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Abstract Background Aerophagia is caused by the swallowing of excessive air and associated with various gastrointestinal symptoms. Aerophagia is diagnosed based on the observation of the occurrence of excessive air swallowing or ingestion; however, it tends to be difficult and often delayed. Early recognition and diagnosis of aerophagia are required to avoid unnecessary diagnostic investigations or serious clinical complications. Given that multichannel intraluminal impedance–pH measurement can discriminate gas, liquid, and mixed swallows, it can be useful for the diagnosis of aerophagia. Case presentation A 7-year-old girl presented to us with vomiting, and abdominal radiography showed dilatation of the stomach and intestine with no signs of mechanical obstruction. After successful conservative treatment, her symptoms recurred. Along with frequent visible and audible air swallowing, computed tomography (CT) revealed a severely dilated stomach with organoaxial volvulus. Multichannel intraluminal impedance–pH measurement was performed for further exploration. Patients showed numerous air swallows, particularly in the daytime during the 24-h recording period. She was diagnosed with aerophagia complicated by gastric volvulus. Given that she had a mental disorder and psychological counseling was difficult, laparoscopic anterior gastropexy and gastrostomy were performed to correct the gastric volvulus and decompression of gastric dilation by gastrostomy. Conclusions In addition to clinical symptoms, multichannel intraluminal impedance–pH measurement may help more accurately and objectively diagnose aerophagia. Further studies of air swallowing patterns may be useful for understanding the pathophysiological mechanism of aerophagia.

Abstract This study aims to identify factors influencing the alleviation of knee joint symptoms in patients with rheumatoid arthritis treated with biologic or target synthetic disease-modifying antirheumatic drugs (b/tsDMARDs). Among 2321 patients who started b/tsDMARDs between 2010 and 2023, we focused on 295 patients who had knee swelling or tenderness at the initiation of b/tsDMARDs and continued b/tsDMARDs at least 3 months, with recorded knee symptoms 6 months later. Symptom relief after 6 months was 78.2% for interleukin 6 (IL-6) inhibitors, 68.6% for Janus kinase (JAK) inhibitors, 65.8% for tumor necrosis factor (TNF) inhibitors, and 57.6% for cytotoxic T lymphocyte-associated antigen-4-Ig (CTLA4-Ig). The initial use of b/tsDMARDs and the use of IL-6 inhibitors in comparison to CTLA4-Ig emerged as a significant factor associated with the improvement of knee joint symptoms. Among 141 patients who underwent knee radiography at baseline and two years later, the deterioration in knee joint radiographs was 7.7% for IL-6 inhibitors, 6.3% for JAK inhibitors, 21.9% for TNF inhibitors, and 25.9% for CTLA4-Ig. The use of IL-6 inhibitors was a significant factor associated with the improvement of knee joint symptoms and the inhibition of joint destruction compared to CTLA4-Ig.

Abstract Background The biological mechanisms underlying the differential response to abatacept in patients with rheumatoid arthritis (RA) are unknown. Here, we aimed to identify cellular, transcriptomic, and proteomic features that predict resistance to abatacept in patients with RA. Methods Blood samples were collected from 22 RA patients treated with abatacept at baseline and after 3 months of treatment. Response to treatment was defined by the European League Against Rheumatism (EULAR) response criteria at 3 months, and seven patients were classified as responders and the others as non-responders. We quantified gene expression levels by RNA sequencing, 67 plasma protein levels, and the expression of surface molecules (CD3, 19, and 56) by flow cytometry. In addition, three gene expression data sets, comprising a total of 27 responders and 50 non-responders, were used to replicate the results. Results Among the clinical characteristics, the number of monocytes was significantly higher in the non-responders before treatment. Cell type enrichment analysis showed that differentially expressed genes (DEGs) between responders and non-responders were enriched in monocytes. Gene set enrichment analysis, together with single-cell analysis and deconvolution analysis, identified that Toll-like receptor 5 (TLR5) and interleukin-17 receptor A (IL17RA) pathway in monocytes was upregulated in non-responders. Hepatocyte growth factor (HGF) correlated with this signature showed higher concentrations in non-responders before treatment. The DEGs in the replication set were also enriched for the genes expressed in monocytes, not for the TLR5 and IL17RA pathway but for the oxidative phosphorylation (OXPHOS) pathway. Conclusions Monocyte-derived transcriptomic features before treatment underlie the differences in abatacept efficacy in patients with RA. The pathway activated in monocytes was the TLR5 and IL17RA-HGF signature in the current study, while it was the OXPHOS pathway in the replication set. Elevated levels of HGF before treatment may serve as a potential biomarker for predicting poor responses to abatacept. These findings provide insights into the biological mechanisms of abatacept resistance, contributing valuable evidence for stratifying patients with RA.

