Psychological distress and changes in the activity of systemic lupus erythematosus

M. M. Ward1,2,, A. S. Marx1 and N. N. Barry2

1 VA Palo Alto Health Care System, Palo Alto, CA and
2 Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA


    Abstract
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Objective. To determine if changes in depressive symptoms or anxiety lead to changes in the activity of systemic lupus erythematosus (SLE).

Methods. Twenty-three patients with SLE were examined prospectively every 2 weeks for up to 40 weeks. At each assessment, patients completed the Centers for Epidemiologic Studies—Depression scale (CES-D), the State subscale of the State-Trait Anxiety Inventory and a global assessment of the activity of their SLE by visual analogue scale. SLE activity was also assessed at each visit by physician global assessment, the Systemic Lupus Activity Measure (SLAM), the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and the European Consensus Lupus Activity Measure (ECLAM).

Results. Changes in depression and anxiety were positively correlated with simultaneous changes in the patient global assessment of SLE activity and in the SLAM, but not with changes in the physician global assessment, SLEDAI or ECLAM. Depression and anxiety scores were also correlated with patient global assessments and SLAM scores 2 weeks later, but lagged scores were not significantly associated with the patient global assessment or SLAM after controlling for current depression and anxiety scores. The associations between depression and anxiety scores and the SLAM were not present when SLAM scores were modified to exclude ratings of depression and fatigue. No measure of SLE activity increased in the 2 weeks immediately after a large increase in CES-D or State Anxiety scores.

Conclusions. Depression and anxiety scores parallel changes in patients' assessments of the activity of their SLE. We found no evidence to support the hypothesis that psychological distress causes increased SLE activity.

KEY WORDS: Systemic lupus erythematosus, Depression, Anxiety, Patient assessment.


    Introduction
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Patients and clinicians widely believe that stress can cause exacerbations of systemic lupus erythematosus (SLE) [1, 2], but the evidence supporting this association is limited. Retrospective assessments by patients of the causes of exacerbations are subject to misattribution and provide no indication of the frequency with which stressful events do not lead to worsening of SLE [3]. Psychological distress represents patients' interpretations and the perceived impact of stressful events. As an intermediate measure in the relationship between stress and illness, psychological distress is a useful measure for the study of this association. Many cross-sectional studies have reported significant associations between measures of depression, anxiety or psychological distress and measures of SLE activity [49]. However, these studies cannot determine if psychological distress leads to increased SLE activity or if more active SLE leads patients to be more depressed or anxious. In one of two longitudinal studies, no association was found between psychological distress and laboratory measures of SLE activity [10]. Another study reported significant associations between changes in depression and anxiety and subsequent worsening of patient-reported joint, skin and abdominal symptoms, but did not include measures of SLE activity other than patient-reported symptoms [11]. In this time-intensive prospective longitudinal study, we examined the association between changes in depressive symptoms and anxiety and changes in SLE activity, measured not only by patient self-assessments but also by physician assessments and standardized quantitative measures.


    Methods
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Patients
Participants were recruited from the Stanford University Medical Center or VA Palo Alto rheumatology clinics, and from the practices of local rheumatologists. Inclusion criteria were (i) classification of SLE by the revised American College of Rheumatology criteria [12]; (ii) age 18 yr or older; (iii) English fluency and literacy; (iv) clinical evidence of some degree of SLE activity as determined by the patient's rheumatologist. Potential participants were excluded if they were unable to provide informed consent or if they expected to be unavailable for regular follow-up appointments. Because we recruited a volunteer sample, we have no information on patients who were eligible for the study but chose not to participate. The study protocol was approved by the Stanford University Panel on Human Subjects in Medical Research.

Study protocol
The goal of this prospective longitudinal study was to examine changes in SLE activity over time. Participants were assessed every 2 weeks for up to 40 weeks (20 assessments). Twenty-five participants were enrolled, but we report results for the 23 patients who completed at least three assessments.

