Browse

Search for: rheumatoid arthritis    methotrexate    autoimmune disease    biomarker    gene expression    GWAS    HLA genes    non-HLA genes   

ID PMID Title PublicationDate abstract
34681884 Therapeutic Effect of α-MSH in Primary Cultured Orbital Fibroblasts Obtained from Patient 2021 Oct 18 Inflammation, hyaluronan production, and adipogenesis are the main pathological events leading to thyroid eye disease (TED). α-Melanocytemelanocyte-stimulating hormone (α-MSH) is a well-known tridecapeptidetreatment for several inflammatory disorders including sepsis syndrome, acute respiratory distress syndrome, rheumatoid arthritis, and encephalitis. Here, we investigated the effect of α-MSH treatment on TED. The 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and Lactate Dehydrogenase (LDH) assays were performed to analyze the effect of α-MSH on cell viability and it's toxicity. Using primary cultures of orbital fibroblasts from TED patients and non-TED as control, we examined the effects of α-MSH on proinflammatory cytokine production induced by interleukin (IL)-1β, further analyzed by real-time reverse transcription-polymerase chain reaction (qPCR) and western blotting. Immunofluorescence staining assay and qPCR were performed to examine proopiomelanocortin (POMC) expression, the upstream neuropeptide of α-MSH in TED patients and non-TED control. Treatment with non-cytotoxic concentrations of α-MSH resulted in the dose-dependent inhibition of mRNA and protein levels (p < 0.05) for IL-1β-induced inflammatory cytokines: IL-6, IL-8, MCP-1, ICAM-1, and COX-2. The expression of POMC mRNA and protein were significantly higher in TED patients compared to non-TED control (p < 0.05). Our data show significant inhibitory effects of α-MSH on inflammation, POMC production in orbital fibroblasts. At present, this is the first in vitro preclinical evidence of α-MSH therapeutic effect on TED. These findings indicate that POMC and α-MSH may play a role in the immune regulation of TED and can be a potential therapeutic target.
34626489 Prevalence, symptoms and risk factor profile of rumination syndrome and functional dyspeps 2021 Dec BACKGROUND: Rumination syndrome is a functional gastroduodenal disorder characterised by effortless regurgitation of recently ingested food. Emerging evidence reports duodenal eosinophilic inflammation in a subset, suggesting a shared pathophysiology with functional dyspepsia (FD). AIM: To assess the clinical features of rumination syndrome and FD in a community-based study. METHODS: We mailed a survey assessing gastrointestinal symptoms, diet and psychological symptoms to 9835 residents of Olmsted County, MN, USA in 2017-2018; diagnostic codes were obtained from linked clinical records. The two disorders were assessed as mutually exclusive in 'pure' forms with a separate overlap group, all compared to a control group not meeting criteria for either. Prevalence of associations, and univariate and independent associations with predictors were assessed by logistic regression. RESULTS: Prevalence of rumination syndrome and FD were 5.8% and 7.1%, respectively; the overlap was 3.83-times more likely than expected by chance. Independent predictors for rumination (odds ratio (OR), 95% confidence interval (CI)) were female gender (1.79, 1.21-2.63), smoking (1.89, 1.28-2.78), gluten-free diet (1.58, 1.14-2.19), allergic rhinitis (1.45, 1.01-2.08) and depression (1.10, 1.05-1.16). FD was independently associated with female gender, depression, non-coeliac wheat sensitivity, migraine, irritable bowel syndrome and somatic symptoms. A similar reported efficacy (≥54%) of low fat or dairy-free diets was found with both disorders (P = 0.53 and P = 1.00, respectively). The strongest independent associations with overlapping FD and rumination syndrome were a history of rheumatoid arthritis (3.93, 1.28-12.06) and asthma (3.02, 1.44-6.34). CONCLUSION: Rumination syndrome overlaps with FD with a shared risk factor profile, suggesting a common pathophysiology.
