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Keywords:

  • Fatigue;
  • Systemic lupus erythematosus;
  • Physical function;
  • Exercise;
  • Maximal oxygen consumption

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. Acknowledgements
  9. REFERENCES

Objective

Patients with systemic lupus erythematosus (SLE) have poor physical fitness as measured by maximal oxygen uptake (VO2max), which is associated with disability and fatigue. The purpose of this study was to validate, in this population, the Siconolfi Step Test (SST) developed to predict VO2max in healthy individuals.

Methods

Thirty patients with well-controlled SLE were tested on a cycle ergometer until volitional exhaustion, and 25 women and 4 men (mean ± SD age 48 ± 14 years, weight 71.5 ± 13.7 kg) fulfilled the criteria for maximal effort. VO2max measured during this incremental test was compared with VO2max predicted by the SST using Bland and Altman 95% limits of agreement (LOA) and intraclass correlation coefficient (ICC). The SST was repeated twice to assess its reliability.

Results

The ICC between predicted and measured VO2max (mean ± SD 1.67 ± 0.41 liters/minute versus 1.57 ± 0.39 liters/minute) was moderately high (0.73, P < 0.001). Bland and Altman analysis revealed a trend for a positive bias (P = 0.083) and 95% LOA of ±0.58 liters/minute. There was a very high ICC (0.97, P < 0.001) between VO2max predicted by the first and second SST (mean ± SD 1.66 ± 0.40 liters/minute versus 1.67 ± 0.41 liters/minute), and no significant bias (P = 0.500). The 95% LOA were ±0.20 liters/minute.

Conclusion

The results demonstrate that the SST is well tolerated, reasonably valid, and highly reliable in patients with well-controlled SLE. Therefore, this simple, submaximal exercise test might be useful for assessing physical fitness in clinical practice and epidemiologic studies.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. Acknowledgements
  9. REFERENCES

Patients with systemic lupus erythematosus (SLE) have poor physical fitness as measured by maximal oxygen uptake (VO2max), which ranges between 17.4 ml/kg/minute and 23.1 ml/kg/minute (1–3). Reduced VO2max is an important predictor of physical disability in patients with SLE (1) and correlates significantly with the symptom of fatigue (2). Therefore, routine assessment of physical fitness in clinical practice might be useful to identify and monitor patients with SLE who would benefit from aerobic exercise training programs to improve exercise tolerance and fatigue (4). A simple measure of VO2max would also be useful for epidemiologic studies on coronary heart disease (CHD) in patients with SLE because the contribution of poor physical fitness to increased cardiac risk in this population is currently unknown and is likely to be substantial (5). Unfortunately, direct measurements of VO2max during incremental exercise tests require expensive equipment, well-trained personnel, and maximal effort from the patient. A more practical alternative to maximal exercise tests is the use of prediction equations based on 1) the relationship between heart rate (HR), VO2, and workload during steady-state submaximal exercise, and 2) age-predicted maximum HR (6). To our knowledge, only one such submaximal exercise test has been validated in patients with rheumatic diseases (7). This test consists of walking at a self-selected pace for 2 periods of 4 minutes at 0% and 5% incline. However, only 5 of the 30 patients involved in that study had SLE. Therefore, the validity of this predictive test remains uncertain in this specific population. Moreover, this test requires a motorized treadmill, which might limit the applicability of this submaximal walking test in clinical practice and epidemiologic studies. Therefore, the goal of the present study was to assess the validity and reliability of the Siconolfi Step Test (SST), originally developed in healthy individuals (8), to predict VO2max in patients with SLE. This test is submaximal, very short (3–9 minutes of exercise), and does not require expensive and bulky equipment or highly trained personnel. However, predictive exercise tests tend to be population specific and cross-validation in a group of patients with SLE is required before the SST can be used in this population.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. Acknowledgements
  9. REFERENCES

Patients.

Thirty adults with SLE who were willing to take part in the study and were able to give written informed consent were recruited for this criterion validity study. All patients had to fulfill the American College of Rheumatology 1997 revised criteria for SLE (9). Patients were excluded if they had severe cardiopulmonary pathology, history of ischemic heart disease, severe myositis, active nephritis, active neurologic disease, or pregnancy. Clearance for participation in the study was given by consultant rheumatologists from the rheumatology departments in Ysbyty Gwynedd, Ysbyty Glan Clwyd, and Maelor Wrexham Hospital. The study was approved by the North West Wales Local Research Ethics Committee.

Exercise tests and procedures.

