The prevalence and associations of fatigue in systemic lupus erythematosus

C. M. Tench, I. McCurdie2, P. D. White1 and D. P. D'Cruz

Bone and Joint Research Unit and
1 Department of Psychological Medicine, St Bartholomew's and The Royal London School of Medicine and Dentistry, London and
2 Barts and the London NHS Trust, London, UK


    Abstract
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Objective. This study assessed the prevalence and associations of fatigue in systemic lupus erythematosus (SLE).

Methods. Questionnaires were used to measure self-reported fatigue, disease activity, sleep quality, quality of life, anxiety and depression in 120 out-patients with SLE.

Results. Abnormal fatigue was reported by 97 (81%) patients, and 71 (60%) patients reported poor sleep quality. Fatigue correlated negatively with all measures of functioning. Fatigue scores were up to 33% higher in patients with active disease [Systemic Lupus Activity Measure (SLAM >=3)] than in patients with inactive disease (SLAM >3) (P < 0.05). There were significant correlations between fatigue and disease activity, sleep quality, anxiety and depression.

Conclusion. Fatigue is a common complaint of patients with SLE and is associated with diminished ability to function. Apart from treating the primary disease, it may also be worthwhile to treat mood disorders and insomnia in order to reduce fatigue and improve quality of life.

KEY WORDS: SLE, Fatigue, Disease activity, Sleep quality, Depression.


    Introduction
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Fatigue is one of the commonest and often the most disabling symptom experienced by individuals with systemic lupus erythematosus (SLE) and affects up to 80% of patients [1]. In the majority of cases the cause of fatigue in SLE is not known. However, it is likely to result from a number of contributing factors, such as disease activity [1, 2, 3], mood disorder [1, 4], poor sleep patterns [4], low levels of aerobic fitness [5] and associated fibromyalgia [6, 7], whose relative influences will vary both among patients and within the same person over time. The relationship between fatigue and disease activity is controversial. Wysenbeek et al. [2] showed that SLE patients with fatigue had significantly more arthritis and lower lymphocyte counts than SLE patients who had no fatigue. There was also a significant correlation between fatigue and a disease activity index. Similarly, Krupp et al. [1] showed a significant correlation between fatigue and the physician's rating of disease activity and Zonana-Nacach et al. [3] showed a weak but significant correlation between fatigue and the Systemic Lupus Activity Measure (SLAM). However, Wang et al. [8] and Bruce et al. [9] failed to show any association. There is a consensus, however, that even patients with quiescent lupus continue to experience marked fatigue. We have embarked upon a prospective study of potential therapies of fatigue in SLE. This study represents our baseline data on this population and assesses the prevalence and severity of fatigue in out-patients with SLE and its relationship with disease activity, disease damage, sleep disturbance, quality of life and mood.


    Methods
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
We studied 120 consecutive female patients who fulfilled the updated American College of Rheumatology classification criteria for SLE [10, 11] and were assessed during their out-patient clinic appointment at the Connective Tissue Disease Clinic in the Rheumatology Department of St Bartholomew's and The London NHS Trust. Self-reported fatigue was measured using three fatigue questionnaires: the Fatigue Severity Score (FSS) [12], the Chalder Fatigue Scale (CFS) [13] and a visual analogue scale (VAS) [14]. The FSS is a nine-item questionnaire, each item being scored from 1 to 7 and an overall score computed in the range of 1 to 7. The CFS is a 14-item questionnaire, each item being scored from 0 to 3, generating a score between 0 and 42. The VAS comprises four separate visual analogue scales measuring both physical and mental fatigue before and after exertion, generating a total score of between 0 and 400 and also mental and physical fatigue component scores, each between 0 and 200. In all three fatigue questionnaires, a higher score indicates increasing severity of fatigue. The FSS has been validated in SLE and the CFS and VAS have been validated and are widely used in the field of chronic fatigue syndrome.