34616125 NaHCO(3)- and NaCl-Type Hot Springs Enhance the Secretion of Inflammatory Cytokine Induced 2021 Oct BACKGROUND: Background: Hot springs have been traditionally used as an alternative treatment for a wide range of diseases, including rheumatoid arthritis, bronchial asthma, diabetes, hypertension, psoriasis and atopic dermatitis. However, the clinical effects and therapeutic mechanisms associated with hot springs remain poorly defined. OBJECTIVE: The purpose of this study was to demonstrate the different effects of hot springs on cellular viability and secretion of inflammatory cytokines on keratinocyte in two geographically representative types of hot springs: NaHCO(3)-type and NaCl-type, which are the most common types in South Korea. METHODS: We performed WST-1, BrdU measurements, human inflammatory cytokine arrays and enzyme-linked immunosorbent assay in HaCaT cells stimulated with toll-like receptor 3 by polyinosinicpolycytidylic acid. RESULTS: The interaction effects of cell viability and cell proliferation were not significantly different regardless of polyinosinic-polycytidylic acid stimulation and cultured hot springs type. Cytokine array and enzymelinked immunosorbent assay analysis showed increased expression of inflammatory cytokines such as interleukin6 and granulocyte-macrophage colony-stimulating factor by polyinosinic-polycytidylic acid stimulation, with expression levels differing according to hot springs hydrochemical composition. Cytokine reduction was not significant. CONCLUSION: The effects and mechanisms of hot springs treatment in keratinocytes were partially elucidated.
34607212 A retrospective cross-sectional study on tinnitus prevalence and disease associations in t 2021 Nov Tinnitus is a highly prevalent disorder with heterogenous presentation and limited treatment options. Better understanding of its prevalence and disease and lifestyle risk factor associations in the general population is necessary to identify the underlying mechanisms. To this end, we quantified the prevalence of tinnitus and identified disease and lifestyle risk factors associated with tinnitus within a general population cohort. For this study, we used the Lifelines population-based cohort study to perform a retrospective cross-sectional study. Lifelines is a large, multi-generational, prospective cohort study that includes over 167,000 participants (or 10% of the population) from the northern Netherlands. For this study, conducted between 2018 and 2021, data from the Lifelines population-based cohort study was used to perform a cross-sectional study. Adult participants (age ≥ 18 years) with data on tinnitus perception (collected once between 2011 and 2015) were included in this study. An elastic-net regression analysis was performed with tinnitus as the dependent variable and parameters of diseases and lifestyle risk factors (collected once between 2006 and 2014)-including hearing problems, cardiovascular disease, metabolic disorders, psychiatric disorders, thyroid disease, inflammatory disease, and functional somatic syndromes-as the independent variables. Among 124,609 participants, N = 8,011 (6.4%) reported perceiving tinnitus constantly (CT: constant tinnitus) and N = 39,625 (31.8%) reported perceiving tinnitus constantly or occasionally (AT: any tinnitus). Our analysis identified 38 parameters that were associated with AT and 48 parameters that were associated with CT. Our study identified established disease associates with tinnitus, including problems with hearing (OR 8.570 with CT), arrythmia (OR 1.742 with CT), transient ischemic attack (OR 1.284 with AT), diabetes mellitus (OR 1.014 with AT) and psychiatric disorders, including major depressive disorder (OR 1.506 with CT). Factors related to lifestyle associated with tinnitus included waist-hip ratio (OR 1.061 with CT) and smoking (OR 1.028 with AT). Novel disease associates with CT were identified for inflammatory diseases, including rheumatoid arthritis (OR 1.297) and ulcerative colitis (OR 1.588), thyroid disease (as evidenced by the use of thyroid medication) (OR 1.298), and functional somatic syndromes, including chronic fatigue syndrome (OR 1.568). In addition to validating established disease associates in a general population cohort, this study identified novel associations with tinnitus and several disease categories, including functional somatic syndromes, inflammatory diseases, and thyroid disease. Future work will be necessary to identify whether (common) mechanisms underly tinnitus and these associated disorders. Lifelines is an important new resource available for future studies investigating tinnitus in the general population.
