Aerobic Exercise Program Followed by Cold Water Immersion: Effects on Arthritis Patients Arterial Stiffness

The first visit or selection visit, will be the opportunity for the investigator to submit the Information Notice and Informed Consent about. A second visit or visit of inclusion will be the occasion of the return of the signed informed consent of the subject. This visit will include a clinical examination for the detection of a pathology likely to contraindicate the practice of a physical activity and a resting electrocardiogram. The investigator will record the data for each subject, and check the eligibility criteria. Patient's treatments will not be interrupted throughout the program.

The typical rehabilitation sessions will be performed according to the intermittent exercise followed by a cold water immersion recovery at 17 ° Celsius for 15 minutes. The total duration of the rehabilitation session will be approximately 50 minutes and the sessions should be separated by at least 48 hours with a frequency of 3 sessions per week by 6 weeks, totalizing 17 sessions.

The typical sessions will be conducted as follows: intermittent exercise on a cycle ergometer for 30 minutes in sub-maximal intensity; application of the BORG scale; immersion in cold water at 17 ° C for 15 minutes and application of the cold water tolerance scale. The subject's heart rate will be recorded continuously for the duration of the sessions by a heart rate monitor (Polar Electro, Finland).

Intermittent exercise consists of six 5-minute cycles with a succession of work (high: 1 minute, moderate: 4 minutes). The high intensity work phase will be adjusted to achieve a target Heart Rate (HR) corresponding to HR rest + 70% HR reserve (HR reserve = (200 - age) - HR rest). The low intensity work phase will be adjusted to achieve a maximum target HR corresponding to HR rest + 50% HR reserve. In total, the exercise has a sub maximal intensity, commonly used in exercise rehabilitation studies conducted on various pathologies. It is an intensity capable of promoting cardiovascular benefits without representing a severe intensity for the patient.

The target intensity for intermittent work is controlled by monitoring the HR. To achieve the desired , patients will be asked to adjust their pedaling frequency. The patient therefore adapts his pedaling frequency in accordance with the target HR to switch from one workload to another. During the rehab sessions, the wattage and pedaling frequency will be recorded. The cycloergometer used will be of the brand Monark (type 839E).

Measurements will be made before, in the middle and at the end of the program (before 1st, 10th and after 17th session (S1, S10 \& S17). These examinations are commonly performed in the follow-up of rheumatoid arthritis:

1. / The blood sample will be taken at the elbow crease by a clinical research nurse. There will be a total of three blood samples of approximately 7 mL of blood for subjects who are doing the entire program and only two blood tests for other subjects. Venous blood samples will be used to determine serum marker concentrations of C-reactive protein inflammation. The investigators will also perform the assay of two other blood markers of IL-6 inflammation and TNF-alpha classically used in the clinical follow-up of this kind of patient.
2. / The clinical examinations will consist in the evaluation of the DAS-28 as well as an ultrasound of the joints. The Disease Activity Score (DAS) and its derivatives have been developed and validated by Dutch authors and considered the best test for the RA classification by the European League Against Rheumatism (EULAR). Several studies have shown that there is a very good correlation between the evaluation of RA activity on only 28 joints compared to 44 or 66. DAS-28 includes pain rating for joint pressure and joint swelling on the proximal interphalangeal (PPI), metacarpophalangeal (MCP) joints of the hands, wrists, elbows, shoulders, and knees. DAS-28 has the advantage of being more quickly achieved and of not rating rare joints such as distal interphalangeal or temporomandibular. It is however often criticized because it does not evaluate the joints of the feet which are on the contrary very frequently painful or inflammatory in this disease. Nevertheless, DAS-28 is currently the most frequently used score for the assessment of RA activity, whether in clinical studies or in routine practice. The articular ultrasound will be performed with an ESAOTE mylab five device on 32 joints of the hands, wrists and feet using a qualitative synovitic score in B mode and Doppler mode, each rated from 0 to 32, for a total score ranging from 0 to 64.
3. / The assessment of functional disability, physical activity and quality of life and well-being will be done using questionnaires: HAQ, SQUASH and SF-36. The Health Assessment Questionnaire (HAQ) is a tool to measure specific functional disability for rheumatoid arthritis. The evaluation covers 8 areas of daily activity. Four types of answers are possible: a score of 0 to 3, where "0" means the absence of disability, while a score of "3" corresponds to a maximum disability. The Short Questionnaire to Assess Helath Enhancing Physical Activity (SQUASH) is a questionnaire that assesses average energy expenditure over a week. The questions are grouped into four different themes: commuting activities (going back and forth between home and work / study), leisure activities, home activities, work activity. For each type of activity, it is therefore required to indicate the average time spent per day, the number of days per week and the intensity of effort felt among three possible choices (calm, moderate and intense). The set of reported activities is calculated by multiplying the average time (in minutes) for an activity by its intensity coefficient corresponding to MET intervals. All activity scores are then summed to give the total score. The short-form 36 (SF-36) will be used to assess the quality of life and well-being. The SF-36 consists of 36 items, 35 of which are grouped into 8 multi-item scales that measure physical functioning, physical role, body pain, general health, vitality, social functioning, emotional role and mental health. The 8 SF-36 scales are scored on a scale of 0-100, with higher scores indicating a better quality of life. During the first session (S1), the target intensity is controlled by monitoring the heart rate as described above. The wattage and pedaling frequency achieved during the first session (S1) will be reproduced for the other series of measurements (S9 and S17). The measurements will be carried out at the first session of the protocol (S1) and then every 3 rehabilitation sessions (S5, S9, S13 and S17). These sessions will have a total duration of approximately 75 minutes.

