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ID PMID Title PublicationDate abstract
29421221 Folate-Conjugated Superoxide Dismutase Adsorbed Over Antioxidant Mimicking Nanomatrix Fram 2018 Jun Rheumatoid arthritis (RA) is an autoimmune disease occurring in larger population, characterized by synovial inflammation followed by destruction of joint. Major concerned factor for cause of RA has been related to oxidative stress due to environmental toxicity and immune imbalance. Reactive oxygen species generated from macrophages communes series of oxidation at cellular and genetic level and leads to generation of inflammatory cytokines for provoking inflammation in RA. Superoxide dismutase and catalase are supposed to be potential antioxidant enzymes to scavange free radicals. However, many clinical studies report reduced potency of enzyme due to lack of its targeting efficacy. Therefore, the aim of the work involves development of nanomatrix mimicking as catalase over which folate-linked superoxide dismutase was adsorbed for a macrophage targeting. The developed formulation was optimized, characterized for morphological studies, enzyme loading efficiency, protein activity, and in vitro drug release. Quantification of interleukin 6 was performed by indirect enzyme linked immunosborent assay over macrophage cell lines to determine in vitro treatment efficacy. It is concluded that the prepared system can act as enzyme reservoir to deliver acid labile enzymes in controlled form to efficiently treat RA.
29789121 Aire is not essential for regulating neuroinflammatory disease in mice transgenic for huma 2018 Sep The human autoimmune disease-associated HLA alleles HLA-DR2b (DRB1*1501) and HLA-DR4 (DRB1*0401) are strongly linked to increased susceptibility for multiple sclerosis (MS) and rheumatoid arthritis (RA), respectively. The underlying mechanisms are not fully understood, but these MHC alleles may shape the repertoire of pathogenic T cells via central tolerance. The transcription factor autoimmune regulator (AIRE) promotes central T cell tolerance via ectopic expression of tissue-specific antigens (TSAs). Aire deficiency in humans causes autoimmune polyendocrinopathy syndrome type 1 (APS1), and Aire knockout mice (Aire(-/-)) develop spontaneous autoimmune pathology characterized by multi-organ lymphocytic infiltrates. Here, we asked whether impaired TSAs gene expression in the absence of Aire promoted spontaneous MS- or RA-like autoimmune pathology in the context of human HLA alleles in HLA-DR2b or HLA-DR4 transgenic (tg) mice. The results show that reduced TSAs gene expression in the thymus of Aire-deficient HLA-DR2b or HLA-DR4 tg mice corresponded to mild spontaneous inflammatory infiltrates in salivary glands, liver, and pancreas. Moreover, Aire-deficiency modestly enhanced experimental autoimmune encephalomyelitis (EAE) in HLA-DR tg mice, but the animals did not show signs of spontaneous neuroinflammation or arthritis. No significant changes were observed in CD4(+) T cell numbers, T cell receptor (TCR) distribution, regulatory T cells (Treg), or antigen-induced cytokine production. Abrogating Treg function by treatment with anti-CTLA-4 or anti-CD25 mAb in Aire-deficient HLA-DR tg mice did not trigger EAE or other autoimmune pathology. Our results suggest a redundant role for Aire in maintaining immune tolerance in the context of autoimmune disease-associated human HLA alleles.
29314183 Fixed dosing of intravenous tocilizumab in rheumatoid arthritis. Results from a population 2018 Apr AIMS: Intravenous tocilizumab is currently dosed on body weight, although a weak correlation between body weight and clearance has been described. The aim of the study was to assess the current dosing strategy and provide a scientific rational for dosing using a modelling and simulation approach. METHODS: Serum concentrations and covariates were obtained from intravenous tocilizumab treated subjects at a dose of 4, 6 or 8 mg every 28 days. A population pharmacokinetic analysis was performed using nonlinear mixed effects modelling. The final model was used to simulate tocilizumab exposure to assess a dosing strategy based on body weight or fixed dosing, using as target a cumulative area under the curve at 24 weeks of treatment above 100 × 10(3)  μg h ml(-1) . RESULTS: A one-compartment disposition model with parallel linear and nonlinear elimination best described the concentration-time data. The typical population mean values for clearance, apparent volume of distribution, maximum elimination rate and Michaelis-Menten constant were 0.0104 l h(-1) , 4.83 l, 0.239 mg h(-1) and 4.22 μg ml(-1) , respectively. Interindividual variability was included for clearance (17.0%) and volume of distribution (30.8%). Significant covariates for clearance were patient body weight and C-reactive protein serum levels. An estimated exponent for body weight of 0.360 confirms the weak relationship with tocilizumab clearance. Simulations demonstrate that patients with lower weights are at risk of underdosing if the weight-based dosing approach is used. However, fixed-dosing provides a more consistent drug exposure regardless of weight category. CONCLUSIONS: Our study provides evidence to support fixed dosing of intravenous tocilizumab in rheumatoid arthritis patients since it reduces variability in tocilizumab exposure among weight categories compared to the current weight-based dosing approach.
