担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE: Few studies have explored whether the involvement of patients in shared decision-making (SDM) is beneficial to the management of systemic lupus erythematosus (SLE). Therefore, this study investigated the relationship between patient participation in SDM and their trust in physicians using data from the TRUMP2-SLE study. METHODS: Data regarding the nine-item Shared Decision-Making Questionnaire (SDM-Q-9 scores), Trust in Physician Scale (TIPS) scores, and Abbreviated Wake Forest Physician Trust Scale (A-WFPTS) scores for interpersonal trust in a physician and trust in the medical profession were collected from patients with SLE who visited the outpatient clinics of five facilities in Japan through a self-administered questionnaire. The relationships between these scores were analyzed by general linear models with cluster-robust variance. RESULTS: This study included 433 patients with SLE. The median baseline TIPS and A-WFPTS (attending physician version) scores were 82 (73-93) and 80 (70-95), respectively. A higher baseline SDM-Q-9 score was correlated with an increase in the TIPS score at 1 year (coefficient per 10-pt increase, 0.94 pt [95%CI 0.16-1.72]). A higher baseline SDM-Q-9 score was correlated with a higher A-WFPTS score for interpersonal trust (coefficient per 10-pt increase, 2.20 pt [1.44-2.96]). The baseline SDM-Q-9 score was also correlated with an increase in the general physician version of A-WFPTS score at 1 year (coefficient per 10-pt increase, 1.29 pt [0.41-2.18]). CONCLUSION: Engagement of patients with SLE in SDM elevates their trust in the attending physicians and healthcare providers, potentially enhancing doctor-patient relationships and overall healthcare trust.

DOI： 10.1002/acr.25409

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.2169/internalmedicine.4793-24

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

BACKGROUND: Pneumocystis jirovecii pneumonia (PCP) is an opportunistic infection in patients undergoing immunosuppressive therapy, such as glucocorticoid (GC) medication, for systemic autoimmune diseases like systemic lupus erythematosus (SLE). Despite the confirmed effectiveness of PCP prophylaxis, its clinical administration, especially in conjunction with GC dosage, remains unclear. We aimed to describe the clinical practice of PCP prophylaxis in association with SLE in Japan, evaluate the relationship between GC dosage and PCP prophylaxis, and explore the practice patterns associated with PCP prophylaxis. METHODS: This cross-sectional study used data from the Lupus Registry of Nationwide Institutions in Japan from 2016 to 2021 and included patients diagnosed with SLE. Using descriptive statistics, multivariate analysis, and decision tree analysis, we examined the prevalence of PCP prophylaxis and its association with the GC dosage. RESULTS: Out of 1,460 patients, 21% underwent PCP prophylaxis. The frequency of prophylaxis decreased with a decrease in GC dosage. After adjusting for confounders, logistic regression revealed the odds ratio of PCP prophylaxis increased with higher prednisolone (PSL) doses: 3.7 for 5 ≤ PSL < 7.5 mg, 5.2 for 7.5 ≤ PSL < 10 mg, 9.0 for 10 ≤ PSL < 20 mg, and 43.1 for PSL ≥ 20 mg, using PSL < 5 mg as the reference. Decision tree analysis indicated that a PSL dosage of < 11 mg/day and immunosuppressant use were key determinants of PCP prophylaxis. CONCLUSION: This study provides valuable insights into PCP prophylaxis practices in patients with SLE in Japan, underscoring the importance of GC dosage and concomitant immunosuppressant use.

DOI： 10.1186/s13075-024-03434-2

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その他リンク： https://link.springer.com/article/10.1186/s13075-024-03434-2/fulltext.html

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Patient trust plays a central role in the patient-physician relationship. This study aimed to determine whether the number of outpatient visits with a covering rheumatologist is associated with patient trust in their usual rheumatologist. METHODS: Japanese adults with systemic lupus erythematosus (SLE) who met the 1997 revised classification criteria of the American College of Rheumatology and had outpatient visits with a covering rheumatologist in the past year were included. We used the 11-item Japanese version of the modified Trust in Physician Scale (range 0-100) to assess patient trust. A general linear model with cluster-robust variance estimation was used to evaluate the association between the number of outpatient visits with covering rheumatologists and the patient's trust in their usual rheumatologist. RESULTS: Of the 515 enrolled participants, 421 patients with SLE were included in our analyses. Patients were divided into groups according to the number of outpatient visits with a covering rheumatologist in the past year as follows: no visits (59.9%; reference group), one to three visits (24.2%; low-frequency group), and four or more visits (15.9%; high-frequency group). The median Trust in Physician Scale score was 81.8 (interquartile range: 72.7-93.2). Both the low-frequency group (mean difference: -3.03; 95% confidence interval [CI] -5.93 to -0.80) and high-frequency group (mean difference: -4.17; 95% CI -7.77 to -0.58) exhibited lower trust in their usual rheumatologist. CONCLUSION: This study revealed that the number of outpatient visits with a covering rheumatologist was associated with lower trust in a patient's usual rheumatologist.

DOI： 10.1186/s13075-024-03428-0

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担当区分：筆頭著者,　最終著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.2169/internalmedicine.4645-24

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE: Late-onset systemic lupus erythematosus (LoSLE) is known to possess characteristics different from those of early-onset SLE (EoSLE), thereby making their diagnosis difficult. This study aimed to assess the characteristic features of LoSLE in Japan, a model country with a super-aged society. METHODS: Data were obtained from the Lupus Registry of Nationwide Institutions, which includes a multicenter cohort of patients with SLE in Japan who satisfied the 1997 American College of Rheumatology revised classification criteria for SLE. Data were compared between patients with LoSLE (≥50 years old at onset) and EoSLE (<50 years old at onset). To identify factors associated with LoSLE, binary logistic regression was used for the multivariate analysis, and missing values were complemented by multiple imputations. We also conducted a sub-analysis for patients diagnosed within 5 years of onset. RESULTS: Out of 929 enrolled patients, 34 were excluded owing to a lack of data regarding onset age. Among the 895 remaining patients, 100 had LoSLE, whereas 795 had EoSLE. The male-to-female ratio was significantly higher in the LoSLE group than in the EoSLE group (0.32 vs 0.11, p < 0.001). With respect to SLEDAI components at onset, patients with LoSLE exhibited a higher frequency of myositis (11.9% vs 3.75%, p = 0.031), lower frequency of skin rash (33.3% vs 67.7%, p < 0.001), and lower frequency of alopecia (7.32% vs 24.7%, p = 0.012). No significant differences in overall disease activity at onset were observed between the two groups. Regarding medical history, immunosuppressants were more commonly used in EoSLE. A multivariate analysis revealed that a higher male proportion and a lower proportion of new rash at onset were independent characteristic features of LoSLE. We also identified late onset as an independent risk factor for a high SDI score at enrollment and replicated the result in a sub-analysis for the population with a shorter time since onset. CONCLUSIONS: We clarified that LoSLE was characterized by a higher male proportion, a lower frequency of skin rash and a tendency to organ damage. Now that the world is faced with aging, our results may be helpful at diagnosis of LoSLE.

DOI： 10.1177/09612033241281507

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Clinical and Experimental Rheumatology  

DOI： 10.55563/clinexprheumatol/8j7rbr

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVES: This study aimed to understand the status quo of medical treatments of the primary disease and pregnancy outcomes in patients with Takayasu arteritis (TAK) and children's birth outcomes. METHODS: This study retrospectively enrolled patients with TAK who conceived after the disease onset and were managed at medical facilities participating in the Japan Research Committee of the Ministry of Health, Labor, and Welfare for Intractable Vasculitis. RESULTS: This study enrolled 51 cases and 68 pregnancies 2019-2021. Of these, 48 cases and 65 pregnancies (95.6%) resulted in delivery and live-born babies. The median age of diagnosis and delivery was 22 and 31, respectively. Preconception therapy included prednisolone (PSL) in 51 (78.5%, median 7.5 mg/day), immunosuppressants in 18 (27.7%), and biologics in 12 (18.5%) pregnancies. Six cases underwent surgical treatment before pregnancy. Medications during pregnancy included PSL in 48 (73.8%, median: 9 mg/day), immunosuppressants in 13 (20.0%), and biologics in 9 (13.8%) pregnancies. Enlargement of an aneurysm was reported in one pregnancy, which might be associated with increased circulating plasma volume. TAK relapsed in 4 (6.2%) and 8 (12.3%) pregnancies during pregnancy and after delivery, respectively. Additionally, 13/62 (20.9%) preterm infants and 17/59 (28.8%) low birth weight infants were observed, and none had serious postnatal abnormalities. Of the 51 confirmed infants, 42 (82.4%) were exclusively breastfed or mixed with formula. CONCLUSION: Most pregnancies in TAK were manageable with PSL at ≤10 mg/day. Relapse during pregnancy and postpartum occurred in <20% of pregnancies.

DOI： 10.1093/mr/roae068

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE: Few studies have explored whether the involvement of patients in shared decision-making (SDM) is beneficial to the management of systemic lupus erythematosus (SLE). Therefore, this study investigated the relationship between patient participation in SDM and their trust in physicians using data from the TRUMP2-SLE study. METHODS: Data regarding the nine-item Shared Decision-Making Questionnaire (SDM-Q-9 scores), Trust in Physician Scale (TIPS) scores, and Abbreviated Wake Forest Physician Trust Scale (A-WFPTS) scores for interpersonal trust in a physician and trust in the medical profession were collected from patients with SLE who visited the outpatient clinics of five facilities in Japan through a self-administered questionnaire. The relationships between these scores were analyzed by general linear models with cluster-robust variance. RESULTS: This study included 433 patients with SLE. The median baseline TIPS and A-WFPTS (attending physician version) scores were 82 (73-93) and 80 (70-95), respectively. A higher baseline SDM-Q-9 score was correlated with an increase in the TIPS score at 1 year (coefficient per 10-pt increase, 0.94 pt [95%CI 0.16-1.72]). A higher baseline SDM-Q-9 score was correlated with a higher A-WFPTS score for interpersonal trust (coefficient per 10-pt increase, 2.20 pt [1.44-2.96]). The baseline SDM-Q-9 score was also correlated with an increase in the general physician version of A-WFPTS score at 1 year (coefficient per 10-pt increase, 1.29 pt [0.41-2.18]). CONCLUSION: Engagement of patients with SLE in SDM elevates their trust in the attending physicians and healthcare providers, potentially enhancing doctor-patient relationships and overall healthcare trust.

DOI： 10.1002/acr.25409

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVES: To efficiently detect somatic UBA1 variants and establish a clinical scoring system predicting patients with pathogenic variants in VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome. METHODS: Eighty-nine Japanese patients with clinically suspected VEXAS syndrome were recruited [81 males and 8 females; median onset age (IQR) 69.3 years (62.1-77.6)]. Peptide nucleic acid-clamping PCR (PNA-PCR), regular PCR targeting exon 3 clustering UBA1 variants, and subsequent Sanger sequencing were conducted for variant screening. Partitioning digital PCR (pdPCR) or targeted amplicon deep sequencing (TAS) was also performed to evaluate the variant allele frequency (VAF). We developed our clinical scoring system to predict UBA1 variant-positive and ‑negative patients and assessed the diagnostic value of our system using receiver operating characteristic (ROC) curve analysis. RESULTS: Forty patients with reported pathogenic UBA1 variants (40/89, 44.9%) were identified, including a case having a variant with VAF of 1.7%, using a highly sensitive method. Our clinical scoring system considering >50 years of age, cutaneous lesions, lung involvement, chondritis, and macrocytic anaemia efficiently predicted patients with UBA1 variants (the area under the curve for the scoring total was 0.908). CONCLUSIONS: Genetic screening with the combination of regular PCR and PNA-PCR detected somatic UBA1 variants with high sensitivity and specificity. Our scoring system could efficiently predict patients with UBA1 variants.

DOI： 10.1093/rheumatology/kead425

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SAGE Publications  

Objectives

This study investigated the clinically relevant factors for headaches in patients with systemic lupus erythematosus (SLE) using a registry from a Japanese multicenter cohort.

Methods

This cross-sectional study analysed the clinical information of patients with SLE who experienced headache episodes using the Migraine Disability Assessment (MIDAS) questionnaire. Significant findings in the comparisons between patients with headache (HA patients) and those without headache (non-HA patients) and in the comparisons depending on the grades of headache-induced disability in daily life based on the MIDAS scores were evaluated. Multivariate logistic regression analyses were performed to identify the relevant factors for headache.

Results

We analyzed 369 patients (median age, 45 years; female, 90.8%), including 113 HA patients who were significantly younger than non-HA patients ( p &lt; .005). HA patients had significantly higher frequencies of photosensitivity, rashes, and mucosal ulcers than non-HA patients ( p &lt; .05). Age and photosensitivity were significantly associated with headache (odds ratio (OR) 0.93, 95% confidence interval (CI) 0.95–0.99; OR 2.11, 95% CI 1.29–3.49, respectively). In the HA patients, hypocomplementemia was significantly associated with a disability of more than mild grade (OR 2.89, 95% CI 1.14–7.74), while rash was significantly observed in those presenting with moderate and severe disability.

Conclusion

This study suggests that photosensitivity is a relevant manifestation of headache in patients with SLE. Persistent hypocomplementemia can contribute to headache-induced disability in daily life, whereas a rash may be a dominant manifestation in patients presenting with moderate/severe headache-induced disability.

DOI： 10.1177/09612033241254168

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その他リンク： https://journals.sagepub.com/doi/full-xml/10.1177/09612033241254168

記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVES: The predictive validity of disease-specific quality of life (QOL) remains unknown in patients with systemic lupus erythematosus (SLE), although disease-specific measures are equally or more responsive to changes than generic QOL. We aimed to examine the predictive validity of the Lupus patient-reported outcome (PRO) for damage accrual. METHODS: Patients with SLE and ≥2 measurements over time were included in Japanese nationwide multicentre registry (LUNA). The Lupus PRO questionnaire contains both health-related (HR) and non-HR-QOL measures. Damage accrual was evaluated using the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI). We examined the association between the Lupus-PRO score at baseline and longitudinal SDI scores using mixed-effects models adjusted for prognostic factors. RESULTS: Among 1295 patients, those with higher HR-QOL of Lupus PRO at baseline demonstrated a significantly lower increase in SDI (-0.005/year, 95% confidence interval [CI]: -0.007 to - 0.004, p < 0.001). According to the categorisation of HR-QOL based on tertile, a similar dose-dependent effect of HR-QOL on longitudinal SDI was identified (second vs first tertile category: -0.101/year, 95% CI: -0.172 to - 0.030; third tertile category: -0.211/year, 95% CI: -0.281 to - 0.142). Non-HR-QOL was not significantly associated with the SDI scores. Among the HR-QOL domains, cognition, procreation, and physical health were significantly associated with the total SDI scores over time. HR-QOL was associated with corticosteroid-dependent and -independent SDI scores. CONCLUSION: A higher HR-QOL of Lupus PRO was associated with a lower increase in SDI scores. Our findings imply the importance of disease-specific HR-QOL measurements in assessing prognosis.

