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ID PMID Title PublicationDate abstract
30269670 Interleukin-18 is associated with the presence of interstitial lung disease in rheumatoid 2019 Mar OBJECTIVE: Serum interleukin-18 (IL-18) levels are increased in patients with interstitial lung disease (ILD). In addition, IL-18 levels are increased in patients with rheumatoid arthritis (RA) and are associated with arthritis activity. We determined whether increased IL-18 levels are associated with ILD in RA. METHOD: RA patients were enrolled using an RA cohort database. Plasma IL-18 levels were measured by enzyme-linked immunosorbent assay. ILD was determined by a pulmonologist and a radiologist based on chest radiography and computed tomography findings. IL-18 levels for RA with ILD and RA without ILD were compared. Associations between ILD and various markers including IL-18 and confounding factors (e.g. smoking history) were investigated by logistic regression analysis. Diagnostic values of IL-18 for the presence of ILD were investigated using receiver operating characteristics curve analysis. RESULTS: ILD was complicated in 8.2% (n = 26) of the study population (N = 312). Plasma IL-18 levels were higher for RA patients with ILD than for RA patients without ILD (721.0 ± 481.4 vs 436.8 ± 438.9 pg/mL, p < 0.001). IL-18, Krebs von den Lungen-6, and anti-cyclic citrullinated peptide antibody titre and glucocorticoid doses were independently associated with the presence of ILD during multivariate logistic regression analysis. Sensitivity and specificity of IL-18 levels for the detection of ILD in RA patients were 65.3% and 76.3%, respectively (area under the curve = 0.73). CONCLUSION: Plasma IL-18 levels were higher for RA patients with ILD than for those without ILD. Increased IL-18 levels were associated with the presence of ILD.
30911117 ACPAs promote IL-1β production in rheumatoid arthritis by activating the NLRP3 inflammaso 2020 Mar OBJECTIVES: Anti-citrullinated protein antibodies (ACPAs) are a group of autoantibodies targeted against citrullinated proteins/peptides and are informative rheumatoid arthritis (RA) biomarkers. ACPAs also play a crucial role in RA pathogenesis, and their underlying mechanism merits investigation. METHODS: Immunohistochemical (IHC) assays were carried out to determine IL-1β levels in ACPA(+) and ACPA(-) RA patients. PBMC-derived monocytes were differentiated into macrophages before stimulation with ACPAs purified from RA patients. The localization and interaction of molecules were analyzed by confocal microscopy, co-IP, and surface plasmon resonance. RESULTS: In our study, we found that IL-1β levels were elevated in ACPA(+) RA patients and that ACPAs promoted IL-1β production by PBMC-derived macrophages. ACPAs interacted with CD147 to enhance the interaction between CD147 and integrin β1 and, in turn, activate the Akt/NF-κB signaling pathway. The nuclear localization of p65 promoted the expression of NLRP3 and pro-IL-1β, resulting in priming. Moreover, ACPA stimulation activated pannexin channels, leading to ATP release. The accumulated ATP bound to the P2X7 receptor, leading to NLRP3 inflammasome activation. CONCLUSIONS: Our study suggests a new hypothesis regarding IL-1β production in RA involving ACPAs, which may be a potential therapeutic target in RA treatment.
28958842 Visceral leishmaniasis in a patient with rheumatoid arthritis treated with methotrexate. 2019 Nov A large number of complications have been associated with rheumatoid arthritis (RA), those of infectious etiology being of special relevance. Their high incidence is closely linked to the use of immunosuppressive medication. The spectrum of agents causing opportunistic infections in patients with RA is very broad; however, there are relatively few cases of Leishmania infection, especially in patients not being treated with biological drugs.
