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ID PMID Title PublicationDate abstract
34442451 Uncovering the Imprints of Chronic Disease on Patients' Lives and Self-Perceptions. 2021 Aug 18 Rheumatoid arthritis (RA) patients face psychological hardship due to physical discomfort, disabilities, and anxieties. Previous research indicated a bidirectional relationship and patient desire for emotional support from providers. This study examined lesser-understood RA experiences across the psychological and social contexts in relation to self-perception through the patients' expression of their struggles with these burdens. We conducted four semistructured focus groups and eleven interviews (total n = 31). A codebook was developed and refined through iterative transcript coding via NVivo-12. Four emerging themes were identified by inductive, thematic analysis: (1) the patients' healthy appearances were a myth, with subthemes revealing a conflict between an inclination to hide the disease and a desire for validation, while feeling embarrassed by symptom manifestations and disappointment at withdrawal from social interactions; (2) an identity crisis due to diminished functionality, autonomy, and sense of self; (3) RA constantly occupied the mind, as its unpredictability dictated daily schedules and altered plans; and (4) the disease's chronic nature influenced personal outlook to worry about or accept the uncertainty. Even with effective treatment, the invisibility of the disease, the fear and anticipation of flare-ups, and identity clashes caused emotional distress. The insights offer a different perspective on personalized medicine, complementing clinical treatments based on genetic or biomarker profile. For patient-centered holistic care, education is needed to prompt both patients and providers to discuss psychological issues for more customized, integrated interventions. The findings can help inform healthcare teams and families in recognizing and supporting these physical-psychological intertwined experiences, thereby ameliorating patients' wellbeing.
35046940 Low-Dose Radiotherapy Leads to a Systemic Anti-Inflammatory Shift in the Pre-Clinical K/Bx 2021 Osteoarthritis (OA) is the leading degenerative joint disease in the western world and leads, if left untreated, to a progressive deterioration of joint functionality, ultimately reducing quality of life. Recent data has shown, that especially OA of the ankle and foot are among the most frequently affected regions. Current research in OA points towards a complex involvement of various cell and tissue types, often accompanied by inflammation. Low-dose radiotherapy (LDRT) is widely used for the treatment of degenerative and inflammatory diseases. While the reported analgesic effects are well known, the underlying molecular mechanisms are only poorly understood. We therefore correlated a clinical approach, looking at pain reduction in 196 patients treated with LDRT with a pre-clinical approach, utilizing the K/BxN serum transfer mouse model using flow cytometry and multiplex ELISA for analysis. While an improvement of symptoms in the majority of patients was found, patients suffering from symptoms within the tarsi transversa show a significantly lower level of improvement. Further, a significant impact of therapy success was detected depending on whether only one or both feet were affected. Further, patients of younger age showed a significantly better outcome than older ones while needing fewer treatment series. When looking on a cellular level within the mouse model, a systemic alteration of immune cells namely a shift from CD8+ to CD4+ T cells and reduced numbers of DCs was observed. A general reduction of inflammatory cytokines was detected, with significant alterations in IL-4 and IL-17 levels, all of which could potentially be responsible for the highly effective clinical improvement in patients. Taken together our data indicate that LDRT can be regarded as a highly effective treatment option for patients suffering from OA of the foot and ankle, in terms of analgesic effects, especially in younger patients. Furthermore, the observed effects are mediated by an interplay of cellular and soluble immune factors, as observed in the K/BxN serum transfer model. With this interdisciplinary approach we aim to encourage the usage of LDRT as an additive treatment strategy not only as a last resort, but also earlier in the course of disease.
