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BACKGROUND: Patients with rheumatoid arthritis (RA) have frequent thrombotic events with endothelial dysfunction. Von Willebrand factor (VWF) has been shown to bind neutrophil extracellular traps (NETs) and NETs are part of RA etiology. OBJECTIVES: This study aims to elucidate whether this prothrombotic status exacerbates inflammation in arthritis. Here we focus on the involvement of A Disintegrin And Metalloprotease with ThromboSpondin type 1 motif, member 13 (ADAMTS-13), an enzyme cleaving VWF and its effect on NET deposition and RA development. METHODS: We evaluated the influence of the Adamts13 gene and recombinant human ADAMTS-13 (rhADAMTS-13) on arthritis in the mouse models of collagen-induced arthritis (CIA). We also assessed VWF and NETs in synovial tissue. RESULTS: Several Adamts13(−/−) mice developed arthritis, while Adamts13(+/+) siblings did not. Synovial tissue from Adamts13(−/−) showed accumulation of NETs. Treatment of DBA/1 J mice, an arthritis-susceptible strain, with well-tolerated doses of rhADAMT13 reduced arthritis incidence and alleviated the severity of arthritis. Mice treated with rhADAMT13 presented less serum interleukin 6 and less bone erosion determined by micro-computed tomography. The effects on arthritis severity were observed both when administering rhADAMTS-13 prophylactically and also when given after arthritis has developed. In both conditions, rhADAMTS-13 reduced VWF and NET deposition on proliferated synovial tissue evaluated by immunoblotting. CONCLUSIONS: Our results demonstrate the inhibitory role of Adamts13 in murine arthritis and the effectiveness of rhADAMTS-13 treatment. Additionally, this study suggests that deposition of VWF in the synovium and subsequent pathogenic NET retention promotes arthritis. Treatment with rhADAMTS-13 provides a potential therapeutic approach targeting inflammation and pro-thrombotic state in arthritis.

Neutrophils with intact multilobulated nuclei show ASC speck formation and high histone H3 citrullination in patients with severe COVID-19. In murine neutrophils, ASC speck forms transiently at the microtubule organizing center, before nuclear rounding, early in NETosis. Abstract Infection by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) engages the inflammasome in monocytes and macrophages and leads to the cytokine storm in COVID-19. Neutrophils, the most abundant leukocytes, release neutrophil extracellular traps (NETs), which have been implicated in the pathogenesis of COVID-19. Our recent study shows that activation of the NLRP3 inflammasome is important for NET release in sterile inflammation. However, the role of neutrophil inflammasome formation in human disease is unknown. We hypothesized that SARS-COV-2 infection may induce inflammasome activation in neutrophils. We also aimed to assess the localization of inflammasome formation, (i.e. ASC speck assembly), and timing relative to NETosis in stimulated neutrophils by real time video microscopy. Neutrophils isolated from severe COVID-19 patients demonstrated that approximately 2% of neutrophils in both the peripheral blood and tracheal aspirates presented ASC speck. ASC speck was observed in neutrophils with an intact poly-lobulated nucleus, suggesting early formation during neutrophil activation. Additionally, 40% of nuclei were positive for citrullinated histone H3, and there was a significant correlation between speck formation and nuclear histone citrullination. Time-lapse microscopy in LPS-stimulated neutrophils from fluorescent ASC reporter mice showed that ASC speck formed transiently and at the microtubule organizing center, long before NET release. Our study shows that ASC speck is present in neutrophils from COVID-19 patients with respiratory failure and that it forms early in NETosis. Our findings suggest that inhibition of neutrophil inflammasomes may be beneficial in COVID-19.

Background Although there is increasing use of 18F-FDG PET/CT in the diagnostic procedure for IgG4-related disease (IgG4-RD), little is known about the quantification of 18F-FDG PET/CT. We aimed to evaluate the utility of the quantification of 18F-FDG PET/CT in the diagnosis of IgG4-RD by analyzing the relation between 18F-FDG PET/CT findings and histopathologic findings. Methods Twenty-one patients with IgG4-RD, in whom 18F-FDG PET/CT was performed at the time of diagnosis between November 2011 and July 2018, were enrolled. Tissue biopsy was performed at 24 sites in 21 patients. To perform quantitative analysis of 18F-FDG PET/CT imaging, the highest standardized uptake value (SUV) of the pixels (SUVmax) and the average SUV (SUVmean) within the biopsied lesion were measured. The SUVmean of the liver was also measured as a reference. Results The mean age at diagnosis was 64.6 ± 11.9 years, and the median serum IgG4 level was 650 mg/dl. Histological findings were consistent with IgG4-RD (histopathology-positive) at 19 out of 24 sites. Although there was no significant difference in the values of SUVmax between histopathology-positive and histopathology-negative tissues, the values of SUVmean were significantly higher in the histopathology-positive tissue than those in the histopathology-negative tissue (4.98 and 3.54, respectively P mean/liver were also higher in the histopathology-positive tissue (2.17 and 1.52, respectively P mean to determine which of multiple lesions should be biopsied, a receiver operating characteristic (ROC) curve was constructed. ROC curve analysis indicated SUVmean=4.07 or SUVmean/liver = 1.66 as a cut-off value that could discriminate IgG4-RD-related lesions. Conclusions Our present study suggested that quantitative analysis of 18FDG-PET/CT imaging might be useful for selecting the biopsy site in IgG4-RD. The calculation of SUVmean, not of SUVmax, is important for evaluating IgG4-RD-related lesions in 18F-FDG PET/CT imaging.

