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ID PMID Title PublicationDate abstract
34757259 Post COVID-19 hospitalizations in patients with chronic inflammatory diseases - A nationwi 2021 Dec OBJECTIVE: To study long term consequences of hospitalization for COVID-19 in patients with chronic inflammatory diseases. We studied the risk of subsequent hospitalizations in patients with chronic inflammatory diseases, who survived a hospitalization for COVID-19, compared to other patients who had been hospitalized for COVID-19. DESIGN AND SETTING: Population based cohort study based on Danish nationwide health registers. The study population included all adult patients in Denmark who had been discharged alive after a hospitalization with COVID-19 from March 1, 2020 to July 31, 2021. POPULATION: From the study population, the exposed cohort constituted patients who had inflammatory bowel diseases (IBD), rheumatoid arthritis (RA), spondyloarthropathy (SpA), or psoriatic arthritis (PsA) prior to hospitalization for COVID-19, and the unexposed cohort constituted those without these diseases. MAIN OUTCOME MEASURES: We estimated the adjusted Hazard Rate (aHR) for the following outcomes: overall risk of hospitalization, cardiovascular diseases, respiratory diseases, blood and blood-forming organs, nervous system diseases, infections, sequelae of COVID-19, and death. RESULTS: A total of 417 patients with IBD/RA/SpA/PsA were discharged alive after COVID-19, and 9,248 patients without these diseases. Across the different outcomes examined, the median length of follow up was 6.50 months in the exposed cohort (25-75% percentiles: 4.38-8.12), and among the unexposed the median time of follow up was 6.59 months (25-75% percentiles: 4.17-8.49). Across different analyses, we consistently found a significantly increased risk of hospitalizations due to respiratory diseases (aHR 1.27 (95% CI 1.02-1.58)) and infections (aHR 1.55 (95% CI 1.26-1.92)). In sensitivity analyses, the overall risk of hospitalization was aHR 1.15 (95% CI 0.96-1.38) and the risk of hospitalization due to cardiovascular diagnoses was aHR 1.14 (95% CI 0.91-1.42). During the time of follow up, the risk of nervous system diagnoses or death was not increased in patients with IBD/RA/SpA/PsA. CONCLUSIONS: After hospitalization with COVID-19, patients with IBD/RA/SpA/PsA had an increased risk of subsequent hospitalizations for a number of categories of diseases, compared to other patients who have been hospitalized with COVID-19. These results are disturbing and need to be examined further. The implication of our results is that clinicians should be particularly alert for post COVID-19 symptoms from several organ systems in patients with IBD/RA/SpA/PsA.
34572149 Interleukin-26 Has Synergistic Catabolic Effects with Palmitate in Human Articular Chondro 2021 Sep 21 The inflammatory cytokine interleukin-26 (IL-26) is highly expressed in the serum and synovial fluid of patients with inflammatory arthritis. The effect of IL-26 on human articular chondrocytes (HACs) remains unclear. Obesity is associated with disability of patients with rheumatoid arthritis and disease activity in those with ankylosing spondylitis. The saturated free fatty acid palmitate with IL-1β can synergistically induce catabolic effects in HACs. The aim of this study was to evaluate the effects of IL-26 and palmitate in HACs. In this study, palmitate markedly synergizes the IL-26-induced proinflammatory effects and matrix protease, including COX-2, IL-6, and MMP-1, in HACs via the toll-like receptor 4 (TLR4)-ERK1/2-c-Jun signal transduction pathway. The synergistic catabolic effects of palmitate and IL-26 were attenuated by inhibitors of TLR4 (TAK242), ERK1/2 (U0126), or c-Jun (SP600125) in HACs and cartilage matrix. In addition, metformin, a potential inhibitor of TLR4, also decreased expression of COX-2 and IL-6 induced by co-incubation with IL-26 and palmitate. IL-26 and palmitate synergistically induced expression of inflammatory and catabolic mediators, resulting in articular cartilage matrix breakdown. The present study also revealed a possible mechanism and therapeutic targets against articular cartilage degradation by increased saturated fatty acids in patients with inflammatory arthritis.