34305602 α-Mangostin Alleviated Inflammation in Rats With Adjuvant-Induced Arthritis by Disrupting 2021 A previously identified anti-rheumatic compound α-mangostin (MAN) possesses notable metabolism regulatory properties. In this study, we investigated the immune implication of MAN-altered fat metabolism on adjuvant-induced arthritis (AIA) in rats. Seven days after AIA induction, the rats received oral treatment of MAN at 50 mg/kg/day for 30 days. Metabolic indicators and basic clinical parameters were evaluated using samples collected on day 20 and 38 since immunization. Expression of nicotinamide phosphoribosyltransferase (NAMPT), sirtuin 1 (SIRT1), peroxisome proliferator activated receptor gamma (PPAR-γ), stearoyl-coa desaturase 1 (SCD-1), toll like receptor 4 (TLR4), prostaglandin-endoperoxide synthase 2 (COX-2), (p)-JNK, (p)-p65 and IL-1β were investigated by either RT-qPCR or immunobloting methods. In in vitro experiments, we treated (pre)-adipocytes with monocytes/macrophages and MAN, and investigated the changes of macrophages brought by pre-adipocytes co-culture. Generally, MAN restored the impaired fat anabolism in AIA rats, indicated by increased fat reservoir, leptin and adiponectin secretion, and PPAR-γ and SCD-1 expression. Meanwhile, it decreased circulating IL-1β and IL-6 levels, restored serological lipid profile changes, and relieved oxidative stresses, demonstrating potent therapeutic effects on AIA. AIA rats-derived monocytes inhibited mRNA PPAR-γ and SCD-1 expression in pre-adipocytes. Contrarily, MAN facilitated adipocyte differentiation in vitro, and increased free fatty acids production. It also significantly increased PPAR-γ and SCD-1 expression, which can be abrogated by PPAR-γ inhibitor T0070907. Similarly, lipopolysaccharide-primed macrophages inhibited PPAR-γ expression in the co-cultured pre-adipocytes, which was reversed by MAN. In the same co-culture system, lipopolysaccharide-induced inflammation was amplified by the co-existence of pre-adipocytes. More secretion of IL-1β and IL-6 and higher levels expression of COX-2, p-JNK, p-p65 and TLR4 were observed in lipopolysaccharide-treated macrophages when co-cultured by pre-adipocytes. The intensified inflammatory situation was eased by MAN. The treatment with pre-adipocytes culture medium achieved similar effects. Medium from lipopolysaccharide-treated adipocytes promoted IL-1β, IL-6 and MCP-1 production in separately cultured macrophages, and COX-2, p-JNK, p-p65 and TLR4 expression were increased at the meantime. MAN treatment on pre-adipocytes impaired these changes. It suggests that fat anabolism in AIA rats was deficient due to increased energy expenditure caused by inflammatory conditions. MAN restored fat metabolism homeostasis by up-regulating PPAR-γ, and reshaped secretion profile of adipocytes.
34367157 Integrated Bioinformatics and Validation Reveal Potential Biomarkers Associated With Progr 2021 BACKGROUND: Primary Sjögren's syndrome (pSS) is a chronic systemic autoimmune disease of the exocrine glands characterized by specific pathological features. Previous studies have pointed out that salivary glands from pSS patients express a unique profile of cytokines, adhesion molecules, and chemokines compared to those from healthy controls. However, there is limited evidence supporting the utility of individual markers for different stages of pSS. This study aimed to explore potential biomarkers associated with pSS disease progression and analyze the associations between key genes and immune cells. METHODS: We combined our own RNA sequencing data with pSS datasets from the NCBI Gene Expression Omnibus (GEO) database to identify differentially expressed genes (DEGs) via bioinformatics analysis. Salivary gland biopsies were collected from 14 pSS patients, 6 non-pSS patients, and 6 controls. Histochemical staining and transmission electron micrographs (TEM) were performed to macroscopically and microscopically characterize morphological features of labial salivary glands in different disease stages. Then, we performed quantitative PCR to validate hub genes. Finally, we analyzed correlations between selected hub genes and immune cells using the CIBERSORT algorithm. RESULTS: We identified twenty-eight DEGs that were upregulated in pSS patients compared to healthy controls. These were mainly involved in immune-related pathways and infection-related pathways. According to the morphological features of minor salivary glands, severe interlobular and periductal lymphocytic infiltrates, acinar atrophy and collagen in the interstitium, nuclear shrinkage, and microscopic organelle swelling were observed with pSS disease progression. Hub genes based on above twenty-eight DEGs, including MS4A1, CD19, TCL1A, CCL19, CXCL9, CD3G, and CD3D, were selected as potential biomarkers and verified by RT-PCR. Expression of these genes was correlated with T follicular helper cells, memory B cells and M1 macrophages. CONCLUSION: Using transcriptome sequencing and bioinformatics analysis combined with our clinical data, we identified seven key genes that have potential value for evaluating pSS severity.
