Browse

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

ID PMID Title PublicationDate abstract
31371927 From drug-delivery device to disease management tool: a study of preferences for enhanced 2019 PURPOSE: To quantify rheumatology patient preferences and willingness to pay (WTP) for features differentiating enhanced from standard self-injection devices and to investigate differences among subgroups. PATIENTS AND METHODS: Patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), and axial spondyloarthritis (axSpA) were recruited in the UK. A discrete-choice experiment was used to elicit preferences; respondents were presented with 10 choices between 3 different devices: a free standard disposable device, and 2 hypothetical reusable devices characterized by presence/absence of skin sensor, injection speed control, on-screen instructions, injection reminders, electronic log, and large grip. Every hypothetical device included a cost component to assess WTP for each enhanced feature. A random-parameters logit model was used to estimate preference weights and WTP. RESULTS: Data were collected from 323 respondents by electronic survey (15/11/2017-15/02/2018; RA: 108; PsA: 103; axSpA: 112). On average, the skin sensor was the most preferred feature (£30), followed by injection speed control, injection reminders, electronic log (~£20 each), on-screen instructions (~£12), and a device with a small, rather than large grip (~£7). Similar preferences for attributes were observed across condition subgroups except for grip size: axSpA patients preferred small grip (~£27); PsA patients preferred large grip (~£19). Overall, respondents preferred reusable devices with all enhanced features (WTP value: £85) over the standard device. RA patients exhibited a higher WTP (£145) than PsA (£102) or axSpA (£62) for the same enhanced device. CONCLUSION: Patients positively valued reusable self-injection devices with enhanced features, which may improve patient experience, potentially improving treatment adherence, clinical, and economic outcomes.
30947875 Rheumatologic Diseases and the Liver. 2019 May A variety of rheumatologic disorders may affect the liver. There is a significant epidemiologic, genetic, and immunologic overlap between immune-mediated rheumatologic disorders and autoimmune liver diseases. There is an increased frequency of autoimmune liver diseases, such as primary biliary cholangitis, autoimmune hepatitis, primary sclerosing cholangitis, or overlap syndrome, in patients with systemic lupus erythematosus, rheumatoid arthritis, Sjögren syndrome, systemic sclerosis, vasculitis, and other immune-related diseases. Non-immune-mediated rheumatologic diseases such as gouty arthritis may also have hepatic manifestations. Furthermore, medications used to treat rheumatologic diseases occasionally cause liver dysfunction. Conversely, primary immune-mediated and non-immune-mediated liver disorders may present with rheumatologic manifestations.
30507064 The Contribution of PTPN22 to Rheumatic Disease. 2019 Apr One of the unresolved questions in modern medicine is why certain individuals develop a disorder such as rheumatoid arthritis (RA) or lupus, while others do not. Contemporary science indicates that genetics is partly responsible for disease development, while environmental and stochastic factors also play a role. Among the many genes that increase the risk of autoimmune conditions, the risk allele encoding the W620 variant of protein tyrosine phosphatase N22 (PTPN22) is shared between multiple rheumatic diseases, suggesting that it plays a fundamental role in the development of immune dysfunction. Herein, we discuss how the presence of the PTPN22 risk allele may shape the signs and symptoms of these diseases. Besides the emerging clarity regarding how PTPN22 tunes T and B cell antigen receptor signaling, we discuss recent discoveries of important functions of PTPN22 in myeloid cell lineages. Taken together, these new insights reveal important clues to the molecular mechanisms of prevalent diseases like RA and lupus and may open new avenues for the development of personalized therapies that spare the normal function of the immune system.