All participants attended 2 testing sessions in the physiology laboratory of the School of Sport, Health and Exercise Sciences, University of Wales-Bangor. These 2 visits were separated by 1–2 weeks and were scheduled for the same time of the day. Participants were instructed to avoid any strenuous activity for 24 hours prior to testing and to avoid a heavy meal, caffeine, or nicotine within 3 hours of testing. In the first visit, patients' height and weight were measured using standard equipment and procedures and body mass index was calculated as weight in kg/height in m2. Hemoglobin concentration was also measured (B-hemoglobin; Hemocue AB, Ängelholm, Sweden). After this evaluation, patients performed the SST described in detail elsewhere (8). Briefly, patients were required to step up and down a portable 10-inch bench for 3 minutes at a rate of 17 steps per minute, which was kept constant with the help of a metronome. HR was monitored continuously during the test by telemetry (model S810; Polar, Kempele, Finland) and was recorded at the end of the stage. If target HR (65% of the predicted [220 minus age] maximum HR) was reached, the protocol was terminated. Otherwise, a second stage (26 steps per minute) and, eventually, a third stage (34 steps per minute) were completed with 1 minute of rest between each stage. The steady-state absolute VO2 at each stage was calculated according to the following equations (8):

  • equation image

Then, each patient's uncorrected VO2max was estimated using the mathematical version of the original Astrand-Ryhming nomogram (10) developed by Steven Siconolfi (personal communication):

  • equation image

where %VO2max is calculated as (0.769 × stage HR) – 48.5 for men and (0.667 × stage HR) – 42 for women. Alternatively, the uncorrected VO2max can be predicted using the original graphic version of the Astrand-Ryhming nomogram (10).

Finally, the uncorrected VO2max calculated from the above equations was entered in the following equations developed by Siconolfi et al (8) to predict VO2max according to age and sex:

  • equation image
  • equation image

At the end of this first testing session, patients were familiarized with the maximal exercise test to be performed in the second visit.

On the second testing session, participants repeated the SST and, after a minimum of 30 minutes of rest, performed an incremental exercise test on a cycle ergometer (874E, Monark, Vansbro, Sweden) keeping a constant pedaling rate of 50 revolutions per minute. This protocol consisted of 2 minutes with no resistance followed by increments of 25W every 2 minutes until volitional exhaustion. Throughout the test, expired gases and flow were analyzed breath by breath using an automated system (600Ergo Test; ZAN Messgeräte, Oberthulba, Germany) from which VO2 and carbon dioxide production (VCO2) were calculated and averaged every 30 seconds. The highest VO2 recorded during the test (our criterion measure) was considered to be maximal when the criteria used in the original validation study by Siconolfi et al (8) were met. These criteria were 1) a plateau defined as a difference <0.25 liters/minute between the 2 final VO2 measurements obtained every 30 seconds, and 2) a respiratory quotient (VCO2/VO2) for the last measurement ≥1.0.

When describing patient characteristics, VO2max values are reported relative to body mass (ml/kg/minute) because this is the measure of physical fitness commonly used for comparative purposes. For validity and reliability analyses, however, we used absolute VO2max values (liters/minute) because these are the values directly measured by the automated breath-by-breath analysis system and predicted by the equations developed by Siconolfi et al (8).

Clinical measures.

Disease activity was assessed using the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and damage was assessed by the Systemic Lupus International Collaborating Clinics (SLICC) damage index. These measures were completed by each patient's consultant rheumatologist within a maximum of 3 weeks from exercise testing. Fatigue was self-assessed by the patients using the Fatigue Severity Scale previously validated in SLE (11).

Statistical analysis.

Data are reported as the mean ± SD for normally distributed variables; otherwise, data are reported as the median (interquartile range). The criterion validity of VO2max predicted from the SST was assessed using the 95% limits of agreement (LOA) by Bland and Altman (12), paired t-test, and intraclass correlation coefficient (ICC) against VO2max measured during the cycling test. Standard error of the estimate (SEE) was also calculated. Reliability of predicted VO2max was assessed using 95% LOA, paired t-test, and ICC between the first and second visit SST. Coefficient of variation (CV) was also calculated. For validity and reliability, 2-way, mixed-effects, single-measure models of ICC were used. For validity, methods of VO2max assessment (measured during the cycling test versus predicted from the SST) were a fixed effect whereas the participants were a random effect. For reliability, the first and second visit SST were a fixed effect whereas the participants were a random effect. Significance level was set at 0.05 for all analyses.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. Acknowledgements
  9. REFERENCES

Patient characteristics.