34295332 The Transcriptome of Paired Major and Minor Salivary Gland Tissue in Patients With Primary 2021 BACKGROUND: While all salivary glands (SGs) can be involved in primary Sjögren's syndrome (pSS), their respective role in pathogenesis remains unclear. Our objective was to assess immunopathway activation in paired parotid and labial gland tissue from biopsy-positive and biopsy-negative pSS and non-SS sicca patients. METHODS: Paraffin-embedded, paired parotid and labial salivary gland tissue and peripheral blood mononuclear cells were obtained from 39 pSS and 20 non-SS sicca patients. RNA was extracted, complementary DNA libraries were prepared and sequenced. For analysis of differentially expressed genes (DEGs), patients were subdivided based on fulfillment of ACR-EULAR criteria and histopathology. RESULTS: With principal component analysis, only biopsy-positive pSS could be separated from non-SS sicca patients based on SG gene expression. When comparing the transcriptome of biopsy-positive pSS and biopsy-negative non-SS sicca patients, 1235 and 624 DEGs (FDR<0.05, log2FC<-1 or >1) were identified for parotid and labial glands, respectively. The number of DEGs between biopsy-negative pSS and non-SS sicca patients was scarce. Overall, transcript expression levels correlated strongly between parotid and labial glands (R(2) = 0.86, p-value<0.0001). Gene signatures present in both glands of biopsy-positive pSS patients included IFN-α signaling, IL-12/IL-18 signaling, CD3/CD28 T-cell activation, CD40 signaling in B-cells, DN2 B-cells, and FcRL4+ B-cells. Signature scores varied considerably amongst pSS patients. CONCLUSION: Transcriptomes of paired major and minor SGs in pSS were overall comparable, although significant inter-individual heterogeneity in immunopathway activation existed. The SG transcriptome of biopsy-negative pSS was indistinguishable from non-SS sicca patients. Different patterns of SG immunopathway activation in pSS argue for personalized treatment approaches.
33886574 Hypomethylation mediates genetic association with the major histocompatibility complex gen 2021 Differential methylation of immune genes has been a consistent theme observed in Sjögren's syndrome (SS) in CD4+ T cells, CD19+ B cells, whole blood, and labial salivary glands (LSGs). Multiple studies have found associations supporting genetic control of DNA methylation in SS, which in the absence of reverse causation, has positive implications for the potential of epigenetic therapy. However, a formal study of the causal relationship between genetic variation, DNA methylation, and disease status is lacking. We performed a causal mediation analysis of DNA methylation as a mediator of nearby genetic association with SS using LSGs and genotype data collected from 131 female members of the Sjögren's International Collaborative Clinical Alliance registry, comprising of 64 SS cases and 67 non-cases. Bumphunter was used to first identify differentially-methylated regions (DMRs), then the causal inference test (CIT) was applied to identify DMRs mediating the association of nearby methylation quantitative trait loci (MeQTL) with SS. Bumphunter discovered 215 DMRs, with the majority located in the major histocompatibility complex (MHC) on chromosome 6p21.3. Consistent with previous findings, regions hypomethylated in SS cases were enriched for gene sets associated with immune processes. Using the CIT, we observed a total of 19 DMR-MeQTL pairs that exhibited strong evidence for a causal mediation relationship. Close to half of these DMRs reside in the MHC and their corresponding meQTLs are in the region spanning the HLA-DQA1, HLA-DQB1, and HLA-DQA2 loci. The risk of SS conferred by these corresponding MeQTLs in the MHC was further substantiated by previous genome-wide association study results, with modest evidence for independent effects. By validating the presence of causal mediation, our findings suggest both genetic and epigenetic factors contribute to disease susceptibility, and inform the development of targeted epigenetic modification as a therapeutic approach for SS.