DOI： 10.1093/rheumatology/keae341

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Frontiers Media SA  

Background

Little is known about the relationship between the disease activity of Behçet disease (BD) and the incidence of inflammatory major organ events.

Objectives

In this prospective registry study, we investigated the association between the Behçet Disease Current Activity Form (BDCAF) and incidence of inflammatory major organ events, defined as the inflammation of the ocular, central nervous, intestinal, and vascular systems in BD.

Methods

We enrolled participants from Japanese multicenter prospective cohorts. The BDCAF was evaluated annually. BD-related symptoms, including inflammatory major organ events, were monitored. The association between BDCAF and inflammatory major organ events was analyzed by time-to-event analysis. An unsupervised clustering of the participants’ BDCAF, therapeutic agents, and multiple serum cytokines was also performed to examine their association with inflammatory major organ events.

Results

A total of 260 patients were included. The patients had a median BDCAF score of 2 [Interquartile range, 1-3] at the enrolment and remained disease active at 1- and 2-year follow-ups, indicating residual disease activity in BD. Patients with a BDCAF score of 0 had a longer inflammatory major organ event-free survival at 52 weeks than those with a score of 1 or higher (p=2.2 x 10^-4). Clustering analysis revealed that patients who did not achieve remission despite treatment with tumor necrosis factor inhibitors had high serum inflammatory cytokine levels and incidences of inflammatory major organ events. Among the elevated cytokines, IL-6 was associated with inflammatory major organ events.

Conclusion

This study suggests that treatment strategies targeting overall disease activity and monitoring residual serum IL-6 may help prevent inflammatory major organ events in BD.

DOI： 10.3389/fimmu.2024.1354969

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVES: The aim of the article is to investigate the associations of disease duration and anti-cyclic citrullinated peptide antibody (ACPA) status with the effectiveness of abatacept in biologic-naïve patients with rheumatoid arthritis (RA). METHODS: We performed post hoc analyses of the Orencia® Registry in Geographically Assembled Multicenter Investigation (ORIGAMI) study of biologic-naïve RA patients aged ≥20 years with moderate disease activity who were prescribed abatacept. Changes in the Simplified Disease Activity Index (SDAI) and Japanese Health Assessment Questionnaire (J-HAQ) at 4, 24, and 52 weeks of treatment were analysed in patients divided according to ACPA serostatus (positive/negative), disease duration (<1/≥1 year), or both. RESULTS: SDAI scores decreased from baseline in all groups. SDAI scores tended to decrease more in the ACPA-positive group and disease duration <1-year group than in the ACPA-negative group and disease duration ≥1-year group, respectively. In the disease duration <1-year group, SDAI tended to decrease more in the ACPA-positive group than in the ACPA-negative group. Disease duration was independently associated with the change in SDAI and SDAI remission at Week 52 in multivariable regression models. CONCLUSIONS: These results suggest that starting abatacept within 1 year of diagnosis was associated with greater effectiveness of abatacept in biologic-naïve patients with RA and moderate disease activity.

DOI： 10.1093/mr/road045

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Previous studies have shown conflicting evidence regarding the incidence of cancer in patients with systemic lupus erythematosus (SLE) compared with that in healthy individuals. Calcineurin inhibitors (CNIs) such as cyclosporine and tacrolimus have been widely used to treat SLE; however, their effects on cancer risk remain unclear. We aimed to investigate the incidence of cancer in patients with SLE and determine the potential association between CNI use and cancer risk. METHODS: The standardized incidence ratio (SIR) of cancer among patients with lupus in the Lupus Registry of Nationwide Institutions (LUNA) was calculated based on the age-standardized incidence rate of cancer reported by Japan's Ministry of Health, Labour and Welfare. We also examined the association between CNI exposure and cancer risk, while considering potential confounding factors. The analysis accounted for confounding variables such as age, sex, smoking history, maximum glucocorticoid dose, treatment history with cyclophosphamide, ongoing hydroxychloroquine, Systemic Lupus International Collaboration Clinics/American College of Rheumatology Damage Index (SDI) value (excluding cancer occurrence), comorbidity of diabetes mellitus, and smoking history. RESULTS: The study included 704 patients with SLE (625 females; 88.8%) with a median age of 44 years [interquartile range (IQR) = 34-55] years. The median past maximum glucocorticoid dose was 40 mg/day [IQR = 30-60 mg/day], and the SDI at registration was 1 [IQR = 0-2]. Among the patients, 246 (35.1%) had smoking histories, and 38 (5.4%) experienced cancer complications. Gynecological malignancies accounted for 63.2% of all cancers. The SIR of cancer in the LUNA cohort was 1.08 (95% confidence interval [CI] = 0.74-1.43). No statistically significant risks of cancer were found in relation to CNI treatment history; the odds ratio using multiple logistic regression was 1.12 (95% CI = 0.42-3.00), the risk ratio using standardization was 1.18 (95% CI = 0.47-2.16), and the risk ratio using inverse probability weighting was 1.8 (95% CI = 0.41-4.66). CONCLUSIONS: The incidence of cancer in patients with SLE in the LUNA cohort did not significantly differ from that in the general population. These findings suggest that CNI treatment in this cohort did not pose a risk factor for cancer development.

DOI： 10.1186/s13075-024-03285-x

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE: Differences in communication styles based on physicians' personality traits have been identified, particularly in primary care, and these physician-related factors can be important in building patient-physician trust. This study examined the effects of rheumatologists' personality traits on patients' trust in their attending rheumatologists. METHODS: This cross-sectional study included adult Japanese patients with systemic lupus erythematosus (SLE) at 5 academic medical centers between June 2020 and August 2021. The exposures were the Big 5 personality traits (ie, extraversion, agreeableness, openness, conscientiousness, and emotional stability) of attending rheumatologists using the Japanese version of the 10-Item Personality Inventory scale (1-7 points each). The outcome was the patients' trust in their attending rheumatologist using the Japanese version of the 5-item Wake Forest Physician Trust Scale (0-100 points). A general linear model was fitted. RESULTS: The study included 505 patients with a mean age of 46.8 years; 88.1% were women. Forty-three attending rheumatologists (mean age: 39.6 years; 23.3% female) were identified. After multivariable adjustment, higher extraversion and agreeableness were associated with higher trust (per 1-point increase, 3.76 points [95% CI 1.07-6.45] and 4.49 points [95% CI 1.74-7.24], respectively), and higher conscientiousness was associated with lower trust (per 1-point increase, -2.17 points [95% CI -3.31 to -1.03]). CONCLUSION: Whereas higher extraversion and agreeableness of attending rheumatologists led to higher patient trust in their rheumatologist, overly high conscientiousness may lead to lower trust resulting from the physicians' demand of responsibility and adherence to instructions from patients with SLE.

DOI： 10.3899/jrheum.2023-0603

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE: The relationship between FMF and pregnancy outcomes remains unclear. This systematic review and meta-analysis aimed to clarify this association. METHODS: Electronic databases-PubMed, Web of Science, Cochrane, and EMBASE-were searched on 20 December 2022, using specific search terms. Case-control, cohort, and randomized clinical trial studies comparing patients with FMF and healthy controls were considered eligible. We excluded systematic reviews, meta-analyses, case series with fewer than five cases, republished articles without new findings on pregnancy outcomes, studies targeting paternal FMF, and those not published in English. The results were summarized in the form of odds ratios (ORs) and 95% CIs, using a random-effects model. This study was registered in the University hospital Medical Information Network Clinical Trials Registry (Japan) as UMIN000049827. RESULTS: The initial electronic search identified 611 records, of which 9 were included in this meta-analysis (177 735 pregnancies, 1242 with FMF, and 176 493 healthy controls). FMF was significantly associated with increased odds of preterm deliveries (OR, 1.67; 95% CI, 1.05-2.67; I2 = 22%) and insignificantly associated with increased odds of fetal growth restriction (OR, 1.45; 95% CI, 0.90-2.34; I2 = 0%) and hypertensive disorders during pregnancy (OR, 1.28; 95% CI, 0.87-1.87; I2 = 0%). CONCLUSION: FMF was significantly associated with preterm delivery and insignificantly associated with fetal growth restriction and hypertensive disorders. All of the included studies were observational studies. Treatment characteristics were not fully collected from the articles, and further analysis of treatments for FMF in pregnancy is still warranted.

DOI： 10.1093/rheumatology/kead417

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Oxford University Press (OUP)  

Abstract

Objectives

To unravel the mechanisms underlying cell death in the vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome using peripheral blood samples and to assess the clinical value of this knowledge.

Methods

Nine patients undergoing treatment for VEXAS syndrome at Yokohama City University Hospital were included in this study. Monocytes and neutrophils were isolated from peripheral blood and then monocytes were differentiated into polarized macrophages. Viable cell counts, cell death assays and measurements of various indicators such as high mobility group box 1 (HMGB1) concentration, extracellular adenosine triphosphate (ATP) concentration, annexin V level and caspase 1, 3 and 7 activities were performed.

Results

Elevated cell death of monocytes and neutrophils was observed in VEXAS syndrome patients, as indicated by cultured cell counts and cell death assays. Annexin V assays and measurements of caspase 1, 3 and 7 activities suggested increased apoptosis and pyroptosis in these cells. Serum HMGB1 levels were significantly elevated in VEXAS syndrome patients and decreased after prednisolone (PSL) dose escalation. Monocytes and neutrophils from the VEXAS group exhibited heightened extracellular ATP secretion, which was significantly reduced by soluble PSL co-culture.

Conclusion

This study confirms increased cell death of monocytes and neutrophils and damage-associated molecular patterns in VEXAS syndrome, and these findings may be valuable for drug screening, therapeutic strategies and as biomarkers.

DOI： 10.1093/rap/rkae065

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その他リンク： https://academic.oup.com/rheumap/article-pdf/8/2/rkae065/58164487/rkae065.pdf

記述言語：英語   掲載種別：研究論文（学術雑誌）  

INTRODUCTION: Patients with adult-onset Still's disease (AOSD) are at risk of developing macrophage activation syndrome (MAS), a life-threatening condition. Some cases of MAS have been reported following the use of biological agents, highlighting the need to identify contributing factors. This study aims to examine the characteristics of MAS in patients with AOSD treated with anakinra (ANA) or tocilizumab (TCZ). METHODS: A systematic search was conducted across four online databases to identify studies reporting the incidence rates of MAS in patients with AOSD treated with ANA or TCZ. Meta-analysis was performed using a random-effects model and the generic inverse variance method to estimate the pooled incidence rates. The difference in incidence rates of MAS between TCZ and ANA was assessed. Additionally, we analyzed laboratory data and clinical features of AOSD cases at our institution, stratifying them into two groups: those who developed MAS after TCZ administration and those who did not. RESULTS: Of the 455 screened articles, we included five ANA and six TCZ studies. The pooled incidence rates of MAS were 1.50% (95% confidence interval [CI], 0-3.36) for ANA (345 patients) and 14.01% (95% CI 4.51-23.51) for TCZ (94 patients). MAS incidence was significantly higher in the TCZ group (P = 0.01). Among the 17 patients from our institution, the six patients who developed MAS had significantly higher white blood cell and neutrophil counts, as well as elevated levels of lactate dehydrogenase, C-reactive protein, and ferritin before TCZ induction (P < 0.05). CONCLUSIONS: In patients with AOSD, the manifestation of MAS is influenced by multiple causative factors. Consequently, the administration of TCZ should be approached with caution, particularly in patients exhibiting elevated inflammatory markers. TRIAL REGISTRATION: This study was registered with the Clinical Trial Registry of the University Hospital Medical Information Network (Japan) as UMIN000049243.

DOI： 10.1007/s40744-023-00600-x

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is a new disease entity with autoinflammatory disorders (AID) driven by somatic variants in UBA1 that frequently co-exists with myelodysplastic syndromes (MDS). Clinicopathological and molecular features of Japanese cases with VEXAS-associated MDS remain elusive. We previously reported high prevalence of UBA1 variants in Japanese patients with relapsing polychondritis, in which 5 cases co-occurred with MDS. Here, we report clinicopathological and variant profiles of these 5 cases and 2 additional cases of MDS associated with VEXAS syndrome. Clinical characteristics of these cases included high prevalence of macrocytic anemia with marked cytoplasmic vacuoles in myeloid/erythroid precursors and low bone marrow (BM) blast percentages. All cases were classified as low or very low risk by the revised international prognostic scoring system (IPSS-R). Notably, 4 out of 7 cases showed significant improvement of anemia by treatment with prednisolone (PSL) or cyclosporin A (CsA), suggesting that an underlying inflammatory milieu induced by VEXAS syndrome may aggravate macrocytic anemia in VEXAS-associated MDS. Targeted deep sequencing of blood samples suggested that MDS associated with VEXAS syndrome tends to involve a smaller number of genes and lower risk genetic lesions than classical MDS.

DOI： 10.1007/s12185-023-03598-8

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE: Providing appropriate health information to patients with systemic lupus erythematosus (SLE) is advantageous in the treatment decision-making process. We aimed to investigate how online health information-seeking behaviors affect shared decision-making (SDM) in patients with SLE. METHODS: This cross-sectional study included 464 patients with SLE from five institutions. The main exposure was time spent on the internet per day, divided into four categories (none, <1 h, 1- < 2 h, ≥2 h). Participants categorized their preferred first source of health information as physicians, the internet, or other media. The outcome was the degree of SDM measured via the 9-item Shared Decision-Making Questionnaire (SDM-Q-9). A general linear model was applied. RESULTS: Compared to no internet use, longer internet use was associated with a higher SDM-Q-9 score: <1 h, 6.9 points (95% confidence interval [CI] 0.32 to 13.6) and ≥2 h, 8.75 points, (95% CI 0.61 to 16.9). The SDM-Q-9 did not differ between the individuals who chose physicians and those who chose the Internet as their preferred first source of health information (-2.1 points, 95% CI -6.7 to 2.6). Individuals who chose other media had significantly lower SDM-Q-9 scores than those who chose physicians (-7.6 points, 95% CI -13.2 to -1.9). CONCLUSIONS: The present study suggests that SDM between physicians and patients is positively associated with online information-seeking behavior, with no negative influence associated with accessing the Internet before clinical consultations. Rheumatologists may need to introduce their patients to websites offering high-quality health information to establish a good physician-patient relationship for SDM.