31634789 Therapeutic treatment of a novel selective JAK3/JAK1/TBK1 inhibitor, CS12192, in rat and m 2019 Dec Rheumatoid arthritis (RA) is a representative autoimmune disease characterized by chronic inflammation and joint destruction. Although biological inhibitors such as TNF-α and IL-6 antibodies have achieved success in clinical therapy, small molecule inhibitors against the Janus kinases (JAKs) involved in the signaling pathways of various cytokine receptors have gained more attraction as safe and efficacious options. In this study, we identified CS12192 as a novel selective JAK3/JAK1/TBK1 inhibitor and investigated its pharmacological effects on the experimental arthritis models in rat and mouse. We found that CS12192 showed a more selective inhibitory activity on JAK3, and to a less extent on JAK1 and TBK1, that were verified by decreased activation of p-STATs and p-IRF3 as well as down-regulation of IFN gene expression in the cultured cells with relevant stimuli. Furthermore, oral treatment with CS12192 dose-dependently ameliorated the disease severity, hind paw swelling, body weight loss, and bone destruction in rat models of adjuvant-induced arthritis (AIA) and collagen-induced arthritis (CIA). In a mouse CIA model, CS12192 also attenuated the disease severity, which was correlated with the suppressed CD4(+) T cell activation and Th17 function, as well as the reduced cytokine levels in sera and pro-inflammatory cytokine and chemokine gene expression in joint tissue. Corroboratively, RANKL-induced osteoclast formation was inhibited by CS12192. Thus, these results suggest that CS12192 as a novel selective JAK inhibitor has therapeutic potential for the treatment of RA and may provide a new strategy for the control of autoimmune diseases.
30864105 Indirect Treatment Comparison of the Efficacy and Safety of Sarilumab Monotherapy in Rheum 2019 Apr INTRODUCTION: To evaluate the comparative efficacy and safety of subcutaneous sarilumab 200 mg monotherapy administered every 2 weeks (q2w) versus other monotherapies of biologic, targeted and conventional synthetic disease-modifying antirheumatic drugs (bDMARDs, tsDMARDs, csDMARDs) at recommended doses for treatment of rheumatoid arthritis in patients who are intolerant of or inadequate responders to csDMARDs (csDMARD-IR). METHODS: A systematic literature review and network meta-analysis (NMA) were conducted on 24-week efficacy outcomes: Health Assessment Questionnaire Disability Index (HAQ-DI) score, American College of Rheumatology (ACR) 20/50/70 criteria, and European League Against Rheumatism Disease Activity Score 28-joint count erythrocyte sedimentation rate (DAS28) < 2.6. In addition, serious infections and serious adverse events (SI/SAE) were examined at 24 weeks. RESULTS: Nine trials were selected for the NMA. Sarilumab 200 mg showed superiority versus adalimumab monotherapy on all efficacy outcomes and versus tofacitinib monotherapy on ACR20. Compared with csDMARDs, sarilumab 200 mg showed superiority on ACR 20/50/70 criteria and DAS28 < 2.6 but had similar efficacy on HAQ-DI. Efficacy of sarilumab 200 mg was similar versus certolizumab, etanercept, tofacitinib and tocilizumab 8 mg/kg monotherapy across all efficacy outcomes. SI/SAE appeared similar for sarilumab 200 mg versus all comparators. CONCLUSION: In csDMARD-IR patients, sarilumab 200 mg monotherapy has superior efficacy and similar safety versus csDMARDs, superior efficacy and similar safety versus adalimumab, and similar efficacy and safety versus bDMARDs and tsDMARDs. FUNDING: Sanofi and Regeneron Pharmaceuticals, Inc.
30569405 Effectiveness of Acupuncture on Pain, Physical Function and Health-Related Quality of Life 2019 Sep OBJECTIVE: To identify and synthesize the most recent available evidence of effectiveness of acupuncture on pain, physical function and health-related quality of life (HRQoL) in patients with rheumatoid arthritis (RA). METHODS: A comprehensive search of 12 Western and Chinese databases was undertaken from their inception up to end of 2016. Randomized controlled trials (RCTs), concerning patients with RA treated with needle acupuncture, written in English, Portuguese, German or Chinese were included. Primary outcomes included pain, physical function and HRQoL. Secondary outcomes included morning stiffness, functional impairment, number of tender and swollen joints and serum concentrations of inflamatory markers. Methodological quality was assessed by three independent reviewers using the standardized critical appraisal instrument from the Joanna Briggs Institute Meta-Analysis of Statistics Assessment and Review Instrument. RESULTS: Twenty-two studies met the inclusion criteria. Of those, 9 studies were excluded after assessment of their methodological quality. The remaining 13 original RCTs included 974 patients. Ten of these studies published in China, showed favorable statistical significant effects of acupuncture in relieving symptoms of RA compared with controls. CONCLUSIONS: Evidence suggests that acupuncture interventions may have a positive effect in pain relief, physical function and HRQoL in RA patients. However, due to the heterogeneity and methodologic limitations of the studies included in this systematic review, evidence is not strong enough to produce a best practice guideline.