34212822 Increased salivary syndecan-1 level is associated with salivary gland function and inflamm 2022 May OBJECTIVE: Syndecan-1 (SDC-1), a transmembrane heparin sulphate proteoglycan predominantly expressed on epithelial cells, also exists in a soluble form through ectodomain shedding. SDC-1 expression and shedding may be modulated in the inflammatory milieu of primary Sjögren's syndrome (SS). We investigated SDC-1 expression in minor salivary glands (MSGs) and analysed the association between salivary or plasma levels of SDC-1 and clinical parameters in SS. METHOD: We measured salivary and plasma SDC-1 levels via an enzyme-linked immunosorbent assay and assessed the salivary flow rates (SFRs) in 70 patients with SS and 35 healthy subjects. Disease activity indices, serological markers, salivary gland scintigraphy, and MSG biopsy were evaluated in patients with SS. RESULTS: SDC-1 expression was upregulated on ductal epithelial cells in inflamed salivary glands. Salivary SDC-1 levels in patients significantly exceeded those in healthy subjects [median (interquartile range) 49.0 (20.7-79.1) vs 3.7 (1.7-6.3) ng/mL, p < 0.001] and inversely correlated with SFRs (r = -0.358, p = 0.032) and ejection fractions of the parotid (r = -0.363, p = 0.027) and submandibular (r = -0.485, p = 0.002) glands in salivary gland scintigraphy. Plasma SDC-1 levels were significantly correlated with the EULAR Sjögren's Syndrome Disease Activity Index (r = 0.507, p < 0.001) and EULAR Sjögren's Syndrome Patient Reported Index (r = 0.267, p = 0.033). Focus scores were correlated with salivary SDC-1 levels (r = 0.551, p = 0.004). CONCLUSIONS: Salivary and plasma SDC-1 levels may constitute potential biomarkers for salivary gland function and disease activity, respectively, in SS.
34332492 Autoantibody against the Rab6A/Rab6B in primary autoimmune cerebellar ataxia associated wi 2021 Oct 15 In the current study we report a novel autoantibody against Purkinje cells in a patient with primary autoimmune cerebellar ataxia (PACA) associated with Sjogren's syndrome (SS). Tissue-based indirect immunofluorescence assay (TBA) of the patient's serum and cerebrospinal fluid (CSF) revealed IgG antibody to Purkinje cells and the granular layer of the rat cerebellum. Rab6A was identified as autoantigen by mass spectrometry (MS) and Western blotting, and the interactions between Rab6A or its homologous Rab6B and autoantibody in patient serum were verified by recombinant cell-based assay (CBA) and neutralization experiments. This autoantibody may represent a novel biomarker in the diagnosis of PACA.
34239943 An Update on the Pathogenic Role of Macrophages in Adult-Onset Still's Disease and Its Imp 2021 Increasing evidence indicates a pivotal role of macrophages in innate immunity, which contributes to the pathogenesis of adult-onset Still's disease (AOSD). Despite the available reviews that summarized the pathogenic role of proinflammatory cytokines in AOSD, a systematic approach focusing on the crucial role of macrophages in this disease is still lacking. This review summarizes the updated functions of macrophages in AOSD and their implication in clinical manifestations and therapeutics. We searched the MEDLINE database using the PubMed interface and reviewed the English-language literature as of 31 March 2021, from 1971 to 2021. We focus on the existing evidence on the pathogenic role of macrophages in AOSD and its implication in clinical characteristics and novel therapeutics. AOSD is an autoinflammatory disease mainly driven by the innate immune response. Among the innate immune responses, macrophage activation is a hallmark of AOSD pathogenesis. The pattern recognition receptors (PRRs) on macrophages recognize pathogen-associated molecular patterns and damage-associated molecular patterns and subsequently cause overproduction of proinflammatory cytokines and recruit adaptive immunity. Some biomarkers, such as ferritin and gasdermin D, reflecting macrophage activation were elevated and correlated with AOSD activity. Given that macrophage activation with the overproduction of proinflammatory cytokines plays a pathogenic role in AOSD, these inflammatory mediators would be the therapeutic targets. Accordingly, the inhibitors to interleukin- (IL-) 1, IL-6, and IL-18 have been shown to be effective in AOSD treatment. Gaining insights into the pathogenic role of macrophages in AOSD can aid in identifying disease biomarkers and therapeutic agents for this disease.
