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Kocadag HB, Weischendorff S, De Pietri S, Nielsen CH, Rathe M, Als-Nielsen B, Hasle H, Juul A, Müller K, Sørum ME. Upregulation of Insulin-like Growth Factor-I in Response to Chemotherapy in Children with Acute Lymphoblastic Leukemia. Int J Mol Sci 2024; 25:9582. [PMID: 39273528 PMCID: PMC11394967 DOI: 10.3390/ijms25179582] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2024] [Revised: 08/21/2024] [Accepted: 08/30/2024] [Indexed: 09/15/2024] Open
Abstract
The treatment of childhood cancer is challenged by toxic side effects mainly due to chemotherapy-induced organ damage and infections, which are accompanied by severe systemic inflammation. Insulin-like growth factor I (IGF-I) is a key regulating factor in tissue repair. This study investigated associations between the circulating IGF-I levels and chemotherapy-related toxicity in pediatric acute lymphoblastic leukemia (ALL). In this prospective study, we included 114 patients (age: 1-17 years) with newly diagnosed ALL treated according to The Nordic Society of Paediatric Haematology and Oncology (NOPHO) ALL2008 protocol between 2013 and 2018. The patients' plasma levels of IGF-I, and the primary binding protein, IGFBP-3, were measured weekly during the first six weeks of treatment, including the induction therapy. The patients' systemic inflammation was monitored by their C-reactive protein (CRP) and interleukin (IL)-6 levels and their intestinal epithelial damage by their plasma citrulline levels. IGF-I and IGFBP-3 were converted into sex-and age-adjusted standard deviation scores (SDS) using 1621 healthy children as reference. At ALL diagnosis, IGF-I levels were decreased (median (quartiles): -1.2 SDS (-1.9 to -0.5), p = 0.001), but increased significantly following the initiation of chemotherapy, peaking on day 8 (0.0 SDS (from -0.8 to 0.7), p < 0.001). This increase correlated with the levels of CRP (rho = 0.37, p < 0.001) and IL-6 (rho = 0.39, p = 0.03) on day 15, when these markers reached maximum levels. A larger IGF-I increase from day 1 to 15 correlated with a slower recovery rate of the intestinal damage marker citrulline from day 15 to 29 (rho = -0.28, p = 0.01). Likewise, IGFBP-3 was reduced at diagnosis, followed by an increase after treatment initiation, and was highly correlated with same-day IGF-I levels. This study demonstrates a chemotherapy-induced increase in IGF-I, with a response that appears to reflect the severity of tissue damage and systemic inflammation, preceding CRP and IL-6 increases. IGF-I may have potential as an early reactive biomarker for acute toxicity in patients with ALL.
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Affiliation(s)
- Helin Berna Kocadag
- Department of Pediatrics and Adolescent Medicine, Copenhagen University Hospital-Rigshospitalet, 2100 Copenhagen, Denmark
| | - Sarah Weischendorff
- Department of Pediatrics and Adolescent Medicine, Copenhagen University Hospital-Rigshospitalet, 2100 Copenhagen, Denmark
| | - Silvia De Pietri
- Department of Pediatrics and Adolescent Medicine, Copenhagen University Hospital-Rigshospitalet, 2100 Copenhagen, Denmark
| | - Claus Henrik Nielsen
- Institute for Inflammation Research, Copenhagen University Hospital-Rigshospitalet, 2100 Copenhagen, Denmark
| | - Mathias Rathe
- Hans Christian Andersen Children's Hospital, Odense University Hospital, 5000 Odense, Denmark
| | - Bodil Als-Nielsen
- Department of Pediatrics and Adolescent Medicine, Copenhagen University Hospital-Rigshospitalet, 2100 Copenhagen, Denmark
| | - Henrik Hasle
- Department of Pediatrics, Aarhus University Hospital, 8200 Aarhus, Denmark
| | - Anders Juul
- Department of Growth and Reproduction, Copenhagen University Hospital-Rigshospitalet, 2100 Copenhagen, Denmark
- Department of Clinical Medicine, University of Copenhagen, 2200 Copenhagen, Denmark
- International Research Centre for Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Copenhagen University Hospital-Rigshospitalet, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Klaus Müller
- Department of Pediatrics and Adolescent Medicine, Copenhagen University Hospital-Rigshospitalet, 2100 Copenhagen, Denmark
- Institute for Inflammation Research, Copenhagen University Hospital-Rigshospitalet, 2100 Copenhagen, Denmark
- Department of Clinical Medicine, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Maria Ebbesen Sørum
- Department of Pediatrics and Adolescent Medicine, Copenhagen University Hospital-Rigshospitalet, 2100 Copenhagen, Denmark
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Lange A, Kostadinova L, Damjanovska S, Gad I, Syed S, Siddiqui H, Yousif P, Kowal CM, Shive C, Burant C, Singer N, Bej T, Al-Kindi S, Wilson B, Mattar M, Zidar DA, Anthony DD. Red Cell Distribution Width and Absolute Lymphocyte Count Associate With Biomarkers of Inflammation and Subsequent Mortality in Rheumatoid Arthritis. J Rheumatol 2023; 50:166-174. [PMID: 36319020 PMCID: PMC9898085 DOI: 10.3899/jrheum.211411] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/09/2022] [Indexed: 11/07/2022]
Abstract
OBJECTIVE Morbidity and mortality in rheumatoid arthritis (RA) is partly mitigated by maintaining immune and hematologic homeostasis. Identification of those at risk is challenging. Red cell distribution width (RDW) and absolute lymphocyte count (ALC) associate with cardiovascular disease (CVD) and mortality in the general population, and with disease activity in RA. How these variables relate to inflammation and mortality in RA was investigated. METHODS In a retrospective single Veterans Affairs (VA) Rheumatology Clinic cohort of 327 patients with RA treated with methotrexate (MTX)+/- a tumor necrosis factor (TNF) inhibitor (TNFi), we evaluated RDW and ALC before and during therapy and in relation to subsequent mortality. Findings were validated in a national VA cohort (n = 13,914). In a subset of patients and controls, we evaluated inflammatory markers. RESULTS In the local cohort, high RDW and low ALC prior to MTX treatment was associated with subsequent mortality over 10 years (both P < 0.001). The highest mortality was observed in those with both high RDW and low ALC. This remained after adjusting for age and comorbidities and was validated in the national RA cohort. In the immunology cohort, soluble and cellular inflammatory markers were higher in patients with RA than in controls. ALC correlated with age, plasma TNF receptor II, natural killer HLA-DR mean fluorescence intensity, and CD4CM/CD8CM HLA-DR/CD38%, whereas RDW associated with age and ALC. MTX initiation was followed by an increase in RDW and a decrease in ALC. TNFi therapy added to MTX resulted in an increase in ALC. CONCLUSION RDW and ALC before disease-modifying antirheumatic drug therapy are associated with biomarkers of monocyte/macrophage inflammation and subsequent mortality. The mechanistic linkage between TNF signaling and lymphopenia found here warrants further investigation.
