Fatigue in systemic lupus erythematosus: a randomized controlled trial of exercise

C. M. Tench, J. McCarthy2, I. McCurdie3, P. D. White1 and D. P. D'Cruz

Bone and Joint Research Unit and
1 Department of Psychological Medicine, Barts and The London, Queen Mary's School of Medicine and Dentistry,
2 National Sports Medicine Institute and
3 Barts and The London NHS Trust, London, UK


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Objective. To test the efficacy of a graded aerobic exercise programme in treating fatigue in systemic lupus erythematosus.

Methods. Ninety-three patients with systemic lupus erythematosus without active disease in any major organ were randomized, using a minimization protocol, to 12 weeks of graded exercise therapy, relaxation therapy or no intervention.

Results. Analysis by intention to treat showed that 16 of the 33 (49%) patients in the exercise group rated themselves as ‘much’ or ‘very much’ better compared with eight out of 29 (28%) in the relaxation group and five out of 32 (16%) in the control group ({chi}2=8.3, df=2, P=0.02). Fatigue improved significantly on one out of three measures after exercise therapy and there was a trend for fatigue to improve on all measures after exercise.

Conclusion. These findings support the use of appropriately prescribed graded aerobic exercise in the management of patients with fatigue and systemic lupus erythematosus.

KEY WORDS: Fatigue, Exercise, SLE, Randomized controlled trial.


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patients with systemic lupus erythematosus (SLE) report greater fatigue than healthy sedentary controls [1], and this may be related to physical deconditioning, depression, poor sleep quality, disease activity, associated fibromyalgia or a combination of all five [28]. Physical deconditioning may be caused by reduced physical activity, and indeed some patient information leaflets recommend frequent periods of rest to cope with the fatigue of SLE. Graded exercise therapy provides physical and psychological benefits in a number of different conditions, including depression [9], fibromyalgia [10] and chronic fatigue syndrome [11]. However, there has been little research into the effects of exercise therapy on fatigue in SLE.

In a randomized trial we compared the physiological, symptomatic and functional changes associated with a 12-week programme of either aerobic exercise therapy or relaxation therapy or no intervention.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patients
Ninety-three female patients fulfilling the American College of Rheumatology (ACR) revised classification criteria for SLE [12, 13] were recruited to the study. Patients were excluded if they had evidence of active severe myositis, nephritis, neurological involvement or cardiac or pulmonary disease. Pregnant patients and patients under 16 or over 55 yr were also excluded. All patients had been on stable therapy for the previous 2 months (29 patients were taking <=7.5 mg prednisolone, 53 were taking hydroxychloroquine and 21 were taking azathioprine) and none of the patients exercised more than once per week. Thirty-one eligible patients declined to participate in the study. Ethical approval was obtained from the district research ethics committee and all subjects gave valid and informed consent before entering the study.

Power calculation
In a previous study of exercise therapy and fibromyalgia, 50% of patients considered themselves moderately improved by the treatment compared with 10% of controls receiving flexibility training [10]. By assuming similar treatment responses with {alpha}=0.05 and a power of 90%, we calculated that 30 subjects would be required for each group.

Methods
Symptomatic measures
Fatigue was measured with the Fatigue Severity Score (FSS) [14], the Chalder Fatigue Scale [15] and a visual analogue scale (VAS) [16]. Quality of sleep was assessed using the Pittsburgh Sleep Quality Index (PSQI) [17], functional status was measured using the Medical Outcomes Study Short-Form Health Survey (SF-36) [18] and anxious and depressed moods were assessed using the Hospital Anxiety and Depression scale (HAD) [19]. Disease activity was measured using the Systemic Lupus Activity Measure (SLAM) [20] and disease damage was measured using the Systemic Lupus International Collaborating Clinics (SLICC)/ACR Damage Index [21]. A single rheumatologist performed all assessments of disease activity and damage.

Physiological assessments
The physiological assessments have been described in detail in a previous study [1] and included peak oxygen consumption (VO2peak), maximum ventilation, maximum heart rate and recovery heart rate measured during a walking test carried out on a motor-driven treadmill, and body mass index.

