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Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by elevated interferon (IFN) signature genes. Galectin-9 (Gal-9) is a β-galactoside-binding lectin that is reportedly useful as a biomarker for IFN gene signatures. In a cross-sectional study of Japanese patients with recent-onset SLE, we aimed to determine whether raised serum Gal-9 levels were associated with the disease activity or organ damage seen in SLE patients. The current study included 58 Japanese patients with SLE and 31 age-matched healthy individuals. Disease activity and organ damage were assessed using SLE Disease Activity 2000 (SLEDAI-2K) and Systemic Lupus International Collaborating Clinics (SLICC) damage index. Serum and cerebrospinal fluid (CSF) Gal-9 concentrations were quantified using ELISA. Correlation analyses between Gal-9 and clinical parameters including disease activity were performed. Serum levels of Gal-9 were significantly increased in patients with SLE compared with the control group (16.6 ng/ml, [interquartile range (IQR); 3.6-59.7] versus 4.74 ng/ml, [IQR; 3.0-9.5], p<0.0001). Gal-9 was significantly correlated with disease activity measures in the SLEDAI-2K. Serum Gal-9 levels were significantly greater in patients with SLE-related organ involvement (23.1 ng/ml, [IQR; 5.1-59.7] versus 12.5ng/ml, [IQR; 3.6-39.0], p = 0.013). Whereas there was no difference in serum levels of CXCL10 or M2BPGi between patients with and without SLE-related organ involvement. Serum levels of Gal-9 were significantly higher in SLE patients with active renal involvement determined by BILAG renal score (A-B) compared to those without active renal involvement (C-E). Whereas there was no significant difference in serum levels of Gal-9 between SLE patients with or without active other organ involvements (neurological or hematological) determined by BILAG score. SLE patients with detectable circulating IFN-α had raised serum Gal-9 levels. Levels of Gal-9 were significantly higher in the CSF from patients with recent-onset neuropsychiatric SLE (NPSLE) than in those from non-SLE controls (3.5 ng/ml, [IQR; 1.0-27.2] versus 1.2 ng/ml, [IQR; 0.9-2.1], p = 0.009). Gal-9 could be a serologic marker of disease activity and organ involvement in SLE patients. Future studies evaluating the role of Gal-9 in the SLE phenotype may provide insights into SLE pathogenesis.

Janus kinase (JAK) inhibitors (JAKis) are effective therapeutic agents against rheumatoid arthritis (RA). However, patients having RA with particular risk factors may have a higher incidence of adverse effects (AEs), including major cardiovascular events (MACE) and infections. In this multicenter cohort study, we aimed to clarify the risk factors affecting the drug retention of JAKis in patients with RA. We retrospectively evaluated patients with RA who received their first JAKi (tofacitinib, baricitinib, upadacitinib, or filgotinib) at our institute. The clinical outcomes, including AEs, were recorded, particularly MACE and serious infections. The drug retention rates were analyzed using the Kaplan-Meier method, and risk factors affecting drug retention rates were determined using a multivariable Cox regression hazards model. Overall 184 patients with RA receiving their first use of baricitinib (57.6%), tofacitinib (23.9%), upadacitinib (12.0%), or filgotinib (6.5%) were included in this study. Fifty-six (30.4%) patients discontinued JAKi treatment owing to ineffectiveness (9.2%) or AEs, including infections (21.2%). The overall drug retention rates were significantly lower in patients treated with pan-JAKi than in those treated with JAK1 inhibitors (p = 0.03). In the Cox regression model, the presence of baseline high RA disease activity, use of glucocorticoid and treatments with pan-JAKis were associated with reduced drug retention rates of JAKis (p < 0.001, p = 0.01 and 0.04, respectively). Pan-JAKi treated patients with high disease activity had significantly lower drug retention rates (p < 0.001). In a real-world setting, the drug retention rates of JAKis were reduced mainly by treatment discontinuation owing to AEs. Treatment with pan-JAKis and high baseline RA disease activity were identified as predictive factors for the discontinuation of JAKis. Lower drug retention rates were found in patients receiving pan-JAKis with high disease activity than in those without high disease activity.

