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Dai X, Fan Y, Zhao X. Systemic lupus erythematosus: updated insights on the pathogenesis, diagnosis, prevention and therapeutics. Signal Transduct Target Ther 2025; 10:102. [PMID: 40097390 PMCID: PMC11914703 DOI: 10.1038/s41392-025-02168-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2024] [Revised: 11/26/2024] [Accepted: 01/26/2025] [Indexed: 03/19/2025] Open
Abstract
Systemic lupus erythematosus (SLE) is a chronic inflammatory illness with heterogeneous clinical manifestations covering multiple organs. Diversified types of medications have been shown effective for alleviating SLE syndromes, ranging from cytokines, antibodies, hormones, molecular inhibitors or antagonists, to cell transfusion. Drugs developed for treating other diseases may benefit SLE patients, and agents established as SLE therapeutics may be SLE-inductive. Complexities regarding SLE therapeutics render it essential and urgent to identify the mechanisms-of-action and pivotal signaling axis driving SLE pathogenesis, and to establish innovative SLE-targeting approaches with desirable therapeutic outcome and safety. After introducing the research history of SLE and its epidemiology, we categorized primary determinants driving SLE pathogenesis by their mechanisms; combed through current knowledge on SLE diagnosis and grouped them by disease onset, activity and comorbidity; introduced the genetic, epigenetic, hormonal and environmental factors predisposing SLE; and comprehensively categorized preventive strategies and available SLE therapeutics according to their functioning mechanisms. In summary, we proposed three mechanisms with determinant roles on SLE initiation and progression, i.e., attenuating the immune system, restoring the cytokine microenvironment homeostasis, and rescuing the impaired debris clearance machinery; and provided updated insights on current understandings of SLE regarding its pathogenesis, diagnosis, prevention and therapeutics, which may open an innovative avenue in the fields of SLE management.
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Affiliation(s)
- Xiaofeng Dai
- National Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, P. R. China.
| | - Yuting Fan
- Tissue Engineering and Stem Cell Experiment Center, Tumor Immunotherapy Technology Engineering Research Center, Department of Immunology, College of Basic Medical Sciences, Guizhou Medical University, Guiyang, 550004, P. R. China
- Department of Gastroenterology, the Affiliated Hospital of Guizhou Medical University, Guiyang, 550001, P. R. China
| | - Xing Zhao
- Tissue Engineering and Stem Cell Experiment Center, Tumor Immunotherapy Technology Engineering Research Center, Department of Immunology, College of Basic Medical Sciences, Guizhou Medical University, Guiyang, 550004, P. R. China.
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Dreher M, Petros S, Engelhardt S, Geselle L, Baab J, Wicke T, Schwarting A. ActiLup: is it feasible? High-intensity interval training in systemic lupus erythematosus patients with fatigue: protocol for a prospective, monocentric proof-of-concept study. BMJ Open Sport Exerc Med 2025; 11:e002403. [PMID: 39974335 PMCID: PMC11836837 DOI: 10.1136/bmjsem-2024-002403] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2024] [Accepted: 01/06/2025] [Indexed: 02/21/2025] Open
Abstract
The symptoms of active systemic lupus erythematosus (SLE) potentially lead to inactivity, muscle loss and social isolation. In addition to medical treatment, the current EULAR recommendations describe the relevance of physical activity, exercise and training as a non-pharmacological management option in patients with SLE. A positive interaction between fatigue and the basic health-promoting effects of exercise is well established. Still unclear is what kind of training, setting, and intensity show optimal objective and subjective outcomes. The study will include 40 adult SLE patients with moderate to severe fatigue. The study lasts 28 weeks and is divided into a 12-week "real-world" monitoring phase before rehabilitation, a 4-week inpatient rehabilitation phase, and a 12-week maintenance activity and training phase after the rehabilitation. The parameters consisted of physical performance parameters, laboratory parameters, physician and patient-related questionnaires and activity data based on a fitness watch. During rehabilitation, patients receive individual high-intensity interval training (HIIT), basic endurance training and functional interval training. This proof-of-concept trial aims to investigate if high-intensity interval training is feasible and how VO2peak is increased. Additionally, the effect of the severity of fatigue measured by patient-related outcomes and the number of anti-NR2 antibodies is focussed. This study was approved by the Ethics Committee of the Medical Association of Rhineland-Palatinate and complies with the standards of the Declaration of Helsinki. All participants will sign a written informed consent. Trial registration number: DRKS00022933.
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Affiliation(s)
- Matthias Dreher
- Division of Rheumatology and Clinical Immunology, Department of Internal Medicine I, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
- Center for Autoimmunity, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
| | - Sameer Petros
- Rheumatology Center Rhineland-Palatinate, Bad Kreuznach, Germany
| | - Sarah Engelhardt
- Division of Rheumatology and Clinical Immunology, Department of Internal Medicine I, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
| | - Laura Geselle
- Division of Rheumatology and Clinical Immunology, Department of Internal Medicine I, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
| | - Johannes Baab
- Rheumatology Center Rhineland-Palatinate, Bad Kreuznach, Germany
| | - Tobias Wicke
- Division of Rheumatology and Clinical Immunology, Department of Internal Medicine I, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
| | - Andreas Schwarting
- Division of Rheumatology and Clinical Immunology, Department of Internal Medicine I, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
- Center for Autoimmunity, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
- Rheumatology Center Rhineland-Palatinate, Bad Kreuznach, Germany
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Hao S, Zhang Y, Tong X, Ding F, Wang R, Zhang J, Feng D, Niu X, Huang W. Glucocorticoids on bone remodeling in systemic lupus erythematosus mice. Pediatr Res 2025:10.1038/s41390-025-03861-0. [PMID: 39856231 DOI: 10.1038/s41390-025-03861-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2024] [Revised: 12/06/2024] [Accepted: 12/28/2024] [Indexed: 01/27/2025]
Abstract
BACKGROUND Systemic lupus erythematosus requires glucocorticoids for management. This study investigates how glucocorticoids influence bone in a SLE mouse model, focusing on bone mineral density (BMD), microstructure, and remodeling markers. METHODS MRL/lpr and C57BL/6 mice were administered dexamethasone or saline as a control for 4-weeks. Bone assessments included analyses of BMD, bone structure, and serum levels of RANKL and OPG. RESULTS Dexamethasone decreased BMD and altered cortical and trabecular bone thickness in both MRL/lpr and C57BL/6 mice. In C57BL/6 mice, cortical bone exhibited increased catabolism while trabecular bone showed signs of increased anabolism, whereas MRL/lpr mice did not show significant changes in bone turnover. Both strains experienced weight loss, with a significant decrease in femur length observed only in C57BL/6 mice. Dexamethasone exacerbated BMD reduction in MRL/lpr mice and halted its increase in C57BL/6 mice. C57BL/6 mice exhibited notable changes in cortical and trabecular bone structure, while MRL/lpr mice didn't. After receiving dexamethasone, both strains showed higher serum RANKL levels, especially in C57BL/6 mice. OPG decreased in both strains. CONCLUSION Both glucocorticoids and SLE contribute to abnormal bone remodeling through RANKL/OPG pathway. IMPACT Glucocorticoid (GC) treatment in a mouse model of systemic lupus erythematosus (SLE) leads to significant changes in bone parameters, including decreased bone mineral density (BMD) and alterations in bone structure. Those change are associated with the modulation of RANKL and OPG expression. Both GC and inflammation in SLE contribute to BMD reduction, and GC may have a certain protective effect on bone in the early stage of chronic inflammation. GC can upregulate RANKL expression and downregulate OPG expression in vivo. During a state of chronic inflammation, RANKL expression increases. However, OPG may not exert a significant influence on inflammatory stimulation.
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Affiliation(s)
- Sheng Hao
- Department of Nephrology, Rheumatology and Immunology, Shanghai Children's Hospital, School of medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yuyun Zhang
- Department of Nephrology, Rheumatology and Immunology, Shanghai Children's Hospital, School of medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Xiaowei Tong
- Department of Nephrology, Rheumatology and Immunology, Shanghai Children's Hospital, School of medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Fangkai Ding
- Department of Nephrology, Rheumatology and Immunology, Shanghai Children's Hospital, School of medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Runjie Wang
- Department of Nephrology, Rheumatology and Immunology, Shanghai Children's Hospital, School of medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Jing Zhang
- Department of Nephrology, Rheumatology and Immunology, Shanghai Children's Hospital, School of medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Dan Feng
- Department of Nephrology, Rheumatology and Immunology, Shanghai Children's Hospital, School of medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Xiaoling Niu
- Department of Nephrology, Rheumatology and Immunology, Shanghai Children's Hospital, School of medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Wenyan Huang
- Department of Nephrology, Rheumatology and Immunology, Shanghai Children's Hospital, School of medicine, Shanghai Jiao Tong University, Shanghai, China.
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Suárez A, Tobío-Parada U, Rodríguez-Carrio J, Martínez-Zapico A, Pérez-Álvarez ÁI, Suárez-Díaz S, Caminal-Montero L, López P. Circulating Levels of Low-Density Granulocytes and Cell-Free DNA as Predictors of Cardiovascular Disease and Bone Deterioration in SLE Patients. Thromb Haemost 2024. [PMID: 39542026 DOI: 10.1055/a-2467-6826] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2024]
Abstract
OBJECTIVE The present work evaluates the predictive value of low-density granulocytes (LDGs) for the development of cardiovascular disease (CVD) and/or bone deterioration (BD) in a 6-year prospective study in systemic lupus erythematosus (SLE). Considering the high SLE-LDG capacity to form neutrophil extracellular traps (NETs), circulating levels of total cell-free DNA (cirDNA) and relative amounts of mitochondrial and nuclear DNA (mtDNA and nDNA, respectively) were tested as LDG-associated biomarkers to identify SLE patients at risk of CVD and BD. MATERIAL AND METHODS The frequency of total blood LDGs, as well as the CD16negCD14neg (nLDG) and CD16posCD14low (pLDG) subsets, was quantified by flow cytometry in 33 controls and 144 SLE patients. Total cirDNA and relative amounts of mitochondrial (mtDNA) and nuclear (nDNA) cell-free DNA were measured by fluorometry or qPCR in plasma from a subgroup of 117 patients and 23 controls at enrolment. RESULTS AND CONCLUSION Our findings showed increased blood levels of SLE-nLDGs at enrolment associated with prospective CVD development (pCVD) and the presence of BD, thus revealing LDG expansion as a predictor of both comorbidities in SLE progression. The amounts of the different types of circulating DNA analyzed were increased in patients, especially those presenting with traditional CV risk factors or subclinical atheromatosis. Similar to nLDGs, the nDNA concentration could predict the development of pCVD in SLE, supporting the quantification of cirDNA levels as a surrogate marker of LDGs in clinical practice.
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Affiliation(s)
- Ana Suárez
- Department of Functional Biology, Immunology Area, Faculty of Medicine, University of Oviedo, Oviedo, Spain
- Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain
| | - Uxía Tobío-Parada
- Department of Functional Biology, Immunology Area, Faculty of Medicine, University of Oviedo, Oviedo, Spain
- Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain
| | - Javier Rodríguez-Carrio
- Department of Functional Biology, Immunology Area, Faculty of Medicine, University of Oviedo, Oviedo, Spain
- Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain
| | - Aleida Martínez-Zapico
- Department of Internal Medicine, Hospital Universitario Central de Asturias, Oviedo, Spain
- Department of Neurology, Hospital Universitario Central de Asturias, Oviedo, Spain
| | - Ángel I Pérez-Álvarez
- Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain
- Department of Neurology, Hospital Universitario Central de Asturias, Oviedo, Spain
| | - Silvia Suárez-Díaz
- Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain
- Department of Internal Medicine, Hospital Universitario Central de Asturias, Oviedo, Spain
| | - Luis Caminal-Montero
- Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain
- Department of Internal Medicine, Hospital Universitario Central de Asturias, Oviedo, Spain
| | - Patricia López
- Department of Functional Biology, Immunology Area, Faculty of Medicine, University of Oviedo, Oviedo, Spain
- Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain
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Patt YS, Ben-Shabat N, Fisher L, Sharif K, Arow M, Lassman S, Watad A, Skuja V, Shtewe AH, McGonagle D, Amital H. Increased risk of osteoporosis and femoral neck fractures in patients with familial Mediterranean fever-a large retrospective cohort study. Rheumatology (Oxford) 2024; 63:2128-2134. [PMID: 37769238 DOI: 10.1093/rheumatology/kead526] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2023] [Revised: 08/21/2023] [Accepted: 09/21/2023] [Indexed: 09/30/2023] Open
Abstract
OBJECTIVES The direct impact of inflammatory conditions and their therapy with corticosteroids contribute to an increased risk of osteoporosis with associated fractures. Familial Mediterranean fever (FMF) is an autoinflammatory disorder not commonly treated with corticosteroids. Evidence regarding FMF association with osteoporosis and femur fractures is anecdotal. We aimed to evaluate the incidence and risk of osteoporosis and femoral neck fracture in FMF patients compared with the general population. METHODS A retrospective cohort study using the electronic database of Clalit Health Services of all FMF patients first diagnosed between 2000 and 2016 and controls was conducted including age- and sex-matched controls in a 1:1 ratio. Follow-up continued until the first diagnosis of osteoporosis or fracture. Risk for these conditions was compared using univariate and multivariate Cox regression models. RESULTS A total of 9769 FMF patients were followed for a median period of 12.5 years. Of these, 304 FMF patients were diagnosed with osteoporosis compared with 191 controls, resulting in an incidence rate (per 10 000 persons-years) of 28.8 and 17.8, respectively, and a crude hazard ratio of 1.62 (95% CI 1.35, 1.93; P < 0.001). Patients were diagnosed with osteoporosis at a considerably younger age than controls [60.1 (s.d. 12.4) vs 62.5 (s.d. 11.0) years; P = 0.028]. A total of 56 FMF patients were diagnosed with femoral neck fracture compared with 35 controls, resulting in an incidence rate of 5.3 and 3.3, respectively, and a crude HR of 1.60 (95% CI 1.05, 2.44; P < 0.05). CONCLUSION FMF patients are at increased risk for osteoporosis and consequently femur fracture. Our findings emphasize the importance of considering bone health in the management of FMF patients.
