Effect of Remotely Supervised Weight Loss and Exercise Training Versus Lifestyle Counseling on Cardiovascular Risk and Clinical Outcomes in Older Adults With Rheumatoid Arthritis: A Randomized Controlled Trial.

OBJECTIVE: To compare a remotely supervised weight loss and exercise intervention to lifestyle counseling for effects on cardiovascular disease risk, disease activity, and patient-reported outcomes in older patients with rheumatoid arthritis (RA) and overweight/obesity. METHODS: Twenty older (60-80 years), previously sedentary participants with seropositive RA and overweight/obesity were randomized to 16 weeks of either Supervised Weight loss and Exercise Training (SWET) or Counseling Health As Treatment (CHAT). The SWET group completed aerobic training (150 minutes/week moderate-to-vigorous intensity), resistance training (two days/week), and a hypocaloric diet (7% weight loss goal). The CHAT control group completed two lifestyle counseling sessions followed by monthly check-ins. The primary outcome was a composite metabolic syndrome z-score (MSSc) derived from fasting glucose, triglycerides, high density lipoprotein-cholesterol, minimal waist circumference, and mean arterial pressure. Secondary outcomes included RA disease activity and patient-reported outcomes. RESULTS: Both groups improved MSSc (absolute change -1.67 ± 0.64 in SWET; -1.34 ± 1.30 in CHAT; P < 0.01 for both groups) with no between-group difference. Compared with CHAT, SWET significantly improved body weight, fat mass, Disease Activity Score-28 C-reactive protein, and patient-reported physical health, physical function, mental health, and fatigue (P < 0.04 for all between-group comparisons). Based on canonical correlations for fat mass, cardiorespiratory fitness, and leg strength, component-specific effects were strongest for (1) weight loss improving MSSc, physical health, and mental health; (2) aerobic training improving physical function and fatigue; and (3) resistance training improving Disease Activity Score-28 C-reactive protein. CONCLUSION: In older patients with RA and overweight/obesity, 16 weeks of remotely supervised weight loss, aerobic training, and resistance training improve cardiometabolic health, patient-reported outcomes, and disease activity. Less intensive lifestyle counseling similarly improves cardiovascular disease risk profiles, suggesting an important role for integrative interventions in the routine clinical care of this at-risk RA population.

Rheumatoid arthritis T cell and muscle oxidative metabolism associate with exercise-induced changes in cardiorespiratory fitness.

Rheumatoid arthritis (RA) T cells drive autoimmune features via metabolic reprogramming that reduces oxidative metabolism. Exercise training improves cardiorespiratory fitness (i.e., systemic oxidative metabolism) and thus may impact RA T cell oxidative metabolic function. In this pilot study of RA participants, we took advantage of heterogeneous responses to a high-intensity interval training (HIIT) exercise program to identify relationships between improvements in cardiorespiratory fitness with changes in peripheral T cell and skeletal muscle oxidative metabolism. In 12 previously sedentary persons with seropositive RA, maximal cardiopulmonary exercise tests, fasting blood, and vastus lateralis biopsies were obtained before and after 10 weeks of HIIT. Following HIIT, improvements in RA cardiorespiratory fitness were associated with changes in RA CD4 + T cell basal and maximal respiration and skeletal muscle carnitine acetyltransferase (CrAT) enzyme activity. Further, changes in CD4 + T cell respiration were associated with changes in naïve CD4 + CCR7 + CD45RA + T cells, muscle CrAT, and muscle medium-chain acylcarnitines and fat oxidation gene expression profiles. In summary, modulation of cardiorespiratory fitness and molecular markers of skeletal muscle oxidative metabolism during exercise training paralleled changes in T cell metabolism. Exercise training that improves RA cardiorespiratory fitness may therefore be valuable in managing pathologically related immune and muscle dysfunction.Trial registration: ClinicalTrials.gov, NCT02528344. Registered on 19 August 2015.

Using Machine Learning to Identify Organ System Specific Limitations to Exercise via Cardiopulmonary Exercise Testing.