The number of biological DMARDs (bDMARDs) used in elderly patients with rheumatoid arthritis (RA) has increased in recent years. We aimed to compare the drug retention rates and safety of abatacept (ABT) and tocilizumab (TCZ) in elderly patients with RA. A total 125 elderly patients with RA (>65 years) who began therapy with either ABT (n = 47) or TCZ (n = 78) between 2014 and 2021 at our institute were enrolled. We compared the drug retention rate and clinical response at 24 weeks between elderly patients with RA treated with ABT and those treated with TCZ. Adverse events (AEs) and the reasons for drug discontinuation were assessed. There was no significant difference in demographic characteristics except for the use of glucocorticoid between the ABT and TCZ groups. There was no significant difference in the drug retention rate between the ABT and TCZ groups. Furthermore, there was no significant difference in the discontinuation rates due to the lack of effectiveness between these two groups. The proportions of the patients archiving low disease activity at 24 weeks did not differ significantly between the two groups. Whereas, the discontinuation rates due to AEs, including interstitial lung disease (ILD), seemed higher in the TCZ group than in the ABT group. In TCZ-treated group, the concomitant use of methotrexate (MTX) significantly increased the incidences of AEs leading to the discontinuation of TCZ. Whereas these was no significant impact of concomitant use of MTX on the incidences of AEs leading to discontinuation in ABT-treated group. In elderly patients with RA treated with ABT and TCZ, drug retention rates were equivalent between the two groups. There were some differences in safety profiles between ABT and TCZ, and the rates of discontinuation due to AEs, including ILD, seem to be lower with ABT than with TCZ in elderly patients with RA.

BackgroundThe ORAL Surveillance trial showed a potentially higher incidence of malignancy and major adverse cardiovascular events (MACEs) associated with tofacitinib than those associated with tumor necrosis factor (TNF) inhibitors (TNFis). However, few studies have compared the safety of non-TNFis or other Janus kinase (JAK) inhibitors (JAKis). This study was aimed at comparing the incidence rates (IRs) of malignancies and MACEs in patients with rheumatoid arthritis (RA) treated using interleukin-6 (IL-6) inhibitors (IL-6is) or JAKis.MethodsWe retrospectively analyzed 427 patients with RA who were treated using an IL-6i (n = 273) or a JAKi (n = 154). We determined the IRs of malignancy and MACEs, and the standardized incidence ratio (SIR) of malignancies and investigated factors related to malignancy and MACEs. After adjusting the clinical characteristic imbalance by propensity score matching (PSM), we compared the IRs of adverse events between the JAKi and IL-6i groups.ResultsAfter PSM, the observational period was determined to be 605.27 patient-years (PY), and the median observational period was determined to be 2.28 years. We identified seven cases of malignancy (IR: 2.94 per 100 PY) in the JAKi-treated group and five cases (IR: 1.36 per 100 PY) in the IL-6i-treated group after PSM. The IR of MACEs was 2.56 and 0.83 (per 100 PY) in the JAKi- and IL-6i-treated groups. The IRRs of JAKi-treated patients versus IL-6i-treated patients were 2.13 (95% confidence interval (CI): 0.67–7.42) for malignancy and 3.03 (95% CI: 0.77–15.21) for MACE. There were no significant differences in IRR for malignancy and MACE between both groups after PSM. Univariate and multivariable Cox regression analyses revealed that older age and JAKi use were independent risk factors for malignancy, while older age, hypertension, and JAKi use were independent risk factors for MACEs. The overall malignancy SIR was significantly higher in the JAKi-treated group compared to the general population (2.10/100 PY, 95% CI: 1.23–2.97).ConclusionThe IRs of malignancy and MACE in patients with RA after PSM were comparable between IL-6i-treated and JAKi-treated patients. However, the SIR of malignancy in JAKi treatment was significantly higher than in the general population; therefore, further safety studies comparing JAKi to non-TNFi biologic disease-modifying antirheumatic drugs (bDMARDs) are needed.

Anti-citrullinated peptide antibodies (ACPA) and inflammatory cytokines play important roles in the development of rheumatoid arthritis (RA). T cell immunoglobulin and mucin-domain containing-3 (TIM-3) is an immune-checkpoint molecule involved in inhibitory signaling. Galectin-9 (Gal-9) mediated ligation of TIM-3 induces the amelioration of autoimmune diseases. TIM-3 is expressed in synovial osteoclasts and involved in the rheumatoid bone destruction. The aim of this study was to investigate the relationships between inflammatory cytokines and immune-checkpoint molecules in RA patients. Serum levels of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), soluble TIM-3 (sTIM-3) and Gal-9 were determined by ELISA. Patients were stratified into two groups based on ACPA titers: low-medium ACPA (ACPA <200 U/mL) and high ACPA (ACPA ≥200 U/mL). Serum levels of cytokines or immune-checkpoint molecules were evaluated between RA patients with low-medium ACPA titers and high ACPA titers. Elevated serum levels of inflammatory cytokines were correlated with DAS28-ESR in RA patients. Although serum levels of sTIM-3 were elevated in RA patients, significant correlations between sTIM-3 and cytokines (IL-6 or TNF-α) were observed exclusively in RA patients with low-medium ACPA titers (<200 U/mL). Serum levels of IL-6 and TNF-α levels were significantly correlated with elevated Gal-9 levels regardless of ACPA status. A significant correlation between IL-6 and Gal-9 was observed in RA patients without advanced joint damage. Conversely, a significant correlation between TNF-α and Gal-9 was observed in RA patients with advanced joint damage. Our data indicated that there are positive correlations between circulating inflammatory cytokines and checkpoint molecules in RA patients and these interactions can be modulated by ACPA status or joint damage stage.