At each assessment, patients completed a questionnaire about their symptoms and current medications, provided a medical history, had a physical examination and underwent laboratory testing. Included in the questionnaire was the Centers for Epidemiological Studies—Depression scale (CES-D) and the State subscale of the State-Trait Anxiety Inventory [13, 14]. The CES-D is a 20-item scale that asks about the frequency of depressive thoughts and feelings in the past week. The possible range of scores on the CES-D is from 0 to 60, higher scores indicating more depressive symptoms. Previous research has suggested that four items on the CES-D (‘I felt that everything I did was an effort’, ‘I felt hopeful about the future’, ‘My sleep was restless’, ‘I could not get going’) may be related more to somatic problems than psychological problems in patients with rheumatic diseases [15]. Therefore, we also analysed scores on the CES-D with these items excluded. The State subscale of the State-Trait Anxiety Inventory is a 20-item scale that asks about the intensity of current feelings of disquiet, nervousness or tension. The possible range of scores on the State Anxiety scale is from 20 to 80, higher scores indicating greater anxiety. In addition to completing these scales, patients were asked to rate the current activity of their SLE on a 15-cm visual analogue scale labelled 0=not active and 100=extremely active.

At each assessment, the evaluating rheumatologist also scored a global assessment of the activity of the patient's SLE on a 15-cm visual analogue scale labelled 0=not active and 100=extremely active. On the basis of the medical history, physical examination and results of laboratory tests, the physicians also scored three standardized measures of SLE activity at each assessment, the Systemic Lupus Activity Measure (SLAM), the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and the European Consensus Lupus Activity Measure (ECLAM) [1618]. The SLAM scores the presence and severity of 24 clinical manifestations and eight laboratory measures of SLE (possible range 0–86). The SLEDAI assesses 16 clinical manifestations and eight laboratory measures (possible range 0–105). The ECLAM scores 20 clinical manifestations and 11 laboratory tests (possible range 0–10). Higher scores on each measure indicate more active SLE. Initial studies support the validity of these measures [16, 19, 20]. Each participant was examined by the same rheumatologist throughout the study. We used three different standardized measures of SLE activity to determine if any associations with the CES-D or State Anxiety scale depended on the particular measure used, or if each of the three standardized measures demonstrated similar associations.

Statistical analysis
We assessed the relationship between depression and anxiety and changes in SLE activity over time by correlating scores on the CES-D and State Anxiety scale with five measures of SLE activity: the patient and physician global assessments and the SLAM, SLEDAI and ECLAM. We first estimated correlations between simultaneous changes in these measures. Secondly, CES-D and State anxiety scores were correlated with measures of SLE activity obtained 2 weeks later. Thirdly, for those SLE activity measures that were correlated with lagged scores of the CES-D and State Anxiety scale, we tested whether the lagged score was significantly associated with the SLE activity measure after adjusting for current scores on the CES-D and State Anxiety scale. The latter analysis provided a test of whether changes in depression or anxiety consistently predicted changes in SLE activity.

We used pooled time series regression analysis to calculate correlations over time between measures [21]. This technique is a modification of classical linear regression that accommodates multiple time-ordered observations on multiple subjects in a single regression model. These models estimate the within-patient correlations between measures, estimating the degree to which changes in one measure correlate with changes in another measure. The effects of differences among patients in characteristics such as age, sex, disease duration, medications and baseline levels of depression or SLE activity were eliminated by including one indicator variable for each patient in the regression models (i.e. a fixed effects model) [22]. The correlations between measures derived from these models are therefore partial correlations, having been adjusted for between-patient differences. Separate models were estimated for the association of CES-D scores and State Anxiety scores and each measure of SLE activity. The large number of assessments (n=415) provided sufficient statistical power (ß=0.20; {alpha}=0.05 two-tailed) to detect correlations of 0.10 or larger as statistically significant.

Because frequent minor changes in either CES-D or State Anxiety scores might obscure important associations between large changes in depression or anxiety and subsequent changes in SLE activity, we also computed changes in each SLE activity measure over the 2-week interval that followed the 2-week interval of greatest increase (worsening) in CES-D or State Anxiety score for each patient. For example, if the greatest increase in the CES-D for a patient occurred between assessments 6 and 7, we computed changes in the SLE activity measures between assessments 7 and 8. If marked increases in depression or anxiety affected future SLE activity, scores for the activity measures should increase during this interval. We tested whether the means of these changes in activity scores were significantly different from 0 using t-tests. All analyses were performed using SAS programs (Statistical Analysis Systems, Cary, NC, USA).


    Results
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Nineteen women and four men participated in the study (Table 1Go). Baseline scores on the SLE activity measures indicated mild to moderate SLE activity and scores on the CES-D and State Anxiety scale indicated moderate depressive symptoms and anxiety at study entry. Two patients had previous clinical evidence of central nervous system involvement (one with mild organic brain syndrome and one with myelitis).