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Affiliation(s)
- Yonatan Shneor Patt
- Department of Internal Medicine B and Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Tel-Hashomer, Israel
- Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Niv Ben-Shabat
- Department of Internal Medicine B and Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Tel-Hashomer, Israel
- Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Lior Fisher
- Department of Internal Medicine B and Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Tel-Hashomer, Israel
- Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Kassem Sharif
- Department of Internal Medicine B and Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Tel-Hashomer, Israel
- Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
- Department of Gastroenterology, Sheba Medical Center, Tel-Hashomer, Israel
| | - Mohamad Arow
- Department of Internal Medicine B and Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Tel-Hashomer, Israel
- Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Simon Lassman
- Department of Internal Medicine B and Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Tel-Hashomer, Israel
- St George's Hospital, University of London, London, UK
| | - Abdulla Watad
- Department of Internal Medicine B and Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Tel-Hashomer, Israel
- Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
- Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UK
| | - Vita Skuja
- Department of Internal Medicine, Riga Stradins University, Riga, Latvia
- Anti-Aging Institute, Health Center 4, Riga, Latvia
| | - Anan H Shtewe
- Department of Orthopedic Surgery, Spine Surgery Service, Sheba Medical Center, Tel-Hashomer, Israel
| | - Dennis McGonagle
- Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UK
- NIHR Leeds Musculoskeletal Biomedical Research Unit, Chapel Allerton, Leeds Teaching Hospital Trust, Leeds, UK
| | - Howard Amital
- Department of Internal Medicine B and Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Tel-Hashomer, Israel
- Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
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Trentin F, Signorini V, Manca ML, Cascarano G, Gualtieri L, Schilirò D, Valevich A, Cardelli C, Carli L, Elefante E, Ferro F, Stagnaro C, Zucchi D, Tani C, Mosca M. Gender differences in SLE: report from a cohort of 417 Caucasian patients. Lupus Sci Med 2023; 10:10/1/e000880. [PMID: 37185240 PMCID: PMC10151995 DOI: 10.1136/lupus-2022-000880] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Accepted: 03/27/2023] [Indexed: 05/17/2023]
Abstract
BACKGROUND SLE is an autoimmune disease that predominantly affects women. As most epidemiological and interventional studies are on populations with a clear female prevalence, the influence of gender in disease course, drug response and damage accrual is yet to be fully explored and comprehended. OBJECTIVES To describe gender differences in disease course, comorbidities, use of medications and long-term outcomes of a large cohort of patients with SLE. METHODS Retrospective gender-based analysis of prospectively collected data from a monocentric cohort of Caucasian patients with SLE with at least 1 year of follow-up. RESULTS 417 patients were included, 51 men and 366 women. Men displayed a significantly higher median age at disease onset and diagnosis and a higher prevalence of late-onset SLE, serositis at disease onset, antiphospholipid syndrome (APS) and use of mycophenolate within the first year of disease. Women had a higher prevalence of haematological abnormalities, a higher cumulative exposure to azathioprine and higher cumulative dose of glucocorticoids at 5 years. Male patients had a shorter time to first damage item and a higher prevalence of damage at 1 and 5 years, but this association was no longer significant when late-onset patients were excluded. No differences were found in prevalence of childhood onset, delay between onset and diagnosis, time to renal involvement and histology, cumulative autoantibody positivity, number of flares and hospitalisations, median SLE Damage Index score, type of damage, age and time to first cardiovascular event, chronic kidney disease and death. CONCLUSIONS In our cohort, clinical manifestations and disease course were similar in male and female patients; however, male patients displayed higher prevalence of APS and early damage accrual probably due to the later disease onset. These data highlight the importance of an intensive follow-up, prevention and treatment of complications in this category of patients, especially in the first years of disease.
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Affiliation(s)
- Francesca Trentin
- Rheumatology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Viola Signorini
- Rheumatology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Maria Laura Manca
- Department of Clinical and Experimental Medicine and Department of Mathematics, University of Pisa, Pisa, Italy
| | - Giancarlo Cascarano
- Rheumatology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Luca Gualtieri
- Rheumatology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Davide Schilirò
- Rheumatology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Anastasiya Valevich
- Rheumatology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Chiara Cardelli
- Rheumatology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
- Department of Medical Biotechnologies, University of Siena, Siena, Italy
| | - Linda Carli
- Rheumatology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Elena Elefante
- Rheumatology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Francesco Ferro
- Rheumatology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Chiara Stagnaro
- Rheumatology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Dina Zucchi
- Rheumatology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
- Department of Medical Biotechnologies, University of Siena, Siena, Italy
| | - Chiara Tani
- Rheumatology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Marta Mosca
- Rheumatology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
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Chevet B, Figueroa-Parra G, Yang JX, Hocaoglu M, Osei-Onomah SA, Hulshizer CA, Gunderson TM, Cornec D, Barbour KE, Greenlund KJ, Crowson CS, Duarte-García A. Utilization of preventive services in a systemic lupus erythematosus population-based cohort: a Lupus Midwest Network (LUMEN) study. Arthritis Res Ther 2022; 24:211. [PMID: 36050780 PMCID: PMC9434086 DOI: 10.1186/s13075-022-02878-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2022] [Accepted: 07/24/2022] [Indexed: 12/03/2022] Open
Abstract
BACKGROUND Systemic lupus erythematosus (SLE) is a disease that can lead to damage of multiple organs and, along with certain treatments, increase the risk of developing cancer, cardiovascular disease, diabetes, osteoporosis, and infections. Preventive services are particularly important in patients with SLE to mitigate the aforementioned risks. We aimed to evaluate the trends of preventive services utilization in patients with systemic lupus erythematosus, compared with non-SLE population. METHODS All ≥19-year-old patients in the Lupus Midwest Network (LUMEN) registry, a population-based cohort, with SLE on January 1, 2015, were included and matched (1:1) by sex, age, race, and county to non-SLE comparators. Among both groups, we compared the rates of screenings for breast and cervical cancer, hypertension, hyperlipidemia, diabetes mellitus, and osteoporosis as well as immunizations. RESULTS We included 440 SLE patients and 430 non-SLE comparators. The probability of breast cancer screening among women with SLE was similar to comparators (hazard ratio [HR] 1.09, 95% CI 0.85-1.39), while cervical cancer screening was lower (HR 0.75, 95% CI 0.58-0.96). Hypertension screening was higher among patients with SLE (HR 1.35, 95% CI 1.13-1.62); however, hyperlipidemia screening was similar to comparators (HR 1.16, 95% CI 0.96-1.41). Diabetes and osteoporosis screenings were more likely to be performed for SLE patients than for comparators (HR 2.46, 95% CI 2.11-2.87; and HR 3.19, 95% CI 2.31-4.41; respectively). Influenza and pneumococcal immunizations were higher among SLE patients (HR 1.31, 95% CI 1.12-1.54; and HR 2.06, 95% CI 1.38-3.09; respectively), while zoster vaccination was similar (HR 1.17, 95% CI 0.81-1.69). CONCLUSIONS The trends of utilization of preventive services by SLE patients vary according to screening or vaccine compared with the general population. Considering these differences, we demonstrate an opportunity for improvement, particularly in cervical cancer, hyperlipidemia, and osteoporosis screenings and vaccinations.
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Affiliation(s)
- Baptiste Chevet
- Division of Rheumatology, Mayo Clinic, Rochester, 200 First Street SW, MN, 55905, USA
- Division of Rheumatology, Brest Teaching Hospital; LBAI, UMR1227, Univ Brest, Inserm, CHU de Brest, Brest, France
| | | | - Jeffrey X Yang
- Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA
| | - Mehmet Hocaoglu
- Division of Rheumatology, Mayo Clinic, Rochester, 200 First Street SW, MN, 55905, USA
| | | | | | - Tina M Gunderson
- Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA
| | - Divi Cornec
- Division of Rheumatology, Brest Teaching Hospital; LBAI, UMR1227, Univ Brest, Inserm, CHU de Brest, Brest, France
| | - Kamil E Barbour
- Division of Population Health, National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention, Atlanta, GA, USA
| | - Kurt J Greenlund
- Division of Population Health, National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention, Atlanta, GA, USA
| | - Cynthia S Crowson
- Division of Rheumatology, Mayo Clinic, Rochester, 200 First Street SW, MN, 55905, USA
- Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA
| | - Alí Duarte-García
- Division of Rheumatology, Mayo Clinic, Rochester, 200 First Street SW, MN, 55905, USA.
- Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery, Mayo Clinic, Rochester, MN, USA.
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8
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Martel D, Saxena A, Belmont HM, Honig S, Chang G. Fatty Acid Composition of Proximal Femur Bone Marrow Adipose Tissue in Subjects With Systemic Lupus Erythematous Using 3 T Magnetic Resonance Spectroscopy. J Magn Reson Imaging 2022; 56:618-624. [PMID: 34964533 PMCID: PMC10023192 DOI: 10.1002/jmri.28038] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Revised: 12/09/2021] [Accepted: 12/10/2021] [Indexed: 11/08/2022] Open
Abstract
BACKGROUND Systemic lupus erythematosus (SLE) is a chronic, inflammatory disease with common musculoskeletal manifestations, notably reductions in bone quality. Bone marrow adipose tissue composition and quantity has been previously linked to bone quality and may play a role in SLE pathophysiology but has not been thoroughly studied. PURPOSE To use magnetic resonance spectroscopy (MRS) to investigate bone marrow adipose tissue quantity and composition in proximal femur subregions of untreated SLE patients compared to controls and treated patients. STUDY TYPE Prospective. SUBJECTS A total of 64 female subjects: 28 SLE, 15 glucocorticoid (GC)-treated SLE and 21 matched controls. FIELD STRENGTH/SEQUENCE Stimulated echo acquisition mode (STEAM) sequence at 3 T. ASSESSMENT MRS was performed at multiple echo times in the femoral neck and trochanter regions and fatty acids (FA) composition was computed. STATISTICAL TESTS Intergroup comparisons were carried out using ANOVA. A P value < 0.05 was considered statistically significant. RESULTS SLE patients had significantly higher saturated FA compared to controls in both the femoral neck (+0.12) and trochanter (+0.11), significantly lower monounsaturated FA in the trochanter compared to controls (-0.05), and significantly lower polyunsaturated FA in the femoral neck compared to both controls (-0.07) and SLE patients on GC therapy (-0.05). DATA CONCLUSION SLE patients have altered proximal femur marrow fat metabolism, which may reflect a manifestation of, or play a role in, the altered inflammatory response of these patients. EVIDENCE LEVEL 2 TECHNICAL EFFICACY: Stage 2.
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Affiliation(s)
- Dimitri Martel
- New York Langone Health, Department of Radiology, New York, New York, USA
| | - Amit Saxena
- New York Langone Health, Division of Rheumatology, Hospital for Joint Diseases, New York, New York, USA
| | - Howard Michael Belmont
- New York Langone Health, Division of Rheumatology, Hospital for Joint Diseases, New York, New York, USA
| | - Stephen Honig
- New York Langone Health, Osteoporosis Center, Hospital for Joint Diseases, New York, New York, USA
| | - Gregory Chang
- New York Langone Health, Department of Radiology, New York, New York, USA
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Ishida T, Yuri H, Nakamura E, Isoda K, Wada Y, Kotani T, Takeuchi T. Low pre-pregnant body mass index is a risk factor for the decrease of postpartum bone mineral density in systemic lupus erythematosus patients received glucocorticoid therapy. Lupus 2022; 31:848-854. [PMID: 35440212 DOI: 10.1177/09612033221094710] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
OBJECTIVES This study investigated postpartum bone mineral density (BMD) in patients with systemic lupus erythematosus (SLE) receiving long-term glucocorticoid (GC) therapy, assessed risk factors for decreased postpartum BMD, and evaluated change of BMD after postpartum initiation or restarting of osteoporosis drugs. METHODS We retrospectively examined 30 SLE patients who gave birth and 31 non-pregnant SLE patients. In the postpartum SLE patients, BMD was measured after delivery and 1 year later. Multivariate analyses were performed to assess risk factors for decreased BMD in postpartum SLE patients. RESULTS Patient age at pregnancy was 34.5 ± 4.5 years, and SLE duration was 9.7 ± 6.0 years. The mean prednisolone dose was 9.7 ± 3.2 mg/day. Body mass index (BMI) was 21.6 ± 2.2 kg/m2, with 13 women (43%) experiencing their first delivery. Postpartum BMD was 1.080 ± 0.120 g/cm2 in the lumbar spine and 0.834 ± 0.109 g/cm2 in the total hip. Bone loss occurred in six patients (21%) in the lumbar spine and 11 patients (37%) in the total hip. Postpartum lumbar spine BMD was significantly reduced compared to that in the non-pregnant group (1.143 ± 0.120 g/cm2, p = 0.048). Multivariate analysis identified gestational age and low BMI before pregnancy as risk factors for hip bone loss. CONCLUSION Postpartum BMD significantly decrease in SLE patients receiving long-term GC, and low BMI before pregnancy was a risk factor for the decrease. Preconception care to prevent osteoporosis and that regularly monitors BMD after delivery are needed.
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Affiliation(s)
- Takaaki Ishida
- Division of Rheumatology, Department of Internal Medicine (IV), 13010Osaka Medical and Pharmaceutical University Hospital, Osaka, Japan.,Department of Internal Medicine, Santamaria Hospital, Osaka, Japan
| | - Hiramatsu Yuri
- Division of Rheumatology, Department of Internal Medicine (IV), 13010Osaka Medical and Pharmaceutical University Hospital, Osaka, Japan
| | - Eri Nakamura
- Division of Rheumatology, Department of Internal Medicine (IV), 13010Osaka Medical and Pharmaceutical University Hospital, Osaka, Japan
| | - Kentaro Isoda
- Division of Rheumatology, Department of Internal Medicine (IV), 13010Osaka Medical and Pharmaceutical University Hospital, Osaka, Japan.,Department of Rheumatology and Allergology, National Hospital Organization Osaka Minami Medical Center, Osaka, Japan
| | - Yumiko Wada
- Division of Rheumatology, Department of Internal Medicine (IV), 13010Osaka Medical and Pharmaceutical University Hospital, Osaka, Japan
| | - Takuya Kotani
- Division of Rheumatology, Department of Internal Medicine (IV), 13010Osaka Medical and Pharmaceutical University Hospital, Osaka, Japan
| | - Tohru Takeuchi
- Division of Rheumatology, Department of Internal Medicine (IV), 13010Osaka Medical and Pharmaceutical University Hospital, Osaka, Japan
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10
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Nordqvist J, Engdahl C, Scheffler JM, Gupta P, Gustafsson KL, Lagerquist MK, Carlsten H, Islander U. A tissue-selective estrogen complex as treatment of osteoporosis in experimental lupus. Lupus 2022; 31:143-154. [PMID: 35062848 PMCID: PMC8832562 DOI: 10.1177/09612033211067984] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Osteoporosis is a common secondary complication in patients with systemic lupus erythematosus (SLE). Current osteoporosis treatment with bisphosphonates has some negative side effects and there is a lack of data regarding newer treatments options for SLE associated osteoporosis. The tissue-selective estrogen complex (TSEC) containing conjugated estrogens and the selective estrogen receptor modulator bazedoxifene (Bza) is approved for treatment of postmenopausal vasomotor symptoms and prevention of osteoporosis. However, it has not been evaluated for treatment of osteoporosis in postmenopausal SLE patients. Ovariectomized MRL/lpr mice constitute a model for postmenopausal lupus that can be used for osteoporosis studies. We used this model in a set of experiments where the mice were treated with different doses of 17β-estradiol-3-benzoate (E2), Bza, or TSEC (E2 plus Bza), administered in the early or late phases of disease development. The skeleton was analyzed by dual-energy X-ray absorptiometry, peripheral quantitative computed tomography, and high-resolution microcomputed tomography. The lupus disease was assessed by determination of proteinuria, hematuria, and lupus disease markers in serum. Treatment with medium dose TSEC administered in early disease protected ovariectomized MRL/lpr mice from trabecular bone loss, while there were no differences in lupus disease parameters between treatments. This is the first experimental study to investigate TSEC as a potential new therapy for osteoporosis in postmenopausal SLE.
