Arthritis & Rheumatology最新文献

Objective: Interstitial lung disease (ILD) is a common and potentially lethal complication of systemic sclerosis (SSc). Screening by high-resolution computed tomography (HRCT) is recommended in all patients with risk factors, including early disease. Little is known on late presentations of ILD. This study aimed to characterize the incidence, risk factors, and outcomes of late-onset SSc-ILD.

Methods: Study participants enrolled in the Canadian Scleroderma Research Group cohort from 2004 to 2020 without prevalent ILD were included. Incidence and risk factors for ILD (on HRCT) were compared according to disease duration above (late) and below (earlier) seven years from the first non-Raynaud manifestation. Risk of ILD progression was compared using Kaplan-Meier and multivariable Cox models.

Results: Overall, 199 (21%) of 969 patients developed incident ILD over a median of 2.4 (interquartile range 1.2-4.3) years. The incidence rate in late SSc (3.7/100 person-years) was lower than in earlier SSc (relative risk 0.68, 95% confidence interval [CI] 0.51-0.92). Risk factors for incident ILD included male sex, diffuse subtype, myositis, antitopoisomerase I autoantibodies, and higher C-reactive protein levels. Patients with late-onset ILD were also less frequently White and more frequently had arthritis and anti-RNA-polymerase III autoantibodies. Lung disease severity was similar between late- and earlier-onset SSc-ILD (forced vital capacity 88% and 87%, diffusion capacity of the lungs for carbon monoxide 64% and 62%, respectively). Progression rates were also similar between late- and earlier-onset SSc-ILD (log rank P = 0.8, hazard ratio 1.11, 95% CI 0.58-2.10).

Conclusion: ILD can present in late SSc. Risk factors and progression rates overlapped with earlier-onset SSc-ILD. Surveillance for ILD should continue in longstanding SSc. Frequency and modality of monitoring remain to be defined.

Objective: Adult-onset Still disease (AOSD) is a systemic autoinflammatory disorder (AID) of unknown etiology. Genetic studies have been limited. Here, we conducted detailed genetic and inflammatory biomarker analysis of a large cohort with AOSD to investigate the underlying pathology and identify novel targets for potential treatment.

Methods: We investigated AOSD cases (n = 60) for rare germline and somatic variants using whole exome sequencing with virtual gene panels. Transcriptome profiles were investigated by bulk RNA sequencing whole blood. Cytokine profiling was performed on an extended patient cohort (n = 106) alongside measurements of NLRP3 inflammasome activation using a custom assay and type I interferon (IFN) score using a novel method.

Results: We observed higher than expected frequencies of rare germline variants associated with monogenic AIDs in AOSD cases (AOSD 38.4% vs healthy controls [HCs] 20.4%) and earlier onset of putative somatic variants associated with clonal hematopoiesis of indeterminate potential. Transcriptome profiling revealed a positive correlation between Still Activity Score and gene expression associated with the innate immune system. ASC/NLRP3 specks levels and type I IFN scores were significantly elevated in AOSD cases compared with HCs (P = 0.0001 and 0.0015, respectively), in addition to several cytokines: interleukin (IL)-6 (P < 0.0001), IL-10 (P < 0.0075), IL-12p70 (P = 0.0005), IL-18 (P < 0.0001), IL-23 (P < 0.0001), IFN-α2 (P = 0.0009), and IFNγ (P = 0.0002).

Conclusion: Our study shows considerable genetic complexity within AOSD and demonstrates the potential utility of the ASC/NLRP3 specks assay for disease stratification and targeted treatment. The enriched genetic variants identified may not by themselves be sufficient to cause disease, but may contribute to a polygenic model for AOSD.

Objective: Myeloid-derived suppressor cells (MDSCs) contribute to the pathogenesis of systemic lupus erythematosus (SLE), in part due to promoting the survival of plasma cells. FoxO1 expression in monocytic MDSCs (M-MDSCs) exhibits a negative correlation with the SLE Disease Activity Index score. This study aimed to investigate the hypothesis that M-MDSC-specific FoxO1 deficiency enhances aberrant B cell function in aggressive SLE.

Methods: We used GEO data sets and clinical cohorts to verify the clinical significance of FoxO1 expression and circulating M-MDSCs. Using Cre-LoxP technology, we generated myeloid FoxO1 deficiency mice (mFoxO1^-/-) to establish murine lupus-prone models. The transcriptional stage was assessed by integrating chromatin immunoprecipitation (ChIP)-sequencing with transcriptomic analysis, luciferase reporter assay, and ChIP-quantitative polymerase chain reaction. Methylated RNA immunoprecipitation sequencing, RNA sequencing, and CRISPR-dCas9 were used to identify N⁶-adenosine methylation (m⁶A) modification. In vitro B cell coculture experiments, capmatinib intragastric administration, m⁶A-modulated MDSCs adoptive transfer, and sample validation of patients with SLE were performed to determine the role of FoxO1 on M-MDSCs dysregulation during B cell autoreacted with SLE.

Results: We present evidence that low FoxO1 is predominantly expressed in M-MDSCs in both patients with SLE and lupus mice, and mice with myeloid FoxO1 deficiency (mFoxO1^-/-) are more prone to B cell dysfunction. Mechanically, FoxO1 inhibits mesenchymal-epithelial transition factor protein (Met) transcription by binding to the promoter region. M-MDSCs FoxO1 deficiency blocks the Met/cyclooxygenase2/prostaglandin E₂ secretion pathway, promoting B cell proliferation and hyperactivation. The Met antagonist capmatinib effectively mitigates lupus exacerbation. Furthermore, alkB homolog 5 (ALKBH5) targeting catalyzes m⁶A modification on FoxO1 messenger RNA in coding sequences and 3' untranslated regions. The up-regulation of FoxO1 mediated by ALKBH5 overexpression in M-MDSCs improves lupus progression. Finally, these correlations were confirmed in untreated patients with SLE.

Conclusion: Our findings indicate that effective inhibition of B cells mediated by the ALKBH5/FoxO1/Met axis in M-MDSCs could offer a novel therapeutic approach to manage SLE.