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TABLE 1.  Characteristics of the participants at study entry (n=23)

 
Nineteen participants (83%) completed all 20 assessments, and one participant each completed 17, 8, 7 and 3 assessments (total=415 assessments). Sixty-seven per cent of assessments occurred at intervals of 13–15 days. Participants experienced substantial changes in psychological distress during the study. The CES-D and State Anxiety scores changed (increased or decreased) by more than 50% of their baseline values in 22 patients (96%) and 12 patients (52%) respectively. The median within-patient change in the CES-D during the study was 19 points (range of within-patient changes 6–42) and the median within-patient change in the State Anxiety scale was 22 points (range 4–38). Participants also experienced substantial changes in SLE activity. Scores on the patient global assessment, physician global assessment, SLAM, SLEDAI and ECLAM changed (increased or decreased) by more than 50% of their baseline values in 19 patients (83%), 20 patients (87%), 16 patients (70%), 23 patients (100%) and 22 patients (96%) respectively. For these measures, the median within-patient changes (ranges) were as follows: patient global assessment 46 (17–80); physician global assessment 27 (6–56); SLAM 8 (2–14); SLEDAI 8 (0–22); and ECLAM 3 (0.5–4.5).

Scores on the CES-D and State Anxiety scales were significantly correlated with simultaneous changes in patients' global assessments of their SLE activity (Table 2Go). CES-D and State Anxiety scores were also significantly correlated with simultaneous changes in the SLAM, but not with the physician global assessment or ECLAM. State anxiety scores were significantly negatively correlated with changes in the SLEDAI, an association contrary to that hypothesized. We suspected that the correlation of the CES-D and State Anxiety scores with the SLAM, but not with the other standardized SLE activity measures, was due to the inclusion of depression in the SLAM and the potential for greater weighting of fatigue in this measure. Deleting scores for depression and fatigue from the SLAM eliminated its association with the CES-D (partial r=0.03) and the State Anxiety scale (partial r=-0.002). Modification of the CES-D to eliminate the four somatic items did not alter the associations between depression and SLE activity measures.


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TABLE 2.  Partial correlations between current and 2-week lagged values of the CES-D, the CES-D modified to exclude four somatic items, and the State Anxiety scale and each SLE activity measure

 
Scores on the CES-D and State Anxiety scale were significantly correlated with patients' global assessments of SLE activity 2 weeks later, indicating that psychological distress may lead to greater symptoms (Table 2Go). However, depression and anxiety scale scores did not precede changes in SLE activity as measured by the physician global assessment or ECLAM. Lagged scores of the State Anxiety scale were significantly negatively correlated with changes in the SLEDAI. Scores on the CES-D and State Anxiety scale were significantly correlated with scores on the SLAM 2 weeks later, but did not precede future SLAM scores if depression and fatigue were excluded from this measure (partial r=0.03 for CES-D; partial r=-0.003 for State Anxiety scale).

Lagged scores on the CES-D (ß=0.03; P=0.82) were not associated with the patient global assessment after accounting for current CES-D scores (ß=0.38; P=0.002). Lagged scores on the State Anxiety scale (ß=0.03; P=0.77) were not associated with the patient global assessment after accounting for current State Anxiety scale scores (ß=0.58; P<0.0001). Similarly, lagged scores on the CES-D (P=0.21) and State Anxiety scale (P=0.13) were not associated with the SLAM after accounting for current CES-D and State Anxiety scale scores (both P<0.0001). These findings indicate that the CES-D and State Anxiety scores parallel but do not predict changes in the patient global assessment or SLAM. Analyses using scores lagged by 4 weeks demonstrated associations that were weaker than those using scores lagged by 2 weeks.

We also computed changes in each SLE activity measure over the 2 weeks following the largest increase in CES-D scores. The mean increase in CES-D score was 13.5 (range 6–30), indicating substantial increases in depressive symptoms. However, these increases in depression were not followed by worsening SLE activity (Table 3Go). In fact, patients' global assessments of the activity of their SLE decreased by a mean of 11.3 points (on a 0–100 scale) in the subsequent 2 weeks, indicating that patients thought their SLE was less active. In addition, physicians' global assessments decreased by a mean of 5.3 points (on a 0–100 scale) over these intervals. There were no significant changes in the SLAM, SLEDAI or ECLAM following these large increases in depression scale scores. There were no significant changes in any SLE activity measure following large increases in the State Anxiety score (mean increase 15.7; range 4–25).