31877657 Addition of a Viral Immunomodulatory Domain to Etanercept Generates a Bifunctional Chemoki 2019 Dec 20 The inhibition of tumor necrosis factor (TNF) through the use of either antibodies or soluble receptors is a highly effective strategy for the clinical control of chronic inflammatory conditions such as rheumatoid arthritis. Different viruses have similarly exploited this concept by expressing a set of specifically tailored secreted TNF decoy receptors to block host inflammatory responses. Poxviruses have been shown to encode at least two distinct molecules, termed Cytokine response modifier D (CrmD) and CrmB, in which a TNF inhibitor is combined with a chemokine inhibitor on the same molecule. The ectromelia virus CrmD protein was found to be a critical determinant of virulence in vivo, being able to control local inflammation to allow further viral spread and the establishment of a lethal infection. Strikingly, both the TNF and the chemokine inhibitory domains are required for the full activity of CrmD, suggesting a model in which inhibition of TNF is supported by the concomitant blockade of a reduced set of chemokines. Inspired by this model, we reasoned that a similar strategy could be applied to modify the clinically used human TNF receptor (etanercept), producing a generation of novel, more effective therapeutic agents. Here we show the analysis of a set of fusion proteins derived from etanercept by addition of a viral chemokine-binding protein. A bifunctional inhibitor capable of binding to and blocking the activity of TNF as well as a set of chemokines is generated that is active in the prevention of arthritis in a murine disease model.
31315147 Therapeutic drug monitoring of infliximab in spondyloarthritis. A review of the literature 2019 Oct Available evidence indicates that a therapeutic drug monitoring strategy leads to major cost savings related to the anti-tumour necrosis factor-α therapy in both inflammatory bowel disease and rheumatoid arthritis (RA) patients, with no negative impact on efficacy. However, although the systematic use of therapeutic drug monitoring could potentially be beneficial and economically acceptable to drug dose optimization, it is not justifiable for all drugs. Infliximab (IFX) is a chimeric monoclonal immunoglobulin G1 targeting tumour necrosis factor. It has been approved for the treatment of immuno-inflammatory diseases, including RA, ankylosing spondylitis, psoriatic arthritis, Crohn's disease and ulcerative colitis. IFX's pharmacokinetics is highly variable and influences clinical response in chronic inflammatory diseases. Clinical response increases with IFX trough concentrations in RA, ankylosing spondylitis, inflammatory bowel disease and psoriatic patients. Target concentrations predictive of good clinical response were proposed in RA, Crohn's disease and ulcerative colitis. The purpose of this article is to review the current literature surrounding IFX serum concentrations and their related parameters with disease activity in patients with spondyloarthritis. Gathering information about the efficacy of IFX in patients with spondyloarthritis and relating IFX serum concentrations to disease activity were the main goals of this study.
30905213 A portfolio of biologic self-injection devices in rheumatology: how patient involvement in 2019 Dec Biologic drugs (e.g. anti-tumor necrosis factors) are effective treatments for multiple chronic inflammatory diseases including rheumatoid arthritis, axial spondyloarthritis, and psoriatic arthritis. Administration of biologic drugs is usually via subcutaneous self-injection, which provides many patient benefits compared to infusions including increased flexibility, reduced costs, and reduced caregiver burden. However, it is also associated with challenges such as needle phobia, patient treatment misconceptions and incorrect drug administration, and can be impacted by dexterity problems. Evidence suggests these problems, along with other drug administration challenges (e.g. patient forgetfulness, busy lifestyles, and polypharmacy), can reduce patient adherence to treatment. To combat these challenges, patient feedback has been used to develop a range of self-injection devices, including pre-filled syringes, pre-filled pens, and electronic injection devices. Providing different devices for drug administration gives patients the opportunity to choose a device that addresses the challenges they face as an individual. Research suggests involving patients in medical device development, providing patients with a choice of devices and enrolling individuals in patient support programs can empower patients to take control of their treatment journey. By providing a portfolio of self-injection devices, designed based on patient needs, patient experience will improve, potentially improving adherence and hence, long-term treatment outcomes.