DOI： 10.1177/09612033231200104

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVES: There is a high prevalence of burnout among rheumatologists. Grit, which is defined as possessing perseverance and a passion to achieve long-term goals, is predictive of success in many professions; however, whether grit is associated with burnout remains unclear, especially among academic rheumatologists, who have multiple simultaneous responsibilities. Thus, the purpose of this study was to examine the associations between grit and self-reported burnout components-professional efficacy, exhaustion, and cynicism-in academic rheumatologists. METHODS: This cross-sectional study involved 51 rheumatologists from 5 university hospitals. The exposure was grit, measured using mean scores for the 8-item Short Grit Scale (range, 1-5 [5 = extremely high grit]). The outcome measures were mean scores for 3 burnout domains (exhaustion, professional efficacy, and cynicism; range, 1-6; measured using the 16-item Maslach Burnout Inventory-General Survey). General linear models were fitted with covariates (age, sex, job title [assistant professor or higher vs lower], marital status, and having children). RESULTS: Overall, 51 physicians (median age, 45 years; interquartile range, 36-57; 76% men) were included. Burnout positivity was found in 68.6% of participants (n = 35/51; 95% confidence interval [CI], 54.1, 80.9). Higher grit was associated with higher professional efficacy (per 1-point increase; 0.51 point; 95% CI, 0.18, 0.84) but not with exhaustion or cynicism. Being male and having children were associated with lower exhaustion (-0.69; 95% CI, -1.28, -0.10; p = 0.02; and -0.85; 95% CI, -1.46, -0.24; p = 0.006). Lower job title (fellow or part-time lecturer) was associated with higher cynicism (0.90; 95% CI, 0.04, 1.75; p = 0.04). CONCLUSIONS: Grit is associated with higher professional efficacy among academic rheumatologists. To prevent burnout among staff, supervisors who manage academic rheumatologists should assess their staff's individual grit.

DOI： 10.1097/RHU.0000000000001989

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Frontiers Media SA  

Objectives

Infection is a leading cause of death in patients with systemic lupus erythematosus (SLE). Alt hough hydroxychloroquine (HCQ) has been reported to inhibit infection, evidence from Asian populations remains insufficient. We investigated this effect in Japanese SLE patients.

Methods

Data from the Lupus Registry of Nationwide Institutions were used in this study. The patients were ≥20 years old and met the American College of Rheumatology (ACR) classification criteria revised in 1997. We defined “severe infections” as those requiring hospitalization. We analyzed the HCQ’s effect on infection suppression using a generalized estimating equation (GEE) logistic regression model as the primary endpoint and performed a survival analysis for the duration until the first severe infection.

Results

Data from 925 patients were used (median age, 45 [interquartile range 35–57] years; female, 88.1%). GEE analysis revealed that severe infections were significantly associated with glucocorticoid dose (odds ratio [OR] 1.968 [95% confidence interval, 1.379–2.810], p&amp;lt;0.001), immunosuppressants (OR 1.561 [1.025–2.380], p=0.038), and baseline age (OR 1.043 [1.027–1.060], p&amp;lt;0.001). HCQ tended to suppress severe infections, although not significantly (OR 0.590 [0.329–1.058], p=0.077). Survival time analysis revealed a lower incidence of severe infections in the HCQ group than in the non-HCQ group (p&amp;lt;0.001). In a Cox proportional hazards model, baseline age (hazard ratio [HR] 1.029 [1.009–1.050], p=0.005) and HCQ (HR 0.322 [0.142–0.728], p=0.006) were significantly related to incidence.

Conclusion

HCQ may help extend the time until the occurrence of infection complications and tends to decrease infection rates.

DOI： 10.3389/fimmu.2023.1227403

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE: Poor medication adherence among patients with SLE is a critical problem associated with adverse outcomes. This study examined the relationship between trust in one's physician and goal-oriented thinking, hope and medication adherence among Japanese patients with SLE who were ethnically matched to their physicians. METHODS: This cross-sectional study was conducted in the rheumatology outpatient clinics at five academic centres. Patients with SLE who were prescribed oral medications were included. The main exposures were trust in one's physician measured via the 5-item Japanese version of the Wake Forest Physician Trust Scale and the 18-item Health-related Hope Scale, with each score ranging from 0 to 100 points. Medication adherence was measured using the 12-item Medication Adherence Scale with scores ranging from 5 to 60 points. A general linear model was created after adjusting for demographics, socioeconomic status, disease activity, disease duration, basic health literacy, depression, medication variables, experiencing adverse effects and concerns regarding lupus medications. RESULTS: Altogether, 373 patients with SLE were included. The mean age of the patients was 46.4 years; among them, 329 (88.2%) were women. Both trust in one's physician (per 10-point increase: 0.86, 95% CI 0.49, 1.22) and the Health-related Hope score (per 10-point increase: 0.66, 95% CI 0.35, 0.97) were associated with better medication adherence. CONCLUSIONS: This study demonstrated that patients' health-related hope and trust in their rheumatologist were both associated with better medication adherence in SLE.

DOI： 10.1093/rheumatology/keac565

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVES: Although personality characteristics of patients with SLE affect their disease activity and damage, it is unclear whether those of attending physicians affect the outcomes of patients with SLE. Grit is a personality trait for achieving long-term goals that may influence the decision-making for continuing treatment plans for patients. We aimed to evaluate the relationship between the grit of attending physicians and achievement of treatment goals in patients with SLE. METHODS: This cross-sectional study was conducted at five referral hospitals. The main exposure was 'consistency of interest' and 'perseverance of effort' of the attending physicians, measured by the Short Grit Scale. The primary outcome was achievement of a lupus low disease activity state (LLDAS). The association between physicians' grit score and LLDAS was analysed by generalized estimating equation (GEE) logistic regression with cluster robust variance estimation, with adjustment for confounders. RESULTS: The median (interquartile range) total, consistency and perseverance scores of 37 physicians were 3.1 (2.9-3.6), 3.3 (2.8-3.8) and 3.3 (3.0-3.5), respectively. Among the 386 patients, 154 (40%) had achieved LLDAS. Low consistency score (≤2.75) in physicians was related to LLDAS achievement independently using GEE logistic regression. The score of the question 'I often set a goal but later choose to pursue a different one' was significantly higher in patients achieving LLDAS. CONCLUSIONS: Difficulty of attending physicians to change treatment goals might be related to lower LLDAS achievement in patients with SLE.

DOI： 10.1093/rheumatology/keac612

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.2169/internalmedicine.1490-22

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE: Patients who trust their physicians have been shown to demonstrate good medication adherence, self-management, and favorable disease outcomes. This study examines how trust in physicians is affected by functional health literacy (HL) and by broader concepts of HL, including communicative HL and critical HL, among patients with systemic lupus erythematosus (SLE). METHODS: This was a cross-sectional study using baseline data from the Trust Measurement for Physicians and Patients with SLE (TRUMP2-SLE) study, an ongoing multicenter cohort study conducted at 5 academic centers. The 14-item Functional, Communicative, and Critical Health Literacy Scale assessed the 3 dimensions of HL; each item of the scale was scored on a 4-point Likert scale, ranging from 1 to 4. Outcomes were trust in one's physician and trust in physicians in general using the 5-item Wake Forest Physician Trust Scale, which ranged from 0 to 100 points. General linear models were fit. RESULTS: A total of 362 patients with SLE were included. Trust in one's physician increased with higher functional and communicative HL (per 1-point increase: mean difference 3.39, 95% CI 0.39-6.39, and mean difference 5.88, 95% CI 2.04-9.71, respectively). Trust in physicians in general increased with higher communicative HL and decreased with higher critical HL (per 1-point increase: mean difference 7.09, 95% CI 2.34-11.83, and mean difference -6.88, 95% CI -11.72 to -2.04, respectively). Longer internet use was associated with both higher communicative and critical HL. CONCLUSION: The findings suggest that rheumatologists need to improve their communication to match each patient's HL, which may foster trust and lead to improved self-management and outcomes in SLE. They also suggest that the formation of the rheumatologist-patient relationship may negate the effect of high critical HL in building trust.

DOI： 10.3899/jrheum.220678

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVES: With the increased use of immune checkpoint inhibitors (ICIs), arthralgia has been the most commonly reported musculoskeletal immune-related adverse events (irAEs). We aimed to characterise arthralgia and its association with overall survival (OS). METHODS: Randomised controlled trials (RCTs) reporting data for ICI-induced arthralgia from four online databases were comprehensively investigated. Odds ratios (OR) with 95% confidence intervals (CI) were calculated for arthralgia using a random effects model meta-analysis. Individual patient data were reconstructed from RCTs, assessing OS in patients with or without ICI-induced arthralgia. We also retrospectively collected data on the clinical features and outcomes of ICI-induced arthralgia in the Yokohama City University (YCU) registry. RESULTS: We analysed 14,377 patients from 24 RCTs. The OR of ICI-induced arthralgia was 1.37 (95% CI 1.20-1.56). Of the 369 patients in YCU registry, 50 (13.6%) developed ICI-induced arthralgia. Among them, 30 had other grade ≥2 irAEs; noticeably more frequently vs. those without arthralgia (OR 1.92, 95% CI 1.04-3.52). By irAE types, a significant difference was found for relative adrenal insufficiency (OR 3.88, 95% CI 1.80-8.39). In the YCU registry, patients with (vs. without) ICI-induced arthralgia had better OS (log-rank, P < 0.001). OS results were validated from RCT patients with matched cancer types, drugs, and time to arthralgia onset (hazard ratio 0.34, 95% CI 0.17-0.65, P < 0.001). CONCLUSION: If arthralgia develops after ICIs, another irAE, such as relative adrenal insufficiency, may have developed. The incidence of arthralgia was associated with better OS and patients' condition must be carefully evaluated to determine optimal management.

DOI： 10.1093/rheumatology/keac519

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE: Fatigue is one of the most common complaints and is a potentially modifiable issue in systemic lupus erythematosus (SLE). Studies suggest that alcohol consumption has a protective effect against the development of SLE; however, an association between alcohol consumption and fatigue in patients with SLE has not been studied. Here, we assessed whether alcohol consumption was associated with fatigue using lupus patient-reported outcomes (LupusPRO). METHODS: This cross-sectional study, conducted between 2018 and 2019, included 534 patients (median age, 45 years; 87.3% female) from 10 institutions in Japan. The main exposure was alcohol consumption, which was defined as the frequency of drinking [<1 day/month (none group), ≤1 day/week (moderate group), and ≥2 days/week (frequent group)]. The outcome measure was the Pain Vitality domain score in LupusPRO. Multiple regression analysis was performed as the primary analysis after adjusting for confounding factors, such as age, sex, and damage. Subsequently, the same analysis was performed as a sensitivity analysis after multiple imputations (MIs) for missing data (n = 580). RESULTS: In total, 326 (61.0%) patients were categorized into the none group, 121 (22.7%) into the moderate group, and 87 (16.3%) into the frequent group. The frequent group was independently associated with less fatigue compared with none group [β = 5.98 (95% CI 0.19-11.76), p = 0.04], and the results did not substantially deviate after MI. CONCLUSIONS: Frequent drinking was associated with less fatigue, which highlights the need for further longitudinal studies focusing on drinking habits in patients with SLE.

DOI： 10.1177/09612033231159471

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Immune checkpoint inhibitors (ICIs) have been a breakthrough in cancer therapy. ICI therapy is generally better tolerated than cytotoxic chemotherapy; however, hematological adverse events (AEs) have not been fully analyzed. Hence, we performed a meta-analysis to evaluate the incidence and risk of ICI-related hematological AEs. METHODS: A systematic literature search was performed using PubMed, EMBASE, Cochrane Library, and the Web of Science Core Collection. Phase III randomized controlled trials (RCTs) involving ICI combination regimens were selected. The experimental group received ICIs with systemic treatment, and the control group received only the same systemic treatment. Odds ratios (ORs) for anemia, neutropenia, and thrombocytopenia were calculated using a random-model meta-analysis. RESULTS: We identified 29 RCTs with 20,033 patients. The estimated incidence rates for anemia of all grades and grades III-V were 36.5% (95% confidence interval (CI) 30.23 - 42.75) and 4.1% (95% CI 3.85 - 4.42), respectively. The incidence of neutropenia (all grades 29.7%, grades III-V 5.3%) and thrombocytopenia (all grades 18.0%, grades III-V 1.6%) was also calculated. CONCLUSION: Treatment with ICIs seemed unlikely to increase the incidence of anemia, neutropenia, and thrombocytopenia in all grades. However, programmed cell death-1 receptor ligand inhibitors significantly increased the risk of grades III-V thrombocytopenia (OR 1.53; 95% CI 1.11 - 2.11). Further research is needed to examine the potential risk factors.

DOI： 10.14740/jh1090

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

INTRODUCTION: Patients with systemic lupus erythematosus (SLE) frequently change attending physicians. The number of changes in attending physicians is related to the accumulated organ damage in patients with diabetes mellitus and inflammatory bowel disease, although similar results are not known for patients with SLE. This study investigated whether the number of attending physicians after the onset of SLE is associated with organ damage. METHODS: Patients with SLE were enrolled in a multicenter registry of 14 institutions (the Lupus Registry of Nationwide Institutions). Patients with a disease duration of 6 months to 10 years were included. Exposure was defined as the number of attending physicians. The primary outcome was the Systemic Lupus International Collaborating Clinics/American College of Rheumatology damage index (SDI). The secondary outcomes were corticosteroid- and non-corticosteroid-related damage. Multiple logistic regression analysis was used to estimate the association between the number of attending physicians and SDI, adjusting for potential confounders, including age, sex, disease duration, number of hospitalizations due to SLE, disease activity at diagnosis, and emotional health. RESULTS: Of the 702 patients, 86.5% were women (median age 46 years, interquartile range 35-58). The disease duration was 7.3 years (4.3-11.3), the number of hospitalizations due to SLE was 1 (1-3), the number of attending physicians was 3 (2-4), and SDI was 0 points (0-1). The number of attending physicians was significantly associated with SDI [odds ratio (OR) 1.14, 95% confidence interval (CI) 1.03-1.26]. In the secondary outcome, the number of attending physicians was significantly associated with corticosteroid-related damage (OR 1.22, 95% CI 1.09-1.38). The number of attending physicians was not significantly associated with non-corticosteroid-related damage (OR 1.08, 95% CI 0.99-1.19). CONCLUSIONS: This study showed that SDI could increase as the number of attending physicians increases. The impact of changing attending physicians warrants greater attention for SLE and other diseases.

