Publications by authors named "Yuichi Maeda"

47 Publications

DOCK2 is involved in the host genetics and biology of severe COVID-19.

Nature 2022 Aug 8. Epub 2022 Aug 8.

Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Suita, Japan.

Identifying the factors underlying severe COVID-19 in the host genetics is an emerging issue. We conducted a genome-wide association study (GWAS) involving 2,393 Japanese COVID-19 cases collected in initial pandemic waves with 3,289 controls, which identified a variant on 5q35 (rs60200309-A) near DOCK2 associated with severe COVID-19 in younger (<65 ages) patients (n=440, odds ratio=2.01, P=1.2×10). This risk allele was prevalent in East Asians but rare in Europeans, showing a value of non-European GWAS. RNA-seq of 473 bulk peripheral blood identified decreasing effect of the risk allele on DOCK2 expression in younger patients. DOCK2 expression was suppressed in severe forms of COVID-19. Single cell RNA-seq analysis (n=61) identified cell type-specific downregulation of DOCK2 and COVID-19-specific decreasing effects of the risk allele on DOCK2 in non-classical monocytes. Immunohistochemistry of lung specimens from severe COVID-19 pneumonia showed suppressed DOCK2. Moreover, inhibition of DOCK2 function using CPYPP induced much more severe pneumonia in a Syrian hamster model of SARS-CoV-2 infection characterized as weight loss, lung edema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 plays an important role in the host immune response to SARS-CoV-2 infection and development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target.
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http://dx.doi.org/10.1038/s41586-022-05163-5DOI Listing
August 2022

Multi-trait and cross-population genome-wide association studies across autoimmune and allergic diseases identify shared and distinct genetic component.

Ann Rheum Dis 2022 Jun 26. Epub 2022 Jun 26.

Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan

Objectives: Autoimmune and allergic diseases are outcomes of the dysregulation of the immune system. Our study aimed to elucidate differences or shared components in genetic backgrounds between autoimmune and allergic diseases.

Methods: We estimated genetic correlation and performed multi-trait and cross-population genome-wide association study (GWAS) meta-analysis of six immune-related diseases: rheumatoid arthritis, Graves' disease, type 1 diabetes for autoimmune diseases and asthma, atopic dermatitis and pollinosis for allergic diseases. By integrating large-scale biobank resources (Biobank Japan and UK biobank), our study included 105 721 cases and 433 663 controls. Newly identified variants were evaluated in 21 778 cases and 712 767 controls for two additional autoimmune diseases: psoriasis and systemic lupus erythematosus. We performed enrichment analyses of cell types and biological pathways to highlight shared and distinct perspectives.

Results: Autoimmune and allergic diseases were not only mutually classified based on genetic backgrounds but also they had multiple positive genetic correlations beyond the classifications. Multi-trait GWAS meta-analysis newly identified six allergic disease-associated loci. We identified four loci shared between the six autoimmune and allergic diseases (rs10803431 at , OR=1.07, p=2.3×10, rs2053062 at , OR=0.90, p=2.9×10, rs2210366 at , OR=1.07, p=2.5×10 in Japanese and rs4529910 at , OR=0.96, p=1.9×10 across ancestries). Associations of rs10803431 and rs4529910 were confirmed at the two additional autoimmune diseases. Enrichment analysis demonstrated link to T cells, natural killer cells and various cytokine signals, including innate immune pathways.

Conclusion: Our multi-trait and cross-population study should elucidate complex pathogenesis shared components across autoimmune and allergic diseases.
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http://dx.doi.org/10.1136/annrheumdis-2022-222460DOI Listing
June 2022

Longitudinal alterations of the gut mycobiota and microbiota on COVID-19 severity.

BMC Infect Dis 2022 Jun 24;22(1):572. Epub 2022 Jun 24.

Laboratory of Immune Regulation, Department of Microbiology and Immunology, Graduate School of Medicine, Osaka University, Suita, Japan.

Background: The impact of SARS-CoV-2 infection on the gut fungal (mycobiota) and bacterial (microbiota) communities has been elucidated individually. This study analyzed both gut mycobiota and microbiota and their correlation in the COVID-19 patients with severe and mild conditions and follow-up to monitor their alterations after recovery.

Methods: We analyzed the gut mycobiota and microbiota by bacterial 16S and fungal ITS1 metagenomic sequencing of 40 severe patients, 38 mild patients, and 30 healthy individuals and reanalyzed those of 10 patients with severe COVID-19 approximately 6 months after discharge.

Results: The mycobiota of the severe and mild groups showed lower diversity than the healthy group, and in some, characteristic patterns dominated by a single fungal species, Candida albicans, were detected. Lower microbial diversity in the severe group was observed, but no differences in its diversity or community structure were detected between the mild and healthy groups. The microbiota of the severe group was characterized by an increase in Enterococcus and Lactobacillus, and a decrease in Faecalibacterium and Bacteroides. The abundance of Candida was positively correlated with that of Enterococcus in patients with COVID-19. After the recovery of severe patients, alteration of the microbiota remained, but the mycobiota recovered its diversity comparable to that of mild and healthy groups.

Conclusion: In mild cases, the microbiota is stable during SARS-CoV-2 infection, but in severe cases, alterations persist for 6 months after recovery.
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http://dx.doi.org/10.1186/s12879-022-07358-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9233337PMC
June 2022

Genome-Wide Association Study of Intracranial Artery Stenosis Followed by Phenome-Wide Association Study.

Transl Stroke Res 2022 Jun 14. Epub 2022 Jun 14.

Department of Neurosurgery, Faculty of Medicine, The University of Tokyo, Tokyo, 113-8655, Japan.

The genetic background of intracranial artery stenosis (ICAS), a major cause of ischemic stroke, remains elusive. We performed the world's first genome-wide association study (GWAS) of ICAS using DNA samples from Japanese subjects, to identify the genetic factors associated with ICAS and their correlation with clinical features. We also conducted a phenome-wide association study (PheWAS) of the top variant identified via GWAS to determine its association with systemic disease. The GWAS involved 408 patients with ICAS and 349 healthy controls and utilized an Asian Screening Array of venous blood samples. The PheWAS was performed using genotypic and phenotypic data of the Biobank Japan Project, which contained information on 46 diseases and 60 quantitative trait data from > 150,000 Japanese individuals. The GWAS revealed that the East Asian-specific functional variant of RNF213, rs112735431 (c.14429G > A, p.Arg4810Lys), was associated with ICAS (odds ratio, 12.3; 95% CI 5.5 to 27.5; P = 7.8 × 10). Stratified analysis within ICAS cases demonstrated that clinical features of those with and without the risk allele were different. PheWAS indicated that high blood pressure and angina were significantly associated with RNF213 rs112735431. The first GWAS of ICAS, which stratifies subpopulations within the ICAS cases with distinct clinical features, revealed that RNF213 rs112735431 was the most significant variant associated with ICAS. Thus, RNF213 rs112735431 shows potential as an important clinical biomarker that characterizes pleiotropic risk in various vascular diseases, such as blood pressure and angina, thereby facilitating personalized medicine for systemic vascular diseases in East Asian populations.
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http://dx.doi.org/10.1007/s12975-022-01049-wDOI Listing
June 2022

Factors affecting drug retention of Janus kinase inhibitors in patients with rheumatoid arthritis: the ANSWER cohort study.

