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Background: Janus kinase inhibitors are an effective option for achieving sustained remission or low disease activity in patients with rheumatoid arthritis (RA) following inadequate response to conventional synthetic disease-modifying anti-rheumatic drugs. Filgotinib is a Janus kinase 1-preferential inhibitor available in two doses for moderate-to-severe RA. We report the long-term efficacy and safety of filgotinib., Methods: In the ongoing long-term extension study FINCH 4 (NCT03025308), patients continue filgotinib 200 mg or 100 mg from FINCH 1, 2 or 3 or receive filgotinib 200 mg or 100 mg de novo. Efficacy assessments up to week 156 include American College of Rheumatology 20% response (ACR20), Disease Activity Score 28 using C-reactive protein of <2.6, Clinical Disease Activity Index of ≤2.8, Simplified Disease Activity Index of ≤3.3 and Boolean remission (1.0 and 2.0) with non-responder imputation., Results: In patients with an inadequate response to methotrexate, 60.2% and 54.6% receiving de novo filgotinib 200 mg and 100 mg had an ACR20 at week 156, respectively, as did 67.3% and 59.5% of those who continued filgotinib 200 mg and 100 mg. At week 156, Boolean remission 1.0 was achieved by 18.8% and 15.4% of patients treated with de novo filgotinib 200 mg and 100 mg, respectively, and by 21.1% and 18.5% when Boolean 2.0 criteria were applied. Similar efficacy data were seen in patients from FINCH 2 and 3. Safety data were consistent with the known safety profile of filgotinib., Conclusion: In FINCH 4, filgotinib 200 mg and 100 mg (continuous or de novo) demonstrated sustained efficacy up to week 156 in patients enrolled from FINCH 1, 2 or 3, with no unexpected safety results., Competing Interests: Competing interests: MHB reports consultancy fees from AbbVie, Boehringer Ingelheim, CESAS Medical, Galapagos, Gilead and Pfizer (all paid to host institution); speaker fees from AbbVie (paid to host institution); and grant/research support from Gilead (paid to host institution). DA reports consultancy fees, speaker fees and grant/research support from AbbVie, Eli Lilly, Galapagos, Gilead, Janssen, Merck, Novartis, Pfizer, Sandoz and Sanofi. BGC reports consultancy fees from AbbVie, Celltrion, Eli Lilly, Galapagos, Gilead, Janssen and Roche-Chugai; and speaker fees from AbbVie, Celltrion, Eli Lilly, Galapagos, Janssen, Pfizer and Roche-Chugai. YT reports speaker fees and/or honoraria from AbbVie, Asahi Kasei, AstraZeneca, Boehringer Ingelheim, BMS, Chugai, Eli Lilly, Eisai, Gilead, GSK, Pfizer, Taisho and Taiho; and research grants from Asahi Kasei, Chugai, Eisai, Mitsubishi Tanabe and Taisho. RC reports consultancy fees from AbbVie, Accord, Eli Lilly, Fresenius Kabi, Galapagos, MSD, Novartis, Pfizer and UCB; and speaker fees from AbbVie, Amgen, BMS, Celltrion, Eli Lilly, Fresenius Kabi, Galapagos, Janssen, MSD, Novartis, Pfizer and UCB. HS-K reports consultancy fees and speaker fees from AbbVie, Eli Lilly, Galapagos and Pfizer. TT reports consultancy fees from AbbVie, Astellas Pharma, Eli Lilly Japan and Gilead; and speaker fees and/or honoraria from AbbVie, Astellas Pharma, Eisai, Eli Lilly Japan, Gilead and Pfizer Japan. J-EG reports consultancy fees from AbbVie, BMS, Eli Lilly, Galapagos, Gilead, MSD, Novartis and Pfizer; and grant/research support from AbbVie, BMS, Lilly and Pfizer. RB reports consultancy fees from AstraZeneca, Galapagos, Janssen, Novartis and Pfizer; speaker fees from AbbVie, Amgen, BMS, Eli Lilly, Galapagos, Janssen, MSD, Novartis, Pfizer, Roche and Sanofi; and grant/research support from AbbVie and Roche. PV reports consultancy fees from Celltrion, Eli Lilly, Galapagos, Gilead, Nordic Pharma and Sidekick Health; speaker fees from AbbVie, Eli Lilly, Galapagos and Roularta; and grant/research support from Galapagos and Pfizer. AZ-S has no disclosures of interest to report. FDL is a former employee of, and shareholder in, Galapagos. EVEO reports consultancy fees from Galapagos and Janssen and is a shareholder in UCB. VR is a former employee of Galapagos and current employee of GSK Vaccines. PE reports consultancy fees from AbbVie, BMS, Boehringer Ingelheim, Eli Lilly, Galapagos, Gilead and Novartis; speaker fees from AbbVie, Boehringer Ingelheim, Eli Lilly, Gilead, Novartis and Samsung; and grant/research support from AbbVie, BMS, Eli Lilly and Samsung., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Study Design: A retrospective study., Purpose: To identify factors involved in surgical site infections (SSIs) after spinal instrumentation surgery performed at a single institution., Overview of Literature: SSIs after spinal instrumentation surgery are a serious complication. Despite reports on risk factors for SSIs in spine surgery, limited studies are related to spinal instrumentation surgery., Methods: In total, 828 patients (338 males and 490 females; mean age, 65.0 years) who underwent spinal instrumentation surgery from 2013 to 2021 in Kyorin University School of Medicinewere retrospectively investigated. Patients were divided into the SSI (group I) and non-SSI (group N) groups. Patient characteristics, comorbidity, laboratory, and surgical factors were investigated. Univariate analysis was performed for each item, and multivariate logistic regression analysis was performed for items with significant differences., Results: Fifteen patients (1.85%) had SSIs. Univariate analysis revealed significant differences between groups I and N in history of steroid use, serum albumin, C-reactive protein, number of fixed vertebrae, and perioperative blood transfusion. Multivariate logistic regression analysis showed that a history of steroid use (odds ratio [OR], 5.38; 95% confidence interval [CI], 1.41-20.49; p=0.014), serum albumin (OR, 0.34; 95% CI, 0.13-0.84; p=0.020), and perioperative blood transfusion (OR, 5.85; 95% CI, 1.46-23.50; p=0.013) were independent risk factors for SSIs., Conclusions: The results of this study indicate that preoperative nutritional intervention, appropriate management of anemia, and intraoperative and postoperative bleeding control may decrease the incidence of SSIs. However, this study has several limitations, including its retrospective design, analysis of a few SSI cases, and inclusion of various surgical approaches and disease types. Future studies that address these limitations are desirable.

Objective: Baricitinib is an oral, reversible and selective inhibitor of Janus kinase (JAK)1 and JAK2 that is approved as monotherapy or in combination with methotrexate for the treatment of adults with moderate-to-severe active rheumatoid arthritis (RA) who have responded inadequately to disease-modifying antirheumatic drugs. Evidence supporting the approved monotherapy indication is growing in real-world settings that reflect routine clinical practice., Methods: Results of separate analyses of real-world data from the observational prospective RA-BE-REAL, Erlangen Baricitinib cohort, the BSRBR-RA, and Swiss Clinical Quality Management in Rheumatic Diseases (SCQM) registries, and the retrospective ORBIT-RA and SUSTAIN long-term chart reviews were reported, documenting baseline data and outcomes for a total of 932 patients with active RA receiving baricitinib as monotherapy. Findings were contrasted with those from a total of 850 patients receiving the drug as combination therapy. All analyses were descriptive and completed in September 2022., Results: Across the patient registries and observational studies, 39.4%-69.6% of patients received baricitinib monotherapy for the treatment of active RA. In these patients, after about 6-12 months of treatment, 40.7%-93.8% and 55.6%-88.0% achieved remission or low disease activity according to the composite measures of disease activity 28-joint count and Clinical Disease Activity Index, respectively. Treatment continuation/discontinuation rates differed across the studies., Conclusion: These findings suggest that baricitinib monotherapy can be a suitable treatment option in routine clinical practice for patients with RA, when used in accordance with current guidelines.

Objectives: We characterised changes in absolute lymphocyte counts (ALCs) and lymphocyte subset counts (LSCs), and their relationship to incidence of serious infection events (SIEs) and herpes zoster (HZ) events in Japanese patients with moderate to severe rheumatoid arthritis enrolled in the tofacitinib clinical programme., Methods: Data included 765 patients receiving tofacitinib in Phase 2, Phase 3, and long-term extension studies. ALCs/LSCs and incidence rates (patients with events/100 patient-years) of SIEs and HZ were analysed over 75 months., Results: Median ALCs were generally stable over 75 months of treatment. Transient numerical increases from baseline in median LSCs were observed at Month 3; LSCs were generally lower than baseline for Months 36-75. SIE/HZ incidence rates were higher in patients with ALC <0.5 × 103 cells/mm3 versus those with ALC ≥0.5 × 103 cells/mm3 during tofacitinib treatment. Baseline LSCs were similar in patients with/without SIEs or HZ events., Conclusions: SIE/HZ risk was highest in patients with ALC <0.5 × 103 cells/mm3, supporting this threshold as clinically relevant for defining increased SIE/HZ risk in Japanese patients with rheumatoid arthritis receiving tofacitinib. However, SIEs and HZ events did not necessarily occur simultaneously with confirmed lymphopenia, preventing conclusions on possible causal relationships being drawn., (© Japan College of Rheumatology 2024. Published by Oxford University Press.)

Chemotherapy-induced ovarian toxicity in patients with cancer significantly affects future fertility depending on the age of initiation of treatment. However, the mechanisms underlying the age-related depletion of the ovarian reserve are not well understood. We investigated the effects of chemotherapy on pre- and postpubertal ovarian reserves in a mouse model. Juvenile (3-week-old) and adult (8-week-old) mice were injected with vehicle or cyclophosphamide (CPA;100 mg/kg). We assessed the short-term effects at 24 h and 72 h after injection and the long-term effects at 10 and 12 weeks of age by counting the follicles. The number of primordial follicles in the juvenile group was significantly reduced by CPA treatment compared with that in the adult group. To elucidate the mechanisms of this depletion, we performed immunostaining for γH2AX, cleaved PARP1, and FOXO3 at 24 h post-treatment. CPA-treated juvenile mice had a significantly higher proportion of γH2AX-positive primordial follicles, indicating double-strand DNA breaks. By contrast, 4-hydroperoxy CPA, an activated analog of CPA, induced γH2AX-positive primordial follicles in both groups in vitro, suggesting age-dependent differences in humoral ovarian microenvironment. Moreover, the level of cleaved PARP1 was specifically elevated in CPA-treated juvenile mice. However, primordial follicle activation was unaffected in the CPA-treated groups, as assessed by FOXO3 translocation. In conclusion, our findings suggest that ovaries in juveniles are more susceptible to DNA damage and subsequent apoptosis, leading to a higher rate of primordial follicle depletion. Therefore, it is crucial to recognize that cancer treatment, especially in children, can exert a substantial influence on future fertility., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024. Published by Elsevier B.V.)