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Affiliation(s)
- Jauquline Nordqvist
- Department of Rheumatology and Inflammation Research, 70712University of Gothenburg Sahlgrenska Academy, Goteborg, Sweden
| | - Cecilia Engdahl
- Department of Rheumatology and Inflammation Research, 70712University of Gothenburg Sahlgrenska Academy, Goteborg, Sweden.,Department of Internal Medicine and Clinical Nutrition, 70712University of Gothenburg Sahlgrenska Academy, Goteborg, Sweden
| | - Julia M Scheffler
- Department of Rheumatology and Inflammation Research, 70712University of Gothenburg Sahlgrenska Academy, Goteborg, Sweden.,Department of Internal Medicine and Clinical Nutrition, 70712University of Gothenburg Sahlgrenska Academy, Goteborg, Sweden
| | - Priti Gupta
- Department of Rheumatology and Inflammation Research, 70712University of Gothenburg Sahlgrenska Academy, Goteborg, Sweden
| | - Karin L Gustafsson
- Department of Internal Medicine and Clinical Nutrition, 70712University of Gothenburg Sahlgrenska Academy, Goteborg, Sweden
| | - Marie K Lagerquist
- Department of Internal Medicine and Clinical Nutrition, 70712University of Gothenburg Sahlgrenska Academy, Goteborg, Sweden
| | - Hans Carlsten
- Department of Rheumatology and Inflammation Research, 70712University of Gothenburg Sahlgrenska Academy, Goteborg, Sweden
| | - Ulrika Islander
- Department of Rheumatology and Inflammation Research, 70712University of Gothenburg Sahlgrenska Academy, Goteborg, Sweden.,Department of Internal Medicine and Clinical Nutrition, 70712University of Gothenburg Sahlgrenska Academy, Goteborg, Sweden
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11
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Zhu L, Zhang J, Wang J, Lv X, Pu D, Wang Y, Men Q, He L. Uncoupled bone remodeling is characteristic of bone damage in premenopausal women with new-onset systemic lupus erythematosus. Lupus 2021; 30:1116-1123. [PMID: 33832361 DOI: 10.1177/09612033211005067] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
OBJECTIVE To investigate the mechanism underlying systemic lupus erythematosus (SLE)-related bone loss by evaluating the bone mineral density (BMD) and bone turnover markers (BTMs) in premenopausal patients with new-onset SLE without any treatment. METHODS BMD and BTMs of 106 premenopausal patients with new-onset SLE and 64 gender-, age- and body mass index (BMI)-matched healthy controls were analyzed. BMD was determined using dual energy X-ray absorptiometry (DXA). Serum BTMs were measured. RESULTS Hip and lumbar spine BMD in premenopausal patients with new-onset SLE was significantly decreased compared with healthy controls. Higher rate of osteoporosis was observed in new-onset SLE patients (25% vs. 1%). Moreover, uncoupled bone remodeling evidenced by an increase in bone resorption marker β-CTX (685.9 ± 709.6 pg/mL vs. 395.4 ± 326.0 pg/mL, P < 0.05) and decrease in bone formation markers PINP (37.4 ± 33.0 ng/mL vs. 46.1 ± 20.9 ng/mL, P < 0.05) and OC (11.4 ± 9.8 ng/mL vs. 18.2 ± 8.6 ng/mL, P < 0.05) was observed in premenopausal patients with new-onset SLE compared with healthy controls. Univariate correlation analyses showed negative correlations between OC and SLE Disease Activity Index (SLEDAI), and positive correlations between β-CTX and SLEDAI. SLE patients positive for dsDNA, nucleosome showed lower OC and higher β-CTX. CONCLUSION Premenopausal patients with new-onset SLE had decreased BMD and abnormal bone metabolism with increased β-CTX and decreased OC and P1NP levels, indicating uncoupled bone remodeling in new-onset SLE patients. Disease activity and abnormal immunity, especially the amount of antibodies in SLE patients, were strongly associated with abnormality of bone metabolism.
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Affiliation(s)
- Li Zhu
- Department of Rheumatology and Immunology, First Affiliated Hospital of Xi'an, JiaoTong University, Xi'an, China
| | - Jing Zhang
- Department of Rheumatology and Immunology, First Affiliated Hospital of Xi'an, JiaoTong University, Xi'an, China
| | - Jing Wang
- Department of Rheumatology and Immunology, First Affiliated Hospital of Xi'an, JiaoTong University, Xi'an, China
| | - Xiaohong Lv
- Department of Rheumatology and Immunology, First Affiliated Hospital of Xi'an, JiaoTong University, Xi'an, China
| | - Dan Pu
- Department of Rheumatology and Immunology, First Affiliated Hospital of Xi'an, JiaoTong University, Xi'an, China
| | - Yanhua Wang
- Department of Rheumatology and Immunology, First Affiliated Hospital of Xi'an, JiaoTong University, Xi'an, China
| | - Qian Men
- Department of Rheumatology and Immunology, First Affiliated Hospital of Xi'an, JiaoTong University, Xi'an, China
| | - Lan He
- Department of Rheumatology and Immunology, First Affiliated Hospital of Xi'an, JiaoTong University, Xi'an, China
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12
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Li L, Xie H, Lu N, Esdaile JM, Aviña-Zubieta JA. Impact of Systemic Lupus Erythematosus on the Risk of Newly Diagnosed Hip Fracture: A General Population-Based Study. Arthritis Care Res (Hoboken) 2021; 73:259-265. [PMID: 31758639 DOI: 10.1002/acr.24112] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2019] [Accepted: 11/19/2019] [Indexed: 01/26/2023]
Abstract
OBJECTIVE Hip fractures have serious consequences, including a 1-year mortality rate of 30%. Population-based studies on hip fractures in individuals with systemic lupus erythematosus (SLE) are scarce. Our objective was to assess the independent risk of hip fractures in patients with newly diagnosed SLE compared to the general population, accounting for baseline and time-varying confounders. METHODS A cohort of all patients with incident SLE who received health care between January 1, 1997 and March 31, 2015 was assembled. The primary outcome was the occurrence of the first hip fracture since the study entry date. Individuals without SLE were randomly selected from the general population and matched (5:1) to those with SLE based on age, sex, and index year. Cumulative incidence was calculated after accounting for competing risks of death. Marginal structural Cox models were used to estimate the impact of SLE on hip fractures, adjusting for baseline and time-dependent covariates (i.e., glucocorticoid use and the number of outpatient, inpatient, and rheumatologist visits). RESULTS Among 5,047 individuals with incident SLE and 25,235 individuals without SLE (86% female, mean age 40 years), we found 73 and 272 hip fractures during 78,915 and 395,427 person-years, respectively. The crude incidence rate ratio was 1.34 (95% confidence interval [95% CI] 1.02-1.75). After adjusting for baseline covariates, the hazard ratio (HR) was 1.86 (95% CI 1.37-2.52). After further adjustment for time-dependent covariates, the HR remained significant at 1.62 (95% CI 1.06-2.48). CONCLUSION Patients with newly diagnosed SLE have a 62% increased risk of hip fractures compared to individuals without SLE. For patients with SLE, this result has important implications for prevention of osteoporosis, which may lead to hip fractures.
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Affiliation(s)
- Lingyi Li
- Arthritis Research Canada, Richmond, British Columbia, Canada
| | - Hui Xie
- Arthritis Research Canada, Richmond, and Simon Fraser University, Burnaby, British Columbia, Canada
| | - Na Lu
- Arthritis Research Canada, Richmond, British Columbia, Canada
| | - John M Esdaile
- Arthritis Research Canada, Richmond, and University of British Columbia, Vancouver, British Columbia, Canada
| | - J Antonio Aviña-Zubieta
- Arthritis Research Canada, Richmond, and University of British Columbia, Vancouver, British Columbia, Canada
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13
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Boone JB, Wheless L, Camai A, Tanner SB, Barnado A. Low prevalence of bone mineral density testing in patients with systemic lupus erythematosus and glucocorticoid exposure. Lupus 2020; 30:403-411. [PMID: 33307984 DOI: 10.1177/0961203320979735] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
SummaryPatients with systemic lupus erythematosus (SLE) have an increased risk of developing osteoporosis and fractures due to systemic inflammation and glucocorticoids (GCs). Professional organizations recommend bone mineral density (BMD) testing in SLE patients on GCs, especially within 6 months of initiation. Using a validated algorithm, we identified SLE patients in an electronic health record cohort with long-term GC exposure (≥90 days). Our primary outcome was ever BMD testing. We assessed the impact of patient and provider factors on testing. We identified 693 SLE cases with long-term GC exposure, 41% of whom had BMD testing performed. Only 18% of patients had BMD testing within 6 months of GC initiation. In a logistic regression model for BMD testing, male sex (OR = 0.49, 95% CI 0.27 - 0.87, p = 0.01) was associated with being less likely to have BMD testing after adjusting for race and ethnicity. In contrast, older age (OR = 1.04, p < 0.001) and nephritis (OR = 1.83, p = 0.003) were associated with being more likely to have BMD testing after adjusting for race and ethnicity. Bone health in SLE patients remains an area in need of improvement with attention to patients who are younger and male.
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Affiliation(s)
- J B Boone
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Lee Wheless
- Department of Dermatology, Data Science Institute, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Alex Camai
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - S Bobo Tanner
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - April Barnado
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
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14
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Kariniemi S, Rantalaiho V, Virta LJ, Puolakka K, Sokka-Isler T, Elfving P. Multimorbidity among incident Finnish systemic lupus erythematosus patients during 2000-2017. Lupus 2020; 30:165-171. [PMID: 33086917 PMCID: PMC7768886 DOI: 10.1177/0961203320967102] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
The objective of the study was to examine the risk of other morbidities among patients with systemic lupus erythematosus (SLE). A total of 1006 adult new-onset SLE patients were identified during 1.1.2000- 31.12.2014 from the register of Social Insurance Institution. For each case three general population controls matched according to age, sex and place of residence at the index day were sampled from the population register. Both groups were followed up from the index date until the end of 2017 or until death. The national register on specialized care was explored to gather broadly their 12 organ-specific morbidities, which were found among 91.2% of SLE patients and 66.7% of comparators. The rate ratio (RR) was elevated in almost all disease groups. Musculoskeletal, cardiovascular and genitourinary conditions were the most common comorbidities with RRs of 1.82 (1.68 to 1.97), 1.91 (1.76 to 2.08) and 1.91 (1.73 to 2.09), respectively. Men with SLE had a significantly higher risk for diseases of the genitourinary system and endocrine, nutritional and metabolic diseases compared to women with SLE. The risk of concurrent morbidities is essential to note in the care of SLE patients.
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Affiliation(s)
- Simo Kariniemi
- School of Medicine, University of Eastern Finland, Kuopio, Finland.,Department of Medicine, Kuopio University Hospital, Kuopio, Finland
| | - Vappu Rantalaiho
- Centre for Rheumatic Diseases, Tampere University Hospital, Tampere, Finland.,Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Lauri J Virta
- Research Department, Social Insurance Institution, Turku, Finland
| | | | - Tuulikki Sokka-Isler
- Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland.,Jyväskylä Central Hospital, Jyväskylä; Finland
| | - Pia Elfving
- Department of Medicine, Kuopio University Hospital, Kuopio, Finland
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15
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Metzger CE, Anand Narayanan S, Phan PH, Bloomfield SA. Hindlimb unloading causes regional loading-dependent changes in osteocyte inflammatory cytokines that are modulated by exogenous irisin treatment. NPJ Microgravity 2020; 6:28. [PMID: 33083525 PMCID: PMC7542171 DOI: 10.1038/s41526-020-00118-4] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2019] [Accepted: 08/18/2020] [Indexed: 12/11/2022] Open
Abstract
Disuse-induced bone loss is characterized by alterations in bone turnover. Accruing evidence suggests that osteocytes respond to inflammation and express and/or release pro-inflammatory cytokines; however, it remains largely unknown whether osteocyte inflammatory proteins are influenced by disuse. The goals of this project were (1) to assess osteocyte pro-inflammatory cytokines in the unloaded hindlimb and loaded forelimb of hindlimb unloaded rats, (2) to examine the impact of exogenous irisin during hindlimb unloading (HU). Male Sprague Dawley rats (8 weeks old, n = 6/group) were divided into ambulatory control, HU, and HU with irisin (HU + Ir, 3×/week). Lower cancellous bone volume, higher osteoclast surfaces (OcS), and lower bone formation rate (BFR) were present at the hindlimb and 4th lumbar vertebrae in the HU group while the proximal humerus of HU rats exhibited no differences in bone volume, but higher BFR and lower OcS vs. Con. Osteocyte tumor necrosis factor-α (TNF-α), interleukin-17 (IL-17), RANKL, and sclerostin were elevated in the cancellous bone of the distal femur of HU rats vs. Con, but lower at the proximal humerus in HU rats vs. Con. Exogenous irisin treatment increased BFR, and lowered OcS and osteocyte TNF-α, IL-17, RANKL, and sclerostin in the unloaded hindlimb of HU + Ir rats while having minimal changes in the humerus. In conclusion, there are site-specific and loading-specific alterations in osteocyte pro-inflammatory cytokines and bone turnover with the HU model of disuse bone loss, indicating a potential mechanosensory impact of osteocyte TNF-α and IL-17. Additionally, exogenous irisin significantly reduced the pro-inflammatory status of the unloaded hindlimb.
