Prediction model for developing neuropsychiatric systemic lupus erythematosus in lupus patients.

OBJECTIVE: This study aimed to construct a predictive model for assessing the risk of development of neuropsychiatric systemic lupus erythematosus (NPSLE) among patients with SLE based on clinical, laboratory, and meteorological data. METHODS: A total of 2232 SLE patients were included and were randomly assigned into training and validation sets. Variables such as clinical and laboratory data and local meteorological data were screened by univariate and least absolute shrinkage and selection operator (LASSO) logistic regression modelling. After 10-fold cross-validation, the predictive model was built by multivariate logistic regression, and a nomogram was constructed to visualize the risk of NPSLE. The efficacy and accuracy of the model were assessed by receiver operating characteristic (ROC) curve and calibration curve analysis. Net clinical benefit was assessed by decision curve analysis. RESULTS: Variables that were included in the predictive model were anti-dsDNA, anti-SSA, lymphocyte count, hematocrit, erythrocyte sedimentation rate, pre-albumin, retinol binding protein, creatine kinase isoenzyme MB, Nterminal brain natriuretic peptide precursor, creatinine, indirect bilirubin, fibrinogen, hypersensitive C-reactive protein, CO, and mild contamination. The nomogram showed a broad prediction spectrum; the area under the curve (AUC) was 0.895 (0.858-0.931) for the training set and 0.849 (0.783-0.916) for the validation set. CONCLUSION: The model exhibits good predictive performance and will confer clinical benefit in NPSLE risk calculation. Key Points • Clinical, laboratory, and meteorological data were incorporated into a predictive model for neuropsychiatric systemic lupus erythematosus (NPSLE) in SLE patients. • Anti-dsDNA, anti-SSA, LYM, HCT, ESR, hsCRP, IBIL, PA, RBP, CO, Fib, NT-proBNP, Crea, CO, and mild contamination are predictors of the development of NPSLE and may have potential for research. • The nomogram has good predictive performance and clinical value and can be used to guide clinical diagnosis and treatment.

SHP2: its association and roles in systemic lupus erythematosus.

OBJECTIVE: Systemic lupus erythematosus (SLE) is an autoimmune inflammatory disease. Src homology 2 domain containing protein tyrosine phosphatase (SHP2) is a member of the protein tyrosine phosphatases (PTPs) family. To date, relationship between SHP2 and SLE pathogenesis is not elucidated. METHOD: We measured plasma levels of SHP2 in 328 SLE patients, 78 RA patients, 80 SS patients and 79 healthy controls by ELISA, and discussed association of SHP2 in SLE patients, potential of plasma SHP2 as a SLE biomarker. Moreover, histological and serological changes were evaluated by flow cytometry, HE/Masson examination, immunofluorescence test in pristane-induced lupus mice after SHP2 inhibitor injection to reveal role of SHP2 in lupus development. RESULTS: Results indicated that SHP2 plasma levels were upregulated in SLE patients and correlated with some clinical, laboratory characteristics such as proteinuria, pyuria, and may be a potential biomarker for SLE. After SHP2 inhibitor treatment, hepatosplenomegaly and histological severity of the kidney in lupus mice were improved. SHP2 inhibitor reversed DCs, Th1, and Th17 cells differentiation and downregulated inflammatory cytokines (IL-4, IL-6, IL-10, IL-17A, IFN-γ and TNF-α) and autoantibodies (ANA, anti-dsDNA) production in pristane-lupus mice. CONCLUSION: In summary, SHP2 correlated with SLE pathogenesis and promoted the development of lupus.

Alteration of Gut Microbiota in Individuals at High-Risk for Rheumatoid Arthritis Associated With Disturbed Metabolome and the Initiation of Arthritis Through the Triggering of Mucosal Immunity Imbalance.