30657123 The impact of different rheumatic diseases on health-related quality of life: a comparison 2019 Jan 15 BACKGROUND: Given the high prevalence of rheumatic diseases, there is a need to determine which conditions have the greatest impact on health-related quality of life (HRQoL). The main aim of this study was to explore the HRQoL scores among 14 different rheumatic diseases and to compare them with the results of a selecting sample of healthy controls. METHODS: 2633 patients of an ongoing cohort have been enrolled. Rheumatic diseases were classified into five diagnostic groups: inflammatory rheumatic diseases, connective tissue disorders, symptomatic peripheral osteoarthritis, soft tissue disorders, and osteoporosis. For comparison were used 649 healthy controls. The HRQoL was evaluated with the Medical Outcomes Study Short-Form 36 Health Survey (SF-36), the EuroQol five Dimensions (EQ-5D) questionnaire, and the Short-Form six Dimensions (SF-6D) questionnaire. RESULTS: The five major rheumatic disease groups, compared to healthy people, significantly impaired all eight health concepts of the SF-36 (p <0.0001). Similar results were found for EQ-5D and SF-6D. The patients with inflammatory rheumatic diseases have poorer self-reported health status than those without arthritis in all domains of living, but particularly with respect to scales measuring aspects of physical functioning or mobility, role limitation due to physical health problems and usual activities, and bodily pain. Rheumatoid arthritis had the largest negative impact on HRQoL, followed by fibromyalgia, vertebral fractures due to osteoporosis, hip osteoarthritis, and systemic sclerosis. CONCLUSIONS: Our results indicate that rheumatic diseases have a clearly detrimental effect on the HRQoL, and physical domain is more impaired than mental and social ones.
31804172 Characteristics of coexisting localized scleroderma and inflammatory arthritis. 2019 Dec 3 OBJECTIVE: Localized scleroderma (LS), including morphea and linear scleroderma, is an autoimmune disease where excessive subcutaneous collagen deposits lead to thickening, scarring, and fibrosis of the tissues. LS coexisting with inflammatory arthritis is less well-described but has been reported in as many as 20% of 53 LS patients in a recent cohort. Herein, we describe a cohort of 8 children with both LS and inflammatory arthritis. The objective of this study is to determine the characteristics of inflammatory arthritis in children with LS and their response to treatment regimens. MATERIALS AND METHODS: A retrospective chart review was completed on patients less than 19 years of age who were diagnosed with either morphea or linear scleroderma at the Children of Alabama center from 2004-2018. Patients were identified using ICD-9 and ICD-10 diagnostic codes. Records were reviewed for additional diagnostic codes, exams, and laboratory findings confirming coexisting inflammatory arthritis and LS. RESULTS: A total of 87 patients with a diagnosis of either morphea or linear scleroderma were identified. Eight (9%) had coexisting inflammatory arthritis according to the diagnostic codes with documented active arthritis. Median age of initial rheumatic disease diagnosis was 7.5 years. A majority of patients with both LS and inflammatory arthritis were female (62.5%). Half of the patients (n=4, 50%) had LS lesions over arthritic joints. All of the identified patients were diagnosed with a form of juvenile idiopathic arthritis (JIA). The JIA diagnoses varied widely in 3 (37.5%) patients with rheumatoid factor (RF) negative polyarticular JIA, 2 (25%) with oligoarticular JIA, 2 (25%) with psoriatic JIA, and 1 (12.5%) with enthesitis-related JIA. The timing of onset of LS and inflammatory arthritis varied widely. Three (37.5%) patients had LS lesions preceding clinical arthritis, and three (37.5%) had arthritis before the appearance of LS. Two (25%) patients had both LS and arthritis at the time of diagnosis. All patients received methotrexate (MTX) during their disease course with only 3 (37.5%) receiving systemic steroids during treatment. All 8 patients showed resolution of LS lesions. However, 6 of the 8 patients demonstrated active arthritis on combination MTX and TNFi therapy. CONCLUSION: In this cohort of pediatric LS, 9% of patients had coexisting inflammatory arthritis. The characteristics of this cohort varied widely. All patients received MTX initially and showed a resolution of LS lesions. However, in the majority of patients, the arthritis failed to respond to MTX and TNFi combination therapy. These results suggest that inflammatory arthritis coexisting with LS may be less likely to respond to traditional inflammatory arthritis or JIA therapies.