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Affiliation(s)
- Alyssa Lange
- A. Lange, MS, L. Kostadinova, MD, S. Damjanovska, MD, I. Gad, MD, S. Syed, MD, H. Siddiqui, MD, P. Yousif, MD, C.M. Kowal, BS, C. Burant, PhD, T. Bej, MS, S. Al-Kindi, MD, B. Wilson, PhD, M. Mattar, MD, D.A. Zidar, MD, PhD, Department of Medicine, VA Medical Center and VA GRECC, Case Western Reserve University
| | - Lenche Kostadinova
- A. Lange, MS, L. Kostadinova, MD, S. Damjanovska, MD, I. Gad, MD, S. Syed, MD, H. Siddiqui, MD, P. Yousif, MD, C.M. Kowal, BS, C. Burant, PhD, T. Bej, MS, S. Al-Kindi, MD, B. Wilson, PhD, M. Mattar, MD, D.A. Zidar, MD, PhD, Department of Medicine, VA Medical Center and VA GRECC, Case Western Reserve University
| | - Sofi Damjanovska
- A. Lange, MS, L. Kostadinova, MD, S. Damjanovska, MD, I. Gad, MD, S. Syed, MD, H. Siddiqui, MD, P. Yousif, MD, C.M. Kowal, BS, C. Burant, PhD, T. Bej, MS, S. Al-Kindi, MD, B. Wilson, PhD, M. Mattar, MD, D.A. Zidar, MD, PhD, Department of Medicine, VA Medical Center and VA GRECC, Case Western Reserve University
| | - Ibtissam Gad
- A. Lange, MS, L. Kostadinova, MD, S. Damjanovska, MD, I. Gad, MD, S. Syed, MD, H. Siddiqui, MD, P. Yousif, MD, C.M. Kowal, BS, C. Burant, PhD, T. Bej, MS, S. Al-Kindi, MD, B. Wilson, PhD, M. Mattar, MD, D.A. Zidar, MD, PhD, Department of Medicine, VA Medical Center and VA GRECC, Case Western Reserve University
| | - Sameena Syed
- A. Lange, MS, L. Kostadinova, MD, S. Damjanovska, MD, I. Gad, MD, S. Syed, MD, H. Siddiqui, MD, P. Yousif, MD, C.M. Kowal, BS, C. Burant, PhD, T. Bej, MS, S. Al-Kindi, MD, B. Wilson, PhD, M. Mattar, MD, D.A. Zidar, MD, PhD, Department of Medicine, VA Medical Center and VA GRECC, Case Western Reserve University
| | - Husna Siddiqui
- A. Lange, MS, L. Kostadinova, MD, S. Damjanovska, MD, I. Gad, MD, S. Syed, MD, H. Siddiqui, MD, P. Yousif, MD, C.M. Kowal, BS, C. Burant, PhD, T. Bej, MS, S. Al-Kindi, MD, B. Wilson, PhD, M. Mattar, MD, D.A. Zidar, MD, PhD, Department of Medicine, VA Medical Center and VA GRECC, Case Western Reserve University
| | - Patrick Yousif
- A. Lange, MS, L. Kostadinova, MD, S. Damjanovska, MD, I. Gad, MD, S. Syed, MD, H. Siddiqui, MD, P. Yousif, MD, C.M. Kowal, BS, C. Burant, PhD, T. Bej, MS, S. Al-Kindi, MD, B. Wilson, PhD, M. Mattar, MD, D.A. Zidar, MD, PhD, Department of Medicine, VA Medical Center and VA GRECC, Case Western Reserve University
| | - Corinne M Kowal
- A. Lange, MS, L. Kostadinova, MD, S. Damjanovska, MD, I. Gad, MD, S. Syed, MD, H. Siddiqui, MD, P. Yousif, MD, C.M. Kowal, BS, C. Burant, PhD, T. Bej, MS, S. Al-Kindi, MD, B. Wilson, PhD, M. Mattar, MD, D.A. Zidar, MD, PhD, Department of Medicine, VA Medical Center and VA GRECC, Case Western Reserve University
| | - Carey Shive
- C. Shive, PhD, Department of Medicine, VA Medical Center and VA GRECC, and Department of Pathology, Case Western Reserve University
| | - Christopher Burant
- A. Lange, MS, L. Kostadinova, MD, S. Damjanovska, MD, I. Gad, MD, S. Syed, MD, H. Siddiqui, MD, P. Yousif, MD, C.M. Kowal, BS, C. Burant, PhD, T. Bej, MS, S. Al-Kindi, MD, B. Wilson, PhD, M. Mattar, MD, D.A. Zidar, MD, PhD, Department of Medicine, VA Medical Center and VA GRECC, Case Western Reserve University
| | - Nora Singer
- N. Singer, MD, Division of Rheumatology, MetroHealth Medical Center, Case Western Reserve University
| | - Taissa Bej
- A. Lange, MS, L. Kostadinova, MD, S. Damjanovska, MD, I. Gad, MD, S. Syed, MD, H. Siddiqui, MD, P. Yousif, MD, C.M. Kowal, BS, C. Burant, PhD, T. Bej, MS, S. Al-Kindi, MD, B. Wilson, PhD, M. Mattar, MD, D.A. Zidar, MD, PhD, Department of Medicine, VA Medical Center and VA GRECC, Case Western Reserve University
| | - Sadeer Al-Kindi
- A. Lange, MS, L. Kostadinova, MD, S. Damjanovska, MD, I. Gad, MD, S. Syed, MD, H. Siddiqui, MD, P. Yousif, MD, C.M. Kowal, BS, C. Burant, PhD, T. Bej, MS, S. Al-Kindi, MD, B. Wilson, PhD, M. Mattar, MD, D.A. Zidar, MD, PhD, Department of Medicine, VA Medical Center and VA GRECC, Case Western Reserve University
| | - Brigid Wilson
- A. Lange, MS, L. Kostadinova, MD, S. Damjanovska, MD, I. Gad, MD, S. Syed, MD, H. Siddiqui, MD, P. Yousif, MD, C.M. Kowal, BS, C. Burant, PhD, T. Bej, MS, S. Al-Kindi, MD, B. Wilson, PhD, M. Mattar, MD, D.A. Zidar, MD, PhD, Department of Medicine, VA Medical Center and VA GRECC, Case Western Reserve University
| | - Maya Mattar
- A. Lange, MS, L. Kostadinova, MD, S. Damjanovska, MD, I. Gad, MD, S. Syed, MD, H. Siddiqui, MD, P. Yousif, MD, C.M. Kowal, BS, C. Burant, PhD, T. Bej, MS, S. Al-Kindi, MD, B. Wilson, PhD, M. Mattar, MD, D.A. Zidar, MD, PhD, Department of Medicine, VA Medical Center and VA GRECC, Case Western Reserve University
| | - David A Zidar
- A. Lange, MS, L. Kostadinova, MD, S. Damjanovska, MD, I. Gad, MD, S. Syed, MD, H. Siddiqui, MD, P. Yousif, MD, C.M. Kowal, BS, C. Burant, PhD, T. Bej, MS, S. Al-Kindi, MD, B. Wilson, PhD, M. Mattar, MD, D.A. Zidar, MD, PhD, Department of Medicine, VA Medical Center and VA GRECC, Case Western Reserve University
| | - Donald D Anthony
- D.D. Anthony, MD, PhD, Department of Medicine, VA Medical Center and VA GRECC, and Department of Pathology, and Division of Rheumatology, MetroHealth Medical Center, Case Western Reserve University, Cleveland, Ohio, USA.
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Anti-Arthritic Effect of the Hydroethanolic Root Extract of Psydrax subcordata in Rats. Adv Pharmacol Pharm Sci 2022; 2022:9748382. [PMID: 36061079 PMCID: PMC9433293 DOI: 10.1155/2022/9748382] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2022] [Revised: 07/18/2022] [Accepted: 07/23/2022] [Indexed: 11/20/2022] Open
Abstract
Background In Ghana, decoctions of various parts of Psydrax subcordata, Bridson (Rubiaceae) are employed in the management of inflammatory conditions. However, not much scientific data is available to back such folkloric use of the plant. This study, therefore, seeks to investigate the chronic anti-inflammatory activity of hydroethanolic root extract of Psydrax subcordata (PSRE) using the adjuvant-induced arthritis model in rats. Methods Freund's adjuvant-induced arthritis model was used to assess the ameliorative effects of PSRE in chronic inflammation. The effect of PSRE on tissue and joint integrity in arthritis was also evaluated by histopathology and microscopy. The effect of PSRE on oxidative markers and serum transforming growth factor (TGF) beta 1 was also determined via chemical assays. Results Oral PSRE (30–300 mg/kg) inhibited both ipsilateral and contralateral paw arthritis when given prophylactically and therapeutically in rats. It reduced paw defect on X-ray with histologically-reduced inflammatory cells and synovial hyperplasia. Finally, PSRE significantly reduced TGF-beta 1 levels and raised antioxidants such as reduced glutathione, catalase, and superoxide dismutase levels in arthritic rats. Conclusion The findings show that hydroethanolic root extract of Psydrax subcordata possesses anti-inflammatory properties in rodents.
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The association between change of soluble tumor necrosis factor receptor R1 (sTNF-R1) measurements and cardiovascular and all-cause mortality-Results from the population-based (Cardiovascular Disease, Living and Ageing in Halle) CARLA study 2002-2016. PLoS One 2020; 15:e0241213. [PMID: 33104754 PMCID: PMC7588092 DOI: 10.1371/journal.pone.0241213] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2020] [Accepted: 10/09/2020] [Indexed: 01/15/2023] Open
Abstract
Aims Single measurements of higher levels of soluble tumor necrosis factor receptor I (sTNF-R1) have been shown to be associated with increased risk of mortality. However, up to date, little is known about the underlying temporal dynamics of sTNF-R1 concentrations and their relation with mortality. We aimed to characterize the effect of changes in sTNFR-1 levels on all-cause and cardiovascular mortality, independent from other established risk factors for mortality, including other inflammatory markers. Methods We used data of the population based cohort study CARLA and included 1408 subjects with sTNF-R1 measured at baseline (2002–2006) and first follow-up (2007–2010). Cox proportional hazard models were used to assess the association of baseline and follow-up sTNF-R1 measurements with all-cause and cardiovascular mortality during ~10 years since the first follow-up after adjusting for relevant confounders. Results Based on 211 deaths among 1408 subjects, per each doubling of the baseline sTNF-R1, the risk of all-cause mortality was increased by about 30% (Hazard ratio 1.28, 95% Confidence Interval 0.6–2.7), while per each doubling of the follow-up level of sTNF-R1 mortality was 3-fold (3.11, 1.5–6.5) higher in a model including both measurements and adjusting for confounders. The results were mainly related to the cardiovascular mortality (5.9, 2.1–16.8 per each doubling of follow up sTNF-R1 value). Conclusion Solely the follow-up value, rather than its change from baseline, predicted future mortality. Thus, while sTNF-R1 levels are associated with mortality, particularly cardiovascular, over a long-time period in the general population, if they change, the earlier measurements play no or little role.
