Detecting gastrointestinal manifestations in patients with systemic sclerosis using anti-gAChR antibodies

Background: Patients with systemic sclerosis (SSc) complicated by gastrointestinal dysmotility are difficult to treat and have high mortality. To clarify the pathogenesis of gastrointestinal manifestations, we aimed to demonstrate the association among the clinical features of SSc, the serological markers, the autoantibodies against nicotinic acetylcholine receptor at autonomic ganglia (gAChR). Methods: Fifty patients were enrolled and divided into two groups according to the presence or absence of gastrointestinal manifestations, and the characteristics were analyzed between these two groups. We measured biomarkers and the autoantibodies against two gAChRα3 and β4 subunits to test sera samples. Furthermore, patients were classified based on the presence or absence of anti-gAChR autoantibodies, and their clinical features were compared. Results: In patients with SSc and gastrointestinal manifestations, digital ulcers were more frequent (p = 0.050) and VEGF expression was significantly higher (p = 0.038). Seven subjects with SSc were seropositive for α3 subunit, whereas one patient was seropositive for β4 subunit. The mean level of anti-gAChRα3 autoantibodies in SSc patients with gastrointestinal manifestations was significantly higher than that in SSc patients without gastrointestinal manifestations (p = 0.001). The group of patients with SSc and gAChR autoantibodies had significantly higher endostatin levels (p = 0.046). Conclusions: This study is the first to demonstrate that clinical characteristics of SSc patients with seropositivity for gAChR autoantibodies. Patients with SSc have circulating autoantibodies against gAChR, which may contribute to gastrointestinal manifestations associated with this disease, suggesting that gAChR-mediated autonomic neurotransmission may provide a pathomechanism for gastrointestinal dysmotility in SSc

Intravenous cyclophosphamide treatment for systemic lupus erythematosus with severe autonomic disorders confirmed by head-up tilt table test: A case series

Autonomic disorders are common in patients with systemic lupus erythematosus (SLE), but the therapeutic strategy and methods for evaluating the effects of therapy have not been established. We describe the three cases of SLE patients who developed severe autonomic disorders as demonstrated by the head-up tilt table test (HUT). All three patients were treated by intensive immunosuppressive treatments including intravenous cyclophosphamide (IVCY); their HUT results all became negative. Our cases suggest that IVCY treatment can be a good therapeutic option for severe autonomic disorders in SLE patients. The HUT is a useful objective method for the diagnosis of and the evaluation of longitudinal therapeutic effects on autonomic disorders in SLE patients with orthostatic intolerance

Methotrexate Alters the Expression of microRNA in Fibroblast-like Synovial Cells in Rheumatoid Arthritis

We aimed to investigate the effect of methotrexate (MTX) on microRNA modulation in rheumatoid arthritis fibroblast-like synovial cells (RA-FLS). RA-FLS were treated with MTX for 48 h. We then performed miRNA array analysis to investigate differentially expressed miRNAs. Transfection with miR-877-3p precursor and inhibitor were used to investigate the functional role of miR-877-3p in RA-FLS. Gene ontology analysis was used to investigate the cellular processes involving miR-877-3p. The production of cytokines/chemokines was screened by multiplex cytokine/chemokine bead assay and confirmed by ELISA and quantitative real-time PCR. The migratory and proliferative activities of RA-FLS were analyzed by wound healing assay and MKI-67 expression. MTX treatment altered the expression of 13 miRNAs (seven were upregulated and six were downregulated). Among them, quantitative real-time PCR confirmed that miR-877-3p was upregulated in response to MTX (1.79 ± 0.46-fold, p < 0.05). The possible target genes of miR-877-3p in RA-FLS revealed by the microarray analysis were correlated with biological processes. The overexpression of miR-877-3p decreased the production of GM-CSF and CCL3, and the overexpression of miR-877-3p inhibited migratory and proliferative activity. MTX altered the miR-877-3p expression on RA-FLS, and this alteration of miR-877-3p attenuated the abundant production of cytokines/chemokines and proliferative property of RA-FLS