Objective To investigate the role of calcium/calmodulin-dependent protein kinase IV (CaMK4) in the development of joint injury in a mouse model of arthritis and patients with RA. Methods Camk4-deficient, Camk4flox/floxLck-Cre, and mice treated with CaMK4 inhibitor KN-93 or KN-93 encapsulated in nanoparticles tagged with CD4 or CD8 antibodies were subjected to collagen-induced arthritis (CIA). Inflammatory cytokine levels, humoral immune response, synovitis, and T-cell activation were recorded. CAMK4 gene expression was measured in CD4+ T cells from healthy participants and patients with active RA. Micro-CT and histology were used to assess joint pathology. CD4+ and CD14+ cells in patients with RA were subjected to Th17 or osteoclast differentiation, respectively. Results CaMK4-deficient mice subjected to CIA displayed improved clinical scores and decreased numbers of Th17 cells. KN-93 treatment significantly reduced joint destruction by decreasing the production of inflammatory cytokines. Furthermore, Camk4flox/floxLck-Cre mice and mice treated with KN93-loaded CD4 antibody-tagged nanoparticles developed fewer Th17 cells and less severe arthritis. CaMK4 inhibition mitigated IL-17 production by CD4+ cells in patients with RA. The number of in vitro differentiated osteoclasts from CD14+ cells in patients with RA was significantly decreased with CaMK4 inhibitors. Conclusion Using global and CD4-cell-targeted pharmacologic approaches and conditionally deficient mice, we demonstrate that CaMK4 is important in the development of arthritis. Using ex vivo cell cultures from patients with RA, CaMK4 is important for both Th17 generation and osteoclastogenesis. We propose that CaMK4 inhibition represents a new approach to control the development of arthritis.

Background Immunoglobulin G4-related disease (IgG4-RD) is characterized by increased serum IgG4 concentration and infiltration of IgG4+ plasma cells in the affected organs. The present study aimed to characterize the serum levels of coinhibitory checkpoint molecule, T cell immunoglobulin and mucin-containing-molecule-3 (TIM-3), and its ligand, galectin-9 (Gal-9), among IgG4-related disease in patients with IgG4-RD patients with various organ involvements. Methods Serum samples were collected from untreated 59 patients with IgG4-RD, 13 patients with rheumatoid arthritis, and 37 healthy controls (HCs). HCs lacked chronic medical diseases or conditions and did not take prescription medications or over-the-counter medications within 7 days. Patients with IgG4-RD (n = 57) were subdivided into those with visceral involvement (n = 38) and those without visceral involvement (n = 21). Serum levels of Gal-9 and soluble TIM-3 (sTIM-3) were determined using enzyme-linked immunosorbent assay (ELISA). The results were compared with the clinical phenotypes of IgG4-RD. Results In untreated patients with IgG4-RD, serum levels of Gal-9 and sTIM-3 were significantly higher than in RA patients as well as in healthy controls. There were significant correlations between the serum levels of Gal-9 or sTIM-3 and serum levels of IgG, BAFF, or sIL-2R. However, there was no significant correlation between the serum levels of Gal-9 or sTIM-3 and serum IgG4 concentrations. Serum levels of sTIM-3 were significantly higher in a subset of patients with visceral involvements than in those without visceral involvements. However, there was no significant difference in the serum levels of Gal-9 between IgG4-RD patients with and without visceral involvements, although both Gal-9 and sTIM-3 were elevated in untreated IgG4-RD patients, and the levels of these checkpoint molecules remained unchanged after steroid therapy. Conclusion Serum levels of Gal-9 and sTIM-3 were significantly elevated in untreated patients with IgG4-RD. Furthermore, serum levels of sTIM-3 were significantly higher in IgG4-RD patients with visceral involvements. These checkpoint molecules could be a potentially useful biomarker for IgG4-RD and for assessing the clinical phenotypes of IgG4-RD.

