Common variation near IRF6 is associated with IFN-β-induced liver injury in multiple sclerosis

Multiple sclerosis (MS) is a disease of the central nervous system treated with disease-modifying therapies, including the biologic, interferon-β (IFN-β). Up to 60% of IFN-β-exposed MS patients develop abnormal biochemical liver test results1,2, and 1 in 50 experiences drug-induced liver injury3. Since genomic variation contributes to other forms of drug-induced liver injury4,5, we aimed to identify biomarkers of IFN-β-induced liver injury using a two-stage genome-wide association study. The rs2205986 variant, previously linked to differential expression of IRF6, surpassed genome-wide significance in the combined two-stage analysis (P = 2.3 × 10-8, odds ratio = 8.3, 95% confidence interval = 3.6-19.2). Analysis of an independent cohort of IFN-β-treated MS patients identified via electronic medical records showed that rs2205986 was also associated with increased peak levels of aspartate aminotransferase (P = 7.6 × 10-5) and alkaline phosphatase (P = 4.9 × 10-4). We show that these findings may be applicable to predicting IFN-β-induced liver injury, offering insight into its safer use

2% chlorhexidine gluconate aqueous versus 2% chlorhexidine gluconate in 70% isopropyl alcohol for skin disinfection prior to percutaneous central venous catheterisation: the ARCTIC randomised controlled feasibility trial

Objective: Catheter-related sepsis (CRS) is a major complication with significant morbidity and mortality. Evidence is lacking regarding the most appropriate antiseptic for skin disinfection before percutaneous central venous catheter (PCVC) insertion in preterm neonates. To inform the feasibility and design of a definitive randomised controlled trial (RCT) of two antiseptic formulations, we conducted the Antiseptic Randomised Controlled Trial for Insertion of Catheters (ARCTIC) feasibility study to assess catheter colonisation, sepsis, and skin morbidity.Design: Feasibility RCT.Setting: Two UK tertiary-level neonatal intensive care units.Patients: Preterm infants born <34 weeks’ gestation scheduled to undergo PCVC insertion.Interventions: Skin disinfection with either 2% chlorhexidine gluconate (CHG)-aqueous or 2% CHG-70% isopropyl alcohol (IPA) before PCVC insertion and at removal.Primary outcome: Proportion in the 2% CHG-70% IPA arm with a colonised catheter at removal.Main feasibility outcomes: Rates of: (1) CRS, catheter-associated sepsis (CAS), and CRS/CAS per 1,000 PCVC days; (2) recruitment and retention; (3) data completeness.Safety outcomes: Daily skin morbidity scores recorded from catheter insertion until 48 hours post-removal.Results: 116 babies were randomised. Primary outcome incidence was 4.1% (95% confidence interval: 0.9% to 11.5%). Overall catheter colonisation rate was 5.2% (5/97); CRS 2.3/1000 catheter days; CAS 14.8/1000 catheter days. Recruitment, retention and data completeness were good. No major antiseptic-related skin injury was reported.Conclusions: A definitive comparative efficacy trial is feasible, but the very low catheter colonisation rate would make a large-scale RCT challenging due to the very large sample size required. ARCTIC provides preliminary reassurance supporting potential safe use of 2% CHG-70% IPA and 2% CHG-aqueous in preterm neonates

Associations between the gut microbiota and host immune markers in pediatric multiple sclerosis and controls

BACKGROUND: As little is known of association(s) between gut microbiota profiles and host immunological markers, we explored these in children with and without multiple sclerosis (MS). METHODS: Children ≤18 years provided stool and blood. MS cases were within 2-years of onset. Fecal 16S rRNA gene profiles were generated on an Illumina Miseq platform. Peripheral blood mononuclear cells were isolated, and Treg (CD4(+)CD25(hi)CD127(low)FoxP3(+)) frequency and CD4(+) T-cell intracellular cytokine production evaluated by flow cytometry. Associations between microbiota diversity, phylum-level abundances and immune markers were explored using Pearson’s correlation and adjusted linear regression. RESULTS: Twenty-four children (15 relapsing-remitting, nine controls), averaging 12.6 years were included. Seven were on a disease-modifying drug (DMD) at sample collection. Although immune markers (e.g. Th2, Th17, Tregs) did not differ between cases and controls (p > 0.05), divergent gut microbiota associations occurred; richness correlated positively with Th17 for cases (r = +0.665, p = 0.018), not controls (r = −0.644, p = 0.061). Bacteroidetes inversely associated with Th17 for cases (r = −0.719, p = 0.008), not controls (r = +0.320, p = 0.401). Fusobacteria correlated with Tregs for controls (r = +0.829, p = 0.006), not cases (r = −0.069, p = 0.808). CONCLUSIONS: Our observations motivate further exploration to understand disruption of the microbiota-immune balance so early in the MS course. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12883-016-0703-3) contains supplementary material, which is available to authorized users