Cardiopulmonary Exer cise Testing (CPET) is a unique physiologic medical test used to evaluate human response to progressive maximal exercise stress. Depending on the degree and type of deviation from the normal physiologic response, CPET can help identify a patient's specific limitations to exercise to guide clinical care without the need for other expensive and invasive diagnostic tests. However, given the amount and complexity of data obtained from CPET, interpretation and visualization of test results is challenging. CPET data currently require dedicated training and significant experience for proper clinician interpretation. To make CPET more accessible to clinicians, we investigated a simplified data interpretation and visualization tool using machine learning algorithms. The visualization shows three types of limitations (cardiac, pulmonary and others); values are defined based on the results of three independent random forest classifiers. To display the models' scores and make them interpretable to the clinicians, an interactive dashboard with the scores and interpretability plots was developed. This machine learning platform has the potential to augment existing diagnostic procedures and provide a tool to make CPET more accessible to clinicians.

Making Cardiopulmonary Exercise Testing Interpretable for Clinicians.

ABSTRACT: Cardiopulmonary exercise testing (CPET) is a dynamic clinical tool for determining the cause for a person's exercise limitation. CPET provides clinicians with fundamental knowledge of the coupling of external to internal respiration (oxygen and carbon dioxide) during exercise. Subtle perturbations in CPET parameters can differentiate exercise responses among individual patients and disease states. However, perhaps because of the challenges in interpretation given the amount and complexity of data obtained, CPET is underused. In this article, we review fundamental concepts in CPET data interpretation and visualization. We also discuss future directions for how to best use CPET results to guide clinical care. Finally, we share a novel three-dimensional graphical platform for CPET data that simplifies conceptualization of organ system-specific (cardiac, pulmonary, and skeletal muscle) exercise limitations. Our goal is to make CPET testing more accessible to the general medical provider and make the test of greater use in the medical toolbox.

Altered skeletal muscle metabolic pathways, age, systemic inflammation, and low cardiorespiratory fitness associate with improvements in disease activity following high-intensity interval training in persons with rheumatoid arthritis.

BACKGROUND: Exercise training, including high-intensity interval training (HIIT), improves rheumatoid arthritis (RA) inflammatory disease activity via unclear mechanisms. Because exercise requires skeletal muscle, skeletal muscle molecular pathways may contribute. The purpose of this study was to identify connections between skeletal muscle molecular pathways, RA disease activity, and RA disease activity improvements following HIIT. METHODS: RA disease activity assessments and vastus lateralis skeletal muscle biopsies were performed in two separate cohorts of persons with established, seropositive, and/or erosive RA. Body composition and objective physical activity assessments were also performed in both the cross-sectional cohort and the longitudinal group before and after 10 weeks of HIIT. Baseline clinical assessments and muscle RNA gene expression were correlated with RA disease activity score in 28 joints (DAS-28) and DAS-28 improvements following HIIT. Skeletal muscle gene expression changes with HIIT were evaluated using analysis of covariance and biological pathway analysis. RESULTS: RA inflammatory disease activity was associated with greater amounts of intramuscular adiposity and less vigorous aerobic exercise (both p < 0.05). HIIT-induced disease activity improvements were greatest in those with an older age, elevated erythrocyte sedimentation rate, low cardiorespiratory fitness, and a skeletal muscle molecular profile indicative of altered metabolic pathways (p < 0.05 for all). Specifically, disease activity improvements were linked to baseline expression of RA skeletal muscle genes with cellular functions to (1) increase amino acid catabolism and interconversion (GLDC, BCKDHB, AASS, PYCR, RPL15), (2) increase glycolytic lactate production (AGL, PDK2, LDHB, HIF1A), and (3) reduce oxidative metabolism via altered beta-oxidation (PXMP2, ACSS2), TCA cycle flux (OGDH, SUCLA2, MDH1B), and electron transport chain complex I function (NDUFV3). The muscle mitochondrial glycine cleavage system (GCS) was identified as critically involved in RA disease activity improvements given upregulation of multiple GCS genes at baseline, while GLDC was significantly downregulated following HIIT. CONCLUSION: In the absence of physical activity, RA inflammatory disease activity is associated with transcriptional remodeling of skeletal muscle metabolism. Following exercise training, the greatest improvements in disease activity occur in older, more inflamed, and less fit persons with RA. These exercise training-induced immunomodulatory changes may occur via reprogramming muscle bioenergetic and amino acid/protein homeostatic pathways. TRIAL REGISTRATION: ClinicalTrials.gov , NCT02528344 . Registered on 19 August 2015.

