Variants of genes implicated in type 1 interferon pathway and B-cell activation modulate the EULAR response to rituximab at 24 weeks in rheumatoid arthritis
RMD OPEN
Authors: Juge, Pierre-Antoine; Gazal, Steven; Constantin, Arnaud; Mariette, Xavier; Combe, Bernard; Tebib, Jacques; Dougados, Maxime; Sibilia, Jean; Le Loet, Xavier; Dieude, Philippe
Abstract
Background The type 1 interferon (IFN) pathway has been identified to potentially affect the response to rituximab (RTX) for rheumatoid arthritis (RA), which suggests the contribution of type 1 IFN pathway genes such as IFN regulatory factor 5 and 7 (IRF5 and IRF7), tyrosine kinase 2 (TYK2), signal transducer and activator of transcription 4 (STAT4) and osteopontin (SPP1). Our objective was to study functional variants of these IFN pathway genes as predictors of the European League Against Rheumatism (EULAR) response to RTX for RA at week 24 (W24). Methods Logistic regression analysis with a stepwise multivariate model adjusted for sex, age and DAS28-CRP (Disease Activity Score in 28 joints with C reactive protein) in 115 patients from the SMART randomised studywas used to analyse the association between the candidate variants and W24 EULAR response. Because the variant TNFSF13B rs9514828 was previously found associated with RTX response in the same population, it was included in the analysis. Results The combination of IRF5 rs2004640, SPP1 rs9138 and TNFSF13B rs9514828 was strongly associated with good/moderate EULAR response to RTX at W24: p=9.34x10(-6), OR 11.37 (95% CI 4.03 to 35.28), positive predictive value 91% and negative predictive value 54%. Conclusion Our results support the contribution of the IRF5, SPP1 and TNFSF13B genotypic combination in the response to RTX for RA at W24.
Increased hepatic and circulating chemokine and osteopontin expression occurs early in human NAFLD development
PLOS ONE
Authors: Kriss, Michael; Golden-Mason, Lucy; Kaplan, Jeffrey; Mirshahi, Faridoddin; Setiawan, V. Wendy; Sanyal, Arun J.; Rosen, Hugo R.
Abstract
Background & aims Non-alcoholic steatohepatitis (NASH), a subtype of non-alcoholic fatty liver disease (NAFLD) that can lead to fibrosis, cirrhosis, and hepatocellular carcinoma, is characterized by hepatic inflammation. Despite evolving therapies aimed to ameliorate inflammation in NASH, the transcriptional changes that lead to inflammation progression in NAFLD remain poorly understood. The aim of this pilot study was to define transcriptional changes in early, non-fibrotic NAFLD using two independent biopsy-proven NAFLD cohorts. Methods We extracted RNA from liver tissue of 40 patients with biopsy-proven NAFLD based on NAFLD Activity Score (NAS) (23 patients with NAS <= 3, 17 with NAS >= 5) and 21 healthy controls, and we compared changes in expression of 594 genes involved in innate immune function. Using plasma from an independent cohort of 67 patients with NAFLD and 15 healthy controls, we validated the gene changes observed using a multiplex protein assay. Results Compared to healthy controls, NAFLD patients with NAS >= 5 had differential expression of 211 genes, while those with NAS <= 3 had differential expression of only 14 genes. Notably, osteopontin (SPP1) (3.74-fold in NAS <= 3, 8.28-fold in NAS >= 5) and CXCL10 (2.27-fold in NAS <= 3, 8.28-fold in NAS >= 5) gene expression were significantly upregulated with histologic progression of NAFLD. Plasma osteopontin (SPP1) and CXCL10 are significantly increased in the presence of NAFLD, regardless of histologic grade. In addition, the plasma levels of these two proteins distinguish clearly between the presence or absence of NAFLD (AUC>0.90). Conclusions Osteopontin (SPP1) and CXCL10 are upregulated early in non-fibrotic NAFLD and may serve as valuable non-invasive biomarkers.