The positivity of anti-citrullinated protein/peptide antibodies (ACPAs) is a clinically useful diagnostic and prognostic marker in rheumatoid arthritis (RA). However, the significance of ACPA titer and its fluctuation remain unclear. This study aimed to assess the role of ACPA titer and its fluctuation on disease activity and the prognosis of RA.Data obtained from the Kyoto University Rheumatoid Arthritis Management Alliance (KURAMA) cohort was analyzed. Patients whose ACPA was measured at least twice between 2011 and 2019 and whose ACPA was positive at least once were included in this study. The association between the clinical variable and ACPA titer or its change was investigated.ACPA titer was measured in a total of 3286 patients, 1806 of whom were ACPA-positive at least once. Among them, the ACPA titer level was measured more than once in 1355 patients. Very weak correlation was observed between the ACPA titer level and disease activity. Additionally, there was no trend in the fluctuation of ACPA titer level in each patient; ACPA titer level fluctuated in some patients, but not in others. Patients with high variable levels of ACPA titer were more likely to relapse from remission. In the analysis of two consecutive ACPA measurements, the titer changes predicted the relapse from remission within a year of the second measurement.The ACPA titer level fluctuated in some patients. Very weak correlation was observed between the ACPA titer level and disease activity. Fluctuation in ACPA titer level predicted relapse from remission in patients with RA.
An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.
This study analyzes the relationship between the implementation and information disclosure of environmental continuous improvement (e-CI) in sustainable supply chain management. The analyzed data relates to e-CI delivered from 19 manufacturing industry types in Japan. A degenerated Charnes-Cooper-Rhodes model, a proposed model for data envelopment analysis, is also used for the analysis. The obtained result is a classification of types of manufacturing industries from the perspective of their capabilities in both e-CI implementation and information disclosure to systematically discover emphatic indicators of these two activities in each manufacturing industry type.
The factors contributing to the efficacy of abatacept in patients with rheumatoid arthritis (RA) remain unknown.
Objectives
We aimed to identify cellular, transcriptomic, and proteomic features that predict responses or resistance to abatacept.
Methods
Blood samples were collected from 22 RA patients treated with abatacept at the initiation and after three months of treatment. Response to treatment was defined based on the EULAR response criteria, and seven patients were classified as responders and the others as non-responders. We quantified gene expression levels in peripheral blood mononuclear cells (PBMCs) by RNA-Seq, 67 plasma protein levels by multiplexed immunoassay, and the expression of surface molecules (CD3, 19, and 56) by flow cytometry, in addition to collecting clinical characteristics. Additionally, three gene expression data sets concerning the efficacy of abatacept[1–3], comprising 37 responders and 50 non-responders in total, were used to replicate the current study. We compared the gene expression of responders versus non-responders in each set and meta-analyzed the results.
Results
Among the clinical characteristics, the number of monocytes was significantly higher in the non-responders before treatment (p = 0.01). Regarding the transcriptome data, we found 952 differentially expressed genes (DEGs) between the responders and the non-responders before treatment initiation. A cell-type enrichment analysis showed that the DEGs were enriched in monocytes (p = 8.7 × 10-212, Figure 1A). Additionally, gene set enrichment analysis showed enrichment in the gene module, including MYD88 and TIRAP, with the strongest significance among all of the pathways tested. When we estimated the expression of MYD88 and TIRAP in monocytes by deconvolution analysis, the non-responders had higher expression before treatment initiation (p = 0.04 and 0.03, respectively). Among the 67 protein levels, two exhibited a correlation with the expression of the module (p < 0.05). Of these, hepatocyte growth factor (HGF), which is produced by monocytes, was present at significantly higher concentrations in non-responders before treatment (p = 0.02). The analysis of the replication sets identified 1,695 DEGs. These were also enriched for the genes expressed in monocytes (p = 2.9 × 10-90, Figure 1B) but not for the module detected in the current study. Among the DEGs, those expressed in monocytes were enriched for the genes involved in the aerobic electron transport system in mitochondria based on gene set enrichment analysis.