30299246 Implication of CXCL5 (epithelial neutrophil-activating peptide 78) in the development of i 2019 May OBJECTIVES: The chemokine molecule CXCL5 (C-X-C motif chemokine ligand 5, also known as epithelial neutrophil activating peptide 78 -ENA78-) constitutes a link between obesity, inflammation and insulin resistance (IR) in the general population. CXCL5 has also been found to play a role in rheumatoid arthritis (RA) pathogenesis. Since chronic inflammation promotes IR and impairs pancreatic beta cell function in RA patients, we assessed the role of CXCL5 in the development of IR in RA. METHODS: Cross-sectional study that encompassed 141 non-diabetic patients with RA. IR assessed by homeostatic model assessment (HOMA2), insulin and C-peptide serum levels and lipid profile, and CXCL5 serum levels were studied. Regression analysis was performed to evaluate how CXCL5 was related to IR, disease activity, and disease characteristics in RA patients. RESULTS: HOMA2-IR indexes showed high values for both IR and beta cell production (%B), and low insulin sensitivity (%S) in patients with RA. C reactive protein (beta coef. 0.2 [95%CI -1.5-1.9], p=0.80) and disease activity through DAS28 (beta coef. 13 [95%CI -14-41], p=0.34) revealed no relation with CXCL5. Other disease characteristics, such as disease duration, serological status, or use of methotrexate or anti-TNF alpha therapies, were not associated with CXCL5 serum levels. While glucocorticoids were related to insulin, C-peptide serum levels, and HOMA2-IR and HOMA2-%B-C peptide, the use of prednisone was not associated with CXCL5 serum levels. Insulin and C peptide serum levels and IR indexes showed strong correlations among each other, but not with CXCL5 (insulin r2=-0.034, p=0.69; C peptide r2=-0.050, p=0.56). CONCLUSIONS: CXCL5 is not related to IR in RA patients. Therefore, the mechanisms leading to IR in patients with RA may be different from those in the general population.
30342345 Novel anti-inflammatory target of geniposide: Inhibiting Itgβ1/Ras-Erk1/2 signal pathway 2018 Dec Geniposide (GE) is an active component isolated from the fruit of Gardenia jasminoides Ellis that has anti-inflammatory and other pharmacological effects; however, the underlying mechanism of GE action has not been elucidated in rheumatoid arthritis (RA). Previous studies have shown that GE plays a therapeutic role in RA via regulation of the integrin beta 1 (Itgβ1)-mediated Ras-Erk1/2 signalling pathway. However, the specific mechanism of GE action on Itgβ1 has not been clarified. Recent evidence indicates that microRNAs (miRNAs) are involved in the development of RA. In this study, we developed a miRNA-124a-based synoviocyte repair strategy. We demonstrated that miRNA-124a can directly inhibit the expression of the Itgβ1 gene and decrease TNF-α-stimulated cell proliferation in vitro. MH7A cells were obtained from the patient with RA and treated with GE in the presence of TNF-α (10 ng/mL). Additionally, we demonstrated that the expression of miRNA-124a can be regulated by GE. GE upregulated the expression of miRNA-124a and decreased the expression of Itgβ1 at the mRNA and protein levels. The results of the present study are the first to suggest that GE inhibits TNF-α-stimulated cell proliferation and blocks the activation of the Ras-Erk1/2 pathway via the upregulation of miRNA-124a expression. Our study elucidates the role of miRNA-124a as a protected miRNA in RA and may provide a novel strategy for the diagnosis and treatment of RA in the future.