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Sultana S, Bishayi B. Potential anti-arthritic and anti-inflammatory effects of TNF-α processing inhibitor-1 (TAPI-1): A new approach to the treatment of S. aureus arthritis. Immunobiology 2019; 225:151887. [PMID: 31822434 DOI: 10.1016/j.imbio.2019.11.022] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2019] [Accepted: 11/26/2019] [Indexed: 12/22/2022]
Abstract
Treatment of septic arthritis has become more challenging due to the rise of multidrug resistant strains of Staphylococcus aureus (S. aureus) in recent years. Failure of antibiotic therapies has compelled to initiate the search for new alternatives. This study aimed to unveil the potential anti-arthritic effects of TAPI-1 (TNF-α processing inhibitor-1), an inhibitor that inhibits TACE (TNF-α converting enzyme) mediated release of soluble TNF-α and its receptors along with attenuation of other inflammatory and joint destructive factors responsible for the progression of arthritis. Male Swiss albino mice were inoculated with live S. aureus (5 × 106 cells/mouse) for the development of septic arthritis. TAPI-1 was administered intraperitoneally (10 mg/kg body weight) post S. aureus infection at regular intervals. Throughout the experiment, the severity of arthritis was obtained to be significantly low after TAPI-1 administration. Arthritis index and histopathology confirmed effectiveness of TAPI-1 in mitigating inflammation induced paw swelling and less bone-cartilage destruction in the arthritic knee joints. Lower levels of soluble tumor necrosis factor alpha (sTNF-α) and soluble tumor necrosis factor alpha receptor-1 (sTNFR-1) were detected in the TAPI-1 treated group suggesting TAPI-1 mediated blocking of TACE with subsequent inhibition of TNF-α signalling. Treatment with TAPI-1 lowered the levels of reactive species; matrix metalloproteinase-2 (MMP-2), receptor activator of nuclear factor kappa-B ligand (RANKL) and osteopontin (OPN) denoting less matrix degradation and less osteoclastic bone resorption. Together, this experimental work authenticates TAPI-1 as an alternative therapeutic intervention for the treatment of S. aureus arthritis.
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Affiliation(s)
- Sahin Sultana
- Department of Physiology, Immunology and Microbiology Laboratory, University of Calcutta, University Colleges of Science and Technology, 92 APC Road, Calcutta 700 009, West Bengal, India
| | - Biswadev Bishayi
- Department of Physiology, Immunology and Microbiology Laboratory, University of Calcutta, University Colleges of Science and Technology, 92 APC Road, Calcutta 700 009, West Bengal, India.
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Levels of soluble tumor necrosis factor receptor 1 and 2, gender, and risk of myocardial infarction in Northern Sweden. Atherosclerosis 2018; 272:41-46. [DOI: 10.1016/j.atherosclerosis.2018.03.020] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2017] [Revised: 01/23/2018] [Accepted: 03/08/2018] [Indexed: 01/29/2023]
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Carlsson AC, Ruge T, Kjøller E, Hilden J, Kolmos HJ, Sajadieh A, Kastrup J, Jensen GB, Larsson A, Nowak C, Jakobsen JC, Winkel P, Gluud C, Ärnlöv J. 10-Year Associations Between Tumor Necrosis Factor Receptors 1 and 2 and Cardiovascular Events in Patients With Stable Coronary Heart Disease: A CLARICOR (Effect of Clarithromycin on Mortality and Morbidity in Patients With Ischemic Heart Disease) Trial Substudy. J Am Heart Assoc 2018; 7:e008299. [PMID: 29686027 PMCID: PMC6015281 DOI: 10.1161/jaha.117.008299] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2017] [Accepted: 03/01/2018] [Indexed: 12/27/2022]
Abstract
BACKGROUND We aimed to assess the associations and predictive powers between the soluble receptors for tumor necrosis factor (TNF)-α (TNFR1 and TNFR2) and cardiovascular outcomes in patients with stable coronary heart disease. METHODS AND RESULTS CLARICOR (Effect of Clarithromycin on Mortality and Morbidity in Patients With Ischemic Heart Disease) is a randomized clinical trial comparing clarithromycin with placebo in patients with stable coronary heart disease. The primary outcome was a composite of nonfatal acute myocardial infarction, unstable angina pectoris, cerebrovascular disease, and all-cause mortality. Patients were followed up for 10 years; discovery sample, those assigned placebo (1204 events in n=1998); and replication sample, those assigned clarithromycin (1220 events in n=1979). We used Cox regression adjusted for C-reactive protein level, established cardiovascular risk factors, kidney function, and cardiovascular drugs. After adjustments, higher serum levels of TNFR1 and TNFR2 were associated with the composite outcome in the discovery sample (hazard ratio per SD increase, 1.13; 95% confidence interval, 1.05-1.22; P=0.001 for TNFR1; hazard ratio, 1.16; 95% confidence interval, 1.08-1.24; P<0.001 for TNFR2). The associations were similar in the replication sample. The associations with the composite outcome were mainly driven by acute myocardial infarction, cardiovascular mortality, and noncardiovascular mortality. The addition of TNFR1 and TNFR2 to established cardiovascular risk factors improved prediction only modestly (<1%). CONCLUSIONS Increased concentrations of circulating TNFR1 and TNFR2 were associated with increased risks of cardiovascular events and mortality in patients with stable coronary heart disease. Yet, the utility of measuring TNFR1 and TNFR2 to improve risk prediction in these patients appears limited. CLINICAL TRIAL REGISTRATION URL: https://www.clinicaltrials.gov. Unique identifier: NCT00121550.
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Affiliation(s)
- Axel C Carlsson
- Division of Family Medicine and Primary Care, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Huddinge, Sweden
- Department of Medical Sciences, Cardiovascular Epidemiology, Uppsala University, Uppsala, Sweden
| | - Toralph Ruge
- Department of Emergency Medicine, Karolinska University Hospital, Stockholm, Sweden
| | - Erik Kjøller
- Department of Cardiology, Herlev Hospital, Copenhagen University Hospital, Copenhagen, Denmark
| | - Jørgen Hilden
- Section of Biostatistics, University of Copenhagen, Copenhagen, Denmark
| | - Hans Jørn Kolmos
- Department of Clinical Microbiology, Odense University Hospital, Odense, Denmark
| | - Ahmad Sajadieh
- Copenhagen University Hospital of Bispebjerg and Frederiksberg, Copenhagen, Denmark
| | - Jens Kastrup
- Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | | | - Anders Larsson
- Department of Medical Sciences, Uppsala University, Uppsala, Sweden
| | - Christoph Nowak
- Division of Family Medicine and Primary Care, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Huddinge, Sweden
| | - Janus Christian Jakobsen
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Rigshospitalet, Copenhagen, Denmark
- Copenhagen University Hospital, Copenhagen, Denmark
- Department of Cardiology, Holbæk Hospital, Holbæk, Denmark
| | - Per Winkel
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Rigshospitalet, Copenhagen, Denmark
| | - Christian Gluud
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Rigshospitalet, Copenhagen, Denmark
| | - Johan Ärnlöv
- Division of Family Medicine and Primary Care, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Huddinge, Sweden
- School of Health and Social Studies, Dalarna University, Falun, Sweden
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Mattisson IY, Björkbacka H, Wigren M, Edsfeldt A, Melander O, Fredrikson GN, Bengtsson E, Gonçalves I, Orho-Melander M, Engström G, Almgren P, Nilsson J. Elevated Markers of Death Receptor-Activated Apoptosis are Associated with Increased Risk for Development of Diabetes and Cardiovascular Disease. EBioMedicine 2017; 26:187-197. [PMID: 29208468 PMCID: PMC5836474 DOI: 10.1016/j.ebiom.2017.11.023] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2017] [Revised: 11/17/2017] [Accepted: 11/23/2017] [Indexed: 02/06/2023] Open
Abstract
Background An increased rate of cell death by apoptosis has been implicated in both diabetes and atherosclerosis. Apoptosis can be induced through activation of the death receptors TNF receptor 1 (TNFR-1), TRAIL receptor 2 (TRAILR-2) and Fas. Soluble forms of these receptors are found in plasma. The objective of this study was to determine if soluble death receptors are markers of receptor-activated apoptosis and predict risk for development of diabetes and cardiovascular events. Methods Fas ligand was used to induce apoptosis in peripheral blood mononuclear cells and INS-1 pancreatic β-cells and release of TNFR-1, TRAILR-2 and Fas measured by ELISA. Proximity Extension Assay was used to analyze plasma levels of TNFR-1, TRAILR-2 and Fas in baseline samples of 4742 subjects in the Malmö Diet and Cancer Study and related to development of diabetes and cardiovascular events during 19.2 years of follow-up. Results Activation of apoptosis by Fas ligand was associated with release of soluble Fas, TNFR-1 and TRAILR-2 in both cell types. Circulating levels of all three receptors were higher in subjects with diabetes and correlated with markers of impaired glucose metabolism in non-diabetic subjects. Among the latter, those in the highest tertile of soluble Fas, TNFR-1 and TRAILR-2 had increased risk for development of diabetes and cardiovascular events. These associations became weaker when adjusting for cardiovascular risk factors in Cox regression models, but remained significant for TRAILR-2 with incident diabetes, cardiovascular mortality, myocardial infarction and ischemic stroke, and for TNFR-1 with myocardial infarction. Conclusion The present study demonstrates an association between several cardiovascular risk factors and elevated levels of circulating markers of apoptotic cell death. It also shows that subjects with high levels of these biomarkers have increased risk of diabetes and CVD. This implies that soluble death receptors are markers of β-cell and vascular injury and potentially could be used as surrogate markers of therapeutic efficiency in risk factor interventions. •Receptor-activated apoptosis is associated with release of soluble death receptors that act as biomarkers of apoptosis •Several cardiovascular risk factors including markers of impaired glucose metabolism associate with elevated plasma levels of death receptors •Subjects with high plasma levels of death receptors have an increased risk of diabetes and cardiovascular disease Atherosclerosis has been proposed to develop in response to chronic arterial injury caused by cardiovascular risk factors. The present study provides clinical evidence for this hypothesis by demonstrating an association between several cardiovascular risk factors and elevated levels of circulating markers of apoptotic cell death and that subjects with high levels of these biomarkers have increased risk of cardiovascular mortality, MI and stroke. These observations point to the possibility that the plasma level of soluble death receptors can be used as surrogate markers of arterial injury and atherosclerotic disease activity in cardiovascular interventions. Finally, our findings imply that soluble death receptors also may serve as biomarkers of the damage caused by metabolic stress to β-cells and risk for development of type 2 diabetes.
