第984回千葉医学会例会・第33回肺癌研究施設例会

<p>The baseline (pre) and the peak (post) values of anti-DNA Ab (Farr) (A), IgG-anti-dsDNA Ab (B), IgM-anti-dsDNA Ab (C), and IgG-anti-ssDNA Ab (D). The upper limit normal values are indicated by dashed lines. The post values are the highest titers observed during the follow-up periods. Each dot represents a single serum sample, and the data are presented as mean ± SEM. A paired <i>t</i>-test for intra-group comparison or the Mann-Whitney test for inter-group comparison was used. ns: not significant.</p

Plasma sLOX-1 is a potent biomarker of clinical remission and disease activity in patients with seropositive RA

<p><i>Objectives</i>: Soluble lectin-like oxidized low-density lipoprotein receptor 1 (sLOX-1) is present in the circulation and synovial fluid in patients with rheumatoid arthritis (RA). The aim of this study was to assess whether sLOX-1 level is associated with clinical remission and disease activity in patients with RA.</p> <p><i>Methods</i>: Clinical and laboratory data were analyzed for 282 patients with RA. Plasma sLOX-1 level was measured by enzyme-linked immunosorbent assay (ELISA). The remission status and sLOX-1 levels were compared between four groups of patients based on the positivity of rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPAs). Relationships between sLOX-1 level and the 28-joint Disease Activity Score with erythrocyte sedimentation rate (DAS28-ESR) were analyzed by multivariate logistic regression.</p> <p><i>Results</i>: The patients in the RF + ACPA + group tended to exhibit higher sLOX-1 levels when compared to the other three groups. In the RF + ACPA + group, the sLOX-1 level was significantly higher in the non-remission group than in the remission group, irrespective of treatment. Multivariate logistic regression showed significant correlations between sLOX-1 level and DAS28-ESR.</p> <p><i>Conclusions</i>: sLOX-1 level might be a useful biomarker for assessing clinical remission and disease activity in double-positive RA patients.</p

Serum cytokine levels before and 12 months after IFX treatment.

<p>The pre- and post-treatment levels of IL-6, IFN-γ, IFN-α2 and BAFF were compared between ADA-positive (+) and ADA-negative (-) groups. Data are presented as mean + SEM. A paired <i>t</i>-test for intra-group comparison and the Mann-Whitney test for inter-group comparison were used.</p

Anti-drug antibody (ADA) is associated with reduced clinical response.

<p>(A) Treatment efficacy defined as low disease activity (LDA) or remission at 6 months. Percentages and absolute numbers of each group of patients are indicated below the graphs. ADA positivity was based on the assessment of 6 months. Fisher’s exact test was used for comparison. (B) Cumulative drug retention rates. A log-rank test was used for comparison between the two groups.</p

Neutrophils Are Essential As A Source Of Il-17 In The Effector Phase Of Arthritis

<div><p>Objective</p><p>Th17 has been shown to have a pivotal role in the development of arthritis. However, the role of IL-17 in the T cell-independent effector phase has not fully been examined. We investigated whether IL-17 is involved in the effector phase of arthritis by using K/BxN serum-induced arthritis model.</p><p>Methods</p><p>K/BxN serum was transferred into IL-17 knockout (KO) mice, SCID mice and their control mice, and arthritis was evaluated over time. In order to clarify the source of IL-17 in the effector phase, neutrophils or CD4+ T cells collected from IL-17 KO or control mice were injected into IL-17 KO recipient mice together with K/BxN serum. To examine if neutrophils secrete IL-17 upon stimulation, neutrophils were stimulated with immune complex in vitro and IL-17 in the supernatant was measured by ELISA.</p><p>Results</p><p>K/BxN serum-induced arthritis was much less severe in IL-17 KO mice than in WT mice. Since K/BxN serum-transferred SCID mice developed severe arthritis with high serum IL-17 concentration, we speculated neutrophils are the responsible player as an IL-17 source. When wild type (WT) but not IL-17 KO neutrophils were co-injected with K/BxN serum into IL-17 KO mice, arthritis was exacerbated, whereas co-injection of WT CD4+ T cells had no effect. In vitro, stimulation of neutrophils with immune complexcaused IL-17 secretion.</p><p>Conclusions</p><p>Neutrophils are essential as a source of IL-17 in the effector phase of arthritis. The trigger of secreting IL-17 from neutrophils may be immune complex.</p></div

Clinical features of the patients enrolled in this study.

<p>Clinical features of the patients enrolled in this study.</p

Identification of DNA-Dependent Protein Kinase Catalytic Subunit (DNA-PKcs) as a Novel Target of Bisphenol A