DOI： 10.1007/s40744-022-00528-8

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Oxford University Press (OUP)  

Abstract

Objectives

We aimed to evaluate the efficacy and safety of hematopoietic stem cell transplantation (HSCT) in patients with systemic sclerosis (SSc).

Methods

A systematic literature review and meta-analysis were carried out. We compared survival outcomes using the Kaplan-Meier method with patient-level data between HSCT and intravenous pulse cyclophosphamide (IVCY). Additionally, the incidence rate of treatment-related deaths with HSCT was pooled using a random-effect model.

Results

Of the 2,091 articles screened, 22 were included: 3 randomized controlled trials and 19 observational studies. HSCT studies showed significant improvement in the skin thickness score and lung function. Despite treatment-related deaths being higher in HSCT than in IVCY, the Kaplan-Meier analysis showed a high survival rate 2 years post-transplant (log-rank, P=0.004). The pooled frequency of transplant-related death from 700 SSc patients was 6.30% (95% confidence interval 4.21-8.38). However, the estimated frequency of treatment-related deaths has been reducing over the last decade.

Conclusion

HSCT is an effective treatment for SSc, but the optimal indications must be carefully determined by balancing the risks.

DOI： 10.1093/mr/roac026

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担当区分：責任著者   記述言語：英語  

Cryptococcal meningitis (CM) is a life-threatening disease that primarily affects patients with human immunodeficiency virus (HIV). Antifungal therapy with antiretroviral treatment (ART) usually leads to the clinical remission of CM; however, in some cases, these treatments exacerbate intracranial inflammation because of paradoxical inflammatory reaction or immune reconstitution inflammatory syndrome (IRIS). Here we report two CM cases that presented atypical clinical courses attributed to paradoxical inflammatory reactions. The first case was a 43-year-old man with headache and vertigo diagnosed with CM and HIV. The patient's CM not only was refractory to the antifungal combination therapy of liposomal amphotericin B (L-AMB) and fluconazole (FLCZ) but suddenly worsened because of a paradoxical inflammatory reaction after 18 days of treatment. He passed away from brain herniation on day 23. The second case was a 43-year-old man diagnosed with CM and HIV. After receiving antifungal therapy and ART, the patient's status was stable for more than 3 years with undetectable HIV-RNA. He suddenly presented with brain inflammation and was diagnosed with IRIS due to CM (CM-IRIS). His brain lesions were migratory and refractory to various antifungal therapies such as L-AMB, FLCZ, flucytosine, and intrathecal amphotericin B. Although the cryptococcal antigen in the patient's cerebrospinal fluid gradually diminished after continuous antifungal therapies, his cognitive function declined, and right hemiparesis persisted. These two cases of CM presented atypical clinical courses, presumably because of paradoxical inflammatory reactions. It should be noted that the onset of CM-IRIS may not necessarily depend on the timing of ART initiation.

DOI： 10.1016/j.jiac.2022.11.002

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担当区分：筆頭著者,　責任著者   記述言語：英語  

DOI： 10.2169/internalmedicine.1199-22

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Frontiers Media SA  

To date, research on the role of the brainstem and spinal cord in motor behavior has relied on in vitro preparations of the neonatal rodent spinal cord, with or without the brainstem; their spatial and temporal scope are subject to technical limitations imposed by low oxygen tension in deep tissues. Therefore, we created an arterially perfused in situ preparation that allowed us to investigate functional interactions in the CNS from the neonatal to adult period. Decerebrated rodents were kept alive via total artificial cardiopulmonary bypass for extracorporeal circulation; the plasma oxygen and ion components needed for survival were supplied through the blood vessels. Interferon regulatory factor 8 (IRF8) is a transcription factor that promotes myeloid cell development and stimulates innate immune responses. In the brain, IRF8 is expressed only in microglia and directs the expression of many genes that serve microglial functions. Recent evidence indicates that IRF8 affects behavior and modulates Alzheimer’s disease progression in a mouse model. However, whether this immune deficiency arising from the absence of IRF8 influences the development of the neuronal network in the spinal cord is unknown. We applied the above methodology to mice of all ages and electrophysiologically explored whether the absence of IRF8 influences the development of lumbar central pattern generator (CPG) networks. In mice of all ages, bilateral neuronal discharges by the normal CPG networks activated by the modulated sympathetic tone via descending pathways at high flow rates became organized into discharge episodes punctuated by periods of quiescence. Similar discharge episodes were generated by the adult CPG networks (≥P14 days) activated by drug application. However, discharge episodes elicited by activating the neonatal-juvenile CPG networks (&amp;lt;P14 days) occurred alternately on the left and right sides. Interestingly, discharge episodes elicited by the CPG networks in adult IRF8 knockout mice (P11–12 weeks) consisted of those elicited by the CPG networks of both periods. Thus, it was suggested that growing up with immunodeficiency due to loss of IRF8 might interfere with the normal development of functions exerted by the lumbar CPG network because IRF8 plays a role in the normal development of the lumbar CPG network.

DOI： 10.3389/fnins.2023.1234215

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Japanese Society of Internal Medicine  

DOI： 10.2169/internalmedicine.9471-22

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1093/mr/roab098

Web of Science

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE: It is still unclear how glucocorticoids (GCs) affect the long-term clinical course of patients with SLE. The objective of this study is to explore the factors associated with GC-free treatment status. METHODS: Using data from the lupus registry of nationwide institutions, GC dose at registration was compared between short, middle and long disease durations of <5, 5-20 and ≥20 years, respectively. After excluding patients who never used GC, we evaluated the relationship between GC-free status and chronic damage using Systemic Lupus International Collaborating Clinics Damage Index. RESULTS: GC doses at enrolment of the 1019 patients were as follows: GC-free in 101 (10%); 0<prednisolone (PSL) ≤5 mg/day in 411 (40%); 5<PSL ≤7.5 in 169 (17%); 7.5<PSL ≤10 in 194 (19%) and PSL≥10 in 144 (14%) patients. Of the patients who were not currently using GCs, patients who never used GC more frequently had short disease duration (66% with short, 23% with middle and 17% with long disease duration, p=0.00029). Univariate analysis of patients who underwent GC treatment showed that patients without GCs exhibited older age, lower disease activity, less immunosuppressant and hydroxychloroquine use and higher C3 levels. Among patients with a disease duration of ≥20 years, GC-free status was more frequent in patients without chronic damage (11% vs 4%, p=0.023). After adjusting for age, sex and disease activity, no chronic damage accrual was associated with GC-free status (OR 3.6, 95% CI 1.1 to 11.3). CONCLUSION: Even in the patients with long disease duration, one-point GC-free treatment status might be related to no chronic damage accrual.

DOI： 10.1136/lupus-2022-000772

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Disseminated nontuberculous mycobacterial infection (DNTM) is typically observed in immunocompromised hosts. Recently, it has been reported that healthy individuals with serum neutralizing autoantibodies for interferon (IFN)-γ can also develop DNTM. We herein report a case of anti-IFN-γ antibody-seropositive DNTM caused by Mycobacterium kansasii with symptoms mimicking TAFRO or POEMS syndrome, including anasarca, organomegaly, skin pigmentation, polyneuropathy, osteosclerotic change, thrombocytopenia, serum M protein, high C-reactive protein level, and reticulin fibrosis. The combination of antimicrobial chemotherapy with glucocorticoid and intravenous immunoglobulin improved his symptoms. Glucocorticoids may be an effective method of suppressing the production of anti-IFN-γ antibodies in DNTM.

DOI： 10.2169/internalmedicine.8366-21

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

Abstract

Background

Infection is a major cause of mortality in patients with systemic lupus erythematosus (SLE). Therefore, minimizing the risk of infection is an important clinical goal to improve the long-term prognosis of SLE patients. Treatment with ≥7.5 mg prednisolone (PSL) or equivalent has been reported to increase the risk of infections. However, it remains unclear whether &lt;7.5 mg PSL or equivalent dose affects the risk of infection in SLE patients. This study evaluated the association between the occurrence of infection in patients with SLE and low-dose glucocorticoid (GC) usage, especially &lt;7.5 mg PSL or equivalent, to explore the GC dose that could reduce infection occurrence.

Methods

This prospective cohort study included patients from the Japanese multicenter registry of patients with SLE (defined as ≥4 American College of Rheumatology 1997 revised criteria) over 20 years of age. The PSL dose was categorized as PSL 0–2.5, 2.6–5.0, 5.1–7.5, and 7.6–15.0 mg. The primary outcome was infection requiring hospitalization. We conducted a multivariable analysis using time-dependent Cox regression analysis to assess the hazard ratio of infection occurrence compared with a dose of 0–2.5 mg PSL or equivalent in the other three PSL dose groups. Based on previous reports and clinical importance, the covariates selected were age, sex, and concurrent use of immunosuppressants with GC. In addition, two sensitivity analyses were conducted.

Results

The mean age of the 509 SLE patients was 46.7 years; 89.0% were female, and 77.2% used multiple immunosuppressants concomitantly. During the observation period, 52 infections requiring hospitalization occurred. The incidence of infection with a PSL dose of 5.0–7.5 mg was significantly higher than that in the PSL 0–2.5 mg group (adjusted hazard ratio: 6.80, 95% confidence interval: 2.17–21.27). The results of the two sensitivity analyses were similar.

Conclusions

Our results suggested that the use of 5.0–7.5 mg PSL or equivalent could pose an infection risk in SLE patients. This finding indicates that PSL dose should be reduced to as low as possible in SLE patients to avoid infection.

DOI： 10.1186/s13075-022-02869-9

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その他リンク： https://link.springer.com/article/10.1186/s13075-022-02869-9/fulltext.html

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Although vitamin D concentration is reportedly associated with the pathogenesis and pathology of systemic lupus erythematosus (SLE), benefits of vitamin D supplementation in SLE patients have not been elucidated, to our knowledge. We investigated the clinical impacts of vitamin D supplementation in SLE. METHODS: A cross-sectional analysis was performed using data from a lupus registry of nationwide institutions. We evaluated vitamin D supplementation status associated with disease-related Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI) as a parameter of long-term disease activity control. RESULTS: Of the enrolled 870 patients (mean age: 45 years, mean disease duration: 153 months), 426 (49%) received vitamin D supplementation. Patients with vitamin D supplementation were younger (43.2 vs 47.5 years, P < 0.0001), received higher doses of prednisolone (7.6 vs 6.8 mg/day, P = 0.002), and showed higher estimated glomerular filtration rates (79.3 vs 75.3 mL/min/1.73m2, P = 0.02) than those without supplementation. Disease-related SDI (0.73 ± 1.12 vs 0.73 ± 1.10, P = 0.75), total SDI, and SLE Disease Activity Index (SLEDAI) did not significantly differ between patients receiving and not receiving vitamin D supplementation. Even after excluding 136 patients who were highly recommended vitamin D supplementation (with age ≥ 75 years, history of bone fracture or avascular necrosis, denosumab use, and end-stage renal failure), disease-related SDI, total SDI, and SLEDAI did not significantly differ between the two groups. CONCLUSIONS: Even with a possible Vitamin D deficiency and a high risk of bone fractures in SLE patients, only half of our cohort received its supplementation. The effect of vitamin D supplementation for disease activity control was not observed.

DOI： 10.1371/journal.pone.0270569

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記述言語：英語  

Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome is an autoinflammatory disease caused by somatic variants in the UBA1 gene that lead to severe systemic inflammation and myelodysplastic syndrome. Although no standard therapy has been established yet, azacitidine and bone marrow transplantation have been reported to be promising possibilities; however, the indications for these treatments are problematic and not necessarily applicable to all patients. We previously reported the results of short-term treatment with tocilizumab (TCZ) and glucocorticoids in three patients with VEXAS syndrome. In this paper, we report that the combination of TCZ and glucocorticoids allowed the patients to continue treatment for at least one year without significant disease progression. Glucocorticoids were able to be reduced from the start of TCZ. Adverse events were herpes zoster, skin ulceration after cellulitis, and decreased blood counts. The results suggest the significance of this treatment as a bridge therapy for the development of future therapies.

DOI： 10.3389/fimmu.2022.901063

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Frontiers Media SA  

Behçet’s disease (BD) is a systemic inflammatory disease characterized by recurrent oral ulcers, genital ulcers, cutaneous inflammation, and uveitis. In addition, other potentially life-threatening lesions may occur in the intestinal tract, blood vessels, and central nervous system. This heterogeneity of the BD phenotype hampers development of a targeted treatment strategy. The pathogenesis of BD is not fully elucidated, but it is likely that genetically susceptible people develop BD in response to environmental factors, such as microbiome factors. Genetic analyses have identified various BD susceptibility loci that function in HLA-antigen presentation pathways, Th1 and Th17 cells, and autoinflammation related to monocytes/macrophages, or that increase levels of pro-inflammatory cytokines, reduce levels of anti-inflammatory cytokines, or act in dysfunctional mucous barriers. Our functional analyses have revealed that impairment of M2 monocyte/macrophage-mediated anti-inflammatory function through IL-10 is crucial to BD pathogenesis. We, therefore, propose that BD is an M1-dominant disease. In this review, we describe the roles of monocytes and macrophages in BD and consider the potential of these cells as therapeutic targets.

DOI： 10.3389/fimmu.2022.852297

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Oxford University Press (OUP)  

<title>Abstract</title>
<sec>
<title>Objectives</title>
No large-scale registration study has comprehensively evaluated the activities of daily living (ADL) in patients with Behçet’s disease.


</sec>
<sec>
<title>Methods</title>
The Japanese government provided us with a dataset of confirmed or suspected Behçet’s disease cases derived from ongoing national registration. ADL were categorized and analysed into four categories in patients who satisfied the International Criteria for Behçet’s Disease.