Animal exposure over the life-course and risk of multiple sclerosis: A case-control study within two cohorts of US women

Background: Whether animal exposure and specifically the timing of such exposure alters multiple sclerosis (MS) risk is unclear. We examined whether animal exposure was associated with MS risk, and whether risk differed by the participants age.Methods: We conducted a case-control study within the Nurses' Health Study ((NHS)/NHSII cohorts). Overall, 151 women with MS and 235 controls, matched by age and study cohort, completed an animal exposure history questionnaire. Animal exposure pre-MS onset was assessed as 'any' exposure, then by the participants age, and animal family. Conditional logistic regression was used to estimate relative MS risks, adjusted (adj.RR) for potential confounders.Results: 'Any' animal exposure was reported by 136 (90.1%) MS cases compared to 200 (85.1%) matched controls, with dog exposure being the most common [120 (79.5%) cases vs. 170 (72.3%) controls]. There was no association between 'any' animal exposure and MS risk (adj.RR:1.52;95%CI:0.76-3.04). However, both 'any' animal and specifically dog exposure at ages 10-14 years were associated with an increased MS risk (adj.RR:1.67;95%CI:1.05-2.66 and 1.76;95%CI:1.12-2.78, respectively).Conclusion: Animal exposure, and specifically dog exposure, in early adolescence was associated with an increased risk of MS. Further work is needed to confirm this finding.</p

Multiple Sclerosis in Older Adults: The Clinical Profile and Impact of Interferon Beta Treatment

Background. We examined (1) patient characteristics and disease-modifying drug (DMD) exposure in late-onset (LOMS, ≥50 years at symptom onset) versus adult-onset (AOMS, 18–<50 years) MS and (2) the association between interferon-beta (IFNβ) and disability progression in older relapsing-onset MS adults (≥50 years). Methods. This retrospective study (1980–2004, British Columbia, Canada) included 358 LOMS and 5627 AOMS patients. IFNβ-treated relapsing-onset MS patients aged ≥50 (regardless of onset age, 90) were compared with 171 contemporary and 106 historical controls. Times to EDSS 6 from onset and from IFNβ eligibility were examined using survival analyses. Results. LOMS patients (6%) were more likely to be male, with motor onset and a primary-progressive course, and exhibit faster progression and were less likely to take DMDs. Nonetheless, 57% were relapsing-onset, of which 31% were prescribed DMDs, most commonly IFNβ. Among older relapsing-onset MS adults, no significant association between IFNβ exposure and disability progression was found when either the contemporary (hazard ratio [HR]: 0.46; 95% CI: 0.18–1.22) or historical controls (HR: 0.54; 95% CI: 0.20–1.42) were considered. Conclusion. LOMS differed clinically from AOMS. One-third of older relapsing-onset MS patients were prescribed a DMD. IFNβ exposure was not significantly associated with reduced disability in older MS patients

Feasibility of Using a Nationally Representative Telephone Survey to Monitor Multiple Sclerosis Prevalence in the United States

Background: Multiple sclerosis (MS) is the most common chronic neurologic disease of young adults, placing a heavy burden on patients, families, and the healthcare system. Ongoing surveillance of the incidence and prevalence of MS is critical for health policy and research, but feasible options are limited in the United States and many other countries. We investigated the feasibility of monitoring the prevalence of MS using a large national telephone survey of the adult US population. Methods: We developed questions to estimate the lifetime prevalence and age of onset of MS using the US-based Behavioral Risk Factor Surveillance System (BRFSS) and piloted these questions in 4 states (MN, RI, MD, and TX). There was a total of 45,198 respondents aged 18 years and above. Analyses investigated individual state and combined prevalence estimates along with health-related comorbidities and limitations. MS prevalence estimates from the BRFSS were compared to estimates from multi-source administrative claims and traditional population-based methods. Results: The estimated lifetime prevalence of self-reported MS (per 100,000 adults) was 682 (95% CI 528-836); 384 (95% CI 239-529) among males and 957 (95% CI 694-1,220) among females. Estimates were consistent across the 4 states but much higher than recently published estimates using population-based administrative claims data. This was observed for both national results and for MS prevalence estimates from other studies within specific states (MN, RI, and TX). Prevalence estimates for Caucasian, African American, and Hispanic respondents were 824, 741, and 349 per 100,000 respectively. Age and sex distributions were consistent with prior epidemiologic reports. Comorbidity and functional limitations were more pronounced among female than male respondents. Conclusions: While yielding higher overall MS prevalence estimates compared to recent studies, this large-scale self-report telephone method yielded relative prevalence estimates (e.g., prevalence patterns of MS by sex, age, and race-ethnicity) that were generally comparable to other surveillance approaches. With certain caveats, population-based telephone surveys may eventually offer the ability to investigate novel disease correlates and are relatively feasible, and affordable. Further work is needed to create a valid question set and methodology for case ascertainment before this approach could be adopted to accurately estimate MS prevalence