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Affiliation(s)
- Corinne E Metzger
- Department of Health and Kinesiology, Texas A&M University, College Station, TX USA
| | - S Anand Narayanan
- Department of Medical Physiology, Texas A&M Health Science Center, Temple, TX USA
| | - Peter H Phan
- Department of Health and Kinesiology, Texas A&M University, College Station, TX USA
| | - Susan A Bloomfield
- Department of Health and Kinesiology, Texas A&M University, College Station, TX USA
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16
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Sirufo MM, De Pietro F, Bassino EM, Ginaldi L, De Martinis M. Osteoporosis in Skin Diseases. Int J Mol Sci 2020; 21:E4749. [PMID: 32635380 PMCID: PMC7370296 DOI: 10.3390/ijms21134749] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Revised: 06/30/2020] [Accepted: 07/01/2020] [Indexed: 12/14/2022] Open
Abstract
Osteoporosis (OP) is defined as a generalized skeletal disease characterized by low bone mass and an alteration of the microarchitecture that lead to an increase in bone fragility and, therefore, an increased risk of fractures. It must be considered today as a true public health problem and the most widespread metabolic bone disease that affects more than 200 million people worldwide. Under physiological conditions, there is a balance between bone formation and bone resorption necessary for skeletal homeostasis. In pathological situations, this balance is altered in favor of osteoclast (OC)-mediated bone resorption. During chronic inflammation, the balance between bone formation and bone resorption may be considerably affected, contributing to a net prevalence of osteoclastogenesis. Skin diseases are the fourth cause of human disease in the world, affecting approximately one third of the world's population with a prevalence in elderly men. Inflammation and the various associated cytokine patterns are the basis of both osteoporosis and most skin pathologies. Moreover, dermatological patients also undergo local or systemic treatments with glucocorticoids and immunosuppressants that could increase the risk of osteoporosis. Therefore, particular attention should be paid to bone health in these patients. The purpose of the present review is to take stock of the knowledge in this still quite unexplored field, despite the frequency of such conditions in clinical practice.
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Affiliation(s)
- Maria Maddalena Sirufo
- Department of Life, Health and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy; (M.M.S.); (F.D.P.); (E.M.B.); (L.G.)
- Allergy and Clinical Immunology Unit, Center for the Diagnosis and Treatment of Osteoporosis, AUSL 04 64100 Teramo, Italy
| | - Francesca De Pietro
- Department of Life, Health and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy; (M.M.S.); (F.D.P.); (E.M.B.); (L.G.)
- Allergy and Clinical Immunology Unit, Center for the Diagnosis and Treatment of Osteoporosis, AUSL 04 64100 Teramo, Italy
| | - Enrica Maria Bassino
- Department of Life, Health and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy; (M.M.S.); (F.D.P.); (E.M.B.); (L.G.)
- Allergy and Clinical Immunology Unit, Center for the Diagnosis and Treatment of Osteoporosis, AUSL 04 64100 Teramo, Italy
| | - Lia Ginaldi
- Department of Life, Health and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy; (M.M.S.); (F.D.P.); (E.M.B.); (L.G.)
- Allergy and Clinical Immunology Unit, Center for the Diagnosis and Treatment of Osteoporosis, AUSL 04 64100 Teramo, Italy
| | - Massimo De Martinis
- Department of Life, Health and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy; (M.M.S.); (F.D.P.); (E.M.B.); (L.G.)
- Allergy and Clinical Immunology Unit, Center for the Diagnosis and Treatment of Osteoporosis, AUSL 04 64100 Teramo, Italy
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17
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Gao L, Liesveld J, Anolik J, Mcdavid A, Looney RJ. IFN β signaling inhibits osteogenesis in human SLE bone marrow. Lupus 2020; 29:1040-1049. [PMID: 32515653 DOI: 10.1177/0961203320930088] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Bone marrow mesenchymal stem cells are multipotent adult stem cells that can differentiate into osteoblasts, adipocytes, and chondrocytes. Our recently published data demonstrate that systemic lupus erythematous bone marrow mesenchymal stem cells produce increased quantities of interferon β based on a positive feedback loop involving the innate signaling molecule mitochondrial antiviral signaling protein. Moreover, this pathway contributes to human systemic lupus erythematous bone marrow mesenchymal stem cell senescence-like features. Here we investigate the differentiation defects of systemic lupus erythematous bone marrow mesenchymal stem cells and the potential for therapeutic interventions. METHODS The six systemic lupus erythematous patients recruited in this study satisfy the American College of Rheumatology 1997 classification criteria for systemic lupus erythematous. Systemic Lupus Erythematous Disease Activity Index-2K was used to determine disease activity. Systemic lupus erythematous bone marrow mesenchymal stem cells were isolated with Ficoll centrifugation and phenotyped using flow cytometry. In vitro studies included real-time polymerase chain reaction and western blotting. RESULTS We compared six age-paired bone marrow aspirates from healthy controls and systemic lupus erythematous patients. Systemic lupus erythematous bone marrow mesenchymal stem cells display significantly reduced alkaline phosphatase staining, as well as reduced expression of osteogenic markers alkaline phosphatase, Runt-related transcription factor 2, and bone sialoprotein. When healthy bone marrow mesenchymal stem cells were treated with interferon β for 6 hours, expression of these same osteogenic markers was markedly reduced. Conversely the application of interferon β neutralizing antibody enhanced the expression of osteoblastogenesis markers. When the underlying mechanisms for interferon β inhibition of osteoblastogenesis were investigated, we found that IFNβ pre-treatment activates the inhibitory Smad6 and Smad7 expression through JAK1/STAT1, leading to reduced Smad1 phosphorylation and nuclear translocation. CONCLUSIONS Our present work suggests that interferon β affects osteogenesis. By revealing the essential role of interferon β on systemic lupus erythematous bone marrow mesenchymal stem cell differentiation, our study sheds light on systemic lupus erythematous pathogenesis and provides a new potential therapeutic target for the bone complications found in systemic lupus erythematous.
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Affiliation(s)
- Lin Gao
- University of Rochester Medical Center, USA
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18
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Nordqvist J, Lagerquist MK, Grahnemo L, Koskela A, Islander U, Carlsten H. Osteoporosis in a murine model of postmenopausal lupus. Lupus 2019; 29:58-66. [PMID: 31825765 DOI: 10.1177/0961203319893759] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
BACKGROUND/OBJECTIVE Postmenopausal women with systemic lupus erythematosus have an increased risk of osteoporosis and associated fractures. Their increased osteoporosis risk is probably caused by a high level of inflammation, use of glucocorticoids, impaired kidney function, and early menopause as these are known risk factors for osteoporosis. Due to these risk factors and the lack of safe and effective treatments, new therapies for the treatment of osteoporosis in this group of patients are needed. Ovariectomized MRL/lpr mice constitute a well-established model for studies of postmenopausal systemic lupus erythematosus; however, it is not clear to what extent this experimental model is associated with the development of osteoporosis. Thus, the aim of this study was to characterize the skeleton of ovariectomized MRL/lpr mice to determine the suitability of this model in studies of prospective new therapies for osteoporosis in postmenopausal systemic lupus erythematosus patients. METHODS Skeletal parameters were measured in MRL/lpr mice and MRL/++ control mice, using peripheral quantitative computed tomography, high-resolution micro-computed tomography and biomechanical analyses. mRNA expression of bone-remodeling markers was measured by quantitative polymerase chain reaction and serological markers of lupus disease were evaluated using ELISA. RESULTS Total bone mineral density was reduced in MRL/lpr mice compared with MRL/++ mice and MRL/lpr mice had reduced cortical and trabecular bone thickness compared with MRL/++ mice. In line with the low bone mass of MRL/lpr mice, gene expression analysis of cortical bone from these mice indicated an increased osteoclast activity as well as a decreased osteoblastogenesis and osteoblast activity, compared with MRL/++ mice. CONCLUSION Ovariectomized MRL/lpr mice constitute a valuable experimental model for studies of osteoporosis development in postmenopausal systemic lupus erythematosus and this model is thus suitable for future studies of osteoporosis treatment in systemic lupus erythematosus.
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Affiliation(s)
- J Nordqvist
- Department of Rheumatology and Inflammation Research, Centre for Bone and Arthritis Research, University of Gothenburg, Sweden
| | - M K Lagerquist
- Department of Internal Medicine and Clinical Nutrition, Centre for Bone and Arthritis Research, University of Gothenburg, Sweden
| | - L Grahnemo
- Department of Internal Medicine and Clinical Nutrition, Centre for Bone and Arthritis Research, University of Gothenburg, Sweden
| | - A Koskela
- Department of Anatomy and Cell Biology, University of Oulu, Finland
| | - U Islander
- Department of Internal Medicine and Clinical Nutrition, Centre for Bone and Arthritis Research, University of Gothenburg, Sweden
| | - H Carlsten
- Department of Rheumatology and Inflammation Research, Centre for Bone and Arthritis Research, University of Gothenburg, Sweden
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19
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Gu C, Zhao R, Zhang X, Gu Z, Zhou W, Wang Y, Guo J, Bao Y, Sun C, Dong C, Gao J. A meta-analysis of secondary osteoporosis in systemic lupus erythematosus: prevalence and risk factors. Arch Osteoporos 2019; 15:1. [PMID: 31802295 DOI: 10.1007/s11657-019-0667-1] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2019] [Accepted: 11/05/2019] [Indexed: 02/03/2023]
Abstract
PURPOSE This study aimed to evaluate the prevalence and risk factors of secondary osteoporosis (OP) in patients with systemic lupus erythematosus (SLE) and provide a theoretical basis for clinical prevention and treatment of SLE. METHODS Take systematic review and meta-analysis of relevant studies. Data sources are CINAHL databases, PubMed, Embase, Wan Fang, Weipu, and CNKI databases. Eligibility criteria are cross-sectional or case-control studies which analyzed the prevalence and risk factors of OP in SLE. Two authors independently screened all studies; a third author verified and identify controversial studies. The quality of the included articles was evaluated. Stata 11 and Rev-Man 5.2 software were used for data processing. RESULTS Thirty-one articles were included, with a total sample size of 3089 SLE, including 529 OP cases and 2560 non-OP cases. Meta-analysis showed that the prevalence of OP among SLE was 16% (95% CI (0.12, 0.19)). The risk of OP in SLE cases compared with controls was significantly greater with OR of 2.03 (95% CI 1.33-3.10, P = 0.001). Age, disease duration, cumulative glucocorticoid dose, duration of glucocorticoid therapy, SLICC, and menopause had significant differences between two groups. No statistical differences of daily glucocorticoid dose, SLEDAI, and BMI were found between OP and non-OP cases. CONCLUSIONS Our study found a statistically significant increased risk of OP in SLE patients compared with controls. SLE patients should be actively screened for OP and its consequences. Larger longitudinal studies are needed to confirm this possible association. The prevalence of OP in SLE was 16%. Compared with controls, the risk of OP in SLE was 2.03. There were significant differences of age, disease duration, cumulative glucocorticoid dose, time of glucocorticoid, SLICC, and menopause, while daily glucocorticoid dose, SLEDAI, and BMI had no statistical differences between OP and non-OP cases.
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Affiliation(s)
- Chaoyu Gu
- Medical College, Nantong University, 19th Qixiu Road, Nantong, 226001, China
| | - Rui Zhao
- Department of Nursing, Affiliated Hospital of Nantong University, 20th Xisi Road, Nantong, 226001, China
| | - Xiaomei Zhang
- Department of Nursing, Affiliated Hospital of Nantong University, 20th Xisi Road, Nantong, 226001, China
| | - Zhifeng Gu
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, 20th Xisi Road, Nantong, 226001, China.,Department of Rheumatology, Affiliated Hospital of Nantong University, 20th Xisi Road, Nantong, 226001, China
| | - Wei Zhou
- Department of Nursing, Affiliated Hospital of Nantong University, 20th Xisi Road, Nantong, 226001, China
| | - Yilin Wang
- Department of Nursing, Affiliated Hospital of Nantong University, 20th Xisi Road, Nantong, 226001, China
| | - Jiaxin Guo
- Department of Nursing, Affiliated Hospital of Nantong University, 20th Xisi Road, Nantong, 226001, China
| | - Yanfeng Bao
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, 20th Xisi Road, Nantong, 226001, China
| | - Chi Sun
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, 20th Xisi Road, Nantong, 226001, China
| | - Chen Dong
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, 20th Xisi Road, Nantong, 226001, China. .,Department of Rheumatology, Affiliated Hospital of Nantong University, 20th Xisi Road, Nantong, 226001, China. .,Center for Geriatrics Research, Affiliated Hospital of Nantong University, 20th Xisi Road, Nantong, 226001, China.
| | - Jianlin Gao
- Center for Geriatrics Research, Affiliated Hospital of Nantong University, 20th Xisi Road, Nantong, 226001, China.
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Abstract
Osteoporotic fracture is a major cause of morbidity in patients with systemic lupus erythematosus (SLE). Mice lacking Fc gamma receptor IIb (FcγRIIB) spontaneously develop lupus-like disease or SLE at 6-month-old. The aim of this study was to investigate whether FcγRIIB deletion induces osteopenia. μCT analysis indicated that deleting FcγRIIB did not affect cancellous bone microarchitecture in 3-month-old mice in which SLE had not yet developed. However, 6- and 10-month-old FcγRIIB−/− males that developed an SLE-like phenotype were osteopenic and FcγRIIB deletion resulted in decreased cancellous bone volume. Histomorphometry confirmed a significant decrease in cancellous bone volume in 6- and 10-month-old FcγRIIB−/− males. The osteoclast number was increased without any change in osteoblast number. In vitro assays indicated that deleting FcγRIIB increased osteoclast differentiation while alkaline phosphatase activity and mineralization were unaltered. These changes were associated with increases in steady-state mRNA levels for the osteoclast marker genes Trap and Ctsk. Moreover, FcγRIIB−/− mice had higher level of serum TNFα, a proinflammatory cytokine. A soluble TNFα receptor, etanercept, prevented cancellous bone loss in FcγRIIB−/− mice. Our results indicate that FcγRIIB indirectly regulates cancellous bone homeostasis following SLE development. FcγRIIB deletion induces inflammatory bone loss due to increased TNFα-mediated bone resorption without any change in bone formation in mice with SLE-like syndrome.
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21
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Metzger CE, Gong S, Aceves M, Bloomfield SA, Hook MA. Osteocytes reflect a pro-inflammatory state following spinal cord injury in a rodent model. Bone 2019; 120:465-475. [PMID: 30550849 DOI: 10.1016/j.bone.2018.12.007] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2018] [Revised: 12/06/2018] [Accepted: 12/10/2018] [Indexed: 12/11/2022]
Abstract
Profound bone loss occurs following spinal cord injury (SCI) resulting in a high incidence of fractures. While likely caused in part by loss of weight-bearing, there is greater bone loss following SCI when compared to that observed in other disuse animal models. Patients with SCI have a protracted inflammatory response, with elevated circulating levels of pro-inflammatory markers. This chronic inflammation could compound the bone loss attributed to disuse and the loss of neural signaling. To assess this, we examined inflammatory markers and bone turnover regulators in osteocytes from rats with a moderate spinal contusion injury (SCI) and intact controls (CON). We counted osteocytes positive for cytokines [tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-17 (IL-17), and interleukin-10 (IL-10)], osteoclastogenesis regulators RANKL and OPG, and the bone formation inhibitor sclerostin, 32 days after the spinal contusion. By day 9 post-injury, the majority of SCI rats had recovered significant locomotor function and were bearing weight on their hindlimbs. However, despite weight-bearing, peripheral QCT scans demonstrated lower bone mass due to SCI in the proximal tibia metaphysis compared to CON. SCI animals also had lower cancellous bone volume, lower bone formation rate (BFR), lower osteoid surface (OS), and higher osteoclast surface (Oc.S). Tibial mid-shaft periosteal BFR was also lower after SCI. Immunohistochemical staining of the distal femur bone revealed cancellous osteocytes positive for TNF-α, IL-6, IL-17, and IL-10 were elevated in SCI animals relative to intact controls. Protein expression of RANKL+, OPG+, and sclerostin+ osteocytes was also higher in SCI rats. At the cortical midshaft, osteocyte TNF-α, IL-6, and sclerostin were statistically higher in SCI vs. CON. With regression analysis, inflammatory factors were associated with changes in bone turnover. In conclusion, inflammatory factors as well as altered mechanical loading influence bone turnover following a moderate SCI. Treatments aimed at minimizing fracture risk after SCI may need to target both the chronically altered inflammatory state as well as disuse-induced bone loss.