31721461 Comparison of methods of quantifying global synovial metabolic activity with FDG-PET/CT in 2019 Dec AIM: 2-deoxy-2-[(18) F]fluoro-d-glucose positron emission tomography/computed tomography (FDG-PET/CT) can portray increased glycolysis due to inflammation in rheumatoid arthritis (RA). The aim of this study was to evaluate and compare the reliability and construct validity of two methods of quantifying RA disease activity using FDG-PET/CT. METHOD: Nineteen RA patients and 19 healthy controls matched to sex and age underwent prospective FDG-PET/CT imaging. Metabolic and volumetric metrics were calculated using fixed and adaptive thresholding techniques and partial volume correction. Fixed thresholds segmented regions above average maximum physiological uptake in controls. Differences of means between RA and controls were assessed using t tests, and discrimination was assessed using receiver operating characteristics. Spearman correlation analysis was used to assess associations between FDG-PET/CT measures and clinical assessments of disease activity. RESULTS: All FDG-PET/CT measures were substantially different and nearly non-overlapping between RA and controls (all P < .001). Area under the curve (AUC) for adaptive threshold parameters ranged from 0.986 to 0.997, and AUC for fixed threshold parameters ranged from 0.898 to 0.945. PET parameters were found to correlate positively with various clinical features, namely C-reactive protein, erythrocyte sedimentation rate, interleukin (IL)-6, IL-1, and swollen joint count. CONCLUSION: All FDG-PET/CT parameters reflecting global RA disease activity differentiated between RA and controls, indicating high clinical utility to diagnose and assess RA. Adaptive thresholds can be used in a wider setting without control data, but methods utilizing fixed thresholds were more reproducible and more closely associated with indications of inflammation.
30999929 Efficacy and safety of namilumab, a human monoclonal antibody against granulocyte-macropha 2019 Apr 18 BACKGROUND: Namilumab (AMG203), an immunoglobulin G1 monoclonal antibody that binds with high affinity to granulocyte-macrophage colony-stimulating factor (GM-CSF), was evaluated in a phase II randomized, double-blind, placebo-controlled study to investigate the efficacy and safety in patients with rheumatoid arthritis (RA) with an inadequate response to methotrexate (MTX-IR) or anti-tumour necrosis factor therapy (TNF-IR). METHODS: Subcutaneous namilumab (20, 80, or 150 mg) or placebo was administered at baseline and weeks 2, 6, and 10 in patients on stable background methotrexate therapy who were with MTX-IR or TNF-IR. Primary endpoint was mean change from baseline in the 28-joint Disease Activity Score, C-reactive protein version (DAS28-CRP) at week 12 comparing each of the three doses of namilumab to placebo. Safety and tolerability were assessed by adverse events (AEs) and pulmonary parameters. Results were analysed using the per-protocol population. RESULTS: One hundred eight patients from Europe and Japan (48.4 ± 12.02 years old; 77.8% female; mean DAS28-CRP 5.60-5.79; rheumatoid factor/anti-citrullinated protein antibodies + 75%) were randomized to placebo or namilumab 20, 80, or 150 mg (n = 27, 28, 25, and 28, respectively). Ninety-two were MTX-IR; 16 were TNF-IR. At week 12, a statistically significant difference in DAS28-CRP (p = 0.005) was seen for namilumab 150 mg versus placebo and separation was seen as early as week 2 for namilumab 150 mg (p < 0.05), with higher ACR50 and response rates versus placebo at week 12. A dose-response effect was observed across the DAS28-CRP endpoint with separation versus placebo evident from week 2. The most common treatment-emergent AEs were nasopharyngitis (18.5%, 17.9%, 4.0%, 14.3%), dyspnoea (0.0%, 3.6%, 8.0%, 10.7%), bronchitis (7.4%, 3.6%, 4.0%, 3.6%), and headache (3.7%, 3.6%, 12.0%, 0.0%) for placebo and 20, 80, or 150 mg of namilumab, respectively. No serious infections were observed. One serious AE (myocardial infarction) was observed with 150 mg of namilumab. There was no apparent dose relationship for AEs. A biomarker-based disease activity score showed a dose-dependent decrease at week 12. CONCLUSIONS: This phase II study demonstrates the benefit of inhibiting macrophage activity targeting the GM-CSF for RA. The study met its primary endpoint with a clear dose-response effect. An acceptable tolerability profile was demonstrated over the 12-week study. TRIAL REGISTRATION: ClinicalTrials.gov, NEXUS; NCT02379091 , submitted November 28, 2014.
