ANKRD55 and DHCR7 are novel multiple sclerosis risk loci.

Multiple sclerosis (MS) shares some risk genes with other disorders hallmarked by an autoimmune pathogenesis, most notably IL2RA and CLEC16A. We analyzed 10 single-nucleotide polymorphisms (SNPs) in nine risk genes, which recently emerged from a series of non-MS genome-wide association studies (GWAS), in a Spanish cohort comprising 2895 MS patients and 2942 controls. We identified two SNPs associated with MS. The first SNP, rs6859219, located in ANKRD55 (Chr5), was recently discovered in a meta-analysis of GWAS on rheumatoid arthritis (RA), and emerged from this study with genome-wide significance (odds ratio (OR) = 1.35; P = 2.3 × 10(-9)). The second SNP, rs12785878, is located near DHCR7 (Chr11), a genetic determinant of vitamin D insufficiency, and showed a size effect in MS similar to that recently observed in Type 1 diabetes (T1D; OR = 1.10; P = 0.009). ANKRD55 is a gene of unknown function, and is flanked proximally by the IL6ST-IL31RA gene cluster. However, rs6859219 did not show correlation with a series of haplotype-tagging SNPs covering IL6ST-IL31RA, analyzed in a subset of our dataset (D'< 0.31; r(2)< 0.011). Our results expand the number of risk genes shared between MS, RA and T1D.

Functional outcomes of patients with NORSE and FIRES treated with immunotherapy: A systematic review.

OBJECTIVE: To determine the frequency of good functional outcomes in patients with NORSE and FIRES treated with immunotherapy. METHODS: We performed a systematic search of the MedLine and EMBASE databases to gather studies including at least 5 patients with NORSE or FIRES and at least one patient treated with immunotherapy, and reporting functional outcomes. Good functional outcome was defined as a modified Rankin Scale (mRS) score ≤ 2 (or an equivalent measure) at the last available follow-up assessment. Only patients with known functional outcomes were included in the analysis. RESULTS: We analyzed 16 studies including a total of 161 patients with NORSE. Six studies were carried out only with FIRES patients (n = 64). Of the 161 patients with NORSE, 141 (87.5%) received immunotherapy. Outcome data were available for 135, 56 of whom (41.4%) achieved good functional outcomes. Twenty-four of the 58 patients with FIRES treated with immunotherapy and for whom outcome data were available achieved good functional outcomes (41.3%). Mortality rates in patients with NORSE and FIRES treated with immunotherapy were 20/121 (16.5%) and 6/58 (10.3%), respectively. By type of immunotherapy, good functional outcomes were achieved in 36/89 patients receiving glucocorticoids (40.4%), 27/71 patients receiving IV immunoglobulins (38%), 11/37 patients treated with plasma exchange (29.7%), 5/17 patients receiving rituximab (29.4%), and 2/13 patients receiving cyclophosphamide (15.3%). CONCLUSION: Despite the lack of randomised clinical trials, immunotherapy is frequently prescribed to patients with NORSE and FIRES. However, rates of functional dependence and mortality remain high in these patients. Second-line therapies achieved lower rates of good outcomes, probably because they were administered to patients with more severe, refractory disease.

Impact of SARS-CoV-2 infection on neurodegenerative and neuropsychiatric diseases: a delayed pandemic? / Influencia de la infección SARS-CoV-2 sobre enfermedades neurodegenerativas y neuropsiquiátricas: ¿una pandemia demorada?

INTRODUCTION: SARS-CoV-2 was first detected in December 2019 in the Chinese city of Wuhan and has since spread across the world. At present, the virus has infected over 1.7 million people and caused over 100 000 deaths worldwide. Research is currently focused on understanding the acute infection and developing effective treatment strategies. In view of the magnitude of the epidemic, we conducted a speculative review of possible medium- and long-term neurological consequences of SARS-CoV-2 infection, with particular emphasis on neurodegenerative and neuropsychiatric diseases of neuroinflammatory origin, based on the available evidence on neurological symptoms of acute SARS-CoV-2 infection. DEVELOPMENT: We systematically reviewed the available evidence about the pathogenic mechanisms of SARS-CoV-2 infection, the immediate and lasting effects of the cytokine storm on the central nervous system, and the consequences of neuroinflammation for the central nervous system. CONCLUSIONS: SARS-CoV-2 is a neuroinvasive virus capable of triggering a cytokine storm, with persistent effects in specific populations. Although our hypothesis is highly speculative, the impact of SARS-CoV-2 infection on the onset and progression of neurodegenerative and neuropsychiatric diseases of neuroinflammatory origin should be regarded as the potential cause of a delayed pandemic that may have a major public health impact in the medium to long term. Cognitive and neuropsychological function should be closely monitored in COVID-19 survivors.

Early development of anti-natalizumab antibodies in MS patients.

The purpose of this study is to monitor the development of anti-natalizumab antibodies to evaluate their first appearance in multiple sclerosis patients, since their presence has been associated with a reduction in the efficacy of the treatment and an increase of adverse events. A total of 134 multiple sclerosis patients were included in the trial. Anti-natalizumab antibodies were monthly detected by ELISA up to the first year of treatment and subsequently, a determination was made at 18 months. 15.7% of the patients were positive, being 7.5% transiently positive and 8.2% persistently positive. The first appearance of anti-natalizumab antibodies occurred after the first month of treatment onset in 72% of positive patients; 18% did so after the second month, and 9.7% after the third month. Antibodies were never detected for the first time after the fourth infusion. The development of anti-natalizumab antibodies occurs very early after treatment onset. This observation should be considered when standardizing the follow up of patients treated with this drug in order to minimize the risks and optimize the treatment.

Gene expression in IFNß signalling pathway differs between monocytes, CD4 and CD8 T cells from MS patients.

IFNß exerts its activity through the interaction with IFNAR, through activation of the JAK/STAT pathway. We analyzed the changes in IFNAR1, IFNAR2, STAT1, STAT2, Tyk2, JAK1, IRF9 and MxA gene expressions after prolonged IFNß treatment, in isolated mononuclear-cell subpopulations from MS patients, by real time PCR. The effect of IFNß on gene expression differed depending on the subpopulation assessed. The data suggest that CD8+ T cells are the most influenced by prolonged IFNß therapy as IFNAR2, Tyk2, IRF9 and Jak1 expressions were decreased, whereas MxA expression was increased in these cells.