31943973 Responses to Cytokine Inhibitors Associated with Cellular Composition in Models of Immune- 2020 Jan OBJECTIVE: Immune-mediated inflammatory arthritis (IMIA) is a heterogeneous group of diseases including rheumatoid arthritis (RA), psoriatic arthritis (PsA), and spondyloarthritis (SpA). Disease-modifying antirheumatic drugs (DMARDs) target very different cellular components of the disease processes. Characterization of the pathobiological subtypes of IMIA could provide more specific treatment approaches for each disease. For example, RA has been proposed to consist of at least three synovial pathotypes (lymphoid, myeloid, and fibroid), and only a subgroup of RA patients have erosive disease. The objective of this study was to evaluate the effects of various DMARDs on different synovial cell subsets using human ex vivo models of IMIA. METHODS: Synovial fluid and blood samples were obtained from a study population consisting of patients with RA, PsA, or peripheral SpA with at least one swollen joint (n = 18). The DMARDs used in this study were methotrexate, adalimumab, etanercept, tocilizumab, anakinra, ustekinumab, secukinumab, tofacitinib, and baricitinib. Paired synovial fluid mononuclear cells (SFMCs), peripheral blood mononuclear cells (PBMCs), and fibroblast-like synovial cells (FLSs) were used in three different previously optimized ex vivo models. RESULTS: In SFMCs cultured for 48 hours, all DMARDs except anakinra decreased the production of monocyte chemoattractant protein (MCP)-1. In SFMCs cultured for 21 days, only the two tumor necrosis factor alpha (TNFα) inhibitors adalimumab and etanercept decreased the secretion of tartrate-resistant acid phosphatase (P < 0.01, P < 0.001). In the FLS and PBMC 48-hour co-cultures, only tocilizumab (P < 0.001) and the two Janus kinase inhibitors tofacitinib and baricitinib (both P < 0.05) decreased the production of MCP-1 by around 50%. CONCLUSION: TNFα inhibition was effective in preventing inflammatory osteoclastogenesis, whereas tocilizumab, tofacitinib, and baricitinib had superior efficacy in cultures dominated by FLSs. Taken together, this study reveals that responses to cytokine inhibitors associate with cellular composition in models of IMIA. In particular, this study provides new evidence on the differential effect of DMARDs on leukocytes compared with stromal cells.
30808625 Achieving remission in psoriatic arthritis by early initiation of TNF inhibition: a double 2019 May OBJECTIVES: Early initiation of effective treatment favours remission in rheumatoid arthritis, but it remains unknown if the same concept applies to psoriatic arthritis (PsA). Therefore, this study investigated whether the combination of golimumab plus methotrexate (MTX) as a first-line treatment is superior to MTX alone in inducing remission in PsA. METHODS: This investigator-initiated, multicentre, double-blind, randomised, placebo-controlled trial included 51 MTX and bDMARD-naive patients with PsA fulfilling the CASPAR criteria and with active disease at baseline (≥3 swollen joint count/tender joint count). Patients were randomised to golimumab (50 mg SC monthly)+MTX (n=26) (TNFi arm) or matched placebo+MTX (n=25) (MTX arm). MTX was started 15 mg/week and increased to 25 mg/week over 8 weeks. The primary endpoint was percentage of patients achieving Disease Activity Score (DAS) remission (<1.6) at week 22. Safety was assessed throughout the study. RESULTS: The primary efficacy endpoint was achieved by 81% in the TNFi arm versus 42 % in the MTX arm (p=0.004). This difference in DAS remission was already observed at week 8. A significant difference in favour of the golimumab+MTX arm at week 22 was also observed for other response criteria such as MDA, ACR20/50/70, disease measures and patient-reported outcomes. The occurrence rates of adverse event and treatment-emergent adverse event were similar in both arms. CONCLUSIONS: In patients with early PsA, DAS remission at week 22 was almost doubled with golimumab+MTX versus MTX alone. This double-blind, randomised, placebo-controlled study supports the concept that early initiation of TNFi in patients with PsA favours remission. TRIAL REGISTRATION NUMBER: NCT01871649.