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Affiliation(s)
- Corinne E Metzger
- Department of Health and Kinesiology, Texas A&M University, College Station, TX, United States of America.
| | - Sammy Gong
- Department of Neuroscience and Experimental Therapeutics, Texas A&M Health Science Center, Bryan, TX, United States of America
| | - Miriam Aceves
- Department of Neuroscience and Experimental Therapeutics, Texas A&M Health Science Center, Bryan, TX, United States of America
| | - Susan A Bloomfield
- Department of Health and Kinesiology, Texas A&M University, College Station, TX, United States of America
| | - Michelle A Hook
- Department of Neuroscience and Experimental Therapeutics, Texas A&M Health Science Center, Bryan, TX, United States of America.
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22
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Metzger CE, Narayanan SA. The Role of Osteocytes in Inflammatory Bone Loss. Front Endocrinol (Lausanne) 2019; 10:285. [PMID: 31139147 PMCID: PMC6527760 DOI: 10.3389/fendo.2019.00285] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2018] [Accepted: 04/18/2019] [Indexed: 01/18/2023] Open
Abstract
Osteoimmunology investigations to-date have demonstrated the significant interactions between bone surface cells, osteoclasts and osteoblasts, and immune cells. However, there is a paucity of knowledge on osteocytes, cells embedded in the bone matrix, and their role in inflammation and inflammatory bone loss. Osteocytes communicate through various mechanisms; directly via dendritic processes and through secretion of proteins that can influence the formation and activity of osteoblasts and osteoclasts. Some osteocyte proteins (e.g., interleukin-6 and RANKL) also have roles within the immune system. In the context of mechanical loading/unloading, the regulatory role of osteocytes is well understood. More recent data on osteocytes in various inflammatory models suggest they may also aid in orchestrating inflammation-induced changes in bone turnover. In inflammatory conditions, osteocytes express multiple pro-inflammatory cytokines which are associated with increases in bone resorption and declines in bone formation. Cytokines are known to also influence cell population growth, maturation, and responsiveness via various signaling modalities, but how they influence osteocytes has not been greatly explored. Furthermore, osteocytes may play regulatory roles in orchestrating bone's response to immunological changes in inflammatory conditions. This review will address what is known about osteocyte biology in physiological conditions and in response to varying immunological conditions, as well as highlight key areas of interest for future investigations.
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Affiliation(s)
- Corinne E. Metzger
- Department of Health and Kinesiology, Texas A&M University, College Station, TX, United States
- *Correspondence: Corinne E. Metzger
| | - S. Anand Narayanan
- Department of Medical Physiology, Texas A&M Health Science Center, Bryan, TX, United States
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Saiworn W, Thim-Uam A, Visitchanakun P, Atjanasuppat K, Chantaraaumporn J, Mokdara J, Chungchatupornchai S, Pisitkun P, Leelahavanichkul A, Poolthong S, Baron R, Lotinun S. Cortical Bone Loss in a Spontaneous Murine Model of Systemic Lupus Erythematosus. Calcif Tissue Int 2018; 103:686-697. [PMID: 30116830 DOI: 10.1007/s00223-018-0464-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2018] [Accepted: 08/08/2018] [Indexed: 01/10/2023]
Abstract
Patients with systemic lupus erythematosus (SLE), a chronic inflammatory disease characterized by loss of T- and B-cell tolerance to autoantigens, are at increased risk for osteoporosis and fractures. Mice deficient in Fc gamma receptor IIb (FcγRIIB) exhibit spontaneous SLE and its restoration rescues the disease. To determine whether deleting FcγRIIB affects cortical bone mass and mechanical properties, we analyzed cortical bone phenotype of FcγRIIB knockouts at different ages. FACS analysis revealed that 6-month-old FcγRIIB-/- mice had increased B220lowCD138+ cells, markers of plasma cells, indicating active SLE disease. In contrast, 3-month-old FcγRIIB-/- mice did not develop the active SLE disease. µCT analysis indicated that FcγRIIB deletion did not affect cortical bone in 3-month-old mutants. However, 6- and 10-month-old FcγRIIB-/- males and females had osteopenic cortical bone and the severity of bone loss increased with disease duration. FcγRIIB deletion decreased cross-sectional area, cortical area, and marrow area in 6-month-old males. Cortical area and cortical thickness were decreased in 10-month-old FcγRIIB-/- males. Lack of FcγRIIB decreased cortical thickness without affecting cortical area in females. However, deletion of a single FcγRIIB allele was insufficient to induce cortical bone loss. The bending strength was decreased in 6- and 10-month-old FcγRIIB-deficient males compared to WT controls. A microindentation analysis demonstrated significantly decreased hardness in both 10-month-old FcγRIIB-/- males and females. Our data indicate that FcγRIIB contributes to the regulation of cortical bone homeostasis subsequent to SLE development and that deletion of FcγRIIB in mice leads to SLE-like disease associated with cortical bone loss and decreased bending strength and hardness.
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Affiliation(s)
- Worasit Saiworn
- Department of Physiology and Skeletal Disorders Research Unit, Faculty of Dentistry, Chulalongkorn University, Bangkok, Thailand
| | - Arthid Thim-Uam
- Inter-Department Program of Biomedical Sciences, Faculty of Graduate School, Chulalongkorn University, Bangkok, Thailand
| | - Peerapat Visitchanakun
- Department of Physiology and Skeletal Disorders Research Unit, Faculty of Dentistry, Chulalongkorn University, Bangkok, Thailand
| | - Korakot Atjanasuppat
- Department of Physiology and Skeletal Disorders Research Unit, Faculty of Dentistry, Chulalongkorn University, Bangkok, Thailand
| | - Jiratha Chantaraaumporn
- Department of Physiology and Skeletal Disorders Research Unit, Faculty of Dentistry, Chulalongkorn University, Bangkok, Thailand
| | - Jutarat Mokdara
- Department of Physiology and Skeletal Disorders Research Unit, Faculty of Dentistry, Chulalongkorn University, Bangkok, Thailand
| | - Sirintra Chungchatupornchai
- Department of Physiology and Skeletal Disorders Research Unit, Faculty of Dentistry, Chulalongkorn University, Bangkok, Thailand
| | - Prapaporn Pisitkun
- Division of Allergy, Immunology, and Rheumatology, Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Asada Leelahavanichkul
- Division of Immunology, Department of Microbiology, Faculty of Medicine, and Skeletal Disorders Research Unit, Faculty of Dentistry, Chulalongkorn University, Bangkok, Thailand
| | - Suchit Poolthong
- Department of Prosthodontics and Skeletal Disorders Research Unit, Faculty of Dentistry, Chulalongkorn University, Bangkok, Thailand
| | - Roland Baron
- Division of Bone and Mineral Research, Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, MA, USA
- Harvard Medical School, Department of Medicine, Endocrine Unit, Massachusetts General Hospital, Boston, MA, USA
| | - Sutada Lotinun
- Department of Physiology and Skeletal Disorders Research Unit, Faculty of Dentistry, Chulalongkorn University, Bangkok, Thailand.
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24
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Elalouf O, Keeling SO, Touma Z. Subcutaneous belimumab in the treatment of systemic lupus erythematosus. Immunotherapy 2018; 10:1163-1173. [PMID: 30105936 DOI: 10.2217/imt-2018-0061] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Systemic lupus erythematosus is a chronic autoimmune disease with various clinical manifestations, organ involvement and laboratory findings. The disease can involve any organ including skin, joints, kidneys, central and peripheral nervous system, cardiovascular system and more. Currently, the cornerstone of treatment includes antimalarial and immunosuppressive medications and glucocorticosteroids. Recently, great effort has been invested in finding more targeted drugs for achieving better control of the disease with less adverse events. Intravenous belimumab was the first and only biologic drug to be approved by the US FDA and Health Canada for lupus over the last 50 years, and recently was studied in subcutaneous form. This paper will review the major belimumab trials with a focus on the subcutaneous form.
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Affiliation(s)
- Ofir Elalouf
- Centre for Prognosis Studies in the Rheumatic Diseases, Toronto Western Hospital, University of Toronto Lupus Clinic, Toronto, Ontario, Canada
| | | | - Zahi Touma
- Department of Medicine, Centre for Prognosis Studies in the Rheumatic Diseases, Toronto Western Hospital, University of Toronto Lupus Clinic, Toronto, Ontario, Canada
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25
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Bultink IEM. Bone Disease in Connective Tissue Disease/Systemic Lupus Erythematosus. Calcif Tissue Int 2018; 102:575-591. [PMID: 28900675 PMCID: PMC5904226 DOI: 10.1007/s00223-017-0322-z] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2017] [Accepted: 09/05/2017] [Indexed: 01/07/2023]
Abstract
This article reviews recent advances in the research of the mechanisms of bone loss, as well as clinical features, economic impact and therapeutic implications of osteoporosis and fractures in patients with systemic lupus erythematosus (SLE) as an illustration of bone disease in a complex systemic autoimmune connective tissue disease. Recent studies demonstrated an increased incidence of osteoporosis and peripheral and vertebral fractures in patients with SLE. The aetiology of bone loss in SLE is multifactorial, including clinical osteoporosis risk factors, systemic inflammation, serological factors, metabolic factors, hormonal factors, possibly genetic factors and medication-induced adverse effects. The incidence of symptomatic fractures in patients with SLE is increased 1.2-4.7-fold and age, disease duration, glucocorticoid use, previous cyclophosphamide use, seizures and a prior cerebrovascular event have been identified as important risk factors. Moreover, a high prevalence of morphometric vertebral fractures was demonstrated, while one in three of these patients has normal bone density, which finding points to the multifactorial aetiology of fractures in SLE. The clinical consequences and economic burden of osteoporosis and fractures as glucocorticoid treatment-related adverse events and the high frequency of glucocorticoid therapy underline the importance of reducing glucocorticoid treatment and prescribing steroid-sparing agents. No data on fall risk and its determinants and the relationship with the occurrence of fractures in patients with SLE are currently available. Fall risk might be increased in lupus patients for several reasons. In addition, the recently reported high prevalence (20%) of frailty in SLE patients may contribute to the increased fracture incidence. Therefore, the relationships between fall risk, frailty and fracture occurrence in SLE might be interesting subjects for future studies.
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Affiliation(s)
- Irene E M Bultink
- Department of Rheumatology, Amsterdam Rheumatology and immunology Center, VU University Medical Center, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands.
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26
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Hafez EA, ElBakry SA, Ibrahim SI, Morad CS, Hamza SA, Abd El-Khalik DM. Assessment of fracture risk in a cohort of Egyptian female Systemic Lupus erythematosus patients. THE EGYPTIAN RHEUMATOLOGIST 2018; 40:85-91. [DOI: 10.1016/j.ejr.2017.07.006] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/02/2023]
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27
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Franceschi C, Garagnani P, Morsiani C, Conte M, Santoro A, Grignolio A, Monti D, Capri M, Salvioli S. The Continuum of Aging and Age-Related Diseases: Common Mechanisms but Different Rates. Front Med (Lausanne) 2018; 5:61. [PMID: 29662881 PMCID: PMC5890129 DOI: 10.3389/fmed.2018.00061] [Citation(s) in RCA: 540] [Impact Index Per Article: 77.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2018] [Accepted: 02/20/2018] [Indexed: 12/11/2022] Open
Abstract
Geroscience, the new interdisciplinary field that aims to understand the relationship between aging and chronic age-related diseases (ARDs) and geriatric syndromes (GSs), is based on epidemiological evidence and experimental data that aging is the major risk factor for such pathologies and assumes that aging and ARDs/GSs share a common set of basic biological mechanisms. A consequence is that the primary target of medicine is to combat aging instead of any single ARD/GSs one by one, as favored by the fragmentation into hundreds of specialties and sub-specialties. If the same molecular and cellular mechanisms underpin both aging and ARDs/GSs, a major question emerges: which is the difference, if any, between aging and ARDs/GSs? The hypothesis that ARDs and GSs such as frailty can be conceptualized as accelerated aging will be discussed by analyzing in particular frailty, sarcopenia, chronic obstructive pulmonary disease, cancer, neurodegenerative diseases such as Alzheimer and Parkinson as well as Down syndrome as an example of progeroid syndrome. According to this integrated view, aging and ARDs/GSs become part of a continuum where precise boundaries do not exist and the two extremes are represented by centenarians, who largely avoided or postponed most ARDs/GSs and are characterized by decelerated aging, and patients who suffered one or more severe ARDs in their 60s, 70s, and 80s and show signs of accelerated aging, respectively. In between these two extremes, there is a continuum of intermediate trajectories representing a sort of gray area. Thus, clinically different, classical ARDs/GSs are, indeed, the result of peculiar combinations of alterations regarding the same, limited set of basic mechanisms shared with the aging process. Whether an individual will follow a trajectory of accelerated or decelerated aging will depend on his/her genetic background interacting lifelong with environmental and lifestyle factors. If ARDs and GSs are manifestations of accelerated aging, it is urgent to identify markers capable of distinguishing between biological and chronological age to identify subjects at higher risk of developing ARDs and GSs. To this aim, we propose the use of DNA methylation, N-glycans profiling, and gut microbiota composition to complement the available disease-specific markers.