Conclusion
Monocyte-derived transcriptomic features before treatment underlay the differences in abatacept efficacy. The pathway activated in monocytes was the MYD88/TIRAP-HGF axis in the current study, but that pathway in the replication set was the aerobic electron transport system. Overall, our results highlight the contribution of monocytes as the cells responsible for abatacept-treatment resistance and the heterogeneity of activated pathways within them.
References
[1]Nakamura, S. et al. Identification of baseline gene expression signatures predicting therapeutic responses to three biologic agents in rheumatoid arthritis: a retrospective observational study. Arthritis Res. Ther. 18, (2016). [2]Triaille, C. et al. Common Transcriptomic Effects of Abatacept and Other DMARDs on Rheumatoid Arthritis Synovial Tissue. Front. Immunol. 12, (2021). [3]Derambure, C. et al. Pre-silencing of genes involved in the electron transport chain (ETC) pathway is associated with responsiveness to abatacept in rheumatoid arthritis. Arthritis Res. Ther. 19, (2017).
Acknowledgements
This study received funding from Astellas Pharma Inc.
Disclosure of Interests
Takeshi Iwasaki: None declared, Ryu Watanabe Speakers bureau: Asahi Kasei, Chugai, Eli Lilly, GSK, and Sanofi, Grant/research support from: AbbVie, Hiromu Ito Grant/research support from: Bristol Myers, Takayuki Fujii Speakers bureau: Asahi Kasei Pharma, Abbvie, Jansen, Tanabe Mitsubishi Pharma, and Eisai Co LTD, Koichiro Ohmura: None declared, Hiroyuki Yoshitomi: None declared, Koichi Murata Speakers bureau: AbbVie GK, Eisai Co., Ltd., Pfizer Inc., Chugai Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Pfizer Inc., Bristol-Myers Squibb, Daiichi Sankyo Co. Ltd., and Asahi Kasei Pharma Corp., Grant/research support from: Daiichi Sankyo Co. Ltd, Kosaku Murakami Speakers bureau: Bristol Myers, Ono Pharmaceutical, Akira Onishi Speakers bureau: Pfizer Inc., Bristol-Myers Squibb., Asahi Kasei Pharma Corp., Chugai Pharmaceutical Co. Ltd., Eli Lilly Japan K.K, Ono Pharmaceutical Co., UCB Japan Co., Mitsubishi Tanabe Pharma Co., Eisai Co. Ltd., Abbvie Inc., Takeda Pharmaceutical Co. Ltd., and Daiichi Sankyo Co. Ltd., Grant/research support from: Pfizer Inc., Bristol-Myers Squibb., Advantest, Ayumi, and the Health Care Science Institute., Employee of: Department of Advanced Medicine for Rheumatic Diseases is supported by Nagahama City, Shiga, Japan, Toyooka City, Hyogo, Japan, and five pharmaceutical companies (Mitsubishi Tanabe Pharma Co., Chugai Pharmaceutical Co. Ltd, UCB Japan Co. Ltd, AYUMI Pharmaceutical Co., and Asahi Kasei Pharma Corp.). It is also supported by grants from Daiichi Sankyo Co. Ltd. Above-mentioned pharmaceutical companies were not involved in the study design, data collection and analysis, manuscript writing, and manuscript submission., Masao Tanaka Speakers bureau: AbbVie GK, Asahi Kasei Pharma Corp., Astellas Pharma Inc., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Eisai Co., Ltd., Eli Lilly Japan K.K., Janssen Pharmaceutical K.K., Pfizer Inc., Tanabe Mitsubishi Pharma Corp., UCB Japan Co., Ltd.., Grant/research support from: AbbVie GK, Eisai Co., Ltd., Kyowa Kirin Co., Ltd. Taisho Pharmaceutical Co., Ltd. Teijin Pharma, Ltd.., Employee of: M.T. belongs to the department financially supported by two local governments in Japan (Nagahama City, Shiga and Toyooka City, Hyogo) and five pharmaceutical companies (Tanabe Mitsubishi Pharma Corp., Chugai Pharmaceutical Co., Ltd., Ayumi Pharmaceutical Corp., Asahi Kasei Pharma Corp. and UCB Japan Co., Ltd.)