The impact of lifestyle modification on metabolic pathways in older adults with overweight/obesity and rheumatoid arthritis: a secondary exploratory analysis of the SWET-RA study.
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2025-06
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Abstract
Background
Rheumatoid arthritis (RA) is associated with increased cardiometabolic risk due to inflammation and traditional risk factors, both of which can be mitigated by lifestyle modifications. This study examines metabolic pathways influenced by lifestyle changes and related to improved cardiometabolic risk.Methods
This is a secondary exploratory analysis of the Supervised Weight loss and Exercise Training (SWET) study, in which twenty older adults with RA and overweight/obesity were randomized to 16 weeks of SWET or a counseling program. Baseline and post-intervention measures included mass spectrometry (MS) and nuclear magnetic resonance (NMR) metabolites and lipoproteins; cardiometabolic risk parameters; and RA clinical outcomes. Principal components analysis (PCA) reduced MS change scores into change factors. Between-group differences were assessed with t-tests and linear regression. Within-group differences were assessed with Wilcoxon-signed rank tests. Spearman's rank correlated MS change factors and NMR change scores with clinical outcomes.Results
Group differences were minimal. In all participants, improvements in metabolic syndrome score were associated with increases in PCA Factor 1 (short- and medium-chain acylcarnitines) and ketone bodies (ρ=-0.57, unadjusted p = 0.009, adjusted p = 0.04; ρ=-0.45, unadjusted p = 0.049, adjusted p = 1.00) and decreases in large low-density lipoprotein particles (LDLp) and large high-density lipoprotein particles (HDLp) (ρ = 0.48, unadjusted p = 0.03, adjusted p = 1.00; ρ = 0.48, unadjusted p = 0.03, adjusted p = 1.00). Improvements in RA disease activity (DAS-28ESR) were associated with reductions in very large triglyceride-rich lipoprotein particles (TRLp) (ρ = 0.60, unadjusted p = 0.01, adjusted p = 0.48). Improvements in patient-reported physical health were associated with reductions in HDL-c, ApoA1 concentrations, and medium HDLp (ρ=-0.50, unadjusted p = 0.03, adjusted p = 1.00; ρ=-0.47, unadjusted p = 0.04, adjusted p = 1.00; ρ=-0.45, unadjusted p = 0.047, adjusted p = 1.00). Improvements in patient-reported mental health were associated with decreases in high-density lipoprotein 6 (H6) particles (ρ=-0.60, unadjusted p = 0.03, adjusted p = 1.00), medium HDLp (ρ=-0.54, unadjusted p = 0.01, adjusted p = 0.48), and LDL size (ρ=-0.52, unadjusted p = 0.02, adjusted p = 0.96).Conclusion
In older adults with RA and overweight/obesity, both intensive supervised weight loss and exercise and lifestyle-based counseling influenced metabolic pathways, enhancing lipid metabolism (e.g., reductions in large LDLp) and metabolic flexibility (e.g., increases in fasting ketones and short- and medium-chain acylcarnitines). However, reductions in HDL-related measures should be interpreted cautiously as they may not reflect improved cardiometabolic risk.Trial registration
ClinicalTrials.gov, NCT04356183, 04/17/2020.Type
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Kim, Grace, Leanna M Ross, Alyssa M Sudnick, Johanna L Johnson, Carl F Pieper, Margery A Connelly, Olga Ilkayeva, Michael J Muehlbauer, et al. (2025). The impact of lifestyle modification on metabolic pathways in older adults with overweight/obesity and rheumatoid arthritis: a secondary exploratory analysis of the SWET-RA study. BMC rheumatology, 9(1). p. 68. 10.1186/s41927-025-00525-8 Retrieved from https://hdl.handle.net/10161/33846.
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Scholars@Duke
Leanna Ross
Dr. Ross's research focuses on understanding the mechanisms by which exercise interventions elicit short- and long-term cardiometabolic health benefits. As cardiometabolic disease remains the leading cause of morbidity and mortality in the United States, the goal of her translational research is to enhance the development of evidence-based, precision exercise interventions that optimally prevent and treat disease.
Areas of Research Interest
Exercise dose-response and cardiometabolic health
Insulin action and glucose homeostasis
Legacy health benefits of exercise
Heterogeneity of response to exercise intervention
Precision lifestyle medicine
Epidemiology of physical activity and cardiorespiratory fitness
Carl F. Pieper
Analytic Interests.
1) Issues in the Design of Medical Experiments: I explore the use of reliability/generalizability models in experimental design. In addition to incorporation of reliability, I study powering longitudinal trials with multiple outcomes and substantial missing data using Mixed models.