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Affiliation(s)
- Claudio Franceschi
- Institute of Neurological Sciences, University of Bologna, Bellaria Hospital, Bologna, Italy
| | - Paolo Garagnani
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy.,Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institutet at Huddinge University Hospital, Stockholm, Sweden.,Applied Biomedical Research Center (CRBA), S. Orsola-Malpighi Polyclinic, Bologna, Italy.,CNR Institute of Molecular Genetics, Unit of Bologna, Bologna, Italy
| | - Cristina Morsiani
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy
| | - Maria Conte
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy
| | - Aurelia Santoro
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy.,Interdepartmental Center "L. Galvani" (CIG), University of Bologna, Bologna, Italy
| | - Andrea Grignolio
- Unit and Museum of History of Medicine, Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
| | - Daniela Monti
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Florence, Italy
| | - Miriam Capri
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy.,Interdepartmental Center "L. Galvani" (CIG), University of Bologna, Bologna, Italy
| | - Stefano Salvioli
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy.,Interdepartmental Center "L. Galvani" (CIG), University of Bologna, Bologna, Italy
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Mori Y, Baba K, Kogure A, Izumiyama T, Matsuda M, Mori N, Ishii T, Itoi E. Assessment of the risk of low bone mineral density in premenopausal Japanese female patients with systemic lupus erythematosus. J Orthop 2018; 15:89-93. [PMID: 29657446 DOI: 10.1016/j.jor.2018.01.029] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2017] [Accepted: 01/14/2018] [Indexed: 11/19/2022] Open
Abstract
Background The aim of this study was to assess the relationships between clinical parameters and bone mineral density (BMD) in Japanese female patients with systemic lupus erythematosus (SLE). Methods A total of female 136 SLE patients without menopause were retrospectively assessed to identify associations between age, disease duration, body mass index (BMI), glucocorticoid usage and disease activity and BMD based on the treatment with or without bisphosphonate. There were 71 patients treated with bisphosphonate (bisphosphonate group) and 65 patients without (non-bisphosphonate group). We evaluated the impact of age, disease duration, BMI, serologic SLE markers, glucocorticoid use on BMD of the anterior-posterior (AP) and lateral lumbar spine, total hip and femoral neck using univariate and multivariate linear regression analyses of both bisphosphonate and non-bisphosphonate groups. Results Multivariate linear regression analyses showed that in non-bisphosphonate group disease duration was negatively associated with BMD of AP spine and femoral neck, whereas in bisphosphonate group these negative associations were not present. However, multivariate linear regression analyses showed a significant relationship between BMI and BMD of the AP spine, femoral neck and total hip, regardless of bisphosphonate treatment. Conclusions Bisphosphonate treatment eliminated the negative relationships between disease duration and the BMD of the spine and hip. AP spine and hip BMD in patients with SLE depend on BMI, regardless of bisphosphonate use. SLE serologic markers and glucocorticoid use were not negatively associated with generalized bone loss. SLE patients with low BMI have a high risk of generalized bone loss, and should be assessed and treated to prevent osteoporosis even before menopause.
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Affiliation(s)
- Yu Mori
- Department of Orthopaedic Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo machi, Aobaku, Sendai, Miyagi, 980-8574, Japan
| | - Kazuyoshi Baba
- Department of Orthopaedic Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo machi, Aobaku, Sendai, Miyagi, 980-8574, Japan
| | - Atsushi Kogure
- Department of Orthopaedic Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo machi, Aobaku, Sendai, Miyagi, 980-8574, Japan
| | - Takuya Izumiyama
- Department of Orthopaedic Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo machi, Aobaku, Sendai, Miyagi, 980-8574, Japan
| | - Michiharu Matsuda
- Department of Orthopaedic Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo machi, Aobaku, Sendai, Miyagi, 980-8574, Japan
| | - Naoko Mori
- Department of Diagnostic Radiology, Tohoku University Graduate School of Medicine, 1-1 Seiryo machi, Aobaku, Sendai, Miyagi, 980-8574, Japan
| | - Tomonori Ishii
- Department of Hematology and Rheumatology, Tohoku University Graduate School of Medicine, 1-1 Seiryo machi, Aobaku, Sendai, Miyagi, 980-8574, Japan
| | - Eiji Itoi
- Department of Orthopaedic Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo machi, Aobaku, Sendai, Miyagi, 980-8574, Japan
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29
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Touma Z, Gladman DD. Current and future therapies for SLE: obstacles and recommendations for the development of novel treatments. Lupus Sci Med 2017; 4:e000239. [PMID: 29344386 PMCID: PMC5761306 DOI: 10.1136/lupus-2017-000239] [Citation(s) in RCA: 72] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2017] [Revised: 10/30/2017] [Accepted: 11/13/2017] [Indexed: 01/09/2023]
Abstract
SLE is a serious, debilitating autoimmune disease that affects various organs and body systems. Of all the heterogeneous autoimmune diseases, SLE is perhaps the most heterogeneous. Patients with SLE, who are primarily female, have diverse disease manifestations and severity. SLE is characterised by substantial concentrations of autoantibodies against nuclear antigens, which are thought to be caused by immune cell dysregulation. Until recently, several immunosuppressant agents were used to treat this disease. Efforts to develop drugs against targets potentially involved in disease mechanisms have resulted in the identification and use of BAFF (B-cell activating factor)/APRIL (a proliferation-inducing ligand) inhibitors to treat SLE. Drugs in late-stage development that focus on pathways that are dysregulated in SLE include those that target the interferon pathway, T-cell signalling and B-cell signalling. New therapeutic agents are still necessary because of the unmet medical needs associated with this disease, including insufficient disease control, poor health-related quality of life, comorbidities, toxicity of the majority of therapies and diminished survival. Despite the substantial long-term investment of research, clinical activity and resources for identifying new treatments for this disease, only one new therapy, the biological belimumab, has been approved in the past 50 years. Efforts to develop drugs to address these needs are challenged by problems associated with disease heterogeneity, variable disease mechanisms and trial design. This review provides an overview of current and future treatments, discusses challenges in the SLE drug development process and offers recommendations for overcoming these challenges.
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Affiliation(s)
- Zahi Touma
- Centre for Prognosis Studies in the Rheumatic Diseases, University of Toronto, Lupus Clinic, Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada
| | - Dafna D Gladman
- Centre for Prognosis Studies in the Rheumatic Diseases, University of Toronto, Lupus Clinic, Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada
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Briot K, Geusens P, Em Bultink I, Lems WF, Roux C. Inflammatory diseases and bone fragility. Osteoporos Int 2017; 28:3301-3314. [PMID: 28916915 DOI: 10.1007/s00198-017-4189-7] [Citation(s) in RCA: 122] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2016] [Accepted: 08/01/2017] [Indexed: 12/19/2022]
Abstract
Systemic osteoporosis and increased fracture rates have been described in chronic inflammatory diseases such as rheumatoid arthritis, spondyloarthritis, systemic lupus erythematosus, inflammatory bowel diseases, and chronic obstructive pulmonary disease. Most of these patients receive glucocorticoids, which have their own deleterious effects on bone. However, the other main determinant of bone fragility is the inflammation itself, as shown by the interactions between the inflammatory mediators, the actors of the immune system, and the bone remodelling. The inflammatory disease activity is thus on top of the other well-known osteoporotic risk factors in these patients. Optimal control of inflammation is part of the prevention of osteoporosis, and potent anti-inflammatory drugs have positive effects on surrogate markers of bone fragility. More data are needed to assess the anti-fracture efficacy of a tight control of inflammation in patients with a chronic inflammatory disorder. This review aimed at presenting different clinical aspects of inflammatory diseases which illustrate the relationships between inflammation and bone fragility.
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Affiliation(s)
- K Briot
- Department of Rheumatology, Cochin Hospital, Assistance-Publique-Hôpitaux de Paris, Paris, France.
- Hôpital Cochin, Service de Rhumatologie, 27, Rue du Faubourg, St. Jacques, 75014, Paris, France.
- INSERM UMR 1153, Paris, France.
| | - P Geusens
- Department of Internal Medicine, Subdivision of Rheumatology, Maastricht University Medical Center, Maastricht, The Netherlands
- Hasselt University, Hasselt, Belgium
| | - I Em Bultink
- Department of Rheumatology, Amsterdam Rheumatology and Immunology Center, VU University Medical Center, Amsterdam, The Netherlands
| | - W F Lems
- Department of Rheumatology, Amsterdam Rheumatology and Immunology Center, VU University Medical Center, Amsterdam, The Netherlands
| | - C Roux
- Department of Rheumatology, Cochin Hospital, Assistance-Publique-Hôpitaux de Paris, Paris, France
- Hôpital Cochin, Service de Rhumatologie, 27, Rue du Faubourg, St. Jacques, 75014, Paris, France
- INSERM UMR 1153, Paris, France
- Paris Descartes University, Paris, France
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Salman-Monte TC, Torrente-Segarra V, Vega-Vidal AL, Corzo P, Castro-Dominguez F, Ojeda F, Carbonell-Abelló J. Bone mineral density and vitamin D status in systemic lupus erythematosus (SLE): A systematic review. Autoimmun Rev 2017; 16:1155-1159. [DOI: 10.1016/j.autrev.2017.09.011] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
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Kotze LMDS, Costa CT, Cavassani MF, Nisihara RM. Alert for bone alterations and low serum concentrations of vitamin D in patients with intestinal inflammatory disease. Rev Assoc Med Bras (1992) 2017; 63:13-17. [PMID: 28225873 DOI: 10.1590/1806-9282.63.01.13] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2016] [Accepted: 06/26/2016] [Indexed: 01/10/2023] Open
Abstract
BACKGROUND Inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), are characterized by chronic inflammation of the intestine that can reduce the absorption of nutrients such as vitamin D and calcium. OBJECTIVE To investigate bone alterations and serum levels of vitamin D in patients with IBD. METHOD This was a cross-sectional study based on a review of medical records of patients from a private office in Curitiba, PR, Brazil. Serum levels of vitamin D and bone densitometry were measured at diagnosis of IBD. A total of 105 patients were included; 38 (58.4%) with CD; 27 (41.6%) with UC and 40 with irritable bowel syndrome (IBS) as comparison group. RESULTS When compared to patients with UC, CD patients showed a higher prevalence of bone alterations, being 15.8% with osteoporosis and 36.8% with osteopenia. In UC, bone alterations occurred in 29.6% of cases, 3.7% with osteoporosis and 25.9% with osteopenia. As for vitamin D levels, among CD patients, 10.5% had vitamin deficiency, 65.8% insufficiency and 23.7% were sufficient. In UC, 7.4% of cases had deficiency, 74.1% insufficiency and 18.5% had sufficient serum levels of vitamin D. In the group with IBS, deficiency was observed in 17.5% of cases, insufficiency in 55% and sufficiency in 27.5% of them. There was no significant difference between groups. CONCLUSION IBD patients have a high prevalence of bone changes, especially those with CD. Serum levels of vitamin D are below the recommended in all the evaluated groups.
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García-Carrasco M, Mendoza-Pinto C, León-Vázquez MDLL, Méndez-Martínez S, Etchegaray-Morales I, Montiel-Jarquín Á, Enriquez-Guerra MA, Muñóz-Guarneros M, Gálvez-Romero JL, Soto-Santillán P, Cervera R. Incidence of Vertebral Fractures in Women with Systemic Lupus Erythematosus After 8 Years of Follow-Up. Calcif Tissue Int 2017; 101:291-299. [PMID: 28508265 DOI: 10.1007/s00223-017-0286-z] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2017] [Accepted: 04/22/2017] [Indexed: 01/02/2023]
Abstract
The aim of this study was to evaluate possible associations between potential risk factors and the occurrence of established vertebral fractures (VF) in Mexican patients with systemic lupus erythematosus (SLE). Consecutive patients with SLE were enrolled in a prospective, observational study from 2006 to 2015. Information on potential risk factors, including demographics, clinical data, and bone mineral density (BMD) at the lumbar spine and hip on dual-energy X-ray absorptiometry was collected at baseline and follow-up. Semiquantitative analysis was used to determine incident VF on lateral thoracic and lumbar radiographs, defined as any vertebral body graded normal at baseline and at least mildly deformed (20-25% reduction or more in any vertebral height) during follow-up. Differences in baseline characteristics were assessed in patients with and without new radiographic VF. Of 110 SLE patients included, with a median follow-up of 8 (IQR 8-9) years, 22 (20%) had radiographic VF at baseline; 35 (32%) patients had a new VF. The annual incidence rate of new morphometric VF was 3.5 (95% CI 2.4-4.91) per 100 patient/years. Most fractures were mild or moderate and biconcave shaped. Incident VF were significantly associated with baseline BMD at the total hip and longer disease duration. Cumulative glucocorticoid dose, postmenopausal status, and previous prevalent VF were not associated with VF. In this SLE cohort in daily clinical practice, new VF were frequently present in SLE patients, especially those with longer disease duration and low-hip BMD.
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Affiliation(s)
- Mario García-Carrasco
- Systemic Autoimmune Diseases Research Unit, Hospital General Regional 36-CIBIOR, Instituto Mexicano del Seguro Social, Av. 10 Poniente 2721, Amor, 72090, Puebla, Puebla, Mexico
- Department of Immunology and Rheumatology, Medicine School, Benemérita Universidad Autónoma de Puebla, Puebla, Mexico
| | - Claudia Mendoza-Pinto
- Systemic Autoimmune Diseases Research Unit, Hospital General Regional 36-CIBIOR, Instituto Mexicano del Seguro Social, Av. 10 Poniente 2721, Amor, 72090, Puebla, Puebla, Mexico.
- Department of Immunology and Rheumatology, Medicine School, Benemérita Universidad Autónoma de Puebla, Puebla, Mexico.
| | - María de la Luz León-Vázquez
- Systemic Autoimmune Diseases Research Unit, Hospital General Regional 36-CIBIOR, Instituto Mexicano del Seguro Social, Av. 10 Poniente 2721, Amor, 72090, Puebla, Puebla, Mexico
| | | | - Ivet Etchegaray-Morales
- Systemic Autoimmune Diseases Research Unit, Hospital General Regional 36-CIBIOR, Instituto Mexicano del Seguro Social, Av. 10 Poniente 2721, Amor, 72090, Puebla, Puebla, Mexico
| | - Álvaro Montiel-Jarquín
- Jefatura de División de Investigación en Salud, UMAE, Hospital de Traumatología, Instituto Mexicano del Seguro Social, Puebla, Puebla, Mexico
| | | | - Margarita Muñóz-Guarneros
- Secretary of Research and Postgraduate Studies, Medicine School, Benemérita Universidad Autónoma de Puebla, Puebla, Mexico
| | - José Luis Gálvez-Romero
- Immunology Department, Hospital Instituto de Seguridad y Servicios Sociales de los Trabajadores del Estado, Puebla, Mexico
| | - Pamela Soto-Santillán
- Systemic Autoimmune Diseases Research Unit, Hospital General Regional 36-CIBIOR, Instituto Mexicano del Seguro Social, Av. 10 Poniente 2721, Amor, 72090, Puebla, Puebla, Mexico
| | - Ricard Cervera
- Department of Autoimmune Diseases, Hospital Clinic, Catalonia, Spain
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Abstract
PURPOSE OF REVIEW The article reviews recent advances in the research of fractures in patients with systemic lupus erythematosus (SLE), highlighting their clinical, scientific, and economic impact. RECENT FINDINGS Recent studies demonstrated an increased incidence of osteoporosis and symptomatic fractures in patients with SLE and age, disease duration, disease severity, and glucocorticoid use are important risk factors. A high prevalence of vertebral fractures was demonstrated, while one in three of these patients has normal bone density, which illustrates the multifactorial cause of fractures in SLE. Screening for vertebral fractures is important, as they often occur asymptomatically, but are associated with a reduced quality of life, increased future fracture risk, an increased mortality risk, and may have therapeutic implications. A recently developed Delphi consensus revealed the high economic burden of fractures as a glucocorticoid-related adverse event in SLE, whereas the majority of patients use glucocorticoids. SUMMARY Recent studies revealed an increased incidence of symptomatic fractures and a relatively high prevalence of vertebral fractures in patients with SLE, and provided new insights into their multifactorial aetiology. The clinical consequences and high economic burden of fractures as glucocorticoid-related adverse events underline the importance of reducing glucocorticoid therapy and use of steroid-sparing agents.