Pharmacists' roles in cachexia care are unclear. This study aimed to clarify the knowledge and practice of cachexia care and identify factors related to the practice of cachexia care among pharmacists. Information on the knowledge and practice of cachexia care was obtained. Components of practicing multimodal care were evaluated. Participants were categorized into two groups according to practicing multimodal care levels. Comparisons were made between the groups, and multiple regression analysis was employed. Of the 451 pharmacists, 243 responded. They were categorized into the Practicing group (n = 119) and Not practicing group (n = 124). Significant differences were observed for the number of advanced cancer patients/month, frequency of caring for them, and involvement in training programs on cachexia. The Practicing group had significantly better knowledge about cachexia. The Practicing group used guidelines, items, and symptoms more frequently to detect cachexia. The Practicing group tended to detect cachexia and initiate interventions in earlier phases and in patients with a better status. Multivariate logistic regression analysis showed that the most significant factor was the regular provision of care (odds ratio, 2.07; 95% confidence interval, 1.10-3.92). The regular provision of care was associated with the practice of multimodal care.

Introduction: Sex-determining region Y-related high-mobility group box 17 protein (SOX17), a proangiogenic transcription factor, is specifically expressed in tumor endothelial cells (TECs) of implanted Lewis lung carcinoma. However, the expression profile of SOX17 is largely unknown in human lung cancer. We aimed to elucidate SOX17 expression in cancer cells and the tumor microenvironment of lung adenocarcinoma., Methods: In the present study, we examined SOX17 expression in whole-tissue specimens of 83 lung adenocarcinomas by immunohistochemistry., Results: SOX17 immunoreactivity was minimal in lung adenocarcinoma cells, except in five non-mucinous adenocarcinomas in situ. SOX17 was also expressed in cultured A549 lung adenocarcinoma cells, which is widely used as a model of malignant alveolar type II epithelial cells. Notably, SOX17 immunoreactivity was found in endothelial cells of tumor-penetrating vessels in 19 of 83 lung adenocarcinoma tissue specimens, with statistical significance to stromal infiltration of CD8 + T cells (p < 0.01) but was not associated with the number of tertiary lymph nodes. Although not statistically significant, SOX17 immunoreactivity was related to favorable patient outcomes., Conclusion: Our findings indicate that SOX17 might play a pleiotropic role in lung adenocarcinoma in cancer cells and stromal niches. SOX17-mediated CD8 + T-cell-rich tumor microenvironment might attract interest in improving the effect of cancer immunotherapy., (© 2024 The Author(s). Thoracic Cancer published by John Wiley & Sons Australia, Ltd.)

Objectives: The usefulness of methotrexate-polyglutamates (MTX-PGs) concentration for management of rheumatoid arthritis has been debated. We aimed to clarify the association of MTX-PGs concentration with efficacy and safety in MTX-naïve patients initiating MTX in a prospective interventional clinical trial., Methods: The MIRACLE trial enrolled 300 MTX-naïve patients. Oral MTX was initiated and increased to the maximum tolerated dose by week 12. Patients who did not achieve remission according to the Simplified Disease Activity Index at week 24 were randomised to either the continued dose or reduced dose group and were started on subcutaneous adalimumab. We measured the concentrations of MTX-PGs in erythrocytes using liquid chromatography-tandem mass spectrometry and analysed the association of these concentrations with efficacy and safety., Results: The mean concentration of total MTX-PGs increased with an increasing dose of MTX and continued to elevate for another 12 weeks after the dose was fixed. At week 24, the total MTX-PGs concentration was 110.5 (SD 43.8) nmol/L with MTX dose of 12.6 (3.0) mg/week (0.23 (0.07) mg/kg/week). During MTX monotherapy, the higher MTX-PGs concentration was an independent factor for lower disease activity; however, this association disappeared after adalimumab initiation in patients with continued MTX dose. Hepatotoxicity was related to the higher MTX-PGs concentration regardless of adalimumab use. The total MTX-PGs concentration was significantly elevated by lower estimated glomerular filtration rate, serum albumin and body mass index., Conclusions: The MIRACLE trial demonstrated that higher total MTX-PGs concentration in erythrocytes is related to the higher efficacy and lower safety of MTX., Trial Registration Number: NCT03505008., Competing Interests: Competing interests: HTam received honoraria from AbbVie, Eisai; support for attending meetings from PhRMA. KI received grants from Mitsubishi-Tanabe, Eli Lilly; honoraria from AbbVie, Eisai, Pfizer, Mitsubishi-Tanabe, Janssen, Novartis, UCB, Daiichi-Sankyo, Eli Lilly, Gilead Sciences, AstraZeneca, Asahi Kasei, Chugai, Bristol-Myers Squibb. TM received consulting fees from Eisai, Gilead Sciences; honoraria from Eisai, AbbVie, Eli Lilly, Gilead Sciences, Asahi Kasei. KS received grants/research support from Novartis, Astellas, AbbVie, Bristol-Myers Squibb, Yuhan; consulting fees from KD Bio. SH received grants from AbbVie, Asahi Kasei, Chugai, Eisai, Eli Lily, Otsuka, Taisho, UCB; honoraria from AbbVie, Asahi-Kasei, Astellas, AstraZeneca, Ayumi, Bristol-Myers Squibb, Boehringer Ingelheim, Chugai, Daiichi-Sankyo, Eisai, Eli Lilly, Gilead Sciences, Glaxo SmithKline, Janssen, Nihon-Shinyaku, Novartis, Otsuka Pharmaceutical, Pfizer, Taisho, Tanabe-Mitsubishi, UCB; participated on advisory boards of AbbVie, Astellas, Bristol Myers Squibb, Eisai, Eli Lilly, Gilead Sciences, Janssen, Taisho, UCB. SS received honoraria from AbbVie, Pfizer. HY received grants from AbbVie, Boehringer Ingelheim, Gilead Sciences, Nippon Shinyaku, Asahi Kasei, Chugai, Eisai, Mitsubishi-Tanabe, Taisho; honoraria from AbbVie, Asahi Kasei, Astellas, Daiichi Sankyo, Eisai, Eli Lilly, Pfizer, Janssen, Sanofi, Teijin, Boehringer Ingelheim, Bayer, Viatris, Kissei, Takeda, Mitsubishi-Tanabe, Chugai, Novartis. MK received grants and royalties from MBL; consulting fees from Boehringer Ingelheim, Mochida, Kissei, GSK, AstraZeneca, Mitsubishi-Tanabe, Janssen, Biogen; received honoraria from Boehringer Ingelheim, Chugai, Asahi Kasei; participated on advisory board of Argenx. TI received honoraria from Asahi Kasei, GSK, Chugai, Pfizer, Eli Lilly, Boehringer-Ingelheim, AstraZeneca. HK received a grant from Pfizer, AbbVie, Asahi Kasei, Boehringer Ingelheim, Chugai, Eisai, Mitsubishi-Tanabe, Taisho; consulting fees from Sanofi; honoraria from AbbVie, Asahi Kasei, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai, Eisai, Eli Lilly, Janssen, Mitsubishi-Tanabe, Novartis, Pfizer. TK received grant/research support from AbbVie, Astellas, Chugai; honoraria from AbbVie, Astellas, Bristol-Myers Squibb, Chugai, Daiichi-Sankyo, Eli Lilly, Pfizer, Eisai, Taisho, UCB; participated on board of JCR subcommittee on Guidelines for RA Therapeutics. YN is a shareholder and employee of Eisai. MM is a shareholder and employee of Eisai. HM is an employee of Eisai. YS received honoraria from Mochida. WT received consulting fees and honoraria from Eli Lilly, Eisai; honoraria from Pfizer. TT received consulting fees from AbbVie, Eli Lilly, Gilead Sciences, Mitsubishi-Tanabe, Taisho; honoraria from AbbVie, Astellas, AstraZeneca, Chugai, Eisai, Eli Lilly, Gilead Sciences, Janssen, Mitsubishi-Tanabe, Pfizer, Taisho. YK received grants from AbbVie, Asahi Kasei, Ayumi, Boehringer Ingelheim, Chugai, Eisai, Gilead Sciences, Mitsubishi-Tanabe, Taisho, UCB; consulting fees from AbbVie, Asahi Kasei, Bristol-Myers Squibb, Eli Lilly, Gilead Sciences, Pfizer, Taisho, UCB; honoraria from AbbVie, Asahi Kasei, Astellas, AstraZeneca, Ayumi, Bristol-Myers Squibb, Chugai, Daiichi-Sankyo, Eisai, Eli Lilly, Gilead, Glaxo SmithKline, Janssen, Mitsubishi-Tanabe, Novartis, Pfizer, Sanofi, Taisho, UCB. The other coauthors declare no relevant conflicts of interest., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ on behalf of EULAR.)

Background: Rheumatoid arthritis-associated interstitial lung disease (RA-ILD) is a major complication of rheumatoid arthritis (RA), but effective treatment remains an unmet need in its management. Our aim was to evaluate the therapeutic efficacy of abatacept for RA-ILD. Methods: This observational retrospective study included patients with RA-ILD treated with abatacept between 2012 and 2021. Indices of RA disease activity and interstitial lung disease (Disease Activity Score in 28 joints using C-reactive Protein [DAS28-CRP], Simplified Disease Activity Index [SDAI], Clinical Disease Activity Index [CDAI], serum Krebs von den Lungen-6 levels, % forced vital capacity [%FVC], and semi-quantified chest high-resolution computed tomography scores) were evaluated before and 1 year after the start of abatacept administration. Results: Overall, 38 patients were included. DAS28-CRP, SDAI, and CDAI were significantly improved (all with p < 0.0001). Total ground-glass opacity scores were decreased in both patients with usual interstitial pneumonia (UIP)-like patterns and with non-UIP-like patterns ( p = 0.008 and <0.002, respectively). Total fibrosis scores were also decreased in the UIP-like pattern group ( p < 0.042). The %FVC remained stable. Conclusions: Abatacept significantly improves RA disease activity and reduces pulmonary inflammation in patients with RA-ILD.

Introduction: High baseline neutrophil-to-lymphocyte ratio (NLR) in rheumatoid arthritis (RA) has been associated with positive responses to biologic tumor necrosis factor inhibition and negative responses to conventional synthetic disease-modifying antirheumatic drug (csDMARD) triple therapy. Datasets from three randomized clinical trials in patients with RA were used to test the hypothesis that baseline NLR is associated with improved clinical response to filgotinib in methotrexate (MTX)-naïve or MTX-experienced RA populations., Methods: Patients from FINCH 1 (inadequate response to MTX, MTX-IR; NCT02889796), FINCH 2 (inadequate response to biologic DMARDs; NCT02873936), and FINCH 3 (MTX-naïve; NCT02886728) were classified as baseline NLR-High or baseline NLR-Low based on a previously published cut point of 2.7. In total, 3365 patients were included across the three studies. Differences in clinical outcomes and patient-reported outcomes (PROs) were determined using linear-regression models., Results: Control-arm patients (placebo + MTX/placebo + csDMARD) classified as NLR-High exhibited worse continuous clinical and PRO responses at week 12 across clinical trials compared to NLR-Low patients. In contrast, NLR-High patients who received FIL 200 mg + MTX/csDMARD exhibited consistently better responses after 12 weeks compared to NLR-Low patients across clinical trials, clinical endpoints, and PROs. These trends were most prominent among the MTX-IR population., Conclusion: The 2.7 baseline NLR cut point could be used to enrich for patients most likely to benefit from the addition of filgotinib to background MTX/csDMARD. Use of baseline NLR as part of therapeutic decision-making would not require additional diagnostics and could contribute to improved outcomes for patients with RA., Trial Registration: Clinicaltrials.gov: NCT02889796; NCT02873936; NCT02886728., (© 2024. The Author(s).)