OBJECTIVE: In this study, we aimed to decipher the gut microbiome (GM) and serum metabolic characteristic of individuals at high risk for rheumatoid arthritis (RA) and to investigate the causative effect of GM on the mucosal immune system and its involvement in the pathogenesis of arthritis. METHODS: Fecal samples were collected from 38 healthy individuals and 53 high-risk RA individuals with anti-citrullinated protein antibody (ACPA) positivity (Pre-RA), 12 of 53 Pre-RA individuals developed RA within 5 years of follow-up. The differences in intestinal microbial composition between the healthy controls and Pre-RA individuals or among Pre-RA subgroups were identified by 16S ribosomal RNA sequencing. The serum metabolite profile and its correlation with GM were also explored. Moreover, antibiotic-pretreated mice that received GM from the healthy control or Pre-RA groups were then evaluated for intestinal permeability, inflammatory cytokines, and immune cell populations. Collagen-induced arthritis (CIA) was also applied to test the effect of fecal microbiota transplantation (FMT) from Pre-RA individuals on arthritis severity in mice. RESULTS: Stool microbial diversity was lower in Pre-RA individuals than in healthy controls. The bacterial community structure and function significantly differed between healthy controls and Pre-RA individuals. Although there were differences to some extent in the bacterial abundance among the Pre-RA subgroups, no robust functional differences were observed. The metabolites in the serum of the Pre-RA group were dramatically different from those in the healthy controls group, with KEGG pathway enrichment of amino acid and lipid metabolism. Moreover, intestinal bacteria from the Pre-RA group increased intestinal permeability in FMT mice and zonula occludens-1 expression in the small intestine and Caco-2 cells. Moreover, Th17 cells in the mesenteric lymph nodes and Peyer's patches were also increased in mice receiving Pre-RA feces compared to healthy controls. The changes in intestinal permeability and Th17-cell activation prior to arthritis induction enhanced CIA severity in PreRA-FMT mice compared with HC-FMT mice. CONCLUSION: Gut microbial dysbiosis and metabolome alterations already occur in individuals at high risk for RA. FMT from preclinical individuals triggers intestinal barrier dysfunction and changes mucosal immunity, further contributing to the development of arthritis.

IL-38, a potential therapeutic agent for lupus, inhibits lupus progression.

BACKGROUND: Previous studies reported that IL-38 was abnormally expressed in patients with systemic lupus erythematosus (SLE). However, the involvement of IL-38 in the pathophysiology of SLE remains unknown. METHODS: The therapeutic potential of IL-38 was tested in pristane-treated wild-type (WT) and IL-38-/- mice. Thus, SLE was induced via pristane in WT and IL-38-/- mice. Afterwards, the liver, spleen, and kidney of each mouse were obtained. The flow cytometric analysis of the immune cells, serologic expression of inflammatory cytokines and autoantibodies, renal histopathology, and inflammatory signaling were evaluated. RESULTS: WT mice with pristane-induced lupus exhibited hepatomegaly, splenomegaly, severe kidney damages, increased lymphoproliferation, enhanced lymphoproliferation, and upregulated inflammatory cytokines, such as IL-6, IL-13, IL-17A, MIP-3α, IL-12p70, and IFNγ, and elevated levels of autoantibodies, such as ANA IgG, anti-dsDNA IgG, and total IgG. IL-38-/- mice whose lupus progressed, had elevated cells of CD14+, CD19+, CD3+, and Th1, upregulated inflammatory cytokines and autoantibodies, and severe pathological changes in kidney. Administration of recombinant murine IL-38 to pristane-treated IL-38-/- mice improved their renal histopathology, which depended on ERK1/2, JNK1/2, p38, NF-κB p65, and STAT5 signaling pathways. CONCLUSION: IL-38 regulates SLE pathogenesis. Furthermore, targeting IL-38 is critical in the treatment of SLE.

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.

Association of CD40 Gene Polymorphisms With Systemic Lupus Erythematosus and Rheumatoid Arthritis in a Chinese Han Population.

Systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) are complex autoimmune diseases. CD40 participates in inflammatory response, and promotes fibroblast proliferation, leading to occurrence and progression of SLE, RA. This study explores CD40 gene polymorphisms in SLE and RA patients from a Chinese Han population. Two hundred SLE patients, 340 RA patients, and 900 healthy controls were enrolled. Genomic DNA was extracted from peripheral blood, and six polymorphisms of CD40 gene (rs3765456, rs1569723, rs73115010, rs13040307, rs1883832, and rs4810485) were detected by KASP method. Frequencies of rs1569723 genotypes AA, AC, AA+AC were significantly higher in RA patients as compared to those in healthy controls (P = 0.049, P = 0.024, P = 0.022). Frequencies of genotypes CT, CC+CT of rs1883832, and GT, GG+GT of rs4810485 were significantly higher in RA patients as compared to those in healthy controls (P = 0.012, P = 0.018, P = 0.009, P = 0.015). RA patients carrying rs13040307 C allele and rs73115010 T allele showed increased number of swollen joints. Moreover, frequency of allele T of rs13040307 was lower in SLE patients with positive anti-dsDNA and hematuria as compared to that in patients without these parameters (P = 0.038, P = 0.045). There were increased frequencies of genotype TT, allele T for rs13040307 and lower frequencies of genotype TT, allele T for rs73115010 in lupus patients with myositis (all P<0.05). Interestingly, frequencies of rs1569723 A allele, rs4810485 T allele were higher in SLE patients with myositis, and frequencies of rs3765456 A allele, rs1883832 T allele were lower in SLE patients with myositis (All P<0.05). In conclusion, CD40 gene polymorphisms may associate with susceptibility to SLE and RA.

Association of IL-35 expression and gene polymorphisms in rheumatoid arthritis.

Interleukin (IL)-35 is the newest member of the IL-12 family. It is expressed in many immune cells and has been recognized as a novel inflammatory cytokine that may have bifunctional properties. Recent findings have indicated that the expression of IL-35 is abnormal in rheumatoid arthritis (RA) patients. However, the results were inconsistent. In this study, 400 RA patients were recruited to evaluate serum levels of IL-35 in a Chinese Han population by enzyme-linked immunosorbent assay. The association of IL-35 gene polymorphisms and RA genetic susceptibility was investigated in 400 RA patients and 612 healthy controls. The results showed that serum levels of IL-35 were elevated in 100 RA patients compared to 51 healthy controls, relating to disease activity and synovial fluid IL-35 expression in the training cohort. Another independent 300 RA patients and 369 other rheumatic disease patients (98 lupus, 95 osteoarthritis, 95 gout, 42 Sjogren's syndrome and 39 ankylosing spondylitis patients) confirmed that serum levels of IL-35 were elevated in RA patients, and serum IL-35 has good diagnostic ability for differentiating RA from the other rheumatic diseases. The genotyping of 10 IL-35 polymorphisms, including rs2227314, rs2243115, rs2243123, rs2243131, rs568408, rs583911, rs428253, rs4740, rs9807813 and rs4905, revealed that rs2227314, rs2243131, rs9807813, and rs583911 were correlated with RA risk. Different genotypes (rs2227314, rs583911, and rs9807813) exhibited different expression of IL-35. These findings demonstrate that serum levels of IL-35 are increased in RA patients and that IL-35 polymorphisms are correlated with RA risk.

IL-38: A novel cytokine in systemic lupus erythematosus pathogenesis.

IL-38 is a newly identified cytokine that belongs to the IL-1 family. In our previous study, we found elevated plasma levels of IL-38 in patients with systemic lupus erythematosus (SLE). However, the clear relationship of IL-38 expression in plasma, peripheral blood mononuclear cells (PBMCs) and clinical and laboratory features needs elucidation. Additionally, we evaluated the possible role of IL-38 in regulating production of inflammatory cytokines in PBMCs in vitro. A pristane-induced murine lupus model was used to further demonstrate the effects of IL-38 on cytokines in vivo and discuss the significance of IL-38 in lupus development. The results showed that mRNA expression of IL-38 in PBMCs of patients with SLE was elevated compared with volunteers, and expression of IL-38 in both plasma and PBMCs was strongly related to clinical features, such as haematuria and proteinuria, and correlated with a SLEDAI score. Plasma levels of TNF-α, IL-1ß, IL-6 and IL-23 were elevated in patients with SLE and were related to plasma levels of IL-38. In vitro, PBMCs of patients with SLE stimulated with IL-38 showed a decreased expression of the four inflammatory cytokines compared with PBMCs of patients without treatment. Interestingly, IL-38 administration in lupus mice significantly reduced the development of lupus, such as reduced proteinuria, improved histological examinations of the kidneys and down-regulated inflammatory cytokines. In conclusion, IL-38 may suppress synthesis of pro-inflammatory cytokines and therefore regulate lupus pathogenesis.