34001167 Findings and feasibility of major salivary gland ultrasound in childhood-onset systemic lu 2021 May 17 BACKGROUND: Childhood-onset systemic lupus erythematosus (cSLE) is a complex autoimmune disorder with multi-organ manifestations and can be associated with other rheumatic diseases including Sjögren's syndrome (SS). Salivary gland ultrasound (SGUS) represents a noninvasive tool to screen for salivary gland disease in rheumatic disease patients. The aims of this cross-sectional study were to determine feasibility of major SGUS in a clinic setting and to identify characteristics in a cohort of cSLE patients (without confirmed SS) that may be associated with salivary gland abnormalities consistent with secondary SS. METHODS: Patients with SLE onset prior to age 18 were recruited. Patients completed questionnaires rating symptoms and underwent major SGUS examination. Disease and demographic differences were compared between cSLE patients with abnormal SGUS vs. cSLE patients with normal SGUS using t-tests and Fisher's exact tests. RESULTS: Thirty-one cSLE patients were recruited, 84% were female, 55% were Caucasian. The average disease duration among all patients was 5 years. Average time to complete the SGUS examination and scoring protocol was 7 min. 35% of SGUS scores were abnormal and significantly associated with IgG level at diagnosis, and anti-Ro and anti-La antibodies. CONCLUSIONS: This is one of the first studies to our knowledge that assesses major SGUS in a cohort of patients with cSLE without prior diagnoses of SS. The SGUS protocol was feasible to perform by rheumatologists in a clinic setting. Although the sample size was small, SGUS abnormalities were identified in one-third of patients. IgG level at diagnosis and anti-Ro and anti-La antibodies may be associated with SGUS abnormalities.
34226730 Lyme arthritis: linking infection, inflammation and autoimmunity. 2021 Aug Infectious agents can trigger autoimmune responses in a number of chronic inflammatory diseases. Lyme arthritis, which is caused by the tick-transmitted spirochaete Borrelia burgdorferi, is effectively treated in most patients with antibiotic therapy; however, in a subset of patients, arthritis can persist and worsen after the spirochaete has been killed (known as post-infectious Lyme arthritis). This Review details the current understanding of the pathogenetic events in Lyme arthritis, from initial infection in the skin, through infection of the joints, to post-infectious chronic inflammatory arthritis. The central feature of post-infectious Lyme arthritis is an excessive, dysregulated pro-inflammatory immune response during the infection phase that persists into the post-infectious period. This response is characterized by high amounts of IFNγ and inadequate amounts of the anti-inflammatory cytokine IL-10. The consequences of this dysregulated pro-inflammatory response in the synovium include impaired tissue repair, vascular damage, autoimmune and cytotoxic processes, and fibroblast proliferation and fibrosis. These synovial characteristics are similar to those in other chronic inflammatory arthritides, including rheumatoid arthritis. Thus, post-infectious Lyme arthritis provides a model for other chronic autoimmune or autoinflammatory arthritides in which complex immune responses can be triggered and shaped by an infectious agent in concert with host genetic factors.
33332679 Adult-onset still's disease and treatment results with tocilizumab. 2021 Mar AIMS: Adult-onset Still's disease (AOSD) is a rare and non-familial auto-inflammatory disorder. Increased levels of IL-6 and other pro-inflammatory cytokines have been shown in AOSD. To evaluate the efficacy and safety profile of tocilizumab (TCZ), an IL-6 receptor antagonist monoclonal antibody, in AOSD. METHODS: Thirty-nine patients followed up with the diagnosis of AOSD between 2013 and 2019 were retrospectively evaluated and the 16 patients (10 Female/6 Male) treated with TCZ for refractory AOSD were included in the study group. Among the remaining 23 patients 16 had non-biological treatments and had no important complications at the presentation. TCZ was given to patients at a dose of 4-8 mg/kg every 4 weeks. Patients were evaluated after 3-6 months of TCZ treatment for side effects, inflammatory and clinical response and concomitant treatments. RESULTS: In TCZ (+) patients, the majority were female (62.5%), the mean age at disease onset was 38.5 ± 17.9 (20-81) years, and the most common symptoms and signs were myalgia (81.3%), fever (81.3%) and skin eruptions (75%). There was no difference between TCZ (+) and TCZ (-) groups for age, sex and clinical presentations. There was a significant decrease in dose of prednisolone, sedimentation rate, leucocyte count, C-reactive protein and ferritin levels and improvement in all clinical complaints after TCZ treatment. There were no relapses during the treatment. Three patients are in remission and under follow-up without any treatment after cessation of TCZ (4 months-3 years). No exacerbation of disease yet seen in those patients. CONCLUSIONS: TCZ is an effective and well-tolerated treatment option for treatment resistant AOSD and contributes to the glucocorticoid-sparing. Since TCZ is a new drug in the treatment of AOSD, further studies are needed to assess whether the complications reported during the treatment are because of TCZ or natural course of the disease or coincidental findings.