31055232 Estradiol replacement therapy regulates innate immune response in ovariectomized arthritic 2019 Jul Neuroendocrine changes are essential factors contributing to the progression and development of rheumatoid arthritis. However, the role of estrogen in the innate immunity during arthritis development is still controversial. Here, we evaluated the effect of estrous cycle, ovariectomy, estradiol replacement therapy and treatment with estrogen receptor (ER)α and ERβ specific agonists on joint edema formation, neutrophil recruitment, and articular levels of cytokines/chemokines in murine zymosan-induced arthritis. Our results showed that articular inflammation of proestus/estrus was similar to metaestus/diestrus animals indicating that the inflammatory response in acute arthritis is not affected by the estrous cycle. However, ovariectomy increased joint swelling, neutrophil migration, and TNF-α level. Treatment for six consecutive days with estradiol cypionate re-established the acute inflammation in ovariectomized arthritic mice to responses similar to those in SHAM-proestrus/estrus or naive mice. Moreover, treatment with propylpyrazoletriol and diarylpropionitrile, two ERα and ERβ selective agonists, respectively, inhibited both edema and neutrophil recruitment. Finally, the non-genomic properties of estradiol were analyzed with an acute treatment with β-estradiol-water soluble, which reduced the edema only. In the present study, estradiol replacement therapy improves the innate immune responses in ovariectomized arthritic mice by activating nuclear estrogen receptors. These results suggest that estradiol can induce a protective anti-inflammatory effect in arthritis during ovaries failure, as observed in the menopause.
31857588 Small molecules that inhibit TNF signalling by stabilising an asymmetric form of the trime 2019 Dec 19 Tumour necrosis factor (TNF) is a cytokine belonging to a family of trimeric proteins; it has been shown to be a key mediator in autoimmune diseases such as rheumatoid arthritis and Crohn's disease. While TNF is the target of several successful biologic drugs, attempts to design small molecule therapies directed to this cytokine have not led to approved products. Here we report the discovery of potent small molecule inhibitors of TNF that stabilise an asymmetrical form of the soluble TNF trimer, compromising signalling and inhibiting the functions of TNF in vitro and in vivo. This discovery paves the way for a class of small molecule drugs capable of modulating TNF function by stabilising a naturally sampled, receptor-incompetent conformation of TNF. Furthermore, this approach may prove to be a more general mechanism for inhibiting protein-protein interactions.
31856793 Oral health in children and adolescents with juvenile idiopathic arthritis - a systematic 2019 Dec 19 BACKGROUND: Observational studies examining the association between oral health and juvenile idiopathic arthritis (JIA) among children and adolescents have reported inconsistent findings. The aims of this systematic review and meta-analysis were to ascertain a potential difference in oral health and oral health-related quality of life (OHRQoL) among children and adolescents with JIA and healthy peers, and to assess the association of prevalence of oral diseases/conditions, temporomandibular disorders (TMD), including temporomandibular joint (TMJ) diseases, in relation to activity and severity of JIA. METHOD: Medline Ovid, Embase, CINAHL, SweMed+ and Cochrane Library were searched up to 25 November 2018. All articles published in English, German and Scandinavian languages focusing on children and adolescents with JIA and without JIA in relation to oral health measures, were considered. Two authors independently evaluated observational studies for inclusion. The study quality was assessed using modified Newcastle Ottawa Scale. Meta-analysis was performed for studies focusing on dental caries as an outcome. RESULTS: Nineteen articles met the inclusion criteria, covering a range of oral diseases/conditions and OHRQoL. Eighteen studies had cross-sectional design. No mean difference of dmft/DMFT indices (decayed/missed/filled teeth) was observed between the JIA - and healthy group. None of the oral health measures including dental erosive wear, enamel defects, dental maturation and OHRQoL, indicated better oral health among children and adolescents with JIA compared to healthy group. However, periodontal conditions and TMD were more predominant among children and adolescents with JIA compared to healthy peers. CONCLUSIONS: Based on the cross-sectional studies, periodontal diseases and TMD were found to be more frequent in children and adolescents with JIA compared to healthy peers. Furthermore, more high-quality studies with large sample size are needed before we infer any concrete conclusion regarding the association between the prevalence of oral and TMJ diseases or oral conditions in relation to activity and severity of JIA.
