a clinical trial adjudication committee for Medimmune. Dr. Wingerchuk has received personal compensation in an editorial capacity for The Neurologist. Dr. Wingerchuk has received research su Dr. Mandrekar has nothing to disclose. Dr. Jacobson has nothing to disclose. Dr. Sagen has nothing to disclose. Dr. Schmeling has nothing to disclose. Dr. Fryer has nothing to disclose. Dr. Matiello has nothing to disclose. Dr. Kale has nothing to disclose. Dr. Borders Robinson has nothing to disclose. Dr. Pittock has received (royalty or license fee or contractual rights) payments from Peripherin-Specific Autoantibodies as a Marker for Neurological and Endocrinological Disease.

Epidemiology of Aquaporin-4 Autoimmunity and Neuromyelitis Optica Spectrum: A Comparison of Two Ethnically Divergent Populations (P3.003)

Gut dysbiosis and lack of short chain fatty acids in a Chinese cohort of patients with multiple sclerosis

The nuclear factor κB (NF-κB) signaling cascade has been implicating in a broad range of biological processes, including inflammation, cell proliferation, differentiation, and apoptosis. The past three decades have witnessed a great progress in understanding the impact of aberrant NF-κB regulation on human autoimmune and inflammatory disorders. In this review, we discuss how aberrant NF-κB activation contributes to multiple sclerosis, a typical inflammatory demyelinating disease of the central nervous system, and its involvement in developing potential therapeutic targets.

/pdf/nuclear-factor-kb-nf-kb-mediated-inflammation-in-multiple-3jcsebv2fl.pdf

Nuclear Factor κB (NF-κB)-Mediated Inflammation in Multiple Sclerosis

Multiple sclerosis (MS) is an immune-mediated demyelinating disease of the central nervous system. Growing evidence has proven that T helper 17 (Th17) cells are one of the regulators of neuro-inflammation mechanisms in MS disease. Researchers have demonstrated that some microRNAs (miRNAs) are associated with disease activity and duration, even with different MS patterns. MiRNAs regulate CD4+ T cells to differentiate towards various T cell subtypes including Th17 cells. In this review, we discuss the possible mechanisms of miRNAs in MS pathophysiology by regulating CD4+ T cell differentiation into Th17 cells, and potential miRNAs targets for current disease-modifying treatments.

Dysregulated MicroRNA Involvement in Multiple Sclerosis by Induction of T Helper 17 Cell Differentiation.

Objective: To evaluate the efficacy and safety of low-dose mycophenolate mofetil (MMF, 1,000 mg/day) treatment of neuromyelitis optica spectrum disorders (NMOSDs).

Methods: This study was a multicenter, open, prospective, follow-up clinical trial. The data include retrospective clinical data from the pretreatment phase and prospective data from the post-treatment phase. From September 2014 to February 2017, NMOSD patients seropositive for aquaporin 4-IgG (AQP4-IgG) were treated with low-dose MMF.

Results: Ninety NMOSD patients were treated with MMF for a median duration of 18 months (range 6–40 months). The median annual recurrence rate (ARR) decreased from 1.02 before treatment to 0 (P < 0.0001) after treatment, and the Expanded Disability Status Scale (EDSS) score decreased from 4 to 3 (P < 0.0001). The EDSS score was significantly lower (P = 0.038) after the first 90 days of treatment. The serum AQP4-IgG titer decreased in 50 cases (63%). The median Simple McGill pain score (SF-MPQ) was reduced in 65 patients (88%) with myelitis from 17 (range 0–35) to 11 (range 0–34) after treatment (P < 0.0001). The median Hauser walking index (Hauser Walk Rating Scale) was reduced from 2 (range 1–9) before treatment to 1 (range 0–7) after treatment (P < 0.0001). Adverse events were documented in 43% of the patients, and eight patients discontinued MMF due to intolerable adverse events. Fourteen (16%) of the total patients discontinued MMF after our last follow-up for various reasons and switched to azathioprine or rituximab.

Conclusion: Low-dose MMF reduced clinical relapse and disability in NMOSD patients in South China. However, some patients still suffered from adverse events at this dosage.

Clinical Trial Registration: www.ClinicalTrials.gov, identifier : {"type":"clinical-trial","attrs":{"text":"NCT02809079","term_id":"NCT02809079"}}NCT02809079.

/pdf/low-dose-mycophenolate-mofetil-for-treatment-of-pk0e7ura8g.pdf

Yifan Zhou

Papers

Gut dysbiosis and lack of short chain fatty acids in a Chinese cohort of patients with multiple sclerosis

Nuclear Factor κB (NF-κB)-Mediated Inflammation in Multiple Sclerosis

Dysregulated MicroRNA Involvement in Multiple Sclerosis by Induction of T Helper 17 Cell Differentiation.

Low-Dose Mycophenolate Mofetil for Treatment of Neuromyelitis Optica Spectrum Disorders: A Prospective Multicenter Study in South China.

Infections in neuromyelitis optica spectrum disorder.