Background: The postoperative prognosis of patients with interstitial lung disease (ILD) and lung cancer is poor. Recently, the ILD-gender-age-physiology (GAP) index was identified as a clinical prognostic factor for patients with ILD. This study investigated the ILD-GAP index and oncological factors regarding postoperative outcomes., Methods: We retrospectively reviewed 87 lung cancer patients with comorbid ILD who underwent curative resection at our institution between April 2005 and December 2019. Short-term postoperative outcomes and overall survival (OS) based on the ILD-GAP index were examined. OS rates after surgery were calculated using the Kaplan-Meier method, and group differences were analyzed using the Log-Rank test. Univariate and multivariate analyses for OS were performed using the Cox regression model., Results: Multivariate analyses revealed ILD-GAP index ≥ 4 [Hazard ratio, 3.349; 95% confidence interval 1.375-8.155; P = 0.008] as a factor associated with OS. In the ILD-GAP index ≥ 4 group, no deaths occurred from primary lung cancer, with respiratory-related deaths being the most common, and exacerbation of ILD was more frequent (P = 0.007). Regarding perioperative results, a significant difference was observed in 90-day mortality (2.7% vs. 23.0% [P = 0.022]), and more patients required home oxygen therapy (14.9% vs. 69.2% [P < 0.001]) in the ILD-GAP index ≥ 4 group., Conclusions: An ILD-GAP index ≥ 4 indicated a poor prognostic factor for patients with surgically treated lung cancer. Careful consideration of surgical indications is essential for patients with an ILD-GAP index ≥ 4., (© 2024. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

Objectives: To evaluate the long-term efficacy of once-daily baricitinib 4 mg or 2 mg in patients with active rheumatoid arthritis who had inadequate response (IR) to MTX, csDMARDs or bDMARDs., Methods: Data from three completed phase III studies-RA-BEAM (MTX-IR), RA-BUILD (csDMARD-IR) and RA-BEACON (bDMARD-IR)-and one completed long-term extension study (RA-BEYOND) were analysed up to 6.5 years [340 weeks (RA-BEAM) and 336 weeks (RA-BUILD and RA-BEACON)]. Low disease activity (LDA) [Simplified Disease Activity Index (SDAI) ≤11], clinical remission (SDAI ≤3.3) and physical function [Health Assessment Questionnaire Disability Index (HAQ-DI) ≤0.5] were the main outcomes assessed. Completer and non-responder imputation (NRI) analyses were conducted on each population., Results: At week 340 or 336, LDA was achieved in 37%/83% of MTX-IR, 35%/83% of csDMARD-IR and 23%/73% of bDMARD-IR patients treated with baricitinib 4 mg, assessed by NRI/completer analyses, respectively. Remission was achieved in 20%/40% of MTX-IR, 13%/32% of csDMARD-IR and 9%/30% of bDMARD-IR patients treated with baricitinib 4 mg, assessed by NRI/completer analyses, respectively. HAQ-DI ≤0.5 was reached in 31%/51% of MTX-IR, 25%/46% of csDMARD-IR and 24%/38% of bDMARD-IR patients treated with baricitinib 4 mg, assessed by NRI/completer analyses, respectively., Conclusion: Treatment with baricitinib 4 mg or 2 mg demonstrated efficacy up to 6.5 years with maintained LDA/remission results across SDAI, CDAI and DAS28-hsCRP consistent with previously reported data, and was well tolerated., Trial Registration: United States National Library of Medicine clinical trials database www.clinicaltrials.gov; RA-BEYOND; NCT01885078., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

We aimed to clarify the long-term safety and efficacy of rituximab (RTX) as a remission induction therapy following severe relapse in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). We retrospectively collected the data of patients with severely relapsed AAV from a Japanese multicentre cohort. The primary exposure was RTX use; the primary outcome was complete remission (CR) proportions at week 24. Baseline characteristics were compared between the RTX and non-RTX groups. We performed multivariate logistic regression analysis and one-to-one propensity score matching analysis as a sensitivity analysis. Totally, 100 patients were enrolled: 52 in the RTX group and 48 in the non-RTX group. Baseline characteristics were comparable between the two groups, except for age, AAV subtype and ANCA serotype. The median age was 71 vs. 75 years, and the PR3-ANCA positivity rate was 44.2% vs. 18.8% in the RTX and non-RTX groups, respectively. No significant difference was observed in CR proportions at week 24 between the two groups (79.2% vs. 68.1%, p = 0.321), with an adjusted odds ratio of 1.27 (95% confidence interval [CI] 0.47-3.51). At week 48, CR proportions were significantly higher in the RTX group (91.7% vs. 64.9%, p = 0.005), with an adjusted odds ratio of 2.95 (95% CI 0.97-9.91). Serious infection rates were lower in the RTX group than in the non-RTX group, with no statistically significant difference. RTX was not superior to conventional immunosuppressive therapies at week 24 but showed significantly favourable results at week 48 for severely relapsed AAV., (© 2024. The Author(s).)

Objective: We focused to analyze the time-course changes at pre- and post-flare of T peripheral helper (Tph) cells and circulating T follicular helper (Tfh) cells in the blood of patients with systemic lupus erythematosus (SLE) with lupus low disease activity state (LLDAS) before flare., Methods: This study included inactive (n = 29) and active (n = 55) patients with SLE. Tph subsets, Tfh subsets, CD11c hi B cells, and plasma cells in the blood were determined by flow cytometry. The blood levels of cytokines including interferons (IFNs) were measured by electrochemiluminescence assay or cytokine beads array., Results: Active SLE patients exhibited the increased frequency of Tph1, Tph2, Tfh1, and Tfh2 subsets when compared to inactive patients, but no clear changes in the other subsets. During the treatment with medications, Tph1, Tph2, and Tfh2 subsets were significantly reduced along with disease activity and Tph1 and Tph2 subsets were positively correlated with SLE disease activity index (SLEDAI). The time course analysis of patients at pre- and post-flare revealed that in the patients at LLDAS before flare, Tph subsets and Tfh subsets were relatively low levels. At the flare, Tph cells, particularly Tph1 and Tph2 subsets, were increased and correlated with SLEDAI. Furthermore, the blood levels of IFN-α2a, IFN-γ, and IFN-λ1 were low in the patients with LLDAS before flare but these IFNs, particularly IFN-λ1, were increased along with flare., Conclusion: Increased frequency of Tph1 and Tph2 subsets and elevated levels of serum IFN-λ1 are presumably critical for triggering of flare in SLE., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Background: While AKI requiring renal replacement therapy (AKI-RRT) is associated with increased mortality in heterogeneous inpatient populations, the epidemiology of AKI-RRT in hospitalized patients with cirrhosis is not fully known. Herein, we evaluated the association of etiology of AKI with mortality in hospitalized patients with cirrhosis and AKI-RRT in a multicentric contemporary cohort., Methods: This is a multicenter retrospective cohort study using data from the HRS-HARMONY consortium, which included 11 U.S. hospital network systems. Consecutive adult patients admitted in 2019 with cirrhosis and AKI-RRT were included. The primary outcome was 90-day mortality, and the main independent variable was AKI etiology, classified as hepatorenal syndrome (HRS-AKI) vs. other (non-HRS-AKI). AKI etiology was determined by at least two independent adjudicators. We performed Fine and Gray sub-distribution hazard analyses adjusting for relevant clinical variables., Results: Of 2,063 hospitalized patients with cirrhosis and AKI, 374 (18.1%) had AKI-RRT. Among these, 65 (17.4%) had HRS-AKI and 309 (82.6%) non-HRS-AKI, which included ATN in most cases (62.6%). Continuous RRT (CRRT) was used as the initial modality in 264 (71%) of patients, while intermittent hemodialysis (IHD) was utilized in 108 (29%). The HRS-AKI (vs. non-HRS-AKI) group received more vasoconstrictors for HRS management (81.5% vs. 67.9%), while the non-HRS-AKI group received more mechanical ventilation (64.3% vs. 50.8%) and more CRRT (vs. IHD) as the initial RRT modality (73.9% vs. 56.9%). In the adjusted model, HRS-AKI (vs. non-HRS-AKI) was not independently associated with increased 90-day mortality (sHR=1.36, 95% CI: 0.95-1.94)., Conclusions: In this multicenter contemporary cohort of hospitalized adult patients with cirrhosis and AKI-RRT, HRS-AKI was not independently associated with an increased risk of 90-day mortality when compared to other AKI etiologies. The etiology of AKI appears less relevant than previously considered when evaluating the prognosis of hospitalized adult patients with cirrhosis and AKI requiring RRT., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Nephrology.)

Clostridium perfringens, which produces C. perfringens enterotoxin (CPE), is a major causative agent of food poisoning owing to its gastrointestinal symptoms. Genotyping is important for identifying the etiological agent in outbreaks of C. perfringens. We attempted to genotype strains isolated from an outbreak of food poisoning in Toyama in 2023 using single nucleotide polymorphism (SNP) analysis. The strains of C. perfringens were isolated from a piece of curry food consumed by all patients and from the feces of the patients and employees. The cpe gene was detected in isolates from patients and curry food. The cpe-negative isolates were found in patients who consumed curry foods and in employees. The results of the SNP analysis suggest that the patient- and curry-derived isolates were likely from the same source but were unlikely to be related to the employee-derived isolates. The results of the SNP and pulsed-field gel electrophoresis (PFGE) analyses were consistent, indicating that the patient- and curry-derived isolates came from the same source. SNP analysis, a whole-genome-based genotyping method, is a promising alternative to the traditional PFGE method. Further studies are needed to accumulate more experience with genotyping using SNP analysis for the epidemiological investigation of outbreaks of C. perfringens.

The signature feature of the 'strange metal' state of high-T c cuprates-its linear-in-temperature resistivity-has a coefficient α 1 that correlates with T c , as expected were α 1 derived from scattering off the same bosonic fluctuations that mediate pairing. Recently, an anomalous linear-in-field magnetoresistance (=γ 1 H) has also been observed, but only over a narrow doping range, leaving its relation to the strange metal state and to the superconductivity unclear. Here, we report in-plane magnetoresistance measurements on three hole-doped cuprate families spanning a wide range of temperatures, magnetic field strengths and doping. In contrast to expectations from Boltzmann transport theory, γ 1 is found to correlate universally with α 1 . A phenomenological model incorporating real-space inhomogeneity is proposed to explain this correlation. Within this picture, superconductivity in hole-doped cuprates is governed not by the strength of quasiparticle interactions with a bosonic bath, but by the concentration of strange metallic carriers., (© 2024. The Author(s).)

