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
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Abstract |
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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.
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Introduction |
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Methods |
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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.
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Results |
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Sixty-one (51%) patients were taking prednisolone, at a median dose of 5 mg (interquartile range 07.5). 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; MannWhitney test). There was no difference in fatigue scores between patients taking azathioprine and those not taking this drug (MannWhitney 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 (KruskalWallis test).
The median fatigue, sleep and depression scores are shown in Table 1. There was a strong correlation between scores for the three fatigue questionnaires (FSS vs CFS, r = 0.6, 95% confidence interval (CI) 0.20.8; FSS vs VAS totals r = 0.6, 95% CI 0.20.8; CFS vs VAS totals r = 0.6 95% CI 0.20.8, P < 0.001).
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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 0.34.0 mU/l) and mildly low free thyroxine concentrations (9.6, 9.1 and 10.8 pmol/l; normal range 1125 pmol/l).
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Discussion |
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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.
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Acknowledgments |
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Notes |
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References |
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