Arthritis & Rheumatology最新文献

Objective: To report 52-week safety and efficacy of ianalumab from phase 2b dose-finding study in patients with Sjögren's disease (SjD).

Methods: Patients randomly received (1:1:1:1) ianalumab (5, 50, or 300 mg) or placebo subcutaneously every 4 weeks till week 24 (treatment period [TP]1). At week 24, patients on 300 mg were re-randomized to continue 300 mg or receive placebo till week 52 (TP2), patients on placebo were switched to ianalumab 150 mg, while patients on 5 and 50 mg directly entered post treatment safety follow-up. Patients who discontinued treatment early or completed treatment entered safety follow-up (≥20 weeks).

Results: During TP1, 190 patients were randomized (placebo=49, 5 mg=47, 50 mg=47, 300 mg=47). Of these 190 patients, 90 (47.4 %; 43 continued 300 mg and 47 received placebo) entered TP2, and 81/90 (90.0%) completed the study treatment. By week 52, efficacy was sustained in patients who continued 300 mg in TP2 (ESSDAI, ESSPRI, PaGA, PhGA change from week 24: -1.45, -0.46, -4.69, -6.86, respectively). Stimulated salivary flow rates and autoantibody levels numerically improved in the 300 mg group. Treatment-emergent adverse events were not dose-dependent, except for injection-site reactions. Cases of decreased neutrophil counts (CTCAE v4.03 grade 3 according to laboratory listings) were observed in 3 patients during the post-treatment follow-up, occurring at 3.5, 5.5, and 3 months, after the last ianalumab administration. None were associated with infection except one incidental finding of asymptomatic cytomegalovirus infection (IgM+).

Conclusion: In patients with SjD, ianalumab 300 mg demonstrated sustained efficacy through week 52 and a favorable safety profile up to two years of follow-up.

Objective: Interstitial lung disease (ILD) is a common and potentially lethal complication of systemic sclerosis (SSc). Screening by 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: Subjects enrolled in the Canadian Scleroderma Research Group (CSRG) 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) 7 years from first non-Raynaud manifestation. Risk of ILD progression was compared using Kaplan-Meier and multivariable Cox models.

Results: Overall, 199/969 (21%) patients developed incident ILD over a median of 2.4 [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%CI:0.51-0.92). Risk factors for incident ILD included male sex, diffuse subtype, myositis, anti-topoisomerase 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 (FVC 88% and 87%, DLCO 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.

Objectives: Adult-onset Still's disease (AOSD) is systemic autoinflammatory disorder of unknown aetiology. Genetic studies have been limited. Here, we conducted detailed genetic and inflammatory biomarker analysis of a large AOSD cohort 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 autoinflammatory disorders in AOSD cases (AOSD 38.4% vs healthy controls 20.4%), and earlier onset of putative somatic variants associated with clonal haematopoiesis of indeterminate potential. Transcriptome profiling revealed positive correlation between Still's activity score (SAS) 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 to healthy controls (p=0.0001 and 0.0015 respectively), in addition to several cytokines: 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).

Conclusions: 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. Forkhead box protein O1 (FoxO1) expression in monocytic MDSCs (M-MDSCs) exhibits a negative correlation with the SLE Disease Activity Index (SLEDAI) score. This study aimed to investigate the hypothesis that M-MDSCs specific FoxO1 deficiency enhances aberrant B cell function in aggressive SLE.

Methods: We used GEO datasets and clinical cohorts to verify the FoxO1 expression and circulating M-MDSCs clinical significance. Using Cre-LoxP technology, we generated myeloid FoxO1 deficiency mice (mFoxO1^-/-) to establish murine lupus-prone models. The transcriptional stage was assessed by integrating ChIP-seq with transcriptomic analysis, luciferase reporter assay and ChIP-qPCR. Methylated RNA immunoprecipitation sequencing, RNA sequencing and CRISPR-dCas9 were used to identify m⁶A modification. In vitro B cell co-culture experiments, Capmatinib intragastric administration, m⁶A-modulated MDSCs adoptive transfer, and SLE patient sample validation 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 SLE patients and lupus mice, and mice with myeloid FoxO1 deficiency (mFoxO1^-/-) are more prone to B cell dysfunction. Mechanically, FoxO1 inhibits Met transcription by binding to the promoter region. M-MDSCs FoxO1 deficiency blocks the Met/COX2/PGE2 secretion pathway, promoting B cell proliferation and hyperactivation. Met antagonist Capmatinib effectively mitigates lupus exacerbation. Furthermore, ALKBH5 targeting catalyzes m⁶A modification on FoxO1 mRNA in CDS and 3'-UTR regions. Upregulation of FoxO1 mediated by ALKBH5 overexpression in M-MDSCs improves lupus progression. Finally, these correlations were confirmed in untreated SLE patients.

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