<div><p>Bisphenol A (BPA) forms the backbone of plastics and epoxy resins used to produce packaging for various foods and beverages. BPA is also an estrogenic disruptor, interacting with human estrogen receptors (ER) and other related nuclear receptors. Nevertheless, the effects of BPA on human health remain unclear. The present study identified DNA-dependent protein kinase catalytic subunit (DNA-PKcs) as a novel BPA-binding protein. DNA-PKcs, in association with the Ku heterodimer (Ku70/80), is a critical enzyme involved in the repair of DNA double-strand breaks. Low levels of DNA-PK activity are previously reported to be associated with an increased risk of certain types of cancer. Although the Kd for the interaction between BPA and a drug-binding mutant of DNA-PKcs was comparatively low (137 nM), high doses of BPA were required before cellular effects were observed (100–300 μM). The results of an <em>in vitro</em> kinase assay showed that BPA inhibited DNA-PK kinase activity in a concentration-dependent manner. In M059K cells, BPA inhibited the phosphorylation of DNA-PKcs at Ser2056 and H2AX at Ser139 in response to ionizing radiation (IR)-irradiation. BPA also disrupted DNA-PKcs binding to Ku70/80 and increased the radiosensitivity of M059K cells, but not M059J cells (which are DNA-PKcs-deficient). Taken together, these results provide new evidence of the effects of BPA on DNA repair in mammalian cells, which are mediated via inhibition of DNA-PK activity. This study may warrant the consideration of the possible carcinogenic effects of high doses of BPA, which are mediated through its action on DNA-PK.</p> </div

Effects of BPA in cultured cells.

<p>(A) Survival of logarithmically growing M059J and M059K cells after exposure to various doses of γ-rays as measured by colony formation. BPA was added to the culture media 3 h prior to irradiation and removed 2 h after irradiation. Cells on the survival curve “M059K+BPA” were treated with BPA at IR dose “0”. The results shown represent the mean from three independent experiments; bar, SE. (B) Expression of DNA-PKcs was detected in M059K, but not in M059J cells.</p

Effectiveness and safety of tocilizumab in achieving clinical and functional remission, and sustaining efficacy in biologics-naive patients with rheumatoid arthritis: The FIRST Bio study

<p><i>Objective</i>: To evaluate effectiveness and safety of tocilizumab (TCZ) in biologic-naive Japanese patients with rheumatoid arthritis (RA) in real-world settings, and to analyze the relationship between disease duration and clinical outcomes.</p> <p><i>Methods</i>: The FIRST Bio study was a postmarketing surveillance study of intravenous TCZ in biologics-naive patients who had a prior inadequate response or were intolerant to ≥1 conventional synthetic disease-modifying antirheumatic drug (csDMARD). Effectiveness, safety, and concomitant csDMARD administration were assessed.</p> <p><i>Results</i>: Of the 839 patients analyzed, 72.3% completed 52 weeks of treatment. The Clinical Disease Activity Index (CDAI) remission rate at week 52 was 36.8%. Contributing factors for CDAI remission were younger age, early disease stage, and no comorbidities. Health Assessment Questionnaire Disability Index ≤0.5 was achieved in 65.1% of patients, and was significantly associated with disease duration. Discontinuation of concomitant methotrexate (MTX) and glucocorticoids (GCs) was possible in 19.3% and 34.1% of patients, respectively, without decreasing remission rate. The incidence (events/100 patient-years) of serious adverse events was 18.09, the most common being infection.</p> <p><i>Conclusion</i>: These data validate the importance of TCZ treatment in the early stages of RA in biologic-naive patients to achieve increased effectiveness. The safety profile of TCZ was reconfirmed. Furthermore, TCZ therapy may allow discontinuation of concomitant MTX and GCs without affecting remission.</p

Comprehensive microRNA Analysis Identifies miR-24 and miR-125a-5p as Plasma Biomarkers for Rheumatoid Arthritis

<div><p>MicroRNAs (miRNAs) are present in human plasma and known as a non-invasive biomarker for cancer detection. Our study was designed to identify plasma miRNAs specific for rheumatoid arthritis (RA) by a comprehensive array approach. We performed a systematic, array-based miRNA analysis on plasma samples from three RA patients and three healthy controls (HCs). Plasma miRNAs with more than four times change or with significant (<i>P</i><0.05) change in expression, or detectable only in RA plasma, were confirmed with plasma from eight RA patients and eight HCs using real-time quantitative PCR. Consistently detectable miRNAs that were significantly different between RA patients and HCs were chosen for further validation with 102 RA patients and 104 HCs. The area under curves (AUC) were calculated after plotting the receiver operating characteristic (ROC) curves. To determine if these miRNAs are specific for RA, the concentrations of these miRNAs were analyzed in 24 patients with osteoarthritis (OA), and 11 patients with systemic lupus erythematosus (SLE). The array analysis and the subsequent confirmation in larger patient cohort identified significant alterations in plasma levels of seven miRNAs. The highest AUC was found for miR-125a-5p, followed in order by miR-24 and miR-26a. Multivariable logistic regression analysis showed that miR-24, miR-30a-5p, and miR-125a-5p were crucial factors for making detection model of RA and provided a formula for <i>E</i>stimated <i>P</i>robability of <i>RA</i> by plasma <i>M</i>iRNA (ePRAM), employing miR-24, miR-30a-5p and miR-125a-5p, which showed increased diagnostic accuracy (AUC: 0.89). The level of miR-24, miR-125a-5p, and ePRAM in OA and SLE patients were lower than that in RA. There was no significant difference in detection for anti-citrullinated protein antibody (ACPA)-positive and ACPA-negative RA patients. These results suggest that the plasma concentrations of miR-24 and miR-125a-5p, and ePRAM are potential diagnostic markers of RA even if patients were ACPA-negative.</p></div