2) Issues in the Analysis of Repeated Measures Designs & Longitudinal Data: Use of Hierarchical Linear Models (HLM) or Mixed Models in modeling trajectories of multiple variables over time (e.g., physical and cognitive functioning and Blood Pressure). My current work involves methodologies in simultaneous estimation of trajectories for multiple variables within and between domains, modeling co-occuring change.
Areas of Substantive interest: (1) Experimental design and analysis in gerontology and geriatrics, and psychiatry,
(2) Multivariate repeated measures designs,
Olga Ilkayeva
Olga Ilkayeva, Ph.D., is the Director of the Metabolomics Core Laboratory at Duke Molecular Physiology Institute. She received her Ph.D. training in Cell Regulation from UT Southwestern Medical Center at Dallas, TX. Her postdoctoral research in the laboratory of Dr. Chris Newgard at Duke University Medical Center focused on lipid metabolism and regulation of insulin secretion. As a research scientist at the Stedman Nutrition and Metabolism Center, Dr. Ilkayeva expanded her studies to include the development of targeted mass spectrometry analyses. Currently, she works on developing and validating quantitative mass spectrometry methods used for metabolic profiling of various biological models with emphasis on diabetes, obesity, cardiovascular disease, and the role of gut microbiome in both health and disease.
Connie Watkins Bales
Research in our laboratory focuses on the role of nutrition (particularly vitamins and minerals) in the prevention and management of chronic diseases in older adults. Previous studies have concerned trace elements and cardiovascular disease, calcium and osteoporosis, and renal synthesis of vitamin D as it relates to bone health. Some of our newest work emphasizes the role of micronutrients as antioxidants and their interaction with the aging process. We are also working on various aspects of energy balance in older adults, ranging from failure to thrive in stroke patients with dysphagia to exercise and nutrition effects in overweight subjects who begin physical training. Thus we have a number of clinical and epidemiological projects on-going, many of which include a strong emphasis on nutrition assessment techniques in middle-aged and elderly subjects.
William Erle Kraus
My training, expertise and research interests range from human integrative physiology and genetics to animal exercise models to cell culture models of skeletal muscle adaptation to mechanical stretch. I am trained clinically as an internist and preventive cardiologist, with particular expertise in preventive cardiology and cardiac rehabilitation. My research training spans molecular biology and cell culture, molecular genetics, and integrative human exercise physiology and metabolism. I practice as a preventive cardiologist with a focus on cardiometabolic risk and exercise physiology for older athletes. My research space has both a basic wet laboratory component and a human integrative physiology one.
One focus of our work is an integrative physiologic examination of exercise effects in human subjects in clinical studies of exercise training in normal individuals, in individuals at risk of disease (such as pre-diabetes and metabolic syndrome; STRRIDE), and in individuals with disease (such as coronary heart disease, congestive heart failure and cancer).
A second focus of my research group is exploration of genetic determinates of disease risk in human subjects. We conduct studies of early onset cardiovascular disease (GENECARD; CATHGEN), congestive heart failure (HF-ACTION), peripheral arterial disease (AMNESTI), and metabolic syndrome. We are exploring analytic models of predicting disease risk using established and innovative statistical methodology.
A third focus of my group’s work is to understand the cellular signaling mechanisms underlying the normal adaptive responses of skeletal muscle to physiologic stimuli, such as occur in exercise conditioning, and to understand the abnormal maladaptive responses that occur in response to pathophysiologic stimuli, such as occur in congestive heart failure, aging and prolonged exposure to microgravity.
Recently we have begun to investigate interactions of genes and lifestyle interventions on cardiometabolic outcomes. We have experience with clinical lifestyle intervention studies, particularly the contributions of genetic variants to interventions responses. We call this Lifestyle Medicopharmacogenetics.
KEY WORDS:
exercise, skeletal muscle, energy metabolism, cell signaling, gene expression, cell stretch, heart failure, aging, spaceflight, human genetics, early onset cardiovascular disease, lifestyle medicine
Brian Andonian
Kim Marie Huffman
Determining the role of physical activity in modulating health outcomes (cardiovascular disease risk) in persons with rheumatologic diseases (rheumatoid arthritis, gout, osteoarthritis)
Integrating clinical rheumatology, basic immunology, metabolism, and exercise science in order to reduce morbidity in individuals with arthritis
Evaluating relationships between circulating and intra-muscular metabolic intermediates and insulin resistance in sedentary as well as individuals engaging in regular exercise
Addressing the role of physical activity in modulating inflammation, metabolism, and functional health in aging populations
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