Disease activity was measured using the Systemic Lupus Activity Measure (SLAM) [15] and the European Consensus Lupus Activity Measure (ECLAM) [16]. Both these measures include a component question on fatigue, which contributes to the total score. These measures were chosen for two reasons: first, ECLAM is in routine clinical use in our clinic; secondly, both SLAM and ECLAM have been shown to be the global score disease activity indices which are most sensitive to change [17]. We plan to investigate both how fatigue and disease activity change over time and the effects of possible therapies on fatigue in SLE. Disease damage was measured using the Systemic Lupus International Collaborating Clinics (SLICC)/ACR Damage Index [18]. Quality of sleep was assessed using the Pittsburgh Sleep Quality Index (PSQI) [19]. This is a self-rated questionnaire comprising 19 different items, generating an overall score between 0 and 21, a higher score indicating poorer sleep quality. Functional status was measured using the Medical Outcomes Study Short Form Health Survey (SF-36) [20]. This is a 36-item questionnaire generating component scores for physical function, physical role, bodily pain, general health, vitality, social function, emotional role and mental health. Each component score is between 0 and 100, a higher score indicating better function. Anxious and depressed moods were assessed using the Hospital Anxiety and Depression scale (HAD) [21], which is designed to assess mood in patients with physical disease. It is a 14-item questionnaire generating a separate score for anxiety and depression between 0 and 21, a higher score indicating increasing severity of depression or anxiety. A HAD score of 8 or above suggests possible mood disorder and 10 or above suggests the presence of a pathological mood disorder. Blood samples were taken from all patients at the time of their clinic visit. The blood parameters needed to score the ECLAM and SLAM were measured, and thyroid function tests were also performed to screen for thyroid disorders that might contribute to fatigue.

Statistical analysis
Statistical analysis was done using the SPSS 8.0 for Windows software package. The distribution of fatigue scores suggested that the data were not normally distributed and therefore non-parametric tests were used in all data analyses. Correlation analysis was performed using Spearman's rank correlation coefficient.


    Results
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Complete data were available for all 120 patients. The median age was 38 yr (interquartile range 32–45) and the median disease duration was 36 months (12–79.5). The median ECLAM score was 2.0 (1–8) and the median SLAM score was 6 (3–8). The median SLICC/ACR Damage Index score was 0 (0–1). These patients thus had mild, relatively early disease. There was no significant correlation between fatigue and age, disease duration and SLICC/ACR Damage Index score.

Sixty-one (51%) patients were taking prednisolone, at a median dose of 5 mg (interquartile range 0–7.5). Of these 61 patients, 40 (33% of all the patients) were taking <=7.5 mg/day and 21 (17.5%) were taking >7.5 mg/day of prednisolone. Forty patients (33%) were taking azathioprine (100 or 150 mg), 52 (43%) were taking hydroxychloroquine (200 or 400 mg) and 15 (13%) were taking antidepressants. The patients taking hydroxychloroquine had significantly higher fatigue scores than those not taking this drug (median FSS 5.89 vs 5.27, P = 0.003; CFS 24 vs 20, P = 0.004; VAS total 317 vs 287, P = 0.003; Mann–Whitney test). There was no difference in fatigue scores between patients taking azathioprine and those not taking this drug (Mann–Whitney test). There was no significant difference in fatigue scores between patients not taking prednisolone, those taking <= 7.5 mg/day and those taking >7.5 mg/day (Kruskal–Wallis test).

The median fatigue, sleep and depression scores are shown in Table 1Go. There was a strong correlation between scores for the three fatigue questionnaires (FSS vs CFS, r = 0.6, 95% confidence interval (CI) 0.2–0.8; FSS vs VAS totals r = 0.6, 95% CI 0.2–0.8; CFS vs VAS totals r = 0.6 95% CI 0.2–0.8, P < 0.001).