</sec>
<sec>
<title>Results</title>
Data from 2960 patients (men 38.9%, women 61.1%; median age 39 years) were assessed. While 1767 patients (59.7%) had normal ADL, the others had impaired ADL comprising limited but not assisted [n = 1058 (35.7%)], partially assisted [n = 116 (3.9%)] and fully assisted [n = 19 (0.6%)]. Logistic regression analysis showed that chronic ocular lesions [odds ratio (OR) 1.85 (95% CI 1.46, 2.35), P &amp;lt; 0.001], paralysis [OR 2.51 (95% CI 1.58, 3.97), P &amp;lt; 0.001], psychosis [OR 3.16 (95% CI 2.02, 4.95), P &amp;lt; 0.001] and arthritis [OR 1.69 (95% CI 1.44, 1.99), P &amp;lt; 0.001] led to the risk of impaired ADL. Chronic ocular lesions [OR 3.61 (95% CI 2.27, 5.72), P &amp;lt; 0.001], paralysis [OR 3.43 (95% CI 1.87, 6.30), P &amp;lt; 0.001] and psychosis [OR 3.60 (95% CI 2.00, 6.50), P &amp;lt; 0.001] were related to the requirement of physical assistance (partially or fully assisted), although arthritis [OR 1.39 (95% CI 0.93, 2.06), P = 0.108] was not a significant factor in this model.


</sec>
<sec>
<title>Conclusion</title>
Ocular lesions, neurological manifestations and arthritis affected ADL. Patients with ocular lesions or neurological manifestations more frequently required physical assistance.


</sec>

DOI： 10.1093/rheumatology/keab499

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記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Frontiers Media SA  

The prognosis of rheumatic diseases is generally better than that of malignant diseases. However, some cases with poor prognoses resist conventional therapies and cause irreversible functional and organ damage. In recent years, there has been much research on regenerative medicine, which uses stem cells to restore the function of missing or dysfunctional tissues and organs. The development of regenerative medicine is also being attempted in rheumatic diseases. In diseases such as systemic sclerosis (SSc), systemic lupus erythematosus (SLE), and rheumatoid arthritis, hematopoietic stem cell transplantation has been attempted to correct and reconstruct abnormalities in the immune system. Mesenchymal stem cells (MSCs) have also been tried for the treatment of refractory skin ulcers in SSc using the ability of MSCs to differentiate into vascular endothelial cells and for the treatment of systemic lupus erythematosus SLE using the immunosuppressive effect of MSCs. CD34-positive endothelial progenitor cells (EPCs), which are found in the mononuclear cell fraction of bone marrow and peripheral blood, can differentiate into vascular endothelial cells at the site of ischemia. Therefore, EPCs have been used in research on vascular regeneration therapy for patients with severe lower limb ischemia caused by rheumatic diseases such as SSc. Since the first report of induced pluripotent stem cells (iPSCs) in 2007, research on regenerative medicine using iPSCs has been actively conducted, and their application to rheumatic diseases is expected. However, there are many safety issues and bioethical issues involved in regenerative medicine research, and it is essential to resolve these issues for practical application and spread of regenerative medicine in the future. The environment surrounding regenerative medicine research is changing drastically, and the required expertise is becoming higher. This paper outlines the current status and challenges of regenerative medicine in rheumatic diseases.

DOI： 10.3389/fmed.2022.813952

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Oxford University Press (OUP)  

<title>ABSTRACT</title>
Eosinophilic granulomatosis with polyangiitis (EGPA), which belongs to the anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides, is characterised by eosinophil-rich granulomatous inflammation and small- to medium-sized vessel vasculitis associated with bronchial asthma and eosinophilia. It sometimes causes severe organ damage, of which myocardial damage is one of the most important for determining the prognosis. A case of EGPA-associated myocarditis that was refractory to glucocorticoid therapy and responded successfully to rituximab (RTX) and mepolizumab (MPZ) combination therapy is presented. A 46-year-old woman was diagnosed with EGPA-associated myocarditis due to pre-existing asthma, eosinophilia, mononeuritis multiplex, and eosinophilic myocarditis by myocardial biopsy. Transthoracic echocardiography showed thickening of the cardiac wall, pericardial effusion, and left ventricular hypokinesis. Although the myocarditis was refractory to methylprednisolone pulse therapy followed by oral high-dose prednisolone, the disease activity reached remission with the successful tapering of glucocorticoid after initiation of the RTX and MPZ combination therapy. Combination therapy with RTX and MPZ can be a good treatment option for EGPA-associated myocarditis for which it is difficult to give intravenous cyclophosphamide due to cardiac dysfunction.

DOI： 10.1093/mrcr/rxab022

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

<title>Abstract</title>Pyrin/TRIM20 is expressed in the neutrophils and monocytes/macrophages and regulates caspase-1 activation and interleukin-1β maturation. Although the mutations in the PRY/SPRY domain of pyrin cause familial Mediterranean fever (FMF), the mechanism of how mutated pyrin provokes excessive inflammation in FMF patients is not well understood. The present study investigated the role of pyrin/TRIM20 in inflammation and the pathogenesis of FMF. β₂-Microglobulin (β2MG) was identified as the novel pyrin ligand binding to the PRY/SPRY domain by yeast two-hybrid screenings and co-immunoprecipitation analysis. β2MG was co-localized with pyrin not only in the HEK293 cells overexpressing these proteins but also in the monosodium urate-stimulated human neutrophils in the speck-like structures. The pyrin–β2MG interaction triggered the binding of pyrin and proline–serine–threonine phosphatase interacting protein 1 (PSTPIP1) and then the subsequent recruitment of apoptosis-associated speck-like protein containing caspase recruitment domain (ASC). Caspase-1 p20 subunit, produced by pyrin inflammasome, also interacted with the pyrin PRY/SPRY domain and inhibited the pyrin–β2MG interaction. FMF-associated pyrin mutation M694V did not affect pyrin–β2MG interaction but weakened this inhibition. Our findings suggest that β2MG functions as the pyrin ligand inducing pyrin inflammasome formation and that the FMF-associated pyrin mutations weakened negative feedback of caspase-1 p20 subunit.

DOI： 10.1038/s41598-021-03073-6

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その他リンク： https://www.nature.com/articles/s41598-021-03073-6

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：MDPI AG  

To explore the biological and immunological basis of human rheumatoid arthritis and human atherosclerosis, we planned and reported a detailed design and rationale for Orencia Atherosclerosis and Rheumatoid Arthritis Study (ORACLE Arthritis Study) using highly sensitive, high-throughput, human autoantibody measurement methods with cell-free protein synthesis technologies. Our previous study revealed that subjects with atherosclerosis had various autoantibodies in their sera, and the titers of anti-Th2 cytokine antibodies were correlated with the severity of atherosclerosis. Because rheumatoid arthritis is a representative autoimmune disease, we hypothesized that both rheumatoid arthritis and atherosclerosis are commonly developed by autoantibody-mediated autoimmune processes, leading to incessant inflammatory changes in both articular joint tissues and vessel walls. We planned a detailed examination involving carotid artery ultrasonography, measurements of adhesion molecules, such as ICAM-1 (intercellular adhesion molecule 1) and VCAM-1 (vascular cell adhesion molecule 1) for the evaluation of atherosclerosis progression, and high-throughput, high-sensitivity, autoantibody analyses using cell-free technologies, with detailed examinations of the disease activity of rheumatoid arthritis. Analyses of correlations and associations between biological markers and degrees of carotid atherosclerosis over time under consistent conditions may enable us to understand the biological and humoral immunity background of human atherosclerosis and autoimmune diseases.

DOI： 10.3390/mps4040083

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記述言語：英語  

DOI： 10.1136/annrheumdis-2021-220876

Web of Science

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SAGE Publications  

<sec><title>Background</title> TRIM21 is a member of the tripartite motif family proteins and is one of the autoantigens which react with anti-SS-A antibody (Ab) present in sera of patients with systemic lupus erythematosus (SLE) and Sjögren’s syndrome. Previous studies have shown that TRIM21 dysfunction promotes aberrant B-cell differentiation and Ab production in SLE, and anti-TRIM21 Ab may be related to the TRIM21 dysfunction in human SLE pathogenesis. Here, we examined the relationship between anti-TRIM21 Ab and clinical and immunological characteristics in SLE patients.

</sec><sec><title>Methods</title> Twenty-seven patients with SLE (23 women and four men) before immunosuppressive therapies, who fulfilled the revised 1997 American College of Rheumatology criteria for SLE, and four healthy controls (3 women and one man) were enrolled in the study. SLE patients were divided into two groups according to the seropositivity for anti-TRIM21 Ab. Serum anti-TRIM21 Ab levels were measured using enzyme-linked immunosorbent assays. The serum levels of cytokines and immunoglobulins were measured by cytometer beads arrays. The expression levels of TRIM21 protein in peripheral mononuclear cells (PBMCs) from SLE patients were evaluated by Western blotting.

</sec><sec><title>Results</title> Sixteen and 9 patients showed seronegativity and seropositivity for anti-TRIM21 Ab, respectively. There were no significant differences in the background parameters, including female ratio, age, disease duration, SLE activity, and laboratory data between the two groups. The serum levels of interferon (IFN)-β were significantly higher in patients with anti-TRIM21 Ab as compared with those without anti-TRIM21 Ab ( P = .043). The levels of IgG1 and IgA were significantly higher in SLE patients with anti-TRIM21 Ab as compared with those without anti-TRIM21 Ab ( P = .0022 and .032, respectively). The PBMCs of patients with anti-TRIM21 Ab showed a significantly lower expression of TRIM21 protein as compared with those of patients without anti-TRIM21 Ab ( P = .014).

</sec><sec><title>Conclusions</title> Anti-TRIM21 Ab seropositivity was related to B-cell abnormalities and type I IFN overproduction in SLE patients. These findings suggest that anti-TRIM21 Ab may have an inhibitory effect on TRIM21 functions and be a novel biomarker for the level of dependence on type I IFN overproduction and B-cell abnormalities.

</sec>

DOI： 10.1177/09612033211042293

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その他リンク： http://journals.sagepub.com/doi/full-xml/10.1177/09612033211042293

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Oxford University Press (OUP)  

<title>Abstract</title>
<sec>
<title>Objectives</title>
Elevation of serum IL-18 in adult-onset Still's disease (AOSD) and systemic JIA (sJIA) suggests the role of the inflammasome in these diseases. Gasdermin D is a pore-forming protein playing central roles in inflammasome-mediated inflammation, but its role in rheumatic disease is unknown. We aimed to elucidate the auto-inflammatory mechanisms in AOSD and sJIA.


</sec>
<sec>
<title>Methods</title>
Patients with AOSD, sJIA, hemophagocytic lymphohistiocytosis (HLH) and Behçet's disease followed at Yokohama City University (YCU), or US National Institutes of Health (NIH) were included in the study. Disease activity was evaluated by the modified Pouchot score. Ferritin and N-terminal gasdermin D levels in serum and culture supernatant were measured by ELISA. Primary monocytes (Mo) were stimulated with GM-CSF or M-CSF and differentiated into M1 macrophages (Mφ) or M2Mφ, respectively. The number of Mo/Mφ and their viability were monitored over time.


</sec>
<sec>
<title>Results</title>
Patients with active AOSD and sJIA had increased levels of serum gasdermin D N-terminal, which correlated with serum ferritin and IL-18 levels. Mo-derived Mφ from active AOSD patients showed reduced cell viability and increased cell death. The number of cultured Mφ cells on day nine was negatively correlated with the serum ferritin and gasdermin D levels. Higher ferritin and gasdermin D levels were observed in the M1Mφ culture supernatant of active AOSD patients. Gasdermin D inhibitors reduced the pyroptosis-mediated ferritin release in Mo.


</sec>
<sec>
<title>Conclusion</title>
Elevation of serum gasdermin D N-terminal provides evidence for inflammasome activation triggering gasdermin D-mediated Mo and Mφ pyroptosis in AOSD and possibly sJIA.


</sec>

DOI： 10.1093/rheumatology/keaa814

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BMJ  

<sec><title>Objectives</title>To determine clinical and genetic features of individuals with relapsing polychondritis (RP) likely caused by pathogenic somatic variants in ubiquitin-like modifier activating enzyme 1 (<italic>UBA1</italic>).

</sec><sec><title>Methods</title>Fourteen patients with RP who met the Damiani and Levine criteria were recruited (12 men, 2 women; median onset age (IQR) 72.1 years (67.1–78.0)). Sanger sequencing of <italic>UBA1</italic> was performed using genomic DNA from peripheral blood leukocytes or bone marrow tissue. Droplet digital PCR (ddPCR) and peptide nucleic acid (PNA)-clamping PCR were used to detect low-prevalence somatic variants. Clinical features of the patients were investigated retrospectively.

</sec><sec><title>Results</title><italic>UBA1</italic> was examined in 13 of the 14 patients; 73% (8/11) of the male patients had somatic <italic>UBA1</italic> variants (c.121A&gt;C, c.121A&gt;G or c.122T&gt;C resulting in p.Met41Leu, p.Met41Val or p.Met41Thr, respectively). All the variant-positive patients had systemic symptoms, including a significantly high prevalence of skin lesions. ddPCR detected low prevalence (0.14%) of somatic variant (c.121A&gt;C) in one female patient, which was subsequently confirmed by PNA-clamping PCR.

</sec><sec><title>Conclusions</title>Genetic screening for pathogenic <italic>UBA1</italic> variants should be considered in patients with RP, especially male patients with skin lesions. The somatic variant in <italic>UBA1</italic> in the female patient is the first to be reported.

</sec>

DOI： 10.1136/annrheumdis-2021-220089

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

<title>Abstract</title>The transcription factor IRF5 has been implicated as a therapeutic target for the autoimmune disease systemic lupus erythematosus (SLE). However, IRF5 activation status during the disease course and the effects of IRF5 inhibition after disease onset are unclear. Here, we show that SLE patients in both the active and remission phase have aberrant activation of IRF5 and interferon-stimulated genes. Partial inhibition of IRF5 is superior to full inhibition of type I interferon signaling in suppressing disease in a mouse model of SLE, possibly due to the function of IRF5 in oxidative phosphorylation. We further demonstrate that inhibition of IRF5 via conditional <italic>Irf5</italic> deletion and a newly developed small-molecule inhibitor of IRF5 after disease onset suppresses disease progression and is effective for maintenance of remission in mice. These results suggest that IRF5 inhibition might overcome the limitations of current SLE therapies, thus promoting drug discovery research on IRF5 inhibitors.

