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      Circulating Level of Blood Iron and Copper Associated with Inflammation and Disease Activity of Rheumatoid Arthritis

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          Abstract

          This study aims to compare the concentrations of circulating levels of iron, zinc, and copper in blood samples of rheumatoid arthritis (RA) patients which determine the correlations with inflammation and disease activity. A total of 102 RA patients and 66 healthy controls were enrolled. Circulation of iron, zinc, and copper levels in whole blood were assessed. Hemoglobin, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), anticyclic citrullinated peptide antibody (anti-CCP) levels were collected. A meta-analysis was performed to validate our findings. Single and multiple variate generalized linear regression were applied to identify the correlation between trace elements and clinical characteristics. Blood copper level was significantly higher in RA patients ( P < 0.001), while iron and zinc levels were decreased ( P < 0.001 and P = 0.02, respectively). Meta-analysis confirmed our findings for zinc (SMD =  − 1.17, P < 0.001) and copper (SMD = 1.24, P < 0.001). Copper level was positively correlated with DAS28-CRP ( r = 0.35, P < 0.01), CRP ( r = 0.45, P < 0.01) and ESR ( r = 0.58, P < 0.01). Iron level was negatively correlated with DAS28-CRP ( r =  − 0.37, P < 0.01), CRP ( r =  − 0.46, P < 0.01) and ESR ( r =  − 0.55, P < 0.01). Circulating blood copper was significantly higher and positively correlated with DAS28-CRP and inflammatory markers, while circulating blood iron was decreased and negatively correlated with DAS28-CRP and inflammatory markers in RA patients.

          Supplementary Information

          The online version contains supplementary material available at 10.1007/s12011-022-03148-z.

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          Most cited references28

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          2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative.

          The 1987 American College of Rheumatology (ACR; formerly, the American Rheumatism Association) classification criteria for rheumatoid arthritis (RA) have been criticized for their lack of sensitivity in early disease. This work was undertaken to develop new classification criteria for RA. A joint working group from the ACR and the European League Against Rheumatism developed, in 3 phases, a new approach to classifying RA. The work focused on identifying, among patients newly presenting with undifferentiated inflammatory synovitis, factors that best discriminated between those who were and those who were not at high risk for persistent and/or erosive disease--this being the appropriate current paradigm underlying the disease construct "rheumatoid arthritis." In the new criteria set, classification as "definite RA" is based on the confirmed presence of synovitis in at least 1 joint, absence of an alternative diagnosis that better explains the synovitis, and achievement of a total score of 6 or greater (of a possible 10) from the individual scores in 4 domains: number and site of involved joints (score range 0-5), serologic abnormality (score range 0-3), elevated acute-phase response (score range 0-1), and symptom duration (2 levels; range 0-1). This new classification system redefines the current paradigm of RA by focusing on features at earlier stages of disease that are associated with persistent and/or erosive disease, rather than defining the disease by its late-stage features. This will refocus attention on the important need for earlier diagnosis and institution of effective disease-suppressing therapy to prevent or minimize the occurrence of the undesirable sequelae that currently comprise the paradigm underlying the disease construct "rheumatoid arthritis."
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            Bias in meta-analysis detected by a simple, graphical test.

            Funnel plots (plots of effect estimates against sample size) may be useful to detect bias in meta-analyses that were later contradicted by large trials. We examined whether a simple test of asymmetry of funnel plots predicts discordance of results when meta-analyses are compared to large trials, and we assessed the prevalence of bias in published meta-analyses. Medline search to identify pairs consisting of a meta-analysis and a single large trial (concordance of results was assumed if effects were in the same direction and the meta-analytic estimate was within 30% of the trial); analysis of funnel plots from 37 meta-analyses identified from a hand search of four leading general medicine journals 1993-6 and 38 meta-analyses from the second 1996 issue of the Cochrane Database of Systematic Reviews. Degree of funnel plot asymmetry as measured by the intercept from regression of standard normal deviates against precision. In the eight pairs of meta-analysis and large trial that were identified (five from cardiovascular medicine, one from diabetic medicine, one from geriatric medicine, one from perinatal medicine) there were four concordant and four discordant pairs. In all cases discordance was due to meta-analyses showing larger effects. Funnel plot asymmetry was present in three out of four discordant pairs but in none of concordant pairs. In 14 (38%) journal meta-analyses and 5 (13%) Cochrane reviews, funnel plot asymmetry indicated that there was bias. A simple analysis of funnel plots provides a useful test for the likely presence of bias in meta-analyses, but as the capacity to detect bias will be limited when meta-analyses are based on a limited number of small trials the results from such analyses should be treated with considerable caution.
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              Zinc decreases C-reactive protein, lipid peroxidation, and inflammatory cytokines in elderly subjects: a potential implication of zinc as an atheroprotective agent.

