Effects of 12-week Aerobic Exercise on Arterial Stiffness, Inflammation, and Cardiorespiratory Fitness in Women with Systemic LUPUS Erythematosus: Non-Randomized Controlled Trial

This study assessed the effect of 12-week aerobic exercise on arterial stiffness (primary outcome), inflammation, oxidative stress, and cardiorespiratory fitness (secondary outcomes) in women with systemic lupus erythematosus (SLE). In a non-randomized clinical trial, 58 women with SLE were assigned to either aerobic exercise (n = 26) or usual care (n = 32). The intervention comprised 12 weeks of aerobic exercise (2 sessions × 75 min/week) between 40–75% of the individual’s heart rate reserve. At baseline and at week 12, arterial stiffness was assessed through pulse wave velocity (PWV), inflammatory (i.e., high-sensitivity C-reactive protein [hsCRP], tumor necrosis factor alpha [TFN-α], and inteleukin 6 [IL-6]) and oxidative stress (i.e., myeloperoxidase [MPO]) markers were obtained from blood samples, and cardiorespiratory fitness was assessed (Bruce test). There were no between-group differences in the changes in arterial stiffness (median PWV difference −0.034, 95% CI −0.42 to 0.36 m/s; p = 0.860) or hsCRP, TNF-α, IL-6, and MPO (all p > 0.05) at week 12. In comparison to the control group, the exercise group significantly increased cardiorespiratory fitness (median difference 2.26 minutes, 95% CI 0.98 to 3.55; p = 0.001). These results suggest that 12 weeks of progressive treadmill aerobic exercise increases cardiorespiratory fitness without exacerbating arterial stiffness, inflammation, or oxidative stress in women with SLE.


Introduction
Background 2 Scientific background and explanation of rationale 1-2 Theories used in designing behavioral interventions 2

Participants 3
Eligibility criteria for participants, including criteria at different levels in recruitment/sampling plan (e.g., cities, clinics, subjects) 3 Method of recruitment (e.g., referral, self-selection), including the sampling method if a systematic sampling plan was implemented 3

Recruitment setting 3
Settings and locations where the data were collected 3 Interventions 4 Details of the interventions intended for each study condition and how and when they were actually administered, specifically including: 3-5 Methods used to collect data and any methods used to enhance the quality of measurements 5-6 Information on validated instruments such as psychometric and biometric properties 5-6 Sample Size 7 How sample size was determined and, when applicable, explanation of any interim analyses and stopping rules 6 Assignment Method 8 Unit of assignment (the unit being assigned to study condition, e.g., individual, group, community) 7 Method used to assign units to study conditions, including details of any restriction (e.g., blocking, stratification, minimization) 7 Inclusion of aspects employed to help minimize potential bias induced due to non-randomization (e.g., matching) 7 Blinding (masking) 9 Whether or not participants, those administering the interventions, and those assessing the outcomes were blinded to study condition assignment; if so, statement regarding how the blinding was accomplished and how it was assessed.

7
Unit of Analysis 10 Description of the smallest unit that is being analyzed to assess intervention effects (e.g., individual, group, or community) 7 If the unit of analysis differs from the unit of assignment, the analytical method used to account for this (e.g., adjusting the standard error estimates by the design effect or using multilevel analysis) n/a

Statistical Methods 11
Statistical methods used to compare study groups for primary methods outcome(s), including complex methods of correlated data 7 Statistical methods used for additional analyses, such as a subgroup analyses and adjusted analysis 7 Methods for imputing missing data, if used 7 Statistical software or programs used 7

Participant flow 12
Flow of participants through each stage of the study: enrollment, assignment, allocation, and intervention exposure, follow-up, analysis (a diagram is strongly recommended) 8 o Enrollment: the numbers of participants screened for eligibility, found to be eligible or not eligible, declined to be enrolled, and enrolled in the study 8 o Assignment: the numbers of participants assigned to a study condition 8 o Allocation and intervention exposure: the number of participants assigned to each study condition and the number of participants who received each intervention 8 o Follow-up: the number of participants who completed the follow-up or did not complete the follow-up (i.e., lost to follow-up), by study condition 8 o Analysis: the number of participants included in or excluded from the main analysis, by study condition 8 Description of protocol deviations from study as planned, along with reasons 3, 5

Recruitment 13
Dates defining the periods of recruitment and follow-up 3

Baseline Data 14
Baseline demographic and clinical characteristics of participants in each study condition 7, 9 Baseline characteristics for each study condition relevant to specific disease prevention research 7, 9 Baseline comparisons of those lost to follow-up and those retained, overall and by study condition -Comparison between study population at baseline and target population of interest 7, 9 Baseline equivalence 15 Data on study group equivalence at baseline and statistical methods used to control for baseline differences 7 Numbers analyzed 16 Number of participants (denominator) included in each analysis for each study condition, particularly when the denominators change for different outcomes; statement of the results in absolute numbers when feasible Tables 3,  4, S3, S4, Fig. 2 Indication of whether the analysis strategy was "intention to treat" or, if not, description of how noncompliers were treated in the analyses 7, Tables 3, 4, S3, S4, Fig. 1 Outcomes and estimation 17 For each primary and secondary outcome, a summary of results for each estimation study condition, and the estimated effect size and a confidence interval to indicate the precision Tables 3,  4, S3, S4, Fig. 2 Inclusion of null and negative findings 10-17 Inclusion of results from testing pre-specified causal pathways through which the intervention was intended to operate, if any n/a Ancillary analyses 18 Summary of other analyses performed, including subgroup or restricted analyses, indicating which are pre-specified or exploratory n/a

Adverse events 19
Summary of all important adverse events or unintended effects in each study condition (including summary measures, effect size estimates, and confidence intervals) 7

Interpretation 20
Interpretation of the results, taking into account study hypotheses, sources of potential bias, imprecision of measures, multiplicative analyses, and other limitations or weaknesses of the study 12-13 Discussion of results taking into account the mechanism by which the intervention was intended to work (causal pathways) or alternative mechanisms or explanations 12-13 Discussion of the success of and barriers to implementing the intervention, fidelity of implementation 13 Discussion of research, programmatic, or policy implications 13 Generalizability 21 Generalizability (external validity) of the trial findings, taking into account the study population, the characteristics of the intervention, length of follow-up, incentives, compliance rates, specific sites/settings involved in the study, and other contextual issues  Describe the extent to which the intervention was delivered as planned Page 5 Table S3. Per-protocol analyses assessing the effects of 12-week progressive aerobic exercise on arterial stiffness, inflammation, oxidative stress, and cardiorespiratory fitness in women with systemic lupus erythematosus (participants in the exercise group were included if attendance ≥90%). The analyses were adjusted for baseline values, resting heart rate and changes in self-reported physical activity during the study period. SE, standard error; CI, confidence interval; PWV, pulse wave velocity; hsCRP, high sensitivity C-reactive protein; TNF-α, tumor necrosis factor alpha; IL-6, interleukin-6; MPO, myeloperoxidase. The analyses were adjusted for baseline values, resting heart rate, and changes in self-reported physical activity during the study period. SE, standard error; CI, confidence interval; PWV, pulse wave velocity; hsCRP, high sensitivity C-reactive protein; TNF-α, tumor necrosis factor alpha; IL-6, interleukin-6; MPO, myeloperoxidase. Figure S1. Summary of objective (i.e., heart rate) exercise intensity, session rating of perceived exertion (RPE), and (pre-and post-session) positive affect (feeling scale) during each session of the exercise program. Bpm, beats per minute.