DOI： 10.1038/s41467-021-24609-4

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その他リンク： http://www.nature.com/articles/s41467-021-24609-4

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Oxford University Press (OUP)  

OBJECTIVE: To determine the real-world short-term efficacy and safety of apremilast for Behçet's disease (BD). METHODS: The study included patients who received apremilast for refractory oral ulcers in addition to meeting International Study Group criteria for BD or the revised International Criteria for Behçet's Disease. To assess the efficacy of apremilast, Behçet's disease current activity form (BDCAF) and patients' self-perception of their disease activity were monitored for three months. The disease phenotypes, laboratory data, concomitant medication use, and adverse events were also investigated. RESULTS: Fourteen BD patients were included in the study. Concomitant drug use were as follows: colchicine 92.9%, prednisolone 21.4%, immunosuppressants 28.6%, and tumor-necrosis inhibitor 14.3%. Oral ulcers and BDCAF scores at 3 months showed significant improvement compared to baseline. Adverse events during the study were diarrhea (n = 3, 21.4%), nausea (n = 3, 21.4%), music hallucination (n = 1, 7.1%), and branch retinal vein occlusion (n = 1, 7.1%). Apremilast was discontinued in 1 patient (7.1%) due to nausea. CONCLUSION: Significant improvement in oral ulcer and BDCAF with apremilast was confirmed in real-world BD patients after 3 months. The combination of colchicine and apremilast appears to be well tolerated in BD in the short-term.

DOI： 10.1080/14397595.2020.1830504

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Oxford University Press (OUP)  

Glucocorticoids (GCs) use is associated with increased organ damage in systemic lupus erythematosus (SLE), and the treatment goal is to stop their use. Treatment with hydroxychloroquine (HCQ) without daily GCs may benefit patients by minimising the cumulative dose of GCs, but clinical experience with HCQ monotherapy is limited. To accumulate evidence for initial HCQ monotherapy in SLE, we retrospectively analysed three new SLE patients who visited Yokohama City University Hospital in 2015. The patients were all Japanese females with a mean age of 26.0 ± 5.3 years, high anti-dsDNA antibody titres, no major organ damage, and a mean pre-treatment Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score of 9.3 ± 3.1. During the mean observation period of 3.8 ± 0.8 years, none of them received daily GCs or immunosuppressants, but one of the three patients were treated with short-term oral GCs and NSAIDs for a skin rash or arthralgia flairs. SLEDAI-2K was reduced to 3.3 ± 1.2. No other new SLE symptoms emerged, and the Systemic Lupus International Collaborating Clinics Damage Index (SDI) of them were maintained at 0. None of the patients developed HCQ-related retinal toxicity. Current experience with initial HCQ monotherapy suggests that such a therapeutic strategy may be useful in managing disease activity and preserving cumulative GCs in SLE patients without organ involvements.

DOI： 10.1080/24725625.2021.1881215

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1001/jama.2021.6615

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SAGE Publications  

DOI： 10.1177/09612033211006790

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その他リンク： http://journals.sagepub.com/doi/full-xml/10.1177/09612033211006790

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1186/s13075-021-02466-2

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その他リンク： http://link.springer.com/article/10.1186/s13075-021-02466-2/fulltext.html

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

<title>Abstract</title><sec>
<title>Background</title>
We hypothesized that Behçet’s disease (BD) consists of several clinical subtypes with different severity, resulting in heterogeneity of the disease. Here, we conducted a study to identify clinical clusters of BD.


</sec><sec>
<title>Methods</title>
A total of 657 patients registered in the Yokohama City University (YCU) regional BD registry between 1990 and 2018, as well as 6754 patients who were initially registered in the Japanese Ministry of Health, Labour and Welfare (MHLW) database between 2003 and 2014, were investigated. The YCU registry data regarding the clinical manifestations of BD, human leukocyte antigen (HLA) status, treatments, and hospitalizations were analyzed first, followed by similar analyses of the MHLW for validation. A hierarchical cluster analysis was independently performed in both patient groups.


</sec><sec>
<title>Results</title>
A hierarchical cluster analysis determined five independent clinical clusters in the YCU cohort. Individual counterparts of the YCU clusters were confirmed in the MHLW registry. Recent phenotypical evolutions of BD in Japan, such as increased gastrointestinal (GI) involvement, reduced complete type according to the Japan Criteria, and reduced HLA-B51 positivity were associated with chronologically changing proportions of the clinical clusters.


</sec><sec>
<title>Conclusions</title>
In this study, we identified independent clinical clusters among BD patients in Japan and found that the proportion of each cluster varied over time. We propose five independent clusters namely “mucocutaneous”, “mucocutaneous with arthritis”, “neuro”, “GI”, and “eye.”


</sec>

DOI： 10.1186/s13075-020-02406-6

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その他リンク： http://link.springer.com/article/10.1186/s13075-020-02406-6/fulltext.html

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier BV  

INTRODUCTION: Mild cognitive dysfunction has been implicated in a number of psychiatric diseases and affects social functioning. Although clinical criteria were recently proposed for autoimmune psychosis (AP), biomarkers have not yet been established for the severity and prognosis of cognitive dysfunction. We herein investigated the relationships between 3 types of serum antibodies and cognitive dysfunction in chronic psychiatric patients suspected of AP. METHODS: We included 31 patients suspected of AP and obtained information on their clinical characteristics. Three types of autoantibodies (the anti-N-methyl-D-aspartate receptor (anti-NMDAR Ab), anti-N-terminal of GluN1 (anti-GluN1-NT Ab), and anti-thyroid antibodies) were evaluated in serum. Cognitive function was assessed using Wechsler Adult Intelligence Scale-III. We examined the relationships between serum autoantibodies and cognitive dysfunction in patients using multiple regression models. RESULTS: Serum titers of anti-GluN1-NT Ab significantly contributed to the estimated score of working memory (B= -55.85, β= -0.46, p= 0.01), while no correlation was observed between the other 2 types of antibodies and cognitive function. CONCLUSIONS: The present results indicate the potential of serum anti-GluN1-NT Ab as a biomarker for the severity and prognosis of cognitive dysfunction underlying various psychiatric symptoms in patients with AP. The pathological significance of anti-GluN1-NT Ab needs to be verified in future studies.

DOI： 10.1016/j.neulet.2020.135588

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier BV  

O-linked N-acetylglucosamine (O-GlcNAc) transferase (OGT) is a unique enzyme introducing O-GlcNAc moiety on target proteins, and it critically regulates various cellular processes in diverse cell types. However, its roles in hematopoietic stem and progenitor cells (HSPCs) remain elusive. Here, using Ogt conditional knockout mice, we show that OGT is essential for HSPCs. Ogt is highly expressed in HSPCs, and its disruption induces rapid loss of HSPCs with increased reactive oxygen species and apoptosis. In particular, Ogt-deficient hematopoietic stem cells (HSCs) lose quiescence, cannot be maintained in vivo, and become vulnerable to regenerative and competitive stress. Interestingly, Ogt-deficient HSCs accumulate defective mitochondria due to impaired mitophagy with decreased key mitophagy regulator, Pink1, through dysregulation of H3K4me3. Furthermore, overexpression of PINK1 restores mitophagy and the number of Ogt-deficient HSCs. Collectively, our results reveal that OGT critically regulates maintenance and stress response of HSCs by ensuring mitochondrial quality through PINK1-dependent mitophagy.

DOI： 10.1016/j.celrep.2020.108579

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Oxford University Press (OUP)  

BACKGROUND: How HLA-A26 modulates Behçet's disease (BD) ocular lesions such as iridocyclitis and retinochorioiditis has not been scrutinized. METHODS: Ministry of Health, Labour and Welfare of Japan provided us a database of BD patients who were registered from 2003 to 2014. We selected patients who satisfied International Criteria for BD and whose data for HLA-A26 was available. RESULTS: Eligible 557 patients consisting of 238 men (42.7%) and 319 women (57.3%), whose median age was 38 years old (interquartile range 29-47) were analyzed. Prevalence of general ocular lesions, iridocyclitis, retinochorioiditis, and chronic lesions were 43.1%, 30.7%, 34.1%, and 17.4%, respectively. The prevalence of ocular lesions was higher among HLA-A26 carriers compared to that among HLA-A26 non-carriers with odds ratio (OR) of 2.5 (95% confidence interval (95% CI) 1.8-3.5, p < .001) for general ocular lesions, OR of 2.5 (95% CI 1.7-3.6, p < .001) for iridocyclitis, OR of 2.8 (95% CI 1.9-4.0, p < .001) for retinochorioiditis, and OR of 2.7 (95% CI 1.7-4.3, p < .001) for 'chronic ocular lesion following iridocyclitis or retinochorioiditis'. The HLA-A26 had a similar impact on ocular lesions between HLA-B51 positive and negative cases (Breslow-Day test, p > .05). However, the HLA-A26 had a larger impact on iridocyclitis for men compared to women (Breslow-Day test, p = .040). The male HLA-A26 carriers had higher risk of iridocyclitis with OR of 3.4 (95% CI 2.0-5.9, p < .001), while the OR for women was 1.5 (95% CI 0.9-2.6, p = .146). CONCLUSION: HLA-A26 carriers had higher risk for iridocyclitis and retinochorioiditis. However, the impact was more prominent for men.

DOI： 10.1080/14397595.2019.1705538

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Immune checkpoint inhibitor (ICI)-related myositis is a rare, potentially fatal condition that warrants further studies. Its incidence, clinical features, and prognosis remain poorly understood. To address these gaps, we conducted a systematic review and meta-analysis to evaluate the risk of myositis associated with ICI for solid tumors by analyzing phase III randomized controlled trials of anti-programmed death-1/ligand-1 (PD-1/PD-L1) and anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4). To complement this analysis with clinical data, we evaluated published ICI case reports along with cases from our institutional registry. This registry comprised 422 patients treated with ICIs alone or in combination from September 2014 to June 2021. The analysis revealed an incidence of ICI-related myositis in 6,838 patients in 18 randomized controlled trials of 0.38% (odds ratio 1.96; 95% confidence interval 1.02-3.75) for patients receiving ICIs compared with controls. Detailed analysis of 88 cases from the literature search and our registry showed that myositis induced by PD-1 inhibitors was more frequent than that induced by anti-CTLA-4 agents, revealing a clinically diverse trend including myasthenia gravis and myocarditis. Importantly, having ptosis at the time of onset was significantly associated with the development of concomitant myocarditis (odds ratio 3.81; 95% CI 1.48-9.83), which is associated with poor prognosis. Regarding treatment, most patients received glucocorticoids, and some received immunosuppressants. Our study revealed the incidence of ICI-mediated myositis and the clinical features of myocarditis, highlighting the need for recognition and early intervention.

DOI： 10.3389/fimmu.2021.803410

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Oxford University Press (OUP)  

Objectives: Although intensive immunosuppressive treatment is necessary for the severe cases with polymyositis (PM)/dermatomyositis (DM), the prognostic factors or disease activity indices for PM/DM have not been established. Here we investigated the association between serum microRNA-1 (miR-1) level and clinical course of patients with PM/DM.Methods: We retrospectively reviewed baseline clinical and laboratory findings, treatment regimens and outcomes in patients with PM/DM. The serum samples were collected from PM/DM patients and healthy controls (HC). Serum miR-1 levels were determined by quantitative real-time PCR.Results: Twenty-two patients were recruited. The average serum miR-1 level was significantly higher in the PM/DM as compared to HC (p = .0085) and was decreased by treatment (p = .032). We divided the PM/DM-ILD patients into two groups, high and normal miR-1 groups. Although there were no significant differences in the clinical data and the initial prednisolone (PSL) dose between the two groups, PSL dose at 16 weeks, cumulative PSL dose until 16 weeks, and frequency of serious infections were significantly higher in the high miR-1 group as compared to the normal group (p = .025, .036, and .026, respectively).Conclusion: We propose serum miR-1 as a promising novel biomarker for predicting therapeutic response in PM/DM-ILD.

DOI： 10.1080/14397595.2019.1661584

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Oxford University Press (OUP)  

Objectives: To scrutinize the influence of HLA-B51 to each clinical manifestation of patients with Behçet's disease (BD) using a database of the Ministry of Health, Labour and Welfare of Japan.Methods: The database of newly registered patients with BD was obtained from the Japanese Ministry of Health, Labour and Welfare. Patients who met International Criteria for Behçet's Disease (ICBD) and had data for HLA-B51 were selected and analyzed.Results: Among the 3044 analyzable cases, 1334 (43.8%) were men and 1710 (56.2%) were women; the median age was 38 years (IQR 29-48). HLA-B51 was positive for 1334 (44.5%). Prevalence of selected manifestations was 98.5% for oral ulceration, 85.5% for skin lesion, 42.1% for ocular lesion, 69.1% for genital ulceration, and 29.0% for gastrointestinal symptom. HLA-B51-positive patients had higher risk for ocular lesion (OR 1.59, 95%CI: 1.37-1.84; p < .001) and lower risk for genital ulceration (OR 0.72, 95%CI: 0.62-0.84; p < .001) and gastrointestinal symptom (OR 0.65, 95%CI: 0.55-0.77; p < .001). No significant difference was observed for other organ involvement; oral ulceration, skin lesion, positive pathergy test, arthritis, epididymitis, vascular lesion, or neurological manifestation. Subgroup analyses revealed that HLA-B51 was not related to genital ulceration in the cases with an ICBD score of 6 or higher and that HLA-B51 tended to more largely affect the risk of three manifestations for men compared to that for women.Conclusion: HLA-B51 positive is a risk factor for ocular lesion and vice versa for genital ulceration and gastrointestinal symptoms in patients with Japanese BD.

DOI： 10.1080/14397595.2019.1649103

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担当区分：最終著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Mary Ann Liebert Inc  

Background: Lymphedema includes primary lymphedema (P-LE) and secondary lymphedema (S-LE), which is a chronic progressive disease. The former group is further classified as congenital and acquired P-LE (AP-LE); its etiology is unclear, and only a few studies on its pathophysiology exist. We hypothesized that an autoimmune disease or self-inflammatory mechanism occurs in lymphatic vessels, leading to obstruction. Methods and Results: We enrolled 46 patients with lymphedema who underwent lymphaticovenous anastomosis (LVA) from January to October 2015. Collecting lymph ducts were obtained during LVA. We performed hematoxylin/eosin staining and immunostaining for LYVE-1, IL-1β, IL-6, and TNF-α. There were no substantial histological differences between the two types of lymphedema, whereas some differences in expression of inflammatory cytokines, including interleukin (IL)-1β and tumor necrosis factor (TNF)-α, were observed. Only a few inflammatory cells could be seen around the vessels. Although no significant differences in expression of IL-1β were found between AP-LE and S-LE, TNF-α was more highly expressed in the smooth muscle layer in AP-LE patients than in S-LE patients. There were no significant morphological differences in the collecting ducts of lymphatic vessels between S-LE and P-LE. Nevertheless, higher levels of TNF-α accumulation were found in the thick smooth muscle layer of P-LE patients than in that of S-LE patients. Conclusion: TNF-α-related inflammation in collecting ducts of lymphatic vessels is an important characteristic of the pathology of P-LE. TNF-α inhibitors might improve symptoms of AP-LE.