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TABLE 1. Fatigue, sleep, anxiety and depression scores (n = 120)

 
Scores for all three fatigue questionnaires correlated weakly but significantly with the disease activity scores (Table 2Go). When the disease activity scores were adjusted by removal of the fatigue component in each case (denoted by ECLAM(f) and SLAM(f)), the correlation between disease activity and fatigue became weaker but remained significant (Table 2Go). Forty-six (38%) patients had an ECLAM(f) score of 1 or 0, i.e. had quite inactive disease, and 74 (62%) had an ECLAM(f) score of > 1, i.e. more active disease. Similarly, 39 (33%) patients had a SLAM(f) score of <3 and 81 (67%) had a SLAM(f) score of >=3. The fatigue scores were up to 33% higher in patients with more active disease than in those with inactive SLE (Table 3Go).


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TABLE 2. Correlation between fatigue and disease activity (n = 120)

 

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TABLE 3. A comparison of median fatigue scores between patients with inactive SLE and those with more active SLE (Mann–Whitney test)

 
All scores for the SF-36 components were low (Table 4Go), physical and emotional roles scoring the lowest values. The FSS correlated with the PSQI scores, the HAD scores, and inversely with all components of the SF-36 (Table 5Go). Similar correlations were seen with the CFS and VAS total, but have been omitted for brevity. The PSQI score correlated with disease activity (SLAM, r = 0.36, 95% CI 0.19–0.50, P < 0.001; ECLAM, r = 0.28, 95% CI 0.10–0.43, P = 0.005) and the bodily pain score of the SF-36 (r = - 0.44, 95% CI -0.57 to -0.28, P < 0.001). The PSQI also correlated with HAD anxiety (r = 0.4, 95% CI 0.2–0.4, P < 0.001) and HAD depression (r = 0.4, 95% CI 0.2–0.4, P < 0.001). There was no significant difference in sleep scores between patients not taking prednisolone, those taking <=7.5 mg/day and those taking >7.5 mg/day (Kruskal–Wallis test).


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TABLE 4. SF-36 component scores (n = 120), with normal data for UK female population for comparison

 

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TABLE 5. Correlation between fatigue and sleep, anxiety, depression and all components of the SF-36 (n = 120)

 
The median haemoglobin (Hb) concentration was 12.4 g/dl (interquartile range 11.5–13.1). Only two (2%) patients had an Hb concentration <9 g/dl. There was no significant correlation between Hb and any of the fatigue scores. Sixteen (13%) patients had an Hb concentration <11 g/dl. There was no significant difference in FSS, CFS or VAS total between those with an Hb concentration <11 g/dl and those with an Hb concentration >= 11g/dl (Mann–Whitney test).

There were 76 (63%) patients for whom recent (within the last 6 months) thyroid function tests were available. These were borderline abnormal in three (4%) of the 76 patients, who had mild elevation of the thyrotropin concentration (7.1, 6.8 and 5.1 mU/l; normal range 0.3–4.0 mU/l) and mildly low free thyroxine concentrations (9.6, 9.1 and 10.8 pmol/l; normal range 11–25 pmol/l).


    Discussion
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Fatigue is a very common symptom in the SLE patients attending our out-patient clinics. We found that between 80 and 90% of our patients reported abnormal fatigue, and this finding was consistent when we used different types of questionnaires to measure fatigue. This result is similar to those of other studies [1] and indicates significant morbidity from fatigue even in our cohort of out-patients with relatively mild, early disease.

Our cohort differs from others in the literature [22] in that this is an inception cohort in a newly established connective tissue disease clinic. The patients are relatively young and have a short disease duration and low cumulative damage scores. The clinic philosophy is to keep disease activity and damage to a minimum by using antimalarials and low-dose corticosteroids with immunosuppressives when indicated by multisystem disease.

There was good correlation between the three fatigue questionnaires. The CFS and VAS have been used extensively in the field of chronic fatigue syndrome but to date only the FSS has been used in SLE. The CFS and VAS are therefore tools that could be used in any future research into fatigue in SLE.