Sci Rep 2022 01 7;12(1):134. Epub 2022 Jan 7.

Department of Health and Sport Sciences, Osaka University Graduate School of Medicine, Osaka, Japan.

This multi-center, retrospective study aimed to clarify the factors affecting drug retention of the Janus kinase inhibitors (JAKi) including baricitinib (BAR) and tofacitinib (TOF) in patients with RA. Patients were as follows; females, 80.6%; age, 60.5 years; DAS28-ESR, 4.3; treated with either BAR (n = 166) or TOF (n = 185); bDMARDs- or JAKi-switched cases (76.6%). The reasons for drug discontinuation were classified into four major categories. The drug retention was evaluated at 24 months using the Kaplan-Meier method and multivariate Cox proportional hazards modelling adjusted by confounders. Discontinuation rates for the corresponding reasons were as follows; ineffectiveness (22.3%), toxic adverse events (13.3%), non-toxic reasons (7.2%) and remission (0.0%). Prior history of anti-interleukin-6 receptor antibody (aIL-6R) ineffectiveness significantly increased the risk of treatment discontinuation due to ineffectiveness (p = 0.020). Aging (≥ 75 years) (p = 0.028), usage of PSL ≥ 5 mg/day (p = 0.017) and female sex (p = 0.041) significantly increased the risk of treatment discontinuation due to toxic adverse events. Factors not associated with treatment discontinuation were: number of prior bDMARDs or JAKi, concomitant MTX usage, difference of JAKi, and prior use of TNF inhibitor, CTLA4-Ig or other JAKi.
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http://dx.doi.org/10.1038/s41598-021-04075-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8742057PMC
January 2022

Genetic architecture of microRNA expression and its link to complex diseases in the Japanese population.

Hum Mol Genet 2022 06;31(11):1806-1820

Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita 565-0871, Japan.

Understanding the genetic effects on non-coding RNA (ncRNA) expression facilitates functional characterization of disease-associated genetic loci. Among several classes of ncRNAs, microRNAs (miRNAs) are key post-transcriptional gene regulators. Despite its biological importance, previous studies on the genetic architecture of miRNA expression focused mostly on the European individuals, underrepresented in other populations. Here, we mapped miRNA expression quantitative trait loci (miRNA-eQTL) for 343 miRNAs in 141 Japanese using small RNA sequencing and whole-genome sequencing, identifying 1275 cis-miRNA-eQTL variants for 40 miRNAs (false discovery rate < 0.2). Of these, 25 miRNAs having eQTL were unreported in the European studies, including 5 miRNAs with their lead variant monomorphic in the European populations, which demonstrates the value of miRNA-eQTL analysis in diverse ancestral populations. MiRNAs with eQTL effect showed allele-specific expression (ASE; e.g. miR-146a-3p), and ASE analysis further detected cis-regulatory variants not captured by the conventional miRNA-eQTL mapping (e.g. miR-933). We identified a copy number variation associated with miRNA expression (e.g. miR-570-3p, P = 7.2 × 10-6), which contributes to a more comprehensive landscape of miRNA-eQTLs. To elucidate a post-transcriptional modification in miRNAs, we created a catalog of miRNA-editing sites, including 10 canonical and 6 non-canonical sites. Finally, by integrating the miRNA-eQTLs and Japanese genome-wide association studies of 25 complex traits (mean n = 192 833), we conducted a transcriptome-wide association study, identifying miR-1908-5p as a potential mediator for adult height, colorectal cancer and type 2 diabetes (P < 9.1 × 10-5). Our study broadens the population diversity in ncRNA-eQTL studies and contributes to functional annotation of disease-associated loci found in non-European populations.
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http://dx.doi.org/10.1093/hmg/ddab361DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9169454PMC
June 2022

Whole gut virome analysis of 476 Japanese revealed a link between phage and autoimmune disease.

Ann Rheum Dis 2022 02 8;81(2):278-288. Epub 2021 Dec 8.

Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Osaka, Japan

Objective: The relationship between autoimmune diseases and the gut microbiome has been intensively studied, and several autoimmunity-associated bacterial taxa have been identified. However, much less is known about the roles of the gut virome in autoimmune diseases.

Methods: Here, we performed a whole gut virome analysis based on the shotgun sequencing of 476 Japanese which included patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), multiple sclerosis and healthy control subjects.

Results: Our case-control comparison of the viral abundance revealed that crAss-like phages, which are one of the main components of a healthy gut virome, significantly decreased in the gut of the patients with autoimmune disease, specifically the patients with RA and SLE. In addition, significantly decreased in the gut of the patients with SLE. To understand how these viruses affected the bacteriome, we performed a quantitative virus-bacterium association analysis and clustered regularly interspaced short palindromic repeat-based virus-bacterium interaction analysis. We identified a symbiosis between e and . In addition, multiple bacterial targets of crAss-like phages were identified (eg, spp).

Conclusion: Our data suggest that the gut virome can affect our body either directly or via bacteria. Our analyses have elucidated a previously missing part of the autoimmunity-associated gut microbiome and presented new candidates that contribute to the development of autoimmune diseases.
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http://dx.doi.org/10.1136/annrheumdis-2021-221267DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8761997PMC
February 2022

Identification of conserved SARS-CoV-2 spike epitopes that expand public cTfh clonotypes in mild COVID-19 patients.

J Exp Med 2021 12 14;218(12). Epub 2021 Oct 14.

Laboratory of Molecular Immunology, Immunology Frontier Research Center, Osaka University, Suita, Japan.

Adaptive immunity is a fundamental component in controlling COVID-19. In this process, follicular helper T (Tfh) cells are a subset of CD4+ T cells that mediate the production of protective antibodies; however, the SARS-CoV-2 epitopes activating Tfh cells are not well characterized. Here, we identified and crystallized TCRs of public circulating Tfh (cTfh) clonotypes that are expanded in patients who have recovered from mild symptoms. These public clonotypes recognized the SARS-CoV-2 spike (S) epitopes conserved across emerging variants. The epitope of the most prevalent cTfh clonotype, S864-882, was presented by multiple HLAs and activated T cells in most healthy donors, suggesting that this S region is a universal T cell epitope useful for booster antigen. SARS-CoV-2-specific public cTfh clonotypes also cross-reacted with specific commensal bacteria. In this study, we identified conserved SARS-CoV-2 S epitopes that activate public cTfh clonotypes associated with mild symptoms.
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http://dx.doi.org/10.1084/jem.20211327DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8641254PMC
December 2021

Metagenome-wide association study revealed disease-specific landscape of the gut microbiome of systemic lupus erythematosus in Japanese.