31584777 Characterizing Pruritus in Autoimmune Connective Tissue Diseases. 2019 Oct 1 Background: Autoimmune connective tissue diseases (ACTDs) are a broad range of diseases featured by immune dysregulation, and often have multisystem involvement with prominent skin manifestations. Pruritus is one of the most common symptoms in these diseases, with significant impact on the quality of life of patients. Objective: To characterize the frequency, location, severity, and timing relative to disease onset of pruritus in different ACTDs. Methods: A chart review of all patients seen in the Rheumatology-Dermatology clinic at Massachusetts General Hospital. Results: Itch was a troubling symptom in 83% of dermatomyositis (DM), 61% of systemic lupus erythematosus (SLE), 59% of Sjogren syndrome (SJO), 22% of systemic sclerosis (SSc), and 60% of mixed connective tissue disease. In DM and SLE, itch paralleled the course of inflammatory skin manifestations in 83% and 45%, respectively. Itch in DM is more intense and more treatment resistant in 12% vs 1% in SLE. In contrast, itch in SSc and SJO tended to occur later in the disease course, 86% vs 42%, respectively. Conclusion: Itch is common in all ACTDs and often under-evaluated and under treated. Pruritus is more common and more severe in DM than in SLE. Treatment of pruritus in ACTDs can be challenging, and sometimes multi-modal therapy is warranted. J Drugs Dermatol. 2019;18(10):995-998.
30472652 Phosphatidylinositol 3-kinase delta pathway: a novel therapeutic target for Sjögren's syn 2019 Feb BACKGROUND: The phosphatidylinositol 3-kinase delta isoform (PI3Kδ) belongs to an intracellular lipid kinase family that regulate lymphocyte metabolism, survival, proliferation, apoptosis and migration and has been successfully targeted in B-cell malignancies. Primary Sjögren's syndrome (pSS) is a chronic immune-mediated inflammatory disease characterised by exocrine gland lymphocytic infiltration and B-cell hyperactivation which results in systemic manifestations, autoantibody production and loss of glandular function. Given the central role of B cells in pSS pathogenesis, we investigated PI3Kδ pathway activation in pSS and the functional consequences of blocking PI3Kδ in a murine model of focal sialoadenitis that mimics some features of pSS. METHODS AND RESULTS: Target validation assays showed significant expression of phosphorylated ribosomal protein S6 (pS6), a downstream mediator of the phosphatidylinositol 3-kinase delta (PI3Kδ) pathway, within pSS salivary glands. pS6 distribution was found to co-localise with T/B cell markers within pSS aggregates and the CD138+ plasma cells infiltrating the glands. In vivo blockade of PI3Kδ activity with seletalisib, a PI3Kδ-selective inhibitor, in a murine model of focal sialoadenitis decreased accumulation of lymphocytes and plasma cells within the glands of treated mice in the prophylactic and therapeutic regimes. Additionally, production of lymphoid chemokines and cytokines associated with ectopic lymphoneogenesis and, remarkably, saliva flow and autoantibody production, were significantly affected by treatment with seletalisib. CONCLUSION: These data demonstrate activation of PI3Kδ pathway within the glands of patients with pSS and its contribution to disease pathogenesis in a model of disease, supporting the exploration of the therapeutic potential of PI3Kδ pathway inhibition in this condition.
31490711 Transgenic rice seeds expressing altered peptide ligands against the M3 muscarinic acetylc 2020 Sep Objective: We previously reported that Rag1(-/-) mice inoculated with splenocytes from M3 muscarinic acetylcholine receptor (M3R) knockout mice immunized with an M3R peptide mixture developed sialadenitis-like Sjögren's syndrome (M3R-induced sialadenitis [MIS]). We also found that intravenous administration of altered peptide ligand (APL) of N-terminal 1 (N1), which is one of the T-cell epitopes of M3R, suppressed MIS. In this study, we aimed to evaluate the suppressive ability and its mechanisms of rice seeds expressing N1-APL7 against MIS.Methods: Rice seeds expressing N1 and N1-APL7 were orally administered to MIS mice for 2 weeks. The changes in saliva flow and sialadenitis (salivary gland inflammation) were analyzed. The M3R-specific T-cell response in the spleen and the expression of regulatory molecules in the cervical lymph nodes and mesenteric lymph nodes were also analyzed.Results: Oral administration of N1-APL7-expressing rice seeds significantly recovered reduction in saliva flow and suppressed sialadenitis when compared with treatment with nontransgenic rice seeds and N1 rice seeds. IFNγ production from M3R-reactive T cells tended to decline in the N1-APL7 rice-treated group as compared with those in the other groups. In the N1-APL7 rice-treated group, the mRNA expression levels of Foxp3 in the cervical-lymph-node CD4(+) T cells were higher than those in the other groups.Conclusion: Oral administration of N1-APL7-expressing rice suppressed MIS via suppression of M3R-specific IFNγ and IL-17 production and via enhancement of regulatory molecule expression.Key messagesWe generated N1-peptide- or N1-APL7-expressing rice seeds. Oral administration of N1-APL7-expressing rice seeds significantly recovered the reduction of saliva flow and suppressed sialadenitis via the suppression of M3R specific IFNγ and IL-17 production and via enhancement of regulatory T (Treg) cells.