AbstractAbatacept (ABT) is a biological disease-modifying antirheumatic drug (bDMARDs) for rheumatoid arthritis (RA) when conventional synthetic DMARDs are ineffective. We aimed to evaluate the long-term effects of ABT on joint destruction in patients treated for over 2 years. Radiographic progression was evaluated using the van der Heijde-modified Total Sharp Score (mTSS) by two rheumatologists at ABT initiation and after 2 years. Multivariate logistic regression analysis was used to identify factors associated with structural remission, defined as the mean annual change in mTSS ≤0.5. Among the 111 patients included, 48 discontinued, and 63 continued ABT treatment until radiographic evaluation was performed. The rate of patients who achieved estimated TSS REM (yearly progression of van der Heijde modified total Sharp scores ≤0.5) was significantly lower in ABT-dropouts than in the ABT-continued group (69% vs. 48%, p = .0336 by Fisher’s exact test). Among the continued ABT cases, concomitant glucocorticoid treatment at ABT initiation was the strongest negative predictive factor of estimated TSS REM in univariate and multivariate logistic regression analyses. Radiographic progression after ABT administration should be evaluated separately for dropout and non-dropout cases. Glucocorticoids at the initiation of ABT may serve as a predictive factor for joint destruction in long-term ABT use.

Abstract Background Advances in rheumatoid arthritis (RA) treatment, highlighted by biological disease-modifying antirheumatic drugs (bDMARDs) and targeted synthetic DMARDs (tsDMARDs), have altered the paradigm of RA treatment in the last decade. Therefore, real-world clinical evidence is needed to understand how treatment strategies and outcomes have changed. Methods Using an observational cohort of RA from 2012 to 2021, we collected cross-sectional data of RA patients annually to analyze a trend in RA management. For patients who initiated b/tsDMRDs, we evaluated treatment outcomes between b/tsDMARDs. Mixed-effect models were applied to examine the statistical implications of changes over time in treatment outcomes with a background adjustment. Results We analyzed annual cross-sectional data from 5070 patients and longitudinal data from 1816 patients in whom b/tsDMARDs were initiated between 2012 and 2021. b/tsDMARD use increased, whereas glucocorticoid use decreased from 2012 to 2021. Disease activity and functional disability measures improved over time. The percentage of tsDMARD prescriptions considerably increased. All b/tsDMARDs showed clinical improvements in disease activity and functional disability. Statistically, TNFi showed better short-term improvements in b/tsDMARD-naïve patients, while IL6Ri demonstrated significant long-term benefits. IL6Ri had better retention rates in switched patients. After adjustment for patient characteristics, the annual change of RA disease activity and functional disability fared significantly better from 2012 to 2021. Conclusions With the development of new RA therapeutics, overall treatment outcomes advanced in the past decade.

Abstract Background Machine Learning has been increasingly used in the medical field, including managing patients undergoing hemodialysis. The random forest classifier is a Machine Learning method that can generate high accuracy and interpretability in the data analysis of various diseases. We attempted to apply Machine Learning to adjust dry weight, the appropriate volume status of patients undergoing hemodialysis, which requires a complex decision-making process considering multiple indicators and the patient’s physical conditions. Methods All medical data and 69,375 dialysis records of 314 Asian patients undergoing hemodialysis at a single dialysis center in Japan between July 2018 and April 2020 were collected from the electronic medical record system. Using the random forest classifier, we developed models to predict the probabilities of adjusting the dry weight at each dialysis session. Results The areas under the receiver-operating-characteristic curves of the models for adjusting the dry weight upward and downward were 0.70 and 0.74, respectively. The average probability of upward adjustment of the dry weight had sharp a peak around the actual change over time, while the average probability of downward adjustment of the dry weight formed a gradual peak. Feature importance analysis revealed that median blood pressure decline was a strong predictor for adjusting the dry weight upward. In contrast, elevated serum levels of C-reactive protein and hypoalbuminemia were important indicators for adjusting the dry weight downward. Conclusions The random forest classifier should provide a helpful guide to predict the optimal changes to the dry weight with relative accuracy and may be useful in clinical practice.

Rheumatoid arthritis causes joint inflammation due to immune abnormalities, resulting in joint pain and swelling. In recent years, there have been considerable advancements in the treatment of this disease. However, only approximately 60% of patients achieve remission. Patients with multifactorial diseases shift between states from day to day. Patients may remain in a good or poor state with few or no transitions, or they may switch between states frequently. The visualization of time-dependent state transitions, based on the evaluation axis of stable/unstable states, may provide useful information for achieving rheumatoid arthritis treatment goals. Energy landscape analysis can be used to quantitatively determine the stability/instability of each state in terms of energy. Time-series clustering is another method used to classify transitions into different groups to identify potential patterns within a time-series dataset. The objective of this study was to utilize energy landscape analysis and time-series clustering to evaluate multidimensional time-series data in terms of multistability. We profiled each patient's state transitions during treatment using energy landscape analysis and time-series clustering. Energy landscape analysis divided state transitions into two patterns: "good stability leading to remission" and "poor stability leading to treatment dead-end." The number of patients whose disease status improved increased markedly until approximately 6 months after treatment initiation and then plateaued after 1 year. Time-series clustering grouped patients into three clusters: "toward good stability," "toward poor stability," and "unstable." Patients in the "unstable" cluster are considered to have clinical courses that are difficult to predict; therefore, these patients should be treated with more care. Early disease detection and treatment initiation are important. The evaluation of state multistability enables us to understand a patient's current state in the context of overall state transitions related to rheumatoid arthritis drug treatment and to predict future state transitions.