34535727 Tender and swollen joint counts are poorly associated with disability in chikungunya arthr 2021 Sep 17 Chronic rheumatological manifestations similar to those of rheumatoid arthritis (RA) are described after chikungunya virus infection. We aimed to compare the relevance of joint counts and symptoms to clinical outcomes in RA and chronic chikungunya disease. Forty patients with chronic chikungunya arthralgia and 40 patients with RA were enrolled in a cross-sectional study. The association of tenderness and swelling, clinically assessed in 28 joints, and patient evaluations of pain and musculoskeletal stiffness with modified Health Assessment Questionnaire (HAQ) and quality of life (QoL) assessments were investigated. Tender and swollen joint counts, pain and stiffness scores were all associated with the HAQ disability index in RA (all r > 0.55, p ≤ 0.0002), but only stiffness was significantly associated with disability in chikungunya (r = 0.38, p = 0.02). Joint counts, pain and stiffness were also associated with most QoL domains in RA patients. In contrast, in chikungunya disease, tender joint counts were associated only with one QoL domain and swollen joints for none, while pain and stiffness were associated with several domains. Our results confirm the relevance of joint counts in RA, but suggest that in chronic chikungunya disease, joint counts have more limited value. Stiffness and pain score may be more important to quantify chikungunya arthritis impact.
33934341 Dual effect of IL-7/IL-7R signalling on the osteoimmunological system: a potential therape 2021 Sep The IL-7/IL-7R pathway plays a vital role in the immune system, especially in the inflammatory response. Monocytes/macrophages (osteoclast precursors) have been recently recognized as important participants in the osteoclastogenesis of rheumatoid arthritis (RA) patients. Here, we aimed to investigate the therapeutic potential of IL-7/IL-7R pathway in RA and to determine whether it could restrain osteoclastogenic functions and therefore ameliorate RA. Firstly, collagen-induced arthritis (CIA) mice were administered with IL-7Rα-target antibodies to assess their therapeutic effect on arthritis. We found that blockade of the IL-7/IL-7R pathway protected CIA mice from bone destruction in addition to inducing inflammatory remission, by altering the RANKL/RANK/OPG ratio and consequently decreasing osteoclast formation. To explore the effect and mechanism of this pathway, bone marrow cells were induced to osteoclasts and treated with IL-7, a STAT5 inhibitor or supernatants from T cells. The results showed that the IL-7/IL-7R pathway played a direct inhibitory role in osteoclast differentiation via STAT5 signalling pathway in a RANKL-induced manner. We applied flow cytometry to analyse the effect of IL-7 on T-cell RANKL expression and found that IL-7/IL-7R pathway had an indirect role in the osteoclast differentiation process by enhancing the RANKL expression on T cells. In conclusion, the IL-7/IL-7R pathway exhibited a dual effect on osteoclastogenesis of CIA mice by interacting with osteoimmunology processes and could be a novel therapeutic target for autoimmune diseases such as RA.
33714238 The inhibition of Src kinase suppresses the production of matrix metalloproteinases in fro 2021 Aug 30 BACKGROUND/AIM: The purpose of this study was to investigate the antiarthritic potentials of the inhibition of Src kinase in vivo and in vitro settings. MATERIALS AND METHODS: Arthritis was induced by intradermal injection of chicken type II collagen combined with incomplete Freund’s adjuvant (collagen induced arthritis [CIA] model) in Wistar albino rats. One day after the onset of arthritis, dasatinib, a potent Src kinase inhibitor, (5 mg/kg/day) was given via oral gavage. Tissue Src, Fyn, MAPK and STAT mRNA expressions were determined by real-time polymerase chain reaction. On the other hand, fibroblast like synoviocytes (FLSs) were harvested patients with rheumatoid arthritis (RA) undergoing surgical knee joint replacement. FLSs were stimulated with cytokines and dasatinib was added in different concentrations. MMP –1, –3, and –13 levels in FLSs culture were determined by ELISA. RESULTS: The tissue mRNA expressions of Src, Fyn, MAPK and STATs were increased in the arthritis CIA group compared to the control group. Their mRNA expressions in the CIA + dasatinib group were decreased and similar in the control group. In in vitro setting, MMP –1, –3, and –13 expressions from FLSs induced by IL-1β and TNF-α were increased, while dasatinib suppressed their productions from FLSs. CONCLUSION: The present study shows that the inhibition of Src kinase has antiarthritic potentials in both in vivo and in vitro settings. Src kinase inhibition may be candidate to further research in human RA.