Type I interferons (IFN-I) are pivotal effectors of innate immunity and constitute a central axis of host defense against pathogens. Sensing of exogenous or endogenous nucleic acids by pattern-recognition receptors—exemplified by Toll-like receptors—triggers transcriptional induction of IFN-I. Engagement of the heterodimeric IFN-I receptor on nucleated cells reprograms cellular states via canonical Janus kinase–signal transducer and activator of transcription (JAK–STAT) signaling as well as STAT-independent, noncanonical pathways. This axis is tempered by multilayered regulatory mechanisms, including epigenetic remodeling, and important aspects remain incompletely defined. Dysregulation of IFN-I activity underlies diverse autoimmune disorders, notably systemic lupus erythematosus, wherein IFN-responsive gene signatures stratify disease endotypes, reflect disease activity trajectories, and predict therapeutic responsiveness. In recent years, therapeutic strategies targeting this pathway are now available: anti-IFN-I receptor therapy for systemic lupus erythematosus (SLE) and JAK inhibition for rheumatoid arthritis (RA) and giant cell arteritis (GCA). Altogether, a refined understanding of the IFN-I axis furnishes a pragmatic framework for patient stratification, response prediction, and mechanism-informed therapy design across immune-mediated diseases.

Background The number of biological DMARDs (bDMARDs) used in elderly patients with rheumatoid arthritis (RA) has increased in recent years. We aimed to compare the drug retention rates and safety of abatacept (ABT) and tocilizumab (TCZ) in elderly patients with RA. Methods A total 125 elderly patients with RA (>65 years) who began therapy with either ABT (n = 47) or TCZ (n = 78) between 2014 and 2021 at our institute were enrolled. We compared the drug retention rate and clinical response at 24 weeks between elderly patients with RA treated with ABT and those treated with TCZ. Adverse events (AEs) and the reasons for drug discontinuation were assessed. Results There was no significant difference in demographic characteristics except for the use of glucocorticoid between the ABT and TCZ groups. There was no significant difference in the drug retention rate between the ABT and TCZ groups. Furthermore, there was no significant difference in the discontinuation rates due to the lack of effectiveness between these two groups. The proportions of the patients archiving low disease activity at 24 weeks did not differ significantly between the two groups. Whereas, the discontinuation rates due to AEs, including interstitial lung disease (ILD), seemed higher in the TCZ group than in the ABT group. In TCZ-treated group, the concomitant use of methotrexate (MTX) significantly increased the incidences of AEs leading to the discontinuation of TCZ. Whereas these was no significant impact of concomitant use of MTX on the incidences of AEs leading to discontinuation in ABT-treated group. Conclusions In elderly patients with RA treated with ABT and TCZ, drug retention rates were equivalent between the two groups. There were some differences in safety profiles between ABT and TCZ, and the rates of discontinuation due to AEs, including ILD, seem to be lower with ABT than with TCZ in elderly patients with RA.

Autoinflammation with cytokine dysregulation may be implicated in the pathophysiology of adult-onset Still's disease (AOSD); however, the relationship between galectins and cytokines in patients with active AOSD remains unknown. We aimed to examine the relationship between circulating cytokines/chemokines and galectin-3 (Gal-3) or its ligand, Mac-2 binding protein glycosylation isomer (M2BPGi), in Japanese patients with AOSD. We recruited 44 consecutive patients diagnosed with AOSD according to the Yamaguchi criteria, 50 patients with rheumatoid arthritis (RA) as disease controls, and 27 healthy participants. Serum M2BPGi levels were directly measured using a HISCL M2BPGi reagent kit and an automatic immunoanalyzer (HISCL-5000). Serum Gal-3 concentrations were measured by enzyme-linked immunosorbent assay. The serum levels of 69 cytokines were analyzed in patients with AOSD using a multi-suspension cytokine array. We performed a cluster analysis of each cytokine expressed in patients with AOSD to identify specific molecular networks. Significant increases in the serum concentrations of Gal-3 and M2BPGi were found in the serum of patients with AOSD compared with patients with RA and healthy participants (both p <0.001). There were significant positive correlations between serum Gal-3 levels and AOSD disease activity score (Pouchot score, r=0.66, p <0.001) and serum ferritin levels. However, no significant correlations were observed between serum M2BPGi levels and AOSD disease activity scores (Pouchot score, r = 0.32, p = 0.06) or serum ferritin levels. Furthermore, significant correlations were observed between the serum levels of Gal-3 and various inflammatory cytokines, including interleukin-18, in patients with AOSD. Immunosuppressive treatment in patients with AOSD significantly reduced serum Gal-3 and M2BPGi levels (p = 0.03 and 0.004, respectively). Although both Gal-3 and M2BPGi were elevated in patients with AOSD, only Gal-3 was a useful biomarker for predicting disease activity in AOSD. Our findings suggest that circulating Gal-3 reflects the inflammatory component of AOSD, which corresponds to proinflammatory cytokine induction through inflammasome activation cascades.