Abstract Background Patients with rheumatoid arthritis (RA) are prone to muscle atrophy due to inflammatory cytokines and corticosteroid use and immobility due to joint pain and deformity. Although resistance training is effective and safe in reversing muscle atrophy in RA, some patients are unable to perform a conventional high-load exercise program due to disease-related limitations. This study aims to examine the efficacy of individualized exercise therapy on physical function in elderly patients with RA who are at a high risk for sarcopenia. Methods This study is a single-center, parallel-group, two-arm, healthcare provider- and outcome assessor-blinded, superiority randomized controlled trial with a 1:1 allocation ratio. A total of 160 participants with RA between 60 and 85 years of age with a positive screening test for sarcopenia will be included. The intervention group will receive nutritional guidance and a four-month individualized exercise program in addition to the usual treatment. The control group will receive nutritional guidance in addition to the usual care. The primary endpoint will be physical function assessed using the Short Physical Performance Battery (SPPB) at 4 months. The data on outcome measures will be collected at baseline and at the two- and four-month follow-ups. Linear mixed-effects models for repeated measures will be conducted using the modified intention-to-treat analysis population. Discussion This study will provide evidence on whether a personalized exercise program can improve physical function and quality of life in elderly patients with RA. Some limitations include limited generalizability due to the single-center study and lack of blinding of the patients to the intervention assignment because of the nature of the exercise. Physical therapists may use this knowledge in their daily practice to improve RA treatment. Tailored exercise may enhance the health outcomes of the RA population and contribute to a reduction in healthcare costs. Trial registration The study protocol was retrospectively registered at the University hospital Medical Information Network-Clinical Trial Repository (UMIN-CTR) (registration number: UMIN000044930, https://www.umin.ac.jp/ctr/index-j.htm ) on January 4, 2022.

AbstractThe short-term effect of tocilizumab (TCZ) on the radiographic progression of rheumatoid arthritis has been reported; however, reports on its long-term effects are scarce. In this study, we aimed to evaluate its long-term effects on joint destruction in patients who had been treated with TCZ for at least two years and for whom X-rays were available. Radiographic progression was evaluated with modified Total Sharp Score (mTSS), and structural remission was defined as the mean annual change in mTSS ≤0.5. Of the 59 patients included in this study (median age, 62 years; female, 81.4%), 34 patients (57.6%) achieved structural remission. Patients who achieved structural remission were relatively younger (59 years vs. 64 years, p = .06), had relatively higher proportion of anti-citrullinated protein antibody positivity (91.2% vs. 72.0%, p = .08), relatively lower C-reactive protein level (0.6 mg/dL vs. 2.2 mg/dL, p = .05), and significantly lower erythrocyte sedimentation rate (ESR) level (28.0 mm/h vs 65.5 mm/h, p = .003) than those who did not. Multivariate logistic regression analysis demonstrated that the baseline ESR level was significantly associated with structural remission (odds ratio, 0.98; 95% confidence interval: 0.96–0.99, p = .049). The baseline ESR level is a critical determinant of the long-term effect of TCZ on joint destruction.

Abstract Background Anti-citrullinated protein/peptide antibodies (ACPAs) are present in patients at onset and have important pathogenic roles during the course of rheumatoid arthritis (RA). The characteristics of several molecules recognized by ACPA have been studied in RA, but the positivity rate of autoantibodies against each antigen is not high, and the pathogenic mechanism of each antibody is not fully understood. We investigated the role of anti-citrullinated osteopontin (anti-cit-OPN) antibodies in RA pathogenesis. Methods Enzyme-linked immunosorbent assays on RA patients’ sera were used to detect autoantibodies against OPN. Fibroblast-like synoviocytes (FLS) isolated from RA patients were used to test the binding activity and inflammatory response of OPN mediated by anti-cit-OPN antibodies, and their effect was tested using an inflammatory arthritis mouse model immunized with cit-OPN. Anti-cit-OPN antibody positivity and clinical characteristics were investigated in the patients as well. Results Using sera from 224 RA patients, anti-cit-OPN antibodies were positive in approximately 44% of RA patients, while approximately 78% of patients were positive for the cyclic citrullinated peptide (CCP2) assay. IgG from patients with anti-cit-OPN antibody increased the binding activity of OPN to FLSs, which further increased matrix metalloproteinase and interleukin-6 production in TNF-stimulated FLSs. Mice immunized with cit-OPN antibodies experienced severe arthritis. Anti-cit-OPN antibodies in RA patients decreased the drug survival rate of tumor necrosis factor (TNF) inhibitors, while it did not decrease that of CTLA4-Ig. Conclusions Anti-cit-OPN antibodies were detected in patients with RA. IgG from patients with anti-cit-OPN antibodies aggravated RA, and anti-cit-OPN antibody was a marker of reduced the survival rate of TNF inhibitors in RA patients.