31498070 IL-34 modulates rheumatoid synovial fibroblasts proliferation and migration via ERK/AKT si 2020 May OBJECTIVES: The interface between pro-inflammatory cytokines and rheumatoid synovial fibroblast (sFLS) has central effects on rheumatoid arthritis (RA). The present study aimed to explore the role of IL-34 expression as one of major cytokine implicated in RA. METHODS: We examined the expression of IL-34 after RA sFLS stimulated by IL-1β and TGF-β1 separately by reverse transcription polymerase chain reaction (RT-PCR). Transwell and wound closure techniques were used to detect whether IL-34 is involved in promoting cell migration. Cellular viability was determined via CCK-8 and cultural morphology assays between IL-34 downregulated group and non-transfected counterpart. We also tested the expression of VEGF gene with RT-PCR analysis and activation of the major signalling pathways by western blot in IL-34 down-regulated group, IL-1β or TGF-β1 treated groups. Propidium iodide (PI) staining and fluoresceine isothiocyanate (FITC) Annexin V and propidium iodide apoptosis assay were used to analyse cell cycle arrest and apoptosis separately in IL-34 down-regulated cells. RESULTS: We found that IL-1β significantly enhanced IL-34 expression, while contrarily, TGF-β1 restrained IL-34 gene expression. Transwell and wound closure techniques showed that IL-34 was involved considerably in promoting cell migration. However, IL-34 knock-down restricted sFLS migration possibly through the diminishing of MMP2 and MMP9 expression. Interestingly, IL-34 down-regulated cells exhibited significantly low cellular viability compared with the non-transfected counterpart via CCK-8 and cultural morphology assays. We found that IL-34 down-regulated cells have low VEGF gene expression compared with treated cells. PI staining showed a G0/G1 cell cycle arrest in IL-34 down-regulated cells. FITC Annexin V and propidium iodide apoptosis assay verified that IL-34 down-regulated cells induced massive apoptosis through apoptotic signalling caspase3, while IL-1β treated cells presented termination of cellular apoptosis signalled by BCL-2. Furthermore, we observed IL-34 induced activation of ERK1/2 and AKT pathways while IL-34 down-regulation significantly decreased the activation of these pathways. CONCLUSIONS: Our data add novel insights into the pathogenesis of RA and we suggest that IL-34 plays a dominant role in controlling migration and proliferation of sFLS. Consequently, therapeutic strategies targeting IL-34 could be a potent therapy for RA.
30124939 Passive smoking in childhood increases the risk of developing rheumatoid arthritis. 2019 Jul 1 OBJECTIVES: To investigate the link between smoking status, including childhood and adult passive exposure, and the risk of incident RA. METHODS: The French E3N cohort includes 98 995 female volunteers prospectively followed since 1990. Self-administered questionnaires sent every 2-3 years collected medical events, general, lifestyle and environmental characteristics. RA diagnoses were collected in three successive questionnaires and confirmed if women received reimbursement for an RA-specific medication. The risk of incident RA was estimated using an age-adjusted Cox model that considers smoking status as a time-dependent variable. RESULTS: Among 71 248 women, 371 incident RA cases were confirmed. Ever-smokers not exposed to passive smoking had an increased risk of RA [1.38 (95% CI 1.10, 1.74)]. In never-smokers, passive smoking exposure during childhood was associated with a borderline increased risk of RA in the same range as active smoking in adults, with an hazard ratio (HR) of 1.43 (95% CI 0.97, 2.11). Ever-smokers who also had childhood passive smoking exposure had a higher risk of RA than smokers not exposed during childhood [HR 1.67 (95% CI 1.17, 2.39)], but without a significant difference (P = 0.30). RA began earlier in smokers exposed to childhood passive smoking. CONCLUSION: This study confirms that active smoking is associated with an increased risk of RA. It suggests for the first time that passive exposure to tobacco during childhood might also increase the risk of RA in future light smokers and probably non-smokers. Our results highlight the importance of avoiding any tobacco environment in children, especially in those with a family history of RA.