34577159 Novel c-Jun N-Terminal Kinase (JNK) Inhibitors with an 11H-Indeno[1,2-b]quinoxalin-11-one 2021 Sep 20 c-Jun N-terminal kinase (JNK) plays a central role in stress signaling pathways implicated in important pathological processes, including rheumatoid arthritis and ischemia-reperfusion injury. Therefore, inhibition of JNK is of interest for molecular targeted therapy to treat various diseases. We synthesized 13 derivatives of our reported JNK inhibitor 11H-indeno[1,2-b]quinoxalin-11-one oxime and evaluated their binding to the three JNK isoforms and their biological effects. Eight compounds exhibited submicromolar binding affinity for at least one JNK isoform. Most of these compounds also inhibited lipopolysaccharide (LPS)-induced nuclear factor-κB/activating protein 1 (NF-κB/AP-1) activation and interleukin-6 (IL-6) production in human monocytic THP1-Blue cells and human MonoMac-6 cells, respectively. Selected compounds (4f and 4m) also inhibited LPS-induced c-Jun phosphorylation in MonoMac-6 cells, directly confirming JNK inhibition. We conclude that indenoquinoxaline-based oximes can serve as specific small-molecule modulators for mechanistic studies of JNKs, as well as potential leads for the development of anti-inflammatory drugs.
34520123 Formation of a protein corona on the surface of extracellular vesicles in blood plasma. 2021 Sep In this study we tested whether a protein corona is formed around extracellular vesicles (EVs) in blood plasma. We isolated medium-sized nascent EVs of THP1 cells as well as of Optiprep-purified platelets, and incubated them in EV-depleted blood plasma from healthy subjects and from patients with rheumatoid arthritis. EVs were subjected to differential centrifugation, size exclusion chromatography, or density gradient ultracentrifugation followed by mass spectrometry. Plasma protein-coated EVs had a higher density compared to the nascent ones and carried numerous newly associated proteins. Interactions between plasma proteins and EVs were confirmed by confocal microscopy, capillary Western immunoassay, immune electron microscopy and flow cytometry. We identified nine shared EV corona proteins (ApoA1, ApoB, ApoC3, ApoE, complement factors 3 and 4B, fibrinogen α-chain, immunoglobulin heavy constant γ2 and γ4 chains), which appear to be common corona proteins among EVs, viruses and artificial nanoparticles in blood plasma. An unexpected finding of this study was the high overlap of the composition of the protein corona with blood plasma protein aggregates. This is explained by our finding that besides a diffuse, patchy protein corona, large protein aggregates also associate with the surface of EVs. However, while EVs with an external plasma protein cargo induced an increased expression of TNF-α, IL-6, CD83, CD86 and HLA-DR of human monocyte-derived dendritic cells, EV-free protein aggregates had no effect. In conclusion, our data may shed new light on the origin of the commonly reported plasma protein 'contamination' of EV preparations and may add a new perspective to EV research.
34127819 Induction of antigen-specific tolerance by nanobody-antigen adducts that target class-II m 2021 Nov The association of autoimmune diseases with particular allellic products of the class-II major histocompatibility complex (MHCII) region implicates the presentation of the offending self-antigens to T cells. Because antigen-presenting cells are tolerogenic when they encounter an antigen under non-inflammatory conditions, the manipulation of antigen presentation may induce antigen-specific tolerance. Here, we show that, in mouse models of experimental autoimmune encephalomyelitis, type 1 diabetes and rheumatoid arthritis, the systemic administration of a single dose of nanobodies that recognize MHCII molecules and conjugated to the relevant self-antigen under non-inflammatory conditions confers long-lasting protection against these diseases. Moreover, co-administration of a nanobody-antigen adduct and the glucocorticoid dexamethasone, conjugated to the nanobody via a cleavable linker, halted the progression of established experimental autoimmune encephalomyelitis in symptomatic mice and alleviated their symptoms. This approach may represent a means of treating autoimmune conditions.