Serum sodium concentration within the normal range could act as an indicator of age-related changes such as decrease in muscle strength and impairment of capillary function. Since endothelial injury stimulates endothelial repair by enhancing CD34-positive cell production, the level of serum sodium may be inversely associated with that of circulating CD34-positive cells, thus indicating the degree of age-related endothelial injury. We conducted a cross-sectional study of 246 elderly Japanese men aged 60–69 years. Subjects were stratified by hypertension status because hypertension should act as a strong confounding factor for the analyses performed in this study. Serum sodium concentration was positively associated with handgrip strength in non-hypertensive subjects [standardized parameter estimate (β) = 0.29; p = 0.003], but not for hypertensive subjects (β = 0.01; p = 0.878), while it was inversely associated with circulating CD34-positive cell levels in non-hypertensive subjects [simple correlation coefficient (r) = − 0.28; p = 0.002] but not for hypertensive subjects (r = − 0.07; p = 0.454). For non-hypertensive elderly subjects, serum sodium concentration within the normal range is positively associated with handgrip strength and inversely associated with CD34-positive cells, thus partly indicating the degree of age-related endothelium injury. These associations could prove to be an efficient tool for clarifying the background mechanism governing the decrease in age-related muscle strength., Scientific Reports, 11(1), art.no.1088; 2021

OBJECTIVES: Genome-wide association studies have connected PADI4, encoding peptidylarginine deiminase 4 (PAD4), with rheumatoid arthritis (RA). PAD4 promotes neutrophil extracellular trap (NET) formation. We studied Padi4 origin and NETs in an arthritis model in C57BL/6 mice. METHODS: To permit the effective use of C57BL/6 mice in the collagen-induced arthritis (CIA) model, we introduced the administration of granulocyte colony-stimulating factor (G-CSF) for four consecutive days in conjunction with the booster immunization on day 21. The model evaluated global (Padi4(−/−)) and hematopoietic lineage-specific (Padi4(Vav1Cre/+)) Padi4-deficient mice. RESULTS: G-CSF significantly increased the incidence and severity of arthritis in CIA. G-CSF-treated mice showed elevated citrullinated histone H3 (H3Cit) in plasma while vehicle-treated mice did not. Immunofluorescent microscopy revealed deposition of H3Cit in synovial tissue in G-CSF-treated mice. Padi4(−/−) mice developed less arthritis, demonstrating lower serum interleukin 6 and plasma H3Cit, less citrullinated histone H4 in synovial tissue, and less bone erosion observed by micro-computed tomography than Padi4(+/+) mice in the G-CSF-modified CIA model. Similarly, Padi4(Vav1Cre/+) mice developed less arthritis compared with Padi4(fl/fl) mice, and presented the same phenotype as Padi4(−/−) mice. CONCLUSIONS: We succeeded in developing an arthritis model suitable for use in C57BL/6 mice that was fully compliant with high animal welfare standards. We observed an over 90% incidence of arthritis in male mice and detectable NET markers. This model, with some futures consistent with human RA, demonstrates that hematopoietic PAD4 is an important contributor to arthritis development and may prove useful in future RA research.

A 74-year-old man with interstitial lung disease (ILD) underwent surgical excision of a growing retroperitoneal tumor and was diagnosed with spindle cell sarcoma. Just after the surgery, skin eruption and muscle weakness emerged. Based on his symptoms and examination findings, we diagnosed him with anti-synthetase syndrome (ASS) with positive anti-glycyl-transfer ribonucleic acid synthetase antibody (anti-EJ) as paraneoplastic syndrome. Immunosuppressive treatments kept his progressing ILD stable for 21 months, although an expanding lung metastatic lesion from primary sarcoma was detected. Measurements of myositis-specific antibodies may enable the prediction of the efficacy of immunosuppressive treatments for paraneoplastic syndrome, even if the primary disease becomes progressive., Internal Medicine, 59(16), pp.2071-2076; 2020