Exercise protects against cardiac and skeletal muscle dysfunction in a mouse model of inflammatory arthritis.

Rheumatoid arthritis (RA) is a systemic inflammatory arthritis impacting primarily joints and cardiac and skeletal muscle. RA's distinct impact on cardiac and skeletal muscle tissue is suggested by studies showing that new RA pharmacologic agents strongly improve joint inflammation, but have little impact on RA-associated mortality, cardiovascular disease, and sarcopenia. Thus, the objective is to understand the distinct effects of RA on cardiac and skeletal muscle, and to therapeutically target these tissues through endurance-based exercise as a way to improve RA mortality and morbidity. We utilize the well-characterized RA mouse model, the K/BxN mouse, to investigate cardiac and skeletal muscle pathologies, including the use of wheel-running exercise to mitigate these pathologies. Strikingly, we found that K/BxN mice, like patients with RA, also exhibit both cardiac and skeletal muscle myopathies that were correlated with circulating IL-6 levels. Three months of wheel-running exercise significantly improved K/BxN joint swelling and reduced systemic IL-6 concentrations. Importantly, there were morphological, gene expression, and functional improvements in both the skeletal muscle and cardiac myopathies with exercise. The K/BxN mouse model of RA recapitulated important RA clinical comorbidities, including altered joint, cardiac and skeletal muscle function. These morphological, molecular, and functional alterations were mitigated with regular exercise, thus suggesting exercise as a potential therapeutic intervention to lessen disease activity in the joint and the peripheral tissues, including the heart and skeletal muscle.NEW & NOTEWORTHY RA, even when controlled, is associated with skeletal muscle weakness and greater risk of cardiovascular disease (CVD). Using exercise as a therapeutic against, the progression of RA is often avoided due to fear of worsening RA pathology. We introduce the K/BxN mouse as an RA model to study both myocardial and skeletal muscle dysfunction. We show that endurance exercise can improve joint, cardiac, and skeletal muscle function in K/BxN mice, suggesting exercise may be beneficial for patients with RA.

Skeletal muscle disease in rheumatoid arthritis: the center of cardiometabolic comorbidities?

PURPOSE OF REVIEW: Despite its critical roles in body movement, structure, and metabolism, skeletal muscle remains underappreciated in the context of rheumatoid arthritis. In rheumatoid arthritis, chronic inflammation, physical inactivity, and medication toxicities impair skeletal muscle. These skeletal muscle alterations contribute to continued rheumatoid arthritis disparities in physical function and cardiometabolic health. RECENT FINDINGS: In the prebiologic disease-modifying antirheumatic drug era, rheumatoid arthritis skeletal muscle atrophy was the central feature of 'rheumatoid cachexia,' a hypermetabolic state driven by chronic systemic inflammation and muscle protein degradation. In the current era, rheumatoid arthritis muscle deficits are less visible, yet persist as a key component of 'sarcopenic obesity.' In rheumatoid arthritis sarcopenic obesity, chronic inflammation, physical inactivity, and medication toxicities contribute to muscle contractile deficits, inflammation, altered metabolism, and intramuscular adiposity, a key predictor of rheumatoid arthritis disability and insulin resistance. SUMMARY: Rheumatoid arthritis skeletal muscle disease in the current era is defined by impaired contractile function (poor strength and endurance) and sarcopenic obesity (decreased muscle mass, increased fat mass, and intramuscular adiposity). These muscle impairments contribute to disability and cardiometabolic disease in rheumatoid arthritis. Management should focus on monitoring of rheumatoid arthritis muscle function and body composition, limiting potentially myotoxic drugs, and prescription of exercise training.