29969365 The mechanism of GM-CSF inhibition by human GM-CSF auto-antibodies suggests novel therapeu 2018 Oct Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a hematopoietic growth factor that can stimulate a variety of cells, but its overexpression leads to excessive production and activation of granulocytes and macrophages with many pathogenic effects. This cytokine is a therapeutic target in inflammatory diseases, and several anti-GM-CSF antibodies have advanced to Phase 2 clinical trials in patients with such diseases, e.g., rheumatoid arthritis. GM-CSF is also an essential factor in preventing pulmonary alveolar proteinosis (PAP), a disease associated with GM-CSF malfunction arising most typically through the presence of GM-CSF neutralizing auto-antibodies. Understanding the mechanism of action for neutralizing antibodies that target GM-CSF is important for improving their specificity and affinity as therapeutics and, conversely, in devising strategies to reduce the effects of GM-CSF auto-antibodies in PAP. We have solved the crystal structures of human GM-CSF bound to antigen-binding fragments of two neutralizing antibodies, the human auto-antibody F1 and the mouse monoclonal antibody 4D4. Coordinates and structure factors of the crystal structures of the GM-CSF:F1 Fab and the GM-CSF:4D4 Fab complexes have been deposited in the RCSB Protein Data Bank under the accession numbers 6BFQ and 6BFS, respectively. The structures show that these antibodies bind to mutually exclusive epitopes on GM-CSF; however, both prevent the cytokine from interacting with its alpha receptor subunit and hence prevent receptor activation. Importantly, identification of the F1 epitope together with functional analyses highlighted modifications to GM-CSF that would abolish auto-antibody recognition whilst retaining GM-CSF function. These results provide a framework for developing novel GM-CSF molecules for PAP treatment and for optimizing current anti-GM-CSF antibodies for use in treating inflammatory disorders.
29045049 Germinal Center B Cells Are Essential for Collagen-Induced Arthritis. 2018 Feb OBJECTIVE: Rheumatoid arthritis (RA) is considered to be a prototypical autoimmune disorder. Several mechanisms have been proposed for the known pathologic function of B cells in RA, including antigen presentation, cytokine secretion, and humoral immunity. The aim of this study was to address the function of B lymphocytes in experimental arthritis. METHODS: We mapped the adaptive immune response following collagen-induced arthritis (CIA). We subsequently monitored these responses and disease outcomes in genetically modified mouse strains that lack mature B cell or germinal center (GC) functionality in a B cell-intrinsic manner. RESULTS: Following primary immunization, the draining lymph nodes broadly reacted against type II collagen (CII) with the formation of GCs and T cell activation. Mice that lacked mature B cell function were fully protected against CIA and had a severely attenuated ability to mount isotype-switched humoral immune responses against CII. Almost identical results were observed in mice that were selectively deficient in GC responses. Importantly, GC-deficient mice were fully susceptible to collagen antibody-induced arthritis. CONCLUSION: We identified GC formation and anticollagen antibody production as the key pathogenic functions of B cells in CIA. The role of B cells in RA is likely to be more complex. However, targeting the GC reaction could allow for therapeutic interventions that are more refined than general B cell depletion.
28870784 Isotypes of autoantibodies against differentially expressed novel malondialdehyde-modified 2018 Jan 6 This study identified and validated four differentially expressed novel malondialdehyde (MDA)-modified peptide adducts and evaluated autoantibodies against native and MDA-modified peptides among Taiwanese women patients with rheumatoid arthritis (RA), osteoarthritis (OA) and healthy controls (HCs). Ig kappa chain C region(76-99), alpha-1-antitrypsin(284-298), alpha-2-macroglobulin(824-841), and apolipoprotein B-100(4022-4040) exhibiting 2-fold differences in relative modification ratios were identified by concanavalin A (Con A) affinity chromatography, 1D SDS-PAGE, in-gel digestion, nano-LC/MS/MS and nano-LC/MS using pooled serum-derived Con A-captured proteins from 9 RA and 9 age-matched HCs. Furthermore, the levels of proteins, serum MDA, and MDA-modified protein adducts were further validated against individual serum from 20 RA and 20 HCs, and autoantibodies against native and their MDA-modified peptides used 45 RA, 30 OA and 45 HCs. Levels of serum MDA and MDA-modified protein adducts were significantly higher in RA than HCs but protein levels were not significantly different. Serum Igs G and M against MDA-modified peptides showed better diagnostic performance in differentiating among patients with RA, OA and HCs, with an area under the receiver operating characteristic curve of 0.96-0.98, sensitivity of 88.9%-97.8%, and specificity of 88.9%-100%. Autoantibodies against MDA-modified epitopes become useful clinical biomarkers for RA. BIOLOGICAL SIGNIFICANCE: By using a label-free relative quantitative proteomic analysis of concanavalin A (Con A)-bound serum samples, the current study discovered and validated malondialdehyde (MDA)-modified peptide adducts as novel biomarkers for differentiating between rheumatoid arthritis (RA) patients and healthy controls (HCs). In addition, the serum levels of MDA, proteins, and MDA-modified protein adducts as well as the MDA modification of proteins were determined. Isotypes of autoantibodies against MDA-modified peptide adducts can be used as serological biomarkers for further discriminating among RA patients, osteoarthritis patients and HCs. This strategy can become the basis for identifying potential diagnostic and pathological biomarkers for RA.