31127862 Concomitant Ro/SSA and La/SSB antibodies are biomarkers for the risk of venous thromboembo 2019 Oct BACKGROUND: To assess the risk of incident cardiovascular disease in patients with primary Sjögren's syndrome, overall and stratified by Ro/SSA and La/SSB autoantibody status. METHODS: A cohort of patients with primary Sjögren's syndrome in Sweden (n = 960) and matched controls from the general population (n = 9035) were included, and data extracted from the National Patient Register to identify events of myocardial infarction, cerebral infarction and venous thromboembolism. Hazard ratios were estimated using cox proportional hazard regressions. RESULTS: During a median follow-up of 9.5 years, the overall hazard ratio (HR) was 1.6 (95% CI 1.2-2.1) for myocardial infarction, 1.2 (95% CI 0.9-1.7) for cerebral infarction and 2.1 (95% CI 1.6-2.9) for venous thromboembolism. Patients positive for both Ro/SSA and La/SSB autoantibodies had a substantially higher risk of cerebral infarction (HR 1.7, 95% CI 1.0-2.9) and venous thromboembolism (HR 3.1, 95% CI 1.9-4.8) than the general population. These risks were not significantly increased in Ro/SSA- and La/SSB-negative patients. Among autoantibody-positive patients, the highest HR of cerebral infarction was seen after ≥10 years disease duration (HR 2.8, 95% CI 1.4-5.4), while the HR for venous thromboembolism was highest 0-5 years after disease diagnosis (HR 4.7, 95% CI 2.3-9.3) and remained high throughout disease duration. CONCLUSIONS: Primary Sjögren's syndrome is associated with a markedly increased risk of cardiovascular disease and the presence of Ro/SSA and La/SSB autoantibodies identify the subgroup of patients carrying the highest risk. These findings suggest that monitoring and prevention of cardiovascular disease in this patient group should be considered.
30270548 Expression of ETS1 and LEF1 in salivary glands of Sjögren syndrome patients. 2019 Jan OBJECTIVE: Primary Sjögren's syndrome (pSS) is a systemic autoimmune disease affecting exocrine glands, thereby causing dry mouth and eyes (sicca). Our objective was to determine the expression of pSS pathogenic biomarker MMP9 and its putative transcription factors ETS1 and LEF1, in labial salivary glands of pSS patients. METHODS: Sicca patients were assigned to three groups based on focus score (FS): non-pSS sicca (i.e., GR1 [FS = 0] and GR2 [0 < FS < 1]) and pSS (i.e., GR3 [FS ≥ 1]). We determined the mRNA and protein expression of MMP9, ETS1, and LEF1 in salivary gland biopsies. Also, ETS1-CD4 and LEF1-CD4 co-expression analyses were performed. RESULTS: The mRNA expression of MMP9, ETS1, and LEF1 was upregulated in GR3 compared to GR1 (p < 0.01). Most GR3 salivary gland areas had moderate to high MMP9, ETS1, and LEF1 protein expression compared to GR1 and GR2. Further, ETS1-CD4 and LEF1-CD4 dual staining demonstrated that both salivary gland epithelial cells and lymphocytic infiltrates had increased levels of ETS1 and LEF1. Moreover, there was a strong correlation between ETS1(+)-CD4(-) and LEF1(+)-CD4(-) cells. CONCLUSION: These results suggest, for the first time, a concerted increase in ETS1 and LEF1 expression in salivary gland epithelial cells of pSS patients that is reflective of the etiopathogenesis of pSS.