Ann Rheum Dis 2021 12 23;80(12):1575-1583. Epub 2021 Aug 23.

Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan

Objective: Alteration of the gut microbiome has been linked to the pathogenesis of systemic lupus erythematosus (SLE). However, a comprehensive view of the gut microbiome in SLE and its interaction with the host remains to be revealed. This study aimed to reveal SLE-associated changes in the gut microbiome and its interaction with the host by a comprehensive metagenome-wide association study (MWAS) followed by integrative analysis.

Methods: We performed a MWAS of SLE based on shotgun sequencing of the gut microbial DNA from Japanese individuals ( =47, =203). We integrated the result of the MWAS with the genome-wide association study (GWAS) data and plasma metabolite data.

Results: Via species level phylogenetic analysis, we identified and validated increases of and in the patients with SLE. Microbial gene analysis revealed increases of -derived genes including one involved in redox reaction. Additionally, microbial pathways related to sulfur metabolism and flagella assembly were altered in the patients with SLE. We identified an overlap in the enriched biological pathways between the metagenome and the germline genome by comparing the result of the MWAS and the GWAS of SLE (ie, MWAS-GWAS interaction). α-diversity and β-diversity analyses provided evidence of dysbiosis in the metagenome of the patients with SLE. Microbiome-metabolome association analysis identified positive dosage correlation of acylcarnitine with , an SLE-associated taxon.

Conclusion: Our MWAS followed by integrative analysis revealed SLE-associated changes in the gut microbiome and its interaction with the host, which contribute to our understanding of the relationship between the microbiome and SLE.
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http://dx.doi.org/10.1136/annrheumdis-2021-220687DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8600607PMC
December 2021

Pulmonary artery hypertension prior to the relapse of adult-onset Still's disease.

Respirol Case Rep 2021 May 28;9(5):e00746. Epub 2021 Apr 28.

Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine Osaka University Osaka Japan.

Adult-onset Still's disease (AOSD) is a rare inflammatory autoimmune disorder characterized by fever, skin rash, and arthralgia. Pulmonary artery hypertension (PAH) rarely occurs with AOSD and has not been reported in the absence of typical symptoms of AOSD. A 33-year-old woman was admitted to our hospital with dyspnoea on exertion. Although she had not had symptoms of AOSD for 18 months before her admission, she presented with gradually progressing PAH. Because she had no typical symptoms of AOSD, she was treated with pulmonary vasodilators. However, her PAH did not improve. At one month after vasodilator treatment, she developed a high fever with elevation of ferritin. We determined that her AOSD had relapsed. Immunosuppressants were started and both her AOSD and PAH quickly improved. PAH may develop in the absence of typical symptoms of AOSD and immunosuppressants may be effective in such a case.
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http://dx.doi.org/10.1002/rcr2.746DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8080289PMC
May 2021

Comparison of efficacy between anti-IL-6 receptor antibody and other biological disease-modifying antirheumatic drugs in the patients with rheumatoid arthritis who have knee joint involvement: the ANSWER cohort, retrospective study.

Rheumatol Int 2021 Jul 26;41(7):1233-1241. Epub 2021 Apr 26.

Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka, 565-0871, Japan.

Objective: We aimed to investigate the efficacy of anti-IL-6 receptor antibody (aIL-6) and other biologic disease-modifying antirheumatic drugs (bDMARDs), such as TNF inhibitor and CTLA4-Ig in the treatment of rheumatoid arthritis (RA) in patients with knee joint involvement.

Methods: We retrospectively analyzed 1059 treatment courses of patients with RA who visited our hospitals and were treated with bDMARDs. We categorized them into two groups, with or without knee joint involvement. We investigated the clinical disease activity index (CDAI) at baseline and 12 weeks after the initiation of bDMARDs. We compared the improvement of the markers between aIL-6 and other bDMARDs.

Results: Treatment with aIL-6 significantly increased ΔCDAI (n = 91, 15.4 ± 1.1; mean ± SEM) in patients with knee joint involvement, compared to other bDMARDs (n = 232, 11.0 ± 0.7) at 12 weeks (P = 0.006). Following the multivariate analysis adjusted by the CDAI levels at baseline, age, gender, concomitant use of methotrexate, and the first use of bDMARDs, ΔCDAI levels were significantly higher in aIL-6, compared to other bDMARDs (P = 0.02). However, there was no significant difference in ΔCDAI improvement between aIL-6 (n = 162, 5.9 ± 0.6) and other bDMARDs (n = 573, 6.2 ± 0.4) in patients without swollen knee joints. ΔCDAI levels were equally increased in patients with shoulder and elbow joint involvement.

Conclusion: aIL-6 was more effective in the patients with RA and knee joint involvement, compared to other bDMARDs.
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http://dx.doi.org/10.1007/s00296-021-04862-yDOI Listing
July 2021

Comparison of the drug retention and reasons for discontinuation of tumor necrosis factor inhibitors and interleukin-6 inhibitors in Japanese patients with elderly-onset rheumatoid arthritis-the ANSWER cohort study.

Arthritis Res Ther 2021 04 15;23(1):116. Epub 2021 Apr 15.

Department of Rheumatology and Clinical Immunology, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-chou Kobe-shi, Hyogo, 650-0017, Japan.

Background: This multi-center, retrospective study aimed to clarify retention rates and reasons for discontinuation of either tumor necrosis factor inhibitors (TNFi) or interleukin-6 inhibitors (IL-6i) in patients with elderly-onset rheumatoid arthritis (EORA).

Methods: Patients with rheumatoid arthritis (RA) enrolled in a Japanese multicenter observational registry between 2011 and 2020 were included. EORA was defined as RA with onset at 60 or over. To adjust confounding by indication for treatment with TNFi or IL-6i, a propensity score based on multiple baseline characteristics variables was used to compare the drug retention and causes for discontinuation between TNFi and IL-6i. Adjusted cumulative incidence of drug discontinuation for each reason was compared between the two groups using the Fine-Gray model.