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MESH Headings
- Aged
- Apoptosis/drug effects
- Biomarkers/blood
- Cardiovascular Diseases/diagnosis
- Cardiovascular Diseases/etiology
- Diabetes Mellitus/diagnosis
- Diabetes Mellitus/etiology
- Fas Ligand Protein/pharmacology
- Female
- Genome-Wide Association Study
- Genotype
- Humans
- Leukocytes, Mononuclear/cytology
- Leukocytes, Mononuclear/metabolism
- Male
- Middle Aged
- Polymorphism, Single Nucleotide
- Proportional Hazards Models
- Receptors, Death Domain/blood
- Receptors, Death Domain/genetics
- Receptors, Death Domain/metabolism
- Receptors, TNF-Related Apoptosis-Inducing Ligand/blood
- Receptors, TNF-Related Apoptosis-Inducing Ligand/genetics
- Receptors, Tumor Necrosis Factor, Type I/blood
- Receptors, Tumor Necrosis Factor, Type I/genetics
- Risk Factors
- fas Receptor/blood
- fas Receptor/genetics
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Affiliation(s)
| | | | - Maria Wigren
- Department of Clinical Sciences Malmö, Lund University, Sweden
| | - Andreas Edsfeldt
- Department of Clinical Sciences Malmö, Lund University, Sweden; Department of Cardiology - Coronary diseases, Skåne University Hospital, Sweden
| | - Olle Melander
- Department of Clinical Sciences Malmö, Lund University, Sweden
| | | | - Eva Bengtsson
- Department of Clinical Sciences Malmö, Lund University, Sweden
| | - Isabel Gonçalves
- Department of Clinical Sciences Malmö, Lund University, Sweden; Department of Cardiology - Coronary diseases, Skåne University Hospital, Sweden
| | | | - Gunnar Engström
- Department of Clinical Sciences Malmö, Lund University, Sweden
| | - Peter Almgren
- Department of Clinical Sciences Malmö, Lund University, Sweden
| | - Jan Nilsson
- Department of Clinical Sciences Malmö, Lund University, Sweden.
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9
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Masoud S, Lim PB, Kitas GD, Panoulas V. Sudden cardiac death in patients with rheumatoid arthritis. World J Cardiol 2017; 9:562-573. [PMID: 28824786 PMCID: PMC5545140 DOI: 10.4330/wjc.v9.i7.562] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/25/2016] [Revised: 03/15/2017] [Accepted: 04/19/2017] [Indexed: 02/06/2023] Open
Abstract
An increased cardiovascular morbidity and mortality, including the risk of sudden cardiac death (SCD), has been shown in patients with rheumatoid arthritis (RA). Abnormalities in autonomic markers such as heart rate variability and ventricular repolarization parameters, such as QTc interval and QT dispersion, have been associated with sudden death in patients with RA. The interplay between these parameters and inflammation that is known to exist with RA is of growing interest. In this article, we review the prevalence and predictors of SCD in patients with RA and describe the potential underlying mechanisms, which may contribute to this. We also review the impact of biologic agents on arrhythmic risk as well as cardiovascular morbidity and mortality.
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10
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Gohda T, Maruyama S, Kamei N, Yamaguchi S, Shibata T, Murakoshi M, Horikoshi S, Tomino Y, Ohsawa I, Gotoh H, Nojiri S, Suzuki Y. Circulating TNF Receptors 1 and 2 Predict Mortality in Patients with End-stage Renal Disease Undergoing Dialysis. Sci Rep 2017; 7:43520. [PMID: 28256549 PMCID: PMC5335256 DOI: 10.1038/srep43520] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2016] [Accepted: 01/25/2017] [Indexed: 12/15/2022] Open
Abstract
Relatively high circulating levels of soluble tumor necrosis factor (TNF) receptors (TNFRs: TNFR1, TNFR2) have been associated with not only progression to end-stage renal disease but also mortality in patients with diabetes. It remains unknown whether elevated TNFR levels in haemodialysis patients are associated with mortality. We studied 319 patients receiving maintenance haemodialysis who were followed for a median of 53 months. Circulating markers of TNF pathway (TNFα and TNFRs) were measured with immunoassay. Strong positive correlations between TNFR1 and TNFR2 were observed (r = 0.81, P < 0.0001). During follow-up, 88 (27.6%) patients died of any cause (40 [45.5%] died of cardiovascular disease). In the Cox multivariate model, either TNFR but not TNFα remained a significant independent predictor of all-cause mortality (TNFR1: hazard ratio [HR] 2.34, 95% confidence interval [CI], 1.50–3.64; TNFR2: HR 2.13, 95% CI 1.38–3.29) after adjustment for age, prior cardiovascular disease, predialysis systolic blood pressure, and large systolic blood pressure decline during dialysis session. For cardiovascular mortality, significance was only observed in TNFR1 (TNFR1: HR 2.15, 95% CI 1.13–4.10). Elevated TNFRs levels were associated with the risk of cardiovascular and/or all-cause mortality independent of all relevant covariates in patients undergoing haemodialysis.
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Affiliation(s)
- Tomohito Gohda
- Division of Nephrology, Department of Internal Medicine, Juntendo University Faculty of Medicine, Bunkyo-ku, Tokyo 113-8421, Japan
| | - Shuntaro Maruyama
- Division of Nephrology, Department of Internal Medicine, Juntendo University Faculty of Medicine, Bunkyo-ku, Tokyo 113-8421, Japan
| | - Nozomu Kamei
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Hiroshima Red Cross Hospital and Atomic-bomb Survivors Hospital, Naka-ku, Hiroshima 730-8619, Japan
| | - Saori Yamaguchi
- Division of Nephrology, Department of Internal Medicine, Juntendo University Faculty of Medicine, Bunkyo-ku, Tokyo 113-8421, Japan
| | - Terumi Shibata
- Division of Nephrology, Department of Internal Medicine, Juntendo University Faculty of Medicine, Bunkyo-ku, Tokyo 113-8421, Japan
| | - Maki Murakoshi
- Division of Nephrology, Department of Internal Medicine, Juntendo University Faculty of Medicine, Bunkyo-ku, Tokyo 113-8421, Japan
| | - Satoshi Horikoshi
- Division of Nephrology, Department of Internal Medicine, Juntendo University Faculty of Medicine, Bunkyo-ku, Tokyo 113-8421, Japan
| | - Yasuhiko Tomino
- Division of Nephrology, Department of Internal Medicine, Juntendo University Faculty of Medicine, Bunkyo-ku, Tokyo 113-8421, Japan
| | - Isao Ohsawa
- Department of Internal Medicine, Saiyu Soka Hospital, Soka, Saitama 340-0041, Japan
| | - Hiromichi Gotoh
- Department of Internal Medicine, Saiyu Soka Hospital, Soka, Saitama 340-0041, Japan
| | - Shuko Nojiri
- Clinical Research Support Center (JCRSC), Juntendo University, Bukyo-ku, Tokyo 113-8421, Japan
| | - Yusuke Suzuki
- Division of Nephrology, Department of Internal Medicine, Juntendo University Faculty of Medicine, Bunkyo-ku, Tokyo 113-8421, Japan
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11
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Mortality in patients with rheumatoid arthritis: a 15-year prospective cohort study. Rheumatol Int 2016; 37:487-493. [PMID: 28032180 PMCID: PMC5357293 DOI: 10.1007/s00296-016-3638-5] [Citation(s) in RCA: 145] [Impact Index Per Article: 16.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2016] [Accepted: 12/19/2016] [Indexed: 01/20/2023]
Abstract
The aim of this study was to investigate (a) the mortality in a clinical cohort of patients with established rheumatoid arthritis in comparison with the general Dutch population over 15 years, (b) the trend in the mortality ratio during the study period, and (c) causes of death and compare these with the general population. In 1997, a sample of 1222 patients was randomly selected from the register of a large rheumatology outpatient clinic. Their mortality and primary causes of death between 1997 and 2012 were obtained from Statistics Netherlands. The standardized mortality ratio (SMR) for all-cause mortality and the number of life-years lost in the study period, adjusted for age, sex, and calendar year, were calculated. A linear poisson regression analysis was performed to evaluate change in all-cause SMR over time. Finally, the SMRs for cause-specific mortality were calculated. The mean age of the population at baseline was 60.4 (SD 15.4) years, and 72.6% of the patients were women. The estimated SMR (95% CI) for all-cause mortality was 1.54 (1.41, 1.67) with about one life-year lost over the study period. There was a trend to decreasing SMR (2% annually, p = .07). Mortality was higher compared with the general population for circulatory system diseases, respiratory system diseases, musculoskeletal system diseases, and digestive system diseases (p < .05). The observed mortality among patients with RA was 54% higher than in the general population after adjustment for age, sex and calendar year. More than one life-year was lost over 15 years, and the mortality tended to decrease over time. The mortality was higher for cardiovascular, respiratory, musculoskeletal and digestive diseases.