33964427 Risk factors for complications and revision surgery after anatomic and reverse total shoul 2021 Nov BACKGROUND: Complications and revisions following anatomic (aTSA) and reverse (rTSA) total shoulder arthroplasty have deleterious effects on patient function and satisfaction. The purpose of this study is to evaluate patient-specific, implant-specific and technique-specific risk factors for intraoperative complications, postoperative complications, and the occurrence of revisions after aTSA and rTSA. METHODS: A total of 2964 aTSA and 5616 rTSA patients were enrolled in an international database of primary shoulder arthroplasty. Intra- and postoperative complications, as well as revisions, were reported and evaluated. Multivariate analyses were performed to quantify the risk factors associated with complications and revisions. RESULTS: aTSA patients had a significantly higher complication rate (P = .0026) and a significantly higher revision rate (P < .0001) than rTSA patients, but aTSA patients also had a significantly longer average follow-up (P < .0001) than rTSA patients. No difference (P = .2712) in the intraoperative complication rate was observed between aTSA and rTSA patients. Regarding intraoperative complications, female sex (odds ratio [OR] 2.0, 95% confidence interval [CI] 1.17-3.68) and previous shoulder surgery (OR 2.9, 95% CI 1.73-4.90) were identified as significant risk factors. In regard to postoperative complications, younger age (OR 0.987, 95% CI 0.977-0.996), diagnosis of rheumatoid arthritis (OR 1.76, 95% 1.12-2.65), and previous shoulder surgery (OR 1.42, 95% CI 1.16-1.72) were noted to be risks factors. Finally, in regard to revision surgery, younger age (OR 0.964, 95% CI 0.933-0.998), more glenoid retroversion (OR 1.03, 95% CI 1.001-1.058), larger humeral stem size (OR 1.09, 95% CI 1.01-1.19), larger humeral liner thickness or offset (OR 1.50, 95% CI 1.18-1.96), larger glenosphere diameter (OR 1.16, 95% CI 1.07-1.26), and more intraoperative blood loss (OR 1.002, 95% CI 1.001-1.004) were noted to be risk factors. CONCLUSIONS: Studying the impact of numerous patient- and implant-specific risk factors and determining their impact on complications and revision shoulder arthroplasty can assist surgeons in counseling patients and guide patient expectations following aTSA or rTSA. Care should be taken in patients with a history of previous shoulder surgery, who are at increased risk of both intra- and postoperative complications.
33738722 HPLC methods for choloroquine determination in biological samples and pharmaceutical produ 2021 Jun OBJECTIVE: Review and assess pharmaceutical and clinical characteristics of chloroquine including high-performance liquid chromatography (HPLC)-based methods used to quantify the drug in pharmaceutical products and biological samples. EVIDENCE ACQUISITION: A literature review was undertaken on the PubMed, Science Direct, and Scielo databases using the following keywords related to the investigated subject: 'chloroquine', 'analytical methods', and 'HPLC'. RESULTS: For more than seven decades, chloroquine has been used to treat malaria and some autoimmune diseases, such as lupus erythematosus and rheumatoid arthritis. There is growing interest in chloroquine as a therapeutic alternative in the treatment of HIV, Q fever, Whipple's disease, fungal, Zika, Chikungunya infections, Sjogren's syndrome, porphyria, chronic ulcerative stomatitis, polymorphic light eruption, and different types of cancer. HPLC coupled to UV detectors is the most employed method to quantify chloroquine in pharmaceutical products and biological samples. The main chromatographic conditions used to identify and quantify chloroquine from tablets and injections, degradation products, and metabolites are presented and discussed. CONCLUSION: Research findings reported in this article may facilitate the repositioning, quality control, and biological monitoring of chloroquine in modern pharmaceutical dosage forms and treatments.
33727337 A ligand-receptor interactome platform for discovery of pain mechanisms and therapeutic ta 2021 Mar 16 In the peripheral nervous system, ligand-receptor interactions between cells and neurons shape sensory experience, including pain. We set out to identify the potential interactions between sensory neurons and peripheral cell types implicated in disease-associated pain. Using mouse and human RNA sequencing datasets and computational analysis, we created interactome maps between dorsal root ganglion (DRG) sensory neurons and an array of normal cell types, as well as colitis-associated glial cells, rheumatoid arthritis-associated synovial macrophages, and pancreatic tumor tissue. These maps revealed a common correlation between the abundance of heparin-binding EGF-like growth factor (HBEGF) in peripheral cells with that of its receptor EGFR (a member of the ErbB family of receptors) in DRG neurons. Subsequently, we confirmed that increased abundance of HBEGF enhanced nociception in mice, likely acting on DRG neurons through ErbB family receptors. Collectively, these interactomes highlight ligand-receptor interactions that may lead to treatments for disease-associated pain and, furthermore, reflect the complexity of cell-to-neuron signaling in chronic pain states.