Effects of HLA-DRB1 alleles on susceptibility and clinical manifestations in Japanese patients with adult onset Still’s disease

BackgroundHLA-DRB1 alleles are major determinants of genetic predisposition to rheumatic diseases. We assessed whether DRB1 alleles are associated with susceptibility to particular clinical features of adult onset Still’s disease (AOSD) in a Japanese population by determining the DRB1 allele distributions.MethodsDRB1 genotyping of 96 patients with AOSD and 1,026 healthy controls was performed. Genomic DNA samples from the AOSD patients were also genotyped for MEFV exons 1, 2, 3, and 10 by direct sequencing.ResultsIn Japanese patients with AOSD, we observed a predisposing association of DRB1*15:01 (p = 8.60 × 10−6, corrected p (Pc) = 0.0002, odds ratio (OR) = 3.04, 95% confidence interval (95% CI) = 1.91–4.84) and DR5 serological group (p = 0.0006, OR = 2.39, 95% CI = 1.49–3.83) and a protective association of DRB1*09:01 (p = 0.0004, Pc = 0.0110, OR = 0.34, 95% CI = 0.18–0.66) with AOSD, and amino acid residues 86 and 98 of the DRβ chain were protectively associated with AOSD. MEFV variants were identified in 49 patients with AOSD (56.3%). The predisposing effect of DR5 was confirmed only in patients with AOSD who had MEFV variants and not in those without MEFV variants. Additionally, DR5 in patients with AOSD are associated with macrophage activation syndrome (MAS) and steroid pulse therapy.ConclusionThe DRB1*15:01 and DR5 are both associated with AOSD susceptibility in Japanese subjects. A protective association between the DRB1*09:01 allele and AOSD was also observed in these patients. Our data also highlight the effects of DRB1 alleles in susceptibility to AOSD

Thymus and Activation-regulated Chemokine as a Biomarker for IgG4-related Disease

High serum concentrations of thymus and activation-regulated chemokine (TARC) are observed in allergic diseases such as atopic dermatitis and bronchial asthma. Frequent allergic symptoms have been reported in patients with IgG4-related disease (IgG4-RD). We investigated the pathogenic role of TARC as a biomarker in IgG4-RD patients. We evaluated the serum concentrations of TARC from 29 IgG4-RD patients, 28 primary Sjogren syndrome (pSS) patients, and 23 healthy controls (HCs) by enzyme-linked immunosorbent assay (ELISA). We analyzed the correlations between the TARC concentrations and the subjects’ clinical parameters. To investigate the biological effect of TARC on the pathogenesis of IgG4-RD, we evaluated the in vitro induction of plasmablasts from IgG4-RD patients by TARC. The serum concentrations of TARC in the IgG4-RD patients were significantly higher than those of the pSS patients and HCs. The serum TARC concentration of the IgG4-RD group was positively correlated with the IgG4-RD responder index (IgG4-RD RI) score and with the number of organs involved, but it was not correlated with the serum IgG4 level or eosinophil number in the IgG4-RD patients’ peripheral blood. The patients who had lung involvement had higher serum TARC concentrations. In vitro, TARC clearly induced the formation of plasmablasts from the IgG4-RD patients’ peripheral blood mononuclear cells. Collectively, our data suggest that a systemic increment of TARC may contribute to the development of IgG4-RD through an aberrant induction of plasmablasts

Granulocyte-macrophage colony-stimulating factor and tumor necrosis factor-α in combination is a useful diagnostic biomarker to distinguish familial Mediterranean fever from sepsis