31142478 Altered DNA methylation in children born to mothers with rheumatoid arthritis during pregn 2019 Sep OBJECTIVES: The main objective of this study was to determine whether the DNA methylation profile of children born to mothers with rheumatoid arthritis (RA) is different from that of children born to mothers from the general population. In addition, we aimed to determine whether any differences in methylation are associated with maternal RA disease activity or medication use during pregnancy. METHODS: For this study, genome-wide DNA methylation was measured at cytosine-phosphate-guanine (CpG) sites, using the Infinium Illumina HumanMethylation 450K BeadChip, in 80 blood samples from children (mean age=6.8 years) born to mothers with RA. As controls, blood samples from 354 children (mean age=6.0 years) from the population-based Generation R Study were used. Linear mixed models were performed to investigate differential methylation between the groups, corrected for relevant confounders. RESULTS: A total of 147 CpGs were differentially methylated between blood samples of children born to mothers with RA and the control blood samples. The five most significantly associated CpGs were cg06642177, cg08867893, cg06778273, cg07786668 and cg20116574. The differences in methylation were not associated with maternal RA disease activity or medication use during pregnancy. CONCLUSIONS: DNA methylation at 147 CpGs differed between children born to mothers with RA and children born to mothers from the general population. It remains unknown whether the identified associations are causal, and if so whether they are caused by the disease or treatment. More research, including replication of these results, is necessary in order to strengthen the relevance of our findings for the later-life health of children born to mothers with RA.
30317598 P2X7, a critical regulator and potential target for bone and joint diseases. 2019 Mar Abundant evidence indicted that P2X7 receptor show a essential role in human health and some human diseases including hypertension, atherosclerosis, pulmonary inflammation, tuberculosis infection, psychiatric disorders, and cancer. P2X7 receptor also has an important role in some central nervous system diseases such as neurodegenerative disorders. Recently, more research suggested that P2X7 receptor also plays a crucial role in bone and joint diseases. But the effect of P2X7 receptor on skeletal and joint diseases has not been systematically reviewed. In this article, the role of P2X7 receptor in skeletal and joint diseases is elaborated. The activation of P2X7 receptor can ameliorate osteoporosis by inducing a fine balance between osteoclastic resorption and osteoblastic bone formation. The activation of P2X7 receptor can relieve the stress fracture injury by increasing the response to mechanical loading and inducing osteogenesis. But the activation of P2X7 receptor mediates the cell growth and cell proliferation in bone cancer. In addition, the activation of P2X7 receptor can aggravate the process of some joint diseases such as osteoarthritis, rheumatoid arthritis, and acute gouty arthritis. The inhibition of P2X7 receptor can alleviate the pathological process of joint disease to some extent. In conclusion, P2X7 receptor may be a critical regulator and therapeutic target for bone and joint diseases.
30307604 IL4-10 fusion protein: a novel immunoregulatory drug combining activities of interleukin 4 2019 Jan The objective of this study was to test the capacity of a newly developed fusion protein of interleukin 4 (IL-4) and IL-10 [IL4-10 fusion protein (FP)] to shift multiple pro-inflammatory pathways towards immune regulation, and to inhibit pro-inflammatory activity in arthritis models. The effects of IL4-10 FP in comparison with IL-4, IL-10 and IL-4 plus IL-10 on pro- and anti-inflammatory mediators, T cells and immunoglobulin (Ig) receptors in favour of immunoregulatory activity were studied. In addition, the capacity of IL4-10 FP to inhibit pro-inflammatory activity in ex-vivo and in-vivo arthritis models was investigated. IL4-10 FP robustly inhibited pro-inflammatory cytokine [IL-1β, tumour necrosis factor (TNF)-α, IL-6 and IL-8] production in whole blood cultures, mediated by both the IL-10 and the IL-4 moiety. IL4-10 fusion protein induced IL-1 receptor antagonist (IL-1RA) production and preserved soluble TNF receptor (sTNFR) levels, strongly increasing IL-1RA/IL-1β and sTNFR/TNF-α ratios. In addition, IL4-10 FP strongly inhibited T helper (Th) type 1 and 17 cytokine secretion, while maintaining FoxP3 expression and up-regulating Th2 activity. In addition, while largely leaving expression of activating Fc gamma receptor (FcγR)I, III and Fc epsilon receptor (FcεR) unaffected, it significantly shifted the FcγRIIa/FcγRIIb ratio in favour of the inhibitory FcγRIIb. Moreover, IL4-10 FP robustly inhibited secretion of pro-inflammatory cytokines by rheumatoid arthritis synovial tissue and suppressed experimental arthritis in mice, without inducing B cell hyperactivity. IL4-10 fusion protein is a novel drug, signalling cells to induce immunoregulatory activity that overcomes limitations of IL-4 and IL-10 stand-alone therapy, and therefore has therapeutic potential for inflammatory diseases such as rheumatoid arthritis.