Results: Among a total of 9,550 patients in the registry, 674 TNFi and 297 IL-6i initiators with EORA were identified. Age, the proportion of females, disease duration, and baseline disease activity at the time of TNFi or IL-6i initiation were similar between the two groups. After adjusting for differences in baseline characteristics between the two groups, overall drug discontinuation was significantly lower in the IL-6i as compared to the TNFi (HR = 0.71, 95%CI = 0.59-0.86, p < 0.001). The adjusted cumulative incidence of discontinuation due to lack of effectiveness was lower with the IL-6i (HR = 0.46, 95%CI = 0.33-0.63, p < 0.001) while those due to adverse events (HR = 0.82, 95%CI = 0.56-1.18, p = 0.28) or achievement of clinical remission (HR = 1.09, 95%CI = 0.62-1.91, p = 0.76) were similar between the two groups.

Conclusions: In EORA patients initiating a TNFi or IL-6i, significantly higher drug retention was observed with IL-6i. Discontinuation due to lack of effectiveness was significantly less frequent in IL-6i while discontinuations due to adverse event or achievement of clinical remission were similar between the two groups.
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http://dx.doi.org/10.1186/s13075-021-02496-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8048332PMC
April 2021

Large-scale plasma-metabolome analysis identifies potential biomarkers of psoriasis and its clinical subtypes.

J Dermatol Sci 2021 May 26;102(2):78-84. Epub 2021 Mar 26.

Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan; Laboratory of Statistical Immunology, Immunology Frontier Research Center (WPI-IFReC), Osaka University, Suita, Japan; Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Suita, Japan. Electronic address:

Background: Psoriasis is an immune-mediated skin disease for which the crosstalk between genetic and environmental factors is responsible. To date, no definitive diagnostic criteria for psoriasis yet, and specific biomarkers are required.

Objective: We performed metabolome analysis to identify metabolite biomarkers of psoriasis and its subtypes such as psoriatic arthritis (PsA) and cutaneous psoriasis (PsC).

Methods: We constructed metabolomics profiling of 130 plasma samples (42 PsA patients, 50 PsC patients, and 38 healthy controls) using a nontargeted metabolomics approach.

Results: Psoriasis-control association tests showed that one metabolite (ethanolamine phosphate) was significantly increased in psoriasis samples than in the controls, whereas three metabolites decreased (false discovery rate [FDR] < 0.05; XA0019, nicotinic acid, and 20α-hydroxyprogesterone). In the association test between PsA and PsC, tyramine significantly increased in PsA than in PsC, whereas mucic acid decreased (FDR < 0.05). Molecular pathway analysis of the PsA-PsC association test identified enrichment of vitamin digestion and absorption pathway in PsC (P = 1.3 × 10). Correlation network analyses elucidated that a subnetwork centered on aspartate was constructed among the psoriasis-associated metabolites; meanwhile, the major subnetwork among metabolites with differences between PsA and PsC was primarily formed from saturated fatty acids.

Conclusion: Our large-scale metabolome analysis highlights novel characteristics of plasma metabolites in psoriasis and the differences between PsA and PsC, which could be used as potential biomarkers of psoriasis and its clinical subtypes. These findings contribute to our understanding of psoriasis pathophysiology.
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http://dx.doi.org/10.1016/j.jdermsci.2021.03.006DOI Listing
May 2021

Genetic determinants of risk in autoimmune pulmonary alveolar proteinosis.

Nat Commun 2021 02 15;12(1):1032. Epub 2021 Feb 15.

Department of Respiratory Medicine, Kobe City Medical Center General Hospital, Kobe, Japan.

Pulmonary alveolar proteinosis (PAP) is a devastating lung disease caused by abnormal surfactant homeostasis, with a prevalence of 6-7 cases per million population worldwide. While mutations causing hereditary PAP have been reported, the genetic basis contributing to autoimmune PAP (aPAP) has not been thoroughly investigated. Here, we conducted a genome-wide association study of aPAP in 198 patients and 395 control participants of Japanese ancestry. The common genetic variant, rs138024423 at 6p21, in the major-histocompatibility-complex (MHC) region was significantly associated with disease risk (Odds ratio [OR] = 5.2; P = 2.4 × 10). HLA fine-mapping revealed that the common HLA class II allele, HLA-DRB1*08:03, strongly drove this signal (OR = 4.8; P = 4.8 × 10), followed by an additional independent risk allele at HLA-DPβ1 amino acid position 8 (OR = 0.28; P = 3.4 × 10). HLA-DRB1*08:03 was also associated with an increased level of anti-GM-CSF antibody, a key driver of the disease (β = 0.32; P = 0.035). Our study demonstrated a heritable component of aPAP, suggesting an underlying genetic predisposition toward an abnormal antibody production.
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http://dx.doi.org/10.1038/s41467-021-21011-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884840PMC
February 2021

Drug retention of sarilumab, baricitinib, and tofacitinib in patients with rheumatoid arthritis: the ANSWER cohort study.

Clin Rheumatol 2021 Jul 29;40(7):2673-2680. Epub 2021 Jan 29.

Department of Health and Sport Sciences, Osaka University, Graduate School of Medicine, Osaka, Japan.

Objectives: The aim of this multicenter, retrospective study was to clarify the retention rates of sarilumab (SAR), baricitinib (BAR), and tofacitinib (TOF) in patients with rheumatoid arthritis (RA).

Methods: Patients treated with either SAR (n = 62), BAR (n = 166), or TOF (n = 185) (females, 80.9%; age, 61.0 years; disease duration, 11.1 years; rheumatoid factor positivity, 84.4%; Disease Activity Score in 28 joints using erythrocyte sedimentation rate, 4.3; concomitant prednisolone dose, 5.3 mg/day [47.0%] and methotrexate dose, 8.8 mg/week [58.4%]; biologics- or Janus kinase inhibitors-switched cases 78.4%) were included. The reasons for drug discontinuation were classified into 4 major categories (lack of effectiveness, toxic adverse events, non-toxic reasons, and remission) by each attending physician. The drug retention rate was estimated at 18 months using the Kaplan-Meier method and adjusted for potential confounders by Cox proportional hazards modeling.

Results: The discontinuation rates of SAR, BAR, and TOF for the corresponding reasons were as follows, respectively: lack of effectiveness (15.7%, 15.6%, and 21.5%; P = 0.84), toxic adverse events (15.8%, 12.1%, and 12.3%; P = 0.35), non-toxic reasons (10.9%, 7.7%, and 6.8%; P = 0.35), and remission (0.0%, 2.8%, and 0.0%; P = 1.0). The overall retention rates excluding non-toxic reasons and remission were as follows: 68.8% for SAR, 72.5% for BAR, and 66.7% for TOF (P = 0.54).

Conclusions: After adjustment by potent confounders, SAR, BAR, and TOF showed similar discontinuation rates due to lack of effectiveness and toxic adverse events. Key Points • This is the first retrospective multicenter study that aimed to clarify the retention rates and reasons for discontinuation of SAR, BAR, and TOF in patients with RA.
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http://dx.doi.org/10.1007/s10067-021-05609-7DOI Listing
July 2021

A Metagenome-Wide Association Study of Gut Microbiome in Patients With Multiple Sclerosis Revealed Novel Disease Pathology.