Microbial involvement in the pathogenesis have been suggested in both antineutrophil cytoplasmic antibody-associated vasculitis (AAV) and sarcoidosis, both of which have lung involvement. However, exhaustive research to assess the bacteria in the lung in AAV and in sarcoidosis have not been performed. We sought to elucidate the distinct dysbiotic lung microbiota between AAV and sarcoidosis. We used 16S rRNA gene high-throughput sequencing to obtain the bacterial community composition of bronchoalveolar lavage fluid (BALF) in patients with AAV (n = 16) compared to patients with sarcoidosis (n = 21). The patients had not undergone therapy with immunosuppressive medication when their BALF was acquired. No difference was observed in α-diversity between patients with AAV and patients with sarcoidosis when using all the detected taxa. We defined the taxa of the oral cavity by using the data of oral microbiota of healthy individuals from the Human Microbiome Project (HMP). The analysis using only oral taxa made the difference in α-diversity between AAV and sarcoidosis clearer compared with those using all the detected taxa. Besides, the analysis using detected taxa except for oral taxa also made the difference in α-diversity between AAV and sarcoidosis clearer compared with those using all the detected taxa. A linear negative relationship between the α-diversity and Birmingham vasculitis activity score (BVAS) was detected in the AAV group. The observed p-value for the effect of the disease groups on the s-diversity was small while the effect of other factors including sex and smoking status did not have small p-values. By excluding oral taxa from all the detected taxa, we found a cluster mainly consisted of sarcoidosis patients which was characterized with microbial community monopolized by Erythrobacteraceae family. Our results suggested the importance of considering the influence of oral microbiota in evaluating lung microbiota., Scientific Reports, 10(1), art.no.9466; 2020

A 54-year-old woman developed drop head syndrome (DHS), Raynaud's phenomenon and creatine kinase (CK) elevation. She did not meet the international classification criteria of dermatomyositis/polymyositis, as we observed no muscle weakness, grasping pain or electromyography abnormality in her limbs, and antiaminoacyl tRNA synthetase (ARS) antibody was negative. Cervical magnetic resonance imaging and a muscle biopsy of the trapezius muscle revealed myositis findings as the only clinical observations in muscle. These findings, along with her anti-U1-ribonucleoprotein (RNP) antibody positivity and leukopenia, resulted in a diagnosis of mixed connective tissue disease (MCTD). Prednisolone treatment significantly improved her myositis. To our knowledge, this is the first report of DHS as the only muscle complication of MCTD., Internal medicine, 59(5), pp.729-732; 2020

BackgroundA proportion of patients with immunogloblin G (IgG) 4-related disease (IgG4-RD) have hypocomplementemia. We aimed to identify characteristics of such patients.MethodsWe analyzed the demographic and clinical data and complement levels of 85 patients with IgG4-RD. We defined hypocomplementemia as serum C3 and/or C4 levels below the lower limit of normal at diagnosis. We also compared the characteristics of patients with and without IgG4-RD.ResultsThirty-two (38%) patients had hypocomplementemia at diagnosis. Patients with hypocomplementemia had more lymph node (p < 0.01), lung (p < 0.01), and kidney (p = 0.02) involvement and a higher IgG4-RD responder index than those without (p = 0.05). Additionally, patients with hypocomplementemia had significantly higher IgG (p < 0.01), IgG4 (p < 0.01), and soluble interleukin 2-receptor (sIL-2R) (p < 0.01) levels and total IgG minus IgG4 (p < 0.01). C3 and C4 levels negatively correlated with IgG, IgG4, and sIL-2R levels, total IgG minus IgG4, and number of IgG4-RD responder index: a measure of the disease activity in IgG4-RD. Patients with hypocomplementemia at diagnosis had a significantly higher frequency of relapse (p = 0.024), as determined using the log-rank test. A multivariate logistic regression analysis showed the presence of hypocomplementemia was independently associated with relapse (OR, 6.842; 95% confidence interval [95%CI], 1.684–27.79; p = 0.007).ConclusionsPatients with IgG4-RD with hypocomplementemia have a more active clinical phenotype, suggesting contributions of the complement system in the pathophysiology of IgG4-RD.

Objective: To identify potential biomarkers to distinguish familial Mediterranean fever (FMF) from sepsis. Method: We recruited 28 patients diagnosed with typical FMF (according to the Tel Hashomer criteria), 22 patients with sepsis, and 118 age-matched controls. Serum levels of 40 cytokines were analyzed using multi-suspension cytokine array. We performed a cluster analysis of each cytokine in the FMF and sepsis groups in order to identify specific molecular networks. Multivariate classification (random forest analysis) and logistic regression analysis were used to rank the cytokines by importance and determine specific biomarkers for distinguishing FMF from sepsis. Results: Fifteen of the 40 cytokines were found to be suitable for further analysis. Levels of serum granulocyte-macrophage colony-stimulating factor (GM-CSF), fibroblast growth factor 2, vascular endothelial growth factor, macrophage inflammatory protein-1b, and interleukin-17 were significantly elevated, whereas tumor necrosis factor-α (TNF-α) was significantly lower in patients with FMF compared with those with sepsis. Cytokine clustering patterns differed between the two groups. Multivariate classification followed by logistic regression analysis revealed that measurement of both GM-CSF and TNF-α could distinguish FMF from sepsis with high accuracy (cut-off values for GM-CSF = 8.3 pg/mL; TNF-α = 16.3 pg/mL; sensitivity, 92.9%; specificity, 94.4%; accuracy, 93.4%). Conclusion: Determination of GM-CSF and TNF-α levels in combination may represent a biomarker for the differential diagnosis of FMF from sepsis, based on measurement of multiple cytokines., Arthritis Research and Therapy, 23, art. no. 260; 2021