31696912 Rheumatoid arthritis and the Th1 chemokine MIG. 2019 Nov Monokine induced by interferon (IFN)-γ (MIG) and its receptor chemokine (C-X-C motif) receptor 3 (CXCR)3 seem to play an important role in the pathogenesis of rheumatoid arthritis (RA). MIG expression has been observed in sera, synovial fluid (SF) and synovial tissue of RA patients; it is highly expressed in RA synovium by infiltrating macrophage-like cells and fibroblast-like synoviocytes. A Type-1 helper-response orientated disease was suggested because of the high expression of CXCR3 in SF T cells and the presence of elevated IFN-γ levels. It has been observed a decrease of the inflammation by anti-CXCR3, and anti-MIG molecules, in fact they inhibit CXCR3-enhanced cell migration and pro-inflammatory cytokine expression, leading to an amelioration of the arthritis progression. These findings suggest a possible therapeutic role of these molecules in humans.
30770506 Structural Changes over a Short Period Are Associated with Functional Assessments in Rheum 2019 Jul OBJECTIVE: To investigate the correlation between changes in radiological quantitative assessment with changes in clinical and functional assessment from baseline to 3 months in patients with rheumatoid arthritis (RA). METHODS: Twenty-eight patients with RA [methotrexate (MTX) and anti-tumor necrosis factor-α (TNF-α) group with high disease activity (n = 18); and MTX group with low disease activity (n = 10)] underwent assessments at baseline and 3 months: clinical [28-joint count Disease Activity Score (DAS28)], functional [Health Assessment Questionnaire (HAQ) and Michigan Hand Outcome Questionnaire (MHQ)], and imaging-based [3 Tesla magnetic resonance imaging (MRI) and high-resolution peripheral quantitative computed tomography (HR-pQCT)]. MR images were evaluated semiquantitatively [RA MRI scoring (RAMRIS)] and quantitatively for the volume of synovitis and bone marrow edema (BME) lesions. Erosion volumes were measured using HR-pQCT. RESULTS: After 3 months, the anti-TNF-α group demonstrated an improvement in disease activity through DAS28, HAQ, and MHQ. MRI showed significant decreases in synovitis and BME volume for the anti-TNF-α group, and significant increases in the MTX group. HR-pQCT showed significant decreases in bone erosion volume for the anti-TNF-α group, and significant increases in the MTX group. No significance was observed using RAMRIS. Changes in synovitis, BME, and erosion volumes, but not RAMRIS, were significantly correlated with changes in DAS28, HAQ, and MHQ. CONCLUSION: Quantitative measures were more sensitive than semiquantitative grading when evaluating structural and inflammatory changes with treatment, and were associated with patient clinical and functional outcomes. Multimodality imaging with 3T MRI and HR-pQCT may provide promising biomarkers that help determine disease progression and therapy response.