Front Cell Infect Microbiol 2020 11;10:585973. Epub 2020 Dec 11.

Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan.

While microbiome plays key roles in the etiology of multiple sclerosis (MS), its mechanism remains elusive. Here, we conducted a comprehensive metagenome-wide association study (MWAS) of the relapsing-remitting MS gut microbiome ( = 26, = 77) in the Japanese population, by using whole-genome shotgun sequencing. Our MWAS consisted of three major bioinformatic analytic pipelines (phylogenetic analysis, functional gene analysis, and pathway analysis). Phylogenetic case-control association tests showed discrepancies of eight clades, most of which were related to the immune system (false discovery rate [FDR] < 0.10; e.g., . and ). Gene association tests found an increased abundance of one putative dehydrogenase gene (Clo1100_2356) and one ABC transporter related gene (Mahau_1952) in the MS metagenome compared with controls (FDR < 0.1). Molecular pathway analysis of the microbiome gene case-control comparisons identified enrichment of multiple Gene Ontology terms, with the most significant enrichment on cell outer membrane ( = 1.5 × 10). Interaction between the metagenome and host genome was identified by comparing biological pathway enrichment between the MS MWAS and the MS genome-wide association study (GWAS) results (i.e., MWAS-GWAS interaction). No apparent discrepancies in alpha or beta diversities of metagenome were found between MS cases and controls. Our shotgun sequencing-based MWAS highlights novel characteristics of the MS gut microbiome and its interaction with host genome, which contributes to our understanding of the microbiome's role in MS pathophysiology.
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http://dx.doi.org/10.3389/fcimb.2020.585973DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7759502PMC
June 2021

Oral intake of silica nanoparticles exacerbates intestinal inflammation.

Biochem Biophys Res Commun 2021 01 22;534:540-546. Epub 2020 Nov 22.

Department of Microbiology and Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka, 565-0871, Japan; WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka, 565-0871, Japan; Institute for Open and Transdisciplinary Research Initiative, Osaka University, Suita, Osaka, 565-0871, Japan. Electronic address:

Nanoparticles, i.e., particles with a diameter of ≤100 nm regardless of their composing material, are added to various foods as moisturizers, coloring agents, and preservatives. Silicon dioxide (SiO, silica) nanoparticles in particular are widely used as food additives. However, the influence of SiO nanoparticle oral consumption on intestinal homeostasis remains unclear. The daily intake of 10-nm-sized SiO nanoparticles exacerbates dextran sulfate sodium (DSS)-induced colitis, whereas the daily intake of 30-nm-sized SiO nanoparticles has no influence on intestinal inflammation. The exacerbation of colitis induced by consuming 10-nm-sized SiO nanoparticles was abolished in mice deficient in apoptosis-associated speck-like protein containing a CARD (ASC). Our study indicates that the oral intake of small SiO nanoparticles poses a risk for worsening intestinal inflammation through activation of the ASC inflammasome.
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http://dx.doi.org/10.1016/j.bbrc.2020.11.047DOI Listing
January 2021

Recovery from prolonged thrombocytopenia in patients with TAFRO syndrome: case series and literature review.

Mod Rheumatol Case Rep 2020 07 3;4(2):302-309. Epub 2020 Feb 3.

Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Osaka, Japan.

TAFRO syndrome is a newly proposed disease that is characterised by thrombocytopenia, anasarca, fever, reticulin fibrosis (or renal dysfunction), and organomegaly. Generally, high doses of corticosteroids are recommended for the initial treatment of TAFRO syndrome; however, some patients experience prolonged refractory thrombocytopenia after initiating such therapies. If corticosteroid treatment alone is ineffective, additional immunosuppressive therapies such as cyclosporine A are recommended. Since long-term use of immunosuppressive therapies with TAFRO syndrome sometimes causes serious infection, it is important to recognise the time to recovery from thrombocytopenia. In this study, we investigated how long it took to recover from thrombocytopenia, to aid clinicians in decision-making regarding the need to strengthen treatment for prolonged thrombocytopenia. Here, we describe three of our patients with TAFRO syndrome exhibiting prolonged thrombocytopenia. We also investigated the median period to recovery from this complication (defined as the time to increase the platelet count above 50,000/µL) after the initiation of high-dose corticosteroid treatment in our 3 cases and 38 peer-reviewed cases. We found that it took our patients 61 days to recover from thrombocytopenia; in comparison, our investigation of the 38 peer-reviewed case reports revealed a median recovery time of 47.5 days among previously reported patients. We showed the time to recovery from thrombocytopenia in patients with TAFRO syndrome for the first time. Our findings ought to be useful for decision-making among clinicians regarding the administration of other immunosuppressive treatments in addition to corticosteroid.
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http://dx.doi.org/10.1080/24725625.2020.1717747DOI Listing
July 2020

Refractory liver dysfunction was remarkably improved with chelating agents of Wilson's disease, in a patient with systemic lupus erythematosus-like syndrome after a parvovirus B19 infection.

Mod Rheumatol Case Rep 2021 01 23;5(1):182-187. Epub 2020 Oct 23.

Division of Rheumatology and Allergy, Osaka General Medical Center, Osaka, Japan.

Parvovirus B19 infection has been reported to be associated with systemic lupus erythematosus (SLE). Liver dysfunction is frequently observed in SLE patients. However, liver dysfunction caused by an aberrant copper metabolism is rarely seen in patients with parvovirus B19 infection. We report a rare case of SLE-like and Wilson's disease (WD) mimicking symptoms that were simultaneously triggered by parvovirus B19 infection. A 29-year-old man was admitted to our hospital with high-grade fever, arthralgia, and oral ulcers following a parvovirus B19 infection. Laboratory tests showed elevated transaminase levels, proteinuria, anti-double-stranded DNA antibody, high levels of serum ferritin, and leukocytopenia. He was suspected of having SLE with haemophagocytosis and was treated with high doses of prednisolone. Subsequently, the patient's arthritis symptoms improved and the proteinuria improved. Immunosuppressive therapies improved most of his symptoms except for the high titre of transaminases were alleviated. Laboratory findings indicated low serum levels of ceruloplasmin and copper along with elevated levels of 24-hour urinary copper. Liver biopsy detected copper in hepatocytes. Although the hepatic copper content was relatively low in this case, the dysregulation of copper metabolism was considered to be a main cause of his elevated levels of liver enzymes. Therefore, we started treatment with chelating agents used in WD treatment. At the 2-month follow-up, the liver dysfunction had significantly improved. Our case suggests that in patients with refractory liver dysfunction due to unknown reasons, it is necessary to exclude the possibility that an abnormal copper metabolism had caused an increase in the levels of liver enzymes.
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http://dx.doi.org/10.1080/24725625.2020.1832754DOI Listing
January 2021

Increased levels of plasma nucleotides in patients with rheumatoid arthritis.