32741737 Chinese herbal medicine SS-1 inhibits T cell activation and abrogates T(H) responses in Sj 2021 Jan BACKGROUND/PURPOSE: Sjögren's syndrome (SS) is an autoimmune disease and its conventional treatment has exhibited limited therapeutic efficacy. Traditional Chinese medicine has been demonstrated to ameliorate the sicca symptoms of SS by decreasing the level of T(H)1 and T(H)2 cytokines and increasing salivary flow rate. A newly designed traditional Chinese medicine, SS-1, showed improved efficacy in alleviating the dryness symptoms of SS patients in the National Taiwan SS cohort investigation. Here, we investigated the effect of SS-1 on T cell responses. METHODS: SS-1 was authenticated and its major compounds were verified by high-performance liquid chromatography. We examined the effects of SS-1 on the activation and T(H)1, T(H)2, and T(H)17 polarization of murine T cells. We also determined the level of T(H)1, T(H)2, and T(H)17 cytokine RNA in peripheral blood mononuclear cells of SS patients before and after SS-1 treatment. RESULTS: SS-1 treatment inhibits the activation and T(H)1, T(H)2, and IL-17A(+)IFNγ(+) T(H) polarization of murine T cells. SS-1 treatment also significantly reduces IFN-γ, IL-4, and IL-13 expression, and moderately reduces IL-17A expression in peripheral blood mononuclear cells of SS patients. CONCLUSION: Our results suggest that SS-1 inhibits T cell activation and diminishes T(H)1, T(H)2, and IL-17(+)IFN-γ(+) T(H) responses in SS patients.
30770715 Comorbidities (excluding lymphoma) in Sjögren's syndrome. 2021 May 14 The information about comorbidities (excluding lymphoma) in primary Sjögren's syndrome (pSS) is relatively scarce. Cardiovascular disease, infections, musculoskeletal conditions or malignancy are likely the most relevant comorbid conditions in pSS. Different infections (particularly oral candidal infections) and fibromyalgia are extremely frequent in the daily clinical practice. On the other hand, the incidence of cardiovascular events and cancer in pSS is low, so information about them comes from large epidemiological studies or meta-analysis. For this reason, preclinical vascular disease is investigated by different techniques, demonstrating the presence of early atherosclerosis in pSS patients. Coronary events could be slightly more frequent in pSS than in the general population. The overall risk of malignancy in pSS patients seems to be slightly increased, likely due to excess occurrence of lymphoma. An association between pSS and thyroid cancer might exist, although it should be confirmed by further investigations.
34582486 Snail regulation in fibroblast-like synoviocytes by a histone deacetylase or glycogen synt 2021 BACKGROUND: Snail has been linked to the pathogenesis of rheumatoid arthritis (RA). We plan to investigate the regulation of Snail in response to TNF-α, histone acetylation, and glycogen synthase kinase-3 (GSK)-3 inhibition in fibroblast-like synoviocytes (FLSs). METHODS: FLSs from rats with collagen-induced arthritis (CIA) were collected and treated with TNF-α alone or a combination with trichostatin A (TSA), a pan-histone deacetylase inhibitor and lithium chloride (LiCl), a glycogen synthase kinase-3 (GSK)-3 inhibitor. RESULTS: We demonstrated for the first time that nuclear expression of Snail in FLSs from rats with CIA was correlated with the levels of extracellular TNF-α and acetylation status. Cell proliferation and viability of CIA FLSs were reduced in response to TSA treatment and short-hairpin RNA specific to Snail. LiCl treatment increased Snail and cadherin-11 (Cad-11) expression in CIA FLSs. CONCLUSION: We suggested from this study that targeting TNF-α-histone deacetylase-Snail signaling axis or the Wnt signaling pathway in FLSs might provide therapeutic interventions for the treatment of RA in the future.