In a small number of SLE patients fatigue may be explained partly by other physical problems. Three of our patients had biochemical evidence of subclinical hypothyroidism, and this may have contributed to their fatigue. Anaemia is well known to be associated with symptoms of fatigue and lethargy, but we did not find any correlation between anaemia and fatigue. A possible explanation for this rather unexpected result is that only a very small proportion of the patients had markedly low Hb concentrations. In the majority of cases, however, the cause of fatigue in lupus is unexplained. It is unlikely that one single factor can explain the fatigue in these patients, and it is very likely that many factors together lead to lupus fatigue.

Disease activity
The relationship between fatigue and disease activity is controversial and research in this area is complicated by the fact that two of the commonly used disease activity measures, SLAM and ECLAM, have fatigue as a component score. Wysenbeek et al. [2] showed a correlation between fatigue and a disease activity index and significantly lower lymphocyte counts and C3 levels in SLE patients with fatigue. Zonana-Nacach et al. [3] also showed a weak but significant correlation between fatigue and disease activity using the SLAM. However, Wang et al. [8] and Bruce et al. [9] showed no significant correlation between FSS and the SLE Disease Activity Index (SLEDAI), which does not have a fatigue component score. We have shown that fatigue scores are significantly higher (up to 33%) in patients who have more active SLE than in those whose SLE is inactive or quiescent. However, even patients with quiescent SLE report significant fatigue. In addition, there is only a weak correlation between fatigue and disease activity, and this becomes weaker when the fatigue component is removed from the disease activity scores, suggesting that the relationship between fatigue and disease activity is neither strong nor linear. These findings are supported by our own clinical experience that patients with active disease complain of increasing severity of fatigue; however, those with inactive disease still continue to report significantly disabling fatigue.

The reason why some groups have shown an association between fatigue and disease activity while others have not is interesting and may be related to differences in the characteristics of the patient cohorts. The patients studied by Wang et al. [8] and Bruce et al. [9] were older (mean age 43 yr) and had a longer disease duration (mean 12 yr) and more damage (mean SLICC score 1.5) than those studied by Zonana-Nacach et al. [3] and ourselves. Also, the SLAM includes, or weighs more heavily, more of the subjective aspects of disease activity than SLEDAI and has been shown to be the only activity index in common use that correlates positively with the patient's global assessment of disease activity on a VAS [17]. Obviously, factors other than disease activity, such as poor sleep, mood disorder and possibly low levels of aerobic fitness, must be contributing to fatigue, particularly in those with quiescent SLE.

Sleep quality
Nearly two-thirds of our patients reported poor sleep quality, and this correlated moderately well with all the fatigue scores. There are likely to be many reasons why patients with SLE report poor sleep quality. We have shown a moderate correlation between the PSQI and the SF-36 bodily pain score and a weak correlation with disease activity scores, suggesting that pain from joints or muscles may disturb sleep. There is also a weak correlation between sleep quality and anxiety and depression, suggesting that these disorders are contributing to poor sleep in at least some of the SLE patients. Medication, particularly steroid therapy, is thought to lead to poor sleep quality, although we did not show any significant difference in sleep quality between patients not taking prednisolone, those on low-dose therapy and those taking >7.5 mg per day. This was probably because the dose of prednisolone was not sufficient to disturb sleep.

Anxiety and depression
Abnormal HAD scores, suggesting the presence of anxiety and depression, occurred in a high proportion of our patients. A third of our patients reported HAD depression scores suggestive of a pathological mood disorder, which might deserve treatment in its own right. The fact that only 13% of patients were actually taking antidepressants suggests that depression and anxiety may be underdiagnosed in our patient population. The moderate correlation between HAD depression scores and fatigue indicates that, at least in some patients, depression and anxiety contribute to lupus fatigue.

It is often difficult to determine whether mood disorder is a manifestation of neuropsychiatric SLE or the result of the stresses associated with a chronic illness or other major life events. The American College of Rheumatology includes anxiety and mood disorder within the 19 neuropsychiatric syndromes observed in SLE [23]. However, the case definitions require a clinical evaluation to exclude merely reactive psychological disturbances and suggest that a psychiatric consultation may be required. In this study, mood disorder was assessed using the HAD questionnaire only. None of our patients had a mood disorder requiring a psychiatric consultation at the time of the study. It is therefore difficult to comment on whether the high prevalence of mood disorder present in our patient cohort is a manifestation of neuropsychiatric SLE or merely reflects their chronic ill health.