30421069 Subcutaneous tocilizumab alone or with a csDMARD in rheumatoid arthritis patients: subanal 2019 Mar To assess, in a setting close to real life, the efficacy and safety of weekly subcutaneous tocilizumab (TCZ-SC) 162 mg, alone or with a conventional synthetic DMARD (csDMARD), in moderate-to-severe RA patients with inadequate response to DMARDs or anti-TNFα drugs. This national, multicenter, open-label, phase IIIb trial is part of an umbrella study (TOZURA). Patients were treated for 52 weeks followed by 8 weeks drug-free to evaluate immunogenicity. The primary end point was the Clinical Disease Activity Index (CDAI) change from baseline at weeks 2 and 24. Other efficacy parameters, including sleep quality, and the safety and immunogenicity were also assessed up to week 52. Of 288 patients enrolled in 43 Italian centers, 78.8% received TCZ-SC (86.8% females; mean age 54.7 ± 12.1 years; mean disease duration 7.8 ± 7.5 years; DMARD-IRs 94.7%). Of these, 78.0% completed the 52-week period and 52.0% received concomitant methotrexate. TCZ-SC yielded a significant reduction in median CDAI from baseline already at week 2, which progressed up to week 24 and remained stable thereafter (P < 0.0001 at each time point). A significant, rapid, and sustained improvement of the other efficacy variables was also observed. Patients were deemed as ready for home administration after a median of 2.0 (range 1-8) administrations, with a rate (since the last visit) of 80.6% and 95.5% at weeks 2 and 52, respectively. TCZ-SC displayed low immunogenicity and no unexpected toxicities. TCZ-SC, alone or with a csDMARD, yielded rapid and sustained efficacy in DMARD/anti-TNFα-IR RA patients, with acceptable toxicity. Home administration seems feasible.
29325166 Drug safety and immunogenicity of tumour necrosis factor inhibitors: the story so far. 2018 Nov 1 TNF-α inhibitor (TNFi) therapies have transformed the treatment of several rheumatic musculoskeletal diseases. However, the majority of TNFi's are immunogenic and consequent anti-drug antibodies formation can impact on both treatment efficacy and safety. Several controversies exist in the area of immunogenicity of TNFis and drug safety. While anti-drug antibodies to TNFis have been described in association with infusion reactions; serious adverse events (AEs) such as thromboembolic events, lupus-like syndrome, paradoxical AEs, for example, vasculitis-like events and other autoimmune manifestations have also been reported. The expansion of the biologic armamentarium, new treatment strategies such as introduction/switching to biosimilars and cost-saving approaches such as TNFi tapering, may all have a potential impact on immunogenicity and clinical sequelae. In this review we evaluate how evolution of biologics relates to drug safety and immunogenicity, appraise relevant evidence from trials, spontaneous pharmacovigilance and observational studies and outline the areas of uncertainty that still exist.
29986108 Biologic prescribing decisions following serious infection: results from the British Socie 2018 Dec 1 OBJECTIVES: To establish whether the decision to stop, continue or switch TNF inhibitor (TNFi) therapy to a biologic drug with an alternative mode of action following a serious infection (SI) impacts upon the risk of recurrent SI in patients with RA. METHODS: Patients recruited to the British Society for Rheumatology Biologics Register-RA with at least one episode of SI while on TNFi were included. The biologic treatment decision following SI was considered. A multivariable adjusted Cox proportional hazards model was used to identify predictors of recurrent SI and whether biologic treatment choices influenced future SI risk. RESULTS: In total, 1583 patients suffered at least one SI while on TNFi. Most patients (73%) were recorded as continuing TNFi 60 days after an index SI. The rate of recurrent SI was 25.6% per annum (95% CI: 22.5, 29.2%). The rate of recurrent SI was highest in patients who stopped their TNFi (42.6% per annum, 95% CI: 32.5, 55.7%) and lowest in those who switched biologic drug class (12.1% per annum, 95% CI: 3.9, 37.4%). Compared with patients stopping biologic therapy, patients who continued or switched drug class had significantly lower risk of recurrent SI (drug continuation hazard ratio = 0.54, 95% CI: 0.40, 0.74; drug switch hazard ratio = 0.29, 95% CI: 0.09, 0.95). CONCLUSIONS: Patients who continued or switched their TNFi post-index SI had a lower risk of recurrent SI infection compared with those who stopped the drug. This may be explained by better control of disease activity with reintroduction of biologic therapy, a driving factor for SI or alternatively channelling fitter patients to restart biologic therapy.