The contributions of the complement system have been elucidated in the process of solid organ transplantation, including kidney transplantation. However, the role of complement in liver transplantation is unknown. We sought to elucidate the time-dependent changes of peritransplantational serum complement levels and the relationships with posttransplant outcomes and other immunological biomarkers. We enrolled 82 patients who underwent living-related donor liver transplantation (LDLT). Nine patients (11%) died within 90 days after LDLT (non-survivors). The following immunomarkers were collected preoperatively and at 1, 2, and 4 week(s) after LDLT: serum C3, C4, immunoglobulin G (IgG), and peripheral blood leukocyte populations characterized by CD3, CD4, CD8, CD16, CD19, CD20, CD22, and CD56. Consequently, C3 and C4 increased time-dependently after LDLT. Preoperatively, C3 was negatively correlated with the MELD score, Child–Pugh score, CD16-positive leukocyte percentage, and the CD56-positive leukocyte percentage. Non-survivors had lower levels of C3 at 2 weeks in comparison to survivors (median [interquartile range]: 56 [49-70] mg/dL vs. 88 [71-116] mg/dL, p=0.0059). When the cutoff value of C3 at 2 weeks to distinguish non-survivors was set to 71 mg/dL, the sensitivity, specificity, and area under the ROC curve were 87.5%, 75.0%, and 0.80, respectively. A principal component analysis showed an inverse relationship between the C3 and C4 levels and the percentage of CD8-, CD16-, and CD56-positive leukocytes at 1 and 2 week(s). All non-survivors were included in the cluster that showed higher percentages of CD8-, CD16-, and CD56-positive leukocytes at 2 weeks. In conclusion, we demonstrated the relationship between complement, outcomes, and other immunomarkers in LDLT and suggested the usefulness of C3 at 2 weeks after LDLT in distinguishing the mortality.

Purpose: Age-related reduction in bone marrow activity has been shown to cause anemia, and hypertension and endothelial dysfunction (atherosclerosis) are age-related diseases. However, recent studies have revealed a close association between bone marrow activity and endothelial maintenance. This study aimed to determine the association between elevated reticulocyte levels in conjunction with vigorous bone marrow activity and hypertension and atherosclerosis among the elderly. Study population and Methods: To determine the associations between reticulocyte levels and hypertension and atherosclerosis, we conducted a cross-sectional study of 2,098 elderly Japanese individuals, aged between 60 and 89 years, who had participated in an annual health check-up in 2014. Results: Of the total study population, 1,348 individuals were diagnosed with hypertension (systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg and/or having used antihypertensive medication), and 393 were diagnosed with atherosclerosis (carotid intima-media thickness ≥1.1 mm). Reticulocyte levels were found to be significantly positively associated with hypertension and inversely associated with atherosclerosis. Cardiovascular risk factor-adjusted odds ratios and 95% confidence intervals for hypertension and atherosclerosis, when raised incrementally by 1 standard deviation to determine reticulocyte levels (5.5×104 cells/μL for men and 5.0×104 cells/μL for women), were 1.12 (1.01, 1.25) and 0.83 (0.72, 0.94), respectively. Conclusion: Along with established cardiovascular risk factors, reticulocyte levels in elderly Japanese individuals were found to be positively associated with hypertension and inversely associated with atherosclerosis. This finding may help clarify the background mechanisms concerning the association between bone marrow activity and vascular remodeling.

Background and aims Endothelial injury is well-known as a process that can lead to chronic kidney disease (CKD) and atherosclerosis. Hematopoietic activity is known to be associated inversely with CKD and positively with atherosclerosis. Since bone-derived progenitor cells (CD34-positive cells) contribute to endothelial repair (including the progression of atherosclerosis), understanding the association between CKD and carotid intima-media thickness (CIMT), in relation to circulating CD34-positive cell count, may be an efficient means of clarifying the mechanisms underlying endothelial activity. Methods We conducted a cross-sectional study of 570 elderly Japanese men aged 60–69 years, who underwent a general health check-up. Participants were stratified as per a median circulating CD34-positive cell count (1.01 cells/μL). Results Independent of the known cardiovascular risk factors, CIMT was found to be positively associated with CKD in the participants with high circulating CD34-positive cell counts but not in participants with low counts. Odds ratios were 1.40 (1.04, 1.89) for participants with high and 1.01 (0.72, 1.43) for participants with low circulating CD34-positive cell counts after adjustment for known cardiovascular risk factors at 95% confidence intervals for CKD with one standard deviation increment of CIMT. Conclusions A positive association between CIMT and CKD was observed among participants with high circulating CD34-positive cell counts but not among participants with low counts. Endothelial repair activity might determine the association between CKD and CIMT.

