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ID PMID Title PublicationDate abstract
30142759 Uncommon patterns of antinuclear antibodies recognizing mitotic spindle apparatus antigens 2018 Aug Antinuclear antibodies (ANA) are key biomarkers in the evaluation of rheumatic diseases. The prevalence and clinical significance of uncommon or rare patterns, particularly those directed at the mitotic spindle apparatus (MSA), are not well understood. We aimed to investigate the prevalence and clinical significance of anti-MSA patterns in a Colombian population.During 2013 and 2014, 113,491 consecutive determinations of ANA were studied for the presence of uncommon patterns. Clinical and laboratory data of anti-MSA positive patients were retrospectively collected and analyzed.Of the 113,491 patients tested, 60,501 (53%) were positive for ANA, of which 834 (1.3%) were positive for uncommon/rare patterns of ANA (anti-MSA in 592 cases). Of these 592 cases, complete data were available in 329 patients, of whom 116 had an established diagnosis. Anti-MSA antibodies were the only ANA positive test in 81% patients. At least one fine reactivity was identified in 19/116 (16.3%) of ANA-positive patients, of which anti-Ro was the most prevalent (18/116, 15.5%).The most frequent patterns were nuclear mitotic apparatus (NuMA) (56%) and MSA-2 (25%). The NuMA pattern had the highest ANA titers: mean 320 (range 80-2560) and behaved as monospecific antibodies. The most frequent systemic autoimmune diseases were Sjögren syndrome (SS) (18.1%), rheumatoid arthritis (RA) (13.8%), and systemic lupus erythematosus (SLE) (11%). Undifferentiated connective tissue disease (UCTD) was associated with the centrosome (P < .001), NuMA (P < .02) and MSA-2 (P < .45) patterns. Chronic idiopathic urticaria (CIU) was associated with the NuMA pattern (P < .02) and sensorineural hearing loss (SNHL) was associated with the MSA-2 (P < .001), centrosome (P < .68) and CENP-F (P < .38) patterns, previously unreported findings. Malignancies were found in 8 patients (50% were papillary thyroid cancer).In a large cohort of ANA determinations, uncommon patterns were found in around 1% of cases. The most frequent anti-MSA patterns found were NuMA and MSA-2. More than 50% of patients with anti-MSA had an associated CTD, mainly SS, RA and SLE, and anti-MSA behaved as monospecific antibodies. Other entities of presumed autoimmune origin, like CIU and SNHL, might be associated with these patterns.
30108196 Key roles for lipid mediators in the adaptive immune response. 2018 Jul 2 Chronic inflammation is an underlying feature of many diseases, including chronic obstructive pulmonary disease, rheumatoid arthritis, asthma, and multiple sclerosis. There is an increasing appreciation of the dysregulation of adaptive immunity in chronic inflammatory and allergic diseases. The discovery of specialized pro-resolving lipid mediators (SPMs) that actively promote the resolution of inflammation has opened new avenues for the treatment of chronic inflammatory diseases. Much work has been done focusing on the impact of SPMs on innate immune cells. However, much less is known about the influence of SPMs on the development of antigen-specific adaptive immune responses. This Review highlights the important breakthroughs concerning the effects of SPMs on the key cell types involved in the development of adaptive immunity, namely dendritic cells, T cells, and B cells.
29990326 Prevalence of extraintestinal manifestations in Korean inflammatory bowel disease patients 2018 BACKGROUND: The prevalence of inflammatory bowel disease (IBD) in South Korea is increasing. Although extraintestinal manifestations (EIMs) are an important factor in the clinical outcomes of IBD patients, EIMs have not yet been investigated in Korea. Thus, we conducted a cross-sectional study to assess the prevalence of EIMs in Korean IBD patients. METHODS: The 2014 claims data from the National Health Insurance System (NHIS) of Korea were used. IBD patients were identified by codes for Crohn disease (CD) and ulcerative colitis (UC) in the NHIS registration system for rare or intractable diseases. International Classification of Diseases, Tenth Edition codes were used to identify EIM cases. To estimate the prevalence of EIMs in the general population of Korea, we used national sample data. Standardized prevalence ratios (SPRs) were calculated to compare the prevalence rates of EIMs among IBD patients to those among the general population of Korea. RESULTS: A total of 13,925 CD patients and 29,356 UC patients were identified. CD and UC patients were different in terms of demographics and utilization of medication. Among the 17 EIMs investigated, pyoderma gangrenosum, osteomalacia, Sweet syndrome, and scleritis were observed in very few patients. The SPRs were greater than 1 for all EIMs. Aphthous stomatitis, rheumatoid arthritis, and osteoporosis were highly prevalent in both CD and UC patients, but the SPRs of the EIMs were not high. CONCLUSION: The study confirmed that EIMs are more prevalent among IBD patients than among the general population of Korea. The prevalence of EIMs in IBD patients suggests the need for greater attention and effort in clinical practice.
