Potential application of measuring serum infliximab levels in rheumatoid arthritis management: A retrospective study based on KURAMA cohort data

Infliximab (IFX) therapy has considerably improved the treatment of rheumatoid arthritis (RA). However, some patients still do not respond adequately to IFX therapy, or the efficacy of the treatment diminishes over time. Although previous studies have reported a relationship between serum IFX levels and therapeutic efficacy, the potential applications of IFX therapeutic drug monitoring (TDM) in clinical practice remain unclear. The purpose of this study was to investigate the potential applications of IFX TDM by analyzing a Japanese cohort database. Data were collected retrospectively from the Kyoto University Rheumatoid Arthritis Management Alliance cohort between January 1, 2011, and December 31, 2018. Serum IFX levels were measured using a liquid chromatography-tandem mass spectrometer. Out of the 311 RA patients that used IFX, 41 were eligible for the analysis. Serum IFX levels were significantly higher in responders than in non-responders. An optimal cut-off value was determined to be 0.32 μg/mL based on a receiver operating characteristic curve. At the IFX measurement point, a better therapeutic response was observed in the high IFX group (n = 32) than in the low IFX group (n = 9). Conversely, at the maximum effect point, when DAS28-ESR was the lowest between IFX introduction and measurement points, there were no differences in responder proportions between the low and high IFX groups. IFX primary ineffectiveness could be avoided with appropriate dose escalation without blood concentration measurement in clinical practice. In conclusion, IFX TDM could facilitate the identification of secondary non-responders and in turn, proper IFX use

Different Effects of Eicosapentaenoic and Docosahexaenoic Acids on Atherogenic High-Fat Diet-Induced Non-Alcoholic Fatty Liver Disease in Mice.

Non-alcoholic fatty liver disease (NAFLD), the hepatic manifestation of metabolic syndrome, can progress to steatohepatitis (NASH) and advanced liver damage, such as that from liver cirrhosis and cancer. Recent studies have shown the benefits of consuming n-3 polyunsaturated fatty acids (PUFAs) for the treatment of NAFLD. In the present study, we investigated and compared the effects of the major n-3 PUFAs-eicosapentaenoic acid (EPA, C20:5) and docosahexaenoic acid (DHA, C22:6)-in preventing atherogenic high-fat (AHF) diet-induced NAFLD. Mice were fed the AHF diet supplemented with or without EPA or DHA for four weeks. Both EPA and DHA reduced the pathological features of AHF diet-induced NASH pathologies such as hepatic lobular inflammation and elevated serum transaminase activity. Intriguingly, EPA had a greater hepatic triacylglycerol (TG)-reducing effect than DHA. In contrast, DHA had a greater suppressive effect than EPA on AHF diet-induced hepatic inflammation and ROS generation, but no difference in fibrosis. Both EPA and DHA could be effective for treatment of NAFLD and NASH. Meanwhile, the two major n-3 polyunsaturated fatty acids might differ in a relative contribution to pathological intermediate steps towards liver fibrosis

Attenuated hepatic inflammation and liver injury in mice fed AHF supplemented with EPA or DHA.

<p>Hematoxylin and eosin (H&E) staining of liver sections from representative mice from each treatment group (A), and plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels (B). n = 11–15 per group. ** p < 0.01, *** p < 0.001 versus chow group; # p < 0.05, ### p < 0.001 versus AHF group.</p

Phenotypic comparison of C57BL/6J mice fed the chow, AHF, AHF + EPA, and AHF + DHA diet for 4 weeks.

<p>Phenotypic comparison of C57BL/6J mice fed the chow, AHF, AHF + EPA, and AHF + DHA diet for 4 weeks.</p

Effect of AHF diet supplemented with EPA or DHA on hepatic lipid metabolism-related mRNA and protein levels.

<p>For gene expression and immunoblot analyses, livers were collected from the mice fed a normal chow, an AHF diet, or an AHF diet supplemented with EPA or DHA for four weeks. Quantitative real-time PCR of genes involved in fatty acid and TG synthesis (A), fatty acid oxidation (C), PUFA synthesis (D), lipid storage (E), cholesterol and lipoprotein metabolism (F). Immunoblot analysis for mature SREBP-1 levels (B). n = 13–15 per group. * p < 0.05 versus chow group; # p < 0.05 versus AHF group.</p

Effect of AHF diet supplemented with EPA or DHA on hepaticinflammation.

<p>Representative immunohistochemical staining for F4/80 in liver section form mice fed a normal chow, an AHF diet, or an AHF diet supplemented with EPA or DHA for four weeks (A). Quantitative real-time PCR of genes involved in inflammation in the livers of mice fed a normal chow, an AHF diet, or an AHF diet supplemented with EPA or DHA for four weeks (B). Immunoblot analysis of phosphorylated JNK and total JNK levels and the ratio between phosphorylated and total JNK by densitometry analysis (C). n = 13–15 per group. * p < 0.05 versus chow group; # p < 0.05 versus AHF group.</p

Effect of AHF diet supplemented with EPA or DHA on hepatic oxidative stress.

<p>Representative immunohistochemical staining for Nε-(Hexanoyl) Lysine in liver section form mice fed a normal chow, an AHF diet, or an AHF diet supplemented with EPA or DHA for four weeks (A). Liver 8-OHdG levels in mice fed a normal chow, an AHF diet, or an AHF diet supplemented with EPA or DHA for four weeks (B). Quantitative real-time PCR of genes involved in oxidative stress in the livers of mice fed a normal chow, an AHF diet, or an AHF diet supplemented with EPA or DHA for four weeks (B). n = 13–15 per group. * p < 0.05 versus chow group; # p < 0.05 versus AHF group.</p

Effect of AHF diet supplemented with EPA or DHA on hepatic fibrogenesis.

<p>Quantitative real-time PCR of genes involved in fibrogenesis in the livers of mice fed a normal chow, an AHF diet, or an AHF diet supplemented with EPA or DHA for four weeks (A). Immunoblot analysis of α-SMA levels and the ratio between α-SMA and β-actin by densitometry analysis (B). n = 13–15 per group. * p < 0.05 versus chow group; # p < 0.05 versus AHF group.</p

Effect of EPA and DHA on hepatic lipid content in mice fed AHF diet.

<p>Liver macroscopic picture (A) and hepatic triglyceride (TG) and total cholesterol (T-Cho) levels (B) in mice fed a normal chow, an AHF diet, or an AHF diet supplemented with EPA or DHA for four weeks. n = 12–15 per group. ** p < 0.01, *** p < 0.001 versus chow group; ## p < 0.01, ### p < 0.001 versus AHF group.</p

Hepatic fatty acid composition in mice fed normal chow, AHF, AHF + EPA and AHF + DHA diets for four weeks.

<p>Hepatic fatty acid composition (A) and the n-6/n-3 fatty acid ratio (B) in livers of mice fed a normal chow, an AHF diet, or an AHF diet supplemented with EPA or DHA for four weeks. n = 3–4 per group. * p < 0.05, *** p < 0.001 versus chow group; # p < 0.05, ### p < 0.001 versus AHF group.</p