We herein report a case of a 75-year-old woman who presented with a low-grade fever, repeated cold-induced urticaria, and painful leg edemas with neutrocytosis. Because her mother also had cold-induced urticaria and her skin lesions histologically showed neutrophilic dermatitis, we suspected that she had familial cold autoinflammatory syndrome, a subtype of cryopyrin-associated periodic syndromes. Sequencing of the NLRP3 and MEFV genes revealed that she carried both the p.A439V missense mutation and p.E148Q homozygous mutation, which is commonly detected in familial Mediterranean fever patients. The administration of colchicine reduced the frequency and severity of her skin rash and leg edema.

Aim We conducted this retrospective study to identify objective and comprehensive diagnostic criteria for early-stage rheumatoid arthritis (RA) that are based on ultrasound (US) and serologic findings. Method From August 2014 to May 2016, we recruited 216 consecutive patients at Hospital 1 and 223 consecutive patients at Hospital 2 who were suspected to have RA and underwent US of bilateral hands. In the US of bilateral hands from 22 sites, the findings obtained by grayscale and power Doppler (PD) assessments were each graded on a semi-quantitative scale from 0 to 3. We also examined the assessment of the novel outcome measures in rheumatology (OMERACT)-European League Against Rheumatism (EULAR) combined power Doppler ultrasound score (ie the cPD score) and the Global OMERACT-EULAR Synovitis Score. We used the US findings and the combination of US and serologic findings to evaluate the diagnostic performance of these modalities. Results Seventy patients (32.4%) at Hospital 1 and 59 patients (26.5%) at Hospital 2 were diagnosed as having RA. The best-balanced diagnostic performance at each hospital was achieved using a combination, such as (1) the presence of PD grade ≥2 articular synovitis or (2) the presence of PD grade ≥1 articular synovitis and serologic positivity, as well as by using (1) the presence of cPD grade = 3 or (2) a cPD grade ≥2 and serologic positivity. Conclusion The combination of a PD assessment or the cPD score with the measurement of autoantibodies of rheumatoid factor and/or anti-cyclic citrullinated peptide antibodies can accurately identify patients with early-stage RA.

Recent studies have revealed an inverse association between height and cardiovascular disease and that endothelial progenitor cells(CD34-positive cells) contribute to vascular maintenance, which is associated with cardiovascular disease. However,evidence of the association between height and CD34-positive positive cells among elderly participants is limited. To assess this association, we conducted a cross-sectional study of 231 elderly Japanese men aged 65-69. Since enhanced production of circulating CD34-positive cells in response to endothelial injury might act have a strong confounding effect on the association between height and circulating CD34-positive cells, the median value for the levels of these cells (0.93 cells/μL) was used to stratify the participants.Multivariable linear regression analysis demonstrated that height was significantly positively associated with circulating CD34-positive cells for those participants with low levels of circulating CD34-positive cells (n=114) but not for those with higher levels (n=117), with a multi-adjusted standardized parameter estimate (β) of 0.27 (p=0.008) for low and 0.11 (0.275) for higher circulating CD34-positive cell levels. The positive association is limited to participants with relatively low circulating CD34-positive cell levels, whose productivity of these cells is not activated. Our findings indicate that height is an indicator of vascular maintenance capability in elderly Japanese men., Aging, 11(2), pp.663-672; 2019

OBJECTIVES We investigated the impact of renal involvement at diagnosis on the prognosis of patients with antineutrophilic cytoplasmic antibody (ANCA)-associated vasculitis (AAV). METHODS The relationship between renal involvement at diagnosis, clinical variables at diagnosis, and prognosis (including relapse episodes, initiation of dialysis, and death) was examined in 101 Japanese patients with AAV. RESULTS Sixty-eight patients had renal involvement at diagnosis. The renal-involvement patients had significantly higher ages at diagnosis, significantly lower hemoglobin levels, and significantly lower platelet levels. They had significantly lower C3 levels, but showed no significant difference in C4 levels. Overall survival rate was significantly worse in patients with than in patients without renal involvement (P = 0.003, log-rank test). Multivariable analysis using a logistic regression model demonstrated that C3 contributed to dialysis initiation: odds ratio (per 10 mg/dL of C3): 0.68; range: 0.49-0.90; P = 0.007. A Cox proportional hazard model revealed that the C3 level and age at diagnosis contributed significantly to overall survival: hazard ratio (per 10 mg/dL of C3) 0.81, range 0.69-0.95, P = 0.011; 1.08, 1.02-1.15, P = 0.013, respectively. Renal involvement did not contribute significantly to overall survival. Patients with C3 levels ≥100 mg/dL had a better survival rate than patients with C3 levels