Association of MASP2 levels and MASP2 gene polymorphisms with systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disorder. MASP2 is a mediator that plays an important role in complement system. As dysregulation of the complement system has been demonstrated to correlate with SLE pathogenesis, the role of MASP2 in lupus has not been widely discussed. In the present study, serum levels of MASP2 were evaluated in 61 lupus patients and 98 healthy controls by training cohort, and then a validation cohort including 100 lupus, 100 rheumatoid arthritis, 100 osteoarthritis, 100 gout, 44 Sjogren's syndrome, 41 ankylosing spondylitis patients confirmed the findings. Receiver operating characteristic (ROC) curve analysis determined the discriminatory capacity for serum MASP2. PCR methods tested the association of MASP2 gene polymorphisms (rs7548659, rs17409276, rs2273346, rs1782455 and rs6695096) and SLE risk. Impact of polymorphism on MASP2 serum levels was evaluated as well. Results showed that serum levels of MASP2 were significantly higher in lupus patients and correlated with some clinical, laboratory characteristics in the training cohort, and were much higher as compared to that in different rheumatic diseases patients in the validation cohort. Serum MASP2 showed a good diagnostic ability for lupus. Genotype frequencies and allele frequency of polymorphisms rs7548659, rs2273346 were strongly related to SLE risk, and genotypes of rs17409276, rs1782455, rs76695096 were significantly correlated with lupus genetic susceptibility. Interestingly, patients carrying GA genotype of rs17409276, TT, TC genotype of rs6695096 showed higher levels of serum MASP2. The findings suggested that MASP2 may be a potential disease marker for lupus, and correlate with SLE pathogenesis.

IRAK family in inflammatory autoimmune diseases.

Innate immune signaling plays an important role in inflammation, and dysregulation of signaling components within this pathway has been focused as a critical mediator in initiation, progression of inflammatory autoimmune diseases. Toll-like receptors (TLRs) are the most upstream pattern recognition receptors in the immune cells, detecting pathogen associated molecular patterns, initiating signal transduction, by which interleukin-1 receptor-associated kinase (IRAK) family mediates activating signal from TLRs and interleukin-1 receptor. The family comprises of four members, IRAK1, IRAK2, IRAK-M, IRAK4. The family members have a role in either positive or negative regulation of innate immunity, adaptive immunity and inflammation. Accumulated evidence proves that IRAK performs significantly in the pathogenesis of inflammatory autoimmune disorders. On the one hand, both patients and animal modes reported abnormal expression of the family members. On the other hand, functional study in vivo and in vitro demonstrated that the members are implicated in the development of the diseases. Interestingly, IRAK inhibition has potential therapeutic benefits. In this review, we focus on the family, review the physiological roles in different immune cells, and summarize emerging data for highlighting the importance of them in inflammatory autoimmunity.

Biology of IL-36 Signaling and Its Role in Systemic Inflammatory Diseases.

Interleukin (IL)-36 is a member of the IL-1 superfamily and includes three agonists (IL-36α, IL-36ß, and IL-36γ) and an antagonist (IL-36Ra). IL-36 agonists bind to heterodimeric receptor complexes. Then, the heterotrimer complexes signal via intracellular functional domains, binding to downstream signaling proteins and inducing inflammatory responses. In this review, we summarized the current knowledge about the biological role of IL-36 and its correlation with systemic inflammatory diseases. The information collected will help to increase the understanding of the potential of IL-36 and may give clues for developing novel therapeutic strategies.

Insights into IL-29: Emerging role in inflammatory autoimmune diseases.

Interleukin-29 (IL-29) is a newly discovered member of type III interferon. It mediates signal transduction via binding to its receptor complex and activates downstream signalling pathways, and therefore induces the generation of inflammatory components. Recent studies reported that expression of IL-29 is dysregulated in inflammatory autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus, osteoarthritis, Sjögren's syndrome, psoriasis and systemic sclerosis. Furthermore, functional analysis revealed that IL-29 may involve in the pathogenesis of the inflammatory autoimmune disorders. In this review, we will systematically review the current knowledge about IL-29. The information collected revealed the regulatory role of IL-29 and may give important implications for its potential in clinical treatment.

Altered expression of circular RNA in primary Sjögren's syndrome.