Objectives This multicentre retrospective study in Japan aimed to assess the retention of biological disease-modifying antirheumatic drugs and Janus kinase inhibitors (JAKi), and to clarify the factors affecting their retention in a real-world cohort of patients with rheumatoid arthritis.Methods The study included 6666 treatment courses (bDMARD-naïve or JAKi-naïve cases, 55.4%; tumour necrosis factor inhibitors (TNFi) = 3577; anti-interleukin-6 receptor antibodies (aIL-6R) = 1497; cytotoxic T lymphocyte-associated antigen-4-Ig (CTLA4-Ig) = 1139; JAKi=453 cases). The reasons for discontinuation were divided into four categories (ineffectiveness, toxic adverse events, non-toxic reasons and remission); multivariate Cox proportional hazards modelling by potential confounders was used to analyse the HRs of treatment discontinuation.Results TNFi (HR=1.93, 95% CI: 1.69 to 2.19), CTLA4-Ig (HR=1.42, 95% CI: 1.20 to 1.67) and JAKi (HR=1.29, 95% CI: 1.03 to 1.63) showed a higher discontinuation rate due to ineffectiveness than aIL-6R. TNFi (HR=1.28, 95% CI: 1.05 to 1.56) and aIL-6R (HR=1.27, 95% CI: 1.03 to 1.57) showed a higher discontinuation rate due to toxic adverse events than CTLA4-Ig. Concomitant use of oral glucocorticoids (GCs) at baseline was associated with higher discontinuation rate due to ineffectiveness in TNFi (HR=1.24, 95% CI: 1.09 to 1.41), as well as toxic adverse events in JAKi (HR=2.30, 95% CI: 1.23 to 4.28) and TNFi (HR=1.29, 95%CI: 1.07 to 1.55).Conclusions TNFi (HR=1.52, 95% CI: 1.37 to 1.68) and CTLA4-Ig (HR=1.14, 95% CI: 1.00 to 1.30) showed a higher overall drug discontinuation rate, excluding non-toxicity and remission, than aIL-6R.

Abstract Management of presenteeism in the context of chronic kidney disease (CKD) is essential for disease management, ensuring the workforce’s availability, and reducing health-related costs. The purpose of this case study was to investigate presenteeism, physical function, and exercise habits in three working patients with CKD and discuss their effects. Case 1 was a 71-year-old male security guard; Case 2 was a 72-year-old male agricultural worker; and Case 3 was an 83-year-old male civil engineering employee. Presenteeism was measured using the work functioning impairment scale (WFun), and physical function was measured using grip strength, skeletal muscle mass index, 10 m walk test, short physical performance battery, and exercise habits. The WFun assessment showed that only Case 3 had moderate presenteeism, and the barrier to employment was fatigue. Each value of physical function was higher than the reference value, but Case 3 had the lowest physical function values. All three patients had no exercise habits and were in the interest stage of behavior change. This case report indicates the existence of workers with CKD who need care for presenteeism, even if they have no problems with physical function or activities of daily living. To ensure work productivity in workers with CKD, clinicians may need to evaluate presenteeism, physical function, and exercise habits in addition to popular treatment and care.

BackgroundEstablished assessment tools for patients with rheumatoid arthritis (RA), including disease activity scores (DASs), disease activity indexes (DAIs), visual analog scales (VASs), and health assessment questionnaires (HAQs), are widely used. However, comparative associations between joint involvement and disease status assessment tools have rarely been investigated.MethodsWe included a dataset of 4016 patients from a large RA cohort from 2012 to 2019. The tenderness and swelling of each joint were counted as a symptom, with 70 and 68 affected joints throughout the body, respectively. The relative contribution of various joints to the disease status assessment tools, VAS scores, and functional disability indexes was analyzed using multiple regression analysis.ResultsThe wrist showed the most significant contribution overall, especially in DASs and VASs, while the metacarpophalangeal and proximal interphalangeal joints made significant contributions to DASs and DAIs, but not to VASs and HAQs. The shoulder and the elbow significantly contributed to HAQs, but only the shoulder did to the VASs. The knee universally contributed to all of the tools, but the ankle played a minor but important role in most assessment tools, especially in HAQs. Similar but different contribution ratios were found between the sets of DASs, DAIs, VASs, or HAQs.ConclusionsEach joint makes a unique contribution to these assessment tools. The improvement or aggravation of symptoms in each joint affects the assessment tools in different manners.

Abstract Background The safety and feasibility of stapled intestinal anastomosis have been widely reported in adults. However, the efficacy of stapled anastomosis (SA) in children is unclear. The aim of this study was to perform a systematic review and meta-analysis to evaluate the safety and effectiveness of SA compared with hand-sewn anastomosis (HA) in pediatric patients. Methods A systematic literature search was performed using PubMed, the Cochrane Library, and Scopus databases. Studies comparing outcomes of children aged

Abstract Background This article is a duplicated publication from the Japanese version of “2019 JSDT Guidelines for Peritoneal Dialysis” with permission from the Japanese Society for Dialysis Therapy (JSDT). This clinical practice guideline (CPG) was developed primarily by the Working Group on Revision of Peritoneal Dialysis (PD) Guidelines of the Japanese Society for Dialysis Therapy. Recently, the definition and creation process for CPGs have become far more rigorous; traditional methods and formats no longer adhere to current standards. To improve the reliability of international transmission of our findings, CPGs are created in compliance with the methodologies developed by the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) working group. Part 2 of this PD guideline is the first CPG developed by our society that conforms to the GRADE approach. Methods Detailed processes were created in accordance with the Cochrane handbook and the GRADE approach developed by the GRADE working group. Results Clinical question (CQ)1: Is the use of renin-angiotensin system inhibitors (RAS inhibitors), such as angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB), effective in PD patients? Recommendation: We suggest the usage of RAS inhibitors (ACEI and ARB) in PD patients (GRADE 2C). CQ2: Icodextrin or glucose solution: which is more useful as a dialysate among patients with PD? Recommendation: We suggest using icodextrin when managing body fluids in PD patients (GRADE 2C). CQ3: Is it better to apply or not apply mupirocin/gentamicin ointment to the exit site? Recommendation: We suggest not applying mupirocin/gentamicin ointment to the exit sites of PD patients (GRADE 2C). CQ4: Which surgical approach is more desirable when a PD catheter is placed, open surgery or laparoscopic surgery? No recommendation. CQ5: Which administration route of antibiotics is better in PD patients with peritonitis, intravenous or intraperitoneal? Recommendation: We suggest intraperitoneal administration of antibiotics in PD patients with peritonitis (GRADE 2C). Note: The National Insurance does not currently cover intraperitoneal administration. CQ6: Is peritoneal dialysis or hemodialysis better as the first renal replacement therapy in diabetic patients? No recommendation. Conclusions In the future, we suggest that society members construct their own evidence to answer CQs not brought up in this guideline, and thereby show the achievements of Japan worldwide.