The high mortality rate of colorectal cancer (CRC) highlights the need for new treatment strategies; however, the venous invasion mechanisms in tumor endothelial cells within CRC remain unexplored. Therefore, we investigated the clinicopathological features of SRY-box transcription factor 17 (SOX17) in CRC. Immunohistochemical staining was performed on 55 CRC tissue specimens using a SOX17-specific antibody, followed by Kaplan-Meier and Cox proportional hazards regression analyses. SOX17 immunoreactivity was detected in the endothelial cells of tumor-penetrating vessels in 35/55 CRC samples. Kaplan-Meier analysis indicated that patients with SOX17 immunoreactivity had favorable overall and progression-free survival (log-rank test, P = 0.03 and 0.02, respectively). Notably, tumor endothelial SOX17 immunoreactivity was associated with a favorable prognosis in patients with stage III or IV disease (OS, P = 0.0089; PFS, P = 0.0065). Cox proportional hazard regression analysis indicated that SOX17 immunoreactivity is an independent factor for predicting favorable overall and progression-free survival in CRC (P = 0.02 and 0.01, respectively). The present findings suggest that SOX17 expression in tumor endothelial cells is a potential indicator of favorable prognosis in patients with CRC., Competing Interests: Declaration of Competing Interest No potential conflict of interest was reported by the authors., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

We investigated the thermoelectric and thermal behavior of Fe-V-W-Al-based thin films prepared using the radio frequency magnetron sputtering technique at different oxygen pressures (0.1-1.0 × 10 -2 Pa) and on different substrates (n, p, and undoped Si). Interestingly, at lower oxygen pressure, formation of a bcc-type Heusler structure was observed in deposited samples, whereas at higher oxygen pressure, we have noted the development of an amorphous structure in these samples. Our findings indicate that the moderately oxidized Fe-V-W-Al amorphous thin film deposited on the n -Si substrate possesses a large magnitude of S ∼ -1098 ± 100 μV K -1 near room temperature, which is almost double the previously reported value for thin films. Additionally, the power factor (PF) indicated an enormously large value of ∼33.9 mW m -1 K -2 near 320 K. The thermal conductivity of the amorphous thin film is also found to be 2.75 Wm -1 K -1 , which is quite lower compared to bulk alloys. As a result, the maximum figure of merit is estimated to be extremely high, i.e., ∼3.9 near 320 K, which is among one of the highest reported values so far. The anomalously large value of Seebeck coefficient and PF has been ascribed to the unusual composite effect of the metallic amorphous oxide phase and insulating substrate possessing a large Seebeck coefficient.

Objective: There is a pressing need to understand the pathogenesis of histological findings and identify the biomarkers for predicting the histological severity in lupus nephritis (LN). This study aimed to identify the pathogenic signal pathway and elucidate urinary biomarkers for predicting the presence or severity of histological findings in LN., Methods: Urine samples from patients with biopsy-proven active LN were screened for 1305 proteins using an aptamer-based proteomic assay. The diversity and expansion of individual renal histological features in LN were quantified to identify the urinary proteins associated with the histological findings found in each score. Candidate urinary proteins were validated in a validation cohort. Immunohistochemical staining of the renal tissues was performed to clarify the localisation of the candidate proteins., Results: Cluster analysis extracted five histological subgroups according to their correlations with each histological finding in LN. Protein groups which correlated with each histological subgroup revealed a distinct pathogenesis in LN using pathway analyses. Enzyme-linked immunosorbent assay validation revealed that urinary calgranulin B (S100A9), MCP-1, and IGFBP-5 levels could specifically predict the presence and severity of active glomerular lesions, interstitial inflammation, and interstitial fibrosis, respectively. Immunohistochemical staining revealed the localisation of these proteins in each lesion., Conclusions: Renal histological findings may reflect the different pathogeneses involved in each lesion, and estimating the urinary calgranulin B, MCP-1, and IGFBP-5 levels may be useful in predicting the presence and severity of histological findings in LN., (© 2024 American College of Rheumatology.)

This study reported a copper-catalyzed direct asymmetric aldol reaction between aldehydes and glycine Schiff bases with methyl, allyl, and tert -butyl esters. Additionally, this reaction afforded high yields of syn -β-hydroxy-α-amino esters with excellent enantio- and diastereoselectivities (93-99% ee, up to >99:1 dr). The aldol reaction accepted aromatic, linear aliphatic, and α-substituted aliphatic aldehydes.

Objectives: The lupus low disease activity state (LLDAS) allows for certain clinical and/or serological activity of SLE, provided overall disease activity does not exceed predefined cut-offs. This study aimed to evaluate the outcomes of patients who achieved LLDAS with clinical activity, serological activity only or neither clinical nor serological activity., Methods: Patients with SLE enrolled in a prospective multinational cohort from March 2013 to December 2020 who were in LLDAS at least once were included. Visits that fulfilled both LLDAS and Definition of Remission in SLE (DORIS) criteria were excluded., Results: 2099 patients were included, with median follow-up of 3.5 (IQR 1.3-5.8) years. At 6150 visits, patients were in LLDAS but not DORIS criteria; of these 1280 (20.8%) had some clinical activity, 3102 (50.4%) visits had serological activity only and 1768 (28.8%) visits had neither clinical nor serological activity. Multivariable regression analysis showed that compared with non-LLDAS, all three subsets of LLDAS had a protective association with flares in the ensuing 6 months and damage accrual in the ensuing 36 months. LLDAS with no clinical or serological activity had a significantly stronger protective association with severe flares in the ensuing 6 months compared with LLDAS with clinical activity (HR 0.47, 95% CI (0.27 to 0.82), p=0.007)., Conclusions: LLDAS without any clinical activity accounted for almost 80% of LLDAS visits. This study confirms that all subsets of LLDAS are associated with reduced flare and damage accrual. However, LLDAS without any clinical or serological activity has the strongest protective association with severe flares., Competing Interests: Competing interests: SO'N received consulting fees from AstraZeneca, Biogen, Boehringer Ingelheim; lecture/speaker fees from AstraZeneca, Biogen, Boehringer Ingelheim, Pfizer and GSK and research grants from Aurania, Biogen, Idorsia, Novartis. ZL received consulting fees from Pfizer, Roche, Janssen, Abbott, AbbVie, Bristol-Myers Squibb, MSD, Celgene, Eli Lilly, GSK, Novartis, UCB and have royalties with Pfizer, Roche, Janssen, Abbott, AbbVie, Bristol-Myers Squibb, MSD, Celgene, Eli Lilly, GSK, Novartis, UCB. SS received consulting fees from Pfizer, AstraZeneca, ZP Therapeutics. YK received payment/Honoria from Asahi Kasei, Astellas, AstraZeneca, Chugai, GlaxoSmithKline, Janssen, Mitsubishi Tanabe, Pfizer Japan and Sanofi. MH received speaker’s fee from AbbVie Japan, Ayumi, Boehringer Ingelheim Japan, Bristol-Myers Squibb, Chugai, Eisai, Eli Lilly Japan, GlaxoSmithKline, Kissei Pharmaceutical, Pfizer Japan, Takeda and Teijin; consultant fees from AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Kissei Pharmaceutical and Teijin and research grants from AbbVie Japan GK, Asahi Kasei, Astellas, Ayumi, Bristol-Myers Squibb, Chugai, Daiichi-Sankyo. Eisai, KisseiPharmaceutical, Mitsubishi Tanabe, Nippon Kayaku, Sekisui Medical, Shionogi, Taisho, Takeda and Teijin. TT received grants from Astellas, Asahi Kasei, Chugai, Mitsubishi Tanabe, and consulting fees from Astellas, Chugai. KN received Advisory Board participation fees from AbbVie. YT has received research grants from Eli Lilly, AstraZeneca, AbbVie, Gilead, Chugai, Behringer-Ingelheim, GlaxoSmithKline, Eisai, Taisho, Bristol-Myers, Pfizer and Taiho. AH received research grants from AstraZeneca, and consulting fees from EUSA Pharma (UK), and Speaker/Honoraria from Limbic, Novartis, Moose Republic, AbbVie, Eli Lilly. RK-R received research grants from Novartis and GlaxoSmithKline. EM received research grants and/or consulting fees from AbbVie, AstraZeneca, Biogen, Bristol-Myers Squibb, Eli Lilly, Galapagos, Gilead, Genentech, GlaxoSmithKline, Genentech, Janssen, Novartis, Servier, EMD Serono, Takeda and UCB. MN received research grants and honoraria from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline and Janssen., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: This study aimed to identify useful clinical indicators for predicting the relapse of interstitial lung disease (ILD) complicated with anti-aminoacyl-tRNA synthetase (ARS) antibodies (anti-ARS-ILD), being treated with prednisolone and calcineurin inhibitors., Methods: Fifty patients with anti-ARS-ILD were enrolled between October 2014 and August 2022. All patients were treated with prednisolone and calcineurin inhibitors as remission induction therapy and followed up for over a year with these combination therapies. We examined patients who experienced ILD relapse after immunosuppressive treatment. We explored the risk factors for predicting ILD relapse in these patients by comparing demographic, clinical, laboratory, and radiological findings and treatments between the relapsed and non-relapsed groups on admission., Results: Of the 50 patients, 19 (38%) relapsed during a median follow-up of 4.8 years. Univariate and multivariate Cox regression analyses identified the presence of acute/subacute (A/S)-ILD, higher serum aldolase (ALD) and surfactant protein-D (SP-D) levels, and lower %forced vital capacity (FVC) as risk factors for relapse in patients with anti-ARS-ILD. Using the receiver operating curve analysis, ALD ≥6.3 U/L, SP-D ≥207 ng/mL, and %FVC ≤76.8% were determined as the cut-off levels for indicating a poor prognosis. The 5-year relapse rate was significantly higher in patients with A/S-ILD, serum ALD≥6.3 U/L, serum SP-D ≥207 ng/mL, or %FVC of ≤76.8% than in those without these parameters. ( P =0.009, 0.0005, 0.0007, 0.0004, respectively) Serum ALD levels were significantly correlated with the disease activity indicators of anti-ARS-ILD., Conclusion: The presence of A/S-ILD, higher serum ALD and SP-D levels, and lower %FVC are useful indicators for predicting anti-ARS-ILD relapse., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Matsuda, Kotani, Oe, Okazaki, Kiboshi, Suzuka, Wada, Shoda and Takeuchi.)

Background: This study aimed to clarify recent clinical features and treatment outcomes in Japanese patients with newly diagnosed Takayasu arteritis (TAK) during the first 2 years of treatment., Methods and Results: A nationwide multicenter retrospective cohort study for TAK was implemented to collect data between 2007 and 2014. The primary outcome of the study was clinical remission at Week 24. Of the 184 participants registered, 129 patients with newly diagnosed TAK were analyzed: 84% were female and the mean age at onset was 35 years. Clinical symptoms at diagnosis were mostly associated with large-vessel lesions. Frequent sites of vascular involvement included the carotid artery, subclavian artery, aortic arch, and descending aorta. The mean initial dose of prednisolone administered was 0.68 mg/kg/day, and 59% and 17% of patients received immunosuppressive drugs and biologics, respectively, by Week 104. Clinical remission at Week 24 and sustained clinical remission with daily prednisolone at ≤10 mg at Week 52 were achieved in 107 (82.9%) and 51 (39.5%) patients, respectively. The presence of signs and symptoms linked to large-vessel lesions was associated with failure to achieve sustained clinical remission at Week 52., Conclusions: We elucidated the clinical characteristics, treatment outcomes, and factors associated with failure to achieve sustained clinical remission in patients with newly diagnosed TAK in Japan during the first 2 years of treatment.