., Shuichi Matsuda: None declared, Fumihiko Matsuda: None declared, Akio Morinobu Speakers bureau: AbbVie G.K., Chugai Pharmaceutical Co. Ltd., Eli Lilly Japan K.K., Eisai Co. Ltd., Pfizer Inc., Bristol-Myers Squibb., Mitsubishi Tanabe Pharma Co., Astellas Pharma Inc., and Gilead Sciences Japan., Grant/research support from: AbbVie G.K., Asahi Kasei Pharma Corp., Chugai Pharmaceutical Co. Ltd., Mitsubishi Tanabe Pharma Co. Taisho Pharmaceutical Co., Ltd.,and Eisai Co. Ltd. outside the work., Motomu Hashimoto Speakers bureau: Eli Lilly, Chugai, Mitsubishi Tanabe, Bristol Myers, Eisai, Grant/research support from: AbbVie, Asahi Kasei, Astellas, Bristol Myers, Eisai, Daiichi Sankyo, Eli Lilly, Novartis.
Nematodes of the genus Thelazia were recovered from the cornea and inferior conjunctival sac of an immature Oriental white stork (Ciconia boyciana). The bird hatched and reared at the Toyooka Oriental White Stork Breeding Center, Hyogo Prefecture, Japan, but died of chlamydiosis. There were neither gross nor histopathologic ophthalmic lesions. The eye worm from a bird is believed to be first reported in Japan. As regarding reintroduction plan for the Oriental white stork, control measures for prevent further infection with the eye worm will be needed.
To increase the transmission capacity of 6.6 kV distribution lines economically, 11.4 kV distribution system that is constructed of existing 6.6 kV equipment in use is being examined. For the application of the 11.4 kV distribution system to the real field, we are trying to calculate transient overvoltage by EMTP to decide the rational test voltage of 11.4 kV equipment. So, to confirm the calculation precision of EMTP concerned with transient overvoltage in 11.4 kV distribution line, we had made an experiment measuring the characteristics of overvoltages, which occur in 11.4 kV distribution lines. We compared the calculated waveform with the measured waveform, and investigated the difference of the two. We compared the calculated waveform by EMTP with the measured waveform for some test data, and we found that the range of computing errors were from 1.8% to 10.8%.
Abstract Sarcopenia is an age-related disease with an increased risk of mortality. It is emerging that low serum vitamin D (25(OH)D) affects the sarcopenic state in general, but in rheumatoid arthritis (RA), these associations are not understood although the prevalence of vitamin D insufficiency is high in RA. We conducted a cross-sectional study of older female outpatients from our cohort (KURAMA) database. We measured skeletal muscle mass, handgrip strength, and gait-speed to diagnose severe sarcopenia. The serum 25(OH)D concentration was measured using electrochemiluminescence immunoassay. A total of 156 Patients (sarcopenia:44.9%, severe sarcopenia: 29.5%, and without sarcopenia: 25.6%) were enrolled. Classification of vitamin D status at a cutoff point of median 25(OH)D concentration revealed that low 25(OH)D status was associated with a high prevalence of severe sarcopenia and with low measured values of muscle mass, handgrip, and gait-speed. Furthermore, multiple regression analysis identified that low 25(OH)D status was associated with a high prevalence of severe sarcopenia (OR 6.00; 95% CI 1.99–18.08). In components of sarcopenia, both low physical performance and muscle mass were associated with low 25(OH) status. In conclusion, vitamin D levels are associated with severe sarcopenia and its components, and modification of vitamin D status including vitamin D supplementation may play a role in improving sarcopenia in RA.