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Le B, Waller JL, Radhakrishnan R, Oh SJ, Kheda MF, Nahman NS, Carbone L. Osteoporotic fractures in patients with systemic lupus erythematosus and end stage renal disease. Lupus 2017; 27:17-24. [PMID: 28530467 DOI: 10.1177/0961203317709953] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Background The incidence of end stage renal disease (ESRD) in patients with systemic lupus erythematosus (SLE) is rising. However, the relationship between osteoporotic fractures and SLE in the setting of ESRD remains uninvestigated. The purpose of this study was to compare the frequency of incident osteoporotic fractures in patients with ESRD with and without SLE, to identify risk factors for fractures in patients with SLE and ESRD, and to examine the contribution of these fractures to mortality. Methods Retrospective cohort study of patients with SLE ( n = 716) and a 5% random sample of controls without SLE ( n = 4176) in the United States Renal Data System (USRDS) from years 2006-2008 enrolled in Medicare Part D. Results Fractures occurred in 10.6% ( n = 76) of patients with SLE and ESRD and 12.1% ( n = 507) of patients with ESRD without SLE ( p = 0.24). Older age (adjusted relative risk 1.02, 95% confidence interval 1.01-1.04) was associated with an increased risk for fracture in patients with SLE and ESRD. In multivariable analyses, vertebral and hip fractures more than doubled the risk for mortality. Conclusions The frequency of osteoporotic fractures in patients with SLE and ESRD is similar to the general population of patients with ESRD. Vertebral and hip fractures are significant contributors to mortality in patients with SLE and ESRD. Fracture prevention, in particular, for elderly patients with SLE and ESRD, should be considered. Summary SLE is not an independent risk factor for fractures in patients with ESRD. However, among patients with SLE and ESRD, vertebral and hip fractures are significant contributors to mortality.
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Affiliation(s)
- B Le
- 1 Department of Internal Medicine, Medical College of Georgia at Augusta University, Augusta, Georgia, USA.,2 Charlie Norwood VA Medical Center, Augusta, Georgia, USA
| | - J L Waller
- 3 Department of Biostatistics and Epidemiology, Augusta University, Augusta, Georgia, USA
| | - R Radhakrishnan
- 4 School of Medicine, Medical College of Georgia at Augusta University, Augusta, Georgia, USA
| | - S J Oh
- 5 Division of Rheumatology, Department of Internal Medicine, Medical College of Georgia at Augusta University, Augusta, Georgia, USA
| | - M F Kheda
- 6 Southwest Georgia Nephrology Clinic, PC, Albany, Georgia, USA
| | - N S Nahman
- 1 Department of Internal Medicine, Medical College of Georgia at Augusta University, Augusta, Georgia, USA.,2 Charlie Norwood VA Medical Center, Augusta, Georgia, USA.,7 Division of Nephrology, Department of Internal Medicine, Medical College of Georgia at Augusta University, Augusta, Georgia, USA
| | - L Carbone
- 1 Department of Internal Medicine, Medical College of Georgia at Augusta University, Augusta, Georgia, USA.,2 Charlie Norwood VA Medical Center, Augusta, Georgia, USA.,5 Division of Rheumatology, Department of Internal Medicine, Medical College of Georgia at Augusta University, Augusta, Georgia, USA
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Affiliation(s)
- Luis Alonso González
- Division of Rheumatology, Department of Internal Medicine, School of Medicine, Universidad de Antioquia, Medellín, Colombia
| | - Graciela S. Alarcón
- Department of Medicine, Division of Clinical Immunology and Rheumatology, School of Medicine, The University of Alabama at Birmingham, Birmingham, AL, USA
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Moroni L, Selmi C, Angelini C, Meroni PL. Evaluation of Endothelial Function by Flow-Mediated Dilation: a Comprehensive Review in Rheumatic Disease. Arch Immunol Ther Exp (Warsz) 2017; 65:463-475. [DOI: 10.1007/s00005-017-0465-7] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2016] [Accepted: 03/03/2017] [Indexed: 12/18/2022]
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Cramarossa G, Urowitz MB, Su J, Gladman D, Touma Z. Prevalence and associated factors of low bone mass in adults with systemic lupus erythematosus. Lupus 2016; 26:365-372. [PMID: 27522094 DOI: 10.1177/0961203316664597] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Background Systemic lupus erythematosus (SLE) patients are often treated with glucocorticoids, which place them at risk of bone loss. Objectives The objectives of this article are to determine: (1) the prevalence of low bone mineral density (BMD) and factors associated with low BMD and (2) the prevalence of symptomatic fragility fractures in inception patients of the Toronto Lupus Cohort (TLC). Methods Prospectively collected data from the TLC (1996-2015) of inception patients' first BMD were analyzed. For pre-menopausal women/males <50 years, BMD 'below expected range for age' was defined by Z-score ≤ -2.0 SD. For post-menopausal women/males age 50 or older, osteoporosis was defined by T-score ≤ -2.5 SD and low bone mass by T-score between -1.0 and -2.5 SD. Patients' BMDs were defined as abnormal if Z-score ≤ -2.0 or T-score < -1.0 SD, and the remainder as normal. Descriptive analysis and logistic regression were employed. Results Of 1807 patients, 286 are inception patients with BMD results (mean age 37.9 ± 13.7 years); 88.8% are female. The overall prevalence of abnormal BMD is 31.5%. In pre-menopausal women ( n = 173), the prevalence of BMD below expected range is 17.3%. In post-menopausal women ( n = 81), the prevalence of osteoporosis and low BMD are 12.3% and 43.2%, respectively. Age and cumulative dose of glucocorticoids are statistically significantly associated with abnormal BMD in multivariate analysis. Of 769 inception patients from TLC, 11.1% experienced symptomatic fragility fractures (peripheral and vertebral) over the course of their disease. Conclusion The prevalence of low BMD is high in SLE patients, and is associated with older age and higher cumulative glucocorticoid dose.
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Affiliation(s)
- G Cramarossa
- University of Toronto Lupus Clinic, Centre for Prognosis Studies in the Rheumatic Diseases, University Health Network, Toronto Western Hospital, Toronto, Ontario, Canada
| | - M B Urowitz
- University of Toronto Lupus Clinic, Centre for Prognosis Studies in the Rheumatic Diseases, University Health Network, Toronto Western Hospital, Toronto, Ontario, Canada
| | - J Su
- University of Toronto Lupus Clinic, Centre for Prognosis Studies in the Rheumatic Diseases, University Health Network, Toronto Western Hospital, Toronto, Ontario, Canada
| | - D Gladman
- University of Toronto Lupus Clinic, Centre for Prognosis Studies in the Rheumatic Diseases, University Health Network, Toronto Western Hospital, Toronto, Ontario, Canada
| | - Z Touma
- University of Toronto Lupus Clinic, Centre for Prognosis Studies in the Rheumatic Diseases, University Health Network, Toronto Western Hospital, Toronto, Ontario, Canada
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Liu Y, Cui Y, Zhang X, Gao X, Su Y, Xu B, Wu T, Chen W, Cui L. Effects of salvianolate on bone metabolism in glucocorticoid-treated lupus-prone B6.MRL-Fas (lpr) /J mice. DRUG DESIGN DEVELOPMENT AND THERAPY 2016; 10:2535-46. [PMID: 27563234 PMCID: PMC4984994 DOI: 10.2147/dddt.s110125] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Aim To investigate the bone-protective effects of salvianolate (Sal), a total polyphenol from Radix Salviae miltiorrhizae, on bone tissue in the spontaneous lupus-prone mouse model, B6.MRL-Faslpr/J, undergoing glucocorticoid (GC) treatment. Methods Fifteen-week-old female B6.MRL-Faslpr/J mice were administered either a daily dose of saline (lupus group), prednisone 6 mg/kg (GC group), Sal 60 mg/kg (Sal group); or GC plus Sal (GC + Sal group) for a duration of 12 weeks. Age-matched female C57BL/6J wild-type (WT) mice were used for control. Micro-computed tomography assessments, bone histomorphometry analysis, bone biomechanical test, immunohistochemistry and immunoblotting analysis for bone markers, and renal histology analysis were performed to support our research endeavor. Results Lupus mice developed a marked bone loss and deterioration of mechanical properties of bone due to an increase in bone resorption rather than suppression of bone formation. GC treatment strongly inhibited bone formation in lupus mice. Sal treatment significantly attenuated osteogenic inhibition, and also suppressed hyperactive bone resorption, which recovered the bone mass and mechanical properties of bone in both the untreated and GC-treated lupus mice. Conclusion The data support further preclinical investigation of Sal as a potential therapeutic strategy for the treatment of systemic lupus erythematosus-related bone loss.
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Affiliation(s)
- Yanzhi Liu
- College of Traditional Chinese Medicine, Southern Medical University, Guangzhou City; Department of Pharmacology, Guangdong Key Laboratory for Research and Development of Natural Drugs, Guangdong Medical University, Zhanjiang
| | - Yang Cui
- Department of Rheumatology, Guangdong Provincial People's Hospital, Guangzhou
| | - Xiao Zhang
- Department of Rheumatology, Guangdong Provincial People's Hospital, Guangzhou
| | - Xiang Gao
- Stem Cell Research and Cellular Therapy Center, Affiliated Hospital of Guangdong Medical University, Zhanjiang, People's Republic of China
| | - Yanjie Su
- Department of Pharmacology, Guangdong Key Laboratory for Research and Development of Natural Drugs, Guangdong Medical University, Zhanjiang
| | - Bilian Xu
- Department of Pharmacology, Guangdong Key Laboratory for Research and Development of Natural Drugs, Guangdong Medical University, Zhanjiang
| | - Tie Wu
- Department of Pharmacology, Guangdong Key Laboratory for Research and Development of Natural Drugs, Guangdong Medical University, Zhanjiang
| | - Wenshuang Chen
- Department of Pharmacology, Guangdong Key Laboratory for Research and Development of Natural Drugs, Guangdong Medical University, Zhanjiang
| | - Liao Cui
- College of Traditional Chinese Medicine, Southern Medical University, Guangzhou City; Department of Pharmacology, Guangdong Key Laboratory for Research and Development of Natural Drugs, Guangdong Medical University, Zhanjiang
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Hosokawa T, Oda R, Toyama S, Taniguchi D, Tokunaga D, Fujiwara H, Kubo T. Spontaneous flexor tendon rupture due to an insufficiency fracture of the hamate hook in a patient with systemic lupus erythematosus: A case report. Int J Surg Case Rep 2016; 27:63-65. [PMID: 27552031 PMCID: PMC4995535 DOI: 10.1016/j.ijscr.2016.06.052] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2016] [Revised: 06/30/2016] [Accepted: 06/30/2016] [Indexed: 11/17/2022] Open
Abstract
INTRODUCTION Spontaneous flexor tendon rupture is usually caused by trauma, systemic diseases, or carpal bone and joint disorders. Here we report a case of spontaneous flexor tendon rupture occurring in a systemic lupus erythematosus (SLE) patient following nonunion of the hamate hook after an insufficiency fracture, and which was also associated with tendon degeneration caused by SLE. CASE PRESENTATION A 57-year-old woman was diagnosed with SLE 22 years ago and being treated with oral prednisolone. She became unable to flex her left little finger without any history of trauma or sporting activity. CT showed nonunion of the hamate hook. MRI showed rupture of the flexor digitorum profundus tendon of the little finger. We performed tendon transfer and excision of the hamate hook. She recovered active flexion of the little finger at 4 months postoperatively with full satisfaction. DISCUSSION There was no history of trauma that could have caused nonunion of the hamate hook. We considered that the insufficiency fracture of the hamate hook occurred as a result of osteoporosis caused by SLE and long-term steroid use. Nonunion of the hamate hook caused mechanical attrition of the tendons, and in combination with the tendon degeneration caused by SLE, further resulted in rupture of the flexor tendon. CONCLUSION When we encounter a case of spontaneous flexor tendon rupture in a patient with systemic disease such as SLE or long-term steroid use, attention should be paid to the state of the carpal bones and joints as they sometimes accompany unexpected causes.
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Affiliation(s)
- Toshihiro Hosokawa
- Department of Orthopaedics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan.
| | - Ryo Oda
- Department of Orthopaedics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan.
| | - Shogo Toyama
- Department of Orthopaedics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan.
| | - Daigo Taniguchi
- Department of Orthopaedics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan.
| | - Daisaku Tokunaga
- Department of Orthopaedics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan.
| | - Hiroyoshi Fujiwara
- Department of Orthopaedics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan.
| | - Toshikazu Kubo
- Department of Orthopaedics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan.
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Abstract
Systemic lupus erythematosus (SLE) is an autoimmune disease that can affect many organs, including the skin, joints, the central nervous system and the kidneys. Women of childbearing age and certain racial groups are typically predisposed to developing the condition. Rare, inherited, single-gene complement deficiencies are strongly associated with SLE, but the disease is inherited in a polygenic manner in most patients. Genetic interactions with environmental factors, particularly UV light exposure, Epstein-Barr virus infection and hormonal factors, might initiate the disease, resulting in immune dysregulation at the level of cytokines, T cells, B cells and macrophages. Diagnosis is primarily clinical and remains challenging because of the heterogeneity of SLE. Classification criteria have aided clinical trials, but, despite this, only one drug (that is, belimumab) has been approved for use in SLE in the past 60 years. The 10-year mortality has improved and toxic adverse effects of older medications such as cyclophosphamide and glucocorticoids have been partially offset by newer drugs such as mycophenolate mofetil and glucocorticoid-sparing regimes. However, further improvements have been hampered by the adverse effects of renal and neuropsychiatric involvement and late diagnosis. Adding to this burden is the increased risk of premature cardiovascular disease in SLE together with the risk of infection made worse by immunosuppressive therapy. Challenges remain with treatment-resistant disease and symptoms such as fatigue. Newer therapies may bring hope of better outcomes, and the refinement to stem cell and genetic techniques might offer a cure in the future.