29966856 Cross-cultural adaptation and validity of the Italian version of the Central Sensitization 2018 Oct BACKGROUND: Central sensitization (CS) is an important feature in patients with chronic pain. The Central Sensitization Inventory (CSI) was developed with the goal of detecting the patients' symptoms related to CS. OBJECTIVES: This study aimed at cross-culturally adapting the CSI into Italian, and at assessing its structural and construct validity in patients with different chronic pain disorders. DESIGN: Clinimetric study. METHODS: The Italian version of the CSI (CSI-I) was generated following forward and backward translations, expert committee review, and pilot-testing. Patients with pain for ≥3 months were eligible if diagnosed with: low back pain (LBP), temporomandibular disorder (TMD), hand osteoarthritis (HOA), fibromyalgia (FM), or rheumatoid arthritis (RA). Structural validity was assessed with exploratory factor analysis and parallel analysis based on minimum rank factor analysis; construct validity was evaluated by testing ten hypotheses on: 1) expected differences between relevant subgroups, 2) expected correlations with other instruments measuring pain intensity, physical functioning, psychological functioning, headache symptoms, and pain self-efficacy. RESULTS: 220 patients were included: 35% with LBP, 17% with TMD, 19% with HOA, 9% with FM, and 20% with RA. Factor analyses revealed that the CSI-I is a unidimensional instrument. Construct validity was satisfactory since 80% of the hypotheses were met. CONCLUSIONS: The CSI-I was successfully developed and exhibited satisfactory validity in patients with chronic pain. Its reliability, responsiveness and content validity should be investigated in future studies. Until robust evidence indicates a strong relationship between CS and the CSI-I, caution should be adopted in claiming that the CSI-I measures CS.
29908342 Biocompatible PEGylated Gold nanorods function As cytokinesis inhibitors to suppress angio 2018 Sep Pathological angiogenesis is driven by uncontrolled growth of endothelial cells (ECs), which could lead to retinopathy, tumor and rheumatoid arthritis, etc. ECs must experience multiple cell division process to grow, and cytokinesis is the final step. The present study shows that PEGylated GNRs (PEG-GNRs) specifically target ECs cytokinesis process which results in high ratio of binucleated cells, and these binucleated ECs lose the ability to proliferate. Further data show that PEG-GNRs do not induce toxicity in vitro and in vivo. PEG-GNRs could inhibit ECs proliferation, migration, tube formation and inhibit angiogenesis in ex vivo model. Oxygen induced retinopathy and tumor angiogenesis model further show that PEG-GNRs can inhibit angiogenesis in vivo. Gene expression profiles reveal that PEG-GNRs mainly affect ECs cell division process, and PEG-GNRs treated ECs are arrested in G2/M phase. The mechanism is that PEG-GNRs could disrupt TGFβ pathway, and subsequently suppress the assembly of actin filaments in contractile ring site. These findings indicate that PEG-GNR is a novel cytokinesis inhibitor which can be used to interfere with retinal angiogenesis and tumor.
29751523 Annexin A1 and Autoimmunity: From Basic Science to Clinical Applications. 2018 May 3 Annexin A1 is a protein with multifunctional roles in innate and adaptive immunity mainly devoted to the regulation of inflammatory cells and the resolution of inflammation. Most of the data regarding Annexin A1 roles in immunity derive from cell studies and from mice models lacking Annexin A1 for genetic manipulation (Annexin A1(-/-)); only a few studies sought to define how Annexin A1 is involved in human diseases. High levels of anti-Annexin A1 autoantibodies have been reported in systemic lupus erythematosus (SLE), suggesting this protein is implicated in auto-immunity. Here, we reviewed the evidence available for an association of anti-Annexin A1 autoantibodies and SLE manifestations, in particular in those cases complicated by lupus nephritis. New studies show that serum levels of Annexin A1 are increased in patients presenting renal complications of SLE, but this increment does not correlate with circulating anti-Annexin A1 autoantibodies. On the other hand, high circulating Annexin A1 levels cannot explain per se the development of autoantibodies since post-translational modifications are necessary to make a protein immunogenic. A hypothesis is presented here and discussed regarding the possibility that Annexin A1 undergoes post-translational modifications as a part of neutrophil extracellular traps (NETs) that are produced in response to viral, bacterial, and/or inflammatory triggers. In particular, focus is on the process of citrullination of Annexin A1, which takes place within NETs and that mimics, to some extent, other autoimmune conditions, such as rheumatoid arthritis, that are characterized by the presence of anti-citrullinated peptides in circulation. The description of pathologic pathways leading to modification of Annexin A1 as a trigger of autoimmunity is a cognitive evolution, but requires more experimental data before becoming a solid concept for explaining autoimmunity in human beings.