Benefits and promotion of physical activity in rheumatoid arthritis.

PURPOSE OF REVIEW: The aim of this article is to describe the benefits of physical activity and exercise on rheumatoid arthritis disease activity, functioning, and symptoms; and offer recommendations for promotion of physical activity and exercise among people with rheumatoid arthritis. RECENT FINDINGS: In addition to well-known benefits of exercise such as improving cardiovascular health and metabolic syndrome and reducing obesity, exercise has consistently shown rheumatoid arthritis-specific benefits. Exercise and increases in physical activity improve clinically measured disease activity, reduce symptoms such as fatigue and pain, and improve function and mental health. In spite of these benefits, most people with rheumatoid arthritis are inactive. Patient barriers to engaging in physical activity may include fears of joint damage, rheumatoid arthritis symptoms, and lack of understanding that physical activity improves the symptoms that may be barriers. However, the greatest barrier to healthy levels of physical activity among individuals with rheumatoid arthritis appears to be the lack of direction from healthcare providers. SUMMARY: Exercise is safe and highly beneficial for people with rheumatoid arthritis. Because receiving recommendations from healthcare providers may be the factor most strongly associated with engaging in physical activity or exercise, providers are encouraged to give patients positive messages about the benefits of physical activity and the extremely low risks of harm.

Plasma MicroRNAs in Established Rheumatoid Arthritis Relate to Adiposity and Altered Plasma and Skeletal Muscle Cytokine and Metabolic Profiles.

Background: MicroRNAs have been implicated in the pathogenesis of rheumatoid arthritis (RA), obesity, and altered metabolism. Although RA is associated with both obesity and altered metabolism, expression of RA-related microRNA in the setting of these cardiometabolic comorbidities is unclear. Our objective was to determine relationships between six RA-related microRNAs and RA disease activity, inflammation, body composition, and metabolic function. Methods: Expression of plasma miR-21, miR-23b, miR-27a, miR-143, miR-146a, and miR-223 was measured in 48 persons with seropositive and/or erosive RA (mean DAS-28-ESR 3.0, SD 1.4) and 23 age-, sex-, and BMI-matched healthy controls. Disease activity in RA was assessed by DAS-28-ESR. Plasma cytokine concentrations were determined by ELISA. Body composition was assessed using CT scan to determine central and muscle adipose and thigh muscle tissue size and tissue density. Plasma and skeletal muscle acylcarnitine, amino acid, and organic acid metabolites were measured via mass-spectroscopy. Plasma lipoproteins were measured via nuclear magnetic resonance (NMR) spectroscopy. Spearman correlations were used to assess relationships for microRNA with inflammation and cardiometabolic measures. RA and control associations were compared using Fisher transformations. Results: Among RA subjects, plasma miR-143 was associated with plasma IL-6 and IL-8. No other RA microRNA was positively associated with disease activity or inflammatory markers. In RA, microRNA expression was associated with adiposity, both visceral adiposity (miR-146a, miR-21, miR-23b, and miR-27a) and thigh intra-muscular adiposity (miR-146a and miR-223). RA miR-146a was associated with greater concentrations of cardiometabolic risk markers (plasma short-chain dicarboxyl/hydroxyl acylcarnitines, triglycerides, large VLDL particles, and small HDL particles) and lower concentrations of muscle energy substrates (long-chain acylcarnitines and pyruvate). Despite RA and controls having similar microRNA levels, RA, and controls differed in magnitude and direction for several associations with cytokines and plasma and skeletal muscle metabolic intermediates. Conclusion: Most microRNAs thought to be associated with RA disease activity and inflammation were more reflective of RA adiposity and impaired metabolism. These associations show that microRNAs in RA may serve as an epigenetic link between RA inflammation and cardiometabolic comorbidities.

Trends in cardiorespiratory fitness: The evolution of exercise treadmill testing at a single Academic Medical Center from 1970 to 2012.