33924467 Kurarinone Attenuates Collagen-Induced Arthritis in Mice by Inhibiting Th1/Th17 Cell Respo 2021 Apr 13 Kurarinone is a flavanone, extracted from Sophora flavescens Aiton, with multiple biological effects. Here, we determine the therapeutic potential of kurarinone and elucidate the interplay between kurarinone and the autoimmune disease rheumatoid arthritis (RA). Arthritis was recapitulated by induction of bovine collagen II (CII) in DBA/1 mice as a collagen-induced arthritis (CIA) model. After the establishment of the CIA, kurarinone was given orally from day 21 to 42 (100 mg/kg/day) followed by determination of the severity based on a symptom scoring scale and with histopathology. Levels of cytokines, anti-CII antibodies, and the proliferation and lineages of T cells from the draining lymph nodes were measured using ELISA and flow cytometry, respectively. The expressional changes, including STAT1, STAT3, Nrf2, KEAP-1, and heme oxygenase-1 (HO-1) changes in the paw tissues, were evaluated by Western blot assay. Oxidative stress featured with malondiadehyde (MDA) and hydrogen peroxide (H(2)O(2)) activities in paw tissues were also evaluated. Results showed that kurarinone treatment reduced arthritis severity of CIA mice, as well as their levels of proinflammatory cytokines, TNF-α, IL-6, IFN-γ, and IL-17A, in the serum and paw tissues. T cell proliferation was also reduced by kurarinone even under the stimulation of CII and anti-CD3 antibody. In addition, kurarinone reduced STAT1 and STAT3 phosphorylation and the proportions of Th1 and Th17 cells in lymph nodes. Moreover, kurarinone suppressed the production of MDA and H(2)O(2.) All while promoting enzymatic activities of key antioxidant enzymes, SOD and GSH-Px. In the paw tissues, upregulation of Nrf-2 and HO-1, and downregulation of KEAP-1 were observed. Overall, kurarinone showed an anti-inflammatory effect by inhibiting Th1 and Th17 cell differentiation and an antioxidant effect exerted in part through activating the Nrf-2/KEAP-1 pathway. These beneficial effects in CIA mice contributed to the amelioration of their arthritis, indicating that kurarinone might be an adjunct treatment option for rheumatoid arthritis.
34079556 Lactobacillus casei CCFM1074 Alleviates Collagen-Induced Arthritis in Rats via Balancing T 2021 Gut microbiota and their influence on metabolites are receiving increasing attentions in autoimmune diseases including rheumatoid arthritis (RA). Probiotics become a promising manipulator to prevent or attenuate the progression of arthritis, some evidences suggesting that lactobacilli treatment influence the responses to RA therapy but the underlying mechanisms are limited. By using a collagen-induced arthritis (CIA) rats, the study assessed the effects of two L. casei strains (CCFM1074, CCFM1075) on the immune responses, gut microbiota and plasma metabolites via an integrated cross-omics approach including fecal 16S rRNA high-throughput sequencing and plasma metabolomics. The genome of the two strains was analyzed and compared using whole-genome sequencing approach to further confirm biology functions. CCFM1074 reduced arthritic symptoms while CCFM1075 did not, though both strains down-regulated the plasma IL-6 and Th17 cells proportion. CCFM1074 enhanced the proportion of Treg cells in mesenteric lymph nodes which was significantly associated with SCFAs upregulation, as well as with genomic evidence that CCFM1074 possesses more functional genes involved in carbohydrate metabolism. Moreover, CCFM1074 regulated the gut microbiota, including modulating community structure, decreasing the abundance of Alistipes and Parabacteroides and increasing the abundance of Oscillibacter. The differential metabolites modulated by CCFM1074 including eicosapentaenoic acid and docosapentaenoic acid which involved in unsaturated fatty acids metabolism. Furthermore, alterations of gut microbial community were correlated with the plasma metabolome. In summary, L. casei CCFM1074 alleviated arthritis via rebalancing gut microbiota, immune responses and plasma metabolites.
33817614 An elevated polyclonal free light chain level reflects a strong interferon signature in pa 2021 High amount of polyclonal free light chains (FLC) are reported in systemic autoimmune diseases (SAD) and we took advantage of the PRECISESADS study to better characterize them. Serum FLC levels were explored in 1979 patients with SAD (RA, SLE, SjS, Scl, APS, UCTD, MCTD) and 614 healthy controls. Information regarding clinical parameters, disease activity, medications, autoantibodies (Ab) and the interferon α and/or γ scores were recorded. Among SAD patients, 28.4% had raised total FLC (from 12% in RA to 30% in SLE and APS) with a normal kappa/lambda ratio. Total FLC levels were significantly higher in SAD with inflammation, active disease in SLE and SjS, and an impaired pulmonary functional capacity in SSc, while independent from kidney impairment, infection, cancer and treatment. Total FLC concentrations were positively correlated among the 10/17 (58.8%) autoantibodies (Ab) tested with anti-RNA binding protein Ab (SSB, SSA-52/60 kDa, Sm, U1-RNP), anti-dsDNA/nucleosome Ab, rheumatoid factor and negatively correlated with complement fractions C3/C4. Finally, examination of interferon (IFN) expression as a potential driver of FLC overexpression was tested showing an elevated level of total FLC among patients with a high IFNα and IFNγ Kirou's score, a strong IFN modular score, and the detection in the sera of B-cell IFN dependent factors, such as TNF-R1/TNFRSF1A and CXCL10/IP10. In conclusion, an elevated level of FLC, in association with a strong IFN signature, defines a subgroup of SAD patients, including those without renal affectation, characterized by increased disease activity, autoreactivity, and complement reduction.