29745857 Identification of novel drug targets for diamond-blackfan anemia based on RPS19 gene mutat 2018 Apr 24 BACKGROUND: Diamond-Blackfan anemia (DBA) is a congenital erythroid aplasia that usually presents in infancy. In order to explore the molecular mechanisms of wild and mutated samples from DBA patients were exposed to bioinformatics investigation. Biological network of differentially expressed genes was constructed. This study aimed to identify novel therapeutic signatures in DBA and uncovered their mechanisms. The gene expression dataset of GSE14335 was used, which consists of 6 normal and 4 diseased cases. The gene ontology (GO), as well as Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed, and then protein-protein interaction (PPI) network of the identified differentially expressed genes (DEGs) was constructed by Cytoscape software. RESULTS: A total of 607 DEGs were identified in DBA, including 433 upregulated genes and 174 downregulated genes. GO analysis results showed that upregulated DEGs were significantly enriched in biological processes, negative regulation of transcription from RNA polymerase II promoter, chemotaxis, inflammatory response, immune response, positive regulation of cell proliferation, negative regulation of cell proliferation, response to mechanical stimulus, positive regulation of cell migration, response to lipopolysaccharide, and defence response. KEGG pathway analysis revealed the TNF signalling pathway, Osteoclast differentiation, Chemokine signalling pathway, Cytokine -cytokine receptor interaction, Rheumatoid arthritis, Biosynthesis of amino acids, Biosynthesis of antibiotics and Glycine, serine and threonine metabolism. The top 10 hub genes, AKT1, IL6, NFKB1, STAT3, STAT1, RAC1, EGR1, IL8, RELA, RAC3, mTOR and CCR2 were identified from the PPI network and sub-networks. CONCLUSION: The present study flagged that the identified DEGs and hub genes enrich our understanding of the molecular mechanisms underlying the development of DBA, and might shine some lights on identifying molecular targets and diagnostic biomarkers for DBA.
29657352 Experience of sleep disruption in primary Sjögren's syndrome: A focus group study. 2018 Apr INTRODUCTION: Primary Sjögren's syndrome is the third most common systemic autoimmune rheumatic disease, following rheumatoid arthritis and systemic lupus erythematosus, and results in dryness, fatigue, discomfort and sleep disturbances. Sleep is relatively unexplored in primary Sjögren's syndrome. We investigated the experiences of sleep disturbances from the viewpoint of primary Sjögren's syndrome patients and their partners and explored the acceptability of cognitive behavioural therapy for insomnia. METHOD: We used focus groups to collect qualitative data from 10 patients with primary Sjögren's syndrome and three partners of patients. The data were recorded, transcribed verbatim and analysed using thematic analysis. RESULTS: Five themes emerged from the data: (a) Experience of sleep disturbances; (b) variation and inconsistency in sleep disturbances; (c) the domino effect of primary Sjögren's syndrome symptoms; (d) strategies to manage sleep; (e) acceptability of evidence-based techniques. Sleep disturbances were problematic for all patients, but specific disturbances varied between participants. These included prolonged sleep onset time and frequent night awakenings and were aggravated by pain and discomfort. Patients deployed a range of strategies to try and self-manage. Cognitive behavioural therapy for insomnia was seen as an acceptable intervention, as long as a rationale for its use is given and it is tailored for primary Sjögren's syndrome. CONCLUSION: Primary Sjögren's syndrome patients described a range of sleep disturbances. Applying tailored, evidence-based sleep therapy interventions may improve sleep, severity of other primary Sjögren's syndrome symptoms and functional ability.
