Search

Objective: To investigate transcriptomic and immunophenotypic features of muscle specimens from patients with idiopathic inflammatory myopathy (IIM)., Methods: Bulk RNA-sequencing was performed on muscle biopsy samples from 16 patients with dermatomyositis (DM) and 9 patients with polymyositis (PM). Seven tested positive for anti-aminoacyl t-RNA synthetase antibodies in the DM patients (ARS-DM). We conducted weighted gene coexpression network analysis (WGCNA), differentially expressed gene (DEG) analysis, and gene set variation analysis (GSVA) to assess contributions of specific pathways. Cell proportions in muscle specimens were estimated using a deconvolution approach., Results: WGCNA revealed significant positive correlations between serum creatine kinase (CK) levels and gene modules involved in cellular respiration, phagocytosis, and oxidative phosphorylation (OXPHOS). Significant positive correlations were also observed between CK levels and proportions of CD16-positive and -negative monocytes and myeloid dendritic cells. Notably, DM patients demonstrated enrichment of complement and interferon-α and -γ pathway genes compared to those with PM. Furthermore, ARS-DM demonstrated a higher proportion of Th1 cells and DEGs related to OXPHOS. Additionally, serum Krebs von den Lungen-6 levels correlated with gene modules associated with extracellular matrix and transforming growth factor-β signaling pathway., Conclusion: Our study highlights a significant involvement of monocytes in muscle damage and delineates pathological differences among IIM subtypes. DM was characterized by complement, interferon-α and -γ signaling, whilst ARS-DM was associated with OXPHOS. Distinctive gene expression variations in muscle specimens suggest that different pathologic mechanisms underlie muscle damage in each IIM phenotype., (This article is protected by copyright. All rights reserved.)

Objectives: Anti-melanoma differentiation associated gene 5 antibody (anti-MDA5 Ab)-positive dermatomyositis (DM) is a representative of rapidly progressive interstitial pneumonia. However, its association with thrombotic microangiopathy (TMA), characterized by thrombocytopenia, haemolytic anaemia, and organ dysfunction, has not been defined. This study aimed to elucidate the characteristics of anti-MDA5 Ab-positive DM accompanied by TMA., Methods: We reviewed our hospital records from November 2009 to September 2022. We included patients in accordance with the 2017 European League Against Rheumatism/American College of Rheumatology classification criteria and the criteria of Bohan and Peter. TMA was diagnosed according to the criteria for transplantation-associated TMA proposed by the International Working Group., Results: This study enrolled a total of 26 anti-MDA5 Ab-positive DM patients, four of whom developed TMA. The patients with TMA had an increased urine protein/creatinine ratio. In addition, these four of them showed significantly elevated levels of ferritin and anti-MDA5 Ab titers and were considered to have high disease activity; yet, all of them survived., Conclusions: Our study indicated that anti-MDA5 Ab-positive DM patients with hyperferritinemia, a high anti-MDA5 Ab titer, and an increased urine protein/creatinine ratio should be carefully managed, bearing in mind a complication of TMA., (© Japan College of Rheumatology 2024. Published by Oxford University Press.)

Metabolic dysfunction-associated steatohepatitis (MASH), previously called non-alcoholic steatohepatitis (NASH), is a growing concern worldwide, with liver fibrosis being a critical determinant of its prognosis. Monocyte-derived macrophages have been implicated in MASH-associated liver fibrosis, yet their precise roles and the underlying differentiation mechanisms remain elusive. In this study, we unveil a key orchestrator of this process: long chain saturated fatty acid-Egr2 pathway. Our findings identify the transcription factor Egr2 as the driving force behind monocyte differentiation into hepatic lipid-associated macrophages (hLAMs) within MASH liver. Notably, Egr2-deficiency reroutes monocyte differentiation towards a macrophage subset resembling resident Kupffer cells, hampering hLAM formation. This shift has a profound impact, suppressing the transition from benign steatosis to liver fibrosis, demonstrating the critical pro-fibrotic role played by hLAMs in MASH pathogenesis. Long-chain saturated fatty acids that accumulate in MASH liver emerge as potent inducers of Egr2 expression in macrophages, a process counteracted by unsaturated fatty acids. Furthermore, oral oleic acid administration effectively reduces hLAMs in MASH mice. In conclusion, our work not only elucidates the intricate interplay between saturated fatty acids, Egr2, and monocyte-derived macrophages but also highlights the therapeutic promise of targeting the saturated fatty acid-Egr2 axis in monocytes for MASH management., (© 2024. The Author(s).)