Quality of life
Fatigue correlated moderately or strongly with all components of the SF-36. This was a negative correlation because increasing scores from the fatigue questionnaires indicate increasing severity of fatigue whereas increasing scores on the SF-36 questionnaire indicate better function. This strong correlation might indicate that the reduced quality of life associated with SLE is a major factor contributing to fatigue in this disease, as suggested by Bruce et al. [9]. However, it could also be argued that fatigue and mood disorders are potent causes of reduced quality of life and that it is fatigue that is reducing function and not vice versa.

The finding of significantly higher fatigue scores in patients taking hydroxychloroquine is surprising. One possible reason is that patients with more active disease have an increased severity of fatigue and are also more likely to be prescribed hydroxychloroquine therapy. However, this is not seen with azathioprine or prednisolone therapy and therefore seems an unlikely explanation. The widely held belief that hydroxychloroquine is a useful treatment for fatigue needs to be examined in a prospective study.

Fibromyalgia may also contribute to fatigue in SLE. Investigators in the USA have found that up to 22% of lupus patients have coexistent fibromyalgia [6]; however, in the UK Taylor et al. [7] found that only 11% of SLE patients with fatigue also fulfilled the ACR classification criteria for fibromyalgia. This remains a controversial area and the differences seen may reflect cultural differences between the two populations. We did not set out specifically to address this question, but our own unpublished clinical observations mirror the data of Taylor et al.—fibromyalgia appears to be less common in our patient population than in the USA.

A further factor contributing to fatigue may be deconditioning or the progressive loss of aerobic fitness and muscular power in individuals who become inactive. We have shown that SLE patients have aerobic fitness levels about 65% of those expected in healthy age-matched controls [5], and we are presently carrying out a trial looking at the effects of aerobic exercise on fatigue and sleep in SLE.

In summary, fatigue is a very common symptom in SLE. Like Krupp et al. [1] and McKinley et al. [4], we found significant associations between fatigue and both depression and disease activity. Also, like McKinley [4], we found a significant association between poor sleep quality and fatigue. Our finding that anxiety is also associated with fatigue is new. Treatment of fatigue is difficult and in most cases the cause of fatigue in SLE is unexplained. However, it is probably worth searching for previously undiagnosed hypothyroidism and also for treatable causes of anaemia, which may be contributing towards lupus fatigue. More importantly, we agree with McKinley et al. [4] that strategies for the treatment of fatigue should address comorbid mood disorder and sleep disturbance, which are relatively common.


    Acknowledgments
 
We are grateful for the statistical help and advice of Janice Thomas. This study was supported by a grant from the Joint Research Board of St Bartholomew's Hospital, the British Medical Association Doris Hillier Award and the Arthritis Research Campaign.


    Notes
 
Correspondence to: C. M. Tench, Bone and Joint Research Unit, St Bartholomew's and The Royal London School of Medicine and Dentistry, Turner Street, London E1 2AD, UK. Back