33709166 [Patient safety in the treatment of rheumatic diseases : Laboratory monitoring in methotre 2021 Jun BACKGROUND: Methotrexate (MTX) is the most commonly prescribed disease-modifying drug in the treatment of rheumatic diseases. Regular laboratory testing is recommended to recognize side effects, such as hepatotoxicity and myelotoxicity as well as decreases in renal function that may cause toxic MTX accumulation. Additionally, folic acid is recommended as prophylaxis against specific side effects. In this study we investigated whether laboratory monitoring and prescription of folic acid took place according to published recommendations. MATERIAL AND METHODS: Claims data from the statutory health insurance from 1 January 2009 to 31 December 2013 were retrospectively analyzed. A total of 40,087 adults with a rheumatic diagnosis (ICD10 codes M05-M18), no malignant disease and no previous MTX prescription within 12 months were extracted from the InGef (Institute for Applied Health Research in Berlin, formerly Health Risk Institute) research database. The frequency of recommended laboratory testing, appointments with rheumatologists and the prescription of folic acid prophylaxis were investigated. RESULTS: Of the patients 12,451 began treatment with MTX in the observation period. Between 42% and 46% of recommended blood counts, liver values and kidney function tests and 14% of urinalyses were performed according to recommendations. Of the patients 84% were seen regularly by a rheumatologist and 74% received a prescription for prophylactic folic acid. Serious conditions potentially resulting from MTX treatment were observed in 0.7-3.5 cases/1000 person years. DISCUSSION: Laboratory monitoring in the context of MTX treatment is carried out less frequently than recommended in the literature. Potential MTX-associated serious complications are rare from a practice perspective. On the one hand solutions are needed for a better coordination of laboratory monitoring. On the other hand more empirical evidence is needed regarding the benefits of laboratory monitoring and the appropriate intervals thereof.
33386898 Similar lipid level changes in early rheumatoid arthritis patients following 1-year treat- 2021 Mar To compare changes in low-density lipoprotein cholesterol and other lipids in patients with rheumatoid arthritis (RA) randomised to a 1-year treat-to-target strategy with either adalimumab plus methotrexate or placebo plus methotrexate. Prespecified secondary analyses from the OPERA trial, where 180 early and treatment-naïve RA patients received methotrexate 20 mg once weekly in combination with either placebo or subcutaneous adalimumab 40 mg every other week. Serum lipid levels were measured at baseline and after 1 year. Changes in lipid levels were analysed using mixed linear models based on the intention-to-treat (ITT) population. Overall, 174 patients were included in the ITT population (adalimumab plus methotrexate n = 86; placebo plus methotrexate n = 88). Differences between changes in lipid levels were low-density lipoprotein cholesterol 0.18 mmol/l [95% CI - 0.05 to 0.42], total cholesterol 0.27 mmol/l [- 0.002 to 0.54], high-density lipoprotein cholesterol 0.05 mmol/l [- 0.06 to 0.15], triglycerides 0.11 mmol/l [- 0.08 to 0.29], very-low-density lipoprotein cholesterol 0.03 mmol/l [- 0.05 to 0.12], and non-high-density lipoprotein cholesterol 0.22 mmol/l [- 0.02 to 0.46]. In early RA patients treated to tight control of inflammation over a period of 1 year with either adalimumab plus methotrexate or placebo plus methotrexate, changes in lipid levels were similar. Trial registration number: NCT00660647.
33828163 Life-extended glycosylated IL-2 promotes Treg induction and suppression of autoimmunity. 2021 Apr 7 IL-2 is the master-regulator cytokine for T cell dependent responses and is crucial for proliferation and survival of T cells. However, IL-2-based treatments remained marginal, in part due to short half-life. Thus, we aimed to extend IL-2 half-life by flanking the IL-2 core with sequences derived from the extensively glycosylated hinge region of the NCR2 receptor. We termed this modified IL-2: "S2A". Importantly, S2A blood half-life was extended 14-fold compared to the clinical grade IL-2, Proleukin. Low doses inoculation of S2A significantly enhanced induction of Tregs (CD4(+) Regulatory T cells) in vivo, as compared to Proleukin, while both S2A and Proleukin induced low levels of CD8(+) T cells. In a B16 metastatic melanoma model, S2A treatment was unable to reduce the metastatic capacity of B16 melanoma, while enhancing induction and recruitment of Tregs, compared to Proleukin. Conversely, in two autoimmune models, rheumatoid arthritis and DSS-induced colitis, S2A treatment significantly reduced the progression of disease compared to Proleukin. Our results suggest new avenues for generating long-acting IL-2 for long-standing treatment and a new technique for manipulating short-life proteins for clinical and research uses.