Objective: To identify potential biomarkers to distinguish familial Mediterranean fever (FMF) from sepsis.Method: We recruited 28 patients diagnosed with typical FMF (according to the Tel Hashomer criteria), 22 patients with sepsis, and 118 age-matched controls. Serum levels of 40 cytokines were analyzed using multi-suspension cytokine array. We performed a cluster analysis of each cytokine in the FMF and sepsis groups in order to identify specific molecular networks. Multivariate classification (random forest analysis) and logistic regression analysis were used to rank the cytokines by importance and determine specific biomarkers for distinguishing FMF from sepsis.Results: Fifteen of the 40 cytokines were found to be suitable for further analysis. Levels of serum granulocyte-macrophage colony-stimulating factor (GM-CSF), fibroblast growth factor 2, vascular endothelial growth factor, macrophage inflammatory protein-1b, and interleukin-17 were significantly elevated, whereas tumor necrosis factor-α (TNF-α) was significantly lower in patients with FMF compared with those with sepsis. Cytokine clustering patterns differed between the two groups. Multivariate classification followed by logistic regression analysis revealed that measurement of both GM-CSF and TNF-α could distinguish FMF from sepsis with high accuracy (cut-off values for GM-CSF = 8.3 pg/mL; TNF-α = 16.3 pg/mL; sensitivity, 92.9%; specificity, 94.4%; accuracy, 93.4%).Conclusion: Determination of GM-CSF and TNF-α levels in combination may represent a biomarker for the differential diagnosis of FMF from sepsis, based on measurement of multiple cytokines

Serum amyloid A1 (SAA1) gene polymorphisms in Japanese patients with adult-onset Stillʼs disease

Adult-onset Still\u27s disease (AOSD) is a rare systemic inflammatory disorder in which inflammasome activation plays a pathophysiological role. In view of the inflammatory nature of AOSD, we investigated whether serum amyloid A (SAA) gene polymorphisms affect the susceptibility of patients with AOSD.Eighty-seven Japanese patients with AOSD and 200 healthy Japanese subjects were recruited in this study. The genotypes of the -13C/T SNP in the 5′-flanking region of the SAA1 gene (rs12218) and two SNPs within exon 3 of SAA1 (2995C/T and 3010C/T polymorphisms) were determined using polymerase chain reaction fragment length polymorphism (PCR-RFLP) assay in all subjects. In AOSD patients, exons 1, 2, 3, and 10 of the MEFV gene were also genotyped by direct sequencing.The frequency of the SAA1.3 allele was increased in AOSD patients compared with that in healthy subjects (43.1% versus 37.5%), but the difference was not significant. The −13T allele was more frequently observed in AOSD patients than in healthy subjects (50.6% versus 41.0%, P = .0336). AOSD patients with the −13T allele had been treated with immunosuppressants more frequently than those without this allele. MEFV mutations were detected in 49 patients with AOSD (49/87, 57.3%). AOSD patients with MEFV variants frequently exhibit macrophage activation syndrome, but the difference was not significant (34.7% versus 18.4%, P = .081). Also, there was no significant difference in SAA1 -13C/T allele frequency between AOSD patients with and without MEFV mutations.Our data shows a significant association between T allele of rs12218 and AOSD in Japanese population

Gender Differences in the Prevalence of Chronic Pain and Leisure Time Physical Activity Among US Adults: A NHANES Study

Gender disparities in chronic pain are well documented in the literature. However, little is known regarding the relationship between physical activity (PA) and gender disparities in chronic pain. This study described gender differences in prevalence of chronic pain and PA, and identified a type of leisure time PA that individuals frequently chose in a nationally representative sample of US adults (N = 14,449). Data from the National Health Nutrition Examination Survey 1999&ndash;2004 were analyzed. Individuals were categorized into no chronic pain (NCP), localized chronic pain (LCP), and widespread chronic pain (WCP) groups based on responses to a pain questionnaire. A self-report PA questionnaire was used to estimate the time spent in different types of PA. Women showed higher prevalence of LCP and WCP compared to men. Men spent more hours per week for leisure time PA compared to women, but men and women showed similar prevalence of sufficient PA to meet a PA recommendation (&ge;150 min/week of moderate-to-vigorous intensity PA) across chronic pain categories. However, the prevalence of sufficient PA was substantially higher among men and women with NCP compared to men and women with LCP and WCP. Additionally, both men and women chose walking as the primary type of leisure time PA. Together, gender disparities exist in the prevalence of chronic pain and hours spent for leisure time PA. More research is needed to explore the role of increasing leisure time PA, such as walking, in reducing gender disparities in chronic pain