31449733 Comprehensive Profiling of the Rheumatoid Arthritis Antibody Repertoire. 2020 Feb OBJECTIVE: Autoantibodies against citrullinated proteins are found in 64-89% of rheumatoid arthritis (RA) patients, with 88-99% specificity. This study was undertaken to create an unbiased, comprehensive profile of serum antibodies against the human proteome, including the citrullinome and the homocitrullinome, in RA patients, using a high-density peptide array. METHODS: Our high-density peptide array, consisting of >4.6 million peptides, contained the entire annotated human proteome. The 20,246 proteins were represented as overlapping 16-mer peptides. In addition to native peptides, citrullinated and homocitrullinated peptides were included, as substitutions for arginine and lysine, and provided a comprehensive screen against all possible epitopes. Twenty-six serum samples (from 8 controls and 18 RA patients) were profiled on the high-density peptide array. Using RA-specific epitopes, we constructed an 8-epitope diagnostic biomarker on a Gyrolab xPlore instrument with a cohort of 92 serum samples (from 29 controls and 63 RA patients). The diagnostic biomarker was further validated with an independent cohort of 181 serum samples (from 54 controls and 127 RA patients). RESULTS: In the initial cohort the diagnostic performance of the 8-epitope biomarker yielded 96.6% specificity and 92.1% sensitivity. The overall diagnostic performance in the validation cohort was 94.4% specificity and 85% sensitivity. In both cohorts, the performance of the 8-epitope diagnostic biomarker compared favorably against the Abnova cyclic citrullinated peptide 2 (CCP2) assay. Using data from the peptide array, we identified novel RA-specific epitopes and formed the basis of a new RA diagnostic assay. CONCLUSION: Comprehensive antibody profiling using a high-density peptide array not only identified novel RA-specific epitopes but also allowed us to construct a novel diagnostic biomarker that is as specific as and more sensitive than the Abnova CCP2 assay.
30717793 Anti-citrullinated protein antibodies are associated with osteopenia but not with pain at 2019 Feb 4 BACKGROUND: Anti-citrullinated protein antibodies (ACPA) have been suggested to have a potential role in both bone loss and pain in rheumatoid arthritis (RA), based on studies in vitro and in animal models. Here we addressed if anti-cyclic citrullinated (anti-CCP) antibodies were associated with osteopenia or pain in patients with RA, at the time for diagnosis. METHODS: Baseline data from the BARFOT (Better Anti-Rheumatic PharmacOTherapy) cohort, which consists of patients with RA with a disease duration of 1 year or less, were analyzed. To be included, they should have been assessed by anti-CCP, dual-energy X-ray absorptiometry (DEXA) of lumbar spine and hip, and/or digital X-ray radiogrammetry (DXR) of the metacarpal bones. Osteopenia was defined as a z-score < - 1 SD. Pain VAS > 40 mm, was defined as patient unacceptable pain. Multiple logistic regression analyses were performed to assess whether anti-CCP was independently associated with osteopenia or unacceptable pain. RESULTS: Of the 657 patients, 65% were women, 58% were anti-CCP positive, 37% had osteopenia in the lumbar spine, and 29% had osteopenia in the hip. Sixty-one percent had unacceptable pain at diagnosis. Patients positive for anti-CCP had significantly more frequently osteopenia in the femoral neck and Ward's triangle compared with anti-CCP-negative patients (p = 0.016 and 0.003, respectively). This difference was found in men at any anti-CCP titer, but in women, osteopenia in these hip locations was found only in those with high anti-CCP titers (> 500 IU/ml). Anti-CCP was not associated with osteopenia in the lumbar spine or the metacarpal bones. In multiple logistic regression analyses, anti-CCP was independently associated with osteopenia in the femoral neck and/or Ward's triangle but not with unacceptable pain. Instead, inflammatory variables were independently associated with unacceptable pain. CONCLUSION: These data show that in patients with early RA, anti-CCP positivity was independently associated with osteopenia in the femoral neck and/or Ward, but not in the lumbar spine. In our patients, we could not confirm a recently suggested association between anti-CCP antibodies and pain. Further studies are necessary to explore the possible clinical relevance of interactions between ACPA, bone, and pain found in vitro and in animal models.