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12
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Carlsson AC, Östgren CJ, Nystrom FH, Länne T, Jennersjö P, Larsson A, Ärnlöv J. Association of soluble tumor necrosis factor receptors 1 and 2 with nephropathy, cardiovascular events, and total mortality in type 2 diabetes. Cardiovasc Diabetol 2016; 15:40. [PMID: 26928194 PMCID: PMC4770690 DOI: 10.1186/s12933-016-0359-8] [Citation(s) in RCA: 59] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2015] [Accepted: 02/20/2016] [Indexed: 01/04/2023] Open
Abstract
AIMS/HYPOTHESIS Soluble tumor necrosis factor receptors 1 and 2 (sTNFR1 and sTNFR2) contribute to experimental diabetic kidney disease, a condition with substantially increased cardiovascular risk when present in patients. Therefore, we aimed to explore the levels of sTNFRs, and their association with prevalent kidney disease, incident cardiovascular disease, and risk of mortality independently of baseline kidney function and microalbuminuria in a cohort of patients with type 2 diabetes. In pre-defined secondary analyses we also investigated whether the sTNFRs predict adverse outcome in the absence of diabetic kidney disease. METHODS The CARDIPP study, a cohort study of 607 diabetes patients [mean age 61 years, 44 % women, 45 cardiovascular events (fatal/non-fatal myocardial infarction or stroke) and 44 deaths during follow-up (mean 7.6 years)] was used. RESULTS Higher sTNFR1 and sTNFR2 were associated with higher odds of prevalent kidney disease [odd ratio (OR) per standard deviation (SD) increase 1.60, 95 % confidence interval (CI) 1.32-1.93, p < 0.001 and OR 1.54, 95 % CI 1.21-1.97, p = 0.001, respectively]. In Cox regression models adjusting for age, sex, glomerular filtration rate and urinary albumin/creatinine ratio, higher sTNFR1 and sTNFR2 predicted incident cardiovascular events [hazard ratio (HR) per SD increase, 1.66, 95 % CI 1.29-2.174, p < 0.001 and HR 1.47, 95 % CI 1.13-1.91, p = 0.004, respectively]. Results were similar in separate models with adjustments for inflammatory markers, HbA1c, or established cardiovascular risk factors, or when participants with diabetic kidney disease at baseline were excluded (p < 0.01 for all). Both sTNFRs were associated with mortality. CONCLUSIONS/INTERPRETATIONS Higher circulating sTNFR1 and sTNFR2 are associated with diabetic kidney disease, and predicts incident cardiovascular disease and mortality independently of microalbuminuria and kidney function, even in those without kidney disease. Our findings support the clinical utility of sTNFRs as prognostic markers in type 2 diabetes.
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Affiliation(s)
- Axel C Carlsson
- Division of Family Medicine, Centre for Family Medicine, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Huddinge, Sweden. .,Department of Medical Sciences, Cardiovascular Epidemiology, Uppsala University, Uppsala, Sweden.
| | - Carl Johan Östgren
- Department of Medical and Health Sciences, Linköping University, Linköping, Sweden.
| | - Fredrik H Nystrom
- Department of Medical and Health Sciences, Linköping University, Linköping, Sweden.
| | - Toste Länne
- Department of Medical and Health Sciences, Linköping University, Linköping, Sweden.
| | - Pär Jennersjö
- Department of Medical and Health Sciences, Linköping University, Linköping, Sweden.
| | - Anders Larsson
- Department of Medical Sciences, Cardiovascular Epidemiology, Uppsala University, Uppsala, Sweden.
| | - Johan Ärnlöv
- Department of Medical Sciences, Cardiovascular Epidemiology, Uppsala University, Uppsala, Sweden. .,School of Health and Social Studies, Dalarna University, Falun, Sweden.
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13
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Yamamoto Y, Takemura M, Serrero G, Hayashi J, Yue B, Tsuboi A, Kubo H, Mitsuhashi T, Mannami K, Sato M, Matsunami H, Matuo Y, Saito K. Increased serum GP88 (Progranulin) concentrations in rheumatoid arthritis. Inflammation 2015; 37:1806-13. [PMID: 24803297 DOI: 10.1007/s10753-014-9911-4] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
GP88 (Progranulin; PGRN) is a secreted glycosylated protein with important functions in several processes, including immune response and cancer growth. Recent reports have shown that PGRN is a therapeutic target for rheumatoid arthritis (RA) because of its capability to bind with tumor necrosis factor receptor (TNFR). However, the serum PGRN level in RA patients has not been investigated. We used enzyme-linked immunosorbent assay (ELISA) to quantify the serum levels of PGRN in 417 healthy subjects, 56 patients with RA and 31 patients with osteoarthritis (OA). In RA patients, we also measured the serum TNF-α and sTNFR concentration. Immunohistochemical staining of PGRN was performed using synovectomy tissue of RA patients. The serum PGRN normal range was established as 40.1 ± 8.7 ng/ml. PGRN levels were not influenced by sex or age. A significant increase in serum PGRN levels was observed in RA (50.2 ± 11.1 ng/ml) and OA (45.4 ± 6.6 ng/ml) groups compared to those in age-matched healthy controls (40.4 ± 9.9 ng/ml) (p<0.05, Tukey). Further, PGRN levels in the synovial fluid of RA patients (68.4 ± 3.4 ng/ml) were found to be significantly higher than those in OA patients (35.9 ± 16.8 ng/ml). Immunohistochemical staining of PGRN revealed that the highest positive signal was detected in macrophages. Circulating PGRN in RA patients was weakly associated with TNF-α and sTNFR 2 concentration. Furthermore, PGRN/TNF-α ratio was correlated the stage of the disease in RA patients. The concentrations of serum PGRN in RA were found to be significantly higher than those in age-matched healthy controls, although it remains to be clarified how blood PGRN is related to the pathogenesis of RA. Our results showed that the serum PGRN may be a useful approach to monitor the disease activity in RA patients.
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Affiliation(s)
- Yasuko Yamamoto
- Human Health Sciences, Graduate School of Medicine and Faculty of Medicine, Kyoto University, Kyoto, 606-8507, Japan,
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14
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Carlsson AC, Carrero JJ, Stenvinkel P, Bottai M, Barany P, Larsson A, Ärnlöv J. High levels of soluble tumor necrosis factor receptors 1 and 2 and their association with mortality in patients undergoing hemodialysis. Cardiorenal Med 2015; 5:89-95. [PMID: 25999957 DOI: 10.1159/000371661] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2014] [Accepted: 12/15/2014] [Indexed: 12/15/2022] Open
Abstract
OBJECTIVE Circulating soluble tumor necrosis factor receptors 1 and 2 (sTNFR1 and sTNFR2) are associated with chronic kidney disease (CKD) progression in patients with CKD or diabetes, and with higher mortality. However, data in patients with end-stage renal disease are scarce. Therefore, we analyzed serum levels of sTNFR1 and sTNFR2 and investigated their association with inflammatory markers and mortality in dialysis patients. RESEARCH DESIGN AND METHODS This was a longitudinal cohort study of 207 prevalent patients (median age 66 years, 56% men) undergoing hemodialysis in Stockholm, Sweden. Demographics, clinical characteristics, including comorbidities and laboratory data, were obtained at baseline, together with prospective follow-up for mortality. RESULTS The median sTNFR1 and sTNFR2 levels were 17,680 ng/l [95% confidence interval (CI) 17,023-18,337] and 24,450 ng/l (95% CI 23,721-25,179), respectively. During a follow-up of 31 months (interquartile range, 21-38), 77 patients died. There was no association between the levels of sTNFRs and mortality in Cox regression models, and no consistent trend towards higher or lower mortality was seen in Laplace regression models. sTNFR1 and sTNFR2 levels were highly associated with other inflammatory markers including interleukin-6, pentraxin 3 and TNF-α. CONCLUSIONS Prevalent hemodialysis patients have several-fold higher levels of sTNFRs compared to previous studies in CKD stage 4 patients. As no consistent association between TNFR and mortality was observed, clinical implications of measuring these receptors to predict outcome end-stage renal disease patients provide limited results.