Background: Acute kidney injury (AKI) is common among hospitalized patients. However, the contribution of social determinants of health (SDOH) to AKI risk remains unclear. This study evaluated the association between neighborhood measures of SDOH and AKI development and recovery during hospitalization., Methods: This is a retrospective cohort study of adults without end-stage kidney disease admitted to a large southern U.S. healthcare system from 10/2014 to 9/2017. Neighborhood SDOH measures included: 1) Socioeconomic status: Area Deprivation Index (ADI) scores, 2) Food access: Low Income Low Access (LILA) scores, 3) Rurality: Rural Urban Commuting Area (RUCA) scores, and (4) Residential segregation: dissimilarity and isolation scores. The primary study outcome was AKI based on serum creatinine (SCr)-KDIGO criteria. Our secondary outcome was lack of AKI recovery (requiring dialysis or elevated SCr at discharge). The association of SDOH measures with AKI was evaluated using generalized estimating equation models adjusted for demographics and clinical characteristics., Results: Among 26,769 patients, 26% developed AKI during hospitalization. Compared with those who did not develop AKI, those who developed AKI were older (median 60 vs. 57 years), more commonly men (55% vs. 50%), and more commonly self-identified as Black (38% vs. 33%). Patients residing in most disadvantaged neighborhoods (highest ADI tertile) had 10% (95%CI: 1.02-1.19) greater adjusted odds of developing AKI during hospitalization than counterparts in least disadvantaged areas (lowest ADI tertile). Patients living in rural areas had 25% higher adjusted odds of lack of AKI recovery by hospital discharge (95% CI: 1.07, 1.46). Food access and residential segregation were not associated with AKI development or recovery., Conclusions: Hospitalized patients from the most socioeconomically disadvantaged neighborhoods and from rural areas had higher odds of developing AKI and not recovering from AKI by hospital discharge, respectively. A better understanding of the mechanisms underlying these associations is needed to inform interventions to reduce AKI risk during hospitalization among disadvantaged populations., (Copyright © 2024 by the American Society of Nephrology.)

Background: Acute kidney injury (AKI) is associated with increased mortality and new or progressive chronic kidney disease (CKD). Inflammatory cells play an important role in acute organ injury. We previously demonstrated that serum IL-17A levels were significantly elevated in critically ill patients with AKI and independently associated with hospital mortality. We hypothesize that IL-17A levels are elevated in hospitalized patients with AKI at diagnosis, and sustained elevation after discharge is associated with subsequent CKD incidence or progression., Methods: Observational convenience sampling study of hospital survivors of Stage 2 or 3 AKI and controls without AKI from the ASSESS-AKI study. Patients were classified as progression or non-progression based on a composite of CKD incidence, progression, or end-stage kidney disease. IL-17A levels were evaluated with S-Plex assay (MSD) at 0- (during hospitalization), 3- and 12-month post-discharge, and analyzed along with clinical and biomarker data up to 84 months following discharge., Results: Among 171 AKI and 175 non-AKI participants, IL-17A levels were elevated in AKI vs. non-AKI patients at 0M, 3M and 12M timepoints (p<0.05 for all comparisons). Further, IL-17A levels were elevated in the progression vs. non-progression group at the 3- and 12-month timepoints for outcomes occurring at 3-6 months and 12-84 months, respectively (p<0.05 for both). In adjusted multivariable models, IL-17A levels were not independently associated with progression of kidney disease. IL-17A levels were positively correlated with kidney disease and immune activation biomarkers at all timepoints (p<0.001)., Conclusions: IL-17A was higher in patients with AKI vs. without AKI during hospitalization and up to 1-year post-discharge. IL-17A was higher in patients with progression of kidney disease after hospitalization but not independently associated with subsequent progression of kidney disease in fully adjusted models., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Nephrology.)

Chondroitin sulfate (CS) is a linear polysaccharide chain of alternating residues of glucuronic acid (GlcA) and N-acetylgalactosamine (GalNAc), modified with sulfate groups. Based on the structure, CS chains bind to bioactive molecules specifically and regulate their functions. For example, CS whose GalNAc is sulfated at the C4 position, termed CSA, and CS whose GalNAc is sulfated at both C4 and C6 positions, termed CSE, bind to a malaria protein VAR2CSA and receptor type of protein tyrosine phosphatase sigma (RPTPσ), respectively, in a specific manner. Here, we modified CSA and CSE chains with phosphatidylethanolamine (PE) at a reducing end, attached them to liposomes containing phospholipids and generated CSA and CSE liposomes. The CS-PE was incorporated into the liposome particles efficiently. Inhibition ELISA revealed specific interaction of CSA and CSE with recombinant VAR2CSA and RPTPσ, respectively, more efficiently than CS chains alone. Furthermore, CSE liposome was specifically incorporated into RPTPσ-expressing HEK293T cells. These results indicate CS liposome as a novel and efficient drug delivery system, especially for CS-binding molecules., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: To assess the impact of baseline rheumatoid factor (RF) level on drug concentrations and efficacy of certolizumab pegol (CZP; tumour necrosis factor inhibitor [TNFi] without a crystallisable fragment [Fc]) and adalimumab (ADA; Fc-containing TNFi) in patients with rheumatoid arthritis (RA)., Methods: The phase 4 EXXELERATE study (NCT01500278) was a 104-week, randomised, single-blind (double-blind until week 12; investigator-blind thereafter), head-to-head study of CZP vs ADA in patients with RA. In this post hoc analysis, we report drug concentration and efficacy outcomes stratified by baseline RF quartile (≤Q3 or >Q3)., Results: Baseline data by RF quartiles were available for 453 CZP-randomised and 454 ADA-randomised patients (≤Q3: ≤204 IU/ml; >Q3: >204 IU/ml). From week 12, the area under the curve (AUC) of ADA concentration was lower in patients with RF > 204 IU/ml vs patients with RF ≤ 204 IU/ml; the AUC of CZP concentration was similar in patients with RF ≤ 204 IU/ml and >204 IU/ml. For patients with RF ≤ 204 IU/ml, disease activity score (DAS28)-C-reactive protein (CRP) was similar between CZP- and ADA-treated patients through week 104. For patients with RF > 204 IU/ml, mean DAS28-CRP was lower in CZP- vs ADA-treated patients at week 104. The proportion of patients with RF > 204 IU/ml achieving DAS28-CRP low disease activity at week 104 was greater in CZP- vs ADA-treated patients., Conclusion: CZP was associated with maintained drug concentration and efficacy in patients with RA and high RF and may therefore be a more suitable therapeutic option than TNFis with an Fc fragment in these patients., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Objectives: Anti-IL-6 receptor antibodies are clinically efficacious in the management of RA with an associated increase in Tregs; however, the role of functional Treg subsets has yet to be clarified. This study aimed to evaluate how functional Treg subsets are altered by IL-6 receptor blockade and to analyse the relationship between these Treg subsets and the clinical outcome of RA., Methods: We collected frozen peripheral blood mononuclear cells (PBMCs) from 40 patients with RA who started tocilizumab (TCZ) with or without MTX and 11 healthy controls (HCs). We fractionated Tregs with flow cytometry based on markers of phenotype and function and measured the proportions of detailed Treg subsets sequentially from baseline to week 52., Results: The proportions of resting Tregs (rTregs) and rTregs+activated Tregs (aTregs) were significantly lower in RA patients at baseline than in HCs. The proportions of all those CD127low Tregs, rTregs, aTregs and rTregs+aTregs were significantly increased with TCZ treatment. In patients treated with TCZ without MTX, rTreg were increased. Patients with an increase in the proportion of rTregs at week 12 had significantly less arthritis flares during the observation period., Conclusions: Blocking the IL-6 receptor with TCZ increased the proportion of rTregs, a functional Treg subpopulation. Patients with an early increase in rTregs showed a favourable treatment course and this increase in rTregs may reflect molecular remission induced by IL-6 signal inhibition., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

The viral genome of the high-risk human papillomavirus (HPV), the causative agent of cervical cancer, is stably maintained as extrachromosomal episomes that establish persistent infection. We previously identified homeobox-transcription factor HOXC13 as an important host protein mediating the short-term retention of the HPV16 and HPV18 genomes in normal human immortalized keratinocytes (NIKS). Here, we used CRISPR-Cas9 technology to construct HOXC13 knockout (KO) NIKS cells to determine whether HOXC13 is required for the long-term maintenance of high-risk HPV genomes. HPV16, HPV18, HPV52, and HPV58 whole genomes were transfected into HOXC13 KO cells, and the copy number of viral genomes per cell was monitored over cell passages. Copy numbers of HPV16, HPV52, and HPV58 genomes decreased continuously in HOXC13 KO cells, whereas HPV18 genomes remained stable throughout passages. Thus, HOXC13 is critical for the stable maintenance of the viral genomes of HPV16, HPV52, and HPV58, but not HPV18., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objectives: To evaluate the effectiveness and safety of two different intravenous methylprednisolone (IVMP) pulse doses in patients with severe microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA)., Methods: We emulated a target trial using observational data from the nationwide registry in Japan. Patients with severe glomerulonephritis or diffuse alveolar haemorrhage were selected and pseudo-randomized into three groups using propensity score-based overlap weighting as follows: non-IVMP, IVMP 0.5 g/day and IVMP 1.0 g/day. The primary outcome was all-cause mortality, and the secondary outcomes were composite all-cause mortality and kidney failure, severe relapse and serious infection from 2 to 48 weeks after treatment initiation. To estimate the treatment effects, the Cox proportional hazard model and Fine-Gray subdistribution hazard model were used., Results: In this emulated target trial, of 201 eligible patients (MPA, 175; GPA, 26), 6 (3%) died, 4 (2.0%) had kidney failure, 11 (5.5%) had severe relapse, and 40 (19.9%) had severe infections. Hazard ratios (HR) for IVMP 0.5 g/day and IVMP 1.0 g/day pulse groups compared with non-IVMP pulse were as follows: all-cause mortality 0.46 (95% CI: 0.07, 2.81) and 0.07 (95% CI: 0.01, 0.41), respectively; all-cause mortality/kidney failure 1.18 (95% CI: 0.26, 5.31) and 0.59 (95% CI: 0.08, 4.52), respectively; subdistribution HRs for severe relapse were 1.26 (95% CI: 0.12, 13.70) and 3.36 (95% CI: 0.49, 23.29), respectively; and for serious infection 1.88 (95% CI: 0.76, 4.65) and 0.94 (95% CI: 0.28, 3.13), respectively., Conclusion: IVMP 1.0 g/day pulse may improve 48-week mortality in patients with severe MPA/GPA., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Epstein-Barr virus-positive mucocutaneous ulcer is one of the mature B-cell lymphoproliferative diseases occurring in patients with immune dysfunction including those with immunosuppressive treatment such as methotrexate., Case Presentation: A Japanese elderly man in his 80s with rheumatoid arthritis on methotrexate was admitted to our hospital complaining persistent pharyngeal pain. Laboratory tests revealed severe pancytopenia, elevated C-reactive protein, and increased creatinine levels. An otolaryngological examination showed ulceration of the right tonsil, from which diagnostic biopsy was performed. The diagnosis of Epstein-Barr virus-positive mucocutaneous ulcer was made and bone marrow aspiration revealed hypocellularity and megaloblastic changes. Pancytopenia was improved after discontinuing methotrexate, and repeated bone marrow aspiration test revealed recovery of normal cellularity and disappearance of dysplasia, confirming the diagnosis of methotrexate intoxication. Tonsil ulcer was improved only with discontinuation of methotrexate, which strongly supported the diagnosis of EBV-MCU., Conclusion: Our case suggested that even this best prognosis form of lymphoproliferative disease could lead to fatal complications if not appropriately managed., (© 2024. The Author(s).)