33673704 Fucoxanthin Suppresses Osteoclastogenesis via Modulation of MAP Kinase and Nrf2 Signaling. 2021 Feb 27 Fucoxanthin (FX), a natural carotenoid present in edible brown seaweed, is known for its therapeutic potential in various diseases, including bone disease. However, its underlying regulatory mechanisms in osteoclastogenesis remain unclear. In this study, we investigated the effect of FX on osteoclast differentiation and its regulatory signaling pathway. In vitro studies were performed using osteoclast-like RAW264.7 cells stimulated with the soluble receptor activator of nuclear factor-κB ligand or tumor necrosis factor-alpha/interleukin-6. FX treatment significantly inhibited osteoclast differentiation and bone resorption ability, and downregulated the expression of osteoclast-specific markers such as nuclear factor of activated T cells 1, dendritic cell-specific seven transmembrane protein, and matrix metallopeptidase 9. Intracellular signaling pathway analysis revealed that FX specifically decreased the activation of the extracellular signal-regulated kinase and p38 kinase, and increased the nuclear translocation of phosphonuclear factor erythroid 2-related factor 2 (Nrf2). Our results suggest that FX regulates the expression of mitogen-activated protein kinases and Nrf2. Therefore, FX is a potential therapeutic agent for osteoclast-related skeletal disorders including osteoporosis and rheumatoid arthritis.
33671607 Structure-Based Virtual Screening of Tumor Necrosis Factor-α Inhibitors by Cheminformatic 2021 Feb 22 Tumor necrosis factor-α (TNF-α) is a drug target in rheumatoid arthritis and several other auto-immune disorders. TNF-α binds with TNF receptors (TNFR), located on the surface of several immunological cells to exert its effect. Hence, the use of inhibitors that can hinder the complex formation of TNF-α/TNFR can be of medicinal significance. In this study, multiple chem-informatics approaches, including descriptor-based screening, 2D-similarity searching, and pharmacophore modelling were applied to screen new TNF-α inhibitors. Subsequently, multiple-docking protocols were used, and four-fold post-docking results were analyzed by consensus approach. After structure-based virtual screening, seventeen compounds were mutually ranked in top-ranked position by all the docking programs. Those identified hits target TNF-α dimer and effectively block TNF-α/TNFR interface. The predicted pharmacokinetics and physiological properties of the selected hits revealed that, out of seventeen, seven compounds (4, 5, 10, 11, 13-15) possessed excellent ADMET profile. These seven compounds plus three more molecules (7, 8 and 9) were chosen for molecular dynamics simulation studies to probe into ligand-induced structural and dynamic behavior of TNF-α, followed by ligand-TNF-α binding free energy calculation using MM-PBSA. The MM-PBSA calculations revealed that compounds 4, 5, 7 and 9 possess highest affinity for TNF-α; 8, 11, 13-15 exhibited moderate affinities, while compound 10 showed weaker binding affinity with TNF-α. This study provides valuable insights to design more potent and selective inhibitors of TNF-α, that will help to treat inflammatory disorders.