Treatments
All 93 patients were randomly allocated to the exercise programme, the relaxation programme or to no intervention, using a minimization protocol [22].

Exercise group
The patients were asked to exercise at home at least three times a week for between 30 and 50 min for a period of 12 weeks at a heart rate corresponding to 60% of peak oxygen consumption. The main exercise was walking but patients were encouraged to take other forms of exercise, such as cycling and swimming, and were seen every 2 weeks for a supervised exercise session.

Relaxation group
The patients were asked to listen to a 30-min relaxation audiotape a minimum of three times a week in a darkened, warm and quiet room and were seen every 2 weeks for a supervised relaxation session.

No intervention group
The patients were asked to continue with their normal daily activity pattern and specifically asked to avoid doing any extra physical activities. They were reviewed at follow-up but not seen at other times.

Outcome measures
The main outcome measure was the self-rated clinical global impression change score, which is a validated measure of overall change compared with study onset. It has seven possible scores, from ‘very much worse’ (score 7) to ‘very much better’ (score 1) [23]. Secondary outcome measures included assessments of symptoms, functional capacity and fitness, as described above.

Follow-up
After 12 weeks all patients were reassessed as at baseline. Three months after stopping supervised treatment, patients were reassessed with respect to symptoms and disease activity.

Statistical analysis
Statistical analysis used the SPSS 10.0 for Windows software package (SPSS, Chicago, IL, USA). All patients who underwent random allocation were analysed according to group assignment. The clinical global impression change score was analysed categorically; a score of 1 or 2 was considered clinically important. We compared the proportions of patients rating themselves clinically improved by intention-to-treat analysis by means of {chi}2 analysis with Fisher's exact test for small numbers. One-way ANOVA (analysis of variance) with Bonferroni correction or the Kruskal–Wallis test was used to compare means and medians of each variable in the three groups as appropriate. All P values were two-tailed. We completed follow-up assessments at 12 weeks on eight of the 11 patients who dropped out of treatment and included these data in the intention-to-treat analysis. Patients with missing data were counted as non-improvers for the purpose of the clinical global change score, and for all other secondary outcomes the last available data point was used.


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Baseline data
The 93 patients had a mean age of 39 (S.E.M. 0.8) yr, a median disease duration of 30 (interquartile range 10–84) months, a median SLAM score of 5 (3–8) and a median SLICC/ACR Damage Index score of 0 (0–0). These patients thus had mild, relatively early disease with negligible organ damage. All the patients reported that fatigue was an important symptom at study entry. There were no significant differences between the groups at baseline for disease or patient characteristics, use of medication, or for symptomatic (Table 1Go) or physiological (Table 2Go) measures.


View this table:
[in this window]
[in a new window]
 
TABLE 1. Symptomatic measures in the three groups at baseline and after completing treatment

 

View this table:
[in this window]
[in a new window]
 
TABLE 2. Physiological variables in the three groups at baseline and after completing treatment

 

Treatment results
Table 3Go shows the main outcome of treatment. Sixteen of the 33 (49%) patients in the exercise group rated themselves as ‘much’ or ‘very much’ better compared with eight out of 29 (28%) in the relaxation group and five out of 32 (16%) in the control group ({chi}2=8.3, df=2, P=0.02).


View this table:
[in this window]
[in a new window]
 
TABLE 3. Self-rated clinical global impression change score at 12 weeks

 

At 12 weeks of treatment
After 12 weeks of treatment there was significant improvement in fatigue measured using the Chalder Fatigue Scale, but no significant differences between the groups for any of the other symptomatic measures (Table 1Go) or physiological measures (Table 2Go). There was, however, a significant increase in exercise duration in the exercise group [exercise group 1.7 min (0.6), relaxation group 0.2 (0.4), control group -0.3 (0.4), P=0.01; Bonferroni correction, exercise vs control group P=0.009, exercise vs relaxation group P=0.08].