29485215 Insulin resistance in hidradenitis suppurativa: a case-control study. 2018 May BACKGROUND: The association between chronic inflammatory diseases, such as rheumatoid arthritis and psoriasis, and insulin resistance (IR) has been well established. Hidradenitis suppurativa (HS) is a chronic inflammatory cutaneous disease that affects the apocrine gland-bearing areas of the body. OBJECTIVE: We aimed to determine the prevalence of IR in patients with HS. METHODS: This cross-sectional, case-control study enrolled 137 subjects, 76 patients with HS and 61 age- and gender-matched controls. Demographic data, clinical examination of HS patients, anthropometric measures, cardiovascular risk factors and laboratory studies were recorded. The homeostasis model assessment of IR (HOMA-IR) was calculated in all participants by measuring fasting plasma glucose and insulin levels. RESULTS: The median (IQR) HOMA-IR value in HS patients was significantly higher [2.0 (1.0-3.6)] than in controls [1.5 (0.9-2.3)] (P = 0.01). The prevalence of IR was significantly higher in cases (43.4%) compared with controls (16.4%) (P = 0.001). In the linear regression multivariable analysis after adjusting for age, sex and body mass index (BMI), HS remained as a significant factor for a higher HOMA-IR [2.51 (0.18) vs 1.92(0.21); P = 0.04]. The HOMA-IR value and the prevalence of IR did not differ significantly among HS patients grouped by severity of the disease. CONCLUSION: Our results show an increased frequency of IR in HS. Thus, we suggest HS patients to be evaluated for IR and managed accordingly.
29398253 T cells are influenced by a long non-coding RNA in the autoimmune associated PTPN2 locus. 2018 Jun Non-coding SNPs in the protein tyrosine phosphatase non-receptor type 2 (PTPN2) locus have been linked with several autoimmune diseases, including rheumatoid arthritis, type I diabetes, and inflammatory bowel disease. However, the functional consequences of these SNPs are poorly characterized. Herein, we show in blood cells that SNPs in the PTPN2 locus are highly correlated with DNA methylation levels at four CpG sites downstream of PTPN2 and expression levels of the long non-coding RNA (lncRNA) LINC01882 downstream of these CpG sites. We observed that LINC01882 is mainly expressed in T cells and that anti-CD3/CD28 activated naïve CD4(+) T cells downregulate the expression of LINC01882. RNA sequencing analysis of LINC01882 knockdown in Jurkat T cells, using a combination of antisense oligonucleotides and RNA interference, revealed the upregulation of the transcription factor ZEB1 and kinase MAP2K4, both involved in IL-2 regulation. Overall, our data suggests the involvement of LINC01882 in T cell activation and hints towards an auxiliary role of these non-coding SNPs in autoimmunity associated with the PTPN2 locus.
30119881 Increased sensitivity of Treg cells from patients with PBC to low dose IL-12 drives their 2018 Nov IL-12 is a pro-inflammatory cytokine that induces the production of interferon-γ (IFNγ) and favours the differentiation of T helper 1 (Th1) cells. In the presence of IL-12 human Treg cells acquire a Th1-like phenotype with reduced suppressive activity in vitro. Primary biliary cholangitis (PBC) is an autoimmune cholestatic liver disease characterised by high Th1 and Th17 infiltrating cells, reduced frequencies of Treg cells, and a genetic association with IL-12 signalling. Herein, we sought to evaluate the IL-12 signalling pathway in PBC pathology, by studying human samples from patients with PBC, alongside those with primary Sjögren's syndrome (pSS)(autoimmune disease with IL-12 signalling gene association), primary sclerosing cholangitis (PSC) (cholestatic liver disease without IL-12 gene association) and healthy individuals. Our data revealed that TLR stimulation of PBC (n = 17) and pSS monocytes (n = 6) resulted in significant induction of IL12A mRNA (p < 0.05, p < 0.01, respectively) compared to PSC monocytes (n = 13) and at similar levels to HC monocytes (n = 8). PSC monocytes expressed significantly less IL-12p70 (108 pg/ml, mean) and IL-23 (358 pg/ml) compared to HC (458 pg/ml and 951 pg/ml, respectively) (p < 0.01, p < 0.05). Treg cells from patients with PBC (n = 16) and pSS (n = 3) but not PSC (n = 10) and HC (n = 8) responded to low dose (10 ng/ml) IL-12 stimulation by significant upregulation of IFNγ (mean 277 and 254 pg/ml, respectively) compared to PSC and HC Treg cells (mean 22 and 77 pg/ml, respectively)(p < 0.05). This effect was mediated by the rapid and strong phosphorylation of STAT4 on Treg cells from patients with PBC and pSS (p < 0.05) but not PSC and HC. In the liver of patients with PBC (n = 7) a significantly higher proportion of IL-12Rβ2(+)Tregs (16% on average) was detected (p < 0.05) compared to other liver disease controls (5%)(n = 18) which also showed ex vivo high IFNG and TBET expression. CONCLUSION: Our data show an increased sensitivity of PBC and pSS Treg cells to low dose IL-12 stimulation, providing ongoing support for the importance of the IL12-IL-12Rβ2-STAT4 pathway on Treg cells in disease pathogenesis and potentially treatment.