To assess the efficacy and safety of switching to infliximab (IFX) from other biological disease-modifying anti-rheumatic drugs (bDMARDs) among Japanese patients with rheumatoid arthritis (RA) in daily practice. We examined 24 consecutive RA patients who had not achieved low disease activity (LDA) as the disease activity score-28 for rheumatoid arthritis with erythrocyte sedimentation rate (DAS28-ESR) despite previous bDMARD therapy in this cohort study. We attempted to determine predictive variables that are associated with achieving DAS28-ESR LDA at 22 weeks post-IFX introduction, by performing univariate analysis. The median DAS28-ESR at baseline was 5.41. Sixteen patients (66.7%) had been treated with a tumor necrosis factor inhibitor (TNF-i), and the other eight patients (33.3%) received a non-TNF-i (abatacept or tocilizumab). Nine patients (37.5%) achieved LDA or remission at 22 weeks. Univariate analyses showed that the variable to predict LDA achievement at 22 weeks was tender joints (>8 counts) at baseline (adjusted odds ratio, 0.10; 95% confidence interval, 0.01-0.63; p = .02). Nine adverse events were observed during the study period, and infection requiring hospitalization was observed in one patient. Switching to IFX is effective to achieve LDA or remission for RA patients refractory to bDMARDs.

Objective It remains unclear whether human T-cell leukemia virus type 1 (HTLV-1) infection influences therapeutic responses in patients with rheumatic diseases and whether immunosuppressive treatments increase the risk of HTLV-1-related complications in HTLV-1 carriers with rheumatic diseases. We examined the effects of tocilizumab (TCZ), an interleukin (IL)-6 receptor antagonist, on two HTLV-1-infected T-cell lines (HCT-5 and MT-2) in vitro. Methods We evaluated production of cytokines and chemokines, expression of HTLV-I associated genes, HTLV-1 proviral load (PVL), expression of HTLV-1 structural proteins, and apoptosis. Results There were no significant differences in cytokine and chemokine levels in the culture supernatants of HCT-5 and MT-2 cells treated with phosphate-buffered saline (PBS) or TCZ. No significant differences were detected in mRNA abundance of Tax or HBZ, PVL, expression of the HTLV-1 structural protein GAG, or apoptosis among HCT-5 and MT-2 cells treated with PBS or TCZ. Conclusions TCZ had no effect the cytokine profiles, HTLV-1 gene and protein expression, PVL, or apoptosis in HTLV-1-infected T-cell lines. Thus, TCZ treatment has no effect on HTLV-1 infection in vitro.

Objectives To investigate the appropriate timing, useful findings and combination of magnetic resonance imaging (MRI) and ultrasound (US) for predicting the radiographic progression in early rheumatoid arthritis (RA). Methods Forty-four active RA patients, who examined by both of MRI and US in the symptomatic wrist and finger joints, were recruited in Nagasaki University Hospital from 2010 to 2017 and treated by the treat-to-target therapeutic strategy for 1 year. MRI was evaluated by RA MRI scoring and US by Outcomes Measures in Rheumatology Clinical Trial, respectively. Plain radiographs were assessed by the Genant-modified Sharp score for the symptomatic side in the same manner as MRI and US. Radiographic progression was defined as an annual increase ≥0.75 at 1 year. Factors associated with radiographic progression were analysed. Also, the optimal combination of MRI and US at each timepoint was considered. Results Logistic regression model revealed that MRI-proven bone marrow oedema at baseline and 6 months and joint counts of power-Doppler grade ≥2 articular synovitis at 3 or 6 months were significantly associated with radiographic progression at 1 year. Conclusion This study may suggest the favourable timing and combination of MRI and US at each point to predict radiographic progression in patients with early-stage RA.