33572978 The Worm-Specific Immune Response in Multiple Sclerosis Patients Receiving Controlled Tric 2021 Jan 29 Considering their potent immunomodulatory properties, therapeutic applications of Trichuris suis ova (TSO) are studied as potential alternative treatment of autoimmune disorders like multiple sclerosis (MS), rheumatoid arthritis (RA), or inflammatory bowel disease (IBD). Clinical phase 1 and 2 studies have demonstrated TSO treatment to be safe and well tolerated in MS patients, however, they reported only modest clinical efficacy. We therefore addressed the cellular and humoral immune responses directed against parasite antigens in individual MS patients receiving controlled TSO treatment (2500 TSO p.o. every 2 weeks for 12 month). Peripheral blood mononuclear cells (PBMC) of MS patients treated with TSO (n = 5) or placebo (n = 6) were analyzed. A continuous increase of serum IgG and IgE antibodies specific for T. suis excretory/secretory antigens was observed up to 12 months post-treatment. This was consistent with mass cytometry analysis identifying an increase of activated HLA-DR(high) plasmablast frequencies in TSO-treated patients. While stable and comparable frequencies of total CD4(+) and CD8(+) T cells were detected in placebo and TSO-treated patients over time, we observed an increase of activated HLA-DR(+)CD4(+) T cells in TSO-treated patients only. Frequencies of Gata3(+) Th2 cells and Th1/Th2 ratios remained stable during TSO treatment, while Foxp3(+) Treg frequencies varied greatly between individuals. Using a T. suis antigen-specific T cell expansion assay, we also detected patient-to-patient variation of antigen-specific T cell recall responses and cytokine production. In summary, MS patients receiving TSO treatment established a T. suis-specific T- and B-cell response, however, with varying degrees of T cell responses and cellular functionality across individuals, which might account for the overall miscellaneous clinical efficacy in the studied patients.
33461449 Preparation and Formulation Optimization of Methotrexate-loaded Human Serum Albumin Nanopa 2021 BACKGROUND: Methotrexate (MTX) is the representative drug among the disease- modifying anti-rheumatic drugs. However, the conventional treatment with MTX showed many limitations and side effects. OBJECTIVE: To strengthen the targeting ability and circulation time of MTX in the treatment of rheumatoid arthritis, the present study focused on developing a novel drug delivery system of methotrexate-loaded human serum albumin nanoparticles (MTX-NPs) modified by mannose, which are referred to as MTX-M-NPs. METHODS: Firstly, mannose-derived carboxylic acid was synthesized and further modified on the surface of MTX-NPs to prepare MTX-M-NPs. The formulation of nanoparticles was optimized by the method of central composite design (CCD), with the drug lipid ratio, oil-aqueous ratio, and cholesterol or lecithin weight as the independent variables. The average particle size and encapsulation efficiency were the response variables. The response of different formulations was calculated, and the response surface diagram, contour diagram, and mathematical equation were used to relate the dependent and independent variables to predict the optimal formula ratio. The uptake of MTX-M-NPs by neutrophils was studied through confocal laser detection. Further, MTX-M-NPs were subjected to assessment of the pharmacokinetics profile after intravenous injection with Sprague-Dawley rats. RESULTS: This targeting drug delivery system was successfully developed. Results from Nuclear Magnetic Resonance and Fourier Transform Infrared Spectroscopy analysis can verify the successful preparation of this drug delivery system. Based on the optimized formula, MTX-M-NPs were prepared with a particle size of 188.17 ± 1.71 nm and an encapsulation rate of 95.55 ± 0.33%. MTX-M-NPs displayed significantly higher cellular uptake than MTX-NPs. The pharmacokinetic results showed that MTX-M-NPs could prolong the in vivo circulation time of MTX. CONCLUSION: This targeting drug delivery system laid a promising foundation for the treatment of RA.
33402424 Mammalian-like type II glutaminyl cyclases in Porphyromonas gingivalis and other oral path 2021 Jan 5 The development of a targeted therapy would significantly improve the treatment of periodontitis and its associated diseases including Alzheimer Disease, rheumatoid arthritis, and cardiovascular diseases. Glutaminyl cyclases (QCs) from the oral pathogens Porphyromonas gingivalis, Tannerella forsythia and Prevotella intermedia represent attractive target enzymes for small-molecule inhibitor development, as their action is likely to stabilize essential periplasmic and outer membrane proteins by N-terminal pyroglutamination. In contrast to other microbial QCs that utilize so-called type I enzymes, these oral pathogens possess sequences corresponding to type II QCs, observed hitherto only in animals. However, whether differences between these bacteroidal QCs and animal QCs are sufficient to enable development of selective inhibitors is not clear. To learn more, we recombinantly expressed all three QCs. They exhibit comparable catalytic efficiencies and are inhibited by metal chelators. Crystal structures  of the enzymes from P. gingivalis (PgQC) and T. forsythia (TfQC) reveal a tertiary structure composed of an eight-stranded β-sheet surrounded by seven α-helices, typical of animal type II QCs. In each case, an active site Zn ion is tetrahedrally coordinated by conserved residues. Nevertheless, significant differences to mammalian enzymes are found around the active site of the bacteroidal enzymes. Application of a PgQC-selective inhibitor described here for the first time results in growth inhibition of two P. gingivalis clinical isolates in a dose dependent manner. The insights gained by these studies will assist in the development of highly specific small-molecule bacteroidal QC inhibitors, paving the way for alternative therapies against periodontitis and associated diseases.