ABSTRACT Macrophages are important for repair of injured tissues, but their role in healing after surgical repair of musculoskeletal tissues is not well understood. We used single‐cell RNA sequencing (RNA‐seq), flow cytometry, and transcriptomics to characterize functional phenotypes of macrophages in a mouse anterior cruciate ligament reconstruction (ACLR) model that involves bone injury followed by a healing phase of bone and fibrovascular interface tissue formation that results in bone‐to‐tendon attachment. We identified a novel “surgery‐induced” highly inflammatory CD9+ IL1+ macrophage population that expresses neutrophil‐related genes, peaks 1 day after surgery, and slowly resolves while transitioning to a more homeostatic phenotype. In contrast, CX3CR1+ CCR2+ macrophages accumulated more slowly and unexpectedly expressed an interferon signature, which can suppress bone formation. Deletion of Ccr2 resulted in an increased amount of bone in the surgical bone tunnel at the tendon interface, suggestive of improved healing. The “surgery‐induced macrophages” identify a new cell type in the early phase of inflammation related to bone injury, which in other tissues is dominated by blood‐derived neutrophils. The complex patterns of macrophage and inflammatory pathway activation after ACLR set the stage for developing therapeutic strategies to target specific cell populations and inflammatory pathways to improve surgical outcomes. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

The factors influencing long-term responses to a tumor necrosis factor inhibitor (TNFi) in rheumatoid arthritis (RA) patients currently remain unknown. Therefore, we herein conducted a multi-omics analysis of TNFi responses in a Japanese RA cohort. Blood samples were collected from 27 biological disease-modifying antirheumatic drug (DMARD)-naive RA patients at the initiation of and after three months of treatment with TNFi. Treatment responses were evaluated at one year. Differences in gene expression levels in peripheral blood mononuclear cells (PBMCs), plasma protein levels, drug concentrations, and the presence/absence of anti-drug antibodies were investigated, and a cell phenotypic analysis of PBMCs was performed using flow cytometry. After one year of treatment, thirteen patients achieved clinical remission (responders), while the others did not or switched to other biologics (non-responders). Differentially expressed genes related to treatment responses were enriched for the interferon (IFN) pathway. The expression of type I IFN signaling-related genes was higher in non-responders than in responders before and after treatment (P = 0.03, 0.005, respectively). The expression of type II IFN signaling-related genes did not significantly differ before treatment; however, it increased in non-responders and decreased in responders, with a significant difference being observed after three months of treatment (P = 1.2×10-3). The total number of lymphocytes and C-X-C Motif Chemokine Ligand 10 (CXCL10) protein levels were associated with the type I IFN signature (P = 6.7×10-7, 6.4×10-3, respectively). Hepatocyte growth factor (HGF) protein levels before treatment predicted fold increases in type II IFN (P = 0.03). These IFN signature-related indices (the number of lymphocytes, CXCL10, and HGF) significantly differed between responders and non-responders (P = 0.01, 0.01, and 0.04, respectively). A single-cell analysis revealed that the type I IFN signature was more highly enriched in monocytes than in other cell types. A deconvolution analysis of bulk-RNA sequence data identified CD4+ and CD8+ T cells as the main sources of the type II IFN signature in non-responders. Collectively, the present results demonstrated that the dynamics of the type I and II IFN pathways affected long-term responses to TNFi, providing information on its biological background and potential for clinical applications.

Abstract Osteoporosis is a metabolic bone disease with dysregulated coupling between bone resorption and bone formation, which results in decreased bone mineral density. The MEF2C locus, which encodes the transcription factor MADS box transcription enhancer factor 2, polypeptide C (MEF2C), is strongly associated with adult osteoporosis and osteoporotic fractures. Although the role of MEF2C in bone and cartilage formation by osteoblasts, osteocytes, and chondrocytes has been studied, the role of MEF2C in osteoclasts, which mediate bone resorption, remains unclear. In this study, we identified MEF2C as a positive regulator of human and mouse osteoclast differentiation. While decreased MEF2C expression resulted in diminished osteoclastogenesis, ectopic expression of MEF2C enhanced osteoclast generation. Using transcriptomic and bioinformatic approaches, we found that MEF2C promotes the RANKL-mediated induction of the transcription factors c-FOS and NFATc1, which play a key role in osteoclastogenesis. Mechanistically, MEF2C binds to FOS regulatory regions to induce c-FOS expression, leading to the activation of NFATC1 and downstream osteoclastogenesis. Inducible deletion of Mef2c in mice resulted in increased bone mass under physiological conditions and protected mice from bone erosion by diminishing osteoclast formation in K/BxN serum induced arthritis, a murine model of inflammatory arthritis. Our findings reveal direct regulation of osteoclasts by MEF2C, thus adding osteoclasts as a cell type in which altered MEF2C expression or function can contribute to pathological bone remodeling.