    References
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

  1. Krupp LB, LaRocca NG, Muir J, Steinberg AD. A study of fatigue in systemic lupus erythematosus. J Rheumatol1990;17:1450–2.[ISI][Medline]
  2. Wysenbeek AJ, Leibovici L, Weinberger A, Guedj D. Fatigue in systemic lupus erythematosus. Prevalence and relation to disease expression. Br J Rheumatol1993;32:633–5.[ISI][Medline]
  3. Zonana-Nacach A, Roseman JM, McGwin G, Friedman AW, Baethge BA, Reveille JD et al. Systemic lupus erythematosus in three ethnic groups. VI: Factors associated with fatigue within 5 years of criteria diagnosis. Lupus2000;9:101–9.[ISI][Medline]
  4. McKinley P, Ouellette SC, Winkel G. The contributions of disease activity, sleep patterns and depression to fatigue in systemic lupus erythematosus. Arthritis Rheum1995;38:826–34.[ISI][Medline]
  5. Tench CM, McCurdie I, McCarthy J, D'Cruz DP. The assessment of aerobic capacity in a group of patients with SLE and its association with fatigue, sleep quality and disease activity. Arthritis Rheum1998;41(9 Suppl.):1795.
  6. Middleton GD, McFarlin JE, Lipsky PE. The prevalence and clinical impact of fibromyalgia in systemic lupus erythematosus. Arthritis Rheum1994;37:1181–8.[ISI][Medline]
  7. Taylor J, Skan J, Erb N et al. Lupus patients with fatigue: Is there a link with fibromyalgia syndrome? Rheumatology2000;39:620–3.[Abstract/Free Full Text]
  8. Wang B, Gladman DD, Urowitz MB. Fatigue in lupus is not correlated with disease activity. J Rheumatol1998;25:892–5.[ISI][Medline]
  9. Bruce IN, Mak VC, Hallett DC, Gladmann DD, Urowitz MB. Factors associated with fatigue in patients with systemic lupus erythematosus. Ann Rheum Dis1999;58:379–81.[Abstract/Free Full Text]
  10. Tan EM, Cohen AS, Fries JF et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum1982;25:1271–7.[ISI][Medline]
  11. Hochberg M. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum1997;40:1725–34.[ISI][Medline]
  12. Krupp LB, La Rocca NG, Muir-Nash J, Steinberg AD. The Fatigue Severity Score. Application to patients with multiple sclerosis and systemic lupus erythematosus. Arch Neurol1989;46:1121–3.[Abstract]
  13. Chalder T, Berelowitz G, Pawlikowska T et al. Development of a fatigue scale. J Psychosom Res1993;37:147–53.[ISI][Medline]
  14. White PD, Grover SA, Kangro HO, Thomas JM, Amess J, Care AW. The validity and reliability of a fatigue syndrome that follows glandular fever. Psychol Med1995;25:917–24.[ISI][Medline]
  15. Liang MH, Socher SA, Larson M, Schur PH. Reliability and validity of six systems for the clinical assessment of disease activity in systemic lupus erythematosus. Arthritis Rheum1989;32:1107–18.[ISI][Medline]
  16. Vitali C, Bencivell W, Isenberg DA et al. Disease activity in systemic lupus erythematosus: report of the Consensus Study Group of the European Workshop for Rheumatology Research. II. Identification of the variables indicative of disease activity and their use in the development of an activity score. Clin Exp Rheumatol1991;10:541–7.[ISI]
  17. Ward MM, Marx AS, Nicole Barry N. Comparison of the validity and sensitivity to change of 5 activity indices in systemic lupus erythematosus. J Rheumatol2000;27:3:664–9.[ISI][Medline]
  18. Gladman DD, Ginzler E, Goldsmith C et al. The development and initial validation of the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index in patients with systemic lupus erythematosus. Arthritis Rheum1996;39:363–9.[ISI][Medline]
  19. Buysse DJ, Reynolds CF, Monk TH, Berman SR, Kupfer DJ. The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research. Psychiatr Res1989;28:193–213.[ISI][Medline]
  20. Ware JE, Sherbourne CD. MOS 36-item short form health survey (SF36). Med Care1992;30:473–83.[ISI][Medline]
  21. Zigmond A, Snaith R. The hospital anxiety and depression scale. Acta Psychiatr Scand1983;67:361–70.[ISI][Medline]
  22. Stoll T, Stucki G, Malik J, Pyke S, Isenberg DA. Association of the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index with measures of disease activity and health status in patients with systemic lupus erythematosus. J Rheumatol1997;24:309–13.[ISI][Medline]
  23. ACR ad hoc committee. The American College of Rheumatology nomenclature and case definitions for neuropsychiatric lupus syndromes. Arthritis Rheum1999;42:599–608.[ISI][Medline]
Submitted 28 October 1999; revised version accepted 12 June 2000.