33903928 Stability of housekeeping genes in inflamed joints of spontaneous and collagen-induced art 2021 May BACKGROUND: DBA/1 mice arthritis models have contributed to our understanding of human rheumatoid arthritis (RA) and spondyloarthritis (SpA) pathogenesis, as well as the exploration of therapeutic targets for treatment. Quantitative polymerase chain reaction (qPCR) is an indispensable tool in molecular research, which requires reference gene validation to obtain consistent and reliable results. OBJECTIVE: To determine the stability of candidate reference genes for qPCR in the joint of collagen-induced arthritis (CIA) and spontaneous arthritis (SpAD) DBA/1 mice. METHODS: The expression of eleven commonly used reference genes (ACTB, B2M, EF1a, GAPDH, HMBS, HPRT, PPIB, RPL13A, SDHA, TBP, and YWHAZ) was assessed by qPCR and the data were compared using delta-Ct methods and the geNorm, NormFinder, and RefFinder software packages. Genes identified as stable in each model were used for the quantification of inflammatory cytokines RESULTS: The gene stabilities differed between the two arthritis models in the DBA/1 mice. EF1a and RPL13A were the best reference genes for SpAD, while RPL13A and TBP were the best for the CIA. These genes allowed the data normalization for the quantification of the inflammatory cytokines in both models; these results showed an increase in the expression of IL-1B, IL-12B, IL-17A, and IL-6 in the inflamed joints. The use of different primer sequences for the same reference gene resulted in different relative quantification values. CONCLUSION: This study demonstrates that commonly used reference genes may not be suitable for arthritic tissues from DBA/1 mice, and strengthening the principle that meticulous validation of reference genes is essential before each experiment to obtain valid and reproducible qPCR data for analysis or interpretation.
34598717 Longitudinal analysis of the patient pathways to diagnosis of psoriatic arthritis. 2021 Oct 1 BACKGROUND: The occurrence of health events preceding a psoriatic arthritis (PsA) diagnosis may serve as predictors of diagnosis. We sought to assess patients' real-world experiences in obtaining a PsA diagnosis. METHODS: This retrospective cohort study analyzed MarketScan claims data from January 2006 to April 2019. Included were adult patients with ≥ 2 PsA diagnoses (ICD-9-CM/ICD-10-CM) ≥ 30 days apart with ≥ 6 years of continuous enrolment before PsA diagnosis. Controls were matched 2:1 to patients with PsA. Health events (diagnoses and provider types) were analyzed before PsA diagnosis and additionally stratified by presence of psoriasis. RESULTS: Of 13,661 patients, those with PsA had an increased history of coding for arthritis and dermatologic issues (osteoarthritis [48% vs 22%], rheumatoid arthritis [18% vs 2%], and psoriasis [61% vs 2%]) vs those without PsA. Diagnoses of arthritis, axial symptoms, and tendonitis/enthesitis increased over time preceding PsA diagnosis; notably, a sharp rise in psoriasis diagnoses was observed 6 months before PsA diagnosis. Rheumatology consults were more common immediately preceding a PsA diagnosis. Dermatologists were unlikely to code for arthritis and musculoskeletal issues, while rheumatologists were unlikely to code for psoriasis; general practitioners focused on axial and musculoskeletal symptoms. PsA was most commonly diagnosed by rheumatologists (40%), general practitioners (22%), and dermatologists (7%). CONCLUSIONS: Rheumatologists, general practitioners, and dermatologists diagnosed two thirds of patients with PsA. Musculoskeletal symptoms were common preceding a PsA diagnosis. Greater awareness of patterns of health events may alert healthcare providers to suspect a diagnosis of PsA.