33539810 Uncommon antinuclear antibody patterns as diagnostic indicators. 2021 Apr INTRODUCTION: The clinical significance of common antinuclear antibody (ANA) patterns, such as nuclear homogenous and nuclear speckled patterns with their corresponding specific antibodies, has already been established. However, the clinical relevance of these uncommon ANA patterns have not been well elucidated and these patterns are therefore not reported by most clinical laboratories. We herein report some retrospective data analysis linking patients' clinical status to several uncommon ANA patterns. METHODS: We retrieved and assessed the patient records for ANA reports generated in our hospital over a period of two years. All testing had been performed using the gold standard Indirect Immunofluorescence Assay. RESULTS: Records of 1235 consecutive patients tested for ANA were reviewed. ANA was positive in 330 of these patients with 6.39% found to have uncommon nuclear, cytoplasmic or mitotic sub-patterns. The mitotic spindle (0.89%), cytoplasmic anti-mitochondrial antibodies (0.80%), followed by discrete nuclear dots-multiple (0.72%) were the dominating patterns, with a higher prevalence in females than in males. Systemic lupus erythematosus and rheumatoid arthritis were the two most common autoimmune disorders associated with mitotic spindle fibers and nuclear centromere and nuclear large/coarse speckled ANA patterns. CONCLUSION: The prevalence of these relatively uncommon ANA patterns was higher than expected. Further evaluation of these patterns along with their corresponding antibodies and their clinical utility must be encouraged. We trust this endeavour will provide diagnostic information in autoimmune and other disease conditions.
31221942 A Novel Mucidosphaerium sp. Downregulates Inflammatory Gene Expression in Skin and Articul 2021 Jan CONTEXT: Hot-spring therapy is occasionally used for the treatment of inflammatory diseases. Microorganisms might contribute to the anti-inflammatory functions seen in thermal mud therapies. Natural microorganisms, derived from traditional spa resorts, could be useful as a preventive strategy for alternative medical applications. OBJECTIVE: The aim of the study was to find effective microalgae from prominent hot springs to use for the treatment of inflammatory diseases. DESIGN: The research team performed an in-vitro study. Microalgae, derived from Beppu hot springs, were isolated and homogeneously cultured. SETTING: The study took place at the Saravio Central Institute at Saravio Cosmetics in Oita, Japan and the Department of Bioscience and Biotechnology in the Graduate School of Agriculture at Shinshu University in Nagano, Japan. INTERVENTION: For identification, the 18S ribosomal RNA genes of microalgae were investigated by DNA sequencing and homology search, together with microscopic observation. OUTCOME MEASURES: To examine the pharmacological activities of the algal extracts, real-time polymerase chain reactions were performed, using either primary dermal fibroblasts (DFs), dermal papilla cells (DPCs), or fibroblast-like synoviocytes (FLSs). To test the antioxidant activity, both the oxygen radical absorbance capacity and the generation of intracellular reactive oxygen species (ROS) were evaluated. RESULTS: A novel strain of green algae, Mucidosphaerium sp., was isolated from a Beppu hot spring. The algal extract downregulated gene-expression levels of pro-inflammatory cytokines, such as interleukin-1β (IL-1β), IL-6, and tumor necrosis factor- alpha (TNF-α), in various primary cells pre-exposed to IL-1β. The protein level of the risk factors was concomitantly reduced. In addition, the algal extract suppressed the IL-1β-induced upregulation of cyclooxygenase-2, nerve growth factor, and matrix metalloproteinase-1 (MMP-1) and MMP-3 in DFs. It also inhibited that of MMP-1, -3, and -9 in FLSs. Moreover, the extract inhibited total MMP protease activities. The microalgae decreased the intracellular reactive oxygen species (ROS) level in FLSs with an antioxidant activity of 178.3 ± 0.9 μmol of trolox equivalent/g. CONCLUSIONS: The present study showed that the novel Mucidosphaerium sp., derived from a Beppu hot spring, suppressed inflammatory reactions in both cutaneous and articular cells, partly due to its antioxidative properties. The novel algal strain may be a useful tool as an alternative medicine for skin and joint inflammatory disorders.