29998822 Evaluating IBD-specific antiglycan antibodies in serum of patients with spondyloarthritis 2019 Jan OBJECTIVES: The presence of serological markers associated with inflammatory bowel disease (IBD) has been studied in spondyloarthritis with conflicting results. The anti-glycan antibodies: anti-laminaribioside, anti-chitobioside, and anti-mannobioside carbohydrate antibodies (ALCA, ACCA, and AMCA) are serological markers previously associated with IBD. We aim to investigate the prevalence of these antibodies in spondyloarthritis in comparison with rheumatoid arthritis (RA) patients. METHODS: Serum samples were obtained from consecutive patients with spondyloarthritis and were compared to RA and healthy controls. Anti-glycan antibodies - ALCA, ACCA and AMCA - were assessed using ELISA (Glycominds Ltd, Israel). Demographic characteristics, family history, disease pattern, skin evaluation (for PsA), disease activity and a questionnaire for gastrointestinal symptoms were recorded. RESULTS: Seventy patients were recruited: 36 ankylosing spondylitis (AS) and 28 psoriatic arthritis (PsA). No difference in ALCA or AMCA levels was observed between all the study groups. Significantly higher levels of ACCA were observed in RA patients, compared to healthy controls (p=0.002). One or more of the anti-glycan antibodies was found in 16.7%, and 3.6% of patients with AS and PsA, respectively, compared to 7.3% in healthy controls and 27% in RA (p=0.09). No correlation was found between the presence of anti-glycan antibodies and gastrointestinal symptoms. CONCLUSIONS: Our data fail to show an increased prevalence of anti-glycan antibodies in AS or PsA patients. ACCA were found to be significantly higher in RA patients than in controls, and may serve as an inflammatory biomarker. The present results do not support a role for antiglycan antibodies as biomarkers for spondyloarthritis.
30970284 Urginea indica attenuated rheumatoid arthritis and inflammatory paw edema in diverse anima 2019 Jun 28 ETHNOPHARMACOLOGICAL RELEVANCE: Urginea indica has been used in the traditional system of medicine to treat various inflammatory diseases. AIM OF THE STUDY: Present study investigates the effects of aqueous and ethanolic extracts of U. indica on joint inflammation using different models of acute and chronic inflammation. MATERIALS AND METHODS: FCA-induced arthritic rat model, a model of chronic joint inflammation, was used to evaluate the anti-arthritic effects of plant extracts (500 mg/kg, each extract). Macroscopic arthritic scoring, digital water plethysmometery, and histopathological evaluation (H & E staining) were performed to measure the severity of arthritis. Acute inflammatory models like, carrageenan-, histamine- and serotonin-induced paw edema models were used to evaluate effects of U. indica, and supported by xylene-induced ear edema model. RESULTS: Both extracts significantly inhibited arthritic development, paw edema, bone erosion, pannus formation, and infiltration of inflammatory cells. Treatment with U. indica extracts resulted in almost normalization of altered counts of white blood cells (WBCs), platelets, and red blood cells (RBCs), along with Hb content. Both extracts were found safe in terms of hepatotoxicity and nephrotoxicity as determined by non-significant difference of alanine aminotransferase (ALT), aspartate transaminase (AST), urea, and creatinine levels among all groups. U. indica significantly attenuated carrageenan-induced paw edema. There are several mechanisms involved in the attenuation of carrageenan-induced paw edema; inhibition of autacoids is one of those important mechanisms. The autacoid inhibition was confirmed by reduction of histamine- and serotonin-induced paw edema found in plant extract treated groups. Suppression of xylene-induced ear edema by plant extract further validated the suggested mechanism of autacoid inhibition. GC-MS analysis showed the presence of isopropyl palmitate in the highest quantity (26.852%). CONCLUSIONS: This study validated the folkloric uses of U. indica and showed that plant possessed anti-arthritic and anti-inflammatory properties which might be ascribed to inhibition of autacoids.
31679247 Polymeric Micelles for the Treatment of Rheumatoid Arthritis. 2019 Rheumatoid arthritis (RA) affects around 1% of the world's population and places heavy burdens on patients and society. RA pathogenesis has been studied for centuries, and findings suggest that it is activated by varied factors such as infection, genetic activation, and environmental changes, and travels differential pathways in patients, which increases the difficulty of treatment. There is currently no cure for RA. Current treatments inhibit inflammation, protect joints, and suppress immune cells like macrophages and T-lymphocytes. However, these therapies usually have issues of ineffectiveness, drug resistance, and many side effects. The reason is that therapies like methotrexate (MTX), dexamethasone (Dex), and cyclosporine A (CsA) are very lipophilic and have broad distribution in vivo. Micelles are ideal carriers to increase the solubility, bioavailability, half-life, and targeting of these hydrophobic drugs, and thus can be used for RA treatment. In the past decade, micelle-based therapies have become an attractive new strategy for RA treatment. This review summarizes the merits of micelles for RA, the therapeutic targets for RA, and studies that show the recent progress of developed micelles for RA. We compare the composition, performance, potential merits, and limitations of current therapies, and discusses the future directions of advanced and smart micelles for RA.