坂下 英司

Objectives Compared to conventional disease-modifying antirheumatic drugs (DMARDs), biological DMARDs demonstrate superior efficacy but come with higher costs and increased infection risks. The ability to stop and resume biological DMARD treatment while maintaining remission would significantly alleviate these barriers and anxieties. The objective of this study was to identify biomarkers that can predict an imminent relapse, hopefully enabling the timely resumption of biological DMARDs before relapse occurs. Methods Forty patients with rheumatoid arthritis who had been in remission for more than 12 months were included in the study. The patients discontinued their biological DMARD treatment and were monitored monthly for the next 24 months. Out of the 40 patients, 14 (35%) remained in remission at the end of the 24-month period, while 26 (65%) experienced relapses at different time points. Among the relapse cases, 13 patients experienced early relapse within 6 months, and another 13 patients had late relapse between 6 months and 24 months. Seventy-three cytokines in the sera collected longitudinally from the 13 patients with late relapse were measured by multiplex immunoassay. Using cytokines at two time points, immediately after withdrawal and just before relapse, volcano plot and area under the receiver operating characteristic curves (AUC) were drawn to select cytokines that distinguished imminent relapse. Univariate and multivariate logistic regression analyses were used for the imminent relapse prediction model. Results IL-6, IL-29, MMP-3, and thymic stromal lymphopoietin (TSLP) were selected as potential biomarkers for imminent relapse prediction. All four cytokines were upregulated at imminent relapse time point. Univariate and multivariate logistic regression showed that a combination model with IL-6, MMP-3, and TSLP yielded an AUC of 0.828 as top predictors of imminent relapse. Conclusions This methodology allows for the prediction of imminent relapse while patients are in remission, potentially enabling the implementation of on- and off-treatments while maintaining remission. It also helps alleviate patient anxiety regarding the high cost and infection risks associated with biological DMARDs, which are the main obstacles to benefiting from their superb efficacy.

Epigenetic regulation via epigenetic factors in collaboration with tissue-specific transcription factors is curtail for establishing functional organ systems during development. Brain development is tightly regulated by epigenetic factors, which are coordinately activated or inactivated during processes, and their dysregulation is linked to brain abnormalities and intellectual disability. However, the precise mechanism of epigenetic regulation in brain development and neurogenesis remains largely unknown. Here, we show that Tip60/KAT5 deletion in neural stem/progenitor cells (NSCs) in mice results in multiple abnormalities of brain development. Tip60-deficient embryonic brain led to microcephaly, and proliferating cells in the developing brain were reduced by Tip60 deficiency. In addition, neural differentiation and neuronal migration were severely affected in Tip60-deficient brains. Following neurogenesis in developing brains, gliogenesis started from the earlier stage of development in Tip60-deficient brains, indicating that Tip60 is involved in switching from neurogenesis to gliogenesis during brain development. It was also confirmed in vitro that poor neurosphere formation, proliferation defects, neural differentiation defects, and accelerated astrocytic differentiation in mutant NSCs are derived from Tip60-deficient embryonic brains. This study uncovers the critical role of Tip60 in brain development and NSC maintenance and function in vivo and in vitro.

Abstract Since the advent of biological disease modifying anti-rheumatic drugs (bDMARDs) in the treatment of rheumatoid arthritis (RA), most RA patients receiving such drugs have achieved remission at the expense of cost and infection risk. After bDMARDs are withdrawn, a substantial proportion of patients would have relapses even if they were in complete remission. In our previous report, relapse prediction could be made at the time of bDMARD withdrawal by measuring the serum levels of five cytokines. We report herein that, among 73 cytokines examined, serum levels of only interferon β (IFNβ) at the time of bDMARD withdrawal could predict early relapse (within 5 months) in patients who were categorized to relapse by the five cytokines in our previous report, with a cut-off value of 3.38 in log₂ and AUC of 0.833. High serum levels of IFNβ in the early-relapse group remained high until actual relapse occurred. Therefore, patients who relapse early might be biochemically different from those who relapse late or do not relapse at all. We recommend that patients who are predicted to relapse early continue bDMARDs even if they are in complete remission. This finding contributes to shared decision-making regarding how and when bDMARDs should be discontinued.

Biological disease modifying anti-rheumatic drugs (bDMARDs) show dramatic treatment efficacy in rheumatoid arthritis (RA). Long-term use of bDMARDs, however, has disadvantages such as high costs and infection risk. Therefore, a methodology is needed to predict any future RA relapse. Herein, we report a novel multi-biomarker combination which predicts relapse after bDMARDs-withdrawal in patients in remission. Forty patients with RA in remission for more than 12 months were enrolled. bDMARDs were withdrawn and they were followed monthly for the next 24 months. Fourteen patients (35%) of 40 in the cohort remained in remission at 24 months, whereas 26 (65%) relapsed at various time-points. Serum samples obtained longitudinally from patients in remission were assessed for the relapse-prediction biomarkers and index from 73 cytokines by the exploratory multivariate ROC analysis. The relapse-prediction index calculated from the 5 cytokines, IL-34, CCL1, IL-1β, IL-2 and IL-19, strongly discriminated between patients who relapsed and those who stayed in remission. These findings could contribute to clinical decision-making as to the timing of when to discontinue bDMARDs in RA treatment.

Mitochondrial dysfunction is significantly associated with neurological deficits and age-related neurological diseases. While mitochondria are dynamically regulated and properly maintained during neurogenesis, the manner in which mitochondrial activities are controlled and contribute to these processes is not fully understood. Mitochondrial transcription factor A (TFAM) contributes to mitochondrial function by maintaining mitochondrial DNA (mtDNA). To clarify how mitochondrial dysfunction affects neurogenesis, we induced mitochondrial dysfunction specifically in murine neural stem cells (NSCs) by inactivating Tfam. Tfam inactivation in NSCs resulted in mitochondrial dysfunction by reducing respiratory chain activities and causing a severe deficit in neural differentiation and maturation both in vivo and in vitro. Brain tissue from Tfam-deficient mice exhibited neuronal cell death primarily at layer V and microglia were activated prior to cell death. Cultured Tfam-deficient NSCs showed a reduction in reactive oxygen species produced by the mitochondria. Tfam inactivation during neurogenesis resulted in the accumulation of ATF4 and activation of target gene expression. Therefore, we propose that the integrated stress response (ISR) induced by mitochondrial dysfunction in neurogenesis is activated to protect the progression of neurodegenerative diseases.