25253552 Protective Effect of Zengye Decoction () on Submandibular Glands in Nonobese Diabetic Mice 2019 Jan OBJECTIVE: To investigate the protective effect of Zengye Decoction (, ZYD) on the submandibular glands (SMGs) in nonobese diabetic (NOD) mice. METHODS: Twenty-seven female NOD mice were randomly equally divided into 3 groups: the model group, the hydroxychloroquine (HCQ) group, and the ZYD group. Nine C57/B6 mice served as the normal group. After 1-week acclimation, the HCQ and ZYD groups were intragastrically administered with HCQ and ZYD, respectively, and the normal and model groups were administered with normal saline. Changes in the salivary flow rate were observed. Mice from all 4 groups were sacrificed at the age of 20 weeks. The serum and SMGs were collected. Serum cytokines gamma-interferon (IFN-γ), interleukin-10 (IL-10) were detected by enzyme-linked immunosorbent assay. Histological changes in the submandibular glands were examined by hematoxylin and eosin staining. The mRNA expression of IFN-γ, IL-10 and vasoactive intestinal peptide (VIP) in the submandibular glands were measured by real-time polymerase chain reaction. RESULTS: Compared with the model group, the salivary flow of the ZYD group significantly increased (P<0.05), the extent of the histological changes was ameliorated (P<0.05), and the Th1/Th2 cytokine imbalance was remedied (P<0.05). In the ZYD-treated mice, the VIP mRNA was up-regulated (P<0.05). CONCLUSIONS: ZYD is beneficial in protecting structure and function of SMGs in NOD mice. The mechanism may be associated with the correction of the Th1/Th2 cytokine imbalance, and with the prevention of a progressive decline of the VIP level.
31054295 Comorbidities in Patients With End-Stage Knee OA: Prevalence and Effect on Physical Functi 2019 Nov OBJECTIVE: To investigate the prevalence of comorbidities and their effect on physical function, quality of life (QOL), and pain, in patients with end-stage knee osteoarthritis (OA). DESIGN: A cross-sectional study. SETTING: A rehabilitation facility at university hospital. PARTICIPANTS: Patients (N=577; 503 women and 74 men) diagnosed with end-stage knee OA between October 2013 and June 2018. INTERVENTION: Not applicable. MAIN OUTCOME MEASURES: Comorbidities were as follows: osteoporosis, presarcopenia, degenerative spine disease, diabetes, and hypertension. All patients completed the following performance-based physical function tests: stair-climbing test (SCT), 6-minute walk test (6MWT), timed Up and Go (TUG) test, and gait analysis. Self-reported physical function and pain were measured using Western Ontario McMaster Universities Osteoarthritis Index (WOMAC) and a visual analog scale (VAS), respectively, and self-reported QOL was measured using EuroQoL 5 dimensions (EQ-5D) questionnaire. RESULTS: Univariate analyses revealed that patients with osteoporosis had significantly higher scores in SCT ascent, SCT descent, TUG, WOMAC pain tests, and lower scores in 6MWT, gait speed, and cadence tests than those without osteoporosis. Patients with presarcopenia recorded higher scores in SCT ascent, TUG, EQ-5D, and lower scores in 6MWT and gait speed tests than those without presarcopenia. Patients with degenerative spine disease showed higher scores in WOMAC pain and lower scores in gait speeds than those without degenerative spine disease. Patients with diabetes showed higher scores in SCT ascent than those without diabetes, and patients with hypertension showed lower scores in 6MWT than those without hypertension. After adjusting age, sex, and body mass index, SCT descent retained significant association with osteoporosis, SCT ascent showed independent association with presarcopenia and diabetes, and WOMAC pain revealed significant association with degenerative spine disease. CONCLUSION: The results confirm associations between comorbidities, performance-based and self-reported physical functions, and QOL in patients with end-stage knee OA.