34805205 Association Between a History of Dengue Fever and the Risk of Systemic Autoimmune Rheumati 2021 Purpose: To determine the association between a history of clinically diagnosed dengue infection and the risk of systemic autoimmune rheumatic diseases (SARDs). Methods: Using claims data from the 1997-2013 Taiwanese National Health Insurance Research Database, we included 74,422 patients who were diagnosed with SARDs and 297,688 patients without SARDs who were matched (in a 1:4 ratio) for age, sex, year of SARDs index date, and city of residence. The associations between the development of SARDs and a history of dengue infection (International Classification of Diseases, Ninth Revision, Clinical Modification code 061) were investigated using conditional logistic regression analysis shown as odds ratios (ORs) with 95% confidence intervals (CIs) after adjusting for potential confounders. Results: We included 17,126 patients with systemic lupus erythematosus (SLE), 15,531 patients with Sjogren's syndrome (SS), 37,685 patients with rheumatoid arthritis (RA), 1,911 patients with systemic sclerosis (SSc), 1,277 patients with dermatomyositis (DM), and 892 patients with polymyositis (PM). SLE (OR, 4.55; 95% CI, 2.77-7.46; p <0.001) risk was significantly associated with a history of dengue infection. However, no statistically significant association was found between dengue infection and SS (OR, 1.41; 95% CI, 0.88-2.26; p = 0.155), RA (OR, 1.03; 95% CI, 0.70-1.50; p = 0.888), SSc (OR, 1.97; 95% CI, 0.38-10.29; p = 0.420), DM (OR, 0.54; 95% CI, 0.04-7.27; p = 0.641), or PM (OR, 2.08; 95% CI, 0.23-18.79; p = 0.513). Conclusion: This study revealed that a history of dengue infection was significantly associated with the risk of SLE, but not SS, RA, SSc, DM, or PM.
33815392 The Imbalance of Circulating Follicular T Helper Cell Subsets in Primary Sjögren's Syndro 2021 Since B-cell hyperactivity and pathologic antibody response are key features in the immunopathogenesis of primary Sjögren's syndrome (pSS), the role of follicular T helper (T(FH)) cells as efficient helpers in the survival and differentiation of B cells has emerged. Our aim was to investigate whether a change in the balance of circulating (c)T(FH) subsets and follicular regulatory T (T(FR)) cells could affect the distribution of B cells in pSS. Peripheral blood of 38 pSS patients and 27 healthy controls was assessed for the frequencies of cT(FH) cell subsets, T(FR) cells, and certain B cell subpopulations by multicolor flow cytometry. Serological parameters, including anti-SSA, anti-SSB autoantibodies, immunoglobulin, and immune complex titers were determined as part of the routine diagnostic evaluation. Patients with pSS showed a significant increase in activated cT(FH) cell proportions, which was associated with serological results. Frequencies of cT(FH) subsets were unchanged in pSS patients compared to healthy controls. The percentages and number of cT(FR) cells exhibited a significant increase in autoantibody positive patients compared to patients with seronegative pSS. The proportions of transitional and naïve B cells were significantly increased, whereas subsets of memory B cells were significantly decreased and correlated with autoantibody production. Functional analysis revealed that the simultaneous blockade of cT(FH) and B cell interaction with anti-IL-21 and anti-CD40 antibodies decreased the production of IgM and IgG. Imbalance in T(FH) subsets and T(FR) cells indicates an ongoing over-activated humoral immune response, which contributes to the characteristic serological manifestations and the pathogenesis of pSS.