29626269 Analysis of PD-1 and Tim-3 expression on CD4(+) T cells of patients with rheumatoid arthri 2018 Aug Expression of T cell immunoglobulin and mucin-domain containing-3 (Tim-3) and programmed cell death-1 (PD-1) was studied on CD4(+) T cells of patients with rheumatoid arthritis (RA). Association of Tim-3 and PD-1 expression with disease activity of RA patients was also addressed. A total of 37 RA patients and 31 sex- and age-matched healthy controls were included in this study. Disease activity of RA patients was determined by Disease Activity Score of 28 joints scoring system (DAS28). A three-color flow cytometry method was applied to determine the frequency of Tim-3(+)/PD-1(+)/CD4(+) T cells. To measure the cytokine production, peripheral blood mononuclear cells (PBMCs) were stimulated with PMA/ionomycin. Concentrations of IL-17, IL-10, IFN-γ, and TNF-α were measured in culture supernatants by ELISA. The frequency of PD-1(+)/CD4(+) and Tim-3(+)/PD-1(+)/CD4(+) T cells was significantly higher in patients with RA compared to that in controls (p = 0.0013 and p = 0.050, respectively). The percentage of Tim-3(+)/CD4(+) T cells was similar in patients and controls (p = 0.4498). The RA patients have produced significant higher levels of TNF-α, IL-17, and IFN-γ than those of healthy controls (p = 0.0121, p = 0.0417, and p = 0.0478, respectively). Interestingly, an inverse correlation was found between the frequency of Tim-3(+)/CD4(+) cells and DAS28 of RA patients (r = - 0.4696, p = 0.0493). Similarly, the percentage of Tim-3(+)/PD-1(+)/CD4(+) T cells was also revealed an inverse correlation with DAS28 (r = - 0.5268, p = 0.0493). Moreover, significant positive correlations were detected between the concentrations of TNF-α (r = 0.6418, p = 0.0023) and IL-17 (r = 0.4683, p = 0.0373) with disease activity of RA patients. Our results indicate that Tim-3 and PD-1 are involved in immune dysregulation mechanisms of rheumatoid arthritis and could be considered as useful biomarkers for determination of disease activity and progression.
29037522 Rheumatoid arthritis and risk of chronic obstructive pulmonary disease or asthma among wom 2018 Apr OBJECTIVE: We investigated whether RA increases risk for chronic obstructive pulmonary disease (COPD) or asthma independent of factors occurring before RA onset or mediating these respiratory morbidities after diagnosis, such as cigarette smoking. METHODS: Within the prospective Nurses' Health Study (n = 121,701 women; 1976-2014), we identified an incident RA cohort and matched each woman with RA to 10 comparators without RA by age and year at index date of RA diagnosis, excluding women with COPD or asthma at baseline. Data were obtained through biennial questionnaires and medical records. We used marginal structural models to determine the independent effect of RA on incident COPD or asthma adjusting for confounders and time-varying mediators through inverse probability weighting. RESULTS: We identified 843 women with RA, matched to 8,399 comparators without RA. Mean age was 59.8 years and mean follow-up after index date was 18.6 years (SD = 9.0) for women with RA, and 18.8 years (SD = 9.5) for comparators. We identified 68 (8.1%) incident COPD and 40 (4.7%) asthma cases among women with RA, and 459 (5.5%) COPD and 268 (3.2%) asthma cases among comparators. RA was associated with increased risk of COPD (HR = 1.52, 95% CI: 1.17-1.97) and asthma (HR = 1.55, 95% CI: 1.11-2.16) compared to comparators adjusted for the matching factors of age and calendar year at index date. After further adjustment for confounders and time-varying mediators occurring after index date, including smoking, RA was significantly associated with COPD (HR = 1.68, 95% CI: 1.36-2.07), but not asthma (HR = 1.11, 95% CI: 0.59-2.09) compared to non-RA comparators. Women with seropositive RA (HR = 1.60, 95% CI: 1.17-2.19) and seronegative RA (HR = 1.62, 95% CI: 1.09-2.40) had similar increased risk for COPD compared to non-RA comparators. CONCLUSION: In this prospective cohort study, RA was associated with increased risk for incident COPD, independent of lifestyle confounders and mediators after diagnosis, including smoking.