Dropouts from therapy
Six patients in the exercise group (one with mild disease flare, one with back pain, one with worse fatigue and three too busy) and four in the relaxation group (two too busy, one did not like audio tape and one did not want to participate after randomization) dropped out of treatment (did not attend a single supervised exercise class or return any diary sheets), and one person in the control group unexpectedly left the country. Fourteen patients (five in the relaxation group, five in the control group and four in the exercise group) did not attend for the 12-week physiological assessment. Six of these 14 patients had dropped out of treatment and eight had completed the study but did not wish to repeat the walking test to exhaustion.

Compliance
The median (interquartile range) number of supervised sessions attended by those completing therapy was 5 (4–5) in the exercise group and 4 (2–5) in the relaxation group. The median number of home exercise sessions was 35 (25–40) and the median number home relaxation sessions was 33 (12–36), with a median duration of 30 min for each session.

At 3 months of follow-up
Eighty-three of the original 93 patients were reassessed 3 months after stopping supervised treatment. There was a significant difference in the SF-36 vitality scale between the groups [exercise group, mean (S.E.M.) 51 (4), relaxation group 41 (4), control group 34 (4), one-way ANOVA P=0.015; Bonferroni correction, exercise vs control group P=0.012, others not significant) and the SF-36 role physical scale [exercise group, median (interquartile range) 75 (0–100), relaxation group 0 (0–75), control group 25 (0–50), Kruskal–Wallis P=0.024], but no other significant differences in symptomatic measures, disease activity or damage. Eight of the 33 patients in the exercise group continued to exercise regularly. There was a significant difference at 3 months of follow-up in the VAS fatigue score and Chalder Fatigue Scale of the eight patients who continued to exercise compared with the 25 patients who did not [mean (S.E.M.) VAS, exercise group 195 (23) vs no exercise group 270 (14), P=0.01; median (interquartile range) Chalder Fatigue Scale, exercise group 11 (5–17) vs no exercise group 17 (12–26), P=0.05, FSS not significant].


    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Key findings
Graded exercise therapy leads to significantly greater overall improvement than relaxation therapy or no intervention using intention-to-treat analysis. There was a trend for the subsidiary outcome of fatigue to improve with exercise therapy, but this was significant on only one of the three fatigue measures. This may reflect insensitivity of the fatigue measures used or lack of statistical power to detect a change. Improvements in fatigue were not maintained at the 3-month follow-up, and this may be explained by the fact that only eight patients continued to exercise at the end of supervised therapy. The fact that those patients who continued to exercise after the intervention period had significantly lower fatigue scores compared with those who stopped exercising suggests it is the continuation of exercise that leads to a sustained improvement.

It is interesting that the SF-36 vitality and role physical scales showed significant improvements after exercise therapy at the 3-month follow-up. However, the fact that this was not seen the end of the 12-week intervention period suggests this may not be a reliable finding and may simply reflect sample attrition.

Exercise duration increased by 18% after exercise therapy compared with a 3% reduction in the no intervention group, but there was no significant change in aerobic fitness. This change in exercise duration is likely to be due to improved exercise tolerance and is important because improved exercise capacity may reflect improvements in physical disability. However, this was not supported by any significant changes in self-perceived measures of physical function. There was no flare in disease activity with exercise and there were no serious adverse events.

Comparison with other published studies
The overall improvement after exercise therapy in this study is very similar to the size of effect seen in chronic fatigue syndrome [11]. Similarly, the improvement in fatigue demonstrated in this study after exercise therapy is similar to the improvements seen in other published trials of exercise in SLE. Robb-Nicholson et al. studied 23 patients with SLE and showed a significant change in fatigue after 8 weeks of exercise therapy using a VAS, but no significant difference using the Profile of Mood States fatigue subscale [24]. The size of the effect was very similar, with a mean improvement in fatigue after exercise therapy of 64 on a 400-point scale compared with a mean improvement in fatigue of 61 in this study. Daltroy et al. randomized 37 patients with rheumatoid arthritis and 34 patients with SLE to either stationary bicycling at home for 12 weeks or to no intervention, and showed a significant improvement in fatigue after exercise therapy using the Profile of Mood States fatigue subscale (P=0.03) [25]. However, these results are difficult to interpret because they represent the combined data from both SLE and RA patients. In both these studies there was no flare in disease activity after exercise, which is reassuring.

