72-Week Safety and Tolerability of Dimethyl Fumarate in Japanese Patients with Relapsing-remitting Multiple Sclerosis: Analysis of the Randomised,Double Blind,Placebo-Controlled,Phase III APEX Study and its Open-Label Extension

Introduction

The long-term safety of dimethyl fumarate (DMF) in patients with relapsing-remitting multiple sclerosis (RRMS) has been studied in mainly Caucasian patients. The present interim analysis aimed to evaluate the 72-week safety of DMF in Japanese patients with RRMS.

Methods

Safety data of Japanese subjects enrolled in the 24-week randomised, double-blind, placebo-controlled APEX study (Part I) and its following open-label extension (Part II) were analysed at 72 weeks from the beginning of Part I. In Part I, subjects were randomised to DMF treatment or matching placebo while all subjects received DMF treatment during Part II. Adverse events (AEs) reported throughout the study period were recorded.

Results

Overall, 109 Japanese subjects completed 72 weeks of treatment. The incidence of AEs and serious AEs was 95% and 19%, respectively, in the DMF group compared with 84% and 18%, respectively, in the placebo group at 24 weeks. Common AEs (at least 5%) reported with treatment included nasopharyngitis, flushing, hot flush, gastrointestinal events, pruritus, rash, headache, increased alanine aminotransferase (ALT) and aspartate aminotransferase (AST). AEs led to discontinuation of DMF in 5% of patients and included MS relapse, flushing, abdominal pain, liver disorder and increased ALT/AST. After an initial decrease from baseline of 17% in the DMF group at week 24, the mean lymphocyte counts stabilised and were maintained until week 72. No opportunistic/serious infections nor malignancies were reported with DMF treatment. The incidences of AEs, serious AEs, and discontinuation due to AEs were similar between the DMF and the placebo groups.

Conclusion

The 72-week safety profile of DMF in Japanese patients with RRMS was consistent with previous studies that enrolled mostly Caucasian patients, with a lower incidence of flushing and related symptoms and a lower reduction in the lymphocyte count compared with previous reports.

Trial Registration

ClinicalTrials.gov identifier NCT01838668.

Funding

Biogen Japan Ltd.

     

Diagnostic performance of MRI for pregnant patients with clinically suspected appendicitis

Abdominal Radiology - To evaluate the accuracy of magnetic resonance imaging (MRI) in the diagnosis of acute appendicitis in pregnant patients and the value of additional diffusion-weighted MRI...     

Evaluation of Retinal Nerve Fiber Layer in Patients with Idiopathic Optic Perineuritis using Optical Coherence Tomography

The aim of this study was to assess the effect of idiopathic Optic perineuritis on the retinal nerve fiber layer, and determine the ability of optical coherence tomography to evaluate retinal nerve fiber loss after idiopathic Optic perineuritis. Four patients were assessed in this study. In all cases, average retinal nerve fiber layer was significantly thinner in the affected eye in comparison with the normal reference value and with the value for the contralateral normal eye at 12 months after the onset of optic perineuritis. Our study revealed that retinal nerve fiber layer loss occurs in idiopathic optic nerve sheath inflammation.     

Optical coherence tomography shows early loss of the inferior temporal quadrant retinal nerve fiber layer in autosomal dominant optic atrophy

Purpose

The aim of the study was to evaluate the relationship between visual function and retinal nerve fiber layer thickness (RNFLT) determined using Stratus optical coherence tomography (OCT) in patients with autosomal dominant optic atrophy (ADOA).

Methods

The study was a retrospective, institutional, and comparative case series. Thirty-six consecutive patients with ADOA and 72 age-matched normal controls were compared with regard to RNFLT, best-corrected visual acuity (BCVA), and visual field.

Results

The relative reduction of RNFLT of ADOA patients was most evident in the temporal quadrant (56.8 %), followed by the inferior (35.5 %), superior (27.2 %), and nasal quadrants (26.4 %). In ADOA patients, BCVA decreased with RNFL thinning (p?<?0.001), and was not related to age (p?=?0.210). Papillomacular bundle RNFLT decreased with age throughout the study period of 3.7?±?2.3 years (?3.83?±?9.96 μm, p?=?0.017). The presence of a superotemporal central scotoma (61.1 %) was related to decreased inferotemporal RNFLT (7 and 8 o’clock, p?=?0.016 and p?=?0.036, respectively).

Conclusions

The papillomacular bundle RNFL of ADOA is most vulnerable and progressively damaged with age, despite early temporal RNFL loss. Early loss of inferior temporal RNFL in ADOA is related to superotemporal central scotoma.

     

Correlation between depth and area of retinal nerve fiber layer defect as measured by spectral domain optical coherence tomography

Background

To evaluate the correlation between the depth and area of retinal nerve fiber layer (RNFL) defect, as measured on an RNFL map of spectral-domain optical coherence tomography (SD-OCT).

Methods

The RNFL of 472 glaucoma subjects and of 217 healthy subjects was imaged by an SD-OCT. RNFL defect depth and area on the RNFL map were expressed as an RNFL defect depth percentage index (RDPI) and an RNFL defect area index (RDAI), respectively, according to the following two formulas: 100×[1–{summation of thicknesses of RNFL defects/summation of thicknesses of upper 95th percentile range of age-matched healthy subjects in areas corresponding to defects}]; 100×[number of superpixels of RNFL defects/(46?×?46–superpixels inside optic disc or β zone parapapillary atrophy)]. The best-fitting model describing the relationship between the two parameters was derived by fractional polynomial analysis.