Int Immunol 2021 01;33(2):119-124

Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan.

Novel biomarkers of rheumatoid arthritis (RA), in addition to antibodies against cyclic citrullinated peptides, are required. Metabolome analysis is a promising approach to identify metabolite biomarkers for clinical diagnosis. We adopted a comprehensive non-targeted metabolomics approach combining capillary electrophoresis time-of-flight mass spectrometry (TOFMS) and liquid chromatography TOFMS. We constructed metabolomics profiling of 286 plasma samples of a Japanese population [92 RA patients, 13 systemic lupus erythematosus (SLE) patients and 181 healthy controls). RA case-control association tests showed that seven metabolites exhibited significantly increased levels in RA samples compared with controls (P < 1.0 × 10-4; UTP, ethanolamine phosphate, ATP, GDP, ADP, 6-aminohexanoic acid and taurine), whereas one exhibited a decreased level (xanthine). The plasma levels of these eight metabolites were not significantly different between seropositive and seronegative RA patients (P > 0.05; n = 68 and 24, respectively). The four nucleotide levels (UTP, ATP, GDP and ADP) were significantly higher in the non-treatment patients in comparison between patients with and without treatment (P < 0.014; n = 57 and 35, respectively). Furthermore, we found that none of the four nucleotide levels showed significant differences in SLE case-control association tests (P > 0.2; 13 patients with SLE and the 181 shared controls) and psoriatic arthritis (PsA) case-control association tests (P > 0.11; 42 patients with PsA and 38 healthy controls), indicating disease specificity in RA. In conclusion, our large-scale metabolome analysis demonstrated the increased plasma nucleotide levels in RA patients, which could be used as potential clinical biomarkers of RA, especially for seronegative RA.
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http://dx.doi.org/10.1093/intimm/dxaa059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7846180PMC
January 2021

Comparison of the efficacy and safety of biologic agents between elderly-onset and young-onset RA patients: the ANSWER cohort study.

Rheumatol Int 2020 Dec 29;40(12):1987-1995. Epub 2020 Jul 29.

Department of Rheumatology and Clinical Immunology, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-chou, Kobe, Hyogo, 650-0017, Japan.

The objective of the study was to compare the efficacy and safety of biological disease-modifying antirheumatic drugs (bDMARDs) between elderly-onset rheumatoid arthritis (EORA) and young-onset rheumatoid arthritis (YORA) patients. Patients with rheumatoid arthritis (RA) aged ≧18 years enrolled in a Japanese multicenter observational registry between 2009 and 2018 who had moderate or high disease activity when initiating bDMARDs were included. EORA was defined as RA with onset at 60 or over. After propensity score weighting for differences in confounding factors, generalized estimating equations were used to assess the relationship between the age of RA onset and bDMARD clinical effectiveness at 48 weeks after starting a bDMARD. Among a total of 7183 patients in the registry, 2815 (39.2%) were identified as EORA. The proportion of patients on bDMARDs was lower in the EORA as compared to the YORA (18.3% vs 28.0%, p < 0.001). Of the 989 bDMARD initiators, 364 (36.8%) were identified as EORA. The median follow-up duration was 48 weeks both in the EORA and in the YORA. After adjusting for differences in baseline characteristics between the two age groups, there was no significant difference in Clinical Disease Activity Index scores at 48 weeks (mean difference 1.01, 95% CI = - 0.62 to 2.64, p = 0.22). There was a non-significant trend toward lower remission in EORA (OR = 0.52, 95% CI = 0.24-1.14, p = 0.10), and low disease activity/remission was similar (OR = 0.86, 95% CI = 0.29-2.52, p = 0.77). Drug retention (HR = 0.95, 95% CI = 0.55-1.35, p = 0.78) and discontinuations due to adverse events (HR = 0.78, 95% CI = 0.38-1.18, p = 0.22) were similar between the two age groups after adjustment for confounders. In RA patients initiating bDMARDs, improvements in clinical disease at 48 weeks were similar between EORA and YORA. Drug retention and adverse events discontinuation were similar between the two age groups.
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http://dx.doi.org/10.1007/s00296-020-04660-yDOI Listing
December 2020

Microbiota-derived butyrate limits the autoimmune response by promoting the differentiation of follicular regulatory T cells.

EBioMedicine 2020 Aug 22;58:102913. Epub 2020 Jul 22.

Division of Biochemistry, Faculty of Pharmacy and Graduate School of Pharmaceutical Sciences, Keio University, Minato-ku, Tokyo105-8512, Japan; International Research and Development Center for Mucosal Vaccines, The Institute of Medical Science, The University of Tokyo (IMSUT), Minato-ku, Tokyo108-8639, Japan. Electronic address:

Background: Rheumatoid arthritis (RA) is a chronic debilitating autoimmune disorder with a high prevalence, especially in industrialized countries. Dysbiosis of the intestinal microbiota has been observed in RA patients. For instance, new-onset untreated RA (NORA) is associated with the underrepresentation of the Clostridium cluster XIVa, including Lachnospiraceae, which are major butyrate producers, although the pathological relevance has remained obscure. Follicular regulatory T (T) cells play critical regulatory roles in the pathogenesis of autoimmune diseases, including RA. Reduced number of circulating T cells has been associated with the elevation of autoantibodies and disease severity in RA. However, the contribution of commensal microbe-derived butyrate in controlling T cell differentiation remains unknown.

Methods: We examined the contribution of microbe-derived butyrate in controlling autoimmune arthritis using collagen-induced arthritis (CIA) and SKG arthritis models. We phenotyped autoimmune responses in the gut-associated lymphoid tissues (GALT) in the colon and joint-draining lymph nodes in the CIA model. We developed an in vitro CXCR5Bcl-6Foxp3 T (iT) cell culture system and examined whether butyrate promotes the differentiation of iT cells.

Findings: Microbe-derived butyrate suppressed the development of autoimmune arthritis. The immunization of type II collagen (CII) caused hypertrophy of the GALT in the colon by amplifying the GC reaction prior to the onset of the CIA. Butyrate mitigated these pathological events by promoting T cell differentiation. Butyrate directly induced the differentiation of functional T cells in vitro by enhancing histone acetylation in T cell marker genes. This effect was attributed to histone deacetylase (HDAC) inhibition by butyrate, leading to histone hyperacetylation in the promoter region of the T-cell marker genes. The adoptive transfer of the butyrate-treated iT cells reduced CII-specific autoantibody production and thus ameliorated the symptoms of arthritis.