Thirty patients (26 women, 4 men) were recruited and performed all exercise tests. One female patient was excluded after failing to meet the criteria for the attainment of VO2max during the cycling test, leaving 29 patients for analysis. The characteristics of these patients are presented in Table 1. This group of patients had low disease activity (SLEDAI scores ranging from 0 to 4 with 75% of patients scoring 0) and very little disease damage (SLICC scores ranging from 0 to 1 with 88% of patients scoring 0), and were not anemic and only slightly overweight. However, patients had poor physical fitness and disabling fatigue. As expected, male patients had higher measured and predicted VO2max (mean ± SD 24.5 ± 3.1 ml/kg/minute versus 26.9 ± 6.4 ml/kg/minute) compared with female patients (mean ± SD 22.1 ± 6.3 ml/kg/minute versus 23.2 ± 5.1 ml/kg/minute). Similarly, premenopausal women (n = 10, mean ± SD age 33 ± 8 years) had higher measured and predicted VO2max (mean ± SD 23.7 ± 5.9 ml/kg/minute versus 24.7 ± 4.1 ml/kg/minute) compared with postmenopausal women (n = 15, mean ± SD age 57 ± 9 years, mean ± SD measured and predicted VO2max 21.0 ± 6.5 ml/kg/minute versus 22.2 ± 5.5 ml/kg/minute).

Table 1. Characteristics of the patients with systemic lupus erythematosus (25 women and 4 men) included in the analysis*
CharacteristicValue
  • *

    Values are the mean ± SD unless otherwise indicated. BMI = body mass index; VO2max = maximal oxygen uptake; SLEDAI = Systemic Lupus Erythematosus Disease Activity Index; IQR = interquartile range; SLICC = Systemic Lupus International Collaborating Clinics.

  • These variables are not normally distributed and therefore are expressed as median (IQR).

Age, years48 ± 14
Height, cm164 ± 9
Body mass, kg71.5 ± 13.7
BMI, kg/m226.5 ± 4.5
Hemoglobin, gm/dl13.1 ± 1.3
VO2max, ml/kg/minute 
 Measured22.4 ± 6.0
 Predicted23.7 ± 5.3
Disease duration, years10 ± 9
SLEDAI (0–105), median (IQR)0.0 (0.8)
SLICC damage score (0–46), median (IQR)0.0 (0.0)
Fatigue Severity Scale (1–7), median  (IQR)4.9 (1.2)

None of the patients were receiving beta-blockers at the time of exercise testing. Twelve patients were receiving oral prednisolone with daily dosages ranging between 2 and 10 mg (average dosage 6.5 mg/day). All patients completed the first stage of the SST, with only 3 patients requiring the completion of the second stage to reach their target HR. No patient required the third stage. No adverse event occurred during the study, and patients tolerated well both maximal and submaximal exercise testing.

Validity.

The scatterplot and Bland-Altman plot of VO2max predicted by the second visit SST (mean ± SD 1.67 ± 0.41 liters/minute) against the direct measurement of VO2max during the cycling test (1.57 ± 0.39 liters/minute) are shown in Figures 1 and 2, respectively. There was a moderately high ICC (0.73, P < 0.001) between predicted and measured VO2max and a trend for a positive bias (0.10 liters/minute, P = 0.083). The residuals in the Bland-Altman plot showed no evidence of significant heteroscedasticity. The 95% LOA were ±0.58 liters/minute, and SEE was 0.28 liters/minute. Very similar results were obtained when performing these analyses with the VO2max predicted by the first visit SST (data not shown), suggesting that a familiarization session is not required.

thumbnail image

Figure 1. Validity: scatterplot of maximal oxygen uptake (VO2max) predicted by the second visit Siconolfi Step Test against the direct measurement of VO2max during the cycling test. The diagonal line represents the identity line (slope = 1; intercept = 0).

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thumbnail image

Figure 2. Validity: Bland-Altman plot of maximal oxygen uptake (VO2max) predicted by the second visit Siconolfi Step Test against the direct measurement of VO2max during the cycling test. The solid line within the graph represents the bias, the broken lines represent the upper and lower 95% limits of agreement.

Download figure to PowerPoint

Reliability.

The scatterplot and Bland-Altman plot of VO2max predicted by the first and the second visit SST (mean ± SD 1.66 ± 0.40 liters/minute versus 1.67 ± 0.41 liters/minute) are shown in Figures 3 and 4, respectively. There was a very high ICC (0.97, P < 0.001) between VO2max predicted by the first and second visit SST and a nonsignificant negative bias (−0.01 liters/minute, P = 0.500). The residuals in the Bland-Altman plot showed no evidence of significant heteroscedasticity. The 95% LOA were ±0.20 liters/minute and the CV was 3.2%.

thumbnail image

Figure 3. Reliability: scatterplot of maximal oxygen uptake (VO2max) predicted by the first and second visit Siconolfi Step Test. The diagonal line represents the identity line (slope = 1; intercept = 0).

Download figure to PowerPoint

thumbnail image

Figure 4. Reliability: Bland-Altman plot of maximal oxygen uptake (VO2max) predicted by the first and second visit Siconolfi Step Test. The solid line within the graph represents the bias, the broken lines represent the upper and lower 95% limits of agreement.