33200217 Sirolimus for patients with connective tissue disease-related refractory thrombocytopenia: 2021 Jun 18 OBJECTIVES: Connective tissue disease-related thrombocytopenia (CTD-TP) is a problematic disorder in clinical practice. Because the first-line therapy of glucocorticoid and/or immunosuppressants is not effective for refractory cases, alternative treatment approaches are urgently needed. The present study investigated the efficacy and safety of sirolimus in refractory CTD-TP patients. METHODS: This single-centre, single-arm, phase II study enrolled 20 refractory CTD-TP patients between September 2017 and September 2018 (registered on ClinicalTrials.gov: NCT03688191). Oral sirolimus administration was dose-adjusted to maintain a therapeutic range of 6-15 ng/ml for 6 months. The primary endpoints were partial and complete remission rates at 6 months. RESULTS: Twelve (60%) patients achieved the primary end point with a 50% complete remission rate after 6 months. Among the 14 SLE patients, the overall response rate was 71.4%, with a complete remission rate of 64.3%. None of the primary Sjögren's syndrome cases responded to sirolimus. There was no significant difference in baseline clinical characteristics or lymphocyte subpopulations between responders and non-responders. No severe side effect was detected during the study. CONCLUSION: Sirolimus is an effective and safe treatment option for refractory CTD-TP patients. TRIAL REGISTRATION: https://clinicaltrials.gov, NCT03688191.
32671409 Immune responses after influenza vaccination in patients of primary Sjögren's syndrome. 2021 Jan 5 OBJECTIVES: Influenza vaccination is effective in preventing infections in most people. This study aimed to assess the changes of immune responses in primary Sjögren's Syndrome (pSS) patients after influenza vaccination and determine the safety of influenza vaccination. METHODS: A total of 17 patients with pSS and 16 healthy controls (HCs) were included. Peripheral mononuclear cells were analysed by flow cytometry. Vaccine-specific antibodies were determined by ELISA. Clinical features and serological responses were monitored. RESULTS: The percentages of T follicular helper cell (Tfh) were significantly elevated in HCs after vaccination (P=0.0005), while no significant differences in the levels of Tfh in pSS patients were identified (P=0.1748). The proportions of Th2 cells were significantly decreased after vaccination in both pSS patients and HCs (P<0.05). In contrast, the percentages of Th1 cells and Th17 cells were significantly increased after vaccination in pSS patients (P<0.05), while no significant differences in the percentages of Th1 and Th17 cells were identified in HCs (P>0.05), although a trend towards higher levels of Th1 cells was observed (P=0.0830). No significant changes in the proportions of memory B cells and plasmablasts were observed after vaccination. Patients with pSS developed higher levels of vaccine-specific IgGs compared with HCs (P=0.001). No significant changes in disease manifestations and laboratory parameters were observed after vaccination. No increased vaccination related adverse effect was observed in pSS. CONCLUSION: Our findings suggest the feasibility of applying influenza vaccines to patients with pSS, raising awareness for vaccination among the rheumatology community and involved healthcare professionals.
33485845 Systemic diseases and the cornea. 2021 Mar There is a number of systemic diseases affecting the cornea. These include endocrine disorders (diabetes, Graves' disease, Addison's disease, hyperparathyroidism), infections with viruses (SARS-CoV-2, herpes simplex, varicella zoster, HTLV-1, Epstein-Barr virus) and bacteria (tuberculosis, syphilis and Pseudomonas aeruginosa), autoimmune and inflammatory diseases (rheumatoid arthritis, Sjögren's syndrome, lupus erythematosus, gout, atopic and vernal keratoconjunctivitis, multiple sclerosis, granulomatosis with polyangiitis, sarcoidosis, Cogan's syndrome, immunobullous diseases), corneal deposit disorders (Wilson's disease, cystinosis, Fabry disease, Meretoja's syndrome, mucopolysaccharidosis, hyperlipoproteinemia), and genetic disorders (aniridia, Ehlers-Danlos syndromes, Marfan syndrome). Corneal manifestations often provide an insight to underlying systemic diseases and can act as the first indicator of an undiagnosed systemic condition. Routine eye exams can bring attention to potentially life-threatening illnesses. In this review, we provide a fairly detailed overview of the pathologic changes in the cornea described in various systemic diseases and also discuss underlying molecular mechanisms, as well as current and emerging treatments.