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Wu CH, Chai CY, Tung YC, Lu YY, Su YF, Tsai TH, Tzou RD, Lin CL. Herpes zoster as a risk factor for osteoporosis: A 15-year nationwide population-based study. Medicine (Baltimore) 2016; 95:e3943. [PMID: 27336887 PMCID: PMC4998325 DOI: 10.1097/md.0000000000003943] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/25/2023] Open
Abstract
The objective of this study was to investigate the risk of osteoporosis in patients with herpes zoster (HZ) infection using a nationwide population-based dataset. The Taiwan National Health Insurance Research Database was used to compare data between 11,088 patients aged 20 to 49 years diagnosed with HZ during 1996 to 2010 and a control group of 11,088 patients without HZ. Both cohorts were followed up until the end of 2010 to measure the incidence of osteoporosis. Cox proportional-hazards regression and Kaplan-Meier analyses were used to calculate hazard ratio and cumulative incidences of osteoporosis, respectively. The overall risk of osteoporosis was 4.55 times greater in the HZ group than in the control group (2.48 vs. 0.30 per 1000 person-years, respectively) after adjusting for age, gender, Charlson Comorbidity Index, and related comorbidities. Compared with controls, patients with HZ and subsequent postherpetic neuralgia had a 4.76-fold higher likelihood of developing osteoporosis (95% confidence interval: 2.44-9.29), which was a statistically significant difference (P <0.001). Osteoporosis risk factors included female gender, age, advanced Charlson Comorbidity Index, depression, and postherpetic neuralgia. This study identified HZ is associated with an increased osteoporosis risk. Further evaluation of the value of bone mineral density test in detecting osteoporosis after HZ may be suggested. HZ vaccination could also be evaluated to lower the incidence of HZ and possibly subsequent osteoporosis. Physicians should be alerted to this association to improve early identification of osteoporosis in patients with HZ.
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Affiliation(s)
- Chieh-Hsin Wu
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University
- Department of Neurosurgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University
| | - Chee-Yin Chai
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University
- Department of Pathology, Kaohsiung Medical University Hospital, Kaohsiung Medical University
- Department of Pathology, Faculty of Medicine, College of Medicine, Kaohsiung Medical University
- Institute of Biomedical Sciences, National Sun Yat-Sen University
| | - Yi-Ching Tung
- Department of Public Health and Environmental Medicine, College of Medicine, Kaohsiung Medical University
| | - Ying-Yi Lu
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University
- Department of Dermatology, Kaohsiung Veterans General Hospital
- Cosmetic Applications and Management Department, Yuh-Ing Junior College of Health Care and Management
| | - Yu-Feng Su
- Department of Neurosurgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University
| | - Tai-Hsin Tsai
- Department of Neurosurgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University
| | - Rong-Dar Tzou
- Department of Neurosurgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University
| | - Chih-Lung Lin
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University
- Department of Neurosurgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University
- Department of Neurosurgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
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Paupitz JA, Lima GL, Alvarenga JC, Oliveira RM, Bonfa E, Pereira RMR. Bone impairment assessed by HR-pQCT in juvenile-onset systemic lupus erythematosus. Osteoporos Int 2016; 27:1839-48. [PMID: 26694597 DOI: 10.1007/s00198-015-3461-y] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2015] [Accepted: 12/11/2015] [Indexed: 01/16/2023]
Abstract
UNLABELLED High-resolution peripheral quantitative computed tomography (HR-pQCT) analysis of female juvenile-onset systemic lupus erythematosus (JoSLE) patients revealed trabecular/cortical bone damage and reduced bone strength primarily at the distal radius compared to healthy controls. We demonstrated for the first time that JoSLE patients with vertebral fracture (VF) present trabecular impairment at the distal radius. INTRODUCTION This study investigated the volumetric bone mineral density (vBMD), microarchitecture, and biomechanical features at the distal radius and tibia using HR-pQCT and laboratory bone markers in JoSLE patients compared to controls to determine whether this method discriminates JoSLE patients with or without VF. METHODS We compared 56 female JoSLE patients to age- and Tanner-matched healthy controls. HR-pQCT was performed at the distal radius and tibia. Serum levels of the amino-terminal pro-peptide of type I collagen, the C-terminal telopeptide of type I collagen, intact parathormone, sclerostin, and 25-hydroxyvitamin D (25OHD) were evaluated. VFs were analyzed using VFA-dual-energy X-ray absorptiometry (DXA) (Genant's method). RESULTS Reduced density and strength parameters and microarchitecture alterations of cortical and trabecular bones were observed in JoSLE patients compared to controls, primarily at the distal radius (p < 0.05). Patients with VF exhibited a significant decrease in trabecular bone parameters solely at the distal radius (Total.BMD, p = 0.034; Trabecular.BMD [Tb.BMD], p = 0.034; bone volume (BV)/trabecular volume (TV), p = 0.034; apparent modulus, p = 0.039) and higher scores for disease damage (Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SLICC/ACR-DI), p = 0.002). Bone metabolism markers were similar in all groups. Logistic regression analysis of parameters that were significant in univariate analysis revealed that Tb.BMD (OR 0.98, 95 % CI 0.95-0.99, p = 0.039) and SLICC/ACR-DI (OR 7.37, 95 % CI 1.75-30.97, p = 0.006) were independent risk factors for VF. CONCLUSION In conclusion, this study is the first demonstration of bone microstructure and strength deficits in JoSLE patients, particularly at the distal radius. Our results demonstrated that VF was associated with trabecular radius alteration and emphasized the potential detrimental effect of disease damage on this condition.
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Affiliation(s)
- J A Paupitz
- Bone Metabolism Laboratory, Rheumatology Division, Faculdade de Medicina da Universidade de São Paulo, Av Dr Arnaldo, 455, 3° Andar, Sala 3193, Sao Paulo, SP, 01246-903, Brazil
| | - G L Lima
- Bone Metabolism Laboratory, Rheumatology Division, Faculdade de Medicina da Universidade de São Paulo, Av Dr Arnaldo, 455, 3° Andar, Sala 3193, Sao Paulo, SP, 01246-903, Brazil
| | - J C Alvarenga
- Bone Metabolism Laboratory, Rheumatology Division, Faculdade de Medicina da Universidade de São Paulo, Av Dr Arnaldo, 455, 3° Andar, Sala 3193, Sao Paulo, SP, 01246-903, Brazil
| | | | - E Bonfa
- Bone Metabolism Laboratory, Rheumatology Division, Faculdade de Medicina da Universidade de São Paulo, Av Dr Arnaldo, 455, 3° Andar, Sala 3193, Sao Paulo, SP, 01246-903, Brazil
| | - R M R Pereira
- Bone Metabolism Laboratory, Rheumatology Division, Faculdade de Medicina da Universidade de São Paulo, Av Dr Arnaldo, 455, 3° Andar, Sala 3193, Sao Paulo, SP, 01246-903, Brazil.
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Wang X, Yan S, Liu C, Xu Y, Wan L, Wang Y, Gao W, Meng S, Liu Y, Liu R, Xu D. Fracture risk and bone mineral density levels in patients with systemic lupus erythematosus: a systematic review and meta-analysis. Osteoporos Int 2016; 27:1413-1423. [PMID: 26753541 DOI: 10.1007/s00198-015-3449-7] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2015] [Accepted: 12/01/2015] [Indexed: 12/16/2022]
Abstract
Previous studies suggested possible bone loss and fracture risk in patients with systemic lupus erythematosus (SLE). The aim of this systematic review and meta-analysis was to assess the strength of the relationship of SLE with fracture risk and the mean difference of bone mineral density (BMD) levels between SLE patients and controls. Literature search was undertaken in multiple indexing databases on September 26, 2015. Studies on the relationship of SLE with fracture risk and the mean difference of BMD levels between SLE patients and controls were included. Data were combined using standard methods of meta-analysis. Twenty-one studies were finally included into the meta-analysis, including 15 studies on the mean difference of BMD levels between SLE patients and controls, and 6 studies were on fracture risk associated with SLE. The meta-analysis showed that SLE patients had significantly lower BMD levels than controls in the whole body (weighted mean difference [WMD] = -0.04; 95 % CI -0.06 to -0.02; P < 0.001), femoral neck (WMD = -0.06; 95 % CI -0.07 to -0.04; P < 0.001), lumbar spine (WMD = -0.06; 95 % CI -0.09 to -0.03; P < 0.001), and total hip (WMD = -0.05; 95 % CI -0.06 to -0.03; P < 0.001). In addition, the meta-analysis also showed that SLE was significantly associated with increased fracture risk of all sites (relative risk [RR] = 1.97, 95 % CI 1.20-3.25; P = 0.008). Subgroup analysis by adjustment showed that SLE was significantly associated with increased fracture risk of all sites before and after adjusting for confounding factors (unadjusted RR = 2.07, 95 % CI 1.46-2.94, P < 0.001; adjusted RR = 1.22, 95 % CI 1.05-1.42, P = 0.01). Subgroup analysis by types of fracture showed that SLE was significantly associated with increased risks of hip fracture (RR = 1.99, 95 % CI 1.55-2.57; P < 0.001), osteoporotic fracture (RR = 1.36, 95 % CI 1.21-1.53; P < 0.001), and vertebral fracture (RR = 2.97, 95 % CI 1.71-5.16; P < 0.001). This systematic review and meta-analysis provides strong evidence for the relationship of SLE with bone loss and fracture risk.
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Affiliation(s)
- X Wang
- Department of Rheumatology and Immunology, The Affiliated Hospital of Weifang Medical University, Weifang, 261000, Shandong Province, China
| | - S Yan
- Department of Anorectal Surgery, The Affiliated Hospital of Weifang Medical University, Weifang, 261000, China
| | - C Liu
- Clinical Laboratory, First Affiliated Hospital, Nanjing Medical University, Nanjing, 210029, China
| | - Y Xu
- Occupational Safety and Health Research Center of the State Administration of Work Safety, Beijing, 100000, China
| | - L Wan
- Department of Rheumatology and Immunology, The Affiliated Hospital of Weifang Medical University, Weifang, 261000, Shandong Province, China
| | - Y Wang
- Department of Rheumatology and Immunology, The Affiliated Hospital of Weifang Medical University, Weifang, 261000, Shandong Province, China
| | - W Gao
- Department of Rheumatology and Immunology, The Affiliated Hospital of Weifang Medical University, Weifang, 261000, Shandong Province, China
| | - S Meng
- Department of Rheumatology and Immunology, The Affiliated Hospital of Weifang Medical University, Weifang, 261000, Shandong Province, China
| | - Y Liu
- Department of Rheumatology and Immunology, The Affiliated Hospital of Weifang Medical University, Weifang, 261000, Shandong Province, China
| | - R Liu
- Department of Rheumatology and Immunology, The Affiliated Hospital of Weifang Medical University, Weifang, 261000, Shandong Province, China.
| | - D Xu
- Department of Rheumatology and Immunology, The Affiliated Hospital of Weifang Medical University, Weifang, 261000, Shandong Province, China.
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Prevention and Treatment of Bone Disease in Systemic Lupus Erythematosus. CURRENT TREATMENT OPTIONS IN RHEUMATOLOGY 2016. [DOI: 10.1007/s40674-016-0034-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
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Sabio JM. Lupus eritematoso sistémico a día de hoy. Med Clin (Barc) 2016; 146:160-2. [DOI: 10.1016/j.medcli.2015.08.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2015] [Accepted: 08/06/2015] [Indexed: 10/23/2022]
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Sabio JM. Systemic lupus erythematosus today. MEDICINA CLÍNICA (ENGLISH EDITION) 2016; 146:160-162. [DOI: 10.1016/j.medcle.2016.04.061] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/02/2023]
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Abstract
PURPOSE OF REVIEW This manuscript will provide a review of recent publications, examining the correlation of systemic lupus erythematosus (SLE) with changes in bone health and associated osteoporosis, highlighting prevalence, etiology, diagnosis, and treatment. RECENT FINDINGS Studies suggest that bone loss and fractures are associated with SLE, related not only to the disease itself, but also with low vitamin D and treatment side-effects. Understanding the mechanisms of glucocorticoids on bone and the immunologic relationship of vitamin D, as well as recognizing the role of chronic inflammation on bone, allows for better understanding of skeletal side-effects. Further awareness of the association of poor bone health has led to an increased need for prevention and treatment. New imaging and treatment are emerging, although not recommended currently. SUMMARY Loss of bone density culminating in osteoporosis and fracture is a frequent comorbidity in SLE patients at any age and is multifactorial in etiology. Awareness and diagnosis is crucial because of its prevalence and morbidity. Prevention is safe and effective in this high-risk population where diagnostic measures and interventions are underutilized and guidelines are lacking.
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Affiliation(s)
- Cuoghi Edens
- aDepartment of Pediatrics, Division of Pediatric Infectious Diseases and Rheumatology, Rainbow Babies and Children's Hospital bDepartment of Internal Medicine, Division of Rheumatology, University Hospitals Case Medical Center, Cleveland, Ohio, USA
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Lems WF. Fracture risk estimation may facilitate the treatment gap in osteoporosis. Ann Rheum Dis 2015; 74:1943-5. [PMID: 26408569 DOI: 10.1136/annrheumdis-2015-208245] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2015] [Accepted: 09/06/2015] [Indexed: 11/04/2022]
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Bultink IEM, Lems WF. Systemic lupus erythematosus and fractures. RMD Open 2015; 1:e000069. [PMID: 26557383 PMCID: PMC4632145 DOI: 10.1136/rmdopen-2015-000069] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2015] [Revised: 02/14/2015] [Accepted: 02/22/2015] [Indexed: 12/21/2022] Open
Abstract
Since survival of patients with systemic lupus erythematosus (SLE) has improved over the past decades, increasing attention is focused on complications of the disease. Osteoporosis and fractures contribute to damage in the second most frequently involved organ system in SLE: the musculoskeletal system. Recent studies have reported a high frequency of reduced bone mineral density in SLE, and an increased risk of peripheral and vertebral fractures. The incidence of symptomatic fractures is increased 1.2-4.7-fold in patients with SLE. A large population-based study on 4343 patients with SLE and 21 780 age-matched and sex-matched controls, demonstrated previous glucocorticoid use and longer disease duration as important risk factors for symptomatic fractures in SLE. Prevalent vertebral fractures are demonstrated in 18-50% of these relatively young patients, and one in three of these patients has normal bone density. The aetiology of bone loss in SLE is supposed to be multifactorial, involving clinical osteoporosis risk factors, systemic inflammation, serological factors, metabolic factors, hormonal factors, medication-induced adverse effects and, possibly, genetic factors. A 6-year follow-up study on Dutch patients with SLE revealed that low 25-hydroxyvitamin D serum levels, low body mass index and baseline use of antimalarials were associated with bone loss. In addition, a dose-dependent relationship between glucocorticoid use and bone loss was demonstrated in longitudinal studies in SLE. These findings have implications for daily clinical practice, because vitamin D insufficiency is highly frequent in SLE, antimalarials are regarded as 'anchor drugs' for therapy and the majority of patients with SLE are on chronic glucocorticoid treatment.
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Affiliation(s)
- Irene E M Bultink
- Department of Rheumatology , Amsterdam Rheumatology and Immunology Center, VU University Medical Center , Amsterdam , The Netherlands
| | - Willem F Lems
- Department of Rheumatology , Amsterdam Rheumatology and Immunology Center, VU University Medical Center , Amsterdam , The Netherlands
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