OBJECTIVES: This study evaluated expression of circRNA in primary Sjögren's syndrome (pSS) patients so as to find novel biomarkers for pSS screening and discussed possible role of circRNA in pSS. We also evaluated expression profile of circRNA in systemic lupus erythematosus (SLE) patients. METHODS: Microarray analysis detected circRNA expression in PBMCs from five paired pSS, SLE patients, and controls. Then, differentially expressed circRNAs were validated in 30 pSS patients as compared to 30 SLE patients, healthy controls. CircRNAs interacting with miRNAs were discussed by Arraystar's homemade miRNA target prediction software. ROC analysis assessed the diagnostic value. RESULTS: We identified 234 differentially expressed circRNAs in pSS patients and verified five selected circRNAs (including hsa_circRNA_001264, hsa_circRNA_104121, hsa_circRNA_045355, hsa_circRNA_103461, hsa_circRNA_105034). Expression of hsa_circRNA_001264, hsa_circRNA_104121, and hsa_circRNA_045355 was strongly related to some clinical, laboratory parameters, and disease activity index in pSS patients. ROC analysis indicated potential diagnostic ability for the three circRNAs in pSS patients. One hundred and forty-eight circRNAs were differently expressed between lupus patients and controls. CONCLUSION: This study provides evidence that hsa_circRNA_001264, hsa_circRNA_104121, and hsa_circRNA_045355 might be biomarkers for pSS, correlate with pSS etiology.Key Points• Many circRNAs were dysregulated in pSS patients.• Differentially expressed circRNAs correlated with pSS clinical, laboratory features.• CircRNAs may be biomarkers for pSS.

Association of IRF5 rs2004640 polymorphism and systemic lupus erythematosus: A meta-analysis.

BACKGROUND: This study aimed to discuss the relationship between interferon regulatory factor (IRF)5 gene rs2004640 T/G polymorphism and systemic lupus erythematosus (SLE) susceptibility. METHODS: A meta-analysis was calculated on the association between rs2004640 polymorphism and SLE by allelic contrast (T vs G), additive model (TT vs GG), recessive model (TT vs TG + GG) and dominant model (TT + TG vs GG). RESULTS: A total of 28 comparisons were identified, including 11 228 SLE cases and 14 374 controls. Meta-analysis revealed a significant association between allele T and SLE in overall populations (odds ratio [OR] = 1.393, 95% CI: 1.276-1.522, P < 0.001). Stratification by ethnicity indicated strong associations between T allele and SLE in Asians, Europeans and Latin Americans (OR = 1.256, 95% CI: 1.073-1.469, P = 0.004; OR = 1.338, 95% CI: 1.080-1.659, P = 0.008; OR = 1.853, 95% CI: 1.488-2.308, P < 0.001). Results also showed significant associations between the additive model and SLE in all subjects and Asians (OR = 1.999, 95% CI: 1.442-2.771, P < 0.001; OR = 1.544, 95% CI: 1.009-2.362, P < 0.045). In addition, we found significant associations between the dominant model and SLE in all populations and Asians (OR = 1.521, 95% CI: 1.257-1.841, P < 0.001; OR = 1.270, 95% CI: 1.136-1.421, P < 0.001). A marginal association was detected between the recessive mode and SLE in overall subjects (OR = 1.480, 95% CI: 1.022-2.144, P = 0.038). CONCLUSION: The current study suggested that individuals carrying rs2004640 T allele correlated with a high risk of SLE, and the IRF5 rs2004640 polymorphism was associated with SLE susceptibility.

Targeting IL-34 in inflammatory autoimmune diseases.

Interleukin-34 (IL-34) shares a common receptor with macrophage colony-stimulating factor (M-CSF), and can bind to CSF-1R, induces lymphocytes differentiation, proliferation, and regulates the synthesis of inflammatory components. Recent findings reported aberrant expression of IL-34 in several autoimmune disorders, such as lupus, arthritis, systemic sclerosis, inflammatory bowel diseases. The functional analysis further demonstrated that IL-34 may perform significantly in these inflammatory autoimmune disorders. IL-34 might consider as a biomarker for these diseases. I hope this collection of the findings in this review will improve knowledge of the role of IL-34, and targeting IL-34 may give the potential for these autoimmune diseases.

Association between TL1A gene polymorphisms and systemic lupus erythematosus in a Chinese Han population.