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TABLE 3.  Mean changes in SLE activity measures after the 2-week interval of greatest increase in CES-D or State Anxiety scale score for each patient

 
Although there were no associations in the group of patients, individual patients may differ in their response to psychological distress. In only one patient were there consistent changes in all SLE activity measures after a large interval increase in CES-D scores. In this patient, an 11-point increase in the CES-D was followed 2 weeks later by a 16-point increase in patient global assessment, a 4-point increase in physician global assessment, a 6-point increase in both the SLAM and SLEDAI and a 1-point increase in the ECLAM. In only one patient were there consistent changes in all SLE activity measures after a large-interval increase in State Anxiety scores. In this patient, who had a history of mild organic brain syndrome, an 18-point increase in the State Anxiety scale was followed 2 weeks later by a 55-point increase in patient global assessment, a 14-point increase in physician global assessment, and a 5-, 6- and 1.5-point increase in the SLAM, SLEDAI and ECLAM respectively.


    Discussion
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Changes in depressive symptoms and anxiety were found to parallel patients' assessments of the activity of their SLE, but did not predict future changes in their global assessments. Even large increases in depression and anxiety were not followed by worsening of SLE as assessed by the patients. These findings indicate that the worsening noted by patients probably occurred in symptoms or signs that fluctuated rapidly, or at least were not sustained long enough to influence their global assessments of SLE activity 2 weeks later.

Depression and anxiety also were not correlated with current SLE activity as assessed by the physician or by two standardized measures of SLE activity, and did not predict future changes in these measures. The negative correlation between the State Anxiety scale and the SLEDAI provides additional evidence that anxiety does not influence SLE activity. The absence of the hypothesized positive associations with standardized measures indicates that signs of SLE activity probably did not vary with psychological distress, and that most of the association between psychological distress and patients' global assessments was due instead to worsening of symptoms. Adams et al. [11] also reported associations between depression and anxiety and worsening of patient-reported symptoms, but did not include other measures or observers. We did find associations between depressive symptoms and anxiety and current scores on the SLAM, but this association was mediated by ratings of depression and fatigue in the SLAM. Excluding ratings for these symptoms eliminated the association between psychological distress and the SLAM, and suggests that fatigue may be one of the major symptoms that worsens with increased depression and anxiety in patients with SLE. Neither the SLEDAI nor the ECLAM includes ratings of depression, and the SLEDAI does not rate fatigue. The ECLAM rates fatigue, but the contribution of fatigue to the total score was lower for the ECLAM than for the SLAM in our patients. These differences in scoring probably explain the differing associations between measures of psychological distress and the SLAM, SLEDAI and ECLAM.

Patients may be heterogeneous in their responses to psychological distress. Therefore, we also examined responses of individual patients. Associations between increases in depressive symptoms or anxiety and subsequent worsening of SLE activity were present in two patients. Although worsening of SLE followed increases in depressive symptoms or anxiety in these two instances, we cannot necessarily infer a causal relationship. If psychological distress does cause worsening of SLE in individual patients, such patients are rare.

It is possible that psychological distress causes short-term worsening of SLE activity that we were unable to detect with assessments performed at 2-week intervals. It is also possible that study of a larger number of patients or the use of different measures of psychological distress would demonstrate associations we did not detect in this study. In addition, stress may cause worsening of SLE activity without affecting depression or anxiety. This study would not have been able to detect a direct effect of stress (one not mediated by depression or anxiety) on SLE activity. However, our results indicate that, although depressive symptoms and anxiety parallel patients' reporting of SLE activity, psychological distress does not predict future changes in patients' symptoms. We found no evidence to support the hypothesis that psychological distress causes increased signs of SLE activity.


    Acknowledgments
 
This work was supported in part by NIH grant AR20610 to the Stanford University Multipurpose Arthritis Center.


    Notes
 
Correspondence to: M. M. Ward, VA Palo Alto 111G, 3801 Miranda Avenue, Palo Alto, CA 94304, USA. Back


    References
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Submitted 20 January 1999; revised version accepted 16 May 2001. Accepted 22 August 2001