OBJECTIVE: To identify temporal trends in the use of exercise treadmill testing (ETT) and cardiorespiratory fitness (CRF) estimated by ETT in metabolic equivalents (METs). PATIENTS AND METHODS: We compiled an ETT database of all available treadmill tests-including those with concomitant stress echocardiography and nuclear perfusion imaging studies-performed at Duke University Hospital from January 1, 1970- December 31, 2012. Six different ramp protocols were used in these combined modalities. CRF at maximal exertion was estimated using established metrics. Eligible patients were required to have no missing data on maximal treadmill speed, grade, and protocol. RESULTS: The most commonly used ETT protocol was the Bruce (n = 28,877), followed by manual test (n = 7390). Since the 1980's, the use of ETT for clinical purposes declined substantially; there was a decreased trend in utilization of 9.4% over the decades 1990-1999 and 2000-2009. When standard protocol (Bruce) was assessed in isolation, trends in CRF decreased progressively from 1970 to 2012 (mean METs (standard deviation): 11.7 (4.3) to 10.5 (3.5)). After adjusting for baseline comorbidities, the trend was reduced to a lesser degree. CONCLUSIONS: The use of ETT at our institution has declined over time, perhaps due to changes in clinical practice. In patients undergoing ETT using the standard Bruce protocol, CRF decreased progressively over the last five decades. Future studies are needed to clarify the etiology of the decrease in use of such a powerful predictor of clinical outcomes in our medical care environment.

Effect of high-intensity interval training on muscle remodeling in rheumatoid arthritis compared to prediabetes.

BACKGROUND: Sarcopenic obesity, associated with greater risk of cardiovascular disease (CVD) and mortality in rheumatoid arthritis (RA), may be related to dysregulated muscle remodeling. To determine whether exercise training could improve remodeling, we measured changes in inter-relationships of plasma galectin-3, skeletal muscle cytokines, and muscle myostatin in patients with RA and prediabetes before and after a high-intensity interval training (HIIT) program. METHODS: Previously sedentary persons with either RA (n = 12) or prediabetes (n = 9) completed a 10-week supervised HIIT program. At baseline and after training, participants underwent body composition (Bod Pod®) and cardiopulmonary exercise testing, plasma collection, and vastus lateralis biopsies. Plasma galectin-3, muscle cytokines, muscle interleukin-1 beta (mIL-1ß), mIL-6, mIL-8, muscle tumor necrosis factor-alpha (mTNF-α), mIL-10, and muscle myostatin were measured via enzyme-linked immunosorbent assays. An independent cohort of patients with RA (n = 47) and age-, gender-, and body mass index (BMI)-matched non-RA controls (n = 23) were used for additional analyses of galectin-3 inter-relationships. RESULTS: Exercise training did not reduce mean concentration of galectin-3, muscle cytokines, or muscle myostatin in persons with either RA or prediabetes. However, training-induced alterations varied among individuals and were associated with cardiorespiratory fitness and body composition changes. Improved cardiorespiratory fitness (increased absolute peak maximal oxygen consumption, or VO2) correlated with reductions in galectin-3 (r = -0.57, P = 0.05 in RA; r = -0.48, P = 0.23 in prediabetes). Training-induced improvements in body composition were related to reductions in muscle IL-6 and TNF-α (r < -0.60 and P <0.05 for all). However, the association between increased lean mass and decreased muscle IL-6 association was stronger in prediabetes compared with RA (Fisher r-to-z P = 0.0004); in prediabetes but not RA, lean mass increases occurred in conjunction with reductions in muscle myostatin (r = -0.92; P <0.05; Fisher r-to-z P = 0.026). Subjects who received TNF inhibitors (n = 4) or hydroxychloroquine (n = 4) did not improve body composition with exercise training. CONCLUSION: Exercise responses in muscle myostatin, cytokines, and body composition were significantly greater in prediabetes than in RA, consistent with impaired muscle remodeling in RA. To maximize physiologic improvements with exercise training in RA, a better understanding is needed of skeletal muscle and physiologic responses to exercise training and their modulation by RA disease-specific features or pharmacologic agents or both. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02528344 . Registered on August 19, 2015.