30585464 [Toll-like Receptor 4/Nuclear Factor-κB Signaling in Synovial Tissue Is Involved in the A 2018 Nov 25 OBJECTIVE: To observe the effect of moxibustion on Toll-like receptor 4/nuclear factor-κB (TLR 4/NF-κB) signaling in the synovial tissue of the ankle joint in rats with rheumatoid arthritis (RA), so as to analyze its biological mechanism underlying improvement of RA. METHODS: Fifty male SD rats were randomly divided into normal control, model, moxibustion, moxibustion ＋ TLR 4 agonist, and moxibustion ＋ TLR 4 antagonist groups (n＝10 rats in each). The RA model was established by subcutaneous injection of Freund's complete adjuvant (FCA, 0.1 mL/rat) at the right hind-paw and by being raised in a wind (air fan blowing), cold (about 10 ℃) and wet (purling) environment for 20 days. After 3 days of modeling, mild moxibustion was applied to bilateral "Shenshu" (BL 23) and "Zusanli" (ST 36) for 20 minutes, once daily for successive 10 days. The TLR 4 agonist (lipopolysaccharide) or TLR 4 antagonist (TAK-242) (1 mg/mL) was separately administered via the tail vein 30 min before performing moxibustion every time in the agonist group and the antagonist group. The expression of NF-κB inhibitory factor ɑ (IκBɑ), IκB kinase complex β(IκKβ), myeloid differentiation factor 88 (MyD 88), TLR 4, and NF-κB p 65 proteins in the synovial tissue of the ankle joint was detected by using Western blot. RESULTS: Following modeling, the girth of the swollen ankle joint was obviously bigger (P<0.01), and the expression levels of IκBɑ， IκKβ， TLR 4, MyD 88, and NF-κB p 65 proteins in the synovial tissue were considerably increased in the model group relevant to the normal control group (P<0.01). After moxibustion intervention, the girth of the swollen ankle joint and the expression levels of IκBɑ， IκKβ， TLR 4, MyD 88, and NF-κB p 65 proteins were significantly down-regulated in the moxibustion, moxibustion ＋TLR 4 agonist, moxibustion＋TLR 4 antagonist groups compared with the model group (P<0.01, P<0.05). Comparison among the 3 moxibustion groups showed that the lowered levels of ankle-joint girth, and IκBɑ， IκKβ， TLR 4, MyD 88, and NF-κB p 65 expression were significantly smaller in the moxibustion＋TLR 4 agonist group than in the simple moxibustion and moxibustion＋TLR 4 antagonist groups (P<0.05，P<0.01). No significant differences were found between the moxibustion and moxibustion＋TLR 4 antagonist groups in the decreased ankle joint girth and IκBɑ， IκKβ， TLR 4, MyD 88, and NF-κB p 65 expression levels (P>0.05), suggesting that activation of TLR 4 reduced the anti-inflammatory effect of moxibustion intervention. CONCLUSION: Moxibustion can reduce the ankle joint swelling in RA rats, which may be closely associated with its effect in down-regulating the expression of IκBɑ， IκKβ， TLR 4, MyD 88, and NF-κB p 65 proteins and in inhibiting TLR 4/NF-κB signaling in the synovial tissue of the ankle joint.