34244295 Abatacept Promotes Regulatory B Cell Functions, Enhancing Their Ability to Reduce the Th1 2021 Jul 15 Abatacept mimics natural CD152 and competes with CD28 for binding to CD80/CD86 on APC, such as B cells, thereby preventing T cell activation. However, its potential impact on B cells has not been identified. The aim of this study was to assess whether abatacept can potentiate the immunoregulatory properties of B cells in vitro and in patients with rheumatoid arthritis (RA). T and B cells from healthy controls were purified. The suppressor properties of B cells in the presence of abatacept or control IgG1 were evaluated based on the ability of these cells to inhibit the polyclonal expansion (anti-CD3/CD28 stimulation) of T cells or their differentiation into Th1 or Th17 cells. Similar analyses were also performed with cells from RA patients before and 3 mo after abatacept initiation. Abatacept significantly potentiated regulatory B cell regulatory functions by enhancing their ability to produce IL-10 and TGF-β, resulting in the increased generation of regulatory T cells and limited T cell proliferation and differentiation into Th1 and Th17 cells. Interestingly, B cells isolated from patients that received a 3-mo treatment with abatacept had an increased ability to reduce T cell functions, confirming the above observations. Abatacept binding to CD80/CD86 induces and promotes regulatory B cell functions by enhancing the ability of these cells to produce IL-10 and TGF-β in vitro and in RA patients.
33605069 A Proinflammatory Cytokine Network Profile in Th1/Type 1 Effector B Cells Delineates a Com 2021 Aug OBJECTIVE: The effector T cell and B cell cytokine networks have been implicated in the pathogenesis of systemic autoimmune diseases, but the association of these cytokine networks with the heterogeneity of clinical manifestations and immune profiles has not been carefully examined. This study was undertaken to examine whether cytokine profiles can delineate distinct groups of patients in 4 systemic autoimmune diseases (systemic lupus erythematosus, Sjögren's syndrome, rheumatoid arthritis, and systemic sclerosis). METHODS: A total of 179 patients and 48 healthy volunteers were enrolled in the multicenter cross-sectional PRECISE Systemic Autoimmune Diseases (PRECISESADS) study. Multi-low-dimensional omics data (cytokines, autoantibodies, circulating immune cells) were examined. Coculture experiments were performed to test the impact of the cytokine microenvironment on T cell/B cell cross-talk. RESULTS: A proinflammatory cytokine profile defined by high levels of CXCL10, interleukin-6 (IL-6), IL-2, and tumor necrosis factor characterized a distinct group of patients in the 4 systemic autoimmune diseases. In each disease, this proinflammatory cluster was associated with a specific circulating immune cell signature, more severe disease, and higher levels of autoantibodies, suggesting an uncontrolled proinflammatory Th1 immune response. We observed in vitro that B cells reinforce Th1 differentiation and naive T cell proliferation, leading to the induction of type 1 effector B cells and IgG production. This process was associated with an increase in CXCL10, IL-6, IL-2, and interferon-γ production. CONCLUSION: This composite analysis brings new insights into human B cell functional heterogeneity based on T cell/B cell cross-talk, and proposes a better stratification of patients with systemic autoimmune diseases, suggesting that combined biomarkers would be of great value for the design of personalized treatments.
33572654 Neuraminidase Inhibitor Zanamivir Ameliorates Collagen-Induced Arthritis. 2021 Jan 31 Altered sialylation patterns play a role in chronic autoimmune diseases such as rheumatoid arthritis (RA). Recent studies have shown the pro-inflammatory activities of immunoglobulins (Igs) with desialylated sugar moieties. The role of neuraminidases (NEUs), enzymes which are responsible for the cleavage of terminal sialic acids (SA) from sialoglycoconjugates, is not fully understood in RA. We investigated the impact of zanamivir, an inhibitor of the influenza virus neuraminidase, and mammalian NEU2/3 on clinical outcomes in experimental arthritides studies. The severity of arthritis was monitored and IgG titers were measured by ELISA. (2,6)-linked SA was determined on IgG by ELISA and on cell surfaces by flow cytometry. Zanamivir at a dose of 100 mg/kg (zana-100) significantly ameliorated collagen-induced arthritis (CIA), whereas zana-100 was ineffective in serum transfer-induced arthritis. Systemic zana-100 treatment reduced the number of splenic CD138(+)/TACI(+) plasma cells and CD19(+) B cells, which was associated with lower IgG levels and an increased sialylation status of IgG compared to controls. Our data reveal the contribution of NEU2/3 in CIA. Zanamivir down-modulated the T and B cell-dependent humoral immune response and induced an anti-inflammatory milieu by inhibiting sialic acid degradation. We suggest that neuraminidases might represent a promising therapeutic target for RA and possibly also for other antibody-mediated autoimmune diseases.