Download figure to PowerPoint

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. Acknowledgements
  9. REFERENCES

The results of this study demonstrate that the SST is well tolerated, reasonably valid, and highly reliable in patients with well-controlled SLE. Although there was a trend (P = 0.083) for the SST to slightly overestimate the VO2max directly measured during the cycling test (0.10 liters/minute), this positive bias does not invalidate the SST because it is similar to the bias found by Siconolfi et al in healthy patients (8). The reason for this bias is likely to be the different exercise mode used for the estimation (stepping) and direct measurement (cycling) of VO2max. In fact, treadmill and step tests give similar values that are typically 5–11% higher than cycling tests (13–15). Alternatively, a reduction in measured VO2max might have been caused by fatigue induced by the first SST, which was performed in the same visit prior to the maximal bike test. However, the long rest period (≥30 minutes) between these 2 tests, and the moderate duration (3 minutes) and intensity (72% of maximum HR) of the SST argue against this possibility.

The validity of the SST is also supported by an ICC >0.70 between measured and predicted VO2max and the moderate SEE (0.28 liters/minute). This error is similar to that reported for other submaximal exercise tests in healthy individuals (6, 8). Furthermore, our results compare well with those of Minor and Johnson (7) who validated a submaximal walking test in patients with a variety of rheumatic diseases including SLE. Overall, the SST developed in healthy persons cross-validates well in patients with SLE and is well tolerated. However, participants in our study represent a subgroup of patients with SLE with well-controlled disease. Therefore, our results cannot be readily generalized to the full SLE population. Furthermore, even a 10-inch high step might present some difficulties to more disabled patients.

The attractiveness of the SST compared with the treadmill test validated by Minor and Johnson (7) is that the former requires much less expensive equipment that can be easily transported and stored away. These characteristics should favor its application in clinical practice and epidemiologic studies. Nevertheless, health professionals should be aware of the relatively high margin of error of the SST when predicting VO2max in individual patients as revealed by the wide 95% LOA (Figure 2). Therefore, the SST cannot be used when precise individual assessment of physical fitness is required.

The very high ICC, low CV, nonsignificant bias, and relatively narrow 95% LOA (Figure 4) demonstrate that the SST is highly reliable in patients with SLE. Again, these results compare well with reliability studies of other exercise tests (6) including that validated by Minor and Johnson (7). Because HR at a fixed submaximal workload is highly sensitive to changes in physical fitness, the SST might be used as an outcome measure in large multicenter trials of exercise therapy in patients with SLE (6). However, further longitudinal validation studies are necessary to confirm this hypothesis.

The importance of physical fitness assessment in SLE is underlined by the mean VO2max (22.4 ml/kg/minute) measured in our patients, which is similar to the mean VO2max found by Tench et al (23.1 ml/kg/minute) (1) and is slightly higher than the mean values found by Forte et al (17.4 ml/kg/minute) (3) and Keyser et al (19.2 ml/kg/minute) (2). These discrepancies might be due to the exercise mode used for testing, characteristics of patients recruited, and criteria for maximal effort. Regardless of these differences, all studies clearly demonstrate that physical fitness is poor in patients with SLE, including nonanemic, nonobese patients with well-controlled disease such as those included in our study. If we consider that moderate activities of daily living require up to 21 ml/kg/minute (2), it is no surprise that low VO2max contributes to physical disability and fatigue in SLE because patients are forced to use a high percentage of their functional reserve (1, 2). Furthermore, we calculated that only 26% of our cohort had a VO2max higher than 85% of the normal predicted value (5). This finding is clinically relevant given that women with an exercise capacity less than 85% of their predicted value have twice as high a risk of death from all causes (2.44 for cardiac disease) than women with a normal VO2max (5). Unfortunately, available epidemiologic studies on CHD in patients with SLE have focused on other traditional risk factors (e.g., high cholesterol) and inflammation (16), and have not included a measure of VO2max. Therefore, the contribution of reduced exercise capacity toward increased cardiac risk has yet to be determined in this population. Poor physical fitness is a highly modifiable risk factor for CHD, and we hope that the validation of a simple, inexpensive, submaximal exercise test to predict VO2max in patients with SLE will facilitate future research in this important area. The association between the HR response to exercise per se and mortality (17) also warrants further investigation in this population.

AUTHOR CONTRIBUTIONS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. Acknowledgements
  9. REFERENCES

Dr. Marcora had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study design. Marcora.

Acquisition of data. Casanova, Fortes, Maddison.

Analysis and interpretation of data. Casanova, Fortes, Maddison, Marcora.

Manuscript preparation. Casanova, Fortes, Marcora.

Statistical analysis. Casanova, Fortes, Marcora.

Study supervision. Maddison, Marcora.

Acknowledgements

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. Acknowledgements
  9. REFERENCES

We would like to thank Mrs. Catriona Clements and all other members of the North Wales Lupus UK Group involved in this study, and Mr. Andrea Bosio for his valuable assistance during exercise testing.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. Acknowledgements
  9. REFERENCES