30552173 Genetic variation at the glycosaminoglycan metabolism pathway contributes to the risk of p 2019 Mar OBJECTIVE: Psoriatic arthritis (PsA) is a chronic inflammatory arthritis affecting up to 30% of patients with psoriasis (Ps). To date, most of the known risk loci for PsA are shared with Ps, and identifying disease-specific variation has proven very challenging. The objective of the present study was to identify genetic variation specific for PsA. METHODS: We performed a genome-wide association study in a cohort of 835 patients with PsA and 1558 controls from Spain. Genetic association was tested at the single marker level and at the pathway level. Meta-analysis was performed with a case-control cohort of 2847 individuals from North America. To confirm the specificity of the genetic associations with PsA, we tested the associated variation using a purely cutaneous psoriasis cohort (PsC, n=614) and a rheumatoid arthritis cohort (RA, n=1191). Using network and drug-repurposing analyses, we further investigated the potential of the PsA-specific associations to guide the development of new drugs in PsA. RESULTS: We identified a new PsA risk single-nucleotide polymorphism at B3GNT2 locus (p=1.10e-08). At the pathway level, we found 14 genetic pathways significantly associated with PsA (p(FDR)<0.05). From these, the glycosaminoglycan (GAG) metabolism pathway was confirmed to be disease-specific after comparing the PsA cohort with the cohorts of patients with PsC and RA. Finally, we identified candidate drug targets in the GAG metabolism pathway as well as new PsA indications for approved drugs. CONCLUSION: These findings provide insights into the biological mechanisms that are specific for PsA and could contribute to develop more effective therapies.
29927106 Pathogenic Citrulline-Multispecific B Cell Receptor Clades in Rheumatoid Arthritis. 2018 Dec OBJECTIVE: Anti-citrullinated protein antibodies (ACPAs) have proven highly useful as biomarkers for rheumatoid arthritis (RA). However, composition and functionality of the associated autoreactive B cell repertoire have not been directly assessed. We aimed to selectively investigate citrullinated autoantigen-specific B cell receptors (BCRs) involved in RA and initiate studies on their pathogenicity. METHODS: Blood samples were obtained from patients in a University of Minnesota cohort with ACPA-positive RA (n = 89). Tetramer sets bearing citrullinated filaggrin peptide cfc1 or citrullinated α-enolase peptide were constructed to specifically capture autoreactive B cells from the unaltered, polyclonal repertoire in RA patients. Citrullinated peptide tetramer-bound B cells were subjected to flow cytometric cell sorting and single-cell IGH, IGK, and IGL gene sequencing for B cell lineage determinations. BCR gene sequences were also expressed as recombinant monoclonal antibodies (mAb) for direct evaluation of citrullinated autoantigen binding and effector functionality. RESULTS: Using citrullinated peptide tetramer enrichment to investigate single autoreactive blood B cells, we identified biased V-region gene usage and conserved junction arrangements in BCRs from RA patients. Parsimonious clustering of related immunoglobulin gene nucleotide sequences revealed clonal expansions of rare individual B cell clades, in parallel with divergent sequence mutations. Correspondingly, recombinant mAb generated from such BCR lineages demonstrated citrulline-dependent cross-reactivity extending beyond the citrullinated peptides used for B cell capture. A pair of citrullinated autoantigen-specific mAb with cross-reactive binding profiles also promoted arthritis in mice. CONCLUSION: Our findings suggest that broad ACPA specificities in RA arise from a restricted repertoire of evolving citrulline-multispecific B cell clades with pathogenic potential.
30366278 Monocytes in rheumatoid arthritis: Circulating precursors of macrophages and osteoclasts a 2018 Dec Rheumatoid arthritis (RA) is a chronic systemic, autoimmune and inflammatory disease represented as synovitis, pannus formation, adjacent bone erosions, and joint destruction. The major cells involved in the perpetuation of RA pathogenesis are CD4(+) T-cells (mainly Th1 cells and Th17 cells), fibroblasts like synoviocytes (FLS), macrophages and B cells. Other autoimmune cells such as dendritic cells, neutrophils, mast cells, and monocytes also contribute to RA pathogenesis. Monocytes are mainly bone marrow (BM) derived cells in the circulation. The chemokine receptors CCR2 and CX3CR1 expressed by monocytes interact with chemokine ligands CCL2 (MCP-1) and CX3CL1 (fractalkine) respectively produced by FLS and this interaction promotes their migration and recruitment into RA synovium. Activated monocytes on their surface exhibit upregulated antigenic expressions such as CD14, CD16, HLA-DR, toll-like receptors (TLRs), and adhesion molecules B1 and B2 integrins. RA monocytes interconnect with other cells in a positive loop manner in the propagation of the rheumatoid process. They skew towards mainly intermediate monocyte subsets (CD14(++) CD16(+)) which produce proinflammatory cytokines such as TNF-α, IL-1β, and IL-6. Moreover, the predominant intermediate monocytes in RA differentiate into M1-macrophages which play a major role in synovial inflammation. Demonstrations suggest monocytes with CD14(+) and CD16(-) expression (classical monocytes?) differentiate to osteoclasts which are the cells responsible for bone erosion in RA synovial joints. Th17 cells induce the production of RANKL by FLS which promotes osteoclastogenesis. Cytokines mainly TNF-α, IL-1β, and IL-6 amplify osteoclastogenesis. Hence, monocytes are the circulating precursors of macrophages and osteoclasts in RA. AIM OF THE REVIEW: To enlighten the identity of monocytes, the antigenic expression on monocyte surface and their cytokines role in RA. We also emphasize about the chemokine receptors expressed by monocytes subsets and chemotaxis of circulating monocytes into RA synovium. Additionally, we review monocytes as the circulating precursors of macrophages and osteoclasts in RA joints and their heterogeneity and plasticity role in RA.