Our previous studies showed elevated tumor necrosis factor-like ligand 1 aberrance (TL1A) expression in systemic lupus erythematosus (SLE). However, TL1A polymorphisms with SLE susceptibility remain to be elucidated. In addition, we made meta-analysis to evaluate the relationship of TL1A polymorphisms and autoimmune diseases owing to inconsistent results. The present research was carried out by 404 SLE, 150 primary Sjogren's syndrome (pSS) patients, and 574 healthy individuals. Three TL1A polymorphisms (rs3810936, rs6478109, rs7848647) were genotyped using TaqMan genotyping assay. Then, the meta-analysis was performed by collecting the present case-control study and previously published research. Results showed that genotypes of rs3810936, rs7848647 were different between SLE patients and healthy controls, whereas no significant association was observed in the three polymorphisms and pSS patients. Genotypes distribution of rs6478109, rs7848647 were strongly related to lupus nephritis within SLE (p = 0.004, p = 0.011), respectively. Moreover, combined meta-analysis consisted of ten comparative research involving 4,305 patients and 5,600 controls. An association between autoimmune diseases and rs6478109 polymorphism was found. Our findings indicate that gene polymorphisms (rs3810936, rs7848647) of TL1A might correlate with lupus.

Elevated expression of interleukin-37 in patients with rheumatoid arthritis.

AIM: This study aims to discuss plasma and messenger RNA (mRNA) levels of interleukin (IL)-37 in rheumatoid arthritis (RA) patients and evaluate the potential of plasma IL-37 as a biomarker for RA. METHOD: Plasma IL-37 levels and IL-37 mRNA relative concentrations were measured by enzyme-linked immunosorbent assay (ELISA) and quantitative reverse transcriptase-polymerase chain reaction (RT-PCR). We discussed the association of IL-37 levels and clinical, laboratory parameters in RA patients in a training cohort. Plasma IL-37 levels were tested for discriminatory capacity by receiver operating characteristic (ROC) curve analysis. We then validated plasma IL-37 expression in a cohort of 598 patients (230 RA, 107 systemic lupus erythematosus [SLE], 100 osteoarthritis [OA], 62 gout, 51 primary Sjögren's syndrome [pSS], 48 ankylosing spondylitis [AS]). RESULTS: Both plasma levels of IL-37 and mRNA levels of IL-37 were elevated in RA patients compared to those in healthy controls in the training cohort, and there was a good diagnostic ability to predict RA (area under the curve [AUC] = 0.97). Plasma IL-37 levels were significantly related to Disease Activity Score of 28 joints - erythrocyte sedimentation rate (DAS28-ESR) (rs  = 0.459, P < 0.001). The levels of IL-37 mRNA were related to plasma IL-37 levels (rs  = 0.642, P < 0.001), DAS28-ESR (r = 0.641, P < 0.001) and C-reactive protein (rs  = 0.603, P < 0.001). In the validation cohort, when plasma IL-37 in RA patients compared with that in SLE, OA, gout, pSS and AS patients, the AUC was 0.86, 0.87, 0.91, 0.87, 0.92, respectively. CONCLUSION: IL-37 expression was increased in RA patients, and correlated with disease activity. IL-37 may be a biomarker for the diagnosis of RA.

Gene polymorphisms and serum levels of TL1A in patients with rheumatoid arthritis.

Recent findings showed elevated expression of tumor necrosis factor (TNF)-like ligand 1A (TL1A) in rheumatoid arthritis (RA) patients and arthritis mice. However, whether TL1A gene polymorphisms may correlate with RA susceptibility needs to be discussed. This case-control study was performed on 350 RA patients and 556 healthy subjects to identify TL1A genetic variants (rs3810936, rs6478109, and rs7848647) and their possible association with TL1A levels, susceptibility to and severity of RA. Odds ratio and 95% confidence interval were calculated to represent the correlation between TL1A polymorphisms and RA. The TL1A serum levels were evaluated. Results showed that frequencies of TC, TT + TC genotypes of rs3810936, rs7848647 in RA patients were significantly lower in RA patients compared with controls. Patients with C allele showed more severe disease course (disease activity index: erythrocyte sedimentation rate, rheumatoid factor) than in carriers of T allele. However, the allele or genotype frequencies of rs6478109 were not associated with RA. In addition, TL1A genetic variants conferred higher TL1A levels in RA patients compared with controls. In conclusion, these findings indicated an association between TL1A rs3810936, rs7848647 variation and the susceptibility of RA in a sample of Chinese individuals, and TL1A may correlate with severity of RA.