30246031 Sex Differences in Correlation with Gene Expression Levels between Ifi200 Family Genes and 2018 BACKGROUND: The HIN-200 family genes in humans have been linked to several autoimmune diseases-particularly to systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Recently, its human counterpart gene cluster, the Ifi200 family in mice, has been linked to spontaneous arthritis disease (SAD). However, many immune-mediated diseases (including RA and SLE) show gender difference. Understanding whether or not and how these genes play a role in sex difference in immune-mediated diseases is essential for diagnosis/treatment. METHODS: This study takes advantage of the whole genome gene expression profiles of recombinant inbred (RI) strain populations from female and male mice to analyze potential sex differences in a variety of genes in disease pathways. Expression levels and regulatory QTL of Ifi200 family genes between female and male mice were first examined in a large mouse population, including RI strains derived from C57BL/6J, DBA/2J (BXD), and classic inbred strains. Sex similarities and differences were then analyzed for correlations with gene expression levels between genes in the Ifi200 family and four selected gene sets: known immune Ifi200 pathway-related genes, lupus-relevant genes, osteoarthritis- (OA-) and RA-relevant genes, and sex hormone-related genes. RESULTS: The expression level of Ifi202b showed the most sex difference in correlation with known immune-related genes (the P value for Ifi202b is 0.0004). Ifi202b also showed gender difference in correlation with selected sex hormone genes, with a P value of 0.0243. When comparing coexpression levels between Ifi200 genes and lupus-relevant genes, Ifi203 and Ifi205 showed significant sex difference (P values: 0.0303 and 0.002, resp.). Furthermore, several key genes (e.g., Csf1r, Ifnb1, IL-20, IL-22, IL-24, Jhdm1d, Csf1r, Ifnb1, IL-20, IL-22, IL-24, and Tgfb2 that regulate sex differences in immune diseases) were discovered. CONCLUSIONS: Different genes in the Ifi200 family play different roles in sex difference among dissimilar pathways of these four gene groups.
29290173 Comparison of Specialty Medication Use for Common Chronic Inflammatory Diseases Among Heal 2018 Jan BACKGROUND: The Affordable Care Act of 2010 allows the purchase of health insurance through special marketplaces called "health exchanges." The majority of individuals enrolling in the exchanges were previously uninsured, older, and sicker than other commercially insured members. Early evidence also suggests that exchange plan members use more costly specialty drugs compared with other commercially insured members. OBJECTIVES: To (a) examine patient characteristics and specialty drug use for common chronic inflammatory diseases (CIDs) among exchange plan members compared with other commercially insured members and (b) explore variations in specialty drug use within exchange plans by metal tiers (bronze, silver, gold, and platinum), as well as across local markets. METHODS: This analysis included adults aged ≥ 18 years who were enrolled in exchange plans (exchange population) and other commercial health plans (nonexchange population). The primary outcome was the likelihood of using specialty drugs prescribed to treat common CIDs, such as rheumatoid arthritis, ankylosing spondylitis, Crohn's disease, ulcerative colitis, psoriatic arthritis, and psoriasis. The adjusted likelihood of using CID specialty drugs was calculated from logistic regression controlling for prevalence of CIDs and other health risk factors. RESULTS: A total of 931,384 exchange plan members and 2,682,855 nonexchange plan members were included in the analysis. Compared with the nonexchange population, the exchange population was older, more likely to be female, had more comorbid conditions, but filled fewer prescriptions. The 2 groups were similar in terms of CID prevalence. The observed likelihood of CID specialty drug use was 20.0% lower in the exchange versus the nonexchange populations (341 users per 100,000 exchange members vs. 427 users per 100,000 nonexchange members; P < 0.001). Within the exchange population, the observed likelihood of CID specialty drug use was 132 per 100,000 bronze plan members (69.1% lower than nonexchange); 326 per 100,000 silver plan members (23.5% lower than nonexchange); 579 per 100,000 gold plan members (35.6% higher than nonexchange); and 672 per 100,000 platinum plan members (57.5% higher than nonexchange). All differences were statistically significant at P < 0.001. There were also large differences by local market, ranging from 49.1% lower to 75.8% higher CID use in the exchange population than in the nonexchange population. After adjustment, the exchange population was 16.6% less likely to use CID specialty drugs than the nonexchange population (P < 0.001). Large variation in specialty drug use within the exchange plan metal tiers was reduced. After adjustment, the higher use of CID specialty drugs among the exchange population in certain local plans was no longer statistically significant. CONCLUSIONS: Members insured through exchange plans were older and sicker than those with nonexchange plans, but they did not use more CID specialty drugs compared with the nonexchange population. Large variations were seen among the exchange plan metal tiers and by local markets, which were often related to the risk profiles of exchange plan enrollees. DISCLOSURES: Funding for this study was provided by Anthem. Anthem had no role in study design, data interpretation, manuscript development, or the decision to publish. Chen, Gautam, DeVries, and Sylwestrzak are employees of HealthCore, a wholly owned subsidiary of Anthem. Richards is an employee of Anthem. Ruggieri is a former employee of Anthem and a current employee of MedImpact Healthcare Systems. Study concept and design were contributed by Ruggieri, Richards, DeVries, and Sylwestrzak. Chen took the lead in data collection, along with Gautam. Data interpretation was performed by Chen, along with the other authors. The manuscript was written by Chen, Gautam, Sylwestrzak, and DeVries and revised by Chen, Gautam, and Sylwestrzak, along with the other authors.