Stiffness of resting lumbar myofascia in healthy young subjects quantified using a handheld myotonometer and concurrently with surface electromyography monitoring.

This study aimed to non-invasively quantify passive stiffness of superficial myofascia at a lower lumbar (L3-L4) anatomical level in young healthy male and female subjects and investigate its possible morphological variation. Resting prone lumbar myofascial measurements were quantified using MyotonPro(®) and statistically analyzed in 20 young healthy individuals over 3-weekly intervals, concurrently with surface electromyography (sEMG). Averaged mean ± SE stiffness (Newton/meter) over three weeks was significantly (p < 0.001) greater in males (247.8 ± 11.3) than females (208.4 ± 11.3), on the right (237.7 ± 12.8) than left sides (218.5 ± 12.3), at 10-min (231.4 ± 9.1) than initial baseline (224.8 ± 9.1) values. A polymorphism of stiffness values in 10 male and 10 female subjects was suggested by box plot analyses of the 3 weekly measurements and greater inter-individual than intra-individual variances. Greater knowledge of lumbar myofascial stiffness can improve understanding of their contributions in health and chronic low back disorders.

Greater Resting Lumbar Extensor Myofascial Stiffness in Younger Ankylosing Spondylitis Patients Than Age-Comparable Healthy Volunteers Quantified by Myotonometry.

OBJECTIVE: To quantify resting lumbar erector myofascial stiffness in younger patients with ankylosing spondylitis (AS) and age-comparable healthy control subjects using a handheld mechanical impulse-based myotonometric device. DESIGN: A case-control study of 24 patients with AS and 24 age-comparable healthy control subjects. SETTING: University physical therapy department. PARTICIPANTS: Patients with AS (men: n=19; women: n=5; total: N=24) and healthy volunteers (men: n=19; women: n=5; total: N=24) without low back pain (age range, 18-46y). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: Lumbar myofascial stiffness. RESULTS: At the initial measurements, median stiffness (Nm) of the averaged right- and left-sided values was greater (P=.021) in 24 patients with AS than 24 control subjects (268.9 vs 238.9, respectively). Repeated measurements after a 10-minute prone resting period were also greater (P=.007) in patients with AS than control subjects (281.0 vs 241.4, respectively). The 48 averaged right- and left-sided values from baseline and 10-minute measurements were compared in each subject group. The patients with AS more frequently (P=.012) had stiffness values >250 Nm (35 [72.9%] vs 22 [45.8%] in control subjects). CONCLUSIONS: Lumbar myofascial stiffness was greater in 24 patients with AS than in the control subjects. A hypothesized biomechanical concept of increased resting lumbar myofascial stiffness in AS may be supported by this preliminary controlled study.

Integrative structural biomechanical concepts of ankylosing spondylitis.

Ankylosing spondylitis (AS) is not fully explained by inflammatory processes. Clinical, epidemiological, genetic, and course of disease features indicate additional host-related risk processes and predispositions. Collectively, the pattern of predisposition to onset in adolescent and young adult ages, male preponderance, and widely varied severity of AS is unique among rheumatic diseases. However, this pattern could reflect biomechanical and structural differences between the sexes, naturally occurring musculoskeletal changes over life cycles, and a population polymorphism. During juvenile development, the body is more flexible and weaker than during adolescent maturation and young adulthood, when strengthening and stiffening considerably increase. During middle and later ages, the musculoskeletal system again weakens. The novel concept of an innate axial myofascial hypertonicity reflects basic mechanobiological principles in human function, tissue reactivity, and pathology. However, these processes have been little studied and require critical testing. The proposed physical mechanisms likely interact with recognized immunobiological pathways. The structural biomechanical processes and tissue reactions might possibly precede initiation of other AS-related pathways. Research in the combined structural mechanobiology and immunobiology processes promises to improve understanding of the initiation and perpetuation of AS than prevailing concepts. The combined processes might better explain characteristic enthesopathic and inflammatory processes in AS.