Objective: To identify potential biomarkers to distinguish adult-onset Still's disease (AOSD) from sepsis. Method: We recruited 70 patients diagnosed with AOSD according to the Yamaguchi criteria, 22 patients with sepsis, and 118 age-matched controls. Serum levels of 40 cytokines were analyzed using multi-suspension cytokine array. We performed a cluster analysis of each cytokine in the AOSD and sepsis groups in order to identify specific molecular networks. Further, multivariate classification (random forest analysis) and logistic regression analysis were used to rank the cytokines by their importance and determine specific biomarkers for distinguishing AOSD from sepsis. Results: Seventeen of the 40 cytokines were found to be suitable for further analyses. The serum levels of eleven were significantly higher in patients with AOSD than healthy controls. Levels of serum fibroblast growth factor 2 (FGF-2), vascular endothelial growth factor (VEGF), granulocyte colony-stimulating factor (G-CSF), and interleukin (IL)-18 were significantly elevated in patients with AOSD compared with those with sepsis, and cytokine clustering patterns differed between these two groups. Multivariate classification followed by logistic regression analysis revealed that measurement of both FGF-2 and IL-18 could distinguish AOSD from sepsis with high accuracy (cutoff value for FGF-2 = 36 pg/mL; IL-18 = 543 pg/mL, sensitivity 100%, specificity 72.2%, accuracy 93.8%). Conclusion: Determination of FGF-2 and IL-18 levels in combination may represent a biomarker for the differential diagnosis of AOSD from sepsis, based on the measurement of multiple cytokines., Arthritis research & therapy, 22(1), art.no.108; 2020

Our previous study showed that the effectiveness of tumor necrosis factor (TNF) inhibitors was attenuated in anti-human T-cell leukemia virus type 1 (HTLV-1) antibody-positive patients with rheumatoid arthritis (RA). We aimed to evaluate the effectiveness and safety of non-TNF inhibitors in anti-HTLV-1 antibody-positive patients with RA. We reviewed patients with RA who received abatacept or tocilizumab as the first biologic agent. We used the data of patients treated with TNF inhibitors from our previous study to compare the effectiveness between the anti-HTLV-1 antibody-positive patients treated with TNF inhibitors and non-TNF inhibitors using the inverse probability of treatment weights (IPTW) method. A total of 359 patients were divided into anti-HTLV-1 antibody-negative and -positive patients of 332 and 27, respectively. No statistically significant difference was observed in the change in the clinical disease activity index between the anti-HTLV-1 antibody-positive and -negative patients. The results using the IPTW method showed a significant association between the non-TNF inhibitors treatment and a better response. None of the patients developed adult T-cell leukemia/lymphoma or HTLV-1-associated myelopathy/tropical spastic paraparesis during the 24 weeks. Our results indicate that non-TNF inhibitors treatment is safety, and the effectiveness is not attenuated also in anti-HTLV-1 antibody-positive patients.

Background: Biological disease-modifying antirheumatic drugs (bDMARDs) and targeted synthetic (ts) DMARDs are important in rheumatoid arthritis (RA) treatment. The risk of hospitalized infection associated with bDMARDs/tsDMARDs in RA patients is unclear. Methods: We retrospectively analyzed the cases of the 275 RA patients with 449 treatment episodes who were administered a bDMARD/tsDMARD at Nagasaki University Hospital in July 2003-January 2015. We determined the incidence and risk factors of infection requiring hospitalization in the patients during a 3-year observation period. Results: Thirty-five (12.7%) of the patients experienced a hospitalized infection. The hospitalized infection risk did not differ significantly among several bDMARDs/tsDMARDs. A multivariate analysis revealed that the comorbidities of chronic lung disease (adjusted HR 5.342, 95% CI 2.409-12.42, p < 0.0001) and the initiation of bDMARDs/tsDMARDs before 2010 (adjusted HR 4.266, 95% CI 1.827-10.60, p = 0.0007) are significant independent risk factors for hospitalized infection. Compared to the before-2010 group, the group of patients whose treatment initiated in 2010 or later showed higher patient ages at the initiation of bDMARD/tsDMARD treatment and a higher rate of the use of prophylaxis with an antituberculosis agent, whereas the disease activities and number of the patients who received >5?mg of prednisolone were lower in the after-2010 group. Conclusions: This is the first report that the frequency of hospitalized infection significantly decreased when the patients were treated with a bDMARD or tsDMARD after 2010. Our results indicate that the updated announcement of diagnosis and treatment criteria might contribute to a reduced risk of hospitalized infection and a better understanding of the use of bDMARDs/tsDMARDs by rheumatologists., Journal of immunology research, 2018, 6259010; 2018

A 44-year-old Japanese man with a 14-year history of limited cutaneous systemic sclerosis (SSc) was admitted with a fever, hypertension, anemia, thrombocytopenia, and renal dysfunction. On admission, hypertension, hyperreninemia, acute renal dysfunction,hemolytic anemia, and thrombocytopenia led to the diagnosis of scleroderma renal crisis (SRC) complicated with thrombotic microangiopathy (TMA). The patient had also been infected with influenza B virus almost six days before admission. Following treatment with plasma exchange,an angiotensin-converting enzyme inhibitor, and an anti-virus agent, his general condition improved. He had no risk factors for SRC.In SSc patients, an influenza virus infection might trigger SRC complicated with TMA., Internal medicine, 58(3), pp.441-445; 2019