30249301 Metabolomic alterations associated with Behçet's disease. 2018 Sep 24 BACKGROUND: The diagnosis of Behçet's disease (BD) remains challenging due to the lack of diagnostic biomarkers. This study aims to identify potential serum metabolites associated with BD and its disease activity. METHODS: Medical records and serum samples of 24 pretreated BD patients, 12 post-treated BD patients, and age-matched healthy controls (HC) were collected for metabolomics and lipidomics profiling using UPLC-QTOF-MS and UPLC-QTOF-MS(E) approaches. Additionally, serum samples from an independent cohort of BD patients, disease controls including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Takayasu's arteritis (TA), Crohn's disease (CD) patients, and HC were collected for further validation of two potential biomarkers using UPLC-QTOFMS analysis. RESULTS: Unsupervised principal component analysis (PCA) showed a clear separation of metabolomics profiles of BD patients from HC. Statistical analysis of the data revealed differential metabolites between BD patients and HC. The serum levels of some phosphatidylcholines (PCs) were found to be significantly lower in BD patients, while the levels of several polyunsaturated fatty acids (PUFAs) were increased markedly in the BD group compared with HC. Furthermore, the serum level of two omega-6 PUFAs, linoleic acid (LA) and arachidonic acid (AA), were dramatically decreased in patients with remission. A validation cohort confirmed that the serum LA and AA levels in BD patients were significantly higher than those in HC and patients with RA, SLE, TA, and CD. In addition, receiver operating characteristic (ROC) analysis indicated good sensitivity and specificity. CONCLUSIONS: The serum metabolomics profiles in BD patients are altered. Serum LA and AA are promising diagnostic biomarkers for BD.
30413189 VZV-specific T-cell levels in patients with rheumatic diseases are reduced and differentia 2018 Nov 9 BACKGROUND: Varicella zoster virus (VZV)-specific cellular immunity is essential for viral control, and the incidence of VZV reactivation is increased in patients with rheumatic diseases. Because knowledge of the influence of antirheumatic drugs on specific cellular immunity is limited, we analyzed VZV-specific T cells in patients with rheumatoid arthritis (RA) and seronegative spondylarthritis (SpA), and we assessed how their levels and functionality were impacted by disease-modifying antirheumatic drugs (DMARDs). A polyclonal stimulation was carried out to analyze effects on general effector T cells. METHODS: CD4 T cells in 98 blood samples of patients with RA (n = 78) or SpA (n = 20) were quantified by flow cytometry after stimulation with VZV antigen and the polyclonal stimulus Staphylococcus aureus enterotoxin B (SEB), and they were characterized for expression of cytokines (interferon-γ, tumor necrosis factor [TNF]-α, interleukin [IL]-2) and markers for activation (CD69), differentiation (CD127), or functional anergy programmed death 1 molecule [PD-1], cytotoxic T-lymphocyte antigen 4 [CTLA-4]. Results of patients with RA were stratified into subgroups receiving different antirheumatic drugs and compared with samples of 39 healthy control subjects. Moreover, direct effects of biological DMARDs on cytokine expression and proliferation of specific T cells were analyzed in vitro. RESULTS: Unlike patients with SpA, patients with RA showed significantly lower percentages of VZV-specific CD4 T cells (median 0.03%, IQR 0.05%) than control subjects (median 0.09%, IQR 0.16%; p < 0.001). Likewise, SEB-reactive CD4 T-cell levels were lower in patients (median 2.35%, IQR 2.85%) than in control subjects (median 3.96%, IQR 4.38%; p < 0.05); however, expression of cytokines and cell surface markers of VZV-specific T cells did not differ in patients and control subjects, whereas SEB-reactive effector T cells of patients showed signs of functional impairment. Among antirheumatic drugs, biological DMARDs had the most pronounced impact on cellular immunity. Specifically, VZV-specific CD4 T-cell levels were significantly reduced in patients receiving TNF-α antagonists or IL-6 receptor-blocking therapy (p < 0.05 and p < 0.01, respectively), whereas SEB-reactive T-cell levels were reduced in patients receiving B-cell-depleting or IL-6 receptor-blocking drugs (both p < 0.05). CONCLUSIONS: Despite absence of clinical symptoms, patients with RA showed signs of impaired cellular immunity that affected both VZV-specific and general effector T cells. Strongest effects on cellular immunity were observed in patients treated with biological DMARDs. These findings may contribute to the increased susceptibility of patients with RA to VZV reactivation.