Interpretation: Accordingly, microbiota-derived butyrate serves as an environmental cue to enhance T cells, which suppress autoantibody production in the systemic lymphoid tissue, eventually ameliorating RA. Our findings provide mechanistic insights into the link between the gut environment and RA risk.

Funding: This work was supported by AMED-Crest (16gm1010004h0101, 17gm1010004h0102, 18gm1010004h0103, and 19gm1010004s0104 to KH), the Japan Society for the Promotion of Science (JP17KT0055, JP16H01369, and JP18H04680 to KH; JP17K15734 to DT), Keio University Special Grant-in-Aid for Innovative Collaborative Research Projects (KH), Keio Gijuku Fukuzawa Memorial Fund for the Advancement of Education and Research (DT), the SECOM Science and Technology Foundation (KH), the Cell Science Research Foundation (KH), the Mochida Memorial Foundation for Medical and Pharmaceutical Research (DT), the Suzuken Memorial Foundation (KH and DT), the Takeda Science Foundation (KH and DT), The Science Research Promotion Fund, and The Promotion and Mutual Aid Corporation for Private Schools of Japan (KH).
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http://dx.doi.org/10.1016/j.ebiom.2020.102913DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7387783PMC
August 2020

Drug retention of 7 biologics and tofacitinib in biologics-naïve and biologics-switched patients with rheumatoid arthritis: the ANSWER cohort study.

Arthritis Res Ther 2020 06 15;22(1):142. Epub 2020 Jun 15.

Department of Orthopaedic Surgery, Osaka University, Graduate School of Medicine, Osaka, Japan.

Background: This multi-center, retrospective study aimed to clarify retention rates and reasons for discontinuation of 7 biological disease-modifying antirheumatic drugs (bDMARDs) and tofacitinib (TOF), one of the janus kinase inhibitors, in bDMARDs-naïve and bDMARDs-switched patients with rheumatoid arthritis (RA).

Methods: This study assessed 3897 patients and 4415 treatment courses with bDMARDs and TOF from 2001 to 2019 (2737 bDMARDs-naïve courses and 1678 bDMARDs-switched courses [59.5% of switched courses were their second agent], female 82.3%, baseline age 57.4 years, disease duration 8.5 years; rheumatoid factor positivity 78.4%; Disease Activity Score in 28 joints using erythrocyte sedimentation rate 4.3; concomitant prednisolone [PSL] dose 6.1 mg/day [usage 42.4%], and methotrexate [MTX] dose 8.5 mg/week [usage 60.9%]). Treatment courses included abatacept (ABT; n = 663), adalimumab (ADA; n = 536), certolizumab pegol (CZP; n = 226), etanercept (ETN; n = 856), golimumab (GLM; n = 458), infliximab (IFX; n = 724), tocilizumab (TCZ; n = 851), and TOF (n = 101/only bDMARDs-switched cases). Drug discontinuation reasons (categorized into lack of effectiveness, toxic adverse events, non-toxic reasons, or remission) and rates were estimated at 36 months using Gray's test and statistically evaluated after adjusted by potential clinical confounders (age, sex, disease duration, concomitant PSL and MTX usage, starting date, and number of switched bDMARDs) using the Fine-Gray model.

Results: Cumulative incidence of drug discontinuation for each reason was as follows: lack of effectiveness in the bDMARDs-naïve group (from 13.7% [ABT] to 26.9% [CZP]; P < 0.001 between agents) and the bDMARDs-switched group (from 18.9% [TCZ] to 46.1% [CZP]; P < 0.001 between agents); toxic adverse events in the bDMARDs-naïve group (from 4.6% [ABT] to 11.2% [ETN]; P < 0.001 between agents) and the bDMARDs-switched group (from 5.0% [ETN] to 15.7% [TOF]; P = 0.004 between agents); and remission in the bDMARDs-naïve group (from 2.9% [ETN] to 10.0% [IFX]; P < 0.001 between agents) and the bDMARDs-switched group (from 1.1% [CZP] to 3.3% [GLM]; P = 0.9 between agents).

Conclusions: Remarkable differences were observed in drug retention of 7 bDMARDs and TOF between bDMARDs-naïve and bDMARDs-switched cases.
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http://dx.doi.org/10.1186/s13075-020-02232-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7296929PMC
June 2020

Response to: 'Can sexual dimorphism in rheumatoid arthritis be attributed to the different abundance of ?' by Liu .

Ann Rheum Dis 2022 03 25;81(3):e37. Epub 2020 Mar 25.

Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan

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http://dx.doi.org/10.1136/annrheumdis-2020-217264DOI Listing
March 2022

Drug retention of secondary biologics or JAK inhibitors after tocilizumab or abatacept failure as first biologics in patients with rheumatoid arthritis -the ANSWER cohort study.

Clin Rheumatol 2020 Sep 11;39(9):2563-2572. Epub 2020 Mar 11.

Department of Orthopaedic Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan.

Objectives: The aim of this multicenter, retrospective study was to clarify the retention of secondary biological disease-modifying antirheumatic drugs (bDMARDs) or Janus kinase inhibitors (JAKi) in patients with rheumatoid arthritis (RA) who were primarily treated by tocilizumab (TCZ) or abatacept (ABT) as first bDMARDs.

Method: Patients who were treated by either TCZ (n = 145) or ABT (n = 76) and then switched to either tumor necrosis factor inhibitors (TNFi), TCZ, ABT, or JAKi (including only cases switched from TCZ) from 2001 to 2019 (female 81.0%, age 59.5 years, disease duration 8.8 years; rheumatoid factor positivity 75.4%; Disease Activity Score in 28 joints using C-reactive protein 3.7; concomitant prednisolone (PSL) dose 6.0 mg/day (51.8%) and methotrexate (MTX) dose 8.0 mg/week (56.1%); 81.9% discontinued first bDMARDs due to lack of effectiveness) were included. Drug retention and discontinuation reasons were estimated at 24 months using the Kaplan-Meier method and adjusted for potential confounders by Cox proportional hazards modeling.

Results: Drug retentions for each of the reasons for discontinuation were as follows: lack of effectiveness in TCZ-switched group (TNFi (59.5%), ABT (82.2%), and JAKi (84.3%); TNFi vs. ABT; P = 0.009) and ABT-switched group (TNFi (79.6%) and TCZ (92.6%); P = 0.053). Overall retention excluding non-toxic reasons and remission for discontinuation were TNFi (49.9%), ABT (72.7%), and JAKi (72.6%) (TNFi vs. ABT; P = 0.017) in the TCZ-switched group and TNFi (69.6%) and TCZ (72.4%) (P = 0.44) in the ABT-switched group.