Objective: We assess the clinical characteristics of patients with cryopyrin-associated periodic syndrome (CAPS) in Japan and evaluate the real-world efficacy and safety of interleukin-1 (IL-1) inhibitors, primarily canakinumab., Methods: Clinical information was collected retrospectively, and serum concentrations of canakinumab and cytokines were analyzed., Results: A total of 101 patients were included, with 86 and 15 carrying heterozygous germline and somatic mosaic mutations, respectively. We identified 39 mutation types, and the common CAPS-associated symptoms corresponded with those in previous reports. Six patients (5.9% of all patients) died, with four of the deaths caused by CAPS-associated symptoms. Notably, 73.7% of patients (100%, 79.6%, and 44.4% of familial cold autoinflammatory syndrome, Muckle-Wells syndrome, and chronic infantile neurological cutaneous articular syndrome/neonatal onset multisystem inflammatory disease, respectively) achieved complete remission with canakinumab, and early therapeutic intervention was associated with better auditory outcomes. In some patients, canakinumab treatment stabilized the progression of epiphysial overgrowth and improved height gain, visual acuity, and renal function. However, 23.7% of patients did not achieve inflammatory remission with crucial deterioration of organ damage, with two dying while receiving high-dose canakinumab treatment. Serological analysis of canakinumab and cytokine concentrations revealed that the poor response was not related to canakinumab shortage. Four inflammatory nonremitters developed inflammatory bowel disease (IBD)-unclassified during canakinumab treatment. Dual biologic therapy with canakinumab and anti-tumor necrosis factor-α agents was effective for IBD- and CAPS-associated symptoms not resolved by canakinumab monotherapy., Conclusion: This study provides one of the largest epidemiologic data sets for CAPS. Although early initiation of anti-IL-1 treatment with canakinumab is beneficial for improving disease prognosis, some patients do not achieve remission despite a high serum concentration of canakinumab. Moreover, IBD may develop in CAPS after canakinumab treatment., (© 2024 American College of Rheumatology.)

The dynamic change of redox conditions is a key factor in emission of elemental mercury (Hg 0 ) from riparian soils. The objective of this study was to elucidate the influences of redox conditions on Hg 0 emission from riparian soils. Soil suspension experiments were conducted to measure Hg 0 emission from five Hg-contaminated soil samples in two redox conditions (i.e., treated with air or with N 2 ). In four of the five samples, Hg 0 emission was higher in air treatment than on N 2 treatment. Remaining one soil, which has higher organic matter than other soils, showed no distinct difference in Hg 0 production between air and N 2 treatment. In soil suspensions subject to N 2 treatment, the dissolved organic carbon (DOC) and Fe 2+ concentrations were 3.38- to 1.34-fold and 1.44- to 2.28-fold higher than those in air treatment, respectively. Positive correlations were also found between the DOC and Fe 2+ (r = 0.911, p < 0.01) and Hg 2+ (r = 0.815, p < 0.01) concentrations in soil solutions, suggesting Fe 2+ formation led to the release of DOC, which bound to Hg 2+ in the soil and, in turn, limited the availability of Hg 2+ for reduction to Hg 0 in N 2 treatment. On the other hand, for remaining one soil, more Hg 2+ might be adsorbed onto the DOM in the air treatment, resulted in the inhibition of Hg 0 production in air treatment. These results imply that the organic matter is important to prevent Hg 0 production by changing redox condition. Further study is needed to prove the role of organic matter in the production of Hg 0 ., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)