• (Before exercise) rest extended by 15 minutes; a first evaluation (arterial pressures, elasticity of large and small arteries and the velocity of the radial and distal pulse wave, cutaneous temperature, etc.) of about 7 minutes in the extended position.
• (After the exercise) second elongated evaluation identical to the previous evaluation. The time between the end of the exercise and the start of the measurement will be controlled and identical for all subjects and measurement series.
• (After immersion) Third evaluation in lying position identical to the previous evaluation. The time between the end of the immersion and the start of the measurement will be controlled and identical for all subjects and measurements. The measurements:

1. / Assessment of arterial stiffness will be performed by analyzing the pressure wave (a) and measuring the velocity of the pulse wave (b). a / HDI Pulse WaveTM CR-2000 tonometry device (HDI Hyperdiagnostics Inc., Eagan, Minnesota, USA): measurement of brachial arterial pressures and assessment of compliance of large and small arteries. This device records the shape of the pulse wave at the level of the radial artery using a sensor placed on the wrist (non-invasive measurement): the analysis of the shape of this wave makes it possible to obtain information on the compliance blood. The sensor will be positioned at the radial site used for VOP measurement. The HDI device includes a brachial cuff that makes it possible to measure arterial pressures simultaneously with the measurement of arterial stiffness. The systolic and diastolic blood pressure values will be collected at each resting phase. b / The assessment of central arterial stiffness will be performed by measuring the pulse wave velocity on the carotid-femoral segment. The evaluation of the arterial stiffness of the territories concerned (legs) or not (arms) by the exercises, will be carried out by the respective measurements of the pulse wave velocity on the carotid-distal and carotid-radial segments. These evaluations are carried out using the complior system (Complior SP®, Artech Medical, Pantin, France).
2. / The skin temperature at the level of the thigh and the arm using a probe for recording the skin temperature: probes MLT409 / A Skin Temperature Probe (transducer ML309 Thermistor Pod - ADInstruments ) fixed on the skin by a hypoallergenic adhesive.
3. / At the end of each exercise, the subject is called to refer to the perception scale Borg, 1998: it goes from 6 to 20 points (where 6 means: "No effort" and 20: "maximum effort" ), and to indicate to the operator the number that corresponds best to the perception of his effort. The Borg Scale provides information on the subject's subjective perception of different parameters, such as stress or pain.
4. / The perception of cold water tolerance will be evaluated with the aid of a visual analogue scale (0-100 mm), at the first, fifth, tenth and fifteenth minute of submerged recovery.

The patient can stop his participation at any time without justification and can ask all the information he wants to the investigator or the operator. In case of exacerbation of the disease in relation to the results of the DAS-28 scale, the patient will leave the study.

The study may be stopped by decision of the competent administrative authority, the sponsor, the coordinating investigator.

Each patient will be able to leave the study by decision of one of these parties but also by decision of a co-investigator or by decision of the interested person himself, according to the regulation and as it is mentioned in the consent .