Acute Response to Exercise in Patients With Rheumatoid Arthritis

Study Overview
=================
Brief Summary
-----------------
Rheumatoid arthritis (RA) is a chronic inflammatory disease that affects the joints, causing pain, edema, physical disability and poor quality of life. In addition, RA patients are at increased risk of developing cardiovascular disease (CVD) and premature death. The most effective pharmacological treatment is the use of biological agents that inhibit the action of specific substances, such as interleukin 6 (IL-6) and tumor necrosis factors (TNF). Physical exercise is considered a first-line non-pharmacological treatment in RA, improving inflammatory and metabolic profile, functional capacity, fatigue and preventing the onset of CVD. There is evidence that IL-6, when secreted as a result of exercise, brings several benefits. However, there is no study investigating the interaction between biological IL-6 blocking agents and exercise on metabolic responses, such as insulin sensitivity and glucose uptake, in patients with RA. To answer this question, adult women diagnosed with RA and healthy controls will be recruited for an acute session of exercise. RA patients will be divided into 2 groups, according to the pharmacological treatment (tocilizumab or anti-TNF). The acute responses of insulin sensitivity after an acute session of exercise will be assessed by the hyperinsulinemic euglycemic clamp, and the molecular pathways will be assessed by muscle biopsy and gene and protein expression analysis. Positron emission tomography-magnetic resonance imaging (PET/MRI) will be performed to quantify skeletal muscle glucose uptake.

Official Title
-----------------
Impact of Interleukin-6 Receptor Blockade on Acute Response to Exercise on Insulin Sensitivity and Muscle Glucose Uptake in Patients With Rheumatoid Arthritis

Conditions
-----------------
Rheumatoid Arthritis

Intervention / Treatment
-----------------
* Behavioral: Exercise


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Adult women diagnosed with rheumatoid arthritis under pharmacological treatment, for at least 6 months, with a monoclonal antibody against the interleukin-6 receptor or TNF-alpha inhibitors; Stable dose of monoclonal antibody against the interleukin-6 receptor or TNF-alpha inhibitors in the previous 3 months; Exclusion Criteria: Any physical limitation or disability that preclude exercise participation; Participation in a structured exercise program in the previous 12 months;

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: RA patients will be divided into 2 groups, according to the pharmacological treatment (tocilizumab or anti-TNF). A third group will be composed by healthy controls. The acute responses of insulin sensitivity after an acute session of exercise will be assessed by the hyperinsulinemic euglycemic clamp, and the molecular pathways will be assessed by muscle biopsy and gene and protein expression analysis. Positron emission tomography-magnetic resonance imaging (PET/MRI) will be performed to quantify skeletal muscle glucose uptake.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: IL-6 blockade<br>RA patients under pharmacological treatment with interleukin-6 blockade. | Behavioral: Exercise<br>* Thirty minutes of aerobic exercise in a treadmill.<br>|
| Experimental: Anti-TNF-alpha<br>RA patients under pharmacological treatment with anti-TNF-alpha. | Behavioral: Exercise<br>* Thirty minutes of aerobic exercise in a treadmill.<br>|
| Experimental: Healthy controls<br>Healthy participants. | Behavioral: Exercise<br>* Thirty minutes of aerobic exercise in a treadmill.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Insulin sensitivity | Acute effect of exercise on insulin sensitivity assessed by the hyperinsulinemic euglycemic clamp. | 1 hour post-exercise | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Insulin sensitivity-related molecular pathway (Western Blotting) | Insulin sensitivity-related molecular pathway will be assessed by Western Blotting. | Baseline and 4 hours post-exercise | 
| Insulin sensitivity-related molecular pathway (RT-PCR) | Insulin sensitivity-related molecular pathway will be assessed by Real-Time Polymerase Chain Reaction (RT-PCR). | Baseline and 4 hours post-exercise | 
| Skeletal muscle glucose uptake | Positron emission tomography-magnetic resonance imaging (PET/MRI) will be performed to quantify skeletal muscle glucose uptake. | 3 hours post-exercise |