Effectiveness and Safety of Golimumab in the Treatment of Ulcerative Colitis: 52-Week Results from Post-Marketing Surveillance in Japan.

Introduction: Real-world evidence for the effectiveness and safety of golimumab (GLM) in patients with ulcerative colitis (UC) is limited. The aim of this study was to investigate the 52-week effectiveness and safety of GLM treatment for UC. Methods: This prospective, multicentre, post-marketing surveillance study is conducted in 393 patients with UC in Japan (UMIN000027542). Clinical remission (partial Mayo score ≤2), adverse drug reactions (ADRs) and their predictors, and treatment persistence were analysed. Results: The safety analysis sets comprised 391 patients. Patients in clinical remission at baseline were excluded, and 336 were used for effectiveness analysis. Clinical remission was 47.9%, 48.5%, 44.6%, and 39.6% at weeks 6, 22, 36, and 52, respectively, in the intent-to-treat analysis. In biologic-naive patients, clinical remission was slightly higher than that in biologic-experienced patients. At week 52, patients who concomitantly used corticosteroids at baseline showed numerically lower clinical remission rates than non-users of corticosteroids (34.9% vs. 44.5%). Multivariate analysis showed that smoking history (p = 0.040, odds ratio [OR] = 1.911, 95% confidence interval [CI] 1.030-3.546) was an independent factor associated with clinical remission at week 52. ADRs occurred in 71 patients (18.2%) and included 9 cases of rash. Serious ADRs occurred in 40 patients (10.2%), including 8 cases of UC exacerbation. Additionally, the presence of comorbidities was associated with ADR incidence (p = 0.010, OR = 2.000, 95% CI: 1.183-3.380). Conclusion: The real-world effectiveness of GLM treatment was confirmed in biologic-naive and experienced populations. The safety profile of GLM treatment was consistent with previous findings.

Real-world data for golimumab treatment in patients with ulcerative colitis in Japan: interim analysis in post-marketing surveillance.

BACKGROUND/AIMS: Golimumab (GLM) is an anti-tumor necrosis factor-α drug approved for treating moderate-to-severe active ulcerative colitis (UC). A 52-week post-marketing surveillance (PMS) was initiated to evaluate its safety and effectiveness in patients with UC in Japan. We present an interim report of the ongoing PMS. METHODS: Patients received 200 mg of subcutaneous GLM at week 0, 100 mg at week 2, and 100 mg 4 weekly thereafter. The safety analysis set included 392 patients with UC, and the effectiveness analysis set 387 patients. Safety and effectiveness were assessed at week 6. RESULTS: Adverse drug reactions (ADRs) were reported in 8.2% (32/392) and serious ADRs in 4.6% (18/392). The most frequent ADRs were infection and infestation (3.3%), with herpes zoster being the most common. ADRs were significantly higher in patients with concomitant corticosteroid use (odds ratio [OR], 3.45; 95% confidence interval [CI], 1.40-9.68). No significant difference in ADR incidence was observed between patients aged ≥65 and <65 years (OR, 1.23; 95% CI, 0.35-3.47). Six-week effectiveness of GLM was confirmed by a decrease in the partial Mayo score (-2.3; 95% CI, -2.6 to -2.1) and C-reactive protein levels (-0.64; 95% CI, -0.92 to -0.36), including in the biologics-experienced population. CONCLUSIONS: The safety and effectiveness of GLM at week 6 in a real-world setting were demonstrated in patients with UC in Japan. ADR patterns were consistent with previous reports with no new safety signals. Concomitant corticosteroid use may be associated with increased ADR incidence. The final results of the ongoing PMS are necessary for further evaluation.

Biomechanical factors affecting energy cost during running utilising different slopes.

This study aimed to examine the characteristics of electromyography (EMG) and kinematics of the supporting leg affecting energy cost while running at incline, level, and decline slopes. Twelve male Japanese middle- and long-distance runners volunteered for this study. The subjects were asked to run at 13.5 km·h-1 on a treadmill under three slope conditions. Sagittal plane kinematics and the EMG of the lower limb muscles, respiratory gases were recorded. Energy cost differed significantly between slopes, being the lowest in decline slope and the greatest in incline slope. Integrated EMG (iEMG) of leg extensor muscles was greater in the incline slope than in the decline slope, and iEMG of the gastrocnemius and soleus muscles correlated positively with energy cost. The knee and ankle joint kinematics were associated with energy cost during running. In incline slope, the knee and ankle joints were more extended (plantarflexed) to lift the body. These movements may disturb the coordination between the ankle and knee joints. The gastrocnemius muscle would do greater mechanical work to plantarflex the ankle joint rather than transfer mechanical energy as well as greater mechanical work of mono-articular muscles. These muscular activities would increase energy cost.

Longitudinal characterization of diet-induced genetic murine models of non-alcoholic steatohepatitis with metabolic, histological, and transcriptomic hallmarks of human patients.

Non-alcoholic steatohepatitis (NASH) is a fast-growing liver disease in the Western world. Currently, only a few animal models show both the metabolic and histological features of human NASH. We aimed to explore murine NASH models in a time dependent manner that exhibit metabolic, histological and transcriptomic hallmarks of human NASH. For this, the murine strains C57BL/6J, ob/ob, and KK-Ay were used and three types of nutritional regimes were administered: normal chow diet (NCD); high-fat, high-fructose, and high-cholesterol diet (fast food diet; FFD); or choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD), for 2, 4, 8, 12, 18, 24, and 30 weeks. All strains under the FFD and CDAHFD regimes developed steatohepatitis. Among the strains treated with FFD, the non-alcoholic fatty liver disease (NAFLD) activity score, fibrosis progression and metabolic abnormalities such as hyperinsulinemia and obesity were more pronounced in ob/ob mice than in C57BL/6J and KK-Ay mice. In ob/ob mice fed FFD, the development of hepatic crown-like structures was confirmed. Furthermore, molecular pathways involved in steatohepatitis and fibrosis showed significant changes from as early as 2 weeks of starting the FFD regime. Ob/ob mice fed FFD showed metabolic, histological, and transcriptomic dysfunctions similar to human NASH, suggesting their potential as an experimental model to discover novel drugs for NASH.

An inhibitor of acylCoA: cholesterol acyltransferase increases expression of ATP-binding cassette transporter A1 and thereby enhances the ApoA-I-mediated release of cholesterol from macrophages.

The effect of inhibition of acylCoA: cholesterol acyltransferase (ACAT) was studied on high density lipoprotein (HDL) metabolism. An inhibitor of ACAT, MCC-147, was given mouse peritoneal macrophages and expression of ATP-binding cassette transporter A1 (ABCA1) was examined. ABCA1 was increased both at the mRNA and protein levels, only when the cells are cholesterol-loaded and thereby the inhibitor decreased esterified cholesterol and increased unesterified cholesterol. In this condition, the ACAT inhibitor increased reversible binding of apoA-I to the cells and enhanced apoA-I-mediated release of cellular cholesterol and phospholipid, but did not influence nonspecific cellular cholesterol efflux to lipid microemulsion. It was therefore concluded that the ACAT inhibitor increased the release of cholesterol from the cholesterol-loaded macrophages by increasing the expression of ABCA1, putatively through shifting cholesterol distribution from the esterified to the free compartments.