Omega-3 and Exercise in Rheumatoid Arthritis People

Role of Specialized Pro-resolving Mediators on Inflammation, Cardiometabolic Health, Disease Progression, and Quality of Life in Patients With Rheumatoid Arthritis After Omega-3 PUFA Supplementation and Aerobic Exercise Training.

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by autoantibody production and synovial membrane damage. It significantly impairs overall function and quality of life. Consumption of omega-3 (n-3) polyunsaturated fatty acids (PUFAs) and regular aerobic exercise (AEx) training are reported to have positive effects on the progression of RA. However, the mechanisms behind these benefits are still inconclusive. This study aims to investigate the effects of n-3 PUFA supplementation and AEx training on disease progression, cardiometabolic health, and quality of life, and their association with the plasma and synovial fluid levels of specialized pro-resolving mediators (SPMs) in subjects with RA. The study consists of a 16-week intervention period, during which participants will be randomly assigned in a double-blinded manner to one of four groups: placebo control (PLA), PLA+AEx, n-3, or n-3+AEx. The PLA groups will be given a gelatin-filled capsule, while the n-3 groups will be given n-3 PUFAs equivalent to 2.5 g/d of docosahexaenoic acid and 0.5 g/d of eicosapentaenoic acid. The AEx groups will exercise thrice per week on a stationary electronically braked cycle ergometer at 60-70% of their VO2peak for 50-60 minutes. Before and after the intervention, participants will undergo RA-specific and functional measurements, peak aerobic capacity test, and a dietary and physical activity assessment. Venous blood and synovial fluid from the knee joint will be collected. Changes in disease progression, cardiometabolic health, quality of life, and erythrocyte membrane composition to assess n-3 incorporation, SPM levels, inflammatory markers, and gene expression from blood and synovial fluid will be analyzed. The study aims to elucidate the SPMs that regulate the inflammatory gene expression pathways and associate them with improvements in disease progression, cardiometabolic health, and quality of life after n-3 PUFA supplementation and AEx training.

Research hypothesis: N-3 PUFA and AEx will have synergistic effects on disease progression, cardiometabolic health, and quality of life in individuals with RA, and these changes will be associated with SPM production in blood and synovial fluid. General aim: To investigate the effects of n-3 PUFA supplementation and AEx training on disease progression, cardiometabolic health, and quality of life and their association with the plasma and synovial fluid levels of SPMs in individuals with RA. Specific aims: To compare the effects of n-3 PUFA supplementation, AEx training, and the combination of both on disease progression, cardiometabolic health, and quality of life in individuals with RA. To compare the effects of n-3 PUFA supplementation, AEx, and the combination of both on the plasma and synovial fluid levels of the SPMs in individuals with RA. To examine the relationship between the plasma levels of the n-3 PUFA derived SPMs with systemic disease progression, cardiometabolic health, and quality of life in individuals with RA Study design 88 Participants will be recruited from hospitals and private clinics in the central region of Chile, whereas all the interventions regarding AEx will be carried out at the Universidad de O'Higgins and the Hospital Regional de Rancagua. All institutions are in the Región del Libertador Bernardo O'Higgins, Chile. This study consists of a 16-week intervention with n-3 PUFAs and/or aerobic exercise (AEx) training. The subjects will be randomly assigned in a double-blinded manner to one of four groups: placebo control (PLA), PLA+AEx, n-3, or n-3+AEx. A stratified randomized assignment (by block) process will be employed to ensure that the experimental groups are balanced for disease activity, pharmacological treatment, sex, and age. The training sessions will be conducted at the Laboratorio de Ciencias del Ejercicio en el Ciclo Vital (Lab-CERVITAL), Universidad de O'Higgins. The week before intervention the participants will perform RA specific tests (e.g., Disease Activity Score-28) and functional measurements (e.g., handgrip strength), peak aerobic capacity test, a dietary and physical activity assessment, and blood samples will be collected. Subsequently, participants will start their 16-week intervention (PLA, PLA+AEx, n-3, or n-3+AEx). At the end of the intervention the same initial measurements, questionnaires, and assessments will be collected. In a subgroup of participants (n=24 in total or n=6 per group) extraction of synovial fluid will be performed before and after the intervention. The participants will be supplemented with either 5 capsules per day of Omega UP (Newscience, Chile) equivalent to 2.5 g/d of DHA and 0.5 g/d of EPA or a placebo filled gelatin capsule. The current doses are within the limits recommended by the European Food Safety Authority and have been shown to be safe, to be incorporated into cell membranes, and to produce significant improvements in overall health in individuals with RA. Capsules will be placed into de-identified bottles by people not involved in the study and provided to the participants to ensure double blinding. The exercise intervention will be performed according to the recommendations from the European Alliance of Associations for Rheumatology (EULAR) consisting of aerobic type exercise training three times per week, on non-consecutive days, with a total time of 20-60 minutes. The AEx will be performed on a stationary electronically braked cycle ergometer starting at 40-50% of VO2peak for 20 minutes. The intensity and volume of cycling will then be gradually increased to target at least 60-70% of VO2peak for 50-60 minutes over the final 10 weeks. Heart rate, power output and rating of perceived exertion (RPE) will be monitored during training intervention. Statistical analysis Results will be expressed as mean ± SD. A two-way ANOVA with repeated measures followed by Fisher's least significant difference post-test for multiple comparisons between groups will be used. Linear regression models will be constructed to examine the association between SPMs and clinical, functional, and health parameters, accounting for participant age, sex, and BMI as covariates. A value of p<0.05 will be considered statistically significant.