DOI： 10.1089/lrb.2019.0046

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その他リンク： https://www.liebertpub.com/doi/pdf/10.1089/lrb.2019.0046

担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Frontiers Media SA  

TRIM21 is one of the autoantigens that reacts with an anti-SS-A antibody (Ab) present in patients with systemic lupus erythematosus (SLE) and Sjögren's syndrome. TRIM21 is thought to play a role in B-cell proliferation and apoptosis, among other activities. Here we examined a pathological role of TRIM21 in SLE. Trim21-deficient MRL/lpr mice were generated by backcrossing Trim21-deficient C57BL/6 mice to MRL/lpr mice. The levels of serum anti-dsDNA Ab and urine protein at 28 weeks of age were significantly higher in Trim21-deficient MRL/lpr mice as compared to wild-type MRL/lpr mice (p = 0.029 and 0.003, respectively). Resting B cells from Trim21-deficient mice showed significantly higher abilities to differentiate into plasmablasts and to produce Ab as compared with control mice. Due to the reduction of TRIM21-mediated ubiquitylation, IRF5 protein expression was increased in Trim21-deficient MRL/lpr mice (p = 0.021), which correlated with increased plasmablast generation and immunoglobulin production. B cells from SLE patients with anti-TRIM21 Ab seropositivity also showed a significantly higher ability to differentiate into plasmablasts as compared with those without anti-TRIM21 Ab or healthy controls. These results suggest that TRIM21 dysfunction contributes to SLE pathogenesis by promoting B-cell differentiation, for which anti-TRIM21 Ab may be partly responsible.

DOI： 10.3389/fimmu.2020.00098

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Oxford University Press (OUP)  

Optic perineuritis (OPN), which is an inflammatory disorder affecting the optic nerve sheath, is one of the rare complications in granulomatosis with polyangiitis (GPA). Although several groups have reported that immunosuppressive therapies are generally effective against GPA-associated OPN, so far, there is little information as to other options for refractory cases. Here we demonstrate a case of GPA-associated OPN, which is refractory to potent immunosuppressive therapy including high-dose glucocorticoid, intravenous cyclophosphamide and rituximab therapy, and effective application of therapeutic plasma exchange. We also report here that CSF IL-6 levels may serve as a new biomarker for GPA-associated OPN.

DOI： 10.1080/24725625.2019.1649857

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Wiley  

AIM: To determine characteristics of rheumatoid arthritis (RA) patients in Japan who received the same biological disease-modifying antirheumatic drugs (bDMARDs) for at least 6 months and to identify factors associated with successful down-titration of bDMARDs dependent on shared decision-making. METHODS: We included consecutive RA patients who received the same bDMARD with low disease activity or remission for at least 6 months in our two university hospitals. Patients treated with the bDMARD standard dose were defined as SD, while those treated with bDMARD down-titration were defined as DT. We retrospectively reviewed clinical charts and compared data between the two groups. RESULTS: Of 288 patients with RA, 204 (70.8%) and 84 (29.2%) continued standard dose treatment and underwent down-titration treatment, respectively. Sixty-six of 84 (78.6%) down-titration-treated patients continued to show low disease activity or remission, whereas 18 (21.4%) relapsed 18.9 ± 24.4 months after bDMARD down-titration was started. Univariate predictor analysis showed that the probable factors of down-titration were no history of bDMARD treatment (P = .001) and low initial Disease Activity Assessment of 28 joint score (P = .048). Other clinical characteristics had no significant relationship with successful down-titration. CONCLUSIONS: Thus, bDMARD-naïve patients and those with low initial disease activity are more likely to agree to attempt down-titration. However, the timing and method of down-titration should be made in shared decision-making between patients and rheumatologists.

DOI： 10.1111/1756-185X.13692

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その他リンク： https://onlinelibrary.wiley.com/doi/full-xml/10.1111/1756-185X.13692

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Oxford University Press (OUP)  

Background: Clinical data of patients with entro-, vasculo-, and neuro-variant possible Behçet's disease (BD) based on Japanese criteria has not yet comprehensively reported. Methods: This ongoing nation-wide registration has been carried out by the Japanese Ministry of Health, Labour and Welfare. The Ministry asked physicians who diagnosed a patient with confirmed or possible BD to register the patient data by filling out a registration form. The Ministry provided us with the dataset after unlinkable anonymization. We analyzed 2003-2014 database generated from the early stage new cases. Results: Among the 7950 analyzable cases, 694 (8.7%) had variant-type possible BD without satisfying complete/incomplete criteria. Of the 694 patients, 479, 46, and 169 had entero-, vasculo-, and neuro-variant possible BD, respectively. Out of these 694 patients, 35 (5.0%) and 154 (22.2%) satisfied the International Study Group criteria and the International Criteria of BD, respectively. Entero-variant possible patients rarely (1.8%) had ocular lesions. Patients with vasculo-variant possible BD were featured by low genital ulceration risk (6.8%) and frequent positive HLA-B51 (60.0%). Neuro-variant possible BD was featured by high median age at registration (48 year). Vasculo- (69.6%) and neuro-variant (68.6%) BD patients showed clear male dominance. Epididymitis was very rare among variant-type possible BD men. Conclusion: We analyzed 694 early-stage variant-type possible BD cases. We believe the data from our study will contribute to further international discussion regarding BD diagnostic criteria and clarification of the clinical presentations of the Japanese variant-type possible BD patients.

DOI： 10.1080/14397595.2018.1494501

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Oxford University Press (OUP)  

OBJECTIVES: This study aimed to identify patients with high-probability of ocular involvement of Behçet's disease (BD). METHODS: The Japanese Ministry of Health, Labour and Welfare provided dataset of ongoing nationwide BD registration project. A patient who had confirmed BD and who was suspected to have BD was registered. We mainly analyzed newly registered patients who had the data for all demographic and diagnostic parameters regardless of fulfilment of any diagnostic criteria. RESULTS: Among 3213 patients with confirmed or possible BD, 1382 (43.0%) were men and 1831 (57.0%) were women with a median age of 38 years (interquartile range (IQR) 30-49 years). The median duration between onset and registration was 0 year (IQR 0-3). A binomial multivariable logistic regression analysis revealed that being female (odds ratio (OR) 0.63, 95% confidence interval (CI) 0.53-0.75, p < .001), duration since onset (OR 1.33 per 10 years, 95% CI 1.18-1.51, p < .001), genital ulceration (OR 0.28, 95% CI 0.23-0.34, p < .001), and gastrointestinal symptoms (OR 0.36, 95% CI 0.30-0.44, p < .001) were related to the ocular lesion. Analyses based on data of 2800 patients who satisfied International criteria of BD, age-, sex-, duration-based subgroup analyses, analyses targeting iridocyclitis and retino-uveitis, and analysis including patients with missing data confirmed that the four factors were associated with the probability of eye involvement. CONCLUSION: The ocular involvement did not accompany with genital ulcer or gastrointestinal symptoms at the early stage of BD.

DOI： 10.1080/14397595.2018.1457424

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Japanese Circulation Society  

BACKGROUND: Many patients with collagen disease (CD), particularly scleroderma (SSc), develop critical limb ischemia (CLI), which leads to limb amputation. However, conventional therapies, including revascularization via surgical bypass, showed poor outcomes in CLI patients with CD. Many CLI patients with SSc showed poor responses to combination therapies including intravenous iloprost, PDE-5 inhibitors, and bosentan. Therefore, new methods of improving the peripheral circulation for limb salvage are required. This study was a subanalysis of the long-term clinical outcomes after autologous bone marrow-derived mononuclear cells (BM-MNC) in CLI patients with SSc. Methods and Results: We assessed no-option CLI patients with CD who underwent BM-MNC implantation at 10 institutes; 69 patients (39 with SSc-related diseases (SSc group) and 30 with other CDs (non-SSc group)), were included. The median follow-up duration was 36.5 months. The 10-year overall survival rate was 59.1% in the SSc group and 82.4% in the non-SSc group. The 10-year major amputation-free rates were 97.4% and 82.6%, respectively. The number of major or minor amputations in the SSc group trended to be less than that in the non-SSc group. Significant improvements in visual analog scale scores were observed in both groups. CONCLUSIONS: The BM-MNC implantation may be feasible in no-option CLI patients with CD. In the SSc group, limb salvage rate tended to be higher than in the non-SSc group.

DOI： 10.1253/circj.CJ-18-1044

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担当区分：筆頭著者,　最終著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Japanese Society of Internal Medicine  

DOI： 10.2169/internalmedicine.1657-18

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Oxford University Press (OUP)  

OBJECTIVES: TRIM21 is an E3 ubiquitin ligase for interferon regulatory factors (IRFs) that are involved in innate and acquired immunity. Here, we evaluated the role of TRIM21 in the interferon (IFN) signature of systemic lupus erythematosus (SLE). METHODS: Twenty SLE patients and 24 healthy controls were enrolled in this study. We analyzed mRNA expression of TRIM21, type I IFN, and IFN-inducible genes in peripheral blood mononuclear cell (PBMC). The protein levels of IRFs were assessed by Western blotting in PBMCs cultured with or without MG-132. RESULTS: The expression of TRIM21 mRNA and protein was significantly higher in SLE PBMCs as compared to healthy controls. There was a correlation between TRIM21 mRNA expression and SLE activities. In contrast to a negative correlation between mRNA expression level of TRIM21 and those of type I IFNs in healthy controls, we found a positive correlation between them in anti-TRIM21 antibody-positive SLE patients. Neither positive nor negative correlation was observed in the autoantibody-negative SLE patients. Western-blotting analysis revealed impaired ubiquitin-dependent proteasomal degradation of IRFs in SLE PBMCs. CONCLUSION: Our study showed ubiquitin-dependent proteasomal degradation of IRFs was impaired in anti-TRIM21 antibody-dependent and -independent fashions, leading to amplification of IFN signature in SLE.

DOI： 10.1080/14397595.2018.1436028

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1080/24725625.2017.1413931

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

BACKGROUND: Low C-C chemokine receptor 1 (CCR1) and interleukin (IL)-10 expression is associated with risk of Behçet's disease (BD). The objective of the present study was to clarify the pathological roles of CCR1 and IL10 loci identified by previous BD genome-wide association studies (GWASs). METHODS: M1 and M2 macrophages (Mφ) were differentiated with granulocyte-macrophage colony-stimulating factor or macrophage colony-stimulating factor (M-CSF) from peripheral monocytes of healthy control subjects (HC) and patients with BD. Expression of CD68 and CD163 was evaluated to test for Mφ polarization. CCR1 and IL-10 messenger RNA (mRNA) and protein expression was compared according to CCR1 and IL10 single-nucleotide polymorphism (SNP) genotypes. The migratory ability of M1 and M2 Mφ toward CCR1 ligand macrophage inflammatory protein (MIP)-1α was compared. The ratio of M1 and M2 Mφ in skin lesions of BD and systemic sclerosis (SSc), which was reported to be M2 Mφ-dominant, was compared. To examine the plasticity of polarized Mφ, the differentiated cells were cultured with either the same or the other culture condition. RESULTS: Preferential expression of CD163, CCR1, and IL-10 was found in M2 Mφ compared with M1 Mφ. M2 Mφ migrated more sensitively to low concentrations of MIP-1α than M1 Mφ did. BD-derived M1 Mφ showed higher CCR1 surface expression than HC-derived M1 Mφ did. IL10 and CCR1 mRNA expression differences were observed by GWAS-identified SNP genotypes in polarized Mφ. BD skin lesions showed M1 Mφ predominance compared with SSc skin lesions. A plasticity assay revealed that M-CSF restored IL-10 synthesis and reduced IL-6 production by M1 Mφ. CONCLUSIONS: The present study reveals that GWAS-identified SNPs contribute to M1 Mφ-predominant inflammation in BD. Our data also suggest that the skewed Mφ polarization is correctable by immunological intervention.

DOI： 10.1186/s13075-018-1613-0

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その他リンク： http://link.springer.com/article/10.1186/s13075-018-1613-0/fulltext.html

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

DOI： 10.1186/s13075-018-1568-1

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その他リンク： http://link.springer.com/article/10.1186/s13075-018-1568-1/fulltext.html

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: The Therapeutic Angiogenesis by Cell Transplantation (TACT) trial demonstrated the efficacy and safety of autologous bone marrow-derived mononuclear cells (BM-MNCs) in patients with critical limb ischemia (CLI). The present study aimed to assess the long-term clinical outcomes of therapeutic angiogenesis using autologous BM-MNC implantation under advanced medical treatment in Japan.Methods and Results:The study was retrospective, observational, and non-controlled. We assessed no-option CLI patients who had BM-MNC implantation performed in 10 institutes. Overall survival (OS), major amputation-free (MAF), and amputation-free survival (AFS) rates were primary endpoints of this study. The median follow-up duration was 31.7 months. The 10-year OS rate was 46.6% in patients with arteriosclerosis obliterans (ASO) (n=168), 90.5% in patients with thromboangiitis obliterans (TAO) (n=108), and 67.6% in patients with collagen disease-associated vasculitis (CDV) (n=69). The 10-year MAF rate was 70.1%, 87.9%, and 90.9%, respectively. The 10-year AFS rate was 37.8%, 80.9%, and 61.2%, respectively. Major adverse cardiovascular events occurred in 6.0% of patients with ASO, 1.9% of patients with TAO, and no patients with CDV. CONCLUSIONS: Therapeutic angiogenesis using autologous BM-MNC implantation may be feasible and safe in patients with no-option CLI, particularly those with CLI caused by TAO or CDV.