Objectives: to Determine Whether Magnetic Resonance Imaging (mri) Findings Reflect the Pathological Features of Inflammatory Myopathies: Methods: Patients with idiopathic inflammatory myopathies (IIMs) diagnosed using the 2017 EULAR/ACR classification criteria in our university between 2005 and 2020 were retrospectively reviewed. IIMs were subclassified into the anti-ARS syndrome (ASSD), immune-mediated necrotizing myositis (IMNM), Dermatomyositis DM and others. Fat-suppressed T2-weighted MRI and muscle biopsy specimens were assessed in IIMs followed by the comparison among the four subgroups., Results: MRI findings were available for 62 patients and histopathological findings were available for 27 patients. Perifascicular atrophy or necrosis in the muscle tissues from the patients with IIM was more frequently observed in patients with subcutaneous and fascial high signal intensity (HSI) on MRI than those without. Four-group comparison among ASSD, IMNM, DM and others revealed HSI in fasciae on MRI was more frequently observed in patients with ASSD and DM than others. Perifascicular atrophy or necrosis in muscle tissues was more frequently observed in patients with ASSD than in others., Conclusion: Patients with ASSD had distinct MRI features compared with anti-ARS negative patients. The fascial high signal intensity on MRI may reflect distinctive pathological features of muscles., (© Japan College of Rheumatology 2024. Published by Oxford University Press.)

Objectives: To update the long-term safety profile of filgotinib, a Janus kinase-1 preferential inhibitor, in patients with moderate-to-severe rheumatoid arthritis., Methods: Data from seven trials were integrated (NCT01888874, NCT01894516, NCT02889796, NCT02873936, NCT02886728, NCT02065700 and NCT03025308). Patients received once-daily filgotinib 100 mg or 200 mg. Exposure-adjusted incidence rates (EAIRs)/100 patient-years of exposure (PYE) were calculated for treatment-emergent adverse events (TEAEs). Post hoc analyses assessed patients aged <65 and ≥65 years., Results: Patients (N=3691) received filgotinib for a median (maximum) of 3.8 (8.3) years (12 541 PYE). Rates of TEAEs of interest: serious infections, malignancies, major adverse cardiovascular events (MACE) and venous thromboembolism were stable over time and comparable between doses. In the overall population, numerically lower EAIR (95% CI)/100 PYE of herpes zoster was observed for filgotinib 100 mg versus 200 mg (1.1 (0.8 to 1.5) vs 1.5 (1.2 to 1.8)). Incidence of serious infections, herpes zoster, MACE, malignancies and all-cause mortality was higher in patients aged ≥65 versus <65 years. In patients aged ≥65 years, EAIRs (95% CI)/100 PYE for non-melanoma skin cancer (NMSC) (0.4 (0.1 to 1.1) vs 1.4 (0.8 to 2.2)), malignancies excluding NMSC (1.0 (0.5 to 1.9) vs 2.0 (1.3 to 2.9)) and all-cause mortality (1.3 (0.7 to 2.2) vs 1.6 (1.0 to 2.5)) were numerically lower for filgotinib 100 mg versus 200 mg., Conclusions: In the overall population, TEAEs of interest were stable over time and similar between filgotinib 100 mg and 200 mg dose groups, except for herpes zoster. A dose-dependent relationship between malignancies and all-cause mortality was suggested in patients ≥65 years old., Competing Interests: Competing interests: GRB reports consultancy fees from AbbVie, Amgen, BMS, Galapagos, Lilly, Pfizer and Sanofi; and speakers’ bureau fees from AbbVie, Amgen, BMS, Chugai, Galapagos, Lilly, Pfizer and Sanofi. J-EG reports consultancy fees from AbbVie, BMS, Galapagos, Gilead, Lilly, MSD, Novartis and Pfizer; and grant/research support from BMS and Pfizer. RC reports consultancy fees from AbbVie, Fresenius, Galapagos, Lilly, Pfizer, Novartis and UCB; speakers’ bureau fees from AbbVie, Amgen, BMS, Celltrion, Fresenius, Galapagos, Janssen, Lilly, Novartis, Pfizer and UCB. KLW reports consultancy fees from AbbVie, AstraZeneca, BMS, Eli Lilly & Company, Galapagos, Gilead, GSK, Novartis, Pfizer, Regeneron, Roche, Sanofi and UCB; and grant/research support from BMS and Pfizer. YT has received speaker fees and/or honoraria from AbbVie, Asahi Kasei, AstraZeneca, BMS, Boehringer Ingelheim, Chugai, Eisai, Eli Lilly, Gilead, GSK, Taiho, Taisho and Pfizer; and research grants from Asahi Kasei, Chugai, Eisai, Mitsubishi Tanabe and Taisho. EVEO is a consultant for Galapagos. VR is a former employee of, and shareholder in, Galapagos. PVH is a consultant for AOP Health, Aspen and Galapagos; and a previous employee of Janssen, MSD and Schering-Plough. KVB is an employee of, and shareholder in, Galapagos. TT reports consultancy fees from AbbVie GK, Astellas, Chugai, Eli Lilly Japan, Gilead, Janssen Pharma K.K., Mitsubishi Tanabe and Pfizer Japan; speakers’ bureau fees from AbbVie GK, AYUMI, BMS, Chugai, Daiichi Sankyo, Eisai, Eli Lilly Japan, Gilead, Janssen Pharma K.K., Mitsubishi Tanabe, Pfizer Japan and Sanofi K.K.; and research/grant support from AbbVie GK, Asahi Kasei, Astellas, AYUMI, Chugai, Daiichi Sankyo, Eisai, Eli Lilly Japan, Mitsubishi Tanabe, Nippon Kayaku and UCB Japan. RW acted as an adviser and speaker for Celltrion, Galapagos and Gilead. DA reports consultancy fees, speakers’ bureau fees and grant/research support from AbbVie, Eli Lilly, Galapagos, Gilead, Janssen, Merck, Novartis, Pfizer, Sandoz and Sanofi., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ on behalf of EULAR.)

Microbial volatile organic compounds (VOCs) emitted from fungi are known as their secondary metabolites from environmental sources. However, their physiological roles remain to be unclear. Even though the roles are still unknown, VOCs are deliberately released to convey information to both homologous and non-homologous organisms. We investigated the effects of single VOCs (hexanal, benzaldehyde, heptanal, 2-ethyl-1-hexanol, 3-octanone, 2-undecanone, 3-octanol, 2-Phenylethanol, 2-phenyl-2-propanol, phenylbenzaldehyde, 2-pentadecanone, β-trans-bergamotene, β-bisabolene, 2-methyl-5 -(1-methylethyl)pyrazine) on the fungal growth. In parallel, application of the co-culturing system in a growth chamber allowed free gas and VOCs exchange between emitter colonies of Fusarium solani and Aspergillus fumigatus, or between colonies of different growth stages of the same species. Distinct self-inhibition occurred by the emitters of fungal growing colonies against receiver ones on the stage of conidial germination or against the younger colonies at an earlier stage in both fungi. Similarly, the phenomenon of allelopathy appeared to work between growing colonies of F. solani and the germinating conidia or young colonies of A. fumigatus or vice versa. Solid phase microextraction-gas chromatography/mass spectrometry revealed VOCs compounds of each fungi. In F. solani, hexanal and benzaldehyde appeared to be significant inhibitors for colony growth. Benzaldehyde inhibited filamentous growth but not conidial germination. In A. fumigatus, heptanal seemed to be an equivalent effector. The inhibitory effect of benzaldehyde was more distinct on the A. fumigatus conidial germination than its filamentous growth., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Takeuchi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Aflatoxins are toxic metabolites produced by Aspergillus spp. Because aflatoxins are potent carcinogens in humans and animals, many countries have set regulatory limits for aflatoxins in foods to prevent dietary exposure. From a global food safety perspective, in 2023, the Codex Alimentarius Commission established the maximum level (ML) of total aflatoxins in certain cereals and cereal-based products, including polished rice. Therefore, validated analytical methods for aflatoxin detection are necessary., Objective: In this study, a high performance liquid chromatography (HPLC)-fluorescence method coupled with multifunctional column clean-up and trifluoroacetic acid derivatization was developed for the determination of aflatoxin levels in polished rice., Methods: Our method was validated in a single laboratory study using aflatoxin-spiked materials, followed by an inter-laboratory validation study. Twelve laboratories participated in the inter-laboratory validation study, and five polished rice test samples artificially contaminated with aflatoxins were analyzed., Results: In a single laboratory study, the ranges of mean recoveries of aflatoxin B1, B2, G1, G2, and total aflatoxins were 101%, 100-103%, 93-96%, 95-98%, and 97-99%, respectively. The relative standard deviations for within-day and between-day variations were all ≤ 4.4%. In the inter-laboratory validation study, the relative standard deviations for repeatability and reproducibility were from 0.7 to 2.7% and 3.3 to 8.9% for all analytes, respectively., Conclusion: In response to the Codex ML and method performance criteria for aflatoxins in polished rice, an analytical method based on HPLC-fluorescence detection was developed. All method performance parameters estimated from the testing results of the single-laboratory and inter-laboratory validation studies met the criteria required by the Codex., Highlights: Single- and inter-laboratory studies for the validation of an analytical method for aflatoxin level determination in polished rice were successfully performed. This analytical method will be suitable to determine aflatoxin levels around the Codex ML set for polished rice., (© The Author(s) 2024. Published by Oxford University Press on behalf of AOAC INTERNATIONAL. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: This study aimed to evaluate the long-term safety and efficacy profiles of ozoralizumab in patients with rheumatoid arthritis (RA) from the OHZORA, NATSUZORA and HOSHIZORA trials., Methods: This study conducted an integrated analysis of the three trials. Patients who completed the OHZORA trial with concomitant treatment of ozoralizumab and methotrexate (MTX) or the NATSUZORA trial without MTX were eligible to participate in the long-term extension HOSHIZORA trial. Safety assessment was performed in the safety analysis set, and the incidence rate per 100 person-year (PY) was calculated for a summary of adverse events (AEs) and AEs of special interests (AESIs). The efficacy was analysed in terms of disease activity index response rates and functional remission., Results: The OHZORA and NATSUZORA trials enrolled 521 patients, of whom 401 patients entered the HOSHIZORA trial and 279 completed the long-term extension treatment with a mean treatment duration of 200 weeks and total exposure of 1419.34 PY in all enrolled patients. Of the patients, 96.9% demonstrated ≥1 AEs, which is mostly mild to moderate. One death was observed, but no conspicuous AEs emerged and no specific concerns in AESIs were found through the long-term administration. The efficacy assessment revealed the maintained American College of Rheumatology response rates of 20%, 50%, and 70% during the trials., Conclusion: This integrated analysis revealed no new safety concerns, and the efficacy was maintained in patients with RA under long-term ozoralizumab administration., Trial Registration Number: jRCT2080223971, jRCT2080223973, NCT04077567., Competing Interests: Competing interests: YT has received speaking fees and/or honoraria from AbbVie, Eisai, Chugai, Eli Lilly, Boehringer Ingelheim, GlaxoSmithKline, Taisho, AstraZeneca, Daiichi Sankyo, Gilead, Pfizer, UCB, Asahi Kasei, Astellas, received research grants from Boehringer Ingelheim, Taisho, Chugai. TT has received speaking fees and/or honoraria from AstraZeneca, Astellas Pharma, AbbVie, Chugai Pharmaceutical, Eisai, Eli Lilly Japan, Gilead Sciences, Mitsubishi-Tanabe Pharma, Taisho Pharmaceutical Holding, Pfizer Japan, Janssen Pharmaceutical, received consulting fees from AbbVie, Gilead Sciences, Mitsubishi-Tanabe Pharma, Taisho Pharmaceutical Holding, Eli Lilly Japan. YM, MK and HY are employees of Taisho Pharmaceutical., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To investigate transcriptomic and immunophenotypic features of muscle specimens from patients with idiopathic inflammatory myopathy (IIM)., Methods: Bulk RNA-sequencing was performed on muscle biopsy samples from 16 patients with dermatomyositis (DM) and 9 patients with polymyositis (PM). Seven tested positive for anti-aminoacyl t-RNA synthetase antibodies in the DM patients (ARS-DM). We conducted weighted gene coexpression network analysis (WGCNA), differentially expressed gene (DEG) analysis, and gene set variation analysis (GSVA) to assess contributions of specific pathways. Cell proportions in muscle specimens were estimated using a deconvolution approach., Results: WGCNA revealed significant positive correlations between serum creatine kinase (CK) levels and gene modules involved in cellular respiration, phagocytosis, and oxidative phosphorylation (OXPHOS). Significant positive correlations were also observed between CK levels and proportions of CD16-positive and -negative monocytes and myeloid dendritic cells. Notably, DM patients demonstrated enrichment of complement and interferon-α and -γ pathway genes compared to those with PM. Furthermore, ARS-DM demonstrated a higher proportion of Th1 cells and DEGs related to OXPHOS. Additionally, serum Krebs von den Lungen-6 levels correlated with gene modules associated with extracellular matrix and transforming growth factor-β signaling pathway., Conclusion: Our study highlights a significant involvement of monocytes in muscle damage and delineates pathological differences among IIM subtypes. DM was characterized by complement, interferon-α and -γ signaling, whilst ARS-DM was associated with OXPHOS. Distinctive gene expression variations in muscle specimens suggest that different pathologic mechanisms underlie muscle damage in each IIM phenotype., (This article is protected by copyright. All rights reserved.)