34819385 Health-related quality of life and disability in adults with juvenile idiopathic arthritis 2021 Nov OBJECTIVE: To compare physical disability, mental health, fatigue and health-related quality of life (HRQoL) across juvenile idiopathic arthritis (JIA) categories in adulthood and between JIA and adult-onset rheumatic diseases. METHODS: Cross-sectional analysis nested in a cohort of adult patients with JIA registered in the Rheumatic Diseases Portuguese Register (Reuma.pt). Physical disability (Health Assessment Questionnaire-Disability Index), mental health symptoms (Hospital Anxiety and Depression Scale), fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue Scale (FACIT-F)) and HRQoL (EuroQol-5D (EQ5D) and Short Form (SF-36)) were compared across JIA categories. Patients with polyarticular JIA and enthesis-related arthritis (ERA) JIA were compared respectively to patients with rheumatoid arthritis (RA) and spondyloarthritis (SpA), matched for gender and age, adjusted for disease duration and activity. RESULTS: 585 adult patients with JIA were included. Comparison across JIA categories showed that persistent oligoarthritis and patients with ERA reported a higher score in EQ5D and SF-36 physical component when compared with other JIA categories.Polyarticular JIA reported less disability and fatigue than patients with RA (median Health Assessment Questionnaire of 0.25 vs 0.63; p<0.001 and median FACIT-F score 42 vs 40 ; p=0.041). Polyarticular JIA had also better scores on EQ5D and all domains of SF-36, than patients with RA. Patients with ERA reported less depression and anxiety symptoms (0% vs 14.8%; p=0.003% and 9% vs 21.3%; p=0.002) and less fatigue symptoms (45 vs 41; p=0.01) than patients with SpA. CONCLUSION: Persistent oligoarticular JIA and ERA are the JIA categories in adulthood with better HRQoL. Overall, adult polyarticular and patients with ERA JIA have lower functional impairment and better quality-of-life than patients with RA and SpA.
33230538 Deep phenotyping of synovial molecular signatures by integrative systems analysis in rheum 2021 Jul 1 OBJECTIVE: RA encompasses a complex, heterogeneous and dynamic group of diseases arising from molecular and cellular perturbations of synovial tissues. The aim of this study was to decipher this complexity using an integrative systems approach and provide novel insights for designing stratified treatments. METHODS: An RNA sequencing dataset of synovial tissues from 152 RA patients and 28 normal controls was imported and subjected to filtration of differentially expressed genes, functional enrichment and network analysis, non-negative matrix factorization, and key driver analysis. A naïve Bayes classifier was applied to the independent datasets to investigate the factors associated with treatment outcome. RESULTS: A matrix of 1241 upregulated differentially expressed genes from RA samples was classified into three subtypes (C1-C3) with distinct molecular and cellular signatures. C3 with prominent immune cells and proinflammatory signatures had a stronger association with the presence of ACPA and showed a better therapeutic response than C1 and C2, which were enriched with neutrophil and fibroblast signatures, respectively. C2 was more occupied by synovial fibroblasts of destructive phenotype and carried highly expressed key effector molecules of invasion and osteoclastogenesis. CXCR2, JAK3, FYN and LYN were identified as key driver genes in C1 and C3. HDAC, JUN, NFKB1, TNF and TP53 were key regulators modulating fibroblast aggressiveness in C2. CONCLUSIONS: Deep phenotyping of synovial heterogeneity captured comprehensive and discrete pathophysiological attributes of RA regarding clinical features and treatment response. This result could serve as a template for future studies to design stratified approaches for RA patients.