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Affiliation(s)
- Axel C Carlsson
- Centre for Family Medicine, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Huddinge, Sweden ; Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden
| | - Juan-Jesús Carrero
- Department of Clinical Science, Intervention and Technology, Stockholm, Sweden
| | - Peter Stenvinkel
- Department of Clinical Science, Intervention and Technology, Stockholm, Sweden
| | - Matteo Bottai
- Division of Biostatistics, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Peter Barany
- Department of Clinical Science, Intervention and Technology, Stockholm, Sweden
| | - Anders Larsson
- Department of Medical Sciences, Uppsala University, Uppsala, Sweden
| | - Johan Ärnlöv
- Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden ; School of Health and Social Studies, Dalarna University, Falun, Sweden
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15
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Carlsson AC, Juhlin CC, Larsson TE, Larsson A, Ingelsson E, Sundström J, Lind L, Arnlöv J. Soluble tumor necrosis factor receptor 1 (sTNFR1) is associated with increased total mortality due to cancer and cardiovascular causes - findings from two community based cohorts of elderly. Atherosclerosis 2014; 237:236-42. [PMID: 25255422 DOI: 10.1016/j.atherosclerosis.2014.09.005] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2014] [Revised: 08/15/2014] [Accepted: 09/06/2014] [Indexed: 10/24/2022]
Abstract
BACKGROUND Experimental evidence support soluble receptors for tumor necrosis factor alpha as important mediators of the underlying pathology leading to cardiovascular disease and cancer. However, prospective data concerning the relation between circulating soluble tumor necrosis factor receptor-1 (sTNFR1) and mortality in humans are lacking. We aimed to explore and validate the association between sTNFR1 and mortality, and to explore the influence of other established risk factors for mortality, including other inflammatory markers. METHODS The association between serum sTNFR1and the risk for mortality was investigated in two community-based cohorts of elderly: the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS; women 50%, n = 1005, mean age 70 years, median follow-up 7.9 years) and the Uppsala Longitudinal Study of Adult Men (ULSAM, n = 775, mean age 77 years, median follow-up 8.1 years). RESULTS In total, 101 participants in PIVUS and 274 in ULSAM died during follow-up. In multivariable Cox regression models adjusted for inflammation, lifestyle and established cardiovascular risk factors, one standard deviation (SD) higher sTNFR1 was associated with a hazard ratio (HR) for mortality of 1.37, 95% confidence interval (CI) 1.17-1.60, in PIVUS and HR 1.22, 95% CI 1.10-1.37 in ULSAM. Moreover, circulatings TNFR1 was associated with cardiovascular mortality (HR per SD of sTNFR1, 1.24, 95% CI 1.07-1.44) and cancer mortality (HR per SD of sTNFR1, 1.32, 95% CI 1.11-1.57) in the ULSAM cohort. High levels of sTNFR1 identified individuals with increased risk of mortality among those with high as well as low levels of systemic inflammation. CONCLUSIONS An association between circulating sTNFR1 and an increased risk for mortality was found and validated in two independent community-based cohorts. The future clinical role of sTNFR1 to identify high risk patients for adverse outcomes and mortality has yet to be determined.
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Affiliation(s)
- Axel C Carlsson
- Centre for Family Medicine, Department of Neurobiology, Care Sciences, and Society, Karolinska Institutet, Huddinge, Sweden; Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
| | | | - Tobias E Larsson
- Department of Clinical Science, Intervention and Technology, Renal Unit, Karolinska Institutet, Stockholm, Sweden; Department of Nephrology, Karolinska University Hospital, Stockholm, Sweden
| | - Anders Larsson
- Department of Medical Sciences, Uppsala University, Uppsala, Sweden
| | - Erik Ingelsson
- Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden
| | - Johan Sundström
- Department of Medical Sciences, Uppsala University, Uppsala, Sweden
| | - Lars Lind
- Department of Medical Sciences, Uppsala University, Uppsala, Sweden
| | - Johan Arnlöv
- Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden; School of Health and Social Studies, Dalarna University, Falun, Sweden
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16
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Lazzerini PE, Capecchi PL, Acampa M, Galeazzi M, Laghi-Pasini F. Arrhythmic risk in rheumatoid arthritis: the driving role of systemic inflammation. Autoimmun Rev 2014; 13:936-44. [PMID: 24874445 DOI: 10.1016/j.autrev.2014.05.007] [Citation(s) in RCA: 70] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2014] [Accepted: 05/20/2014] [Indexed: 01/08/2023]
Abstract
When compared to the general population, patients with rheumatoid arthritis (RA) have an overall standard mortality ratio of approximately two, with more than 50% of premature deaths attributable to cardiovascular disease (CVD). Moreover, RA patients were twice as likely to experience sudden cardiac death (SCD) compared with non-RA subjects, as a putative consequence of an increased incidence of malignant arrhythmias. Accordingly, mounting data indicate that in patients affected with RA the risk of developing rhythm disturbances, particularly tachyarrhythmias, is high. Although a number of papers reviewing the problem of cardiovascular involvement in RA are currently available, the main focus is on the mechanisms of accelerated atherosclerosis and related ischemic consequences in the clinical setting. On the contrary, only little consideration has been specifically given to the arrhythmic risk so far. In the light of this concern, in the present paper we reviewed the topic with the aim to put together the apparently fragmentary existing information, with particular attention to the putative role of chronic systemic inflammation characterizing the disease. In fact, although the underlying mechanisms accounting the arrhythmogenic substrate in RA are probably intricate, the leading role seems to be played by inflammatory activation, able to promote arrhythmias either indirectly, by accelerating the development of structural CVD, and directly by affecting cardiac electrophysiology. In this view, lowering inflammatory burden through an increasingly tight control of disease activity may represent the most effective intervention to reduce arrhythmic risk and prevent life-threatening complications in these patients.
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Affiliation(s)
- Pietro Enea Lazzerini
- Department of Medical Sciences, Surgery and Neurosciences, University of Siena, Italy.
| | | | | | - Mauro Galeazzi
- Department of Medical Sciences, Surgery and Neurosciences, University of Siena, Italy
| | - Franco Laghi-Pasini
- Department of Medical Sciences, Surgery and Neurosciences, University of Siena, Italy
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17
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Ankylosing spondylitis and rheumatoid arthritis: serum levels of TNF-α and Its soluble receptors during the course of therapy with etanercept and infliximab. BIOMED RESEARCH INTERNATIONAL 2014; 2014:675108. [PMID: 24783218 PMCID: PMC3982245 DOI: 10.1155/2014/675108] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/15/2014] [Accepted: 02/27/2014] [Indexed: 12/14/2022]
Abstract
The effects of the TNF-α blockers infliximab or etanercept on the levels of TNF-α, TNF-receptor 1 (TNF-R1), and TNF-receptor 2 (TNF-R2), as well as the levels of the inflammation markers CRP and IL-6, were measured in ankylosing spondylitis (AS) and rheumatoid arthritis (RA) patients receiving treatment with either compound. We found that RA patients tend to have higher levels of TNF-α than both healthy individuals and AS patients prior to treatment (P < 0.05). We measured greatly increased levels of TNF-α in both the AS and RA etanercept patient groups during the course of treatment, while in the infliximab treated patients, the amount of TNF-α measured remained unchanged. Elevated TNF-α in the etanercept treated patients does not appear to be a significant risk factor for the spontaneous development of further autoimmune diseases in our study group. Increased levels of TNF-R1 were determined in both AS (P < 0.05) and RA (P < 0.001) patients when compared to healthy controls. In AS patients, the levels of TNF-R1 dropped significantly when treated with either infliximab (P < 0.01) or etanercept (P < 0.001). In contrast, the levels of this receptor remained unchanged in RA patients treated with either compound.
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18
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Chen X, Lu J, An M, Ma Z, Zong H, Yang J. Anti-inflammatory effect of resveratrol on adjuvant arthritis rats with abnormal immunological function via the reduction of cyclooxygenase-2 and prostaglandin E2. Mol Med Rep 2014; 9:2592-8. [PMID: 24676467 DOI: 10.3892/mmr.2014.2070] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2014] [Accepted: 03/07/2014] [Indexed: 11/05/2022] Open
Abstract
Rheumatoid arthritis (RA) is a chronic inflammatory disease with unknown etiology. The present study investigated the anti-inflammatory effect of resveratrol on rats with adjuvant arthritis (AA) with abnormal immunological function via the reduction of cyclooxygenase-2 (COX-2) and prostaglandin E2 (PGE2). AA model rats were established by injection of complete Freund's adjuvant and alterations in the rats secondary paw swelling and the polyarthritic scores were observed. Pathological examination of joint tissues was observed by hematoxylin and eosin staining. The proliferation of spleen cells was examined using a 3-(4,5-dimethylthiazol-2‑yl)-2,5-diphenyltetrazolium bromide assay in vitro. The protein expression of COX-2 in the synovial tissues was detected by western blotting. The level of PGE2 in the serum was assayed using an ELISA kit. The results demonstrated that resveratrol (10 or 50 mg/kg) was able to significantly reduce paw swelling and decrease the arthritis scores. Compared with the AA model rats, a significant reduction in the proliferation of concanavalin A-stimulated spleen cells was observed, articular cartilage degeneration with synovial hyperplasia and inflammatory cell infiltration was suppressed and the production of COX-2 and PGE2 in AA rats was reduced by treatment with resveratrol. These results suggest that resveratrol has significant anti-inflammatory effects on AA rats, which may be associated with the reduction of COX-2 and PGE2 inflammatory mediators.
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Affiliation(s)
- Xiaoyu Chen
- Department of Histology and Embryology, Anhui Medical University, Hefei, Anhui 230032, P.R. China
| | - Jinseng Lu
- Department of Histology and Embryology, Anhui Medical University, Hefei, Anhui 230032, P.R. China
| | - Mei An
- Department of Histology and Embryology, Anhui Medical University, Hefei, Anhui 230032, P.R. China
| | - Zhongfei Ma
- Department of Histology and Embryology, Anhui Medical University, Hefei, Anhui 230032, P.R. China
| | - Hexiang Zong
- Department of Histology and Embryology, Anhui Medical University, Hefei, Anhui 230032, P.R. China
| | - Jun Yang
- Department of Histology and Embryology, Anhui Medical University, Hefei, Anhui 230032, P.R. China
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Abstract
Despite 2 decades of advances in therapy of diabetic patients, the prevalence of diabetic nephropathy among patients with diabetes has not decreased. However, large-scale multicenter studies have achieved great success in terms of the reduction of albuminuria, suggesting that albuminuria might not be an accurate surrogate marker for slowing the rate of renal function decline. It is important to be able to identify individuals at high risk for renal function decline, or ultimately, end-stage kidney disease (ESKD) and its associated cardiovascular disease (CVD). More sensitive early biomarkers, other than albuminuria and the estimated glomerular filtration rate (eGFR), should be required. Recently, serum concentrations of soluble tumor necrosis factor (TNF), receptor 1 (TNFR1), and TNFR2 have predicted future GFR loss and ESKD in patients of a wide variety of stages and both types of diabetes. Longitudinal interventional studies are needed to validate these biomarkers in a broad range of populations prior to implementation in routine diabetes management.