DOI： 10.1253/circj.CJ-17-0510

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

DOI： 10.1186/s13075-017-1506-7

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Oxford University Press (OUP)  

Objective: To evaluate diagnostic test accuracy of US compared with MRI for the detection of synovitis in RA patients. Methods: A systematic literature search was performed in the PubMed, EMBASE, Cochrane Library and Web of Science Core Collection databases. Studies evaluating the diagnostic test accuracy of US for synovitis detected by MRI as the reference standard for wrist, MCP, PIP and knee joints were included. To assess the overall accuracy, we calculated the diagnostic odds ratio using a DerSimonian-Laird random effects model and the area under the curve (AUC) for the hierarchical summary receiver operating characteristics using Holling's proportional hazards models. The summary estimate of the sensitivity and specificity were obtained using the bivariate model. Results: Fourteen of 601 identified articles were included in the review. The diagnostic odds ratio was 11.6 (95% CI 5.6, 24; I2 = 0%), 28 (95% CI 12, 66; I2 = 11%), 23 (95% CI 6.5, 84; I2 = 19%) and 5.3 (95% CI 0.60, 48; I2 = 0%) and the AUC was 0.81, 0.91, 0.91 and 0.61 for wrist, MCP, PIP and knee joints, respectively. The summary estimates of sensitivity and specificity were 0.73 (95% CI 0.51, 0.87)/0.78 (95% CI 0.46, 0.94), 0.64 (95% CI 0.43, 0.81)/0.93 (95% CI 0.88, 0.97), 0.71 (95% CI 0.33, 0.93)/0.94 (95% CI 0.89, 0.97) and 0.91 (95% CI 0.56, 0.99)/0.60 (95% CI 0.20, 0.90) for wrist, MCP, PIP and knee joints, respectively. Conclusion: US is a valid and reproducible technique for detecting synovitis in the wrist and finger joints. It may be considered for routine use as part of the standard diagnostic tools in RA.

DOI： 10.1093/rheumatology/kex036

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掲載種別：研究論文（学術雑誌）  

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掲載種別：研究論文（学術雑誌）   出版者・発行元：BMJ  

<sec><title>Introduction</title>Antineutrophil cytoplasm antibody-associated vasculitis (AAV) is a form of systemic vasculitis. The current standard induction therapy with the combination of high-dose glucocorticoids and cyclophosphamide or rituximab has high remission rates of 80%–90%. However, it is also associated with various side effects, including death due to infection or cardiovascular disease. There is an unmet medical need of a new therapy to reduce side effects.

</sec><sec><title>Methods and analysis</title>This is a phase IV multicentre, open-label, randomised controlled trial that aims to evaluate the efficacy and safety of a new remission induction regimen with the combination of low-dose glucocorticoids and rituximab. Newly diagnosed patients with AAV will be assessed for eligibility at 34 tertiary rheumatology/nephrology centres in Japan. One hundred and forty patients will be randomised (1:1) to receive low-dose prednisolone (0.5 mg/kg daily) plus rituximab (375 mg/m²weekly) or high-dose prednisolone (1 mg/kg daily) plus rituximab. The trial consists of remission induction and maintenance phases. The primary endpoint of the study is the remission rate at 6 months (induction phase). Relapse and long-term safety profile will also be assessed until 24 months (maintenance phase).

</sec><sec><title>Ethics and dissemination</title>The protocol was first approved by the Institutional Review Board of Chiba University Hospital (reference number: G25051), and then approved by each participating site. The trial was registered at the University hospital Medical Information Network (UMIN) clinical registry (UMIN000014222) and ClinicalTrials.gov registry (<ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="clintrialgov" xlink:href="NCT02198248">NCT02198248</ext-link>). The Low-dose Glucocorticoid Vasculitis Induction Study (LoVAS) trial is currently ongoing and is due to finish in September 2019. The findings of this trial will be disseminated to participants through peer-reviewed publications and presented at national and international conferences in accordance with the Consolidated Standards of Reporting Trials (CONSORT) Statement.

</sec><sec><title>Trial registration number</title>UMIN000014222;<ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="clintrialgov" xlink:href="NCT02198248">NCT02198248</ext-link>.

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DOI： 10.1136/bmjopen-2017-018748

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1093/rheumatology/kex285

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1080/14397595.2016.1265726

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/s41598-017-09938-z

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その他リンク： http://www.nature.com/articles/s41598-017-09938-z

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.jns.2017.05.059

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1080/14397595.2016.1222650

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1080/14397595.2016.1206173

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1080/24725625.2017.1291176

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掲載種別：研究論文（学術雑誌）  

DOI： 10.1136/ANNRHEUMDIS-2017-EULAR.4059

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1186/s13075-016-1115-x

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.2169/internalmedicine.55.6297

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.3109/14397595.2015.1069458

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.3109/14397595.2015.1054099

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.4049/jimmunol.1402064

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.3109/14397595.2015.1026025

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.3109/14397595.2014.974305

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：The American Association of Immunologists  

The IFN regulatory factor family member 8 (IRF8) regulates differentiation of lymphoid and myeloid lineage cells by promoting or suppressing lineage-specific genes. How IRF8 promotes hematopoietic progenitors to commit to one lineage while preventing the development of alternative lineages is not known. In this study, we report an IRF8-EGFP fusion protein reporter mouse that revealed previously unrecognized patterns of IRF8 expression. Differentiation of hematopoietic stem cells into oligopotent progenitors is associated with progressive increases in IRF8-EGFP expression. However, significant induction of IRF8-EGFP is found in granulocyte-myeloid progenitors and the common lymphoid progenitors but not the megakaryocytic-erythroid progenitors. Surprisingly, IRF8-EGFP identifies three subsets of the seemingly homogeneous granulocyte-myeloid progenitors with an intermediate level of expression of EGFP defining bipotent progenitors that differentiation into either EGFP(hi) monocytic progenitors or EGFP(lo) granulocytic progenitors. Also surprisingly, IRF8-EGFP revealed a highly heterogeneous pre-pro-B population with a fluorescence intensity ranging from background to 4 orders above background. Interestingly, IRF8-EGFP readily distinguishes true B cell committed (EGFP(int)) from those that are noncommitted. Moreover, dendritic cell progenitors expressed extremely high levels of IRF8-EGFP. Taken together, the IRF8-EGFP reporter revealed previously unrecognized subsets with distinct developmental potentials in phenotypically well-defined oligopotent progenitors, providing new insights into the dynamic heterogeneity of developing hematopoietic progenitors.

DOI： 10.4049/jimmunol.1301939

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担当区分：筆頭著者   掲載種別：研究論文（学術雑誌）   出版者・発行元：Oxford University Press (OUP)  

DOI： 10.3109/14397595.2013.857800

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVES: To determine whether ultrasonography (US) predicts Boolean remission in rheumatoid arthritis (RA) patients who had achieved disease activity score in 28 joints (DAS28)-based remission criteria. METHODS: Thirty-one RA patients in DAS28-based clinical remission were recruited. US semiquantitatively determined Gray scale (GS) and power Doppler (PD) signal scores in the bilateral wrists and all metacarpophalangeals and proximal interphalangeals. Total GS score and total PD score were calculated as the sum of individual scores for each joint. RESULTS: Among 22 RA patients, who maintained DAS28 remission for 2 years, 16 met Boolean remission criteria at the end of study. Both total GS and total PD scores at baseline were significantly lower in Boolean remission group than non-remission group. There was no significant difference in other baseline parameters, including duration of disease, duration of remission, mTSS, and disease activity composite parameters between the two groups. Among the factors for Boolean remission criteria at 2 years, patient global assessment score was associated with total GS score at the entry, while swollen joint count was related to total PD score. CONCLUSIONS: Null or low grade of GS and PD findings in US are associated with achieving Boolean remission. Thus, US is essential for assessment and prediction of "deeper remission" of RA.

DOI： 10.3109/14397595.2013.857800

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.immuni.2013.11.022

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER  

Although "clinical remission" has been a realistic goal of treatment in rheumatoid arthritis (RA), there is evidence that subclinical synovitis is associated with ongoing structural damage even after clinical remission is achieved. In the study reported here, we assessed whether ultrasonography (US) can predict progressive joint destruction during clinical remission of RA.
Thirty-one patients with RA in clinical remission based on the disease activity score in 28 joints were recruited for this study. Bilateral wrists and all of the metacarpophalangeal and proximal interphalangeal (PIP) joints were examined by power Doppler (PD) ultrasonography (US), and the PD signals were scored semiquantitatively in each joint. The total PD score was calculated as the sum of individual scores for each joint.
Among 22 RA patients who maintained clinical remission during the 2-year follow-up period, seven showed radiographic progression. Radiographic progression was strongly associated with total PD score at entry, with all patients showing radiographic progression having a total PD score of a parts per thousand yen2 at entry and none of the patients with a total PD score of a parts per thousand currency sign1 showing any radiographic progression. There was no significant association of therapeutic agents with progressing or non-progressing cases.
PD-US detects synovitis causing joint destruction even when the patient is in clinical remission. Thus, remission visible on US is essential to reach "true remission" of RA.

DOI： 10.1007/s10165-012-0690-1

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1155/2012/606195

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その他リンク： http://downloads.hindawi.com/journals/jir/2012/606195.xml

担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Hindawi Limited  

DOI： 10.1155/2012/718237

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その他リンク： http://downloads.hindawi.com/journals/ijr/2012/718237.xml

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1002/art.33497

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.molimm.2010.12.017

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.4049/jimmunol.0990103

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.4049/jimmunol.0804121

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.4049/jimmunol.176.6.3611

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1007/s10165-006-0472-8

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担当区分：筆頭著者   記述言語：日本語   掲載種別：学位論文（博士）  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1083/jcb.200308141

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/j.1356-9597.2004.00717.x

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記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

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CiNii Books

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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記述言語：日本語   掲載種別：学位論文（その他）  

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総ページ数：319   担当ページ：pp209-210, 215-218   記述言語：日本語   著書種別：教科書・概説・概論

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総ページ数：312   担当ページ：pp257-258   記述言語：日本語   著書種別：教科書・概説・概論

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担当区分：筆頭著者   記述言語：日本語   掲載種別：記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）   出版者・発行元：(株)日本プランニングセンター  

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担当区分：筆頭著者,　責任著者   記述言語：日本語   掲載種別：記事・総説・解説・論説等（学術雑誌）   出版者・発行元：(有)科学評論社  

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記述言語：日本語   出版者・発行元：関東リウマチ研究会  

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担当区分：筆頭著者   記述言語：日本語   出版者・発行元：(有)科学評論社  

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担当区分：最終著者   記述言語：日本語   出版者・発行元：(有)科学評論社  

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記述言語：日本語   出版者・発行元：(株)医学書院  

DOI： 10.11477/mf.1402228167

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記述言語：日本語   出版者・発行元：関東リウマチ研究会  

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担当区分：筆頭著者,　最終著者,　責任著者   記述言語：日本語   掲載種別：記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）   出版者・発行元：(有)科学評論社  

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担当区分：最終著者   記述言語：日本語   掲載種別：記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）   出版者・発行元：(有)科学評論社  

J-GLOBAL

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担当区分：筆頭著者   記述言語：日本語   掲載種別：記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）   出版者・発行元：(有)科学評論社  

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記述言語：日本語   出版者・発行元：関東リウマチ研究会  

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記述言語：日本語   出版者・発行元：関東リウマチ研究会  

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担当区分：筆頭著者   記述言語：日本語   掲載種別：記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）   出版者・発行元：(株)先端医学社  

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その他リンク： https://search.jamas.or.jp/link/ui/2018138133

担当区分：筆頭著者,　最終著者,　責任著者   記述言語：日本語   掲載種別：記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）   出版者・発行元：(株)メヂカルフレンド社  

J-GLOBAL

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担当区分：筆頭著者,　最終著者,　責任著者   記述言語：日本語   掲載種別：記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）   出版者・発行元：(株)メヂカルフレンド社  

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担当区分：筆頭著者,　最終著者,　責任著者   記述言語：日本語   掲載種別：記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）   出版者・発行元：(株)医学書院  

DOI： 10.11477/mf.1402224901

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記述言語：日本語   出版者・発行元：関東リウマチ研究会  

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記述言語：日本語   出版者・発行元：(株)医学書院  

DOI： 10.11477/mf.1402224669

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記述言語：日本語   掲載種別：記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）   出版者・発行元：株式会社医学書院  

DOI： 10.11477/mf.1402224480

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記述言語：日本語   掲載種別：記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）   出版者・発行元：株式会社医学書院  

DOI： 10.11477/mf.1402224343

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記述言語：日本語   掲載種別：記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）   出版者・発行元：(株)北隆館  

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その他リンク： https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-26461468/

記述言語：日本語   掲載種別：記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）   出版者・発行元：株式会社医学書院  

DOI： 10.11477/mf.1402224236

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記述言語：日本語   出版者・発行元：関東リウマチ研究会  

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記述言語：日本語   掲載種別：記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）   出版者・発行元：株式会社医学書院  

DOI： 10.11477/mf.1402223827

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記述言語：日本語   出版者・発行元：関東リウマチ研究会  

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記述言語：日本語   掲載種別：書評論文，書評，文献紹介等  

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記述言語：日本語   出版者・発行元：関東リウマチ研究会  

J-GLOBAL

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記述言語：日本語   出版者・発行元：関東リウマチ研究会  

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記述言語：日本語   出版者・発行元：関東リウマチ研究会  

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記述言語：日本語   出版者・発行元：関東リウマチ研究会  

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記述言語：日本語   出版者・発行元：日本内科学会-関東地方会  

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記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

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記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

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記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

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記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

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記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

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記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

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記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

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記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

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記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

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記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

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記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

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記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

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記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

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記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

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記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

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記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

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記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

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記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

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記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

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記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

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記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

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記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

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記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

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記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

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記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

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記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

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記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

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記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

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記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

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記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

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記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

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記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

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記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

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記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

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記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

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記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

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記述言語：日本語   出版者・発行元：日本リウマチ学会-関東支部  

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記述言語：日本語   出版者・発行元：日本リウマチ学会-関東支部  

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記述言語：日本語   出版者・発行元：日本リウマチ学会-関東支部  

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記述言語：日本語   出版者・発行元：日本リウマチ学会-関東支部  

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記述言語：日本語   出版者・発行元：(一社)日本臨床検査医学会  

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記述言語：日本語   出版者・発行元：(一社)日本骨粗鬆症学会  

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記述言語：日本語   出版者・発行元：日本内科学会-関東地方会  

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記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

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記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

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記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

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記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

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記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

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記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

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記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

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記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

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記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

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記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

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記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

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記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

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記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

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記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

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記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

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記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

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記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

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記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

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記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

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記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

J-GLOBAL

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記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

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記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

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記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

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記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

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記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

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記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

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記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会