The fact that aerobic fitness did not change after exercise therapy is surprising. Robb-Nicholson et al. found a 19% improvement in VO2peak after exercise therapy, although this just failed to reach significance, and a 12% improvement in exercise duration [24]. Patients with chronic fatigue syndrome have also been shown to increase their VO2peak by 13% after 12 weeks of exercise therapy [11] and healthy sedentary normal subjects by between 5 and 10% [26]. The fact that the patients in this study did not significantly increase their aerobic fitness probably reflects the relatively easy exercise programme they were given (only 90 min of exercise per week at its maximum and only 60% of vo2max level of intensity). In addition, poor compliance with therapy may have been a factor.

Limitations of this study
The limitations of this study include the fact that patients with very active disease or serious organ involvement were excluded by design and that 31 eligible patients declined to participate, mostly citing a lack of spare time due to family or work commitments. This limits the generalizability of the results, particularly to those with more end-organ damage.

Summary
These findings support the use of appropriately prescribed graded aerobic exercise in the management of fatigue in patients with SLE. Exercise can be safely prescribed without exacerbating disease activity and leads to overall improvement when compared with relaxation therapy or no intervention. Greater improvement probably requires more intensive and/or frequent exercise, and sustained improvement probably requires continued exercise after the formal supervised programme is over.


    Acknowledgments
 
The authors would like to thank Janice Thomas for her help with statistical advice, and Veronica Vleck and David Bentley for their help with exercise testing and running the aerobic fitness classes. CMT was funded by the Arthritis Research Campaign (TO519), the Joint Research Board of St Bartholomew's Hospital (XMKY) and the British Medical Association Doris Hillier Award.


    Notes
 
Correspondence to: C. M. Tench, Rheumatology Department, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK. E-mail: colin.tench3{at}which.net Back