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Affiliation(s)
- Tomohito Gohda
- Division of Nephrology, Department of Internal Medicine, Juntendo University, Faculty of Medicine, Hongo 2-1-1, Bunkyo-ku, Tokyo, 113-8421, Japan
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20
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Schnabel RB, Yin X, Larson MG, Yamamoto JF, Fontes JD, Kathiresan S, Rong J, Levy D, Keaney JF, Wang TJ, Murabito JM, Vasan RS, Benjamin EJ. Multiple inflammatory biomarkers in relation to cardiovascular events and mortality in the community. Arterioscler Thromb Vasc Biol 2013; 33:1728-33. [PMID: 23640499 DOI: 10.1161/atvbaha.112.301174] [Citation(s) in RCA: 77] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
OBJECTIVE Evidence suggests that chronic low-grade inflammation and oxidative stress are related to cardiovascular disease (CVD) and mortality. APPROACH AND RESULTS We examined 11 established and novel biomarkers representing inflammation and oxidative stress (C-reactive protein, fibrinogen, interleukin-6, intercellular adhesion molecule-1, lipoprotein-associated phospholipase-A2 [mass and activity], monocyte chemoattractant protein-1, myeloperoxidase, CD40 ligand, P-selectin, and tumor necrosis factor receptor II [TNFRII]) in relation to incident major CVD and mortality in the community. We studied 3035 participants (mean age, 61 ± 9 years; 53% women). During follow-up (median, 8.9 years), 253 participants experienced a CVD event and 343 died. C-reactive protein (hazard ratio [HR] reported per SD ln-transformed biomarker, 1.18; 95% confidence interval [CI], 1.02-1.35; nominal P=0.02) and TNFRII (HR, 1.15; 95% CI, 1.01-1.32; nominal P=0.04) were retained in multivariable-adjusted models for major CVD, but were not significant after adjustment for multiple testing. The biomarkers related to mortality were TNFRII (HR, 1.33; 95% CI, 1.19-1.49; P<0.0001), ICAM-1 (HR, 1.24; 95% CI, 1.12-1.37; P<0.0001), and interleukin-6 (HR, 1.25; 95% CI, 1.12-1.39; P<0.0001). The addition of these markers to the model, including traditional risk factors, increased discrimination and reclassification for risk of death (P<0.0001), but not for CVD. CONCLUSIONS Of 11 inflammatory biomarkers tumor necrosis factor receptor II was related to cardiovascular disease and mortality in the Framingham Heart Study. The combination of TNFRII with C-reactive protein in relation to CVD and with interleukin-6 to mortality increased the predictive ability in addition to CVD risk factors for total mortality but not for incident CVD.
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Affiliation(s)
- Renate B Schnabel
- Framingham Heart Study, National Heart, Lung, and Blood Institute, Framingham, MA, USA
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Amaya-Amaya J, Sarmiento-Monroy JC, Mantilla RD, Pineda-Tamayo R, Rojas-Villarraga A, Anaya JM. Novel risk factors for cardiovascular disease in rheumatoid arthritis. Immunol Res 2013; 56:267-86. [PMID: 23584985 DOI: 10.1007/s12026-013-8398-7] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
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Mattey DL, Nixon NB, Dawes PT. Association of circulating levels of MMP-8 with mortality from respiratory disease in patients with rheumatoid arthritis. Arthritis Res Ther 2012; 14:R204. [PMID: 23031278 PMCID: PMC3580516 DOI: 10.1186/ar4042] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2012] [Accepted: 10/02/2012] [Indexed: 12/21/2022] Open
Abstract
Introduction Matrix metalloproteinases (MMPs) are implicated in the destruction of the joint and have been shown to be strongly associated with inflammation in rheumatoid arthritis (RA). Circulating MMPs have also been associated with cardiovascular disease in the general population, and are predictive of cardiovascular mortality. The purpose of the present study was to determine whether circulating levels of MMPs are predictive of mortality in RA. Methods A multiplex suspension array system (Luminex®) was used to measure levels of MMPs (1, 2, 3, 8 and 9) in sera taken at recruitment of RA patients (n = 487) in a study of factors associated with mortality in RA. Patients were tracked on the National Health Service Central Register for notification of death, and the relationship between baseline MMP levels and mortality was analysed using Cox proportional hazards regression analysis. Results At the time of follow-up, 204/486 patients had died, of which 94 (46.1%) had died of circulatory diseases, 49 of malignancy (24.0%), and 42 (20.6%) of respiratory diseases. In a stepwise analysis which included all MMPs, only MMP-8 was significantly associated with all cause mortality (P = 0.0007, 0.6% hazard ratio increase per ng/ml). No association was found between MMP levels and mortality due to circulatory disease or malignancy. However MMP-8 levels were strongly associated with mortality due to respiratory disease (P < 0.0001, 1.3% hazard ratio increase per ng/ml). The association with respiratory disease related mortality remained highly significant in multivariate models which included smoking as well as markers of severity and disease activity such as rheumatoid factor, nodular disease, and C-reactive protein (CRP). Conclusions The serum level of MMP-8 is a strong predictor of mortality in RA, especially that due to respiratory disease. This finding is consistent with increased activation of neutrophils in RA and identifies serum MMP-8 as a useful marker for increased risk of premature death.
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Chen Y, Dawes PT, Packham JC, Mattey DL. Interaction between smoking and functional polymorphism in the TGFB1 gene is associated with ischaemic heart disease and myocardial infarction in patients with rheumatoid arthritis: a cross-sectional study. Arthritis Res Ther 2012; 14:R81. [PMID: 22513132 PMCID: PMC3446455 DOI: 10.1186/ar3804] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2012] [Revised: 03/15/2012] [Accepted: 04/18/2012] [Indexed: 04/03/2023] Open
Abstract
INTRODUCTION Transforming growth factor-beta1 (TGF-beta1) is a pleiotropic cytokine that plays important roles in immunity and inflammation. Some studies have suggested that polymorphism in the TGFB1 gene is associated with heart disease in the general population. The purpose of the present study was to determine whether common single-nucleotide polymorphisms (SNP) in the TGFB1 gene are associated with ischaemic heart disease (IHD) and/or myocardial infarction (MI) in patients with rheumatoid arthritis (RA), and to investigate the influence of smoking on any association. METHODS PCR-based assays were used to determine the genotypes of TGFB1 SNPs including TGFB1-509 C/T (rs1800469, in the promoter region), +868 T/C (rs1800470, in exon 1) and +913 G/C (rs1800471, in exon 1) in 414 subjects with established RA. Genotyping for the +868 SNP was also carried out on a second study population of RA patients (n = 259) with early disease. Serum levels of TGF-beta1 were measured using a commercial ELISA kit. Smoking history and IHD/MI status were obtained on each patient. Associations with IHD/MI were assessed using contingency tables and logistic regression analyses. RESULTS The heterozygous genotype of TGFB+868 was associated with an increased risk of IHD (OR 2.14, 95% CI 1.30 - 3.55) and MI (OR 2.42, 95% CI 1.30-4.50), compared to the homozygous genotypes combined. Smoking was an independent risk for IHD and MI, and evidence of interaction between smoking and TGFB+868 was found. Multivariate analyses indicated that the strongest associations with IHD and MI were due to the combined effect of the TGFB1+868 TC genotype and smoking (OR 2.75, 95% CI 1.59-4.75; and OR 2.58 95% CI 1.33-4.99, respectively), independent of other cardiovascular risk factors. The association of the +868 TC genotype and evidence of +868 TC-smoking interaction with IHD were replicated in a second population of RA patients with early disease. Serum TGF-beta1 levels were not associated with TGFB1 genetic variations, smoking or IHD/MI status. CONCLUSIONS Interaction between smoking and polymorphism in the TGFB1 gene may influence the risk of IHD and MI in patients with RA.
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Affiliation(s)
- Ying Chen
- Haywood Rheumatology Centre, Haywood Hospital, High Lane, Burslem, Stoke-on-Trent, Staffordshire, ST6 7AG, UK
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BOEHNCKE WOLFHENNING, GLADMAN DAFNAD, CHANDRAN VINOD. Cardiovascular Comorbidities in Psoriasis and Psoriatic Arthritis: Pathogenesis, Consequences for Patient Management, and Future Research Agenda: A Report from the GRAPPA 2009 Annual Meeting. J Rheumatol 2011; 38:567-71. [DOI: 10.3899/jrheum.101124] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Psoriasis is often associated with other diseases, substantially adding to the patient’s burden of disease. Recent epidemiologic studies have demonstrated an increased cardiovascular morbidity among patients with psoriasis and psoriatic arthritis (PsA), which contributes to their reduced life expectancy. At the meeting of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) adjacent to the International Federation of Psoriasis Associations (IFPA) congress, members discussed the pathogenetic aspects of this association and resulting consequences for the management of patients with psoriasis and PsA. A future research agenda was considered.