32930047 Clinical features and prognosis of nocardiosis in patients with connective tissue diseases 2021 May OBJECTIVES: To investigate the clinical features and prognosis of nocardiosis complicated by connective tissue diseases (CTDs). METHODS: We examined patients with CTDs who were diagnosed with nocardiosis from October 2004 to 2019. We retrospectively investigated patient characteristics and therapeutic outcomes. We then performed a comparison between survivors and non-survivors. RESULTS: Fourteen patients were examined. Underlying CTDs were systemic lupus erythematosus (28.6%), vasculitis syndrome (28.6%), rheumatoid arthritis (21.4%), adult Still disease (14.3%) and dermatomyositis (7.1%). Infected organs were lung (85.7%), brain (42.9%), skin/cutaneous lesions (28.6%) and muscle (7.1%). Disseminated infections were seen in nine patients (64.3%). At the onset of nocardiosis, all patients were given prednisolone (23.2 ± 11.9 mg/day). Only two patients (14.3%) were given TMP-SMX for prophylaxis of pneumocystis pneumonia. Relapse occurred in one patient (7.1%) and four patients (28.6%) died from nocardiosis for a cumulative survival rate at 52 weeks of 76.9%. In a comparison of survivors (71.4%) and non-survivors (28.6%), cutaneous lesions were significantly more frequent in the latter (10 vs 75%, p = .04) with an odds ratio of 27.0 (95% CI: 1.7-453.4). CONCLUSION: Cutaneous lesions as a result of dissemination might be a risk factor for nocardiosis mortality in patients with CTDs.
34530431 Influence of Janus Kinase Inhibitors on the Neuronal Activity as a Proof-of-Concept Model 2022 BACKGROUND: Itching is considered to be a subjective symptom of the activation of neurosensory structures by different signal molecules and trigger factors. The signaling cascades responsible for it are closely linked to inflammatory processes. This explains why itching also occurs in many inflammatory diseases. One of these signaling cascades is mediated by Janus kinases (JAKs). Recently, it could be shown on a molecular level that Janus kinase 1 (JAK1) directly activates frontal cortex neurons and thus can cause chronic itching. OBJECTIVES: This study deals with the influence of different JAK inhibitors (JAKi) on the activity of chip-based neural networks of cultured frontal cortex neurons by investigating neurophysiological activity parameters. This in vitro model provides information on dose-dependent effects of model substances with different specificity regarding the inhibition of different JAKs. METHODS: Tofacitinib (pan-JAKi), baricitinib (JAK1/2i), and upadacitinib (JAK1i) in a concentration range from 10 nmol/L to 50 μmol/L were tested in a microelectrode array neurochip culture system. RESULTS: The results show that the inhibition of the neuronal activity of frontal cortex neurons increases with JAK1 selectivity and is dependent on concentration. CONCLUSION: These observations are supported by data from clinical studies in atopic dermatitis and psoriasis. The clinical relevance of these results must be proven by further clinical studies with subjective and objective parameters for itching.
34251326 Role of adiponectin in non-diabetic patients with rheumatoid arthritis undergoing anti-IL- 2022 May OBJECTIVES: Adiponectin is an adipokine that plays a relevant role in the development of metabolic syndrome (MetS), a complication that increases the risk of cardiovascular (CV) disease in patients with rheumatoid arthritis (RA). Accordingly, we assessed for the first time the short-term effect of anti-IL-6 receptor tocilizumab (TCZ) administration on adiponectin serum levels in RA patients and explored the potential association of adiponectin levels with MetS features, other CV risk factors and demographic and clinical characteristics of these patients. METHODS: Adiponectin serum levels were evaluated in 50 non-diabetic RA patients, undergoing TCZ treatment, immediately prior to (pre-infusion) and 60 minutes after the end of a TCZ intravenous infusion (post-infusion). RESULTS: No significant differences in adiponectin levels pre- and post-TCZ infusion were found in RA patients (p=0.69). Patients with obesity exhibited decreased basal levels of adiponectin with respect to those non-obese (p=0.03). Additionally, a negative association of adiponectin basal levels with body mass index, insulin, insulin/glucose index, C-peptide and leptin levels (p<0.01; p=0.02; p=0.03; p=0.03 and p=0.01, respectively), as well as a positive correlation with HDL-cholesterol levels (p<0.001) was seen. CONCLUSIONS: Our results support the claim that low adiponectin may contribute to the development of MetS and, consequently, CV disease in RA. Anti-IL-6 therapy does not seem to exert a short-term effect on adiponectin levels.