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 

  1. Tench C, Bentley D, Vleck V, Ian McCurdie, White P, D'Cruz D. Aerobic fitness, fatigue, and physical disability in systemic lupus erythematosus. J Rheumatol 2002;29:474–81.[ISI][Medline]
  2. Tench CM, McCurdie I, White PD, D'Cruz DP. The prevalence and associations of fatigue in systemic lupus erythematosus. Rheumatology 2000;39:1249–54.[Abstract/Free Full Text]
  3. Krupp LB, LaRocca NG, Muir J, Steinberg AD. A study of fatigue in systemic lupus erythematosus. J Rheumatol 1990;17:1450–2.[ISI][Medline]
  4. Wysenbeek AJ, Leibovici L, Weinberger A, Guedj D. Fatigue in systemic lupus erythematosus. Prevalence and relation to disease expression. Br J Rheumatol 1993;32:633–5.[ISI][Medline]
  5. Zonana-Nacach A, Roseman JM, McGwin G Jr et al. Systemic lupus erythematosus in three ethnic groups. VI. Factors associated with fatigue within 5 years of criteria diagnosis. LUMINA Study Group. Lupus in Minority Populations: Nature vs Nurture. Lupus 2000;9:101–9.[ISI][Medline]
  6. McKinley PS, Ouellette SC, Winkel GH. The contributions of disease activity, sleep patterns, and depression to fatigue in systemic lupus erythematosus. A proposed model. Arthritis Rheum 1995;38:826–34.[ISI][Medline]
  7. Middleton GD, McFarlin JE, Lipsky PE. The prevalence and clinical impact of fibromyalgia in systemic lupus erythematosus. Arthritis Rheum 1994;37:1181–8.[ISI][Medline]
  8. Taylor J, Skan J, Erb N et al. Lupus patients with fatigue—is there a link with fibromyalgia syndrome? Rheumatology 2000;39:620–3.[Abstract/Free Full Text]
  9. Weyerer S, Kupfer B. Physical exercise and psychological health. Sports Med 1994;17:108–16.[ISI][Medline]
  10. McCain GA, Bell DA, Mai FM, Halliday PD. A controlled study of the effects of a supervised cardiovascular fitness training program on the manifestations of primary fibromyalgia. Arthritis Rheum 1988;31:1135–41.[ISI][Medline]
  11. Fulcher KY, White PD. Randomised controlled trial of graded exercise in patients with the chronic fatigue syndrome. Br Med J 1997;314:1647–52.[Abstract/Free Full Text]
  12. Tan EM, Cohen AS, Fries JF et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1982;25:1271–7.[ISI][Medline]
  13. Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1997;40:1725.[ISI][Medline]
  14. Krupp LB, LaRocca NG, Muir-Nash J, Steinberg AD. The fatigue severity scale. Application to patients with multiple sclerosis and systemic lupus erythematosus. Arch Neurol 1989;46:1121–3.[Abstract]
  15. Chalder T, Berelowitz G, Pawlikowska T et al. Development of a fatigue scale. J Psychosom Res 1993;37:147–53.[CrossRef][ISI][Medline]
  16. White PD, Grover SA, Kangro HO, Thomas JM, Amess J, Clare AW. The validity and reliability of the fatigue syndrome that follows glandular fever. Psychol Med 1995;25:917–24.[ISI][Medline]
  17. Buysse DJ, Reynolds CF 3rd, Monk TH, Berman SR, Kupfer DJ. The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research. Psychiatry Res 1989;28:193–213.[CrossRef][ISI][Medline]
  18. Ware JE, Sherbourne CD. The MOS 36-item short-form health survey (SF-36). I. Conceptual framework and item selection. Med Care 1992;30:473–83.[ISI][Medline]
  19. Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand 1983;67:361–70.[ISI][Medline]
  20. Liang MH, Socher SA, Larson MG, Schur PH. Reliability and validity of six systems for the clinical assessment of disease activity in systemic lupus erythematosus. Arthritis Rheum 1989;32:1107–18.[ISI][Medline]
  21. Gladman D, Ginzler E, Goldsmith C et al. The development and initial validation of the Systemic Lupus International Collaborating Clinics/American College of Rheumatology damage index for systemic lupus erythematosus. Arthritis Rheum 1996;39:363–9.[ISI][Medline]
  22. Taves DR. Minimization: a new method of assigning patients to treatment and control groups. Clin Pharmacol Ther 1974;15:443–53.[ISI][Medline]
  23. Guy W. Assessment manual for psychopharmacology. Rockville: US Department of Health, Education and Welfare, 1976.
  24. Robb-Nicholson LC, Daltroy L, Eaton H et al. Effects of aerobic conditioning in lupus fatigue: a pilot study. Br J Rheumatol 1989;28:500–5.[ISI][Medline]
  25. Daltroy LH, Robb-Nicholson C, Iversen MD, Wright EA, Liang MH. Effectiveness of minimally supervised home aerobic training in patients with systemic rheumatic disease. Br J Rheumatol 1995;34:1064–9.[ISI][Medline]
  26. Blomqvist CG, Saltin B. Cardiovascular adaptations to physical training. Annu Rev Physiol 1983;45:169–89.[CrossRef][ISI][Medline]
Submitted 29 April 2002; Accepted 28 January 2003





This Article
Abstract
Full Text (PDF)
All Versions of this Article:
42/9/1050    most recent
keg289v1
Alert me when this article is cited
Alert me if a correction is posted
Services
Email this article to a friend
Similar articles in this journal
Similar articles in ISI Web of Science
Similar articles in PubMed
Alert me to new issues of the journal
Add to My Personal Archive
Download to citation manager
Search for citing articles in:
ISI Web of Science (8)
Disclaimer
Request Permissions
Google Scholar
Articles by Tench, C. M.
Articles by D'Cruz, D. P.
PubMed
PubMed Citation
Articles by Tench, C. M.
Articles by D'Cruz, D. P.
Related Collections
Systemic Lupus Erythematosus and Autoimmunity
Fibromyalgia