Abstract Background Icodextrin enhances peritoneal filtration for patients on peritoneal dialysis (PD). However, clinically important outcomes have not yet been analyzed using authentic, objective statistical methods. The present systematic review aimed to determine the risks and benefits of icodextrin compared with a glucose-based solution with respect to clinically important and patient-centered outcomes. Methods We systematically investigated only randomized controlled trials (RCTs) by adopting the Cochrane Database of Systematic Review (2014) and searched the CENTRAL, MEDLINE, and EMBASE databases for eligible studies reported in the literature. The quality of the evidence was assessed using the GRADE approach. Results We finally evaluated important outcomes in 13 RCTs. Icodextrin significantly decreased the number of reported episodes of uncontrolled fluid overload in four RCTs that involved 236 patients (relative risk [RR], 0.31; 95% confidence interval [CI], 0.12 to 0.82; moderate certainty evidence). However, the inclusion of icodextrin for peritoneal ultrafiltration did not significantly differ in six RCTs involving 252 patients (mean difference [MD], 186.76 mL; 95% CI, − 47.08 to 420.59; low certainty evidence). Regarding other clinically important outcomes, all-cause mortality in 10 RCTs involving 1106 patients (RR, 0.75; 95% CI, 0.33 to 1.71; low certainty evidence) and technical survival in five RCTs involving 470 patients (RR, 0.57; 95%CI, 0.29 to 1.12; low certainty evidence) were not significant. Urine volume in four RCTs involving 136 patients, residual renal function in five RCTs involving 181 patients and peritoneal function measured as the ratio of solute concentration in dialysate and plasma (D/P ratio) in two RCTs involving 105 patients were not specifically affected by icodextrin, and the results for adverse events were similar between icodextrin and glucose PD solutions. Conclusion Icodextrin could relieve uncontrolled fluid overload without adding risk. However, a significant effect on clinically relevant outcomes such as technical survival and overall patient survival was not suggested. More trials are required to increase the statistical power and to verify the value of icodextrin in clinical practice. Trial registration PROSPERO, CRD42018104360

Participation in exercise during early life (i.e., childhood through adolescence) enhances response inhibition; however, it is unclear whether participation in exercise during early life positively predicts response inhibition in later life. This historical cohort study was designed to clarify whether participation in exercise (e.g., structured sports participation) during early life predicts response inhibition in adulthood and if so, to reveal the brain connectivity and cortical structures contributing to this association. We analyzed data derived from 214 participants (women = 104, men = 110; age: 26‒69 years). Results indicated that participation in exercise during childhood (before entering junior high school; ≤ 12 years old) significantly predicted better response inhibition. No such association was found if exercise participation took place in early adolescence or later (junior high school or high school; ≥ 12 years old). The positive association of exercise participation during childhood with response inhibition was moderated by decreased structural and functional connectivity in the frontoparietal (FPN), cingulo-opercular (CON), and default mode networks (DMN), and increased inter-hemispheric structural networks. Greater cortical thickness and lower levels of dendritic arborization and density in the FPN, CON, and DMN also moderated this positive association. Our results suggest that participation in exercise during childhood positively predicts response inhibition later in life and that this association can be moderated by changes in neuronal circuitry, such as increased cortical thickness and efficiency, and strengthened inter-hemispheric connectivity.

Multiple sclerosis (MS), the most prevalent inflammatory disease of the central nervous system (CNS), is characterized by damaged to myelin sheaths and oligodendrocytes. Because MS patients have variable clinical courses and disease severities, it is important to identify biomarkers that predict disease activity and severity. In this study, we assessed the frequencies of serum autoantibodies against mature oligodendrocytes in MS patients using a tissue-based immunofluorescence assay (IFA) to determine whether anti-oligodendrocyte antibodies are associated with the clinical features of MS patients and whether they might be a biomarker to assess CNS tissue damage in MS patients. We assessed the binding of serum autoantibodies to mouse oligodendrocytes expressing Nogo-A, a reliable mature oligodendrocyte marker, by IFA with mouse brain and sera from 147 MS patients, comprising 103 relapsing–remitting MS (RRMS), 22 secondary progressive MS (SPMS), and 22 primary progressive MS (PPMS) patients, 38 neuromyelitis optica spectrum disorder (NMOSD) patients, 23 other inflammatory neurological disorder (OIND) patients, and 39 healthy controls (HCs). Western blotting (WB) was performed using extracted mouse cerebellum proteins and IgG from anti-oligodendrocyte antibody-positive MS patients. Tissue-based IFA showed that anti-oligodendrocyte antibodies were positive in 3/22 (13.6%) PPMS and 1/22 (4.5%) SPMS patients but not in RRMS, NMOSD, and OIND patients or HCs. WB demonstrated the target CNS proteins recognized by serum anti-oligodendrocyte antibodies were approximately 110 kDa and/or 150 kDa. Compared with anti-oligodendrocyte antibody-negative MS patients, MS patients with anti-oligodendrocyte antibodies were significantly older at the time of serum sampling, scored significantly higher on the Expanded Disability Status Scale and the Multiple Sclerosis Severity Score, and had a higher frequency of mental disturbance. Although the clinical significance of anti-oligodendrocyte antibodies is still unclear because of their low frequency, anti-oligodendrocyte autoantibodies are potential biomarkers for monitoring the disease pathology and progression in MS.