30568345 INASL Guidelines on Management of Hepatitis B Virus Infection in Patients receiving Chemot 2018 Dec Hepatitis B Virus (HBV) reactivation in patients receiving chemotherapy, biologicals, immunosupressants, or corticosteroids is emerging to be an important cause of morbidity and mortality in patients with current or prior exposure to HBV infection. These patients suffer a dual onslaught of illness: one from the primary disease for which they are receiving the culprit drug that led to HBV reactivation, and the other from HBV reactivation itself. The HBV reactivation not only leads to a compromised liver function, which may culminate into hepatic failure; it also adversely impacts the treatment outcome of the primary illness. Hence, identification of patients at risk of reactivation before starting these drugs, and starting treatment aimed at prevention of HBV reactivation is the best strategy of managing these patients. There are no Indian guidelines on management of HBV infection in patients receiving chemotherapy, biologicals, immunosupressants, or corticosteroids for the treatment of rheumatologic conditions, malignancies, inflammatory bowel disease, dermatologic conditions, or solid-organ or bone marrow transplantation. The Indian National Association for Study of the Liver (INASL) had set up a taskforce on HBV in 2016, with a mandate to develop consensus guidelines for management of various aspects of HBV infection, relevant to India. In 2017 the taskforce had published the first INASL guidelines on management of HBV infection in India. In the present guidelines, which are in continuation with the previous guidelines, the issues on management of HBV infection in patients receiving chemotherapy, biologicals, immunosupressants, or corticosteroids are addressed.
30598166 Human-Disease Phenotype Map Derived from PheWAS across 38,682 Individuals. 2019 Jan 3 Phenome-wide association studies (PheWASs) have been a useful tool for testing associations between genetic variations and multiple complex traits or diagnoses. Linking PheWAS-based associations between phenotypes and a variant or a genomic region into a network provides a new way to investigate cross-phenotype associations, and it might broaden the understanding of genetic architecture that exists between diagnoses, genes, and pleiotropy. We created a network of associations from one of the largest PheWASs on electronic health record (EHR)-derived phenotypes across 38,682 unrelated samples from the Geisinger's biobank; the samples were genotyped through the DiscovEHR project. We computed associations between 632,574 common variants and 541 diagnosis codes. Using these associations, we constructed a "disease-disease" network (DDN) wherein pairs of diseases were connected on the basis of shared associations with a given genetic variant. The DDN provides a landscape of intra-connections within the same disease classes, as well as inter-connections across disease classes. We identified clusters of diseases with known biological connections, such as autoimmune disorders (type 1 diabetes, rheumatoid arthritis, and multiple sclerosis) and cardiovascular disorders. Previously unreported relationships between multiple diseases were identified on the basis of genetic associations as well. The network approach applied in this study can be used to uncover interactions between diseases as a result of their shared, potentially pleiotropic SNPs. Additionally, this approach might advance clinical research and even clinical practice by accelerating our understanding of disease mechanisms on the basis of similar underlying genetic associations.