This study consists of a 16-week intervention with omega-3 polyunsaturated fatty acids (n-3 PUFAs) and/or aerobic exercise (AEx) training. The subjects will be randomly assigned in a double-blinded manner to one of four groups: placebo control (PLA), PLA+AEx, n-3, or n-3+AEx. The training sessions will be conducted at the Laboratorio de Ciencias del Ejercicio en el Ciclo Vital (Lab-CERVITAL), Universidad de O'Higgins. The week before intervention the participants will perform RA-specific tests (e.g., Disease Activity Score-28) and functional measurements (e.g., handgrip strength), peak aerobic capacity test, a dietary and physical activity assessment, and blood samples will be collected. Subsequently, participants will start their 16-week intervention (PLA, PLA+AEx, n-3, or n-3+AEx). At the end of the intervention the same initial measurements, questionnaires, and assessments will be collected.

The masking process will ensure that both the participants and the investigators involved in the study remain unaware of the treatment assignments throughout the entire duration of the study. A unique identification code will be assigned to each participant upon enrollment, which conceals their treatment allocation. The allocation sequence will be generated by a person not directly involved in the study. The capsules in the experimental intervention and the control treatment, will be packaged identically to maintain visual similarity. The packaging materials and labeling will be designed to be indistinguishable between the two groups. In addition, all outcome assessments and data collection procedures will be performed by personnel who are blinded to the treatments.

The participants will be supplemented with 5 capsules per day of a placebo-filled gelatin capsule and will perform aerobic type exercise training three times per week, on non-consecutive days, with a total time of 20-60 minutes per day.

The participants will be supplemented with 5 capsules per day of Omega UP (Newscience, Chile) equivalent to 2.5 g/d of DHA and 0.5 g/d of EPA.

The participants will be supplemented with 5 capsules per day of Omega UP (Newscience, Chile) equivalent to 2.5 g/d of DHA and 0.5 g/d of EPA and will perform aerobic type exercise training three times per week, on non-consecutive days, with a total time of 20-60 minutes per day.

The participants will be supplemented with 5 capsules per day of a placebo-filled gelatin capsule for 16 weeks.

The participants will be supplemented with 5 capsules per day of Omega UP (Newscience, Chile) equivalent to 2.5 g/d of DHA and 0.5 g/d of EPA for 16 weeks.

The participants will perform aerobic-type exercise training three times per week, on non-consecutive days, with a total time of 20-60 minutes per day for 16 weeks.

The participant starts in a seated position, stands up upon command, walks 3 meters, turns around, walks back to the chair, and sits down. The time stops when the subject is seated

Evaluates lower extremity functional performance using timed measures of standing balance, a 4-meter walk, and five repetitive chair stands

Incremental cycling test to exhaustion using a recumbent cycle ergometer to measure aerobic capacity.

Dietary record using image-assisted method over three days (two consecutive weekdays and one weekend day)

Real-time PCR will be carried out to quantify the changes in the expression of genes associated with inflammatory pathways and oxylipin synthesis

Quantitative extraction of total lipids from erythrocytes, plasma, and synovial fluid will be carried out.

Inclusion Criteria: Patients with rheumatoid arthritis with moderate disease activity as defined by the Disease Activity Score 28 (DAS28) > 2.6 and < 5.1. Participants taking nonsteroidal anti-inflammatory drugs (NSAIDs), glucocorticoids, or disease-modifying anti-rheumatic drugs (DMARDs) will be eligible; however, the dosages of these agents must be constant at least four weeks before, must remain within this limit throughout the study, and prednisone dose should not be higher than 7.5 mg/d Exclusion Criteria: Individuals diagnosed with gastrointestinal or metabolic diseases, regular alcohol abuse, smokers, and dietary supplement intake (e.g., fish oil capsules) or consumption of fish > 2 times per week. Individuals that perform regular aerobic exercise (> 150 min moderate intensity per week) or have any physical or biomechanical limitations to complete the exercise program Individuals that present blood levels of aspartate aminotransferase, alanine transaminase, or creatinine higher than 1.5 times the maximum normal limit and total bilirubin levels of more than 1.8 mg/dL