Results

Logarithmic fit was determined to be the best-fitting model in describing the relationship of the RDPI against the RDAI (y?=?53.4?+?3.7 ln(x) and y?=?50.9?+?5.9 ln(x) in superior and inferior hemifields, respectively). The expected RDAIs at the point where the RDPI and RDAI rates of change were the same were 3.7 and 5.9 %; the corresponding upper 95 % confidence interval limits of the RDPI 59.0 and 61.8 % in the superior and inferior hemifields, respectively.

Conclusions

The correlation between the RNFL defect depth and area, as derived from the RNFL map, was best described by the logarithmic fit. Changes were more marked in depth than in area, especially for mild localized defects.

     

The Association between Choroidal Thickness Variations and Response to Intravitreal Bevacizumab in Central Serous Chorioretinopathy

PurposeTo analyze differences in the subfoveal choroidal thickness (SFChT) between bevacizumab responders (BevRs) and nonresponders (BevNRs) in patients with idiopathic central serous chorioretinopathy (CSC).MethodsThe medical records of 30 unilateral chronic CSC patients who were treated with intravitreal bevacizumab (IVB) as a first line treatment were reviewed. Patients were categorized as BevNRs when CSC did not completely resolve after a minimum of 3 IVB treatments. Enhanced depth imaging-optical coherence tomography was used and SFChT was measured before and after treatment. Choroidal hyperpermeability was also evaluated using indocyanine angiography.ResultsTwenty and 10 eyes were classified as BevRs or BevNRs, respectively. The mean number of IVB treatments was 2.22 ± 0.89 in BevRs, and 4.80 ± 1.03 in BevNRs. Compared with BevNRs, BevRs demonstrated significantly greater pretreatment SFChT (441.25 ± 88.09 vs. 364.10 ± 61.97 µm); SFChT reduction following IVB was significantly greater in BevRs than BevNRs. SFChT in the unaffected eyes was also greater in BevRs than BevNRs. Choroidal hyperpermeability was detected less frequently in BevNRs (hypofluorescence on late-phase, 0.0% and 33.3% in BevNRs and BevRs, respectively; p= 0.049).ConclusionsCompared with CSC eyes that did not respond well to IVB, BevRs demonstrated significantly thicker SFChT at baseline, greater reduction in SFChT after IVB treatment, and hyperfluorescence on late-phase indocyanine green angiography. We recommend IVB injection as the first-line therapy for CSC eyes with relatively high SFChT and hyperfluorescence on late-phase indocyanine green angiography.     

Correlations Between the Incidence of National Notifiable Infectious Diseases and Public Open Data,Including Meteorological Factors and Medical Facility Resources

Objectives:

This study was performed to investigate the relationship between the incidence of national notifiable infectious diseases (NNIDs) and meteorological factors, air pollution levels, and hospital resources in Korea.

Methods:

We collected and stored 660 000 pieces of publicly available data associated with infectious diseases from public data portals and the Diseases Web Statistics System of Korea. We analyzed correlations between the monthly incidence of these diseases and monthly average temperatures and monthly average relative humidity, as well as vaccination rates, number of hospitals, and number of hospital beds by district in Seoul.

Results:

Of the 34 NNIDs, malaria showed the most significant correlation with temperature (r=0.949, p<0.01) and concentration of nitrogen dioxide (r=-0.884, p<0.01). We also found a strong correlation between the incidence of NNIDs and the number of hospital beds in 25 districts in Seoul (r=0.606, p<0.01). In particular, Geumcheon-gu was found to have the lowest incidence rate of NNIDs and the highest number of hospital beds per patient.

Conclusions:

In this study, we conducted a correlational analysis of public data from Korean government portals that can be used as parameters to forecast the spread of outbreaks.     

Comparison of Abdominal Visceral Adipose Tissue Area Measured by Computed Tomography with That Estimated by Bioelectrical Impedance Analysis Method in Korean Subjects

We evaluated the concordance between visceral fat area (VFA) estimated by bioelectrical impedance analysis (BIA) or computed tomography (CT) in Korean subjects with a wide range in age and body mass index (BMI). In 1006 individuals (mean age 55.2 ± 11.8 (19–87) years, mean BMI 26.0 ± 3.5 (17–46) kg/m², 48.9% men), VFA quantified by CT was compared with VFA using multifrequency BIA machines within 15 days. Concordance rates were compared by age or BMI using correlation analysis, Bland-Altman plots, and intraclass correlation coefficient (ICC). Using BIA data, we established a regression formula to reflect CT-VFA. The mean VFAs by CT and BIA were 131.9 ± 57.3 cm² and 110.5 ± 33.9 cm², respectively (r = 0.605, p < 0.001). The mean difference was 21.4 ± 45.6 cm², tending to increase with BMI. In women with BMI <25 kg/m² or age <50 years, the VFAs by BIA were similar to those by CT (ICC = 0.496 in BMI <25 kg/m² and ICC = 0.638 in age <50 years). However, the difference was greater in men with BMI ≥25 kg/m² or age ≥50 years. Applying our formula, the difference between estimations decreased to 0.2 ± 38.2cm². VFA estimated by BIA correlated well with that by CT, but a more accurate formula is needed to match CT data, particularly in older men or subjects with a high BMI.