32926312 A network analysis framework of genetic and nongenetic risks for type 2 diabetes. 2021 Jun Both genetic and nongenetic factors have been found to be associated with type 2 diabetes, however, the correlation between them is still unclear. In the present study, we aimed to fully decipher the nongenetic and genetic factor association network for type 2 diabetes. We identified risk factors for type 2 diabetes by systematically searching for related meta-analyses and genome-wide association studies (GWAS) database. Among a total of 27,822 studies screened, 202 articles were eligible, from which 174 nongenetic factors and 210 genetic factors associated with type 2 diabetes were identified. Then, we obtained 584 associations between the nongenetic and genetic factors of type 2 diabetes, based on which a risk factor association network was conducted. The nongenetic factors could be classified into seven categories according to the Global Burden of Diseases (GBD). Of these seven categories of nongenetic factors, five were found to be correlated with genes associated with type 2 diabetes, including environmental risks, behavioral risks, metabolic risks, related disease of type 2 diabetes, and treatments. Specifically, air pollutants of environmental risks, alcohol using of behavioral risks, obesity of metabolic risks, rheumatoid arthritis of related disease risk, and simvastatin of treatment was correlated with the largest number of genes. In summary, the correlation between genetic factors and nongenetic factors identified in this study indicates that there is a common phenotype-genotype association in type 2 diabetes, with the combinations of genotypes ("genetic signature") clustering in phenotypes related to type 2 diabetes. Thus, we should take a systematic approach to explore the relationship of various factors for type 2 diabetes, as well as other noncommunicable diseases.
34920714 Nitro-fatty acids decrease type I interferons and monocyte chemoattractant protein 1 in ex 2021 Dec 17 BACKGROUND: Inflammatory arthritis including rheumatoid arthritis (RA) and spondyloarthritis (SpA) is characterized by inflammation and destruction of the joints. Approximately one third of patients do not respond to first-line treatments. Nitro-fatty acids are bioactive lipids with anti-inflammatory properties and tissue-protective functions. The nitro-fatty acid 10-NO(2)-oleic acid (10-NO(2)-OA) is being tested in clinical trials for patients with fibrotic and inflammatory conditions. Here, we tested whether 10-NO(2)-OA could inhibit immune reactions involved in the inflammatory and joint destructive processes in inflammatory arthritis. METHODS: Synovial fluid and blood samples were obtained from 14 patients with active RA or SpA. The in vitro models consisted of synovial fluid mononuclear cells (SFMCs) cultured for 48 h, SFMCs cultured for 21 days, and fibroblast-like synovial cells (FLSs) co-cultured with peripheral blood mononuclear cells (PBMCs) for 48 h. Cells were treated with or without 10-NO(2)-OA or the tumor necrosis factor alpha (TNFα) inhibitor etanercept. Supernatants were analyzed for type I interferon, monocyte chemoattractant protein-1 (MCP-1), matrix metalloproteinase 3 (MMP3) and tartrate resistant acid phosphatase (TRAP). RESULTS: In SFMCs cultured for 48 h, 10-NO(2)-OA dose-dependently decreased the secretion of bioactive type I interferons and MCP-1 but not MMP3 (P = 0.032, P = 0.0001, and P = 0.58, respectively). Both MCP-1 and MMP3 were decreased by etanercept (P = 0.0031 and P = 0.026, respectively). In SFMCs cultured for 21 days, 10-NO(2)-OA significantly decreased the production of MCP-1 but not TRAP (P = 0.027 and P = 0.1523, respectively). Etanercept decreased the production of TRAP but not MCP-1 (P < 0.001 and P = 0.84, respectively). In co-cultures of FLSs and PBMCs, 10-NO(2)-OA decreased the production of MCP-1 (P < 0.0001). This decrease in MCP-1 production was not seen with etanercept treatment (P = 0.47). CONCLUSION: 10-NO(2)-OA decreased the release of MCP-1 in three models of inflammatory arthritis. Of particular interest, 10-NO(2)-OA inhibited type I interferon, and 10-NO(2)-OA was more effective in reducing MCP-1 production in cultures dominated by FLSs compared with etanercept. Our results encourage clinical investigations of 10-NO(2)-OA in patients with inflammatory arthritis.