Background Galectin-9 (Gal-9) is involved in the regulatory process of immune responses or inflammation. The aim of the present study is to characterize circulating Gal-9 in patients with rheumatoid arthritis (RA) and its relationship with RA disease activity and phenotype. Methods A total of 116 RA patients and 31 age-matched healthy controls were included in this study. Disease activity of RA patients was determined by Disease Activity Score of 28 joint scoring system (DAS28-ESR). Levels of Gal-9 in serum were determined by enzyme-linked immunosorbent assay (ELISA). Results Serum levels of Gal-9 were significantly higher in patients with RA compared to those in controls (median 7577 pg/ml [interquartile range (IQR) 5570–10,201] versus 4738 pg/ml [IQR 4267–5630], p  = 0.001). There were significant differences in serum Gal-9 between RA patients with and without RA-ILD (9606 pg/ml [IQR 8522–12,167] versus 7078 pg/ml [IQR 5225–9447], p  < 0.001) or those with and without advanced joint damage (stage II–IV, 9606 pg/ml [IQR 8522–12,167] versus 7078 pg/ml [IQR 5225–9447], p  < 0.001). Although serum levels of Gal-9 correlated with the titers of ACPA ( r  = 0.275, p  = 0.002), levels of ACPA titers conferred the different relationship, between serum Gal-9 and inflammatory mediators or RA disease activity. Although Gal-9 was correlated with ACPA titers ( r  = 0.508, p  = 0.002), there was no correlation between Gal-9 levels and erythrocyte sedimentation rate (ESR), matrix metalloproteinase-3 (MMP-3), or DAS28-ESR in RA patients with high titers of ACPA (> 200 U/ml). Conversely, Gal-9 was correlated with MMP-3 ( r  = 0.300, p  = 0.007) or DAS28-ESR ( r  = 0.331, p  = 0.004) but not with ACPA titer in RA patients with low titers of ACPA titers (< 200 U/ml). Conclusions Serum levels of Gal-9 were increased in RA patients and associated with RA disease activity in RA patients without high titers of ACPA. The levels of ACPA titers may influence the values of circulating Gal-9 in RA patients with various clinical phenotypes. These data suggest that Gal-9 possessed the properties of pro-inflammatory or arthropathic biomarker under the status of ACPA titers.

Objectives Carcinoembryonic-antigen-related cell-adhesion molecule 1 (CEACAM1) is an adhesion molecule that acts as a coinhibitory receptor in the immune system. We previously demonstrated that CEACAM1 is predominantly expressed on peripheral blood neutrophils in patients with RA. The aim of the present study was to investigate the effects of Janus kinase inhibitors (JAKi) on cytokine-activated human neutrophils and CEACAM1 expression. Methods Peripheral blood neutrophils were obtained from healthy subjects. Isolated neutrophils were stimulated with tumor necrosis factor-alpha (TNF-α) or granulocyte–macrophage colony-stimulating factor (GM-CSF) in the presence or absence of JAKi. The expression of CEACAM1 in peripheral blood neutrophils was analyzed by flow cytometry. Protein phosphorylation of signal transducer and activator of transcription (STAT)1, STAT3, and STAT5 was assessed by western blot using phospho-specific antibodies. Results We found that TNF-α-induced CEACAM1 expression was marginally suppressed after pretreatment with pan-JAK inhibitor, tofacitinib. Moreover, TNF-α induced STAT1 and STAT3 phosphorylation at the late stimulation phase (4 to 16 h). The expressions of CEACAM1 on neutrophils were markedly up-regulated by GM-CSF not by interleukin (IL)-6 stimulation. All JAKi inhibited GM-CSF-induced CEACAM1 expressions on neutrophils, however, the inhibitory effects of baricitinib were larger compared to those of tofacitinib or filgotinib. Moreover, CEACAM1 was marginally upregulated in interferon (IFN)-γ stimulated neutrophils. Similarly, JAKi inhibited IFN-γ-induced CEACAM1 expressions on neutrophils. Conclusions We demonstrated that JAKi prevent GM-CSF-induced CEACAM1 expression in neutrophils, and JAKi-induced inhibition depends on their selectivity against JAK isoforms. These findings suggest that JAKi can modulate the expression of CEACAM1 in cytokine-activated neutrophils, thereby limiting their activation.