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Chen Y, Dawes PT, Packham JC, Mattey DL. Interaction between smoking and polymorphism in the promoter region of the VEGFA gene is associated with ischemic heart disease and myocardial infarction in rheumatoid arthritis. J Rheumatol 2011; 38:802-9. [PMID: 21362767 DOI: 10.3899/jrheum.101095] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
OBJECTIVE To determine whether variants in the vascular endothelial growth factor A (VEGFA) gene are associated with ischemic heart disease (IHD) and/or myocardial infarction (MI) in patients with rheumatoid arthritis (RA), and whether there is evidence of a gene-smoking interaction. METHODS PCR-RFLP assays were used to determine the genotypes of VEGFA single-nucleotide polymorphisms (SNP) including VEGFA-2578A/C (rs699947), -460C/T (rs833061), +405C/G (rs2010963), and +936C/T (rs3025039) in 418 subjects with RA. Smoking history was obtained on each patient, and IHD and MI status was recorded. Associations with IHD/MI were assessed using contingency tables and logistic regression analyses. RESULTS Strong linkage disequilibrium was detected among VEGFA-2578, -460, and +405. SNP located in the VEGFA promoter region (-2578, -460) were found to be associated with IHD and MI, whereas +405 and +936, in the 5'-untranslated region (UTR) and 3'-UTR, respectively, were not. Haplotype analysis suggested that the A/C/G haplotype was associated with increased risk of IHD (OR 2.37, 95% CI 1.22-4.62) and MI (OR 4.10, 95% CI 1.45-11.49). Smoking was also independently associated with IHD and MI, and evidence of interaction between smoking and the VEGFA promoter SNP was found. Multivariate analyses indicated that the strongest associations with IHD and MI were due to the combined effect of the VEGFA-2578 A allele and smoking (OR 3.52 and 7.11, respectively), independent of risk factors such as age, sex, diabetes, C-reactive protein, hypercholesterolemia, and hypertension. CONCLUSION Interaction between smoking and polymorphism in the VEGFA gene is associated with IHD and MI in patients with RA.
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Affiliation(s)
- Ying Chen
- Staffordshire Rheumatology Centre, The Haywood, High Lane, Burslem, Stoke-on-Trent, Staffordshire, England, UK
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Canete JD, Albaladejo C, Hernandez MV, Lainez B, Pinto JA, Ramirez J, Lopez-Armada MJ, Rodriguez-Cros JR, Engel P, Blanco FJ, Sanmarti R. Clinical significance of high levels of soluble tumour necrosis factor- receptor-2 produced by alternative splicing in rheumatoid arthritis: a longitudinal prospective cohort study. Rheumatology (Oxford) 2010; 50:721-8. [DOI: 10.1093/rheumatology/keq381] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
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Sander O. [The safety of biologics : a risk-benefit assessment of treating rheumatoid arthritis with biologics based on registry data on mortality]. Z Rheumatol 2010; 69:788-94. [PMID: 21063827 DOI: 10.1007/s00393-010-0641-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
The aim of this study is a risk-benefit assessment of treating rheumatoid arthritis with biologics based on registry data on mortality.UK, Sweden and Spain have published evaluable data on mortality. A parallel control group was conducted in the UK. Sweden and Spain used an historical cohort for comparison.Central registries supported British and Swedish research by sending details on all deaths. The variety of possible confounders prevents direct comparisons of the registers and safe predictions for individual patients.The death rate in TNF-inhibitor-treated patients is higher than in the general population but lower than in the control groups with RA. Thus comorbidities are not balanced, the weighted mortality rate scaled down the difference between exposed patients and controls. When TNF-inhibitors are given for the usual indication, mortality is reduced compared to conventional therapy.
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Affiliation(s)
- O Sander
- Klinik für Endokrinologie, Diabetologie und Rheumatologie, Heinrich-Heine-Universität Düsseldorf, Moorenstr. 5, 40225, Düsseldorf.
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AN HONGYAN, CHANDRA VASUDHA, PIRAINO BARBARA, BORGES LUIS, GECZY CAROLYN, McNEIL HPATRICK, BRYANT KATHERINE, TEDLA NICODEMUS. Soluble LILRA3, a Potential Natural Antiinflammatory Protein, Is Increased in Patients with Rheumatoid Arthritis and Is Tightly Regulated by Interleukin 10, Tumor Necrosis Factor-α, and Interferon-γ. J Rheumatol 2010; 37:1596-606. [DOI: 10.3899/jrheum.091119] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Objective.Leukocyte immunoglobulin-like receptor A3 (LILRA3) belongs to a family of cell-surface receptors with inhibitory or activating functions. LILRA3 lacks transmembrane and cytoplasmic domains, suggesting that it may be secreted. LILRA3 has high homology to activating LILRA1 and A2, hence may act as a soluble agonist/antagonist to these receptors. Individuals lacking the LILRA3 gene have higher incidence of multiple sclerosis and Sjögren’s syndrome, suggesting LILRA3 may be antiinflammatory. LILRA3 mRNA was detected in monocytes and mast cells but no protein expression has ever been described. Our aim was to examine LILRA3 protein expression in serum and synovial fluid of patients with rheumatoid arthritis (RA) and determine its in vitro regulation.Methods.We developed a new ELISA to examine levels of LILRA3 in serum, synovial fluid, and/or culture supernatants from controls and patients with RA, degenerative arthritis, or gout. We used qRT-PCR and flow cytometry to determine the expression and cytokine-mediated regulation of LILRA3.Results.LILRA3 protein is constitutively present in normal serum, with significantly higher concentrations in patients with RA. Serum LILRA3 concentrations from RA patients correlated with disease activity and levels in synovial fluid. Treatment of monocytes with interleukin 10 or interferon-γ significantly upregulated while tumor necrosis factor-α significantly downregulated LILRA3 mRNA and protein expression.Conclusion.We show for the first time that LILRA3 is significantly increased in serum of patients with RA and is tightly regulated by key cytokines involved in pathogenesis of RA. These results suggest that LILRA3 may play a role in chronic inflammatory conditions such as RA.
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Tanasescu C, Jurcut C, Jurcut R, Ginghina C. Vascular disease in rheumatoid arthritis: from subclinical lesions to cardiovascular risk. Eur J Intern Med 2009; 20:348-54. [PMID: 19524171 DOI: 10.1016/j.ejim.2008.09.005] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2008] [Revised: 07/31/2008] [Accepted: 09/04/2008] [Indexed: 12/13/2022]
Abstract
Rheumatoid arthritis (RA) is one of the most prevalent and complex inflammatory diseases affecting primarily the joints, but also associating several extra-articular features. The vascular disease in RA encompasses a large spectrum of lesions, from rheumatoid vasculitis to atherosclerotic lesions. During the last years the importance of the vascular disease related to atherosclerosis in terms of cardiovascular morbidity and global mortality became evident in RA. The inflammatory hypothesis of atherosclerosis in RA implies that mediators originating from the inflamed synovial tissue or from the liver may have systemic vascular consequences, leading to endothelial dysfunction and structural abnormalities of the vessels. Hence, the global management of patients with RA must include the improvement of cardiovascular risk in parallel with the management of joint disease.
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Affiliation(s)
- Coman Tanasescu
- Department of Internal Medicine, Colentina Clinical Hospital, Bucharest, Romania.
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Karlson EW, Chibnik LB, Tworoger SS, Lee IM, Buring JE, Shadick NA, Manson JE, Costenbader KH. Biomarkers of inflammation and development of rheumatoid arthritis in women from two prospective cohort studies. ARTHRITIS AND RHEUMATISM 2009; 60:641-52. [PMID: 19248103 PMCID: PMC2715148 DOI: 10.1002/art.24350] [Citation(s) in RCA: 97] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
OBJECTIVE To examine the association of biomarkers of inflammation with preclinical rheumatoid arthritis (RA). METHODS A nested case-control study was performed using samples from 2 large, prospectively studied cohorts of women (the Women's Health Study [WHS] and the Nurses' Health Study [NHS]). Blood samples obtained prior to symptom onset in women who later developed RA were selected as incident RA cases, and 3 controls per case were randomly chosen, matched for age, menopausal status, postmenopausal hormone use, and day, time, and fasting status at the time of collection. Plasma was tested for levels of interleukin-6 (IL-6), soluble tumor necrosis factor receptor II (sTNFRII) (as a proxy for TNFalpha), and high-sensitivity C-reactive protein. Relationships between biomarkers and RA were assessed using conditional logistic regression models, adjusting for age, body mass index, smoking habits, ethnicity, and reproductive factors. RESULTS In 93 incident cases in the NHS and 77 incident cases in the WHS, the mean time between blood collection and the onset of RA symptoms was 5.2 years (range 0.3-12 years). Median IL-6 and sTNFRII levels were significantly higher in preclinical RA cases compared with matched controls in the NHS (P = 0.03 and P = 0.003, respectively) though not in the WHS. Pooled analysis of the NHS and WHS cohorts demonstrated significant association of sTNFRII with RA (relative risk 2.0 [95% confidence interval 1.1-3.6], P for trend = 0.004), and a modest association of IL-6 with RA (relative risk 1.4 [95% confidence interval 0.8-2.5], P for trend = 0.06). CONCLUSION Levels of sTNFRII, a biomarker typically associated with active RA, were elevated up to 12 years prior to the development of RA symptoms and were positively associated with incident RA in these nested case-control studies. Studies with repeated assessments of biomarkers prior to RA development may provide further insight into the timing of biomarker elevation in preclinical RA.
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Affiliation(s)
- Elizabeth W Karlson
- Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
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