Objectives: This post hoc analysis of the RAJ2 study assessed long-term safety and effectiveness of peficitinib 100 mg/day for treatment of rheumatoid arthritis., Methods: Eligible patients previously completed two Phase 3 (RAJ3 and RAJ4) studies of peficitinib in Asia. All patients received peficitinib 100 mg/day at RAJ2 Week (W)0; dose change to 50 mg/day or 150 mg/day was permitted. Safety endpoints included treatment-emergent adverse events and laboratory test results. Effectiveness endpoints included peficitinib exposure pattern, achievement of Clinical Disease Activity Index (CDAI) remission by peficitinib exposure pattern at W0 and W48, and association of demographics/characteristics with CDAI remission at W0 and W48., Results: Overall, no new safety findings were reported at W48, and renal function was unaffected. Of patients included in effectiveness analyses at W48, 70.9% (451/636) had maintained peficitinib 100 mg/day since W0. Of patients who achieved CDAI remission at W0 and maintained peficitinib 100 mg/day to W48, 50.3% (79/157) maintained CDAI remission to W48. Low disease activity and a lower number of prior disease-modifying antirheumatic drugs were significantly associated with CDAI remission at W48., Conclusions: Long-term peficitinib treatment at a dose of 100 mg/day was generally well tolerated and, following induction therapy, maintained effectiveness through to W48., (© Japan College of Rheumatology 2023. Published by Oxford University Press.)

Objectives: The current study assesses the utility of matrix metalloprotease-3 (MMP-3) as a biomarker for joint damage in patients with rheumatoid arthritis receiving peficitinib., Methods: Rheumatoid arthritis patients with inadequate response to methotrexate were randomised to peficitinib 100 mg, peficitinib 150 mg, or placebo, combined with methotrexate, for 52 weeks; patients receiving placebo switched to peficitinib 100/150 mg at Week (W)12/28. This post hoc analysis investigated association between MMP-3 above/below upper limit of normal (ULN) at W12/28 and radiographic progression [modified total Sharp score (mTSS), joint space narrowing score, or erosion score >0.5] at W52 or swollen joint count 66 at W28, stratified by baseline glucocorticoid use and renal function., Results: MMP-3 levels decreased in both peficitinib-treated groups but more slowly in patients with baseline glucocorticoids and those with radiographic progression at W52. There was no clear correlation between MMP-3 change from baseline (CFB) at W12, CFB in mTSS, joint space narrowing score, or erosion score at W52, or CFB in swollen joint count 66 at W28. More patients with MMP-3 ≤ULN versus >ULN at W12 had radiographic non-progression at W52. MMP-3 normalisation at W12 was significantly associated with mTSS non-progression at W52., Conclusions: Normalisation of MMP-3 at W12 may be a predictor for subsequent non-progression of joint damage at W52., (© Japan College of Rheumatology 2023. Published by Oxford University Press.)

There have been no prior reports of direct myocardial damage caused by Streptococcus suis (S. suis) , and understanding the clinical course of myocardial involvement is crucial for early diagnosis and initiation of treatment for this infection. A male pig farmer presented as an outpatient with a fever and sore throat, but within hours, his cardiac function declined, and his general condition deteriorated. Despite receiving comprehensive treatment, he succumbed to complications associated with toxic shock-like syndrome (TSLS). Blood cultures identified S. suis , and myocardial pathology revealed the presence of this bacterium in necrotic areas. This case marks the first reported instance of myocardial damage accompanied by TSLS due to S. suis , highlighting the significance of this infection., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Hayasaka et al.)

Galectins are β-galactoside-binding animal lectins involved in various biological functions, such as host defense. Galectin-2 and -3 are members of the galectin family that are expressed in the stomach, including the gastric mucosa and surface mucous cells. Galectin-3 exhibits aggregation and bactericidal activity against Helicobacter pylori in a β-galactoside-dependent manner. We previously reported that galectin-2 has the same activity under neutral pH conditions. In this study, the H. pylori aggregation activity of galectin-2 was examined under weakly acidic conditions, in which H. pylori survived. Galectin-2 agglutinated H. pylori even at pH 6.0, but not at pH 5.0, correlating with its structural stability, as determined using circular dichroism. Additionally, galectin-2 binding to the lipopolysaccharide (LPS) of H. pylori cultured under weakly acidic conditions was investigated using affinity chromatography and Western blotting. Galectin-2 could bind to H. pylori LPS containing H type I, a Lewis antigen, in a β-galactoside-dependent manner. In contrast, galectin-3 was structurally more stable than galectin-2 under acidic conditions and bound to H. pylori LPS containing H type I and Lewis X. In conclusion, galectin-2 and -3 might function cooperatively in the defense against H. pylori in the stomach under different pH conditions.

Objective: To assess safety of baricitinib in Japanese patients with rheumatoid arthritis in real-world clinical practice., Methods: This all-case post-marketing surveillance study included patients initiating baricitinib for rheumatoid arthritis from September 2017 to April 2019. Treatment duration was recorded. Safety data were collected for up to 3 years from baricitinib initiation (up to 4 weeks post discontinuation in discontinuing patients)., Results: Safety analyses included 4720 patients; 2580 (54.7%) were ≥65 years old. Baricitinib persistence rate was 45.4% (3 year Kaplan-Meier analysis); the most common discontinuation reason was insufficient effectiveness (n = 1005, 21.3%). Serious adverse events occurred in 600 patients (incidence rate 10.42/100 patient-years; 95% confidence interval, 9.76-11.09). There were 39 deaths (incidence rate 0.43 [0.30-0.57]/100 patient-years). Incidence rate per 100 patient-years for adverse events of special interest were herpes zoster 4.68 (4.22-5.14), serious infection 3.05 (2.68-3.41), malignancy 1.09 (0.87-1.30), major adverse cardiovascular events 0.35 (0.23-0.48) and venous thromboembolism 0.25 (0.15-0.36). Incidence rates did not increase with prolonged exposure., Conclusions: No new safety concerns were identified during this 3 year post-marketing surveillance study of baricitinib in Japanese patients with rheumatoid arthritis. Patients and clinicians should be cognizant of herpes zoster and other serious infection risks during baricitinib treatment, especially in the first 6 months., (© Japan College of Rheumatology 2024. Published by Oxford University Press.)

Background: Ultrasonography is not chosen as the common imaging modality to diagnose spinal cord diseases. The present report indicates good diagnostic efficacy of ultrasonography for identifying spinal cord compressed by subcutaneous mass when scanning through the defected vertebral laminae and spinous process., Case Description: A five-month-old female Holstein calf presented with progressive hindlimb paralysis following a surgical resection of a back mass conducted at 21 days of age. The mass was subsequently histopathologically diagnosed as a pulmonary choristoma. Alongside hindlimb paralysis, the calf developed a swollen back at the lumbar region where the mass was removed. This suggested regrowth of the resected mass, causing injury to the underlying spinal cord. Ultrasonography identified the subcutaneous involvement of the capsular mass, which had three anechoic cavities separated by the echogenic septal structures. The spinal cord could be ultrasonographically demonstrated as adjacent to the mass through the defected vertebral laminae and spinous process in the second and third lumbar vertebras. Ultrasound-guided centesis allowed the collection of purulent exudates in which Escherichia coli was isolated. Myelography and subsequent computed tomography (CT) revealed a partial blockage of the intradural flow of contrast media at the levels of the second and third lumbar vertebras, diagnosed as spina bifida on the CT images. When applying ultrasonography to the spinal cord within a saline pool soon after the subcutaneous abscess was successfully resected, the spinal cord was characterized by the interrupted and partly extended hyperechogenic line of the central canal within the echogenic parenchyma. The echotexture of the spinal cord showed damage due to compression from the subcutaneous abscess. The animal had a sub-optimal postoperative outcome, including limited improvement of the neurological signs., Conclusion: In the present case, combining ultrasonography, radiography (myelography), and CT was very effective for diagnosing spina bifida, with the subcutaneous abscess inducing spinal cord compression. Additionally, using intraoperative ultrasonographic scanning to evaluate the degree of spinal cord damage can contribute to predicting the postoperative outcome., Competing Interests: The authors declare that there is no conflict of interest.