30406140 Technetium-99 Conjugated with Methylene Diphosphonate Ameliorates Glucocorticoid Induced O 2018 Technetium-99 conjugated with methylene diphosphonate ((99)Tc-MDP) is an effective anti-inflammatory drug in treating rheumatoid arthritis (RA) for over 15 years in China. However, as a special form of bisphosphonate, the antiosteoporotic effect of (99)Tc-MDP is unclear. We systematically investigated the effects of (99)Tc-MDP on cancellous and cortical bone, respectively, in glucocorticoid induced osteoporosis (GIO) animal models. Forty-eight Sprague-Dawley rats were randomly divided into six groups: blank, negative control, high dose, medium dose, low dose, and positive control groups. After dexamethasone was given to all groups except the blank group to induce osteoporosis, the rats in different groups were treated with saline, MDP, or different doses of (99)Tc-MDP. After treatment, all rats were sacrificed, and their tibiae and femora were analyzed with microcomputed tomography (micro-CT), histology and biomechanics. Micro-CT analyses showed that (1) (99)Tc-MDP reversed glucocorticoid induced bone microarchitecture destruction by increasing BV/TV, Tb.Th, and Tb.N and decreasing BS/BV, Tb.Sp, and TBPf; (2) effect of (99)Tc-MDP increased as its dosage increased; and (3) (99)Tc-MDP could improve cortical bone thickness while MDP failed to do so. Micro-CT spatial structure analysis and histology also yielded consistent results, indicating that (99)Tc-MDP increased trabecular number and connectivity morphologically. Secondly, biomechanics revealed that (99)Tc-MDP can enhance the extrinsic stiffness of bone by changing bone geometry. Finally, (99)Tc-MDP could inhibit osteoclastogenesis in PBMCs in human. In conclusion, (99)Tc-MDP exerted antiosteoporotic effect by improving both cancellous and cortical bone, as well as increasing extrinsic bone stiffness which might be attributed to the its inhibition of osteoclast differentiation. The antiosteoporotic effect of (99)Tc-MDP may suggest a potential clinical application for patients with GIO.
30388167 Effects of pay for performance on risk incidence of infection and of revision after total 2018 As the world's population ages, the number of people receiving total knee arthroplasty (TKA) has been on the rise. Although patients with diabetes mellitus are known to face greater risks of TKA postoperative infection and revision TKA owing to diabetic complications, studies on whether such patients' participation in pay for performance (P4P) programs influences the incidence rates of TKA postoperative infection or revision TKA are still lacking. This study examined the 2002-2012 data of Taiwan's National Health Insurance Research Database to conduct a retrospective cohort analysis of diabetic patients over 50 years old who have received TKA. To reduce any selection bias between patients joining and not joining the P4P program, propensity score matching was applied. The Cox proportional hazards model was used to examine the influence of the P4P program on TKA postoperative infection and revision TKA, and the results indicate that joining P4P lowered the risk of postoperative infection (HR = 0.91, 95% CI: 0.77-1.08), however, which was not statistically significant, and significantly lowered the risk of revision TKA (HR = 0.53, 95% CI: 0.39-0.72). Being younger and male, having multiple comorbid conditions or greater diabetic severity, receiving care at regional or public hospitals, and not having a diagnosis of degenerative or rheumatoid arthritis were identified as factors for higher risk of TKA postoperative infection for patients with diabetes. As for the risk of revision TKA, postoperative infection and being younger were identified as factors for a significantly higher risk (p < 0.05).
30349392 Familial aggregation and heritability of type 1 diabetes mellitus and coaggregation of chr 2018 PURPOSE: To estimate the extent of familial aggregation of type 1 diabetes (T1D) and coaggregation of related chronic diseases and assess the relative contribution of environmental and genetic factors on the risks. PATIENTS AND METHODS: This population-based study used the Taiwan National Health Insurance database to reconstruct family structure and identify people with T1D and other chronic diseases between 1999 and 2015. Relative risks (RRs) for T1D and other chronic diseases and heritability of T1D were estimated. Heritability was estimated using the polygenic liability model. RESULTS: Validation of family structure found the positive predictive value to be 98.7% for maternal links and 98.6% for paternal links. Having an affected twin, first-degree relative, or spouse was associated with an adjusted RR (95% CI) of 553.66 (427.59-716.89), 32.49 (28.66-36.84), and 2.17 (0.31-15.40) for T1D, respectively. Based on the polygenic liability model, heritability, shared and non-shared contributions to T1D, and variances were 66.50%, 10.86%, and 22.64%, respectively. A family history of T1D was associated with an RR (95% CI) of 1.51 (1.20-1.89) for rheumatoid arthritis, 1.66 (1.21-2.26) for Sjögren's syndrome, 1.48 (1.09-2.01) for systemic lupus erythematosus, 1.24 (1.14-1.35) for simple goiter, 1.16 (1.04-1.31) for non-toxic nodular goiter, 1.61 (1.49-1.74) for thyrotoxicosis, 1.78 (1.57-2.01) for acquired hypothyroidism, 1.66 (1.40-1.98) for thyroiditis, and 1.15 (0.97-1.37) for epilepsy. CONCLUSION: These data highlight the importance of the genetic contribution to T1D and confirm the coaggregation of autoimmune and metabolic diseases with T1D.