              Chronic inflammation and oxidative stress are common risk factors for atherosclerosis. Zinc is an essential micronutrient that can function as an antiinflammatory and antioxidative agent, and as such, it may have atheroprotective properties. We hypothesized that zinc down-regulates the production of atherosclerosis-related cytokines/molecules in humans. To examine these effects, we conducted a randomized, double-blinded, placebo trial of zinc supplementation in elderly subjects. We recruited 40 healthy elderly subjects (aged 56-83 y) and randomly assigned them to 2 groups. One group was given an oral dose of 45 mg zinc/d as a gluconate for 6 mo. The other group was given a placebo. Cell culture models were conducted to study the mechanism of zinc as an atheroprotective agent. After 6 mo of supplementation, the intake of zinc, compared with intake of placebo, increased the concentrations of plasma zinc and decreased the concentrations of plasma high-sensitivity C-reactive protein (hsCRP), interleukin (IL)-6, macrophage chemoattractant protein 1 (MCP-1), vascular cell adhesion molecule 1 (VCAM-1), secretory phospholipase A2, and malondialdehyde and hydroxyalkenals (MDA+HAE) in elderly subjects. Regression analysis showed that changes in concentrations of plasma zinc were inversely associated with changes in concentrations of plasma hsCRP, MCP-1, VCAM-1, and MDA+HAE after 6 mo of supplementation. In cell culture studies, we showed that zinc decreased the generation of tumor necrosis factor-alpha, IL-1beta, VCAM-1, and MDA+HAE and the activation of nuclear transcription factor kappaB and increased antiinflammatory proteins A20 and peroxisome proliferator-activated receptor-alpha in human monocytic leukemia THP-1 cells and human aortic endothelial cells compared with zinc-deficient cells. These findings suggest that zinc may have a protective effect in atherosclerosis because of its antiinflammatory and antioxidant functions.
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                Author and article information

                Contributors
                Shicheng.Guo@wisc.edu
                hedongyi1967@shutcm.edu.cn
                Journal
                Biol Trace Elem Res
                Biol Trace Elem Res
                Biological Trace Element Research
                Springer US (New York )
                0163-4984
                1559-0720
                28 March 2022
                28 March 2022
                2023
                : 201
                : 1
                : 90-97
                Affiliations
                [1 ]GRID grid.412540.6, ISNI 0000 0001 2372 7462, Department of Rheumatology, , Shanghai Guanghua Hospital, Shanghai University of Traditional Chinese Medicine, ; Shanghai, 200052 China
                [2 ]GRID grid.479672.9, Department of Rheumatology, , The Second Affiliated Hospital of Shandong University of Traditional Chinese Medicine, ; Jinan, Shandong, 250001 China
                [3 ]Arthritis Institute of Integrated Traditional and Western Medicine, Shanghai Chinese Medicine Research Institute, Shanghai, 200052 China
                [4 ]GRID grid.14003.36, ISNI 0000 0001 2167 3675, Department of Medical Genetics, , School of Medicine and Public Health, University of Wisconsin-Madison, ; Madison, WI USA
                Article
                3148
                10.1007/s12011-022-03148-z
                9823016
                35344152
                fd714855-398c-44d7-846d-7a7464d4e2ed
                © The Author(s) 2022

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 18 January 2022
                : 1 February 2022
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 81774114
                Award ID: 82074234
                Award Recipient :
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                © Springer Science+Business Media, LLC, part of Springer Nature 2023

                Biochemistry
                rheumatoid arthritis,copper,iron,zinc,disease activity,das28-crp
                Biochemistry
                rheumatoid arthritis, copper, iron, zinc, disease activity, das28-crp

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