Background: Validation of protective associations of the lupus low disease activity state (LLDAS) against flare, irreversible damage, health-related quality of life, and mortality has enabled the adoption of treat-to-target strategies in patients with systemic lupus erythematosus (SLE). Previous validation studies were of short duration, limiting the ability to detect longer term signals in flare rate and irreversible damage. In addition, previous studies have focused on percent time at target, rather than actual periods of time that are more useful in clinical practice and trials. We assessed long-term protective associations of LLDAS and remission, and specifically examined protective thresholds of sustained LLDAS and remission., Methods: Patients aged 18 years or older with SLE were followed up from May 1, 2013, to Dec 31, 2020 in a prospective, multinational, longitudinal cohort study. Patients were recruited from 25 centres in 12 countries. Multi-failure time-to-event analyses were used to assess the effect of sustained LLDAS on irreversible damage accrual (primary outcome; measured with the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index) and flare (key secondary outcome; measured with the SELENA Flare Index), with dose exposure and threshold effects studied. Sustained LLDAS or remission were defined as two or more consecutive visits over at least 3 months in the respective state. This study is registered with ClinicalTrials.gov, NCT03138941., Findings: 3449 patients were followed up for a median of 2·8 years (IQR 1·1-5·6), totalling 37 662 visits. 3180 (92·2%) patients were women, and 3031 (87·9%) were of Asian ethnicity. 2506 (72·7%) patients had sustained LLDAS at least once. Any duration of sustained LLDAS or remission longer than 3 months was associated with reduced damage accrual (LLDAS: hazard ratio 0·60 [95% CI 0·51-0·71], p<0·0001; remission: 0·66 [0·57-0·76], p<0·0001) and flare (LLDAS: 0·56 [0·51-0·63], p<0·0001; remission: 0·66 [0·60-0·73], p<0·0001), and increasing durations of sustained LLDAS corresponded to increased protective associations. Sustained DORIS remission or steroid-free remission were less attainable than LLDAS., Interpretation: We observed significant protective associations of LLDAS and remission against damage accrual and flare, establish a threshold of 3 months sustained LLDAS or remission as protective, and demonstrate deepening protection with longer durations of sustained LLDAS or remission., Funding: The Asia Pacific Lupus Collaboration receives project support grants from AstraZeneca, Bristol Myers Squibb, EMD Sereno, GSK, Janssen, Eli Lilly, and UCB., Competing Interests: Declaration of interests RK-R received grants from GSK and Novartis. SVN received consulting fees from Biogen, Boehringer Ingelheim, Astra Zeneca, Idorsia; payment for lectures from AstraZeneca, Boehringer Ingelheim, GSK, and Roche; participation in advisory board for Biogen; and leadership of societies, unpaid (CEO of Rheumatology Educational Trust Foundation, and Head of the SLE Special Interest Group at the Philippine Rheumatology Association). ZL received consulting fees from Pfizer, Roche, Janssen, Abbott, AbbVie, Bristol Myers Squibb, MSD, Celgene, Eli Lilly, GSK, Novartis, and UCB, and has royalties with Pfizer, Roche, Janssen, Abbott, AbbVie, Bristol Myers Squibb, MSD, Celgene, Eli Lilly, GSK, Novartis, and UCB. SS received consulting fees from Pfizer, AstraZeneca, and ZP Therapeutics. YK received payment or honoraria from GlaxoSmithKline, AstraZeneca, Sanofi, Pfizer Japan, Janssen Pharmaceutical, Chugai Pharmaceutical, Asahi Kasei Pharma, Astellas Pharma, and Mitsubishi Tanabe Pharma Corporation. MH received institutional research grants from GSK and Novartis; and honoraria for lectures from AstraZeneca and Astellas Pharma. ZZ received payment or honoraria from AbbVie, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, GSK, Novartis, Pfizer, Roche, Sanofi, Janssen, and UCB; and participation in advisory board for Beigene. JK received speaker fees from GSK and Asahi Kasei. TT received grants from Astellas, Asahi Kasei, Chugai, and Mitsubishi Tanabe, and consulting fees from Astellas and Chugai. FG is Director of the Board of the Australian Rheumatology Association. KN received Advisory Board participation fees from AbbVie. YT received research grants from Boehringer Ingelheim, Taisho, and Chugai; and speaker fees or honoraria from AbbVie, Eisai, Chugai, Eli Lilly, Boehringer Ingelheim, GSK, Taisho, AstraZeneca, Daiichi-Sankyo, Gilead, Pfizer, UCB, Asahi-kasei, and Astellas. AH received a research grant from AstraZeneca; consulting fees from EUSA Pharma (UK); and speaker fees or honoraria from Limbic, Novartis, Moose Republic, AbbVie, and Eli Lilly. MN received an Investigator Grant from the National Health and Medical Research Council of Australia (NHMRC GNT1176538); research grants from Janssen and Boehringer Ingelheim; consulting fees from AstraZeneca and GSK; honoraria for presentations from AstraZeneca, GSK, and Boehringer Ingelheim; and support for conference attendance from Boehringer Ingelheim. EFM received consulting fees from AstraZeneca, Biogen, Bristol Myers Squibb, Eli Lilly, Genetech, Janssen, Novartis, Servier, and EMD Serono. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Extracellular vesicles (EVs) serve as an intrinsic system for delivering functional molecules within our body, playing significant roles in diverse physiological phenomena and diseases. Both native and engineered EVs are currently the subject of extensive research as promising therapeutics and drug delivery systems, primarily due to their remarkable attributes, such as targeting capabilities, biocompatibility, and low immunogenicity and mutagenicity. Nevertheless, their clinical application is still a long way off owing to multiple limitations. In this context, the Science Board of the Pharmaceuticals and Medical Devices Agency (PMDA) of Japan has conducted a comprehensive assessment to identify the current issues related to the quality and safety of EV-based therapeutic products. Furthermore, we have presented several examples of the state-of-the-art methodologies employed in EV manufacturing, along with guidelines for critical processes, such as production, purification, characterization, quality evaluation and control, safety assessment, and clinical development and evaluation of EV-based therapeutics. These endeavors aim to facilitate the clinical application of EVs and pave the way for their transformative impact in healthcare., (© 2024. The Author(s).)

Importance: Delirium is common among older hospitalized adults. In addition to presenting immediate management issues, delirium can increase the long-term risk of dementia, institutionalization, and mortality. Delirium is associated with disrupted sleep, and prior studies suggest that some specific sleep-promoting agents may reduce delirium., Objective: To evaluate the orexin receptor antagonist suvorexant for reducing delirium in older adults at high risk for delirium after hospitalization., Design, Setting, and Participants: This double-blind, placebo-controlled, phase 3 randomized clinical trial was conducted at 50 hospitals in Japan between October 22, 2020, and December 23, 2022. The study population included Japanese adults aged 65 to 90 years who were at high risk for delirium (mild cognitive impairment or mild dementia, history of delirium at prior hospitalization, or both) and had been hospitalized for acute disease or elective surgery. Data analysis was performed between January 23 and March 13, 2023., Intervention: Participants were randomized 1:1 to suvorexant (15 mg) or placebo taken at bedtime for up to 7 days while in the hospital., Main Outcomes and Measures: Delirium, the primary end point, was diagnosed according to Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria while participants were hospitalized. The treatment difference in the proportion of participants with delirium was analyzed., Results: This study included 203 participants: 101 were treated with suvorexant (mean [SD] age, 81.5 [4.5]; years; 52 men [51.5%] and 49 women [48.5%]) and 102 received placebo (mean [SD] age, 82.0 [4.9] years; 45 men [44.1%] and 57 women [55.9%]). There were 17 participants with delirium (16.8%) in the suvorexant group compared with 27 (26.5%) in the placebo group (difference, -8.7% [95% CI, -20.1% to 2.6%]; P = .13). Adverse events were similar between the 2 groups., Conclusions and Relevance: In this randomized clinical trial of suvorexant in older adults at high risk for delirium after hospitalization, fewer participants taking suvorexant had delirium compared with placebo, but the difference was not statistically significant. Further studies are needed to determine whether suvorexant may be useful for reducing delirium, particularly delirium with a hyperactive component, in this population., Trial Registration: ClinicalTrials.gov Identifier: NCT04571944.

Objective: To assess whether Lupus Low Disease Activity State (LLDAS) attainment is associated with favorable outcomes in patients with recent onset systemic lupus erythematosus (SLE)., Methods: Data from a 13-country longitudinal SLE cohort were collected prospectively between 2013 and 2020. An inception cohort was defined based on disease duration < 1 year at enrollment. Patient characteristics between inception and noninception cohorts were compared. Survival analyses were performed to examine the association between LLDAS attainment and damage accrual and flare., Results: Of the total 4106 patients, 680 (16.6%) were recruited within 1 year of SLE diagnosis (inception cohort). Compared to the noninception cohort, inception cohort patients were significantly younger, had higher disease activity, and used more glucocorticoids, but had less organ damage at enrollment. Significantly fewer inception cohort patients were in LLDAS at enrollment than the noninception cohort (29.6% vs 52.3%, P < 0.001), but three-quarters of both groups achieved LLDAS at least once during follow-up. Limiting analysis only to patients not in LLDAS at enrollment, inception cohort patients were 60% more likely to attain LLDAS (hazard ratio 1.37, 95% CI 1.16-1.61, P < 0.001) than noninception cohort patients and attained LLDAS significantly faster. LLDAS attainment was significantly protective against flare in both the inception and noninception cohorts. A total of 88 (13.6%) inception cohort patients accrued organ damage during a median 2.2 years of follow-up., Conclusion: LLDAS attainment is protective from flare in recent onset SLE. Significant protection from damage accrual was not observed because of low rates of damage accrual in the first years after SLE diagnosis. (ClinicalTrials.gov: NCT03138941)., (Copyright © 2024 by the Journal of Rheumatology.)

Objectives: To investigate if disease activity among elderly RA patients >75 years of age has changed over time in the real-world clinical setting., Methods: Data from an observational multicentre registry of RA patients in Japan were analysed. The primary outcome was to evaluate the changes in the proportion of very elderly RA patients (>75 years) who achieved remission and low disease activity (LDA), from 2014 to 2021. The secondary outcome was to identify factors associated with remission and LDA by comparing demographic and clinical characteristics among the patients who had a study visit within the study period, using multivariate logistic regression., Results: A total of 32 161 patient visits were identified from 2014 to 2021. The proportion of patients >75 years of age increased from 16.5% to 26.9%, with biologics and targeted synthetic DMARDs (b/tsDMARDs) use increasing and glucocorticoids use decreasing, while conventional synthetic DMARDs use remained relatively stable. The proportion of RA patients >75 years of age achieving remission and LDA significantly increased from 62.2% to 78.2% (P for trend < 0.001). A negative factor associated with achieving remission and LDA was glucocorticoid use, seropositivity and a history of previous b/tsDMARDs use while MTX use was associated positively, independent of other predictors., Conclusions: In our cohort, disease activity among very elderly RA patients has improved over time. The study suggests the importance of using a treat-to-target approach in very elderly RA patients to improve clinical outcomes., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)