29563614 A critical epitope in CD147 facilitates memory CD4(+) T-cell hyper-activation in rheumatoi 2019 Jun The abnormal activation of CD4(+)CD45RO(+) memory T (Tm) cells plays an important role in the pathogenesis of rheumatoid arthritis (RA). Previous studies have shown that CD147 participates in T-cell activation. However, it remains unclear whether CD147 is involved in abnormal Tm-cell activation in RA patients. In this study, we demonstrated that CD147 was predominantly upregulated in Tm cells derived from RA patients. The anti-CD147 mAb 5A12 specifically inhibited Tm-cell activation and proliferation and further restrained osteoclastogenesis. Using a structural-functional approach, we depicted the interface between 5A12 and CD147. This allowed us to identify two critical residues, Lys63 and Asp65, as potential targets for RA treatment, as the double mutation K63A/D65A inhibited Tm-cell activation, mimicking the neutralization by 5A12. This study provides not only a theoretical basis for a "CD147-Tm/Osteoclast-RA chain" for the potential prevention and treatment of RA or other T-cell-mediated autoimmune diseases but also a new target for related drug design and development.
29540066 A Systematic Review of Biological Mechanisms of Fatigue in Chronic Illness. 2018 Jul Fatigue, a commonly reported symptom, is defined as an overwhelming, debilitating, and sustained sense of exhaustion that decreases the ability to function and carry out daily activities. To date, cancer researchers have been in the forefront in investigating the possible biological mechanisms of fatigue, identifying inflammation, dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, and activation of the autonomic nervous system. The purpose of this systematic review is to describe fatigue and what is known about the biological mechanisms described in cancer in five chronic, noninfectious illnesses: heart failure, multiple sclerosis, chronic kidney disease, rheumatoid arthritis, and chronic obstructive pulmonary disease. We searched PubMed and EMBASE using fatigue as a major Medical subject headings (MeSH) heading with each individual disease added as a search term followed by each biological mechanism. We included only primary research articles published in English between 1996 and 2016 describing studies conducted in adult humans. We identified 26 relevant articles. While there is some evidence that the biological mechanisms causing fatigue in cancer are also associated with fatigue in other chronic illnesses, more research is needed to explore inflammation, the HPA axis, and the autonomic nervous system, and other mechanisms in relation to fatigue in a variety of chronic illnesses.
29247155 CXCL10 and TRAIL Are Upregulated by TXNDC5 in Rheumatoid Arthritis Fibroblast-like Synovio 2018 Mar OBJECTIVE: Thioredoxin domain containing 5 (TXNDC5) is highly expressed in synovial membranes of rheumatoid arthritis (RA). Our study aimed to investigate the pathogenic role of TXNDC5 in RA. METHODS: PCR arrays, CCK-8 assays, flow cytometry, and transwell migration assays were used to analyze cultured rheumatoid arthritis synovial fibroblasts (RASF). RESULTS: Increased CXCL10 and tumor necrosis factor-related apoptosis-inducing ligand levels were detected in RASF transfected with anti-TXNDC5 small interfering RNA (siRNA), and decreased expression was detected in RASF transfected with TXNDC5-expressing plasmids. Significantly attenuated RASF proliferation and migration, and increased RASF apoptosis, were observed in the siRNA-transfected RASF. CONCLUSION: Downregulation of TXNDC5 could contribute to RASF antiangiogenic and proapoptotic features through the suppression of CXCL10 and TRAIL (tumor necrosis factor-related apoptosis-inducing ligand).