Summary: MYC activates different metabolic programs in a cell-type- and cell-status-dependent manner. However, the role of MYC in inflammatory macrophages has not yet been determined. Metabolic and molecular analyses reveal that MYC, but not hypoxia inducible factor 1 (HIF1), is involved in enhancing early glycolytic flux during inflammatory macrophage polarization. Ablation of MYC decreases lactate production by regulating lactate dehydrogenase (LDH) activity and causes increased inflammatory cytokines by regulating interferon regulatory factor 4 (IRF4) in response to lipopolysaccharide. Moreover, myeloid-specific deletion of MYC and pharmacological inhibition of the MYC/LDH axis enhance inflammation and the bacterial clearance in vivo. These results elucidate the potential role of the MYC/LDH/IRF4 axis in inflammatory macrophages by connecting early glycolysis with inflammatory responses and suggest that modulating early glycolytic flux mediated by the MYC/LDH axis can be used to open avenues for the therapeutic modulation of macrophage polarization to fight against bacterial infection.

Abstract Objective To characterize the CSF cytokine profile in chronic inflammatory demyelinating polyneuropathy (CIDP) patients with IgG4 anti‐neurofascin 155 (NF155) antibodies (NF155+ CIDP) or those lacking anti‐NF155 antibodies (NF155− CIDP). Methods Twenty‐eight CSF cytokines/chemokines/growth factors were measured by multiplexed fluorescent immunoassay in 35 patients with NF155+ CIDP, 36 with NF155− CIDP, and 28 with non‐inflammatory neurological disease (NIND). Results CSF CXCL8/IL‐8, IL‐13, TNF‐α, CCL11/eotaxin, CCL2/MCP‐1, and IFN‐γ were significantly higher, while IL‐1β, IL‐1ra, and G‐CSF were lower, in NF155+ CIDP than in NIND. Compared with NF155− CIDP, CXCL8/IL‐8 and IL‐13 were significantly higher, and IL‐1β, IL‐1ra, and IL‐6 were lower, in NF155+ CIDP. CXCL8/IL‐8, IL‐13, CCL11/eotaxin, CXCL10/IP‐10, CCL3/MIP‐1α, CCL4/MIP‐1β, and TNF‐α levels were positively correlated with markedly elevated CSF protein, while IL‐13, CCL11/eotaxin, and IL‐17 levels were positively correlated with increased CSF cell counts. IL‐13, CXCL8/IL‐8, CCL4/MIP‐1β, CCL3/MIP‐1α, and CCL5/RANTES were decreased by combined immunotherapies in nine NF155+ CIDP patients examined longitudinally. By contrast, NF155− CIDP had significantly increased IFN‐γ compared with NIND, and exhibited positive correlations of IFN‐γ, CXCL10/IP‐10, and CXCL8/IL‐8 with CSF protein. Canonical discriminant analysis of cytokines/chemokines revealed that NF155+ and NF155− CIDP were separable, and that IL‐4, IL‐10, and IL‐13 were the three most significant discriminators. Interpretation Intrathecal upregulation of type 2 helper T (Th2) cell cytokines is characteristic of IgG4 NF155+ CIDP, while type 1 helper T cell cytokines are increased in CIDP regardless of the presence or absence of anti‐NF155 antibodies, suggesting that overproduction of Th2 cell cytokines is unique to NF155+ CIDP.

Abstract Background Corticosteroids are widely used to reduce the urine protein levels of patients with immunoglobulin A nephropathy (IgAN). However, their potential preventive effects on end-stage kidney disease (ESKD) are unclear. Methods We previously performed a large-scale, long-term multicenter cohort study of patients with biopsy-proven IgAN treated between 1981 and 2013 (n = 1923). Based on the results, we reported that corticosteroids pulse therapy was potentially effective for the treatment of patients with an eGFR ≥30 ml/min/1.73m2 and a urine protein amount of ≥1 g/gCr. In the present study, we extracted 766 patients with chronic kidney disease (CKD), stage G3–G4 (15 ≤ estimated glomerular filtration rate [eGFR]

Allergic diseases are associated with central and peripheral nervous system diseases such as autism spectrum disorders and eosinophilic granulomatosis with polyangiitis, which frequently causes mononeuritis multiplex. Thus, it is possible that patients with an atopic constitution might develop multifocal inflammation in central and peripheral nervous system tissues. In a previous study in Japan, we reported a rare form of myelitis with persistent neuropathic pain (NeP) in patients with allergic disorders. However, the underlying mechanism of allergic inflammation-related NeP remains to be elucidated. First, we analyzed the effect of allergic inflammation on the nociceptive system in the spinal cord. Mice with atopy showed microglial and astroglial activation in the spinal cord and tactile allodynia. In a microarray analysis of isolated microglia from the spinal cord, endothelin receptor type B (EDNRB) was the most upregulated cell surface receptor in mice with atopy. Immunohistochemical analysis demonstrated EDNRB expression was upregulated in microglia and astroglia. The EDNRB antagonist BQ788 abolished glial activation and allodynia. These findings indicated that allergic inflammation induced widespread glial activation through the EDNRB pathway and NeP. Second, we investigated whether autoantibody-mediated pathogenesis underlies allergic inflammation-related NeP. We detected specific autoantibodies to small dorsal root ganglion (DRG) neurons and their nerve terminals in the dorsal horns of NeP patients with allergic disorders. An analysis of IgG subclasses revealed a predominance of IgG2. These autoantibodies were mostly colocalized with isolectin B4- and P2X3-positive unmyelinated C-fiber type small DRG neurons. By contrast, immunostaining for S100β, a myelinated DRG neuron marker, showed no colocalization with patient IgG. Immunoprecipitation and liquid chromatography-tandem mass spectrometry identified plexin D1 as a target autoantigen. Patients with anti-plexin D1 antibodies often present with burning pain and thermal hyperalgesia. Immunotherapies, including plasma exchange, are effective for NeP management. Therefore, anti-plexin D1 antibodies may be pathogenic for immune-mediated NeP, especially under allergic inflammation conditions. Thus, allergic inflammation may induce NeP through glial inflammation in the spinal cord and the anti-plexin D1 antibody-mediated impairment of small DRG neurons.