Conclusions: Switching to ABT in TCZ-treated patients led to higher retention as compared with TNFi. Switching to TCZ in ABT-treated patients tended to lead to higher retention due to effectiveness, although total retention was similar as compared with TNFi. Key Point • This is the first retrospective, multi-center study aimed to clarify the retention rates of secondary bDMARDs or JAKi in patients with RA who were primarily being treated by TCZ or ABT as the first bDMARDs.
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http://dx.doi.org/10.1007/s10067-020-05015-5DOI Listing
September 2020

Comparison of Japanese and Indian intestinal microbiota shows diet-dependent interaction between bacteria and fungi.

NPJ Biofilms Microbiomes 2019;5(1):37. Epub 2019 Dec 20.

1Department of Microbiology and Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka, 565-0871 Japan.

The bacterial species living in the gut mediate many aspects of biological processes such as nutrition and activation of adaptive immunity. In addition, commensal fungi residing in the intestine also influence host health. Although the interaction of bacterium and fungus has been shown, its precise mechanism during colonization of the human intestine remains largely unknown. Here, we show interaction between bacterial and fungal species for utilization of dietary components driving their efficient growth in the intestine. Next generation sequencing of fecal samples from Japanese and Indian adults revealed differential patterns of bacterial and fungal composition. In particular, Indians, who consume more plant polysaccharides than Japanese, harbored increased numbers of and . spp. showed strong growth responses to the plant polysaccharide arabinoxylan in vitro. Furthermore, the culture supernatants of spp. grown with arabinoxylan promoted rapid proliferation of . Arabinose was identified as a potential growth-inducing factor in the culture supernatants. spp. exhibited a growth response to xylose, but not to arabinose, whereas proliferated in response to both xylose and arabinose. spp., but not , colonized the intestine of germ-free mice. However, successfully colonized mouse intestine already harboring . These findings demonstrate a proof of concept that fungal members of gut microbiota can facilitate a colonization of the intestine by their bacterial counterparts, potentially mediated by a dietary metabolite.
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http://dx.doi.org/10.1038/s41522-019-0110-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6925221PMC
June 2020

Host-microbiota interactions in rheumatoid arthritis.

Exp Mol Med 2019 12 11;51(12):1-6. Epub 2019 Dec 11.

Laboratory of Immune Regulation, Department of Microbiology and Immunology, Graduate School of Medicine, WPI Immunology Frontier Research Center, Osaka University, Suita, Japan.

The gut microbiota has been proposed to be an important environmental factor in the development of rheumatoid arthritis (RA). Here, we review a growing body of evidence from human and animal studies that supports the hypothesis that intestinal microbiota play a role in RA. Previous studies from we and others showed an altered composition of the microbiota in early RA patients. A recent study demonstrated that Prevotella species are dominant in the intestine of patients in the preclinical stages of RA. In addition, Prevotella-dominated microbiota isolated from RA patients contributes to the development of Th17 cell-dependent arthritis in SKG mice. Moreover, it was reported that periodontal bacteria correlates with the pathogenesis of RA. In this review, we discuss the link between oral bacteria and the development of arthritis. However, many questions remain to be elucidated in terms of molecular mechanisms for the involvement of intestinal and oral microbiota in RA pathogenesis.
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http://dx.doi.org/10.1038/s12276-019-0283-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6906371PMC
December 2019

Metagenome-wide association study of gut microbiome revealed novel aetiology of rheumatoid arthritis in the Japanese population.

Ann Rheum Dis 2020 01 7;79(1):103-111. Epub 2019 Nov 7.

Department of Statistical Genetics, Osaka University School of Medicine Graduate School of Medicine, Suita, Japan

Objective: The causality and pathogenic mechanism of microbiome composition remain elusive in many diseases, including autoimmune diseases such as rheumatoid arthritis (RA). This study aimed to elucidate gut microbiome's role in RA pathology by a comprehensive metagenome-wide association study (MWAS).

Methods: We conducted MWAS of the RA gut microbiome in the Japanese population ( =82, =42) by using whole-genome shotgun sequencing of high depth (average 13 Gb per sample). Our MWAS consisted of three major bioinformatic analytic pipelines (phylogenetic analysis, functional gene analysis and pathway analysis).

Results: Phylogenetic case-control association tests showed high abundance of multiple species belonging to the genus (e.g., ) in the RA case metagenome. The non-linear machine learning method efficiently deconvoluted the case-control phylogenetic discrepancy. Gene functional assessments showed that the abundance of one redox reaction-related gene (R6FCZ7) was significantly decreased in the RA metagenome compared with controls. A variety of biological pathways including those related to metabolism (e.g., fatty acid biosynthesis and glycosaminoglycan degradation) were enriched in the case-control comparison. A population-specific link between the metagenome and host genome was identified by comparing biological pathway enrichment between the RA metagenome and the RA genome-wide association study results. No apparent discrepancy in alpha or beta diversities of metagenome was found between RA cases and controls.

Conclusion: Our shotgun sequencing-based MWAS highlights a novel link among the gut microbiome, host genome and pathology of RA, which contributes to our understanding of the microbiome's role in RA aetiology.
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http://dx.doi.org/10.1136/annrheumdis-2019-215743DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6937407PMC
January 2020

The family history of rheumatoid arthritis in anti-cyclic citrullinated peptide antibody-positive patient is not a predictor of poor clinical presentation and treatment response with modern classification criteria and treatment strategy: the ANSWER cohort study.

Rheumatol Int 2020 Feb 16;40(2):217-225. Epub 2019 Oct 16.

Department of Orthopaedic Surgery, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawahara-cho, Shogoin, Kyoto, Japan.

A family history of rheumatoid arthritis (RA) is a strong risk factor for developing RA, affecting both genetically and environmentally. However, whether family history provides clinically relevant information in the modern classification and treatment remains largely unknown. This study aimed to determine whether a family history of RA is associated with a different clinical presentation of RA and treatment response. We retrospectively evaluated the demographic data and disease activity of newly diagnosed RA patients at baseline, 1 year, and 2 years after onset, using the ANSWER (Kansai consortium for the well-being of rheumatic disease patients) cohort data. Thirty-one patients (11.9%) among 260 newly diagnosed RA patients had a family history of RA up to second degree. There was no significant difference in the age at onset, time from onset to first visit, sex, positivity or value of rheumatoid factor or anti-cyclic citrullinated peptide antibody (ACPA), or disease activity between patients with and without a family history of RA. However, patients who had a family history of RA and were ACPA positive showed significantly lower erythrocyte sedimentation rate, and C-reactive protein. Disease activity in patients with a family history was not worse at baseline, after 1 year or 2 years of treatment. The Larsen score 2 years after onset was equivalent between the patients with and without a family history of RA in ACPA-positive patients. Family history of RA in ACPA-positive patients is not associated with high disease activity at baseline and is not a predictor of poor outcome 2 years after onset.
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http://dx.doi.org/10.1007/s00296-019-04464-9DOI Listing
February 2020
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