Inter-alpha-trypsin inhibitor heavy chain 4: A serologic marker relating to disease risk, activity, and treatment outcomes of rheumatoid arthritis.

OBJECTIVE: Inter-alpha-trypsin inhibitor heavy chain 4 (ITIH4) regulates immunity and inflammation, but its clinical role in rheumatoid arthritis (RA) patients remains unclear. Hence, this study was conducted to explore the association of circulating ITIH4 with disease risk, clinical features, inflammatory cytokines, and treatment outcomes of RA. METHODS: After the enrollment of 93 active RA patients and 50 health controls (HCs), their serum ITIH4 level was analyzed by enzyme-linked immunosorbent assay (ELISA). For RA patients only, serum ITIH4 level at week (W) 6 and W12 after treatment was also analyzed. Besides, serum tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1ß, IL-6, and IL-17A at baseline of RA patients were also detected by ELISA. RESULTS: ITIH4 was downregulated in RA patients (151.1 (interquartile range (IQR): 106.2-213.5) ng/mL) than in HCs (306.8 (IQR: 238.9-435.1) ng/mL) (p < 0.001). Furthermore, ITIH4 was negatively related to C-reactive protein (CRP) (rs  = -0.358, p < 0.001) and 28-joint disease activity score using erythrocyte sedimentation rate (DAS28-ESR) (rs  = -0.253, p = 0.014) in RA patients, but not correlated with other clinical features (all p > 0.05). Besides, ITIH4 was negatively linked with TNF-α (rs  = -0.337, p = 0.001), IL-6 (rs  = -0.221, p = 0.033), and IL-17A (rs  = -0.368, p < 0.001) in RA patients, but not correlated with IL-1ß (rs  = -0.195, p = 0.061). Moreover, ITIH4 was gradually elevated in RA patients from baseline to W12 after treatment (p < 0.001). Additionally, the increment of ITIH4 at W6 and W12 was linked with treatment response and remission in RA patients (all p < 0.05). CONCLUSION: Circulating ITIH4 possesses clinical utility in monitoring disease risk, inflammation, disease activity, and treatment outcomes of RA.

Bioinformatics analyses of gene expression profile identify key genes and functional pathways involved in cutaneous lupus erythematosus.

BACKGROUND: Lupus erythematosus is an autoimmune disease that causes damage to multiple organs ranging from skin lesions to systemic manifestations. Cutaneous lupus erythematosus (CLE) is a common type of lupus erythematosus (LE), but its molecular mechanisms are currently unknown. The study aimed to explore changes in the gene expression profiles and identify key genes involved in CLE, hoping to uncover its molecular mechanism and identify new targets for CLE. METHOD: We analyzed the microarray dataset (GSE109248) derived from the Gene Expression Omnibus (GEO) database, which was a transcriptome profiling of CLE cutaneous lesions. The differentially expressed genes (DEGs) were identified, and the functional annotation of DEGs was performed with Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. Protein-protein interaction (PPI) network was also constructed to identify hub genes involved in CLE. RESULT: A total of 755 up-regulated DEGs and 405 down-regulated DEGs were identified. GO enrichment analysis showed that defense response to virus, immune response, and type I interferon signaling pathway were the most significant enrichment items in DEGs. The KEGG pathway analysis identified 51 significant enrichment pathways, which mainly included systemic lupus erythematosus, osteoclast differentiation, cytokine-cytokine receptor interaction, and primary immunodeficiency. Based on the PPI network, the study identified the top 10 hub genes involved in CLE, which were CXCL10, CCR7, FPR3, PPARGC1A, MMP9, IRF7, IL2RG, SOCS1, ISG15, and GSTM3. By comparison between subtypes, the results showed that ACLE had the least DEGs, while CCLE showed the most gene and functional changes. CONCLUSION: The identified hub genes and functional pathways found in this study may expand our understanding on the underlying pathogenesis of CLE and provide new insights into potential biomarkers or targets for the diagnosis and treatment of CLE. Key Points • The bioinformatics analysis based on CLE patients and healthy controls was performed and 1160 DEGs were identified • The 1160 DEGs were mainly enriched in biological processes related to immune responses, including innate immune response, type I interferon signaling pathway, interferon-γ-mediated signaling pathway, positive regulation of T cell proliferation, regulation of immune response, antigen processing, and presentation via MHC class Ib and so on • KEGG pathway enrichment analysis indicated that DEGs were mainly enriched in several immune-related diseases and virus infection, including systemic lupus erythematosus, primary immunodeficiency, herpes simplex infection, measles, influenza A, and so on • The hub genes such as CXCL10, IRF7, MMP9, CCR7, and SOCS1 may become new markers or targets for the diagnosis and treatment of CLE.

Dehydroevodiamine suppresses inflammatory responses in adjuvant-induced arthritis rats and human fibroblast-like synoviocytes.

Dehydroevodiamine (DHE) is an effective natural active substance extracted from Euodiae Fructus, which is a widely used herbal drug in traditional Chinese medicine. The focus of this study was to test the possibility of using DHE in the treatment of rheumatoid arthritis (RA) diseases. A rat model of adjuvant-induced arthritis (AIA) was generated using Complete Freund's Adjuvant (CFA). Body weight changes, arthritis scores, ankle pathology, tumor necrosis factor-alpha (TNF-α), interleukin-1ß(IL-1ß), interleukin-6 (IL-6), and interleukin-17 (IL-17) secretion, as well as matrix metalloproteinase (MMP) expression in joint tissue, were measured as indicators of viability of DHE medicated AIA rats. Human fibroblast-like synoviocytes (MH7A cells) were connected to check these impacts. The results confirmed that DHE administration had an excellent therapeutic impact on the AIA rat model, substantially relieving joint swelling, inhibiting synovial pannus hyperplasia, and decreasing joint scores. In addition, the serum enzyme-linked immunosorbent assay (ELISA) showed that DHE treatment reduced the expression of pro-inflammatory factors in AIA rats. The immunohistochemical results showed that DHE treatment could reduce the synthesis of MMPs such as matrix metalloproteinase-1(MMP-1) and matrix metalloproteinase-3 (MMP-3) in the ankle tissue of AIA rats. In vitro, DHE inhibited cell proliferation, mRNA transcription, protein synthesis of proinflammatory factors such as IL-1ßand IL-6, and matrix metalloproteinases such as MMP-1 and MMP-3. Furthermore, DHE inhibited the phosphorylation levels of p38, JNK, and ERK proteins in TNF-α-treated MH7A cells.This work assessed the effect of DHE in AIA rats and revealed its mechanism in vitro.