Abstract Background The pathology of multiple system atrophy cerebellar-type (MSA-C) includes glial inflammation; however, cerebrospinal fluid (CSF) inflammatory cytokine profiles have not been investigated. In this study, we determined CSF cytokine/chemokine/growth factor profiles in MSA-C and compared them with those in hereditary spinocerebellar ataxia (SCA). Methods We collected clinical data and CSF from 20 MSA-C patients, 12 hereditary SCA patients, and 15 patients with other non-inflammatory neurological diseases (OND), and measured 27 cytokines/chemokines/growth factors using a multiplexed fluorescent bead-based immunoassay. The size of each part of the hindbrain and hot cross bun sign (HCBS) in the pons was studied by magnetic resonance imaging. Results Granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-6, IL-7, IL-12, and IL-13 levels were significantly higher in MSA-C and SCA compared with OND. In MSA-C, IL-5, IL-6, IL-9, IL-12, IL-13, platelet-derived growth factor-bb, macrophage inflammatory protein (MIP)-1α, and GM-CSF levels positively correlated with anteroposterior diameters of the pontine base, vermis, or medulla oblongata. By contrast, in SCA patients, IL-12 and MIP-1α showed significant negative correlations with anteroposterior diameters of the pontine base, and unlike MSA-C, there was no cytokine with a positive correlation in SCA. IL-6 was significantly higher in MSA-C patients with the lowest grade of HCBS compared with those with the highest grade. Macrophage chemoattractant protein-1 (MCP-1) had a significant negative correlation with disease duration only in MSA-C patients. Tumor necrosis factor-alpha, IL-2, IL-15, IL-4, IL-5, IL-10, and IL-8 were all significantly lower in MSA-C and SCA compared with OND, while IL-1ra, an anti-inflammatory cytokine, was elevated only in MSA-C. IL-1β and IL-8 had positive correlations with Unified Multiple System Atrophy Rating Scale part 1 and 2, respectively, in MSA-C. Conclusions Although CSF cytokine/chemokine/growth factor profiles were similar between MSA-C and SCA, pro-inflammatory cytokines, such as IL-6, GM-CSF, and MCP-1, correlated with the disease stage in a way higher at the beginning only in MSA-C, reflecting early stronger intrathecal inflammation.

Generalized lymphatic anomaly (GLA) is characterized by diffuse or multicentric proliferation of dilated lymphatic vessels resembling common lymphatic malformation, and thoracic lesions can be related to a poor prognosis. Sirolimus, an inhibitor of the mammalian target of rapamycin, is effective against vascular anomalies with few severe adverse drug reactions. Here, we report the case of a patient with intractable hemothorax pleural effusion due to GLA who was treated with sirolimus and experienced disseminated intravascular coagulation. Although a standard treatment for GLA has not been established, pleural fluid might be reduced using the Kampo medicine Eppikajyutsuto.

Objectives: We aimed to determine the clinical impact of plasma homocysteine levels on disease activity and clinical remission in patients with rheumatoid arthritis (RA). Methods: A cross-sectional study was conducted using KURAMA (Kyoto University Rheumatoid Arthritis Management Alliance) database. We enrolled 291 female patients, who were treated in a treat-to-target manner. We measured plasma total homocysteine using a liquid chromatography-tandem mass spectrometry system and collected clinical data including a 28-joint RA disease activity score-erythrocyte sedimentation rate (DAS28-ESR). Clinical remission of disease activity was defined as a DAS28-ESR < 2.6. Results: In a univariable analysis, the plasma homocysteine concentration was significantly and positively associated with DAS-28-ESR and was higher in the non-remission group than in the remission group. The cutoff value of the plasma homocysteine level was calculated to be 7.9 nmol/mL by the test of the receiver operating characteristic curve analysis. In a multivariable analysis, after adjusting for clinically relevant variables, the high homocysteine level remained a significant positive association for DAS28-ESR (estimate 0.27, P =.0019) and a positive factor for the presence of RA non-remission (odds ratio 2.39, P =.0071). Conclusions: Increased plasma homocysteine levels showed a significant positive association with current disease activity and the nonremission state in female patients with RA under treat-to-target treatment. The findings suggest the potential utility of plasma homocysteine as a disease state marker reflecting conditions that are treatment failure and difficult to remission and may provide clinical evidence on the interplay between homocysteine and inflammatory activation in RA. [ABSTRACT FROM AUTHOR]